CN104418867B

CN104418867B - As the compound of PI3K/mTOR inhibitor, Preparation Method And The Use

Info

Publication number: CN104418867B
Application number: CN201310376114.1A
Authority: CN
Inventors: 程建军; 秦继红
Original assignee: SHANGHAI HUILUN TECHNOLOGY Co Ltd
Current assignee: Shanghai Huilun Pharmaceutical Co ltd
Priority date: 2013-08-26
Filing date: 2013-08-26
Publication date: 2016-12-28
Anticipated expiration: 2033-08-26
Also published as: CN104418867A

Abstract

A kind of compound as PI3K/mTOR inhibitor disclosed by the invention, for having below general formula (IA) or the compound of (IB), wherein, R¹Selected from hydrogen, halogen, alkyl, alkoxyl, amido, or and R²Formed and ring；R²Selected from hydrogen, amido, sulfoamido, sulfonylurea group, alkyl, alkoxyl, or and R¹Formed and ring；R³Selected from hydrogen, C₁‑C₆Alkyl；R⁴Selected from hydrogen, amido, amide groups or sulfoamido；R⁵Selected from hydrogen, halogen, alkyl or alkoxyl.The invention also discloses this as the compound of PI3K/mTOR inhibitor preparation method with as medicine in order to treat the purposes of the relevant cancer of the disease relevant to PI3K/mTOR, particularly PI3K/mTOR；.

Description

compound as PI3K/mTOR inhibitor, 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

During tumorigenesis and development, the "PI 3K (phosphatilinosol 3-kinase) -Akt (PKB, protein kinase B) -mtor (mammalian target of rapamycin)" signaling pathway controls numerous cell biological processes including tumor cell apoptosis, transcription, translation, metabolism, angiogenesis, and regulation of the cell cycle. Over-activation of this signaling pathway disturbs cell growth and survival, leading to increased tumor cell proliferation, malignant metastasis, and development of common drug resistance. The blocking of the signal path of PI3K-Akt-mTOR can inhibit the growth of tumor cells and even promote the apoptosis of the tumor cells. Therefore, the channel is a hot target for developing novel antitumor drugs. (NatureReviews drug discovery2009,8, 627-644).

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 type I, type II and type III. 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. 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). (Nature Reviews Cancer2008,8,665-

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. Rapamycin compounds such as Sirolimus, Everolimus and Temsirolimus acting on mTOR have been on the market as drugs, and thus mTOR has been identified as an effective target for treating tumors. (Nature Reviews Cancer2006,6,729-

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. (Anticancer Research2012,32,2463-

The invention provides the PI3K/mTOR inhibitor with novel structure and strong biological activity, and the deep research on the compound can possibly obtain a novel anti-tumor medicament with different characteristics from the existing clinical research compound.

Disclosure of Invention

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

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

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

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

As a first aspect of the present invention, a compound which is a PI3K/mTOR inhibitor is a compound having the following general formula (IA) or (IB):

wherein,

R¹selected from hydrogen, halogen, alkyl, alkoxy, amino, or form a fused ring with R2;

R²selected from hydrogen, amino, sulfonylAmino, sulfonylureido, alkyl, alkoxy, or form a fused ring with R1;

R³selected from hydrogen, C₁-C₆An alkyl group;

R⁴selected from hydrogen, amine, amide or sulfonamide groups;

R⁵selected from hydrogen, halogen, alkyl or alkoxy.

And, R¹～R⁵The alkyl, alkoxy, amine, amide, urea, sulfonamide, sulfonylurea groups described in (a) can be optionally substituted with one or more groups including alkyl, alkenyl, alkynyl, halogen, alkoxy, aryl, heteroaryl, heterocyclyl, amino, amine, cyano, nitro, carboxyl, ester, carbamoyl, sulfonyl, or sulfonamide groups.

In some embodiments of the invention, R¹Selected from chlorine, methoxy or with R²And is a benzene ring.

In some embodiments of the invention, R²Selected from sulfonamido, sulfonylureido or with R¹And is a benzene ring.

In some embodiments of the invention, R³Selected from hydrogen, methyl.

In some embodiments of the invention, R⁴Selected from hydrogen, amine groups.

In some embodiments of the invention, R⁵Is hydrogen.

The present invention includes, but is not limited to, compounds wherein the substituents are defined as follows: r in the general formula (IA) or (IB)¹Selected from chlorine, methoxy or with R²And is a benzene ring, with R²Selected from sulfonamido, sulfonylureido or with R¹And is a benzene ring; r³Is selected from methyl; r⁴Selected from hydrogen or amine groups; r⁵Is hydrogen.

The compound of the present invention may be any one of the following structures (I-1) to (I-27):

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

The compounds of general formula (IA) or (IB) are pharmaceutically acceptable derivatives.

The compounds of general formula (IA) or (IB) 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.

As a second aspect of the present invention, there is provided a process for producing the above compound, wherein the compound represented by the general formula (IA) can be produced by:

the method comprises the following steps:

when R is⁴Is H, R¹、R²、R³，R⁵As mentioned above, the preparation of the compounds of formula (IA) is carried out by: 3-amino-4-hydroxy-6-bromoquinoline compound (A) and carboxylic acid R³COOH is cyclized to prepare a quinoline oxazole compound (B), and further, a bromine atom and boric acid ester (C) are subjected to Suzuki coupling reaction to prepare a compound shown in a general formula (IA), wherein the specific reaction formula is as follows:

the above groups

The second method comprises the following steps:

when R is⁴Is H, R¹、R²、R³，R⁵As mentioned above, the preparation of the compounds of formula (IA) is carried out by: 3-amino-4-hydroxy-6-bromoquinoline compound (A) and carboxylic acid R³COOH is subjected to cyclization to prepare a quinoline and oxazole compound (B), bromine in the molecule of the oxazole and quinoline compound (B) is converted into a boric acid ester (D), and the boric acid ester (D) is further subjected to Suzuki coupling with bromide (E) to prepare a compound shown in a general formula (IA), wherein the specific reaction formula is as follows:

the above groups

The third method comprises the following steps:

when R is⁴Is amino, amido, sulfonamido, ureido, R¹、R²、R³，R⁵As described above, the 3-amino-4-hydroxy-6-bromoquinoline compound (A) and the carboxylic acid R are reacted with³COOH is subjected to cyclization to prepare a quinoline oxazole compound (B), the quinoline oxazole compound (B) is subjected to quinoline-2-site activation through nitrogen atom oxidation, quinoline-2-amino (J) is further introduced, a compound (K) is prepared through corresponding conversion, and the compound (K) and boric acid ester (C) are further subjected to Suzuki coupling to prepare a compound shown in a general formula (IA)The specific reaction formula is as follows:

the above groups

As a second aspect of the present invention, there is provided a process for producing the above compound, wherein the compound represented by the general formula (IB) can be produced by:

the method comprises the following steps:

when R is⁴Is H, R¹、R²、R³，R⁵As described above, 3-amino-4-hydroxy-6-bromoquinoline compound (a) and Carbonyldiimidazole (CDI) reagent are cyclized to prepare quinoxalin-2-one compound (F), amide nitrogen atom is further alkylated to obtain brominated quinoxalin-2-one compound (G), and brominated quinoxalin-2-one compound (G) and borate (C) are subjected to Suzuki coupling to prepare the compound represented by general formula (IB), and the specific reaction formula is as follows:

the above groups

Method two

When R is⁴Is H, R¹、R²、R³，R⁵As described above, 3-amino-4-hydroxy-6-bromoquinolines (A) are cyclized with Carbonyldiimidazole (CDI) reagent to prepare quinolinooxazol-2-ones (F), and the amide nitrogen atom is further alkylatedObtaining brominated quinoline oxazole-2-ketone compound (G), then converting the brominated quinoline oxazole-2-ketone compound (G) into corresponding boric acid ester (H), and then carrying out Suzuki coupling with bromide (E) to prepare the compound shown in the general formula (IB), wherein the specific reaction formula is as follows:

the above groups

Method III

When R is⁴Is amino, amido, sulfonamido, ureido, R¹、R²、R³，R⁵As mentioned above, 3-amino-4-hydroxy-6-bromoquinoline compound (a) and Carbonyldiimidazole (CDI) reagent are cyclized to prepare quinoxalin-2-one compound (F), amide nitrogen atom is further alkylated to obtain brominated quinoxalin-2-one compound (G), then quinoline nitrogen atom of brominated quinoxazole-2-one compound (G) is oxidized and activated, further quinoline-2-amino (L) is introduced, compound (M) is prepared by corresponding transformation, and then 6-position bromine atom and borate (C) are Suzuki coupled to prepare compound shown in general formula (IB), which has the following specific reaction formula:

the above groups

The pharmaceutical composition as a third aspect of the present invention, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of general formula (IA) or/and general formula (IB) 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 general formula (IA) or/and general formula (IB) 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 (IA) or/and general formula (IB) 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 of the general formula (IA) or/and the general formula (IB) in preparing the article for regulating the catalytic activity of the PI3K/mTOR signaling pathway.

As the fourth aspect of the invention, the use of the pharmaceutically acceptable derivatives of the compounds of general formula (IA) or/and general formula (IB) in the preparation of a preparation for modulating the catalytic activity of the PI3K/mTOR signaling pathway.

As a fourth aspect of the invention, the use of a pharmaceutically acceptable salt of a compound of formula (IA) or/and formula (IB) for the preparation of a product for modulating the catalytic activity of the PI3K/mTOR signalling 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 compounds of general formula (IA) and (IB) related by the invention can also be used for researching biological or pharmacological phenomena of a PI3K-Akt-mTOR signaling pathway and comparing and evaluating novel PI3K or PI3K/mTOR dual inhibitors.

Detailed Description

The present invention provides compounds of general formula (IA), (IB) as defined above, methods of preparing such compounds, pharmaceutical compositions for preparing 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, cyclopropyl, n-butyl, t-butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, 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 "alkoxy" as used herein (alone OR as part of another group) refers to an alkyl group attached through an oxygen atom, such as — OR, where R is the alkyl group, preferably an alkyl group having 1 to 6 carbon atoms.

The term "amino" (used alone or as part of another group) as used herein refers to-NH₂. An "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, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, carbonyl, or carboxyl. In some embodiments, two substituents of an amine group forming a ring, such as azetidine, tetrahydropyrrole, piperidine, piperazine, morpholine, homomorpholine, etc., attached at a substitution position with a nitrogen atom, are also within the scope of the amine groups described herein.

The term "sulfonamide group" refers toWherein Ra is said alkyl, aryl or heteroaryl; r' is hydrogen or said alkyl.

The term "sulfonylurea" refers toWherein Rb is the amine group; r' is hydrogen or said alkyl.

The term "amide" refers toWherein Rc is the alkyl, aryl or heteroaryl group; r' is hydrogen or said alkyl.

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

The term "aryl" as used herein (alone or as part of another group) refers to monocyclic or polycyclic aromatic rings, e.g., phenyl, substituted phenyl, and the like, as well as 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" 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), and the like, wherein R, R', 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, alkynyl, aryl, nitro, cyano, hydroxy, alkoxy, alkylthio, -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 "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 anti-cancer drugs such as aurora kinase (aurora kinase) inhibitors, biological response modifiers, growth inhibitors, 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, phenethylamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, 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 hydrogen is replaced by "deuterium" or "tritium", or labeled with 18F-fluorine: (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 a therapeutically effective amount of a compound of general formula (IA) or/and general formula (IB) as defined above in combination (simultaneously or sequentially) with at least one other anti-cancer agent to a patient in need of such treatment. In a preferred embodiment, the proliferative disease is cancer.

In particular, the compounds of formula (IA) or/and formula (IB) may be used to treat 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 general formula (IA) or/and general formula (IB) may also be used for the treatment of any disease process characterized by an abnormal proliferation of cells, such as benign prostate hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis occurring after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxic shock and fungal infections.

The compounds of formula (IA) or/and formula (IB) may modulate the level of RNA and DNA synthesis in a cell. 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 general formula (IA) or/and general formula (IB) 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 (IA) or/and general formula (IB) can be used 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 (IA) or/and formula (IB) may generally be prepared as follows. Tautomers and solvates (e.g., hydrates, ethanolates) of the compounds of general formulae (IA), (IB) are also within the scope of the present 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 can 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 method comprises the following steps:

the above groups

The second method comprises the following steps:

when R is⁴Is H, R¹、R²、R³，R⁵As mentioned above, the preparation of the compounds of formula (IA) is carried out by: 3-amino-4-hydroxy-6-bromoquinoline compound (A) and carboxylic acid R³COOH is subjected to cyclization to prepare the quinoline and oxazole compound (B), then bromine in the molecule of the oxazole and quinoline compound (B) is converted into boric acid ester (D), and the boric acid ester (D) is further reacted with bromine in the oxazole and quinoline compound (B)Carrying out Suzuki coupling on the bromide (E) to prepare a compound shown as a general formula (IA), wherein the specific reaction formula is as follows:

the above groups

The third method comprises the following steps:

when R is⁴Is amino, amido, sulfonamido, ureido, R¹、R²、R³，R⁵As described above, the 3-amino-4-hydroxy-6-bromoquinoline compound (A) and the carboxylic acid R are reacted with³COOH is subjected to cyclization to prepare a quinoline oxazole compound (B), the quinoline oxazole compound (B) is subjected to quinoline-2-position activation through nitrogen atom oxidation, quinoline-2-amino (J) is further introduced, a compound (K) is prepared through corresponding conversion, and the compound (K) is further subjected to Suzuki coupling with a boric acid ester (C) to prepare a compound shown in a general formula (IA), wherein the specific reaction formula is as follows:

the above groups

the method comprises the following steps:

when R is⁴Is H, R¹、R²、R³，R⁵As described above, the 3-amino-4-hydroxy-6-bromoquinoline compound(A) Cyclizing the derivative and a Carbonyldiimidazole (CDI) reagent to prepare a quinoxalin-2-one compound (F), further alkylating an amide nitrogen atom to obtain a brominated quinoxalin-2-one compound (G), and carrying out Suzuki coupling on the brominated quinoxalin-2-one compound (G) and a boric acid ester (C) to prepare a compound shown in a general formula (IB), wherein the specific reaction formula is as follows:

the above groups

Method two

When R is⁴Is H, R¹、R²、R³，R⁵As mentioned above, 3-amino-4-hydroxy-6-bromoquinoline compound (a) is cyclized with Carbonyldiimidazole (CDI) reagent to prepare quinoxalin-2-one compound (F), amide nitrogen atom is further alkylated to obtain brominated quinoxalin-2-one compound (G), and then brominated quinoxazin-2-one compound (G) is converted into corresponding boronic acid ester (H), followed by Suzuki coupling with bromide (E) to prepare the compound represented by general formula (IB), which has the following specific reaction formula:

the above groups

Method III

the above groups

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 compounds of the present invention, the compounds of formula (IA), (IB) 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 -, β -or γ -cyclodextrin, preferably β -cyclodextrin, at 20 ℃ to 80 ℃ or the acidic protons of the compounds of formula (IA), (IB) as defined in the summary of the invention above may be blended with cyclodextrin in the form of an aqueous solution of a salt thereof (e.g. sodium or potassium salt) and then with an equivalent acid (e.g. HCl or H salt) followed by blending with cyclodextrin₂SO₄) 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 compounds of formula (IA) and (IB) are oily and crystalline, they can be converted into the corresponding cyclodextrin inclusion compound by adding an aqueous solution of cyclodextrin under 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 can be prepared by one skilled in the art using known methods. See, for example, Croft, A.P. et al, "Synthesis of chemical modified Cyclodextrins", Tetrahedron1983,39,9, 1417-. Suitable cyclodextrins include the various types which may be used to prepare inclusion complexes with compounds of formulae (IA), (IB) 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 compounds of general formula (IA), (IB) are 2: 1 (Cyclodextrin: Compound).

The pharmaceutical compositions comprising as active ingredient a compound of general formula (IA) or/and general formula (IB) 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 ethylene oxide with fatty acids (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 partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate or a condensation product of ethylene oxide with partial esters derived from mixtures of fatty acids and hexitol ethers (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 poured 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 general formula (IA) or/and general formula (IB) 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 (IA) or/and formula (IB) 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 20 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 a combined preparation is not suitable, the compounds of general formula (IA) or/and (IB) 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 general formula (IA) or/and general formula (IB) may be administered before or after the 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 synthetic routes, and those skilled in the art can obtain compounds not specifically recited by applying similar procedures from appropriate starting materials.

Examples

The following examples (for preparing the compounds of the invention) and biological test examples (assays for demonstrating 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.

Example 1:

compound I-1: preparation of 2-methyl-8- (quinolin-3-yl) oxazolo [4,5-c ] quinoline, having the formula:

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 the addition, the mixture was heated to 40 ℃ and then cooled, and nitromethane (9.325g,152.76mmol) was added dropwise while maintaining the temperature at 40-45 ℃. After dropping, the temperature is kept at 40-45 ℃ until the solid completely disappears, and a red clear solution appears. The reaction mixture was then heated to 50-55 ℃ for 2-5 minutes, cooled to 30 ℃ and poured into ice (21 g) and acidified with concentrated hydrochloric acid (41.7 mL), and the resulting reaction mixture was 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 1 h, 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, the resulting solid was filtered, washed with a small amount of acetone and dried, and the resulting crude 3-amino-4-hydroxy-6-bromoquinoline hydrochloride (3.07g,86%) was used directly as it wasAnd (4) carrying out one-step reaction. LC-MS (ESI +) 239,241[ M +1]]⁺。

And 4, step 4: 3-amino-4-hydroxy-6-bromoquinoline hydrochloride (400mg,1.45mmol) was dissolved in acetic anhydride (5mL), and anhydrous sodium acetate (154mg,1.57mmol) was added and heated to reflux for 4 hours. Cooled to room temperature, concentrated sulfuric acid (0.1 mL) was added, and the mixture was heated to reflux and stirred for 2 hours. The reaction mixture was cooled to room temperature, poured into water (30mL), stirred until homogeneous, concentrated sodium hydroxide solution was added and extracted with dichloromethane. The dichloromethane extracts are combined, washed with saturated brine, dried, concentrated and subjected to column chromatography (dichloromethane: methanol =100:1) to obtain 8-bromo-2-methyloxazolo [4, 5-c)]Quinoline (262mg, 69%). LC-MS (ESI +): 263,265[ M +1]]⁺。

And 5: 8-bromo-2-methyloxazolo [4,5-c]Quinoline (132mg,0.50mmol) was dissolved in 1, 4-dioxane (10mL) and water (2.0mL), quinoline-3-boronic acid (173mg,1.0mmol), Pd (dppf) Cl was added₂(36mg,0.05mmol) and Cs₂CO₃(489mg,1.50 mmol). Replacing with nitrogen for three times, heating to 100 deg.C, reacting for 3 hr, cooling to room temperature, extracting with ethyl acetate, mixing extractive solutions, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (ethyl acetate: petroleum ether = 4: 1) to obtain 2-methyl-8- (quinoline-3-yl) oxazolo [4, 5-c)]Quinoline (125 mg, 80%). LC-MS (ESI +):312[ M +1]]⁺。¹H NMR(300MHz,DMSO-d₆)9.01(s,1H),8.62(d,1H,J=3.6Hz),8.32-7.98(m,5H),7.90-7.57(m,3H),2.77(s,3H)。

Example 2:

compound I-2: preparation of N- (2-chloro-5- (2-methyloxazolo [4,5-c ] quinolin-8-yl) pyridin-3-yl) -4-fluorophenylsulphonamide the reaction formula is as follows:

step 1: 2-chloro-3-amino-5-bromopyridine (500mg,2.46mmol) was dissolved in THF (10mL)LiHMDS (7.4mL,7.4mmol) was added, stirring was continued for ten minutes, 4-fluorobenzenesulfonyl chloride (1.44g,7.4mmol) was added, stirring was continued overnight at room temperature, dichloromethane (20mL) was added for dilution, washing was performed with saturated sodium bicarbonate, extraction was performed with dichloromethane (4 × 30mL), the organic phases were combined, dried, concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate =20:1) to give 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 (petroleum ether: ethyl acetate =10:1) to give (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid (861mg, 99%). LC-MS (ESI +) 331[ M +1]]⁺。

And step 3: reacting 8-bromo-2-methyloxazolo [4,5-c ]]Quinoline (75mg,0.285mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL) and (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid (141mg,0.428mmol), Pd (dppf) Cl was added₂(21mg,0.029mmol) and Cs₂CO₃(279mg,0.855mmol) nitrogen was substituted for three times, then heated to 100 ℃ for reaction for 3 hours, cooled to room temperature, diluted with dichloromethane (30mL), extracted with water, the organic phase was separated off, the aqueous phase was adjusted to pH 7-8 with 1N hydrochloric acid, extracted with dichloromethane (3 × 10mL), combined with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol = 80: 1) to give N- (2-chloro-5- (2-methyloxazolo [4,5-c ])]Quinolin-8-yl) pyridin-3-yl) -4-fluorophenylsulfonamide (91 mg, 68%). LC-MS (ESI +):469[ M +1]]⁺。¹H NMR(300MHz,DMSO-d₆)9.24(s,1H),8.23(d,1H,J=9.0Hz),8.03(d,2H,J=9.9Hz),7.90(d,1H,J=10.8Hz),7.81(t,2H,J=6.9Hz),7.73(s,1H),7.28(t,2H,J=8.7Hz),2.80(s,3H)。

Example 3:

compound I-3: preparation of 4-fluoro-N- (2-methoxy-5- (2-methyloxazolo [4,5-c ] quinolin-8-yl) pyridin-3-yl) benzenesulfonamide, the reaction formula is as follows:

step 1: 2-methoxy-3-amino-5-bromopyridine (500mg,2.5mmol) was dissolved in tetrahydrofuran (10mL), LiHMDS (7.4mL,7.4mmol) was added, stirring was continued for ten minutes, 4-fluorobenzenesulfonyl chloride (1.44g,7.4mmol) was added, and stirring was continued 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 subjected to column chromatography (petroleum ether: ethyl acetate =20:1) to give N- (5-bromo-2-methoxypyridin-3-yl) -4-fluorobenzenesulfonamide (770mg, 87%). 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 (petroleum ether: ethyl acetate =10:1) to give 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide (861mg, 99%). LC-MS (ESI +) 409[ M +1]]⁺。

And step 3: reacting 8-bromo-2-methyloxazolo [4,5-c ]]Quinoline (75mg,0.285mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL) and 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide (177mg,0.428mmol), Pd (dppf) Cl was added₂(21mg,0.029mmol) and Cs₂CO₃(279mg,0.855 mmol). Replacing with nitrogen for three times, heating to 100 deg.C, reacting for 3 hr, cooling to room temperature, diluting with dichloromethane (30mL), adding water, extracting, separating organic phase, adjusting pH of water phase with 1N hydrochloric acid to obtain water phase7-8, extracted with dichloromethane (3 × 10mL), the dichloromethane solution dried, concentrated, and the residue chromatographed (dichloromethane: methanol = 80: 1) to give 4-fluoro-N- (2-methoxy-5- (2-methyloxazolo [4, 5-c)]Quinolin-8-yl) pyridin-3-yl) benzenesulfonamide (45 mg, 34%). LC-MS (ESI +) 465[ M +1]]⁺；¹H NMR(300MHz,DMSO-d₆)10.12(br,1H),9.26(s,1H),8.51(s,1H),8.27(t,2H,J=11.0Hz),8.04(d,2H,J=15.3Hz),7.83(t,2H,J=6.6Hz),7.42(t,2H,J=8.7Hz),3.68(s,3H),2.79(s,3H)。

Following the procedures of examples 2 and 3,2, 4-difluorobenzenesulfonyl chloride was substituted for 4-fluorobenzenesulfonyl chloride to prepare the following compounds I-4 and I-5, respectively:

example 6:

compound I-6: preparation of N- (2-chloro-5- (2-methyloxazolo [4,5-c ] quinolin-8-yl) pyridin-3-yl) methanesulfonamide, the reaction formula is as follows:

step 1: 2-chloro-3-amino-5-bromopyridine (2.5g,12.05mmol) was dissolved in pyridine (30mL), methanesulfonyl chloride (4.66mL,60.25mmol) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure, and methanol (50mL) and 1, 4-dioxane (50mL) were added to the residue, followed by addition of anhydrous potassium carbonate (16.65g,120.5mmol), heating to 60 ℃ and stirring for 5 hours. After cooling to room temperature, the reaction mixture was poured into water (500mL) and adjusted to pH5 with concentrated hydrochloric acid. Extraction with ethyl acetate, combination of organic phases, washing with water and saturated brine respectively, drying, concentration, and column chromatography of the residue (petroleum ether: ethyl acetate =10:1) gave N- (5-bromo-2-chloropyridin-3-yl) methanesulfonamide (2.70g, 79%). LC-MS (ESI +):285[ M +1 ].

Step 2: under the protection of nitrogen, 8-bromo-2-methyloxazolo [4,5-c]Quinoline (2.63 g,10 mmol) was dissolved in 1, 4-dioxane (100mL) and pinacol diboron (5.08 g,20mmol), Pd (dppf) Cl was added₂(732 mg, 1mmol) and KOAc (1.47 g,15mmol), heating to 100 deg.C, stirring for 5 hr, concentrating, and performing silica gel column chromatography to obtain (2-methyloxazolo [4, 5-c)]Quinolin-8-yl) boronic acid (2.12 g, 93%).

And step 3: reacting (2-methyl oxazolo [4, 5-c)]Quinolin-8-yl) boronic acid (114mg,0.50mmol) was dissolved in 1, 4-dioxane (10mL) and water (1.5mL), N- (5-bromo-2-chloropyridin-3-yl) methanesulfonamide (157 mg, 0.55 mmol), Pd (dppf) Cl was added₂(37 mg,0.05mmol) and Cs₂CO₃(245 mg,0.75 mmol), the reaction solution was fully purged with nitrogen, heated to 100 ℃ and stirred for 1 hour. Cooling to room temperature, adjusting pH with 1N hydrochloric acid 5-6, concentrating, and performing silica gel column chromatography to obtain N- (2-chloro-5- (2-methyloxazolo [4, 5-c)]Quinolin-8-yl) pyridin-3-yl) methanesulfonamide (141mg, 73%). MS (ESI +):389[ M + H ]];¹HNMR(300MHz,DMSO-d₆)10.03(br,1H),9.43(s,1H),9.05(s,1H),8.50-8.51(m,1H),7.93-8.21(m,3H),3.52(s,3H),2.85(s,3H)。

Example 7:

compound I-7: preparation of N- (2-methoxy-5- (2-methyloxazolo [4,5-c ] quinolin-8-yl) pyridin-3-yl) methanesulfonamide, the reaction formula is as follows:

step 1: 2-methoxy-3-amino-5-bromopyridine (1g,4.925mmol) was dissolved in pyridine (15mL), MsCl (1.9mL,24.626mmol) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated to dryness, and methanol (20mL) and 1, 4-dioxane (20mL) were added to the residue, and anhydrous potassium carbonate (16.81g,49.25mmol) was added thereto, followed by heating to 60 ℃ for 5 hours. The reaction solution was poured into water (100mL)And the pH was adjusted to =5 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 (petroleum ether: ethyl acetate =10:1) to give N- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide (994mg, 72%). LC-MS (ESI +):281,283[ M +1]]⁺。

Step 2: reacting (2-methyl oxazolo [4, 5-c)]Quinolin-8-yl) boronic acid (114mg,0.50mmol) was dissolved in 1, 4-dioxane (10mL) and water (1.5mL), N- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide (154mg, 0.55 mmol), Pd (dppf) Cl was added₂(37 mg,0.05mmol) and Cs₂CO₃(245 mg,0.75 mmol), the reaction solution was fully purged with nitrogen, heated to 100 ℃ and stirred for 1 hour. Cooling to room temperature, adjusting pH with 1N hydrochloric acid 5-6, concentrating, and performing silica gel column chromatography to obtain N- (2-methoxy-5- (2-methyloxazolo [4, 5-c)]Quinolin-8-yl) pyridin-3-yl) methanesulfonamide (117 mg, 61%). MS (ESI +) 385M + H];¹HNMR(300MHz,DMSO-d₆)9.46(s,1H),9.01(s,1H),8.52(m,1H),7.91-8.07(m,3H),3.91(s,3H),3.52(s,3H),2.86(s,3H)。

Following the procedures of examples 6 and 7, by replacing methanesulfonyl chloride therein with cyclopropylsulfonyl chloride (CAS: 139631-62-2) and dimethylaminosulfonyl chloride (CAS: 13360-57-1), respectively, the following compounds I-8, I-9, I-10 and I-11, respectively, were prepared:

example 12:

compound I-12: preparation of N- (5- (4-amino-2-methyloxazolo [4,5-c ] quinolin-8-yl) -2-chloropyridin-3-yl) -4-fluorophenylsulphonamide the reaction scheme is:

step 1: reacting 8-bromo-2-methyloxazolo [4,5-c ]]Quinoline (980mg,3.725mmol) was dissolved in a mixed solution of N, N-dimethylacetamide (15mL) and petroleum ether (30mL), and mCPBA (1.021g,5.066mmol) was added in portions. After the addition, the mixture was stirred at room temperature for 2 hours. Additional mCPBA (481mg,0.64mmol) was added and stirring continued for 1.5 h. Filtering, washing the filtered substance with N, N-dimethylacetamide/petroleum ether =1/2 (20mL), drying, dissolving in a mixed solution of dichloromethane (40mL), methanol (20mL) and water (20mL), adding potassium carbonate (612mg,4.428mmol), stirring for reaction for 30 minutes, separating the organic phase, extracting the aqueous phase with dichloromethane three times, combining the organic phases, washing with saturated common salt water, drying, concentrating, and performing column chromatography on the residue (dichloromethane: methanol = 80: 1) to obtain 8-bromo-2-methyloxazole [4,5-c ] -2]quinoline-5-N-oxide (702mg, 56%). LC-MS (ESI +) 279,281[ M +1]]⁺。

Step 2: 8-bromo-2-methyloxazole [4,5-c]quinoline-5-N-oxide (600mg,2.15mmol) was dissolved in a mixed solvent of dichloromethane (40mL) and methanol (20mL), cooled to 0 deg.C, aqueous ammonia (5mL) was added, and a solution of p-methylbenzenesulfonyl chloride (1.23g,6.45mmol) in dichloromethane (10mL) was added dropwise. After dropping, the mixture was warmed to room temperature and stirred for 2 hours. Concentrating the reaction solution to dryness, and performing column chromatography on the residue (dichloromethane: methanol =20:1) to obtain 8-bromo-2-methyloxazolo [4, 5-c)]Quinolin-4-amino (255 mg, 42%). LC-MS (ESI +):278,280[ M +1]]⁺。

And step 3: reacting 8-bromo-2-methyloxazolo [4,5-c ]]Quinoline-4-amino (100mg,0.36mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL) and (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid (178mg,0.539mmol), Pd (dppf) Cl was added₂(26mg,0.036mmol) and Cs₂CO₃(176mg,0.539 mmol). Replacing with nitrogen for three times, heating to 100 deg.C, reacting for 3 hr, cooling to room temperature, diluting with dichloromethane (30mL), adding water, extracting, separating organic phase, adjusting water phase with 1N hydrochloric acid to pH to 7-8, extracted with dichloromethane (3 × 10mL), the dichloromethane solution dried, concentrated, and the residue separated by column chromatography (dichloromethane: methanol =40:1) to give N- (5- (4-amino-2-methyloxazolo [4, 5-c)]Quinolin-8-yl) -2-chloropyridin-3-yl) -4-fluorophenylsulfonamide (54mg, 31%). LC-MS (ESI +):484[ M +1]]+；¹H NMR(300MHz,DMSO-d₆)8.66(s,1H),8.06(s,1H),7.98(s,1H),7.79-7.83(m,3H),7.68-7.72(m,1H),7.45(t,2H,J=6.0Hz),7.26(br,2H),2.73(s,3H)。

Example 13:

compound I-13: preparation of N- (5- (4-amino-2-methyloxazolo [4,5-c ] quinolin-8-yl) -2-methoxypyridin-3-yl) -4-fluorobenzenesulfonamide of the formula:

the method comprises the following steps: reacting 8-bromo-2-methyloxazolo [4,5-c ]]Quinoline-4-amino (100mg,0.36mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL) and 4-fluoro-N- (2-methoxy-5- (pinacolboronato) pyridin-3-yl) benzenesulfonamide (220mg,0.539mmol), Pd (dppf) Cl was added₂(26mg,0.036mmol) and Cs₂CO₃(176mg,0.539mmol) nitrogen substitution three times, heating to 100 ℃ for reaction for 3 hours, cooling to room temperature, diluting with dichloromethane (30mL), adding water for extraction, separating off the organic phase, adjusting the pH of the aqueous phase to 7-8 with 1N hydrochloric acid, extracting with dichloromethane (3 × 10mL), drying the dichloromethane solution, concentrating, and separating the residue by column chromatography (dichloromethane: methanol =40:1) to obtain N- (5- (4-amino-2-methyloxazolo [4,5-c ] oxazole [4,5-c ]]Quinolin-8-yl) -2-methoxypyridin-3-yl-4-fluorobenzenesulfonamide (92 m)_g,53%）。LC-MS(ESI+):480[M+1]⁺；¹H NMR(300MHz,DMSO-d₆)10.06(br,1H),8.37(s,1H),7.65-7.95(m,6H),7.42(t,2H,J=8.9Hz),7.05(br,2H),3.66(s,3H),2.72(s,3H)。

Example 14:

compound I-14: preparation of 3-methyl-8- (quinolin-3-yl) oxazolo [4,5-c ] quinolin-2 (3H) -one according to the following reaction scheme:

step 1: 3-amino-4-hydroxy-6-bromoquinoline (3.0 g, 12.5 mmol) was dissolved in THF (100mL) under nitrogen and heated to reflux. Under reflux, carbonyldiimidazole (2.64 g, 16.29 mmol) was added portionwise and stirring under reflux was continued for 3 hours after the addition was completed. Cooled to room temperature, filtered, and the solid washed with dichloromethane (50mL) and dried to obtain the crude 8-bromo-oxazolo [4,5-c ] quinolin-2 (3H) -one.

Step 2: 8-bromo-oxazolo [4,5-c ] quinolin-2 (3H) -one (2.3 g, 4.35 mmol) was dissolved in N, N-dimethylformamide (60mL), cooled in an ice-water bath, NaH (60%, 699mg, 8.69 mmol) was added, and stirred for 20 min. Methyl iodide (1.23g, 4.35 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled with ice water, quenched with 1N hydrochloric acid, and adjusted to pH5-6, water (300 mL) was added, extracted with ethyl acetate (3X 100mL), the ethyl acetate phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 8-bromo-3-methyloxazolo [4,5-c ] quinolin-2 (3H) -one (600mg, two-step yield 17%).

And step 3: 8-bromo-3-methyloxazolo [4,5-c]Quinolin-2 (3H) -one (140mg,0.50mmol) was dissolved in 1, 4-dioxane (10mL) and water (2.0mL), quinoline-3-boronic acid (173mg,1.0mmol), Pd (dppf) Cl was added₂(36mg,0.05mmol) and Cs₂CO₃(489mg,1.50 mmol). Replacing with nitrogen for three times, heating to 100 deg.C, reacting for 3 hr, cooling to room temperature, extracting with ethyl acetate, mixing extractive solutions, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (ethyl acetate: petroleum ether = 3: 1) to obtain 3-methyl-8- (quinoline-3-yl) oxazolo [4, 5-c)]Quinolin-2 (3H) -one (116 mg, 71%). MS (ESI +) 328[ M +1]]⁺。¹H NMR(300MHz,DMSO-d₆)9.07(s,1H),8.65(d,1H,J=3.6Hz),8.33-8.01(m,5H),7.90-7.61(m,3H),3.50(s,3H)。

Following the procedure of example 14, compounds I-15, C of the following table, respectively, were prepared by Suzuki coupling of 8-bromo-3-methyloxazolo [4,5-c ] quinolin-2 (3H) -one with 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide, (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid, 2, 4-difluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide, (6-chloro-5- (2, 4-difluorobenzenesulfonamido) pyridin-3-yl) boronic acid, respectively, Compound I-16, compound I-17, and compound I-18:

example 19:

compound I-19: preparation of N- (2-methoxy-5- (3-methyl-2-oxo-2, 3-dihydrooxazolo [4,5-c ] quinolin-8-yl) pyridin-3-yl) methanesulfonamide, the reaction formula is as follows:

step 1: under the protection of nitrogen, 8-bromo-3-methyloxazolo [4,5-c]Quinolin-2 (3H) -one (1.08 g, 3.87 mmol) was dissolved in 1, 4-dioxane (100mL) and pinacol diboron (1.97 g, 7.74 mmol), Pd (dppf) Cl was added₂(281 mg, 0.389 mmol) and KOAc (725 mg, 5.80 mmol), heating to 100 ℃, stirring for 5 hours, concentrating, and performing silica gel column chromatography to obtain 3-methyl-8-pinacol boronate-oxazolo [4, 5-c)]Quinolin-2 (3H) -one (1.2 g, 95%).

Step 2: under the protection of nitrogen, 3-methyl-8-pinacol borate-oxazolo [4, 5-c)]Quinolin-2 (3H) -one (100mg,0.306mmol) was dissolved in 1, 4-dioxane (9mL) and water (1.5mL) and addedN- (5-bromo-2-methoxypyridin-3-yl) methanesulfonamide (95 mg, 0.337 mmol), Pd (dppf) Cl₂(23 mg, 0.031 mmol) and Cs₂CO₃(150mg,0.460mmol), heated to 100 ℃ and stirred for 1 hour. Cooling to room temperature, adjusting pH with 1N hydrochloric acid 5-6, concentrating, and performing silica gel column chromatography to obtain N- (2-methoxy-5- (3-methyl-2-oxo-2, 3-dihydrooxazolo [4, 5-c)]Quinolin-8-yl) pyridin-3-yl) methanesulfonamide (86 mg, 70%). MS (ESI)⁺):401[M+H];¹HNMR(300MHz,DMSO-d₆)9.42(s,1H),9.00(s,1H),8.50-8.51(m,1H),7.98-8.22(m,3H),3.98(s,3H),3.51(s,3H),3.11(s,3H)。

Following the procedure of example 19, 3-methyl-8-pinacolboronic acid ester-oxazolo [4,5-c ] quinolin-2 (3H) -one was separately Suzuki coupled with the corresponding bromopyridyl sulfonamide to afford compounds I-20, I-21, I-22, I-23, and I-24, respectively, of the following table:

example 25:

compound I-25: preparation of 4-amino-3-methyl-8- (quinolin-3-yl) oxazolo [4,5-c ] quinolin-2 (3H) -one according to the following reaction scheme:

step 1: 8-bromo-3-methyloxazolo [4,5-c ] quinolin-2 (3H) -one (2.80 g,10 mmol) was dissolved in a mixed solution of N, N-dimethylacetamide (28mL) and petroleum ether (56mL) and mCPBA (4.03g,20mmol) was added in portions. After the addition, the mixture was stirred at room temperature for 2 hours. After filtration, the filtrate was washed with N, N-dimethylacetamide/petroleum ether =1/2 (50mL), dried, and dissolved in a mixed solution of dichloromethane (80mL), methanol (40mL), and water (40mL), potassium carbonate (2.07g,15mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Standing, separating organic phase, extracting water phase with dichloromethane, mixing organic phases, washing with saturated salt water, drying, concentrating, and performing column chromatography (dichloromethane: methanol = 80: 1) to obtain 8-bromo-3-methyl-2-oxo-2, 3-dihydrooxazolo [4,5-c ] quinoline-5-nitroxide (1.21g, 41%).

Step 2: 8-bromo-3-methyl-2-oxo-2, 3-dihydrooxazolo [4,5-c]Quinoline-5-nitrogen oxide (1.21g,4.1mmol) was dissolved in a mixed solvent of dichloromethane (60mL) and methanol (30mL), cooled to 0 deg.C, aqueous ammonia (10mL) was added, and a solution of p-methylbenzenesulfonyl chloride (2.35g,12.3mmol) in dichloromethane (20mL) was added dropwise. After dropping, the mixture was warmed to room temperature and stirred for 2 hours. Concentrating the reaction solution to dryness, and performing column chromatography (dichloromethane: methanol =20:1) to obtain 4-amino-8-bromo-3-methyloxazolo [4, 5-c)]Quinolin-2 (3H) -one (470 mg, 39%). LC-MS (ESI +):294,296[ M +1]]⁺。

And step 3: 4-amino-8-bromo-3-methyloxazolo [4,5-c]Quinolin-2 (3H) -one (147 mg,0.50mmol) was dissolved in 1, 4-dioxane (10mL) and water (2.0mL), quinoline-3-boronic acid (173mg,1.0mmol), Pd (dppf) Cl was added₂(36mg,0.05mmol) and Cs₂CO₃(489mg,1.50 mmol). Replacing with nitrogen for three times, heating to 100 deg.C, reacting for 3 hr, cooling to room temperature, extracting with ethyl acetate, mixing extractive solutions, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (dichloromethane: methanol = 50: 1) to obtain 4-amino-3-methyl-8- (quinolin-3-yl) oxazolo [4,5-c]Quinolin-2 (3H) -one (80 mg, 47%). MS (ESI +):343[ M +1]]⁺。¹H NMR(300MHz,DMSO-d₆)8.67(d,1H,J=3.6Hz),8.34-8.03(m,5H),7.90-7.61(m,3H),6.49(br,2H),3.51(s,3H)。

Following the procedure of example 25, a Suzuki coupling reaction of 4-amino-8-bromo-3-methyloxazolo [4,5-c ] quinolin-2 (3H) -one with (6-chloro-5- (4-fluorobenzenesulfonamido) pyridin-3-yl) boronic acid, 4-fluoro-N- (2-methoxy-5- (pinacolboronic acid) pyridin-3-yl) benzenesulfonamide, respectively, was carried out to afford compound I-26, compound I-27:

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 obvious analogues of the above intermediates and carrying out the preparation of the compounds of general formulae (IA), (IB) as described in the present aspect.

Biological example 1:

the compounds of the invention have half Inhibitory Concentrations (IC) against PI3K α, PI3K β, PI3K, PI3K gamma and mTOR₅₀) Measurement of

1. Raw materials

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

p110/p85a, available from Millipore, cat No. 14-604-K;

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

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

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

Kinase-Glo Plus L μ Minesce-Kinase Assay, available from Promage, cat No. V3771;

ADP-Glo Kinase Assay 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) 1x mTOR kinase buffer

50mM HEPES,pH7.5

10mM MgCl₂

1mM EGTA

3mM MnCl

0.01%Tween-20

2mM DTT

2) 1 XPI 3K alpha, PI3K kinase buffer

50mM HEPES,pH7.5

3mM MgCl₂

1mM EGTA

100mM NaCl

0.03%CHAPS

2mM DTT

3) 1 XPI 3K beta, PI3K gamma kinase buffer

50mM HEPES,pH7.5

3mM MgCl₂

1mM EGTA

100mM NaCl

0.03%CHAPS

2mM DTT

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) Configuring 2 times substrate solution by using 1 time kinase buffer solution mTOR, PI3K α, PI3K β and PI3K_γAnd PI3K are respectively the final concentration of the substrate solution of the five enzyme reaction systems

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_γ1 hour, PI3K2 hours.

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.L of Kinase-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 of 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:

Percent inhibition=(Lance signal-min)/(max-min)*100

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

Percent inhibition=(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 MS Excel and curve fitted using graphpad 5.0.

IC of partial compound of the invention to PI3K α, PI3K β, PI3K gamma, PI3K and mTOR five enzymes₅₀The test results are shown in the following table:

biological example 2: half Inhibitory Concentration (IC) of the compound of the present invention against tumor Cell proliferation was measured using Cell Titer-Glo luciferase kit₅₀）

1. Raw materials

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

a549 cell line purchased from ATCC, cat.no. ccl-185, Lot No. 7502546;

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

BT474 cell line, purchased from ATCC, Cat. No. HTB-20, Lot No. 5188737;

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

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

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

CellTiter Glo assay kit, available from Promega, Cat. No. G7571, Lot. No. 256984;

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

2. Experimental methods

2.1 cell plating

Preparing a complete culture medium: and mixing the mixture completely.

Cell lines with good growth status were selected.

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.

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-.

The cell supernatant in the centrifuge tube was aspirated.

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

Counting was performed using a Vi-Cell XR cytometer.

The cell suspension was adjusted to the appropriate concentration.

The cell suspension was added to a 96-well bottom-transmural white plate at 100 uL/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-cate+10％FBS+1％PS

2.3 preparation and addition of Compounds:

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).

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.

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

Incubate at 37 ℃ for a specified time.

2.4 detection and analysis

The cell morphology was observed under an inverted microscope.

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

The cell activity assay reagent was added to the plate at 100. mu.L/well.

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

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

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).

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. A compound which is a PI3K/mTOR inhibitor, being a compound having the following general formula (IA) or (IB):

wherein,

R¹selected from chlorine, methoxy, or with R²A benzene ring is formed;

R²is selected fromWherein Ra is methyl, cyclopropyl, optionally one or more fluoro substituted phenyl, Rb is dimethylamino, R' is hydrogen; or with R¹A benzene ring is formed;

R³selected from hydrogen, methyl;

R⁴selected from hydrogen;

R⁵selected from hydrogen.

2. A compound which is a PI3K/mTOR inhibitor, characterized in that the compound is any one of the following structures (I-1) to (I-27):

3. a compound according to any one of claims 1 or2 as a PI3K/mTOR inhibitor, wherein the compound is in the form of a pharmaceutically acceptable salt.

4. A compound according to claim 3, wherein the pharmaceutically acceptable salt is in the form of a salt with an acid, as a PI3K/mTOR inhibitor.

5. The compound of claim 4, wherein the acid is selected from the group consisting of hydrochloride, hydrobromide, methanesulfonate, sulfate, phosphate, acetate, trifluoroacetate, trifluoromethanesulfonate, p-toluenesulfonate, tartrate, maleate, fumarate, succinate and malate.

6. A process for the preparation of a compound of formula (IA) according to claim 1, wherein the compound of formula (IA) is prepared by the steps of: 3-amino-4-hydroxy-6-bromoquinoline compound (A) and carboxylic acid R³COOH is cyclized to prepare a quinoline oxazole compound (B), and further, a bromine atom and boric acid ester (C) are subjected to Suzuki coupling reaction to prepare a compound shown in a general formula (IA), wherein the specific reaction formula is as follows:

the above groups

7. A process for the preparation of a compound of formula (IA) according to claim 1, wherein the compound of formula (IA) is prepared by the steps of: 3-amino-4-hydroxy-6-bromoquinoline compound (A) and carboxylic acid R³COOH is subjected to cyclization to prepare a quinoline and oxazole compound (B), bromine in the molecule of the oxazole and quinoline compound (B) is converted into a boric acid ester (D), and the boric acid ester (D) is further subjected to Suzuki coupling with bromide (E) to prepare a compound shown in a general formula (IA), wherein the specific reaction formula is as follows:

the above groups

8. A process for the preparation of compounds of formula (IB) according to claim 1, characterized in that 3-amino-4-hydroxy-6-bromoquinolines (a) are cyclized with Carbonyldiimidazole (CDI) reagent to prepare quinoxazol-2-ones (F), the amide nitrogen atom is further alkylated to obtain brominated quinoxazol-2-ones (G), and brominated quinoxazol-2-ones (G) are Suzuki coupled with borate (C) to prepare compounds of formula (IB), the specific reaction formula is as follows:

the above groups

9. A process for the preparation of compounds of formula (IB) according to claim 1, characterized in that 3-amino-4-hydroxy-6-bromoquinolines (a) are cyclized with Carbonyldiimidazole (CDI) reagent to prepare quinoxazol-2-ones (F), the amide nitrogen atom is further alkylated to obtain brominated quinoxazol-2-ones (G), which are then converted to the corresponding boronic esters (H) followed by Suzuki coupling with bromides (E) to prepare compounds of formula (IB), the specific reaction being as follows:

the above groups

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10, 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.

12. A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of a compound according to any one of claims 3 to 5 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12, 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.

14. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the manufacture of a preparation for modulating the catalytic activity of the PI3K/mTOR signaling pathway.

15. Use of a pharmaceutical composition according to any one of claims 10 to 13 in the manufacture of a medicament for the treatment of a disease associated with the PI3K/mTOR signalling pathway.

16. The use of claim 15, wherein the disease associated with the PI3K/mTOR signaling pathway is cancer.

17. The use of claim 16, wherein the cancer is a cancer of the head and neck, respiratory system, digestive system, urinary system, skeletal system, gynecological, hematological, or other type.

18. The use of claim 17, wherein the head and neck cancer is thyroid cancer, nasopharyngeal cancer, meningeal cancer, acoustic neuroma, pituitary tumor, oral cancer, craniopharyngioma, thalamic and brainstem tumor, angiogenetic tumor, or intracranial metastatic tumor.

19. The use of claim 17, wherein the respiratory cancer is lung cancer.

20. The use of claim 17, wherein the cancer of the digestive system is liver cancer, stomach cancer, esophageal cancer, colorectal cancer, rectal cancer, colon cancer or pancreatic cancer.

21. The use of claim 17, wherein the cancer of the urinary system is renal cancer, bladder cancer, prostate cancer, or testicular cancer.

22. The use of claim 17, wherein the skeletal system cancer is bone cancer.

23. The use according to claim 17, wherein the gynaecological cancer is breast cancer, cervical cancer or ovarian cancer.

24. The use of claim 17, wherein the hematological cancer is leukemia, malignant lymphoma or multiple myeloma.

25. The use of claim 17, wherein the other type of cancer is malignant melanoma, glioma, or skin cancer.