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

Abstract

The invention belongs to the technical field of medicines, and 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. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to 4-methylquinazoline derivatives, their preparation methods, uses and pharmaceutical compositions. Background Art

[0002] Phosphatidylinositol 3-kinase (PI3K) belongs to the lipid kinase family, which is widely present in cells and participates in the regulation of various cellular functions such as cell proliferation, differentiation, apoptosis, signal transduction, and glucose transport. According to different structures and functions, PI3K can be divided into three major categories: I, II, and III. Among them, the most intensively studied is class I PI3K, which includes four subtypes: α, β, γ, and δ, all of which are heterodimers composed of a regulatory subunit (p85) and a catalytic subunit (p110); PI3Kγ and PI3Kδ are mainly distributed in white blood cells, while the other two subtypes, PI3Kα and PI3Kβ, are widely distributed in various cells. As the main downstream effector of receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR), PI3K catalyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-trisphosphate (PIP3), thereby transmitting the signals of various growth factors and cytokines into the cell. PIP3, as a second messenger in the cell, can activate serine / threonine protein kinase (protein kinase B, AKT) and downstream effectors, including mammalian target of rapamycin (mTOR), thereby regulating various cellular functions.

[0003] The abnormal activation of the PI3K signaling pathway is closely related to the formation and development of various human tumors such as breast cancer, lung cancer, melanoma, and lymphoma. These abnormalities can be caused by gene mutations, including mutations in PI3K itself and other genes related to the PI3K signaling pathway (such as PTEN, AKT, MTOR, etc.). These mutations lead to the continuous activation of the PI3K signaling pathway and promote the abnormal proliferation and survival of tumor cells. Due to the key role of the PI3K signaling pathway in various cancers, it has become an important target for cancer treatment. Targeted drugs against PI3K have been developed and entered clinical trials to inhibit the abnormal activation in the PI3K signaling pathway. Currently, six PI3K inhibitors, namely Idelalisib, Copanlisib, Alpelisib, Duvelisib, Umbralisib, and Leniolisib, have been approved by the FDA for marketing; in addition, there are multiple PI3K inhibitors in the clinical trial stage, and their indications include not only tumors but also autoimmune diseases such as psoriasis, rheumatoid arthritis, ulcerative colitis, and other diseases related to class I PI3K such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

[0004] Therefore, the development of new PI3K inhibitors is expected to provide new options and treatments for the treatment of various malignant diseases, including tumors. Summary of the Invention

[0005] The present invention aims to provide a novel class of PI3K inhibitors, as well as methods for their preparation, pharmaceutical compositions, and uses. These PI3K inhibitors exhibit potent inhibitory activity against PI3K, thereby providing improved preventive and / or therapeutic effects against PI3K-mediated diseases such as tumors, autoimmune diseases, kidney disease, cardiovascular disease, inflammation, metabolic / endocrine dysfunction, or neurological disorders, while also reducing adverse reactions and the development of drug resistance. Furthermore, the inventors have discovered that these inhibitors exhibit a limited inhibitory effect against BRD4.

[0006] In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0007] In one aspect, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts:

[0008]

[0009] in:

[0010] R is selected from 2,4-difluorophenylsulfonylamino, fluorine, hydrogen, 2-chloro-4-fluorophenylsulfonylamino, 5-chlorothiophene 2-sulfonylamino;

[0011] A is oxygen or

[0012] B is wherein n is an integer from 1 to 15;

[0013] Or, B is wherein m is an integer from 1 to 8;

[0014] Or, B is wherein o and p are independently 0, 1, 2 or 3, and q and r are independently 1, 2 or 3;

[0015] Or, B is wherein q, r, s, and t are independently 1, 2, or 3;

[0016] Or, B is Wherein a is an integer of 0-5, b is 0 or 1, and the R1 group is selected from the groups represented by the following structures (R1-1)-(R1-15):

[0017]

[0018] Alternatively, B is wherein q and r are independently 1, 2 or 3, and the R2 group is wherein c is an integer from 1 to 5; or the R2 group is selected from the groups represented by the following formulae (R2-1)-(R2-3):

[0019]

[0020] In a preferred embodiment, the present invention provides a compound of formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, wherein: A is oxygen, B is

[0021] wherein:

[0022] n is an integer from 2 to 8;

[0023] m is an integer from 1 to 6;

[0024] o and p, q and r, s and t are independently 1 or 2 simultaneously;

[0025] a and b are 0, and the R1 group is Alternatively, a is 3, b is 0, and the R1 group is Alternatively, a is 3, b is 1, and the R1 group is

[0026] The R2 group is wherein c is 2, 3 or 4; or the R2 group is selected from

[0027] In a preferred embodiment, the present invention provides a compound of formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, wherein: A is B is wherein:

[0028] q and r are 1 or 2 simultaneously;

[0029] a is 0, b is 1, and the R1 group is

[0030] In a further preferred embodiment, R is 2,4-difluorophenylsulfonamido. Specifically, the compounds according to the present invention are selected from the following compounds:

[0031]

[0032]

[0033] The first aspect of the technical solution of the present invention provides a preparation method of the compound, its stereoisomers, geometric isomers, and tautomers, which includes the following steps:

[0034]

[0035] (1) Using compound A as the starting material, preparing compound B through a nucleophilic substitution reaction or Mitsunobu reaction;

[0036] (2) Reacting compound B with a substituted pyridine-3-boronic acid pinacol ester through a Suzuki reaction to prepare compound C;

[0037] (3) Reacting compound C with trifluoroacetic acid to prepare compound D;

[0038] (4) Reacting compound D with a carboxylic acid through a condensation reaction to prepare the compound of formula (I) or a pharmaceutically acceptable salt; wherein, R is 2,4-difluorophenylsulfonylamino.

[0039] The second aspect of the technical solution of the present invention further provides a second method for preparing the compound, its stereoisomers, geometric isomers, and tautomers described in the first aspect, which includes the following steps:

[0040]

[0041] (1) Using compound A as the starting material, preparing compound E through a nucleophilic substitution reaction with tert-butyl bromobutyrate;

[0042] (2) Reacting compound E with a substituted pyridine-3-boronic acid pinacol ester through a Suzuki reaction to prepare compound F;

[0043] (3) Reacting compound C with trifluoroacetic acid to prepare compound G;

[0044] (4) Reacting compound G with a carboxylic acid through a condensation reaction to prepare compound H;

[0045] (5) Reacting compound H with trifluoroacetic acid to prepare compound I;

[0046] (6) Reacting compound I with a carboxylic acid through a condensation reaction to prepare the compound of formula (I) or a pharmaceutically acceptable salt; wherein, R is 2,4-difluorophenylsulfonylamino.

[0047] The second aspect of the technical solution of the present invention further provides a third method for preparing the compound, its stereoisomers, geometric isomers, and tautomers described in the first aspect, which includes the following steps:

[0048]

[0049] (1) Using compound J as the starting material, reacting with substituted pyridine-3-boronic acid pinacol ester to prepare compound K through Suzuki reaction;

[0050] (2) Reacting compound K with trifluoroacetic acid to prepare compound L;

[0051] (3) Reacting compound L with a ketone through reductive amination to prepare compound M;

[0052] (4) Reacting compound M with trifluoroacetic acid to prepare compound N;

[0053] (6) Reacting compound N with a carboxylic acid through condensation reaction to prepare the compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein, R is 2,4-difluorophenylsulfonylamino.

[0054] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises the compound described in the first aspect, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier and / or excipient; preferably, the pharmaceutical composition further comprises one or more pharmaceutical active ingredients for preventing and / or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunctions or neurological diseases other than the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and / or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunctions or neurological diseases.

[0055] In another aspect, the present invention also provides a pharmaceutical preparation, which comprises at least one of the above-mentioned compounds, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts and optionally a pharmaceutically acceptable carrier or / and excipient; preferably, the pharmaceutical preparation is selected from the following pharmaceutical dosage forms: parenteral administration preparations, such as injection solutions or suspensions; enteral administration preparations, such as oral preparations, such as tablets or capsules; topical administration preparations, such as lotions, gels, ointments, emulsions, nasal administration preparations, suppositories, transdermal administration preparations or ophthalmic preparations.

[0056] In another aspect, the present invention also provides the use of the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a drug for preventing and / or treating PI3K-mediated diseases; preferably, the PI3K-mediated diseases are selected from tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunctions or neurological diseases. In other words, the present invention also provides a method for preventing and / or treating PI3K-mediated diseases, the method comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of the compound or its pharmaceutically acceptable salt, or the pharmaceutical composition; preferably, the PI3K-mediated diseases are selected from tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunctions or neurological diseases.

[0057] In another aspect, the present invention also provides the use of the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a drug for preventing and / or treating BRD4-mediated diseases; preferably, the BRD4-mediated diseases are selected from tumors, inflammatory diseases, obesity, fatty liver (NASH (non-alcoholic steatohepatitis) or otherwise), diabetes, arteriosclerosis, arterial stent occlusion, heart failure, cachexia, graft-versus-host disease, bromodomain-related infectious diseases, parasites, malaria, treatment of trypanosomes, and compositions and methods for reducing male fertility. In other words, the present invention also provides a method for preventing and / or treating BRD4-mediated diseases, the method comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of the compound or its pharmaceutically acceptable salt, or the pharmaceutical composition; preferably, the BRD4-mediated diseases are selected from tumors, inflammatory diseases, obesity, fatty liver (NASH (non-alcoholic steatohepatitis) or otherwise), diabetes, arteriosclerosis, arterial stent occlusion, heart failure, cachexia, graft-versus-host disease, bromodomain-related infectious diseases, parasites, malaria, treatment of trypanosomes, and compositions and methods for reducing male fertility.

[0058] The present invention achieves the following beneficial technical effects: The compound of the present invention shows significant inhibitory activity against PI3Kα in in vitro enzyme activity tests, with an IC 50 in the range of 0.1 - 10 nM; the compound of the present invention shows relatively significant inhibitory activity against BRD4 in in vitro enzyme activity tests, with an IC 50 in the range of 20 - 20000 nM. The compound of the present invention can act as a dual inhibitor of PI3K / BRD4.

[0059] Some of the terms used in the present invention are defined below. Other undefined terms have meanings commonly known to those skilled in the art.

[0060] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0061] "Sulfonylamino" refers to the group R b -S(=O)2-NH-, where each R b are independently substituted with 2,4-difluorophenyl.

[0062] 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 a target protein or polypeptide.

[0063] The term "tumor" includes, but is not limited to, solid tumors and hematologic tumors, such as cancer of the bladder, bone or blood, brain, breast, cervix, colon, endometrium, esophagus, eye, head and neck, kidney, liver, lymph nodes, lung, oral cavity, ovary, pancreas, prostate, rectum, stomach, testicle, larynx, and uterus.

[0064] The term "effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application described below, including but not limited to disease treatment. The effective amount may vary depending on: the intended application (in vivo or in vitro); the individual and disease condition being treated, e.g., the individual's weight and age, the severity of the disease; the mode of administration, etc. The effective amount can be readily determined by one of ordinary skill in the art.

[0065] "Optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with halogen" means that halogen may but need not be present, and that the description includes instances where the alkyl is substituted with halogen and instances where the alkyl is not substituted with halogen.

[0066] The compounds of the present invention also include isotope-labeled compounds thereof. 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 an atomic mass number different from the atomic mass number commonly found in nature. Examples of isotopes suitable for the present invention include, but are not limited to: isotopes of hydrogen 2 H and 3 H; isotope of carbon 11 C. 13 C and 14 C; isotope of chlorine 36 Cl; isotopes of fluorine 18 F; isotope of iodine 123 I and 125 I; Isotopes of nitrogen13 N and 15 N; oxygen isotopes 15 O, 17 O and 18 O; phosphorus isotopes 32 P and sulfur isotopes 35 S.

[0067] Also included within the scope of the present invention are various solvates and hydrates of the compounds or salts thereof of the present invention, as well as their polymorphs.

[0068] The term "solvate" refers to a compound that further includes a solvent, either stoichiometric or non-stoichiometric, bound by non-covalent intermolecular forces. The solvate may 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 complexes that may include, for example, from 1 to about 100, or from 1 to about 10, or from 1 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.

[0069] Prodrugs of the compounds of the present invention are also included within the scope of the present invention. Certain derivatives of the compounds of the present invention have weak or no pharmacological activity per se, but when these derivatives are administered in vivo or to the body, they can be converted, for example, by hydrolysis cleavage, into the compounds of the present invention having pharmacological activity, and these derivatives are called "prodrugs". Further information on the use 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).

[0070] The compounds of the present invention include pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salts" refers to salts that are pharmaceutically acceptable and have 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 of the present invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0071] When the compounds of the present invention are used as drugs, they are usually administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier, diluent, or excipient are also included within the scope of the present invention. The carriers, adjuvants, and excipients used herein include any and all solvents, diluents, or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. suitable for the desired specific dosage form. 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, various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed, the contents of which are incorporated herein by reference.

[0072] The composition according to the present invention can be administered by any route suitable for the condition to be treated. In particular, it can be administered in the following forms: parenterally, for example in the form of an injectable solution or suspension; enterally, for example orally, for example in the form of tablets or capsules; topically, for example in the form of a lotion, gel, ointment or emulsion or in the form of a nasal or rectal suppository. Topical administration is, for example, administration to the skin. Another form of topical administration is administration to the eye.

[0073] The pharmaceutical composition can be administered in solid, semi-solid, liquid or gaseous form, or can be in the form of a dry powder, such as a lyophilized form. The pharmaceutical composition can be packaged in a form convenient for delivery, including, for example, solid dosage forms such as capsules, cachets, tablets, gelatin, paper, tablets, suppositories, pellets, pills, lozenges and troches. The type of packaging will generally depend on the route of administration. Implantable sustained-release formulations and transdermal formulations are also covered.

[0074] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene block copolymers, lanolin, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; tragacanth 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; diols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants can also be present in the composition, at the discretion of the formulator.

[0075] The compounds of the present invention can be used alone or in combination with other therapeutic agents for treating the diseases or disorders (such as cancer) described in the present invention. In certain embodiments, the compounds of the present invention are combined with a second compound having anti-highly proliferative properties or for treating highly proliferative diseases (such as cancer) in a pharmaceutical combination formulation, or in an administration regimen as combination therapy. The second compound of the pharmaceutical combination formulation or the dosing regimen preferably has an activity complementary to that of the compounds of the present invention so that they do not have an adverse effect on each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of the present invention are combined with other anti-tumor drugs.The anti-tumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, carmustine; metal platinum-based drugs, including but not limited to carboplatin, cisplatin, oxaliplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, irinotecan; antibiotics, including but not limited to annamycin, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, plicamycin; anti-microtubule or anti-mitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, doxorubicin; anti-metabolites, including but not limited to fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine; antibodies, including but not limited to Herceptin, bevacizumab; hormones, including but not limited to letrozole, vorazole, tamoxifen, toremifene, fulvestrant, flutamide, nilutamide, triptorelin; kinase inhibitors, EGFR kinase inhibitors, including but not limited to gefitinib, erlotinib, lapatinib, afatinib; VEGFR inhibitors, including but not limited to sorafenib, regorafenib, 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, including but not limited to ibrutinib; B-RAF inhibitors, including but not limited to vemurafenib; cyclin-dependent kinase CDK4 / 6 inhibitors, palbociclib; mTOR inhibitors, including but not limited to rapamycin, everolimus; deacetylase inhibitors, including but not limited to vorinostat; PD1 / PDL1 antibodies, Keytruda (pembrolizumab), Opdivo (nivolumab).

[0076] The fourth aspect of the technical solution of the present invention is to provide the use of the compound described in the first aspect, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition described in the third aspect in the preparation of a drug for preventing and / or treating PI3K-mediated diseases.

[0077] The PI3K-mediated diseases include tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic disorders, endocrine disorders or neurological diseases. Detailed implementation manners

[0078] The present invention will be further described in detail below in conjunction with the specific implementation manners. The examples given are only for clarifying the present invention, rather than limiting the scope of the present invention.

[0079] Examples

[0080] Example 1: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethyl)acetamide

[0081]

[0082] Step 1: Synthesis of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide

[0083]

[0084] 2,4-Difluorobenzenesulfonyl chloride (5.102 g, 24 mmol, 1.20 equiv) was added to a mixed solution of 5-bromo-2-methoxypyridin-3-amine (4.061 g, 20 mmol, 1.00 equiv), DMAP (244 mg, 2 mmol, 0.10 equiv), and pyridine (2.40 mL, 30 mmol, 1.50 equiv) in dichloromethane (50 mL). The mixture was stirred overnight at 25 °C under an argon atmosphere. Then the solvent was removed under reduced pressure, and purification by silica gel column chromatography (EA:PE = 1:5) gave the product as a white solid (3.792 g, yield 50%). N-(5-Bromo-2-methoxy-3-pyridinyl)-2,4-difluorobenzenesulfonamide (3.792 g, 10 mmol, 1.0 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.050 g, 12 mmol, 1.20 equiv), and potassium acetate (1.960 g, 20 mmol, 2.00 equiv) were dissolved in 1,4-dioxane (40 mL) and degassed, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (731 mg, 1 mmol, 0.10 equiv) was added. The resulting reaction mixture was degassed and backfilled with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 5 h until the reaction was complete. Then the solvent was removed under reduced pressure, and purification by silica gel column chromatography (EA:PE = 1:5) gave the product as a white solid (2.131 g, yield 50%).

[0085] Step 2: Synthesis of tert-butyl (2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethyl)carbamate

[0086]

[0087] At room temperature, tert-butyl (2-bromoethyl)carbamate (268 mg, 1.2 mmol, 1.20 equiv) was added to a solution of 6-bromo-4-methylquinazolin-8-ol (239 mg, 1 mmol, 1.00 equiv) and potassium carbonate (552 mg, 4 mmol, 4.00 equiv) in acetonitrile, and then the mixture was stirred at 70 °C for 5 h. The reaction was monitored by TLC and LC-MS. When the raw materials were completely reacted, it was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 4:1) to obtain the product as a pale yellow solid (328 mg, yield 86%).

[0088] 11H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.06 (t, J = 5.6 Hz, 1H), 4.33 - 4.18 (m, 2H), 3.49 - 3.36 (m, 2H), 2.85 (s, 3H), 1.37 (s, 9H).

[0089] Step 3: Synthesis of tert-butyl (2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethyl)carbamate

[0090]

[0091] Dissolve tert-butyl (2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethyl)carbamate (190 mg, 0.5 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (256 mg, 0.6 mmol, 1.20 equiv) and 2N potassium carbonate (207 mg, 1.5 mmol, 3.00 equiv) in 1,4-dioxane (40 mL) and degas, then add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (37 mg, 0.05 mmol, 0.10 equiv). Degas the resulting reaction mixture and backfill with argon (three cycles), then stir in an argon atmosphere at 100 °C for 5 h until the reaction is complete. Then remove the solvent under reduced pressure and purify by silica gel column chromatography (EA:PE = 3:5) to obtain the product as a pale yellow solid (240 mg, yield 80%).

[0092] 1 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.05 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.5, 6.2 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.57 (ddd, J = 10.4, 9.1, 2.5 Hz, 1H), 7.26 - 7.16 (m, 1H), 7.10 (t, J = 5.7 Hz, 1H), 4.35 - 4.28 (m, 2H), 3.66 (s, 3H), 3.44 (td, J = 7.4, 1.5 Hz, 2H), 2.94 (s, 3H), 1.37 (s, 9H).

[0093] Step 4: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethyl)acetamide

[0094]

[0095] At room temperature, dissolve tert-butyl (2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethyl)carbamate (200 mg, 0.3 mmol, 1.0 equiv) in 2 mL of dichloromethane solution, and slowly add trifluoroacetic acid (68 μL, 0.9 mmol, 3.00 equiv). Stir at room temperature for 1 hour. Then remove the solvent and the remaining trifluoroacetic acid under reduced pressure to obtain a yellow solid (131 mg, yield 90%). At 0 °C, add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (154 mg, 0.4 mmol, 1.50 equiv) to a dichloromethane solution of N-(5-(8-(2-aminoethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (130 mg, 0.27 mmol, 1.00 equiv), (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (119 mg, 0.3 mmol, 1.10 equiv) and DIPEA (140 μL, 0.8 mmol, 3.00 equiv). After stirring for 30 min, stir at room temperature for 8 h, and monitor the reaction by TLC and LC-MS. When the raw materials are completely reacted, wash the reaction solution with water and saturated sodium chloride solution three times each. The organic phase is recovered, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (EA:PE = 3:2) to obtain the product as a pale yellow solid (0.186 mg, yield 78%).

[0096] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.72 - 8.67 (m, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.89 - 7.76 (m, 2H), 7.60 (s, 1H), 7.46 (t, J = 10.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.2 Hz, 3H), 4.54 (dd, J = 8.6, 5.5 Hz, 1H), 4.36 (s, 2H), 3.70 (s, 3H), 3.46 - 3.15 (m, 4H), 2.95 (s, 3H), 2.57 (s, 3H), 2.38 (s, 3H), 1.52 (s, 3H).

[0097] Example 2: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)propyl)acetamide

[0098]

[0099] Step 1: Synthesis of tert-Butyl (3-((6-bromo-4-methylquinazolin-8-yl)oxy)propyl)carbamate

[0100]

[0101] According to the method of Step 2 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 3-bromopropylcarbamate as a yellow solid (349 mg, yield 88%).

[0102] 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 2.0 Hz, 1H), 7.97 (q, J = 2.2 Hz, 1H), 7.50 (q, J = 2.0 Hz, 1H), 6.97 (t, J = 5.7 Hz, 1H), 4.21 (t, J = 6.1 Hz, 2H), 3.17 (q, J = 6.4 Hz, 2H), 2.86 (s, 3H), 1.95 (p, J = 6.5 Hz, 2H), 1.37 (s, 9H).

[0103] Step 2: Synthesis of tert-Butyl (3-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)propyl)carbamate

[0104]

[0105] According to the method of Step 3 in Example 1, the title compound was synthesized as a pale yellow solid (237 mg, yield 77%) from tert-butyl (3-((6-bromo-4-methylquinazolin-8-yl)oxy)propyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide.

[0106] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.07 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.76 (td, J = 8.6, 6.3 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.26 - 7.17 (m, 1H), 7.01 (t, J = 5.3 Hz, 1H), 4.31 (t, J = 6.1 Hz, 2H), 3.66 (s, 3H), 3.21 (q, J = 6.5 Hz, 2H), 2.95 (s, 3H), 1.99 (p, J = 6.5 Hz, 2H), 1.37 (s, 9H).

[0107] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-((6-(5-((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)propyl)acetamide

[0108]

[0109] According to the method of Step 4 in Example 1, first, a yellow solid (178 mg, yield 90%) was obtained by reacting tert-butyl (3-((6-(5-((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)propyl)carbamate with trifluoroacetic acid. Then, the title compound was synthesized as a pale yellow solid (217 mg, yield 70%) from N-(5-(8-(3-aminopropoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid.

[0110] 1 1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.57 (t, J = 5.2 Hz, 2H), 8.15 (s, 1H), 8.01 (s, 1H), 7.94 (td, J = 8.5, 6.3 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.52 (s, 4H), 7.35 (td, J = 8.5, 2.5 Hz, 1H), 4.70 (dd, J = 8.4, 5.9 Hz, 1H), 4.57 - 4.47 (m, 2H), 3.83 (s, 3H), 3.70 - 3.44 (m, 4H), 3.10 (s, 3H), 2.71 (s, 3H), 2.65 (s, 3H), 2.50 (s, 3H), 1.67 (s, 3H).

[0111] Example 3: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyl)acetamide

[0112]

[0113] Step 1: Synthesis of tert-Butyl (4-((6-bromo-4-methylquinazolin-8-yl)oxy)butyl)carbamate

[0114]

[0115] According to the method of Step 2 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 4-bromobutylcarbamate as a yellow solid (328 mg, yield 80%).

[0116] 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 6.90 (t, J = 5.8 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.08 - 2.96 (m, 2H), 2.86 (s, 3H), 1.82 (dq, J = 8.6, 6.5 Hz, 2H), 1.65 - 1.50 (m, 2H), 1.37 (s, 9H).

[0117] Step 2: Synthesis of tert-Butyl (4-((6-(5-((2,4-Difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyl)carbamate

[0118]

[0119] According to the method of Step 3 in Example 1, the title compound was synthesized as a yellow solid (261 mg, yield 83%) from tert-Butyl (4-((6-bromo-4-methylquinazolin-8-yl)oxy)butyl)carbamate and 2,4-Difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)phenyl)sulfonamide.

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.06 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.6, 6.2 Hz, 1H), 7.68 - 7.53 (m, 2H), 7.26 - 7.15 (m, 1H), 6.92 (t, J = 5.8 Hz, 1H), 4.28 (t, J = 6.4 Hz, 2H), 3.66 (s, 3H), 3.03 (p, J = 8.0, 7.4 Hz, 2H), 2.94 (s, 3H), 1.89 - 1.81 (m, 2H), 1.69 - 1.59 (m, 2H), 1.36 (s, 9H).

[0121] Step 3: Synthesis of (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-((6-(5-((2,4-Difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyl)acetamide

[0122]

[0123] According to the method of Step 4 in Example 1, tert-butyl 4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyl)carbamate reacted with trifluoroacetic acid to obtain a yellow solid (227 mg, yield 77%). Then, N-(5-(8-(4-aminobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (197 mg, yield 80%).

[0124] 1 H NMR (500 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.35 (t, J = 5.9 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.77 (td, J = 8.5, 6.2 Hz, 1H), 7.62 - 7.50 (m, 2H), 7.44 - 7.34 (m, 4H), 7.21 (td, J = 8.6, 2.7 Hz, 1H), 4.59 - 4.51 (m, 1H), 4.31 (t, J = 6.5 Hz, 2H), 3.66 (s, 3H), 3.35 - 3.26 (m, 2H), 3.24 - 3.16 (m, 2H), 2.94 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 2.00 - 1.87 (m, 2H), 1.78 - 1.70 (m, 2H), 1.57 (s, 3H).

[0125] Example 4: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(5-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)pentyl)acetamide

[0126]

[0127] Step 1: Synthesis of tert-butyl (5-((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)carbamate

[0128]

[0129] According to the method of Step 2 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 5-bromopentylcarbamate as a yellow solid (360 mg, yield 85%).

[0130] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.93 (s, 1H), 7.50 (s, 1H), 6.80 (t, J = 5.7 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 2.94 (d, J = 6.5 Hz, 2H), 2.85 (s, 3H), 1.85 - 1.80 (m, 2H), 1.48 - 1.44 (m, 4H), 1.36 (s, 9H).

[0131] Step 2: Synthesis of tert-butyl (5-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)pentyl)carbamate

[0132]

[0133] According to the method of Step 3 in Example 1, the title compound was synthesized from tert-butyl (5-((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (283 mg, yield 88%).

[0134] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.06 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.77 (td, J = 8.6, 6.2 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.26 - 7.17 (m, 1H), 6.81 (t, J = 5.7 Hz, 1H), 4.26 (t, J = 6.4 Hz, 2H), 3.66 (s, 3H), 3.00 - 2.92 (m, 5H), 1.89 - 1.83 (m, 2H), 1.49 (p, J = 3.5 Hz, 4H), 1.35 (s, 9H).

[0135] Step 3: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(5-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)pentyl)acetamide

[0136]

[0137] According to the method of Step 4 in Example 1, tert-butyl (5-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)pentyl)carbamate was first reacted with trifluoroacetic acid to obtain a yellow solid (131 mg, yield 90%). Then, N-(5-(8-((5-aminopentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (187 mg, yield 75%).

[0138] 1 H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.24 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.78 (td, J = 8.6, 6.3 Hz, 1H), 7.55 - 7.52 (m, 2H), 7.42 - 7.38 (m, 4H), 7.20 (td, J = 8.5, 2.5 Hz, 1H), 4.51 (dd, J = 8.3, 5.9 Hz, 1H), 4.30 - 4.19 (m, 2H), 3.67 (s, 3H), 3.31 - 3.11 (m, 5H), 2.94 (s, 3H), 2.56 (s, 3H), 2.36 (s, 3H), 1.92 - 1.88 (m, 2H), 1.59 - 1.54 (m, 7H).

[0139] Example 5: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(6-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexyl)acetamide

[0140]

[0141] Step 1: Synthesis of tert-butyl (6-((6-bromo-4-methylquinazolin-8-yl)oxy)hexyl)carbamate

[0142]

[0143] [[ID=|11]]According to the method of Step 2 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 6-bromohexylcarbamate as a yellow solid (359 mg, yield 82%).

[0144] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 6.77 (t, J = 5.8 Hz, 1H), 4.18 (t, J = 6.5 Hz, 2H), 2.91 (q, J = 6.5 Hz, 2H), 2.86 (s, 3H), 1.88 - 1.77 (m, 2H), 1.36 (s, 15H).

[0145] Step 2: Synthesis of tert-butyl (6-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexyl)carbamate

[0146]

[0147] According to the method of Step 3 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline, tert-butyl 6-bromohexylcarbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)phenyl)sulfonamide as a yellow solid (253 mg, yield 77%).

[0148] 11H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.06 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.6, 6.2 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.26 - 7.17 (m, 1H), 6.77 (t, J = 5.6 Hz, 1H), 4.26 (t, J = 6.4 Hz, 2H), 3.66 (s, 3H), 2.94 (s, 5H), 1.86 (p, J = 6.7 Hz, 2H), 1.53 - 1.32 (m, 15H).

[0149] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(6-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexyl)acetamide

[0150]

[0151] According to the method of Step 4 in Example 1, tert-butyl (6-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexyl)carbamate was first reacted with trifluoroacetic acid to obtain a yellow solid (116 mg, yield 77%). Then, N-(5-(8-((6-aminohexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (205 mg, yield 81%).

[0152] 11H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.20 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.78 (td, J = 8.5, 6.3 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.49 - 7.38 (m, 4H), 7.20 (td, J = 8.5, 2.5 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.26 (t, J = 6.7 Hz, 2H), 3.67 (s, 3H), 3.29 - 3.05 (m, 4H), 2.94 (s, 3H), 2.57 (s, 3H), 2.35 (s, 3H), 1.87 (h, J = 6.5 Hz, 2H), 1.58 (s, 3H), 1.58 - 1.37 (m, 6H).

[0153] Example 6: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(7-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptyl)acetamide

[0154]

[0155] Step 1: Synthesis of tert-Butyl (7-((6-bromo-4-methylquinazolin-8-yl)oxy)heptyl)carbamate

[0156]

[0157] According to the method of Step 2 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 7-bromoheptylcarbamate as a yellow solid (375 mg, yield 83%).

[0158] 1 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 6.74 (t, J = 5.8 Hz, 1H), 4.17 (t, J = 6.5 Hz, 2H), 2.93 - 2.87 (m, 2H), 2.86 (s, 3H), 1.82 (p, J = 6.7 Hz, 2H), 1.54 - 1.41 (m, 2H), 1.41 - 1.19 (m, 15H).

[0159] Step 2: Synthesis of tert-butyl (7-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptyl)carbamate

[0160]

[0161] According to the method of Step 3 in Example 1, the title compound was synthesized from tert-butyl (7-((6-bromo-4-methylquinazolin-8-yl)oxy)heptyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (267 mg, yield 80%).

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.76 (td, J = 8.6, 6.2 Hz, 1H), 7.63 - 7.53 (m, 3H), 7.21 (td, J = 8.3, 2.6 Hz, 1H), 4.27 (t, J = 6.5 Hz, 2H), 3.92 (s, 2H), 3.66 (s, 3H), 3.33 (s, 3H), 2.95 (s, 3H), 2.91 (q, J = 6.9 Hz, 3H), 1.92 - 1.81 (m, 2H), 1.38 - 1.33 (m, 12H).

[0163] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(7-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptyl)acetamide

[0164]

[0165] According to the method in step 4 of Example 1, tert-butyl (7-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptyl)carbamate was first reacted with trifluoroacetic acid to obtain a yellow solid (124 mg, yield 90%). Then, N-(5-(8-((6-aminohexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (162 mg, yield 70%).

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.20 - 8.12 (m, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.6, 6.3 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.50 - 7.38 (m, 5H), 7.20 (td, J = 8.5, 2.5 Hz, 1H), 4.50 (dd, J = 8.2, 5.9 Hz, 1H), 4.26 (t, J = 6.5 Hz, 2H), 3.67 (s, 3H), 3.30 - 3.03 (m, 3H), 2.94 (s, 3H), 2.58 (s, 3H), 2.38 (s, 3H), 1.86 (p, J = 6.7 Hz, 2H), 1.60 (s, 3H), 1.56 - 1.27 (m, 9H).

[0167] Example 7: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octyl)acetamide

[0168]

[0169] Step 1: Synthesis of tert-butyl (8-((6-bromo-4-methylquinazolin-8-yl)oxy)octyl)carbamate

[0170]

[0171] According to the method of step 2 in Example 1, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 8-bromooctylcarbamate as a yellow solid (419 mg, yield 90%).

[0172] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 6.76 (t, J = 5.6 Hz, 1H), 4.17 (t, J = 6.5 Hz, 2H), 2.90 (q, J = 6.6 Hz, 2H), 2.85 (s, 3H), 1.88 - 1.77 (m, 2H), 1.38 - 1.34 (m, 19H).

[0173] Step 2: Synthesis of tert-butyl (8-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octyl)carbamate

[0174]

[0175] According to the method of step 3 in Example 1, the title compound was synthesized from tert-butyl (8-((6-bromo-4-methylquinazolin-8-yl)oxy)octyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (250 mg, yield 73%).

[0176] 1 H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.92 - 7.82 (m, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.34 (s, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.01 - 6.89 (m, 2H), 5.29 (s, 1H), 4.26 (t, J = 6.8 Hz, 2H), 3.96 (s, 3H), 3.48 (s, 2H), 3.13 - 3.06 (m, 2H), 2.97 (s, 3H), 2.11 - 1.98 (m, 2H), 1.57 - 1.51 (m, 2H), 1.50 - 1.28 (m, 15H).

[0177] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octyl)acetamide

[0178]

[0179] According to the method of Step 4 in Example 1, tert-butyl (8-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octyl)carbamate was first reacted with trifluoroacetic acid to obtain a yellow solid (142 mg, yield 90%). Then, N-(5-(8-((8-aminooctyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (176 mg, yield 75%).

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.06 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.18 (t, J = 5.6 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.76 (td, J = 8.5, 6.2 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.49 - 7.37 (m, 4H), 7.21 (td, J = 8.5, 2.5 Hz, 1H), 4.50 (dd, J = 8.2, 6.0 Hz, 1H), 4.25 (t, J = 6.5 Hz, 2H), 3.66 (s, 3H), 3.30 - 3.05 (m, 3H), 2.95 (s, 3H), 2.58 (s, 3H), 2.36 (s, 3H), 1.87 (t, J = 7.3 Hz, 2H), 1.59 (s, 3H), 1.55 - 1.30 (m, 11H).

[0181] Example 8: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethyl)acetamide

[0182]

[0183] Step 1: Synthesis of tert-butyl (2-(2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethoxy)ethyl)carbamate

[0184]

[0185] To a solution of 6-bromo-4-methyl-8-hydroxyquinazoline (0.24 g, 1.0 mmol, 1.0 equiv) and tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (246 mg, 1.2 mmol, 1.2 equiv) in tetrahydrofuran (15 ml) was added dropwise triphenylphosphine (393 mg, 1.5 mmol, 1.5 equiv) and diethyl azodicarboxylate (208 mg, 1.2 mmol, 1.2 equiv) in tetrahydrofuran (15 ml) at 0°C under an argon atmosphere. After 30 minutes of addition, the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC and LC-MS. Upon completion, the reaction mixture was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and concentrated. The crude product was further purified by column chromatography (EA / DCM = 3 / 7) to give 366 mg of pure desired product in an 86% yield.

[0186] 1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),7.93(d,J=1.9Hz,1H),7.52(d,J=1.9Hz,1H),6.85(t,J=5.7Hz,1H),4. 38-4.24(m,2H),3.88-3.81(m,2H),3.51(t,J=6.0Hz,2H),3.13(q,J=5.9Hz,2H),2.84(s,3H),1.34(s,9H).

[0187] Step 2: Synthesis of tert-butyl (2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethyl)carbamate

[0188]

[0189] According to the method of step 3 in Example 1, the title compound was synthesized from tert-butyl (2-(2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethoxy)ethyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (258 mg, yield 80%).

[0190] 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.62 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.31 (td, J = 8.5, 6.3 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.76 (td, J = 8.5, 2.5 Hz, 1H), 6.43 (t, J = 5.8 Hz, 1H), 3.99 - 3.94 (m, 2H), 3.49 - 3.41 (m, 3H), 3.08 (t, J = 6.0 Hz, 2H), 2.87 (s, 2H), 2.68 (q, J = 6.1 Hz, 2H), 2.50 (s, 3H), 0.89 (s, 9H).

[0191] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-((6-(5-((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethyl)acetamide

[0192]

[0193] According to the method of Step 4 in Example 1, tert-butyl (2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethyl)carbamate was first reacted with trifluoroacetic acid to obtain a yellow solid (147 mg, yield 90%). Then, N-(5-(8-(2-(2-aminoethoxy)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (180 mg, yield 72%).

[0194] 1 H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.36 (t, J = 5.7 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.79 (td, J = 8.5, 6.3 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.57 - 7.49 (m, 1H), 7.45 - 7.36 (m, 4H), 7.20 (td, J = 8.5, 2.5 Hz, 1H), 4.55 - 4.49 (m, 1H), 4.48 - 4.38 (m, 2H), 3.94 (t, J = 4.6 Hz, 2H), 3.68 (s, 3H), 3.63 (t, J = 5.8 Hz, 2H), 3.44 - 3.18 (m, 4H), 2.94 (s, 3H), 2.57 (s, 3H), 2.36 (s, 3H), 1.56 (s, 3H).

[0195] Example 9: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)methoxy)ethyl)acetamide

[0196]

[0197] Step 1: Synthesis of tert-butyl (2-(2-(2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethyl)carbamate

[0198]

[0199] According to the method of Step 1 in Example 8, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate as a pale yellow solid (413 mg, yield 88%).

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 6.74 (t, J = 5.8 Hz, 1H), 4.36 - 4.30 (m, 2H), 3.90 - 3.83 (m, 2H), 3.67 - 3.61 (m, 2H), 3.56 - 3.51 (m, 2H), 3.39 (t, J = 6.1 Hz, 2H), 3.09 - 3.03 (m, 2H), 2.86 (s, 3H), 1.35 (s, 9H).

[0201] Step 2: Synthesis of tert-butyl (2-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethyl)carbamate

[0202]

[0203] According to the method of Step 3 in Example 1, the title compound was synthesized from tert-butyl (2-(2-(2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (266 mg, yield 77%).

[0204] 11H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.07 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.6, 6.2 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.58 (ddd, J = 10.5, 9.1, 2.5 Hz, 1H), 7.22 (td, J = 8.2, 2.3 Hz, 1H), 6.74 (t, J = 5.7 Hz, 1H), 4.47 - 4.40 (m, 2H), 3.95 - 3.82 (m, 2H), 3.73 - 3.64 (m, 5H), 3.59 - 3.53 (m, 2H), 3.42 - 3.36 (m, 2H), 3.06 (q, J = 6.0 Hz, 2H), 2.95 (s, 3H), 1.34 (s, 9H).

[0205] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)methoxy)ethyl)acetamide

[0206]

[0207] According to the method of Step 4 in Example 1, first react tert-butyl (2-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethyl)carbamate with trifluoroacetic acid to obtain a yellow solid (159 mg, yield 90%). Then react N-(5-(8-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide with (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[�,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid to synthesize the title compound as a pale yellow solid (199 mg, yield 76%).

[0208] 11H NMR (500 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.46 - 8.43 (m, 1H), 8.29 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.79 (td, J = 8.6, 6.3 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.52 (td, J = 9.8, 2.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.20 (td, J = 8.5, 2.6 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.45 - 4.40 (m, 2H), 3.95 - 3.90 (m, 2H), 3.68 (s, 6H), 3.63 - 3.56 (m, 2H), 3.48 (t, J = 5.9 Hz, 2H), 3.33 - 3.16 (m, 3H), 2.94 (s, 3H), 2.58 (s, 3H), 2.38 (s, 3H), 1.59 (s, 3H).

[0209] Example 10: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)

[0210]

[0211] Step 1: Synthesis of tert-Butyl (2-(2-(2-(2-((6-Bromo-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

[0212]

[0213] According to the method of Step 1 in Example 8, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate as a pale yellow solid (417 mg, yield 81%).

[0214] 11H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 6.73 (t, J = 5.8 Hz, 1H), 4.37 - 4.30 (m, 2H), 3.90 - 3.83 (m, 2H), 3.64 (dd, J = 5.9, 3.6 Hz, 2H), 3.59 - 3.43 (m, 6H), 3.35 (t, J = 6.1 Hz, 2H), 3.04 (q, J = 6.0 Hz, 2H), 2.86 (s, 3H), 1.35 (s, 9H).

[0215] Step 2: Synthesis of tert-butyl (2-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethyl)carbamate

[0216]

[0217] According to the method of Step 3 in Example 1, the title compound was synthesized from tert-butyl (2-(2-(2-(2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (301 mg, yield 82%).

[0218] 1 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.07 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.76 (td, J = 8.6, 6.3 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.62 - 7.54 (m, 1H), 7.26 - 7.17 (m, 1H), 6.74 (t, J = 6.6 Hz, 1H), 4.47 - 4.42 (m, 2H), 3.96 - 3.87 (m, 2H), 3.72 - 3.62 (m, 5H), 3.59 - 3.55 (m, 2H), 3.53 - 3.45 (m, 4H), 3.35 (t, J = 6.1 Hz, 2H), 3.03 (q, J = 6.0 Hz, 2H), 2.96 (s, 3H), 1.34 (s, 9H).

[0219] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)

[0220]

[0221] According to the method of Step 4 in Example 1, first react tert-butyl (2-(2-(2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethoxy)ethoxy)ethyl)carbamate with trifluoroacetic acid to obtain a yellow solid (171 mg, yield 90%). Then synthesize the title compound as a pale yellow solid (197 mg, yield 72%) from N-(5-(8-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid.

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.05 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.27 (t, J = 5.5 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.76 (td, J = 8.6, 6.2 Hz, 1H), 7.71 - 7.54 (m, 2H), 7.49 - 7.36 (m, 4H), 7.21 (td, J = 8.3, 2.5 Hz, 1H), 4.49 (dd, J = 8.1, 5.9 Hz, 1H), 4.43 (dd, J = 5.8, 3.5 Hz, 2H), 3.94 - 3.81 (m, 2H), 3.72 - 3.62 (m, 4H), 3.62 - 3.50 (m, 5H), 3.44 (t, J = 5.9 Hz, 2H), 3.32 - 3.14 (m, 7H), 2.95 (s, 2H), 2.58 (s, 3H), 2.38 (s, 3H), 1.59 (s, 3H).

[0223] Example 11: (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(14-((6-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-3,6,9,12-tetraoxatetradecyl)acetamide

[0224]

[0225] Step 1: Synthesis of tert-butyl (14-((6-bromo-4-methylquinazolin-8-yl)oxy)-3,6,9,12-tetraoxatetradecyl)carbamate

[0226]

[0227] According to the method of Step 1 in Example 8, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl)carbamate as a pale yellow solid (390 mg, yield 70%).

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 6.73 (d, J = 6.1 Hz, 1H), 4.38 - 4.31 (m, 2H), 3.90 - 3.83 (m, 2H), 3.68 - 3.61 (m, 2H), 3.57 - 3.45 (m, 10H), 3.37 - 3.33 (m, 2H), 3.04 (q, J = 6.0 Hz, 2H), 2.87 (s, 3H), 1.36 (s, 9H).

[0229] Step 2: Synthesis of tert-butyl (14-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-3,6,9,12-tetraoxatetradecyl)carbamate

[0230]

[0231] According to the method of step 3 in Example 1, the title compound was synthesized as a yellow solid (315 mg, yield 81%) from tert-butyl (14-((6-bromo-4-methylquinazolin-8-yl)oxy)-3,6,9,12-tetraoxatetradecyl)carbamate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide.

[0232] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.07 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.6, 6.3 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.22 (td, J = 8.6, 2.5 Hz, 1H), 6.73 (t, J = 5.7 Hz, 1H), 4.44 (dd, J = 5.8, 3.5 Hz, 2H), 3.94 - 3.88 (m, 2H), 3.71 - 3.64 (m, 5H), 3.60 - 3.55 (m, 2H), 3.54 - 3.43 (m, 8H), 3.36 - 3.34 (m, 2H), 3.07 - 3.01 (m, 2H), 2.95 (s, 3H), 1.35 (s, 9H).

[0233] Step 3: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(14-((6-(((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-3,6,9,12-tetraoxatetradecyl)acetamide

[0234]

[0235] According to the method of Step 4 in Example 1, tert-butyl (14-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-3,6,9,12-tetraoxatetradecyl)carbamate was reacted with trifluoroacetic acid to obtain a yellow solid (183 mg, 90% yield). The title compound was synthesized as a light yellow solid (186 mg, 65% yield) from N-(5-(8-((14-amino-3,6,9,12-tetrahydrotetradecyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid.

[0236] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.06(s,1H),8.56(d,J=2.4Hz,1H),8.26(t,J=5.7Hz,1H),8.11(d,J=2.4Hz,1H),7 .92(d,J=1.7Hz,1H),7.76(td,J=8.6,6.3Hz,1H),7.64(d,J=1.7Hz,1H),7.58(ddd,J=10.4,9.1,2.5Hz,1H),7.50-7.37(m ,4H),7.26-7.17(m,1H),4.50(dd,J=8.1,6.0Hz,1H),4.47-4.40(m,2H),3.94-3.87(m,2H),3.70-3.64(m,5H),3.60-3.55 (m,2H),3.55-3.48(m,8H),3.43(t,J=5.9Hz,2H),3.33-3.15(m,4H),2.95(s,3H),2.58(s,3H),2.38(s,3H),1.60(s,3H).

[0237] Example 12: (S)-N-(5-(8-((1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0238]

[0239] Step 1: Synthesis of tert-Butyl 3-((6-bromo-4-methylquinazolin-8-yl)oxy)azetidine-1-carboxylate

[0240]

[0241] According to the method of Step 1 in Example 8, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 3-hydroxyazetidine-1-carboxylate as a pale yellow solid (283 mg, yield 72%).

[0242] 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 5.25 (tt, J = 6.4, 3.8 Hz, 1H), 4.43 - 4.39 (m, 2H), 3.96 - 3.89 (m, 2H), 2.87 (s, 3H), 1.39 (s, 9H).

[0243] Step 2: Synthesis of tert-Butyl 3-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)azetidine-1-carboxylate

[0244]

[0245] According to the method of Step 3 in Example 1, the title compound was synthesized from tert-butyl 3-((6-bromo-4-methylquinazolin-8-yl)oxy)azetidine-1-carboxylate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (261 mg, yield 85%).

[0246] 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.09 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.77 (td, J = 8.6, 6.3 Hz, 1H), 7.58 (td, J = 10.0, 9.2, 2.5 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.22 (td, J = 8.5, 2.5 Hz, 1H), 5.39 (dt, J = 6.4, 2.5 Hz, 1H), 4.44 (s, 2H), 3.97 (dd, J = 9.7, 3.9 Hz, 2H), 3.66 (s, 3H), 2.96 (s, 3H), 1.40 (s, 9H).

[0247] Step 3: Synthesis of (S)-N-(5-(8-((1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)azetidin-3-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0248]

[0249] According to the method of Step 5 in Example 1, first react tert-butyl 3-((6-(5-(((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)azetidine-1-carboxylate with trifluoroacetic acid to obtain a yellow solid (138 mg, yield 90%). Then react N-(5-(8-(azetidin-3-yloxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide with (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid to synthesize the title compound as a pale yellow solid (193 mg, yield 80%).

[0250] 1 H NMR (500 MHz, Chloroform-d) δ 9.26 (s, 1H), 8.16 (t, J = 11.5 Hz, 1H), 8.03 (td, J = 8.9, 4.6 Hz, 1H), 7.89 (s, 1H), 7.78 - 7.73 (m, 1H), 7.44 - 7.39 (m, 3H), 7.36 - 7.27 (m, 2H), 7.13 - 7.03 (m, 1H), 6.97 - 6.94 (m, 2H), 5.43 - 5.31 (m, 1H), 5.24 - 5.14 (m, 1H), 4.86 - 4.69 (m, 2H), 4.68 - 4.53 (m, 1H), 4.48 - 4.32 (m, 1H), 3.96 (s, 3H), 3.59 - 3.24 (m, 2H), 3.01 (s, 3H), 2.66 (s, 3H), 2.40 (s, 3H), 1.67 (s, 3H).

[0251] Example 13: (S)-N-(5-(8-((1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0252]

[0253] Step 1: Synthesis of tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylate

[0254]

[0255] According to the method of Step 1 in Example 8, the title compound was synthesized from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 4-hydroxypiperidine-1-carboxylate as a pale yellow solid (329 mg, yield 78%).

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 4.92 (tt, J = 7.8, 3.6 Hz, 1H), 3.77 - 3.67 (m, 2H), 3.23 (t, J = 10.5 Hz, 2H), 2.85 (s, 3H), 2.02 - 1.93 (m, 2H), 1.70 - 1.57 (m, 2H), 1.41 (s, 9H).

[0257] Step 2: Synthesis of tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylate

[0258]

[0259] According to the method of Step 3 in Example 1, the title compound was synthesized from tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylate and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide as a yellow solid (282 mg, yield 88%).

[0260] 11H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.64 - 7.54 (m, 1H), 7.26 - 7.17 (m, 1H), 5.05 (dt, J = 8.0, 4.2 Hz, 1H), 3.79 - 3.71 (m, 2H), 3.66 (s, 3H), 3.26 (s, 2H), 2.95 (s, 3H), 2.04 - 1.97 (m, 2H), 1.74 - 1.62 (m, 2H), 1.40 (s, 9H).

[0261] Step 3: (S)-N-(5-(8-((1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0262]

[0263] According to the method of Step 4 in Example 1, first react tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylate with trifluoroacetic acid to obtain a yellow solid (146 mg, yield 90%). Then, synthesize the title compound from 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperidin-4-yloxy)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid as a pale yellow solid (187 mg, yield 75%).

[0264] 11H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 5.7 Hz, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.82 - 7.75 (m, 2H), 7.62 - 7.40 (m, 6H), 7.21 (t, J = 8.8 Hz, 1H), 5.17 (s, 1H), 4.61 (t, J = 6.8 Hz, 1H), 4.12 - 3.88 (m, 2H), 3.75 - 3.56 (m, 5H), 3.06 (q, J = 7.3 Hz, 1H), 2.96 (s, 3H), 2.60 (s, 3H), 2.41 (s, 3H), 2.12 - 1.85 (m, 2H), 1.79 - 1.53 (m, 4H), 1.16 (t, J = 7.3 Hz, 2H).

[0265] Example 14: (S)-N-(5-(8-(4-(4-(2-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0266]

[0267] Step 1: Synthesis of tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)butanoate

[0268]

[0269] To a mixed solution of 6-bromo-4-methyl-8-hydroxyquinazoline (239 mg, 1.00 mmol, 1.0 equiv) and tert-butyl 4-bromobutanoate (245 mg, 1.10 mmol, 1.1 equiv) in N,N-dimethylformamide (15 mL) was added K2CO3 (414 mg, 3.00 mmol, 3.0 equiv). The reaction mixture was heated at 65 °C for 8 h (overnight). After completion of the reaction was monitored by TLC, the crude mixture was poured into saturated aqueous sodium chloride solution and extracted 5 times with ethyl acetate. The organic phase was collected and further extracted 2 times with water, and dried over anhydrous Na2SO4. The solvent was evaporated to give a residue, which was purified by column chromatography to afford the title compound as a pale yellow solid (339 mg, 89%).

[0270] 11H NMR (400 MHz, Chloroform-d) δ 9.20 (s, 1H), 7.79 (s, 1H), 7.31 (d, J = 1.9 Hz, 1H), 4.25 (t, J = 6.5 Hz, 3H), 2.89 (s, 4H), 2.51 (d, J = 7.1 Hz, 2H), 2.28 (d, J = 6.9 Hz, 2H), 1.47 - 1.40 (s, 9H).

[0271] Step 2: Synthesis of tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butanoate

[0272]

[0273] According to the method of Step 3 in Example 1, tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)butanoate was reacted with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide to give the title compound as a yellow solid (258 mg, yield 86%).

[0274] 1 1H NMR (500 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.88 (td, J = 8.2, 5.8 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.37 - 7.30 (m, 2H), 6.96 (t, J = 8.3 Hz, 2H), 4.33 (t, J = 6.5 Hz, 2H), 3.96 (s, 3H), 2.97 (s, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.30 (p, J = 6.8 Hz, 2H), 1.44 (s, 9H).

[0275] Step 3: Synthesis of (S)-tert-butyl 4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazine-1-carboxylate

[0276]

[0277] According to the method of Step 4 in Example 1, the title compound was synthesized from tert-butyl piperazine-1-carboxylate and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid as a pale yellow solid (150 mg, yield 88%).

[0278] 1 H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.40 (m, 4H), 4.63 - 4.53 (m, 1H), 3.69 - 3.55 (m, 4H), 3.50 - 3.41 (m, 4H), 3.13 (qd, J = 7.3, 4.1 Hz, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H), 1.43 (s, 9H).

[0279] Step 4: Synthesis of (S)-N-(5-(8-(4-(4-(2-(4-(chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0280]

[0281] According to the method of Step 4 in Example 1, first tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butanoate and tert-butyl (S)-4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazine-1-carboxylate were reacted with trifluoroacetic acid respectively to obtain a yellow solid (126 mg, yield 90%). Then (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(piperazin-1-yl)ethan-1-one and 4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butanoic acid were used to synthesize the title compound as a pale yellow solid (215 mg, yield 80%).

[0282] 11H NMR (500 MHz, Chloroform-d) δ 9.20 (d, J = 9.4 Hz, 1H), 8.20 (t, J = 2.4 Hz, 1H), 8.04 (d, J = 3.7 Hz, 1H), 7.93 - 7.84 (m, 1H), 7.66 (s, 1H), 7.48 - 7.28 (m, 6H), 6.97 (q, J = 9.9, 9.0 Hz, 2H), 4.80 - 4.76 (m, 1H), 4.41 (d, J = 6.7 Hz, 2H), 3.95 (s, 3H), 3.88 - 3.64 (m, 3H), 3.61 - 3.44 (m, 3H), 2.97 (s, 3H), 2.73 - 2.68 (m, 3H), 2.65 (s, 3H), 2.40 - 2.37 (m, 5H), 2.10 - 1.81 (m, 3H), 1.66 (s, 3H).

[0283] Example 15: (S)-N-(5-(8-(4-(3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetyl)piperazin-1-yl)azetidin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0284]

[0285] Step 1: Synthesis of tert-butyl (S)-3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetyl)piperazin-1-yl)azetidine-1-carboxylate

[0286]

[0287] According to the method of Step 4 in Example 1, the title compound was synthesized from tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetic acid as a pale yellow solid (170 mg, yield 91%).

[0288] 11H NMR (400 MHz, DMSO-d6) δ 7.52 - 7.40 (m, 4H), 4.57 (t, J = 6.7 Hz, 1H), 3.86 (s, 2H), 3.74 - 3.55 (m, 4H), 3.48 (s, 1H), 3.17 - 3.10 (m, 4H), 2.69 (s, 4H), 2.59 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H), 1.38 (s, 9H).

[0289] Step 2: Synthesis of (S)-N-(5-(8-(4-(3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)azetidin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0290]

[0291] According to the method of Step 4 in Example 1, first react tert-butyl (S)-3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)azetidine-1-carboxylate with trifluoroacetic acid to obtain a yellow solid (141 mg, yield 90%). Then, synthesize the title compound as a pale yellow solid (204 mg, yield 72%) from 4-((6-(5-((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butanoic acid and (S)-1-(4-(azetidin-3-yl)piperazin-1-yl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ethan-1-one.

[0292] 11H NMR (500 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 7.92 - 7.86 (m, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 7.38 (t, J = 7.7 Hz, 3H), 7.34 - 7.28 (m, 2H), 7.01 - 6.92 (m, 2H), 4.77 (t, J = 6.6 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.18 (t, J = 8.0 Hz, 1H), 4.06 - 4.00 (m, 2H), 3.95 (s, 3H), 3.92 - 3.76 (m, 1H), 3.68 (td, J = 15.9, 7.0 Hz, 2H), 3.55 - 3.49 (m, 2H), 3.19 - 3.12 (m, 4H), 2.97 (s, 3H), 2.65 (s, 3H), 2.52 - 2.20 (m, 7H), 1.83 - 1.79 (m, 2H), 1.66 (s, 3H), 1.34 (t, J = 7.3 Hz, 1H).

[0293] Example 16: (S)-N-(5-(8-(4-(4-(2-(4-(-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0294]

[0295] Step 1: Synthesis of tert-butyl (S)-4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetyl)piperazin-1-yl)piperidine-1-carboxylate

[0296]

[0297] According to the method of Step 4 in Example 1, the title compound was synthesized from tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetic acid as a pale yellow solid (168 mg, yield 86%).

[0298] 11H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.30 (m, 4H), 4.57 (t, J = 6.8 Hz, 1H), 4.48 - 4.13 (m, 2H), 3.71 - 3.55 (m, 1H), 3.11 - 3.05 (m, 4H), 2.59 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H), 1.40 (s, 9H), 1.28 - 1.24 (m, 8H), 1.22 - 1.16 (m, 4H).

[0299] Step 2: Synthesis of (S)-N-(5-(8-(4-(4-(2-(4-(-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0300]

[0301] According to the method of Step 4 in Example 1, first react tert-butyl (S)-4-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetyl)piperazin-1-yl)piperidine-1-carboxylate with trifluoroacetic acid to obtain a yellow solid (149 mg, yield 90%). Then, synthesize the title compound as a pale yellow solid (233 mg, yield 80%) from 4-((6-(5-((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyric acid and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)-1-(4-(piperidin-4-yl)piperazin-1-yl)ethan-1-one.

[0302] 11H NMR (500 MHz, Chloroform-d) δ 9.20 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 8.04 (t, J = 2.0 Hz, 1H), 7.93 - 7.85 (m, 1H), 7.68 - 7.64 (m, 1H), 7.41 - 7.36 (m, 3H), 7.34 - 7.29 (m, 2H), 7.02 - 6.92 (m, 2H), 4.78 (t, J = 6.6 Hz, 1H), 4.39 (td, J = 6.3, 2.5 Hz, 2H), 3.95 (d, J = 3.1 Hz, 3H), 3.75 - 3.64 (m, 4H), 3.59 - 3.52 (m, 4H), 2.97 (s, 3H), 2.72 - 2.47 (m, 12H), 2.41 - 2.35 (m, 6H), 1.98 - 1.77 (m, 4H), 1.66 (s, 3H).

[0303] Example 17: (S)-N-(5-(8-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0304]

[0305] According to the method of Step 4 in Example 1, first react tert-butyl 4-(6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)piperazine-1-carboxylate with trifluoroacetic acid to obtain a yellow solid (142 mg, yield 90%). Then, synthesize the title compound as a pale yellow solid (211 mg, yield 86%) from 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperazin-1-yl)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid.

[0306] 11H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.75 - 7.71 (m, 1H), 7.45 - 7.38 (m, 2H), 7.35 - 7.27 (m, 4H), 7.00 - 6.91 (m, 2H), 4.89 - 4.82 (m, 1H), 4.27 - 4.13 (m, 2H), 4.11 - 3.89 (m, 4H), 3.73 - 3.64 (m, 2H), 3.60 - 3.47 (m, 2H), 3.46 - 3.33 (m, 1H), 2.99 (s, 3H), 2.68 (s, 3H), 2.41 (s, 3H), 1.95 (s, 2H), 1.69 (s, 3H).

[0307] Example 18: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)piperazine-1-carbonyl)phenyl)acetamide

[0308]

[0309] Step 1: Synthesis of tert-Butyl (S)-4-(2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)benzoate

[0310]

[0311] According to the method of Step 4 in Example 1, the title compound was synthesized from tert-Butyl p-aminobenzoate and (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid as a pale yellow solid (159 mg, yield 92%).

[0312] 11H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.90 - 7.83 (m, 2H), 7.78 - 7.71 (m, 2H), 7.51 - 7.38 (m, 4H), 4.61 (t, J = 7.1 Hz, 1H), 3.59 - 3.50 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 1.65 - 1.61 (m, 3H), 1.53 (s, 9H).

[0313] Step 2: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)piperazine-1-carbonyl)phenyl)acetamide

[0314]

[0315] According to the method of Step 4 in Example 1, first react tert-butyl (S)-4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)benzoate with trifluoroacetic acid to obtain a yellow solid (140 mg, yield 90%). Then react 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperazin-1-yl)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide and (S)-4-(2-(4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)benzoic acid to synthesize the title compound as a pale yellow solid (194 mg, yield 70%).

[0316] 1 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.08 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.83 - 7.70 (m, 3H), 7.61 - 7.38 (m, 9H), 7.20 (td, J = 8.7, 2.5 Hz, 1H), 4.62 (t, J = 7.1 Hz, 1H), 3.92 - 3.73 (m, 4H), 3.67 (s, 3H), 3.59 - 3.51 (m, 2H), 3.48 (s, 4H), 2.95 (s, 3H), 2.61 (s, 3H), 2.42 (s, 3H), 1.63 (s, 3H).

[0317] (S)-N-(5-(8-(4-(4-(2-(4-(Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)benzoyl)piperazin-1-yl)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0318]

[0319] Step 1: Synthesis of tert-butyl 4-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)piperazine-1-carbonyl)phenyl)piperazine-1-carboxylate

[0320]

[0321] According to the method of Step 4 in Example 1, the title compound was synthesized as a pale yellow solid (176 mg, yield 72%) from 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid and 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperazin-1-yl)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide.

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.09 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.76 (td, J = 8.6, 6.3 Hz, 1H), 7.66 - 7.54 (m, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.22 (td, J = 8.6, 2.5 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.79 (s, 4H), 3.66 (s, 3H), 3.49 - 3.44 (m, 8H), 3.23 - 3.19 (m, 4H), 2.95 (s, 3H), 1.42 (s, 9H).

[0323] Step 2: Synthesis of (S)-N-(5-(8-(4-(4-(2-(4-(Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)benzoyl)piperazin-1-yl)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0324]

[0325] According to the method of step 4 in Example 1, tert-butyl 4-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)piperazine-1-carbonyl)phenyl)piperazine-1-carboxylate was first reacted with trifluoroacetic acid to obtain a yellow solid (139 mg, yield 90%). Then, 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(4-(piperazin-1-yl)benzoyl)piperazine-1-carbonyl)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (143 mg, yield 72%).

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.78 (q, J = 7.8 Hz, 1H), 7.56 - 7.38 (m, 10H), 7.20 (t, J = 8.5 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.60 (t, J = 6.7 Hz, 1H), 3.90 - 3.75 (m, 5H), 3.75 - 3.61 (m, 6H), 3.50 - 3.46 (m, 3H), 3.43 - 3.20 (m, 5H), 2.95 (s, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.63 (s, 3H), 1.23 (s, 2H).

[0327] Example 20: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-carbonyl)phenyl)acetamide

[0328]

[0329] According to the method of step 4 in Example 1, the title compound was obtained as a pale yellow solid (131 mg, yield 77%) by reacting 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperidin-4-yloxy)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide with (S)-4-(2-(4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)benzoic acid.

[0330] 1 H NMR (500 MHz, Chloroform-d) δ 9.20 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.86 (q, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.43 - 7.36 (m, 7H), 7.32 (dd, J = 8.6, 2.2 Hz, 2H), 6.94 (q, J = 9.2, 8.4 Hz, 2H), 4.95 (dq, J = 7.4, 3.6 Hz, 1H), 4.66 (t, J = 6.4 Hz, 1H), 3.95 (s, 3H), 3.82 - 3.74 (m, 1H), 3.59 - 3.50 (m, 2H), 3.13 (d, J = 7.7 Hz, 1H), 2.97 (s, 3H), 2.68 (s, 3H), 2.40 (s, 3H), 2.23 - 1.95 (m, 4H), 1.68 (s, 3H), 1.32 (td, J = 7.3, 1.5 Hz, 2H).

[0331] Example 21: (S)-N-(5-(8-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazacyclohexan-6-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0332]

[0333] Step 1: Synthesis of tert-butyl 6-((6-bromo-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0334]

[0335] According to the method of Step 1 in Example 8, the title compound was obtained as a pale yellow solid (312 mg, yield 72%) by reacting tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate with 6-bromo-4-methylquinazolin-8-ol.

[0336] 1 H NMR (500 MHz, Chloroform-d) δ 9.16 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 4.76 - 4.73 (m, 1H), 4.00 (s, 2H), 3.92 (s, 2H), 2.91 - 2.78 (m, 5H), 2.64 - 2.54 (m, 2H), 1.40 (s, 9H).

[0337] Step 2: Synthesis of tert-butyl 6-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0338]

[0339] According to the method of Step 3 in Example 1, the title compound was obtained as a yellow solid (275 mg, yield 84%) by reacting tert-butyl 6-((6-bromo-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide.

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.05 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.76 (td, J = 8.5, 6.2 Hz, 1H), 7.64 - 7.54 (m, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.22 (td, J = 8.3, 2.4 Hz, 1H), 5.04 - 4.96 (m, 1H), 3.97 (s, 2H), 3.92 (s, 1H), 3.86 (s, 2H), 3.67 (s, 3H), 3.56 (s, 1H), 2.94 (s, 3H), 2.85 (ddd, J = 9.9, 6.8, 3.0 Hz, 1H), 2.41 - 2.31 (m, 1H), 1.37 (s, 9H)

[0341] Step 3: Synthesis of (S)-N-(5-(8-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0342]

[0343] According to the method of Step 4 in Example 1, first react tert-butyl 6-((6-(5-(((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate with trifluoroacetic acid to obtain a yellow solid (209 mg, yield 90%). Then react N-(5-(8-((2-azaspiro[3.3]heptan-6-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid to synthesize the title compound as a pale yellow solid (202 mg, yield 80%).

[0344] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.86 - 7.75 (m, 2H), 7.56 - 7.35 (m, 7H), 7.24 - 7.15 (m, 1H), 5.06 (dq, J = 13.9, 6.7 Hz, 1H), 4.58 - 4.34 (m, 3H), 4.11 - 3.88 (m, 2H), 3.70 (s, 3H), 3.19 (dtd, J = 31.0, 15.5, 7.2 Hz, 4H), 3.03 - 2.84 (m, 5H), 2.62 - 2.57 (m, 3H), 2.40 (s, 3H), 1.62 (s, 3H).

[0345] Example 22: (S)-N-(5-(8-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)-2-azaspiro[3.5]nonan-7-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0346]

[0347] Step 1: Synthesis of tert-butyl 7-((6-bromo-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate

[0348]

[0349] According to the method of step 1 in Example 8, tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate was reacted with 6-bromo-4-methylquinazolin-8-ol to give the title compound as a light yellow solid (383 mg, 83% yield).

[0350] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),7.93(s,1H),7.59(s,1H),4.70(s,1H),3.7 1-3.44(m,4H),2.83(s,3H),1.91-1.85(m,4H),1.64-1.58(m,4H),1.37(s,9H).

[0351] Step 2: Synthesis of tert-butyl 7-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate

[0352]

[0353] According to the method of step 3 in Example 1, tert-butyl 7-((6-bromo-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate was reacted with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)3-pyridyl)benzenesulfonamide to produce the title compound as a yellow solid (300 mg, 88% yield).

[0354] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.65 (s, 1H), 7.27 - 7.17 (m, 2H), 4.85 (s, 1H), 3.66 (s, 3H), 2.95 (s, 3H), 1.96 - 1.89 (m, 6H), 1.67 - 1.60 (m, 6H), 1.38 (s, 9H).

[0355] Step 3: Synthesis of (S)-N-(5-(8-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazocinan-6-yl)acetyl)-2-azaspiro[3.5]non-7-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0356]

[0357] According to the method of Step 4 in Example 1, first react tert-butyl 7-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate with trifluoroacetic acid to obtain a yellow solid (157 mg, yield 90%). Then react N-(5-(8-((2-azaspiro[3.5]non-7-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazocin-6-yl)acetic acid to synthesize the title compound as a pale yellow solid (211 mg, yield 81%).

[0358] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 2.8 Hz, 1H), 8.51 - 8.47 (m, 1H), 8.04 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.78 (td, J = 8.6, 6.4 Hz, 1H), 7.69 (s, 1H), 7.56 (t, J = 9.9 Hz, 1H), 7.52 - 7.41 (m, 5H), 7.21 (td, J = 8.6, 2.5 Hz, 1H), 4.89 (s, 1H), 4.50 (td, J = 7.0, 1.5 Hz, 1H), 4.20 - 4.13 (m, 1H), 4.07 (t, J = 9.1 Hz, 1H), 3.68 (s, 3H), 2.95 (s, 3H), 2.59 (s, 4H), 2.41 (s, 4H), 2.09 - 1.93 (m, 5H), 1.78 - 1.68 (m, 5H), 1.63 (s, 3H).

[0359] Example 23: (S)-N-(5-(8-((3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazocan-6-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0360]

[0361] Step 1: Synthesis of tert-butyl 9-((6-bromo-4-methylquinazolin-8-yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylate

[0362]

[0363] According to the method of Step 1 in Example 8, tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate was reacted with 6-bromo-4-methylquinazolin-8-ol to obtain the title compound as a pale yellow solid (343 mg, yield 70%).

[0364] 11H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 4.72 (dt, J = 8.4, 4.4 Hz, 1H), 4.08 - 3.98 (m, 3H), 2.85 (s, 3H), 1.88 (q, J = 7.1, 5.9 Hz, 2H), 1.76 - 1.61 (m, 4H), 1.45 - 1.36 (m, 11H), 1.36 - 1.29 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[0365] Step 2: Synthesis of tert-butyl 9-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylate

[0366]

[0367] According to the method of Step 3 in Example 1, 9-((6-bromo-4-methylquinazolin-8-yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester reacts with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide to give the title compound as a yellow solid (295 mg, yield 83%).

[0368] 1 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.80 - 7.72 (m, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.59 (ddd, J = 10.8, 9.2, 2.4 Hz, 1H), 7.22 (td, J = 8.3, 2.7 Hz, 2H), 3.92 (s, 3H), 3.66 (s, 3H), 3.52 (s, 1H), 2.94 (s, 3H), 1.96 - 1.86 (m, 3H), 1.73 - 1.68 (m, 5H), 1.47 - 1.41 (m, 2H), 1.41 - 1.37 (m, 12H).

[0369] Step 3: Synthesis of (S)-N-(5-(8-((3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazacyclohexan-6-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0370]

[0371] According to the method of Step 4 in Example 1, first react tert-butyl 9-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-3-azaspiro[5.5]undecane-3-carboxylate with trifluoroacetic acid to obtain a yellow solid (165 mg, yield 90%). Then, synthesize the title compound as a pale yellow solid (204 mg, yield 76%) from N-(5-(8-((3-azaspiro[5.5]undecan-9-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazacyclohexan-6-yl)acetic acid.

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 3.6 Hz, 1H), 8.56 - 8.51 (m, 1H), 8.10 - 8.05 (m, 1H), 7.91 (s, 1H), 7.77 (q, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (t, J = 9.0 Hz, 1H), 7.4 (q, J = 8.3 Hz, 5H), 7.26 - 7.18 (m, 1H), 4.87 (s, 1H), 4.61 - 4.56 (m, 1H), 3.74 - 3.5 (m, ) 3.48 (q, J = 5.7 Hz, 2H), 3.44 - 3.34 (m, 4H), 2.95 (s, 3H), 2.59 (s, 3H), 2.41 (s, 3H), 2.04 - 1.91 (m, 2H), 1.86 - 1.69 (m, 4H), 1.63 (s, 3H), 1.57 - 1.31 (m, 2H).

[0373] Example 24: (S)-N-(5-(8-(3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0374]

[0375] Step 1: Synthesis of 6-bromo-8-(3-bromopropoxy)-4-methylquinazoline

[0376]

[0377] 1,3-Dibromopropane (2.02 g, 10 mmol, 10.00 equiv) was added to a solution of 6-bromo-4-methylquinazolin-8-ol (239 mg, 1 mmol, 1.00 equiv) and potassium carbonate (414 mg, 3 mmol, 3.00 equiv) in acetonitrile at room temperature. The mixture was stirred at 70°C for 4 hours and monitored by TLC and LC-MS. After complete reaction, the starting material was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 7:3) to afford the product as a yellow solid (320 mg, 89% yield).

[0378] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.97(d,J=1.9Hz,1H),7.57(d,J=1.9Hz,1H) ,4.31(t,J=6.0Hz,2H),3.74(t,J=6.6Hz,2H),2.85(s,3H),2.37(p,J=6.3Hz,2H).

[0379] Step 2: Synthesis of N-(5-(8-(3-bromopropoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0380]

[0381] According to the method in Step 3 of Example 1, 6-bromo-8-(3-bromopropoxy)-4-methylquinazoline was reacted with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)3-pyridyl)benzenesulfonamide to produce the title compound as a yellow solid (261 mg, 45% yield).

[0382] 11H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.57 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.22 (td, J = 8.3, 2.6 Hz, 3H), 3.92 (s, 2H), 3.66 (s, 3H), 2.96 (s, 3H), 1.26 - 1.21 (m, 4H).

[0383] Step 3: Synthesis of (S)-N-(5-(8-(3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0384]

[0385] At room temperature, N-(5-(8-(3-bromopropoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (173 mg, 0.3 mmol, 1.00 equiv) was added to a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(piperazin-1-yl)ethan-1-one (141 mg, 0.3 mmol, 1.00 equiv) and potassium carbonate (124 mg, 0.9 mmol, 3.00 equiv) in acetonitrile, and then the reaction mixture was stirred at 70 °C for 7 hours. The reaction was monitored by TLC and LC-MS. After the raw materials were completely reacted, the reaction mixture was concentrated under reduced pressure, and the product was obtained as a brown solid (192 mg, yield 66%) by silica gel column chromatography (DCM:MA = 7:1).

[0386] 11H NMR (500 MHz, Chloroform-d) δ 9.21 (d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.41 - 7.36 (m, 2H), 7.35 - 7.28 (m, 4H), 7.02 - 6.88 (m, 2H), 4.80 - 4.77 (m, 1H), 4.39 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.87–3.54 (m, 7H), 2.97 (s, 3H), 2.75 - 2.60 (m, 7H), 2.53 (s, 1H), 2.38 (s, 3H), 2.32 - 2.22 (m, 2H), 1.66 (s, 3H).

[0387] Example 25: (S)-N-(5-(8-(3-(3-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperazin-1-yl)azetidin-1-yl)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0388]

[0389] According to the method of Step 3 in Example 26, the title compound was synthesized as a pale yellow solid (187 mg, yield 61%) by reacting N-(5-(8-(3-bromopropoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide with (S)-1-(4-(azetidin-3-yl)piperazin-1-yl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)ethan-1-one.

[0390] 11H NMR (500 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.88 (q, J = 7.7 Hz, 1H), 7.67 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.6 Hz, 3H), 6.96 (t, J = 8.5 Hz, 2H), 4.78 (t, J = 6.6 Hz, 1H), 4.37 (s, 2H), 4.13 (d, J = 9.7 Hz, 2H), 3.94 (s, 3H), 3.83 - 3.65 (m, 6H), 3.54 (dd, J = 15.9, 7.3 Hz, 1H), 3.17 - 3.10 (m, 6H), 2.97 (s, 3H), 2.66 (s, 3H), 2.45 (s, 2H), 2.39 (s, 3H), 2.29 (s, 3H), 1.67 (s, 3H).

[0391] Example 26: (S)-N-(5-(8-(3-(4-(1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)piperazin-1-yl)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0392]

[0393] According to the method of Step 3 in Example 26, the title compound was synthesized as a pale yellow solid (198 mg, yield 63%) by reacting N-(5-(8-(3-bromopropoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide with (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-1-(4-(piperidin-4-yl)piperazin-1-yl)ethan-1-one.

[0394] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.80 (td, J = 8.6, 6.4 Hz, 1H), 7.61 - 7.39 (m, 7H), 7.20 (td, J = 8.4, 2.5 Hz, 1H), 4.57 (t, J = 6.6 Hz, 1H), 4.41 - 4.30 (m, 3H), 4.16 (d, J = 13.2 Hz, 1H), 3.69 (s, 3H), 3.66 - 3.55 (m, 1H), 3.44 - 3.32 (m, 1H), 3.13 (d, J = 13.2 Hz, 1H), 3.11 - 3.05 (m, 4H), 2.94 (s, 3H), 2.69 - 2.46 (m, 4H), 2.41 (s, 3H), 2.15 - 2.01 (m, 2H), 1.86 - 1.73 (s, 2H), 1.62 (s, 3H), 1.28 - 1.24 (m, 8H), 1.22 (t, J = 12.1 Hz, 1H).

[0395] Example 27: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)ethyl)acetamide

[0396]

[0397] Step 1: Synthesis of tert-Butyl (2-(4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)ethyl)carbamate

[0398]

[0399] According to the method of Step 3 in Example 26, the title compound was synthesized as a pale yellow solid (162 mg, yield 79%) by reacting 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperidin-4-yloxy)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide with tert-butyl (2-bromoethyl)carbamate.

[0400] 11H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.78 (td, J = 8.5, 6.3 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.57 - 7.47 (m, 1H), 7.19 (td, J = 8.4, 2.5 Hz, 1H), 6.70 - 6.66 (m, 1H), 4.84 (s, 1H), 3.69 (s, 3H), 3.07 (q, J = 6.5 Hz, 2H), 2.94 (s, 3H), 2.89 - 2.77 (m, 2H), 2.46 - 2.31 (m, 4H), 2.10 - 1.99 (m, 2H), 1.85 - 1.72 (m, 2H), 1.38 (s, 9H).

[0401] Step 2: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)ethyl)acetamide

[0402]

[0403] According to the method of Step 4 in Example 1, first, tert-butyl (2-(4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)ethyl)carbamate was reacted with trifluoroacetic acid to obtain a yellow solid (125 mg, yield 90%). Then, N-(5-(8-((1-(2-aminoethyl)piperidin-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (165 mg, yield 80%).

[0404] [[ID="> 11H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.36 (s, 1H), 8.24 - 8.13 (m, 2H), 7.93 (s, 1H), 7.89 - 7.74 (m, 2H), 7.64 (s, 1H), 7.55 - 7.37 (m, 5H), 7.23 - 7.14 (m, 1H), 4.84 (s, 1H), 4.51 (t, J = 7.1 Hz, 1H), 3.70 (s, 3H), 3.35 - 3.16 (m, 6H), 2.94 (s, 3H), 2.90 - 2.80 (m, 2H), 2.58 (s, 3H), 2.42 - 2.37 (m, 5H), 2.12 - 1.99 (m, 2H), 1.86 - 1.74 (m, 2H), 1.61 (s, 3H).

[0405] Example 28: (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)propyl)acetamide

[0406]

[0407] Step 1: Synthesis of tert-Butyl (3-(4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)propyl)carbamate

[0408]

[0409] According to the method of Step 3 in Example 26, the title compound was synthesized as a pale yellow solid (162 mg, yield 86%) by reacting 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperidin-4-yloxy)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide with tert-butyl (3-bromopropyl)carbamate.

[0410] 11H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.87 - 7.67 (m, 3H), 7.62 (d, J = 1.7 Hz, 1H), 7.51 - 7.41 (m, 1H), 7.22 - 7.12 (m, 1H), 6.84 - 6.78 (m, 1H), 4.88 - 4.80 (m, 1H), 3.71 (s, 3H), 3.00 - 2.91 (m, 6H), 2.44 - 2.33 (m, 4H), 1.87 - 1.73 (m, 2H), 1.64 - 1.54 (m, 2H), 1.40 - 1.35 (m, 12H).

[0411] Step 2: Synthesis of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-(4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)propyl)acetamide

[0412]

[0413] According to the method of Step 4 in Example 1, first react tert-butyl (3-(4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)propyl)carbamate with trifluoroacetic acid to obtain a yellow solid (125 mg, yield 90%). Then, react N-(5-(8-((1-(3-aminopropyl)piperidin-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid to synthesize the title compound as a pale yellow solid (170 mg, yield 83%).

[0414] 11H NMR (500 MHz, Chloroform-d) δ 9.17 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.84 (td, J = 8.6, 5.9 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 1.7 Hz, 1H), 7.31 - 7.26 (m, 3H), 6.97 - 6.89 (m, 2H), 4.81 (s, 1H), 4.64 (dd, J = 8.1, 6.0 Hz, 1H), 3.93 (s, 3H), 3.61 - 3.53 (m, 1H), 3.43 (dt, J = 12.3, 6.2 Hz, 1H), 3.37 - 3.28 (m, 2H), 3.15 - 3.04 (m, 2H), 2.96 (s, 3H), 2.86 - 2.68 (m, 3H), 2.63 (s, 3H), 2.38 (s, 3H), 2.34 - 2.24 (m, 2H), 2.22 - 2.11 (m, 3H), 1.86 (t, J = 7.2 Hz, 2H), 1.65 (s, 3H).

[0415] Example 29: (S)-N-(5-(8-(1-((1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0416]

[0417] Step 1: Synthesis of tert-butyl 4-((4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0418]

[0419] According to the method of Step 3 in Example 26, the title compound was synthesized as a pale yellow solid (135 mg, yield 68%) by reacting 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(piperidin-4-yloxy)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide with tert-butyl 4-(bromomethyl)piperidine-1-carboxylate.

[0420] 11H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.27 - 8.19 (m, 2H), 7.85 - 7.65 (m, 3H), 7.60 - 7.50 (m, 1H), 7.44 (td, J = 9.8, 2.5 Hz, 1H), 7.16 (ddd, J = 9.8, 7.6, 2.5 Hz, 1H), 3.96 - 3.88 (m, 3H), 3.72 (s, 3H), 2.92 (s, 3H), 2.85 - 2.59 (m, 5H), 2.30 - 2.15 (m, 4H), 2.09 - 1.99 (m, 1H), 1.82 - 1.62 (m, 7H), 1.39 (s, 9H).

[0421] Step 2: Synthesis of (S)-N-(5-(8-(1-((1-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0422]

[0423] According to the method of Step 4 in Example 1, tert-butyl 4-((4-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate was first reacted with trifluoroacetic acid to obtain a yellow solid (106 mg, yield 90%). Then, 2,4-difluoro-N-(2-methoxy-5-(4-methyl-8-(1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)quinazolin-6-yl)pyridin-3-yl)benzenesulfonamide and (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid were used to synthesize the title compound as a pale yellow solid (133 mg, yield 79%).

[0424] 11H NMR (500 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.19 - 8.15 (m, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.89 (t, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.48 - 7.29 (m, 6H), 6.98 - 6.93 (m, 2H), 4.81 (td, J = 6.5, 3.2 Hz, 1H), 4.73 (s, 1H), 4.64 (d, J = 11.8 Hz, 1H), 4.26 (dd, J = 24.1, 13.2 Hz, 1H), 3.97 (s, 3H), 3.78 - 3.53 (m, 2H), 3.25 - 3.13 (m, 1H), 3.01 - 2.95 (m, 5H), 2.69 - 2.64 (m, 4H), 2.52 (s, 2H), 2.42 - 2.37 (m, 5H), 2.25 (s, 2H), 2.11 (s, 2H), 2.04 - 1.82 (m, 3H), 1.67 (s, 3H), 1.41 - 1.10 (m, 2H).

[0425] Example 30: (S)-N-(5-(8-((1'-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)-[1,4'-dipiperidin]-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0426]

[0427] Step 1: Synthesis of tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)-[1,4'-dipiperidine]-1'-carboxylate

[0428]

[0429] According to the method of Step 1 in Example 8, the title compound was obtained as a yellowish-brown solid (394 mg, yield 78%) by reacting tert-butyl 4-hydroxy-[1,4'-dipiperidine]-1'-carboxylate with 6-bromo-4-methylquinazolin-8-ol.

[0430] 11H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 4.75 - 4.66 (m, 1H), 3.96 (d, J = 13.0 Hz, 2H), 2.85 (s, 5H), 2.48 - 2.40 (m, 3H), 2.09 - 1.97 (m, 2H), 1.76 - 1.64 (m, 5H), 1.39 (s, 10H), 1.29 (qd, J = 12.0, 4.0 Hz, 2H).

[0431] Step 2: Synthesis of tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-[1,4'-bipiperidine]-1'-carboxylate

[0432]

[0433] According to the method of Step 3 in Example 1, tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)-[1,4'-bipiperidine]-1'-carboxylate reacts with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridin-3-yl)benzenesulfonamide to give the title compound as a yellow solid (305 mg, yield 84%).

[0434] 1 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.62 (d, J = 1.7 Hz, 1H), 7.48 (td, J = 9.8, 2.5 Hz, 1H), 7.18 (tt, J = 8.3, 1.4 Hz, 1H), 4.81 (dt, J = 8.6, 4.4 Hz, 1H), 3.97 (d, J = 12.8 Hz, 2H), 3.70 (s, 3H), 2.93 (s, 5H), 2.78 - 2.63 (m, 3H), 2.06 (d, J = 10.5 Hz, 2H), 1.84 - 1.67 (m, 5H), 1.41 - 1.26 (m, 12H).

[0435] Step 3: Synthesis of (S)-N-(5-(8-((1'-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetyl)-[1,4'-dipiperidin]-4-yl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0436]

[0437] According to the method of Step 4 in Example 1, first react tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfamoyl)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)-[1,4'-dipiperidin]-1'-carboxylate with trifluoroacetic acid to obtain a yellow solid (169 mg, yield 90%). Then react N-(5-(8-([1,4'-dipiperidin]-4-yloxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide with (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid to synthesize the title compound as a pale yellow solid (218 mg, yield 80%).

[0438] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.0 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.78 (td, J = 8.5, 6.3 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.57 - 7.41 (m, 6H), 7.20 (td, J = 8.5, 2.5 Hz, 1H), 4.87 (s, 1H), 4.57 (dd, J = 7.5, 5.9 Hz, 1H), 4.43 (d, J = 12.6 Hz, 1H), 4.22 (d, J = 13.1 Hz, 1H), 3.70 - 3.67 (m, 11H), 3.40 (td, J = 16.4, 6.3 Hz, 1H), 3.14 (t, J = 13.0 Hz, 1H), 2.94 (s, 5H), 2.80 - 2.70 (m, 1H), 2.61 - 2.57 (m, 3H), 2.41 (s, 3H), 1.84 - 1.79 (m, 4H), 1.62 (s, 3H).

[0439] Pharmacological activity evaluation

[0440] Experimental Example 1: Kinase Activity Test of PI3Kα

[0441] The effect of the compounds of the present invention on PI3Kα was evaluated using an in vitro kinase activity test. A luciferase-based luminescence detection method was used to measure the kinase activity of PI3Kα by detecting the level of ADP generated in the kinase reaction, thereby reflecting the inhibitory level of the compounds on the kinase activity of PI3Kα. Kinase-Glo TM The kinase activity detection kit was purchased from Promega Corporation. PI3Kα kinase and substrate PIP2 were purchased from Invitrogen. OptiPlate TM -384 white 384-well plates were used for the test. All detections were carried out at room temperature. The kinase buffer included 50 mM Hepes (pH 7.5), 3 mM MgCl2, 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS, and 2 mM DTT. The PI3Kα kinase was diluted to a kinase solution of 6.6 nM with the kinase buffer. The substrate solution included 100 μM PIP2 and 50 μM ATP. The test compounds were diluted to 10 mM in 100% DMSO and then serially diluted 10-fold in 100% DMSO to form 10 different concentrations. Then the compounds diluted in 100% DMSO were diluted 25-fold in 1× kinase buffer. 2.5 μL of the diluted compound solution and 2.5 μL of the PI3Kα kinase solution were added to each well of the 384-well plate. The reaction was initiated by adding 5 μL of the substrate solution to each well, with a final reaction volume of 10 μL, an ATP concentration of 25 μM, a PIP2 concentration of 50 μM, and a PI3Kα kinase concentration of 1.65 nM. The 384-well plate was placed in the dark and reacted at room temperature for 1 hour, and then 10 μL of Kinase-Glo TM reagent was added to each well to terminate the reaction, incubated for 15 minutes, and then the luminescence was read on an EnVision 2104 multi-label microplate reader.

[0442] The percentage of inhibition was calculated based on the following formula:

[0443] % Inhibition = 100 - (max - sample RLU) / (max - min) * 100%

[0444] where sample RLU is the luminescence reading at a given compound concentration, min is the reading of the DMSO control, and max is the reading of the no-enzymatic activity control. The IC 50 value of the compound was calculated using the XLfit program in Excel, and the results are shown in Table 1.

[0445] Experimental Example 2: BRD4 (D1, D2) Activity Inhibition Experiment

[0446] The experiment used the HTRF assay method. The compound sample powder was dissolved in DMSO to prepare the compound stock solution. The compound stock solution was diluted 1000-fold to the starting concentration required for the experiment, and then transferred to a 384-well Echo plate (Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom). The compound was serially diluted to the set number of concentration points using an automatic micropipette (Precision PRC384U). The wells containing only DMSO on the Echo plate were used to set the negative control wells in the experiment. 20 nL of the compound was transferred from the above-diluted Echo 384-well plate to a 384-well reaction plate using an ultrasonic nanoliter liquid handling system (Echo 550). For the positive control wells, 20 nL of the highest concentration of the positive reference compound was transferred, and for the negative control wells, 20 nL of DMSO was transferred. The reaction buffer (Binding Domain detection buffer 2, Cisbio) containing BRD4 (D1, D2) and peptide substrate was added to the 384-well plate, 10 μL per well. Then, the reaction buffer containing the detection reagents Anti-GST-TB2+Cryptate and SA-XL-665 was added, 10 μL per well. The final reaction volume was 20 μL. The final concentrations of the components in the reaction system were as follows: BRD4 (D1, D2) = 3 nM, peptide substrate = 3 nM, Anti-GST-TB2+Cryptate = 0.25x, SA-XL-665 = 0.375x, DMSO concentration ratio = 0.1%. After adding the detection solution, the mixture was incubated at room temperature for 3 hours, and then the reaction plate was placed in an enzyme-linked immunosorbent assay (ELISA) reader Envision to read the signal values (ex 340 nm, em 665 / 615 nm).

[0447] Copy the values from the ELISA reader. The maximum value refers to the reading of the negative control, and the minimum value refers to the reading of the positive control. Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%. The curve was fitted using the formula Y = Bottom + (Top - Bottom) / (1 + (IC50 / X)^HillSlope) to obtain the IC50 value, where Y is the inhibition rate and X is the compound concentration.

[0448] Experimental Example 3: KYSE 450 cell proliferation inhibition activity test

[0449] KYSE450 cells in the logarithmic growth phase were selected. After digestion with trypsin, they were inoculated in a 96-well culture plate with DMED culture medium containing 10% fetal bovine serum at a cell density of 3,000 cells / 100 μl and cultured at 37 °C in 5% CO2 for 24 h. After 24 h, the culture medium was discarded, and the cells were cultured in serum-free medium (or medium containing 1-5% serum) for starvation for 24 h (or overnight). Before the experiment, the medium was changed to 180 μl of fresh complete medium. In the experimental group, 20 μl of DMEM complete medium containing samples at different concentrations (the final concentrations of monomeric compounds were 0.1875 μM, 0.375 μM, 0.75 μM, 1.5 μM, 3 μM, and 6 μM) was added. In the control group, the culture medium containing an equal volume of solvent was changed. The cells were cultured at 37 °C in 5% CO2 for 72 h. The culture medium was discarded, and 100 μL of serum-free medium containing 10% CCK-8 was added to each well. The culture plate was incubated in the incubator for 1-4 h, and the absorbance at 450 nm was measured with an enzyme-linked immunosorbent assay (ELISA) reader to calculate the inhibition rate.

[0450] Table 1: Inhibitory activities of the compounds in the examples against PI3K kinase

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458] Table 2: Inhibitory activities of the compounds in the examples against BRD4

[0459]

[0460]

[0461] Table 3: Proliferation inhibitory activities of the compounds in the examples against KYSE 450 cells

[0462]

[0463]

[0464]

Claims

1. A compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof represented by formula (I): Wherein: R is selected from 2,4-difluorophenylsulfonylamino 、 fluorine, hydrogen, 2-chloro-4-fluorophenylsulfonylamino, 5-chlorothiophene-2-sulfonylamino; A is oxygen or B is Wherein: m is an integer from 1 to 8; n is an integer from 1 to 15; o and p, q and r, s and t are each independently 0, 1, 2 or 3 simultaneously; a is an integer from 0 to 5, b is 0 or 1, and the R1 group is selected from the groups represented by the structures of formulae (R1-1)-(R1-15) below: Alternatively, B is wherein said q and r are independently 1, 2 or 3, and the R2 group is wherein said c is an integer from 1 to 5; or, the R2 group is selected from the groups represented by the structures of the following formulas (R2-1)-(R2-3):

2. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, characterized in that, where A is oxygen and B is wherein: m is an integer from 1 to 6; n is an integer from 2 to 8; o and p, q and r, s and t are each independently 1 or 2 simultaneously; a and b are 0, and the R1 group is Alternatively, a is 3, b is 0, and the R1 group is Alternatively, a is 3, b is 1, and the R1 group is The R2 group is wherein c is 2, 3 or 4; or the R2 group is selected from 3. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, characterized in that, The described A is B is Wherein: q and r are 1 or 2 simultaneously; a is 0, b is 1, and the R1 group is 4. A compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that, R is selected from 2,4-difluorophenylsulfonamido.

5. The compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound is selected from:

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises at least one compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and optionally a pharmaceutically acceptable carrier and / or excipient.

7. The pharmaceutical composition according to claim 6, wherein The pharmaceutical composition further comprises a pharmaceutically active ingredient other than the compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof.

8. Use of the compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to any one of claims 6 or 7, in the preparation of a medicament for preventing and / or treating PI3K-mediated diseases.

9. Use according to claim 8, characterized in that, The PI3K-mediated diseases include tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic disorders, endocrine disorders or neurological diseases.

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