Novel chromene-benzimidazole derivative or pharmaceutically acceptable salt thereof, and use thereof

Abstract

The present invention relates to: a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof; and a composition for preventing or treating cancer, the composition comprising the derivative as an active ingredient. The chromene-benzimidazole derivative according to the present invention is activated in cancer cells to inhibit tubulin polymerization and suppress the C-terminal domain of Hsp90, thereby blocking the cell cycle of cancer cells, inducing apoptosis, and inhibiting the activity of oncoproteins, and thus can be used as a novel dual-target anticancer drug for preventing or treating cancer, preferably for preventing or treating triple-negative breast cancer.

Description

Novel cromen-benzimidazole derivatives or pharmaceutically acceptable salts thereof and their uses

[0001] The present invention relates to cromen-benzimidazole derivatives or pharmaceutically acceptable salts thereof and uses thereof.

[0002] Patients with triple-negative breast cancer (TNBC; ER-, PR-, HER2-) account for 10–15% of all breast cancer patients. Due to a lack of hormone receptors (ER (estrogen receptor), PR (progesterone receptor)) and HER2 protein, they do not benefit from hormone therapy or HER2 targeted therapies. Currently, standard treatment for triple-negative breast cancer relies entirely on general cytotoxic chemotherapy agents (taxene or anthracycline). Because there are no established targeted therapies, treatment strategies for this subtype are less diverse compared to breast cancer. Even more serious is that recurrence occurs within 2–3 years in most patients following surgery or chemotherapy, and metastasis to other organs such as the lungs, liver, brain, and bones is easily induced, impacting patient survival rates.

[0003] The 5-year overall survival rate for patients diagnosed with stage III is 55% or less, and for patients with advanced-stage cancer, the 5-year overall survival rate is very low at 30% or less. It is a very serious disease in which most of these patients ultimately die within a few years.

[0004] Meanwhile, HER2-positive breast cancer (HER2+), characterized by the overexpression of the HER2 protein or HER2 gene amplification, is a subtype accounting for approximately 15–20% of all breast cancers, and it is known that tumor proliferation and metastasis are promoted by the upregulation of HER2 signaling. For HER2-positive breast cancer, HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab, antibody-drug conjugates (ADCs), and HER2-inhibiting small molecule tyrosine kinase inhibitors have been developed and are used as standard treatments. However, primary or acquired resistance to these HER2-targeted therapies occurs in a significant number of patients, and problems such as recurrence and metastasis during or after treatment still persist. In particular, distant metastases, including brain metastasis, are frequently observed in patients with HER2-positive breast cancer, and existing HER2-targeted therapies alone often fail to sufficiently improve survival time and quality of life. Therefore, there is a need to develop anticancer drugs with novel mechanisms of action that can bypass or complementarily inhibit HER2 signaling, such as therapeutic agents that target key intracellular molecules involved in the growth and survival of HER2-positive breast cancer, such as microtubules or Hsp90.

[0005] Microtubules are a major component of the cytoskeleton and consist of tubulin heteropolymers composed of α- and β-subunits. Microtubules perform various cellular functions, including intracellular transport, polarity maintenance, intracellular signal transduction, cell migration, and proliferation. During mitosis, they form spindle fibers to facilitate the process in which chromosomes align at the center of the cell and then separate to opposite poles. Since the failure of spindle fibers to function properly inhibits cell division and leads to apoptosis, microtubules are attracting attention as targets for anticancer drugs.

[0006] Drugs targeting microtubules are broadly divided into two groups: those that stabilize microtubules and those that destabilize them. First, microtubule stabilizers include taxanes, paclitaxel (Taxol), and decetaxel, which act to prevent microtubule depolymerization and enhance polymerization. Most microtubule stabilizers bind to taxane-binding sites or the overlapping sites of β-tubulin. Second, microtubule destabilizers include colchicine and vinca alkaloids, which bind to colchicine-binding sites or vinca-binding sites. Drugs targeting the microtubules themselves are effective at lower concentrations than those affecting microtubule polymers, and they share the characteristic of consequently inhibiting cell mitosis. Therefore, there is a need to develop potential tubulin polymerization inhibitors as anticancer agents.

[0007] Heat shock protein 90 (Hsp90) is one of the most abundant molecular chaperones in eukaryotic cells and is involved in the folding, stabilization, activation, or complex formation of target proteins known as 'client proteins'. Hsp90 plays a role in various biological functions related to cell growth, differentiation, and survival by regulating the stabilization and activity of various kinases, transcription factors, signaling molecules, and enzymes under normal and stress conditions. Furthermore, Hsp90 contributes to biological evolution and the maintenance of disease states by acting as a buffer for unstable proteins within the cell. In particular, Hsp90 is receiving significant attention as a target for anticancer drugs, as it has been revealed that approximately 50 proteins involved in the development of cancer cells, including Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, and hTERT, are client proteins of Hsp90. Hsp90 inhibitors induce the simultaneous degradation of various cancer-causing proteins by the proteasome, highlighting their potential as anticancer agents applicable to various types of cancer, and are showing positive results in several phases of ongoing clinical trials.

[0008] The technical problem that the present invention aims to solve is to provide a cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof.

[0009] In addition, another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer comprising the above-mentioned cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by a person skilled in the art from the description below.

[0011] To solve the above problem, the present invention provides a cromen-benzimidazole derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof:

[0012]

[0013] In the above chemical formula 1,

[0014] R 1 C5-C with substituted or unsubstituted 20 aryl groups, substituted or unsubstituted C4-C 20 heteroaryl groups, substituted or unsubstituted C3-C 20 It is either a cycloalkyl group and 5-methoxy-2,2-dimethyl-2H-chromene, and

[0015] The above aryl group is phenyl or naphthyl, and

[0016] The above heteroaryl group is any one of pentodioxol, pyridyl, pyrimidinyl, and benzothiophen, and

[0017] The above cycloalkyl group is adamantyl or cyclohexyl, and

[0018] Where the above phenyl is substituted, acetylamino, halogen, methyl, -CF3, phenyl, -CN, tert-butyl, substituted or unsubstituted methoxy(-OCH3), cyclopentyloxy, adamanthyloxy, dimethyladamanthyloxy, tert-butoxy, isobutoxy, hydroxy, triazole, piperidine, -NR 2 R 3 It is substituted with one or more selected from the group consisting of thiophene and tetrazole, and

[0019] The above R 2 , R 3 Each is independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen alkyl, hydroxyethyl, methoxycarbonyl, and phenyl, and

[0020] The above X is O or S.

[0021] According to one side,

[0022] In the above [Chemical Formula 1],

[0023] When the methoxy group substituted on the above phenyl is substituted, it is substituted with one or more selected from the group consisting of phenyl (which may be unsubstituted or substituted with a halogen), 2-phenylethyl, adamantyl, and adamantylmethyl, and

[0024] The piperidine substituted on the phenyl group above may be unsubstituted or substituted with a methyl group, and

[0025] The thiophene substituted on the phenyl group above may be unsubstituted or substituted with methyl, and

[0026] The tetrazole substituted on the phenyl above may be unsubstituted or substituted with ethyl or cyclopropylmethyl.

[0027] According to one side,

[0028] In the above [Chemical Formula 1],

[0029] The above pyridyl is unsubstituted or substituted with any one of CN, halogen, benzyloxy, tert-butyl, cyclopropyl, and adamantyl, and

[0030] The above pyrimidinyl is unsubstituted or substituted with methoxy or methyl, and

[0031] The above cyclohexyl is unsubstituted or substituted with phenyl, and

[0032] The above adamantyl may be unsubstituted or substituted with methyl.

[0033] According to one side,

[0034] In the above [Chemical Formula 1],

[0035] The above R1 may be any one selected from the group consisting of the following:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] and

[0052] .

[0053] According to one aspect, the chromene-benzimidazole derivative represented by [Chemical Formula 1] may be any one selected from the group consisting of the following compounds:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

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[0065]

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[0070]

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[0100]

[0101]

[0102]

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[0115]

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[0123]

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[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131] and

[0132] .

[0133] According to one aspect, the cromen-benzimidazole derivative may have both the effect of inhibiting tubulin polymerization and the effect of inhibiting the C-terminal domain of Hsp90.

[0134] According to one aspect, the pharmaceutically acceptable salt of the cromen-benzimidazole derivative may be one or more selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipose salt, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

[0135] According to another embodiment of the present invention, a pharmaceutical composition for the prevention or treatment of cancer is provided, comprising the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0136] According to one aspect, the pharmaceutical composition may induce apoptosis by arresting the cancer cell cycle.

[0137] According to one aspect, the pharmaceutical composition may induce denaturation and degradation of oncoproteins.

[0138] According to one aspect, the cancer may be one or more selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, and bronchial cancer.

[0139] According to one side, the cancer may be triple-negative breast cancer.

[0140] In addition, the present invention provides a method for preventing or treating cancer comprising the step of administering the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof to an individual.

[0141] In addition, the present invention provides the use of the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of cancer.

[0142] In addition, the present invention provides a method for diagnosing cancer comprising the step of administering the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof to an individual.

[0143] In addition, the present invention provides the use of the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof for the manufacture of a drug for cancer diagnosis.

[0144] The present invention relates to a cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof and a composition for the prevention or treatment of cancer comprising said derivative as an active ingredient. The cromen-benzimidazole derivative of the present invention is activated in cancer cells to inhibit tubulin polymerization and simultaneously inhibits the C-terminal domain of Hsp90 protein. When administered to an individual, it blocks the cancer cell cycle, induces apoptosis, and inhibits the activity of oncoproteins, thereby exhibiting cytotoxicity and simultaneously providing an anticancer effect. Therefore, the compound of the present invention and the composition containing it can be used as a novel dual-target anticancer composition for the prevention or treatment of cancer, preferably for the prevention or treatment of triple-negative breast cancer.

[0145] Figures 1 to 8 are graphs showing the change in cell viability when human triple-negative breast cancer cell lines (MDA-MB-231) and HER2-positive breast cancer cell lines (JIMT-1) were treated with cromen-benzimidazole derivatives of Formulas 1-1 to 1-79, respectively.

[0146] Figures 9 to 11 are graphs showing cell viability and IC50 values ​​calculated therefrom when chromene derivative active substances (compounds 1-2, 1-40, 1-41, 1-42, 1-43, 1-48, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-60, 1-62 and 1-74) were treated in triple-negative breast cancer cell line MDA-MB-231.

[0147] Figure 12 is a photograph showing morphological changes in cells observed under an optical microscope after treatment with chromene derivative active substances (compounds 1-42, 1-51, 1-52 and 1-54) in triple-negative breast cancer cell line MDA-MB-231.

[0148] Figure 13 shows the results of analysis using Annexin V / PI double staining and flow cytometry after treating triple-negative breast cancer cell line MDA-MB-231 with chromene derivative active substances (compounds 1-42, 1-51, 1-52 and 1-54).

[0149] Figure 14 is a Western blot showing the change in expression of apoptosis-related proteins when chromene derivative active substances (compounds 1-42, 1-51, 1-52 and 1-54) were treated in triple-negative breast cancer cell line MDA-MB-231.

[0150] Figure 15 is a Western blot showing the change in HSP90 client protein expression after treatment with chromene derivative active substances (compounds 1-42, 1-51, 1-52 and 1-54) in triple-negative breast cancer cell line MDA-MB-231.

[0151] Figure 16 shows cell viability and IC50 when chromene derivative compound 1-42 was treated in blood cancer cell line HL-60, liver cancer cell line HepG2, lung cancer cell line H1299, colorectal cancer cell line HCT116, and ovarian cancer cell line SKOV3. 50 This is a graph showing the values.

[0152] Figure 17 shows cell viability and IC50 when chromene derivative compound 1-52 was treated in blood cancer cell line HL-60, liver cancer cell line HepG2, lung cancer cell line H1299, colorectal cancer cell line HCT116, and ovarian cancer cell line SKOV3. 50 This is a graph showing the values.

[0153] The inventors have confirmed that benzimidazole derivatives possess an anticancer effect by inhibiting the division of cancer cells through cell cycle arrest by inhibiting tubulin synthesis, and that cromen derivatives can possess an anticancer effect by inhibiting the C-terminal domain of Hsp90. Furthermore, by confirming the possibility of activating both mechanisms of action by combining benzimidazole and cromen within a single compound molecule, the inventors intend to provide a novel dual-target anticancer drug in the form of a cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof. Additionally, the present invention provides a compound in which the benzimidazole and cromen are linked by a urea or thiourea matrix.

[0154] From the above results, the present invention provides a cromen-benzimidazole derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof:

[0155]

[0156] In the above chemical formula 1,

[0157] R 1 C5-C with substituted or unsubstituted 20 aryl groups, substituted or unsubstituted C4-C 20 heteroaryl groups, substituted or unsubstituted C3-C 20 It is either a cycloalkyl group and 5-methoxy-2,2-dimethyl-2H-chromene, and

[0158] The above aryl group is phenyl or naphthyl, and

[0159] The above heteroaryl group is any one of pentodioxol, pyridyl, pyrimidinyl, and benzothiophen, and

[0160] The above cycloalkyl group is adamantyl or cyclohexyl, and

[0161] Where the above phenyl is substituted, acetylamino, halogen, methyl, -CF3, phenyl, -CN, tert-butyl, substituted or unsubstituted methoxy(-OCH3), cyclopentyloxy, adamanthyloxy, dimethyladamanthyloxy, tert-butoxy, isobutoxy, hydroxy, triazole, piperidine, -NR 2 R 3 It is substituted with one or more selected from the group consisting of thiophene and tetrazole, and

[0162] The above R 2 , R 3 Each is independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen alkyl, hydroxyethyl, methoxycarbonyl, and phenyl, and

[0163] The above X is O or S.

[0164] In the present invention, the term “substitution” refers to a reaction that replaces an atom or atomic group contained in a molecule of a compound with another atom or atomic group.

[0165] In the present invention, the term “chain type” refers to a molecule having a chain-type structure. A chain-type structure is a chemical structure in which carbon atoms are connected in a chain shape, and includes a straight chain type and a branched type.

[0166] In the present invention, the terms “cyclic” or “cyclo” refer to a structure in which the two ends of a chain formed in the backbone of an organic compound are joined to form a ring shape.

[0167] In the present invention, the term “linear or branched alkyl group” means a monovalent linear or branched hydrocarbon residue consisting only of carbon and hydrogen atoms having 1 to 6 carbon atoms.

[0168] In the present invention, the terms “cyclic alkyl group” or “cycloalkyl group” refer to a cyclic saturated hydrocarbon residue.

[0169] Examples of the above alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.

[0170] In the present invention, the term “cycloalkyl group” refers to a monocyclic or polycyclic carbon ring compound that is typically saturated or partially unsaturated but not aromatic, and means, for example, a cycloalkane-type hydrocarbon group having 3 to 12 carbon atoms. Such cycloalkyl groups may optionally be unsubstituted, monosubstituted, or polysubstituted, and include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0171] In the present invention, the term “heterocycloalkyl group” typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may optionally be unsubstituted, single-substituted, or multi-substituted, and at least one of the heteroatoms in its structure is selected from N, O, or S.

[0172] In the present invention, the term "aryl group" refers to an unsaturated aromatic ring compound having 3 to 12 carbon atoms having a single ring (e.g., phenyl) or a plurality of condensed rings (e.g., naphthyl). Examples of such aryl groups include, but are not limited to, phenyl, naphthyl.

[0173] In the present invention, the term “heteroaryl group” refers to a single ring or a plurality of condensed rings in which at least one of the atoms constituting the ring is a heteroatom of N, O, or S. Examples of such heteroaryl groups include, but are not limited to, pyridyl groups, pyrimidinyl groups, pyrazinyl groups, oxazolyl groups, furyl groups, etc.

[0174] In the present invention, the term “alkoxy group” means an alkyl group (-OR) bonded with oxygen. Examples of such alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups, butoxy groups.

[0175] In the present invention, the “halogen group” may be fluorine (F), chloride (Cl), bromine (Br), or iodine (I), etc.

[0176] According to one side,

[0177] In the above [Chemical Formula 1],

[0178] When the methoxy group substituted on the above phenyl is substituted, it is substituted with one or more selected from the group consisting of phenyl (which may be unsubstituted or substituted with a halogen), 2-phenylethyl, adamantyl, and adamantylmethyl, and

[0179] The piperidine substituted on the phenyl group above may be unsubstituted or substituted with a methyl group, and

[0180] The thiophene substituted on the phenyl group above may be unsubstituted or substituted with methyl, and

[0181] The tetrazole substituted on the phenyl above may be unsubstituted or substituted with ethyl or cyclopropylmethyl.

[0182] According to one side,

[0183] In the above [Chemical Formula 1],

[0184] The above pyridyl is unsubstituted or substituted with any one of CN, halogen, benzyloxy, tert-butyl, cyclopropyl, and adamantyl, and

[0185] The above pyrimidinyl is unsubstituted or substituted with methoxy or methyl, and

[0186] The above cyclohexyl is unsubstituted or substituted with phenyl, and

[0187] The above adamantyl may be unsubstituted or substituted with methyl.

[0188] According to one side,

[0189] In the above [Chemical Formula 1],

[0190] The above R1 may be any one selected from the group consisting of the following:

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] and

[0207] .

[0208] According to one aspect, the chromene-benzimidazole derivative represented by [Chemical Formula 1] may be any one selected from the group consisting of the following compounds:

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

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[0221]

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[0240]

[0241]

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[0280]

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[0283]

[0284]

[0285]

[0286]

[0287] and

[0288] .

[0289] The cromen-benzimidazole derivative of the present invention or a pharmaceutically acceptable salt thereof is specifically activated in cancer cells to inhibit tubulin polymerization and induce apoptosis, and can inhibit the activity of oncoproteins by inhibiting the C-terminal domain of Hsp90, so it can be used as a pharmaceutical composition for cancer prevention or treatment containing the same as an active ingredient.

[0290] In one embodiment of the present invention, the pharmaceutical composition may induce apoptosis by arresting the cell cycle of cancer cells, or induce denaturation and degradation of oncoproteins, and preferably perform both mechanisms.

[0291] In the present invention, the term “oncoprotein” refers to a protein that regulates cell growth and division, which can promote the formation of cancer cells and the progression of cancer due to gene mutations or abnormalities in expression regulation. In particular, for the purposes of the present invention, the oncoprotein may be a client protein of Hsp90, and preferably may be Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, hTERT, ERK, p-ERK, STAT3, c-MET, etc.

[0292] In the present invention, the term “pharmaceuticalally acceptable salt” refers to a formulation of a compound that does not cause severe irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt may be obtained by reacting the compound of the present invention with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc. In addition, the compound of the present invention may be obtained by reacting it with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)methylamine, and amino acid salts such as arginine and lysine.

[0293] In addition, the above-mentioned cromen-benzimidazole derivative or its pharmaceutically acceptable salt may include not only the pharmaceutically acceptable salt but also all salts, hydrates, and solvates that can be prepared by conventional methods.

[0294] In addition, the present invention may provide a method for the prevention, treatment, and / or diagnosis of cancer comprising the step of administering the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof to an individual.

[0295] In the present invention, the term "prevention" refers to any act of suppressing or delaying the occurrence, spread, or recurrence of cancer by administering the composition of the present invention, and the term "treatment" refers to any act of improving or beneficially altering the symptoms of the said disease by administering the composition of the present invention.

[0296] In the present invention, the term "pharmaceutical composition" means one prepared for the purpose of preventing or treating a disease, and can be used by being formulated into various forms according to conventional methods. For example, it can be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and can be used by being formulated into external preparations, suppositories, and sterile injectable solutions.

[0297] In the present invention, "included as an active ingredient" means that the corresponding ingredient is included in an amount necessary or sufficient to realize the desired biological effect. In actual application, the amount included as an active ingredient is determined as an amount for treating the target disease, taking into account factors that do not cause other toxicities, and may vary depending on various factors such as, for example, the disease or condition being treated, the form of the composition administered, the size of the subject, or the severity of the disease or condition. A person skilled in the art to which the present invention pertains can empirically determine the effective amount of an individual composition without involving excessive experimentation.

[0298] In addition, the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers in addition to the active ingredients described above, depending on each formulation.

[0299] The above-mentioned pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures of one or more of these components, and may further include other conventional additives such as antioxidants, buffers, and bacteriostatic agents as needed. Additionally, by additionally adding diluents, dispersants, surfactants, binders, and lubricants, it may be formulated into injectable formulations such as aqueous solutions, suspensions, and emulsions, or into pills, capsules, granules, or tablets. Furthermore, it may be preferably formulated according to each disease or component by appropriate methods in the art or by using methods disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton, PA).

[0300]

[0301] The composition of the present invention may be administered orally or parenterally in a pharmaceutically effective amount according to the intended method, and the term “pharmaceutically effective amount” of the present invention means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects, and the effective dose level may be determined based on factors including the patient’s health status, severity, drug activity, sensitivity to the drug, method of administration, time of administration, route of administration and elimination rate, duration of treatment, drugs used in combination or concurrently, and other factors well known in the medical field.

[0302] Accordingly, the pharmaceutical composition of the present invention can be administered to an individual to prevent, treat, and / or diagnose cancer, and said cancer may be skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, or bronchial cancer, etc., but is not limited thereto, preferably may be a cancer having a higher acidity than normal cells and cytotoxicity inhibited by a tubulin polymerization inhibitor, and non-limiting examples include breast cancer, preferably triple-negative breast cancer, etc.

[0303] In the present invention, the term “individual” is not limited to mammals such as livestock or humans that require prevention, treatment, and / or diagnosis of cancer, but preferably may be a human.

[0304] The pharmaceutical composition of the present invention can be formulated into various forms for administration to individuals, and representative formulations for parenteral administration are injectable formulations, preferably isotonic aqueous solutions or suspensions. Injectable formulations can be prepared according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. For example, each component can be dissolved in saline solution or buffer solution to form an injectable formulation. Additionally, formulations for oral administration include, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers, and these formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and a lubricant (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). The above tablet may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally may further include a disintegrant such as starch, agar, alginic acid or its sodium salt, an absorbent, a coloring agent, a flavoring agent and / or a sweetener. The above formulation may be prepared by conventional mixing, granulation, or coating methods.

[0305] In addition, the pharmaceutical composition of the present invention may further include adjuvants such as preservatives, hydrating agents, emulsification promoters, salts or buffers for osmotic pressure regulation, and other therapeutically useful substances, and may be formulated according to conventional methods.

[0306] The pharmaceutical composition according to the present invention may be administered via various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular, and the dosage of the active ingredient may be appropriately selected according to various factors such as the route of administration, the patient's age, gender, body weight, and severity of the patient. In addition, the composition of the present invention may be administered in combination with known compounds that can enhance the desired effect.

[0307] The pharmaceutical composition according to the present invention may be administered to humans and animals by route of administration, either orally or parenterally, such as intravenously, subcutaneously, intranasally, or intraperitoneally. Oral administration includes sublingual application. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as drip methods.

[0308] In the pharmaceutical composition of the present invention, the total effective amount of the cromen-benzimidazole derivative or its pharmaceutically acceptable salt according to the present invention may be administered to a patient as a single dose, or administered via a fractionated treatment protocol in which multiple doses are administered over a long period. Although the content of the active ingredient in the pharmaceutical composition of the present invention may vary depending on the severity of the disease, it may typically be administered repeatedly several times a day at an effective dose of 100 μg to 3,000 mg per single dose for adults. However, the effective dose for the patient may be determined by considering various factors such as the patient's age, weight, health status, gender, severity of the disease, diet, and excretion rate, as well as the route of administration and frequency of treatment.

[0309] In addition, the pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, and method of administration as long as it exhibits the effects of the present invention, and the pharmaceutical composition of the present invention may additionally include a known anticancer agent as an active ingredient in addition to the cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof, and may be used in combination with other treatments known for the treatment of these diseases.

[0310]

[0311] The terms used in the embodiments are for illustrative purposes only and should not be interpreted as intended to be limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as "comprising" or "having" are intended to indicate the existence of the features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof.

[0312] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the embodiments pertain. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0313]

[0314] Hereinafter, embodiments are described in detail with reference to the attached drawings. However, various modifications may be made to the embodiments, and thus the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, and substitutions to the embodiments are included within the scope of the rights.

[0315] In addition, when describing with reference to the attached drawings, identical components are assigned the same reference numeral regardless of drawing symbols, and redundant descriptions thereof are omitted. When describing embodiments, if it is determined that a detailed description of related prior art could unnecessarily obscure the essence of the embodiment, such detailed description is omitted.

[0316]

[0317] [Example]

[0318] Example 1. Preparation of Cromen-Benzimidazole Derivatives

[0319] Chemical formulas 1-1 to 1-74 were prepared according to Method 1 below, and 1-75 to 1-79 were prepared according to Method 2 below.

[0320] Method 1

[0321]

[0322] Method 2

[0323]

[0324] All chemical reagents used were commercially available. 1 The 1H NMR spectrum was recorded at Bruker Avance III 400 MHz, and TMS was used as an internal standard.

[0325]

[0326] Synthesis of the chemical formula 1-1(N-(4-(5-(3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ureido)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide).

[0327]

[0328] To a 5 mL toluene solution of 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (0.117 g, 0.5 mmole), triethylamine (0.068 g, 0.09 mL, 0.66 mmol) and diphenyl phosphoryl azide (DPPA, 0.210 g, 0.763 mmoles, 1.5 eq) were added sequentially, and the mixture was stirred at room temperature for 1 hour. Then, the pre-prepared N-(4-(5-amino-1H-benzo[d]imidazol-2-yl)phenyl)acetamide (0.136 g, 0.51 mmol) and triethylamine (0.205 g, 0.276 mL, 2.02 mmol) were added sequentially, respectively, and 110 o The reaction was carried out at C for 5 hours. The reaction mixture was cooled and the solvent removed, and then separated and purified by silica gel column chromatography to obtain the pure product N-(4-(5-(3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ureido)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide 1 (0.18 g).

[0329] 73% yield

[0330] 1H NMR (400 MHz, DMSO-d6) δ 12.66(bs, 1H), 10.17(s, 1H), 9.21(bs, 1H), 8.10-8.03(m, 3H), 7.96(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.74(d, J=8.8Hz, 2H), 7.53(d, J=8.4hz, 1H), 6.97(d, J=8.8Hz, 1H), 6.56(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.75(s, 3H), 2.09(s, 3H), 1.37(s, 6H)

[0331]

[0332] 1.2 Synthesis of Chemical Formula 1-2(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(naphthalen-2-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0333]

[0334] Compound 2 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(naphthalen-2-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0335] 77% yield

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 12.91(bs, 1H), 9.279bs, 1H), 8.67(s, 1H), 8.29(d, J=8.0Hz, 1H), 8.13-8.00(m, 5H), 7.88(d, J=8.8Hz, 1H), 7.60(m, 3H), 7.02(d, J=9.2Hz, 1H), 6.56(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0337]

[0338] 1.3 Synthesis of Chemical Formula 1-3(1-(2-(benzo[d][1,3]dioxol-5-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0339]

[0340] Compound 3 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(benzo[d][1,3]dioxol-5-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0341] 75% yield

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 12.61(bs, 1H), 9.21(bs, 1H), 9.09(bs, 1H), 7.95(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.66(m, 2H), 7.52(d, J=8.8Hz, 1H), 7.109d, J=8.0Hz, 1H), 6.96(d, J=6.8Hz, 1H), 6.56(t, 2H), 6.12(s, 2H), 5.84(d, J=10.0Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0343]

[0344] 1.4 Synthesis of Chemical Formula 1-4(1-(2-(3-chlorophenyl)-1H-benzo[d]imidazol-6-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0345]

[0346] Compound 4 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-chlorophenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0347] 87% yield

[0348] 1 H NMR (400 MHz, DMSO-d6) δ 12.85(bs, 1H), 9.26(bs, 1H), 8.17(s, 1H), 8.11(s, 2H), 8.00(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.56(m, 3H), 7.01(bs, 1H), 6.56(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0349]

[0350] 1.5 Synthesis of Chemical Formula 1-5(1-(2-(4-bromophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0351]

[0352] Compound 5 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-bromophenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0353] 86% yield

[0354] 1H NMR (400 MHz, DMSO-d6) δ 12.81 (bs, 1H), 9.25 (bs, 1H), 8.11 (m, 3H), 8.03 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.76 (d, J = 8.4Hz, 2H), 7.56(m, 1H), 7.00(s, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0355]

[0356] 1.6 Synthesis of Chemical Formula 1-6(1-(2-(3,5-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0357]

[0358] 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and

[0359] Compound 6 was prepared by reacting 2-(3,5-difluorophenyl)-1H-benzo[d]imidazol-5-amine in the same way as Compound 1.

[0360] 83% yield

[0361] 1 H NMR (400 MHz, DMSO-d6) δ 12.98(bs, 1H), 9.289bs, 1H), 8.13(bs, 1H), 8.03(s, 1H), 7.84(m, 3H), 7.61(d, J=8.8Hz, 1H), 7.49(m, 1H), 7.02(d, J=6.8Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0362]

[0363] 1.7 Synthesis of Chemical Formula 1-7(1-(2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0364]

[0365] Compound 7 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0366] 78% yield

[0367] 1 H NMR (400 MHz, DMSO-d6) δ 12.90(bs, 1H), 9.27(bs, 1H), 8.37(bs, 1H), 8.12(m, 2H), 8.01(s, 1H), 7.84(m, 2H), 7.59(d, J=8.4Hz, 1H), 7.02(d, J=8.4Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0368] 1.8 Synthesis of Chemical Formula 1-8(1-(2-(3-chloro-2-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0369]

[0370] Compound 8 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-chloro-2-fluorophenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0371] 79% yield

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 12.57(s, 1H), 9.28(bs, 1H), 8.15(m, 2H), 8.03(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.74(m, 1H), 7.60(m, 1H), 7.43(m, 1H), 7.07(d, J=10.0Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0373]

[0374] 1.9 Synthesis of Chemical Formula 1-9(1-(2-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0375]

[0376] Compound 9 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2-chloro-4-methylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0377] 81% yield

[0378] 1 H NMR (400 MHz, DMSO-d6) δ 12.46(bs, 1H), 9.23(bs, 1H), 8.11(s, 1H), 8.01(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.80(d, J=8.0Hz, 1H), 7.58(d, 8.4Hz, 1H), 7.48(s, 1H), 7.33(d, J=8.0Hz, 1H), 7.01(d, J=8.4hz, 1H), 6.56(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.75(s, 3H), 2.39(s, 3H), 1.37(s, 6H)

[0379]

[0380] 1.10 Synthesis of Chemical Formula 1-10(1-(2-(2,4-dimethylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0381]

[0382] Compound 10 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2,4-dimethylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0383] 87% yield

[0384] 1 H NMR (400 MHz, DMSO-d6) δ 12.49(bs, 1H), 9.21(bs, 1H), 8.10(bs, 1H), 7.989s, 1H), 7.87(d, J=8.8Hz, 1H), 7.64(d, J=8.0Hz, 1H), 7.56(d, J=8.8Hz, 1H), 7.13(m, 2H), 6.98(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.59(s, 3H), 2.35(s, 3H), 1.37(s, 6H)

[0385]

[0386] 1.11 Synthesis of Chemical Formula 1-11(1-(2-(2,5-dimethylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0387]

[0388] Compound 11 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2,5-dimethylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0389] 88% yield

[0390] 1 H NMR (400 MHz, DMSO-d6) δ 12.44(bs, 1H), 9.21(bs, 1H), 8.10(bs, 1H), 7.98(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.56(s, 1H), 7.54(bs, 1H), 7.24(m, 2H), 6.99(d, J=8.8Hz, 1H), 6.55(m, 2H), 3.74(s, 3H), 2.56(s, 3H), 2.36(s, 3H), 1.37(s, 6H)

[0391]

[0392] 1.12 Synthesis of Chemical Formula 1-12(1-(2-(3,4-dimethylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0393]

[0394] Compound 12 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3,4-dimethylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0395] 89% yield

[0396] 1H NMR (400 MHz, DMSO-d6) δ 12.66(bs, 1H), 9.21(bs, 1H), 8.10(bs, 1H), 7.95(d, J=12.4Hz, 2H), 7.84(m, 2H), 7.52(d, J=8.4Hz, 1H), 7.30(d, J=8.0Hz, 1H), 6.97(d, J=8.4Hz, 1H), 6.55(t, 2H), 5.84(d J=10.0Hz, 1H), 3.74(s, 3H), 2.32(s, 3H), 2.29(s, 3H), 1.37(s, 6H)

[0397]

[0398] 1.13 Synthesis of Chemical Formula 1-13(1-(2-(3,5-dimethylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0399]

[0400] Compound 13 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3,5-dimethylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0401]

[0402] 85% yield

[0403] 1 H NMR (400 MHz, DMSO-d6) δ 12.64(bs, 1H), 9.22(bs, 1H), 8.10(bs, 1H), 7.95(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.78(m, 2H), 7.53(d, J=8.4Hz, 1H), 7.11(s, 1H), 6.97(d, J=6.8Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.379s, 6H), 1.37(s, 6H)

[0404]

[0405] 1.14 Synthesis of Chemical Formula 1-14(1-(2-(3-fluoro-2-methylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0406]

[0407] Compound 14 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-fluoro-2-methylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0408] 87% yield

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 12.74(bs, 1H), 9.24(bs, 1H), 8.11(bs, 1H), 7.99(s, 1H), 7.85(m, 3H), 7.56(d, J=8.0Hz, 1H), 7.46(m, 1H), 6.99(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 2.31(s, 3H), 1.37(s, 6H)

[0410]

[0411] 1.15 Synthesis of Chemical Formula 1-15(1-(2-(3-fluoro-4-methylphenyl)-1H-benzo[d]imidazol-6-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0412]

[0413] Compound 15 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-fluoro-4-methylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0414] 86% yield

[0415] 1 H NMR (400 MHz, DMSO-d6) δ 12.57(bs, 1H), 9.24(bs, 1H), 8.11(s, 1H), 8.02(s, 1H), 7.87(d, J=8.0Hz, 1H), 7.59(d, J=8.0Hz, 2H), 7.42(m, 1H), 7.33(m, 1H), 7.00(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 2.31(s, 3H), 1.37(s, 6H)

[0416]

[0417] 1.16 Synthesis of the chemical formula 1-16(1-(2-(2,4-bis(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0418]

[0419] Compound 16 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2,4-bis(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0420] 80% yield

[0421] 1H NMR (400 MHz, DMSO-d6) δ 12.80 (bs, 1H), 9.26 (bs, 1H), 8.26 (s, 2H), 8.12 (m, 2H), 8.04 (bs, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.69 (bs, 1H), 7.04(bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0422]

[0423] 1.17 Synthesis of Chemical Formula 1-17(1-(2-(2-chloro-4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0424]

[0425] Compound 17 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2-chloro-4-fluorophenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0426] 84% yield

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 12.56(bs, 1H), 9.24(bs, 1H), 8.11(s, 1H), 8.03(s, 1H), 7.95(m, 1H), 7.87(d, J=8.0Hz, 1H), 7.68(d, J=8.0Hz, 1H), 7.57(bs, 1H), 7.44(m, 1H), 7.02(bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0428]

[0429] 1.18 Synthesis of Chemical Formula 1-18(1-(2-([1,1'-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0430]

[0431] Compound 18 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-([1,1'-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0432] 83% yield

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (bs, 1H), 9.25 (bs, 1H0, 8.46 (s, 1H), 8.14 (m, 2H), 8.08 (s, 1H), 7.87 (m, 1H), 7.81 (m, 3H), 7.65(m, 1H), 7.56(m, 3H), 7.46(m, 1H) 7.01(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0434]

[0435] 1.19 Synthesis of Chemical Formula 1-19(1-(2-(3-(tert-butyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0436]

[0437] Compound 19 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-(tert-butyl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0438] 85% yield

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (bs, 1H), 9.23 (bs, 1H), 8.20 (s, 1H), 8.08 (bs, 1H), 8.01 (s, 1H), 7.92 (m, 1H), 7.85 (m, 1H), 7.55(m, 3H), 6.98(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 15H)

[0440]

[0441] 1.20 Synthesis of Chemical Formula 1-20(1-(2-(4-fluoro-3-methylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0442]

[0443] Compound 20 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-fluoro-3-methylphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0444] 91% yield

[0445] 1H NMR (400 MHz, DMSO-d6) δ 12.70 (bs, 1H), 9.23 (bs, 1H), 8.10 (m, 2H), 7.98 (s, 2H), 7.86 (d, J = 8.0Hz, 1H), 7.549d, J = 8.0Hz, 1H), 7.32(m, 1H), 6.99(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 2.34(s, 3H), 1.37(s, 6H)

[0446]

[0447] 1.21 Synthesis of Chemical Formula 1-21(1-(2-(4-cyano-3-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0448]

[0449] Compound 21 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 4-(5-amino-1H-benzo[d]imidazol-2-yl)-2-fluorobenzonitrile in the same manner as Compound 1.

[0450] 82% yield

[0451] 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (bs, 1H), 9.30 (bs, 1H), 8.12 (m, 4H), 8.03 (bs, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.6 (bs, 1H), 7.06 (bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0452]

[0453] 1.22 Synthesis of Chemical Formula 1-22(1-(2-(4-cyano-2-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0454]

[0455] Compound 22 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 4-(5-amino-1H-benzo[d]imidazol-2-yl)-3-fluorobenzonitrile in the same manner as Compound 1.

[0456] 85% yield

[0457] 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (bs, 1H), 9.31 (bs, 1H), 8.39 (m, 1H), 8.09 (m, 3H), 7.87 (d, J = 8.0Hz, 2H), 7.65 (d, H = 8.0Hz, 1H), 7.09(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0458]

[0459] 1.23 Synthesis of Chemical Formula 1-23(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0460]

[0461] Compound 23 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0462] 90% yield

[0463] 1 H NMR (400 MHz, DMSO-d6) δ 12.84(bs, 1H), 9.25(bs, 1H), 9.27(s, 1H), 8.34(m, 1H), 8.11(s, 1H), 8.01(s, 1H), 7.86(d, J=8.0Hz, 1H), 7.58(d, H=8.0Hz, 1H), 7.44(d, J=8.0Hz, 1H), 7.00(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 2.55(s, 3H), 1.37(s, 6H)

[0464]

[0465] 1.24 Synthesis of Chemical Formula 1-24(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(5-methylpyridin-2-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0466]

[0467] Compound 24 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-methylpyridin-2-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0468] 79% yield

[0469] 1H NMR (400 MHz, DMSO-d6) δ 12.89 (bs, 1H), 9.24 (bs, 1H), 8.56 (s, 1H), 8.18 (m, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.80(m, 1H), 7.57(d, H=8.0Hz, 1H), 7.06(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 2.39(s, 3H), 1.37(s, 6H)

[0470]

[0471] 1.25 Synthesis of Formula 1-25 (1-(2-(2-cyano-3-methylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0472]

[0473] Compound 25 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-amino-1H-benzo[d]imidazol-2-yl)-6-methylbenzonitrile in the same manner as Compound 1.

[0474] 81% yield

[0475] 1 H NMR (400 MHz, DMSO-d6) δ 12.87(bs, 1H), 9.28(bs, 1H), 8.17(s, 1H), 8.05(bs, 1H), 7.87(d, J=8.0Hz, 2H), 7.78(m, 1H), 7.61(d, H=8.0Hz, 1H), 7.03(bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 2.60(s, 3H), 1.37(s, 6H)

[0476]

[0477] 1.26 Synthesis of Chemical Formula 1-26(1-(2-(2-cyanophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0478]

[0479] Compound 26 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-amino-1H-benzo[d]imidazol-2-yl)benzonitrile in the same manner as Compound 1.

[0480] 82% yield

[0481] 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (bs, 1H), 9.28 (bs, 1H), 8.13 (s, 1H), 8.07 (m, 3H), 7.88 (m, 2H), 7.69 (m, 2H), 7.03 (bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0482]

[0483] 1.27 Synthesis of Chemical Formula 1-27(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0484]

[0485] Compound 27 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-methoxyphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0486] 74% yield

[0487] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (bs, 1H), 9.20 (bs, 1H), 8.10 (m, 3H), 7.96 (s, 1H), 7.86 (d, J = 8.0Hz, 1H), 7.51 (d, H = 8.0Hz, 1H), 7.11(d, J=8.0Hz, 2H), 6.96(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.84(s, 3H), 3.74(s, 3H), 1.37(s, 6H)

[0488]

[0489] 1.28 Synthesis of Chemical Formula 1-28(1-(2-(3-fluoro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0490]

[0491] Compound 28 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 4-(5-amino-1H-benzo[d]imidazol-2-yl)-2-fluorophenol in the same manner as Compound 1.

[0492] 69% yield

[0493] 1 H NMR (400 MHz, DMSO-d6) δ 12.61(bs, 1H), 10.41(bs, 1H), 9.20(bs, 1H), 8.10(s, 1H), 7.95(s, 1H), 7.86(d, J=8.0Hz, 2H), 7.78(m, 1H), 7.51(d, J=8.0Hz, 1H), 7.08(m, 1H), 6.97(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0494]

[0495] 1.29 Synthesis of Formula 1-29 (1-(2-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0496]

[0497] Compound 29 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0498] 74% yield

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (bs, 1H), 9.27 (bs, 1H), 8.17 (m, 3H), 8.00 (m, 2H), 7.86 (d, J = 8.0Hz, 1H), 7.60 (m, 1H), 7.09 (bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0500]

[0501] 1.30 Synthesis of Formula 1-30 (1-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0502]

[0503] Compound 30 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0504] 72% yield

[0505] 1 H NMR (400 MHz, DMSO-d6) δ 12.63(bs, 1H), 9.29(bs, 1H), 8.46(m, 1H), 8.16(s, 1H), 8.06(bs, 1H), 7.97(d, J=12.0Hz, 1H), 7.87(d, J=8.0Hz, 1H), 7.78(d, J=8.0Hz, 1H), 7.62(bs, 1H), 7.08(bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0506]

[0507] 1.31 Synthesis of Chemical Formula 1-31(1-(2-(3,5-dihydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0508]

[0509] Compound 31 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0510] 38% yield

[0511] 1H NMR (400 MHz, DMSO-d6) δ 12.58(bs, 1H), 9.51(s, 2H), 9.21(bs, 1H), 8.10(bs, 1H), 7.94(s, 1H), 7.86(d, J=8.0Hz, 1H), 7.52(m, 1H), 7.36(m, 1H), 6.98(m, 2H), 6.55(m, 2H), 6.32(s, 1H), 5.84(d. J=12Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0512]

[0513] 1.32 Synthesis of Formula 1-32 (1-(2-(4-hydroxy-2-methylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0514]

[0515] Compound 32 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 4-(5-amino-1H-benzo[d]imidazol-2-yl)-3-methylphenol in the same manner as Compound 1.

[0516] 43% yield

[0517] 1 H NMR (400 MHz, DMSO-d6) δ12.24(bs, 1H), 9.75(s, 1H), 9.17(bs, 1H), 8.06(bs, 1H), 7.94(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.57(d, J=8.0Hz, 1H), 7.51(d, J=8.8Hz, 1H), 6.95(d, J=8.4Hz, 1H), 6.74(s, 2H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 2.55(s, 3H), 1.37(s, 6H)

[0518]

[0519] 1.33 Synthesis of Formula 1-33 (1-(2-(4-hydroxy-3-methylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0520]

[0521] Compound 33 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 4-(5-amino-1H-benzo[d]imidazol-2-yl)-2-methylphenol in the same manner as Compound 1.

[0522] 46% yield

[0523] 1 H NMR (400 MHz, DMSO-d6) δ 12.42(bs, 1H), 9.81(bs, 1H), 9.18(bs, 1H), 8.09(s, 1H), 7.87(m, 3H), 7.75(m, 1H), 7.49(d, J=8.4Hz, 1H), 6.88(m, 2H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 2.21(s, 3H), 1.37(s, 6H)

[0524]

[0525] 1.34 Synthesis of Chemical Formula 1-34 (1-(2-(6-cyanopyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0526]

[0527] Compound 34 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 5-(5-amino-1H-benzo[d]imidazol-2-yl)picolinonitrile in the same manner as Compound 1.

[0528] 84% yield

[0529] 1 H NMR (400 MHz, DMSO-d6) δ 13.20(bs, 1H), 9.45(s, 1H), 9.44(s, 1H), 8.65(d, J=8.0Hz, 1H), 8.23(d, J=8.4Hz, 1H), 8.14(s, 1H), 8.04(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.62(d, J=8.4Hz, 1H), 7.01(bs, 1H), 6.55(m, 2H), 5.84(d. J=12Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0530]

[0531] 1.35 Synthesis of Chemical Formula 1-35(1-(2-(5-fluoropyridin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0532]

[0533] Compound 35 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-fluoropyridin-2-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0534] 89% yield

[0535] 1H NMR (400 MHz, DMSO-d6) δ 12.94(s, 1H), 9.27(bs, 1H), 8.73(s, 1H), 8.34(bs, 1H), 8.11(s, 1H), 7.94(m, 2H), 7.90(d, J=15.6Hz, 1H), 7.60(d, J=8.4Hz, 1H), 7.06(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d. J=10Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0536]

[0537] 1.36 Synthesis of Chemical Formula 1-36(1-(2-(benzo[b]thiophen-5-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0538]

[0539] Compound 36 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(benzo[b]thiophen-5-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0540] 73% yield

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (bs, 1H), 9.24 (bs, 1H), 8.68 (bs, 1H), 8.16 (m, 3H), 8.01 (s, 1H), 7.89 (m, 2H), 7.59 (m, 2H), 7.00(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=10Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0542]

[0543] 1.37 Synthesis of Chemical Formula 1-37(1-(2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0544]

[0545] Compound 37 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0546] 78% yield

[0547] 1 H NMR (400 MHz, DMSO-d6) δ 12.85(bs, 1H), 9.42(s, 1H), 9.26(bs, 1H), 8.30(m, 3H), 8.07(m, 4H), 7.87(d, J=8.4Hz, 1H), 7.59(d, J=8.4Hz, 1H), 7.01(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d. J=9.6Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0548]

[0549] 1.38 Synthesis of Chemical Formula 1-38(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(2-methoxypyrimidin-5-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0550]

[0551] Compound 38 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2-methoxypyrimidin-5-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0552] 66% yield

[0553] 1 H NMR (400 MHz, DMSO-d6) δ 9.25(s, 3H), 8.12(s, 1H), 8.00(s, 1H), 7.84(d, J=8.8Hz, 1H), 7.58(d, J=8.8Hz, 1H), 7.27(m, 1H), 7.16(m, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 4.02(s, 3H), 3.74(s, 3H), 1.37(s, 6H)

[0554]

[0555] 1.39 Synthesis of Chemical Formula 1-39(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(2-methylpyrimidin-5-yl)-1H-benzo[d]imidazol-5-yl)urea).

[0556]

[0557] Compound 39 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2-methylpyrimidin-5-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0558] 67% yield

[0559] 1H NMR (400 MHz, DMSO-d6) δ 13.02(bs, 1H), 9.33(s, 2H), 9.27(bs, 1H), 8.12(s, 1H), 8.03(bs, 1H), 7.86(d, J=8.8Hz, 1H), 7.59(bs, 1H), 7.03(bs, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.71(s, 3H), 1.37(s, 6H)

[0560]

[0561] 1.40 Synthesis of Chemical Formula 1-40(1-(2-(4-((4-fluorobenzyl)oxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0562]

[0563] Compound 40 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-((4-fluorobenzyl)oxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0564] 70% yield

[0565] 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (bs, 1H), 9.20 (bs, 1H), 8.08 (m, 3H), 7.96 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.55 (m, 3H), 7.27 (m, 2H), 7.19(d, J=8.4Hz, 2H), 6.96(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 5.18(s, 2H), 3.74(s, 3H), 1.37(s, 6H)

[0566]

[0567] 1.41 Synthesis of Formula 1-41 (1-(2-(4-(benzyloxy)-3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0568]

[0569] Compound 41 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(benzyloxy)-3-chlorophenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0570] 74% yield

[0571] 1 H NMR (400 MHz, DMSO-d6) δ12.69(bs, 1H), 9.23(bs, 1H), 8.20(s, 1H), 8.10(m, 2H), 7.96(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.52(m, 3H), 7.44(m, 3H), 7.37(m, 1H), 6.97(m, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 5.31(s, 3H), 3.74(s, 3H), 1.37(s, 6H)

[0572]

[0573] 1.42 Synthesis of Chemical Formula 1-42(1-(2-((1S,3r)-adamantan-1-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0574]

[0575] Compound 42 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-((1S,3r)-adamantan-1-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0576] 86% yield

[0577] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (bs, 1H), 9.11 (bs, 1H), 8.05 (s, 1H), 7.83 (m, 2H), 7.41 (d, J = 8.8Hz, 1H), 6.92 (d, J = 8.4Hz, 1H), 6.55(m, 2H), 5.83(d, J=10.0Hz, 1H), 3.73(s, 3H), 2.07(s, 3H), 2.03(s, 6H), 1.76(s, 6H), 1.36(s, 6H)

[0578]

[0579] 1.43 Synthesis of Chemical Formula 1-43(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(piperidin-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0580]

[0581] Compound 43 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(piperidin-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0582] 85% yield

[0583] 1H NMR (400 MHz, DMSO-d6) δ 12.45(bs, 1H), 9.17(bs, 1H), 8.08(s, 1H), 7.96(m, 3H), 7.87(d, J=8.8Hz, 1H), 7.47(d, J=8.4Hz, 1H), 7.05(d, J=8.8Hz, 2H), 6.94(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 3.28(s, 4H), 1.60(s, 6H), 1.37(s, 6H)

[0584]

[0585] 1.44 Synthesis of Chemical Formula 1-44 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-phenylcyclohexyl)-1H-benzo[d]imidazol-5-yl)urea)

[0586]

[0587] Compound 44 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-phenylcyclohexyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0588] 79% yield

[0589] 1H NMR (400 MHz, DMSO-d6) δ 12.04(bs, 1H), 9.12(bs, 1H), 8.07(s, 1H), 7.84-7.69(s, 2H), 7.42(d, J=8.4Hz, 1H), 7.30(s, 4H), 7.19(m, 1H), 6.91(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.83(d, J=10.0Hz, 1H), 3.73(s, 3H), 2.88(m, 1H), 2.61(m, 2H), 2.19(d, J=12.0Hz, 2H), 1.95(d, J=12.4Hz, 2H), 1.73(m, 2H), 1.68(m, 2H), 1.37(s, 6H)

[0590]

[0591] 1.45 Synthesis of Chemical Formula 1-45(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(4-methylpiperidin-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0592]

[0593] Compound 45 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(4-methylpiperidin-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0594] 83% yield

[0595] 1H NMR (400 MHz, DMSO-d6) δ 12.45(bs, 1H), 9.17(bs, 1H), 8.08(bs, 1H), 7.94(m, 3H), 7.86(d, J=8.8Hz, 1H), 7.47(d, J=8.4Hz, 1H), 7.06(d, J=8.8Hz, 2H), 6.94(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.85(d, J=12.4Hz, 2H), 3.74(s, 3H), 2.76(m, 2H), 1.72(d, J=10.8Hz, 2H), 1.56(m, 1H), 1.37(s, 6H), 1.23(m, 2H), 0.96(s, 3H)

[0596]

[0597] 1.46 Synthesis of Chemical Formula 1-46(1-(2-(4-(dipropylamino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0598]

[0599] Compound 46 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(dipropylamino)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0600] 70% yield

[0601] 1H NMR (400 MHz, DMSO-d6) δ 12.31(bs, 1H), 9.159bs, 1H), 8.08(s, 1H), 7.90(m, 4H), 7.44(d, J=8.4Hz, 1H), 6.92(d, J=8.4Hz, 1H), 6.75(d, J=8.8Hz, 2H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 3.31(m, 4H), 1.58(q, 4H), 1.37(s, 6H), 0.97(t, 6H)

[0602]

[0603] 1.47 Synthesis of Chemical Formula 1-47 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(pyrimidin-5-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0604]

[0605] Compound 47 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(pyrimidin-5-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0606] 78% yield

[0607] 1 H NMR (400 MHz, DMSO-d6) δ 13.11(bs, 1H), 9.44(s, 2H), 9.27(s, 2H), 8.139s, 1H), 8.03(bs, 1H), 7.86(d, J=8.8Hz, 1H), 7.61(bs, 1H), 7.12(bs, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0608]

[0609] 1.48 Synthesis of formula 1-48 (1-(2-(4-((2-chloroethyl)(methyl)amino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0610]

[0611] Compound 48 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(pyrimidin-5-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0612] 68% yield

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 12.42(bs, 1H), 9.16(bs, 1H), 8.08(s, 1H), 7.98(m, 3H), 7.86(d, J=8.8Hz, 1H), 7.73(s, 1H), 7.46(d, J=8.4Hz, 1H), 6.94(d, J=8.8Hz, 1H), 6.87(d, J=8.4Hz, 2H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.78(s, 4H), 3.74(s, 3H), 1.37(s, 6H)

[0614]

[0615] 1.49 Synthesis of Formula 1-49 (1-(2-(4-((2-hydroxyethyl)(methyl)amino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0616]

[0617] Compound 49 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-((4-(5-amino-1H-benzo[d]imidazol-2-yl)phenyl)(methyl)amino)ethanol in the same manner as Compound 1.

[0618] 13% yield

[0619] 1 H NMR (400 MHz, DMSO-d6) δ12.37(bs, 1H), 9.15(bs, 1H), 9.04(s, 1H), 7.90(m, 4H), 7.45(d, J=8.8Hz, 1H), 6.93(d, J=8.8Hz, 1H), 6.82(d, J=8.8Hz, 2H), 6.55(m, 2H), 5.84(d, J=9.60Hz, 1H), 4.75(t, 1H), 3.59(m, 2H), 3.58(m, 2H), 3.01(s, 3H), 3.74(s, 3H), 1.37(s, 6H)

[0620]

[0621] 1.50 Synthesis of Chemical Formula 1-50(1-(2-(4-isobutoxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0622]

[0623] Compound 50 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-isobutoxyphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0624] 84% yield

[0625] 1H NMR (400 MHz, DMSO-d6) δ 12.55(bs, 1H), 9.19(bs, 1H), 8.06(m, 3H), 7.95(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.51(d, J=8.8Hz, 1H), 7.10(d, J=8.8Hz, 2H), 6.96(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.84(d, J=9.4Hz, 2H), 3.74(s, 3H), 1.36(s, 6H), 1.01(d, J=6.8Hz, 6H)

[0626]

[0627] 1.51 Synthesis of Chemical Formula 1-51(1-(2-(4-(tert-butoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0628]

[0629] Compound 51 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(tert-butoxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0630] 83% yield

[0631] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (bs, 1H), 9.21 (bs, 1H), 8.04 (m, 3H), 7.97 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.14(d, J=8.8Hz, 2H), 6.96(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.36(s, 15H)

[0632]

[0633] 1.52 Synthesis of Chemical Formula 1-52(1-(2-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0634]

[0635] Compound 52 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0636] 81% yield

[0637] 1 H NMR (400 MHz, DMSO-d6) δ 11.86(bs, 1H), 9.11(bs,1H), 8.03(s, 1H), 7.85(m, 2H), 7.65(s, 1H), 7.40(d, J=8.4Hz, 1H), 6.93(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.83(d, J=10.0Hz, 1H), 3.73(s, 3H), 2.15(m, 1H), 1.85(s, 2H), 1.69(q, 2H), 1.43(m, 2H), 1.37(s, 6H), 1.22(s, 2H), 0.88(s, 6H)

[0638]

[0639] 1.53 Synthesis of formula 1-53 (methyl(4-(5-(3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ureido)-1H-benzo[d]imidazol-2-yl)phenyl)carbamate)

[0640]

[0641] Compound 53 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with methyl (4-(5-amino-1H-benzo[d]imidazol-2-yl)phenyl)carbamate in the same manner as Compound 1.

[0642] 80% yield

[0643] 1 H NMR (400 MHz, DMSO-d6) δ 12.58(bs, 1H), 9.93(s, 1H), 9.22(bs, 1H), 8.07(m, 3H), 8.02(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.61(d, J=8.4Hz, 2H), 7.52(d, J=8.4Hz, 1H), 6.97(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0644]

[0645] 1.54 Synthesis of Chemical Formula 1-54 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(phenylamino)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0646]

[0647] Compound 54 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(phenylamino)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0648] 81% yield

[0649] 1H NMR (400 MHz, DMSO-d6) δ 12.46(bs, 1H), 9.18(bs, 1H), 8.54(s, 1H), 8.09(bs, 1H), 7.98(m, 3H), 7.87(d, J=8.8Hz, 1H), 7.49(d, J=8.4Hz, 1H), 7.30(m, 2H), 7.18(m, 4H), 6.92(m, 2H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0650]

[0651] 1.55 Synthesis of the chemical formula 1-55(1-(2-(4-((3r,5r,7r)-adamantan-1-ylmethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0652]

[0653] Compound 55 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-((3r,5r,7r)-adamantan-1-ylmethoxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0654] 76% yield

[0655] 1H NMR (400 MHz, DMSO-d6) δ 12.54(bs, 1H), 9.19(bs, 1H), 8.06(m, 3H), 7.94(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.50(d, J=8.8Hz, 1H), 7.10(d, J=8.8Hz, 2H), 6.96(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 3.62(s, 2H), 1.99(s, 3H), 1.63(m, 6H), 1.65(s, 6H), 1.37(s, 6H)

[0656]

[0657] 1.56 Synthesis of Chemical Formula 1-56(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-phenethoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0658]

[0659] Compound 56 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-phenethoxyphenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0660] 73% yield

[0661] 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (bs, 1H), 9.19 (bs, 1H), 8.09 (m, 3H), 7.94 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 7.11(d, J=8.8Hz, 2H), 6.96(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 4.28(t, 2H), 3.74(s, 3H), 3.08(t, 2H), 1.37(s, 6H)

[0662]

[0663] 1.57 Synthesis of Chemical Formula 1-57(1-(2-(4-(cyclopentyloxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0664]

[0665] Compound 57 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(cyclopentyloxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0666] 79% yield

[0667] 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (bs, 1H), 9.19 (bs, 1H), 8.06 (m, 3H), 7.94 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 7.06(d, J=8.8Hz, 2H), 6.95(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 4.91(m, 1H), 3.74(s, 3H), 1.97(m, 2H), 1.73(m, 4H), 1.61(m, 2H), 1.37(s, 6H)

[0668]

[0669] 1.58 Synthesis of formula 1-58 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0670]

[0671] Compound 58 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0672] 78% yield

[0673] 1 H NMR (400 MHz, DMSO-d6) δ 12.03(s, 1H), 9.18(bs, 1H), 8.10(bs, 1H), 8.00-7.85(m, 3H), 7.51(d, J=8.4Hz, 1H), 7.00(d, J=8.0Hz, 1H), 6.69(m, 2H), 6.54(m, 2H), 5.91(d, J=10.0Hz, 1H),5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 3.72(s, 3H), 1.43(s, 6H), 1.37(s, 6H)

[0674]

[0675] 1.59 Synthesis of Chemical Formula 1-59(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(thiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0676]

[0677] Compound 59 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(thiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0678] 80% yield

[0679] 1H NMR (400 MHz, DMSO-d6) δ 12.75(bs, 1H), 9.24(bs, 1H), 8.12(m, 3H), 8.03(s, 2H), 7.92(d, J=8.0Hz, 2H), 7.85(s, 1H), 7.68(s, 2H), 7.55(m, 1H), 6.99(m, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.75(s, 3H), 1.37(s, 6H)

[0680]

[0681] 1.60 Synthesis of the chemical formula 1-60(1-(2-(3-fluoro-4-(thiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0682]

[0683] Compound 60 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(3-fluoro-4-(thiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0684] 74% yield

[0685] 1 H NMR (400 MHz, DMSO-d6) δ 12.87(bs, 1H), 9.25(bs, 1H), 8.12(s, 1H), 8.00(m, 3H), 7.94(m, 2H), 7.87(d, J=8.8Hz, 1H), 7.74(d, J=5.2Hz, 1H), 7.62(d, J=5.2Hz, 1H), 7.55(m, 1H), 7.02(m, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0686]

[0687] 1.61 Synthesis of Chemical Formula 1-61(1-(2-(2,3-difluoro-4-(thiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0688]

[0689] Compound 61 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2,3-difluoro-4-(thiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0690] 68% yield

[0691] 1 H NMR (400 MHz, DMSO-d6) δ 12.60(bs, 1H), 9.28(bs, 1H), 8.13(s, 1H), 8.08(s, 1H), 8.03(m, 2H), 7.87(d, J=8.8Hz, 1H), 7.77(m, 2H), 7.64(m, 2H), 7.08(m, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0692]

[0693] 1.62 Synthesis of Formula 1-62 (1-(2-(2,3-difluoro-4-(2-methylthiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0694]

[0695] Compound 62 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(2,3-difluoro-4-(2-methylthiophen-3-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0696] 69% yield

[0697] 1 H NMR (400 MHz, DMSO-d6) δ 12.59 (bs, 1H), 9.28 (bs, 1H), 8.13 (s, 1H), 8.03 (m, 2H), 7.87 (d, J = 8.8Hz, 1H), 7.70 (s, 1H), 7.68 (m, 1H), 7.60(m, 1H), 7.33(s, 1H), 7.01(m, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.58(s, 3H), 1.37(s, 6H)

[0698]

[0699] 1.63 Synthesis of Formula 1-63 (1-(2-(4-(2-ethyl-2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0700]

[0701] Compound 63 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(2-ethyl-2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0702] 64% yield

[0703] 1H NMR (400 MHz, DMSO-d6) δ 12.91(bs, 1H), 9.27(bs, 1H), 8.33(d, J=8.0Hz, 2H), 8.24(d, J=8.4Hz, 2H), 8.13(s, 1H), 8.03(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.60(m, 1H), 7.02(m, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 4.80(t, 2H), 3.74(s, 3H), 1.60(q, 3H), 1.37(s, 6H)

[0704]

[0705] 1.64 Synthesis of formula 1-64 (1-(2-(4-(2-(cyclopropylmethyl)-2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0706]

[0707] Compound 64 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(2-(cyclopropylmethyl)-2H-tetrazol-5-yl)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0708] 67% yield

[0709] 1H NMR (400 MHz, DMSO-d6) δ 12.91(bs, 1H), 9.27(bs, 1H), 8.33(d, J=8.0Hz, 2H), 8.24(d, J=8.4Hz, 2H), 8.13(s, 1H), 8.03(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.60(m, 1H), 7.02(m, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 4.67(d, J=7.6Hz, 2H), 3.74(s, 3H), 1.47(m, 1H), 1.37(s, 6H), 0.65(m, 2H), 0.53(m, 2H)

[0710]

[0711] 1.65 Synthesis of Chemical Formula 1-65(1-(2-(5-cyanopyridin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0712]

[0713] Compound 65 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 6-(5-amino-1H-benzo[d]imidazol-2-yl)nicotinonitrile in the same manner as Compound 1.

[0714] 46% yield

[0715] 1 H NMR (400 MHz, DMSO-d6) δ 13.23(s, 1H), 9.33(s, 1H), 9.17(s, 1H), 8.40(m, 2H), 8.13(s, 1H), 8.01(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.65(d, J=8.4Hz, 1H), 7.09(d, J=8.0Hz, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0716]

[0717] 1.66 Synthesis of Chemical Formula 1-66(1-(2-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0718]

[0719] Compound 66 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0720] 72% yield

[0721] 1 H NMR (400 MHz, DMSO-d6) δ 12.75(bs, 1H), 9.24(bs, 1H), 8.92(s, 1H), 8.33(d, J=8.0Hz, 1H), 8.11(s, 1H), 8.00(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.50(m, 1H), 7.48(m, 2H), 7.39(m, 2H), 7.34(m, 1H), 7.08(d, J=8.8Hz, 1H), 6.97(m, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 5.44(s, 2H), 3.74(s, 3H), 1.37(s, 6H)

[0722]

[0723] 1.67 Synthesis of Chemical Formula 1-67(1-(2-(6-(tert-butyl)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0724]

[0725] Compound 67 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(6-(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0726] 76% yield

[0727] 1 H NMR (400 MHz, DMSO-d6) δ 12.85 (bs, 1H), 9.22 (m, 2H), 8.39 (d, J = 8.0Hz, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.87 (d, J = 8.8Hz, 1H), 7.60(d, J=8.4Hz, 1H), 7.57(m, 1H), 7.00(m, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.36(s, 15H)

[0728]

[0729] 1.68 Synthesis of Chemical Formula 1-68(1-(2-(5-cyclopropylpyridin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0730]

[0731] Compound 68 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-cyclopropylpyridin-2-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0732] 72% yield

[0733] 1H NMR (400 MHz, DMSO-d6) δ 12.87(bs, 1H), 9.24(bs, 1H), 8.55(s, 1H), 8.13(m, 2H), 7.93(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.58(m, 2H), 7.05(d, J=8.8Hz, 1H), 6.58(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.08(m, 1H), 1.36(s, 6H), 1.07(m, 2H), 0.85(m, 2H)

[0734]

[0735] 1.69 Synthesis of Chemical Formula 1-69(1-(2-(6-cyclopropylpyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0736]

[0737] Compound 69 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(6-cyclopropylpyridin-3-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0738] 75% yield

[0739] 1 H NMR (400 MHz, DMSO-d6) δ 12.85(bs, 1H), 9.25(s, 1H), 9.12(d, J=9.6Hz, 1H), 8.28(m, 1H), 8.13(s, 1H), 8.01(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.55(d, J=8.8Hz, 1H), 7.45(m, 1H), 6.99(d, J=8.4Hz, 1H), 6.58(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.18(m, 1H), 1.37(s, 6H), 1.03(m, 4H)

[0740]

[0741] 1.70 Synthesis of the chemical formula 1-70(1-(2-(4-((3s,5s,7s)-adamantan-1-yloxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0742]

[0743] Compound 70 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-((3s,5s,7s)-adamantan-1-yloxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0744] 76% yield

[0745] 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (bs, 1H), 9.21 (bs, 1H), 8.11 (m, 3H), 7.98 (s, 1H), 7.87 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.8Hz, 1H), 7.13(d, J=8.4Hz, 2H), 6.95(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.16(bs, 2H), 1.1.87(s, 6H), 1.61(m, 6H), 1.37(s, 6H)

[0746]

[0747] 1.71 Synthesis of formula 1-71 (1-(2-(4-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)oxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0748]

[0749] 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and

[0750] Compound 71 was prepared by reacting 2-(4-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)oxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0751] 69% yield

[0752] 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (bs, 1H), 9.22 (bs, 1H), 8.11 (m, 3H), 7.98 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.8Hz, 1H), 7.12(d, J=8.4Hz, 2H), 6.95(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.21(s, 1H), 1.73(s, 2H), 1.50(q, 4H), 1.37(s, 6H), 1.26(q, 4H), 1.11(s, 2H), 0.86(s, 6H)

[0753]

[0754] 1.72 Synthesis of Chemical Formula 1-72(1-(2-(4-(2-((3R,5R)-adamantan-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0755]

[0756] Compound 72 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(4-(2-((3R,5R)-adamantan-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0757] 73% yield

[0758] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (bs, 1H), 9.21 (bs, 1H), 8.11 (m, 3H), 7.94 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 7.09(d, J=8.8Hz, 2H), 6.96(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 4.12(m, 2H), 3.74(s, 3H), 1.95(s, 2H), 1.67(m, 6H), 1.59(s, 6H), 1.61(m, 2H), 1.37(s, 6H)

[0759]

[0760] 1.73 Synthesis of Chemical Formula 1-73(1-(2-(6-((3R,5R)-adamantan-1-yl)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0761]

[0762] Compound 73 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(6-((3R,5R)-adamantan-1-yl)pyridin-3-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0763] 71% yield

[0764] 1 H NMR (400 MHz, DMSO-d6) δ 12.90(bs, 1H), 9.25(s, 1H), 9.22(bs, 1H), 8.39(m, 1H), 8.12(bs, 1H), 8.02(s, 1H), 7.87(d, J=8.4Hz, 1H), 7.59(d, J=8.4Hz, 1H), 7.54(d, J=8.4Hz, 1H), 7.00(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.09(s, 3H), 1.99(s, 6H), 1.76(s, 6H), 1.37(s, 6H)

[0765]

[0766] 1.74 Synthesis of Chemical Formula 1-74(1-(2-(5-((3R,5R)-adamantan-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0767]

[0768] Compound 74 was prepared by reacting 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid with 2-(5-((3R,5R)-adamantan-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-5-amine in the same manner as Compound 1.

[0769] 69% yield

[0770] 1H NMR (400 MHz, DMSO-d6) δ 12.90(bs, 1H), 9.25(bs, 1H), 8.69(s, 1H), 8.22(m, 1H), 8.10(s, 1H), 7.95(s, 2H), 7.87(d, J=8.8Hz, 1H), 7.58(d, J=8.8Hz, 1H), 7.05(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.10(s, 3H), 1.99(s, 6H), 1.77(s, 6H), 1.37(s, 6H)

[0771]

[0772] 1.75 Synthesis of the chemical formula 1-75(1-(2-(4-(tert-butoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea).

[0773]

[0774] Step 1] Synthesis of 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene

[0775] In a pre-prepared methylene chloride (7 mL) solution of 5-methoxy-2,2-dimethyl-2H-chromen-6-amine (1.1 g, 0.534 mmol)

[0776] 1,1-thiocarbonyl diimidazole (1.0 g, 0.564 mmol) was slowly added dropwise in THF (40 mL) at room temperature and reacted for 1 hour. The solvent was removed by vacuum evaporation of the reaction mixture, and the oily liquid was separated and purified by silica gel column chromatography using ethyl acetate and n-hexane (1:3, v / v) to prepare the compound 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene (500 mg).

[0777]

[0778] Step 2] Synthesis of 1-(2-(4-(tert-butoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea

[0779] 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene (0.110 g, 0.4 mmol) and 2-(4-(tert-butoxy)phenyl)-1H-benzo[d]imidazol-5-amine (0.07 g, 0.2 mmol) were reacted at room temperature for 20 hours, after which the solvent was removed by vacuum evaporation. The oily liquid was separated and purified by silica gel column chromatography using ethyl acetate and n-hexane (1:1, v / v) to prepare the compound 1-(2-(4-(tert-butoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea75.

[0780] 81% yield

[0781] 1 H NMR (400 MHz, DMSO-d6) δ 12.79(s, 1H), 9.82(bs, 1H), 9.07(bs, 1H), 8.08(d, J=8.0Hz, 2H), 7.86(bs, 1H), 7.49(bs, 1H), 7.35(s, 1H), 7.16(m, 1H), 7.15(d, J=8.8Hz, 2H), 6.56(m, 2H), 5.80(d, J=10.0Hz, 1H), 3.76(s, 3H), 1.38(s, 6H), 1.37(s, 9H) (80.5%)

[0782]

[0783] 1.76 Synthesis of the chemical formula 1-76(1-(2-(4-((3r,5r,7r)-adamantan-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea).

[0784]

[0785] Compound 76 was prepared by reacting 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene with 2-(4-((3r,5r,7r)-adamantan-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine using the same preparation method as [2] of [Compound 75].

[0786] 76% yield

[0787] 1 H NMR (400 MHz, DMSO-d6) δ 12.83(bs, 1H), 9.83(bs, 1H), 9.06(bs, 1H), 8.10(d, J=7.6Hz, 2H), 7.85(bs, 1H), 7.49(m, 1H), 7.48(d, J=8.0Hz, 2H), 7.35(m, 1H), 7.10(m, 1H), 6.56(m, 2H), 5.80(d, J=10.0Hz, 1H), 3.76(s, 3H), 2.08(s, 3H), 1.99(s, 6H), 1.76(m, 6H), 1.38(s, 6H)

[0788]

[0789] 1.77 Synthesis of Formula 1-77 (1-(2-(4-((1R,2r,3S,5r)-adamantan-2-ylmethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea)

[0790]

[0791] Compound 77 was prepared by reacting 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene with 2-(4-((3r,5r,7r)-adamantan-1-ylmethoxy)phenyl)-1H-benzo[d]imidazol-5-amine using the same preparation method as [Method 2] of [Compound 75].

[0792] 77% yield

[0793] 1 H NMR (400 MHz, DMSO-d6) δ 12.76(bs, 1H), 9.81(bs, 1H), 9.04(bs, 1H), 8.08(d, J=8.0Hz, 2H), 7.81(s, 1H), 7.45(d, J=8.4Hz, 1H), 7.36(m, 1H), 7.19(m, 1H), 7.11(d, J=8.8Hz, 1H), 6.56(m, 2H), 5.80(d, J=10.0Hz, 1H), 3.75(s, 3H), 3.62(s, 2H), 1.99(s, 2H), 1.72(m, 5H), 1.65(s, 8H), 1.38(s, 6H)

[0794]

[0795] 1.78 Synthesis of the chemical formula 1-78(1-(2-(4-(tert-butyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea).

[0796]

[0797] Compound 78 was prepared by reacting 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene with 2-(4-(tert-butyl)phenyl)-1H-benzo[d]imidazol-5-amine using the same method as [2] of [Compound 75].

[0798] 80% yield

[0799] 1H NMR (400 MHz, DMSO-d6) δ 12.87(bs, 1H), 9.83(bs, 1H), 9.06(bs, 1H), 8.09(d, J=7.6Hz, 2H), 7.86(s, 1H), 7.49(m, 3H), 7.33(m, 1H), 7.10(m, 1H), 6.56(m, 2H), 5.80(d, J=10.0Hz, 1H), 3.76(s, 3H), 1.38(s, 6H), 1.33(s, 9H)

[0800]

[0801] 1.79 Synthesis of Chemical Formula 1-79(1-(2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)thiourea).

[0802]

[0803] Compound 79 was prepared by reacting 6-isothiocyanato-5-methoxy-2,2-dimethyl-2H-chromene with 2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-amine using the same preparation method as [Method 2] of [Compound 75].

[0804] 79% yield

[0805] 1 H NMR (400 MHz, DMSO-d6) δ 12.83(bs, 1H), 9.82(bs, 1H), 9.04(bs, 1H), 8.04(d, J=7.6Hz, 2H), 7.84(bs, 1H), 7.59(m, 1H), 7.45(m, 1H), 7.25(d, J=8.0Hz, 2H), 7.10(m, 1H), 6.55(m, 2H), 5.80(d, J=10.0Hz, 1H), 3.76(s, 3H), 1.99(m, 1H),1.38(s, 6H), 1.01(m, 2H), 0.78(m, 2H)

[0806]

[0807] Example 2. Confirmation of anticancer activity of cromen-benzimidazole derivative

[0808] 2.1 Cell viability screening of cromen-benzimidazole derivatives

[0809] Human triple-negative breast cancer (TNBC) cell line MDA-MB-231 (Cell seeding numbers: 0.8(M231) x 10 4 cells / wells (confluency ≥ 25%) and HER2-positive breast cancer (HER2+ BC) cell line JIMT-1 (Cell seeding numbers: 0.8(JIMT) x 10 4 cells / wells (confluency ≥ 25%)) were used in the experiment.

[0810] The above cell lines were each cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), streptomycin-penicillin (100 U / mL), and Fungizone (0.625 μg / mL) under 5% CO2, 37°C conditions.

[0811] In the above human breast cancer cell lines MDA-MB-231 and JIMT-1, cromen-benzimidazole derivatives of Formulas 1-1 to 1-79 were treated at various concentrations of 0, 1, and 5 μM, respectively, for 72 hours, and cell viability was measured using the MTS assay technique. For the MTS assay, cells were attached to a 96-well plate for 24 hours, then treated with the cromen-benzimidazole derivatives for 72 hours, followed by color development with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) for 4 hours, and the absorbance was measured at 490 nm using a Spectramax Plus384 microplate analyzer.

[0812] The measured results are shown in Figures 1 to 8. As a result, it was confirmed that most of the cromen-benzimidazole derivatives of Formulas 1-1 to 1-79 inhibited cell viability in a concentration-dependent manner in the human breast cancer cell lines MDA-MB-231 and JIMT-1.

[0813]

[0814] 2.2 Confirmation of Apoptotic Effects of Cromen-Benzimidazole Derivatives

[0815] The anticancer activity of cromen derivative active ingredients (chemical formulas 1-2, 1-40, 1-41, 1-42, 1-43, 1-48, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-60, 1-62, and 1-74) was evaluated in triple-negative breast cancer cell line MDA-MB-231. The cell culture conditions and MTS assay conditions were the same as in Example 2.

[0816] Specifically, MDA-MB-231 cells were seeded into a 96-well plate and allowed to adhere for 24 hours, after which the chromene derivative active ingredients (1-2, 1-40, 1-41, 1-42, 1-43, 1-48, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-60, 1-62, and 1-74) were treated at different concentrations (0, 0.01, 0.1, 0.5, 1, and 5 μM) for 72 hours. Subsequently, cell viability at each concentration was measured using the MTS assay technique.

[0817] Non-linear regression analysis was performed based on the acquired cell viability data to determine the IC50 of each compound 50 The values ​​were calculated. Cell viability curve and the corresponding IC. 50 The values ​​are shown in FIGS. 9 to 11. As a result, all of the chromene derivative active substances (1-2, 1-40, 1-41, 1-42, 1-43, and 1-48) inhibited the viability of MDA-MB-231 cells in a concentration-dependent manner, and exhibited excellent IC50 values ​​in the nanomolar (nM) concentration range. 50 It was confirmed that it represents a value.

[0818]

[0819] Example 3. Confirmation of activity and applicable cancer types of cromen-benzimidazole derivatives

[0820] 3.1 Observation of Cell Morphological Changes

[0821] The apoptosis-inducing effect of the chromene derivative active ingredient of the present invention on triple-negative breast cancer cell line MDA-MB-231 was evaluated through changes in cell morphology. The cell culture conditions were performed in the same manner as in Example 2.1.

[0822] Specifically, MDA-MB-231 cells were seeded into a 96-well plate and allowed to adhere for 24 hours, after which the chromene derivative active ingredients, compounds 1-42, 1-51, 1-52, and 1-54, were treated at different concentrations (0, 0.05, 0.1, and 0.5 μM), respectively, for 48 hours. After treatment, morphological changes in the cells were observed using an optical microscope in each well without removing the medium, and the results are shown in Figure 12.

[0823] As a result, in the group treated with the above-mentioned chromene derivative active substances (1-42, 1-51, 1-52 and 1-54), typical apoptotic patterns such as cell shrinkage, cell body atrophy, reduced adhesion, and broken cell debris were observed compared to the control group (0 μM), and it was confirmed that these changes increased in a concentration-dependent manner as the concentration of the compound increased.

[0824]

[0825] 3.2 Confirmation of Apoptosis Induction by Cromen-Benzimidazole Derivatives

[0826] The degree of apoptosis induction by the chromene derivative active ingredient of the present invention in triple-negative breast cancer cell line MDA-MB-231 was evaluated by Annexin V / PI double staining. Cell culture conditions were performed in the same manner as in Example 2.1.

[0827] Specifically, MDA-MB-231 cells were attached to a culture dish and treated with chromene derivative active ingredients, compounds 1-42, 1-51, 1-52, and 1-54, for 48 hours each. After treatment, both suspension and adhered cells were collected, washed with PBS, and then stained with Annexin V and propidium iodide (PI) according to the protocol of a commercial Annexin V / PI staining kit. The stained cells were analyzed using a flow cytometer, and Annexin V-positive / PI-negative cells (early apoptosis) and Annexin V-positive / PI-positive cells (late apoptosis) were quantified, respectively.

[0828] The results are shown in Figure 13. It was confirmed that the proportion of early and late apoptotic cell populations significantly increased in all groups treated with chromene derivative active substances (1-42, 1-51, 1-52 and 1-54) compared to the control group, indicating that the active substances induce apoptosis in MDA-MB-231 cells.

[0829]

[0830] 3.3 Confirmation of Changes in Apoptosis-Related Protein Expression by Cromen-Benzimidazole Derivatives

[0831] Changes in apoptosis-related signaling proteins following treatment with the chromene derivative active ingredient of the present invention in triple-negative breast cancer cell line MDA-MB-231 were evaluated using Western blot. Cell culture conditions were performed in the same manner as in Example 2.1.

[0832] Specifically, MDA-MB-231 cells were seeded into culture dishes and allowed to adhere for 24 hours. Subsequently, the cells were treated with chromene derivative active ingredients, compounds 1-42, 1-51, 1-52, and 1-54, at various concentrations (0, 0.05, 0.1, and 0.5 μM), for 48 hours. After treatment, the cells were collected, proteins were extracted using lysis buffer, separated by SDS-PAGE, and transferred to a PVDF membrane. Subsequently, an immunoassay was performed using primary antibodies against PARP, cleaved caspase-3, cleaved caspase-7, and cleaved caspase-8, as well as their corresponding secondary antibodies. Changes in the expression of apoptosis-related proteins were observed by developing colorimetric reactions with ECL reagent. β-actin was used for loading and as an internal control.

[0833] The results are shown in Fig. 14. In the groups treated with compounds 1-42, 1-51, 1-52, and 1-54, a decrease in total protein expression of PARP and an increase in cleaved PARP were observed compared to the control group (0 μM), and it was confirmed that the expression of the active cleaved form of caspase-3, caspase-7, and caspase-8 increased in a concentration-dependent manner. From these results, it was found that the chromene derivative active substances mediated apoptosis in MDA-MB-231 cells by activating the caspase chain reaction and inducing PARP cleavage.

[0834]

[0835] 3.4 Confirmation of Regulation of HSP90 Substrate Protein Expression by Cromen Derivative Active Substances

[0836] Changes in the expression of HSP90 client proteins following treatment with the chromene derivative active ingredient of the present invention in triple-negative breast cancer cell line MDA-MB-231 were evaluated using Western blot. Cell culture conditions were performed in the same manner as in Example 2.1.

[0837] Specifically, MDA-MB-231 cells were seeded into culture dishes and allowed to adhere for 24 hours, after which they were treated with chromene derivative active ingredients, compounds 1-42, 1-51, 1-52, and 1-54, at different concentrations (0, 0.05, 0.1, and 0.5 μM), respectively, for 48 hours. After treatment, the cells were harvested, proteins were extracted, separated by SDS-PAGE, and transferred to a PVDF membrane. Subsequently, an immunoassay was performed using primary and secondary antibodies against EGFR, c-MET, JAK2, STAT3, and Survivin, which are known HSP90 substrate proteins, and protein bands were detected using ECL reagent. GAPDH was used as an internal control to correct for protein loading.

[0838] The results are shown in Fig. 15. In the group treated with the chromene derivative active substances of the present invention (1-42, 1-51, 1-52 and 1-54), the expression of p-EGFR protein, the activated form of EGFR, was significantly reduced compared to the control group (0 μM), and at the same time, it was confirmed that the expression of c-MET, JAK2, STAT3, and Survivin proteins decreased in a concentration-dependent manner as the concentration of the compound increased. From these results, it was found that the chromene derivative active substances inhibit the stability of multiple substrate proteins by regulating the function of HSP90, and thereby effectively inhibit signaling pathways involved in cancer cell survival and proliferation.

[0839]

[0840] 3.5 Confirmation of Anticancer Activity of Cromen Derivatives by Cancer Type

[0841] To confirm the anticancer activity of the chromene derivative compounds 1-42 and 1-52 of the present invention in different cancer types, blood cancer cell line HL-60, liver cancer cell line HepG2, lung cancer cell line H1299, colorectal cancer cell line HCT116, and ovarian cancer cell line SKOV3 were used. Each cell line was cultured at 37°C and 5% CO₂ using the culture conditions and media recommended by the manufacturer.

[0842] The above cell lines were seeded into a 96-well plate and allowed to attach or stabilize for 24 hours, after which they were treated with chromene derivative compounds 1-42 or 1-52 at different concentrations (0, 0.01, 0.1, 0.5, 1, and 5 μM) for 48 hours. After treatment, cell viability at each concentration was measured using the MTS assay technique. Specifically, after compound treatment, the MTS reagent was added to each well and reacted for a set period of time (e.g., 4 hours), and then the absorbance at 490 nm was measured to calculate the relative cell viability (%) compared to the control group (0 μM treatment group).

[0843] Non-linear regression analysis was performed based on the acquired concentration-response data to determine the IC50 of compounds 1-42 and 1-52 in each cell line. 50 Values ​​were calculated, and the results are shown in Fig. 16 (Compound 1-42) and Fig. 17 (Compound 1-52), respectively. As a result, in all the aforementioned carcinoma cell lines (HL-60, HepG2, H1299, HCT116, and SKOV3), chromene derivative compounds 1-42 and 1-52 significantly inhibited cell viability in a concentration-dependent manner and exhibited excellent IC50 values ​​in the nanomolar (nM) concentration range. 50 It was confirmed that it exhibits a value. Through this, it was confirmed that the chromene derivative compounds 1-42 and 1-52 of the present invention are effective substances having effective anticancer activity against various types of cancer other than breast cancer.

[0844]

[0845]

[0846] Although the embodiments have been described above with reference to the limited drawings, those skilled in the art can apply various technical modifications and variations based on the above. For example, suitable results may be achieved even if the described techniques are performed in a different order than described, and / or if the components of the described system, structure, device, circuit, etc. are combined or assembled in a form different from described, or replaced or substituted by other components or equivalents.

[0847] Therefore, other implementations, other embodiments, and equivalents to the claims also fall within the scope of the claims set forth below.

Claims

1. Cromen-benzimidazole derivatives represented by the following [Chemical Formula 1] or pharmaceutically acceptable salts thereof: In the above chemical formula 1, R 1 C5-C with substituted or unsubstituted 20 aryl groups, substituted or unsubstituted C4-C 20 heteroaryl groups, substituted or unsubstituted C3-C 20 It is either a cycloalkyl group and 5-methoxy-2,2-dimethyl-2H-chromene, and The above aryl group is phenyl or naphthyl, and The above heteroaryl group is any one of pentodioxol, pyridyl, pyrimidinyl, and benzothiophen, and The above cycloalkyl group is adamantyl or cyclohexyl, and Where the above phenyl is substituted, acetylamino, halogen, methyl, -CF3, phenyl, -CN, tert-butyl, substituted or unsubstituted methoxy(-OCH3), cyclopentyloxy, adamanthyloxy, dimethyladamanthyloxy, tert-butoxy, isobutoxy, hydroxy, triazole, piperidine, -NR 2 R 3 It is substituted with one or more selected from the group consisting of thiophene and tetrazole, and The above R 2 , R 3 Each is independently selected from the group consisting of hydrogen, C1-C3 alkyl, halogen alkyl, hydroxyethyl, methoxycarbonyl, and phenyl, and The above X is O or S.

2. In Paragraph 1, In the above [Chemical Formula 1], When the methoxy group substituted on the above phenyl is substituted, it is substituted with one or more selected from the group consisting of phenyl (which may be unsubstituted or substituted with a halogen), 2-phenylethyl, adamantyl, and adamantylmethyl, and The piperidine substituted on the phenyl group above may be unsubstituted or substituted with a methyl group, and The thiophene substituted on the phenyl group above may be unsubstituted or substituted with methyl, and A cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof in which the tetrazole substituted with the phenyl is unsubstituted or substituted with ethyl or cyclopropylmethyl.

3. In Paragraph 1, In the above [Chemical Formula 1], The above pyridyl is unsubstituted or substituted with any one of CN, halogen, benzyloxy, tert-butyl, cyclopropyl, and adamantyl, and The above pyrimidinyl is unsubstituted or substituted with methoxy or methyl, and The above cyclohexyl is unsubstituted or substituted with phenyl, and The above adamantyl is a cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof that is unsubstituted or methyl-substituted.

4. In Paragraph 1, In the above [Chemical Formula 1], The above R1 is any one of the following cromen-benzimidazole derivatives or pharmaceutically acceptable salts thereof selected from the group consisting of: and .

5. A cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof characterized in that the cromen-benzimidazole derivative represented by [Chemical Formula 1] above is selected from the group consisting of the following compounds: and .

6. In Paragraph 1, The above cromen-benzimidazole derivative is characterized by having both an effect of inhibiting tubulin polymerization and an effect of inhibiting the C-terminal domain of Hsp90, and is a cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof.

7. In Paragraph 1, A cromen-benzimidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt of the above-mentioned cromen-benzimidazole derivative is one or more selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipose salt, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

8. A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient a cromen-benzimidazole derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. In Paragraph 8, The above pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer, characterized by inducing apoptosis by arresting the cancer cell cycle.

10. In Paragraph 8, The above pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of cancer, characterized by inducing denaturation and degradation of oncoproteins.

11. In Paragraph 8, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the above cancer is one or more selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, blood cancer, thymic cancer, urethral cancer, and bronchial cancer.

12. In Paragraph 8, A pharmaceutical composition for the prevention or treatment of cancer, characterized in that the cancer is triple-negative breast cancer.

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