CN111646973B - Polysubstituted quinazoline derivative and preparation method, pharmaceutical composition and application thereof - Google Patents

Polysubstituted quinazoline derivative and preparation method, pharmaceutical composition and application thereof Download PDF

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CN111646973B
CN111646973B CN201910161874.8A CN201910161874A CN111646973B CN 111646973 B CN111646973 B CN 111646973B CN 201910161874 A CN201910161874 A CN 201910161874A CN 111646973 B CN111646973 B CN 111646973B
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quinazoline
methoxy
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许恒
陈晓光
张可辉
来芳芳
林松文
伏蓉
金晶
季鸣
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Abstract

The invention relates to polysubstituted quinazoline derivatives, a preparation method, a pharmaceutical composition and application thereof. The polysubstituted quinazoline derivative is shown in a formula (I), is a PI3K/HDAC dual inhibitor, and can be used for preventing and/or treating diseases related to PI3K and/or HDAC activity, such as tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolism/endocrine dysfunction or neurological diseases.

Description

Polysubstituted quinazoline derivative and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the technical field of pharmacy, and relates to a polysubstituted quinazoline derivative, and a preparation method, a pharmaceutical composition and application thereof.
Background
Phosphatidylinositol 3-kinase (PI 3K) is a Phosphatidylinositol kinase widely present in cells and involved in the regulation of various cell functions such as cell proliferation, differentiation, apoptosis, signal transduction, and glucose transport. PI3K can be classified into three major groups I, II and III according to their structure and function, among which the most studied class I PI3K contains four subtypes, α, β, γ and δ, which are heterodimers composed of a regulatory subunit (p85) and a catalytic subunit (p 110); PI3K γ and PI3K δ are mainly distributed in leukocytes, and the other two subtypes, PI3K α and PI3K β, are widely distributed in various cells. PI3K is a downstream protein of Receptor Tyrosine Kinase (RTK) and G protein-coupled receptor (GPCR), and activates protein kinase b (akt) by phosphorylation of corresponding phospholipids, thereby transducing various cytokine signals outside the cell into the cell. The abnormality of the PI3K signal channel is closely related to the formation and development of various diseases, for example, the gene PIK3CA coding for p110 alpha has a large amount of amplification and mutation in a plurality of tumor tissues, and the inhibition of the PI3K activity obviously retards the cell cycle, thereby inhibiting the proliferation of cells. Three PI3K inhibitors are currently approved by the FDA for marketing, namely Idelalisib, Copanlisib, and Duvelisib; in addition, a plurality of PI3K inhibitors are in clinical trial, and the indications include autoimmune diseases such as psoriasis, rheumatoid arthritis, ulcerative colitis, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease and other diseases related to the class I PI3K besides tumors.
Acetylation modification of proteins is a common post-translational modification. Histidine Deacetylase (HDAC) is an enzyme that hydrolyzes and removes the lysine N-acetyl group of Histone, and plays an important role in the structural modification of chromosome and the regulation of gene transcription. Under normal conditions, HDACs remove acetyl modification of histones, which facilitates the binding of DNA to histones, makes the structure of nucleosomes more compact, and various transcription factors cannot recognize specific sequences on DNA, thereby reducing the transcription level of genes. HDAC has been proved to have higher expression level in various tumor cells such as gastric cancer, colorectal cancer and cervical cancer; in tumor cells, inhibition of HDAC activity can induce the expression of cancer suppressor genes by activating DNA transcription, thereby achieving the goal of treating cancer. The HDAC inhibitors Vorinostat, Romidepsin, Belinostat and Panobinostat have been approved by the FDA for marketing for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma and multiple myeloma, and several HDAC inhibitors are in clinical trials.
In recent years, documents (such as Pei, et al. cancer Cell 2016,29(3):311-323) report that a synergistic effect exists between an HDAC inhibitor and a PI3K inhibitor, and the proliferation of the MYC high-expression medulloblastoma can be effectively inhibited, so that a new idea is provided for future anticancer drug treatment. Currently, the dual PI3K/HDAC inhibitor CUDC-907 of the american Curis company has entered phase II clinical trials and has been identified by the FDA fast review (fast track) for the treatment of relapsed/refractory diffuse large B-cell lymphoma. Therefore, the development of a novel dual inhibitor of PI3K and HDAC not only can improve the antitumor activity by utilizing the synergistic effect of the two inhibitors, but also is expected to overcome the drug resistance problem caused by a PI3K inhibitor or an HDAC inhibitor, and has wide application prospect and practical value.
Disclosure of Invention
The technical problem solved by the present invention is to provide a novel PI3K/HDAC dual inhibitor, a preparation method, a pharmaceutical composition and a use thereof, wherein the PI3K/HDAC dual inhibitor has strong inhibitory activity on PI3K and/or HDAC, thereby having better prevention and/or treatment effects on diseases mediated by PI3K and/or HDAC, such as tumor, autoimmune disease, renal disease, cardiovascular disease, inflammation, metabolism/endocrine function disorder or neurological disease.
In order to solve the technical problem, the invention provides the following technical scheme:
in a first aspect of the technical scheme of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0001984930190000021
wherein:
R1selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-4Alkoxy, cyano, C1-4Alkylsulfonylamino group, C3-6Cycloalkylsulfonamido, phenylsulfonamido, or 5-6 membered heteroarylsulfonamido;wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with 1 to 5 halogens;
a is
Figure BDA0001984930190000022
Wherein n is an integer of 1 to 10; or, A is
Figure BDA0001984930190000023
Wherein said R2Selected from hydrogen or C1-6Alkyl, m is an integer from 1 to 10.
In a further preferred embodiment, A is
Figure BDA0001984930190000024
Wherein n is an integer of 1 to 8.
In another further preferred embodiment, A is
Figure BDA0001984930190000031
Wherein, R is2Selected from methyl, ethyl, propyl or isopropyl, and m is 2,3 or 4.
In another preferred embodiment, the present invention provides a compound or pharmaceutically acceptable salt of formula (I):
wherein
A is
Figure BDA0001984930190000032
Wherein n is an integer of 1 to 10;
preferably, n is an integer of 1,2,3, 4, 5, 6, 7, 8
Or, A is
Figure BDA0001984930190000033
Wherein said R2Selected from hydrogen or C1-6Alkyl, m is an integer from 1 to 10;
preferably, said R is2Selected from methyl, ethyl, propyl or isopropyl, and m is 2,3 or 4.
R1Selected from hydrogen, fluoro, methoxy, cyano, methylsulfonylamino,Cyclopropylsulfonamido, 2, 4-difluorophenylsulfonamido, 2-chloro-4-fluorophenylsulfonamido, 4-fluorophenylsulfonamido or 5-chlorothiophene-2-sulfonamido.
In particular, preferred compounds according to the invention are the following:
Figure BDA0001984930190000041
Figure BDA0001984930190000051
in a second aspect of the present invention, there is provided a method for preparing the compound, comprising the steps of:
Figure BDA0001984930190000061
(1) taking the compound A as a starting material, and preparing a compound B through nitration reaction;
(2) preparing a compound C from the compound B through a reduction reaction;
(3) preparing a compound D from the compound C through bromination reaction;
(4) reacting the compound D with ammonium formate and formamide to prepare a compound E;
(5) deprotecting the methyl group of compound E to produce a universal intermediate F;
(6) reacting the compound F with corresponding ethyl bromo-carboxylate to prepare a compound G;
(7) preparing a compound H from the compound G and substituted pyridine-3-boric acid or substituted pyridine-3-boronic acid pinacol ester through a Suzuki reaction;
(8) reacting the compound H with hydroxylamine to obtain the compound.
The second aspect of the present technical solution also provides another method for preparing the compound, which comprises the steps of:
Figure BDA0001984930190000071
(1) preparing a compound I by carrying out a Mitsunobu reaction on the compound F and a corresponding alcohol or carrying out a substitution reaction on the compound F and a corresponding bromide;
(2) deprotecting the Boc of compound I to produce compound J;
(3) reacting the compound J with 2-chloropyrimidine-5-carboxylic acid ethyl ester to prepare a compound K;
(4) preparing a compound L by a Suzuki reaction of the compound K and substituted pyridine-3-boric acid or substituted pyridine-3-boronic acid pinacol ester;
(5) reacting the compound L with hydroxylamine to obtain the compound.
A third aspect of the present invention provides a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and/or excipient; preferably, the pharmaceutical composition further comprises one or more pharmaceutically active ingredients for preventing and/or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolism/endocrine function disorders or neurological diseases, other than the compound or the pharmaceutically acceptable salt thereof; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and/or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolism/endocrine function disorders or neurological diseases.
In yet another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of said compounds or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or/excipient; preferably, the pharmaceutical formulation is selected from the following pharmaceutical dosage forms: parenteral formulations, such as injection solutions or suspensions; enterally administered formulations, e.g., oral formulations such as tablets or capsules; formulations for topical administration, for example lotions, gels, ointments, creams, nasal preparations, suppositories, transdermal preparations or ophthalmic preparations.
In still another aspect, the present invention also provides a use of the compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for the preparation of a medicament for preventing and/or treating tumors, autoimmune diseases, kidney diseases, cardiovascular diseases, inflammation, metabolism/endocrine dysfunction, or neurological diseases. In other words, the present invention provides a method for preventing and/or treating tumors, autoimmune diseases, renal diseases, cardiovascular diseases, inflammations, metabolism/endocrine functions or neurological diseases, which comprises administering a prophylactically and/or therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject in need thereof.
Some of the terms used in the present invention are defined below, and other undefined terms have meanings well known to those skilled in the art.
Halogen means fluorine, chlorine, bromine or iodine.
C1-4Alkoxy means an-O-alkyl group, wherein the alkyl group contains 1,2,3, 4 carbon atoms and is straight, branched or cyclic. Examples of such groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, cyclopropyloxy or cyclobutoxy.
C1-4Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups having 1,2,3, 4 carbon atoms. Examples of such groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl.
C1-6Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups having 1,2,3, 4, 5, 6 carbon atoms. Examples of such groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl.
C3-6Cycloalkyl refers to a saturated monocyclic, fused, spiro or polycyclic structure having 3,4, 5, 6 carbon ring atoms. Examples of such groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl.
5-6 membered heteroaryl refers to 5-6 membered aromatic heterocyclic groups including, but not limited to: 5-membered heteroaryl: furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (1,2, 4-triazolyl, 1,3, 4-triazolyl or 1,2, 3-triazolyl), thiadiazolyl (1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,2, 3-thiadiazolyl or 1,2, 4-thiadiazolyl), and oxadiazolyl (1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-oxadiazolyl or 1,2, 4-oxadiazolyl); and 6-membered heteroaryl: pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. Preferred heteroaryl groups are thienyl, thiazolyl, pyridyl, pyrimidinyl.
"optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "alkyl optionally substituted with halo" means that halo may, but need not, be present, and the description includes instances where alkyl is substituted with halo and instances where alkyl is not substituted with halo.
The compounds of the present invention also include isotopically-labeled compounds thereof, in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass number different from the atomic mass number usually found in nature. Examples of isotopes suitable for the invention include, but are not limited to: isotopes of hydrogen2H and3h; isotopes of carbon11C、13C and14c; isotopes of chlorine36Cl; isotopes of fluorine18F; isotopes of iodine123I and125i; isotopes of nitrogen13N and15n; isotopes of oxygen15O、17O and18o; isotopes of phosphorus32Isotopes of P and sulfur35S。
Various hydrates and solvates of the compound or salt thereof described in the present invention and polymorphs (polymorphisms) thereof are also included in the scope of the present invention.
Prodrugs of the compounds described herein are also included within the scope of the invention. Some derivatives of the compounds described in the present invention have weak pharmacological activity or no pharmacological activity themselves, but when these derivatives are administered into or onto the body, they may be converted into the compounds described in the present invention having pharmacological activity by means of, for example, hydrolytic cleavage, and the like, and these derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, vol.14, ACS Symposium Series (t.higuchi and w.stella) and Bioreversible Carriers in Drug Design, Pergamon Press,1987(ed.e.b.roche, American Pharmaceutical Association).
The compounds of the present invention include pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts are salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts are described in detail in j.pharma.sci.,1977,66,1-19 by Berge et al, which is incorporated herein by reference. The compounds of the present invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic bases, or inorganic and organic acids, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, dihydrogenphosphate, metaphosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, caprylate, or a mixture thereof, Citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.
When used as a medicament, the compounds of the present invention are generally administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions of the compounds of the present invention and a pharmaceutically acceptable carrier, diluent or excipient are also included within the scope of the present invention. Carrier as used hereinThe bodies, adjuvants, excipients include any and all solvents, diluents or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as appropriate to the particular dosage form desired. In Remington: the Science and Practice of Pharmacy, 21stedition，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, disclose various carriers for the formulation of pharmaceutically acceptable compositions and known techniques for their preparation, the contents of which are incorporated herein by reference.
The compositions of the present invention may be administered by any route suitable for the condition to be treated. In particular by administration in the form: parenterally, e.g., in the form of injectable solutions or suspensions; enterally, e.g., orally, e.g., in tablet or capsule form; topically, for example in the form of a lotion, gel, ointment or cream or in the form of a nasal or suppository. Topical application is, for example, application to the skin. Another form of topical administration is to the eye.
The pharmaceutical compositions may be administered in solid, semi-solid, liquid or gaseous form, or may be in a dry powder, such as lyophilized form. Pharmaceutical compositions can be packaged in a form convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally depend on the route of administration. Implantable sustained release formulations, as well as transdermal formulations, are also contemplated.
Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid or potassium sorbate, partial glyceride mixtures 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, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; and phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
The compounds of the present invention may be used alone or in combination with other therapeutic agents for the treatment of the diseases or conditions described herein, such as cancer. In certain embodiments, the compounds of the present invention are combined in a pharmaceutical combination formulation, or as a combination therapy in a dosing regimen, with a second compound having anti-hyperproliferative properties or for the treatment of a hyperproliferative disease, such as cancer. The second compound of the pharmaceutical combination or dosing regimen preferably has complementary activities to the compounds of the present invention such 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 the invention are combined with other anti-tumor agents. The anti-tumor medicine comprises: alkylating agents, including but not limited to cyclophosphamide, mechlorethamine, melphalan, meconium, carmustine; platinoids including but not limited to carboplatin, cisplatin, oxaliplatin; topoisomerase inhibitors including, but not limited to, topotecan, camptothecin, topotecan, irinotecan; antibiotics, including but not limited to, anthracyclines, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; anti-microtubule or anti-mitotic agents including, but not limited to, paclitaxel, vinorelbine, docetaxel, doxorubicin; antimetabolites including, but not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine (mecaptoprine), thioguanine, and gemcitabine; antibodies, including but not limited to herceptin, bevacizumab; hormones including, but not limited to, letrozole (letrozole), vorozole (vorozole), tamoxifen, toremifene, fulvestrant, flutamide, nilutamide, triptorelin; a class of kinase inhibitors, EGFR kinase inhibitors, including but not limited to gefitinib (gefitinib), erlotinib (erlotinib), lapatinib (lapatinib), afatinib (afatinib); VEGFR inhibitors including, but not limited to, Sorafenib (Sorafenib), regrafenib (Regorafenib), Sunitinib (Sunitinib), Cabozantinib (Cabozantinib), Pazopanib (Pazopanib), vandetanib (vandetanib), axitinib (axitinib); ALK inhibitors including, but not limited to, Crizotinib (Crizotinib), ceritinib (ceritinib), Alectinib; Bcr-Abl inhibitors, including but not limited to Imatinib (Imatinib), panatinib (Ponatinib), Nilotinib (Nilotinib), Dasatinib (Dasatinib); BTK inhibitors, including but not limited to Ibrutinib (Ibrutinib); B-RAF inhibitors, including but not limited to Vemurafenib (Vemurafenib); cyclin-dependent kinase CDK4/6 inhibitors, Palbociclib (Palbociclib); mTOR inhibitors, including but not limited to rapamycin (rapamycin), everolimus (everolimus); sirtuin inhibitors, including but not limited to vorinostat (vorinostat); PD1/PDL1 antibody, Keytruda (Pembrolizumab), Opdivo (Nivolumab).
In a fourth aspect of the present invention, there is provided a use of the compound of the first aspect or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the third aspect, in the preparation of a medicament for preventing and/or treating a PI3K and/or HDAC mediated disease, wherein the PI3K and/or HDAC mediated disease includes cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorder or neurological disease.
The beneficial technical effects are as follows: the compounds of the present invention showed significant inhibitory activity against PI3K α in an in vitro kinase activity assay. The compounds of the invention show significant inhibitory activity against HDAC in vitro protein level activity assays. The compound of the invention has strong in vitro antiproliferative activity on human colon cancer cells HCT 116.
Detailed Description
The following are specific examples of the present invention, which further describe the technical solutions of the present invention, but the scope of the present invention is not limited to these examples. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
Preparation method
The compounds of the present invention may be synthesized according to the synthetic schemes herein and/or by techniques well known in the art. For example, the compounds provided by the present invention can be prepared according to the following general synthetic methods.
In one general synthetic approach, compounds of formula (I) were prepared according to method-1.
Method-1
Figure BDA0001984930190000121
Specifically, in the method-1, the polysubstituted quinazoline derivative provided by the invention can be prepared through an 8-step reaction. For example, compound A is used as a starting material, compound B is prepared through nitration reaction, and compound C is obtained through reduction reaction; performing bromination reaction on the compound C to obtain a compound D, and reacting the compound D with ammonium formate and formamide to obtain a compound E with a quinazoline skeleton; removing methyl from the compound E to obtain a general intermediate F; carrying out substitution reaction on the compound F and corresponding ethyl bromocarboxylate to obtain a compound G; carrying out Suzuki reaction on the compound G and substituted pyridine-3-boric acid or substituted pyridine-3-boronic acid pinacol ester to prepare a compound H; and carrying out hydroxylamine hydrolysis reaction on the compound H to obtain the polysubstituted quinazoline derivative.
In another general synthetic method, a compound of formula (I) is prepared according to method-2.
Method-2
Figure BDA0001984930190000131
Specifically, in the synthesis method-2, the polysubstituted quinazoline derivative provided by the invention can be prepared through a 10-step reaction. For example, compound F undergoes a Mitsunobu reaction with the corresponding alcohol, or a substitution reaction with the corresponding bromide, to give compound I; removing Boc protection from the compound I to obtain a compound J, and reacting the compound J with 2-chloropyrimidine-5-carboxylic acid ethyl ester to obtain a compound K; carrying out Suzuki reaction on the compound K and substituted pyridine-3-boric acid or substituted pyridine-3-boronic acid pinacol ester to prepare a compound L; and carrying out hydroxylamine hydrolysis reaction on the compound L to obtain the polysubstituted quinazoline derivative.
The compounds of the present invention may be synthesized according to one or more of the synthetic schemes herein and/or by techniques well known in the art. One skilled in the art will recognize that the synthetic methods of certain embodiments described in detail herein can be readily adapted to synthesize other embodiments. In some embodiments, the compounds described herein may be prepared by an appropriate combination of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as alfa aesar (china) chemical ltd, or are readily prepared using synthetic methods commonly used in the art.
1H NMR spectra were recorded on instruments operated at 400MHz or 500 MHz. H NMR spectra were obtained as a solution (reported in ppm) using CDCl3(7.26ppm) or DMSO-d6(2.50ppm) or internal tetramethylsilane (0.00ppm) as reference standard. When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants given are in hertz (Hz).
In the following preparations and examples, "Me" means methyl, "Et" means ethyl, "Boc" means t-butyloxycarbonyl, "PE" means petroleum ether, "EtOAc" means ethyl acetate, "MeOH" means methanol, "DMSO-d6"refers to deuterated dimethylsulfoxide," DCM "refers to dichloromethane," rt "refers to room temperature," mL "refers to mL," mmol "refers to millimole," μ M "refers to micromole," nM "refers to nanomole," and "deg.C" refers to degrees Celsius.
Example 1: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000141
Step 1: synthesis of 2-nitro-3-methoxyacetophenone
Figure BDA0001984930190000142
Placing 65% nitric acid (1L) into a 2L eggplant-shaped bottle, adding 3-methoxyacetophenone (180g, 1.20mol) under vigorous stirring, reacting at room temperature for 72 hours, pouring the reaction liquid into 4L of ice water, separating out orange yellow solid, filtering, washing filter cakes with water (1L) and absolute ethyl alcohol (1L) in sequence, and drying to obtain a product which is light yellow solid (89.2g, the yield is 38%).
1H NMR(400MHz,CDCl3)δ7.53(dd,J＝8.4,7.9Hz,1H),7.37(dd,J＝7.9,1.1Hz,1H),7.24(dd,J＝8.4,1.0Hz,1H),3.93(s,3H),2.58(s,3H).
MS(ESI+)m/z 195.9[M+H]+.
Step 2: synthesis of 2-amino-3-methoxyacetophenone
Figure BDA0001984930190000143
2-nitro-3-methoxyacetophenone (46.1g, 0.24mol) was dissolved in a mixed solvent of THF/EtOH/water (400mL/400mL/200mL), ammonium chloride (25.3g, 0.47mol), reduced iron powder (52.9g, 0.94mol) were added with stirring, refluxed for 2 hours, and celite was filtered to remove insoluble solids, the solvent was evaporated under reduced pressure, dissolved in dichloromethane (300mL), washed with water (300mL) and saturated brine (200mL) in this order, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure and used in the next reaction without purification.
1H NMR(400MHz,CDCl3)δ7.33(dd,J＝8.4,0.8Hz,1H),6.84(dd,J＝7.6,0.8Hz,1H),6.57(dd,J＝8.4,7.6Hz,1H),3.87(s,3H),2.57(s,3H).
MS(ESI+)m/z 166.1[M+H]+.
And 3, step 3: synthesis of 2-amino-3-methoxy-5-bromoacetophenone
Figure BDA0001984930190000151
2-amino-3-methoxyacetophenone (39g, 0.236mol) was dissolved in dichloromethane (500mL), N-bromosuccinimide (43.4g, 0.244mol) was added in portions with stirring, and after reaction at room temperature for 3 hours, water (500mL) was added, dichloromethane (200mL) was extracted three times, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (PE: EtOAc ═ 3:1) to obtain the product as a pale yellow solid (43.0g, yield 74.6%).
1H NMR(400MHz,CDCl3)δ7.44(d,J＝2.0Hz,1H),6.90(d,J＝2.0Hz,1H),3.87(s,3H),2.55(s,3H).
MS(ESI+)m/z 243.9,246.0[M+H]+.
And 4, step 4: synthesis of 4-methyl-6-bromo-8-methoxy quinazoline
Figure BDA0001984930190000152
2-amino-3-methoxy-5-bromoacetophenone (7.59g, 31mmol) was dissolved in formamide (90mL), ammonium formate (9.11g, 144mmol) was added, argon was pumped three times, the reaction was allowed to react at 150 ℃ for 10 hours, water (500mL) was added to quench the reaction, ethyl acetate (80 mL. times.10) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM: EtOAc: 2:1) to give the product as a pale yellow solid (4.2g, 53.5% yield).
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.98(d,J＝1.9Hz,1H),7.53(d,J＝1.9Hz,1H),4.00(s,3H),2.86(s,3H).
MS(ESI+)m/z 253.0,255.0[M+H]+.
And 5: synthesis of 4-methyl-6-bromo-8-hydroxyquinazoline
Figure BDA0001984930190000161
6-bromo-4-methyl-8-methoxyquinazoline (4.2g, 16.6mmol) was dissolved in 1, 2-dichloroethane (250mL), aluminum trichloride (6.75g, 50.6mmol) was added with stirring, the reaction was carried out at 80 ℃ for 2 hours, and then ice water (250mL) was added for quenching, dichloromethane (60 mL. times.5) was added for extraction, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM: MeOH. RTM. 15:1) to obtain the product as a brown solid (2.2g, yield 55%).
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.09(s,1H),7.85(d,J＝1.9Hz,1H),7.40(d,J＝1.9Hz,1H),2.85(s,3H).
MS(ESI+)m/z 239.0,240.9[M+H]+.
Step 6: synthesis of 4-methyl-6-bromo-8- (heptanoic acid ethyl ester-7-oxy) quinazoline
Figure BDA0001984930190000162
6-bromo-4-methyl-8-hydroxyquinazoline (0.6g, 2.51mmol) was dissolved in anhydrous acetonitrile (20mL), 7-bromoheptanoic acid ethyl ester (0.615mL, 3.01mmol) and anhydrous potassium carbonate (0.7g, 5.02mmol) were added, reacted at 86 ℃ for 16 hours, the solvent was evaporated under reduced pressure, dichloromethane (30mL) was added, insoluble solids were removed by filtration, washed successively with water (30mL) and saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE: EtOAc ═ 1:2) to give the product as a pale yellow solid (0.89g, 90% yield).
1H NMR(400MHz,CDCl3)δ9.22(s,1H),7.81(d,J＝1.9Hz,1H),7.32(d,J＝1.8Hz,1H),4.21(t,J＝6.8Hz,2H),4.13(q,J＝7.1Hz,2H),2.96(s,3H),2.32(t,J＝7.5Hz,2H),2.09–1.97(m,2H),1.68(dt,J＝15.1,7.4Hz,2H),1.62–1.52(m,2H),1.50–1.40(m,2H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 395.2,397.0[M+H]+.
And 7: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline
Figure BDA0001984930190000163
4-methyl-6-bromo-8- (ethylheptanoate-7-oxy) quinazoline (44mg, 0.11mmol) and 2-methoxy-5-pyridineboronic acid (26mg, 0.17mmol) were dissolved in toluene/water (3mL/1mL), 2N aqueous potassium carbonate (0.17mL, 0.34mmol) was added, argon was pumped three times, PdCl was added2(dppf) (8mg, 0.011mmol), reaction at 80 ℃ for 8 hours, celite filtration to remove insoluble solids, extraction with ethyl acetate (10 mL. times.3), drying over anhydrous sodium sulfate, filtration, concentration, and purification by silica gel column chromatography (PE: EtOAc ═ 1:6) to afford the product as a pale yellow solid (40mg, 85% yield).
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.48(d,J＝2.3Hz,1H),7.89(dd,J＝8.6,2.5Hz,1H),7.70(d,J＝1.3Hz,1H),7.35(d,J＝1.1Hz,1H),6.89(d,J＝8.5Hz,1H),4.27(t,J＝6.8Hz,2H),4.11(q,J＝7.1Hz,2H),4.00(d,J＝1.8Hz,3H),2.98(s,3H),2.30(t,J＝7.5Hz,2H),2.09–1.99(m,2H),1.66(dd,J＝15.2,7.6Hz,2H),1.56(dd,J＝15.3,7.7Hz,2H),1.49–1.40(m,2H),1.26–1.21(t,3H).
MS(ESI+)m/z 424.2[M+H]+.
And 8: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000171
4-methyl-6- (2-methoxy-5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline (60mg, 0.14mmol) was dissolved in anhydrous methanol (3mL), potassium hydroxide (78mg, 1.4mmol) and 50% hydroxylamine aqueous solution (0.28mL, 4.2mmol) were added, the reaction was allowed to react at room temperature for 2 hours, the reaction was cooled in an ice bath to adjust the pH to about 5-6, and a pale yellow solid was obtained by filtration and recrystallization from anhydrous methanol to obtain the product as a white solid (34mg, yield 60%).
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.06(s,1H),8.74(d,J＝2.5Hz,1H),8.65(s,1H),8.28(dd,J＝8.6,2.6Hz,1H),7.96(d,J＝1.3Hz,1H),7.66(d,J＝1.3Hz,1H),6.98(d,J＝8.6Hz,1H),4.28(t,J＝6.5Hz,2H),3.93(s,3H),2.95(s,3H),1.97(t,J＝7.3Hz,2H),1.91–1.81(m,2H),1.52(dt,J＝14.8,7.4Hz,4H),1.37(d,J＝6.8Hz,2H).
MS(ESI+)m/z 411.0[M+H]+.
Example 2: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyacetamido-2-oxy) quinazoline
Figure BDA0001984930190000181
Step 1: synthesis of 4-methyl-6-bromo-8- (ethyl acetate-2-oxy) quinazoline
Figure BDA0001984930190000182
The title compound was synthesized according to the method of step 6 in example 1 from ethyl 2-bromoacetate.
1H NMR(400MHz,CDCl3)δ9.10(s,1H),7.77(d,J＝1.8Hz,1H),7.14(d,J＝1.8Hz,1H),4.87(s,2H),4.22(q,J＝7.1Hz,2H),2.82(s,3H),1.22(t,J＝7.1Hz,3H).
MS(ESI+)m/z 325.0,327.0[M+H]+.
And 2, step: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethyl acetate-2-oxy) quinazoline
Figure BDA0001984930190000183
The title compound was synthesized from 4-methyl-6-bromo-8- (ethyl acetate-2-oxy) quinazoline according to the method of step 7 in example 1.
1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.42(d,J＝2.3Hz,1H),7.82(dd,J＝8.6,2.6Hz,1H),7.75(d,J＝1.6Hz,1H),7.29(d,J＝1.6Hz,1H),6.85(d,J＝8.7Hz,1H),5.00(s,2H),4.25(q,J＝7.1Hz,2H),3.98(s,3H),2.95(s,3H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 354.0[M+H]+.
And step 3: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyacetamide-2-oxy) quinazoline
Figure BDA0001984930190000191
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethyl acetate-2-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,MeOD-d4)δ9.14(s,1H),8.63(d,J＝2.6Hz,1H),8.19(dd,J＝8.7,2.6Hz,1H),8.09(d,J＝1.6Hz,1H),7.76(d,J＝1.6Hz,1H),6.98(d,J＝8.6Hz,1H),4.96(s,2H),4.01(s,3H),3.07(s,3H).
MS(ESI+)m/z 341.1[M+H]+.
Example 3: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxybutyramide-4-oxy) quinazoline
Figure BDA0001984930190000192
Step 1: synthesis of 4-methyl-6-bromo-8- (ethyl butyrate-4-oxy) quinazoline
Figure BDA0001984930190000193
The title compound was synthesized from ethyl 4-bromobutyrate according to the method of step 6 in example 1.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),7.79(d,J＝1.5Hz,1H),7.31(s,1H),4.27(t,J＝6.4Hz,2H),4.15(q,J＝7.1Hz,2H),2.90(s,3H),2.60(t,J＝7.1Hz,2H),2.31(p,J＝6.8Hz,2H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 353.0，355.0[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (butyric acid ethyl ester-4-oxy) quinazoline
Figure BDA0001984930190000201
The title compound was synthesized from 4-methyl-6-bromo-8- (ethyl butyrate-4-oxy) quinazoline according to the method of step 7 in example 1.
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.42(d,J＝2.3Hz,1H),7.83(dd,J＝8.6,2.5Hz,1H),7.64(d,J＝1.5Hz,1H),7.33(d,J＝1.4Hz,1H),6.81(d,J＝8.5Hz,1H),4.29(t,J＝6.4Hz,2H),4.08(q,J＝7.1Hz,2H),3.94(s,3H),2.89(s,3H),2.56(t,J＝7.1Hz,2H),2.27(p,J＝6.7Hz,2H),1.18(t,J＝7.1Hz,3H).
MS(ESI+)m/z 382.2[M+H]+.
And step 3: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxybutyramide-4-oxy) quinazoline
Figure BDA0001984930190000202
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (butyric acid ethyl ester-4-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,MeOD-d4)δ9.05(s,1H),8.58(d,J＝1.6Hz,1H),8.20–8.04(dd,J＝8.51.6Hz,1H),7.95(s,1H),7.64(s,1H),6.95(d,J＝8.5Hz,1H),4.37(t,J＝5.6Hz,2H),3.99(s,3H),3.01(s,3H),2.44(m,2H),2.36–2.23(m,2H).
MS(ESI+)m/z 369.1[M+H]+.
Example 4: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxybutyramide-4-oxy) quinazoline
Figure BDA0001984930190000203
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (ethyl butyrate-4-oxy) quinazoline
Figure BDA0001984930190000211
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (ethyl butyrate-4-oxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.17(d,J＝2.2Hz,1H),8.02(d,J＝2.2Hz,1H),7.90–7.81(m,1H),7.67(d,J＝1.2Hz,1H),7.30–7.23(d,J＝1.2Hz,1H),6.98–6.92(m,2H),4.35–4.29(m,2H),4.11(q,J＝7.1Hz,2H),3.95(s,3H),2.99(s,3H),2.63(t,J＝6.8Hz,2H),2.43–2.20(m,2H),1.24(t,J＝7.1Hz,3H).
MS(ESI+)m/z 572.9[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxybutyramide-4-oxy) quinazoline
Figure BDA0001984930190000212
The title compound was synthesized from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (ethyl butyrate-4-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.29(s,1H),9.03(s,1H),8.71(d,J＝2.1Hz,1H),8.56(d,J＝2.1Hz,1H),8.13–8.10(m,1H),7.92(d,J＝1.1Hz,1H),7.77–7.72(m,1H),7.62–7.56(m,2H),7.24–7.20(m,1H),4.30(t,J＝6.0Hz,2H),3.66(s,3H),2.96(s,3H),2.25(t,J＝7.2Hz,2H),2.11–2.09(m,2H).
MS(ESI+)m/z 560.1[M+H]+.
Example 5: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxypentanamide-5-oxy) quinazoline
Figure BDA0001984930190000221
Step 1: synthesis of 4-methyl-6-bromo-8- (ethyl valerate-5-oxy) quinazoline
Figure BDA0001984930190000222
The title compound was synthesized from ethyl 5-bromovalerate according to the method of step 6 in example 1.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),7.77(d,J＝1.6Hz,1H),7.26(d,J＝1.6Hz,1H),4.19(t,J＝6.6Hz,2H),4.11(q,J＝7.1Hz,2H),2.89(d,J＝0.7Hz,3H),2.40(t,J＝7.4Hz,2H),2.08–2.00(m,2H),1.91–1.83(m,2H),1.25–1.21(t,J＝7.1Hz,3H).
MS(ESI+)m/z 367.1,369.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethyl valerate-5-oxy) quinazoline
Figure BDA0001984930190000223
The title compound was synthesized from 4-methyl-6-bromo-8- (ethyl valerate-5-oxy) quinazoline following the procedure of step 7 in example 1.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.49(d,J＝1.7Hz,1H),7.89(dd,J＝8.4,2.0Hz,1H),7.71(d,J＝1.5Hz,1H),7.36(d,J＝1.5Hz,1H),6.89(d,J＝8.5Hz,1H),4.30(t,J＝6.5Hz,2H),4.12(q,J＝7.1Hz,2H),4.01(s,3H),2.98(s,3H),2.43(t,J＝7.3Hz,2H),2.08(m,2H),1.96–1.86(m,2H),1.24(t,J＝7.1Hz,3H).
MS(ESI+)m/z 396.1[M+H]+.
And step 3: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxypentanamide-5-oxy) quinazoline
Figure BDA0001984930190000231
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethylpentanoate-5-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,MeOD-d4)δ9.04(s,1H),8.56(d,J＝1.9Hz,,1H),8.13(dd,J＝8.5,1.8Hz,1H),7.90(d,J＝1.5Hz,1H),7.58(d,J＝1.5Hz,1H),6.94(d,J＝8.6Hz,1H),4.34(m,2H),3.98(s,3H),3.00(s,3H),2.33(t,J＝6.7Hz,2H),1.98(m,4H).
MS(ESI+)m/z 383.1[M+H]+.
Example 6: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxypentanamide-5-oxy) quinazoline
Figure BDA0001984930190000232
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (ethyl valerate-5-oxy) quinazoline
Figure BDA0001984930190000233
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (ethyl valerate-5-oxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridinyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.19(d,J＝2.2Hz,1H),8.05(d,J＝2.2Hz,1H),7.96–7.82(m,1H),7.67(d,J＝1.2Hz,1H),7.38–7.28(d,J＝1.2Hz,1H),7.04–6.86(m,2H),4.38–4.27(m,2H),4.13(q,J＝7.1Hz,2H),3.98(s,3H),3.49(s,1H),3.04(s,3H),2.45(t,J＝6.8Hz,2H),2.30–2.10(m,2H),1.98–1.88(m,2H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 587.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxypentanamide-5-oxy) quinazoline
Figure BDA0001984930190000241
The title compound was synthesized from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonamido) -5-pyridyl) -8- (ethyl valerate-5-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,MeOD-d4)δ9.03(s,1H),8.32(d,J＝2.2Hz,1H),8.06(d,J＝2.2Hz,1H),7.95–7.85(m,1H),7.78(d,J＝1.2Hz,1H),7.45(d,J＝1.2Hz,1H),7.27–7.15(m,1H),7.06(m,1H),4.30(d,J＝4.9Hz,2H),3.82(s,3H),2.97(s,3H),2.34(t,J＝6.4Hz,2H),2.07–1.90(m,4H).
MS(ESI+)m/z 574.1[M+H]+.
Example 7: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000242
Step 1: synthesis of 4-methyl-6-bromo-8- (ethyl hexanoate-6-oxy) quinazoline
Figure BDA0001984930190000243
The title compound was synthesized from ethyl 6-bromohexanoate according to the method of step 6 in example 1.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),7.82(d,J＝1.9Hz,1H),7.33(d,J＝1.7Hz,1H),4.22(t,J＝6.7Hz,2H),4.13(q,J＝7.1Hz,2H),2.98(s,3H),2.35(t,J＝7.4Hz,2H),2.13–1.93(m,2H),1.76(m 2H),1.67–1.49(m,2H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 381.1,383.0[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline
Figure BDA0001984930190000251
The title compound was synthesized from 4-methyl-6-bromo-8- (ethyl hexanoate-6-oxy) quinazoline according to the method of step 7 in example 1.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.48(d,J＝1.7Hz,1H),7.89(dd,J＝8.4,2.0Hz,1H),7.70(d,J＝1.5Hz,1H),7.35(d,J＝1.5Hz,1H),6.89(d,J＝8.2Hz,1H),4.28(t,J＝6.0Hz,2H),4.12(q,J＝7.1Hz,2H),4.01(s,3H),2.98(s,3H),2.35(t,J＝7.3Hz,2H),2.13–2.01(m,2H),1.84–1.70(m,2H),1.66–1.55(m,2H),1.24(t,J＝7.1Hz,3H).
MS(ESI+)m/z 409.9[M+H]+.
And 3, step 3: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000252
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.05(s,1H),8.72(d,J＝2.3Hz,1H),8.69(s,1H),8.26(dd,J＝8.6,2.4Hz,1H),7.93(d,J＝1.3Hz,1H),7.64(d,J＝1.2Hz,1H),6.97(d,J＝8.6Hz,1H),4.26(t,J＝6.4Hz,2H),3.93(s,3H),2.93(s,3H),2.01(t,J＝7.2Hz,2H),1.92–1.82(m,2H),1.69–1.57(m,2H),1.55–1.44(m,2H).
MS(ESI+)m/z 396.9[M+H]+.
Example 8: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000261
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline
Figure BDA0001984930190000262
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (ethyl hexanoate-6-oxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.16(s,1H),8.02(s,1H),7.86(d,J＝5.3Hz,1H),7.63(s,1H),7.35–7.31(m,1H),7.27–7.24(m,1H),7.00–6.91(m,2H),4.32–4.23(m,2H),4.10(q,J＝7.1Hz,2H),3.94(d,J＝1.2Hz,3H),2.96(s,3H),2.34(t,J＝7.3Hz,2H),2.10–2.00(m,2H),1.74–1.67(m,2H),1.59–1.50(m,2H),1.22(t,J＝7.1Hz,3H).
MS(ESI+)m/z 600.9[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000271
The title compound was synthesized according to the method of step 8 in example 1 from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),10.34(s,1H),9.07(s,1H),8.67(d,J＝1.4Hz,1H),8.56(d,J＝2.3Hz,1H),8.10(d,J＝2.3Hz,1H),7.91(d,J＝1.3Hz,1H),7.76(td,J＝8.5,6.5Hz,1H),7.65–7.55(m,2H),7.22(td,J＝8.5,2.3Hz,1H),4.27(t,J＝6.4Hz,2H),3.66(s,3H),2.95(s,3H),2.01(t,J＝7.2Hz,2H),1.93–1.81(m,2H),1.69–1.58(m,2H),1.57–1.45(m,2H).
MS(ESI+)m/z 588.1[M+H]+.
Example 9: 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000272
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline
Figure BDA0001984930190000273
The title compound was synthesized according to the method of step 7 of example 1 from 4-methyl-6-bromo-8- (ethyl hexanoate-6-oxy) quinazoline and N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) methanesulfonamide.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.24(d,J＝2.2Hz,1H),8.07(d,J＝2.2Hz,1H),7.69(d,J＝1.4Hz,1H),7.31(d,J＝1.2Hz,1H),6.81(s,1H),4.27(q,J＝7.0Hz,2H),4.13–4.09(m,2H),4.08(s,3H),3.04(s,3H),2.96(s,3H),2.33(t,J＝7.4Hz,2H),2.11–2.01(m,2H),1.76–1.70(m,2H),1.66–1.45(m,2H),1.30–1.17(t,J＝7.0Hz,3H).
MS(ESI+)m/z 503.0[M+H]+.
And 2, step: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000281
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.08(s,1H),8.67(s,1H),8.55(d,J＝2.3Hz,1H),8.08(d,J＝2.3Hz,1H),7.93(d,J＝1.6Hz,1H),7.63(d,J＝1.5Hz,1H),4.28(t,J＝6.4Hz,2H),4.00(s,3H),3.10(s,3H),2.95(s,3H),2.01(t,J＝7.6Hz,2H),1.92–1.79(m,2H),1.66–1.56(m,2H),1.56–1.44(m,2H).
MS(ESI+)m/z 490.2[M+H]+.
Example 10: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000282
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline
Figure BDA0001984930190000291
The title compound was synthesized according to the method of step 7 in example 1 from 4-methyl-6-bromo-8- (ethyl hexanoate-6-oxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.23(d,J＝1.8Hz,1H),7.67(s,1H),7.63(dd,J＝10.8,1.9Hz,1H),7.29(d,J＝0.6Hz,1H),4.25(t,J＝6.4Hz,2H),4.15–4.06(m,5H),2.95(s,3H),2.33(t,J＝7.3Hz,2H),2.11–1.98(m,2H),1.79–1.66(m,2H),1.64–1.51(m,2H),1.21(t,J＝7.2Hz,3H).
MS(ESI+)m/z 428.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxyhexanamide-6-oxy) quinazoline
Figure BDA0001984930190000292
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (ethyl hexanoate-6-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.07(s,1H),8.67(s,1H),8.60(d,J＝2.1Hz,1H),8.36(dd,J＝12.0,2.1Hz,1H),8.03(d,J＝1.6Hz,1H),7.70(d,J＝1.5Hz,1H),4.28(t,J＝6.5Hz,2H),4.03(s,3H),2.96(s,3H),2.01(t,J＝7.4Hz,2H),1.92–1.81(m,2H),1.68–1.57(m,2H),1.54–1.43(m,2H).
MS(ESI+)m/z 415.2[M+H]+.
Example 11: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonamido) -5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000301
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline
Figure BDA0001984930190000302
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (heptanoic acid ethyl ester-7-oxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.16(s,1H),8.02(s,1H),7.85(d,J＝5.5Hz,1H),7.62(s,1H),7.35–7.30(m,1H),7.28–7.25(m,1H),7.01–6.86(m,2H),4.30–4.22(m,2H),4.09(q,J＝7.1Hz,2H),3.94(d,J＝1.2Hz,3H),2.96(s,3H),2.29(t,J＝7.3Hz,2H),2.09–2.00(m,2H),1.73–1.62(m,2H),1.59–1.50(m,2H),1.47–1.38(m,2H),1.22(t,J＝7.1Hz,3H).
MS(ESI+)m/z 615.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000303
The title compound was synthesized from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonamido) -5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.35(s,2H),9.07(s,1H),8.65(s,1H),8.55(d,J＝2.3Hz,1H),8.09(d,J＝2.3Hz,1H),7.90(d,J＝1.4Hz,1H),7.76(td,J＝8.5,6.4Hz,1H),7.64–7.54(m,2H),7.22(td,J＝8.5,2.4Hz,1H),4.27(t,J＝6.5Hz,2H),3.66(s,3H),2.95(s,3H),1.97(t,J＝7.3Hz,2H),1.92–1.79(m,2H),1.60–1.47(m,4H),1.42–1.30(m,2H).
MS(ESI+)m/z 602.0[M+H]+.
Example 12: 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000311
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline
Figure BDA0001984930190000312
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (heptanoic acid ethyl ester-7-oxy) quinazoline and N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) methanesulfonamide.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.27(d,J＝1.9Hz,1H),8.09(d,J＝1.9Hz,1H),7.71(s,1H),7.35(s,1H),6.84(s,1H),4.28(t,J＝6.8Hz,2H),4.11(q,J＝7.1Hz,2H),4.10(s,3H),3.06(s,3H),3.01(s,3H),2.31(t,J＝7.5Hz,2H),2.15–1.93(m,2H),1.77–1.63(m,2H),1.63–1.51(m,2H),1.49–1.40(m,2H),1.24(t,J＝7.1Hz,3H).
MS(ESI+)m/z 517.0[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000321
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,MeOD)δ9.02(s,1H),8.38(d,J＝1.8Hz,1H),8.10(d,J＝1.8Hz,1H),7.85(s,1H),7.54(s,1H),6.84(s,1H),4.30(t,J＝6.6Hz,2H),4.08(s,3H),3.07(s,3H),3.01(s,3H),2.12(t,J＝7.5Hz,2H),2.00–1.97(m,2H),1.71–1.56(m,4H),1.48–1.45(m,2H).
MS(ESI+)m/z 503.0[M+H]+.
Example 13: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000322
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline
Figure BDA0001984930190000323
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (heptanoic acid ethyl ester-7-oxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.26(d,J＝1.8Hz,1H),7.71(s,1H),7.66(dd,J＝10.8,1.9Hz,1H),7.35(d,J＝0.8Hz,1H),4.28(t,J＝6.6Hz,2H),4.17–4.06(m,5H),3.02(s,3H),2.32(t,J＝7.4Hz,2H),2.12–1.97(m,2H),1.75–1.63(m,2H),1.62–1.52(m,2H),1.54–1.40(m,2H),1.24(t,J＝7.1Hz,3H).
MS(ESI+)m/z 442.2[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxyheptanamide-7-oxy) quinazoline
Figure BDA0001984930190000331
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (heptanoic acid ethyl ester-7-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.07(s,1H),8.60(s,1H),8.36(d,J＝12.0Hz,1H),8.02(s,1H),7.70(s,1H),4.28(t,J＝6.5Hz,2H),4.03(s,3H),2.96(s,3H),1.97(t,J＝7.3Hz,2H),1.92–1.81(m,2H),1.61–1.44(m,4H),1.43–1.31(m,2H).
MS(ESI+)m/z 429.2[M+H]+.
Example 14: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyoctanoyl-8-oxy) quinazoline
Figure BDA0001984930190000332
Step 1: synthesis of 4-methyl-6-bromo-8- (ethyl octanoate-8-oxy) quinazoline
Figure BDA0001984930190000333
The title compound was synthesized from ethyl 8-bromooctanoate according to the method of step 6 in example 1.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),7.77(d,J＝1.8Hz,1H),7.26(d,J＝1.8Hz,1H),4.17(t,J＝6.9Hz,2H),4.10(q,J＝7.1Hz,2H),2.89(s,3H),2.28(t,J＝7.5Hz,2H),2.05–1.94(m,2H),1.68–1.58(m,2H),1.56–1.47(m,2H),1.46–1.31(m,4H),1.23(t,J＝7.1Hz,3H).
MS(ESI+)m/z 409.0,411.0[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (octanoic acid ethyl ester-8-oxy) quinazoline
Figure BDA0001984930190000341
The title compound was synthesized from 4-methyl-6-bromo-8- (ethyl octanoate-8-oxy) quinazoline according to the method of step 7 in example 1.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.46(s,1H),7.87(d,J＝7.7Hz,1H),7.67(s,1H),7.33(s,1H),6.86(d,J＝8.1Hz,1H),4.24(t,J＝5.9Hz,2H),4.08(q,J＝7.1Hz,2H),3.98(s,3H),2.96(s,3H),2.26(t,J＝7.4Hz,2H),2.09–1.95(m,2H),1.66–1.56(m,2H),1.56–1.46(m,2H),1.44–1.31(m,4H),1.21(t,J＝7.1Hz,3H).
MS(ESI+)m/z 437.9[M+H]+.
And step 3: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxyoctanoyl amide-8-oxy) quinazoline
Figure BDA0001984930190000342
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (ethyl octanoate-8-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.06(s,1H),8.74(d,J＝2.4Hz,1H),8.65(s,1H),8.27(dd,J＝8.6,2.5Hz,1H),7.95(d,J＝1.2Hz,1H),7.66(d,J＝1.1Hz,1H),6.98(d,J＝8.6Hz,1H),4.28(t,J＝6.5Hz,2H),3.93(s,3H),2.95(s,3H),1.95(t,J＝7.3Hz,2H),1.91–1.81(m,2H),1.56–1.45(m,4H),1.40–1.32(m,2H),1.31–1.21(m,2H).
MS(ESI+)m/z 425.1[M+H]+.
EXAMPLE 15 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxyoctanoylamino-8-oxy) quinazoline
Figure BDA0001984930190000351
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (octanoic acid ethyl ester-8-oxy) quinazoline
Figure BDA0001984930190000352
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (ethyl octanoate-8-oxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.20(d,J＝2.1Hz,1H),8.08–8.01(d,J＝2.1Hz,1H),7.93–7.84(m,1H),7.68(d,J＝1.1Hz,1H),7.33(d,J＝1.1Hz,1H),7.03–6.89(m,2H),4.35–4.23(m,2H),4.12(q,J＝7.1Hz,2H),3.98(s,3H),3.06(s,3H),2.30(t,J＝7.5Hz,2H),2.14–2.02(m,2H),1.71–1.53(m,4H),1.49–1.36(m,4H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 629.0[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxyoctanoyl amide-8-oxy) quinazoline
Figure BDA0001984930190000353
The title compound was synthesized according to the procedure for step 8 of example 1 from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonamido) -5-pyridyl) -8- (octanoic acid ethyl ester-8-oxy) quinazoline.
1H NMR(400MHz,MeOD-d4)δ8.99(s,1H),8.30(s,1H),8.04(s,1H),7.85(dd,J＝14.5,8.2Hz,1H),7.75(s,1H),7.44(s,1H),7.21(t,J＝9.3Hz,1H),7.06(t,J＝8.0Hz,1H),4.26(t,J＝5.1Hz,2H),3.81(s,3H),2.95(s,3H),2.10(t,J＝7.3Hz,2H),2.03–1.92(m,2H),1.72–1.53(m,4H),1.51–1.36(m,4H).
MS(ESI+)m/z 615.9[M+H]+.
Example 16: 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxyoctanoyl amide-8-oxy) quinazoline
Figure BDA0001984930190000361
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (ethyl octanoate-8-oxy) quinazoline
Figure BDA0001984930190000362
The title compound was synthesized according to the method of step 7 in example 1 from 4-methyl-6-bromo-8- (ethyl octanoate-8-oxy) quinazoline and N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) methanesulfonamide.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.27(d,J＝1.4Hz,1H),8.09(d,J＝1.4Hz,1H),7.71(s,1H),7.35(s,1H),6.85(s,1H),4.27(t,J＝6.7Hz,2H),4.16–4.07(m,5H),3.06(s,3H),3.01(s,3H),2.29(t,J＝7.5Hz,2H),2.10–1.98(m,2H),1.72–1.59(m,2H),1.59–1.51(m,2H),1.50–1.33(m,4H),1.24(t,J＝7.1Hz,3H).
MS(ESI+)m/z 531.0[M+H]+.
And 2, step: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxyoctanoyl amide-8-oxy) quinazoline
Figure BDA0001984930190000371
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (ethyl octanoate-8-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,MeOD-d4)δ9.01(s,1H),8.37(d,J＝2.2Hz,1H),8.10(d,J＝2.2Hz,1H),7.86(s,1H),7.53(s,1H),4.30(t,J＝6.5Hz,2H),4.08(s,3H),3.07(s,3H),2.99(s,3H),2.10(t,J＝7.4Hz,2H),2.05–1.93(m,2H),1.70–1.57(m,4H),1.51–1.36(m,4H).
MS(ESI+)m/z 518.0[M+H]+.
Example 17: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxyoctanoyl-amide-8-oxy) quinazoline
Figure BDA0001984930190000372
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (octanoic acid ethyl ester-8-oxy) quinazoline
Figure BDA0001984930190000373
The title compound was synthesized according to the method of step 7 in example 1 from 4-methyl-6-bromo-8- (ethyl octanoate-8-oxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.24(d,J＝1.8Hz,1H),7.67(s,1H),7.64(dd,J＝10.8,1.9Hz,1H),7.30(d,J＝0.5Hz,1H),4.25(t,J＝6.8Hz,2H),4.15–4.04(m,5H),2.97(s,3H),2.27(t,J＝7.5Hz,2H),2.09–1.97(m,2H),1.69–1.58(m,2H),1.58–1.48(m,2H),1.46–1.29(m,4H),1.22(t,J＝7.1Hz,3H).
MS(ESI+)m/z 456.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxyoctanoyl amide-8-oxy) quinazoline
Figure BDA0001984930190000381
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (ethyl octanoate-8-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.05(s,1H),8.66(s,1H),8.57(d,J＝2.0Hz,1H),8.32(dd,J＝12.0,1.9Hz,1H),7.98(d,J＝1.3Hz,1H),7.65(d,J＝1.2Hz,1H),4.26(t,J＝6.5Hz,2H),4.02(s,3H),2.93(s,3H),1.96(t,J＝7.3Hz,2H),1.91–1.79(m,2H),1.57–1.43(m,4H),1.38–1.25(m,4H).
MS(ESI+)m/z 443.0[M+H]+.
Example 18: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000382
Step 1: synthesis of 4-methyl-6-bromo-8- (nonanoic acid ethyl ester-9-oxy) quinazoline
Figure BDA0001984930190000383
The title compound was synthesized from ethyl 9-bromononanoate according to the method of step 6 in example 1.
1H NMR(400MHz,)δ9.21(s,1H),7.79(d,J＝1.9Hz,1H),7.29(d,J＝2.0Hz,1H),4.19(t,J＝6.9Hz,2H),4.12(q,J＝7.1Hz,2H),2.92(s,3H),2.28(t,J＝7.5Hz,2H),2.06–1.96(m,2H),1.67–1.57(m,2H),1.57–1.47(m,2H),1.43–1.29(m,6H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 423.1,425.1[M+H]+.
And 2, step: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (nonanoic acid ethyl ester-9-oxy) quinazoline
Figure BDA0001984930190000391
The title compound was synthesized from 4-methyl-6-bromo-8- (nonanoate ethyl-9-oxy) quinazoline according to the method of step 7 in example 1.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.25(d,J＝2.1Hz,1H),7.68(d,J＝1.5Hz,1H),7.65(dd,J＝10.8,2.1Hz,1H),7.31(d,J＝1.4Hz,1H),4.26(t,J＝6.9Hz,2H),4.15–4.06(m,5H),2.97(s,3H),2.27(t,J＝7.5Hz,2H),2.09–1.97(m,2H),1.67–1.57(m,2H),1.56–1.48(m,2H),1.44–1.30(m,6H),1.23(t,J＝7.1Hz,3H).
MS(ESI+)m/z 451.9[M+H]+.
And step 3: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000392
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (nonanoate ethyl-9-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.06(s,1H),8.74(d,J＝2.5Hz,1H),8.64(d,J＝1.6Hz,1H),8.27(dd,J＝8.6,2.6Hz,1H),7.96(d,J＝1.3Hz,1H),7.66(d,J＝1.2Hz,1H),6.98(d,J＝8.6Hz,1H),4.28(t,J＝6.5Hz,2H),3.93(s,3H),2.95(s,3H),2.00–1.81(m,4H),1.58–1.43(m,4H),1.43–1.20(m,6H).
MS(ESI+)m/z 438.9[M+H]+.
Example 19: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000401
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (nonanoic acid ethyl ester-9-oxy) quinazoline
Figure BDA0001984930190000402
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (nonanoate-9-oxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.19(d,J＝2.1Hz,1H),8.05(d,J＝2.1Hz,1H),7.92–7.84(m,1H),7.67(d,J＝1.0Hz,1H),7.32(d,J＝1.0Hz,1H),7.01–6.90(m,2H),4.34–4.23(m,2H),4.12(q,J＝7.1Hz,2H),3.98(s,3H),3.05(s,3H),2.28(t,J＝7.5Hz,2H),2.11–2.00(m,2H),1.66–1.51(m,4H),1.48–1.30(m,6H),1.25(t,J＝7.1Hz,3H).
MS(ESI+)m/z 643.0[M+H]+.
And 2, step: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000403
The title compound was synthesized according to the method of step 8 in example 1 from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (nonanoic acid ethyl ester-9-oxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ10.33(s,2H),9.07(s,1H),8.65(s,1H),8.56(d,J＝2.2Hz,1H),8.10(d,J＝2.2Hz,1H),7.90(d,J＝0.9Hz,1H),7.76(dd,J＝14.9,8.4Hz,1H),7.65–7.54(m,2H),7.22(t,J＝7.7Hz,1H),4.27(t,J＝6.4Hz,2H),3.66(s,3H),2.95(s,3H),1.94(t,J＝7.3Hz,2H),1.91–1.82(m,2H),1.57–1.44(m,4H),1.43–1.20(m,6H).
MS(ESI+)m/z 629.9[M+H]+.
Example 20: 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000411
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (nonanoic acid ethyl ester-9-oxy) quinazoline
Figure BDA0001984930190000412
The title compound was synthesized according to the procedure of step 7 of example 1 from 4-methyl-6-bromo-8- (nonanoate-ethyl-9-oxy) quinazoline and N- (2-methoxy-5-boronic acid pinacol ester-3-pyridyl) methanesulfonamide.
1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.22(s,1H),8.05(s,1H),7.65(s,1H),7.29(s,1H),7.12(s,1H),4.22(t,J＝5.7Hz,2H),4.13–4.00(m,5H),3.03(s,3H),2.92(s,3H),2.23(t,J＝7.5Hz,2H),2.06–1.88(m,2H),1.64–1.48(m,4H),1.42–1.29(m,6H),1.19(t,J＝7.1Hz,3H).
MS(ESI+)m/z 544.9[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000421
The title compound was synthesized according to the method of step 8 in example 1 from 4-methyl-6- (2-methoxy-3-methanesulfonamido-5-pyridyl) -8- (nonanoate ethyl ester-9-oxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.07(s,1H),8.64(s,1H),8.55(d,J＝1.8Hz,1H),8.08(d,J＝2.2Hz,1H),7.92(s,1H),7.62(s,1H),4.28(t,J＝6.5Hz,2H),4.00(s,3H),3.10(s,3H),2.95(s,3H),1.94(t,J＝7.3Hz,2H),1.91–1.82(m,2H),1.57–1.44(m,4H),1.38–1.23(m,6H).
MS(ESI+)m/z 532.0[M+H]+.
Example 21: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000422
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (nonanoic acid ethyl ester-9-oxy) quinazoline
Figure BDA0001984930190000423
The title compound was synthesized according to the procedure for step 7 of example 1 from 4-methyl-6-bromo-8- (nonanoate-9-oxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.25(d,J＝2.1Hz,1H),7.68(d,J＝1.5Hz,1H),7.65(dd,J＝10.8,2.1Hz,1H),7.31(d,J＝1.4Hz,1H),4.26(t,J＝6.9Hz,2H),4.15–4.06(m,5H),2.97(s,3H),2.27(t,J＝7.5Hz,2H),2.09–1.97(m,2H),1.67–1.57(m,2H),1.56–1.48(m,2H),1.44–1.30(m,6H),1.23(t,J＝7.1Hz,3H).
MS(ESI+)m/z 470.0[M+H]+.
And 2, step: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-hydroxynonanamide-9-oxy) quinazoline
Figure BDA0001984930190000431
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (nonanoate ethyl-9-oxy) quinazoline according to the method of step 8 in example 1.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.07(s,1H),8.64(d,J＝1.7Hz,1H),8.60(d,J＝2.0Hz,1H),8.36(dd,J＝12.0,2.1Hz,1H),8.02(d,J＝1.5Hz,1H),7.69(d,J＝1.5Hz,1H),4.28(t,J＝6.5Hz,2H),4.03(s,3H),2.95(s,3H),1.94(t,J＝7.3Hz,2H),1.91–1.82(m,2H),1.55–1.45(m,4H),1.37–1.21(m,6H).
MS(ESI+)m/z 457.1[M+H]+.
Example 22: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-hydroximic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000432
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-N-methyl-2-aminoethoxy) quinazoline
Figure BDA0001984930190000433
6-bromo-4-methyl-8-hydroxyquinazoline (1g, 4.18mmol) was dissolved in anhydrous tetrahydrofuran (30mL), triphenylphosphine (1.646g, 6.28mmol) and N-Boc-N-methylaminoethanol (1.1g, 6.28mmol) were added, argon was purged three times, diethyl azodicarboxylate (0.988mL, 6.28mmol) was added with stirring, reacted overnight at room temperature, concentrated, and purified by silica gel column chromatography (PE: EtOAc ═ 1:1) to give the product as a yellow oil (1.46g, 88% yield).
1H NMR(400MHz,CDCl3)δ9.18(s,1H),7.82(d,J＝1.8Hz,1H),7.30(d,J＝1.8Hz,1H),4.30(t,J＝5.9Hz,2H),3.77(t,J＝5.9Hz,2H),3.04(s,3H),2.89(s,3H),1.45(s,9H).MS(ESI+)m/z 396.1,398.1[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (N-methyl-2-aminoethoxy) quinazoline
Figure BDA0001984930190000441
4-methyl-6-bromo-8- (N-Boc-N-methyl-2-aminoethoxy) quinazoline (1.46g, 3.68mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (10mL) was added, the reaction was carried out at room temperature for 1.5 hours, the solvent was evaporated under reduced pressure, and the reaction mixture was directly subjected to the next reaction without purification.
MS(ESI+)m/z 296.1,298.1[M+H]+.
And step 3: synthesis of 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000442
The 4-methyl-6-bromo-8- (N-methyl-2-aminoethoxy) quinazoline (1.09g, 3.68mmol) obtained in the above step was dissolved in anhydrous acetonitrile (60mL), ethyl 2-chloro-5-pyrimidinecarboxylate (1.17g, 5.52mmol) and N, N-diisopropylethylamine (1.43g, 11.04mmol) were added, reacted at room temperature for 16 hours, the solvent was evaporated under reduced pressure, water (100mL) and dichloromethane (60mL × 3) were added for extraction, and dried over anhydrous sodium EtOAc, filtered, concentrated, and purified by silica gel column chromatography (PE: 2:1) to obtain the product as a pale yellow solid (1.07g, 65% yield).
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.92(s,2H),7.84(d,J＝1.8Hz,1H),7.61(d,J＝1.8Hz,1H),4.51(t,J＝6.2Hz,2H),4.36(d,J＝7.1Hz,2H),4.25(t,J＝6.2Hz,2H),3.45(s,3H),2.97(s,3H),1.37(t,J＝7.1Hz,3H).
MS(ESI+)m/z 446.1,448.1[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000451
4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline (50mg, 0.112mmol) and 2-methoxy-5-pyridineboronic acid (21mg, 0.135mmol) were dissolved in toluene and water (3mL/1mL), 2N aqueous potassium carbonate (0.17mL, 0.34mmol) was added, argon was pumped three times, PdCl was added2(dppf) (8mg, 0.011mmol), reaction at 80 ℃ for 8 hours, celite filtration to remove insoluble solids, extraction with ethyl acetate (10 mL. times.3), drying over anhydrous sodium sulfate, filtration, concentration, and purification by silica gel column chromatography (PE: EtOAc ═ 1:6) to afford the product as a pale yellow solid (37mg, 70% yield).
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.86(s,2H),8.51(d,J＝2.3Hz,1H),7.88(dd,J＝8.6,2.5Hz,1H),7.73(d,J＝1.4Hz,1H),7.65(d,J＝1.3Hz,1H),6.89(d,J＝8.5Hz,1H),4.59(t,J＝6.5Hz,2H),4.34(q,J＝7.1Hz,2H),4.25(t,J＝6.4Hz,2H),4.02(s,3H),3.42(s,3H),2.99(s,3H),1.37(t,J＝7.1Hz,3H).
MS(ESI+)m/z 475.1[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-hydroximino-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000452
4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline (30mg, 0.063mmol) was dissolved in anhydrous methanol (2mL), potassium hydroxide (36mg, 0.63mmol) and 50% aqueous hydroxylamine solution (0.126mL, 1.89mmol) were added, the reaction was reacted at room temperature for 2 hours, the reaction was cooled in an ice bath to adjust pH to about 5-6, filtered to give a pale yellow solid, and recrystallized from anhydrous methanol to give the product as a white solid (17mg, yield 57%).
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.05(s,1H),9.00(s,1H),8.73(d,J＝2.2Hz,1H),8.68(s,2H),8.25(dd,J＝8.6,1.7Hz,1H),7.97(s,1H),7.75(s,1H),6.96(d,J＝8.6Hz,1H),4.52(t,J＝5.6Hz,2H),4.16(t,J＝5.6Hz,2H),3.93(s,3H),3.36(s,3H),2.94(s,3H).
MS(ESI+)m/z 462.0[M+H]+.
Example 23: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000461
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-2-aminoethoxy) quinazoline
Figure BDA0001984930190000462
The title compound was synthesized according to the procedure for step 1 of example 22 from 4-methyl-6-bromo-8-hydroxyquinazoline and N-Boc-bromoethylamine.
1H NMR(400MHz,CDCl3)δ9.16(s,1H),7.80(d,J＝1.8Hz,1H),7.30(d,J＝1.8Hz,1H),5.71(s,1H),4.23(t,J＝3.8Hz,2H),3.69(t,J＝3.8Hz,2H),2.89(s,3H),1.42(s,9H).
MS(ESI+)m/z 382.1,384.1[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (2-aminoethoxy) quinazoline
Figure BDA0001984930190000463
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-2-aminoethoxy) quinazoline according to the method of step 2 in example 22.
MS(ESI+)m/z 282.1,284.1[M+H]+.
And step 3: synthesis of 4-methyl-6-bromo-8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000471
The title compound was synthesized from 4-methyl-6-bromo-8- (2-aminoethoxy) quinazoline according to the method of step 3 of example 22.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.92(s,1H),8.77(s,1H),7.80(d,J＝1.8Hz,1H),7.43(d,J＝1.8Hz,1H),6.68(t,J＝5.7Hz,1H),4.32(q,J＝7.1Hz,2H),4.13–4.01(m,4H),2.88(s,3H),1.23(t,J＝7.2Hz,3H).
MS(ESI+)m/z 432.0,434.0[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000472
The title compound was synthesized according to the method of step 4 of example 22 from 4-methyl-6-bromo-8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.91(s,1H),8.83(s,1H),8.27(d,J＝2.1Hz,1H),7.76(d,J＝2.1Hz,1H),7.66(dd,J＝10.7,2.1Hz,1H),7.41(d,J＝1.5Hz,1H),4.50(t,J＝3.8Hz,2H),4.34(q,J＝7.1Hz,2H),4.16–4.10(m,5H),3.02(s,3H),1.37(t,J＝7.1Hz,3H).
MS(ESI+)m/z 479.1[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-hydroximic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000481
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline according to the method of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.06(s,1H),8.99(s,1H),8.61(d,J＝1.8Hz,2H),8.36(dd,J＝12.0,1.6Hz,1H),8.07–8.00(m,2H),7.82(s,1H),4.46(t,J＝6.0Hz,2H),4.03(s,3H),3.90–3.80(m,2H),2.96(s,3H).
MS(ESI+)m/z 466.1[M+H]+.
Example 24: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-hydroxamic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000482
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-3-aminopropoxy) quinazoline
Figure BDA0001984930190000483
The title compound was synthesized according to the procedure for step 1 of example 22 from 4-methyl-6-bromo-8-hydroxyquinazoline and N-Boc-3-bromopropylamine.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),7.80(d,J＝1.8Hz,1H),7.28(d,J＝1.7Hz,1H),6.05(s,1H),4.28(t,J＝5.8Hz,2H),3.44(t,J＝4.9Hz,2H),2.90(s,3H),2.22–2.12(m,2H),1.45(s,9H).
MS(ESI+)m/z 396.1,398.1[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (3-aminopropoxy) quinazoline
Figure BDA0001984930190000491
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-3-aminopropoxy) quinazoline according to the method of step 2 in example 22.
MS(ESI+)m/z 296.1,298.1[M+H]+.
And 3, step 3: synthesis of 4-methyl-6-bromo-8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000492
The title compound was synthesized from 4-methyl-6-bromo-8- (3-aminopropoxy) quinazoline following the procedure in step 3 of example 22.
1H NMR(400MHz,CDCl3)δ9.27(s,1H),8.88–8.79(m,2H),7.82(d,J＝1.9Hz,1H),7.31(d,J＝1.8Hz,1H),4.41–4.29(m,4H),3.90–3.81(m,2H),2.91(s,3H),2.40–2.27(m,2H),1.37(t,J＝7.1Hz,3H).
MS(ESI+)m/z 446.0,448.1[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000493
The title compound was synthesized according to the procedure for step 4 of example 22 from 4-methyl-6-bromo-8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.90–8.79(m,2H),8.25(s,1H),7.75(s,1H),7.66(dd,J＝10.5,0.5Hz,1H),7.38(s,1H),4.50–4.40(m,2H),4.35(q,J＝7.1Hz,2H),4.11(s,3H),3.95–3.86(m,2H),3.02(s,3H),2.42–2.32(m,2H),1.37(t,J＝7.0Hz,3H).
MS(ESI+)m/z 493.2[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-hydroximic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000501
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline according to the method of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.08(s,1H),8.96(s,1H),8.66–8.58(m,2H),8.35(d,J＝11.9Hz,1H),8.03(s,1H),7.93(t,J＝5.5Hz,1H),7.72(s,1H),4.40(t,J＝5.8Hz,2H),4.03(s,3H),3.58(dd,J＝12.4,6.4Hz,2H),2.96(s,3H),2.21–2.10(m,2H).
MS(ESI+)m/z 480.1[M+H]+.
Example 25: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridinyl) -8- (N- (5-hydroxamic acid-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000511
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-4-aminobutoxy) quinazoline
Figure BDA0001984930190000512
The title compound was synthesized according to the procedure for step 1 of example 22 from 4-methyl-6-bromo-8-hydroxyquinazoline and N-Boc-4-hydroxybutylamine.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),7.79(d,J＝1.8Hz,1H),7.28(d,J＝1.8Hz,1H),4.21(t,J＝6.2Hz,2H),3.23(t,J＝6.4Hz,2H),2.92(s,3H),2.09–2.00(m,2H),1.81–1.72(m,2H),1.43(s,9H).
MS(ESI+)m/z 410.1,412.1[M+H]+.
And 2, step: synthesis of 4-methyl-6-bromo-8- (4-aminobutoxy) quinazoline
Figure BDA0001984930190000513
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-4-aminobutoxy) quinazoline following the procedure in step 2 of example 22.
MS(ESI+)m/z 310.0,312.1[M+H]+.
And step 3: synthesis of 4-methyl-6-bromo-8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000514
The title compound was synthesized from 4-methyl-6-bromo-8- (4-aminobutoxy) quinazoline according to the method of step 3 in example 22.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.84(s,1H),8.78(s,1H),7.77(d,J＝1.8Hz,1H),7.23(d,J＝1.8Hz,0H),6.75(t,J＝4.6Hz,1H),4.32(q,J＝7.1Hz,2H),4.23(t,J＝6.0Hz,2H),3.61(q,J＝6.6Hz,2H),2.88(s,3H),2.18–2.03(m,2H),1.91(p,J＝6.9Hz,2H),1.34(t,J＝7.1Hz,3H).
MS(ESI+)m/z 460.1,462.1[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000521
The title compound was synthesized according to the method of step 4 of example 22 from 4-methyl-6-bromo-8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.89(s,1H),8.80(s,1H),8.26(d,J＝1.8Hz,1H),7.71(d,J＝1.8Hz,1H),7.66(dd,J＝10.8,1.9Hz,1H),7.31(d,J＝1.8Hz,1H),4.35(q,J＝7.0Hz,4H),4.11(s,3H),3.68(q,J＝5.9Hz,2H),3.00(s,3H),2.21–2.09(m,2H),2.02–1.92(m,2H),1.37(t,J＝7.1Hz,3H).
MS(ESI+)m/z 507.1[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N- (5-hydroxamic acid-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000522
The title compound was synthesized from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridinyl) -8- (N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline according to the method of step 5 of example 22.
1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.06(s,1H),8.95(s,1H),8.67–8.54(m,2H),8.35(dd,J＝12.0,2.0Hz,1H),8.02(d,J＝1.5Hz,1H),7.89(t,J＝5.8Hz,1H),7.70(d,J＝1.4Hz,1H),4.33(t,J＝6.3Hz,2H),4.03(s,3H),3.43(q,J＝6.6Hz,2H),2.95(s,3H),1.99–1.88(m,2H),1.84–1.73(m,2H).
MS(ESI+)m/z 494.1[M+H]+.
Example 26: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000531
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000532
The title compound was synthesized according to the procedure for step 4 of example 22 from 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridinyl) benzenesulfonamide.
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.33(s,1H),9.07(s,1H),8.99(s,1H),8.69(s,2H),8.53(s,1H),8.09(d,J＝1.8Hz,1H),7.91(d,J＝1.0Hz,1H),7.76(td,J＝8.5,6.5Hz,1H),7.69(s,1H),7.60–7.52(m,1H),7.20(td,J＝8.4,2.1Hz,1H),4.52(t,J＝5.7Hz,2H),4.17(t,J＝5.6Hz,2H),3.66(s,3H),3.38(s,3H),2.95(s,3H).
MS(ESI+)m/z 666.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-methyl-N- (5-hydroximino-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000541
The title compound was synthesized from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonamido) -5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline following the procedure of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.33(s,1H),9.07(s,1H),8.99(s,1H),8.69(s,2H),8.53(s,1H),8.09(d,J＝1.8Hz,1H),7.91(d,J＝1.0Hz,1H),7.76(td,J＝8.5,6.5Hz,1H),7.69(s,1H),7.60–7.52(m,1H),7.20(td,J＝8.4,2.1Hz,1H),4.52(t,J＝5.7Hz,2H),4.17(t,J＝5.6Hz,2H),3.66(s,3H),3.38(s,3H),2.95(s,3H).
MS(ESI+)m/z 653.1[M+H]+.
Example 27: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000542
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000551
The title compound was synthesized according to the procedure for step 4 of example 22 from 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.87(s,2H),8.28(d,J＝1.5Hz,1H),7.71(s,1H),7.65(dd,J＝10.8,1.5Hz,1H),7.61(s,1H),4.59(t,J＝6.4Hz,2H),4.33(q,J＝7.1Hz,2H),4.24(t,J＝6.3Hz,2H),4.10(s,3H),3.40(s,3H),2.98(s,3H),1.36(t,J＝7.1Hz,3H).
MS(ESI+)m/z 493.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000552
The title compound was synthesized according to the method of step 5 of example 22 from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.07(s,1H),8.99(s,1H),8.68(s,2H),8.60(d,J＝2.0Hz,1H),8.36(dd,J＝12.0,2.0Hz,1H),8.05(d,J＝1.5Hz,1H),7.79(d,J＝1.4Hz,1H),4.53(t,J＝5.8Hz,2H),4.17(t,J＝5.8Hz,2H),4.03(s,3H),3.37(s,3H),2.96(s,3H).
MS(ESI+)m/z 480.2[M+H]+.
Example 28: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-hydroximic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000561
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-N-methyl-3-aminopropoxy) quinazoline
Figure BDA0001984930190000562
The title compound was synthesized according to the method of step 1 of example 22 from 6-bromo-4-methyl-8-hydroxyquinazoline and N-Boc-3-methylamino-1-propanol.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),7.81(d,J＝1.9Hz,1H),7.29(d,J＝1.9Hz,1H),4.31(t,J＝6.1Hz,2H),3.67(t,J＝5.9Hz,2H),3.12(s,3H),2.89(s,3H),2.41–2.36(m,2H),1.45(s,9H).
MS(ESI+)m/z 410.0,412.1[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (N-methyl-3-aminopropoxy) quinazoline
Figure BDA0001984930190000563
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-N-methyl-3-aminopropoxy) quinazoline according to the method of step 2 of example 22.
MS(ESI+)m/z 310.0,312.0[M+H]+.
And step 3: synthesis of 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000571
The title compound was synthesized from 4-methyl-6-bromo-8- (N-methyl-3-aminopropoxy) quinazoline according to the method of step 3 in example 22.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.81(s,2H),7.81(d,J＝1.5Hz,1H),7.28(d,J＝1.5Hz,1H),4.34(q,J＝7.1Hz,2H),4.29(t,J＝6.3Hz,2H),4.01(t,J＝6.8Hz,2H),3.29(s,3H),2.93(s,3H),2.38(p,J＝6.5Hz,2H),1.37(t,J＝7.1Hz,3H).
MS(ESI+)m/z 460.0,462.0[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000572
The title compound was synthesized from 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline according to the method of step 4 of example 22.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.77(s,2H),8.45(d,J＝2.2Hz,1H),7.84(dd,J＝8.6,2.4Hz,1H),7.70(s,1H),7.31(s,1H),6.87(d,J＝8.5Hz,1H),4.39–4.25(m,4H),4.04–3.97(m,5H),3.26(s,3H),2.97(s,3H),2.45–2.33(m,2H),1.33(t,J＝7.1Hz,3H).
MS(ESI+)m/z 489.1[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-hydroximino-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000581
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline according to the method of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.08(s,1H),8.73(d,J＝2.5Hz,1H),8.62(s,2H),8.26(dd,J＝8.7,2.6Hz,1H),7.98(d,J＝1.2Hz,1H),7.68(d,J＝1.3Hz,1H),6.98(d,J＝8.7Hz,1H),4.37(t,J＝6.0Hz,2H),3.94(s,3H),3.90(t,J＝7.0Hz,2H),3.19(s,3H),2.96(s,3H),2.25–2.15(m,2H).
MS(ESI+)m/z 476.1[M+H]+.
Example 29: 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000582
Step 1: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000591
The title compound was synthesized according to the procedure for step 4 of example 22 from 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline and 2, 4-difluoro-N- (2-methoxy-5-boronic acid pinacol ester-3-pyridinyl) benzenesulfonamide.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.77(s,2H),8.16(d,J＝2.2Hz,1H),8.02(d,J＝2.2Hz,1H),7.86(dd,J＝14.6,8.5Hz,1H),7.65(d,J＝1.3Hz,1H),7.35(s,1H),7.03–6.89(m,2H),4.35–4.27(m,4H),4.01(t,J＝6.9Hz,2H),3.95(s,3H),3.28(s,3H),2.98(s,3H),2.44–2.36(m,2H),1.33(t,J＝7.1Hz,3H).
MS(ESI+)m/z 680.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonylamino) -5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000592
The title compound was synthesized from 4-methyl-6- (2-methoxy-3- (2, 4-difluorobenzenesulfonamido) -5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline according to the method of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.30(s,1H),9.09(s,1H),8.97(s,1H),8.63(s,2H),8.56(s,1H),8.12(d,J＝1.6Hz,1H),7.93(d,J＝1.2Hz,1H),7.74(td,J＝8.4,6.3Hz,1H),7.64(s,1H),7.61–7.52(m,1H),7.20(td,J＝8.4,2.0Hz,1H),4.36(t,J＝5.6Hz,2H),3.90(t,J＝6.8Hz,2H),3.67(s,3H),3.19(s,3H),2.96(s,3H),2.22–2.17(m,2H).
MS(ESI+)m/z 667.1[M+H]+.
Example 30: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000601
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000602
The title compound was synthesized according to the method of step 4 of example 22 from 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.76(s,2H),8.22(d,J＝1.2Hz,1H),7.69(s,1H),7.61(dd,J＝10.8,1.2Hz,1H),7.28(d,J＝0.4Hz,1H),4.39–4.24(m,4H),4.08(s,3H),3.99(t,J＝6.6Hz,2H),3.26(s,3H),2.97(s,3H),2.45–2.32(m,2H),1.33(t,J＝7.1Hz,3H).
MS(ESI+)m/z 507.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -3-aminopropoxy) quinazoline
Figure BDA0001984930190000611
The title compound was synthesized according to the method of example 22, step 5, from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -3-aminopropoxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.08(s,1H),8.97(s,1H),8.62(s,2H),8.57(s,1H),8.33(d,J＝12.0Hz,1H),8.02(s,1H),7.70(s,1H),4.36(t,J＝5.9Hz,2H),4.02(s,3H),3.89(t,J＝6.9Hz,2H),3.19(s,3H),2.95(s,3H),2.24–2.12(m,2H).
MS(ESI+)m/z 494.1[M+H]+.
Example 31: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridinyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000612
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-N-methyl-4-aminobutoxy) quinazoline
Figure BDA0001984930190000613
The title compound was synthesized according to the method of step 1 of example 22 from 6-bromo-4-methyl-8-hydroxyquinazoline and N-Boc-4-methylamino-1-butanol.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),7.78(d,J＝1.7Hz,1H),7.29(d,J＝1.7Hz,1H),4.21(t,J＝6.5Hz,2H),3.29(t,J＝6.8Hz,2H),2.92(s,3H),2.83(s,3H),2.03–1.91(m,2H),1.82–1.70(m,2H),1.41(s,9H).
MS(ESI+)m/z 424.0,426.1[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (N-methyl-4-aminobutoxy) quinazoline
Figure BDA0001984930190000621
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-N-methyl-4-aminobutoxy) quinazoline according to the method of step 2 in example 22.
MS(ESI+)m/z 324.0,326.1[M+H]+.
And step 3: synthesis of 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000622
The title compound was synthesized from 4-methyl-6-bromo-8- (N-methyl-4-aminobutoxy) quinazoline according to the method of step 3 in example 22.
1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.81(s,2H),7.77(d,J＝1.8Hz,1H),7.27(d,J＝1.7Hz,1H),4.30(q,J＝7.1Hz,2H),4.23(t,J＝6.5Hz,2H),3.82(t,J＝7.2Hz,2H),3.23(s,3H),2.89(s,3H),2.08–1.98(m,2H),1.94–1.85(m,2H),1.33(t,J＝7.2Hz,3H).
MS(ESI+)m/z 474.1,476.1[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000623
The title compound was synthesized according to the method of step 4 of example 22 from 4-methyl-6-bromo-8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.81(s,2H),8.25(d,J＝1.7Hz,1H),7.70(s,1H),7.65(dd,J＝10.7,1.7Hz,1H),7.33(d,J＝1.7Hz,1H),4.38–4.28(m,4H),4.10(s,3H),3.84(t,J＝6.8Hz,2H),3.24(s,3H),3.00(s,3H),2.14–2.03(m,2H),1.99–1.89(m,2H),1.35(t,J＝7.1Hz,3H).
MS(ESI+)m/z 521.1[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-hydroxamic acid-2-pyrimidinyl) -4-aminobutoxy) quinazoline
Figure BDA0001984930190000631
The title compound was synthesized according to the method of step 5 of example 22 from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-methyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -4-aminobutoxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.66(s,2H),8.57(s,1H),8.33(d,J＝12.0Hz,1H),7.99(s,1H),7.67(s,1H),4.32(t,J＝5.2Hz,2H),4.02(s,3H),3.77(t,J＝6.6Hz,2H),3.16(s,5H),2.94(s,3H),1.87–1.73(m,4H).
MS(ESI+)m/z 508.1[M+H]+.
Example 32: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-ethyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000632
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-N-ethyl-2-aminoethoxy) quinazoline
Figure BDA0001984930190000641
The title compound was synthesized according to the method of step 1 of example 22 from 6-bromo-4-methyl-8-hydroxyquinazoline and N-Boc-2-ethylamino-1-ethanol.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),7.82(d,J＝1.3Hz,1H),7.46(d,J＝1.3Hz,1H),4.36(t,J＝6.1Hz,2H),3.75(t,J＝6.1Hz,2H),3.39(q,J＝6.0Hz,2H),2.94(s,3H),1.47(s,9H),1.14(t,J＝6.0Hz,3H).
MS(ESI+)m/z 410.1,412.2[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (N-ethyl-2-aminoethoxy) quinazoline
Figure BDA0001984930190000642
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-N-ethyl-2-aminoethoxy) quinazoline according to the method of step 2 in example 22.
MS(ESI+)m/z 310.1,312.2[M+H]+.
And step 3: synthesis of 4-methyl-6-bromo-8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000643
The title compound was synthesized from 4-methyl-6-bromo-8- (N-ethyl-2-aminoethoxy) quinazoline according to the method of step 3 of example 22.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.94(s,1H),8.89(s,1H),7.80(d,J＝1.8,1H),7.71(d,J＝1.8,1H),4.49(t,J＝6.7Hz,2H),4.35(q,J＝7.1Hz,2H),4.15(t,J＝6.7Hz,2H),3.85(q,J＝7.1Hz,2H),2.91(s,3H),1.37(t,J＝7.1Hz,3H),1.25(t,J＝7.0Hz,3H).
MS(ESI+)m/z 460.0,462.1[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000651
The title compound was synthesized according to the method of step 4 of example 22 from 4-methyl-6-bromo-8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2-methoxy-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.87(s,2H),8.53(s,1H),7.91(d,J＝7.7Hz,1H),7.78(s,1H),7.75(s,1H),6.91(d,J＝8.2Hz,1H),4.60(t,J＝4.8Hz,2H),4.34(q,J＝7.1Hz,2H),4.20(t,J＝4.8Hz,2H),3.86(q,J＝6.4Hz,2H),3.03(s,3H),1.37(t,J＝7.1Hz,3H),1.25(t,J＝6.4Hz,3H).
MS(ESI+)m/z 489.2[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-ethyl-N- (5-hydroximic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000652
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline according to the method of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.06(s,1H),9.00(s,1H),8.74(d,J＝2.3Hz,1H),8.69(s,2H),8.26(dd,J＝8.7,2.5Hz,1H),7.99(d,J＝1.0Hz,1H),7.78(s,1H),6.97(d,J＝8.6Hz,1H),4.51(t,J＝6.0Hz,2H),4.12(t,J＝5.9Hz,2H),3.93(s,3H),3.84(q,J＝6.9Hz,2H),2.95(s,3H),1.20(t,J＝6.9Hz,3H).
MS(ESI+)m/z 476.2[M+H]+.
Example 33: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-ethyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000661
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000662
The title compound was synthesized according to the procedure for step 4 of example 22 from 4-methyl-6-bromo-8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.88(s,2H),8.31(s,1H),7.76(s,1H),7.75(s,1H),7.68(d,J＝10.3Hz,1H),4.61(t,J＝4.8Hz,2H),4.34(q,J＝7.1Hz,2H),4.20(t,J＝4.8Hz,2H),4.12(s,3H),3.85(q,J＝7.1Hz,2H),3.03(s,3H),1.37(t,J＝7.1Hz,3H),1.25(t,J＝4.8Hz,4H).
MS(ESI+)m/z 507.2[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-ethyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000671
The title compound was synthesized according to the method of step 5 of example 22 from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-ethyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.07(s,1H),8.99(s,1H),8.69(s,2H),8.59(d,J＝1.7Hz,1H),8.34(dd,J＝11.9,1.6Hz,1H),8.03(s,1H),7.79(s,1H),4.51(t,J＝5.9Hz,2H),4.12(t,J＝5.8Hz,2H),4.02(s,3H),3.84(q,J＝7.0Hz,2H),2.95(s,3H),1.20(t,J＝7.0Hz,5H).
MS(ESI+)m/z 494.2[M+H]+.
Example 34: 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-isopropyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000672
Step 1: synthesis of 4-methyl-6-bromo-8- (N-Boc-N-isopropyl-2-aminoethoxy) quinazoline
Figure BDA0001984930190000673
The title compound was synthesized according to the method of step 1 of example 22 from 6-bromo-4-methyl-8-hydroxyquinazoline and N-Boc-2-isopropylamino-1-ethanol.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),7.79(s,1H),7.24(s,1H),4.42–4.26(m,3H),3.63(t,J＝6.8Hz,2H),2.90(s,3H),1.47(s,9H),1.15(d,J＝6.8Hz,6H).
MS(ESI+)m/z 424.1,426.1[M+H]+.
Step 2: synthesis of 4-methyl-6-bromo-8- (N-isopropyl-2-aminoethoxy) quinazoline
Figure BDA0001984930190000681
The title compound was synthesized from 4-methyl-6-bromo-8- (N-Boc-N-isopropyl-2-aminoethoxy) quinazoline following the procedure in step 2 of example 22.
MS(ESI+)m/z 324.0,326.1[M+H]+.
And 3, step 3: synthesis of 4-methyl-6-bromo-8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000682
The title compound was synthesized from 4-methyl-6-bromo-8- (N-isopropyl-2-aminoethoxy) quinazoline according to the method of step 3 in example 22.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),9.04(s,1H),8.88(s,1H),8.09(d,J＝1.8Hz,1H),7.80(d,J＝1.8Hz,1H),5.23–5.10(m,1H),4.48(t,J＝7.2Hz,2H),4.34(q,J＝7.1Hz,3H),3.97(t,J＝7.2Hz,2H),2.90(s,3H),1.36(t,J＝7.1Hz,3H),1.25(d,J＝6.6Hz,6H).
MS(ESI+)m/z 474.0,476.1[M+H]+.
And 4, step 4: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000691
The title compound was synthesized according to the method of step 4 of example 22 from 4-methyl-6-bromo-8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2-methoxy-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.88(s,2H),8.57(d,J＝2.2Hz,1H),8.07(s,1H),7.97(dd,J＝8.6,2.4Hz,1H),7.74(s,1H),6.93(d,J＝8.5Hz,1H),5.26–5.14(m,1H),4.65–4.55(m,2H),4.35(q,J＝7.1Hz,2H),4.10–4.00(m,5H),3.01(s,3H),1.37(t,J＝7.1Hz,3H),1.28(d,J＝6.8Hz,6H).
MS(ESI+)m/z 503.1[M+H]+.
And 5: synthesis of 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-isopropyl-N- (5-hydroximino-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000692
The title compound was synthesized from 4-methyl-6- (2-methoxy-5-pyridyl) -8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline according to the method of step 5 in example 22.
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.07(s,1H),9.00(s,1H),8.74(d,J＝2.1Hz,1H),8.71(s,2H),8.27(dd,J＝8.7,1.9Hz,1H),7.99(s,1H),7.83(s,1H),6.97(d,J＝8.6Hz,1H),5.09–4.97(m,1H),4.47(t,J＝6.7Hz,2H),4.00(t,J＝6.7Hz,2H),3.93(s,3H),2.96(s,3H),1.28(d,J＝6.7Hz,6H).
MS(ESI+)m/z 490.2[M+H]+.
Example 35: 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-isopropyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000701
Step 1: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000702
The title compound was synthesized according to the procedure for step 4 of example 22 from 4-methyl-6-bromo-8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline and 2-methoxy-3-fluoro-5-pyridineboronic acid.
1H NMR(400MHz,CDCl3)δ9.22(t,1H),8.89(s,2H),8.36(s,1H),8.05(s,1H),7.79–7.70(m,2H),5.27–5.14(m,1H),4.60(t,J＝7.6Hz,2H),4.35(q,J＝7.1Hz,2H),4.13(s,3H),4.06(t,J＝7.6Hz,2H),3.03(s,3H),1.37(t,J＝7.1Hz,3H),1.29(d,J＝6.8Hz,6H).
MS(ESI+)m/z 521.1[M+H]+.
Step 2: synthesis of 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-isopropyl-N- (5-hydroxamic acid-2-pyrimidinyl) -2-aminoethoxy) quinazoline
Figure BDA0001984930190000703
The title compound was synthesized according to the method of step 5 of example 22 from 4-methyl-6- (2-methoxy-3-fluoro-5-pyridyl) -8- (N-isopropyl-N- (5-carboxylic acid ethyl ester-2-pyrimidinyl) -2-aminoethoxy) quinazoline.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.08(s,1H),9.00(s,1H),8.71(s,2H),8.60(d,J＝1.5Hz,1H),8.36(dd,J＝11.8,1.6Hz,1H),8.05(s,1H),7.84(d,J＝1.5Hz,1H),5.11–4.96(m,1H),4.47(t,J＝6.8Hz,2H),4.15–3.96(m,5H),2.97(s,3H),1.28(d,J＝6.7Hz,6H).
MS(ESI+)m/z 508.1[M+H]+.
Evaluation of pharmacological Activity
Experimental example 1: kinase activity assay for PI3K alpha
The effect of the compounds of the invention on PI3K a was evaluated using an in vitro kinase activity assay. The kinase activity of PI3K a was measured by measuring the level of ADP produced in the kinase reaction using a luciferase-based luminescence detection method, which in turn reflects the level of inhibition of PI3K a kinase activity by the compound. Kinase-GloTMThe kinase activity detection kit was purchased from Promega. PI3K alpha kinase and substrate PIP2 were purchased from Invitrogen. Using OptiPlateTM384 white 384 well plates for testing. All assays were performed at room temperature. The kinase buffer included 50mM Hepes (pH 7.5), 3mM MgCl2100mM NaCl, 1mM EGTA, 0.03% CHAPS and 2mM DTT. PI3K alpha kinase was diluted to 6.6nM kinase solution with kinase buffer. The substrate solution comprised 100 μ M PIP2 and 50 μ M ATP. Test compounds were diluted to 10mM in 100% DMSO and then serially diluted 3-fold in 100% DMSO to 10 different concentrations. Compounds diluted in 100% DMSO were then diluted 25-fold in 1 × kinase buffer. mu.L of the diluted compound solution and 2.5. mu.L of PI 3K. alpha. kinase solution were added to each well of a 384-well plate. The reaction was started by adding 5. mu.L of substrate solution per well, with a final reaction volume of 10. mu.L, an ATP concentration of 25. mu.M, a PIP2 concentration of 50. mu.M, and a PI 3K. alpha. kinase concentration of 1.65 nM. The 384-well plate was left to react at room temperature for 1 hour in the dark, and then 10. mu.L of Kinase-Glo was added to each wellTMThe reaction was stopped with reagents, incubated for 15 minutes, and the luminescence was subsequently read on an EnVision 2104 multi-label microplate detector.
Percent inhibition was calculated based on the following equation:
inhibition [% 100- (max-sample RLU)/(max-min) [% 100 ].
Where sample RLU is the luminescence reading at a given compound concentration, min is the reading for the DMSO control, and max is the reading for the no enzyme control. IC of compound was calculated by XLFit program in Excel50The values, results are shown in Table 1.
Experimental example 2: HDAC1 Activity assay
The effect of compounds on HDAC1 activity was tested in an in vitro assay. Recombinant full-length HDAC1 was purchased from BPS Biosciences. 384 well plates were purchased from Perkin Elmer. Compounds were dissolved in DMSO as 10mM stock solutions. Tris buffer was used as the test buffer, and both the compound stock and HDAC1 stock were diluted to the corresponding concentrations with this buffer. The substrate solution contains trypsin and Ac polypeptide. In 384 well plates, 15 μ L of HDAC1 solution and diluted compound solution were added per well and incubated for 15 min at room temperature. Then 10. mu.L of the substrate solution was added and incubated at room temperature for 1 hour. The 384-well plate is placed in a Synergy MX multifunctional microplate reader, and the fluorescence value with the emission wavelength of 460nm is read under the excitation wavelength of 355 nm.
Percent inhibition was calculated based on the following equation:
inhibition [ (% max-signal)/(max-min) [ (% max-signal) ]100
Where signal is the reading at a given compound concentration, min is the reading for the DMSO control, and max is the reading for the no enzyme active control. IC of compound was calculated by XLFit program in Excel50Values, results are shown in table 1.
Table 1: inhibitory Activity on PI3K alpha kinase and HDAC1
Figure BDA0001984930190000721
Figure BDA0001984930190000731
Experimental example 3: determination of tumor cell survival by MTT method
Digesting HCT116 cells (human colon cancer cells) in logarithmic growth phase with 0.25% pancreatin-EDTA to prepare single cell suspension, inoculating 1500 cells/well/100 μ L into 96-well plate overnight, adding fresh culture medium containing different concentrations of test compound and corresponding solvent control, and adding 100 μ L (DMSO final concentration) per well<0.1 percent) of the total flavonoids are continuously cultured at 37 ℃ for 72 hours, 20 mu L of freshly prepared PBS solution containing 5mg/mL MTT is added into each hole for culturing for 4 hours, the supernatant is discarded, 180 mu L of DMSO is added into each hole for dissolving MTT formazan precipitate, a micro oscillator is used for oscillating and uniformly mixing, the optical density value (OD) is measured under the condition of the detection wavelength of 570nm, tumor cells treated by DMSO are used as a control group, the inhibition rate of the compound to be detected on the growth of the tumor cells is calculated by the following formula, and IC is calculated according to the middle effect equation50：
Inhibition (%) - (control mean OD value-dosing mean OD value)/control mean OD value × 100%
The results of the experiments show that all examples show antiproliferative activity on human colon cancer cell HCT 116. ICs of examples 5, 10, 11, 15, 16, 17, 19, 23, 24, 25, 2950The value is in the range of 1.0-10. mu.M. ICs of examples 1,6, 7, 8, 13, 14, 18, 21, 26, 28 and 3150The value is in the range of 0.1-1.0. mu.M. ICs of examples 22, 27, 30, 32, 33, 34 and 3550The values are all less than 0.1. mu.M.
Summary of pharmacological activity:
all examples showed strong inhibitory activity against PI3K α, with the ICs of examples 6, 8 and 1150Values were all less than 1 nM. All examples showed strong inhibitory activity against HDAC1, with the IC of examples 1, 12, 13, 15, 16, 22, 27, 34 and 35 having the best activity50All values were less than 2 nM. All examples showed antiproliferative activity on human colon carcinoma cells HCT116, with the IC's of examples 22, 27, 30, 32, 33, 34 and 3550The values are all less than 0.1. mu.M.

Claims (9)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003593108300000011
wherein:
R1selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-4Alkoxy, cyano, C1-4Alkylsulfonylamino, phenylsulfonylamino; wherein said phenyl is optionally substituted with 1,2,3, 4, 5 halo;
a is
Figure FDA0003593108300000012
Wherein n is an integer of 1 to 10; or, A is
Figure FDA0003593108300000013
Wherein said R2Selected from hydrogen or C1-6Alkyl, m is an integer of 1,2,3 or 4.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein a is
Figure FDA0003593108300000014
Wherein n is an integer of 1,2,3, 4, 5, 6, 7, 8.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is
Figure FDA0003593108300000015
Wherein, R is2Selected from methyl, ethyl, propyl or isopropyl, and m is 2,3 or 4.
4. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R is1Selected from the group consisting of hydrogen, fluoro, methoxy, cyano, methylsulfonylamino, 2, 4-difluorophenylsulfonylamino, 2-chloro-4-fluorophenylsulfonylamino, 4-fluorophenylsulfonylamino.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
Figure FDA0003593108300000021
Figure FDA0003593108300000031
6. a pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and/or excipient.
7. The pharmaceutical composition of claim 6, further comprising a pharmaceutically active ingredient other than said compound or a pharmaceutically acceptable salt thereof.
8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 6 or 7, for the manufacture of a medicament for the prevention and/or treatment of PI3K and/or HDAC mediated diseases.
9. The use according to claim 8, wherein the PI3K and/or HDAC mediated disease is selected from the group consisting of a tumor, an autoimmune disease, a renal disease, a cardiovascular disease, an inflammatory disease, a metabolic/endocrine function disorder and a neurological disease.
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