4-methylquinazoline derivative as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of chemical pharmacy. Relates to 4-methylquinazoline derivatives, and a preparation method, a pharmaceutical composition and application thereof. The 4-methylquinazoline derivative is a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof, is a PI3K inhibitor, and can be used for preventing and / or treating diseases related to PI3K activity, such as tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolism / endocrine dysfunction or nerve diseases.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals. Specifically, this invention relates to 4-methylquinazoline derivatives, their preparation methods, pharmaceutical compositions, and uses. Background Technology

[0002] Phosphatidylinositol 3-kinase (PI3K) belongs to the lipid kinase family. It is widely distributed in cells and participates in the regulation of various cellular functions, including cell proliferation, differentiation, apoptosis, signal transduction, and glucose transport. Based on differences in structure and function, PI3K can be divided into three major classes: I, II, and III. Among them, class I PI3K has been studied the most extensively, including four subtypes: α, β, γ, and δ. All of them are heterodimers composed of a regulatory subunit (p85) and a catalytic subunit (p110). PI3Kγ and PI3Kδ are mainly distributed in leukocytes, while the other two subtypes, PI3Kα and PI3Kβ, are widely distributed in various cell types. PI3K is a downstream effector of receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR). It activates protein kinase B (AKT) by phosphorylating the corresponding phospholipids, thereby transducing various extracellular cytokine signals into the cell (e.g., Stephens et al., Current Opinion in Pharmacology, 2005, 5(4):357-365). Abnormalities in the PI3K signaling pathway are closely related to the formation and development of various diseases. Currently, four PI3K inhibitors, namely Idelalisib, Copanlisib, Alpelisib, and Duvelisib, have been approved by the FDA. In addition, several other PI3K inhibitors are in clinical trials, with indications including not only tumors but also autoimmune diseases such as psoriasis, rheumatoid arthritis, ulcerative colitis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease, as well as other diseases related to class I PI3K.

[0003] Therefore, the development of novel PI3K inhibitors holds promise for providing entirely new options and treatment methods for a variety of malignant diseases, including cancer. Summary of the Invention

[0004] The purpose of this invention is to provide a novel class of PI3K inhibitors, along with their preparation methods, pharmaceutical compositions, and uses. These PI3K inhibitors exhibit strong inhibitory activity against PI3K, thereby providing better preventative and / or therapeutic effects against PI3K-mediated diseases such as tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases, while reducing adverse reactions and the development of drug resistance. Furthermore, the inventors have also discovered that these inhibitors possess a certain inhibitory effect on HDAC.

[0005] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0006] On the one hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] R is selected from hydrogen, fluorine, and methoxy groups;

[0010] A1 is Where m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or A1 is... Where n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and Y is an oxygen atom, a phenyl group, or... Or A1 is Where Z is Where p is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or Z is an oxygen atom, n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0011] A2 is Where q is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or A2 is a carbon-carbon double bond;

[0012] X1, X2, X3, and X4 are each independently selected from hydrogen or fluorine.

[0013] In a preferred embodiment, A1 is Where m is 0.

[0014] In a preferred embodiment, A1 is Where n is 0, 1, 2, 3 or 4, and Y is an oxygen atom, a phenyl group or...

[0015] In a preferred embodiment, A1 is Where Z is Where p is 0 and n is 0 or 1; or Z is an oxygen atom and n is 0 or 1.

[0016] In a preferred embodiment, R is selected from hydrogen, fluorine, and methoxy.

[0017] In a preferred embodiment, X1, X2, X3, and X4 are independently selected from hydrogen or fluorine.

[0018] In a preferred embodiment, A2 is Where q is 0; or A2 is a carbon-carbon double bond.

[0019] Specifically, the compounds according to the present invention are selected from the following compounds:

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026] On the other hand, the present invention provides a method for preparing the compound, which includes the following steps:

[0027]

[0028] (1) The compound shown in formula M undergoes a multi-step reaction, including nucleophilic substitution, condensation reaction of carboxylic acid with n-propylhydrazine derivative, and Suzuki reaction, to obtain the compound shown in formula E.

[0029] (2) The compound shown in formula E is deprotected by the Boc protecting group to obtain the compound shown in formula (I). In the compound shown in formula (I), the substituents A1, A2, R, X1, X2, X3, and X4 are within the same range as in claim 1.

[0030] In another aspect, the present invention provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, diluent, and / or excipient; preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients, other than the compound or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for the prevention and / or treatment of tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases.

[0031] In another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, diluent, or / or excipient; preferably, the pharmaceutical formulation is selected from the following dosage forms: parenteral formulations, such as injectable solutions or suspensions; enteral formulations, such as oral formulations, such as tablets or capsules; topical formulations, such as lotions, gels, ointments, emulsions, nasal formulations, suppositories, transdermal formulations, or ophthalmic formulations.

[0032] In another aspect, the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of PI3K-mediated diseases; preferably, the PI3K-mediated diseases are selected from tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases. In other words, the present invention also provides a method for the prevention and / or treatment of PI3K-mediated diseases, comprising administering to a subject in need a preventive and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition; preferably, the PI3K-mediated diseases are selected from tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases.

[0033] Furthermore, the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of HDAC-mediated diseases; preferably, the HDAC-mediated diseases are selected from tumors, viral infections, parasitic infections, neurodegenerative diseases, inflammation, metabolic diseases, or heart diseases. In other words, the present invention also provides a method for the prevention and / or treatment of HDAC-mediated diseases, the method comprising administering to a subject in need a preventive and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition; preferably, the HDAC-mediated diseases are selected from tumors, viral infections, parasitic infections, neurodegenerative diseases, inflammation, metabolic diseases, or heart diseases.

[0034] This invention achieves the following beneficial technical effects: the compound of this invention shows significant inhibitory activity against PI3Kα in in vitro enzyme activity tests, IC50... 50 Within the range of 0.1-2000 nM; the compounds of this invention also showed certain inhibitory activity against HDAC in in vitro enzyme activity tests, IC50. 50Within the range of 20-7000 nM; the compounds of the present invention can function as dual inhibitors of PI3K / HDAC; furthermore, the compounds of the present invention exhibit strong in vitro antiproliferative activity against human acute monocytic leukemia cells MV4-11 and human acute promyelocytic leukemia cells NB4, with IC50 values ​​for MV4-11 and NB4. 50 The values ​​are in the ranges of 0.01-10 μM and 0.1-10 μM, respectively.

[0035] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0036] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0037] "Sulfoamide" refers to the group R b –S(=O)2–NH–, where each R b Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, or 5-6-membered heteroaryl, unless otherwise specified in the specification, each R b It can be arbitrarily replaced.

[0038] The term "inhibitor" refers to a compound or agent that can inhibit the biological function of a target protein or polypeptide, such as inhibiting the activity or expression of the target protein or polypeptide.

[0039] The term "tumor" includes, but is not limited to, solid tumors and hematologic malignancies, such as bladder cancer, bone or blood cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, laryngeal cancer, and uterine cancer.

[0040] The term "effective amount" refers to the amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application as described below, including but not limited to the treatment of a disease. Effective amounts may vary depending on: the intended application (in vivo or in vitro); or the individual being treated and the disease condition, such as the individual's weight and age, the severity of the disease; the route of administration, etc. Effective amounts can be readily determined by those skilled in the art.

[0041] "Optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility that the event or environment may or may not occur. For example, "optionally halogenated alkyl" means that a halogen may but does not have to be present, and the description includes the possibility that the alkyl group is halogenated and the possibility that the alkyl group is not halogenated.

[0042] The compounds described in this invention also include their isotope-labeled compounds. The term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass number than those normally found in nature. Examples of isotopes suitable for this invention include, but are not limited to, isotopes of hydrogen. 2 H and 3 H; carbon isotopes 11 C 13 C and 14 C; isotopes of chlorine 36 Cl; isotopes of fluorine 18 F; Isotopes of iodine 123 I and 125 I; Nitrogen isotopes 13 N and 15 N; isotopes of oxygen 15 O、 17 O and 18 O; isotopes of phosphorus 32 Isotopes of P and sulfur 35 S.

[0043] Various solvates and hydrates of the compounds or their salts described in this invention, as well as their polymorphs, are also included within the scope of this invention.

[0044] The term "solvent" refers to a compound that also includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. A solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes that may include, for example, one to about 100, one to about 10, one to about 2, about 3, or about 4 solvent or water molecules. The term "polymorph" refers to a compound that exists in two or more different crystalline forms.

[0045] Prodrugs of the compounds described in this invention are also included within the scope of this invention. Some derivatives of the compounds described in this invention possess weak or no pharmacological activity, but when these derivatives are administered into the body, they can be converted into pharmacologically active compounds of this invention through processes such as hydrolysis and cleavage. These derivatives are called "prodrugs". Further information on the uses of prodrugs can be found in *Pro-drugs as Novel Delivery Systems*, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and *Bioreversible Carriers in Drug Design*, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association).

[0046] The compounds described in this invention include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and possesses the pharmacological activity required of the parent compound. Pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic base, or inorganic and organic acid, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrate, glycolate, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0047] When used as a pharmaceutical, the compounds described herein are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers, diluents, or excipients are also included within the scope of this invention. Carriers, excipients, and additives as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired particular dosage form. Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference.

[0048] The compositions of this invention can be administered via any route suitable for the condition to be treated. In particular, administration is possible via: parenteral administration, for example, as an injectable solution or suspension; enteral administration, for example, orally, in tablet or capsule form; topical administration, for example, as a lotion, gel, ointment, or emulsion, or via nasal or suppository form. Topical application is, for example, to the skin. Another form of topical administration is administration to the eye.

[0049] Pharmaceutical compositions can be administered in solid, semi-solid, liquid, or gaseous form, or may be in the form of dry powders, such as lyophilized forms. Pharmaceutical compositions can be packaged in easily deliverable forms, including, for example, solid dosage forms such as capsules, pouches, sachets, gelatin, paper, tablets, suppositories, granules, pills, lozenges, and tablets. The type of packaging will generally depend on the route of administration. Implantable, sustained-release formulations and transdermal formulations are also covered.

[0050] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), and starches (e.g., corn starch). The composition may contain: potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the discretion of the formulation personnel.

[0051] The compounds described in this invention can be used alone or in combination with other therapeutic agents for treating the diseases or conditions described in this invention (e.g., cancer). In some embodiments, the compounds described in this invention are combined in a pharmaceutical combination formulation with a second compound having anti-proliferative properties or for treating highly proliferative diseases (e.g., cancer), or in a dosing regimen as a combination therapy. The second compound in the pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compounds described in this invention so that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of this invention are combined with other antitumor drugs.The antitumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclophosphamide, and carmustine; platinum-based drugs, including but not limited to carboplatin, cisplatin, and oxaliplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, and irinotecan; antibiotics, including but not limited to cyclophosphamide, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and procainoxantrone; antimicrotubule or antimitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, and doxorubicin; and antimetabolites, including but not limited to fluorouracil, methotrexate, cytarabine, and mecaptopurine. Thioguanine and gemcitabine; antibodies, including but not limited to Herceptin and bevacizumab; hormones, including but not limited to Letrazole, Vorazole, tamoxifen, toremifene, fulvestrant, flutamide, nilumethoxazole, and triptorelin; kinase inhibitors, including but not limited to EGFR kinase inhibitors such as gefitinib, erlotinib, lapatinib, and afatinib; and VEGFR inhibitors such as sorafenib and regoraflini. Enib, sunitinib, cabozantinib, pazopanib, vandetanib, axitinib; ALK inhibitors, including but not limited to crizotinib, ceritinib, alectinib; Bcr-Abl inhibitors, including but not limited to imatinib, ponatinib, nilotinib, dasatinib; BTK inhibitors Drugs, including but not limited to ibrutinib; B-RAF inhibitors, including but not limited to vemurafenib; cyclin-dependent kinase CDK4 / 6 inhibitors, such as palbociclib; mTOR inhibitors, including but not limited to rapamycin and everolimus; deacetylase inhibitors, including but not limited to vorinostat; PD1 / PDL1 antibodies, such as Keytruda (pembrolizumab) and Opdivo (nivolumab). Detailed Implementation

[0052] The present invention will be further described in detail below with reference to specific embodiments. The embodiments given are only for illustrating the present invention and are not intended to limit the scope of the present invention.

[0053] Example

[0054] Example 1: {4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propyl) Ethylazine (Ethylazine) methyl ketone

[0055]

[0056] Step 1: Synthesis of 2-amino-5-(6-methoxypyridin-3-yl)acetophenone

[0057]

[0058] 2-Amino-5-bromoacetophenone (2.14 g, 10 mmol) and 2-methoxy-5-pyridineboronic acid (1.68 g, 11 mmol) were dissolved in 1,4-dioxane / water (30 mL / 12 mL), and 3N potassium carbonate aqueous solution (12 mL, 30 mmol) was added. The mixture was purged three times with argon gas, and PdCl2 (dppf) (370 mg, 0.5 mmol) was added. The mixture was reacted at 100 °C for 6 hours. The insoluble solid was removed by diatomaceous earth filtration, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EtOAc = 1:3) to give a pale yellow solid (1.50 g, yield 62.5%).

[0059] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=2.5Hz,1H),7.84(d,J=2.2Hz,1H),7.74(dd,J=8.7,2.6Hz,1H),7.45(dd ,J=8.5,2.2Hz,1H),6.82(d,J=8.5Hz,1H),6.74(d,J=8.5Hz,1H),6.43(s,2H),3.99(s,3H),2.63(s,3H).

[0060] MS(ESI+)m / z 243.3,243.3[M+H] + .

[0061] Step 2: Synthesis of 1-[6-amino-5-bromo-3-(6-methoxypyridin-3-yl)cyclohexyl-2,4-dienyl]aceto-1-one

[0062]

[0063] 2-Amino-5-(6-methoxypyridin-3-yl)acetophenone (240 mg, 1 mmol) was dissolved in anhydrous dichloromethane (20 mL), and NBS (196 mg, 1.1 mmol) was added. The mixture was reacted at room temperature for 2 hours, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography (PE:EtOAc = 1:4) to give a pale yellow solid (227 mg, yield 71.0%).

[0064] 1 H NMR(500MHz, CDCl3)δ8.30(d,J=3.1Hz,1H),7.83(d,J=2.1Hz,1H),7.77(d,J=2.1Hz,1H), 7.71(dd,J=8.5,2.6Hz,1H),6.95(s,2H),6.82(d,J=8.5Hz,1H),3.98(s,3H),2.65(s,3H).

[0065] MS(ESI+)m / z 322.2,322.2[M+H] + .

[0066] Step 3: Synthesis of 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline

[0067]

[0068] 1-[6-amino-5-bromo-3-(6-methoxypyridin-3-yl)cyclohexyl-2,4-dienyl]ethyl-1-one (319 mg, 1 mmol) was dissolved in formamide (20 mL), and ammonium formate (127 mg, 2 mmol) was added. The mixture was purged three times with argon gas and reacted at 150 °C for 10 hours. The reaction was quenched with water (40 mL), extracted with ethyl acetate (20 mL × 10), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:EtOAc = 1:1) to give a pale yellow solid (165 mg, yield 50.6%).

[0069] 1 H NMR (400MHz, DMSO) δ9.17(s,1H),8.72(d,J=2.7Hz,1H),8.64(d,J=2.0Hz,1H),8.45(d,J= 2.0Hz, 1H), 8.27 (dd, J=8.6, 2.7Hz, 1H), 6.95 (d, J=8.6Hz, 1H), 3.92 (s, 3H), 3.00 (s, 3H).

[0070] MS(ESI+)m / z 331.2,331.2[M+H] + .

[0071] Step 4: Synthesis of (1-propyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}ethazol)methane-2-methylpropyl-2-yl ester

[0072]

[0073] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoic acid (2.48 g, 10 mmol) was dissolved in dichloromethane (40 mL), and 1-propylhydrazine-1-carboxylic acid tert-butyl ester (2.09 g, 12 mmol), triethylamine (5.56 mL, 40 mmol), and HATU (5.70 g, 15 mmol) were added. The mixture was reacted at room temperature for 16 hours, diluted with dichloromethane (20 mL), washed successively with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc = 1:3) to give a white solid (3.67 g, yield 91.08%).

[0074] 1 H NMR (500MHz, CDCl3) δ7.86 (s, 2H), 7.75 (d, J = 7.8Hz, 2H), 3.56 (t, J = 7.3Hz, 2H) ,1.62(q,J=7.3Hz,2H),1.53–1.38(m,9H),1.35(s,12H),0.93(t,J=7.4Hz,3H).

[0075] MS(ESI+)m / z 405.3,405.3[M+H] + .

[0076] Step 5: Synthesis of 2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0077]

[0078] The title compound was synthesized from 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and (1-propyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]carbonyl}ethazol)methane-2-methylpropyl-2-yl ester according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0079] MS(ESI+) m / z 528.6,528.6[M+H] + .

[0080] Step 6: Synthesis of {4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl)methyl ketone

[0081]

[0082] The [2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester obtained in the previous step was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain a pale yellow solid.

[0083] 1 H NMR (500MHz, DMSO-D6) δ10.13(s,1H),9.09(s,1H),8.79(dd,J=2.7,0.8Hz,1H ),8.50(d,J=2.1Hz,1H),8.33(dd,J=8.7,2.7Hz,1H),8.30(d,J=2.1Hz,1H),7 .98–7.92(m,2H),7.87–7.81(m,2H),6.98(dd,J=8.7,0.8Hz,1H),3.93(s,3H) ,3.03(s,3H),2.80(t,J=7.1Hz,2H),1.55–1.46(m,2H),0.94(t,J=7.4Hz,3H).

[0084] 13 C NMR (126MHz, DMSO-D6) δ169.03,165.11,163.56,153.95,145.84,145.73,140.54,139.19,138.34,135.90,132.7 6,132.26,131.01,130.76,128.75,128.13,126.53,124.60,122.47,110.67,53.38,53.11,22.09,20.85,11.69.

[0085] MS(ESI+) m / z 428.6 [M+H] + .

[0086] Example 2: {4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propyl) Ethylazine (Ethylazine) methyl ketone

[0087]

[0088] Step 1: Synthesis of 2-amino-5-(5-fluoro-6-methoxypyridin-3-yl)acetophenone

[0089]

[0090] The title compound was synthesized from 2-amino-5-bromoacetophenone and 2-methoxy-3-fluoro-5-pyridineboronic acid according to the method in step 1 of Example 1.

[0091] 1 H NMR(400MHz,CHLOROFORM-D)δ7.96(s,1H),7.95(s,1H),7.51(dd,J=8.6,2.1Hz,1 H),7.39(dd,J=8.4,2.9Hz,1H),6.73(d,J=8.7Hz,1H),3.98(s,3H),2.62(s,3H).

[0092] MS(ESI+)m / z 261.3,261.3[M+H] + .

[0093] Step 2: Synthesis of 1-[6-amino-5-bromo-3-(5-fluoro-6-methoxypyridin-3-yl)cyclohexyl-2,4-dienyl]acet-1-one

[0094]

[0095] The title compound was synthesized from 2-amino-5-(5-fluoro-6-methoxypyridin-3-yl)acetophenone and NBS according to the method in step 2 of Example 1.

[0096] 1 H NMR (500MHz, CDCl3) δ7.97(d,J=2.9Hz,1H),7.96(d,J=2.1Hz,1H),7.83(d,J=2.0Hz,1H),7.37(dd,J=8.3,2.8Hz,1H),3.98(s,3H),2.63(s,3H).

[0097] MS(ESI+) m / z 340.2, 340.2 [M+H] + .

[0098] Step 3: Synthesis of 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline

[0099]

[0100] The title compound was synthesized from 1-[6-amino-5-bromo-3-(5-fluoro-6-methoxypyridin-3-yl)cyclohex-2,4-dienyl]ethyl-1-one according to the method in step 3 of Example 1.

[0101] 1 H NMR(500MHz, CDCl3)δ9.32(s,1H),8.42(d,J=1.8Hz,1H),8.23(d,J=1.8Hz,1H) ,8.10(d,J=2.9Hz,1H),7.52(dd,J=8.0,3.0Hz,1H),4.00(s,3H),3.03(s,3H).

[0102] MS(ESI+) m / z 349.2, 349.2 [M+H] + .

[0103] Step 4: Synthesis of [2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0104]

[0105] The title compound was synthesized from 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline and the product (1-propyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]carbonyl}ethazol)methane-2-methylpropyl-2-yl ester) from step 4 of Example 1. It was used directly in the next reaction without purification.

[0106] MS(ESI+) m / z 546.6,546.6[M+H] + .

[0107] Step 5: Synthesis of {4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl)methyl ketone

[0108]

[0109] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0110] 1H NMR (500MHz, DMSO-D6) δ10.22(s,1H),9.09(s,1H),8.62(d,J=2.1Hz,1H),8.52(d,J=2.1Hz,1H),8.41(dd,J=11.9,2.1Hz,1H),8.33(d ,J=2.1Hz,1H),8.00–7.90(m,2H),7.89–7.82(m,2H),4.01(s,3H),3.03(s,3H),2.83(t,2H),1.62–1.41(m,2H),0.94(t,J=7.4Hz,3H).

[0111] 13 C NMR(126MHz,DMSO-D6)δ169.18,167.25,154.11,152.31(d,J C-F =11.3Hz),146.83(d,JC-F=256.9Hz),145.89,140.49,140.24(d,J C-F =5.7Hz),139.15,134.60,132.73,131.02,130.80,129.13,128.70,126. 56,124.51,122.99,122.93,122.80,53.77,52.59,22.09,20.75,11.65.

[0112] MS(ESI+)m / z 446.5,446.5[M+H] + .

[0113] Example 3: {4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]benzene} 2-propylethazine) methyl ketone

[0114]

[0115] Step 1: Synthesis of 2-amino-5-(5,6-dimethoxypyridin-3-yl)acetophenone

[0116]

[0117] The title compound was synthesized from 2-amino-5-bromoacetophenone and 2,3-dimethoxy-5-pyridineboronic acid according to the method in step 1 of Example 1.

[0118] 1H NMR (500MHz, CDCl3) δ7.90(d,J=2.1Hz,1H),7.84(d,J=2.1Hz,1H),7.45(dd,J=8.5,2.1Hz ,1H),7.21(d,J=2.1Hz,1H),6.75(d,J=8.5Hz,1H),4.12(s,3H),3.96(s,3H),2.64(s,3H).

[0119] MS(ESI+)m / z 273.3,273.3[M+H] + .

[0120] Step 2: Synthesis of 1-[6-amino-5-bromo-3-(5,6-dimethoxypyridin-3-yl)cyclohexyl-2,4-dienyl]aceto-1-one

[0121]

[0122] The title compound was synthesized from 2-amino-5-(5,6-dimethoxypyridin-3-yl)acetophenone and NBS according to the method in step 2 of Example 1.

[0123] 1 H NMR (500MHz, CDCl3) δ7.91–7.86(m,1H),7.86–7.82(m,1H),7.77(d,J=1.8Hz,1H),7.16(s,1H),6.97(s,2H),4.10(s,3H),3.97(s,3H),2.66(s,3H).

[0124] MS(ESI+)m / z 352.2,352.2[M+H] + .

[0125] Step 3: Synthesis of 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline

[0126]

[0127] The title compound was synthesized from 1-[6-amino-5-bromo-3-(5,6-dimethoxypyridin-3-yl)cyclohexyl-2,4-dienyl]ethyl-1-one according to the method in step 3 of Example 1.

[0128] 1H NMR (500MHz, CDCl3) δ9.30 (s, 1H), 8.40 (d, J = 1.8Hz, 1H), 8.15 (d, J = 1.8Hz, 1H), 8. 04(d,J=2.0Hz,1H),7.29(d,J=2.1Hz,1H),4.10(s,3H),4.01(s,3H),3.05(s,3H).

[0129] MS(ESI+)m / z 361.2,361.2[M+H] + .

[0130] Step 4: Synthesis of [2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0131]

[0132] The title compound was synthesized from 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline and the product (1-propyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]carbonyl}ethazol)methane-2-methylpropyl-2-yl ester) from step 4 of Example 1. It was used directly in the next reaction without purification.

[0133] MS(ESI+)m / z 558.7,558.7[M+H] + .

[0134] Step 5: Synthesis of {4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl)methyl ketone

[0135]

[0136] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0137] 1H NMR (500MHz, DMSO-D6) δ10.19(s,1H),9.09(s,1H),8.49(d,J=2.1Hz,1H),8.34(d,J=2.1Hz,1H),8.28(d,J=2.1Hz,1H),7.99–7.92(m,2H) ,7.89–7.81(m,2H),7.80(d,J=2.1Hz,1H),3.94(s,3H),3.93(s,3H),3.04(s,3H),2.82(t,2H),1.58–1.43(m,2H),0.93(t,J=7.4Hz,3H).

[0138] 13 C NMR (126MHz, DMSO-D6) δ169.00,167.27,153.91,145.76,143.88,142.21,140.66,139.14,136.23,135.43,133.08,1 31.64,131.01,130.78,128.77,128.71,126.54,124.53,122.67,117.30,55.83,53.23,52.59,22.10,20.74,11.65.

[0139] MS(ESI+) m / z 458.6 [M+H] + .

[0140] Example 4: {3-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propyl) Ethylazine (Ethylazine) methyl ketone

[0141]

[0142] Step 1: Synthesis of 2-{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0143]

[0144] The title compound was synthesized from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0145] MS(ESI+)m / z 423.3,423.3[M+H] + .

[0146] Step 2: Synthesis of [2-({3-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0147]

[0148] The title compound was synthesized from the product of step 1 in Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline, and the product of step 1 in Example 4: 2-{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester. It was used directly in the next reaction without purification.

[0149] MS(ESI+) m / z 546.6,546.6[M+H] + .

[0150] Step 3: Synthesis of {3-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl)methyl ketone

[0151]

[0152] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({3-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0153] 1 H NMR (500MHz, DMSO-D6) δ10.20(s,1H),9.05(s,1H),8.78(dd,1H),8.57(d,J=2.1 Hz,1H),8.33(d,J=2.1Hz,1H),8.31(dd,J=2.7Hz,1H),7.81(dd,J=7.9,1.7Hz,1 H),7.75(dd,J=10.5,1.7Hz,1H),7.68(t,J=7.6Hz,1H),6.98(dd,1H),3.93(s,3 H),3.04(s,3H),2.80(t,J=7.1Hz,2H),1.55–1.44(m,2H),0.93(t,J=7.4Hz,3H).

[0154] 13C NMR (126MHz, DMSO-D6) δ169.06, 163.85 (d, JC-F = 2.1Hz), 163.61, 159.44 (d, JC-F = 246. 4Hz),154.03,146.08,145.84,138.31,135.84,135.10(d,JC-F=7.1Hz),134.53,133.4 2,132.62(d,JC-F=3.6Hz),128.69(d,JC-F=16.1Hz),127.90,124.21,123.14,122.77( d,JC-F=3.1Hz),113.84(d,JC-F=24.1Hz),110.72,53.41,53.01,21.97,20.87,11.68.

[0155] MS(ESI+) m / z 446.5 [M+H] + .

[0156] Example 5: {3-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]} phenyl}(2-propylethazol) methyl ketone

[0157]

[0158] Step 1: Synthesis of [2-({3-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0159]

[0160] The title compound was synthesized from the product 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 2) and the product (2-{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazolyl)methane-2-methylpropyl-2-yl ester) from step 1 of Example 4. It was used directly in the next reaction without purification.

[0161] MS(ESI+) m / z 564.6,564.6[M+H] + .

[0162] Step 2: Synthesis of {3-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl) methyl ketone

[0163]

[0164] According to the method in step 6 of Example 1, the title compound is obtained by de-Boc protection of [2-({3-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0165] 1 H NMR (500MHz, DMSO-D6) δ10.20 (s, 1H), 9.06 (s, 1H), 8.63 (d, J = 2.1Hz, 1H), 8.62 ( d,J=2.1Hz,1H),8.42(dd,J=11.9,2.1Hz,1H),8.38(d,J=2.1Hz,1H),7.81(dd,J =7.9,1.6Hz,1H),7.75(dd,J=10.5,1.6Hz,1H),7.68(t,J=7.6Hz,1H),4.02(s,3 H),3.05(s,3H),2.80(t,J=7.1Hz,2H),1.55–1.44(m,2H),0.93(t,J=7.4Hz,3H).

[0166] 13 C NMR (126MHz, DMSO-D6) δ169.24, 163.83 (d, JC-F=2.1Hz), 159.43 (d, JC-F=246.7Hz), 154.22, 152.40 (d ,JC-F=11.5Hz),146.88(d,JC-F=257.1Hz),146.27,140.26(d,JC-F=5.7Hz),135.13(d,JC-F=7.1Hz),1 34.59(d,JC-F=4.4Hz), 133.42, 132.62(d,JC-F=3.5Hz), 128.92(d,JC-F=2.1Hz), 128.60(d,JC-F=16.2 Hz),124.14,123.71,122.88(d,JC-F=16.4Hz),122.75(d),113.72,53.82,53.01,21.99,20.86,11.68.

[0167] MS(ESI+) m / z 464.5 [M+H] + .

[0168] Example 6: {4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-3-fluorophenyl}(2- Propylethazine (PPH) methyl ketone

[0169]

[0170] Step 1: Synthesis of 2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-3-fluorophenyl}carbonyl)-1-ethylethazinyl]methane-2-methylpropyl-2-yl ester

[0171]

[0172] The title compound was synthesized from the product 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 3) and the product (2-{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester) from step 1 of Example 4. It was used directly in the next reaction without purification.

[0173] MS(ESI+) m / z 576.6,576.6[M+H] + .

[0174] Step 2: Synthesis of {4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-3-fluorophenyl}(2-propylethazolyl) methyl ketone

[0175]

[0176] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-3-fluorophenyl}carbonyl)-1-ethylethazinyl]methane-2-methylpropyl-2-yl ester.

[0177] 1 H NMR (500MHz, DMSO-D6) δ10.20(s,1H),9.05(s,1H),8.57(d,J=2.1Hz,1H),8.37(d,J=2.1Hz,1H),8.29(d,J=2.1Hz,1H),7.83–7.79(m,2H),7.75(dd ,J=10.5,1.7Hz,1H),7.68(t,J=7.6Hz,1H),3.94(s,3H),3.93(s,3H),3.0 6(s,3H),2.80(t,J=7.1Hz,2H),1.56–1.43(m,2H),0.93(t,J=7.4Hz,3H).

[0178] 13C NMR(126MHz,DMSO-D6)δ169.04,163.84(d,JC-F=2.1Hz),159.45(d,JC-F=246.3Hz),154.02,1 53.96,146.12,143.92,136.18,135.43,135.09(d,JC-F=7.2Hz),134.48,133.76,132.63(d,J C-F =3.5Hz),128.77(d,JC-F=16.2Hz),128.53,124.15,123.29,122.76(d,JC-F=3.2 Hz),117.26,113.82(d,JC-F=24.0Hz),55.82,53.26,53.01,22.00,20.86,11.68.

[0179] MS(ESI+) m / z 476.5 [M+H] + .

[0180] Example 7: {2-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propyl) Ethylazine (Ethylazine) methyl ketone

[0181]

[0182] Step 1: Synthesis of 2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0183]

[0184] The title compound was synthesized from 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0185] MS(ESI+)m / z 423.3,423.3[M+H] + .

[0186] Step 2: Synthesis of [2-({2-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0187]

[0188] The title compound was synthesized from the product of step 1 in Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline, and the product of step 1 in Example 7: 2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester. It was used directly in the next reaction without purification.

[0189] MS(ESI+) m / z 546.6,546.6[M+H] + .

[0190] Step 3: Synthesis of {2-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl)methyl ketone

[0191]

[0192] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({2-fluoro-4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0193] 1 H NMR (500MHz, DMSO-D6) δ9.87(s,1H),9.11(s,1H),8.80(dd,J=2.7,0.8Hz,1H),8.52(d,J=2.1Hz,1H),8.38–8.35(m,1H),8.34–8.32(m,1H) ,7.75–7.65(m,3H),6.99(dd,J=8.7,0.8Hz,1H),3.93(s,3H),3.04(s,3H),2.80(t,J=7.1Hz,2H),1.56–1.45(m,2H),0.93(t,J=7.4Hz,3H).

[0194] 13C NMR(126MHz,DMSO-D6)δ169.14,163.59,162.66,158.56(d,JC-F=248.2Hz),154.04,14 5.89,145.58,141.72(d,JC-F=8.7Hz),138.36,137.77(d,JC-F=1.9Hz),135.91,132.9 1,129.22(d,JC-F=3.5Hz),128.02,126.83(d,JC-F=3.0Hz),124.58,122.88,122.07(d ,JC-F=15.5Hz),118.36(d,JC-F=23.4Hz),110.66,53.39,52.91,22.10,20.76,11.63.

[0195] MS(ESI+) m / z 446.5 [M+H] + .

[0196] Example 8: {2-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl} (2-propylethazo)methyl ketone

[0197]

[0198] Step 1: Synthesis of [2-({2-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0199]

[0200] The title compound was synthesized from the product 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 2) and the product (2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester) from step 1 of Example 7. It was used directly in the next reaction without purification.

[0201] MS(ESI+) m / z 564.6,564.6[M+H] + .

[0202] Step 2: Synthesis of {2-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}(2-propylethazolyl) methyl ketone

[0203]

[0204] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({2-fluoro-4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0205] 1 H NMR (500MHz, DMSO-D6) δ9.90(s,1H),9.11(s,1H),8.63(d,J=2.1Hz,1H),8.55(d,J=2.1Hz,1H),8.42(dd,J=11.9,2.1Hz,1H),8.36(d,J=2. 1Hz,1H),7.77–7.70(m,1H),7.70–7.64(m,2H),4.02(s,3H),3.03(s,3H),2.81(t,J=7.1Hz,2H),1.58–1.41(m,2H),0.93(t,J=7.4Hz,3H).

[0206] 13 C NMR (126MHz, DMSO-D6) δ169.31, 162.66, 158.57 (d, JC-F = 248.2Hz), 154.22, 152.35 (d, JC-F = 11.4Hz), 146.85(d,JC-F=256.9Hz),145.74,141.66,140.31(d,JC-F=5.6Hz),137.76(d,JC-F=1.8Hz),134.62, 132.89,129.19(d,JC-F=3.5Hz),129.03(d,JC-F=1.9Hz),126.89(d,JC-F=3.2Hz),124.51,123.41,12 2.95,122.82,122.01(d,JC-F=15.3Hz),118.38(d,JC-F=23.4Hz),53.79,52.89,22.11,20.71,11.62.

[0207] MS(ESI+) m / z 464.5 [M+H] + .

[0208] Example 9: {4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-2-fluorophenyl}(2- Propylethazine (PPH) methyl ketone

[0209]

[0210] Step 1: Synthesis of [2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-2-fluorophenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0211]

[0212] The title compound was synthesized from the product 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 3) and the product (2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester) from step 1 of Example 7. It was used directly in the next reaction without purification.

[0213] MS(ESI+) m / z 576.6,576.6[M+H] + .

[0214] Step 2: Synthesis of {4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-2-fluorophenyl}(2-propylethazolyl) methyl ketone

[0215]

[0216] According to the method in step 6 of Example 1, the title compound is obtained by de-Boc protection of [2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-2-fluorophenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0217] 1 H NMR (500MHz, DMSO-D6) δ10.52(s,1H),9.10(s,1H),8.52(d,J=2.1Hz,1H),8.36(d,J=2.1Hz,1H),8.29(d,J=2.1Hz,1H),7.81(d,J=2. 1Hz,1H),7.78–7.68(m,3H),3.94(s,3H),3.93(s,3H),3.05(s,3H),2.95(t,J=7.3Hz,2H),1.61–1.52(m,2H),0.95(t,J=7.5Hz,3H).

[0218] 13C NMR(126MHz,DMSO-D6)δ169.15,162.68,158.67(d,JC-F=249.3Hz),154.03,153.97, 145.60,143.91,142.51(d,JC-F=8.7Hz),137.60(d,JC-F=1.8Hz),136.25,135.52,13 3.27,129.37(d),128.63,127.01(d,JC-F=3.1Hz),124.53,123.19,120.87(d,JC-F=1 5.0Hz), 118.51 (d, JC-F=23.1Hz), 117.31, 55.86, 53.26, 52.37, 22.12, 19.67, 11.35.

[0219] MS(ESI+) m / z 476.5 [M+H] + .

[0220] Example 10: (2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1- (2-Propylethazo)prop-2-en-1-one

[0221]

[0222] Step 1: Synthesis of (2E)-3-(4-bromophenyl)prop-2-enoic acid-2-methylprop-2-yl ester

[0223]

[0224] (2E)-3-(4-bromophenyl)prop-2-enoic acid (1.62 g, 10 mmol) and di-tert-butyl dicarbonate (4.36 g, 20 mmol) were dissolved in tert-butanol (40 mL), and 4-(dimethylamino)pyridine (122 mg, 1 mmol) was added. The mixture was reacted at 50 °C for 2 hours, and the solvent was evaporated under reduced pressure. The solution was used directly in the next reaction without purification.

[0225] 1 H NMR (400MHz, DMSO) δ7.69–7.63(m,2H),7.63–7.58(m,2H),7.52(d,J=16.0Hz,1H),6.56(d,J=16.0Hz,1H),1.48(s,9H).

[0226] MS(ESI+)m / z 284.2,284.2[M+H] + .

[0227] Step 2: Synthesis of (2E)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]prop-2-enoic acid-2-methylprop-2-yl ester

[0228]

[0229] (2E)-3-(4-bromophenyl)prop-2-enoic acid-2-methylprop-2-yl ester (2.18 g, 10 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopent-2-yl)-1,3,2-dioxaborhexacyclopentane (2.54 g, 10 mmol) were dissolved in 1,4-dioxane (30 mL), and 2N potassium acetate (1.96 g) was added. The mixture was purged three times with argon gas, and PdCl2 (dppf) (370 mg, 0.5 mmol) was added. The mixture was reacted at 100 °C for 6 hours. The insoluble solid was removed by diatomaceous earth filtration, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EtOAc = 3:1) to obtain a light green solid (2.00, yield 62.5%).

[0230] 1 H NMR (500MHz, CDCl3) δ7.81 (s, 1H), 7.79 (s, 1H), 7.58 (d, J = 15.9Hz, 1H), 7.51 (s ,1H),7.49(d,J=1.6Hz,1H),6.42(d,J=16.0Hz,1H),1.53(s,9H),1.34(s,12H).

[0231] MS(ESI+)m / z 331.2,331.2[M+H] + .

[0232] Step 3: Synthesis of (2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid-2-methylprop-2-yl ester

[0233]

[0234] The title compound will be synthesized from the product of step 3 in Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 2 in Example 10: (2E)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]prop-2-enoic acid-2-methylprop-2-yl ester.

[0235] 1H NMR (500MHz, DMSO-D6) δ9.11(s,1H),8.81(d,J=2.1Hz,1H),8.51(d,J=2.1Hz,1H),8.36(dd,J=8.6,2.1Hz,1H),8.32(d,J=2.1Hz,1H ),7.86–7.80(m,4H),7.65(d,J=16.0Hz,1H),6.99(d,J=8.6Hz,1H),6.62(d,J=16.0Hz,1H),3.94(s,3H),3.04(s,3H),1.51(s,9H).

[0236] MS(ESI+)m / z 454.5,454.5[M+H] + .

[0237] Step 4: Synthesis of (2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid

[0238]

[0239] (2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid-2-methylprop-2-yl ester (415 mg, 1 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The product was used directly in the next reaction without purification.

[0240] MS(ESI+)m / z 398.4,398.4[M+H] + .

[0241] Step 5: Synthesis of {2-[(2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-oxoylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0242]

[0243] The title compound was synthesized from (2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}prop-2-enoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0244] MS(ESI+)m / z 554.7,554.7[M+H] + .

[0245] Step 6: Synthesis of (2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-(2-propylethazolyl)prop-2-en-1-one

[0246]

[0247] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0248] 1 H NMR (500MHz, DMSO-D6) δ9.65 (s, 1H), 9.10 (s, 1H), 8.78 (dd, J = 2.6, 0.8Hz, 1H), 8.48 (d, J = 2. 1Hz,1H),8.33(dd,J=8.6,2.6Hz,1H),8.30(d,J=2.1Hz,1H),7.84–7.79(m,2H),7.71–7.65( m,2H),7.55(d,J=15.8Hz,1H),6.98(d,J=8.6Hz,1H),6.64(d,J=15.8Hz,1H),5.10(s,1H),3 .93(s,3H),3.03(s,3H),2.72(t,J=7.1Hz,2H),1.45(h,J=7.3Hz,2H),0.90(t,J=7.4Hz,3H).

[0249] 13 C NMR (126MHz, DMSO-D6) δ169.01,163.84,163.55,153.89,145.82,145.76,139.33,138.79,138.33,138.22,135.9 0,134.21,132.59,131.38,128.16,126.97,124.64,122.25,120.44,110.66,53.38,53.12,22.10,20.81,11.58.

[0250] MS(ESI+) m / z 454.6 [M+H] + .

[0251] Example 11: (2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]benzene 1-(2-propylethazolyl)prop-2-en-1-one

[0252]

[0253] Step 1: Synthesis of (2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid-2-methylprop-2-yl ester

[0254]

[0255] The title compound was synthesized from the product 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline from step 3 of Example 2 and the product (2E)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]prop-2-enoic acid-2-methylprop-2-yl ester from step 2 of Example 10, according to the method in step 1 of Example 1.

[0256] 1 H NMR (500MHz, DMSO-D6) δ9.15(s,1H),8.51(d,J=2.0Hz,1H),8.27(d,J=2.9Hz,1H),8.26(d,J=2.0Hz,1H),8.16(dd,J=8. 8,2.9Hz,1H),7.87–7.76(m,4H),7.64(d,J=16.0Hz,1H),6.61(d,J=16.0Hz,1H),3.93(s,3H),3.01(s,3H),1.51(s,9H).

[0257] MS(ESI+)m / z 472.5,472.5[M+H] + .

[0258] Step 2: Synthesis of (2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid

[0259]

[0260] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating (2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}prop-2-enoic acid-2-methylprop-2-yl ester. It is then used directly in the next reaction without purification.

[0261] MS(ESI+)m / z 416.5,416.5[M+H] + .

[0262] Step 3: Synthesis of {2-[(2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-oxoylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0263]

[0264] The title compound was synthesized from (2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0265] MS(ESI+)m / z 554.7,554.7[M+H] + .

[0266] Step 4: Synthesis of (2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-(2-propylethazolyl)prop-2-en-1-one

[0267]

[0268] According to the method in step 6 of Example 1, the title compound is generated by deBoc protection of {2-[(2E)-3-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0269] 1 H NMR (500MHz, DMSO-D6) δ9.65 (s, 1H), 9.14 (s, 1H), 8.48 (d, J = 2.1Hz, 1H), 8.26 (d ,J=3.0Hz,1H),8.24(d,J=2.1Hz,1H),8.14(dd,J=8.8,3.0Hz,1H),7.81–7.77(m, 2H),7.70–7.66(m,2H),7.54(d,J=15.8Hz,1H),6.63(d,J=15.8Hz,1H),3.93(s,3 H),3.00(s,3H),2.72(t,J=7.1Hz,2H),1.49–1.41(m,2H),0.90(t,J=7.4Hz,3H).

[0270] 13C NMR(126MHz,DMSO-D6)δ169.10,163.82,156.33,155.54(d,JC-F=291.1Hz ),145.97,138.68,138.24(d,JC-F=15.3Hz),134.83,134.23,133.90,132. 69(d,JC-F=26.0Hz),131.29,127.50(d,JC-F=21.8Hz),127.05,125.94,12 4.15,123.47(d,JC-F=4.7Hz),120.48,54.06,53.11,22.02,20.81,11.57.

[0271] MS(ESI+) m / z 454.6 [M+H] + .

[0272] Example 12: (2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}- 1-(2-propylethazol)prop-2-en-1-one

[0273]

[0274] Step 1: Synthesis of (2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid-2-methylprop-2-yl ester

[0275]

[0276] The title compound was synthesized from the product 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 3) and the product (2E)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]prop-2-enoic acid-2-methylprop-2-yl ester (from step 2 of Example 10). It was used directly in the next reaction without purification.

[0277] MS(ESI+)m / z 484.6,484.6[M+H] + .

[0278] Step 2: Synthesis of (2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid

[0279]

[0280] The title compound was generated by detert-butylating (2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}prop-2-enoic acid-2-methylprop-2-yl ester. It was used directly in the next reaction without purification.

[0281] MS(ESI+) m / z 428.6, 428.6 [M+H] + .

[0282] Step 3: Synthesis of {2-[(2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-oxoylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0283]

[0284] The title compound was synthesized from (2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}prop-2-enoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0285] MS(ESI+)m / z 584.7,584.7[M+H] + .

[0286] Step 4: Synthesis of (2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-(2-propylethazolyl)prop-2-en-1-one

[0287]

[0288] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0289] 1H NMR (500MHz, DMSO-D6) δ9.66 (s, 1H), 9.10 (s, 1H), 8.49 (d, J = 2.1Hz, 1H), 8 .34(d,J=2.1Hz,1H),8.30(d,J=2.1Hz,1H),7.86–7.79(m,3H),7.73–7.65( m,2H),7.55(d,J=15.6Hz,1H),6.64(d,J=15.6Hz,1H),3.94(s,3H),3.93( s,3H),3.05(s,3H),2.72(t,1H),1.55–1.34(m,2H),0.90(t,J=7.3Hz,3H).

[0290] 13 C NMR (126MHz, DMSO-D6) δ169.00,153.91,145.81,143.90,139.33,138.85,138.23,136.26,135.44,134.19,132.94,131. 40,128.84,128.70,127.69,126.97,124.58,122.48,120.43,119.37,117.34,55.84,53.24,53.10,22.13,20.81,11.57.

[0291] MS(ESI+) m / z 484.6 [M+H] + .

[0292] Example 13: 4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propylethyl] [N-(carbonyl)phenyl]benzamide

[0293]

[0294] Step 1: Synthesis of 2-methylpropyl-2-yl 4-({[4-(dihydroxyboryl)phenyl]carbonyl}amino)benzoic acid ester

[0295]

[0296] p-Pinacol benzoyl chloride (369 mg, 2 mmol) was dissolved in dichloromethane (20 mL), and tert-butyl p-aminobenzoate (387 mg, 2 mmol) and triethylamine (0.14 mL, 2 mmol) were added. The mixture was reacted at room temperature for 16 hours, diluted with dichloromethane (20 mL), washed successively with water (50 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc = 2:1) to give a white solid (673 mg, yield 98.7%).

[0297] 1 H NMR (400MHz, DMSO-D6) δ10.52(s,1H),8.25(s,2H),7.98–7.86(m,8H),1.55(s,9H).

[0298] MS(ESI+)m / z 342.2,342.2[M+H] + .

[0299] Step 2: Synthesis of 2-methylpropyl-2-yl benzoate 4-[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]benzoate

[0300]

[0301] The title compound will be synthesized from the product of step 3 of Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 1 of Example 13: 4-({[4-(dihydroxyboryl)phenyl]carbonyl}amino)benzoic acid-2-methylpropyl-2-yl ester, according to the method of step 1 in Example 1.

[0302] 1 H NMR (400MHz, CHLOROFORM-D) δ9.21(s,1H),8.56(d,J=1.8Hz,1H),8.24(d,J=2.1Hz,1H),8.12(d,J=2.1Hz,1H),8.04(d,J=3.0Hz,2H),8.03(s,2H),8 .02(s,1H),7.95(dd,J=8.5,2.6Hz,1H),7.87(d,J=8.4Hz,2H),7.75(d,J= 8.8Hz,2H),6.93(d,J=8.7Hz,1H),4.03(s,3H),3.08(s,3H),1.61(s,9H).

[0303] MS(ESI+) m / z 547.6,547.6[M+H] + .

[0304] Step 3: Synthesis of 4-[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid

[0305]

[0306] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0307] MS(ESI+)m / z 491.5,491.5[M+H] + .

[0308] Step 4: Synthesis of [2-({4-[({4-[6-(6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0309]

[0310] The title compound was synthesized from 4-[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0311] MS(ESI+)m / z 647.8,647.8[M+H] + .

[0312] Step 5: Synthesis of 4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propylethazolyl)carbonyl]phenyl}benzamide

[0313]

[0314] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[({4-[6-(6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester.

[0315] 1H NMR (500MHz, DMSO-D6) δ10.56(s,1H),9.97(s,1H),9.11(s,1H),8.80(dd,J=2 .6,0.8Hz,1H),8.51(d,J=2.1Hz,1H),8.37–8.33(m,2H),8.13–8.06(m,2H),7 .96–7.90(m,4H),7.89–7.82(m,2H),6.99(dd,J=8.6,0.8Hz,1H),3.93(s,3H) ,3.04(s,3H),2.76(t,J=7.1Hz,2H),1.54–1.42(m,2H),0.92(t,J=7.4Hz,3H).

[0316] 13 C NMR (126MHz, DMSO-D6) δ169.07,165.70,164.89,163.58,153.99,145.86,145.75,141.93,141.09,139.09,138.36,135.93,1 33.74,132.79,130.86,130.25,128.13,127.78,127.28,124.63,122.60,119.44,110.69,53.40,53.18,22.11,20.87,11.69.

[0317] MS(ESI+) m / z 547.7 [M+H] + .

[0318] Example 14: 4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propane] [[ ...][[[[[[[[[[[[][[[[[[[[[[][[[[[[[[[][[[[[[[][[[[[[[][[[[[[[][[[[[][[[[[[][[

[0319]

[0320] Step 1: Synthesis of 2-methylpropyl-2-yl benzoate 4-[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]benzoate

[0321]

[0322] The title compound was synthesized from the product 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 2) and the product 4-({[4-(dihydroxyboryl)phenyl]carbonyl}amino)benzoic acid-2-methylpropyl-2-yl ester (from step 1 of Example 13). It was used directly in the next reaction without purification.

[0323] MS(ESI+)m / z 565.6,565.6[M+H] + .

[0324] Step 2: Synthesis of 4-[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]benzoic acid

[0325]

[0326] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0327] MS(ESI+)m / z 509.5,509.5[M+H] + .

[0328] Step 3: Synthesis of [2-({4-[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0329]

[0330] The title compound was synthesized from 4-[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, following the method in step 4 of Example 1. It was used directly in the next reaction without purification.

[0331] MS(ESI+)m / z 665.7,665.7[M+H] + .

[0332] Step 4: Synthesis of 4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propylethazolyl)carbonyl]phenyl}benzamide

[0333]

[0334] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester.

[0335] 1 H NMR (500MHz, DMSO-D6) δ10.55(s,1H),9.96(s,1H),9.15(s,1H),8.53(d,J=2. 0Hz,1H),8.30(d,J=2.0Hz,1H),8.27(d,J=3.0Hz,1H),8.17(dd,J=8.8,3.0Hz, 1H),8.08(d,J=8.7Hz,2H),7.94–7.89(m,4H),7.88–7.83(m,2H),3.94(s,3H) ,3.02(s,3H),2.76(t,J=7.1Hz,2H),1.53–1.43(m,2H),0.92(t,J=7.4Hz,3H).

[0336] 13 C NMR (126MHz, DMSO-D6) δ169.18,165.72,164.88,156.72,156.35,154.49,154 .41,145.96,141.92,140.99,138.05,135.05,133.93,133.82,132.75(d,JC- F=25.5Hz),130.77,130.27,128.04,127.78,127.62,127.45,127.34,126.28 ,124.15,123.41(d,JC-F=4.6Hz),119.40,54.07,53.17,22.03,20.86,11.68.

[0337] MS(ESI+) m / z 565.6 [M+H] + .

[0338] Example 15: 4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4- [(2-propylethazo)carbonyl]phenylbenzamide

[0339]

[0340] Step 1: Synthesis of 4-[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]benzoic acid-2-methylpropyl-2-yl ester]

[0341]

[0342] The title compound was synthesized from the product 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline (from step 3 of Example 3) and the product 4-({[4-(dihydroxyboryl)phenyl]carbonyl}amino)benzoic acid-2-methylpropyl-2-yl ester (from step 1 of Example 13). It was used directly in the next reaction without purification.

[0343] MS(ESI+)m / z 577.7,577.7[M+H] + .

[0344] Step 2: Synthesis of 4-[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]benzoic acid

[0345]

[0346] According to step 4 of Example 10, the title compound was obtained by detert-butylating 4-[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid-2-methylpropyl-2-yl ester. It was used directly in the next reaction without purification.

[0347] MS(ESI+)m / z 521.6,521.6[M+H] + .

[0348] Step 3: Synthesis of [2-({4-[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0349]

[0350] The title compound was synthesized from 4-[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0351] MS(ESI+)m / z 677.8,677.8[M+H] + .

[0352] Step 4: Synthesis of 4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propylethazolyl)carbonyl]phenyl}benzamide

[0353]

[0354] According to the method in step 6 of Example 1, the title compound is obtained by de-Boc protection of [2-({4-[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester.

[0355] 1 H NMR (500MHz, DMSO-D6) δ10.57(s,1H),9.96(s,1H),9.11(s,1H),8.53(d,J=2.1 Hz,1H),8.39(d,J=2.1Hz,1H),8.32(d,J=2.1Hz,1H),8.14–8.06(m,2H),7.95– 7.90(m,4H),7.88–7.84(m,2H),7.84(d,J=2.1Hz,1H),3.95(s,3H),3.94(s,3H ),3.07(s,3H),2.76(t,J=7.0Hz,1H),1.54–1.41(m,2H),0.92(t,J=7.4Hz,3H).

[0356] 13 C NMR (126MHz, DMSO-D6) δ169.08,165.69,164.87,153.99,153.95,145.81,143.93,141.92,141.15,139.08,136.28,135.48,133. 73,133.15,130.88,130.26,128.80,127.77,127.27,124.58,119.47,119.43,117.37,55.87,53.26,53.18,22.14,20.89,11.69.

[0357] MS(ESI+)m / z 477.7 [M+H] + .

[0358] Example 16: 4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propylethyl] [N-(carbonyl)phenyl]benzamide

[0359]

[0360] Step 1: Synthesis of 2-methylpropyl-2-yl 4-[({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoate

[0361]

[0362] The title compound will be synthesized from p-pinacol benzoic acid and tert-butyl p-aminomethylbenzoate according to the method in step 1 of Example 13.

[0363] 1 H NMR (500MHz, CDCl3) δ7.98(d,J=1.8Hz,1H),7.96(d,J=2.0Hz,1H),7.88(d,J=1.8Hz,1H),7.86(d,J=2.0Hz,1H),7.78(d,J=2.0Hz,1H ),7.77(d,J=1.8Hz,1H),7.40(d,J=2.0Hz,1H),7.39(d,J=2.1Hz,1H),6.46(s,1H),4.70(d,J=6.0Hz,2H),1.59(s,9H),1.35(s,12H).

[0364] MS(ESI+) m / z 438.3, 438.3 [M+H] + .

[0365] Step 2: Synthesis of 4-{[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid-2-methylpropyl-2-yl ester

[0366]

[0367] The title compound will be synthesized from the product of step 3 of Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 1 of Example 16: 4-[({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester, according to the method of step 1 in Example 1.

[0368] 1 H NMR(500MHz, CDCl3)δ9.19(s,1H),8.54(s,1H),8.23(s,1H),8.10(s,1H),7.96(q,J=8.2Hz,5H),7.81(s,1H),7.80(s,1H), 7.42(s,1H),7.41(s,1H),6.92(d,J=8.2Hz,1H),6.55(s,1H),4.75(d,J=5.6Hz,2H),4.03(s,3H),3.08(s,3H),1.60(s,9H).

[0369] MS(ESI+)m / z 561.7,561.7[M+H] + .

[0370] Step 3: Synthesis of 4-{[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid

[0371]

[0372] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-{[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoate-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0373] MS(ESI+)m / z 505.7,505.7[M+H] + .

[0374] Step 4: Synthesis of 2-[(4-{[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}phenyl)carbonyl]-1-propylethazol]methane-2-methylpropyl-2-yl ester

[0375]

[0376] The title compound was synthesized from 4-{[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, without purification, and used directly in the next reaction.

[0377] MS(ESI+)m / z 661.8,661.8[M+H] + .

[0378] Step 5: Synthesis of 4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-{4-[(2-propylethazolyl)carbonyl]phenyl}benzamide

[0379]

[0380] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(4-{[({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}phenyl)carbonyl]-1-propylethazolyl}methane-2-methylpropyl-2-yl ester.

[0381] 1H NMR(500MHz,DMSO-D6)δ9.99(s,1H),9.20(t,J=6.1Hz,1H),9.10(s,1H),8.79(d,J=2.7Hz,1H), 8.50(d,J=2.1Hz,1H),8.34(dd,J=8.6,2.7Hz,1H),8.31(d,J=2.1Hz,1H),8.08–7.99(m,2H),7. 91–7.84(m,2H),7.83–7.78(m,2H),7.47–7.36(m,2H),6.98(d,J=8.6Hz,1H),4.58(d,J=6.1Hz, 2H),3.93(s,3H),3.04(s,3H),2.75(t,J=7.1Hz,2H),1.54–1.36(m,2H),0.91(t,J=7.4Hz,3H).

[0382] 13 C NMR (126MHz, DMSO-D6) δ169.04,166.16,165.17,163.57,153.96,145.84,145.75,143.08,140.66,139.20,138.34,135.91,133. 26,132.78,131.78,130.81,128.13,127.14,126.94,126.78,124.61,122.48,110.68,53.39,53.12,42.45,22.10,20.86,11.67.

[0383] MS(ESI+) m / z 561.7 [M+H] + .

[0384] Example 17: 4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-({4-[(2- [propylethazolyl]carbonyl]phenyl]methyl]benzamide

[0385]

[0386] Step 1: Synthesis of 2-methylpropyl-2-yl benzoate of 4-{[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]methyl}benzoate

[0387]

[0388] The title compound was synthesized from the product 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline from step 3 of Example 2 and the product 4-[({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester from step 1 of Example 16, according to the method in step 1 of Example 1.

[0389] 1 H NMR (500MHz, CDCl3) δ9.21 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.98 (d, J = 8.1Hz, 4H), 7.80 (s, 2H), 7. 71(d,J=9.8Hz,1H),7.42(s,1H),7.41(s,1H),6.55(s,1H),4.75(s,2H),4.11(s,3H),3.12(s,3H),1.60(s,9H).

[0390] MS(ESI+) m / z 579.6,579.6[M+H] + .

[0391] Step 2: Synthesis of 4-{[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid

[0392]

[0393] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-{[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoate-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0394] MS(ESI+)m / z 523.5,523.5[M+H] + .

[0395] Step 3: Synthesis of 2-[(4-{[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}phenyl)carbonyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester

[0396]

[0397] The title compound was synthesized from 4-{[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, without purification, and used directly in the next reaction.

[0398] MS(ESI+)m / z 679.8,679.8[M+H] + .

[0399] Step 4: Synthesis of 4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-({4-[(2-propylethazyl)carbonyl]phenyl}methyl)benzamide

[0400]

[0401] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(4-{[({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}phenyl)carbonyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester.

[0402] 1 H NMR(500MHz,DMSO-D6)δ9.98(s,1H),9.20(t,J=6.1Hz,1H),9.11(s,1H),8.65(d,J=2.1Hz,1H), 8.56(d,J=2.1Hz,1H),8.44(dd,J=11.9,2.1Hz,1H),8.36(d,J=2.1Hz,1H),8.07–8.00(m,2H),7 .91–7.86(m,2H),7.84–7.74(m,2H),7.44–7.39(m,2H),4.61(d,J=6.4Hz,1H),4.58(d,J=5.9Hz ,2H),4.03(s,3H),3.05(s,3H),2.75(t,J=7.1Hz,2H),1.51–1.41(m,2H),0.91(t,J=7.4Hz,3H).

[0403] 13C NMR(126MHz,DMSO-D6)δ169.24,166.13,165.16,154.16,152.35(d,JC-F=11.4Hz),14 6.87(d,JC-F=256.9Hz),145.94,143.08,140.54,140.29(d,JC-F=5.8Hz),139.23,134 .65,133.27,132.80,131.77,130.85,129.45,129.19(d,JC-F=2.0Hz),127.13,126.9 3,126.76,124.56,123.07,123.00,122.87,53.81,53.11,42.44,22.12,20.86,11.67.

[0404] MS(ESI+)m / z 579.7 [M+H] + .

[0405] Example 18: 4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-({4-[(2-propanediol ...yl [[[[[[[[[[[[[[[[[[[[[[[[] ...]]][[[[[[[[[[]]][[[[[[[[[]]][[[[[[[[[]][[[[[[[[]

[0406]

[0407] Step 1: Synthesis of 4-{[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid-2-methylpropyl-2-yl ester

[0408]

[0409] The title compound was synthesized from the product 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline from step 3 of Example 3 and the product 4-[({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester from step 1 of Example 16, according to the method in step 1 of Example 1.

[0410] 1 H NMR (500MHz, CDCl3) δ9.17(s,1H),8.23(s,1H),8.10(s,1H),8.09(s,1H),7.97(d,J=8.2Hz,4H),7.80(s,1H),7.79(s,1H),7. 41(s,1H),7.39(s,1H),7.34(s,1H),6.63(s,1H),4.74(d,J=5.6Hz,2H),4.10(s,3H),3.99(s,3H),3.08(s,3H),1.59(s,9H).

[0411] MS(ESI+)m / z 591.7,591.7[M+H] + .

[0412] Step 2: Synthesis of 4-{[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid

[0413]

[0414] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-{[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoate-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0415] MS(ESI+) m / z 535.6,535.6[M+H] + .

[0416] Step 3: Synthesis of 2-[(4-{[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}phenyl)carbonyl]-1-propylethazol]methane-2-methylpropyl-2-yl ester

[0417]

[0418] The title compound was synthesized from 4-{[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0419] MS(ESI+)m / z 691.8,691.8[M+H] + .

[0420] Step 4: Synthesis of 4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]-N-({4-[(2-propylethazolyl)carbonyl]phenyl}methyl)benzamide

[0421]

[0422] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(4-{[({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}carbonyl)amino]methyl}phenyl)carbonyl]-1-propylethazolyl}methane-2-methylpropyl-2-yl ester.

[0423] 1 H NMR(500MHz,DMSO-D6)δ9.99(s,1H),9.20(t,J=6.1Hz,1H),9.10(s,1H),8.51(d,J=2.1Hz,1H) ,8.35(d,J=2.1Hz,1H),8.30(d,J=2.1Hz,1H),8.08–8.01(m,2H),7.90–7.84(m,2H),7.82(d,J= 2.1Hz,1H),7.82–7.79(m,2H),7.44–7.39(m,2H),4.60(d,1H),4.58(d,J=6.1Hz,2H),3.94(s, 3H),3.94(s,3H),3.05(s,3H),2.75(t,J=7.1Hz,2H),1.53–1.39(m,2H),0.91(t,J=7.4Hz,3H).

[0424] 13 C NMR (126MHz, DMSO-D6) δ169.03,166.16,165.17,153.94,145.80,143.92,143.09,140.73,139.20,136.26,135.46,133.25,133.13, 131.77,130.83,129.45,128.81,127.14,126.93,126.77,124.56,122.71,117.35,55.85,53.26,53.11,42.44,24.78,20.86,11.67.

[0425] MS(ESI+) m / z 591.7 [M+H] + .

[0426] Example 19: 2-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-N- ({4-[(2-propylethazo)carbonyl]phenyl}methyl)acetamide

[0427]

[0428] Step 1: Synthesis of 2-methylpropyl-2-yl benzoate 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoate

[0429]

[0430] The title compound was synthesized from [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]acetic acid and tert-butyl p-aminomethylbenzoate according to the method in step 1 of Example 13. It was used directly in the next reaction without purification.

[0431] MS(ESI+)m / z 452.4,452.4[M+H] + .

[0432] Step 2: Synthesis of 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoic acid

[0433]

[0434] According to step 4 of Example 10, the title compound is obtained by detert-butylating 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoate-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0435] MS(ESI+) m / z 396.3,396.3[M+H] + .

[0436] Step 3: Synthesis of 2-methylpropyl-2-yl benzoate 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoate

[0437]

[0438] The title compound was synthesized from 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0439] 1H NMR(500MHz,DMSO-D6)δ10.45(s,1H),8.62(t,1H),7.83–7.69(m,2H),7.64–7.59(m,2H),7.33–7.28(m,4H),4.32 (d,J=5.4Hz,2H),3.52(s,2H),3.36(t,J=12.2Hz,2H),1.56–1.47(m,2H),1.38(s,9H),1.29(s,12H),0.88(t,3H).

[0440] MS(ESI+)m / z 552.5,552.5[M+H] + .

[0441] Step 4: Synthesis of 2-[(4-{[(2-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}acetyl)amino]methyl}phenyl)carbonyl]-1-propylethazol]methane-2-methylpropyl-2-yl ester

[0442]

[0443] The title compound was synthesized from the product of step 3 of Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 3 of Example 19: 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoate-2-methylpropyl-2-yl ester] without purification, and used directly in the next reaction.

[0444] MS(ESI+)m / z 675.8,675.8[M+H] + .

[0445] Step 5: Synthesis of 2-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}-N-({4-[(2-propylethazolyl)carbonyl]phenyl}methyl)acetamide

[0446]

[0447] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(4-{[(2-{4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}acetyl)amino]methyl}phenyl)carbonyl]-1-propylethazolyl}methane-2-methylpropyl-2-yl ester.

[0448] 1H NMR (500MHz, DMSO-D6) δ9.09(s,1H),8.78(dd,J=2.6,0.8Hz,1H),8.72(t,J=6.1Hz,1H),8.47(d,J =2.1Hz,1H),8.33(dd,J=8.6,2.6Hz,1H),8.26(d,J=2.1Hz,1H),7.84(dd,J=62.6,8.3Hz,2H),7.73 –7.67(m,2H),7.45–7.40(m,2H),7.40–7.30(m,2H),6.98(dd,J=8.6,0.8Hz,1H),4.36(d,J=5.4Hz, 2H),3.93(s,3H),3.60(s,2H),3.03(s,3H),2.73(t,2H),1.48–1.36(m,2H),0.89(t,J=7.4Hz,3H).

[0449] 13 C NMR (126MHz, DMSO-D6) δ170.30,170.24,168.92,167.18,163.53,153.81,145.86,145.78,144.68,139.99,138.33,135.92,135.87,135.81, 135.78,132.47,130.69,129.40,128.56,128.26,127.23,127.02,124 .64,121.88,110.67,62.45,53.38,42.15,42.04,25.62,22.08,11.65.

[0450] MS(ESI+) m / z 575.7 [M+H] + .

[0451] Example 20: 2-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-N- ({4-[(2-propylethazo)carbonyl]phenyl}methyl)acetamide

[0452]

[0453] Step 1: Synthesis of 2-[(4-{[(2-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}acetyl)amino]methyl}phenyl)carbonyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester

[0454]

[0455] The title compound will be synthesized from the product of step 3 in Example 2: 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 3 in Example 19: 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester] according to the method of step 1 in Example 1.

[0456] 1 H NMR (500MHz, CDCl3) δ9.21(s,1H),8.31(s,1H),8.21(s,1H),8.08(s,1H),7.71(s,5H),7.45(d,J=7.0Hz,2H),7.30(s,2H),6.11(s,1H) ,4.49(s,2H),4.11(s,3H),3.75(s,2H),3.54(t,J=7.2Hz,2H),3.10(s,3H),1.60(q,J=7.6Hz,2H),1.46(s,9H),0.92(t,J=7.4Hz,3H).

[0457] MS(ESI+)m / z 693.8,693.8[M+H] + .

[0458] Step 2: Synthesis of 2-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-N-({4-[(2-propylethazyl)carbonyl]phenyl}methyl)acetamide

[0459]

[0460] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(4-{[(2-{4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}acetyl)amino]methyl}phenyl)carbonyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester.

[0461] 1H NMR (500MHz, DMSO-D6) δ9.96(s,1H),9.10(s,1H),8.69(t,J=6.1Hz,1H),8.64(d,J=2.1Hz,1H ),8.51(d,J=2.1Hz,1H),8.42(dd,J=11.9,2.1Hz,1H),8.30(d,J=2.1Hz,1H),7.82–7.74(m,2 H),7.74–7.66(m,2H),7.45–7.39(m,2H),7.36–7.31(m,2H),4.35(d,J=5.9Hz,2H),4.02(s,3 H),3.59(s,2H),3.04(s,3H),2.73(t,J=7.1Hz,2H),1.51–1.36(m,2H),0.90(t,J=7.4Hz,3H).

[0462] 13 C NMR (126MHz, DMSO-D6) δ170.24, 169.10, 167.18, 165.10, 154.01, 152.32 (d, JC-F = 11.4Hz), 146. 88(d,JC-F=257.0Hz),146.06,142.84,140.23(d,JC-F=5.7Hz),140.02,135.87,135.81(d,JC-F =1.6Hz),134.61,132.47,131.77,130.74,129.41,129.32(d,JC-F=1.9Hz),128.54,127.25,127 .10,127.03,124.59,122.97,122.84,122.44,53.80,53.09,42.16,41.99,22.11,20.84,11.65.

[0463] MS(ESI+) m / z 593.7 [M+H] + .

[0464] Example 21: 2-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]benzene {4-[(2-propylethazolyl)carbonyl]phenyl}methyl)acetamide

[0465]

[0466] Step 1: Synthesis of 2-[(4-{[(2-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}acetyl)amino]methyl}phenyl)carbonyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester

[0467]

[0468] The title compound was synthesized from the product of step 3 of Example 3: 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline and the product of step 3 of Example 19: 4-[({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]acetyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester] without purification, and used directly in the next reaction.

[0469] MS(ESI+)m / z 705.8,705.8[M+H] + .

[0470] Step 2: Synthesis of 2-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}-N-({4-[(2-propylethazolyl)carbonyl]phenyl}methyl)acetamide

[0471]

[0472] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(4-{[(2-{4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}acetyl)amino]methyl}phenyl)carbonyl]-1-propylethazolyl}methane-2-methylpropyl-2-yl ester.

[0473] 1 H NMR (500MHz, DMSO-D6) δ9.09(s,1H),8.72(t,J=6.0Hz,1H),8.46(d,J=2.1Hz,1H),8.29(d,J= 2.1Hz,1H),8.28(d,J=2.1Hz,1H),7.92–7.87(m,1H),7.80(d,J=2.1Hz,1H),7.79–7.74(m,1H ),7.72–7.66(m,2H),7.46–7.40(m,2H),7.39–7.30(m,2H),4.37(d,J=6.0Hz,2H),3.94(s,3H ),3.93(s,3H),3.60(s,2H),3.04(s,3H),2.74(t,2H),1.58–1.31(m,2H),1.01–0.73(m,3H).

[0474] 13C NMR (126MHz, DMSO-D6) δ170.27,170.21,168.86,167.14,153.85,153.77,145.87,144.65,143.87,139.94,136.19,135.94,135.76,135.73,135 .35,132.79,130.68,129.37,128.89,128.52,127.20,127.00,124.54,1 22.07,117.28,62.42,55.79,53.21,42.12,42.01,25.59,22.07,11.61.

[0475] MS(ESI+) m / z 605.7 [M+H] + .

[0476] Example 22: 2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)-N- ({4-[(2-propylethazo)carbonyl]phenyl}methyl)acetamide

[0477]

[0478] Step 1: Synthesis of {[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]oxy}acetic acid-2-methylpropyl-2-yl ester

[0479]

[0480] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenol (2.20 g, 10 mmol) was dissolved in anhydrous acetonitrile (40 mL), and tert-butyl bromoacetate (2.34 g, 12 mmol) and anhydrous potassium carbonate (4.15 g, 30 mmol) were added. The mixture was reacted at 90 °C for 6 hours, filtered, and the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give a white solid (2.92 g, yield 87.4%).

[0481] 1 H NMR (500MHz, CDCl3) δ7.75(d,J=2.1Hz,1H),7.74(d,J=2.0Hz,1H),6.89(d,J =2.0Hz,1H),6.87(d,J=2.1Hz,1H),4.53(s,2H),1.47(s,9H),1.33(s,12H).

[0482] MS(ESI+)m / z 335.2,335.2[M+H] + .

[0483] Step 2: Synthesis of ({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester

[0484]

[0485] The title compound will be synthesized from the product of step 3 of Example 1: 8-bromo-6-(6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 1 of Example 22: 4-[({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester, according to the method of step 1 in Example 1.

[0486] 1 H NMR(400MHz,CHLOROFORM-D)δ9.20(s,1H),8.55(s,1H),8.20(s,1H),8.16(s,1H),7.95(d,J=7.4Hz,1H),7.68(s,1H ),7.66(s,1H),7.08(s,1H),7.06(s,1H),6.92(d,J=8.5Hz,1H),4.60(s,2H),4.03(s,3H),3.18(s,3H),1.53(s,9H).

[0487] MS(ESI+)m / z 458.5,458.5[M+H] + .

[0488] Step 3: Synthesis of ({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid

[0489]

[0490] The title compound was obtained by detert-butylating ({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester). It was used directly in the next reaction without purification.

[0491] MS(ESI+)m / z 452.4,452.4[M+H] + .

[0492] Step 4: Synthesis of 2-methylpropyl-2-yl benzoate 4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoate

[0493]

[0494] The title compound was synthesized from ({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid and tert-butyl p-aminomethylbenzoate, according to the method in step 4 of Example 1.

[0495] 1 H NMR (500MHz, CDCl3) δ9.20 (s, 1H), 8.54 (d, J = 2.6Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 8.06 (d, J = 2.0Hz, 1H), 7.97 (d,J=2.0Hz,1H),7.96(d,J=2.0Hz,1H),7.94(dd,J=8.5,2.6Hz,1H),7.71(d,J=2.1Hz,1H),7.69(d,J=2.1Hz ,1H),7.36(d,J=2.0Hz,1H),7.35(d,J=2.0Hz,1H),7.09(d,J=2.1Hz,1H),7.07(d,J=2.3Hz,1H),6.99(t,J=5 .8Hz,1H),6.91(d,J=8.7Hz,1H),4.66(s,2H),4.62(d,J=6.1Hz,2H),4.02(s,3H),3.05(s,3H),1.58(s,9H).

[0496] MS(ESI+)m / z 591.7,591.7[M+H] + .

[0497] Step 5: Synthesis of 4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid)

[0498]

[0499] According to step 4 of Example 10, the title compound is obtained by detert-butylating 4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid-2-methylpropyl-2-yl ester). It is then used directly in the next reaction without purification.

[0500] MS(ESI+) m / z 535.6,535.6[M+H] + .

[0501] Step 6: Synthesis of 2-{[4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0502]

[0503] The title compound was synthesized from 4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester) without purification and used directly in the next reaction.

[0504] MS(ESI+)m / z 691.8,691.8[M+H] + .

[0505] Step 7: Synthesis of 2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)-N-({4-[(2-propylethazolyl)carbonyl]phenyl}methyl)acetamide

[0506]

[0507] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of (2-{[4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazolyl)methane-2-methylpropyl-2-yl ester.

[0508] 1 H NMR (500MHz, DMSO-D6) δ10.23 (s, 1H), 9.10 (s, 1H), 8.78 (dd, J = 2.6, 0.8Hz, 1H), 8.44 (d, J=2.1Hz,1H),8.33(dd,J=8.6,2.6Hz,1H),8.24(d,J=2.1Hz,1H),7.83–7.71(m,4H),7.41 –7.33(m,2H),7.15–7.09(m,2H),6.99(dd,J=8.6,0.8Hz,1H),4.67(s,2H),4.43(d,J=5.7 Hz,2H),3.93(s,3H),3.03(s,3H),2.79(t,J=7.2Hz,2H),1.54–1.43(m,2H),0.90(t,3H).

[0509] 13 C NMR (126MHz, DMSO-D6) δ168.90,167.99,167.19,165.18,163.53,157.48,153.77,145.86,145.80,143.00,139.61,138.35,135.90,132.27, 132.03,131.30,130.73,129.36,128.34,127.19,127.07,124.70,121 .59,114.23,110.68,67.08,53.39,52.82,41.62,22.10,20.34,11.53.

[0510] MS(ESI+) m / z 591.7 [M+H] + .

[0511] Example 23: 2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]benzene 4-[(2-propylethazolyl)carbonyl]phenylmethyl)acetamide

[0512]

[0513] Step 1: Synthesis of ({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester

[0514]

[0515] The title compound will be synthesized from the product of step 3 of Example 2: 8-bromo-6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline and the product of step 1 of Example 22: 4-[({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester, according to the method of step 1 in Example 1.

[0516] MS(ESI+) m / z 476.5, 476.5 [M+H] + .

[0517] Step 2: Synthesis of ({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid

[0518]

[0519] According to step 4 of Example 10, the title compound was obtained by detert-butylating ({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester. It was used directly in the next reaction without purification.

[0520] MS(ESI+)m / z 420.4,420.4[M+H] + .

[0521] Step 3: Synthesis of 2-methylpropyl-2-yl benzoate 4-({[2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoate

[0522]

[0523] The title compound was synthesized from ({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid and tert-butyl p-aminomethylbenzoate, according to the method in step 4 of Example 1.

[0524] 1 H NMR (500MHz, CDCl3) δ9.20 (s, 1H), 8.31 (d, J = 2.1Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 8.04 (d, J = 2. 1Hz,1H),7.97(s,1H),7.96(d,J=2.0Hz,1H),7.72(d,J=2.1Hz,1H),7.70(d,J=2.4Hz,1H),7.6 9(d,J=2.1Hz,1H),7.36(s,1H),7.34(s,1H),7.09(d,J=2.1Hz,1H),7.08(d,J=2.3Hz,1H),6.9 9(t,J=6.1Hz,1H),4.66(s,2H),4.62(d,J=6.1Hz,2H),4.11(s,3H),3.07(s,3H),1.58(s,9H).

[0525] MS(ESI+)m / z 609.7,609.7[M+H] + .

[0526] Step 4: Synthesis of 4-({[2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid)

[0527]

[0528] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-({[2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid-2-methylpropyl-2-yl ester). It is then used directly in the next reaction without purification.

[0529] MS(ESI+) m / z 553.6,553.6[M+H] + .

[0530] Step 5: Synthesis of 2-{[4-({[2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0531]

[0532] The title compound was synthesized from 4-({[2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid ester, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0533] MS(ESI+)m / z 709.8,709.8[M+H] + .

[0534] Step 6: Synthesis of 2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)-N-({4-[(2-propylethazyl)carbonyl]phenyl}methyl)acetamide

[0535]

[0536] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of (2-{[4-({[2-({4-[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester.

[0537] 1H NMR (500MHz, DMSO-D6) δ9.96(s,1H),9.10(s,1H),8.78(t,J=6.1Hz,1H),8.61(d,J=2.1H z,1H),8.46(d,J=2.1Hz,1H),8.40(dd,J=11.9,2.1Hz,1H),8.26(d,J=2.1Hz,1H),7.85– 7.70(m,4H),7.39–7.29(m,2H),7.17–7.07(m,2H),4.67(s,2H),4.42(d,J=6.1Hz,2H),4 .02(s,3H),3.02(s,3H),2.73(t,J=7.1Hz,2H),1.53–1.35(m,2H),0.89(t,J=7.4Hz,3H).

[0538] 13 C NMR(126MHz,DMSO-D6)δ169.04,167.97,165.13,157.50,153.94,152.29(d,JC-F=11.4H z),146.86(d,JC-F=257.1Hz),146.03,142.67,140.21(d,JC-F=5.6Hz),139.62,134.62 ,132.23,132.07,131.78,130.61,129.37(d,JC-F=1.7Hz),127.07,127.02,124.62,122 .89(d,JC-F=16.3Hz),122.10,114.20,67.08,53.78,53.10,41.62,22.11,20.85,11.66.

[0539] MS(ESI+) m / z 609.7 [M+H] + .

[0540] Example 24: 2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]benzene 4-[(2-propylethazolyl)carbonyl]phenylmethyl)acetamide

[0541]

[0542] Step 1: Synthesis of ({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester

[0543]

[0544] The product from step 3 of Example 2, 8-bromo-6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline, and the product from step 1 of Example 22, 4-, will be produced according to the method in step 1 of Example 1.

[0545] Synthesize the title compound of [({[4-(dihydroxyboryl)phenyl]carbonyl}amino)methyl]benzoic acid-2-methylpropyl-2-yl ester.

[0546] 1 H NMR (500MHz, CDCl3) δ9.18(s,1H),8.14(d,J=2.1Hz,1H),8.08(d,J=2.1Hz,1H),8.04(d,J=2.0Hz,1H),7.68(s,1H),7.66( s,1H),7.34(d,J=2.1Hz,1H),7.06(s,1H),7.04(s,1H),4.58(s,2H),4.09(s,3H),3.98(s,3H),3.03(s,3H),1.51(s,9H).

[0547] MS(ESI+) m / z 488.6,488.6[M+H] + .

[0548] Step 2: Synthesis of ({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid

[0549]

[0550] According to step 4 of Example 10, the title compound was obtained by detert-butylating ({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester. It was used directly in the next reaction without purification.

[0551] MS(ESI+)m / z 432.5,432.5[M+H] + .

[0552] Step 3: Synthesis of 2-methylpropyl-2-yl benzoate 4-({[2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoate)

[0553]

[0554] The title compound was synthesized from ({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetic acid and tert-butyl p-aminomethylbenzoate, according to the method in step 4 of Example 1.

[0555] 1 H NMR (500MHz, CDCl3) δ9.20 (s, 1H), 8.18 (d, J = 2.0Hz, 1H), 8.09 (d, J = 2.1Hz, 1H), 8.07 (d, J = 2. 0Hz,1H),7.97(d,J=2.0Hz,1H),7.96(d,J=1.8Hz,1H),7.71(d,J=2.1Hz,1H),7.69(d,J=2.1Hz ,1H),7.36(s,1H),7.34(d,J=1.4Hz,2H),7.09(d,J=2.3Hz,1H),7.08(d,J=2.3Hz,1H),7.00(s ,1H),4.66(s,2H),4.62(d,J=6.3Hz,2H),4.10(s,3H),3.99(s,3H),3.09(s,3H),1.58(s,9H).

[0556] MS(ESI+)m / z 622.7,622.7[M+H] + .

[0557] Step 4: Synthesis of 4-({[2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid)

[0558]

[0559] According to step 4 of Example 10, the title compound is obtained by detert-butylating 4-({[2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid-2-methylpropyl-2-yl ester). It is then used directly in the next reaction without purification.

[0560] MS(ESI+) m / z 566.6,566.6[M+H] + .

[0561] Step 5: Synthesis of 2-{[4-({[2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0562]

[0563] The title compound was synthesized from 4-({[2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester) without purification and used directly in the next reaction.

[0564] MS(ESI+)m / z 721.8,721.8[M+H] + .

[0565] Step 6: Synthesis of 2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)-N-({4-[(2-propylethazolyl)carbonyl]phenyl}methyl)acetamide

[0566]

[0567] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of (2-{[4-({[2-({4-[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester.

[0568] 1 H NMR (500MHz, DMSO-D6) δ9.97(s,1H),9.10(s,1H),8.78(t,J=6.2Hz,1H),8.43(d,J=2.1Hz,1H) ,8.28(d,J=2.1Hz,1H),8.26(d,J=2.1Hz,1H),7.80(d,J=2.1Hz,1H),7.79–7.76(m,2H),7.76–7 .73(m,2H),7.41–7.32(m,2H),7.15–7.09(m,2H),4.68(d,J=7.7Hz,2H),4.44(d,J=6.2Hz,2H) ,3.94(s,3H),3.93(s,3H),3.04(s,3H),2.73(t,J=7.1Hz,2H),1.50–1.39(m,2H),0.89(t,3H).

[0569] 13C NMR (126MHz, DMSO-D6) δ168.85,168.08,167.97,165.13,157.47,153.88,15 3.75,145.90,143.90,142.67,139.57(d,JC-F=1.3Hz),136.24,135.39,132 .04,131.77,130.77,129.21,129.01,127.33,127.06,127.02,124.63,121.82,117.34,114.21,67.08,55.83,53.24,53.09,38.24,22.12,20.84,11.65.

[0570] MS(ESI+)m / z 621.7[M+H] + .

[0571] Example 25: [4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)benzene [2-propylethazolyl]methyl ketone

[0572]

[0573] Step 1: Synthesis of 4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}benzoate-2-methylpropyl-2-yl ester

[0574]

[0575] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and tert-butyl p-bromomethylbenzoate according to the method in step 1 of Example 22.

[0576] 1 H NMR(400MHz,CHLOROFORM-D)δ9.24(s,1H),8.02(s,1H),8.00(s,1H),7.82(s,1H ),7.82(s,1H),7.56(s,1H),7.54(s,1H),5.45(s,2H),2.92(s,3H),1.59(s,9H).

[0577] MS(ESI+) m / z 430.3, 430.3 [M+H] + .

[0578] Step 2: Synthesis of 4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}benzoic acid

[0579]

[0580] The title compound was obtained by detert-butylating ({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetic acid-2-methylpropyl-2-yl ester). It was used directly in the next reaction without purification.

[0581] MS(ESI+)m / z 374.2,374.2[M+H] + .

[0582] Step 3: Synthesis of 2-[(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)carbonyl]-1-propylethazol}methane-2-methylpropyl-2-yl ester

[0583]

[0584] The title compound was synthesized from 4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester according to the method in step 4 of Example 1.

[0585] 1 H NMR(400MHz,CHLOROFORM-D)δ9.23(s,1H),7.84(s,1H),7.83(s,1H),7.83(s,1H),7.81(s,1H),7.59(s,1H) ,7.27(s,1H),5.43(s,2H),3.56(t,J=7.3Hz,2H),2.80(s,3H),1.62(q,J=7.4Hz,2H),0.94(t,J=7.4Hz,3H).

[0586] MS(ESI+)m / z 530.4,530.4[M+H] + .

[0587] Step 4: Synthesis of 2-{[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]carbonyl}-1-propylethazol)methane-2-methylpropyl-2-yl ester

[0588]

[0589] The title compound was synthesized from {2-[(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)carbonyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester and 6-methoxypyridine-3-boronic acid, according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0590] MS(ESI+)m / z 558.7,558.7[M+H] + .

[0591] Step 5: Synthesis of 4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]phenyl}oxy)acetyl]amino}methyl)benzoic acid)

[0592]

[0593] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of (2-{[4-({[2-({4-[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]phenyl}oxy)acetyl]amino}methyl)phenyl]carbonyl}-1-propylethazolyl)methane-2-methylpropyl-2-yl ester.

[0594] 1 H NMR(500MHz,DMSO-D6)δ10.00(s,1H),9.04(s,1H),8.68(dd,J=2.6,0.8Hz,1H),8 .22(dd,J=8.6,2.6Hz,1H),7.95(d,J=1.7Hz,1H),7.87–7.80(m,2H),7.76(d,J=1 .7Hz,1H),7.62–7.58(m,2H),6.94(dd,J=8.6,0.8Hz,1H),5.47(s,2H),3.89(s,3 H),2.91(s,3H),2.72(t,J=7.1Hz,2H),1.48–1.38(m,2H),0.87(t,J=7.4Hz,3H).

[0595] 13 C NMR (126MHz, DMSO-D6) δ168.67,167.65,165.58,164.07,154.53,153.71,146.18,141.16,140.50,138.71,136.86,1 33.34,130.09,129.03,127.98,127.81,125.57,114.57,113.25,111.16,70.19,53.91,53.60,22.58,21.37,12.19.

[0596] MS(ESI+) m / z 458.6 [M+H] + .

[0597] Example 26: [4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy] [2-propylethazolyl]methylphenyl](2-propylethazolyl)methyl ketone

[0598]

[0599] Step 1: Synthesis of 2-{[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0600]

[0601] The title compound was synthesized from {2-[(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)carbonyl]-1-propylethazinyl}methane-2-methylprop-2- and 5-fluoro-6-methoxypyridine-3-boronic acid] according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0602] MS(ESI+) m / z 576.6,576.6[M+H] + .

[0603] Step 2: Synthesis of [4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl](2-propylethazol) ketone

[0604]

[0605] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of (2-{[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}methyl)phenyl]carbonyl}-1-propylethazolyl)methane-2-methylpropyl-2-yl ester.

[0606] 1 H NMR (500MHz, DMSO-D6) δ10.03(s,1H),9.09(s,1H),8.58(d,J=2.1Hz,1H),8.35(dd,J=11.9,2.1Hz,1H),8.06(d,J=1.7Hz,1H),7.90–7.86(m,2H), 7.84(d,J=1.7Hz,1H),7.67–7.62(m,2H),5.51(s,2H),4.03(s,3H),2.96 (s,3H),2.75(t,J=7.1Hz,2H),1.54–1.39(m,2H),0.91(t,J=7.4Hz,3H).

[0607] 13C NMR(126MHz,DMSO-D6)δ168.35,165.03,154.05,153.40,152.32(d,JC-F=11.6Hz) ,146.84(d,JC-F=256.9Hz),140.84,140.08(d,JC-F=5.7Hz),139.90,135.03(d,J C-F=1.2Hz),132.84,129.56(d,JC-F=2.9Hz),129.53,127.48,127.46,127.28,12 4.99,122.81,122.68,114.62,112.66,69.73,53.80,53.08,22.08,20.86,11.66.

[0608] MS(ESI+) m / z 476.5 [M+H] + .

[0609] Example 27: [4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl) [Phenyl](2-propylethazol) methyl ketone

[0610]

[0611] Step 1: Synthesis of 2-{[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]carbonyl}-1-propylethazol)methane-2-methylpropyl-2-yl ester

[0612]

[0613] The title compound was synthesized from {2-[(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)carbonyl]-1-propylethazol}methane-2-methylprop-2- and 5,6-dimethoxypyridine-3-boronic acid pinacol ester] according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0614] MS(ESI+)m / z 588.7,588.7[M+H] + .

[0615] Step 2: Synthesis of [4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl](2-propylethazolyl)methyl ketone

[0616]

[0617] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of (2-{[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}methyl)phenyl]carbonyl}-1-propylethazolyl)methane-2-methylpropyl-2-yl ester.

[0618] 1 H NMR(500MHz, DMSO-D6)δ9.06(s,1H),8.18(d,J=2.1Hz,1H),7.99–7.95(m,2H),7.86–7.81(m,1H),7.76(d,J=1.9Hz,1H),7.68–7.64(m, 2H),7.61(d,1H),5.53(s,2H),3.92(s,3H),3.89(s,3H),2.94(s,3H),2.71(t,J=7.1Hz,1H),1.47–1.32(m,2H),0.87(t,J=7.4Hz,3H).

[0619] 13 C NMR (126MHz, DMSO-D6) δ168.18,167.11,153.91,153.85,153.19,143.85,141.80,140.68,136.70,136.69,135.28,129. 57,129.20,127.54,127.51,127.28,125.02,117.25,114.44,113.24,69.66,55.82,53.25,53.07,22.11,20.85,11.66.

[0620] MS(ESI+)m / z 488.6 [M+H] + .

[0621] Example 28: {4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy} [Ethyl)oxy]phenyl}(2-propylethazol) methyl ketone

[0622]

[0623] Step 1: Synthesis of methyl 4-[(2-bromoethyl)oxy]benzoate

[0624]

[0625] The title compound will be synthesized from methyl paraben and 1,2-dibromoethane according to the method in step 1 of Example 22.

[0626] 1H NMR (500MHz, CDCl3) δ8.01(s,1H),7.99(s,1H),6.94(s,1H),6.92(s,1H),4.34(t,J=6.3Hz,2H),3.89(s,3H),3.66(t,J=6.3Hz,2H).

[0627] MS(ESI+)m / z 260.1,260.1[M+H] + .

[0628] Step 2: Synthesis of 4-[(2-bromoethyl)oxy]benzoic acid

[0629]

[0630] Methyl 4-[(2-bromoethyl)oxy]benzoate (2.60 g, 10 mmol) was dissolved in tetrahydrofuran / methanol / water (30 mL / 20 mL / 10 mL), and aluminum hydroxide monohydrate (4.21 g, 100 mmol) was added. The solution was used directly in the next step of the reaction without purification.

[0631] MS(ESI+)m / z 246.1,246.1[M+H] + .

[0632] Step 3: Synthesis of [2-({4-[(2-bromoethyl)oxy]phenyl}carbonyl)-1-propylethazol]methane-2-methylpropyl-2-yl ester

[0633]

[0634] The title compound was synthesized from 4-[(2-bromoethyl)oxy]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester according to the method in step 4 of Example 1.

[0635] 1 H NMR (500MHz, CDCl3) δ7.76(s,1H),7.75(s,1H),6.92(s,2H),4.33(t,J=6.3Hz,2H),3.65(t,J =6.2Hz,2H),3.55(t,J=7.2Hz,2H),1.62(d,J=7.2Hz,2H),1.47(s,9H),0.93(t,J=7.4Hz,3H).

[0636] MS(ESI+)m / z 402.3,402.3[M+H] + .

[0637] Step 4: Synthesis of 2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester

[0638]

[0639] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and [2-({4-[(2-bromoethyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester according to the method in step 1 of Example 22.

[0640] 1 H NMR (400MHz, CHLOROFORM-D) δ9.23(s,1H),7.88(s,1H),7.77(d,J=8.5Hz,2H),7.50(d,J=1.9Hz,1H),6.99(d,J=7.1Hz,2H),4.64(t ,J=4.5Hz,2H),4.57(t,J=4.4Hz,2H),3.56(t,J=7.3Hz,2H),2.97(s,3H),1.63(q,J=7.3Hz,2H),1.46(s,9H),0.94(t,J=7.4Hz,3H).

[0641] MS(ESI+)m / z 560.5,560.5[M+H] + .

[0642] Step 5: Synthesis of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}ethyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0643]

[0644] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 6-methoxypyridine-3-boronic acid) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0645] MS(ESI+)m / z 587.7,587.7[M+H] + .

[0646] Step 6: Synthesis of {4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}(2-propylethazol) ketone

[0647]

[0648] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}ethyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0649] 1 H NMR (500MHz, DMSO-D6) δ9.04 (s, 1H), 8.75 (d, J = 2.7Hz, 1H), 8.28 (dd, J = 8.6, 2. 7Hz,1H),7.99(d,J=1.7Hz,1H),7.94–7.82(m,2H),7.75(d,J=1.7Hz,1H),7.15– 7.08(m,2H),6.98(dd,J=8.6,0.7Hz,1H),4.69(t,2H),4.55(t,2H),3.93(s,3H ),2.95(s,3H),2.74(t,J=7.1Hz,2H),1.45–1.36(m,2H),0.83(t,J=7.4Hz,3H).

[0650] 13 C NMR (126MHz, DMSO-D6) δ168.09,163.50,161.90,160.64,154.23,154.21,153.03,145.73,140.39,138.25,136.45,131. 38,128.58,124.97,114.39,114.13,113.97,113.97,112.31,110.54,67.46,66.56,53.34,52.58,25.61,22.03,11.65.

[0651] MS(ESI+) m / z 487.6 [M+H] + .

[0652] Example 29: {4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]} [Oxyethyl]oxyphenyl](2-propylethazine) methyl ketone

[0653]

[0654] Step 1: Synthesis of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0655]

[0656] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0657] MS(ESI+)m / z 605.7,605.7[M+H] + .

[0658] Step 2: Synthesis of {4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}(2-propylethazol) ketone

[0659]

[0660] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}ethyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0661] 1 H NMR (500MHz, DMSO-D6) δ9.90 (s, 1H), 9.05 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 8.36 ( dd,J=11.9,2.1Hz,1H),8.05(d,J=1.8Hz,1H),7.85–7.80(m,2H),7.78(d,J=1. 8Hz,1H),7.10–7.05(m,2H),4.73–4.66(m,2H),4.58–4.50(m,2H),4.02(s,3H) ,2.96(s,3H),2.74(t,J=7.1Hz,2H),1.54–1.39(m,2H),0.91(t,J=7.4Hz,3H).

[0662] 13C NMR(126MHz,DMSO-D6)δ168.28,164.85,160.64,154.27,153.25,152.28(d,JC-F= 11.4Hz),146.81(d,JC-F=256.8Hz),140.60,140.17(d,JC-F=5.6Hz),135.15,131 .40,129.62(d,JC-F=2.0Hz),128.89,125.65,124.92,122.81(d,JC-F=16.2Hz),1 14.51,114.40,114.15,112.24,67.51,66.54,53.77,53.19,22.06,20.87,11.68.

[0663] MS(ESI+) m / z 505.6 [M+H] + .

[0664] Example 30: {4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]} [Oxyethyl]oxyphenyl](2-propylethazine) methyl ketone

[0665]

[0666] Step 1: Synthesis of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0667]

[0668] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0669] MS(ESI+)m / z 617.7,617.7[M+H] + .

[0670] Step 2: Synthesis of {4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}(2-propylethazol) methyl ketone

[0671]

[0672] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0673] 1 H NMR (500MHz, DMSO-D6) δ9.91 (s, 1H), 9.05 (s, 1H), 8.26 (d, J = 2.1Hz, 1H), 8 .00(d,J=1.7Hz,1H),7.94–7.81(m,2H),7.79–7.74(m,2H),7.14–7.06(m,2 H),4.75–4.66(m,2H),4.61–4.48(m,2H),3.94(s,3H),3.94(s,3H),2.97( s, 3H), 2.74 (t, J = 7.1Hz, 2H), 1.46 (m, J = 7.0Hz, 2H), 0.91 (t, J = 7.4Hz, 3H).

[0674] 13 C NMR (126MHz, DMSO-D6) δ168.11,166.99,164.86,160.67,154.18,153.89,153.05,143.83,140.46,136.85,135.40,131. 41,129.31,128.91,124.95,117.37,114.40,114.32,114.15,112.75,67.54,66.62,55.85,53.23,22.09,20.86,11.68.

[0675] MS(ESI+) m / z 517.6 [M+H] + .

[0676] Example 31: {4-[(3-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl) [Oxy]phenyl}(2-propylethazol) methyl ketone

[0677]

[0678] Step 1: Synthesis of methyl 4-[(3-bromopropyl)oxy]benzoate

[0679]

[0680] The title compound was synthesized from methyl paraben and 1,3-dibromopropane according to the method in step 1 of Example 22. It was used directly in the next reaction without purification.

[0681] MS(ESI+)m / z 274.1,274.1[M+H] + .

[0682] Step 2: Synthesis of 4-[(3-bromopropyl)oxy]benzoic acid

[0683]

[0684] The title compound is generated by hydrolysis of methyl 4-[(3-bromopropyl)oxy]benzoate according to the method in step 2 of Example 28.

[0685] 1 H NMR (400MHz, DMSO) δ7.87 (dd, J=11.4, 8.9Hz, 2H), 7.02 (dd, J=11.4, 8.9Hz, 2H), 4.10 (t, 2H), 3.65 (t, 2H), 2.25 (m, 2H).

[0686] MS(ESI+)m / z 260.1,260.1[M+H] + .

[0687] Step 3: Synthesis of 2-({4-[(3-bromopropyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0688]

[0689] The title compound was synthesized from 4-[(3-bromopropyl)oxy]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester according to the method in step 4 of Example 1.

[0690] 1 H NMR (500MHz, CDCl3) δ7.75 (d, J = 7.5Hz, 2H), 6.94 (s, 2H), 4.16 (t, J = 5.7Hz, 2H), 3.61 (t, J = 6.4Hz, 2H), 3.55(t,J=7.2Hz,2H),2.34(p,J=6.0Hz,2H),1.62(p,J=7.4Hz,2H),1.46(s,9H),0.94(t,J=7.4Hz,3H).

[0691] MS(ESI+) m / z 416.3, 416.3 [M+H] + .

[0692] Step 4: Synthesis of 2-{[4-({3-[(6-bromo-4-methylquinazolin-8-yl)oxy]propyl}oxy)phenyl]carbonyl}-1-propylethazol)methane-2-methylpropyl-2-yl ester

[0693]

[0694] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and [2-({4-[(3-bromopropyl)oxy]phenyl}carbonyl)-1-propylethazol]methane-2-methylpropyl-2-yl ester according to the method in step 1 of Example 22.

[0695] 1 H NMR (500MHz, CDCl3) δ9.21 (s, 1H), 7.81 (d, J = 1.8Hz, 1H), 7.74 (d, J = 8.3Hz, 2H), 7.36 (d, J = 1.8Hz, 1H), 6.95 (s, 2H), 4.43 (t, J = 6.2Hz, 2H), 4.30(t,J=5.7Hz,2H),3.55(t,J=7.3Hz,2H),2.92(s,3H),2.51(p,J=6.0Hz,2H),1.61(p,J=7.3Hz,2H),1.46(s,9H),0.93(t,J=7.4Hz,3H).

[0696] MS(ESI+)m / z 574.5,574.5[M+H] + .

[0697] Step 5: Synthesis of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}propyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0698]

[0699] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]propyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 6-methoxypyridine-3-boronic acid) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0700] MS(ESI+)m / z 601.7,601.7[M+H] + .

[0701] Step 6: Synthesis of {4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl)oxy]phenyl}(2-propylethazol) ketone

[0702]

[0703] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}propyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0704] 1 H NMR (500MHz, DMSO-D6) δ9.86 (s, 1H), 9.06 (s, 1H), 8.73 (dd, J=2.6, 0.8Hz, 1H), 8.26 (dd, J= 8.6,2.6Hz,1H),7.97(d,J=1.8Hz,1H),7.81–7.75(m,2H),7.71(d,J=1.8Hz,1H),7.05–7.01 (m,2H),6.97(dd,J=8.6,0.8Hz,1H),4.48(t,2H),4.29(t,J=6.2Hz,2H),3.93(s,3H),2.94 (s,3H),2.72(t,J=7.1Hz,2H),2.38–2.30(m,2H),1.49–1.40(m,2H),0.90(t,J=7.4Hz,3H).

[0705] 13 C NMR (126MHz, DMSO-D6) δ168.06,164.88,163.51,160.82,154.45,153.08,145.71,140.52,138.25,136.50,128.85, 128.61,125.45,124.97,114.06,113.76,112.18,110.55,65.48,64.49,53.36,53.19,28.57,22.04,20.86,11.67.

[0706] MS(ESI+)m / z 501.6[M+H] + .

[0707] Example 32: {4-[(3-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy} [Propyl)oxy]phenyl}(2-propylethazol) methyl ketone

[0708]

[0709] Step 1: Synthesis of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl)oxy]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0710]

[0711] The product from step 4 of Example 31 will be obtained according to the method in step 1 of Example 1: (2-

[0712] The title compound was synthesized from {[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]propyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid. It was used directly in the next reaction without purification.

[0713] MS(ESI+)m / z 619.7,619.7[M+H] + .

[0714] Step 2: Synthesis of {4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl)oxy]phenyl}(2-propylethazol) ketone

[0715]

[0716] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}propyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0717] 1 H NMR (500MHz, DMSO-D6) δ9.86 (s, 1H), 9.06 (s, 1H), 8.57 (d, J = 2.1Hz, 1H), 8.33 (dd, J =11.9,2.1Hz,1H),8.00(d,J=1.8Hz,1H),7.81–7.76(m,2H),7.73(d,J=1.8Hz,1H), 7.05–7.00(m,2H),4.48(t,2H),4.29(t,J=6.2Hz,2H),4.02(s,3H),2.94(s,3H),2. 72(t,J=7.1Hz,2H),2.34(h,J=6.0Hz,2H),1.51–1.38(m,2H),0.90(t,J=7.4Hz,3H).

[0718] 13C NMR(126MHz,DMSO-D6)δ168.22,164.88,160.81,154.47,153.27,152.25(d,JC-F=1 1.4Hz),146.80(d,JC-F=256.7Hz),140.71,140.11(d,JC-F=5.6Hz),135.17(d,JC-F =1.2Hz),129.62(d,JC-F=2.0Hz),128.84,125.45,124.89,122.79(d,JC-F=16.2Hz ),114.25,114.05,112.08,65.52,64.49,53.76,53.19,28.57,22.04,20.86,11.67.

[0719] MS(ESI+) m / z 519.6 [M+H] + .

[0720] Example 33: {4-[(3-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propane [2-propylethazolyl]methyl ketone

[0721]

[0722] Step 1: Synthesis of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl)oxy]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0723]

[0724] The product from step 4 of Example 31 will be obtained according to the method in step 1 of Example 1: (2-

[0725] The title compound was synthesized from {[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]propyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester. It was used directly in the next reaction without purification.

[0726] MS(ESI+)m / z 631.7,631.7[M+H] + .

[0727] Step 6: Synthesis of {4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl)oxy]phenyl}(2-propylethazol) ketone

[0728]

[0729] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}propyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0730] 1 H NMR (500MHz, DMSO-D6) δ9.86(s,1H),9.06(s,1H),8.23(d,J=2.1Hz,1H),7.97(d,J= 1.8Hz,1H),7.81–7.75(m,2H),7.73(d,J=2.1Hz,1H),7.72(d,J=1.8Hz,1H),7.06–6. 98(m,2H),4.49(t,2H),4.30(t,J=6.2Hz,2H),3.94(s,3H),3.94(s,3H),2.96(s,3H) ,2.72(t,J=7.1Hz,2H),2.40–2.30(m,2H),1.51–1.38(m,2H),0.90(t,J=7.4Hz,3H).

[0731] 13 C NMR (126MHz, DMSO-D6) δ168.06,164.87,160.82,154.36,153.88,153.07,143.80,140.57,136.88,135.36,129.32,128 .85,125.44,124.93,117.36,114.10,114.06,112.59,65.48,64.50,55.84,53.22,53.18,28.60,22.07,20.85,11.67.

[0732] MS(ESI+) m / z 531.6 [M+H] + .

[0733] Example 34: {4-[(3-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}butyl) [Oxy]phenyl}(2-propylethazol) methyl ketone

[0734]

[0735] Step 1: Synthesis of methyl 4-[(3-bromobutyl)oxy]benzoate

[0736]

[0737] The title compound was synthesized from methyl paraben and 1,4-dibromobutane according to the method in step 1 of Example 22. It was used directly in the next reaction without purification.

[0738] MS(ESI+)m / z 288.2,288.2[M+H] + .

[0739] Step 2: Synthesis of 4-[(3-bromobutyl)oxy]benzoic acid

[0740]

[0741] The title compound was generated by hydrolysis of methyl 4-[(3-bromobutyl)oxy]benzoate according to step 2 of Example 28. It was then used directly in the next reaction without purification.

[0742] MS(ESI+)m / z 274.1,274.1[M+H] + .

[0743] Step 3: Synthesis of [2-({4-[(3-bromobutyl)oxy]phenyl}carbonyl)-1-propylethazol]methane-2-methylpropyl-2-yl ester

[0744]

[0745] The title compound was synthesized from 4-[(3-bromobutyl)oxy]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester according to the method in step 4 of Example 1.

[0746] 1 H NMR (500MHz, CDCl3) δ7.75 (s, 2H), 6.91 (d, J = 7.3Hz, 2H), 4.04 (t, J = 6.4Hz, 2H), 3.55 (t, J = 7.2Hz, 2H), 3.51–3. 45(m,2H),2.07(q,J=6.9Hz,2H),2.02–1.93(m,2H),1.64(d,J=7.8Hz,2H),1.46(s,9H),0.93(t,J=7.4Hz,3H).

[0747] MS(ESI+)m / z 430.4,430.4[M+H] + .

[0748] Step 4: Synthesis of 2-{[4-({3-[(6-bromo-4-methylquinazolin-8-yl)oxy]butyl}oxy)phenyl]carbonyl}-1-propylethazol)methane-2-methylpropyl-2-yl ester

[0749]

[0750] The title compound was synthesized from 6-bromo-4-methylquinazoline-8-phenol and [2-({4-[(3-bromopropyl)oxy]phenyl}carbonyl)-1-propylethazol]methane-2-methylpropyl-2-yl ester according to the method in step 1 of Example 22. It was used directly in the next reaction without purification.

[0751] MS(ESI+)m / z 588.5,588.5[M+H] + .

[0752] Step 5: Synthesis of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}butyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0753]

[0754] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]butyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 6-methoxypyridine-3-boronic acid) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0755] MS(ESI+)m / z 615.7,615.7[M+H] + .

[0756] Step 6: Synthesis of {4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}butyl)oxy]phenyl}(2-propylethazol) ketone

[0757]

[0758] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}butyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0759] 1H NMR (500MHz, DMSO-D6) δ9.86 (s, 1H), 9.06 (s, 1H), 8.73 (dd, J = 2.7, 0.7Hz, 1H), 8.26 (dd, J=8.6,2.7Hz,1H),7.95(d,J=1.8Hz,1H),7.81–7.76(m,2H),7.67(d,J=1.8Hz,1H),7.04– 6.99(m,2H),6.97(dd,J=8.6,0.7Hz,1H),4.38(t,2H),4.19(t,2H),3.93(s,3H),2.94(s ,3H),2.73(t,J=7.1Hz,2H),2.07–1.95(m,4H),1.52–1.39(m,2H),0.90(t,J=7.4Hz,3H).

[0760] 13 C NMR (126MHz, DMSO-D6) δ168.01,164.91,163.50,160.98,154.55,153.03,145.68,140.52,138.23,136.49,128.79,128 .68,125.24,124.96,113.99,113.53,111.93,110.57,68.42,67.42,53.35,53.20,25.61,25.17,22.03,20.87,11.68.

[0761] MS(ESI+) m / z 515.6 [M+H] + .

[0762] Example 35: {4-[(3-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]} [Oxy-butyl]oxy-phenyl](2-propylethazine) methyl ketone

[0763]

[0764] Step 1: Synthesis of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}butyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0765]

[0766] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]butyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0767] MS(ESI+)m / z 633.7,633.7[M+H] + .

[0768] Step 2: Synthesis of {4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}butyl)oxy]phenyl}(2-propylethazol) ketone

[0769]

[0770] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}butyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0771] 1 H NMR(500MHz,DMSO-D6)δ9.06(s,1H),8.56(d,J=2.1Hz,1H),8.31(dd,J=11.9,2 .1Hz,1H),7.98(d,J=2.1Hz,1H),7.90–7.76(m,2H),7.67(d,J=2.3Hz,1H),7.11 –6.94(m,2H),4.36(t,J=6.0Hz,2H),4.20(t,J=6.3Hz,2H),4.01(s,3H),2.93(s ,3H),2.26(t,2H),2.10–1.93(m,4H),1.47–1.32(m,2H),0.82(t,J=7.4Hz,3H).

[0772] 13C NMR (126MHz, DMSO-D6) δ168.14, 154.54, 153.17, 152.20 (d, JC-F = 11.5Hz), 146.76 (d, JC-F = 256.8Hz), 140.66, 140.04 (d, JC-F = 5. 7Hz),135.12,129.64,124.85,122.78,122.65,114.00,113.95,111.81,68.43,67.37,62.42,53.71,25.57,25.11,21.99,11.63.

[0773] MS(ESI+)m / z 533.6 [M+H] + .

[0774] Example 36: {4-[(3-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}butane [2-propylethazolyl]methyl ketone

[0775]

[0776] Step 1: Synthesis of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}butyl)oxy]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0777]

[0778] The title compound was synthesized from (2-{[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]butyl}oxy)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0779] MS(ESI+)m / z 645.8,645.8[M+H] + .

[0780] Step 2: Synthesis of {4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}butyl)oxy]phenyl}(2-propylethazol) ketone

[0781]

[0782] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}butyl)oxy]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0783] 1 H NMR (500MHz, DMSO-D6) δ9.86 (s, 1H), 9.07 (s, 1H), 8.23 ​​(d, J = 2.1Hz, 1H), 7.95 (d, J=1.7Hz,1H),7.81–7.76(m,2H),7.73(d,J=2.1Hz,1H),7.68(d,J=1.7Hz,1H),7.0 2–6.98(m,2H),4.37(t,2H),4.19(t,2H),3.94(s,3H),3.94(s,3H),2.96(s,3H),2 .73(t,J=7.1Hz,2H),2.10–1.94(m,4H),1.50–1.41(m,2H),0.90(t,J=7.4Hz,3H).

[0784] 13 C NMR (126MHz, DMSO-D6) δ168.02,164.92,160.98,154.48,153.87,153.03,143.81,140.57,136.87,135.33,129.39,128.80 ,125.25,124.92,117.34,114.00,113.87,112.34,68.47,67.45,55.83,53.22,53.21,25.66,25.21,22.07,20.87,11.68.

[0785] MS(ESI+) m / z 545.7 [M+H] + .

[0786] Example 37: (2E)-3-{4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl] [Oxyethyl]oxyphenyl]-1-(2-propylethazolyl)prop-2-en-1-one

[0787]

[0788] Step 1: Synthesis of methyl (2E)-3-{4-[(2-bromoethyl)oxy]phenyl}prop-2-enoate

[0789]

[0790] The title compound was synthesized from methyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate and 1,2-dibromoethane according to the method in step 1 of Example 22. It was used directly in the next reaction without purification.

[0791] MS(ESI+)m / z 286.1,286.1[M+H] + .

[0792] Step 2: Synthesis of (2E)-3-{4-[(2-bromoethyl)oxy]phenyl}prop-2-enoic acid

[0793]

[0794] The title compound is generated by hydrolysis of methyl (2E)-3-{4-[(2-bromoethyl)oxy]phenyl}prop-2-enoate according to step 2 of Example 28.

[0795] 1 H NMR (500MHz, CDCl3) δ7.73 (d, J = 15.9Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 6.94 (s, 1H) ,6.92(s,1H),6.33(d,J=15.9Hz,1H),4.33(t,J=6.3Hz,2H),3.66(t,J=6.3Hz,2H).

[0796] MS(ESI+)m / z 272.1,272.1[M+H] + .

[0797] Step 3: Synthesis of 2-[(2E)-3-{4-[(2-bromoethyl)oxy]phenyl}-1-oxoylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester

[0798]

[0799] The title compound was synthesized from (2E)-3-{4-[(2-bromoethyl)oxy]phenyl}prop-2-enoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid according to the method in step 4 of Example 1.

[0800] 1H NMR (500MHz, CDCl3) δ7.77(d,J=15.5Hz,1H),7.64(d,J=12.1Hz,1H),7.48(d,J=8.4Hz,1H),6.93(s,1H),6.90(d,J=7.1Hz,1H),6.29(d,J= 15.5Hz,1H),4.31(t,J=6.3Hz,2H),3.65(t,J=6.3Hz,2H),3.52(t,J=7.4Hz,2H),1.59(q,J=7.6Hz,2H),1.47(s,9H),0.92(t,J=7.4Hz,3H).

[0801] MS(ESI+) m / z 428.3, 428.3 [M+H] + .

[0802] Step 4: Synthesis of 2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0803]

[0804] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and {2-[(2E)-3-{4-[(2-bromoethyl)oxy]phenyl}-1-oxoylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester according to the method in step 1 of Example 22.

[0805] 1 H NMR (500MHz, CDCl3) δ9.26 (s, 1H), 7.91 (d, J = 1.7Hz, 1H), 7.70 (d, J = 15.5H z,1H),7.53(s,1H),7.48(s,1H),6.99(s,1H),6.97(s,1H),6.32(d,J=15. 6Hz,1H),4.67(t,J=4.7Hz,2H),4.60(d,J=4.3Hz,2H),3.55(t,J=7.2Hz,2 H), 2.99 (s, 3H), 1.63 (q, J = 7.3Hz, 2H), 1.50 (s, 9H), 0.96 (t, J = 7.4Hz, 3H).

[0806] MS(ESI+)m / z 586.5,586.5[M+H] + .

[0807] Step 5: Synthesis of {2-[(2E)-3-{4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester

[0808]

[0809] The title compound will be synthesized from {2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester and 6-methoxypyridine-3-boronic acid according to the method in step 1 of Example 1.

[0810] 1 H NMR (500MHz, CDCl3) δ9.22 (s, 1H), 8.50 (s, 1H), 7.89 (d, J = 7.0Hz, 1H), 7.78 (s, 1H), 7.66 (d,J=15.0Hz,1H),7.52(s,1H),7.49(s,1H),7.45(s,1H),6.95(s,1H),6.94(s,1H),6.9 1(d,J=8.2Hz,1H),6.28(d,J=16.1Hz,1H),4.71(s,2H),4.59(s,2H),4.03(s,3H),3.52( t,J=7.3Hz,2H),3.02(s,3H),1.60(d,J=7.5Hz,2H),1.47(s,9H),0.92(t,J=7.5Hz,3H).

[0811] MS(ESI+)m / z 614.7,614.7[M+H] + .

[0812] Step 6: Synthesis of (2E)-3-{4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-(2-propylethazol)prop-2-en-1-one

[0813]

[0814] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-{4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0815] 1 H NMR (500MHz, DMSO-D6) δ9.05 (s, 1H), 8.75 (d, J = 2.7Hz, 1H), 8.28 (dd, J = 8.6, 2.7Hz, 1H), 8.0 0(d,J=1.5Hz,1H),7.75(d,J=1.5Hz,1H),7.70–7.63(m,1H),7.56(d,J=16.0Hz,1H),7.54–7 .50(m,1H),7.14–7.04(m,2H),6.98(d,J=8.6Hz,1H),6.39(d,J=16.0Hz,1H),4.68(t,2H),4 .53(t,2H),3.93(s,3H),2.95(s,3H),2.69(t,2H),1.58–1.30(m,2H),0.88(t,J=7.3Hz,3H).

[0816] 13 C NMR (126MHz, DMSO-D6) δ168.10,167.83,163.52,160.00,159.39,154.25,153.04,145.74,143.69,140.40,138.26,136.47,130. 00,129.12,128.59,124.98,116.67,114.99,114.96,113.97,112.32,110.56,67.49,66.57,62.46,53.35,25.62,22.04,11.57.

[0817] MS(ESI+) m / z 514.6 [M+H] + .

[0818] Example 38: (2E)-3-{4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8- [yl]oxy[ethyl]oxy[phenyl]-1-(2-propylethazol)prop-2-en-1-one

[0819]

[0820] Step 1: Synthesis of 2-[(2E)-3-{4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxo-ylidene-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0821]

[0822] The title compound will be synthesized from {2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid, according to the method in step 1 of Example 1.

[0823] 1 H NMR(500MHz, CDCl3)δ9.24(s,1H),8.27(s,1H),7.78(s,1H),7.67(s,1H),7.65(s, 1H),7.52(s,1H),7.48(d,J=8.0Hz,1H),7.44(s,1H),6.96(d,J=9.6Hz,1H),6.93( s,1H),6.28(d,J=15.6Hz,1H),4.71(s,2H),4.59(s,2H),4.11(s,3H),3.52(t,J=7 .4Hz,2H),3.04(s,3H),1.59(q,J=7.4Hz,2H),1.47(s,9H),0.92(t,J=7.4Hz,3H).

[0824] MS(ESI+)m / z 632.7,632.7[M+H] + .

[0825] Step 2: Synthesis of (2E)-3-{4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-(2-propylethazol)prop-2-en-1-one

[0826]

[0827] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-{4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0828] 1H NMR (500MHz, DMSO-D6) δ9.06 (s, 1H), 8.61 (d, J = 2.1Hz, 1H), 8.37 (dd, J = 12.0, 2.1Hz, 1 H),8.06(d,J=1.8Hz,1H),7.78(d,J=1.8Hz,1H),7.68–7.63(m,1H),7.56(d,J=16.0Hz, 1H),7.54–7.49(m,1H),7.10–7.05(m,2H),6.39(d,J=16.0Hz,1H),4.69(t,2H),4.53(t ,2H),4.03(s,3H),2.96(s,3H),2.69(t,J=6.7Hz,2H),1.73–1.29(m,2H),0.90(t,3H).

[0829] 13 C NMR (126MHz, DMSO-D6) δ168.31,167.83,160.00,154.28,153.26,152.29(d,JC-F=11. 3Hz),146.82(d,JC-F=256.7Hz),143.69,140.62,140.19(d,JC-F=5.7Hz),135.17,130 .01,129.65(d,JC-F=1.9Hz),129.11,127.12,124.94,122.84(d,JC-F=16.2Hz),116. 68,115.01,114.97,114.53,112.30,67.51,66.54,62.46,53.78,25.63,22.07,11.58.

[0830] MS(ESI+) m / z 532.6 [M+H] + .

[0831] Example 39: (2E)-3-{4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazole [Lin-8-yl]oxy[ethyl]oxy[phenyl]-1-(2-propylethazol)prop-2-en-1-one

[0832]

[0833] Step 1: Synthesis of 2-[(2E)-3-{4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxo-ylidene-2-enyl]-1-propylethazyl}methane-2-methylpropyl-2-yl ester

[0834]

[0835] The title compound will be synthesized from {2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazol}methane-2-methylprop-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester according to the method in step 1 of Example 1.

[0836] 1 H NMR (500MHz, CDCl3) δ9.23 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.65 (d, J = 16.2Hz, 1H), 7.52 ( s,1H),7.48(d,J=8.0Hz,1H),7.43(s,1H),7.30(s,1H),6.96(d,J=10.8Hz,1H),6.93(s,1H ),6.28(d,J=15.5Hz,1H),4.70(d,J=4.6Hz,2H),4.59(s,2H),4.10(s,3H),3.99(s,3H),3. 52(t,J=7.1Hz,2H),3.02(s,3H),1.59(q,J=7.4Hz,2H),1.47(s,9H),0.92(t,J=7.4Hz,3H).

[0837] MS(ESI+)m / z 644.7,644.7[M+H] + .

[0838] Step 2: Synthesis of (2E)-3-{4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-(2-propylethazolyl)prop-2-en-1-one

[0839]

[0840] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-{4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0841] 1H NMR (500MHz, DMSO-D6) δ9.05 (s, 1H), 8.25 (d, J = 2.1Hz, 1H), 8.00 (d, J = 1.8Hz, 1H), 7.76 (d,J=2.1Hz,1H),7.76(d,J=1.8Hz,1H),7.68–7.63(m,1H),7.56(d,J=16.0Hz,1H),7.5 4–7.50(m,1H),7.12–7.04(m,2H),6.39(d,J=16.0Hz,1H),4.70(t,2H),4.53(t,2H),3. 94(s,3H),3.94(s,3H),2.97(s,3H),2.73–2.64(m,2H),1.50–1.34(m,2H),0.88(t,3H).

[0842] 13 C NMR (126MHz, DMSO-D6) δ168.10,167.83,160.02,159.40,154.17,153.88,153.03,143.82,140.45,136.84,135.39,130.01,129.30, 129.11,127.11,124.94,117.36,116.67,114.99,114.95,114.31,112.75,67.54,66.61,62.46,55.84,53.22,25.62,22.08,11.58.

[0843] MS(ESI+) m / z 544.6 [M+H] + .

[0844] Example 40: (2E)-3-[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}meth] [2-propylethazolyl]-1-(2-propylethazolyl)prop-2-en-1-one

[0845]

[0846] Step 1: Synthesis of (2E)-3-(4-methylphenyl)prop-2-enoic acid-2-methylprop-2-yl ester

[0847]

[0848] (Triphenyl-λ5-methylphosphonylidene)acetic acid-2-methylpropyl-2-yl ester (3.76 g, 10 mmol) was dissolved in tetrahydrofuran (50 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.20 g, 10 mmol) was added. The mixture was stirred at room temperature for 5 minutes. p-Tolualdehyde (3.04 g, 20 mmol) was added, and the mixture was heated at 60 °C for 20 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and the reaction was quenched with 0.05 N hydrochloric acid. The organic solvent was removed under reduced pressure, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the solvent was evaporated under reduced pressure. The mixture was used directly in the next reaction without purification.

[0849] MS(ESI+)m / z 219.3,219.3[M+H] + .

[0850] Step 2: Synthesis of (2E)-3-[4-(bromomethyl)phenyl]prop-2-enoic acid-2-methylprop-2-yl ester

[0851]

[0852] (2E)-3-(4-methylphenyl)prop-2-enoic acid-2-methylprop-2-yl ester (2.18 g, 10 mmol) was dissolved in carbon tetrachloride (50 mL), NBS (1.96 g, 11 mmol) was added, and azobisisobutyronitrile (20 mg) was added. The mixture was reacted at 95 °C for 2 hours. The solid was filtered off, and the mixture was washed with dichloromethane. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give a white solid (1.96 g, yield 66.1%).

[0853] 1 H NMR(400MHz,CHLOROFORM-D)δ7.56(d,J=15.9Hz,1H),7.49(s,1H),7.47(s,1H ),7.40(s,1H),7.38(s,1H),6.37(d,J=15.9Hz,1H),4.49(s,2H),1.53(s,9H).

[0854] MS(ESI+)m / z 298.2,298.2[M+H] + .

[0855] Step 3: Synthesis of (2E)-3-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)prop-2-enoic acid-2-methylprop-2-yl ester

[0856]

[0857] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and (2E)-3-[4-(bromomethyl)phenyl]prop-2-enoic acid-2-methylprop-2-yl ester according to the method in step 1 of Example 22.

[0858] 1 H NMR (400MHz, CHLOROFORM-D) δ9.23(s,1H),7.83(d,J=1.9Hz,1H),7.58(d,J=16.1Hz,1H),7.53(d,J =4.7Hz,4H),7.31(d,J=1.8Hz,1H),6.38(d,J=16.1Hz,1H),5.38(s,2H),2.94(s,3H),1.53(s,9H).

[0859] MS(ESI+)m / z 456.4,456.4[M+H] + .

[0860] Step 4: Synthesis of (2E)-3-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)prop-2-enoic acid

[0861]

[0862] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating (2E)-3-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)prop-2-enoic acid-2-methylprop-2-yl ester. It is then used directly in the next reaction without purification.

[0863] MS(ESI+)m / z 400.3,400.3[M+H] + .

[0864] Step 5: Synthesis of {2-[(2E)-3-{4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}ethyl)oxy]phenyl}-1-oxylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester

[0865]

[0866] The title compound was synthesized from (2E)-3-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)prop-2-enoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid according to the method in step 4 of Example 1.

[0867] 1 H NMR (500MHz, DMSO-D6) δ10.19(s,1H),9.11(s,1H),8.03(d,J=1.9Hz,1H),7.68(s,1H),7.67(d,J=1.9Hz,1H),7.66(s,1H),7.60(s,1H),7.58(s,1 H),7.55(d,J=15.9Hz,1H),6.62(d,J=15.9Hz,1H),5.39(s,2H),3.08(t, 2H),2.88(s,3H),1.52–1.46(m,2H),1.35(s,9H),0.86(t,J=7.3Hz,3H).

[0868] MS(ESI+)m / z 556.5,556.5[M+H] + .

[0869] Step 6: Synthesis of {2-[(2E)-3-[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0870]

[0871] The title compound will be synthesized from {2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester and 6-methoxypyridine-3-boronic acid according to the method in step 1 of Example 1.

[0872] It can be used directly in the next reaction without purification.

[0873] MS(ESI+)m / z 584.7,584.7[M+H] + .

[0874] Step 7: Synthesis of (2E)-3-[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-(2-propylethazolyl)prop-2-en-1-one]

[0875]

[0876] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0877] 1 H NMR (500MHz, DMSO-D6) δ9.07(s,1H),8.73(dd,J=2.6,0.8Hz,1H),8.27(dd,J=8.6,2.6Hz,1H),8.00(d,J=1.7Hz,1H),7.80(d,J=1.7Hz,1H),7 .66–7.56(m,4H),6.99(dd,J=8.6,0.8Hz,1H),5.48(s,2H),3.93(s,3H),2.96(s,3H),2.69(t,J=6.4Hz,2H),1.49–1.32(m,2H),0.88(t,3H).

[0878] 13 C NMR (126MHz, DMSO-D6) δ168.11,163.51,154.04,154.00,153.13,145.63,140.61,138.17,138.05,136.33,136.32,1 28.51,128.50,128.25,128.08,127.66,125.01,113.96,112.66,110.61,69.80,62.43,53.35,25.60,22.03,11.55.

[0879] MS(ESI+) m / z 484.6 [M+H] + .

[0880] Example 41: (2E)-3-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy] [[methyl]phenyl]-1-(2-propylethazolyl)prop-2-en-1-one

[0881]

[0882] Step 1: Synthesis of 2-[(2E)-3-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0883]

[0884] The title compound will be synthesized from {2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazolyl}methane-2-methylprop-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid, according to the method in step 1 of Example 1.

[0885] It can be used directly in the next reaction without purification.

[0886] MS(ESI+)m / z 602.7,602.7[M+H] + .

[0887] Step 2: Synthesis of (2E)-3-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-(2-propylethazolyl)prop-2-en-1-one]

[0888]

[0889] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0890] 1 H NMR (500MHz, DMSO-D6) δ9.66 (s, 1H), 9.08 (s, 1H), 8.58 (d, J = 2.1Hz, 1H), 8.3 6(dd,J=12.5,2.1Hz,1H),8.06(d,J=1.5Hz,1H),7.84(d,J=1.5Hz,1H),7.67– 7.57(m,4H),7.46(d,J=15.7Hz,1H),6.58(d,J=15.7Hz,1H),5.47(s,2H),4.0 2(s,3H),2.96(s,3H),2.70(t,2H),1.50–1.36(m,2H),0.89(t,J=7.4Hz,3H).

[0891] 13C NMR (126MHz, DMSO-D6) δ168.32, 163.75, 154.12, 153.36, 152.31 (d, JC-F=11. 4Hz),146.83(d,JC-F=256.7Hz),140.83,140.07(d,JC-F=5.6Hz),138.03(d,J C-F=9.2Hz),135.04,134.61,129.56,128.29,127.66,124.97,122.75(d,JC-F =16.1Hz),120.50,114.53,112.59,69.90,53.79,53.08,22.07,20.78,11.56.

[0892] MS(ESI+)m / z 502.6[M+H] + .

[0893] Example 42: (2E)-3-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy] [[methyl]phenyl]-1-(2-propylethazolyl)prop-2-en-1-one

[0894]

[0895] Step 1: Synthesis of {2-[(2E)-3-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester

[0896]

[0897] The title compound was synthesized from {2-[(2E)-3-[4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]ethyl}oxy)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazol}methane-2-methylprop-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester, according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[0898] MS(ESI+)m / z 614.7,614.7[M+H] + .

[0899] Step 2: Synthesis of (2E)-3-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-(2-propylethazolyl)prop-2-en-1-one]

[0900]

[0901] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of {2-[(2E)-3-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]-1-oxylideneprop-2-enyl]-1-propylethazyl}methane-2-methylprop-2-yl ester.

[0902] 1 H NMR (500MHz, DMSO-D6) δ9.62 (s, 1H), 9.08 (s, 1H), 8.22 (d, J = 2.1Hz, 1H), 8.00 ( d,J=1.7Hz,1H),7.79(d,J=1.7Hz,1H),7.69(d,J=2.1Hz,1H),7.66–7.56(m,4H ),7.46(d,J=15.7Hz,1H),6.57(d,J=15.7Hz,1H),5.49(s,2H),3.94(s,3H),3. 94(s,3H),2.97(s,3H),2.69(t,J=6.2Hz,1H),1.55–1.30(m,2H),0.89(t,3H).

[0903] 13 C NMR (126MHz, DMSO-D6) δ168.11,153.93,153.88,153.12,143.81,140.67,138.06,136.67,135.24,134.56,129.20, 129.19,128.31,128.14,127.66,124.98,117.21,114.25,113.10,69.85,62.44,55.80,53.22,25.61,22.07,11.55.

[0904] MS(ESI+) m / z 514.6 [M+H] + .

[0905] Example 43: {4-[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl) [Phenyl]phenyl}(2-propylethazolyl)methyl ketone

[0906]

[0907] Step 1: Synthesis of 2-methylpropyl-2-yl 4-(4-methylphenyl)benzoate

[0908]

[0909] The title compound was synthesized from 4-(4-methylphenyl)benzoic acid and di-tert-butyl dicarbonate according to the method in step 1 of Example 10. It was used directly in the next reaction without purification.

[0910] MS(ESI+) m / z 269.4, 269.4 [M+H] + .

[0911] Step 2: Synthesis of 2-methylpropyl-2-yl 4-[4-(bromomethyl)phenyl]benzoate

[0912]

[0913] The title compound was synthesized from 4-(4-methylphenyl)benzoic acid-2-methylpropyl-2-yl ester and NBS according to the method in step 2 of Example 40.

[0914] 1 H NMR(400MHz,CHLOROFORM-D)δ8.07(s,1H),8.05(s,1H),7.63(s,1H),7.61(s,1H ),7.61(s,1H),7.59(s,1H),7.50(s,1H),7.48(s,1H),4.55(s,2H),1.62(s,9H).

[0915] MS(ESI+)m / z 348.3,348.3[M+H] + .

[0916] Step 3: Synthesis of 2-methylpropyl-2-yl 4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)benzoate

[0917]

[0918] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and 4-[4-(bromomethyl)phenyl]benzoic acid-2-methylpropyl-2-yl ester according to the method in step 1 of Example 22.

[0919] 1 H NMR (500MHz, DMSO-D6) δ9.12 (s, 1H), 8.03 (d, J = 1.9Hz, 1H), 8.00–7.96 (m, 2H), 7.84–7.79 (m,4H),7.70(d,J=1.9Hz,1H),7.68–7.65(m,2H),5.43(s,2H),2.88(s,3H),1.57(s,9H).

[0920] MS(ESI+) m / z 506.4, 506.4 [M+H] + .

[0921] Step 4: Synthesis of 4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)benzoic acid

[0922]

[0923] The title compound was obtained by detert-butylating 2-methylpropyl-2-yl 4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)benzoate. It was then used directly in the next reaction without purification.

[0924] MS(ESI+)m / z 451.3,451.3[M+H] + .

[0925] Step 5: Synthesis of 2-{[4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)phenyl]carbonyl}-1-propylethazol)methane-2-methylpropyl-2-yl ester

[0926]

[0927] The title compound was synthesized from 4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0928] 1 H NMR (500MHz, DMSO-D6) δ10.58(s,1H),9.12(s,1H),8.04(d,J=1.9Hz,1H),7.99–7.91(m,2H),7.86–7.80(m,4H),7.71(d,J=1.9 Hz,1H),7.68–7.65(m,2H),5.43(s,2H),3.41(t,2H),2.88(s,3H),1.56–1.50(m,2H),1.46–1.33(m,9H),0.90(t,J=6.8Hz,3H).

[0929] MS(ESI+)m / z 606.5,606.5[M+H] + .

[0930] Step 6: Synthesis of 2-({4-[4-({[6-(6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}methyl)phenyl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0931]

[0932] The title compound will be synthesized from (2-{[4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 6-methoxypyridine-3-boronic acid, according to the method in step 1 of Example 1.

[0933] It can be used directly in the next reaction without purification.

[0934] MS(ESI+)m / z 634.8,634.8[M+H] + .

[0935] Step 7: Synthesis of {4-[4-({[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}(2-propylethazol) ketone

[0936]

[0937] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[4-({[6-(6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}methyl)phenyl]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0938] 1 H NMR (500MHz, DMSO-D6) δ10.07(s,1H),9.08(s,1H),8.75(dd,J=2.6,0.8Hz,1H),8.29(dd,J =8.6,2.6Hz,1H),8.01(d,J=1.9Hz,1H),7.97–7.89(m,2H),7.87–7.82(m,2H),7.81(d,J=1 .9Hz,1H),7.80–7.76(m,2H),7.72–7.67(m,2H),7.00(dd,J=8.6,0.8Hz,1H),5.52(s,2H), 3.94(s,3H),2.96(s,3H),2.77(t,J=7.0Hz,2H),1.55–1.40(m,2H),0.92(t,J=7.4Hz,3H).

[0939] 13C NMR (126MHz, DMSO-D6) δ168.14,164.89,163.54,154.14,153.16,145.68,142.34,140.67,138.79,138.22,136.60,136.38,129.97,1 28.57,128.50,127.71,127.12,126.99,126.80,126.52,125.05,113.95,112.65,110.64,69.83,53.37,53.10,22.06,20.86,11.67.

[0940] MS(ESI+) m / z 534.6 [M+H] + .

[0941] Example 44: {4-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy} [Methyl]phenyl]phenyl}(2-propylethazol) methyl ketone

[0942]

[0943] Step 1: Synthesis of 2-({4-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0944]

[0945] The title compound will be synthesized from (2-{[4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid, according to the method in step 1 of Example 1.

[0946] It can be used directly in the next reaction without purification.

[0947] MS(ESI+)m / z 652.7,652.7[M+H] + .

[0948] Step 2: Synthesis of {4-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}(2-propylethazol) ketone

[0949]

[0950] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[4-({[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester.

[0951] 1 H NMR (500MHz, DMSO-D6) δ10.05 (s, 1H), 9.04 (s, 1H), 8.56 (d, J = 2.1Hz, 1H), 8.3 2(dd,J=11.9,2.1Hz,1H),8.02(d,J=1.8Hz,1H),7.92–7.86(m,2H),7.82(d,J =1.8Hz,1H),7.78–7.72(m,4H),7.67–7.61(m,2H),5.47(s,2H),3.99(s,3H), 2.92(s,3H),2.73(t,J=7.1Hz,2H),1.51–1.38(m,2H),0.88(t,J=7.4Hz,3H).

[0952] 13 C NMR (126MHz, DMSO-D6) δ168.31,167.13,164.90,154.18,153.36,152.31(d,JC-F=11.4Hz),146.84(d ,JC-F=256.9Hz),142.35,140.86,140.08(d,JC-F=5.6Hz),138.81,136.55,135.06,132.09,129.98, 129.58(d,JC-F=2.0Hz),128.52(d,JC-F=2.6Hz),127.73,127.08(d,JC-F=9.6Hz),127.00,126.80,1 26.53,124.98,122.75(d,JC-F=16.3Hz),114.48,112.53,69.90,53.79,53.10,22.07,20.85,11.67.

[0953] MS(ESI+) m / z 552.6 [M+H] + .

[0954] Example 45: {4-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}meth [2-propylethazolyl]methyl ketone

[0955]

[0956] Step 1: Synthesis of 2-({4-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[0957]

[0958] The title compound will be synthesized from (2-{[4-(4-{[(6-bromo-4-methylquinazolin-8-yl)oxy]methyl}phenyl)phenyl]carbonyl}-1-propylethazyl)methane-2-methylpropyl-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester) according to the method in step 1 of Example 1.

[0959] It can be used directly in the next reaction without purification.

[0960] MS(ESI+)m / z 664.8,664.8[M+H] + .

[0961] Step 2: Synthesis of {4-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}(2-propylethazol) ketone

[0962]

[0963] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[4-({[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}methyl)phenyl]phenyl}carbonyl)-1-propylethazol]methane-2-methylpropyl-2-yl ester.

[0964] 1 H NMR (500MHz, DMSO-D6) δ10.08(s,1H),9.09(s,1H),8.24(d,J=2.1Hz,1H),8.01(d,J =1.7Hz,1H),7.95–7.90(m,2H),7.86–7.82(m,2H),7.81(d,J=1.9Hz,1H),7.80–7.7 8(m,2H),7.72(d,J=2.1Hz,1H),7.71–7.68(m,2H),5.53(s,2H),3.95(s,3H),3.94( s,3H),2.98(s,3H),2.77(t,J=7.2Hz,2H),1.54–1.43(m,2H),0.92(t,J=7.4Hz,3H).

[0965] 13 C NMR (126MHz, DMSO-D6) δ168.14,164.89,154.02,153.90,153.15,143.84,142.32,140.71,138.80,136.72,136.62,135.29,129.98,129. 25,128.54,127.72,127.12,126.99,126.79,126.52,125.01,117.27,114.25,113.09,69.86,55.82,53.24,53.10,22.10,20.86,11.67.

[0966] MS(ESI+) m / z 564.7 [M+H] + .

[0967] Example 46: 2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}-N-{4-[(2- [propylethazolyl]carbonyl]phenyl]acetamide

[0968]

[0969] Step 1: Synthesis of 4-[(2-bromoacetyl)amino]benzoic acid-2-methylpropyl-2-yl ester

[0970]

[0971] 193 mg, 1 mmol of tert-butyl para-aminobenzoate was dissolved in 10 mL of dichloromethane. 202 mg, 1 mmol of bromoacetyl bromide and 202 mg, 2 mmol of triethylamine were also dissolved in 10 mL of dichloromethane. The solutions were added dropwise to a three-necked flask containing 10 mL of dichloromethane under ice bath conditions. The ice bath was removed, and the mixture was reacted at room temperature for 1 hour. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and the solvent was evaporated under reduced pressure. The solution was used directly in the next reaction without further purification.

[0972] MS(ESI+)m / z 315.2,315.2[M+H] + .

[0973] Step 2: Synthesis of 4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]acetyl}amino)benzoic acid-2-methylpropyl-2-yl ester)

[0974]

[0975] The title compound will be synthesized from 6-bromo-4-methylquinazoline-8-phenol and 4-[(2-bromoacetyl)amino]benzoic acid-2-methylpropyl-2-yl ester according to the method in step 1 of Example 22.

[0976] 1 H NMR(400MHz,CHLOROFORM-D)δ10.13(s,1H),9.29(s,1H),8.01(s,1H),8.00(d,J=1.9Hz,1H),7.99(s,1H), 7.77(d,J=1.9Hz,1H),7.75(d,J=1.9Hz,1H),7.54(d,J=1.9Hz,1H),4.88(s,2H),2.96(s,3H),1.59(s,9H).

[0977] MS(ESI+)m / z 473.3,473.3[M+H] + .

[0978] Step 3: Synthesis of 4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]benzoic acid-2-methylpropyl-2-yl ester]

[0979]

[0980] The title compound will be synthesized from 4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]acetyl}amino)benzoic acid-2-methylpropyl-2-yl ester and 6-methoxypyridine-3-boronic acid according to the method in step 1 of Example 1.

[0981] 1 H NMR(400MHz,CHLOROFORM-D)δ10.43(s,1H),9.31(s,1H),8.49(s,1H),8.00(d,J=8.7Hz,2H),7.94–7 .78(m,4H),7.64(s,1H),6.92(d,J=8.8Hz,1H),4.97(s,2H),4.03(s,3H),3.05(s,3H),1.59(s,9H).

[0982] MS(ESI+)m / z 501.6,501.6[M+H] + .

[0983] Step 4: Synthesis of 4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]benzoic acid

[0984]

[0985] According to the method in step 4 of Example 10, the title compound is obtained by detert-butylating 4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]benzoic acid-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[0986] MS(ESI+)m / z 445.5,445.5[M+H] + .

[0987] Step 5: Synthesis of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester

[0988]

[0989] The title compound was synthesized from 4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]benzoic acid and tert-butyl 1-propylhydrazine-1-carboxylic acid, according to step 4 of Example 1. It was used directly in the next reaction without purification.

[0990] MS(ESI+)m / z 601.7,601.7[M+H] + .

[0991] Step 6: Synthesis of 2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}-N-{4-[(2-propylethazolyl)carbonyl]phenyl}acetamide

[0992]

[0993] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[0994] 1H NMR (500MHz, DMSO-D6) δ10.66(s,1H),10.02(s,1H),9.15(s,1H),8.72(dd,J=2.7,0. 8Hz,1H),8.26(dd,J=8.6,2.7Hz,1H),8.09(d,J=1.7Hz,1H),7.84(d,J=1.7Hz,1H),7 .83–7.79(m,2H),7.76–7.71(m,2H),6.98(dd,J=8.6,0.8Hz,1H),5.14(s,2H),3.92( s,3H),2.98(s,3H),2.75(t,J=7.1Hz,2H),1.52–1.40(m,2H),0.90(t,J=7.4Hz,3H).

[0995] 13 C NMR (126MHz, DMSO-D6) δ168.54,166.86,164.80,163.59,154.01,153.30,145.68,141.02,140.59,138.20,136. 40,130.53,128.33,128.09,125.12,118.62,115.12,114.48,110.69,69.15,53.40,53.05,22.10,20.70,11.63.

[0996] MS(ESI+)m / z501.6[M+H] + .

[0997] Example 47: 2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}-N-{4- [(2-propylethazo)carbonyl]phenylacetamide

[0998]

[0999] Step 1: Synthesis of 4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]benzoic acid-2-methylpropyl-2-yl ester]

[1000]

[1001] The title compound will be synthesized from 4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]acetyl}amino)benzoic acid-2-methylpropyl-2-yl ester and 5-fluoro-6-methoxypyridine-3-boronic acid, according to the method in step 1 of Example 1.

[1002] 1H NMR (500MHz, CDCl3) δ10.41(s,1H),9.36(s,1H),8.29(s,1H),8.03(s,1H),8.01(s,1H),7.94(s,1H),7.85(s ,1H),7.83(s,1H),7.68(d,J=10.1Hz,1H),7.65(s,1H),5.00(s,2H),4.14(s,3H),3.09(s,3H),1.62(s,9H).

[1003] MS(ESI+) m / z 519.6,519.6[M+H] + .

[1004] Step 2: Synthesis of 4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]benzoic acid

[1005]

[1006] According to step 4 of Example 10, the title compound is obtained by detert-butylating 4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]benzoic acid-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[1007] MS(ESI+)m / z 453.5,453.5[M+H] + .

[1008] Step 3: Synthesis of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[1009]

[1010] The title compound was synthesized from 4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, following the method in step 4 of Example 1. It was used directly in the next reaction without purification.

[1011] MS(ESI+)m / z 619.7,619.7[M+H] + .

[1012] Step 4: Synthesis of 2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}-N-{4-[(2-propylethazyl)carbonyl]phenyl}acetamide

[1013]

[1014] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5-fluoro-6-methoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[1015] 1 H NMR (500MHz, DMSO-D6) δ10.60(s,1H),10.05(s,1H),9.16(s,1H),8.57(d,J= 2.1Hz,1H),8.34(dd,J=11.9,2.1Hz,1H),8.14(d,J=1.8Hz,1H),7.87(d,J=1 .8Hz,1H),7.85–7.79(m,2H),7.77–7.70(m,2H),5.15(s,2H),4.01(s,3H),2 .98(s,3H),2.76(t,J=9.1Hz,2H),1.55–1.39(m,2H),0.90(t,J=7.4Hz,3H).

[1016] 13 C NMR (126MHz, DMSO-D6) δ168.68,166.81,154.02,153.48,152.39,152.30,146.82(d,JC-F=256.8Hz),141.03,140.78,140.07(d,JC-F=5.5H z),135.06,130.51,129.31,128.12,125.03,122.72(d,JC-F=16.4Hz),118.59,115.65,114.43,69.13,53.79,45.65,22.09,20.62,11.59.

[1017] MS(ESI+) m / z 519.6 [M+H] + .

[1018] Example 48: 2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}-N-{4- [(2-propylethazo)carbonyl]phenylacetamide

[1019]

[1020] Step 1: Synthesis of 4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]benzoic acid-2-methylpropyl-2-yl ester]

[1021]

[1022] The title compound was synthesized from 4-({2-[(6-bromo-4-methylquinazolin-8-yl)oxy]acetyl}amino)benzoic acid-2-methylpropyl-2-yl ester and 5,6-dimethoxypyridine-3-boronic acid pinacol ester) according to the method in step 1 of Example 1. It was used directly in the next reaction without purification.

[1023] MS(ESI+)m / z 531.6,531.6[M+H] + .

[1024] Step 2: Synthesis of 4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]benzoic acid

[1025]

[1026] According to step 4 of Example 10, the title compound is obtained by detert-butylating 4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]benzoic acid-2-methylpropyl-2-yl ester. It is then used directly in the next reaction without purification.

[1027] MS(ESI+)m / z 475.5,475.5[M+H] + .

[1028] Step 3: Synthesis of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}acetyl)amino]phenyl}carbonyl)-1-propylethazyl]methane-2-methylpropyl-2-yl ester

[1029]

[1030] The title compound was synthesized from 4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]benzoic acid and 1-propylhydrazine-1-carboxylic acid tert-butyl ester, following the method in step 4 of Example 1. It was used directly in the next reaction without purification.

[1031] MS(ESI+)m / z 631.7,631.7[M+H] + .

[1032] Step 4: Synthesis of 2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl]oxy}-N-{4-[(2-propylethazolyl)carbonyl]phenyl}acetamide

[1033]

[1034] According to the method in step 6 of Example 1, the title compound is generated by de-Boc protection of [2-({4-[(2-{[6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl]oxy}acetyl)amino]phenyl}carbonyl)-1-propylethazolyl]methane-2-methylpropyl-2-yl ester.

[1035] 1 H NMR(500MHz,DMSO-D6)δ10.73(s,1H),10.64(s,1H),9.17(s,1H),8.21(d, J=2.1Hz,1H),8.09(d,J=1.7Hz,1H),7.97–7.89(m,1H),7.83(d,J=1.7Hz,1 H),7.81–7.72(m,3H),7.70(d,J=2.1Hz,1H),5.15(s,2H),3.93(s,3H),3. 90(s,3H),2.99(s,3H),2.74(t,2H),1.54–1.33(m,2H),0.96–0.76(m,3H).

[1036] 13 C NMR (126MHz, DMSO-D6) δ168.56,167.04,166.86,153.96,153.88,153.30,143.86,140.64,136.75,135.29,130.54, 128.97,128.07,125.09,118.68,118.61,117.18,115.46,114.97,69.30,55.76,53.26,53.11,25.63,22.14,11.66.

[1037] MS(ESI+) m / z 531.6 [M+H] + .

[1038] Pharmacological activity evaluation

[1039] Experimental Example 1: PI3Kα Kinase Activity Assay

[1040] The effects of the compounds of this invention on PI3Kα were evaluated using an in vitro kinase activity assay. A luciferase-based cryo-optical assay was used to determine the kinase activity of PI3Kα by detecting the level of ADP produced during the kinase reaction, thereby reflecting the inhibitory level of the compounds on PI3Kα kinase activity. Kinase-Glo TM The kinase activity assay kit was purchased from Promega. PI3Kα kinase and substrate PIP2 were purchased from Invitrogen. OptiPlate was used. TM -384 White 384-well plates were used for testing. All assays were performed at room temperature. Kinase buffer consisted of 50 mM Hepes (pH 7.5), 3 mM MgCl2, 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS, and 2 mM DTT. PI3Kα kinase was diluted to a 6.6 nM kinase solution with kinase buffer. Substrate solution consisted of 100 μM PIP2 and 50 μM ATP. The test compound was diluted to 10 mM in 100% DMSO, and then serially diluted 3-fold in 100% DMSO to 10 different concentrations. The compound diluted in 100% DMSO was then diluted 25-fold in 1× kinase buffer. 2.5 μL of the diluted compound solution and 2.5 μL of PI3Kα kinase solution were added to each well of the 384-well plate. The reaction was initiated by adding 5 μL of substrate solution to each well, with a final reaction volume of 10 μL. The ATP concentration was 25 μM, the PIP2 concentration was 50 μM, and the PI3Kα kinase concentration was 1.65 nM. The 384-well plate was incubated at room temperature in the dark for 1 hour, followed by the addition of 10 μL of Kinase-Glo to each well. TM The reaction was terminated with reagents, incubated for 15 minutes, and then the cold light was read on an EnVision 2104 multi-label microplate reader.

[1041] The inhibition percentage is calculated based on the following formula:

[1042] Inhibition % = 100 – (max-sample RLU) / (max-min) * 100%

[1043] Where sample RLU is the cold light reading at a given compound concentration, min refers to the reading of the DMSO control, and max refers to the reading of the enzyme-free control. The IC50 of the compound is calculated using the XLfit program in Excel. 50 The values ​​are shown in Table 1.

[1044] Experimental Example 2: HDAC1 Activity Test

[1045] The effect of the compound on HDAC1 activity was tested in vitro. Recombinant full-length HDAC1 was purchased from BPSBiosciences. 384-well plates were purchased from Perkin Elmer. The compound was dissolved in DMSO to prepare a 10 mM stock solution. Tris buffer was used as the test buffer, and both the compound stock solution and the HDAC1 stock solution were diluted to the appropriate concentrations with this buffer. The substrate solution contained trypsin and Ac peptide. In each well of the 384-well plate, 15 μL of HDAC1 solution and the diluted compound solution were added, and the plates were incubated at room temperature for 15 minutes. Then, 10 μL of the substrate solution was added, and the plates were incubated at room temperature for 1 hour. The 384-well plates were placed in a Synergy MX multi-plate reader, and the fluorescence values ​​at an excitation wavelength of 355 nm and an emission wavelength of 460 nm were read.

[1046] The inhibition percentage is calculated based on the following formula:

[1047] Inhibition % = (max - signal) / (max - min) * 100%

[1048] Where signal is the reading at a given compound concentration, min refers to the reading for the DMSO control, and max refers to the reading for the enzyme-free control. The IC50 of the compound is calculated using the XLfit program in Excel. 50 The values ​​are shown in Table 1.

[1049] The biological activities of PI3Kα and HDAC1 in some embodiments are presented in Table 1 as semi-quantitative results: IC 50 (A) <150nM, 150nM <IC 50 (B) <1000nM, IC 50 (C)>1000nM.

[1050] Table 1: Inhibitory activity against PI3Kα kinase and HDAC1

[1051]

[1052]

[1053] Experimental Example 3

[1054] Logarithmic growth phase HGC27 (human gastric cancer cells) and HCT116 (human colorectal cancer cells) were seeded at 2000 cells / well / 100 μL in 96-well plates and cultured overnight at 37°C. Fresh culture medium containing different concentrations of the test compound and corresponding solvent controls was added to each well, with 100 μL of DMSO (final concentration <0.1%) added. The plates were then cultured at 37°C for another 72 hours. 20 μL of freshly prepared PBS solution containing 5 mg / mL MTS was added to each well and cultured for 4 hours. After mixing with a micro-shaker, the optical density (OD) was measured at a detection wavelength of 490 nm. DMSO-treated tumor cells served as the control group. The inhibition rate of the test compound on tumor cell growth was calculated using the following formula, and the IC50 was calculated according to the median effect equation. 50 :

[1055] Inhibition rate (%) = (mean OD value of control group - mean OD value of drug-treated group) / mean OD value of control group × 100%

[1056] The antiproliferative activity of the embodiments against HGC27 cells and HCT116 cells is presented in Table 2 as semi-quantitative results: IC50 50 (A) <0.5μM, 0.5μM <IC 50 (B) <1.0μM, IC 50 (C)>1.0μM.

[1057] The results are shown in Table 2 below.

[1058] Table 2: Antiproliferative activity against HGC27 and HCT116 cells

[1059]

[1060]

[1061] Experimental results showed that several examples exhibited anti-proliferative activity against HGC27 and HCT116 cells. For HGC27 cells, the IC50 values ​​of Examples 16, 18, 24, 31, 32, and 46 were [data missing]. 50 The value was less than 0.5 μM. For HCT116 cells, the IC50 values ​​for Examples 17, 30, 31, 32, 37, and 38 were... 50 The value is less than 0.5 μM.

[1062] Summary of pharmacological activities:

[1063] Several examples showed strong inhibitory activity against PI3Kα. Several examples showed strong inhibitory activity against HDAC1. In cell-level proliferation inhibition assays, for HGC27 cells, the IC50 values ​​of Examples 16, 18, 24, 31, 32, and 46 were [missing data]. 50The value was less than 0.5 μM. For HCT116 cells, the IC50 values ​​for Examples 17, 30, 31, 32, 37, and 38 were... 50 The value is less than 0.5 μM.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in: R is selected from hydrogen, fluorine, and methoxy groups; A1 is Where m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or A1 is... Where n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and Y is an oxygen atom, a phenyl group, or... Or A1 is Where Z is Where p is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or Z is an oxygen atom, n is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; A2 is Where q is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or A2 is a carbon-carbon double bond; X1, X2, X3, and X4 are each independently selected from hydrogen or fluorine.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, A1 is Where m is 0.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, A1 is Where n is an integer of 0, 1, 2, 3, or 4, and Y is an oxygen atom, a phenyl group, or...

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, A1 is Where Z is Where p is 0 and n is 0 or 1; or Z is an oxygen atom and n is 0 or 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that, R is selected from hydrogen, fluorine, or methoxy.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, X1, X2, X3, and X4 are each independently selected from hydrogen or fluorine.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, A2 is Where q is 0; or A2 is a carbon-carbon double bond.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

9. A method for preparing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, comprising the following steps: (1) The compound shown in Formula A reacts with substituted pyridine-3-boronic acid or substituted pyridine-3-boronic acid pinacol ester via the Suzuki reaction to give the compound shown in Formula B. (2) The compound shown in formula B undergoes a bromination reaction to give the compound shown in formula C; (3) The compound shown in formula C reacts with ammonium formate and formamide to give the compound shown in formula D; (4) Compound D reacts with substituted pyridine-3-boron pinacol ester via a Suzuki reaction to give compound E; (5) The compound shown in formula E is deprotected by the Boc protecting group to obtain the compound shown in formula (I); or (1) The compound shown in formula F reacts with a bromoalkane via a nucleophilic reaction to give the compound shown in formula G; (2) The compound shown in formula G undergoes a hydrolysis reaction to obtain the compound shown in formula H; (3) The compound shown in formula H undergoes a condensation reaction with Boc-protected n-propylhydrazine to obtain the compound shown in formula J. (4) The compound shown in formula J reacts with 4-methylquinazoline via a nucleophilic reaction to give the compound shown in formula K; (5) The compound shown in formula K reacts with substituted pyridine-3-boronic acid or substituted pyridine-3-boronic acid pinacol ester via the Suzuki reaction to give the compound shown in formula L. (6) The compound shown in formula L is deprotected by the Boc protecting group to obtain the compound shown in formula (I); or (1) The compound shown in formula M reacts with a brominated benzyl group via a nucleophilic reaction to give the compound shown in formula N; (2) The compound shown in formula N is deprotected by the tert-butyl protecting group to obtain the compound shown in formula O; (3) The compound shown in formula O and Boc-protected n-propylhydrazine undergo a condensation reaction to obtain the compound shown in formula P. (4) The compound shown in formula P reacts with substituted pyridine-3-boronic acid or substituted pyridine-3-boronic acid pinacol ester via the Suzuki reaction to give the compound shown in formula Q. (5) The compound shown in formula Q is deprotected by the Boc protecting group to obtain the compound shown in formula (I).

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or at least one compound prepared by the method according to claim 9 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable diluent, carrier, and / or excipient.

11. The pharmaceutical composition according to claim 10, characterized in that, The pharmaceutical composition further comprises a pharmaceutically active ingredient other than the compound or a pharmaceutically acceptable salt thereof.

12. Use of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, the compound prepared by the method of claim 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10 or 11 in the preparation of a medicament for the prevention and / or treatment of PI3K-mediated diseases.

13. The use according to claim 12, characterized in that, The PI3K-mediated diseases are selected from one or more of the following: tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases.

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