CN103936762B

CN103936762B - Morpholine quinolines, Preparation Method And The Use

Info

Publication number: CN103936762B
Application number: CN201310016643.0A
Authority: CN
Inventors: 程建军; 秦继红
Original assignee: Shanghai Huilun Life Science & Technology Co ltd
Current assignee: Shanghai Huilun Pharmaceutical Co ltd
Priority date: 2013-01-17
Filing date: 2013-01-17
Publication date: 2016-02-24
Anticipated expiration: 2033-01-17
Also published as: CN103936762A

Abstract

Morpholine disclosed by the invention quinolines, for having the compound of following general formula (I): wherein, R ¹be selected from C1-C6 alkyl, aryl, amido, C3-C10 cycloalkyl, heterocyclic radical, heteroaryl; R ²be selected from hydrogen, halogen ,-OR ¹⁰; R ³be selected from hydrogen ,-NHR ¹⁰,-NHC (=O) R ¹⁰; R ⁴be selected from hydrogen, C1-C6 alkyl ,-C (=O) R ¹⁰,-S (=O) ₂r ¹⁰; R ⁵, R ⁶be selected from hydrogen, C1-C6 alkyl, halogen; R ⁷, R ⁸be selected from hydrogen, C1-C6 alkyl, halogen, or R ⁷, R ⁸merge into=O; R ⁹be selected from hydrogen, C1-C6 alkyl ,-OR ¹⁰, halogen; Wherein R ¹⁰for hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl; Further, R ^{1 ~ 10}described in alkyl, alkoxyl group, aryl, heteroaryl all optionally can be replaced by one or more group, these groups comprise alkyl, thiazolinyl, alkynyl, halogen, alkoxyl group, aryl, heteroaryl, amino, amido, cyano group, nitro, carboxyl, ester group, amine formyl, alkylsulfonyl, sulfoamido etc.Morpholine disclosed by the invention quinolines as medicine in order to the treatment disease relevant to PI3K/mTOR.

Description

morpholinoquinoline compound, preparation method and application thereof

Technical Field

The invention relates to a compound as a PI3K/mTOR inhibitor, a preparation method thereof, a pharmaceutical composition containing the same as an active ingredient, and application thereof as a medicament for treating diseases related to PI3K/mTOR, in particular to PI3K/mTOR related cancers.

Background

Modern studies have shown that during tumorigenesis, the "PI 3K (phosphatilinosonitol 3-kinase) -Akt (PKB, proteinkinase b) -mtor (mammaliantargetofaramycin)" signaling pathway controls numerous cellular biological processes, including tumor cell apoptosis, transcription, translation, metabolism, angiogenesis, and regulation of the cell cycle. Activation of this signaling pathway disturbs cell growth and survival, leading to accelerated tumor cell proliferation, malignant metastasis, and development of common drug resistance. The blocking of the PI3K-Akt-mTOR signaling pathway can inhibit the growth of tumor cells and even promote the apoptosis of the tumor cells, so the pathway is an important target for the research and development of novel antitumor drugs.

PI3K is an intracellular phosphoinositide kinase that catalyzes the phosphorylation of the 3-hydroxyl group of phosphatidylinositol, mediating the activation of downstream signaling pathways. PI3K can be classified into types I, II and III, and the most widely studied is type I PI3K, which is activated by cell surface receptors. The type I PI3K mainly comprises four subtypes of PI3K alpha, PI3K beta, PI3K and PI3K gamma, wherein PI3K alpha, PI3K beta and PI3K belong to type IA kinases and transmit signals from Receptor Tyrosine Kinases (RTK), G-protein coupled receptors and the like; PI3K γ is a type IB kinase that transmits signals only from G-protein coupled receptors (GPCRs). Research shows that the overexpression, activation or mutation of the type I PI3K in various human tumors is closely related to the occurrence and development of cancers.

In the "PI 3K-Akt-mTOR" signaling pathway, mTOR, which is a downstream signaling molecule for PI3K, is one of the important substrates for Akt. mTOR is a silk/threonine kinase, and inhibition of this signaling molecule has been shown to produce inhibition of tumor cell proliferation. Some rapamycin analogues acting on mTOR have been marketed as drugs, and therefore mTOR has also been identified as a target for treating tumors.

At present, PI3K inhibitors or PI3K/mTOR dual inhibitors have been shown to inhibit tumor growth, and multiple PI3K inhibitors or PI3K/mTOR dual inhibitors have been in clinical study.

Disclosure of Invention

One of the technical problems to be solved by the invention is to provide a morpholinoquinoline compound as a PI3K/mTOR inhibitor.

The second technical problem to be solved by the invention is to provide a method for preparing a morpholine quinoline compound used as a PI3K/mTOR inhibitor.

The invention also provides a pharmaceutical composition containing the morpholine quinoline compound as a PI3K/mTOR inhibitor.

The fourth technical problem to be solved by the invention is to provide the application of the pharmaceutical composition containing the morpholinoquinoline compound as the PI3K/mTOR inhibitor.

The morpholinoquinoline compound as the first aspect of the invention is a compound having the following general formula (I):

wherein,

R¹selected from C1-C6 alkyl, aryl, amino, C3-C10 cycloalkyl, heterocyclyl, heteroaryl;

R²selected from hydrogen, halogen, -OR¹⁰；

R³Selected from hydrogen, -NHR¹⁰，-NHC(=O)R¹⁰；

R⁴Selected from hydrogen, C1-C6 alkyl, -C (= O) R¹⁰，-S(=O)₂R¹⁰；

R⁵，R⁶Selected from hydrogen, C1-C6 alkyl, halogen;

R⁷，R⁸selected from hydrogen, C1-C6 alkyl, halogen, or R⁷，R⁸Merge to = O;

R⁹selected from hydrogen, C1-C6 alkyl, -OR¹⁰Halogen;

wherein R is¹⁰Is hydrogenC1-C6 alkyl, C3-C10 cycloalkyl, aryl, heteroaryl;

and, R^1～10The alkyl, alkoxy, aryl, heteroaryl groups described in (a) can be optionally substituted with one or more groups including alkyl, alkenyl, alkynyl, halogen, alkoxy, aryl, heteroaryl, amino, cyano, nitro, carboxyl, ester, carbamoyl, sulfonyl, sulfonamide, and the like.

In some embodiments of the invention, R¹Selected from 4-fluorophenyl, 2, 4-difluorophenyl, methyl, cyclopropyl and dimethylamino.

In some embodiments of the invention, R²Selected from chlorine and methoxy.

In some embodiments of the invention, R³Selected from hydrogen, -NH₂，-NHC(=O)CH₃。

In some embodiments of the invention, R⁴Selected from hydrogen, methyl, acetyl, methylsulfonyl.

In some embodiments of the invention, R⁵，R⁶Selected from hydrogen, methyl.

In some embodiments of the invention, R⁷，R⁸Selected from hydrogen, or R⁷，R⁸Merge to = O.

In some embodiments of the invention, R⁹Is hydrogen.

The present invention includes, but is not limited to, compounds wherein the substituents are defined as follows: r in the general formula (I)¹Is 4-fluorophenyl, 2, 4-difluorophenyl, methyl, cyclopropyl or dimethylamino, and at the same time: r²Is chlorine or methoxy; r³Is hydrogen, -NH₂or-NHC (= O) CH₃；R⁴Is hydrogen, methyl, acetyl or methylsulfonyl; r⁵，R⁶Is hydrogen or methyl; r⁷，R⁸Is hydrogen, or R⁷，R⁸Merge to = O; r⁹Is hydrogen.

The compound of the present invention may be any one of the following structures (I-1) to (I-67):

the compound of the general formula (I) is any one of enantiomer, diastereoisomer and conformational isomer or a mixture of any two or three of enantiomer, diastereoisomer and conformational isomer.

The compound of the general formula (I) is a pharmaceutically acceptable derivative.

The compounds of general formula (I) according to the invention may be present in the form of pharmaceutically acceptable salts, including salts with acids, such as the hydrochloride, hydrobromide, methanesulfonate, sulfate, phosphate, acetate, trifluoroacetate, trifluoromethanesulfonate, p-toluenesulfonate, tartrate, maleate, fumarate, succinate or malate salts; or sodium salt, potassium salt, magnesium salt, calcium salt with acidic proton substituted by metal ion.

The process for producing the above compound as the second aspect of the present invention is specifically the following process:

(1) when R is³In the case of hydrogen, the preparation of the compounds of formula (I) is carried out by: reacting 3-amino-4-hydroxy-6-bromoquineCyclizing an quinoline or substituted 3-amino-4-hydroxy-6-bromoquinoline and alkylating a nitrogen atom to obtain an intermediate A with a quinoline morpholine structure, and then carrying out Suzuki coupling reaction on the intermediate A and an intermediate B containing substituted pyridine boric acid or boric acid ester to obtain a compound with a general formula (I); or converting bromine of the intermediate A with the quinoline morpholine structure into an intermediate C containing boric acid or boric acid ester, and then carrying out Suzuki coupling reaction on the intermediate C and an intermediate D containing substituted bromopyridine to obtain a compound with a general formula (I); the specific reaction formula is as follows:

(2) when R is³When not hydrogen, the compound of formula (I) is prepared by the following steps: oxidizing and activating nitrogen atoms of the quinoline morpholine intermediates, then carrying out quinoline-2-site-nucleophilic substitution reaction by using a nucleophilic reagent to obtain an intermediate A with a quinoline morpholine structure, and then carrying out Suzuki coupling reaction on the intermediate A with the quinoline morpholine structure and an intermediate B containing substituted pyridine boric acid or boric acid ester to obtain a compound with a general formula (I); or converting bromine of the intermediate A with the quinoline morpholine structure into an intermediate C containing boric acid or boric acid ester, and then carrying out Suzuki coupling reaction on the intermediate C and an intermediate D containing substituted bromopyridine to obtain a compound with a general formula (I); the specific reaction formula is as follows:

in the above reaction formula: r¹、R²、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹As above, group

The pharmaceutical composition as the third aspect of the present invention, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable excipient.

A pharmaceutical composition as a third aspect of the invention, wherein said pharmaceutical composition comprises a therapeutically effective amount of a pharmaceutically acceptable derivative of a compound of formula (I) and a pharmaceutically acceptable excipient.

A pharmaceutical composition as a third aspect of the invention, wherein said pharmaceutical composition comprises a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of general formula (I) and a pharmaceutically acceptable excipient.

The pharmaceutical composition is prepared into tablets, capsules, aqueous suspensions, oily suspensions, dispersible powders, granules, pastilles, emulsions, syrups, creams, ointments, suppositories or injections.

As the fourth aspect of the invention, the application is the application of the compound in the general formula (I) in preparing the catalytic activity products for regulating the PI3K/mTOR signaling pathway.

As the fourth aspect of the invention, the application of the pharmaceutically acceptable derivatives of the compounds in the general formula (I) in preparing the products for regulating the catalytic activity of the PI3K/mTOR signaling pathway is provided.

As the fourth aspect of the invention, the use of the pharmaceutically acceptable salt of the compound shown as the general formula (I) in the preparation of the preparation for regulating the catalytic activity of the PI3K/mTOR signaling pathway.

As the fourth aspect of the invention, the application is the application of the pharmaceutical composition in preparing medicines for treating diseases related to the PI3K/mTOR signaling pathway.

The disease associated with the PI3K/mTOR signaling pathway is cancer.

The cancer is head and neck cancer, respiratory system cancer, digestive system cancer, urinary system cancer, skeletal system cancer, gynecological cancer, hematological cancer or other types of cancer.

The head and neck cancer is thyroid cancer, nasopharyngeal carcinoma, meningeal cancer, auditory neuroma, pituitary tumor, oral cancer, craniopharyngioma, tumor of thalamus and brain stem, tumor of angiogenesis or intracranial metastasis.

The respiratory cancer is lung cancer.

The digestive system cancer is liver cancer, gastric cancer, esophageal cancer, colorectal cancer, rectal cancer, colon cancer or pancreatic cancer.

The cancer of the urinary system is renal cancer, bladder cancer, prostatic cancer or testicular cancer.

The cancer of the skeletal system is bone cancer.

The gynecological cancer is breast cancer, cervical cancer or ovarian cancer;

the hematologic cancer is leukemia, malignant lymphoma or multiple myeloma.

The other type of cancer is malignant melanoma, glioma or skin cancer.

The compound of the general formula (I) can also be used for researching the biological or pharmacological phenomena of a PI3K-Akt-mTOR signaling pathway and comparatively evaluating a novel PI3K or PI3K/mTOR dual inhibitor.

Detailed Description

The present invention provides compounds of general formula (I) as defined above, methods of preparing such compounds, pharmaceutical compositions using such compounds and methods of using such compounds.

Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the terms used throughout the specification (unless otherwise limited in specific instances), whether used individually or as part of a larger group.

Unless otherwise defined, the term "alkyl" (used alone or as part of another group) as used herein refers to a monovalent group derived from an alkane that contains from 1 to 12 carbon atoms. Preferred alkyl groups have 1 to 6 carbon atoms. Alkyl is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. And said "alkyl" may be optionally substituted with a group selected from: alkyl, halogen (e.g., fluorine, chlorine, bromine, iodine), alkoxy, amino/amino, haloalkyl (e.g., trichloromethyl, trifluoromethyl), aryl, aryloxy, alkylthio, hydroxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, urea, or mercapto.

The term "cycloalkyl" (used alone or as part of another group) as used herein refers to a fully or partially saturated hydrocarbon ring of 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. Furthermore, cycloalkyl groups may be substituted. "substituted cycloalkyl" refers to a ring having one, two, or three substituents selected from: halogen, alkyl, substituted alkyl (wherein the substituents are as defined above for the alkyl substituents), alkenyl, alkynyl, nitro, cyano, oxo (= O), hydroxy, alkoxy, alkylthio, -CO₂H、-C(=O)H、-CO₂-alkyl, -C (= O) alkyl, keto, = N-OH, = N-O-alkyl, aryl, heteroaryl, five or six membered ketal (i.e. 1, 3-dioxane or 1, 3-dioxane), -NR 'R ", -C (= O) NR' R", -CO₂NR'R''、-C(=O)NR'R"、-NR'CO₂R"、-NR'C(=O)R"、-SO₂NR ' R ' and-NR ' SO₂R ", wherein each of R 'and R" is independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R ", together form a heterocycloalkyl or heteroaryl ring.

The term "aryl" as used herein (used alone or as part of another group) refers to a monocyclic or polycyclic aromatic ring, e.g., phenylSubstituted phenyl groups, and the like, and fused groups such as naphthyl, phenanthryl, and the like. Thus, an aryl group comprises at least one ring having at least 6 atoms, up to five such rings (of which up to 22 atoms are included), and adjacent carbon atoms or suitable heteroatoms have alternating (conjugated) double bonds between them. Preferred aryl groups contain 6 to 14 carbon atoms in the ring. And the "aryl" group may be optionally substituted with one or more groups including, but not limited to, halogen (such as fluorine, chlorine, bromine), alkyl (such as methyl, ethyl, propyl), substituted alkyl (such as trifluoromethyl), cycloalkyl, alkoxy (such as methoxy or ethoxy), hydroxy, carboxy, carbamoyl (-C (= O) NR' R), alkoxycarbonyl (-CO)₂R), amino/amino, nitro, cyano, alkenyloxy, aryl, heteroaryl, sulfonyl (-SO)₂R), wherein R, R 'and R' are the alkyl groups.

The term "heteroaryl" as used herein (used alone or as part of another group) refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups, which have at least one heteroatom (O, S or N) in at least one ring. The fused rings forming the bicyclic and tricyclic groups described above may contain only carbon atoms and may be saturated or partially saturated, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The nitrogen and sulfur atoms may be oxidized, and the nitrogen atom may be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one ring that is fully aromatic, but the other fused ring or rings may be aromatic or non-aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring.

The "heteroaryl" ring system may contain zero, one, two or three substituents selected from: halogen, alkyl, substituted alkyl, alkenyl, bulky, aryl, nitro, cyano, hydroxy, alkoxyAlkylthio, -CO₂H、-C(=O)H、-CO₂-alkyl, -C (= O) alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, heteroaryl, -NR 'R ", -C (= O) NR' R", -CO₂NR'R"、-C(=O)NR'R"、-NR'CO₂R"、-NR'C(=O)R"、-SO₂NR ' R ' and-NR ' SO₂R ", wherein R 'and R" are each independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R' and R "together form a heterocycloalkyl or heteroaryl ring.

Examples of monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Examples of bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, and the like.

Examples of tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, and the like.

The term "heterocycle" (used alone or as part of another group) as used herein refers to a cycloalkyl (non-aromatic) group in which one carbon atom in the ring is replaced by a heteroatom selected from O, S or N and up to 3 additional carbon atoms may be replaced by the heteroatom. The term "heterocyclyl", as used herein (alone or as part of another group), refers to a stable, saturated or partially unsaturated monocyclic ring system containing 5 to 7 ring atoms (carbon atoms and other atoms selected from nitrogen, sulfur and/or oxygen). The heterocyclic ring may be a5, 6 or 7 membered monocyclic ring and contain one, two or three heteroatoms selected from nitrogen, oxygen and/or sulphur. The heterocyclic ring may be optionally substituted, meaning that the heterocyclic ring may be substituted at one or more substitutable ring positions with one or more groups independently selected from: alkyl, heterocycloalkyl, heteroaryl, alkoxy, nitro, monoalkylamino, dialkylamino, cyano, halogen, haloalkyl, alkanoyl, amino/aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyloxy and aryl, said aryl being optionally substituted with halogen, alkyl and alkoxy. Examples of such heterocycloalkyl groups include, but are not limited to: piperidine, morpholine, homomorpholine, piperazine, thiomorpholine, pyrrolidine and azetidine.

The term "alkoxy" as used herein (alone OR as part of another group) refers to an alkyl group, preferably having 1 to 6 carbon atoms, such as — OR, where R is the alkyl group, attached through an oxygen atom.

The term "amino" (used alone or as part of another group) as used herein refers to-NH₂. The "amino" group may be optionally substituted with one or two substituents (-NR 'R "), where R' and R" may be the same or different, such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, alkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, antelopylalkyl, alkoxyalkyl, alkylthio, carbonyl, or carboxyl. These substituents may be further substituted with a carboxylic acid or any of the alkyl or aryl substituents listed herein. In some embodiments, amino is substituted with carboxy or carbonyl, forming an N-acyl or N-carbamoyl derivative group.

The term "halogen" refers to an independently selected fluorine, chlorine, bromine or iodine.

The term "anti-cancer agent" includes any known agent useful for treating cancer, including: (1) cytotoxic drugs: nitrogen mustards, such as melphalan, cyclophosphamide; platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; (2) antimetabolite antineoplastic agents: 5-fluorouracil, capecitabine, methotrexate, calcium folinate, raltitrexed, purine antagonists (e.g., 6-thioguanine and 6-mercaptopurine); (3) hormones: 17 alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drostandrosterone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, clorenyl estrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, toremifene; (4) tyrosine kinase inhibitors: EGFR inhibitors including Gefitinib (Gefitinib), Erlotinib (Erlotinib), Cetuximab (Cetuximab), Herceptin (Herceptin), and the like; VEGF inhibitors such as anti-VEGF antibodies (Avastin) and small molecule inhibitors such as Sunitinib, Sorafenib, Vandetanib, Pazopanib, Axitinib, and the like; Bcr-Abl inhibitors such as Imatinib, Nilotinib, Dasatinib; src inhibitors, MEK kinase inhibitors, MAPK kinase inhibitors, PI3K kinase inhibitors, c-Met inhibitors, ALK inhibitors, and the like; (5) drugs acting on tubulin such as vinblastine drugs, paclitaxel drugs, epothilone drugs such as Ixabepilone (Ixabepilone), and the like; (6) topoisomerase I inhibitors such as topotecan, irinotecan; (7) histone Deacetylase (HDAC) inhibitors such as Vorinostat, Romidepsin; (8) proteasome inhibitors such as Bortezomib (Bortezomib); (9) other classes of anticancer drugs such as aurora kinase (aurorakinase) inhibitors, biological response modifiers, growth inhibitors, glutamine antagonists, anti-angiogenic and anti-vascular drugs, matrix metalloproteinase inhibitors, and the like.

"mammal" includes humans and domestic animals such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, and the like. Preferably, for the purposes of the present invention, the mammal is a human.

By "pharmaceutically acceptable derivative" is meant any non-toxic salt, ester salt, amide salt, or other derivative that, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.

"pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, dispersant, diluent, preservative, suspending agent, stabilizer, dye/colorant, flavoring agent, surfactant, wetting agent, isotonic agent, solvent, or emulsifier that has been approved by the national food and drug administration as being useful for human or livestock.

"pharmaceutically acceptable salts" include acid addition salts and base addition salts.

"pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effects and properties of the free base, do not have biological or other undesirable consequences, and are formed with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, and organic acids such as, but not limited to, the following: formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, p-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, mucic acid, naphthalene-2-sulfonic acid, Naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, fumaric acid, succinic acid, tartaric acid, thiocyanic acid, undecylenic acid, and the like.

"pharmaceutically acceptable base addition salts" refers to salts that retain the biological effects and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, methylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, isopropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzphetamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperidine, piperazine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, triethylamine, dicyclohexylamine, choline and caffeine.

"pharmaceutical composition" refers to a formulation of a compound of the present invention with a generally accepted vehicle for delivering biologically active compounds to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers, diluents or excipients therefor.

A "therapeutically effective amount" refers to an amount of a compound of the present invention which, when administered to a mammal (preferably a human), is sufficient to effect treatment of a disease or condition associated with the mammal (preferably a human) as defined below. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will depend, for example, on the activity of the particular compound employed; the metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; mode and time of administration; the rate of excretion; combined medication; the severity of the particular condition or disorder; and the individual undergoing treatment, but it can be routinely determined by one of ordinary skill in the art based on his own knowledge and this disclosure.

"treating" or "treatment" as used herein encompasses the treatment of a disease or disorder associated with a mammal, preferably a human, having the disease or disorder associated therewith and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal has a disease but has not yet been diagnosed as having it;

(ii) inhibiting the disease or disorder, i.e., arresting its development;

(iii) ameliorating the disease or condition, i.e., causing regression of the disease or condition;

(iv) stabilizing the disease or condition.

As used herein, the terms "disease" and "condition" may be used interchangeably or may be different, as a particular disease or condition may not have a known predisposition (and thus the cause has not been studied), and therefore has not been considered a disease but merely as an abnormal condition or syndrome, wherein the clinician has more or less identified a particular syndrome.

The compounds of the invention and their structures shown herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, or conformational) forms, which may be defined as (R) -/(S) -or (D) -/(L) -or (R, R) -/(R, S) -/(S, S) -, according to the absolute stereochemical definition for an amino acid. The present invention is meant to include all such possible isomers, as well as their racemic, enantiomerically enriched, and optionally pure forms. Optically active (+) and (-), (R) -and (S) -and (R, R) -/(R, S) -/(S, S) -or (D) -and (L) -isomers can be prepared using chiral synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, High Performance Liquid Chromatography (HPLC) using a chiral column. When the compounds described herein contain an alkenyl double bond or other geometrically asymmetric center, the compounds include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are also included.

"stereoisomers" refers to compounds made up of the same atoms bonded with the same chemical bonds but having different three-dimensional structures, which are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof and includes "enantiomers" which refer to two stereoisomers whose molecules are nonsuperimposable mirror images of each other, and "diastereomers"; diastereoisomers refer to stereoisomers in which the molecules have two or more chiral centers and are in a non-mirror relationship between the molecules.

"tautomer" refers to a proton that moves from one atom of a molecule from an original position to another position on the same molecule. The invention includes tautomers of any of the compounds.

In addition, unless otherwise indicated, the compounds of the present invention also include compounds that differ in structure only in the presence of one or more isotopically enriched atoms. For example, having the structure of the invention except that "deuterium" or "tritium" is used in place of hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the invention. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.

The invention also provides the following methods: proliferative diseases, such as cancer, are treated via modulation of the PI3K/mTOR signalling pathway by administering to a patient in need of such treatment (simultaneously or sequentially) a therapeutically effective amount of a compound of general formula (I) as defined above in combination with at least one other anti-cancer agent. In a preferred embodiment, the proliferative disease is cancer.

In particular, the compounds of formula (I) are useful in the treatment of a variety of cancers, most particularly those that rely on PI3K/mTOR signaling for activation. In general, the compounds of the invention may be used to treat the following cancers:

1. head and neck cancers, including thyroid cancer, nasopharyngeal cancer, meningeal cancer, acoustic neuroma, pituitary tumor, oral cancer, craniopharyngioma, thalamic and brainstem tumors, angiogenetic tumors, intracranial metastases;

2. respiratory cancers, including lung cancer;

3. cancers of digestive system including liver cancer, gastric cancer, esophageal cancer, carcinoma of large intestine, rectal cancer, colon cancer, and pancreatic cancer;

4. urinary system cancers including renal, bladder, prostate, testicular;

5. cancer of the skeletal system, bone cancer;

6. gynecological cancers including breast cancer, cervical cancer, ovarian cancer;

7. hematological cancers including leukemia, malignant lymphoma, multiple myeloma;

8. other types of cancer, including malignant melanoma, glioma, skin cancer.

The compounds of formula (I) may also be used in the treatment of any disease process characterized by abnormal proliferation of cells, such as benign prostate hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxic shock and fungal infections.

The compounds of formula (I) modulate the level of RNA and DNA synthesis in cells. Thus, these agents may be used to treat viral infections (including but not limited to HIV, human papilloma virus, herpes virus, poxviruses, EB virus, sindbis virus and adenovirus).

The compounds of formula (I) are useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of aggressive cancer or inhibiting tumor recurrence by blocking the initial mutagenic event or by blocking the progression of pre-malignant cells that have suffered damage. The compounds of general formula (I) are useful for inhibiting tumor angiogenesis and metastasis.

The compounds of the present invention may also be used in combination (either together or sequentially) with known anticancer agents (including, but not limited to, those mentioned above under "anticancer agents") or anticancer therapies such as radiation therapy.

Certain compounds of formula (I) can generally be prepared according to scheme 1 and scheme 2 below. Tautomers and solvates (e.g., hydrates, ethanolates) of the compounds of formula (I) are also within the scope of the invention. Methods for the preparation of solvates are generally known in the art. Thus, the compounds of the present invention may be in free form or in the form of a hydrate.

In the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, p-methoxybenzyl and the like. Suitable protecting groups for amino groups include t-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, trifluoroacetyl, p-methoxybenzyl and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters. Suitable protecting groups for the NH function of a heteroaryl group such as, for example, an indole or indazole ring include t-butyloxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, 2-trimethylsilanyl-ethoxymethyl, p-methoxybenzyl and the like.

Protecting groups may be added or removed according to methods known to those skilled in the art (Greene, t.w., protective group organic sy-thesis, 1999, 3 rd edition, Wiley) and standard techniques described herein. The protecting group may also be a polymer resin such as Wang resin, Rink resin or 2-chlorotrityl chloride resin.

Also, while these protected derivatives of the compounds of the present invention may not be pharmacologically active themselves, they may be administered to a mammal and then metabolized in vivo to form the compounds of the present invention which are pharmacologically active. Such derivatives are therefore described as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present invention.

The compounds of the general formula (I) according to the invention can be prepared by the following method:

(1) when R is³In the case of hydrogen, the preparation of the compounds of formula (I) is carried out by: cyclizing 3-amino-4-hydroxy-6-bromoquinoline or substituted 3-amino-4-hydroxy-6-bromoquinoline and alkylating nitrogen atoms to obtain an intermediate A with a quinolinomorph structure, and then carrying out Suzuki coupling reaction on the intermediate A and an intermediate B containing substituted pyridine boric acid or boric acid ester to obtain a compound with a general formula (I); or converting bromine of the intermediate A with the quinoline morpholine structure into an intermediate C containing boric acid or boric acid ester, and then carrying out Suzuki coupling reaction on the intermediate C and an intermediate D containing substituted bromopyridine to obtain a compound with a general formula (I); the specific reaction formula is as follows:

Wherein, the following abbreviations are commonly used in the expression process of the present invention:

DMF: n, N-dimethylformamide;

DMSO, DMSO: dimethyl sulfoxide;

THF tetrahydrofuran

CDCl₃: deuterated chloroform;

LC-MS, LC-MS chromatography;

TLC: thin layer chromatography;

¹HNMR: nuclear magnetic resonance hydrogen spectroscopy;

s: a single peak;

d: double peaks;

t: a triplet;

dd: double peak;

br: broad peak;

m: multiple peaks;

h: hour(s)

DEG C: c, centigrade degree;

mol: molar ratio;

mmol: millimole;

ATP is adenosine triphosphate.

Other compounds of the invention not specifically disclosed in the above schemes can be prepared by similar methods using appropriate starting materials by those skilled in the art.

All compounds of the invention prepared as above in free base or acid form can be converted into their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid forms by standard techniques.

The compounds of the present invention include all crystalline forms, amorphous forms, anhydrates, hydrates, solvates, and salts thereof. Furthermore, all compounds of the invention comprising an ester group and an amide group can be converted into the corresponding acids by methods known to the person skilled in the art or by the methods described herein. Likewise, compounds of the invention comprising a carboxylic acid group can be converted into the corresponding esters and amides by methods known to those skilled in the art. Other substitutions and substitutions on the molecule may also be made by methods known to those skilled in the art (e.g., hydrogenation, alkylation, reaction with acid chlorides, etc.).

To prepare the cyclodextrin inclusion complexes of the present invention, the compounds of general formula (I) as defined in the summary of the invention above may be dissolved in a pharmacologically acceptable solvent such as, but not limited to, an alcohol (preferably ethanol), a ketone (e.g. acetone) or an ether (e.g. diethyl ether) and mixed with an aqueous solution of α -cyclodextrin, β -cyclodextrin or γ -cyclodextrin, preferably β -cyclodextrin, at 20 ℃ to 80 ℃; alternatively, the acid of a compound of formula (I) as defined in the summary of the invention above, in the form of an aqueous solution of its salt (e.g. sodium or potassium salt) can be blended with the cyclodextrin, and then blended with a solution of an equivalent amount of acid (e.g. HCl or H2SO 4) to provide the corresponding cyclodextrin inclusion compound.

At this point or after cooling, the corresponding cyclodextrin inclusion compound crystals can crystallize out. Or when the compound of formula (I) is oily and crystalline, it can be converted to the corresponding cyclodextrin inclusion compound by adding an aqueous solution of cyclodextrin with stirring at room temperature for a long period of time (e.g., 1 hour to 14 days). The inclusion compound can then be isolated as a solid or as crystals by filtration and drying.

Cyclodextrins for use in the present invention are commercially available (e.g., from aldrich chemical co.) or are prepared by one skilled in the art using known methods. See, for example, Croft, A.P. et al, "Sy-hesisof chemical lyModifiedcycerodextrins", Tetrahedron1983,39,9, 1417-. Suitable cyclodextrins include the various types of inclusion complexes prepared with compounds of formula (I) above.

By selecting appropriate amounts of cyclodextrin and water, a reproducible inclusion compound of the active substance content can be obtained according to the stoichiometric composition. The inclusion compound may be used in a dry, water-absorbing form or in a form which contains water but is less water-absorbing. Typical molar ratios of cyclodextrin to compound of formula (I) are 2: 1 (Cyclodextrin: Compound).

The pharmaceutical composition comprising the compound of formula (I) as an active ingredient may be in a form suitable for oral administration, for example, as tablets, capsules, aqueous suspensions, oily suspensions, dispersible powders or granules, syrups and the like. Orally-administrable compositions may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients or carriers suitable for the manufacture of tablets. These excipients or carriers may be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium carboxymethylcellulose, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances (such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose) or time delay substances (such as ethyl cellulose, cellulose acetate butyrate) may be used.

The capsule includes hard gelatin capsule and soft gelatin capsule. Hard gelatin capsules are prepared by mixing the active ingredient with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin; soft gelatin capsules are prepared by mixing the active ingredient with a water-soluble carrier, such as polyethylene glycol, or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials and excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be a naturally occurring phosphatide (e.g. lecithin) or a condensation product of an alkylene oxide with a fatty acid (e.g. polyoxyethylene stearate) or a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. heptadecaethylene-oxycetanol) or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (such as polyoxyethylene sorbitol monooleate) or a condensation product of ethylene oxide with a partial ester derived from a mixture of a fatty acid and a hexitol (e.g. polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (for example ethyl or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules comprise the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules can be prepared by the addition of water to prepare an aqueous suspension.

Syrups may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent, a preservative, a flavoring agent, a coloring agent and an antioxidant.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phosphatides (e.g. soy bean lecithin), esters or partial esters derived from mixtures of fatty acids and hexitols (e.g. sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide (e.g. polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening agents, flavouring agents, preservatives and antioxidants.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable carriers and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution and dextrose solution.

The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is first dissolved in a mixture of soybean oil and lecithin. Then, the resulting oil solution was introduced into a mixture of water and glycerin and treated, thereby forming a microemulsion.

Injectable solutions or microemulsions may be introduced into the bloodstream of a patient by local bolus injection or the solution or microemulsion may be administered in a manner so as to maintain a constant circulating concentration of the compound of the invention. To maintain such a constant concentration, a continuous intravenous administration device such as an infusion pump may be used.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular or subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent, for example, a solution in 1, 3-butanediol. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids (such as oleic acid) may be used in the preparation of injectables.

The compounds of formula (I) may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular weights and fatty acid esters of polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., comprising the compounds of formula (I) may be prepared and used.

The compounds of the present invention may be administered in intranasal form by topical use of suitable intranasal vehicles and delivery devices, or by transdermal routes using transdermal skin patches well known to those skilled in the art. The compounds of the present invention may also be administered in the form of suppositories using bases such as: cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular weights, and fatty acid acetates of polyethylene glycols.

When the compounds of the present invention are administered to a human subject, the daily dosage will generally be determined by the prescribing physician, and will generally vary with the age, weight, sex, and response of the patient, as well as the severity of the patient's symptoms. Generally, an effective daily dose for a 70kg patient is about 0.001mg/kg to 100mg/kg, preferably 0.01mg/kg to 50 mg/kg.

If formulated as a fixed dose, these combination products are treated with the compounds of the present invention within the dosage ranges described above and other pharmaceutically active agents within their approved dosage ranges. When the combined preparation is not suitable, the compound of formula (I) may also be administered sequentially with known anticancer or cytotoxic agents. The present invention is not limited by the order of administration; the compounds of formula (I) may be administered before or after administration of known anticancer drug(s) or cytotoxic drug(s).

The compounds of the invention are inhibitors of PI3K/mTOR mediated diseases or PI3K/mTOR mediated disorders. The terms "PI 3K/mTOR mediated disease" and "PI 3K/mTOR mediated disorder" refer to any disease state or other deleterious disorder in which PI3K/mTOR is known to have an effect. The terms "PI 3K/mTOR mediated disease" and "PI 3K/mTOR mediated disorder" also refer to those diseases or disorders that are alleviated by treatment with a PI3K/mTOR inhibitor. Such diseases and disorders include, but are not limited to, cancer and other proliferative disorders.

Thus, the compounds are useful for treating, for example, the following diseases or conditions in mammals, especially humans: stomach, lung, esophagus, pancreas, kidney, colon, thyroid, brain, breast, prostate, and other solid tumors; lymphoma; leukemia; modulating angiogenesis; regulating thrombosis and pulmonary fibrosis.

The compound can also be used for researching biological or pharmacological phenomena of a PI3K-Akt-mTOR signaling pathway and comparing and evaluating a novel PI3K or PI3K/mTOR dual inhibitor.

The compounds referred to herein include, but are not limited to, the types of structures given in the above preparation methods, and those skilled in the art can obtain compounds not specifically recited by applying similar methods from appropriate starting materials.

Examples

The following examples (for preparing the compounds of the invention) and biological test examples (assays to demonstrate the utility of the compounds of the invention) are provided to aid in the practice of the invention and should not be construed as limiting the scope of the invention.

Some compounds of the invention may be prepared by preparing the corresponding intermediates a, B, C and D described below, followed by Suzuki coupling of a in combination with B, or C in combination with D.

Intermediate A-1: 9-bromo-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one

Step 1: a solution of NaOH (18.6g,465mmol) in water (39mL) was cooled and nitromethane (9.3g,153mmol) was added dropwise, maintaining the temperature at 25-30 ℃. After dropping, heating to 40 ℃ and then cooling, nitromethane (9.325g,152.76mmol) was added dropwise, maintaining the temperature at 40-45 ℃. After dropping, it was kept at 40-45 ℃ until the solid completely disappeared and a red clear solution appeared. The reaction mixture was then heated to 50-55 ℃ for 2-5 minutes, cooled to 30 ℃ and poured into 21g of ice, acidified with 41.7mL of concentrated hydrochloric acid, and rapidly added to a mixed solution of 2-amino-5-bromobenzoic acid (30g,138.87mmol) in concentrated hydrochloric acid (13mL) and water (280mL) and stirred at room temperature for 18 hours. Filtration, washing of the filtrate with water, and drying gave 5-bromo-2- ((2-nitroethylenene) amino) benzoic acid (39.9g,100% crude yield). LC-MS (ESI +):287,289 [ M +1]]⁺。

Step 2: 5-bromo-2- ((2-nitroethylenene) amino) benzoic acid (19.93g,69.4mmol) was added to acetic anhydride (360mL), and anhydrous K was added₂CO₃(28.79g,208.276mmol), heated to 90 ℃ and stirred for 1h, cooled, filtered, the filtrate washed with water and dried to give crude 3-nitro-4-hydroxy-6-bromoquinoline (5.936g,31.7%) which is used directly in the next reaction. LC-MS (ESI +) 269,271[ M +1]]⁺。

And step 3: 3-Nitro-4-hydroxy-6-bromoquinoline (4.0g,14.9mmol) was dissolved in 1N NaOH (148mL,148mmol) and sodium metabisulfite (15.3g,87.7mmol) was added portionwise. After the addition, the reaction solution was stirred for 30 minutes in the dark. Cooled to 0 ℃, acidified with 6N hydrochloric acid to pH =7 or so, and the resulting solid filtered, washed with a small amount of acetone and dried to give the crude product 3-amino-4-hydroxy-6-bromoquinoline (3.07g,86%) which was used directly in the next reaction. LC-MS (ESI +) 239,241[ M +1]]⁺。

And 4, step 4: 3-amino-4-hydroxy-6-bromoquinoline (2.0g,8.37mmol) was dissolved in THF (10mL) under ice-bath, and Et was added to the solution₃N (847mg, 8.37mmol), bromoacetyl bromide (1.69 g,8.37mmol) in THF (10mL) was added dropwise and stirred for about 2h and quenched with water. After filtration, the filtrate was extracted with dichloromethane, combined and concentrated together with the residue to give 2-bromo-N- (6-bromo-4-hydroxyquinolin-3-yl) acetamide (2.1 g, 70%).

And 5: 2-bromo-N- (6-bromo-4-hydroxyquinolin-3-yl) acetamide (2.1 g, 5.8 mmol) was dissolved in DMF (20mL) and K was added₂CO₃(403 mg, 2.92 mmol), heated to 50 ℃ and stirred for 4 h. Concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain light yellow solid 9-bromo-2H- [1,4]Oxazino [3,2-c]Quinolin-3 (4H) -one (900 mg, 55%).

Intermediate A-2: 9-bromo-2-methyl- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one

Reacting 9-bromo-2H- [1,4]Oxazino [3,2-c]Quinolin-3 (4H) -one (1.05g,3.76mmol) was dissolved in THF (25mL) and DMF (25mL), cooled to 0 deg.C, NaH (300mg,7.5mmol) was added, and after 15 minutes of reaction, iodomethane (1.07g,7.5mmol) was added, warmed to room temperature and reacted for 3 hours. Adding dichloromethane (100mL) to dilute the reaction solution, washing the organic phase with water, washing with saturated brine, drying, concentrating, and performing column chromatography (DCM: MeOH =100:1) to obtain 9-bromo-2-methyl- [1,4]]Oxazino [3,2-c]Quinolin-3 (4H) -one (397mg, 36%). LC-MS (ESI +) 293,295[ M +1]]⁺。

Intermediate A-3: 9-bromo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinoline

3-amino-4-hydroxy-6-bromoquinoline (2.0g,8.37mmol) was dissolved in acetone (50mL), DMF (12mL) and water (12mL), potassium carbonate (3.47g,25.1mmol) was added, 1, 2-dibromoethane (7.86g,41.83mmol) was added dropwise, and the mixture was stirred under reflux overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and methylene chloride (100mL) and water (20mL) were added to the residue. The pH was adjusted to about 8 with 1N hydrochloric acid, extracted with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM: MeOH =150:1) as a residue to give intermediate A-3(1.15g, 52%). LC-MS (ESI +):265,267[ M +1]]⁺。

Intermediate A-4: 9-bromo-4- (methylsulfonyl) -3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinoline

Intermediate A-3(1.25g,4.73mmol) was dissolved in THF (50mL) and Et was added₃N (1.44g,14.2mmol), MsCl (1.63g,14.2mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and the residue was column chromatographed (DCM: MeOH =100:1) intermediate a-4(1.24g, 76%). LC-MS (ESI +) 343,345[ M +1]]⁺。

Intermediate A-5: 9-bromo-4- (acetyl) -3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinoline

The aforementioned intermediate A-3(400mg,1.51mmol) was dissolved in THF (25mL), triethylamine (611mg,6.03mmol) was added, cooling to 0 ℃ was performed, and acetyl chloride (474mg,6.03mmol) was added under nitrogen. After the addition, the reaction was allowed to warm to room temperature overnight. The reaction solution was concentrated under reduced pressure, and column chromatography (DCM: MeOH =100:1) was performed on the residue to obtain intermediate a-5(456mg, 98%). LC-MS (ESI +) 307,309[ M +1]]⁺。

Intermediate A-6: 9-bromo-4-methyl-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinoline

Intermediate A-2 (500mg, 1.71 mmol) was dissolved in THF (15mL) under nitrogen, borane dimethylsulfide complex (2 NinTHF, 3.5mL, 7mmol) was added dropwise with caution, heated to 50 deg.C and stirred overnight. Cooled to room temperature, 1N hydrochloric acid (7 mL) was added dropwise, heated to reflux and stirred for 1 hour, cooled to room temperature, made alkaline with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, concentrated, and subjected to silica gel column chromatography to give intermediate a-6 (120 mg, 25%).

Intermediate A-7: 9-bromo-2, 2-dimethyl-2H- [1,4] oxazine [3,2-c ] quinolin-3 (4H) -one

Step 1: to a solution of 3-amino-4-hydroxy-6-bromoquinoline (500mg, 2.1mmol) in THF (3mL) under ice-bath was added Et₃N (212mg, 2.1mmol), a solution of 2-bromoisobutyryl bromide (481 mg,2.1mmol) in THF (3mL) was added dropwise and stirred at room temperatureFor 2 hours. A small amount of methanol was added to the reaction solution, and the mixture was concentrated under reduced pressure to obtain 612mg of crude product, which was used directly in the next reaction. (DCM: MeOH =20:1, Rf = 0.5).

Step 2: the crude product obtained in step 1 (612 mg) was dissolved in DMF (10mL), potassium carbonate (218 mg, 1.58 mmol) was added, heated to 50 ℃ and stirred for 5 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give intermediate A-7 (190 mg, 40%) as a pale yellow solid.

Intermediate A-8: 9-bromo-2, 2, 4-trimethyl-2H- [1,4] oxazine [3,2-c ] quinolin-3 (4H) -one

After nitrogen protection, the intermediate A-7 (2.0g, 6.51 mmol) was dissolved in a mixed solvent of DMF (30mL) and THF (30mL), cooled in an ice bath, NaH (60%, 520mg, 13mmol) was added, stirring was carried out for 15 minutes, methyl iodide (1.85 g,13 mmol) was added dropwise, the mixture was warmed to room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give pale yellow solid intermediate A-8 (1.1 g, 53%).

Intermediate A-9: 9-bromo-2, 2, 4-trimethyl-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinoline

Intermediate A-8 (500mg, 1.56 mmol) was dissolved in THF (10mL) under nitrogen, borane dimethyl sulfide complex (2N, THF solution, 3.1mL, 6.2 mmol) was added, heated to 50 deg.C and stirred overnight, TLC showed disappearance of starting material, 1N hydrochloric acid (5mL) was added, heated to reflux for 1h, cooled, made basic with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, concentrated, and chromatographed on silica gel column to give pale yellow gum A-9 (130mg, 27%).

Intermediate B-1: (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid

Step 1, 2-chloro-3-amino-5-bromopyridine (500mg,2.46mmol) is dissolved in THF (10mL), LiHMDS (7.4mL,7.4mmol) is added, stirring is carried out for ten minutes, 4-fluorobenzenesulfonyl chloride (1.44g,7.4mmol) is further added, stirring is carried out at room temperature overnight, dichloromethane (20mL) is added for dilution, washing is carried out with saturated sodium bicarbonate, extraction is carried out with dichloromethane (4 × 30mL), the organic phases are combined, drying and concentration are carried out, and chromatography of the residue is carried out (petroleum ether: ethyl acetate =20:1) to obtain N- (5-bromo-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (770mg, 87%). LC-MS (ESI +), 361,363[ M +1 + ]]⁺。

Step 2: n- (5-bromo-2-chloropyridin-3-yl) -4-fluorobenzenesulfonamide (770mg,2.1mmol) was dissolved in 1, 4-dioxane (25mL) and pinacol diboron (704mg,2.8mmol), Pd (dppf) Cl was added₂(156mg,0.213mmol) and KOAc (628mg,6.396mmol) were purged with nitrogen three times, and then heated to 100 ℃ and stirred for 3 hours. Cooled to room temperature, diluted with ethyl acetate (30mL), washed with water and saturated brine, dried, concentrated, and the residue was subjected to column chromatography (PE: EA =10:1) to give (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid (861mg, 99%). LC-MS (ESI +) 331[ M +1]]⁺。

Intermediate B-2: 4-fluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide

Step 1: 2-methoxy-3-amino-5-bromopyridine (500mg,2.5mmol) was dissolved in THF (10mL), LiHMDS (7.4mL,7.4mmol) was added, reaction was carried out for ten minutes, and 4-fluorobenzenesulfonyl chloride (1.44g,7.4mmol) was added, and stirring was carried out at room temperature overnight. The reaction mixture was diluted with dichloromethane (20mL), washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated, and the residue was column-layeredN- (5-bromo-2-methoxypyridin-3-yl) -4-fluorobenzenesulfonamide (770mg,87%) was obtained by precipitation (PE: EA =20: 1). LC-MS (ESI +) 361,363[ M +1]]⁺。

Step 2: dissolving N- (5-bromo-2-methoxypyridin-3-yl) -4-fluorobenzenesulfonamide (770mg,2.1mmol) in 1, 4-dioxane (25mL), adding pinacol diboron diborate (704mg,2.8mmol), Pd (dppf) Cl₂(156mg,0.21mmol) and KOAc (628mg,6.4 mmol). After nitrogen substitution was performed three times, the mixture was heated to 100 ℃ and stirred for 3 hours, cooled to room temperature, diluted with ethyl acetate (30mL), washed with water and saturated brine, dried, concentrated, and the residue was subjected to column chromatography (PE: EA =10:1) to give 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide (861mg, 99%). LC-MS (ESI +) 409[ M +1]]⁺。

Intermediate B-3 (6-chloro-5- (2, 4-difluorobenzenesulfonylamino) pyridin-3-yl) boronic acid

Replacing 4-fluorobenzenesulfonyl chloride in the preparation process of the intermediate B-1 with 2, 4-difluorobenzenesulfonyl chloride, and simulating the step 1 and the step 2 in the preparation process of the intermediate B-1 to obtain an intermediate B-3. LC-MS:349[ M +1 ].

Intermediate B-4:2, 4-difluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide

Replacing 4-fluorobenzenesulfonyl chloride in the preparation process of the intermediate B-2 with 2, 4-difluorobenzenesulfonyl chloride, and simulating the step 1 and the step 2 in the preparation process of the intermediate B-2 to obtain an intermediate B-4. LC-MS:427[ M +1 ].

Example 1: n- (2-chloro-5- (3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (I-1)

Under the protection of nitrogen, 9-bromo-2H- [1, 4%]Oxazino [3,2-c]Quinolin-3 (4H) -one (100mg,0.360mmol) was dissolved in 1, 4-dioxane (9mL) and H₂O (1.5mL), was added (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid (178 mg, 0.540 mmol), Pd (dppf) Cl₂(27mg, 0.036 mmol) and Cs₂CO₃(105mg,0.323mmol), heating to 100 deg.C, stirring for 3h, concentrating, and subjecting the residue to silica gel column chromatography to obtain white solid, i.e. the target compound I-1 (70 mg, 40%). LC-MS (ESI +) 485(M +1);¹HNMR(300MHz,DMSO-d₆)11.13(s,1H),8.71(s,1H),8.53(s,1H),7.91-8.09(m,4H),7.79-7.84(m,2H),7.42-7.48(m,2H),4.95-4.96(m,2H)。

example 2: n- (2-methoxy-5- (3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (I-2)

Under the protection of nitrogen, 9-bromo-2H- [1, 4%]Oxazino [3,2-c]Quinolin-3 (4H) -one (intermediate) (60mg,0.21mmol) was dissolved in 1, 4-dioxane (9mL) and H₂O (1.5mL) was added 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide (132 mg,0.32mmol), Pd (dppf) Cl₂(17 mg, 0.021 mmol) and Cs₂CO₃(105mg,0.32mmol), heated to 100 ℃ and stirred for 3 h. Cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give a pale yellow solid (65 mg, 63%). LC-MS (ESI +) 485(M +1);¹HNMR(300MHz,DMSO-d₆)11.10(s,1H),10.10(s,1H),8.50(s,1H),8.40(s,1H),7.98-8.00(m,2H),7.79-7.89(m,4H),7.39-7.44(m,2H),4.96(s,2H),3.67(s,1H)。

example 3: n- (2-chloro-5- (4-methyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (I-3)

Reacting 9-bromo-2-methyl- [1, 4%]Oxazino [3,2-c]Quinolin-3 (4H) -one (180mg,0.614mmol) was dissolved in 1, 4-dioxane (12mL) and water (2mL) and (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid (254mg,0.768mmol), Pd (dppf) Cl was added₂(45mg,0.061mmol) and Cs₂CO₃(600mg,1.842mmol) Nitrogen substitution three times then heating to 100 ℃ for 3 hours, cooling to room temperature, diluting with dichloromethane (50mL), extracting with water, separating off the organic phase, adjusting the aqueous phase to pH 7-8 with 1N hydrochloric acid, extracting with dichloromethane (3 × 20mL), drying the dichloromethane solution, concentrating, column chromatography of the residue (DCM: MeOH =80:1) to give the title product (I-3) (27mg, 9%). LC-MS (ESI +):499[ M +1 + ] -]⁺；¹HNMR(300MHz,DMSO-d6)10.59(br,1H),8.93(s,1H),8.73(s,1H),8.00-8.18(m,4H),7.79-7.84(m,2H),7.45(t,2H,J=8.7Hz),5.10(s,2H),3.46(s,3H)。

Example 4: n- (2-methoxy-5- (4-methyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (I-4)

Reacting 9-bromo-2-methyl- [1, 4%]Oxazino [3,2-c]Quinolin-3 (4H) -one (44mg,0.15mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL), and 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide (188mg,0.46mmol), Pd (dppf) Cl was added₂(11mg,0.015mmol) and Cs₂CO₃(147mg,0.45mmol) nitrogen substitution three times then heating to 100 ℃ for 3 hours, cooling to room temperature, diluting with dichloromethane (20mL), extracting with water, separating off the organic phase, adjusting the aqueous phase to pH 7-8 with 1N hydrochloric acid, extracting with dichloromethane (3 × 10mL), drying the dichloromethane solution, concentrating, column chromatography of the residue (DCM: MeOH =80:1) to give the title product (I-4) (20mg, 27%). LC-MS (ESI +):495[ M +1 +) ] [ M +1], []⁺；¹HNMR(300MHz,DMSO-d6)8.83(s,1H),8.40(s,1H),8.02-8.04(m,2H),7.78-7.94(m,4H),7.39-7.47(m,2H),5.04(s,2H),3.68(s,3H),3.45(s,3H)。

Using a procedure analogous to the above example, the compounds listed in the following table can be prepared separately:

intermediate C-1: (3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) boronic acid

9-bromo-2H- [1,4]Oxazino [3,2-c]Quinolin-3 (4H) -one (500mg,1.792mmol) was dissolved in 1, 4-dioxane (40mL) and pinacol diboron (682mg,2.687mmol), Pd (dppf) Cl, was added₂(131mg,0.179mmol) and KOAc (264mg,2.687 mmol). The mixture was heated to 100 ℃ under nitrogen for 3 hours. LC-MS showed reaction completion, the reaction was concentrated to dryness and the residue was column chromatographed (DCM: MeOH =50:1) to give intermediate C-1(247mg, 56%). LC-MS (ESI +) 245[ M +1]]⁺。

Intermediate C-2: (4-methyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) boronic acid

9-bromo-2-methyl- [1, 4%]Oxazino [3,2-c]Quinolin-3 (4H) -one (100mg,0.341mmol) was dissolved in 1, 4-dioxane (10mL) and pinacol diboron (130mg,0.512mmol), Pd (dppf) Cl was added₂(25mg,0.034mmol) and KOAc (100mg,1.023 mmol). The mixture was heated to 100 ℃ under nitrogen for 3 hours. LC-MS showed completion of the reaction, the reaction was concentrated to dryness, dichloromethane (10mL) was added, insoluble materials were filtered off, the filtrate was concentrated to dryness, and column chromatography (DCM: MeOH =100:1) was performed on the residue to give intermediate C-2(83mg, 94%). LC-MS (ESI +) 259[ M +1]⁺。

Intermediate C-3: (2, 2-dimethyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) boronic acid

9-bromo-2, 2-dimethyl-2H- [1,4]Oxazine [3,2-c]Quinolin-3 (4H) -one (600mg,1.954mmol) was dissolved in 1, 4-dioxane (50mL) and pinacol diboron (744mg,2.93mmol), Pd (dppf) Cl was added₂(143mg,0.195mmol) and KOAc (288mg,2.93 mmol). The mixture was heated to 100 ℃ under nitrogen for 3 hours. LC-MS showed complete reaction, the reaction was concentrated to dryness and the residue was chromatographed (DCM: MeOH =50:1)) Compound 2(491mg,92.4%) was obtained. LC-MS (ESI +) 273[ M +1]]⁺。

Intermediate C-4: (2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) boronic acid

9-bromo-2, 2, 4-trimethyl-2H- [1, 4[ ]]Oxazine [3,2-c]Quinolin-3 (4H) -one (800mg,2.491mmol) was dissolved in 1, 4-dioxane (80mL) and pinacol diboron (1.265g,4.982mmol), Pd (dppf) Cl was added₂(182mg,0.249mmol) and KOAc (367mg,3.737 mmol). The mixture was heated to 100 ℃ under nitrogen for 3 hours. LC-MS showed reaction completion, the reaction was concentrated to dryness and the residue was column chromatographed (DCM: MeOH =100:1) to give compound 2(445mg, 62.4%). LC-MS (ESI +):287[ M +1]]⁺。

Intermediate D-1N- (5-bromo-2-chloropyridin-3-yl) methanesulfonamide

2-chloro-3-amino-5-bromopyridine (2.5g,12.05mmol) was dissolved in pyridine (30mL), MsCl (4.66mL,60.25mmol) was added, and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, methanol (50mL) and 1, 4-dioxane (50mL) were added to the residue, anhydrous potassium carbonate (16.65g,120.5mmol) was added thereto, the mixture was heated to 60 ℃ and stirred for 5 hours, cooled to room temperature, the reaction solution was poured into water (500mL), adjusted to ph5 with concentrated hydrochloric acid, extracted with ethyl acetate, the organic phases were combined, washed with water and saturated brine, respectively, dried, concentrated, and the residue was subjected to column chromatography (PE: EA =10:1) to give N- (5-bromo-2-chloropyridin-3-yl) methanesulfonamide (2.70g, 79%). LC-MS (ESI +):285[ M +1 ].

Intermediate D-2N- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide

2-methoxy-3-amino-5-bromopyridine (1g,4.925mmol) was dissolved in pyridine (15mL), MsCl (1.9mL,24.626mmol) was added, and the reaction was allowed to proceed at room temperature for 48 hours. The reaction solution was concentrated to dryness, and methanol (20mL) and 1, 4-dioxane (20mL) were added to the residue, anhydrous potassium carbonate (16.81g,49.25mmol) was added thereto, and the mixture was heated to 60 ℃ for reaction for 5 hours, the reaction solution was poured into water (100mL), pH =5 was adjusted with concentrated hydrochloric acid, extraction was performed with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, respectively, dried, concentrated, and column chromatography was performed on the residue (PE: EA =10:1) to give N- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide (994mg, 71.8%). LC-MS (ESI +):281,283[ M +1]]⁺。

Intermediate D-3: n- (5-bromo-2-chloropyridin-3-yl) cyclopropylsulfonamides

2-chloro-3-amino-5-bromopyridine (2.0g,9.64mmol) was dissolved in THF (30mL), cooled to-5 deg.C, LiHMDS (14.5mL,1M) was added thereto, stirred for 15 minutes, added to the solution cyclopropylsulfonyl chloride (2.03g,14.46mmol), gradually warmed to room temperature and stirred overnight. Methanol (5mL) was added to the reaction mixture, and the solvent was evaporated to dryness and purified by column chromatography to give intermediate D-3 (1.0 g, 33%). LC-MS (ESI +): 311, 313[ M +1]]⁺。

Intermediate D-4: n- (5-bromo-2-methoxypyridin-3-yl) cyclopropylsulfonamide

2-methoxy-3-amino-5-bromopyridine is used for replacing 2-chloro-3-amino-5-bromopyridine in the intermediate D-3 by imitating the preparation method of the intermediate D-3, and then the intermediate D-4 is obtained. LC-MS (ESI +): 306, 308[ M +1]]⁺。

Intermediate D-5N- (5-bromo-2-chloropyridin-3-yl) dimethylaminosulfonylurea

To a solution of 2-chloro-3-amino-5-bromopyridine (500mg,2.41mmol) in pyridine (8mL) was added dimethylaminosulfonyl chloride (2.08g,14.5mmol) and DMAP (29mg,0.24 mmol). The reaction solution was heated to 100 ℃ and reacted for 20 hours under nitrogen protection. The reaction solution was concentrated to dryness, ethyl acetate and water were added, the organic phase was separated off, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried, concentrated, and the residue was purified by column chromatography (PE: EA =20:1) to give a sulfonylurea intermediate (273mg, 36%). LC-MS (ESI +):314,316[ M +1]]⁺。

Intermediate D-6N- (5-bromo-2-methoxypyridin-3-yl) dimethylaminosulfonylurea

To a solution of 2-methoxy-3-amino-5-bromopyridine (500mg,2.463mmol) in pyridine (8mL) was added dimethylaminosulfonyl chloride (2.12g,14.8mmol) and DMAP (29mg,0.25 mmol). The reaction solution was heated to 100 ℃ and reacted for 20 hours under nitrogen protection. The reaction mixture was concentrated to dryness, ethyl acetate and water were added, the organic phase was separated off, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried, concentrated, and the residue was purified by column chromatography (PE: EA =20:1) to obtain intermediate D-6(310mg, 41%). LC-MS (ESI +):310,312[ M +1]]⁺。

Example 27:

intermediate C-1(104mg,0.426mmol) was dissolved in 1, 4-dioxane (18mL) and water (3mL), and intermediate D-1(243mg,0.852mmol), Pd (dppf) Cl was added₂(31mg,0.043mmol) and Cs₂CO₃(208mg,0.639 mmol). After nitrogen substitution, the reaction mixture was heated to 100 ℃ for 1 hour, LC-MS showed completion of the reaction, and the reaction mixture was concentrated to dryness, and the residue was subjected to column chromatography (DCM: MeOH =40:1) to obtain the objective compound (62mg, 36%). LC-MS (ESI +) 405[ M +1]]⁺；¹HNMR(300MHz,DMSO-d6)11.12(br,1H),9.88(br,1H),8.71(s,1H),8.53(s,1H),8.19-8.26(m,2H),7.96-8.05(m,2H),4.95(s,2H),3.18(s,3H)。

Following the procedure of the above example, the intermediates C-1 to C-4 were combined at D-1 to D-6, respectively, to give Suzuki coupling reactions, which gave the following compounds:

intermediate A-10: 5-amino-9-bromo-4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one

Step 1: intermediate A-2(1g,3.41mmol) was dissolved in a mixture of DME (25mL) and PE (50mL) and mCPBA (1.38g,6.82mmol) was added portionwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours, and TLC (DCM: MeOH =20:1) indicated completion of the reaction. Filtration and residue washed with DME/PE =1/2(20mL), dried and the crude product (1.583g,100% crude yield) was used directly in the next reaction. LC-MS (ESI +):309,311[ M +1 [)]⁺。

Step 2: the crude product (1.58g) obtained in step 1 was dissolved in a mixed solution of DCM (40mL), MeOH (20mL) and water (10mL), potassium carbonate (471mg,3.41mmol) was added, the reaction was stirred for 30 minutes, the organic phase was separated off, the aqueous phase was extracted three times with DCM, the organic phases were combined, washed with saturated brine, dried, concentrated, and the residue was subjected to column chromatography (DCM: MeOH =40:1) to obtain (0.69g, 66%). LC-MS (ESI +):309,311[ M +1 [)]⁺。

And step 3: dissolve step 2 (0.69g,2.24mmol) in DCM (40mL) and MeOH (25mL), cool to 0 deg.C, add ammonia (9mL), add dropwise a solution of p-toluenesulfonyl chloride (1.28g,6.72mmol) in DCM (10mL), and warm to room temperature for 6 h after dropwise addition. The reaction was concentrated to dryness and the residue was subjected to column chromatography (DCM/MeOH =60/1) to give intermediate a-10(491mg, 71%). LC-MS (ESI +):308,310[ M +1]]⁺。

Intermediate A-11: 9-bromo-4-methyl-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-5-amino

Intermediate A-10(276mg,0.896mmol) was dissolved in anhydrous THF (20mL) and a 2M borane dimethylsulfide solution (1.79mL,3.582mol) was added dropwise. After dropping, the mixture was heated to 50 ℃ for overnight reaction. 1N hydrochloric acid (10mL) was added and the reaction was heated to reflux for 1 hour. Cooled to room temperature, adjusted to basic pH with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated residue purified by column chromatography (DCM: MeOH =100:1) to afford intermediate a-11(188mg, 71%). LC-MS (ESI +):294,296[ M +1]]⁺。

Intermediate A-12: n- (9-bromo-4-methyl-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-5-yl) acetamide

Acetyl chloride (85mg,1.1mmol) was added to a solution of intermediate A-11(160mg,0.54mmol) and triethylamine (110mg,1.1mmol) in DMF (5mL) and the mixture was heated to 45 ℃ for reaction for 2h, acetic anhydride (0.39mL,4.1mmol) was added and the reaction was continued for 1 h. LC-MS showed completion of the reaction, and the reaction was concentrated to dryness, and the residue was subjected to column chromatography to give intermediate A-12(158mg, 86%). LC-MS (ESI +):336,338[ M +1]]⁺。

Intermediate A-13: 5-amino-9-bromo-2, 2, 4-trimethyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one

The intermediate A-13 can be prepared by replacing the intermediate A-2 with the intermediate A-8 by following the preparation method of the intermediate A-10. LC-MS (ESI +):336,338[ M +1]]⁺。

Example 51:

intermediate A-10 (5-amino-9-bromo-4-methyl-2H- [1, 4)]Oxazino [3,2-c]Quinolin-3 (4H) -one) (100mg,0.33mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL) and intermediate B-1 ((6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid) (161mg,0.49mmol), Pd (dppf) Cl was added₂(22mg,0.033mmol) and Cs₂CO₃(159mg,0.49 mmol). Heat after nitrogen replacement three timesReaction at 100 ℃ for 3 hours, cooling to room temperature, dilution with dichloromethane (30mL), extraction with water, separation of the organic phase, pH adjustment of the aqueous phase to 7-8 with 1N hydrochloric acid, extraction with dichloromethane (3 × 10mL), drying of the dichloromethane solution, concentration, and column chromatography of the residue to give compound I-51(90mg, 54%). LC-MS (ESI +):514[ M +1 + ]]⁺；¹HNMR(300MHz,DMSO-d₆)8.62(s,1H),7.78-7.88(m,5H),7.41-7.58(m,3H),6.63(br,2H),4.84(s,2H),3.32(s,3H)。

Following the procedure of example 51, the following compounds were prepared by combining intermediates a-10 to a-13 with intermediates B-1 to B-4 and performing a Suzuki coupling reaction:

intermediate C-5: (5-amino-4-methyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) boronic acid

The intermediate can be prepared by using the intermediate A-10 as a raw material by imitating the preparation method of the intermediates C-1 to C-4. LC-MS (ESI +) 274[ M +1]]⁺。

Intermediate C-6: (5-amino-2, 2, 4-trimethyl-3-oxo-3, 4-dihydro-2H- [1,4] oxazino [3,2-c ] quinolin-9-yl) boronic acid

The intermediate can be prepared by using the intermediate A-13 as a raw material by imitating the preparation method of the intermediates C-1 to C-4. LC-MS (ESI +) 302[ M +1]]⁺。

The compounds shown in the following table can be prepared by combining intermediates C-5, C-6 with intermediates D-1 to D-6 for Suzuki coupling reactions:

the compounds of the invention may be prepared by the skilled person by subjecting the above intermediates to various combinations according to common general knowledge known in the art, or by preparing analogues which are obvious from the above intermediates and carrying out the preparation of the compounds of formula (I) as described in the present aspect.

Biological example 1: determination of median inhibitory concentration (IC 50) of compounds of the invention against PI3K alpha, PI3K beta, PI3K, PI3K gamma and mTOR

1. Raw materials

1) p110 α/p85a, available from Invitrogen, cat No. PV4788;

2) p110/p85a, available from Millipore, cat Nos. 14-604-K;

3) p 110. beta. from Millipore, cat No. 14-603-K;

4) p110 γ, available from Invitrogen, cat No. pr8641c;

5) mTOR, purchased from Millipore, cat No. 14-770;

6) Kinase-GloPlusL μ Minesece-KinaseAssay, available from Promage, cat No. V3771;

7) ADP-GloKinaseAssay, available from Promage, cat No. v9102/3;

2. experimental methods

2.1 dilution of the Compound

1) The final concentration of the compound to be detected was 1. mu.M, and the compound was first prepared at 100-fold concentration, i.e., 100. mu.M. mu.L of 10mM compound and 90. mu.L of 100% DMSO were added to the first row of wells of a 96-well plate, respectively, to prepare 100. mu.L of 1mM compound. mu.L of 1mM compound and 90. mu.L of 100% DMSO were added to wells in the second row of a 96-well plate, respectively, to prepare 100. mu.L of 100. mu.M compound.

2) In a second row of wells of another 96-well plate, 100. mu.L of the above 100. mu.M compound was added, and 60. mu.L of 100% DMSO was added to the other wells. mu.L of compound from well 2 was added to well 3, and 3-fold dilutions were made sequentially down for a total of 8 concentrations.

3) 100 μ L of 100% DMSO was added to each of the first and twelfth wells.

2.2 intermediate dilution of the Compound

1) Transfer of 4. mu.L of compound to a New 96-well plate

2) Add 96. mu.L of 1 Xkinase buffer

3) Mix by shaking on a plate shaker for 10 minutes.

2.3 transfer of Compounds to the reaction plate

From the above 96-well plate, 2.5. mu.L of the protein was taken out into a 384-well reaction plate, and for example, A1 well of the 96-well plate was transferred into A1 and A2 wells of the 384-well plate, A2 well of the 96-well plate was transferred into A3 and A4 wells of the 384-well plate, and so on.

3. Preparation of 1 Xkinase buffer

1) 1xmTOR kinase buffer

50mMHEPES,pH7.5

10mMMgCl2

1mMEGTA

3mMMnCl

0.01%Tween-20

2mMDTT

2) 1xPI3K alpha, PI3K kinase buffer

50mMHEPES,pH7.5

3mMMgCl2

1mMEGTA

100mMNaCl

0.03%CHAPS

2mMDTT

3) 1xPI3K beta, PI3K gamma kinase buffer

50mMHEPES,pH7.5

3mMMgCl2

1mMEGTA

100mMNaCl

0.03%CHAPS

2mMDTT

4. Preparation of 4 Xkinase solution

1) A 4-fold mTOR solution, PI3K α solution, PI3K β solution, PI3K γ solution, and PI3K solution were prepared using 1-fold kinase buffer. The final concentrations of the kinase solutions were mTOR2.5nM, respectively; PI3K α 1.65 nM; PI3K β 4.8 nM; PI3K γ 7.6 nM; PI3K5.7nM.

2) 2.5mL of 4-fold enzyme solution was transferred to 384-well reaction wells, and 1-fold kinase buffer was added to negative control wells.

3) Oscillating, mixing, standing at room temperature

5. Preparation of 2 Xsubstrate solution

1) A2-fold substrate solution was prepared using 1-fold kinase buffer. The final concentrations of substrate solutions of mTOR, PI3K alpha, PI3K beta, PI3K gamma and PI3K enzyme reaction systems are respectively

mTOR：ULight-4E-BP150nM；ATP10.8μM。

PI3Kα：PIP250μM；ATP25μM。

PI3Kβ：PIP250μM；ATP25μM。

PI3Kγ：PIP250μM；ATP25μM。

PI3K：PIP250μM；ATP25μM。

2) Transfer 5. mu.L of 2-fold substrate solution to 384-well reaction wells to initiate the reaction

3) Oscillating and mixing.

6. Kinase reaction

The 384 well plates were capped and incubated at room temperature for mTOR, PI3K α, PI3K β, and PI3K γ 1 hr, PI3K2 hr.

7. Detection of reaction results

7.1mTOR outcome detection

1) The detection reagent is equilibrated to room temperature.

2) Transfer 10. mu.L of detection reagent to 384-well reaction wells to stop the reaction.

3) Gently shake on a plate shaker for 15 minutes. Equilibrate for 1 hour at room temperature.

7.2 detection of PI3K alpha and PI3K results

1) Kinase-Glo detection reagent was equilibrated to room temperature.

2) Transfer 10. mu.LKINAse-Glo detection reagent to 384-well reaction wells to stop the reaction.

3) Gently shake on a plate shaker for 15 minutes.

7.3PI3K beta and PI3K gamma result detection

1) The ADP-Glo reagent was equilibrated to room temperature.

2) Transfer 5. mu.L of reaction to a new 384-well plate.

3) Transfer 5. mu.L ADP-Glo reagent to 384-well reaction wells to stop the reaction.

4) Gently shake on a plate shaker for 40 minutes.

5) 10. mu.L of the kinase detecting reagent was transferred to each reaction well, shaken for 1 minute, and allowed to stand at room temperature for 1 hour.

8. Data reading

The luminescence values of the samples were read at Envision.

9. Fitting of curves

1) Copying data of luminescence readings from Envision program

2) The value of the luminescence reading is converted to a percentage inhibition by a formula.

mTOR conversion formula:

Percentinhibition=(Lancesignal-min)/(max-min)*100

PI3K α, PI3K β, PI3K γ, and PI3K transform equations:

Percentinhibition=(max-conversion)/(max-min)*100

"max" is the fluorescence reading for the control with no enzyme added; "min" is the sample fluorescence reading with DMSO added as a control.

3) Data were imported into MSExcel and curve fitted using graphpad 5.0.

The results of the IC50 tests on PI3K α, PI3K β, PI3K γ, PI3K and mTOR with some of the compounds of the present invention are shown in the following table:

biological example 2: half inhibitory concentration of the Compound of the present invention on tumor cell proliferation (IC 50) was determined using CellTiter-Glo luciferase kit

1. Raw materials

1) U-87MG cell line, purchased from ATCC, Cat. No. HTB-14, LotNo. 5018014;

2) a549 cell strain purchased from ATCC, cat.no. ccl-185, lotno. 7502546;

3) PC-3 cell line, purchased from ATCC, Cat. No. CRL-1435, LotNo. 7348670;

4) BT474 cell line, purchased from ATCC, Cat. No. HTB-20, LotNo. 5188737;

5) F-12K medium purchased from Invitrogen, Cat.No. 21127-022;

6) EMEM medium, purchased from Invitrogen, cat.no. 11095;

7) 96-well plates, purchased from Corning, cat.no. cls 3903;

8) CellTiterGloassaykit, available from Promega, Cat. No. G7571, Lot. No. 256984;

9) fetal bovine serum, purchased from Invitrogen, Cat.No.10099-141, Lot.No. 8153379.

2. Experimental methods

2.1 cell plating

1) Preparing complete culture medium, and mixing completely.

2) Cell lines with good growth status were selected.

3) The cell culture flask was removed from the incubator and checked for the cell name, culture medium type and cell generation number marked on the flask.

4) Discarding the culture medium, digesting with pancreatin, neutralizing with serum-containing culture medium, and blowing to remove cells. The cell suspension was pipetted into the centrifuge tube and centrifuged at 800-.

5) The cell supernatant in the centrifuge tube was aspirated.

6) Add the appropriate volume of medium to the centrifuge tube and gently blow it to resuspend the cells evenly.

7) Counting was performed using a Vi-CellXR cell counter.

8) The cell suspension was adjusted to the appropriate concentration.

9) The cell suspension was added to a 96-well bottom transmural white plate at 100 μ l/well. Marking the detailed information of cell name, plate density, date, etc., and placing the culture plate in CO₂The incubator was overnight.

2.2 cell assay conditions:

cell line	Number of holes per hole	Incubation time	Medium
				U-87MG	3000	72h	EMEM+10%FBS+1%PS+1x NEAA
A549	2000	72h	F12K+10%FBS+1%PS
				PC-3	3000	72h	F12K+10%FBS+1%PS
BT474	4000	96h	Hybri-care+10%FBS+1%PS

2.3 preparation and addition of Compounds:

1) compound powders were first prepared as 10mM concentration stock in DMSO and then diluted in DMSO at 3-fold gradient to 9 concentration points (the 9 points were all intermediate concentrations).

2) 0.5uL of the compound solution was added to 500uL of the culture medium from the above-mentioned intermediate concentration, and mixed by pipetting to a final DMSO concentration of 0.1% to prepare a compound-containing medium of the final concentration.

3) When the cell culture medium is changed, culture medium containing different compounds is added.

4) Incubate at 37 ℃ for a specified time.

2.4 detection and analysis

1) The cell morphology was observed under an inverted microscope.

2) The cell culture plate was allowed to equilibrate at room temperature for 30 minutes.

3) The cell viability assay reagent was added to the plates at 100. mu.l/well.

4) Cells were induced to lyse by mixing on a plate shaker for 2 minutes.

5) The 96-well plate was left at room temperature for 10 minutes to stabilize the luminescence signal.

6) A white bottom membrane was attached to the bottom of the plate and the plate was measured using Flexstation3 (relative settings: luminescence, integration time 500 ms).

7) The results of the analysis are recorded.

According to the results of the software analysis, the results of the cell proliferation inhibitory activity of some of the compounds of the present invention are shown in the following table:

Claims

1. Morpholino quinolines, are compounds having the following general formula (I):

wherein,

R¹selected from 4-fluorophenyl, 2, 4-difluorophenyl, methyl, cyclopropyl, dimethylamino;

R²selected from hydrogen, halogen, -OR¹⁰；

R³Selected from hydrogen, -NHR¹⁰，-NHC(＝O)R¹⁰；

R⁴Selected from hydrogen, C₁-C₆Alkyl, -C (═ O) R¹⁰，-S(＝O)₂R¹⁰；

R⁵，R⁶Selected from hydrogen, C₁-C₆An alkyl group;

R⁷，R⁸selected from hydrogen, C₁-C₆Alkyl, or R⁷，R⁸Combined to form ═ O;

R⁹selected from hydrogen;

wherein R is¹⁰Is hydrogen, C₁-C₆An alkyl group.

2. The morpholinoquinoline compound of claim 1, wherein R²Selected from chlorine and methoxy.

3. The morpholinoquinoline compound of claim 1, wherein R³Selected from hydrogen, -NH₂，-NHC(＝O)CH₃。

4. The morpholinoquinoline compound of claim 1, wherein R⁴Selected from hydrogen, methyl, acetyl, methylsulfonyl.

5. The morpholinoquinoline compound of claim 1, wherein R⁵，R⁶Selected from hydrogen, methyl.

6. The morpholinoquinoline compound of claim 1, wherein R⁷，R⁸Selected from hydrogen, or R⁷，R⁸Combined to O.

7. Morpholino quinolines according to claim 1, wherein R in formula (I)¹Is 4-fluorophenyl, 2, 4-difluorophenyl, methyl, cyclopropyl or dimethylaminoAnd meanwhile: r²Is chlorine or methoxy; r³Is hydrogen, -NH₂or-NHC (═ O) CH₃；R⁴Is hydrogen, methyl, acetyl or methylsulfonyl; r⁵，R⁶Is hydrogen or methyl; r⁷，R⁸Is hydrogen, or R⁷，R⁸Combined to form ═ O; r⁹Is hydrogen.

8. The morpholinoquinoline compound according to claim 1, wherein the compound of formula (I) is any one of the following structures (I-1) to (I-67):

9. the morpholinoquinoline compound according to claim 1, wherein the compound of formula (I) is any one of enantiomer, diastereomer and conformational isomer or a mixture of any two or three of them.

10. The morpholinoquinoline compound according to claim 1, wherein the compound of formula (I) is present in the form of a pharmaceutically acceptable salt.

11. The morpholinoquinoline compound according to claim 10, wherein the pharmaceutically acceptable salt is a salt with an acid or a salt in which an acidic proton is substituted with a metal ion.

12. The morpholinoquinoline compound according to claim 11, wherein the salt with an acid is a hydrochloride, hydrobromide, methanesulphonate, sulphate, phosphate, acetate, trifluoroacetate, trifluoromethanesulphonate, p-toluenesulphonate, tartrate, maleate, fumarate, succinate or malate salt.

13. The morpholinoquinoline compound according to claim 11, wherein the salt of the acidic proton substituted with a metal ion is a sodium salt, a potassium salt, a magnesium salt or a calcium salt.

14. The method for preparing morpholino quinolines compounds according to claims 1-8, specifically comprising the steps of:

(1) when R is³In the case of hydrogen, the preparation of the compounds of formula (I) is carried out by: cyclizing 3-amino-4-hydroxy-6-bromoquinoline or substituted 3-amino-4-hydroxy-6-bromoquinoline and alkylating nitrogen atoms to obtain an intermediate A with a morpholinoquinoline structure, and then carrying out Suzuki coupling reaction with an intermediate B containing substituted pyridine boric acid or boric acid ester to obtain a compound with a general formula (I); or converting bromine of the intermediate A with the morpholinoquinoline structure into an intermediate C containing boric acid or boric acid ester, and then carrying out Suzuki coupling reaction with an intermediate D containing substituted bromopyridine to obtain a compound with a general formula (I); the specific reaction formula is as follows:

(2) when R is³When not hydrogen, the compound of formula (I) is prepared by the following steps: oxidizing and activating nitrogen atoms of the morpholine-quinoline intermediate, then carrying out quinoline-2-site-nucleophilic substitution reaction by using a nucleophilic reagent to obtain an intermediate A with a morpholine-quinoline structure, and then carrying out Suzuki coupling reaction on the intermediate A with the morpholine-quinoline structure and an intermediate B containing substituted pyridine boric acid or boric acid ester to obtain a compound with a general formula (I); or, will have a morpholino quinoline structureConverting bromine of the intermediate A into an intermediate C containing boric acid or boric acid ester, and then carrying out Suzuki coupling reaction on the intermediate C and an intermediate D containing substituted bromopyridine to obtain a compound with a general formula (I); the specific reaction formula is as follows:

in the above reaction formula: r¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹Each as defined in claims 1 to 8, respectively

15. A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of general formula (I) according to claim 1 and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated as a tablet, capsule, aqueous suspension, oily suspension, dispersible powder, granule, lozenge, emulsion, syrup, cream, ointment, suppository, or injection.

17. A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of general formula (I) according to claim 1 and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is formulated as a tablet, capsule, aqueous suspension, oily suspension, dispersible powder, granule, lozenge, emulsion, syrup, cream, ointment, suppository, or injection.

19. Use of a morpholinoquinoline compound according to claims 1 to 9 wherein is the use of a compound of formula (I) in the preparation of a preparation for modulating the catalytic activity of the PI3K/mTOR signalling pathway.

20. Use of a morpholinoquinoline compound according to claims 1 to 9 wherein is the use of a pharmaceutically acceptable salt of a compound of formula (I) in the preparation of a preparation for modulating the catalytic activity of the PI3K/mTOR signalling pathway.

21. The use of a pharmaceutical composition according to claims 15-18 for the manufacture of a medicament for the treatment of a disease associated with the PI3K/mTOR signalling pathway.

22. The use of claim 21, wherein the disease associated with the PI3K/mTOR signaling pathway is cancer.

23. The use of claim 22, wherein the cancer is a cancer of the head and neck, respiratory system, digestive system, urinary system, skeletal system, gynecological, hematological, or other type.

24. The use of claim 23, wherein the head and neck cancer is thyroid cancer, nasopharyngeal cancer, meningeal cancer, acoustic neuroma, pituitary tumor, oral cancer, craniopharyngioma, thalamic and brainstem tumor, angiogenic tumor, or intracranial metastatic tumor.

25. The use of claim 23, wherein the respiratory cancer is lung cancer.

26. The use of claim 23, wherein the cancer of the digestive system is liver cancer, stomach cancer, esophageal cancer, colorectal cancer, rectal cancer, colon cancer or pancreatic cancer.

27. The use of claim 23, wherein the cancer of the urinary system is renal cancer, bladder cancer, prostate cancer, or testicular cancer.

28. The use of claim 23, wherein the cancer of the skeletal system is bone cancer.

29. The use of claim 23, wherein the gynaecological cancer is breast cancer, cervical cancer or ovarian cancer.

30. The use of claim 23, wherein the hematological cancer is leukemia, malignant lymphoma or multiple myeloma.

31. The use of claim 23, wherein the other type of cancer is malignant melanoma, glioma or skin cancer.