Novel compound inhibiting HSP90 and uses thereof

Abstract

The present invention relates to a novel compound and anticancer uses thereof and, more specifically, provides: a novel compound exhibiting inhibitory activity against HSP90, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for preventing or treating cancer diseases comprising same; and a health functional food composition for preventing or improving cancer diseases comprising the compound.

Description

Novel compounds that inhibit HSP90 and their uses

[0001] This application claims priority to Republic of Korea Patent Application No. 10-2024-0103990, filed on August 5, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a novel compound and its use for anticancer purposes, and more particularly, to a novel compound exhibiting an effect of inhibiting HSP90, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for preventing or treating cancer comprising the same; and a health functional food composition for preventing or improving cancer comprising the compound.

[0003] Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates the folding, stability, and function of substrate proteins, called "client" proteins. These clients include epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), anaplastic lymphoma kinase (Alk), mesenchymal-epidermal transition factor (Met), protein kinase B (Akt), cyclin-dependent kinase 4 (Cdk4), hypoxia inducible factor 1 (HIF-1α), and matrix metalloproteinase 9 (MMP9). Many Hsp90 client proteins are known to induce cancer. Because cancer cells are more dependent on Hsp90 chaperone function than normal cells due to their genetic instability and stressful environment, Hsp90 expression is 2-10 times higher in cancer cells than in normal cells.

[0004] Accordingly, Hsp90 may be a target for effective cancer treatment, as inhibitors of Hsp90 protein activity can simultaneously reduce various oncogenic proteins and may also be effective in treating resistant cancers.

[0005] Therefore, as described in Patent Document 1, Hsp90 inhibitors are attracting significant attention as anticancer agents applicable to a wide range of cancer types, as they can simultaneously reduce various cancer-causing proteins. In particular, Hsp90 has been reported to be effective in treating resistant cancers, as it simultaneously reduces various cancer-causing proteins.

[0006] Hsp90 inhibitors began with the development of the natural substance geldanamycin (GA). In 1994, GA was discovered to induce the degradation of the client protein Src by inhibiting Hsp90. Since then, Hsp90-targeting inhibitors have been actively developed. However, while GA exhibits potent anticancer effects, it suffers from liver toxicity, solubility, and stability issues. To address these issues, GA derivatives such as tanespimycin (17-AAG), alvespimycin (17-DMAG), and retaspimycin were developed. However, these issues remained unresolved due to the structural characteristics of GA.

[0007] [Prior Art Literature]

[0008] [Patent Document]

[0009] (Patent Document 1) Republic of Korea Patent No. 10-2375057

[0010] Against this backdrop, the inventors of the present invention synthesized a novel compound having excellent HSP90 inhibitory activity and confirmed that the effect was superior to or comparable to that of the compound AUY-922, known as an inhibitor of HSP90, thereby completing the present invention.

[0011] Accordingly, the object of the present invention is to provide a novel compound that inhibits HSP90, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0012] In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises the above-mentioned compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] Another object of the present invention is to provide a health functional food composition for preventing or improving cancer, which comprises the above-mentioned compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] To solve the above-described problem, the present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above formula,

[0018] The above R 1 may be substituted or unsubstituted phenyl or benzyl;

[0019] The above R 2 may be H, halogen, oxo, cyano, OH, C1-6 alkyl, C1-6 alkoxy, carbamoyl, carbamoyl-C1-6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C4-C7 cycloalkylalkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C2-C6 alkylcarbonyl, phenoxy, phenylamino, amino, C1-C5 monoalkylamino, C2-C10 dialkylamino, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl;

[0020] wherein X may be CH or N;

[0021] The above n can be an integer from 0 to 3;

[0022] The above R 1When substituted, it is substituted with a substituent independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, C5-C9 heteroaryl, amino, carbonyl, thio, cyano, nitro group, ester, amide, azide, OH, and carboxyl group, and when substituted with multiple substituents, they may be the same or different from each other.

[0023] At this time, the above R 2 may be H, carbamoyl, carbamoyl-C1-6 alkyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl;

[0024] The above n can be 0 or 1;

[0025] The above R 1 When substituted, it is substituted with a substituent independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and OH, and when substituted with multiple substituents, they may be the same or different from each other.

[0026] At this time, the compound may be a compound represented by the following chemical formula 2 or chemical formula 3:

[0027] [Chemical Formula 2]

[0028] or

[0029] [Chemical Formula 3]

[0030] .

[0031] At this time, the stereoisomer may include a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0032] At this time, the compound may inhibit HSP90.

[0033] Additionally, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the above-described compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0034] At this time, the cancer disease may be any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and blood cancer.

[0035] Furthermore, the present invention provides a health functional food composition for preventing or improving cancer, comprising the above-described compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0036] The novel compound provided in the present invention exhibits excellent HSP90 inhibitory activity, and HSP90 has proteins such as Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, and hTERT, which are related to cancer cell development, as client proteins. The novel compound of the present invention, which inhibits the activity of HSP90, can be utilized as an anticancer agent by inducing the effect of simultaneously degrading various cancer-causing proteins by the proteasome, and thus the novel compound of the present invention has high utility value.

[0037] Figure 1 shows the results of evaluating the HSP90 inhibitory activity of compounds H2-1-1, H2-1-2, H2-1-3, and H2-1-4 at various concentrations (0.016, 0.08, 0.4, 2, and 10 μM) and GA at various concentrations (0.01, 0.1, and 1 μM).

[0038] Figure 2 shows the results of evaluating the HSP90 inhibitory activity of compounds H2-1-6, H2-1-6, H2-2-1, and H2-2-3 at various concentrations (0.016, 0.08, 0.4, 2, and 10 μM) and GA at various concentrations (0.01, 0.1, and 1 μM).

[0039] Figure 3 shows the results of evaluating the HSP90 inhibitory activity of compounds H2-2-4, H2-2-5, H2-2-6, and H2-2-1 UNEXPECT at various concentrations (0.016, 0.08, 0.4, 2, and 10 μM) and GA at various concentrations (0.01, 0.1, and 1 μM).

[0040] Figure 4 shows the results of evaluating the HSP90 inhibitory activity of compound H2-2-3 UNEXPECT at various concentrations (0.016, 0.08, 0.4, 2, and 10 μM), AUY-922 at various concentrations (0.0016, 0.008, 0.04, 0.2, and 1 μM), and GA at various concentrations (0.01, 0.1, and 1 μM).

[0041] Figure 5 shows the HSP90 inhibitory activity according to the concentration of compounds H2-1-1, H2-1-2, H2-1-3, H2-1-4, H2-1-5, H2-1-6, H2-2-1, H2-2-3, H2-2-4, H2-2-5, H2-2-6, H2-2-1 UNEXPECT, H2-2-3 UNEXPECT and AUY-922.

[0042] Hereinafter, the present invention will be described in more detail.

[0043] Meanwhile, each description and embodiment disclosed herein can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0044] Furthermore, those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments of the invention described in this application. Furthermore, such equivalents are intended to be encompassed by the present invention.

[0045] As described above, Hsp90 inhibitors can simultaneously reduce various oncogenic proteins and may also be effective in treating resistant cancers. Accordingly, the inventors synthesized novel compounds that inhibit HSP90 activity and confirmed that these compounds exhibit HSP90 activity inhibition comparable to or superior to AUY-922 and GA.

[0046] Accordingly, the first aspect of the present invention relates to a novel compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0047] [Chemical Formula 1]

[0048]

[0049] In the above formula,

[0050] The above R 1 may be substituted or unsubstituted phenyl or benzyl;

[0051] The above R 2is H, halogen, oxo, cyano, OH, halo-C1-6 alkyl, cyano-C1-6 alkyl, C1-6 alkyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, carboxy-C1-6 alkyl, amino-C1-6 alkyl, carbamoyl, carbamoyl-C1-6 alkyl, ureido, ureido-C1-6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C4-C7 cycloalkylalkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, nitro, formyl, C2-C6 alkylcarbonyl, benzene ring, naphthalene ring, heterocyclic ring, phenoxy, phenylamino, amino, C1-C5 monoalkylamino, C2-C10 dialkylamino, C1-C5 monoalkylaminomethyl, C2-C10 dialkylaminomethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl, preferably H, halogen, oxo, cyano, OH, C1-6 alkyl, C1-6 alkoxy, carbamoyl, carbamoyl-C1-6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C4-C7 cycloalkylalkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C2-C6 alkylcarbonyl, phenoxy, phenylamino, amino, C1-C5 monoalkylamino, C2-C10 dialkylamino, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, It may be piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl, most preferably H, carbamoyl, carbamoyl-C1-6 alkyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl;

[0052] wherein X may be CH or N;

[0053] The above n may be an integer from 0 to 3, preferably 0 or 1;

[0054] The above R 1When substituted, it may be substituted with a substituent independently selected from the group consisting of halogen, C1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxy, C6-C20 aryl, C5-C20 heteroaryl, amino, carbonyl, thio, cyano, nitro, ester, amide, azide, OH, and carboxyl group, preferably halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, C5-C9 heteroaryl, amino, carbonyl, thio cyano, nitro group, ester, amide, azide, OH, and carboxyl group, most preferably halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and OH, and when substituted with multiple substituents, they may be the same or different from each other. It could be.

[0055] As used herein, the term "halogen", independently or as part of another substituent, means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, unless otherwise stated. The term "halide", by itself or as part of another substituent, means a fluoride, chloride, bromide, or iodide atom.

[0056] The term "C1-6 alkyl" as used herein refers to a monovalent alkyl group having 1 to 6 carbon atoms, wherein the alkyl may be optionally substituted with one or more substituents. Examples of this term include, but are not limited to, functional groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like. The alkyl and other substituents comprising alkyl moieties described in the present invention include both straight-chain and branched forms.

[0057] The term "C1-6 alkoxy" as used herein refers to the group -OR, where R represents "C1-6 alkyl". Preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, phenoxy, phenylmethoxy, or phenylethoxy.

[0058] The term "C3-C6 cycloalkyl" as used herein applies alone or as part of another group containing one ring and comprising a saturated cyclic hydrocarbon group, including monocycloalkyl forming three to six carbons, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0059] The term "C3-C6 cycloalkoxy" as used herein means -O-cycloalkyl. Examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and the like.

[0060] The term "C4-C7 cycloalkylalkoxy" as used herein refers to an alkoxy substituted with cycloalkyl and containing a total of 4 to 7 carbon atoms, wherein cycloalkyl and alkoxy are as defined above, and include, for example, cyclopropylmethoxy, cyclopropylethoxy, cyclopropylpropoxy, cyclopropylbutoxy, cyclobutymethoxy, cyclobutylethoxy, cyclobutylpropoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, and the like.

[0061] The term “C1-C5 alkylthio” as used herein means -S-alkyl.

[0062] The term "C1-C5 alkylsulfonyl" as used herein means -SO2-(alkyl) including -SO2-CH3, -SO2-CH2CH3, -SO2-(CH2)2CH3, -SO2-(CH2)3CH3, -SO2-(CH2)4CH3, and -SO2-(CH2)5CH3, wherein alkyl is as defined above.

[0063] The term "C2-C6 alkylcarbonyl" as used herein means -C(=O)alkyl, where alkyl is as defined above.

[0064] The term "C1-C5 monoalkylamino" as used herein includes groups in which the nitrogen of -NH2 is bonded to one additional alkyl group. Examples include monomethylamino or monoethylamino.

[0065] The term "C2-C10 dialkylamino" as used herein includes groups in which the nitrogen of -NH2 is bonded to two additional alkyl groups. Examples include dimethylamino or diethylamino.

[0066] The term "aryl" as used herein refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic arrangement) having 6-20 ring carbon atoms and 0 heteroatoms ("C6-C20 aryl") provided in the aromatic ring system. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C14 aryl"; e.g., anthracyl). An aryl group may be described, for example, as a C6-C10-membered aryl, wherein the term "member" refers to a non-hydrogen ring atom within the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group can independently be optionally substituted, for example, unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C6-C20 aryl. In certain embodiments, the aryl group is a substituted C6-C20 aryl.

[0067] The term "heteroaryl" as used herein refers to a radical of a 5-20 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-20 membered heteroaryl"). In heteroaryl groups comprising one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups such that the point of attachment is on either the aryl or heteroaryl ring, in which case the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) may have the point of attachment on either ring, i.e., the ring that carries the heteroatom (e.g., 2-indolyl) or the ring that does not contain the heteroatom (e.g., 5-indolyl). A heteroaryl group may be described, for example, as a 6- to 10-membered heteroaryl, wherein the term "member" refers to a non-hydrogen ring atom within the moiety.

[0068] In the present invention, the compound may be represented by the following chemical formula 2 or chemical formula 3:

[0069] [Chemical Formula 2]

[0070] or

[0071] [Chemical Formula 3]

[0072] .

[0073] In the present invention, the stereoisomer may include a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0074] In a specific embodiment of the present invention, the inhibitory activity of HSP90 of 13 compounds synthesized in the present invention was evaluated, and as a result, it was confirmed through Figures 1 to 5 that compounds H2-1-3 and H2-2-6 exhibited an HSP90 inhibitory effect comparable to or superior to AUY-922, a compound known as an HSP90 inhibitor.

[0075] Therefore, in the present invention, the compound may be characterized by inhibiting HSP90.

[0076] In addition, the second aspect of the present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0077] Since the effect of the compound included in the pharmaceutical composition for preventing or treating cancer of the present invention is the same as that of the compound of the first aspect, its description is omitted.

[0078] The term 'prevention' used in the present invention means any action that suppresses or delays the onset of cancer or related diseases due to the compound of the present invention.

[0079] The term 'treatment' used in the present invention means any action that improves or benefits parameters related to cancer or related diseases, such as the degree of symptoms, by using the compound of the present invention.

[0080] In the present invention, the cancer disease may be any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and blood cancer.

[0081] Preferably, the cancer may be lung cancer.

[0082] The pharmaceutical composition of the present invention may be administered orally or parenterally in various dosage forms. When formulating the composition, it may be prepared using one or more buffers (e.g., saline or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, bulking agents, binders, adjuvants (e.g., aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating agents, or surfactants, diluents, or excipients.

[0083] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing one or more compounds with at least one excipient, such as starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose, and hydroxypropylmethyl-cellulose or gelatin. For example, tablets or sugar-coated tablets can be obtained by mixing an active ingredient with a solid excipient, grinding the mixture, adding a suitable auxiliary agent, and then processing the mixture into a granule mixture.

[0084] In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, or preservatives may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as disintegrants in some cases, and anticoagulants, flavoring agents, emulsifiers, solubilizers, dispersants, flavoring agents, antioxidants, packaging agents, pigments, and preservatives may be additionally included.

[0085] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, or suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, glycerol, and gelatin.

[0086] The composition of the present invention can be administered orally or parenterally, and can be formulated in the form of an injection for parenteral administration into the abdominal cavity, rectum, vein, muscle, or subcutaneously; or a nasal inhaler according to a method known in the art.

[0087] In the case of the above injection, it must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. Examples of suitable carriers for the injection include, but are not limited to, solvents or dispersion media including water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), mixtures thereof, and / or vegetable oils. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol, and 5% dextrose. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal may be additionally included. In addition, the injection may in most cases additionally include isotonic agents such as sugars or sodium chloride.

[0088] For inhalation administration, the compounds used according to the present invention may conveniently be delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or another suitable gas. For pressurized aerosols, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, gelatin capsules and cartridges for use in inhalers or insufflators may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0089] The pharmaceutical composition of the present invention may be a pharmaceutical composition or a quasi-drug composition.

[0090] The term "quasi-drug" used in the present invention refers to products that have a milder effect than pharmaceutical products among products used for the purpose of diagnosing, treating, improving, alleviating, managing or preventing diseases of humans or animals. For example, according to the Pharmaceutical Affairs Act, quasi-drugs are products excluding products used for pharmaceutical purposes, and include products used for treating or preventing diseases of humans or animals, products that have a mild effect on the human body or do not act directly, etc.

[0091] The above-mentioned pharmaceutical composition of the present invention can be manufactured in a formulation selected from the group consisting of body cleanser, disinfectant, detergent, kitchen detergent, cleaning detergent, toothpaste, mouthwash, wet tissue, detergent, soap, hand wash, hair cleanser, hair softener, humidifier filler, mask, ointment, and filter filler, but is not limited thereto.

[0092] The composition of the present invention is administered in a pharmaceutically effective amount. A pharmaceutically effective amount refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level can be determined based on the type and severity of the patient's disease, the activity and sensitivity of the drug to the drug, the time of administration, the route of administration and excretion rate, the duration of treatment, concomitant drugs, and other factors well known in the medical field. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. That is, the total effective amount of the composition of the present invention can be administered to a patient as a single dose, or can be administered as a fractionated treatment protocol in which multiple doses are administered over a long period of time. It is important to consider all of the above factors and administer an amount that achieves the maximum effect with the minimum amount without causing side effects, and this can be easily determined by those skilled in the art.

[0093] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.

[0094] The composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

[0095] In addition, the third aspect of the present invention relates to a food or health functional food composition for preventing or improving cancer, comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0096] The composition and effect of the effective ingredient included in the health functional food composition for preventing or improving cancer of the present invention are the same as the composition and effect of the effective ingredient included in the pharmaceutical composition of the second aspect, and therefore, description thereof is omitted.

[0097] The term "food" used in the present invention includes meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health functional foods, and health foods, and includes all foods in the conventional sense.

[0098] The term "health functional food" used in the present invention means a food manufactured and processed using raw materials or ingredients having functionality useful to the human body according to Act No. 6727 on Health Functional Foods.

[0099] The food composition according to the present invention can be manufactured in various forms according to conventional methods known in the art. General foods include, but are not limited to, beverages (including alcoholic beverages), fruits and processed foods thereof (e.g., canned fruits, bottled fruits, jams, marmalades, etc.), fish, meats and processed foods thereof (e.g., ham, sausages, corned beef, etc.), breads and noodles (e.g., udon, buckwheat noodles, ramen, spagate, macaroni, etc.), fruit juices, various drinks, cookies, taffy, dairy products (e.g., butter, cheese, etc.), edible plant oils, margarine, vegetable proteins, retort foods, frozen foods, various seasonings (e.g., soybean paste, soy sauce, sauces, etc.), and the like. In addition, nutritional supplements include, but are not limited to, capsules, tablets, pills, and the like, and the like, and the like, and the like, may be manufactured by adding the compound of the present invention thereto. In addition, health functional foods are not limited to these, but for example, the compound of the present invention itself can be manufactured into the form of tea, juice, and drinks, and consumed by liquefying, granulating, encapsulating, or powdering so that it can be consumed as a health beverage. In addition, to use the compound of the present invention as a food additive, it can be manufactured into a powder or concentrate form and used.

[0100] When the compound of the present invention is used as a health beverage, the health beverage composition may contain various flavoring agents or natural carbohydrates as additional ingredients, similar to conventional beverages. The natural carbohydrates mentioned above may be monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, and erythritol. The sweetener may be a natural sweetener such as thaumatin and stevia extract; or a synthetic sweetener such as saccharin and aspartame. The proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g, per 100 mL of the composition of the present invention.

[0101] In addition, the compound of the present invention may be contained as an effective ingredient of a health functional food composition for preventing or improving cancer disease, and the amount thereof is not particularly limited to an amount effective to achieve the effect of preventing or improving cancer disease, but is preferably 0.01 to 100 wt% based on the total weight of the entire composition. The health functional food composition of the present invention may be prepared by mixing the compound with other active ingredients known to be effective against cancer-related diseases.

[0102] In addition to the above, the health functional food of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, or carbonating agents. In addition, the health functional food of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, or vegetable drinks. These ingredients may be used independently or in combination.

[0103] In addition, the fourth aspect of the present invention relates to a method for preventing, improving or treating cancer, comprising a step of administering the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0104] The term "subject" as used herein includes, but is not limited to, any animal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig, or rodent). This term does not indicate a specific age or gender. Therefore, it is intended to include all adults, whether female or male.

[0105] In addition, the fifth aspect of the present invention relates to a composition for use in preventing, improving or treating cancer, comprising the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0106] The above composition may be a pharmaceutical composition or a health functional food composition.

[0107] Furthermore, the sixth aspect of the present invention relates to the use of a composition comprising the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a drug or health functional food for the prevention, improvement, or treatment of cancer.

[0108] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0109] <Example 1>

[0110] 1. Synthesis of compounds

[0111] 1-1. Synthesis of compound H2-1-1 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isothiazole-3-carboxamide

[0112]

[0113] Step 1. Synthesis of ethyl 4-(5-isopropyl-2,4-dimethoxyphenyl)-2,4-dioxobutanoate (2)

[0114]

[0115] To a solution of 1-(5-isopropyl-2,4-dimethoxyphenyl)ethan-1-one (5.0 g, 0.02 mol) in THF (30 mL) were added NaH (1.2 g, 0.03 mol) and ethyl methyl oxalate (3.96 g, 0.03 mol) at 0°C. The reaction mixture was stirred at 60°C for 6 h. The reaction mixture was cooled, quenched with water (40 mL), and extracted with EA (40 mL*3). The combined organic layers were concentrated in vacuo to give compound 2 (5.6 g, 87% yield).

[0116] M / Z (ES+) [M+H] + =323.1

[0117] Step 2. Synthesis of ethyl 2-imino-4-(5-isopropyl-2,4-dimethoxyphenyl)-4-oxobutanoate (3)

[0118]

[0119] To a solution of ethyl 4-(5-isopropyl-2,4-dimethoxyphenyl)-2,4-dioxobutanoate (5.6 g, 0.017 mol) in toluene (50 mL) was added NH4OAC (2.1 g, 0.026 mol). The reaction mixture was stirred at 25°C for 10 h. The reaction mixture was washed with H2O (50 mL*3) and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 3 (5.0 g, 91% yield).

[0120] M / Z (ES+) [M+H] + =322.1

[0121] Step 3. Synthesis of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)isothiazole-3-carboxylate (4)

[0122]

[0123] To a solution of ethyl 2-imino-4-(5-isopropyl-2,4-dimethoxyphenyl)-4-oxobutanoate (3 g, 0.009 mol) in THF (30 mL) was added P2S5 (2.89 g, 0.013 mol). The reaction mixture was stirred at 60°C for 2 h. Then, H2O2 was added to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was washed with H2O (50 mL*3) and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 5:1) to give the title compound 4 (400 mg, 13% yield).

[0124] M / Z (ES+) [M+H] + =336.1

[0125] Step 4. Synthesis of ethyl 4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)isothiazole-3-carboxylate (5)

[0126]

[0127] To a solution of 5-(5-isopropyl-2,4-dimethoxyphenyl)isothiazole-3-carboxylate (400 mg, 1.19 mmol) in ACN (12 mL) were added NIS (403 mg, 1.79 mmol) and CAN (66 mg, 0.12 mmol). The reaction mixture was stirred at 70°C for 5 h. The reaction mixture was cooled and concentrated. The residue was purified by FCC (PE:EA = 5:1) to give the title compound 5 (240 mg, 43% yield).

[0128] M / Z (ES+) [M+H] + =462.0

[0129] Step 5. Synthesis of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-thiazole-3-carboxylate (7)

[0130]

[0131] A solution of 4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)isothiazole-3-carboxylate (180 mg, 0.02 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzyl)morpholine (177 mg, 0.03 mol), Pd(PPh3)4 (45 mg, 0.002 mmol) and Na2CO3 in dioxane / H2O (10.0 mL / 2.0 mL) was stirred at 90 °C for 10 h under N2. The reaction mixture was cooled, washed with H2O (50 mL*3) and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 7 (100 mg, 52% yield) as a yellow oil.

[0132] M / Z (ES+) [M+H] + =511.1

[0133] Step 6. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-(morpholinomethyl)phenyl)isothiazole-3-carboxamide (8)

[0134]

[0135] To a solution of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-thiazole-3-carboxylate (100 mg, 0.08 mmol) in EtOH (1 mL) was added EtNH2 (1 mL). The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled and concentrated in vacuo to obtain the crude compound, which was purified by FCC (DCM:MeOH=10:1) to give the title compound 8 (60 mg, 57% yield) as a colorless oil.

[0136] M / Z (ES+) [M+H] + =510.1

[0137] Step 7. Synthesis of 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isothiazole-3-carboxamide (H2-1-1)

[0138]

[0139] To a solution of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-thiazole-3-carboxamide (60 mg, 0.1 mmol) in DCM (4 mL) was added BBr3 (1 M in DCM) (294 mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude compound, which was purified by Prep-HPLC to give the title compound H2-1-1 (11.1 mg, 18% yield) as a yellow solid.

[0140] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J = 5.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.57 (s, 1H), 6.43 (s, 1H), 3.63-3.55 (m, 4H), 3.47 (s, 2H), 3.15-3.08 (m, 2H), 2.83 (dd, J = 13.7, 6.9 Hz, 1H), 2.40 (s, 4H), 0.97 (t, J = 7.2 Hz, 3H), 0.66 (d, J = 6.9 Hz, 6H).

[0141] M / Z (ES+) [M+H] + =482.2.

[0142] 1-2. Synthesis of compound H2-1-2 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxamide

[0143]

[0144] Step 1. Synthesis of methyl 4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxylate (2)

[0145]

[0146] To a solution of ethyl methyl 4-bromothiophene-3-carboxylate (4.0 g, 18.0 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (5.5 g, 18.0 mmol) and Na2CO3 (4.7 g, 45.0 mmol) in Tol / EtOH / H2O (20 mL / 10 mL / 5 mL) was added Pd(PPh3)4 (2079 mg, 1.8 mmol). The reaction mixture was stirred at 90 °C for 10 h under N2. The reaction mixture was cooled to room temperature, slowly poured onto ice, and extracted with EA (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 2 (2.8 g, 49% yield) as a white solid.

[0147] M / Z (ES+) [M+H] + =318.1.

[0148] Step 2. Synthesis of methyl 5-bromo-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxylate (3)

[0149]

[0150] To a solution of methyl 4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxylate (800 mg, 2.5 mmol) in DCM (30 mL) was added Br2 (480 mg, 3 mmol) at 25°C. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL*3). The combined organic layers were concentrated in vacuo. The residue was purified by FCC (PE:EA=4:1) to give compound 3 (200 mg, 20% yield).

[0151] 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.70 - 7.51 (m, 4H), 3.61 (s, 3H), 3.58 - 3.51 (m, 4H), 3.41 (d, J = 9.7 Hz, 2H), 2.34 - 2.32 (m, 4H).

[0152] M / Z (ES+) [M+H] + =396.0

[0153] Step 3. Synthesis of methyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxylate (4)

[0154]

[0155] To a solution of methyl 5-bromo-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxylate (100 mg, 0.25 mmol), (5-isopropyl-2,4-dimethoxyphenyl)boronic acid (57 mg, 0.25 mmol), and Na2CO3 (67 mg, 0.63 mmol) in Tol / EtOH / H2O (8 mL / 4 mL / 2 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol). The reaction mixture was stirred at 90 °C under N2 for 5 h. The reaction mixture was cooled, washed with H2O (20 mL*3), and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 2:1) to obtain the title compound 4 (70 mg, 56% yield).

[0156] M / Z (ES+) [M+H] + =496.2

[0157] Step 4. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxamide (5)

[0158]

[0159] A solution of methyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxylate (70 mg, 0.14 mmol) in EtOH / EtNH2 (2.0 mL / 2.0 mL) was stirred at 70°C for 5 h. The reaction mixture was cooled and concentrated. The residue was purified by FCC (PE:EA = 5:1) to give the title compound 5 (50 mg, 68% yield).

[0160] M / Z (ES+) [M+H] + =509.2.

[0161] Step 5. Synthesis of 6-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-5-(4-(morpholinomethyl)phenyl)thiophene-3-carboxamide (H2-1-2)

[0162]

[0163] To a solution of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-(morpholinomethyl)phenyl)thiophene-3-carboxamide (30 mg, 0.06 mmol) in DCM (4 mL) was added BBr3 (1 M in DCM) (1.8 mL, 1.8 mmol) at 0 °C. The reaction mixture was stirred at 45 °C for 10 h. The reaction mixture was concentrated in vacuo. The residue was then cooled to 0 °C, DCM (20 mL) was added, and the pH was adjusted to 8 with NaHCO3. H2O (50 mL) was added to the mixture and extracted twice with DCM (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by HPLC to give compound H2-1-2 (5.6 mg, 19.4% yield).

[0164] 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.25 (s, 1H), 7.84 (t, J = 5.6 Hz, 1H), 7.66 (s, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.37 (d, J = 15.7 Hz, 2H), 3.61-3.51 (m, 4H), 3.12-3.01 (m, 2H), 2.80 (dd, J = 26.1, 19.1 Hz, 1H), 2.33 (s, 4H), 0.93 (t, J) = 7.2 Hz, 3H), 0.75 (d, J = 6.9 Hz, 6H).

[0165] M / Z (ES+) [M+H] + =481.5.

[0166] 1-3. Synthesis of compound H2-1-3 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)furan-3-carboxamide

[0167]

[0168] Step 1. Synthesis of 1-isopropyl-2,4-dimethoxybenzene (2)

[0169]

[0170] To a solution of 4-isopropylbenzene-1,3-diol (6 g, 0.052 mol) in DMF (50 mL) was added NaH (4.5 g, 0.11 mol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. Then, CH3I (15.7 g, 0.11 mol) was added. The reaction mixture was stirred at 50°C for 3 h. The reaction mixture was cooled to room temperature and slowly poured onto ice. The reaction mixture was extracted with EA (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 2 (6.0 g, 64% yield) as a yellow oil.

[0171] M / Z (ES+) [M+H] + =181.1.

[0172] Step 2. Synthesis of 1-bromo-5-isopropyl-2,4-dimethoxybenzene (3)

[0173]

[0174] To a solution of 1-isopropyl-2,4-dimethoxybenzene (6.0 g, 0.03 mol) in DCM (30 mL) was added TBATB (16.8 g, 0.03 mol) at 25°C. The reaction mixture was stirred at 25°C for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL*3). The combined organic layers were concentrated in vacuo. The residue was purified by FCC to give compound 3 (5 g, 65% yield).

[0175] 1 H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 4.8 Hz, 1H), 6.74 - 6.68 (m, 1H), 3.84 (d, J = 7.2 Hz, 6H), 3.17 - 3.10 (m, 1H)), 1.13 - 1.10 (m, 6H).

[0176] M / Z (ES+) [M+H] + =259.1

[0177] Step 3. Synthesis of 1-iodo-5-isopropyl-2,4-dimethoxybenzene (4)

[0178]

[0179] To a solution of 1-bromo-5-isopropyl-2,4-dimethoxybenzene (5 g, 0.02 mol) in THF (50 mL) was added tBuLi (1.3 M, 17 mL, 0.022 mol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then, I2 (5.6 g, 0.022 mol) was added. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was cooled, washed with H2O (40 mL*3), and extracted with EA (40 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 4 (2 g, 32% yield).

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 6.64 (s, 1H), 3.83 (d, J = 1.2 Hz, 6H), 3.13 - 3.09 (m, 1H), 1.12 - 1.10 (m, 6H).

[0181] / *182M / Z (ES+) [M+H] + =307.1

[0182] Step 4. Synthesis of ((5-isopropyl-2,4-dimethoxyphenyl)ethynyl)trimethylsilane (5)

[0183]

[0184] A solution of TMSA (2.9 g, 29.3 mmol) in 1-iodo-5-isopropyl-2,4-dimethoxybenzene (2000 mg, 6.5 mmol), CuI (435 mg, 2.28 mmol), Pd(tBu3P)2 (455 mg, 0.65 mmol), TEA (1313 mg, 13 mmol), and toluene (40 mL) was stirred at 45 °C for 16 h under N2. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 5 (1300 mg, 72% yield).

[0185] M / Z (ES+) [M+H] + =277.2

[0186] Step 5. Synthesis of 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene (6)

[0187]

[0188] To a solution of ((5-isopropyl-2,4-dimethoxyphenyl)ethynyl)trimethylsilane (1300 mg, 4.6 mmol) in MeOH / CHCl3 (10 mL / 20 mL) was added aqueous NaOH (2 M, 3.5 mL, 6.9 mmol). The reaction mixture was concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 6 (800 mg, 85% yield).

[0189] M / Z (ES+) [M+H] + =205.2.

[0190] Step 6. Synthesis of ethyl (Z)-2-bromo-3-phenoxyacrylate (9)

[0191]

[0192] A solution of TiCl4 (5.2 g, 29.3 mmol) in ethyl 2-bromoacetate (3 g, 18.1 mmol), phenyl formate (2.2 g, 18.1 mmol), TEA (4.5 g, 45.3 mmol), and DCM (40 mL) was stirred at -40 °C for 2 h. The reaction mixture was washed with H2O (50 mL*3) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA=5:1) to give the title compound 9 (1.2 g, 72% yield).

[0193] M / Z (ES+) [M+H] + =271.1

[0194] Step 7. Synthesis of ethyl (E)-4-(5-isopropyl-2,4-dimethoxyphenyl)-2-(phenoxymethylene)but-3-ynoate (10)

[0195]

[0196] A solution of ethyl (Z)-2-bromo-3-phenoxyacrylate (800 mg, 3.9 mmol), Pd(PPh3)4 (225 mg, 0.195 mmol), and CuI (74 mg, 0.39 mmol) dissolved in TEA (20 mL) was stirred at 70°C for 6 h. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA=5:1) to give the title compound 10 (400 mg, 26% yield).

[0197] M / Z (ES+) [M+H] + =395.2

[0198] Step 8. Synthesis of ethyl (Z)-2-bromo-3-phenoxyacrylate (12)

[0199]

[0200] To a solution of ethyl (2E)-4-(5-isopropyl-2,4-dimethoxyphenyl)-2-(phenoxymethylidene)but-3-ynoate (240 mg, 0.6 mmol), 4-[(4-iodophenyl)methyl]morpholine (313 mg, 1.0 mmol), and cesium carbonate (594 mg, 1.8 mmol) in DMF (12 mL) was added Pd(PPh3)4 (35 mg, 0.03 mmol). The reaction mixture was stirred at 70 °C for 3 h. The resulting mixture was cooled, poured into water (100 mL), and extracted three times with EA (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4(S), filtered, and concentrated. The residue was purified by FCC (PE / EA = 4:1) to obtain the title compound 12 (150 mg, 24% yield) as a yellow solid.

[0201] M / Z (ES+) [M+H] + =494.1

[0202] Step 9. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-(morpholinomethyl)phenyl)furan-3-carboxamide (13)

[0203]

[0204] To a solution of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]furan-3-carboxylate (150 mg, 0.3 mmol) in ETOH (1 mL) was added ETNH2 (1 mL). The reaction mixture was stirred at 65 °C for 12 h. The solution was cooled, concentrated in vacuo, and purified by FCC (FE:EA = 1:4) to give compound 13 (100 mg, 66% yield) as a colorless oil.

[0205] M / Z (ES+) [M+H] + =493.0.

[0206] Step 10. Synthesis of 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)furan-3-carboxamide)(H2-1-3)

[0207]

[0208] To a solution of N-ethyl-6-(5-isopropyl-2,4-dimethoxyphenyl)-5-[4-(morpholin-4-ylmethyl)phenyl]pyrimidine-4-carboxamide (90 mg, 0.18 mmol) in DCM (5 mL) was added BBr3 (1 M in DCM) (1.8 mL, 1.8 mmol) at 0 °C. The reaction mixture was stirred at 45 °C for 10 h. The reaction mixture was cooled and concentrated in vacuo. The residue was cooled to 0 °C, DCM (20 mL) was added, the pH was adjusted to 8 with NaHCO3, H2O (50 mL) was added, and the mixture was extracted twice with DCM (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by HPLC to obtain compound H2-1-3 (7.9 mg, 8.8% yield).

[0209] 1 H NMR (400 MHz, DMSO-d6) 11.32 (s, 1H), 9.71 (s, 1H), 9.12 (d, J = 4.6 Hz, 1H), 8.38 (t, J = 5.7 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 21.1 Hz, 1H), 6.27 (s, 1H), 3.61-3.52 (m, 4H), 3.43 (s, 2H), 3.03-2.95 (m, 2H), 2.83 (dt, J = 13.6, 6.8 Hz, 1H), 2.35 (s, 4H), 0.79-0.71 (m, 9H).

[0210] M / Z (ES+) [M+H] + =465.2.

[0211] 1-4. Synthesis of compound H2-1-4 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-1-methyl-4-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide

[0212]

[0213] Step 1. Synthesis of 1-isopropyl-2,4-dimethoxybenzene (2)

[0214]

[0215] To a solution of 4-isopropylbenzene-1,3-diol (15.0 g, 0.10 mol) and K2CO3 (40.9 g, 0.49 mol) in acetone (200 mL) was added CH3I (70.0 g, 0.30 mol). The reaction mixture was stirred at 40°C for 48 h. The reaction mixture was cooled, filtered, and concentrated. The residue was purified by HPLC (H2O / ACN) to give the title compound 2 (14.0 g, 75% yield) as a yellow solid.

[0216] M / Z (ES+) [M+H] + =181.2.

[0217] Step 2. Synthesis of 1-bromo-5-isopropyl-2,4-dimethoxybenzene (3)

[0218]

[0219] A solution of 1-isopropyl-2,4-dimethoxybenzene (14.0 g, 0.08 mol) and NBS (15.5 g, 0.09 mol) dissolved in DCM (200 mL) was stirred at 20 °C for 3 h. The reaction mixture was extracted with DCM (200 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 3:1) to give compound 3 (16.8 g, 79% yield) as a yellow solid.

[0220] M / Z (ES+) [M+H] + =259.1

[0221] Step 3. Synthesis of (5-isopropyl-2,4-dimethoxyphenyl)boronic acid (4)

[0222]

[0223] To a solution of 1-bromo-5-isopropyl-2,4-dimethoxybenzene (16.8 g, 0.065 mol) in THF (500 mL) was added n-BuLi (0.036 L, 0.091 mol) under nitrogen at -78 °C. The reaction mixture was stirred at 78 °C for 1 h. Then, triisopropyl borate (36.8 g, 0.194 mol) was stirred at 25 °C for 4 h. The reaction mixture was quenched with water (800 mL) and extracted with EA (500 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 2:1) to give the title compound 4 (14.8 g, 96% yield) as a white solid.

[0224] M / Z (ES+) [M+H] + =225.1

[0225] Step 4. Synthesis of 5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylate (5)

[0226]

[0227] To a solution of (5-isopropyl-2,4-dimethoxyphenyl)boronic acid (500 mg, 2.23 mmol), methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (488.8 mg, 2.23 mmol), and Na2CO3 (473.1 mg, 4.46 mmol) in dioxane / H2O (10.0 mL / 2.0 mL) was added Pd(PPh3)4 (257.9 mg, 0.22 mmol). The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 2:1) to obtain the title compound 5 (200 mg, 40% yield) as a yellow solid.

[0228] M / Z (ES+) [M+H] + =319.2

[0229] Step 5. Synthesis of methyl 4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylate (6)

[0230]

[0231] To a solution of methyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylate (160 mg, 0.50 mmol) and NIS (147 mg, 0.65 mmol) in ACN (10.0 mL) was added ceric ammonium nitrate (2.8 mg, 0.005 mmol). The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was cooled and concentrated in vacuo to obtain the crude compound, which was purified by FCC (PE:EA = 3:1) to give the title compound 6 (120 mg, 48% yield) as a brown solid.

[0232] M / Z (ES+) [M+H] + =445.0.

[0233] Step 6. Synthesis of methyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-4-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxylate (7)

[0234]

[0235] A solution of methyl 4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-1H-pyrazole-3-carboxylate (108 mg, 0.24 mmol), 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine (88.5 mg, 0.29 mmol), Pd(PPh3)4 (28.1 mg, 0.024 mmol) and Na2CO3 (51.5 mg 0.49 mmol) in dioxane / H2O (10.0 mL / 2.0 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was cooled and extracted with EA (30 mL*3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 1:1) to obtain compound 7 (120 mg, 90% yield) as a yellow oil.

[0236] M / Z (ES+) [M+H] + =494.3.

[0237] Step 7. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-4-(4-(morpholinomethyl)phenyl)-1-pyrazole-3-carboxamide (8)

[0238]

[0239] A solution of methyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-4-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxylate (120 mg, 0.24 mmol) in MeOH / EtNH2 (2 mL / 2 mL) was stirred at 60 °C for 12 h. The reaction mixture was cooled and concentrated. The residue was purified by FCC (PE:EA = 1:1) to give the title compound 8 (60 mg, 46% yield) as a yellow oil.

[0240] M / Z (ES+) [M+H] + =507.3.

[0241] Step 8. Synthesis of 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-1-methyl-4-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide)(H2-1-4)

[0242]

[0243] To a solution of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-1-methyl-4-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide (30 mg, 0.06 mmol) in DCM (3 mL) was added BBr3 (1 M in DCM) (0.6 mL, 0.6 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was cooled to 0 °C, DCM (20 mL) was added, the pH was adjusted to 8 with NaHCO3, H2O (50 mL) was added, and the mixture was extracted twice with DCM (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by HPLC to give H2-1-4 (10.4 mg, 36% yield) as a white solid.

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.43 (s, 1H), 7.99 (t, J = 5.9 Hz, 1H), 7.11-7.00 (m, 4H), 6.44 (d, J = 4.5 Hz, 2H), 3.67 (s, 3H), 3.52 (dd, J = 12.8, 8.3 Hz, 4H), 3.36 (s, 2H), 3.19 (qd, J = 7.2, 3.7 Hz, 2H), 2.91 (dq, J = 13.7, 6.9 Hz, 1H), 2.31 (d, J = 12.0 Hz, 4H), 1.06 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H).

[0245] M / Z (ES+) [M+H] + =479.3.

[0246] 1-5. Synthesis of compound H2-1-5 4-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-3-(4-(morpholinomethyl)phenyl)picolinamide

[0247]

[0248] Step 1. Synthesis of 3-bromo-4-chloropyridine 1-oxide (2)

[0249]

[0250] A mixture of 3-bromo-4-nitropyridine 1-oxide (2 g, 9.18 mmol) in HCl (4 M in CH3OH) (20 mL) was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3. The mixture was concentrated and diluted with water. The aqueous layer was extracted with DCM (40 mL*3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness in a vacuum blow at 40 °C. The residue was purified by flash column chromatography (40 g silica gel, eluting with CH3OH in DCM from 20% to 30%) to give compound 2 (1.5 g, 79%) as a white solid.

[0251] M / Z (ES+) [M+H] + =208

[0252] 1 H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 7.0, 2.0 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H)

[0253] Step 2. Synthesis of 3-bromo-4-chloropicolinonitrile (3)

[0254]

[0255] A solution of 3-bromo-4-chloropyridine 1-oxide (1.9 g, 9.18 mmol), TMSCN (3.64 g, 36.69 mmol), and TEA (3.25 g, 32.12 mmol) in ACN (9 mL) was stirred at 80°C for 5 h. The reaction mixture was quenched with saturated aqueous NaHCO3. The mixture was concentrated and diluted with water. The aqueous layer was extracted with DCM (40 mL*3). The combined organic layers were washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (40 g silica gel, eluted with EtOAc in petroleum ether from 10% to 15%) to give compound 3 (1.7 g, 85%) as a white solid.

[0256] M / Z (ES+) [M+H] + =217

[0257] 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.1 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H)

[0258] Step 3. Synthesis of 4-chloro-3-(4-(morpholinomethyl)phenyl)picolinonitrile (5)

[0259]

[0260] A mixture of 3-bromo-4-chloropicorinonitrile (500 mg, 2.32 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (800 mg, 2.64 mmol), Pd(dppf)Cl2 (338 mg, 0.46 mmol) and Na2CO3 (736 mg, 6.94 mmol) in dioxane (20 mL) was stirred at 100 °C for 4 h under N2. N2. The reaction mixture was cooled and diluted with water. The aqueous layer was extracted with DCM (15 mL*3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (12 g silica gel, eluted from 0 to 15% with CH3OH in DCM) to give compound 5 (620 mg, 85%) as a yellow solid.

[0261] M / Z (ES+) [M+H] + =314

[0262] 1 H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.40-7.34 (m, 2H), 3.79-3.70 (m, 4H), 3.59 (s, 2H), 2.50 (s, 4H)

[0263] Step 4. Synthesis of 4-(5-isopropyl-2,4-dimethoxyphenyl)-3-(4-(morpholinomethyl)phenyl)picolinonitrile (7)

[0264]

[0265] A solution of 4-chloro-3-(4-(morpholinomethyl)phenyl)picorinonitrile (580 mg, 1.85 mmol), (5-isopropyl-2,4-dimethoxyphenyl)boronic acid (540 mg, 2.41 mmol), Pd(OAc)2 (83 mg, 0.37 mmol), CataCXium A (99 mg, 0.28 mmol) and a mixture of Cs2CO3 (1200 mg, 3.68 mmol) in toluene (17 mL) and H2O (1.5 mL) and H2O (1.5 mL) was stirred at 100 °C for 4 h under N2. The reaction mixture was cooled and diluted with water. The aqueous layer was extracted with DCM (15 mL*3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (12 g silica gel, eluted from 0 to 15% with CH3OH in DCM) to give compound 7 (400 mg, 47%) as a yellow solid.

[0266] M / Z (ES+) [M+H] + =458

[0267] 1 H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 5.0 Hz, 1H), 7.56 (d, J = 5.0 Hz, 1H), 7.29 - 7.27 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.64 (s, 1H), 6.30 (s, 1H), 3.81 (s, 3H), 3.72-3.69 (m, 4H), 3.57 (s, 3H), 3.48-3.46 (m, 2H), 3.09-3.07 (m, 1H), 2.44-2.41 (m, 4H), 0.94 (d, J = 6.9 Hz, 6H).

[0268] Step 5. Synthesis of 4-(5-isopropyl-2,4-dimethoxyphenyl)-3-(4-(morpholinomethyl)phenyl)picolinic acid (8)

[0269]

[0270] A mixture of 4-(5-isopropyl-2,4-dimethoxyphenyl)-3-(4-(morpholinomethyl)phenyl) picorinonitrile (350 mg, 0.77 mmol) and 5 M NaOH (14 mL) in CH3OH (14 mL) was stirred at 90 °C for 10 h. The reaction mixture was cooled, acidified, and pH 2-3 was adjusted with 2 M HCl. The mixture was diluted with water and extracted with EtOAc (10 mL*3). The aqueous layer was concentrated to dryness in vacuo. DCM was added to the residue, and the mixture was filtered through Celite. The filtrate was concentrated in vacuo to give compound 8 (590 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0271] M / Z (ES+) [M+H] + =477

[0272] Step 6. Synthesis of N-ethyl-4-(5-isopropyl-2,4-dimethoxyphenyl)-3-(4-(-morpholinomethyl)phenyl)picolinamide (9)

[0273]

[0274] To a mixture of 4-(5-isopropyl-2,4-dimethoxyphenyl)-3-[4-(morpholin-4-ylmethyl)phenyl]pyridine-2-carboxylic acid (590 mg, 1.24 mmol) and ethanamine (84 mg, 1.86 mmol) in DMF (10 mL) were added DIEA (480 mg, 3.71 mmol) and HATU (706 mg, 1.76 mmol) at 20 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (30 g silica gel, eluting with MeOH in CH2Cl2 from 0 to 5%) to give compound 9 (410 mg, 66%) as a gray solid.

[0275] M / Z (ES+) [M+H] + =504.3

[0276] 1 H NMR (400 MHz, CDCl3) δ 8.59-8.54 (m, 1H), 7.93 (s, 1H), 7.43 (d, J = 4.8 Hz, 1H), 7.25-7.21 (m, 1H), 7.12 (d, J = 8.1 Hz, 2H), 6.56 (s, 1H), 6.25 (s, 1H), 4.10 (dd, J = 20.2, 13.1 Hz, 2H), 3.95-3.93 (m, 4H), 3.77 (s, 3H), 3.63 (s, 3H), 3.34 (dd, J = 7.2, 6.0 Hz, 2H), 3.10-3.02 (m, 1H), 2.84 (d, J = 32.0 Hz, 4H), 1.19 (t, J = 7.3 Hz, 3H), 0.96 (t, J = 12.5 Hz, 6H).

[0277] Step 7. Synthesis of 4-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-3-(4-(morpholinomethyl)phenyl)picolinamide (H2-1-5)

[0278]

[0279] CH2Cl2(5mL) To a solution of N-ethyl-4-(5-isopropyl-2,4-dimethoxyphenyl)-3-[4-(morpholin-4-ylmethyl)phenyl]pyridine-2-carboxamide (100 mg, 0.2 mmol) was added BBr3 (0.2 mL, 0.2 mmol) at 0 °C. The resulting mixture was warmed to 20 °C and stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (10 mL) and adjusted to pH = 7 with aq. NaHCO3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xbridge 5u C18 150 x 19 mm; Mobile phase: ACN-H2O (0.1% FA); Gradient: 15% ACN to 100% ACN; Flow rate: 20 mL / min) to give compound H2-1-5 (29 mg, 30.7%) as a white solid.

[0280] M / Z (ES+) [M+H] + =476.2

[0281] 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.14 (s, 1H), 8.44 (d, J = 5.1 Hz, 1H), 8.23 ​​(s, 1H), 7.44 (d, J = 5.0 Hz, 1H), 7.16-6.93 (m, 4H), 6.31 (s, 1H), 6.25 (s, 1H), 3.46 (br s, 4H), 3.05-2.97 (m, 2H), 2.87-2.79 (m, 1H), 2.34-2.19 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H), 0.76 (d, J = 6.8 Hz, 6H)

[0282] 1-6. Synthesis of compound H2-1-6 6-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-5-(4-(morpholinomethyl)phenyl)pyrimidine-4-carboxamide

[0283]

[0284] Step 1. Synthesis of ethyl 5-chloro-6-hydroxypyrimidine-4-carboxylate (2)

[0285]

[0286] To a solution of ethyl 6-hydroxypyrimidine-4-carboxylate (5.0 g, 0.03 mol) in DMF (30 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (4.6 g, 0.02 mol). The reaction mixture was stirred at 25°C for 5 h. The reaction mixture was cooled to room temperature and slowly poured onto ice. The mixture was extracted with EA (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 2 (5.0 g, 83% yield) as a yellow oil.

[0287] M / Z (ES+) [M+H] + =203.1.

[0288] Step 2. Synthesis of ethyl 5,6-dichloropyrimidine-4-carboxylate (3)

[0289]

[0290] To a solution of ethyl 5-chloro-6-hydroxypyrimidine-4-carboxylate (5.0 g, 0.02 mol) in DMF (30 mL) was added thionyl chloride (3.8 g, 0.03 mol) at 0°C. The reaction mixture was stirred at 25°C for 5 h. The reaction mixture was cooled, quenched with water (30 mL), and extracted with EA (30 mL*3). The combined organic layers were concentrated in vacuo. The residue was purified by FCC (PE:EA=4:1) to give compound 3 (3.5 g, 57% yield).

[0291] M / Z (ES+) [M+H] + =221.1

[0292] Step 3. Synthesis of 5-chloro-6-(5-isopropyl-2,4-dimethoxyphenyl)pyrimidine-4-carboxylate (4)

[0293]

[0294] To a solution of ethyl 5-chloro-6-hydroxypyrimidine-4-carboxylate (3.0 g, 15.0 mmol), (5-isopropyl-2,4-dimethoxyphenyl)borandiol (3.6 g, 15.0 mmol), and Na2CO3 (3.9 g, 36.0 mmol) in Tol / EtOH / H2O (15 mL / 5.0 mL / 2.5 mL) was added Pd(PPh3)4 (1710 mg, 1.5 mmol). The reaction mixture was stirred at 90 °C under N2 for 10 h. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA=3:1) to obtain the title compound 4 (900 mg, 18% yield).

[0295] M / Z (ES+) [M+H] + =365.1

[0296] Step 4. Synthesis of ethyl 6-(5-isopropyl-2,4-dimethoxyphenyl)-5-(4-(morpholinomethyl)phenyl)pyrimidine-4-carboxylate (5)

[0297]

[0298] To a solution of ethyl 5-chloro-6-(5-isopropyl-2,4-dimethoxyphenyl)pyrimidine-4-carboxylate (675 mg, 1.8 mmol), 4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine (839 mg, 2.7 mmol) and Cs2CO3 (1500 mg, 4.5 mmol) in dioxane / H2O (10 mL / 20 mL) was added NHC-Pd (119 mg, 0.18 mmol). The reaction mixture was stirred at 100 °C under N2 for 5 h. The reaction mixture was cooled, washed with H2O (50 mL*3) and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 3:1) to obtain the title compound 5 (180 mg, 17% yield).

[0299] M / Z (ES+) [M+H] + =506.1

[0300] Step 5. Synthesis of N-ethyl-6-(5-isopropyl-2,4-dimethoxyphenyl)-5-(4-(morpholinomethyl)phenyl)pyrimidine-4-carboxamide (6)

[0301]

[0302] A solution of ethyl 6-(5-isopropyl-2,4-dimethoxyphenyl)-5-[4-(morpholin-4-ylmethyl)phenyl]pyrimidine-4-carboxylate (180 mg, 0.36 mmol) in EtOH / EtNH2 (2.0 mL / 2.0 mL) was stirred at 70°C for 5 h. The reaction mixture was cooled and concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 6 (90 mg, 45% yield) as a yellow oil.

[0303] M / Z (ES+) [M+H] + =505.0.

[0304] Step 6. Synthesis of 6-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-5-(4-(morpholinomethyl)phenyl)pyrimidine-4-carboxamide (H2-1-6)

[0305]

[0306] To a solution of N-ethyl-6-(5-isopropyl-2,4-dimethoxyphenyl)-5-[4-(morpholin-4-ylmethyl)phenyl]pyrimidine-4-carboxamide (90 mg, 0.18 mmol) in DCM (5 mL) was added BBr3 (1 M in DCM) (1.8 mL, 1.8 mmol) at 0 °C. The reaction mixture was stirred at 45 °C for 10 h. The reaction mixture was concentrated in vacuo. The residue was cooled to 0 °C, DCM (20 mL) was added, the pH was adjusted to 8 with NaHCO3, H2O (50 mL) was added, and the mixture was extracted twice with DCM (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by HPLC to obtain H2-1-6 (7.9 mg, 8.8% yield).

[0307] 1H NMR (400 MHz, DMSO-d6) 11.32 (s, 1H), 9.71 (s, 1H), 9.12 (d, J = 4.6 Hz, 1H), 8.38 (t, J = 5.7 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 21.1 Hz, 1H), 6.27 (s, 1H), 3.61-3.52 (m, 4H), 3.43 (s, 2H), 3.03-2.95 (m, 2H), 2.83 (dt, J = 13.6, 6.8 Hz, 1H), 2.35 (s, 4H), 0.79-0.71 (m, 9H).

[0308] M / Z (ES+) [M+H] + =477.2.

[0309] 1-7. Synthesis of compound H2-2-1 5-benzyl-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide

[0310]

[0311] Step 1. Synthesis of ethyl 5-(acetoxymethyl)isoxazole-3-carboxylate (2)

[0312]

[0313] To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (3.5 g, 0.02 mol) in DCM (40 mL) at 0 °C were added DIEA (5.27 g, 0.04 mol), AC2O (2.29 g, 0.02 mol), and DMAP (0.25 g, 0.002 mol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched with water (50 mL) and extracted with EA (50 mL*3). The combined organic layers were concentrated in vacuo. The residue was purified by FCC to give compound 2 (3.6 g, 84% yield) as a colorless oil.

[0314] M / Z (ES+) [M+H] + =214.2.

[0315] Step 2. Synthesis of ethyl 5-(acetoxymethyl)-4-iodoisoxazole-3-carboxylate (3)

[0316]

[0317] To a solution of ethyl 5-(acetoxymethyl)isoxazole-3-carboxylate (3.6 g, 0.01 mol) in TFA (15 mL) was added NIS (7.59 g, 0.02 mol). The reaction mixture was stirred at 65°C for 12 h. The reaction mixture was cooled and evaporated. The residue was added to ice water (50 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with sat. NaHCO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE / EA = 1 / 1) to give the title compound 3 (4.0 g, 70% yield) as a yellow oil.

[0318] M / Z (ES+) [M+H] + =339.1

[0319] Step 3. Synthesis of ethyl 5-(acetoxymethyl)-4-(4-morpholinomethyl)phenyl)isoxazole-3-carboxylate (4)

[0320]

[0321] Ethyl 5-(acetoxymethyl)-4-iodoisoxazole-3-carboxylate (2.5 g, 0.0074 mol), 4-4-{[4-4-(4-4,4-4,5-5,5-5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine (3.37 g, 0.01 mmol), Pd(PPh3)Cl2 (0.52 g, 0.001 mol), and Na2CO3 (1.57 g, 0.017 mol) in dioxane / H2O (25 mL / 5 mL) were stirred at 90 °C under N2 for 6 h. The reaction mixture was cooled, H2O (50 mL) was added, and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA=1:1) to give the title compound 4 (2.0 g, 62.0% yield) as a yellow oil.

[0322] M / Z (ES+) [M+H] + =389.4

[0323] Step 4. Synthesis of N-ethyl-5-(hydroxymethyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (5)

[0324]

[0325] To a solution of ethyl 5-(acetoxymethyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxylate (1.0 g, 0.003 mol) in EtOH (3 mL) was added ethanamine (3 mL). The reaction mixture was stirred at 70°C for 3 h under sealed tube conditions. The reaction mixture was cooled and concentrated. The residue was purified by FCC (DCM:MeOH=20:1) to give the title compound 5 (900 mg, 85% yield) as a pale yellow oil.

[0326] M / Z (ES+) [M+H] + =346.4

[0327] Step 5. Synthesis of 5-(bromomethyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamid (6)

[0328]

[0329] To a solution of N-ethyl-5-(hydroxymethyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (850 mg, 2.46 mmol) in DCM (30 mL) were added triphenyl phosphine (1.29 g, 4.92 mmol) and CBr4 (1.63 g, 4.92 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to obtain the crude compound, which was purified by FCC (PE:EA= 1:1) to give the title compound 6 (600 mg, 60.1% yield) as a yellow solid.

[0330] M / Z (ES+) [M+H] + =408.3.

[0331] Step 6. 5-Benzyl-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(H2-2-1)

[0332]

[0333] M / Z (ES+) [M+H] + =406.2.

[0334] A solution of 5-(bromomethyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (100 mg, 0.27 mmol), phenylboronic acid (50.2 mg, 0.41 mmol), Na2CO3 (58.26 mg, 0.54 mmol), and Pd(PPh3)4 (31.3 mg, 0.02 mmol) in dioxane / H2O (10 mL / 2 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was cooled, H2O (50 mL) was added, and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was subjected to Prep-HPLC to obtain the title compound H2-2-1 (6.6 mg, 5.82% yield) as a white solid.

[0335] 1 H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.32-7.15 (m, 5H), 7.14-7.07 (m, 2H), 4.14 (s, 2H), 3.72-3.65 (m, 4H), 3.62 (s, 2H), 2.68-2.38 (m, 4H), 1.13 (t, J = 7.3 Hz, 3H).

[0336] 1-8. Synthesis of compound H2-2-3 N-ethyl-5-(2-hydroxybenzyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide

[0337]

[0338] Step 1. Synthesis of N-ethyl-5-(2-hydroxybenzyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (H2-2-3)

[0339]

[0340] 5-(Bromomethyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide (50 mg, 0.12 mmol), 2-hydroxyphenyl)boronic acid (24.1 mg, 0.18 mmol), Na2CO3 (25.4 mg, 0.24 mmol) Pd(PPh3)4 (13.86 mg, 0.012 mmol) in dioxane / H2O (10 mL / 2 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was cooled, H2O (50 mL) was added, and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was subjected to prep-HPLC to give the title compound H2-2-3 (7.6 mg, 14.1% yield) as a white solid.

[0341] M / Z (ES+) [M+H] + =422.2.

[0342] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.32-7.15 (m, 5H), 7.14-7.07 (m, 2H), 4.14 (s, 2H), 3.72-3.65 (m, 4H), 3.62 (s, 2H), 3.30 (dd, J = 9.7, 4.5 Hz, 2H), 2.68-2.38 (m, 4H), 1.13 (t, J = 7.3 Hz, 3H).

[0343] 1-9. Synthesis of compound H2-2-4 N-ethyl-4-(4-(morpholinomethyl)phenyl)-5-(phenylamino)isoxazole-3-carboxamide

[0344]

[0345] Step 1. Synthesis of methylidyne(phenyl)-l4-azane(2)

[0346]

[0347] To a solution of N-phenylformamide (5.0 g, 0.04 mol) in DCM (120 mL) were added TEA (14.0 g, 0.13 mol) and POCl3 (7.0 g, 0.04 mol) at 0°C. The reaction mixture was stirred at 25°C for 1 h. Then, the reaction mixture was cooled to 0°C, pH adjusted to 7 with NaHCO3, and extracted with DCM (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 2 (3.6 g, 87% yield) as a yellow oil.

[0348] Step 2. Synthesis of ethyl (E)-3-bromo-2-(hydroxyimino)propanoate (4)

[0349]

[0350] To a solution of ethyl 3-bromo-2-oxopropanoate (10 g, 0.05 mol) in H2O (10 mL) / CHCl3 (10 mL) was added NH2OH·HCl (in 10 mL of H2O) at 20°C. The reaction mixture was stirred at 20°C for 12 h. The reaction mixture was extracted with DCM (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 2 (7.5 g, 48% yield) as a colorless oil.

[0351] Step 3. Synthesis of ethyl 5-(phenylamino)isoxazole-3-carboxylate (5)

[0352]

[0353] A solution of methylidyne(phenyl)-14-azane (3.6 g, 0.03 mol), ethyl (E)-3-bromo-2-(hydroxyimino)propanoate (7.2 g, 0.03 mol) in DCM (100 mL) and Na2CO3 (9.1 g, 0.09 mol) in DCM (100 mL) was stirred at 25°C for 12 h. The reaction mixture was extracted with DCM (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by FCC (PE:EA= 1:1) to give compound 5 (1.1 g, 13% yield) as a yellow solid.

[0354] M / Z (ES+) [M+H] + =233.1

[0355] Step 4. Synthesis of ethyl 4-bromo-5-(phenylamino)isoxazole-3-carboxylate (6)

[0356]

[0357] A solution of ethyl 5-(phenylamino)isoxazole-3-carboxylate (400 mg, 1.7 mmol) and NBS (245 mg, 1.2 mmol) in ACOH / DCM (3 mL / 3 mL) was stirred at 25 °C for 12 h. The reaction mixture was extracted with DCM (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 1:1) to give compound 6 (300 mg, 56% yield) as a yellow solid.

[0358] / *359M / Z (ES+) [M+H]+=311.1 / 313.1

[0359] Step 5. Synthesis of ethyl 4-(4-(morpholinomethyl)phenyl)-5-(phenylamino)isoxazole-3-carboxylate (8)

[0360]

[0361] A solution of ethyl 4-bromo-5-(phenylamino)isoxazole-3-carboxylate (150 mg, 0.48 mmol), (4-(morpholinomethyl)phenyl)boronic acid (139 mg, 0.63 mmol), Pd(PPh3)4, and CS2CO3 (394 mg, 1.2 mmol) in dioxane / H2O (5.0 mL / 1.0 mL) was stirred at 100 °C for 6 h. The reaction mixture was cooled and extracted with DCM (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 1:1) to give compound 8 (80 mg, 40% yield) as a yellow solid.

[0362] M / Z (ES+) [M+H] + =408.0.

[0363] Step 6. Synthesis of N-ethyl-4-(4-(morpholinomethyl)phenyl)-5-(phenylamino)isoxazole-3-carboxamide (H2-2-4)

[0364]

[0365] A solution of ethyl 4-[4-(morpholin-4-ylmethyl)phenyl]-5-(phenylamino)-1,2-oxazole-3-carboxylate (80 mg, 0.2 mmol) and EtNH2 (1.0 mL, 1 M in MeOH) in EtOH (3 mL) was stirred in a sealed tube at 60 °C for 12 h. The reaction mixture was cooled, concentrated in vacuo, and purified by Prep-HPLC to give H2-2-4 (7.0 mg, 10%) as a white solid.

[0366] 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.78 (t, J = 5.6 Hz, 1H), 7.35-7.19 (m, 6H), 7.08 (dd, J = 8.6, 1.0 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 3.59-3.54 (m, 4H), 3.43 (s, 2H), 3.25-3.17 (m, 2H), 2.34 (s, 4H), 1.06 (t, J = 7.2 Hz, 3H).

[0367] M / Z (ES+) [M+H] + =407.2.

[0368] 1-10. Synthesis of compound 1H2-2-5 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(dimethylamino)benzyl)-N-ethylisoxazole-3-carboxamide

[0369]

[0370] Step 1. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-nitrobenzyl)isoxazole-3-carboxamide (2)

[0371]

[0372] A solution of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (100 mg, 0.22 mmol), 4-(bromomethyl)benzamide (72.93 mg, 0.33 mmol), Pd(PPh3)4 (52.02 mg, 0.04 mmol) and Na2CO3 (47.22 mg, 0.45 mmol) in dioxane / H2O (10.0 mL / 2.0 mL) was The solution was stirred at 100°C under N2 for 6 h. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA=1:4) to give the title compound 2 (50 mg, 44.07% yield) as a colorless oil.

[0373] M / Z (ES+) [M+H] + =454.5.

[0374] Step 2. Synthesis of 4-(4-aminobenzyl)-N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (3)

[0375]

[0376] A solution of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4-nitrobenzyl)isoxazole-3-carboxamide (50 mg, 0.11 mol) and Pd / C (5%) (10 mg, 10%) in EtOAc (8 mL) was stirred at 25 °C for 1 h under H2 gas balon conditions. The reaction mixture was filtered and concentrated. The residue was used directly in the next step as a colorless oil without purification (45 mg, 86.6% yield).

[0377] M / Z (ES+) [M+H] + =424.2

[0378] Step 3. Synthesis of 4-(4-(dimethylamino)benzyl)-N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (4)

[0379]

[0380] To a solution of 4-(4-aminobenzyl)-N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (45 mg, 0.10 mol) in THF (2 mL) was added HCHO (35%) in H2O (15.95 mg, 0.53 mmol) and AcOH (31.92 mg, 0.53 mmol) at 0°C. The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was cooled to 0°C, NaCNBH3 (20.04 mg, 0.31 mmol) was added, and stirred at 20°C for 3 h. Then, H2O (20 mL) was added to the reaction mixture and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound 4 (35 mg, (73.06% yield) was obtained as a colorless oil.

[0381] M / Z (ES+) [M+H] + =452.1

[0382] Step 4. Synthesis of 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(dimethylamino)benzyl)-N-ethylisoxazole-3-carboxamide)(H2-2-5)

[0383]

[0384] To a solution of 4-(4-(dimethylamino)benzyl)-N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (35 mg, 0.07 mmol) in DCM (5 mL) at 0 °C was added BBr3 (1 M in DCM) (0.7 mL, 1.7 mmol). The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was concentrated in vacuo. The residue was cooled to 0 °C, DCM (20 mL) was added, the pH was adjusted to 8 with NaHCO3, H2O (50 mL) was added, and the mixture was extracted twice with DCM (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by Prep-HPLC to obtain compound H2-2-5 (9.3 mg, 32.38% yield).

[0385] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (d, J = 6.8 Hz, 2H), 8.63 (s, 1H), 6.84 (d, J = 10.4 Hz, 3H), 6.57 (s, 1H), 6.50 (s, 1H), 3.84 (s, 2H), 3.25-3.18 (m, 2H), 3.05 (dt, J = 13.6, 6.9 Hz, 1H), 2.80 (s, 6H), 1.05 (dd, J = 8.6, 7.1 Hz, 9H).

[0386] M / Z (ES+) [M+H] + =424.2.

[0387] 1-11. Synthesis of compound H2-2-6 4-(4-carbamoylbenzyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethylisoxazole-3-carboxamide

[0388]

[0389] Step 1. Synthesis of 1-(2,4-dihydroxy-5-isopropylphenyl)ethan-1-one (2)

[0390]

[0391] To a solution of 4-isopropylbenzene-1,3-diol (10 g, 0.06 mol) in boron trifluoride etherate (50 mL) was added AcOH (4.3 g, 0.07 mol). The reaction mixture was stirred at 80°C for 4 h. The reaction mixture was cooled, quenched with water (100 mL), and extracted with EA (100 mL*3). The combined organic layers were concentrated in vacuo. The residue was purified by FCC to give compound 2 (13.0 g, 91% yield) as a yellow solid.

[0392] M / Z (ES+) [M+H] + =195.1.

[0393] Step 2. Synthesis of 1-(5-isopropyl-2,4-dimethoxyphenyl)ethan-1-one (3)

[0394]

[0395] To a solution of cesium carbonate (12 g, 0.03 mol) in 1-(2,4-dihydroxy-5-isopropylphenyl)ethanone (3.0 g, 0.01 mol) and DMF (50 mL) was added CH3I (11 g, 0.18 mol). The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was cooled, washed with H2O (100 mL*3), and extracted with EA (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 5:1) to give the title compound 3 (3.2 g, 50% yield) as a yellow solid.

[0396] M / Z (ES+) [M+H] + =223.1

[0397] Step 3. Synthesis of ethyl 4-(5-isopropyl-2,4-dimethoxyphenyl)-2,4-dioxobutanoate (4)

[0398]

[0399] To a solution of 1-(5-isopropyl-2,4-dimethoxyphenyl)ethanone (3.5 g, 0.016 mol) in THF (100 mL) were added NaH (0.75 g, 0.03 mol) and diethyl oxalate (6.9 g, 0.05 mol) at 20 °C. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled, washed with H2O (100 mL*3), and extracted with EA (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound 4 (4.0 g, 87% yield) as a yellow solid.

[0400] M / Z (ES+) [M+H] + =323.1

[0401] Step 4. Synthesis of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxylate (5)

[0402]

[0403] A solution of ethyl 3-(5-isopropyl-2,4-dimethoxyphenyl)-3-oxopropanoate (4.0 g, 0.01 mol) and hydroxylamine hydrochloride (1.9 g, 0.03 mol) in MeOH (50 mL) was stirred at 60°C for 2 h. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA = 3:1) to give the title compound 5 (2.7 g, 55% yield) as a yellow solid.

[0404] M / Z (ES+) [M+H] + =320.1

[0405] Step 5. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (6)

[0406]

[0407] To a solution of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-1,2-oxazole-3-carboxylate (1000 mg, 3.0 mmol) in EtOH (30 mL) was added EtNH2 (1000 mg, 22 mmol). The reaction mixture was stirred in a sealed tube at 60 °C for 12 h. The reaction mixture was cooled and concentrated in vacuo to obtain the crude compound, which was purified by FCC (PE:EA = 1:1) to give the title compound 6 (1.0 g, 75% yield) as a yellow solid.

[0408] M / Z (ES+) [M+H] + =319.0.

[0409] Step 6. Synthesis of N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (7)

[0410]

[0411] To a solution of ethyl 5-(5-isopropyl-2,4-dimethoxyphenyl)-1,2-oxazole-3-carboxylate (1000 mg, 3.1 mmol) and NIS (1400 mg, 6.3 mmol) in ACN (30.0 mL) was added ceric ammonium nitrate (85 mg, 0.15 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled and concentrated in vacuo to obtain the crude compound, which was purified by FCC (PE:EA = 1:1) to give the title compound 7 (1.1 g, 71% yield) as a yellow solid.

[0412] M / Z (ES+) [M+H] + =445.0.

[0413] Step 7. Synthesis of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (8)

[0414]

[0415] A solution of N-ethyl-4-iodo-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (1.1 g, 2.2 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (864 mg, 6.6 mmol), Pd(PPh3)Cl2 (154 mg, 0.2 mmol), and TEA (666 mg, 6.6 mmol) in dioxane (30 mL) was stirred at 80 °C for 12 h under N2. The reaction mixture was cooled, washed with H2O (50 mL*3), and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE:EA=1:1) to obtain the title compound 8 (600 mg, 55% yield) as a yellow oil.

[0416] M / Z (ES+) [M+H] + =445.0.

[0417] Step 8. Synthesis of 4-(4-carbamoylbenzyl)-N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)isoxazole-3-carboxamide (10)

[0418]

[0419] A solution of N-ethyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole-3-carboxamide (300 mg, 0.67 mmol), 4-(bromomethyl)benzamide (144.5 mg, 0.67 mmol), Pd(PPh3)4 (156.05 mg, 0.13 mmol) and Na2CO3 in dioxane / H2O (10.0 mL / 2.0 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was cooled, washed with H2O (50 mL*3) and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (PE:EA=1:4) to obtain the title compound 10 (70 mg, 23% yield) as a colorless oil.

[0420] M / Z (ES+) [M+H] + =452.0.

[0421] Step 9. Synthesis of 4-(4-carbamoylbenzyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethylisoxazole-3-carboxamide (H2-2-6)

[0422]

[0423] To a solution of N-ethyl-6-(5-isopropyl-2,4-dimethoxyphenyl)-5-[4-(morpholin-4-ylmethyl)phenyl]pyrimidine-4-carboxamide (70 mg, 0.15 mmol) in DCM (5 mL) was added BBr3 (1 M in DCM) (1.5 mL, 1.5 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was cooled and concentrated in vacuo. The residue was cooled to 0 °C, DCM (20 mL) was added, the pH was adjusted to 8 with NaHCO3, H2O (50 mL) was added, and the mixture was extracted twice with DCM (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by Prep-HPLC to obtain compound H2-1-6 (3.4 mg, 5.18% yield).

[0424] 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 2H), 8.66 (t, J = 5.7 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.22 (s, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.86 (s, 1H), 6.50 (s, 1H), 4.01 (s, 2H), 3.24-3.15 (m, 2H), 3.05 (dt, J = 13.8, 6.9 Hz, 1H), 1.03 (dt, J = 7.1, 3.7 Hz, 9H).

[0425] M / Z (ES+) [M+H] + =424.1.

[0426] 1-12. Synthesis of compound H2-2-1 unexpected N-ethyl-5-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)isoxazole-3-carboxamide

[0427]

[0428] Step 1. Synthesis of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (2)

[0429]

[0430] To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (5.0 g, 0.02 mmol) in DCM (100 mL) were added triphenyl phosphine (15.3 g, 0.05 mmol) and CBr4 (19.37 g, 0.05 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 h. Then, the reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL*3). The combined organic layers were concentrated in vacuo. The residue was purified by FCC (PE / EA = 3 / 1) to give compound 2 (4.5 g, 66% yield) as a colorless oil.

[0431] M / Z (ES+) [M+H] + =234.

[0432] Step 2. Synthesis of ethyl 5-benzylisoxazole-3-carboxylate (3)

[0433]

[0434] Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (500 mg, 2.13 mmol), Pd(OAc)2 (23.98 mg, 0.10 mmol), phenylboronic acid (390 mg, 3.2 mmol), Johnphos (63.7 mg, 0.21 mmol), and K2CO3 (885 mg, 6.40 mmol) in DMF (5 mL) were stirred at 140 °C for 20 min under microwave conditions under N2. The reaction mixture was cooled, ice-cold water (50 mL) was added, and extracted with EA (50 mL*3). The combined organic layers were washed with aqueous NaHCO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE / EA = 1 / 1) to give the title compound 3 (250 mg, 50% yield) as a yellow oil.

[0435] M / Z (ES+) [M+H] + =232.1

[0436] Step 3. Synthesis of ethyl 5-(4-iodobenzyl)isoxazole-3-carboxylate (4)

[0437]

[0438] A solution of ethyl 5-benzylisoxazole-3-carboxylate (250 mg, 1.08 mmol) and NIS (267.55 mg, 1.18 mmol) in TFA (10 mL) was stirred at room temperature for 16 h. The solvent was evaporated. The residue was diluted with ice water (50 mL), the pH was adjusted to 7-8, and extracted with EA (30 mL*2). The combined organic layers were washed with NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (3:1 PE / EA) to give the title compound 4 (200 mg, 41.4% yield) as a yellow oil.

[0439] M / Z (ES+) [M+H] +=358.1

[0440] Step 4. Synthesis of ethyl 5-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)isoxazole-3-carboxylate (5)

[0441]

[0442] A solution of ethyl 5-(4-iodobenzyl)isoxazole-3-carboxylate (125 mg, 0.35 mmol), 4-4-{[4-4-(4-4,4-4,5-5,5-5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine (159 mg, 0.52 mmol), NaHCO3 (88 mg, 1.05 mmol), and Pd(PPh3)2Cl2 (24.57 mg, 0.03 mmol) in dioxane / H2O (8 mL / 2.0 mL) was stirred at 100 °C for 6 h under N2. The reaction mixture was cooled, ice-water (20 mL) was added, and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE / EA = 1 / 1) to give the title compound 5 (50 mg, 25.3% yield) as a pale yellow oil.

[0443] M / Z (ES+) [M+H] + =407.1

[0444] Step 5. Synthesis of N-ethyl-5-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)isoxazole-3-carboxamide (H2-2-1 unexpected)

[0445]

[0446] To a solution of ethyl 5-((4'-(morpholinomethyl)-[1,1'-biphenyl]-4-yl)methyl)isoxazole-3-carboxylate (30 mg, 0.02 mmol) in EtOH (1.5 mL) was added ethanamide (1.5 mL, 70% in H2O). The reaction mixture was stirred in a sealed tube at 70°C for 3 h. The reaction mixture was cooled and concentrated. The residue was purified by prep-HPLC (NH4HCO3 / ACN) to give the title compound 2-2-1 unexpected (1.2 mg, 4.1% yield) as a white solid.

[0447] M / Z (ES+) [M+H] + =406.2.

[0448] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 5.3 Hz, 1H), 7.62 (dd, J = 10.5, 8.2 Hz, 4H), 7.38 (d, J = 7.1 Hz, 4H), 6.55 (s, 1H), 4.24 (s, 2H), 3.65 - 3.53 (m, 4H), 3.49 (s, 2H), 3.29-3.19 (m, 2H), 2.37 (s, 4H), 1.08 (t, J = 7.2 Hz, 3H).

[0449] 1-13. Synthesis of compound H2-2-3 unexpected N-ethyl-5-((4-hydroxy-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)methyl)isoxazole-3-carboxamide

[0450]

[0451] Step 1. Synthesis of ethyl 5-(2-methoxybenzyl)isoxazole-3-carboxylate (2)

[0452]

[0453] Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (1.0 g, 0.0043 mol), Pd(OAc)2 (50 mg, 0.0002 mol), (2-methoxyphenyl)boronic acid (650 mg, 0.0043 mol), John Phos (130 mg, 0.004 mol), and K2CO3 (1.78 g, 0.012 mol) dissolved in DMF (8 mL) were stirred at 140 °C for 20 min under microwave conditions under N2. The reaction mixture was cooled, ice-cold water (50 mL) was added, and extracted with EA (50 mL*3). The combined organic layers were washed with NaHCO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE / EA = 1 / 1) to give the title compound 2 (400 mg, 36.1% yield) as a yellow oil.

[0454] m / z (ES+) [M+H] + =262.2

[0455] Step 2. Synthesis of ethyl 5-(5-iodo-2-methoxybenzyl)isoxazole-3-carboxylate (3)

[0456]

[0457] A solution of ethyl 5-(2-methoxybenzyl)isoxazole-3-carboxylate (400 mg, 1.53 mmol) and NIS (378.8 mg, 0.10 mmol) in TFA (10 mL) was stirred at room temperature under N2 for 16 h. The solvent was evaporated. The residue was diluted with ice water (50 mL), the pH was adjusted to 7-8, and extracted with EA (30 mL*2). The combined organic layers were washed with NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (3:1 PE / EA) to give the title compound 3 (350 mg, 50.1% yield) as a yellow oil.

[0458] m / z (ES+) [M+H] + =388.2

[0459] Step 3. Synthesis of ethyl 5-((4-methoxy-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)methyl)isoxazole-3-carboxylate (4)

[0460]

[0461] Ethyl 5-(5-iodo-2-methoxybenzyl)isoxazole-3-carboxylate (300 mg, 0.77 mmol), 4-4-{[4-4-(4-4,4-4,5-5,5-5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}morpholine (352 mg, 1.16 mmol), NaHCO3 (195.3 mg, 2.32 mmol), and Pd(PPh3)2Cl2 (54.4 mg, 0.07 mmol) in dioxane / H2O (16 mL / 4 mL) were stirred at 100 °C for 6 h under N2. Ice water (20 mL) was added to the reaction mixture, and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (PE / EA = 1 / 1) to give the title compound 4 (70 mg, 17.5% yield) as a pale yellow oil.

[0462] M / Z (ES+ ) [M+H] + =437.0

[0463] Step 4. Synthesis of N-ethyl-5-((4-methoxy-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)methyl)isoxazole-3-carboxamide (5)

[0464]

[0465] To a solution of ethyl 5-((4-methoxy-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)methyl)isoxazole-3-carboxylate (30 mg, 0.02 mmol) in EtOH (1.0 mL) was added ethanamide (1.0 mL, 70% in H2O). The reaction mixture was stirred in a sealed tube at 70 °C for 3 h. The reaction mixture was cooled and concentrated. The residue was purified by prep-HPLC (NH4HCO3 / ACN) to give the title compound 5 (30 mg, 81.9% yield) as a white solid.

[0466] m / z (ES+) [M+H] + =436.2.

[0467] Step 5. Synthesis of N-ethyl-5-((4-hydroxy-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)methyl)isoxazole-3-carboxamide (2-2-3 unexpected)

[0468]

[0469] To a solution of N-ethyl-5-((4-methoxy-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)methyl)isoxazole-3-carboxamide (25 mg, 0.05 mmol) in DCM (2.0 mL) was added BBr3 (1 M in DCM) (0.57 mL, 0.57 mmol). The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was concentrated in vacuo. The residue was cooled to 0 °C, DCM (20 mL) was added, the pH was adjusted to 8 with saturated NaHCO3, H2O (10 mL) was added, and the mixture was extracted twice with DCM (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by HPLC to obtain compound 2-2-3 unexpected (2.7 mg, 11.8% yield).

[0470] M / Z (ES+) [M+H] + =422.2.

[0471] 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.65 (s, 1H), 7.46 (dd, J = 12.9, 10.7, 5.3 Hz, 4H), 7.33 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.40 (s, 1H), 4.13 (s, 2H), 3.63-3.54 (m, 4H), 3.46 (s, 2H), 3.22 (dd, J = 7.1, 5.9 Hz, 2H), 2.36 (d, J = 4.1 Hz, 4H), 1.07 (t, J = 7.2 Hz, 3H).

[0472] <Example 2>

[0473] 2. Confirmation of the compound's HSP90 inhibitory effect

[0474] To confirm the HSP90 inhibitory effect of the above 13 compounds, an in vitro enzymatic assay was performed using the HSP90β (N-terminal) Fluorescence Polarization Assay Kit, and the tested compounds are as described in Table 1 below.

[0475] Compound ID Provided Compound Stock Concentration Solubility Solvent Test Range (μM) Intermediate Dilution H2-1-1Liquid 10 mM DMSO 0.016, 0.08, 0.4, 2, 10 10 % DMSO in HSP90 Assay Buffer H2-1-2Liquid 10 mM DMSO 0.016, 0.08, 0.4, 2, 10 10 % DMSO in HSP90 Assay Buffer H2-1-3Liquid 10 mM DMSO 0.016, 0.08, 0.4, 2, 10 10 % DMSO in HSP90 Assay Buffer H2-1-4Liquid 10 mM DMSO 0.016, 0.08, 0.4, 2, 10 10 % DMSO in HSP90 Assay Buffer H2-1-5Liquid 10 mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-1-6Liquid10 mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-2-1Liquid10 mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-2-3Liquid10 mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-2-4Liquid10 mMDMSO0.016, 0.08, 0.4, 2, 1010% DMSO in HSP90 Assay BufferH2-2-5Liquid10 mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-2-6Liquid10 mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-2-1 UNEXPECTLiquid10mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferH2-2-3 UNEXPECTLiquid10mMDMSO0.016, 0.08, 0.4, 2, 1010 % DMSO in HSP90 Assay BufferAUY-922Liquid10 mMDMSO0.0016, 0.008, 0.04, 0.2, 110 % DMSO in HSP90 Assay BufferGeldanamycin*Powder10 mMDMSO0.01, 0.1, 110 % DMSO in HSP90 Assay Buffer.

[0476] *Reference compound.

[0477] All compounds were dissolved in DMSO. Serial dilutions of the compounds were prepared in assay buffer to 10% DMSO, and 10 μl of the dilutions were added to 100 μl reactions, resulting in a final DMSO concentration of 1% in all reactions. The reactions were performed at room temperature for 3 h in a 100 μl mixture containing assay buffer, 5 nM FITC-labeled geldanamycin, HSP90 enzyme (200 ng / reaction), and test compound. Fluorescence intensities were measured using a Tecan Infinite M1000 microplate reader at an excitation of 485 nm and an emission of 530 nm.

[0478] HSP90 N-terminal binding assays were performed in duplicate at each concentration. Fluorescence intensities were converted to fluorescence polarization using Tecan Magellan6 software. Fluorescence polarization data were analyzed using Graphpad Prism, a computer software. Fluorescence polarization (FP) in the absence of compound was included in each data set. t ) was defined as 100% activity. In the absence of HSP90 N-Terminus and compound, fluorescence polarization (FP) of each data set b ) value was defined as 0% activity. The activity in the presence of the compound was calculated according to the following mathematical formula 1. In the following mathematical formula 1, FP is the fluorescence polarization in the presence of the compound.

[0479] [Mathematical Formula 1]

[0480] % Activity = (FP-FPb) / (FPt-FPb)×100%

[0481] The results of evaluating the HSP90 inhibitory effects of compounds H2-1-1, H2-1-2, H2-1-3, and H2-1-4 are shown in Table 2 and Figure 1 below.

[0482] Compound HSP90 Activity [Fluorescence Polarization (mp)] % Activity % Inhibition Repeat 1 Repeat 2 Repeat 1 Repeat 2 No Inhibitor 2072051001000H2-1-1, 0.016 μM 204207991000H2-1-1, 0.08 μM 175180838615H2-1-1, 0.4 μM 125127565743H2-1-1, 2 μM 6871262773H2-1-1, 10 μM 30345794H2-1-2, 0.016 μM 205206991000H2-1-2, 0.08μM170171808119H2-1-2, 0.4μM10099434257H2-1-2, 2μM4546131486H2-1-2, 10μM26273397H2-1-3, 0.016μM20020397983H2-1-3, 0.08μM37339792H2-1-3, 0.4μM24232298H2-1-3, 2μM22211099H2-1-3, 10μM212100100H2-1-4, 0.016μM205206991000H2-1-4, 0.08μM205210991020H2-1-4, 0.4μM20220498992H2-1-4, 2μM206201100971H2-1-4, 10μM19920296983Geldanamycin, 0.01μM188183908811Geldanamycin, 0.1μM102100444356Geldanamycin, 1μM24242298Background2020

[0483] The results of evaluating the HSP90 inhibitory effects of compounds H2-1-5, H2-1-6, H2-2-1, and H2-2-3 are shown in Table 3 and Figure 2 below.

[0484] Compound HSP90 Activity [Fluorescence Polarization (mp)] % Activity % Inhibition Repeat 1 Repeat 2 Repeat 1 Repeat 2 No Inhibitor 207205 100 1000 H2-1-5, 0.016 μM 20420699 1001 H2-1-5, 0.08 μM 2002009797 3 H2-1-5, 0.4 μM 1851858989 1 1 H2-1-5, 2 μM 174171838 1 18 H2-1-5, 10 μM 14114865693 3 H2-1-6, 0.016 μM 209202101980 H2-1-6, 0.08μM200205971002H2-1-6, 0.4μM175187839014H2-1-6, 2μM135141626537H2-1-6, 10μM7476293070H2-2-1, 0.016μM205206991000H2-2-1, 0.08μM207204100991H2-2-1, 0.4μM204210991020H2-2-1, 2μM20520499991H2-2-1, 10μM208205101990H2-2-3, 0.016μM208201101971H2-2-3, 0.08μM2082071011000H2-2-3, 0.4μM20520099972H2-2-3, 2μM2082061011000H2-2-3, 10μM20120297982Geldanamycin, 0.01μM188183908811Geldanamycin, 0.1μM102100444356Geldanamycin, 1μM24242298Background2020

[0485] The results of evaluating the HSP90 inhibitory effects of compounds H2-2-4, H2-2-5, H2-2-6 and H2-2-1 UNEXPECT are shown in Table 4 and Figure 3 below.

[0486] Compound HSP90 Activity [Fluorescence Polarization (mp)] % Activity % Inhibition Repeat 1 Repeat 2 Repeat 1 Repeat 2 No Inhibitor 207 205 100 1000 H2-2-4, 0.016 μM 206 209 100 1010 H2-2-4, 0.08 μM 205 21099 1020 H2-2-4, 0.4 μM 204 20699 1001 H2-2-4, 2 μM 203 20898 1010 H2-2-4, 10 μM 199 20196973 H2-2-5, 0.016 μM 207 204 100 990 H2-2-5, 0.08μM180187869012H2-2-5, 0.4μM95102404458H2-2-5, 2μM4444131387H2-2-5, 10μM29324695H2-2-6, 0.016μM204210991020H2-2-6, 0.08μM171169818020H2-2-6, 0.4μM8377343168H2-2-6, 2μM393410891H2-2-6, 10μM25253397H2-2-1 UNEXPECT, 0.016μM211202102980H2-2-1 UNEXPECT, 0.08μM2092051021000H2-2-1 UNEXPECT, 0.4μM211201102970H2-2-1 UNEXPECT, 2μM20519899963H2-2-1 UNEXPECT, 10μM19319393937Geldanamycin, 0.01μM188183908811Geldanamycin, 0.1μM102100444356Geldanamycin, 1μM24242298Background2020

[0487] The results of evaluating the HSP90 inhibitory effects of compounds H2-2-3 UNEXPECT and AUY-922 are shown in Table 5 and Figure 4 below.

[0488] Compound HSP90 Activity [Fluorescence Polarization (mp)] % Activity % Inhibition Repeat 1 Repeat 2 Repeat 1 Repeat 2 No Inhibitor 207 205 100 1000 H2-2-3 UNEXPECT, 0.016 μM 206 203 10098 1 H2-2-3 UNEXPECT, 0.08 μM 203 2049899 1 H2-2-3 UNEXPECT, 0.4 μM 201 2039798 2 H2-2-3 UNEXPECT 2 μM 202 2019898 2 H2-2-3 UNEXPECT, 10 μM 198 20196974 AUY-922, 0.0016 μM 203 2049899 1 AUY-922, 0.008μM176173848217AUY-922, 0.04μM8789363763AUY-922, 0.2μM26243298AUY-922, 1μM23221199Geldanamycin, 0.01μM188183908811Geldanamycin, 0.1μM102100444356Geldanamycin, 1μM24242298Background2020

[0489] As a result of synthesizing the above results, it was confirmed through Figure 5 that compound H2-2-6 exhibited an HSP90 inhibitory effect comparable to AUY-922, and compound H2-1-3 exhibited an HSP90 inhibitory effect superior to AUY-922, and the IC 50 of each compound is as described in Table 6 below.

[0490] Compound IC50 (μM) Note H2-1-10.5693 H2-1-20.3118 H2-1-30.04201 H2-1-4N / A No activity H2-1-540.93 H2-1-63.709 H2-2-1N / A No activity H2-2-3N / A No activity H2-2-4187.9 H2-2-50.3368 H2-2-60.2382 H2-2-1 unexpected272.8 H2-2-3 unexpected4.355 e+009 No activity determined Auy9220.2603

[0491] The present invention is an invention carried out through the following tasks.

[0492] [National Research and Development Project Supporting This Invention]

[0493] [Project ID] 1465034391

[0494] [Project Number] HR21C0198

[0495] [Ministry Name] Ministry of Health and Welfare

[0496] [Name of Project Management (Specialist) Agency] Korea Health Industry Development Institute

[0497] [Research Project Name] Research-Oriented Hospital Development Project (R&D)

[0498] [Research Project Title] Development of AI-based drug response prediction technology through data-based classification of in vitro patient models.

[0499] [Name of the project performing organization] Seoul Asan Medical Center

[0500] [Research Period] July 1, 2021 - December 31, 2029

Claims

A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above formula, The above R 1 is substituted or unsubstituted phenyl or benzyl; The above R 2 is H, halogen, oxo, cyano, OH, C1-6 alkyl, C1-6 alkoxy, carbamoyl, carbamoyl-C1-6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C4-C7 cycloalkylalkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C2-C6 alkylcarbonyl, phenoxy, phenylamino, amino, C1-C5 monoalkylamino, C2-C10 dialkylamino, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl; wherein X is CH or N; wherein n is an integer from 0 to 3; The above R 1 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, C5-C9 heteroaryl, amino, carbonyl, thio, cyano, nitro, ester, amide, azide, OH, and carboxyl, when substituted, and when substituted with multiple substituents, they are the same or different from each other. In the first paragraph, The above R 2 is H, carbamoyl, carbamoyl-C1-6 alkyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylmethyl, imidazolylmethyl, pyrazolylmethyl or triazolylmethyl; wherein n is 0 or 1; The above R 1 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with a substituent independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and OH, and when substituted with multiple substituents, they are the same or different from each other. In the first paragraph, The compound is a compound represented by the following chemical formula 2 or chemical formula 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] or [Chemical Formula 3] . In claim 1, the stereoisomer is a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, including a racemate, an enantiomer, a diastereomer, a mixture of enantiomers, or a mixture of diastereomers. A compound, a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound inhibits HSP90 in the first claim. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition according to claim 6, characterized in that the pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer. A pharmaceutical composition according to claim 7, characterized in that the cancer disease is any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and blood cancer. A health functional food composition for preventing or improving cancer, comprising a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A health functional food composition for preventing or improving cancer, characterized in that in claim 9, the cancer disease is any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and blood cancer. A method for preventing or treating cancer, comprising administering to a subject in need thereof a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A method for preventing or treating a cancer disease, characterized in that the cancer disease in claim 11 is any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and blood cancer. A pharmaceutical composition for use in the prevention or treatment of cancer, comprising a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for use in the prevention or treatment of cancer, characterized in that the cancer disease in claim 13 is any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and blood cancer. Use of a composition comprising a compound of any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a drug for preventing, improving, or treating cancer. In claim 15, the use is characterized in that the cancer disease is any one selected from the group consisting of non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, rectal cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and blood cancer.

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