Pyridine substituted quinazoline derivatives, processes for their preparation, pharmaceutical compositions and uses thereof

Abstract

The present application belongs to the field of chemical pharmacy, and relates to pyridine-substituted quinazoline derivatives, a preparation method, a pharmaceutical composition and a use thereof. The pyridine-substituted quinazoline derivative is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is a PI3K / CDK dual-target inhibitor, and can be used for preventing and / or treating diseases related to PI3K and CDK activity, such as tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine dysfunction or neurological diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a pyridine-substituted quinazoline derivative that inhibits PI3K and CDK, its preparation method, pharmaceutical composition and use. Background Technology

[0002] Phosphatidylinositol-3-kinases (PI3K) are widely distributed intracellular phosphatidylinositol kinases involved in the regulation of various cellular functions, including cell proliferation, differentiation, apoptosis, signal transduction, and glucose transport. Based on their structure and function, PI3K can be divided into three main classes: I, II, and III. Class I PI3K, the most extensively studied, comprises 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 leukocytes, while the other two subtypes, PI3Kα and PI3Kβ, are widely distributed in various cell types. PI3K is a downstream protein of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). It activates protein kinase B (AKT) by phosphorylating corresponding phospholipids, thereby transducing various extracellular cytokine signals into the cell. Abnormalities in the PI3K signaling pathway are closely related to the formation and development of various diseases. For example, the gene PIK3CA, which encodes p110α, is extensively amplified and mutated in many tumor tissues. Inhibiting PI3K activity will inhibit the transduction of growth factor signals, thereby inhibiting cell proliferation.

[0003] The CDK (Cycle-dependent Kinase) family is a class of serine / threonine kinases that regulate key biological processes such as cell cycle, gene transcription, metabolism, and differentiation by binding to cyclins. The CDK family is mainly divided into two categories: cell cycle-related CDKs (such as CDK1, CDK2, CDK4, and CDK6) and transcriptionally regulated CDKs (such as CDK7 and CDK9). In cell cycle regulation, CDK activity drives the transition of cells from G1 to S phase, DNA replication, and mitosis from G2 to M phase, ensuring normal cell proliferation. Abnormal activation or dysfunction of CDKs is closely related to cancer, manifesting as cell cycle dysregulation, abnormal gene expression, CDK gene mutations or amplification, and inactivation of CDK repressors, thereby promoting tumor development and progression. Significant progress has been made in targeted therapies against CDKs. CDK4 / 6 inhibitors (such as palbociclib, ribociclib, and abemaciclib) have been used in breast cancer treatment, while transcription-related CDK inhibitors (such as CDK7 and CDK9 inhibitors) have shown broad application potential in leukemia and highly transcription-dependent cancers. Research on the CDK family has not only deepened our understanding of cancer development mechanisms but also provided important directions for the development of novel anticancer drugs.

[0004] Recent literature (e.g., Herrera-Abreu, et al. Cancer Research, 2016(76):2301–2313) has reported a synergistic effect between CDK inhibitors and PI3K inhibitors, which can effectively avoid and delay the time of CDK4 / 6 inhibitor resistance in breast cancer patients, providing a new approach for future anticancer drug therapy. Currently, there are no reports of highly active PI3K / CDK dual-target inhibitors. Therefore, developing novel dual inhibitors of PI3K and CDK can not only utilize their synergistic effect to enhance antitumor activity, but also is expected to overcome the inevitable drug resistance problem caused by CDK4 / 6 inhibitors, showing broad application prospects and practical value. Summary of the Invention

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

[0006] 1. A first aspect of the present invention is to provide a compound of formula (I) and a pharmaceutically acceptable salt:

[0007]

[0008] Wherein: R is selected from 2,4-difluorophenylsulfonamide, fluorine, hydrogen, 2-chloro-4-fluorophenylsulfonamide, and 5-chlorothiophene-2-sulfonamide;

[0009] A is O;

[0010] L is in:

[0011] m is an integer from 1 to 8;

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

[0013] o and p, q and r, s and t are each independently 0, 1, 2 or 3;

[0014] a is an integer between 0 and 8, b is 0 or 1, and the R1 group is absent or selected from groups represented by the structures of the following formulas (R1-1)-(R1-15):

[0015]

[0016]

[0017] Or, L is Where q and r are independently 1, 2, or 3, and the R2 basis is none or none. Where c is an integer from 1 to 5; or, the R2 group is selected from the group represented by the structure (R2-1)-(R2-3):

[0018]

[0019] B is

[0020] in:

[0021] d is an integer between 0 and 4.

[0022] 2. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that A is oxygen and L is...

[0023] in:

[0024] m is an integer from 1 to 6;

[0025] n is an integer between 2 and 8;

[0026] o and p, q and r, s and t are each independently 1 or 2 at the same time;

[0027] a and b are O, and R1 basis is... Alternatively, a = 3, b = 0, and R1 radix = 3. Alternatively, a = 3, b = 1, and R1 basis = 3. Alternatively, a can be 1-7, b can be 1, and R1 can be none;

[0028] R2 base is Where c is 2, 3, or 4; or, the R2 basis is selected from...

[0029]

[0030] B is

[0031]

[0032] in:

[0033] d is an integer between 0 and 3.

[0034] 3. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that A is oxygen and L is...

[0035] in:

[0036] q and r are both 1 or 2;

[0037] m is 1-4;

[0038] a is 1-7, b is 1, and R1 basis is zero;

[0039] B is in:

[0040] d is 1.

[0041] 4. The compound according to any one of 1 to 3, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, characterized in that R is selected from 2,4-difluorophenylsulfonylamino or methoxy.

[0042] 5. The compound according to any one of 1 to 4, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from:

[0043]

[0044]

[0045] 6. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises at least one compound described in any one of 1 to 5, a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and / or excipient.

[0046] 7. The pharmaceutical composition according to claim 5, characterized in that the pharmaceutical composition further comprises a pharmaceutically active ingredient other than the compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts.

[0047] Use of any one of the compounds, stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, or any one of the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of PI3K-mediated diseases.

[0048] 9. According to the use of 8, the PI3K-mediated diseases include tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic disorders, endocrine disorders, or neurological diseases.

[0049] A second aspect of the present invention provides a method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, comprising the following steps:

[0050] Option 1:

[0051]

[0052] (1) Starting from compound A, compound B is formed through a nucleophilic substitution reaction;

[0053] (2) Compound B was reacted with palbociclib in a nucleophilic reaction to prepare compound C;

[0054] (3) Compound C was reacted with substituted pyridine-3-borate pinacol ester to prepare compound D via the Suzuki reaction;

[0055] Option 2:

[0056]

[0057] (1) Starting from compound A, compound E is formed through a nucleophilic substitution reaction;

[0058] (2) Compound E was reacted with substituted pyridine-3-boronic acid pinacol ester by the Suzuki reaction to prepare compound F;

[0059] (3) Compound F was hydrolyzed and then condensed with palbociclib to prepare compound G;

[0060] Option 3:

[0061]

[0062] (1) Using compound A as the starting material, compound H is prepared by nucleophilic substitution reaction or Mitsunobu reaction;

[0063] (2) Compound I was prepared by reacting compound H with substituted pyridine-3-borate pinacol ester via the Suzuki reaction;

[0064] (3) Compound F was hydrolyzed and then reacted with palbociclib in a nucleophilic reaction to prepare compound J;

[0065] Option 4:

[0066]

[0067] (1) Compound L was prepared by nucleophilic substitution reaction of compound K with palbociclib;

[0068] (2) Compound L was reacted with a substituted pyridine-3-borate pinacol ester to prepare compound M via the Suzuki reaction;

[0069] Option 5:

[0070]

[0071] (1) Compound N was prepared by the Mitsunobu reaction using compound A as the starting material;

[0072] (2) Compound N was reacted with trifluoroacetic acid to prepare compound O;

[0073] (3) Compound O was synthesized into compound P through a nucleophilic reaction;

[0074] (4) Compound P was reacted with substituted pyridine-3-borate pinacol ester by the Suzuki reaction to prepare compound Q;

[0075] (5) Compound Q was reacted with trifluoroacetic acid to prepare compound R;

[0076] (6) Compound S was prepared by nucleophilic reaction of compound R with palbociclib;

[0077] A third aspect of the present invention is to provide a pharmaceutical composition comprising 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 active pharmaceutical ingredients, other than the compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, for the prevention and / or treatment of tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for the prevention and / or treatment of tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases.

[0078] In another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the aforementioned compounds, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier or / or excipient; preferably, the pharmaceutical formulation is selected from the following dosage forms: parenteral formulations, such as injectable solutions or suspensions; enteral formulations, such as oral formulations, like tablets or capsules; topical formulations, such as lotions, gels, ointments, emulsions, nasal formulations, suppositories, transdermal formulations, or ophthalmic formulations.

[0079] 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 thereof, in the preparation of a medicament for the prevention and / or treatment of PI3K-mediated diseases; preferably, the PI3K-mediated diseases are selected from tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases. In other words, the present invention also provides a method for the prevention and / or treatment of PI3K-mediated diseases, comprising administering to a subject in need a preventive and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition; preferably, the PI3K-mediated diseases are selected from tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic / endocrine disorders, or neurological diseases.

[0080] In another aspect, the present invention also provides the use of the said compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of CDK4 / 6-mediated diseases; preferably, the CDK4 / 6-mediated diseases are selected from tumors, inflammatory diseases, obesity, fatty liver (NASH (non-alcoholic steatohepatitis) or others), diabetes, arteriosclerosis, arterial stent occlusion, heart failure, cachexia, graft-versus-host disease, bromodomain-associated infectious diseases, treatment of parasites, malaria, trypanosomiasis, and compositions and methods for reducing male fertility. In other words, the present invention also provides a method for preventing and / or treating CDK4 / 6-mediated diseases, the method comprising administering to a subject in need a preventive and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition; preferably, the CDK4 / 6-mediated diseases are selected from tumors, inflammatory diseases, obesity, fatty liver disease (NASH (non-alcoholic steatohepatitis) or others), diabetes, arteriosclerosis, arterial stent occlusion, heart failure, cachexia, graft-versus-host disease, bromodomain-associated infectious diseases, treatment of parasites, malaria, trypanosomiasis, and compositions and methods for reducing male fertility.

[0081] This invention achieves the following beneficial technical effects: the compound of this invention shows significant inhibitory activity against PI3Kα in in vitro enzyme activity tests, IC50... 50 Within the range of 0.1-10 nM; the compounds of the present invention showed significant inhibitory activity against CDK4 in in vitro enzyme activity tests, IC50... 50 Within the range of 1-10000 nM, the compounds of this invention can function as dual PI3K / CDK inhibitors.

[0082] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0083] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0084] "Sulfoamide" refers to the group R b –S(=O)2–NH–, where each R b Each of them is independently substituted with 2,4-difluorophenyl.

[0085] The term "inhibitor" refers to a compound or agent that can inhibit the biological function of a target protein or polypeptide, such as inhibiting the activity or expression of the target protein or polypeptide.

[0086] The term "tumor" includes, but is not limited to, solid tumors and hematologic malignancies, such as bladder cancer, bone or blood cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, laryngeal cancer, and uterine cancer.

[0087] The term "effective amount" refers to the amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application as described below, including but not limited to the treatment of a disease. Effective amounts may vary depending on: the intended application (in vivo or in vitro); or the individual being treated and the disease condition, such as the individual's weight and age, the severity of the disease; the route of administration, etc. Effective amounts can be readily determined by those skilled in the art.

[0088] "Optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility that the event or environment may or may not occur. For example, "optionally halogenated alkyl" means that a halogen may but does not have to be present, and the description includes the possibility that the alkyl group is halogenated and the possibility that the alkyl group is not halogenated.

[0089] The compounds described in this invention also include their isotope-labeled compounds. The term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass number than those normally found in nature. Examples of isotopes suitable for this invention include, but are not limited to, isotopes of hydrogen. 2 H and 3 H; carbon isotopes 11 C 13 C and 14 C; isotopes of chlorine 36 Cl; isotopes of fluorine 18 F; Isotopes of iodine 123 I and 125 I; Nitrogen isotopes 13 N and 15 N; isotopes of oxygen 15 O、 17 O and 18 O; isotopes of phosphorus 32 Isotopes of P and sulfur 35 S.

[0090] Various solvates and hydrates of the compounds or their salts described in this invention, as well as their polymorphs, are also included within the scope of this invention.

[0091] The term "solvent" refers to a compound that also includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. A solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes that may include, for example, one to about 100, one to about 10, one to about 2, about 3, or about 4 solvent or water molecules. The term "polymorph" refers to a compound that exists in two or more different crystalline forms.

[0092] Prodrugs of the compounds described in this invention are also included within the scope of this invention. Some derivatives of the compounds described in this invention possess weak or no pharmacological activity, but when these derivatives are administered into the body, they can be converted into pharmacologically active compounds of this invention through processes such as hydrolysis and cleavage. These derivatives are called "prodrugs". Further information on the uses of prodrugs can be found in *Pro-drugs as Novel Delivery Systems*, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and *Bioreversible Carriers in Drug Design*, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association).

[0093] The compounds described in this invention include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and possesses the pharmacological activity required of the parent compound. Pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic base, or inorganic and organic acid, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrate, glycolate, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0094] When used as a pharmaceutical, the compounds described herein are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers, diluents, or excipients are also included within the scope of this invention. Carriers, excipients, and additives as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired particular dosage form. Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference.

[0095] The compositions of this invention can be administered via any route suitable for the condition to be treated. In particular, administration is possible via: parenteral administration, for example, as an injectable solution or suspension; enteral administration, for example, orally, in tablet or capsule form; topical administration, for example, as a lotion, gel, ointment, or emulsion, or via nasal or suppository form. Topical application is, for example, to the skin. Another form of topical administration is administration to the eye.

[0096] Pharmaceutical compositions can be administered in solid, semi-solid, liquid, or gaseous form, or may be in the form of dry powders, such as lyophilized forms. Pharmaceutical compositions can be packaged in easily deliverable forms, including, for example, solid dosage forms such as capsules, pouches, sachets, gelatin, paper, tablets, suppositories, granules, pills, lozenges, and tablets. The type of packaging will generally depend on the route of administration. Implantable, sustained-release formulations and transdermal formulations are also covered.

[0097] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), and starches (e.g., corn starch). The composition may contain: potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the discretion of the formulation personnel.

[0098] The compounds described in this invention can be used alone or in combination with other therapeutic agents for treating the diseases or conditions described in this invention (e.g., cancer). In some embodiments, the compounds described in this invention are combined in a pharmaceutical combination formulation with a second compound having anti-proliferative properties or for treating highly proliferative diseases (e.g., cancer), or in a dosing regimen as a combination therapy. The second compound in the pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compounds described in this invention so that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of this invention are combined with other antitumor drugs.The antitumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclophosphamide, and carmustine; platinum-based drugs, including but not limited to carboplatin, cisplatin, and oxaliplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, and irinotecan; antibiotics, including but not limited to cyclophosphamide, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and procainoxantrone; antimicrotubule or antimitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, and doxorubicin; and antimetabolites, including but not limited to fluorouracil, methotrexate, cytarabine, and mecaptopurine. Thioguanine and gemcitabine; antibodies, including but not limited to Herceptin and bevacizumab; hormones, including but not limited to Letrazole, Vorazole, tamoxifen, toremifene, fulvestrant, flutamide, nilumethoxazole, and triptorelin; kinase inhibitors, including but not limited to EGFR kinase inhibitors such as gefitinib, erlotinib, lapatinib, and afatinib; and VEGFR inhibitors such as sorafenib and regoraflini. Enib, sunitinib, cabozantinib, pazopanib, vandetanib, axitinib; ALK inhibitors, including but not limited to crizotinib, ceritinib, alectinib; Bcr-Abl inhibitors, including but not limited to imatinib, ponatinib, nilotinib, dasatinib; BTK inhibitors Drugs, including but not limited to ibrutinib; B-RAF inhibitors, including but not limited to vemurafenib; cyclin-dependent kinase CDK4 / 6 inhibitors, such as palbociclib; mTOR inhibitors, including but not limited to rapamycin and everolimus; deacetylase inhibitors, including but not limited to vorinostat; PD1 / PDL1 antibodies, such as Keytruda (pembrolizumab) and Opdivo (nivolumab).

[0099] The fourth aspect 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 medicament for the prevention and / or treatment of PI3K-mediated diseases.

[0100] The PI3K-mediated diseases include tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolic disorders, endocrine disorders, or neurological diseases. Detailed Implementation

[0101] The present invention will be further described in detail below with reference to specific embodiments. The embodiments given are only for illustrating the present invention and are not intended to limit the scope of the present invention.

[0102] The compounds described in this invention can be synthesized according to one or more synthetic schemes described herein and / or techniques well known in the art. Those skilled in the art will recognize that the synthetic methods of some embodiments described in detail herein can be readily applied to the synthesis of other embodiments. In some embodiments, the compounds described herein can be prepared by appropriate combinations of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as Alfaisa (China) Chemical Co., Ltd., or can be readily prepared using synthetic methods commonly used in the art.

[0103] ¹H NMR spectra were recorded on instruments operating at 400 MHz, 500 MHz, or 700 MHz. ¹H NMR spectra were obtained in solution form (reported in ppm), using CDCl₃ (7.26 ppm), DMSO-d₆ (2.50 ppm), or the internal standard tetramethylsilane (0.00 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants were given in Hertz (Hz).

[0104] In the following preparation methods and examples, "Me" refers to methyl, "Et" refers to ethyl, "Boc" refers to tert-butyloxycarbonyl, "PE" refers to petroleum ether, "EtOAc" refers to ethyl acetate, "MeOH" refers to methanol, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "CDCl3" refers to deuterated chloroform, "DCM" refers to dichloromethane, "rt" refers to room temperature, "mL" refers to milliliters, "mmol" refers to millimoles, "μM" refers to micromoles, "nM" refers to nanomoles, and "℃" refers to degrees Celsius.

[0105] Example 1: Synthesis of 6-acetyl-8-cyclopentyl-2-((5-(4-(2-(4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl)oxy)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (compound 1)

[0106]

[0107] Step 1: Synthesis of tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylic acid

[0108]

[0109] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.415 g, 12 mmol, 1.2 equiv) was added at 0 °C to an ultradry tetrahydrofuran (37.5 mL) solution of 6-bromo-4-methylquinazolin-8-ol (2.380 g, 10 mmol, 1 equiv) and triphenylphosphine (3.936 g, 15 mmol, 1.5 equiv), followed by degassing and argon backfilling. Diisopropyl azodicarbonate (2.953 mL, 15 mmol, 1.5 equiv) was then slowly added dropwise, and the resulting reaction mixture was degassed and argon backfilled (three cycles). The reaction mixture was slowly heated from 0 °C to room temperature overnight. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:EA = 15:1 then DCM:MeOH = 20:1) to give a brown solid (3.789 g, yield 89.72%). ESI-MS m / z:422.26, 424.20[M+H] + .

[0110] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.01(d,J=1.6Hz,1H),7.72(d,J=1.9Hz,1H),4.95(tt,J=7.8,3.6Hz,1H),3.7 4(dt,J=13.4,4.9Hz,2H),3.27(t,J=11.0Hz,2H),2.88(s,3H),2.06–1.94(m,2H),1.72–1.59(m,2H),1.43(s,9H).

[0111] Step 2: Synthesis of tert-butyl 4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylic acid

[0112]

[0113] 4-((6-bromo-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (2.631 g, 6.23 mmol, 1.0 equiv), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (1.816 g, 6.85 mmol, 1.1 equiv), and 2N potassium carbonate solution (6.23 mL, 12.46 mmol, 2.00 equiv) were dissolved in 1,4-dioxane (35 mL) and degassed. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (455.85 mg, 0.623 mmol, 0.10 equiv) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours until the reaction was complete. The solvent was then removed under reduced pressure, and the product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give a brown oily substance (2.639 g, yield 88.14%). ESI-MS m / z: 481.24 [M+H] +

[0114] 1 H NMR (400MHz, CDCl3) δ9.18(s,1H),8.00(d,J=1.9Hz,1H),7.72(d,J=1.7Hz,1H),7.41(d,J=1.7Hz,1H),7.27(d,J=2.1Hz,1H),4.83(tt,J=7.7 ,3.7Hz,1H),4.07(s,3H),3.98(s,3H),3.96–3.87(m,2H),3.29–3.19( m,2H),2.96(s,3H),2.14–2.04(m,2H),2.00–1.89(m,2H),1.45(s,9H).

[0115] Step 3: Synthesis of 6-(5,6-dimethoxypyridin-3-yl)-4-methyl-8-(piperidin-4-yloxy)quinazoline

[0116]

[0117] DCM (27 mL) was added to a flask containing 2.639 g (5.49 mmol) of 4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (2.639 g, 5.49 mmol) at room temperature, followed by slow dropwise addition of trifluoroacetic acid (12 mL). After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure. The residual solid was added directly to the next step without purification. ESI-MS m / z: 381.1 [M+H] +

[0118] Step 4: Synthesis of tert-butyl 2-(4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)acetate

[0119]

[0120] At room temperature, tert-butyl bromoacetate (801.20 μl, 5.496 mmol, 1 equiv), potassium carbonate (6.3 g, 45.58 mmol, 8.3 equiv), and acetonitrile (33.51 mL) were added sequentially to a flask containing 6-(5,6-dimethoxypyridin-3-yl)-4-methyl-8-(piperidin-4-yloxy)quinazoline (2.091 g, 5.496 mmol, 1 equiv), and the reaction mixture was reacted at 80 °C for 3 h. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the residue was filtered off, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:EA = 20:1 then DCM:MeOH = 15:1) to give a brown solid (2.211 g, yield 81.33%). ESI-MS m / z: 495.19 [M+H] +

[0121] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),8.22(d,J=2.1Hz,1H),7.99(d,J=1.7Hz,1H),7.75(d,J=1.7Hz,1H),7.72(d,J=2.1Hz,1H),5.76(s, 1H),4.96–4.76(m,1H),3.94(brs,6H),3.14(s,2H),2.96(s,3H),2.91–2.77(m,2H),2.10–1.96(m,2H),1.85–1.69(m,2H),1.42(s,9H).

[0122] Step 5: Synthesis of 2-(4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)acetic acid

[0123]

[0124] DCM (30 mL) was added to a flask containing 1.311 g (2.65 mmol, 1 equiv) of 2-(4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)tert-butyl acetate (1.311 g, 2.65 mmol, 1 equiv) at room temperature. Then, trifluoroacetic acid (10 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC and LC-MS. Then, another 10 mL of trifluoroacetic acid was added dropwise, and the reaction was continued at room temperature for 3.5 h. After the starting material had completely reacted, the mixture was concentrated under reduced pressure. The residual solid was added directly to the next step without purification. ESI-MS m / z: 438.70 [M+H] +

[0125] Step Six: Synthesis of 6-acetyl-8-cyclopentyl-2-((5-(4-(2-(4-((6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazoline-8-yl)oxy)piperidin-1-yl)acetyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0126]

[0127] At room temperature, 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1.424 g, 3.182 mmol, 1.2 equiv), triethylamine (5.55 mL, 40 mmol, 15 equiv), HATU (1.178 g, 3.102 mmol, 1.2 equiv), and DCM (20 mL) were added sequentially to a flask containing 2-(4-(6-(5,6-dimethoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)piperidin-1-yl)acetic acid (1.163 g, 2.65 mmol, 1 equiv), [unclear text - possibly a typo, should be '-'], [unclear text - possibly a typo, should be '-'], [unclear text - possibly a typo, should be '-'), ... After the reactants reacted completely, the filtrate was concentrated under reduced pressure, extracted once with DCM, backwashed once with brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.793 g of an oil-solid mixture. This mixture was purified by silica gel column chromatography (DCM:EA = 20:1 then DCM:MeOH = 11:1) to give a yellow solid (1.450 g, yield 63.01%). ESI-HRMS m / z: for C47H54O6N11+ [M+H] + calcd,868.4253; found,868.4277

[0128] 1 H NMR(400MHz, CDCl3)δ9.19(s,1H),8.83(s,1H),8.39(brs,1H),8.20(d,J=9.0Hz,1H),8.07(s,1H),8 .01(s,1H),7.73(s,1H),7.43(s,1H),7.34(d,J=9.1Hz,1H),7.29(s,1H),5.86(p,J=8.8Hz,1H),4.75 (s,1H),4.09(s,3H),4.00(s,3H),3.82(brs,4H),3.45(brs,2H),3.26–3.06(m,6H),2.98(s,3H),2.6 2(brs,2H),2.55(s,3H),2.42–2.24(m,7H),2.19–2.05(m,4H),1.96–1.82(m,2H),1.78–1.63(m,2H).

[0129] Example 2: Synthesis of N-(5-(8-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 2)

[0130]

[0131] Step 1: Synthesis of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide

[0132]

[0133] The product was prepared from 5-bromo-2-methoxypyridine-3-amine (15 g, 20 mmol, 1.00 equiv) as the starting material by a published method (J.Med.Chem.2019,62,8873-8879) to a white solid (11.4 g, two-step yield 36.37%).

[0134] Step 2: 6-Acetyl-2-((5-(4-(6-bromo-4-methylquinazolin-8-yl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidine-

[0135] Synthesis of 7(8H)-ketone

[0136] 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (268.52 mg, 0.6 mmol, 2 equiv) was added to a solution of 6-bromo-8-fluoro-4-methylquinazoline (72.48 mg, 0.3 mmol, 1.00 equiv) and N,N-diisopropylethane (156.77 μl, 0.9 mmol, 3.00 equiv) in N-methylpyrrolidone at room temperature, and then the mixture was microwaved at 120 °C for 4 hours. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to give a pale yellow solid (66 mg, yield 32.90%). ESI-MS m / z: [M+H] +

[0137] 1 H NMR(400MHz, CDCl3)δ9.17(s,1H),8.82(s,1H),8.28(s,1H),8.09(s,1H),7. 87(d,J=1.9Hz,1H),7.52–7.44(m,1H),7.36(d,J=2.0Hz,1H),5.89(p,J=9.0 Hz,1H),3.68–3.59(m,4H),3.55–3.47(m,4H),2.92(s,3H),2.55(s,3H),2.4 3–2.32(m,5H),2.16–2.01(m,3H),1.99–1.86(m,1H),1.71(q,J=5.7Hz,2H).

[0138] Step 3: Synthesis of N-(5-(8-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0139]

[0140] 6-acetyl-2-((5-(4-(6-bromo-4-methylquinazolin-8-yl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (66 mg, 0.1 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl) 1,4-dioxane (5 mL) was dissolved in 3-pyridylbenzenesulfonamide (51.15 mg, 0.12 mmol, 1.20 equiv) and 2N potassium carbonate solution (100 μl, 0.2 mmol, 2.00 equiv) and degassed. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.317 mg, 0.01 mmol, 0.10 equiv) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours until complete. The solvent was then removed under reduced pressure, and the product was purified by silica gel column chromatography (DCM:MeOH = 35:1) to give a pale yellow solid (60 mg, yield 67.57%). ESI-HRMS m / z: for C45H44O5N11F2S + [M+H] + calcd,888.3210; found,888.3236.

[0141] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.14(s,1H),9.10(s,1H),8.96(s,1H),8.56(d,J=2.4Hz,1H),8.18(d ,J=3.0Hz,1H),8.08(d,J=2.4Hz,1H),7.95(s,1H),7.90(d,J=9.0Hz,1H),7.78(q,J=7.8Hz,1H),7.67–7.55( m,2H),7.51(s,1H),7.30–7.19(m,1H),5.92–5.77(m,1H),3.67(s,3H),3.63(brs,4H),3.46(brs,4H),2.96( s,3H),2.43(s,3H),2.31(s,3H),2.29–2.20(m,2H),1.98–1.85(m,2H),1.84–1.73(m,2H),1.68–1.53(m,2H).

[0142] Example 3: Synthesis of N-(5-(8-(2-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 3)

[0143]

[0144] Step 1: Synthesis of 6-acetyl-2-((5-(4-(2-chloroacetyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0145]

[0146] Chloroacetyl chloride (90.352 mg, 0.8 mmol, 2.00 equiv) was added dropwise to an ultradry dichloromethane (5 mL) solution of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (177 mg, 0.395 mmol, 1.00 equiv) and DMAP (97.73 mg, 0.79 mmol, 2 equiv). The mixture was slowly heated to room temperature and allowed to stand overnight. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure and eluted by gradient silica gel column chromatography (DCM:MeOH = 20:1) to obtain a pale yellow solid (144 mg, 69.36%). ESI-MS m / z: 524.13, 526.06 [M+H] +

[0147] 1 H NMR (400MHz, CDCl3) δ8.82(s,1H),8.47(brs,1H),8.29(d,J=9.1Hz,1H),8.01(s,1H),7.41(d,J=9.2Hz,1H),5.86(p,J=8.9Hz,1H),4.12(s,2H) ,3.78(brd,J=37.8Hz,4H),3.22(brd,J=20.7Hz,4H),2.55(s,3H),2.49 –2.27(m,5H),2.17–2.01(m,2H),1.99–1.82(m,2H),1.76–1.63(m,2H).

[0148] Step 2: Synthesis of tert-butyl (2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethyl)carbamate

[0149]

[0150] (2-Bromoethyl)carbamate tert-butyl ester (403.38 mg, 1.8 mmol, 1.20 equiv) was added to a solution of 6-bromo-4-methylquinazolin-8-ol (358.56 mg, 1.5 mmol, 1.00 equiv), potassium carbonate (621.945 mg, 4.5 mmol, 3 equiv), and potassium iodide (24.9 mg, 0.15 mmol, 0.1 equiv) in acetonitrile (7.5 mL) at room temperature. The mixture was then stirred at 80 °C for 5 h, and the reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure and eluted by gradient silica gel column chromatography (PE:EA = 1:1) to give the product as a pale yellow solid (460 mg, yield 80.22%). ESI-MS m / z: 382.05, 384.05 [M+H] +

[0151] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.00(d,J=1.8Hz,1H),7.59(d,J=1.9Hz,1H),7.06( t,J=5.9Hz,1H),4.22(t,J=5.9Hz,2H),3.40(q,J=5.9Hz,2H),2.87(s,3H),1.37(s,9H).

[0152] Step 3: Synthesis of tert-butyl(2-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethyl)carbamate

[0153]

[0154] A solution of tert-butyl (2-((6-bromo-4-methylquinazolin-8-yl)oxy)ethyl)carbamate (460 mg, 1.2 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (613.78 mg, 1.44 mmol, 1.20 equiv), and 2N potassium carbonate (1.2 mL, 2.4 mmol, 2.00 equiv) was dissolved in 1,4-dioxane (8 mL) and degassed. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (87.804 mg, 0.12 mmol, 0.10 equiv) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours until the reaction was complete. The solvent was then removed under reduced pressure, followed by silica gel column chromatography with gradient elution (DCM:MeOH = 20:1) to obtain a pale yellow solid (503 mg, yield 83.60%). ESI-MS m / z: 602.20, 604.18 [M+H] +

[0155] 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.07(s,1H),8.58(d,J=2.4Hz,1H),8 .13(d,J=2.4Hz,1H),7.94(d,J=1.6Hz,1H),7.82–7.72(m,1H),7.69–7.66(m ,1H),7.63–7.53(m,1H),7.28–7.16(m,1H),7.09(t,J=5.6Hz,1H),4.31(t, J=6.0Hz,2H),3.66(s,3H),3.44(q,J=6.0Hz,2H),2.96(s,3H),1.38(s,9H).

[0156] Step 4: Synthesis of N-(5-(8-(2-aminoethoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0157]

[0158] (2-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)ethyl)tert-butyl carbamate (176 mg, 0.293 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1.5 mL) was slowly added. The mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the solvent and residual trifluoroacetic acid were removed under reduced pressure to obtain a dark brown oil, which could be used directly for the next step without purification. ESI-MS m / z: 502.20, 504.18 [M+H] +

[0159] Step 5: Synthesis of N-(5-(8-(2-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)ethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0160]

[0161] 6-Acetyl-2-((5-(4-(2-chloroacetyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (76.648 mg, 0.15 mmol, 1 equiv) was added to a mixed solution of N-(5-(8-(2-aminoethoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (145.44 mg, 0.29 mmol, 1.00 equiv), cesium carbonate (146.619 mg, 0.45 mmol, 3 equiv), acetonitrile (10 mL), and dichloro (10 mL) at room temperature, and the mixture was stirred overnight at 80 °C. The reaction was monitored by TLC and LC-MS. After the reactants reacted completely, the mixture was concentrated under reduced pressure, and the final product was obtained by preparative liquid chromatography. The product was a pale yellow solid (46 mg, yield 31.00%). (ESI-HRMS m / z: for C49H51O7N12F2S) + [M+H] + calcd,989.3687; found,989.3714

[0162] 1H NMR (500MHz, CDCl3) δ9.18(s,1H),8.82(s,1H),8.34(s,1H),8.20(d,J=9.0Hz,1H),8.16(d,J=1.9Hz,1H),8.0 2(d,J=2.1Hz,2H),7.89(q,J=8.0Hz,1H),7.66(s,1H),7.36–7.28(m,2H),6.96(t,J=8.7Hz,2H),5.87(p,J=8. 9Hz,1H),4.46–4.40(m,2H),3.95(s,3H),3.86–3.79(m,4H),3.70(brs,2H),3.39–3.31(m,2H),3.16(brd,J=1 9.6Hz,4H),2.97(s,3H),2.55(s,3H),2.42–2.30(m,5H),2.06(brs,2H),1.93–1.83(m,2H),1.75–1.61(m,2H).

[0163] Example 4: Synthesis of N-(5-(8-(3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 4)

[0164]

[0165] Step 1: Synthesis of tert-butyl(3-((6-bromo-4-methylquinazolin-8-yl)oxy)propyl)carbamate

[0166]

[0167] The title compound was synthesized as a gray solid (530 mg, yield 89.16%) from 6-bromo-4-methyl-8-hydroxyquinazoline and tert-butyl 3-bromopropylcarbamate according to the method in step two of Example 3. ESI-MS m / z: 395.99, 397.99 [M+H] +

[0168] 1H NMR (400MHz, DMSO-d6) δ9.08(s,1H),7.95(s,1H),7.49(s,1H),6.97(t,J=5.8Hz,1H),4.2 0(t,J=6.2Hz,2H),3.17(q,J=6.3Hz,2H),2.85(s,3H),1.95(p,J=6.6Hz,2H),1.37(s,9H).

[0169] Step 2: Synthesis of tert-butyl(3-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)propyl)carbamate

[0170]

[0171] The title compound was synthesized as a gray solid (485 mg, yield 85.54%) from (3-((6-bromo-4-methylquinazolin-8-yl)oxy)propyl)carbamate tert-butyl (364 mg, 0.92 mmol, 1 equiv) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (583.95 mg, 1.37 mmol, 1.5 equiv) according to step three of Example 3. ESI-MS m / z: 616.08 [M+H] +

[0172] 1 H NMR(500MHz, CDCl3)δ9.23(s,1H),8.18(d,J=2.1Hz,1H),8.04(d,J=2.0Hz,1H),7.93–7.84(m,1H),7.69(s,1H),7.32(s,2H),7.28 (s,2H),7.00–6.92(m,2H),4.38(t,J=5.8Hz,2H),3.98(s,3H),3.56–3.43(m,2H),3.03(s,3H),2.20(p,J=5.9Hz,2H),1.46(s,9H).

[0173] Step 3: Synthesis of N-(5-(8-(3-aminopropoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0174]

[0175] tert-butyl(3-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)propyl)carbamate (307.825 mg, 0.5 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1 mL) was slowly added. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the solvent and residual trifluoroacetic acid were removed under reduced pressure to obtain a dark brown oil, which could be used directly for the next step without purification. ESI-MS m / z: 516.08 [M+H] +

[0176] Step 4: Synthesis of N-(5-(8-(3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0177]

[0178] 6-acetyl-2-((5-(4-(2-chloroacetyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (143.57 mg, 0.274 mmol, 1 equiv) was added to N-(5-(8-(3-aminopropoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide ( The reactants were added to an acetonitrile (5 mL) solution containing 257.77 mg (0.5 mmol, 1.82 equiv), cesium carbonate (267.82 mg, 0.822 mmol, 3 equiv), potassium iodide (4.52 mg, 0.0822 mmol, 0.1 equiv), and triethylamine (83.022 mg, 0.822 mmol, 3 equiv), and then stirred overnight at 80 °C. The reaction was monitored by TLC and LC-MS. Once the reactants had completely reacted...

[0179] The product was concentrated under reduced pressure and then subjected to preparative liquid chromatography to obtain a pale yellow solid (17 mg, yield 6.19%). (ESI-HRMS m / z: for C50H53O7N12F2S) + [M+H] + calcd,1003.3843; found,1003.3846

[0180] 1 H NMR (700MHz, CDCl3) δ9.17(s,1H),8.83(s,1H),8.39(s,1H),8.19(d,J=8.9Hz,1H),8.17(d,J=2.3Hz,1H),8.03(d,J=2.9Hz,1H), 8.02(d,J=2.3Hz,1H),7.91–7.86(m,1H),7.64(s,1H),7.34(s,1H),7.32(dd,J=9.1,2.9Hz,1H),6.95(t,J=8.6Hz,2H),5.86(p,J= 8.9Hz,1H),4.44(t,J=6.1Hz,2H),3.94(s,3H),3.79(t,J=5.1Hz,2H),3.75(s,2H),3.63(t,J=5.1Hz,2H),3.20–3.16(m,2H),3.16 –3.11(m,4H),2.95(s,3H),2.54(s,4H),2.37(s,3H),2.36–2.30(m,4H),2.10–2.02(m,2H),1.92–1.83(m,2H),1.73–1.64(m,2H).

[0181] Example 5: Synthesis of N-(5-(8-(4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)butoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 5)

[0182]

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

[0184]

[0185] 4-Hydroxybutylcarbamate (454.2 mg, 2.4 mmol, 1.2 equiv) was added at 0 °C to an ultradry tetrahydrofuran (7.5 mL) solution of 6-bromo-4-methylquinazolin-8-ol (478 mg, 2 mmol, 1 equiv) and triphenylphosphine (787.17 mg, 3 mmol, 1.5 equiv). The mixture was then degassed and purged with argon. Diethyl azodicarbonate (435.4 μl, 3 mmol, 1.5 equiv) was then slowly added dropwise. The resulting reaction mixture was degassed and purged with argon (three cycles). The reaction mixture was slowly heated from 0 °C to room temperature overnight. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:EA = 15:1 then DCM:MeOH = 20:1). The product was a black oily solid (751 mg, yield 91.51%). ESI-MS m / z:410.09, 411.98[M+H] + .

[0186] 1 H NMR(500MHz,DMSO-d6)δ9.09(s,1H),7.95(d,J=1.9Hz,1H),7.51(d,J=1.9Hz,1H),6.82(t,J=5.8Hz,1H),4.1 7(t,J=6.4Hz,2H),2.94(q,J=6.1Hz,2H),2.85(s,3H),1.83(q,J=6.7Hz,2H),1.48–1.42(m,4H),1.36(s,9H).

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

[0188]

[0189] A solution of tert-butyl(4-((6-bromo-4-methylquinazolin-8-yl)oxy)butyl)carbamate (743 mg, 1.81 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (924.94 mg, 2.17 mmol, 1.2 equiv), and 2N potassium carbonate (1.81 mL, 3.62 mmol, 2.0 equiv) was dissolved in 1,4-dioxane (15 mL) and degassed. Then, 131.706 mg (0.18 mmol, 0.10 equiv) of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours until the reaction was complete. The solvent was then removed under reduced pressure, followed by silica gel column chromatography with gradient elution (DCM:MeOH = 20:1) to obtain the product as a gray solid (896 mg, yield 78.61%). ESI-MS m / z: 630.15 [M+H] +

[0190] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.07(s,1H),8.56(d,J=2.3Hz,1H),8.10(d,J=2.4Hz,1H),7.91(d,J=1.7Hz,1H),7.82–7.71(m,1H),7.65–7.5 5(m,2H),7.27–7.17(m,1H),6.85–6.77(m,1H),4.27(t,J=6.4Hz,2H),3.6 6(s,3H),3.03–2.88(m,5H),1.93–1.81(m,2H),1.50(s,4H),1.36(s,9H).

[0191] Step 3: Synthesis of N-(5-(8-(4-aminobutoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0192]

[0193] 125.936 mg (0.2 mmol, 1.0 equiv) of tert-butyl(4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyl)carbamate was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1.5 mL) was slowly added. The mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the solvent and residual trifluoroacetic acid were removed under reduced pressure to obtain a dark brown oil, which could be used directly for the next step without purification. ESI-MS m / z: 530.12 [M+H] +

[0194] Step 4: Synthesis of N-(5-(8-(4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)butoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0195]

[0196] 6-Acetyl-2-((5-(4-(2-chloroacetyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (52.402 mg, 0.1 mmol, 1.0 equiv) was added to a mixed solution of N-(5-(8-(4-aminobutoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (105.91 mg, 0.2 mmol, 2.00 equiv), cesium carbonate (97.5 mg, 0.3 mmol, 3.0 equiv), acetonitrile (5 mL), and dichloro (5 mL) at room temperature, and the mixture was stirred at 65 °C for 6 h. The reaction was monitored by TLC and LC-MS. After one component of the reactants had reacted completely, the mixture was concentrated under reduced pressure, and the final product was obtained by preparative liquid chromatography. The product was a pale yellow solid (18 mg, yield 8.85%). (ESI-HRMS m / z: for C51H55O7N12F2S) + [M+H] + calcd,1017.4000; found,1017.4009

[0197] 1H NMR (700MHz, CDCl3) δ9.16(s,1H),8.82(s,1H),8.29(brs,1H),8.20(d,J=8.9Hz,1H),8.17(d,J=2.1Hz,1H),8.05(d,J=3.0Hz,1H),8.02( d,J=2.2Hz,1H),7.90–7.85(m,1H),7.63(d,J=1.7Hz,1H),7.34(dd,J=9.1,3.0Hz,1H),7.28(d,J=1.9Hz,1H),6.98–6.91(m,2H),5.87(p,J =8.9Hz,1H),4.35–4.30(m,2H),3.95(s,2H),3.84–3.80(m,2H),3.69–3.60(m,4H),3.17(brd,J=5.0Hz,4H),2.96(d,J=2.0Hz,3H),2.88( t,J=7.0Hz,2H),2.54(d,J=1.7Hz,3H),2.41–2.31(m,5H),2.15(q,J=7.0Hz,2H),2.09–2.03(m,2H),1.93–1.84(m,4H),1.72–1.65(m,2H).

[0198] Example 6: Synthesis of N-(5-(8-((5-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)pentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 6)

[0199]

[0200] Step 1: Synthesis of tert-butyl(5-((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)carbamate

[0201]

[0202] 5-Hydroxypentylcarbamate tert-butyl ester (487.87 mg, 2.4 mmol, 1.2 equiv) was added at 0 °C to an ultradry tetrahydrofuran (7.5 mL) solution of 6-bromo-4-methylquinazolin-8-ol (478 mg, 2 mmol, 1.0 equiv) and triphenylphosphine (787.17 mg, 3 mmol, 1.5 equiv). The mixture was then degassed and purged with argon. Diethyl azodicarbonate (435.4 μl, 3 mmol, 1.5 equiv) was then slowly added dropwise. The resulting reaction mixture was degassed and purged with argon (three cycles). The reaction mixture was slowly heated from 0 °C to room temperature overnight. The reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:EA = 15:1 then DCM:MeOH = 20:1). The product was a brownish-red oily solid (674 mg, yield 79.41%). ESI-MS m / z:424.09, 426.00[M+H] + .

[0203] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.96(d,J=1.9Hz,1H),7.52(d,J=2.0Hz,1H),6.80(t,J=5.8Hz,1H),4. 17(t,J=6.5Hz,2H),2.94(q,J=5.9Hz,2H),2.86(s,3H),1.89–1.76(m,2H),1.51–1.42(m,4H),1.36(s,9H).

[0204] Step 2: Synthesis of tert-butyl(5-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)pentyl)carbamate

[0205]

[0206] A solution of tert-butyl(5-((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)carbamate (674 mg, 1.588 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (809.856 mg, 1.9 mmol, 1.2 equiv), and 2N potassium carbonate (1.588 mL, 3.176 mmol, 2.0 equiv) was dissolved in 1,4-dioxane (15 mL) and degassed. Then, 116.34 mg, 0.159 mmol, 0.10 equiv of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours until the reaction was complete. The solvent was then removed under reduced pressure, followed by silica gel column chromatography with gradient elution (DCM:MeOH = 20:1) to obtain the product as a gray solid (823 mg, yield 80.51%). ESI-MS m / z: 644.70 [M+H] +

[0207] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.07(s,1H),8.56(d,J=2.3Hz,1H),8.10(d,J=2.4Hz,1H),7.91(d,J=1.7Hz,1H),7.82–7.71(m,1H),7.65–7.5 5(m,2H),7.27–7.17(m,1H),6.85–6.77(m,1H),4.27(t,J=6.4Hz,2H),3.6 6(s,3H),3.03–2.88(m,5H),1.93–1.81(m,2H),1.50(s,4H),1.36(s,9H).

[0208] Step 3: Synthesis of N-(5-(8-((5-aminopentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0209]

[0210] tert-butyl(5-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)pentyl)carbamate (193.113 mg, 0.3 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1.5 mL) was slowly added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the solvent and residual trifluoroacetic acid were removed under reduced pressure to obtain a dark brown oil, which could be used directly for the next step without purification. ESI-MS m / z: 544.70 [M+H] +

[0211] Step 4: Synthesis of N-(5-(8-((5-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)pentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0212]

[0213] 6-Acetyl-2-((5-(4-(2-chloroacetyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (78.603 mg, 0.15 mmol, 1.0 equiv) was added to a mixed solution of N-(5-(8-(4-aminobutoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (163.077 mg, 0.3 mmol, 2.00 equiv), cesium carbonate (146.619 mg, 0.45 mmol, 3.0 equiv), acetonitrile (10 mL), and dichloro (10 mL) at room temperature, and the reaction was stirred at 65 °C for 12 h. The reaction was monitored by TLC and LC-MS. After one component of the reactants had reacted completely, the mixture was concentrated under reduced pressure, and the final product was obtained by preparative liquid chromatography. The product was a pale yellow solid (55 mg, yield 35.56%). (ESI-HRMS m / z: for C52H57O7N12F2S) + [M+H] + calcd,1031.4156; found,1031.4175

[0214] 1H NMR(500MHz, CDCl3)δ9.21(s,1H),8.82(s,1H),8.28–8.13(m,3H),8.06–8.01(m,2H),7.92–7.83(m,1H),7.63(d,J= 1.6Hz,1H),7.33(dd,J=9.1,2.9Hz,1H),7.27(d,J=1.8Hz,1H),7.00–6.90(m,2H),5.87(p,J=8.9Hz,1H),4.28(t,J=6 .7Hz,2H),3.96(s,3H),3.85–3.79(m,2H),3.64–3.59(m,2H),3.58(s,2H),3.20–3.13(m,4H),2.97(s,3H),2.76(t, J=6.8Hz,2H),2.54(s,3H),2.37(s,3H),2.36–2.31(m,2H),2.11–2.02(m,4H),1.93–1.83(m,2H),1.76–1.62(m,6H).

[0215] Example 7: Synthesis of N-(5-(8-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 7)

[0216]

[0217] Step 1: Synthesis of tert-butyl 2-((6-bromo-4-methylquinazolin-8-yl)oxy)acetate

[0218]

[0219] At room temperature, tert-butyl bromoacetate (234.06 mg, 1.2 mmol, 1.2 equiv), potassium carbonate (414.63 mg, 3 mmol, 3 equiv), potassium iodide (16.6 mg, 0.1 mmol, 0.1 equiv), and acetonitrile (5 mL) were added sequentially to a flask containing 6-bromo-4-methylquinazolin-8-ol (239 mg, 1 mmol, 1 equiv). The reaction mixture was reacted at 80 °C for 4 h, and the reaction was monitored by TLC and LC-MS. After the starting material had reacted completely, the residue was filtered off, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 20:1 gradient elution for 15 min) to give the product as a dark brown solid (252 mg, yield 71.34%). ESI-MS m / z: 296.88, 298.87 [M+H] +

[0220] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.05(d,J=1.9Hz,1H),7.48(d,J=1.8Hz,1H),5.00(s,2H),2.88(s,3H),1.43(s,9H).

[0221] Step 2: Synthesis of tert-butyl 2-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)acetate

[0222]

[0223] A solution of 2-((6-bromo-4-methylquinazolin-8-yl)oxy)tert-butyl acetate (252 mg, 0.71 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (364.91 mg, 0.85 mmol, 1.2 equiv), and 2N potassium carbonate (710 μl, 1.42 mmol, 2.0 equiv) was dissolved in 1,4-dioxane (10 mL) and degassed. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51.9 mg, 0.071 mmol, 0.10 equiv) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 4 hours until the reaction was complete. The solvent was then removed under reduced pressure, followed by silica gel column chromatography with gradient elution (DCM:MeOH = 20:1) to obtain the product as a gray solid (141 mg, yield 34.68%). ESI-MS m / z: 574.13 [M+H] +

[0224] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.08(s,1H),8.53(d,J=2.3Hz,1H),8.11(d,J=2.4Hz,1H),7.98(d,J=1.7Hz,1H ),7.74(td,J=8.6,6.3Hz,1H),7.62–7.53(m,2H),7.21(td,J=8.6,2.5Hz,1H),3.64(s,3H),2.96(s,3H),1.43(s,9H).

[0225] Step 3: Synthesis of 2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)acetic acid

[0226]

[0227] 2-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)tert-butyl acetate (136 mg, 0.238 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) at room temperature, and trifluoroacetic acid (1 mL) was slowly added. The mixture was stirred at room temperature for 2.5 h. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the solvent and residual trifluoroacetic acid were removed under reduced pressure to obtain a dark brown oil, which could be used directly for the next step without purification. ESI-MS m / z: 517.05 [M+H] +

[0228] Step 4: Synthesis of N-(5-(8-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0229]

[0230] 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.223 mmol, 0.95 equiv) was added to a solution of 2-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)acetic acid (122 mg, 0.236 mmol, 1.0 equiv), HATU (108 mg, 0.284 mmol, 1.2 equiv), and triethylamine (295.92 μl, 2.133 mmol, 9 equiv.) in dichloro(5 mL) at room temperature, and the reaction was stirred overnight at room temperature. The reaction was monitored by TLC and LC-MS. After one component of the reactants had reacted completely, the mixture was concentrated under reduced pressure and purified by gradient elution using silica gel column chromatography to obtain the final product (DCM:MeOH = 20:1). The product was a pale yellow solid (50 mg, yield 23.70%). (ESI-HRMS m / z: forC47H46O7N11F2S) + [M+H] + calcd,946.3265; found,946.3284

[0231] 1 H NMR (700MHz, CDCl3) δ9.19(s,1H),8.82(s,1H),8.17(d,J=2.2Hz,1H),8.14(s,1H),8.06–8.01(m,2H),8.00–7.94( m,1H),7.73(d,J=1.9Hz,1H),7.52(s,1H),7.39(s,1H),7.31(s,1H),7.05–6.97(m,1H),6.95(ddd,J=10.4,8.1,2.3 Hz, 1H), 5.84 (p, J = 9.0 Hz, 1H), 5.15 (s, 2H), 3.96 (s, 3H), 3.94 (s, 2H), 3.84 (s, 2H), 3.18–3.09 (m, 4H), 2.98 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H), 2.35–2.29 (m, 2H), 2.08–1.99 (m, 2H), 1.91–1.82 (m, 2H), 1.72–1.61 (m, 2H). (Sulfanamide active hydrogen does not precipitate)

[0232] Example 8: Synthesis of N-(5-(8-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 8)

[0233]

[0234] Step 1: Synthesis of tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)butyrate

[0235]

[0236] The title compound was synthesized as a black solid (190 mg, 99.67% yield) from 6-bromo-4-methyl-8-hydroxyquinazoline (119.52 mg, 0.5 mmol, 1.0 equiv.) and tert-butyl 4-bromobutyrate according to the method in step one of Example 7. ESI-MS m / z: 380.80, 382.87 [M+H] +

[0237] 1 H NMR (400MHz, CDCl3) δ9.20(s,1H),7.79(d,J=1.9Hz,1H),7.31(d,J=1.9Hz,1H),4.25(t ,J=6.5Hz,2H),2.89(s,3H),2.52(t,J=7.2Hz,2H),2.27(p,J=6.9Hz,2H),1.45(s,9H).

[0238] Step 2: Synthesis of tert-butyl 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyrate

[0239]

[0240] The title compound was synthesized as a gray solid (299 mg, 99% yield) from tert-butyl 4-((6-bromo-4-methylquinazolin-8-yl)oxy)butyrate (190 mg, 0.499 mmol, 1 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (256.944 mg, 0.6 mmol, 1.2 equiv.) according to step two of Example 7. ESI-MS m / z: 601.12 [M+H]+

[0241] 1 H NMR (500MHz, CDCl3) δ9.21 (s, 1H), 8.18 (d, J = 2.3Hz, 1H), 8.03 (d, J = 2.2Hz, 1H), 7.88 (td, J = 8.2, 5.8Hz, 1H), 7.65 (d, J = 1.7Hz, 1H), 7.35 (s, 1H), 7. 32(d,J=1.6Hz,1H),6.96(t,J=8.3Hz,2H),4.33(t,J=6.5Hz,2H),3.96(s ,3H),2.97(s,3H),2.54(t,J=7.2Hz,2H),2.35–2.26(m,2H),1.44(s,9H).

[0242] Step 3: Synthesis of 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyric acid

[0243]

[0244] According to the method in step three of Example 7, the title compound was obtained as a dark brown oily substance by hydrolysis of tert-butyl butyrate (299 mg, 0.49 mmol, 1.0 eqiuv.) from 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyrate. ESI-MS m / z: 545.03 [M+H] +

[0245] Step 4: Synthesis of N-(5-(8-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin-3-yl)piperazin-1-yl)-4-oxobutoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0246]

[0247] According to the method in step four of Example 7, the title compound was obtained as a yellow solid (107 mg, yield 22.41%) from 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyric acid (299 mg, 0.49 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (223 mg, 0.498 mmol, 1 equiv.). ESI-HRMS m / z: for C49H50O7N11F2S + [M+H] + calcd,974.3578; found,974.3589

[0248] 1 H NMR (400MHz, CDCl3) δ9.21 (s, 1H), 8.82 (s, 1H), 8.34 (s, 0H), 8.27–8.18 (m, 2H), 8.06 (d, J = 2.3Hz, 1H), 7.98 (d, J = 2. 9Hz,1H),7.94–7.86(m,1H),7.66(d,J=1.7Hz,1H),7.40(d,J=1.7Hz,1H),7.34(d,J=5.0Hz,2H),7.05–6.92(m,2H),5 .86(p,J=8.9Hz,1H),4.42(t,J=6.1Hz,2H),3.96(s,3H),3.83(s,2H),3.72(s,2H),3.14(s,4H),2.97(s,3H),2.73( t,J=6.7Hz,2H),2.54(s,3H),2.47–2.28(m,7H),2.06(dt,J=12.8,6.9Hz,2H),1.93–1.82(m,2H),1.77–1.62(m,2H).

[0249] Example 9: Synthesis of N-(5-(8-((5-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-5-oxopentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 9)

[0250]

[0251] Step 1: Synthesis of tert-butyl 5-((6-bromo-4-methylquinazolin-8-yl)oxy)valerate

[0252]

[0253] The title compound was synthesized as a black solid (177.89 mg, 90% yield) from 6-bromo-4-methyl-8-hydroxyquinazoline (119.52 mg, 0.5 mmol, 1.0 equiv.) and tert-butyl 5-bromopentanoate (142.278 mg, 0.6 mmol, 1.2 equiv.) in step one of Example 7. ESI-MS m / z: 395.02, 397.00 [M+H] +

[0254] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.93(d,J=1.9Hz,1H),7.50(d,J=1.8Hz,1H),4.18(t,J=6. 3Hz, 2H), 2.84 (s, 3H), 2.32 (t, J = 7.4Hz, 2H), 1.89–1.78 (m, 2H), 1.76–1.66 (m, 2H), 1.38 (s, 9H).

[0255] Step 2: Synthesis of tert-butyl 5-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)valerate

[0256]

[0257] The title compound was synthesized as a gray solid (276 mg, 99% yield) from tert-butyl 5-((6-bromo-4-methylquinazolin-8-yl)oxy)valerate (177.89 mg, 0.45 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (256.944 mg, 0.54 mmol, 1.2 equiv.) according to step two of Example 7. ESI-MS m / z: 615.06 [M+H] +

[0258] 1H NMR (400MHz, CDCl3) δ9.21(s,1H),8.18(d,J=2.2Hz,1H),8.03(d,J=2.3Hz,1H),7.93–7.83(m,1H),7.64(d,J=1.6Hz,1H),7.32(s,1H),7.27(d,J =1.7Hz,1H),7.00–6.90(m,2H),4.29(t,J=6.7Hz,2H),3.97(s,3H),2.97 (s,3H),2.35(t,2H),2.13–2.01(m,2H),1.96–1.80(m,2H),1.43(s,9H).

[0259] Step 3: Synthesis of 5-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)valerate

[0260]

[0261] According to the method in step three of Example 7, the title compound was obtained as a dark brown oily substance by hydrolysis of tert-butyl valerate (276 mg, 0.44 mmol, 1.0 eqiuv.) from 5-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)valerate. ESI-MS m / z: 559.07 [M+H] +

[0262] Step 4: Synthesis of N-(5-(8-((5-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-5-oxopentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0263]

[0264] According to the method in step four of Example 7, the title compound was obtained as a yellow solid (17 mg, yield 8.6%) from 4-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)butyric acid (111.72 mg, 0.2 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (107.41 mg, 0.24 mmol, 1.2 equiv.). ESI-HRMS m / z: for C50H52O7N11F2S + [M+H] + calcd,988.3734; found,988.3751

[0265] 1 H NMR (700MHz, DMSO-d6) δ10.13(s,1H),9.07(s,1H),8.95(s,1H),8.52(s,1H),8.08(s,1H),8.06(d,J=3.0Hz,1H),7.90–7.85(m, 2H),7.77(td,J=8.5,6.2Hz,1H),7.60(d,J=1.7Hz,1H),7.57(td,J=9.8,2.5Hz,1H),7.48(dd,J=9.1,3.1Hz,1H),7.21(td,J=8. 4,2.5Hz,1H),5.82(p,J=8.9Hz,1H),4.32(t,J=6.3Hz,2H),3.72–3.59(m,7H),3.20–3.06(m,4H),2.94(s,3H),2.55(t,J=7.5Hz ,2H),2.42(s,3H),2.30(s,3H),2.28–2.20(m,2H),1.97–1.90(m,2H),1.90–1.85(m,2H),1.82–1.74(m,4H),1.62–1.53(m,2H).

[0266] Example 10: Synthesis of N-(5-(8-((6-(4-(6-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-6-oxohexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 10)

[0267]

[0268] Step 1: Synthesis of tert-butyl 6-((6-bromo-4-methylquinazolin-8-yl)oxy)hexanoate

[0269]

[0270] The title compound was synthesized as a black solid (537 mg, yield 87.5%) from 6-bromo-4-methyl-8-hydroxyquinazoline (358.56 mg, 1.5 mmol, 1.0 equiv.) and tert-butyl 6-bromohexanoate (452.09 mg, 0.6 mmol, 1.2 equiv.) according to the method in step one of Example 7. ESI-MS m / z: 409.02, 411.00 [M+H] +

[0271] 1 H NMR (400MHz, DMSO-d6) δ9.07(s,1H),7.94(d,J=1.9Hz,1H),7.51(d,J=1.9Hz,1H),4.17(t,J=6.4Hz,2H), 2.85(s,3H),2.22(t,J=7.2Hz,2H),1.89–1.77(m,2H),1.66–1.53(m,2H),1.52–1.42(m,2H),1.37(s,9H).

[0272] Step 2: Synthesis of tert-butyl hexanoate (6-(6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexanoate)

[0273]

[0274] The title compound was synthesized as a gray solid (xx mg, yield %) from tert-butyl hexanoate (485 mg, 1.185 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (426.24 mg, 1.42 mmol, 1.2 equiv.) according to step two of Example 7. ESI-MS m / z: 629.6 [M+H] +

[0275] 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.06(s,1H),8.56(d,J=2.3Hz,1H),8.10(d,J =2.3Hz,1H),7.90(d,J=1.7Hz,1H),7.76(td,J=8.5,6.2Hz,1H),7.64–7.55(m,2H),7 .22(td,J=8.5,2.5Hz,1H),4.28(t,J=6.5Hz,2H),3.66(s,3H),2.95(s,3H),2.24(t, J=7.1Hz,2H),1.93–1.82(m,2H),1.67–1.56(m,2H),1.56–1.46(m,2H),1.38(s,9H).

[0276] Step 3: Synthesis of 6-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexanoic acid

[0277]

[0278] According to the method in step three of Example 7, the title compound was obtained as a dark brown oily substance by hydrolysis of tert-butyl hexanoate (125.7 mg, 0.2 mmol, 1.0 eqiuv.) from 6-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)oxy)hexanoate m / z: 573.6 [M+H]. +

[0279] Step 4: Synthesis of N-(5-(8-((6-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-6-oxohexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0280]

[0281] According to the method in step four of Example 7, the title compound was obtained as a yellow solid (102 mg, yield 50.90%) from 6-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)hexanoic acid (114.52 mg, 0.2 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (89.508 mg, 0.2 mmol, 1 equiv.). ESI-HRMS m / z: for C50H52O7N11F2S + [M+H] + calcd,988.3734; found,988.3751

[0282] 1 H NMR (700MHz, DMSO-d6) δ10.34(s,1H),10.13(s,1H),9.06(s,1H),8.95(s,1H),8.57(d,J=2.4Hz,1H),8.11(d,J=2.4Hz,1H),8.04(d,J=3. 0Hz,1H),7.90(d,J=1.7Hz,1H),7.86(d,J=9.0Hz,1H),7.76(td,J=8.5,6.2Hz,1H),7.62–7.56(m,2H),7.46(dd,J=9.1,3.1Hz,1H),7.22( td,J=8.4,2.5Hz,1H),5.82(p,J=8.9Hz,1H),4.29(t,J=6.5Hz,2H),3.65(s,3H),3.64–3.59(m,4H),3.12(dt,J=31.0,5.1Hz,4H),2.94(s ,3H),2.42(d,J=5.9Hz,5H),2.30(s,3H),2.27–2.20(m,2H),1.94–1.85(m,4H),1.79–1.73(m,2H),1.68–1.63(m,2H),1.60–1.54(m,4H).

[0283] Example 11: Synthesis of N-(5-(8-((7-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-7-oxoheptyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 11)

[0284]

[0285] Step 1: Synthesis of 7-((6-bromo-4-methylquinazolin-8-yl)oxy)heptanoate of acetate

[0286]

[0287] The title compound was synthesized as a brown solid (718 mg, 90.88% yield) from 6-bromo-4-methyl-8-hydroxyquinazoline (478 mg, 2 mmol, 1.0 equiv.) and ethyl 7-bromoheptanoate (569 mg, 2.4 mmol, 1.2 equiv.) according to the method in step one of Example 7. ESI-MS m / z: 395.08, 397.00 [M+H] +

[0288] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),7.96(d,J=2.0Hz,1H),7.51(d,J=1.9Hz,1H),4.17(t,J=6.5Hz,2H),4.04(q,J=7.1Hz,2H),2.85(s,3H ), 2.29 (t, J = 7.3Hz, 2H), 1.82 (p, J = 6.8Hz, 2H), 1.55 (q, J = 7.7Hz, 2H), 1.47 (q, J = 7.5Hz, 2H), 1.37 (q, J = 7.9Hz, 3H), 1.16 (t, J = 7.1Hz, 3H).

[0289] Step 2: Synthesis of ethyl heptanoate of 7-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptanoate

[0290]

[0291] The title compound was synthesized as a gray solid (803 mg, yield 76.84%) from 7-((6-bromo-4-methylquinazolin-8-yl)oxy)heptanoate (671 mg, 1.7 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (865.26 mg, 1.2 mmol, 1.2 equiv.) according to step two of Example 7. ESI-MS m / z: 615.66 [M+H] +

[0292] 1H NMR (500MHz, DMSO-d6) δ10.35(s,1H),9.07(s,1H),8.57(d,J=2.4Hz,1H),8.11(d,J=2.3Hz, 1H),7.90(d,J=1.7Hz,1H),7.76(td,J=8.5,6.2Hz,1H),7.64–7.56(m,2H),7.22(td,J=8.5,2 .5Hz,1H),4.27(t,J=6.5Hz,2H),4.04(q,J=7.1Hz,1H),3.65(s,3H),2.95(s,3H),2.36–2.2 7(m,2H),1.86(p,J=6.8Hz,2H),1.62–1.47(m,4H),1.43–1.34(m,2H),1.16(t,J=7.1Hz,2H).

[0293] Step 3: Synthesis of 7-((6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptanoic acid

[0294]

[0295] Ethyl 7-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptanoate (184.398 mg, 0.3 mmol, 1.0 equiv) was dissolved in a mixture of methanol (3 mL), tetrahydrofuran (3 mL), and water (1 mL) at room temperature. Lithium hydroxide monohydrate (62.94 mg, 1.5 mmol, 5 equiv) was then added, and the mixture was stirred at room temperature for 2.5 h. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the organic solvent was removed under reduced pressure, and 1N dilute hydrochloric acid was added dropwise until a large amount of solid precipitated, yielding a pale yellow solid (0.164 g, 93.91%). This solid was used directly in the next step without further purification. ESI-MS m / z: 587.50 [M+H] +

[0296] Step 4: Synthesis of N-(5-(8-((7-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-7-oxoheptyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0297]

[0298] According to the method in step four of Example 7, the title compound was obtained as a yellow solid (93 mg, yield 45.76%) from 7-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)heptanoic acid (117.322 mg, 0.2 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (98.459 mg, 0.22 mmol, 1.2 equiv.). ESI-HRMS m / z: for C52H56O7N11F2S + [M+H] + calcd,1016.4047; found,1016.4071

[0299] 1 H NMR (700MHz, DMSO-d6) δ10.34(s,1H),10.13(s,1H),9.07(s,1H),8.94(s,1H),8.56(d,J=2.4Hz,1H),8.11(d,J=2.4Hz,1H),8.06(d,J =3.0Hz,1H),7.90(d,J=1.7Hz,1H),7.87(d,J=9.0Hz,1H),7.76(td,J=8.5,6.2Hz,1H),7.62–7.56(m,2H),7.48(dd,J=9.1,3.0Hz,1H), 7.22(td,J=8.4,2.5Hz,1H),5.82(p,J=8.9Hz,1H),4.28(t,J=6.5Hz,2H),3.65(s,3H),3.63–3.58(m,4H),3.19–3.06(m,4H),2.42(s,3 H),2.38(t,J=7.4Hz,2H),2.30(s,3H),2.27–2.19(m,2H),1.92–1.84(m,4H),1.80–1.73(m,2H),1.62–1.50(m,6H),1.46–1.39(m,2H).

[0300] Example 12: Synthesis of N-(5-(8-((8-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-8-oxooctyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 12)

[0301]

[0302] Step 1: Synthesis of ethyl 8-((6-bromo-4-methylquinazolin-8-yl)oxy)octanoate

[0303]

[0304] The title compound was synthesized as a brown solid (1.037 g, yield 79.03%) from 6-bromo-4-methyl-8-hydroxyquinazoline (717 mg, 3 mmol, 1.0 equiv.) and ethyl 8-bromooctanoate (904.176 mg, 3.6 mmol, 1.2 equiv.) according to the method in step one of Example 7. ESI-MS m / z: 437.25, 439.11 [M+H] +

[0305] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),7.90(d,J=1.9Hz,1H),7.47(d,J=1.9Hz,1H),4.15(t,J=6.5Hz,2H),4.03(q,J=7.1Hz, 2H),2.83(s,3H),2.26(t,J=7.4Hz,2H),1.81(p,J=6.9Hz,2H),1.56–1.39(m,4H),1.39–1.23(m,4H),1.15(t,J=7.1Hz,3H).

[0306] Step 2: Synthesis of ethyl octanoate of 8-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octanoate

[0307]

[0308] The title compound was synthesized as a gray solid (1.344 g, yield 84.19%) from ethyl 8-((6-bromo-4-methylquinazolin-8-yl)oxy)octanoate (1.037 mg, 2.533 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (1.295 g, 3.040 mmol, 1.2 equiv.) according to step two of Example 7. ESI-MS m / z: 629.56 [M+H] +

[0309] 1H NMR (400MHz, DMSO-D6) δ10.33(s,1H),9.07(s,1H),8.57(d,J=2.3Hz,1H),8.10(d,J=2.3Hz,1H ),7.90(d,J=1.7Hz,1H),7.76(td,J=8.5,6.3Hz,1H),7.64–7.54(m,2H),7.22(td,J=8.2,2.4Hz ,1H),4.27(t,J=6.5Hz,2H),4.03(q,J=7.1Hz,2H),3.66(s,3H),3.57(s,2H),2.95(s,3H),2.3 6–2.24(m,2H),1.93–1.81(m,2H),1.66–1.44(m,4H),1.44–1.25(m,4H),1.16(t,J=7.1Hz,3H).

[0310] Step 3: Synthesis of 8-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octanoic acid

[0311]

[0312] Ethyl octanoate (314.35 mg, 0.5 mmol, 1.0 equiv) of 8-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octanoate was dissolved in a mixture of methanol (3 mL), tetrahydrofuran (3 mL), and water (1 mL) at room temperature. Lithium hydroxide monohydrate (62.94 mg, 1.5 mmol, 3 equiv) was then added, and the mixture was stirred at room temperature for 2.5 h. The reaction was monitored by TLC (DCM:MeOH = 20:1) and LC-MS. After complete conversion, the organic solvent was removed under reduced pressure, and 1N dilute hydrochloric acid was added dropwise until a large amount of solid precipitated, yielding a pale white solid (147 mg, 48.95%). This solid was used directly in the next step without further purification. ESI-MS m / z: 601.68 [M+H] +

[0313] Step 4: Synthesis of N-(5-(8-((8-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxy-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-8-oxyoctyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0314]

[0315] According to the method in step four of Example 7, the title compound was obtained as a yellow solid (111 mg, yield 43.97%) from 8-((6-(5-(((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-methylquinazolin-8-yl)oxy)octanoic acid (147 mg, 0.245 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (181 mg, 0.404 mmol, 1.65 equiv.). ESI-HRMS m / z: for C53H58O7N11F2S + [M+H] + calcd,1030.4204; found,1030.4230

[0316] 1 H NMR (500MHz, DMSO-d6) δ10.35(s,1H),10.14(s,1H),9.07(s,1H),8.95(s,1H),8.57(d,J=2.4Hz,1H),8.11(d,J=2.4Hz,1H),8.06(d,J=3. 0Hz,1H),7.90(d,J=1.7Hz,1H),7.87(d,J=9.0Hz,1H),7.76(td,J=8.6,6.2Hz,1H),7.63–7.55(m,2H),7.48(dd,J=9.1,3.0Hz,1H),7.21(t d,J=8.5,2.5Hz,1H),5.82(p,J=8.8Hz,1H),4.28(t,J=6.5Hz,2H),3.65(s,3H),3.61(s,4H),3.21–3.06(m,4H),2.94(s,3H),2.42(s,3H), 2.37(t,J=7.4Hz,2H),2.30(s,3H),2.24(t,J=9.9Hz,2H),1.88(t,J=7.4Hz,4H),1.79–1.74(m,2H),1.61–1.48(m,2H),1.46–1.34(m,2H).

[0317] Example 13: Synthesis of N-(5-(8-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin n-3-yl)piperazin-1-yl)propoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 13)

[0318]

[0319] Step 1: Synthesis of 6-bromo-8-(3-bromopropoxy)-4-methylquinazoline

[0320]

[0321] At room temperature, 1,3-dibromopropane (234.06 mg, 1.2 mmol, 1.2 equiv), potassium carbonate (414.63 mg, 3 mmol, 3 equiv), potassium iodide (16.6 mg, 0.1 mmol, 0.1 equiv), and acetonitrile (5 mL) were added sequentially to a flask containing 6-bromo-8-(3-bromopropoxy)-4-methylquinazoline (239 mg, 1 mmol, 1 equiv). The reaction mixture was reacted at 80 °C for 4 h, and the reaction was monitored by TLC and LC-MS. After the reactants had reacted completely, the residue was filtered off, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 20:1 gradient elution for 15 min) to give a dark brown solid (252 mg, yield 71.34%). ESI-MS m / z: 296.88, 298.87 [M+H] +

[0322] 1 H NMR(400MHz, CDCl3) δ9.21(s,1H),7.82(d,J=1.9Hz,1H),7.35(d,J=1.9Hz,1H), 4.36(t,J=6.0Hz,2H),3.71(t,J=6.2Hz,2H),2.91(s,3H),2.55(p,J=6.1Hz,2H).

[0323] Step 2: Synthesis of 6-acetyl-2-((5-(4-(3-((6-bromo-4-methylquinazolin-8-yl)oxy)propyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0324]

[0325] At room temperature, 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (313 mg, 0.70 mmol, 1 equiv.), potassium carbonate (290.22 mg, 2.1 mmol, 3 equiv.), potassium iodide (11.62 mg, 0.07 mmol, 0.1 equiv.), and acetonitrile (18 mL) were added sequentially to a flask containing 6-bromo-8-(3-bromopropoxy)-4-methylquinazoline (277 mg, 0.77 mmol, 1.1 equiv.), acetonitrile (18 mL). The reaction mixture was incubated overnight at 80 °C, and the reaction was monitored by TLC and LC-MS. After the reactants reacted completely, the residue was filtered off, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 20:1 gradient elution for 15 min) to obtain a yellow solid (218 mg, yield 38.96%). ESI-MS m / z:

[0326] 1 H NMR (400MHz, CDCl3) δ9.21 (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H), 8.16 (d, J = 9.1Hz, 1H), 8 .05(d,J=2.8Hz,1H),7.80(d,J=1.8Hz,1H),7.39–7.30(m,2H),5.87(p,J=8.9Hz,1H), 4.34(t,J=6.6Hz,2H),3.25(s,4H),2.90(s,3H),2.71(s,5H),2.55(s,3H),2.37(s,5H ),2.26(t,J=6.5Hz,2H),2.06(h,J=6.6Hz,2H),1.94–1.81(m,2H),1.72–1.66(m,2H).

[0327] Step 3: Synthesis of N-(5-(8-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin n-3-yl)piperazin-1-yl)propoxy)-4-methylquinazoline-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0328]

[0329] 6-acetyl-2-((5-(4-(3-(((6-bromo-4-methylquinazolin-8-yl)oxy)propyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (218 mg, 0.3 mmol, 1.0 equiv), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborylyl)3-pyridyl)benzenesulfonamide (233.45 mg, 0.548 mmol, 1.82 equiv) and 2N potassium carbonate (300 μl, 0.6 mmol, 2.0 equiv) solution were dissolved in 1,4-dioxane (20 mL) and degassed. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.06 mmol, 0.2 equiv) was added. The resulting reaction mixture was degassed and purged with argon (three cycles), and then stirred at 100 °C under an argon atmosphere for 16 hours until complete. The solvent was then removed under reduced pressure, and the mixture was purified by gradient elution using silica gel column chromatography (DCM:MeOH = 20:1) to give the product as a yellow solid (122 mg, yield 34.68%). ESI-HRMS m / z: for C48H50O6N11F2S + [M+H] + calcd,946.3629; found,946.3588

[0330] 1 H NMR (400MHz, CDCl3) δ9.25(s,1H),8.86(s,1H),8.28(s,1H),8.24–8.16(m,2H),8.07(t,J=2.8Hz, 2H),7.91(td,J=8.5,6.0Hz,1H),7.69(d,J=1.6Hz,1H),7.43–7.32(m,2H),7.30(s,1H),6.99(td, J=7.9,2.5Hz,2H),5.91(p,J=8.9Hz,1H),4.45(t,J=6.6Hz,2H),3.98(s,3H),3.28(s,4H),2.80(s ,6H),2.58(s,3H),2.39(d,J=12.5Hz,7H),2.09(s,2H),1.99–1.84(m,2H),1.72(d,J=5.1Hz,2H).

[0331] Example 14: Synthesis of N-(5-(8-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin n-3-yl)piperazin-1-yl)butoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 14)

[0332]

[0333] Step 1: Synthesis of 6-bromo-8-(4-bromobutoxy)-4-methylquinazoline

[0334]

[0335] The title compound was synthesized as a brown solid (281.67 mg, 75.30% yield) from 6-bromo-4-methyl-8-hydroxyquinazoline (239 mg, 1 mmol, 1.0 equiv.) and 1,4-dibromobutane (2.16 g, 10 mmol, 10 equiv.) according to the method in step one of Example 13. ESI-MS m / z: 373, 375 [M+H] +

[0336] 1 H NMR(400MHz, CDCl3) δ9.21(s,1H),7.80(d,J=1.9Hz,1H),7.29(d,J=1.9Hz,1 H),4.24(t,J=3.7Hz,2H),3.57–3.49(m,2H),2.91(s,3H),2.24–2.10(m,4H).

[0337] Step 2: Synthesis of 6-acetyl-2-((5-(4-(4-((6-bromo-4-methylquinazolin-8-yl)oxy)butyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0338]

[0339] The title compound was synthesized as a pale yellow solid (330 mg, yield 44.55%) from 6-bromo-8-(4-bromobutoxy)-4-methylquinazoline (374.07 mg, 1 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (537.048 mg, 1.2 mmol, 1.2 equiv.) according to step two of Example 13. ESI-MS m / z: 1 H NMR (400MHz, CDCl3) δ9.20 (s, 1H), 8.84 (s, 1H), 8.54 (s, 1H), 8.15 (d, J = 9.1Hz, 1H), 8. 06(d,J=2.9Hz,1H),7.79(d,J=1.9Hz,1H),7.32(dd,J=9.1,3.0Hz,1H),7.30(d,J=1.9H z,1H),5.87(p,J=8.9Hz,1H),4.26(t,J=6.7Hz,2H),3.24(s,4H),2.72(s,4H),2.63–2. 51(m,5H),2.43–2.28(m,5H),2.15–1.98(m,4H),1.95–1.77(m,4H),1.75–1.61(m,2H).

[0340] Step 3: Synthesis of N-(5-(8-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2)-yl)amino)pyridin n-3-yl)piperazin-1-yl)butoxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0341]

[0342] The title compound was synthesized as a yellow solid (138 mg, yield 32.30%) from 6-acetyl-2-((5-(4-(4-(((6-bromo-4-methylquinazolin-8-yl)oxy)butyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (330 mg, 0.445 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (285 mg, 0.669 mmol, 1.5 equiv.) according to step three of Example 13. ESI-HRMS m / z: for C49H52O6N11F2 S + [M+H] + calcd,960.3785; found,960.3784

[0343] 1 H NMR(400MHz, CDCl3)δ9.22(s,1H),8.81(s,1H),8.21–8.13(m,2H),8.07–7.97(m,3 H),7.93–7.82(m,1H),7.65(d,J=1.7Hz,1H),7.36–7.27(m,2H),7.01–6.90(m,2H), 5.87(p,J=9.0Hz,1H),4.35(t,J=6.5Hz,2H),3.26(s,4H),2.87–2.64(m,5H),2.55( s,3H),2.40–2.30(m,4H),2.18–2.01(m,4H),1.98–1.83(m,4H),1.76–1.60(m,2H).

[0344] Example 15: Synthesis of N-(5-(8-((5-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)pentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 15)

[0345]

[0346] Step 1: Synthesis of 6-bromo-8-((5-bromopentyl)oxy)-4-methylquinazoline

[0347]

[0348] The title compound was synthesized as a brown solid (518 mg, yield 66.73%) from 6-bromo-4-methyl-8-hydroxyquinazoline (478 mg, 2 mmol, 1.0 equiv.) and 1,5-dibromopentane (4.599 g, 20 mmol, 10 equiv.) according to the method in step one of Example 13. ESI-MS m / z: 387, 389 [M+H] +

[0349] 1 H NMR (400MHz, CDCl3) δ9.21(d,J=1.6Hz,1H),7.79(t,J=1.7Hz,1H),7.28(d,J=2.1Hz,1H),4.21(t,J= 6.7Hz,2H),3.46(td,J=6.7,1.5Hz,2H),2.90(d,J=1.6Hz,3H),2.17–1.93(m,4H),1.80–1.61(m,2H).

[0350] Step 2: Synthesis of 6-acetyl-2-((5-(4-(5-(((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0351]

[0352] The title compound was synthesized as a pale yellow solid (107 mg, yield 50.99%) from 6-bromo-8-((5-bromopentyl)oxy)-4-methylquinazoline (107.89 mg, 0.278 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (138.73 mg, 0.31 mmol, 1.1 equiv.) according to step two of Example 13. ESI-MS m / z: 379.4

[0353]

[0354] 1H NMR (400MHz, CDCl3) δ9.20 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.15 (d, J = 9.1Hz, 1H), 8.07 (d, J=2.9Hz,1H),7.78(d,J=1.9Hz,1H),7.32(dd,J=9.2,3.0Hz,1H),7.27(s,1H),5.87(p,J=8. 9Hz,1H),4.21(t,J=6.7Hz,2H),3.24(t,J=4.8Hz,4H),2.89(s,3H),2.69(s,4H),2.54(s,3H ),2.50(s,2H),2.42–2.29(m,5H),2.16–1.97(m,4H),1.96–1.81(m,2H),1.78–1.55(m,6H).

[0355] Step 3: Synthesis of N-(5-(8-((5-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)pentyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0356]

[0357] The title compound was synthesized as a yellow solid (51 mg, yield 36.87%) from 6-acetyl-2-((5-(4-(5-(((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (107 mg, 0.142 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (72.46 mg, 0.170 mmol, 1.2 equiv.) according to step three of Example 13. ESI-HRMS m / z: for C50H54O6N11 F2S + [M+H] + calcd,974.3942; found,960.3934

[0358] 1H NMR(400MHz, CDCl3)δ9.25(s,1H),8.86(s,1H),8.37(s,1H),8.27–8.16(m,2H),8.08(d,J=2.6Hz,2H),8.0 0–7.82(m,1H),7.68(d,J=1.7Hz,1H),7.36(dd,J=9.1,2.9Hz,1H),7.32(s,1H),7.31–7.28(m,1H),7.05–6. 90(m,2H),5.91(p,J=8.9Hz,1H),4.33(t,J=6.7Hz,2H),3.99(s,3H),3.26(t,J=4.9Hz,4H),3.01(s,3H),2 .73(s,4H),2.62–2.48(m,5H),2.46–2.31(m,5H),2.22–2.01(m,4H),1.98–1.85(m,2H),1.82–1.60(m,6H).

[0359] Example 16: Synthesis of N-(5-(8-((6-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)hexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (compound 16)

[0360]

[0361] Step 1: Synthesis of 6-bromo-8-((6-bromohexyl)oxy)-4-methylquinazoline

[0362]

[0363] The title compound was synthesized as a brown solid (445.66 mg, yield 55.43%) from 6-bromo-4-methyl-8-hydroxyquinazoline (478 mg, 2 mmol, 1.0 equiv.) and 1,6-dibromohexane (4.599 g, 20 mmol, 10 equiv.) according to the method in step one of Example 13. ESI-MS m / z: 401, 403 [M+H] +

[0364] 1H NMR (400MHz, DMSO-d6) δ9.10(s,1H),7.97(d,J=1.9Hz,1H),7.53(d,J=1.9Hz,1H),4.19(t ,J=6.5Hz,2H),3.55(t,J=6.7Hz,2H),2.86(s,3H),1.93–1.75(m,4H),1.63–1.42(m,4H).

[0365] Step 2: Synthesis of 6-acetyl-2-((5-(4-(6-(((6-bromo-4-methylquinazolin-8-yl)oxy)hexyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0366]

[0367] The title compound was synthesized as a pale yellow solid (100 mg, yield 46.79%) from 6-bromo-8-((6-bromohexyl)oxy)-4-methylquinazoline (112 mg, 0.278 mmol, 1.0 equiv.) and 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (138.74 mg, 0.31 mmol, 1.1 equiv.) according to step two of Example 13. ESI-MS m / z:

[0368] 1 H NMR (400MHz, CDCl3) δ9.21(s,1H),8.83(s,1H),8.43(s,1H),8.16(d,J=9.0Hz,1H),8.06(d,J= 2.9Hz,1H),7.78(dd,J=1.9,0.7Hz,1H),7.33(dd,J=9.1,3.0Hz,1H),7.28(d,J=1.8Hz,1H),5.8 7(p,J=8.9Hz,1H),4.20(t,J=6.7Hz,2H),3.25(s,4H),2.89(s,3H),2.70(s,4H),2.56–2.45(m ,5H),2.37(s,5H),2.10–1.98(m,4H),1.93–1.83(m,2H),1.74–1.53(m,6H),1.51–1.42(m,2H).

[0369] Step 3: Synthesis of N-(5-(8-((6-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)hexyl)oxy)-4-methylquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

[0370]

[0371] The title compound was synthesized as a yellow solid (49 mg, yield 38.14%) from 6-acetyl-2-((5-(4-(5-(((6-bromo-4-methylquinazolin-8-yl)oxy)pentyl)piperazin-1-yl)pyridin-2-yl)amino)-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.13 mmol, 1.0 equiv.) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl)3-pyridyl)benzenesulfonamide (68.20 mg, 0.16 mmol, 1.2 equiv.) according to step three of Example 13. ESI-HRMS m / z: for C51H56O6N11F2S + [M+H] + calcd,988.4098; found,988.4099

[0372] 1 H NMR (400MHz, CDCl3) δ9.22(s,1H),8.82(s,1H),8.23(s,1H),8.21–8.13(m,2H),8.04(d,J=2.3Hz,2H) ,7.92–7.83(m,1H),7.64(d,J=1.6Hz,1H),7.32(dd,J=9.1,2.9Hz,1H),7.27(d,J=7.9Hz,2H),6.95(q ,J=9.2Hz,2H),5.87(p,J=8.9Hz,1H),4.29(t,J=6.7Hz,2H),3.96(s,3H),3.26(s,4H),2.72(s,4H),2 .54(s,5H),2.37(s,5H),2.13–2.01(m,4H),1.91–1.84(m,2H),1.73–1.57(m,6H),1.54–1.44(m,2H).

[0373] Pharmacological activity evaluation

[0374] Experimental Example 1: PI3Kα Kinase Activity Assay

[0375] The effects of the compounds of this invention on PI3Kα were evaluated using an in vitro kinase activity assay. A luciferase-based cryo-optical assay was used to determine the kinase activity of PI3Kα by detecting the level of ADP produced during the kinase reaction, thereby reflecting the inhibitory level of the compounds on PI3Kα kinase activity. Kinase-Glo TM The kinase activity assay kit was purchased from Promega. PI3Kα kinase and substrate PIP2 were purchased from Invitrogen. OptiPlate was used. TM -384 White 384-well plates were used for testing. All assays were performed at room temperature. Kinase buffer consisted of 50 mM Hepes (pH 7.5), 3 mM MgCl2, 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS, and 2 mM DTT. PI3Kα kinase was diluted to a 6.6 nM kinase solution with kinase buffer. Substrate solution consisted of 100 μM PIP2 and 50 μM ATP. The test compound was diluted to 10 mM in 100% DMSO, and then serially diluted 3-fold in 100% DMSO to 10 different concentrations. The compound diluted in 100% DMSO was then diluted 25-fold in 1× kinase buffer. 2.5 μL of the diluted compound solution and 2.5 μL of PI3Kα kinase solution were added to each well of the 384-well plate. The reaction was initiated by adding 5 μL of substrate solution to each well, with a final reaction volume of 10 μL. The ATP concentration was 25 μM, the PIP2 concentration was 50 μM, and the PI3Kα kinase concentration was 1.65 nM. The 384-well plate was incubated at room temperature in the dark for 1 hour, followed by the addition of 10 μL of Kinase-Glo to each well. TM The reaction was terminated with reagents, incubated for 15 minutes, and then the cold light was read on an EnVision 2104 multi-label microplate reader.

[0376] The inhibition percentage is calculated based on the following formula:

[0377] Inhibition % = 100 – (max-sample RLU) / (max-min) * 100%

[0378] Where sample RLU is the cold light reading at a given compound concentration, min refers to the reading of the DMSO control, and max refers to the reading of the enzyme-free control. The IC50 of the compound is calculated using the XLfit program in Excel. 50 Value. IC 50Compounds with an IC50 of 10 nM or less were labeled “A”. Compounds with an IC50 greater than 10 nM and less than or equal to 100 nM were labeled “B”. Compounds with an IC50 greater than 100 nM and less than or equal to 1000 nM were labeled “C”. Compounds with an IC50 greater than 1000 nM were labeled “D”. The results are shown in Table 1.

[0379] Experimental Example 2: Cyclin D1-CDK4 kinase activity assay

[0380] The IC50 inhibition of CDK4 / CycD1 enzyme activity was tested in vitro using the Lance Ultra method. All compounds were prepared to 100-fold initial concentrations with 100% DMSO, then diluted 3-fold with 100% DMSO. 200 nL of each compound was transferred to a 384-well plate (OptiPlate-384) using an Echo 650. 10 μL of CDK4 / CycD1 (final concentration 2 nM) prepared with kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT, 0.01% BSA, and 0.01% Triton X-100) was transferred to each 384-well plate. Kinase buffer was added to the negative control wells. After mixing, incubate at room temperature for 10 minutes. Add the ULight-4E-BP1 peptide-labeled polypeptide and ATP to the kinase buffer to form a substrate solution. Transfer 10 μL of the substrate solution to a 384-well plate to start the reaction. Incubate at room temperature for 30 minutes. Prepare a stop solution (10x Detection Buffer, EDTA Eu-anti-phospho-4E-BP1 antibody). Add 20 μL of the stop solution to the OptiPlate-384-well plate to stop the reaction and incubate at room temperature for 60 minutes. Read the fluorescence values ​​using an Envision 2104 Multilabel Reader. Duplicate the fluorescence readings (Lance signal ratio (665nm / 615nm)). Convert the above data to the inhibition percentage using the formula: Percent inhibition = (max - Sample Lance signal ratio) / (max - min) * 100. "min" is the reading of the control well without enzyme; "max" is the reading of the control well with DMSO. Import the data into MS Excel and use XLFit Excel add-in version 5.4.0.8 to perform curve fitting; fitting formula: Y=Bottom+(Top-Bottom) / (1+(IC50 / X)^HillSlope).

[0381] The results of the Cyclin D1-CDK4 activity inhibition assay are shown in Table 2 below. IC 50 Compounds with an IC50 of 10 nM or less were labeled “A”. Compounds with an IC50 greater than 10 nM and less than or equal to 100 nM were labeled “B”. Compounds with an IC50 greater than 100 nM and less than or equal to 1000 nM were labeled “C”. Compounds with an IC50 greater than 1000 nM were labeled “D”. The results are shown in Table 2.

[0382] Experiment Example 3: MCF-7 Cell Proliferation Inhibition Activity Test

[0383] Logarithmically growing MCF-7 cells were selected, trypsinized, and seeded in DMEM medium containing 10% fetal bovine serum into 96-well plates at a density of 1000 cells / 100 μl per well. The plates were incubated at 37°C with 5% CO2 for 24 h. Subsequently, DMEM complete medium containing HJQ series compounds at varying concentrations was added to the 96-well plates, and the cells were incubated again. After 6 days, diluted CCK-8 stock solution was added to the 96-well plates, and the OD values ​​were measured using a FlexStation 3 (Molecular Devices, USA) to calculate the IC50. 50 Compounds with an IC50 of 100 nM or less were labeled “A”. Compounds with an IC50 greater than 100 nM and less than or equal to 1000 nM were labeled “B”. Compounds with an IC50 greater than 1000 nM and less than or equal to 10000 nM were labeled “C”. Compounds with an IC50 greater than 10000 nM were labeled “D”. The results are shown in Table 3.

[0384] Table 1: Inhibitory activity of compounds in the examples against PI3Kα kinase

[0385] compound <![CDATA[PI3KαIC 50 (nM)]]> 1 B 2 A 3 A 4 A 5 A 6 A 7 B 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A

[0386] Table 2: Inhibitory activity of compounds in the examples against CDK4 kinase

[0387] compound <![CDATA[CDK4 IC 50 (nM)]]> 1 B 2 D 3 B 4 B 5 A 6 A 7 C 8 D 9 D 10 C 11 C 12 C 13 B 14 B 15 B 16 B

[0388] Table 3: Inhibitory activity of compounds in the examples against the proliferation of MCF-7 cells

[0389] compound <![CDATA[MCF-7IC 50 (nM)]]> 1 A 2 B 3 B 4 A 5 A 6 A 7 B 8 A 9 A 10 A 11 B 12 A 13 B 14 A 15 B 16 A

Claims

1. A compound or pharmaceutically acceptable salt of formula (I): in: R is selected from 2,4-difluorophenylsulfonamide, fluorine, hydrogen, 2-chloro-4-fluorophenylsulfonamide, and 5-chlorothiophene-2-sulfonamide; A is O; L is in: 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; a is an integer between 0 and 8, b is 0 or 1, and the R1 group is absent or selected from groups represented by the structures of the following formulas (R1-1)-(R1-15): Or, L is Where q and r are independently 1, 2, or 3, and the R2 basis is none or none. Where c is an integer from 1 to 5; or, the R2 group is selected from the group represented by the structure (R2-1)-(R2-3): B is in: d is an integer between 0 and 4.

2. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that, A is oxygen, and L is... in: m is an integer from 1 to 6; n is an integer between 2 and 8; o and p, q and r, s and t are each independently 1 or 2 at the same time; a and b are O, and R1 basis is... Alternatively, a = 3, b = 0, and R1 radix = 3. Alternatively, a = 3, b = 1, and R1 basis = 3. Alternatively, a can be 1-7, b can be 1, and R1 can be none; R2 base is Where c is 2, 3, or 4; or, the R2 basis is selected from... B is in: d is an integer between 0 and 3.

3. The compound according to claim 1, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, characterized in that, A is oxygen, and L is... in: q and r are both 1 or 2; m is 1-4; a is 1-7, b is 1, and R1 basis is zero; B is in: d is 1.

4. The compound, its stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that, R is selected from 2,4-difluorophenylsulfonamide or methoxy.

5. The compound according to any one of claims 1 to 4, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from:

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

7. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition further comprises a pharmaceutically active ingredient other than the compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts.

8. Use of the compound of any one of claims 1 to 5, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition of any one of claims in the preparation of a medicament for the prevention and / or treatment of PI3K-mediated diseases.

9. The 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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