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 containing the derivative as an active ingredient for preventing or treating cancer. The chromene-benzimidazole derivative of 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 chromene-benzimidazole derivatives or pharmaceutically acceptable salts thereof and uses thereof

[0001] The present invention relates to a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof and its use.

[0002] Patients with triple-negative breast cancer (TNBC; ER-, PR-, HER2-) account for 10-15% of all breast cancer patients and lack hormone receptors (ER (estrogen receptor), PR (progesterone receptor)) and the HER2 protein, making them ineligible for hormonal therapy or HER2-targeted therapies. Currently, the standard treatment for triple-negative breast cancer relies entirely on conventional cytotoxic chemotherapy (taxene or anthracycline). Because there are no established targeted therapies, treatment strategies for other subtypes are less diverse than for breast cancer. Furthermore, most patients experience recurrence within 2-3 years after surgery or chemotherapy, and metastases easily develop in other organs such as the lungs, liver, brain, and bones, reducing patient survival rates.

[0003] The five-year overall survival rate for patients diagnosed with stage III (stage-III) cancer is less than 55%, and for patients with advanced metastases, the five-year survival rate is even lower, at less than 30%. Most of these patients ultimately suffer from a very serious disease that ultimately leads to death within several years.

[0004] Microtubules, a key component of the cytoskeleton, are composed of tubulin heteropolymers composed of α and β subunits. Microtubules perform various cellular functions, including intracellular transport, maintaining polarity, intracellular signaling, cell migration, and proliferation. During mitosis, microtubules form a spindle, which aligns chromosomes at the center of the cell and then separates them toward the poles. Failure of the spindle to function properly inhibits cell division, leading to apoptosis. Therefore, microtubules are attracting attention as potential targets for anticancer drugs.

[0005] Drugs that target microtubules are broadly divided into two groups: those that stabilize microtubules and those that destabilize them. First, microtubule stabilizers, such as taxanes, paclitaxel (Taxol), and decetaxel, prevent microtubule depolymerization and enhance microtubule polymerization. Most microtubule-stabilizing agents bind to the taxane-binding site or the overlapping site on β-tubulin. Second, microtubule destabilizing agents, such as colchicine and vinca alkaloids, bind to the colchicine-binding site or the vinca-binding site. These microtubule-targeting agents are effective at lower concentrations than those that affect microtubule polymerization, and both inhibit mitosis. Therefore, there is a pressing need to develop potential tubulin polymerization inhibitors as anticancer agents.

[0006] Heat shock protein 90 (Hsp90) is one of the most abundant molecular chaperones in eukaryotic cells. It is involved in the folding, stabilization, activation, and complex formation of target proteins, called "client proteins." Hsp90 regulates the stabilization and activity of various kinases, transcription factors, signaling molecules, and enzymes under normal and stress conditions, thereby playing a role in various biological functions related to cell growth, differentiation, and survival. Furthermore, Hsp90 contributes to the evolution of organisms and the maintenance of disease states by acting as a buffer for unstable proteins within cells. In particular, Hsp90 has attracted significant attention as a target for anticancer drugs, as it has been revealed that over 50 proteins, including Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, and hTERT, which are involved in the development of cancer cells, are Hsp90 client proteins. Hsp90 inhibitors have the potential to be used as anticancer agents for various types of cancer by simultaneously inducing proteasome degradation of various cancer-causing proteins, and are showing positive results in clinical trials currently in progress at various stages.

[0007] The technical problem to be achieved by the present invention is to provide a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof.

[0008] In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0010] To solve the above problem, the present invention provides a chromene-benzimidazole derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof:

[0011] [Chemical Formula 1]

[0012]

[0013] In the above chemical formula 1,

[0014] R 1 is hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl group of C1-C6, substituted or unsubstituted C3-C 20 Cycloalkyl group, substituted or unsubstituted C3-C 20 Heterocycloalkyl group, substituted or unsubstituted C3-C 20 Aryl group and substituted or unsubstituted C3-C 20 Any one selected from the group consisting of heteroaryl groups,

[0015] If the above straight-chain or branched alkyl group is substituted, it is substituted with halogen,

[0016] When the above cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is substituted, straight or branched C1-C6 alkyl, C1-C 10 of Substituted with at least one selected from the group consisting of cycloalkyl, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl.

[0017] According to one side, in the above [chemical formula 1],

[0018] R 1 The substituted or unsubstituted straight-chain or branched C1-C6 alkyl group is a substituted or unsubstituted methyl group, and when the methyl group is substituted, it is substituted with a halogen,

[0019] R 1Substituted or unsubstituted C3-C 20 The cycloalkyl group of is an unsubstituted cyclohexyl group,

[0020] R 1 Substituted or unsubstituted C3-C 20 The heterocycloalkyl group is a methylpiperazine group,

[0021] R 1 Substituted or unsubstituted C3-C 20 The aryl group of is a substituted or unsubstituted phenyl group, and when the phenyl group is substituted, it is a straight or branched C1-C6 alkyl, C1-C 10 of Substituted with at least one selected from the group consisting of cycloalkyl, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl,

[0022] R 1 Substituted or unsubstituted C3-C 20 The heteroaryl group may be any one selected from the group consisting of a pyridyl group, a thiophenyl group, and a thiazolyl group.

[0023] According to one side, in the above [chemical formula 1],

[0024] R 1 is a substituted or unsubstituted phenyl group,

[0025] When the above phenyl group is substituted, it may be substituted with at least one selected from the group consisting of methyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, F, Cl, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, methoxy, N,N-dimethylamino, N,N-diethylamino, nitro, phenyl, phenoxy, benzoyloxymethyl, n-pentyloxy, indole, methylpiperazine, and benzoyl.

[0026] According to one aspect, the chromene-benzimidazole derivative represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds:

[0027] [Chemical Formula 1-1]

[0028]

[0029] [Chemical Formula 1-2]

[0030]

[0031] [Chemical Formula 1-3]

[0032]

[0033] [Chemical Formula 1-4]

[0034]

[0035] [Chemical Formula 1-5]

[0036]

[0037] [Chemical Formula 1-6]

[0038]

[0039] [Chemical Formula 1-7]

[0040]

[0041] [Chemical Formula 1-8]

[0042]

[0043] [Chemical Formula 1-9]

[0044]

[0045] [Chemical Formula 1-10]

[0046]

[0047] [Chemical Formula 1-11]

[0048]

[0049] [Chemical Formula 1-12]

[0050]

[0051] [Chemical Formula 1-13]

[0052]

[0053] [Chemical Formula 1-14]

[0054]

[0055] [Chemical Formula 1-15]

[0056]

[0057] [Chemical Formula 1-16]

[0058]

[0059] [Chemical Formula 1-17]

[0060]

[0061] [Chemical Formula 1-18]

[0062]

[0063] [Chemical Formula 1-19]

[0064]

[0065] [Chemical Formula 1-20]

[0066]

[0067] [Chemical Formula 1-21]

[0068]

[0069] [Chemical Formula 1-22]

[0070]

[0071] [Chemical Formula 1-23]

[0072]

[0073] [Chemical Formula 1-24]

[0074]

[0075] [Chemical Formula 1-25]

[0076]

[0077] [Chemical Formula 1-26]

[0078]

[0079] [Chemical Formula 1-27]

[0080]

[0081] [Chemical Formula 1-28]

[0082]

[0083] [Chemical Formula 1-29]

[0084]

[0085] [Chemical Formula 1-30]

[0086]

[0087] [Chemical Formula 1-31]

[0088]

[0089] [Chemical Formula 1-32]

[0090]

[0091] [Chemical Formula 1-33]

[0092]

[0093] [Chemical Formula 1-34]

[0094]

[0095] [Chemical Formula 1-35]

[0096]

[0097] [Chemical Formula 1-36]

[0098]

[0099] [Chemical Formula 1-37]

[0100]

[0101] [Chemical Formula 1-38]

[0102]

[0103] [Chemical Formula 1-39]

[0104]

[0105] [Chemical Formula 1-40]

[0106]

[0107] [Chemical Formula 1-41]

[0108]

[0109] [Chemical Formula 1-42]

[0110]

[0111] [Chemical Formula 1-43]

[0112]

[0113] [Chemical Formula 1-44]

[0114]

[0115] [Chemical Formula 1-45]

[0116]

[0117] [Chemical Formula 1-46]

[0118]

[0119] [Chemical Formula 1-47]

[0120]

[0121] [Chemical Formula 1-48]

[0122]

[0123] [Chemical Formula 1-49]

[0124]

[0125] [Chemical Formula 1-50]

[0126]

[0127] [Chemical Formula 1-51]

[0128]

[0129] [Chemical Formula 1-52]

[0130] and

[0131] [Chemical Formula 1-53]

[0132] .

[0133] According to one side, the chromene-benzimidazole derivative represented by the above [chemical formula 1] may be any one selected from the group consisting of the following compounds.

[0134] [Chemical Formula 1-1]

[0135]

[0136] [Chemical Formula 1-9]

[0137]

[0138] [Chemical Formula 1-10]

[0139]

[0140] [Chemical Formula 1-11]

[0141]

[0142] [Chemical Formula 1-13]

[0143]

[0144] [Chemical Formula 1-15]

[0145]

[0146] [Chemical Formula 1-16]

[0147]

[0148] [Chemical Formula 1-17]

[0149]

[0150] [Chemical Formula 1-19]

[0151] and

[0152] [Chemical Formula 1-22]

[0153] .

[0154] According to one side, the chromene-benzimidazole derivative may have both the effect of inhibiting tubulin polymerization and the effect of inhibiting the C-terminal domain of Hsp90.

[0155] According to one aspect, the pharmaceutically acceptable salt of the chromene-benzimidazole derivative may be at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

[0156] According to another embodiment of the present invention, a pharmaceutical composition for preventing or treating cancer is provided, comprising any one of the above chromene-benzimidazole derivatives, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0157] According to one side, the cancer may be at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine 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, and preferably triple-negative breast cancer.

[0158]

[0159] In addition, the present invention provides a composition for preventing or treating cancer, comprising the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0160] In addition, the present invention provides a method for preventing or treating cancer, comprising a step of administering the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0161] Furthermore, the present invention provides the use of the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of cancer.

[0162] In addition, the present invention provides a method for diagnosing cancer, comprising a step of administering the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0163] Furthermore, the present invention provides the use of the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for cancer diagnosis.

[0164] As one embodiment of the present invention, the pharmaceutical composition may induce apoptosis by arresting the cell cycle of cancer cells, or may induce denaturation and degradation of oncoproteins, and preferably, both mechanisms may be performed.

[0165] In another embodiment of the present invention, the cancer may be at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine 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, leukemia, thymic cancer, urethral cancer, and bronchial cancer, and preferably may be breast cancer, and more preferably may be triple-negative breast cancer.

[0166] The present invention relates to a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer comprising the derivative as an active ingredient, wherein the chromene-benzimidazole derivative of the present invention is activated in cancer cells to inhibit tubulin polymerization and simultaneously inhibit the C-terminal domain of the Hsp90 protein, thereby blocking the cancer cell cycle, inducing apoptosis, and inhibiting the activity of oncoproteins when administered to a subject, thereby exhibiting cytotoxicity and simultaneously obtaining an anticancer effect. Therefore, the compound of the present invention and a composition comprising the same can be used as a novel dual-target anticancer composition for preventing or treating cancer, preferably for preventing or treating triple-negative breast cancer.

[0167] The effects of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

[0168] Figure 1 shows the results of evaluating the change in cell viability through MTS assay after treatment with chromene-benzimidazole derivative compounds (1-1 to 1-8) at different concentrations (0, 1, 5 μM) in triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1.

[0169] Figure 2 shows the results of evaluating the change in cell viability through MTS assay after treatment with chromene-benzimidazole derivative compounds (1-9 to 1-18) at different concentrations (0, 1, 5 μM) in triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1.

[0170] Figure 3 shows the results of evaluating the change in cell viability through MTS assay after treatment with chromene-benzimidazole derivative compounds (1-19 to 1-28) at different concentrations (0, 1, 5 μM) in triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1.

[0171] Figure 4 shows the results of evaluating the change in cell viability through MTS assay after treatment with chromene-benzimidazole derivative compounds (1-29 to 1-38) at different concentrations (0, 1, 5 μM) in triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1.

[0172] Figure 5 shows the results of evaluating the change in cell viability through MTS assay after treatment with chromene-benzimidazole derivative compounds (1-39 to 1-46) at different concentrations (0, 1, 5 μM) in triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1.

[0173] Figure 6 shows the results of evaluating the change in cell viability through MTS assay after treatment with chromene-benzimidazole derivative compounds (1-47 to 1-53) at different concentrations (0, 1, 5 μM) in triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1.

[0174] Figure 7 shows that the chromene-benzimidazole derivative compound (1-1) inhibits cell viability and induces cell death in a concentration-dependent manner in triple-negative breast cancer cell lines MDA-MB-231 and BT549, and induces early and late apoptosis.

[0175] Figure 8 shows that the chromene-benzimidazole derivative inhibits the function of Hsp90 by binding to the C-terminal domain of Hsp90, exerts an anticancer effect by inhibiting tubulin polymerization reaction, reduces the expression and phosphorylation of STAT3, c-MET, ERK, and AKT proteins in MDA-MB-231 and BT549 cell lines, and induces G2 / M phase cell cycle arrest.

[0176] Figure 9 shows the results of MTS assay to confirm the concentration-dependent inhibition of cell viability and IC50 values ​​after treatment with chromene-benzimidazole derivative compounds (1-13, 1-19, 1-22) at various concentrations in triple-negative breast cancer cell lines MDA-MB-231 and JIMT-1.

[0177] Figure 10 shows the results of observing morphological changes of cell cycle arrest and apoptosis through optical microscopy and Western blot techniques after treating MDA-MB-231 cell lines with compounds 1-22 and 1-13, and confirming the expression of Hsp90 complex, Hsp90 substrate protein, tubulin targeting ability, and apoptosis-related proteins.

[0178] Figure 11 shows the effect of chromene-benzimidazole derivative compound 1-22 on blood cancer, liver cancer, lung cancer, colon cancer, and ovarian cancer cell lines.

[0179] Figure 12 shows the effect of chromene-benzimidazole derivative compound 1-13 on blood cancer, liver cancer, lung cancer, colon cancer, and ovarian cancer cell lines.

[0180] Figure 13 shows the results of confirming the concentration-dependent cell viability (MTS assay) inhibitory effect and confirming the IC50 value by treating the triple-negative breast cancer cell line MDA-MB-231 with chromene-benzimidazole derivative compounds (1-9, 1-10, 1-11, 1-15, 1-16, and 1-17).

[0181] Figure 14 shows the results of a comparative evaluation of cell viability of reference compounds with a similar structure to chromene-benzimidazole derivative compounds (1-19 and 1-22) in MDA-MB-231 and JIMT-1 cell lines.

[0182] The present inventors have confirmed that benzimidazole derivatives have anticancer effects by inhibiting tubulin synthesis, thereby arresting the cell cycle and thereby inhibiting cancer cell division, and that chromene derivatives can have anticancer effects by inhibiting the C-terminal domain of Hsp90. They have also confirmed the possibility of activating both mechanisms of action by combining benzimidazole and chromene in a single compound molecule, and thus, they have completed the invention and provide a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof as a novel dual-target anticancer drug.

[0183] From the above results, the present invention provides a chromene-benzimidazole derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof:

[0184] [Chemical Formula 1]

[0185]

[0186] In the above chemical formula 1,

[0187] R 1 is hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl group of C1-C6, substituted or unsubstituted C3-C 20 Cycloalkyl group, substituted or unsubstituted C3-C 20 Heterocycloalkyl group, substituted or unsubstituted C3-C 20 Aryl group and substituted or unsubstituted C3-C 20 Any one selected from the group consisting of heteroaryl groups,

[0188] If the above straight-chain or branched alkyl group is substituted, it is substituted with halogen,

[0189] When the above cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is substituted, straight or branched C1-C6 alkyl, C1-C 10 of Substituted with at least one selected from the group consisting of cycloalkyl, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl.

[0190] In the present invention, the term “substitution” refers to a reaction in which an atom or atomic group included in a molecule of a compound is replaced with another atom or atomic group.

[0191] In the present invention, the term “chain-like” refers to a molecule having a chain-like structure, and the chain-like structure is a chemical structure in which carbon atoms are connected in a chain shape, and there are straight chain-like types and branched chain-like types.

[0192] In the present invention, the term “cyclic” refers to a structure in which both ends of the skeleton of an organic compound are connected to form a ring shape.

[0193] In the present invention, the term “straight-chain 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.

[0194] In the present invention, the term “cyclic alkyl group” or “cycloalkyl group” means a cyclic saturated hydrocarbon residue.

[0195] 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, cyclopentyl, cyclohexyl, and the like.

[0196] In the present invention, the term "heterocycloalkyl group" typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, monosubstituted or polysubstituted, and in the structure of which at least one is selected from a heteroatom of N, O or S.

[0197] In the present invention, the term "aryl group" means an unsaturated aromatic ring compound having 3 to 12 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0198] In the present invention, the term “heteroaryl group” refers to a single ring or multiple condensed rings in which at least one of the atoms constituting the ring has a heteroatom of N, O, or S. Examples of such heteroaryl groups include, but are not limited to, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, an oxazolyl group, a furyl group, and the like.

[0199] In the present invention, the term “alkoxy group” refers to an alkyl group (-OR) bonded to oxygen. Examples of such alkoxy groups include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and the like.

[0200] In the present invention, the “halogen group” may be fluorine (F), chloride (Cl), bromine (Br), or iodine (I).

[0201] As a preferred embodiment of the present invention, the compound represented by the above chemical formula 1 is preferably at least one selected from the group consisting of the following compounds:

[0202] [Chemical Formula 1-1]

[0203]

[0204] [Chemical Formula 1-2]

[0205]

[0206] [Chemical Formula 1-3]

[0207]

[0208] [Chemical Formula 1-4]

[0209]

[0210] [Chemical Formula 1-5]

[0211]

[0212] [Chemical Formula 1-6]

[0213]

[0214] [Chemical Formula 1-7]

[0215]

[0216] [Chemical Formula 1-8]

[0217]

[0218] [Chemical Formula 1-9]

[0219]

[0220] [Chemical Formula 1-10]

[0221]

[0222] [Chemical Formula 1-11]

[0223]

[0224] [Chemical Formula 1-12]

[0225]

[0226] [Chemical Formula 1-13]

[0227]

[0228] [Chemical Formula 1-14]

[0229]

[0230] [Chemical Formula 1-15]

[0231]

[0232] [Chemical Formula 1-16]

[0233]

[0234] [Chemical Formula 1-17]

[0235]

[0236] [Chemical Formula 1-18]

[0237]

[0238] [Chemical Formula 1-19]

[0239]

[0240] [Chemical Formula 1-20]

[0241]

[0242] [Chemical Formula 1-21]

[0243]

[0244] [Chemical Formula 1-22]

[0245]

[0246] [Chemical Formula 1-23]

[0247]

[0248] [Chemical Formula 1-24]

[0249]

[0250] [Chemical Formula 1-25]

[0251]

[0252] [Chemical Formula 1-26]

[0253]

[0254] [Chemical Formula 1-27]

[0255]

[0256] [Chemical Formula 1-28]

[0257]

[0258] [Chemical Formula 1-29]

[0259]

[0260] [Chemical Formula 1-30]

[0261]

[0262] [Chemical Formula 1-31]

[0263]

[0264] [Chemical Formula 1-32]

[0265]

[0266] [Chemical Formula 1-33]

[0267]

[0268] [Chemical Formula 1-34]

[0269]

[0270] [Chemical Formula 1-35]

[0271]

[0272] [Chemical Formula 1-36]

[0273]

[0274] [Chemical Formula 1-37]

[0275]

[0276] [Chemical Formula 1-38]

[0277]

[0278] [Chemical Formula 1-39]

[0279]

[0280] [Chemical Formula 1-40]

[0281]

[0282] [Chemical Formula 1-41]

[0283]

[0284] [Chemical Formula 1-42]

[0285]

[0286] [Chemical Formula 1-43]

[0287]

[0288] [Chemical Formula 1-44]

[0289]

[0290] [Chemical Formula 1-45]

[0291]

[0292] [Chemical Formula 1-46]

[0293]

[0294] [Chemical Formula 1-47]

[0295]

[0296] [Chemical Formula 1-48]

[0297]

[0298] [Chemical Formula 1-49]

[0299]

[0300] [Chemical Formula 1-50]

[0301]

[0302] [Chemical Formula 1-51]

[0303]

[0304] [Chemical Formula 1-52]

[0305] and

[0306] [Chemical Formula 1-53]

[0307] .

[0308] The chromene-benzimidazole derivative or pharmaceutically acceptable salt thereof of the present invention is specifically activated in cancer cells to inhibit tubulin polymerization and induce cell death, and can inhibit the activity of oncoproteins by inhibiting the C-terminal domain of Hsp90, and therefore can be used as a pharmaceutical composition for preventing or treating cancer containing the derivative as an active ingredient.

[0309] As one embodiment of the present invention, the pharmaceutical composition may induce apoptosis by arresting the cell cycle of cancer cells, or may induce denaturation and degradation of oncoproteins, and preferably, both mechanisms may be performed.

[0310] In the present invention, the term "oncoprotein" refers to a protein that regulates cell growth and division, and can promote cancer cell formation and progression due to genetic 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 Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, hTERT, ERK, p-ERK, STAT3, c-MET, etc.

[0311] In the present invention, the term “pharmaceutically acceptable salt” means a formulation of a compound that does not cause serious 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 can be obtained by reacting the compound of the present invention with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc., 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 can be obtained by reacting it with a base to form a salt such as an alkali metal salt such as an ammonium salt, a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt of an amino acid such as arginine or lysine.

[0312] In addition, the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof may include not only a pharmaceutically acceptable salt, but also all salts, hydrates and solvates that can be prepared by a conventional method.

[0313]

[0314] In addition, the present invention can provide a method for preventing, treating, and / or diagnosing cancer, comprising a step of administering the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0315] In the present invention, the term "prevention" means any act of inhibiting or delaying the occurrence, spread or recurrence of cancer by administering the composition of the present invention, and "treatment" means any act of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0316] The term "pharmaceutical composition" in the present invention refers to a composition manufactured for the purpose of preventing or treating a disease, and may be formulated and used in various forms according to conventional methods. For example, it may be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, and may be formulated and used in the form of topical preparations, suppositories, and sterile injectable solutions.

[0317] In the present invention, "including as an active ingredient" means that the ingredient is included in an amount necessary or sufficient to realize a desired biological effect. In actual application, the amount included as an active ingredient can be determined by considering the amount for treating the target disease and not causing other toxicity, and may vary depending on various factors such as the disease or condition being treated, the form of the composition being administered, the size of the subject, or the severity of the disease or condition. A person of ordinary skill in the art to which the present invention pertains can empirically determine the effective amount of an individual composition without undue experimentation.

[0318] In addition, the pharmaceutical composition of the present invention may, depending on each formulation, additionally include one or more pharmaceutically acceptable carriers in addition to the above-described effective ingredients.

[0319] The pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and may further include other conventional additives such as antioxidants, buffers, and bacteriostatic agents, if necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into an injectable formulation such as an aqueous solution, suspension, or emulsion, or into a pill, capsule, granule, or tablet. Furthermore, the composition may be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0320]

[0321] The composition of the present invention can be administered orally or parenterally in a pharmaceutically effective amount depending on the intended method, and the term “pharmaceutically effective amount” of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined based on factors including the patient’s health condition, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field.

[0322] Accordingly, the pharmaceutical composition of the present invention can be administered to a subject to prevent, treat, and / or diagnose cancer, and the cancer may be skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine 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, and is not limited thereto, but preferably, it may be a cancer having a characteristic of higher acidity than normal cells and cytotoxicity being inhibited by a tubulin polymerization inhibitor, and a non-limiting example thereof includes breast cancer, preferably triple-negative breast cancer.

[0323] In the present invention, the term “subject” is not limited to a mammal such as a livestock or a human that requires prevention, treatment, and / or diagnosis of cancer, but may preferably be a human.

[0324] The pharmaceutical composition of the present invention can be formulated in various forms for administration to a subject, and a representative form of a parenteral administration form is an injectable form, preferably an isotonic aqueous solution or suspension. The injectable form can be prepared using a suitable dispersing or wetting agent and a suspending agent according to a technique known in the art. For example, each component can be dissolved in saline or a buffer to be formulated for injection. In addition, oral administration forms 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 tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally may further contain a disintegrating agent such as starch, agar, alginic acid or its sodium salt, an absorbent, a coloring agent, a flavoring agent and / or a sweetening agent. The above formulations may be prepared by conventional mixing, granulating or coating methods.

[0325] In addition, the pharmaceutical composition of the present invention may further include auxiliary agents such as preservatives, wetting agents, emulsifying agents, salts for osmotic pressure control or buffers, and other therapeutically useful substances, and may be formulated according to conventional methods.

[0326] The pharmaceutical composition according to the present invention can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular. The dosage of the active ingredient can be appropriately selected based on various factors, such as the route of administration, the patient's age, sex, weight, and severity of the condition. Furthermore, the composition of the present invention can be administered in combination with known compounds capable of enhancing the desired effect.

[0327] The pharmaceutical composition according to the present invention may be administered to humans or animals orally or parenterally, such as intravenously, subcutaneously, intranasally, or intraperitoneally. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as drip methods.

[0328] In the pharmaceutical composition of the present invention, the total effective amount of the chromene-benzimidazole derivative or the pharmaceutically acceptable salt thereof according to the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease, but can typically be administered repeatedly several times a day at an effective dose of 100 ㎍ to 3,000 mg per administration for an adult. However, the concentration of the chromene-benzimidazole derivative or the pharmaceutically acceptable salt thereof can be determined by taking into consideration various factors such as the route of administration and the number of treatments as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate.

[0329] In addition, the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route, and administration method 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 in addition to the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases.

[0330]

[0331] The terms used in the examples are for illustrative purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as "comprise" or "have" are intended to specify the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, but should be understood to not preclude the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0332] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the embodiments pertain. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0333]

[0334] Hereinafter, embodiments are described in detail with reference to the attached drawings. However, the embodiments may be modified in various ways, and the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, or alternatives to the embodiments are included within the scope of the patent application.

[0335] In addition, when describing with reference to the attached drawings, identical components will be assigned the same reference numerals regardless of the drawing numbers, and redundant descriptions thereof will be omitted. When describing embodiments, if a detailed description of a related known technology is judged to unnecessarily obscure the gist of the embodiment, the detailed description will be omitted.

[0336] [Example]

[0337] Example 1. Preparation of chromene-benzimidazole derivatives

[0338] All chemical reagents used were commercially available. 1 H NMR spectra were recorded on a Bruker Avance III 400 MHz, with TMS used as an internal standard.

[0339]

[0340] 1.1 Synthesis of chemical formula 1-1 (1-(2-chloro-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0341] The chromene-benzimidazole derivative of chemical formula 1-1 was synthesized by the following two methods.

[0342] [Chemical Formula 1-1]

[0343]

[0344] Method 1

[0345]

[0346] To a stirred solution of 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (47 mg, 0.2 mmol) and (PhO)2P(O)N3(DPPA, 46.0 mg, 0.17 mmol) in benzene (2 mL) was added Et3N (0.05 ml, 0.5 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 h and then at 80 °C for 6 h, after which the solvent was removed to obtain the desired residue (crude isocyanate). To the residue, dried toluene (2 ml) was added dropwise and stirred to prepare a solution, which was then slowly added dropwise to a THF (3 ml) solution of 2-chloro-1H-benzo[d]imidazol-5-amine (36.8 mg, 0.22 mmol) as an amine (free amine) and Et3N (0.028 ml, 0.2 mmol). The reaction mixture was stirred at room temperature for 12 hours, and the solvent was removed to obtain the desired residue, which was purified by column chromatography (SiO2,MC:MeOH, 20 / 1, v / v) to obtain the desired compound of chemical formula 1-1 (51 mg, 0.188 mmol) as a white solid.

[0347] Yield 64%

[0348] 1 H NMR (400 MHz, DMSO-d6) δ 12.9 (s, br, 1H), 9.19 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.82 (d,J= 8.6Hz, 1H), 7.42 (d,J= 8.6 Hz, 1H), 7.05 (s, 1H), 6.56 (d,J= 9.9 Hz, 1H), 6.52(d, J = 9.9 Hz, 1H), 5.82 (d,J= 9.9 Hz, 1H), 3.73 (s, 3H), 1.37 (s, 6H).

[0349] Method 2

[0350] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (0.117 g, 0.5 mmol) was dissolved in DMF (2 mL), then 2-chloro-1H-benzo[d]imidazol-5-amine (0.0838 g, 0.5 mmol), HBTU (1-[Bis(dimethylamino)methylene]-1H-benzotriazolium 3-Oxide Hexafluorophosphate, 0.22 g), and N,N-Diisopropylethylamine (DIEA, 0.4 mL) were added, respectively, and the mixture was heated to 100 °C in a microwave reactor. o The reaction was carried out at C for 2 hours. The reaction mixture was diluted with an excess of ethyl acetate, extracted, washed with cold water, and the solvent was removed. The oily reaction mixture was separated by silica gel column chromatography using EtOAC: Hexane, (9 / 1) to obtain the compound of chemical formula 1-1 (0.045 g) as a light brown solid.

[0351] Yield 50%

[0352] 1 H NMR (400 MHz, DMSO-d6) δ 10.59(s, 1H), 10.00(s, 1H), 7.59(s, 1H), 7.39(d, J=8.4Hz, 1H), 7.15(d, J=8.4Hz, 1H), 6.86(d, J=8.0Hz, 1H), 6.64(m, 2H), 5.88(d, J=10.0Hz, 1H), 3.76(s, 3H), 1.41(s, 6H)

[0353]

[0354] 1.2 Synthesis of chemical formula 1-2 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)urea)

[0355] The chromene-benzimidazole derivative of chemical formula 1-2 was synthesized as follows.

[0356] [Chemical Formula 1-2]

[0357]

[0358] Compound 1-2 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(trifluoromethyl)-1H-1,3-benzodiazol-5-amine in a similar manner to method 1 of Example 1-1.

[0359] Yield 65%

[0360] 1 H NMR (400 MHz, DMSO-d6) δ 13.68(bs, 1H), 9.37(bs, 1H), 8.14(s, 2H), 7.85(d, J=8.8Hz, 1H), 7.68(m, 1H), 7.10(m, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0361]

[0362] 1.3 Synthesis of chemical formula 1-3 (1-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0363] The chromene-benzimidazole derivative of chemical formula 1-3 was synthesized as follows.

[0364] [Chemical Formula 1-3]

[0365]

[0366] Compound 1-3 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-cyclohexyl-1H-benzo[d]imidazol-5-amine in a similar manner to method 1 of Example 1-1.

[0367] Yield 66%

[0368] 1 H NMR (400 MHz, DMSO-d6) δ 11.95(bs, 1H), 9.10(bs, 1H), 8.05(bd, 1H), 7.86(d, J=9.2Hz, 2H), 7.40(d, J=8.4Hz, 1H), 6.90(d, J=8.4Hz, 1H), 6.57(m, 2H), 5.83(d, J=9.6Hz, 1H), 3.73(s, 3H), 2.79(m, 1H), 2.02(m, 2H), 1.81(m, 2H), 1.68(m, 2H), 1.36(s, 6H), 1.27(m, 2H), 1.24(m, 2H)

[0369]

[0370] 1.4 Synthesis of chemical formula 1-4 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0371] The chromene-benzimidazole derivative of chemical formula 1-4 was synthesized as follows.

[0372] [Chemical Formula 1-4]

[0373]

[0374] Compound 1-4 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-5-amine in a similar manner to method 1 of Example 1-1.

[0375] Yield 48%

[0376] 1H NMR (400 MHz, DMSO-d6) δ 7.78(s, 1H), 7.22(m, 1H), 7.12(m, 2H), 6.54(m, 2H), 5.78(d, J=10.0Hz, 1H), 3.65(s, 3H), 3.40(m, 4H0, 2.30(m, 4H), 2.19(s, 3H), 1.36(s, 6H)

[0377]

[0378] 1.5 Synthesis of chemical formula 1-5 (1-(1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0379] The chromene-benzimidazole derivative of chemical formula 1-5 was synthesized as follows.

[0380] [Chemical Formula 1-5]

[0381]

[0382] Compound 1-5 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 1H-benzo[d]imidazol-5-amine in a similar manner to method 1 of Example 1-1.

[0383] Yield 73%

[0384] 1 H NMR (400 MHz, DMSO-d6) δ 12.27(bs, 1H), 9.18(bs, 1H), 8.13(m, 2H), 7.85(d, J=8.8Hz, 1H), 7.53(d, J=8.4Hz, 1H), 7.24(m, 1H), 7.12(m, 1H), 6.55(m, 2H), 5.83(d, J=10.0Hz, 1H), 3.73(s, 3H), 1.37(s, 6H)

[0385]

[0386] 1.6 Synthesis of chemical formula 1-6 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(thiophen-2-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0387] The chromene-benzimidazole derivative of chemical formula 1-6 was synthesized as follows.

[0388]

[0389] [Chemical Formula 1-6]

[0390]

[0391] Compound 1-6 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(thiophen-2-yl)-1H-benzo[d]imidazol-5-amine in a similar manner to method 1 of Example 1-1.

[0392] Yield 52%

[0393] 1 H NMR (400 MHz, DMSO-d6) δ 12.82(bs, 1H), 9.23(bs, 1H), 8.11(s, 1H), 7.95(s, 1H), 7.86-7.68(m, 3H), 7.51(d, J=8.8Hz, 1H), 7.39(m, 2H), 6.98(d, J=8.8Hz, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz,1H), 3.74(s, 3H), 1.37(s, 6H)

[0394]

[0395] 1.7 Synthesis of chemical formula 1-7 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(thiazol-4-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0396] The chromene-benzimidazole derivative of chemical formula 1-7 was synthesized as follows.

[0397]

[0398] [Chemical Formula 1-7]

[0399]

[0400] To a toluene (5 mL) 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 sequentially added, and the mixture was stirred at room temperature for 1 hour. Then, a previously prepared mixed solution of 2-(thiazol-4-yl)-1H-benzo[d]imidazol-5-amine (0.108 g, 0.51 mmol) and triethylamine (0.205 g, 0.276 mL, 2.02 mmol) was added, and the mixture was reacted at 110 oC for 5 hours. The reaction mixture was cooled, the solvent was removed, and the product was purified by silica gel column chromatography to obtain the pure product compound 1-7 (0.08 g).

[0401] Yield 36%

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 12.80(bs, 1H), 9.32(s, 1H), 9.22(bs, 1H), 8.41(s, 1H), 8.09(s, 1H), 7.94-7.84(m, 2H), 7.54(d, J=8.8Hz, 1H), 7.04(d, J=8.4Hz, 1H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(6H)

[0403]

[0404] 1.8 Synthesis of chemical formula 1-8 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-phenyl-1H-benzo[d]imidazol-5-yl)urea)

[0405] The chromene-benzimidazole derivative of chemical formula 1-8 was synthesized as follows.

[0406] [Chemical Formula 1-8]

[0407]

[0408] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-phenyl-1H-benzo[d]imidazol-5-amine were reacted as in Example 1-7, and the developing solution was sequentially changed from ethyl acetate and hexane (1:1, v / v) to ethyl acetate and hexane (3:1, v / v) to obtain compound 1-8.

[0409] Yield 72%

[0410] 1 H NMR (400 MHz, DMSO-d6) δ 12.79(bs, 1H), 9.23(bs, 1H), 8.11(m, 3H), 8.00(s, 1H), 7.87(d, J=8.8Hz, 1H), 5.56(m, 3H), 7.42(m, 1H), 6.98(m, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0411]

[0412] 1.9 Synthesis of Chemical Formula 1-9 (1-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0413] The chromene-benzimidazole derivative of chemical formula 1-9 was synthesized as follows.

[0414] [Chemical Formula 1-9]

[0415]

[0416] Compound 1-9 was synthesized by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0417] Yield 50%

[0418] 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.23 (s, 1H), 8.16 (m, 3H), 7.99 (s, 1H), 7.84 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 7.39(m, 2H), 6.99(m, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0419]

[0420] 1.10 Synthesis of chemical formula 1-10 (1-(2-(3-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0421] The chromene-benzimidazole derivative of chemical formula 1-10 was synthesized as follows.

[0422] [Chemical Formula 1-10]

[0423]

[0424] Compound 1-10 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-fluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0425] Yield: 67%

[0426] 1H NMR (400 MHz, DMSO-d6) δ 11.82(s, 1H), 9.26(s, 1H), 8.12(s, 1H), 8.12~7.84(m, 4H), 7.58(m, 2H), 7.33(m, 1H), 6.98(d, J=8.8Hz, 1H), 6.58(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0427]

[0428] 1.11 Synthesis of chemical formula 1-11 (1-(2-(4-chlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0429] The chromene-benzimidazole derivative of chemical formula 1-11 was synthesized as follows.

[0430] [Chemical Formula 1-11]

[0431]

[0432] Compound 1-11 was synthesized by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-chlorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0433] Yield 33%

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 9.24 (s, 1H), 8.14 (m, 3H), 8.00 (s, 1H), 7.86 (d, J = 7.2Hz, 1H), 7.63 (d, J = 7.2Hz, 2H), 7.57(m, 1H), 6.99(m, 1H), 6.58(t, 2H), 5.83(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0435]

[0436] 1.12 Synthesis of chemical formula 1-12 (1-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0437] The chromene-benzimidazole derivative of chemical formula 1-12 was synthesized as follows.

[0438] [Chemical Formula 1-12]

[0439]

[0440] Compound 1-12 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 4-(5-amino-1H-benzo[d]imidazol-2-yl)phenol according to the method of Example 1-7.

[0441] Yield 30%

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 12.46(s, 1H), 9.91(bs, 1H), 9.18(s, 1H), 8.09(s, 1H), 7.95(m, 3H), 7.86(d, J=8.8Hz, 1H), 7.49(d, J=8.4Hz, 1H), 6.90(m, 3H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0443]

[0444] 1.13 Synthesis of chemical formula 1-13 (1-(2-(4-cyanophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0445] The chromene-benzimidazole derivative of chemical formula 1-13 was synthesized as follows.

[0446] [Chemical Formula 1-13]

[0447]

[0448] Compound 1-13 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 4-(5-amino-1H-benzo[d]imidazol-2-yl)benzonitrile according to the method of Example 1-7.

[0449] Yield: 58%

[0450] 1 H NMR (400 MHz, DMSO-d6) δ 13.09(s, 1H), 9.29(s, 1H), 8.33(m, 2H), 8.13(s, 1H), 8.05(m, 3H), 7.86(d, J=8.8Hz, 1H), 7.62(d, J=9.2Hz, 1H), 7.02(d, J=9.2Hz, 1H), 6.58(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0451]

[0452]

[0453] 1.14 Synthesis of Formula 1-14 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0454] The chromene-benzimidazole derivative of chemical formula 1-14 was synthesized as follows.

[0455] [Chemical Formula 1-14]

[0456]

[0457] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine were reacted as in Example 1-7 to obtain compound 1-14 as a light brown solid.

[0458] Yield: 37%

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 13.06(s, 1H), 9.28(s, 1H), 8.34(m, 2H), 8.13(s, 1H), 8.04(s, 1H), 7.93(d, J=8.8Hz, 2H), 7.87(d, J=8.8Hz, 1H), 7.61(d, J=8.8Hz, 1H), 7.03(d, J=10.4Hz, 1H), 6.58(t, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0460]

[0461] 1.15 Synthesis of chemical formula 1-15 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(6-methoxypyridin-3-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0462] The chromene-benzimidazole derivative of chemical formula 1-15 was synthesized as follows.

[0463] [Chemical Formula 1-15]

[0464]

[0465] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(6-methoxypyridin-3-yl)-1H-benzo[d]imidazol-5-amine were reacted as in Example 1-7 to obtain compound 1-15 as a light brown solid.

[0466] Yield: 71%

[0467] 1H NMR (400 MHz, DMSO-d6) δ 12.79(s, 1H), 9.23(s, 1H), 8.92(s, 1H), 8.37(m, 1H), 8.08(s, 1H), 8.00(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.55(d, J=8.4Hz, 1H), 7.01(d, J=8.8Hz, 2H), 6.55(t, 2H), 5.84(d, J=9.6Hz, 1H), 3.94(s, 3H), 3.74(s, 3H), 1.37(s, 6H)

[0468]

[0469] 1.16 Synthesis of chemical formula 1-16 (1-(2-(4-(dimethylamino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0470] The chromene-benzimidazole derivative of chemical formula 1-16 was synthesized as follows.

[0471] [Chemical Formula 1-16]

[0472]

[0473] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(dimethylamino)phenyl)-1H-benzo[d]imidazol-5-amine were reacted as in Example 1-7 to obtain compound 1-16 as a light brown solid.

[0474] Yield: 36%

[0475] 1H NMR (400 MHz, DMSO-d6) δ 12.36(s, 1H), 9.16(s, 1H), 8.08(s, 1H), 7.97(m, 3H), 7.87(d, J=8.4Hz, 1H), 7.46(d, J=8.0Hz, 1H), 6.93(d, J=7.6Hz, 1H), 6.84(d, J=8.4Hz, 2H), 6.589t, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.99(s, 6H), 1.37(s, 6H)

[0476]

[0477] 1.17 Synthesis of chemical formula 1-17 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0478] The chromene-benzimidazole derivative of chemical formula 1-17 was synthesized as follows.

[0479] [Chemical Formula 1-17]

[0480]

[0481] Compound 1-17 was synthesized by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0482] Yield 23%

[0483] 1H NMR (400 MHz, DMSO-d6) δ 12.71(s, 1H), 9.23(ss, 1H), 8.11(s, 1H), 8.00(s, 1H), 7.86(m, 1H), 7.49(m, 3H), 6.98(d, J=8.0Hz, 1H), 6.58(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.90(s, 6H), 3.74(d, J=4.8Hz, 6H), 1.37(s, 6H)

[0484]

[0485] 1.18 Synthesis of chemical formula 1-18 (1-(2-(3,5-dimethoxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0486] The chromene-benzimidazole derivative of chemical formula 1-18 was synthesized as follows.

[0487] [Chemical Formula 1-18]

[0488]

[0489] Compound 1-18 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,5-dimethoxyphenyl)-1H-benzimidazol-5-amine according to the method of Example 1-7.

[0490] Yield 57%

[0491] 1 H NMR (400 MHz, DMSO-d6) δ 12.71(bs, 1H), 9.24(bs, 1H), 8.11(bs, 1H), 8.00(s, 1H), 7.85(m, 1H), 7.57(d, J=8.4Hz, 1H), 7.32(s, 2H), 6.969d, J=8.8Hz, 1H), 6.55(m, 3H), 5.84(d, J=8.8Hz, 1H), 3.85(s, 6H), 3.74(s, 3H), 1.37(s, 6H)

[0492]

[0493] 1.19 Synthesis of chemical formula 1-19 (1-(2-(2,4-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0494] The chromene-benzimidazole derivative of chemical formula 1-19 was synthesized as follows.

[0495] [Chemical Formula 1-19]

[0496]

[0497] Compound 1-19 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,4-difluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0498] Yield 50%

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 12.43(s, 1H), 9.25(s, 1H), 8.26(m, 1H), 8.22(s, 1H), 8.09(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.51(m, 2H), 7.32(m, 1H), 7.05(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 3H)

[0500]

[0501] 1.20 Synthesis of chemical formula 1-20 (1-(2-(2,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0502] The chromene-benzimidazole derivative of chemical formula 1-20 was synthesized as follows.

[0503] [Chemical Formula 1-20]

[0504]

[0505] Compound 1-20 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,4-dichlorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0506] Yield 53%

[0507] 1 H NMR (400 MHz, DMSO-d6) δ 12.59(bs, 1H), 9.26(bs, 1H), 8.12(bs, 1H), 8.049s, 1H), 7.95(q, 1H), 7.86(s, 2H), 7.58(m, 2H), 7.00(d, J=8.4Hz, 1H), 6.54(m, 2H), 5.84(d, J=10.0Hz, 1H),

[0508] 3.74(s, 3H), 1.37(s, 6H)

[0509]

[0510] 1.21 Synthesis of chemical formula 1-21 (1-(2-(2,3-dichlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0511] The chromene-benzimidazole derivative of chemical formula 1-21 was synthesized as follows.

[0512] [Chemical Formula 1-21]

[0513]

[0514] Compound 1-21 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,3-dichlorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0515] Yield 59%

[0516] 1 H NMR (400 MHz, DMSO-d6) δ 12.66(bs, 1H), 9.30(bs, 1H), 8.15(s, 1H), 8.04(s, 1H), 7.84(m, 3H), 7.59(m, 2H), 7.03(m, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0517]

[0518] 1.22 Synthesis of chemical formula 1-22 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(p-tolyl)-1H-benzo[d]imidazol-5-yl)urea)

[0519] The chromene-benzimidazole derivative of chemical formula 1-22 was synthesized as follows.

[0520] [Chemical Formula 1-22]

[0521]

[0522] Compound 1-22 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(p-tolyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0523] Yield 81%

[0524] 1H NMR (400 MHz, DMSO-d6) δ 12.69(s, 1H), 9.22(s, 1H), 8.02(m, 4H), 7.84(m,1H), 7.54(d, J=8.4Hz, 1H), 7.359d, J=7.6Hz, 2H), 6.98(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.38(s, 3H), 1.37(s, 6H)

[0525]

[0526] 1.23 Synthesis of chemical formula 1-23 (1-(2-(4-isopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0527] The chromene-benzimidazole derivative of chemical formula 1-23 was synthesized as follows.

[0528] [Chemical Formula 1-23]

[0529]

[0530] Compound 1-23 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-isopropylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0531] Yield 74%

[0532] 1H NMR (400 MHz, DMSO-d6) δ 12.70(bs, 1H), 9.23(bs, 1H), 8.12(m, 3H), 7.98(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.54(d, J=8.4Hz, 1H), 7.42(d, J=8.4Hz, 2H), 6.98(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.96(q, 1H), 1.379s, 6H), 1.26(d, J=6.8Hz, 6H)

[0533]

[0534] 1.24 Synthesis of chemical formula 1-24 (1-(2-(4-(tert-butyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0535] The chromene-benzimidazole derivative of chemical formula 1-24 was synthesized as follows.

[0536] [Chemical Formula 1-24]

[0537]

[0538] Compound 1-24 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-tert-butylphenyl)-1H-benzimidazol-5-amine according to the method of Example 1-7.

[0539] Yield 55%

[0540] 1H NMR (400 MHz, DMSO-d6) δ 12.65(bs, 1H), 9.21(bs, 1H), 8.10(m, 3H), 7.98(s, 1H), 7.85(m, 1H), 7.57(m, 3H), 6.98(d, J=8.4Hz, 1H), 6.58(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H), 1.33(s, 9H)

[0541]

[0542] 1.25 Synthesis of chemical formula 1-25 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-phenoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0543] The chromene-benzimidazole derivative of chemical formula 1-25 was synthesized as follows.

[0544] [Chemical Formula 1-25]

[0545]

[0546] Compound 1-25 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-phenoxyphenyl)-1H-1,3-benzodiazol-5-amine according to the method of Example 1-7.

[0547] Yield 63%

[0548] 1 H NMR (400 MHz, DMSO-d6) δ 12.73(bs, 1H), 9.22(bs, 1H), 8.15(m, 3H), 7.84(m, 1H), 7.45(m, 3H), 7.25(m, 2H), 7.18(m, 3H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0549]

[0550] 1.26 Synthesis of chemical formula 1-26 (1-(2-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0551] The chromene-benzimidazole derivative of chemical formula 1-26 was synthesized as follows.

[0552] [Chemical Formula 1-26]

[0553]

[0554] Compound 1-26 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0555] Yield 70%

[0556] 1 H NMR (400 MHz, DMSO-d6) δ 12.84(bs, 1H), 9.26(bs, 1H), 8.31(s, 1H), 8.12(s, 2H), 8.00(bs, 1H), 7.86(d, J=8.8Hz, 1H), 7,74(m, 1H), 7.63(m, 2H), 7.01(bs, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0557]

[0558] 1.27 Synthesis of chemical formula 1-27 (1-(2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0559] The chromene-benzimidazole derivative of chemical formula 1-27 was synthesized as follows.

[0560] [Chemical Formula 1-27]

[0561]

[0562] Compound 1-27 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0563] Yield 53%

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 12.62(bs, 1H), 9.21(bs, 1H), 8.10(m, 3H), 7.96(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.53(m, 3H), 7.35(m, 3H), 7.19(d, J=8.4Hz, 2H), 6.96(d, J=8.4Hz, 1H), 6.58(m, 2H), 5.84(d, J=9.6Hz, 1H), 5.20(s, 2H), 3.74(s, 3H), 1.37(s, 6H)

[0565]

[0566] 1.28 Synthesis of formula 1-28 (1-(2-(4-(diethylamino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0567] The chromene-benzimidazole derivative of chemical formula 1-28 was synthesized as follows.

[0568] [Chemical Formula 1-28]

[0569]

[0570] Compound 1-28 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(diethylamino)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0571] Yield 54%

[0572] 1 H NMR (400 MHz, DMSO-d6) δ 12.35(bs, 1H), 9.15(bs, 1H), 8.08(bs, 1H), 7.89(m, 4H), 7.44(d, J=8.0Hz, 1H), 6.92(d, J=9.2Hz, 1H), 6.789d, J=8.4Hz, 2H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 3.42(q, 4H), 1.37(s, 6H), 1.15(t, 6H)

[0573]

[0574] 1.29 Synthesis of chemical formula 1-29 (1-(2-(3,4-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0575] The chromene-benzimidazole derivative of chemical formula 1-29 was synthesized as follows.

[0576] [Chemical Formula 1-29]

[0577]

[0578] Compound 1-29 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,4-difluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0579] Yield 57%

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 12,84(bs, 1H), 9.26(bs, 1H), 8.12(s, 2H), 8.00(s, 2H), 7.86(d, J=8.8Hz, 1H), 7.65(m, 1H), 7.55(m, 1H), 7.00(m, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0581]

[0582] 1.30 Synthesis of chemical formula 1-30 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(pentyloxy)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0583] The chromene-benzimidazole derivative of chemical formula 1-30 was synthesized as follows.

[0584] [Chemical Formula 1-30]

[0585]

[0586] Compound 1-30 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(pentyloxy)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0587] Yield 60%

[0588] 1H NMR (400 MHz, DMSO-d6) δ 12.60(bs, 1H), 9.19(bs, 1H), 8.09(m, 3H), 7.95(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.09(d, J=8.8Hz, 2H), 6.96(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 4.06(m, 2H), 3.74(s, 3H), 1.77(m, 2H), 1.35(m, 4H), 1.37(s, 6H), 0.93(t, 3H)

[0589]

[0590] 1.31 Synthesis of chemical formula 1-31 (1-(2-(5-chloro-2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0591] The chromene-benzimidazole derivative of chemical formula 1-31 was synthesized as follows.

[0592] [Chemical Formula 1-31]

[0593]

[0594] Compound 1-31 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(5-amino-1H-benzo[d]imidazol-2-yl)-4-chlorophenol according to the method of Example 1-7.

[0595] Yield 59%

[0596] 1H NMR (400 MHz, DMSO-d6) δ 13.26(bs, 1H), 9.28(bs, 1H), 8.13(d, J=12.0Hz, 2H), 8.02(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.60(bs, 1H), 7.39(d, J=8.8Hz, 1H), 7.12(m, 1H), 7.06(d, J=8.8Hz, 2H), 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0597]

[0598] 1.32 Synthesis of chemical formula 1-32 (1-(2-(4-(1H-indol-3-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0599] The chromene-benzimidazole derivative of chemical formula 1-32 was synthesized as follows.

[0600] [Chemical Formula 1-32]

[0601]

[0602] Compound 1-32 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(1H-indol-3-yl)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0603] Yield 38%

[0604] 1H NMR (400 MHz, DMSO-d6) δ 12.28(bs, 1H), 11.58(m, 1H), 9.16(bs, 1H), 8.48(m, 1H), 8.10(m, 2H), 7.91(m, 2H), 7.21(m, 3H), 6.95(d, J=8.4Hz, 1H), 6.58(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0605]

[0606] 1.33 Synthesis of chemical formula 1-33 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-propylphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0607] The chromene-benzimidazole derivative of chemical formula 1-33 was synthesized as follows.

[0608] [Chemical Formula 1-33]

[0609]

[0610] Compound 1-33 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-propylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0611] Yield 72%

[0612] 1 H NMR (400 MHz, DMSO-d6) δ 12.70(bs, 1H), 9.21(bs, 1H), 8.10(m, 4H), 7.86(m, 1H), 7.54(d, J=8.8Hz, 1H), 7.36(m, 3H), 6.97(d, J=8.4Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.4Hz, 1H), 3.74(s, 3H), 2.62(m, 2H), 1.65(m, 2H), 1.37(s, 6H), 0.94(t, 3H)

[0613]

[0614] 1.34 Synthesis of Formula 1-34 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0615] The chromene-benzimidazole derivative of chemical formula 1-34 was synthesized as follows.

[0616] [Chemical Formula 1-34]

[0617]

[0618] Compound 1-34 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0619] Yield 58%

[0620] 1 H NMR (400 MHz, DMSO-d6) δ 12.59(bs, 1H), 9.24(bs, 1H), 8.11(s, 1H), 8.04(d, J=8.8Hz, 2H), 7.91(m, 1H), 7.86(d, J=8.8Hz, 2H), 7.46(bs, 1H), 7.16(m, 3H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 4.02(m, 4H), 3.74(s, 3H), 3.10(m, 4H), 2.79(s, 3H), 1.37(s, 6H)

[0621]

[0622] 1.35 Synthesis of chemical formula 1-35 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(o-tolyl)-1H-benzo[d]imidazol-5-yl)urea)

[0623] The chromene-benzimidazole derivative of chemical formula 1-35 was synthesized as follows.

[0624] [Chemical Formula 1-35]

[0625]

[0626] Compound 1-35 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(o-tolyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0627] Yield 73%

[0628] 1 H NMR (400 MHz, DMSO-d6) δ 12.44(bs, 1H), 9.23(bs, 1H), 8.12(s, 1H), 8.00(s, 1H), 7.87(m, 1H), 7.74(d, J=7.4Hz, 1H), 7.57(d, J=8.0Hz, 1H), 7.37(s, 3H), 6.99(d, J=8.8Hz, 1H), 6.58(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.61(s, 3H), 1.37(s, 6H)

[0629]

[0630] 1.36 Synthesis of chemical formula 1-36 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(m-tolyl)-1H-benzo[d]imidazol-5-yl)urea)

[0631] The chromene-benzimidazole derivative of chemical formula 1-36 was synthesized as follows.

[0632] [Chemical Formula 1-36]

[0633]

[0634] Compound 1-36 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(m-tolyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0635] Yield 68%

[0636] 1 H NMR (400 MHz, DMSO-d6) δ 12.75(bs, 1H), 9.23(bs, 1H), 8.11(s, 1H), 7.98(s, 2H), 7.92(m, 1H), 7.87(m, 1H), 7.55(d, J=8.4Hz, 1H), 7.42(m, 1H), 7.29(m, 1H), 6.99(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.41(s, 3H), 1.37(s, 6H)

[0637]

[0638] 1.37 Synthesis of chemical formula 1-37 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0639] The chromene-benzimidazole derivative of chemical formula 1-37 was synthesized as follows.

[0640] [Chemical Formula 1-37]

[0641]

[0642] Compound 1-37 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-methoxyphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0643] Yield 67%

[0644] 1H NMR (400 MHz, DMSO-d6) δ 12.01(s, 1H), 9.21(bs, 1H), 8.30(m, 1H), 8.12(m, 2H), 7.89(m, 1H), 7.54(d, J=8.4Hz, 1H), 7.47(m, 1H), 7.23(m, 1H), 7.11(m, 1H), 6.98(d, J=8.4Hz, 1H) 6.58(m, 2H), 5.84(d, J=10.0Hz, 1H), 4.02(s, 3H), 3.74(s, 3H), 1.37(s, 6H)

[0645]

[0646] 1.38 Synthesis of formula 1-38 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0647] The chromene-benzimidazole derivative of chemical formula 1-38 was synthesized as follows.

[0648] [Chemical Formula 1-38]

[0649]

[0650] Compound 1-38 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0651] Yield 61%

[0652] 1H NMR (400 MHz, DMSO-d6) δ 12.99(bs, 1H), 9.28(bs, 1H), 8.47(m, 2H), 8.13(s, 1H), 8.03(s, 1H), 7.83(m, 3H), 7.60(d, J=8.0Hz, 1H), 7.03(d, J=8.0Hz, 1H), 6.58(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0653]

[0654] 1.39 Synthesis of chemical formula 1-39 (1-(2-(4-benzoylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0655] The chromene-benzimidazole derivative of chemical formula 1-39 was synthesized as follows.

[0656] [Chemical Formula 1-39]

[0657]

[0658] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and (4-(5-amino-1H-benzo[d]imidazol-2-yl)phenyl)(phenyl)methanone were reacted as in Example 1-7 to obtain compound 1-39.

[0659] Yield 73%

[0660] 1H NMR (400 MHz, DMSO-d6) δ 12.99(bs, 1H), 9.28(bs, 1H), 8.32(d, J=7.6Hz, 2H), 8.13(s, 1H), 8.04(bs, 1H), 7.92(d, J=8.0Hz, 2H), 7.87(, J=8.8Hz, 1H), 7.81(d, J=8.0hz, 2H), 7.72(m, 1H), 7.61(m, 2H), 7.02(bs, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0661]

[0662] 1.40 Synthesis of chemical formula 1-40 (1-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0663] The chromene-benzimidazole derivative of chemical formula 1-40 was synthesized as follows.

[0664] [Chemical Formula 1-40]

[0665]

[0666] Compound 1-40 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,5-bis(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0667] Yield 75%

[0668] 1H NMR (400 MHz, DMSO-d6) δ 13.21(bs, 1H), 9.31(bs, 1H), 8.76(s, 2H), 8.23(s, 1H), 8.14(s, 1H), 8.05(bs, 1H), 7.87(d, J=8.8Hz, 1H), 7.64(bs. 1H), 7.04(bs, 1H), 6.56(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0669]

[0670] 1.41 Synthesis of chemical formula 1-41 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0671] The chromene-benzimidazole derivative of chemical formula 1-41 was synthesized as follows.

[0672] [Chemical Formula 1-41]

[0673]

[0674] Compound 1-41 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 22-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0675] Yield 69%

[0676] 1 H NMR (400 MHz, DMSO-d6) δ 12.85(bs, 1H), 9.26(bs, 1H), 8.25(m, 3H), 8.12(bs, 1H), 8.02(s, 1H), 7.87(d, J=9.2Hz, 1H), 7.56(m, 3H), 7.00(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0677]

[0678] 1.42 Synthesis of chemical formula 1-42 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0679] The chromene-benzimidazole derivative of chemical formula 1-42 was synthesized as follows.

[0680] [Chemical Formula 1-42]

[0681]

[0682] Compound 1-42 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0683] Yield 66%

[0684] 1 H NMR (400 MHz, DMSO-d6) δ 12.92(bs, 1H), 9.27(bs, 1H), 8.14(m, 3H), 8.08(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.71(m, 1H), 7.67(m, 1H), 7.58(d, J=8.4Hz, 1H), 7.02(d, J=9.6Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0685]

[0686] 1.43 Synthesis of chemical formula 1-43 (1-(2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0687] The chromene-benzimidazole derivative of chemical formula 1-43 was synthesized as follows.

[0688] [Chemical Formula 1-43]

[0689]

[0690] Compound 1-43 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0691] Yield 69%

[0692] 1 H NMR (400 MHz, DMSO-d6) δ 12.68(bs, 1H), 9.21(bs, 1H), 8.10(bs, 1H), 7.98(m, 3H), 7.87(d, J=8.8Hz, 1H), 7.53(d, J=8.4Hz, 1H), 7.24(d, J=8.4Hz, 2H), 6.97(d, J=8.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.99(m, 1H), 1.37(s, 6H), 1.02(m, 2H), 0.77(m, 2H)

[0693]

[0694] 1.44 Synthesis of chemical formula 1-44 (1-(2-(4-cyclopentylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0695] The chromene-benzimidazole derivative of chemical formula 1-44 was synthesized as follows.

[0696] [Chemical Formula 1-44]

[0697]

[0698] Compound 1-44 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-cyclopentylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0699] Yield 71%

[0700] 1 H NMR (400 MHz, DMSO-d6) δ 12.70(bs, 1H), 9.22(bs, 1H), 8.10(m, 4H), 7.86(d, J=8.8Hz, 1H), 7.54(d, J=8.8Hz, 1H), 7.42(d, J=8.0Hz, 2H), 6.98(d, J=8.0Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 3.06(m, 1H), 2.05(bs, 2H), 1.80(bs, 2H), 1.60(m, 4H), 1.37(s, 6H)

[0701]

[0702] 1.45 Synthesis of chemical formula 1-45 (1-(2-(4-cyclohexylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0703] The chromene-benzimidazole derivative of chemical formula 1-45 was synthesized as follows.

[0704] [Chemical Formula 1-45]

[0705]

[0706] Compound 1-45 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-cyclohexylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0707] Yield 79%

[0708] 1 H NMR (400 MHz, DMSO-d6) δ 12.70(bs, 1H), 9.23(bs, 1H), 8.07(m, 4H), 7.97(d, J=8.8Hz, 1H), 7.54(d, J=8.8Hz, 1H), 7.37(m, 3H), 6.98(d, J=10.4Hz, 1H), 6.55(m, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.83(m, 4H), 1.74(m, 1H), 1.48(m, 4H), 1.37(s, 6H), 1.23(m, 2H)

[0709]

[0710] 1.46 Synthesis of chemical formula 1-46 (1-(2-(4-((1r,3R,5S)-adamantan-1-yl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0711] The chromene-benzimidazole derivative of chemical formula 1-46 was synthesized as follows.

[0712] [Chemical Formula 1-46]

[0713]

[0714] Compound 1-46 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-((1r,3R,5S)-adamantan-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0715] Yield 78%

[0716] 1H NMR (400 MHz, DMSO-d6) δ 12.71(bs, 1H), 9.22(bs, 1H), 8.07(m, 3H), 7.97(s, 1H), 7.87(d, J=8.8Hz, 1H), 7.52(m, 3H), 6.98(d, J=8.8Hz, 1H), 6.55(m, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 2.08(s, 3H), 1.92(s, 6H), 1.76(s, 6H), 1.37(s, 6H)

[0717]

[0718] 1.47 Synthesis of chemical formula 1-47 (1-(2-(3-isopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0719] The chromene-benzimidazole derivative of chemical formula 1-47 was synthesized as follows.

[0720] [Chemical Formula 1-47]

[0721]

[0722] Compound 1-47 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-isopropylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0723] Yield 79%

[0724] 1H NMR (400 MHz, DMSO-d6) δ 12.76(bs, 1H), 9.23(bs, 1H), 8.11(s, 1H), 8.08-7.92(m, 3H), 7.84(m, 1H), 7.56(d, J=8.8Hz, 1H), 7.44(m, 1H), 7.35(m, 1H), 6.99(d, J=8.8Hz, 1H), 6.58(t, 2H), 5.84(d, J=9.6Hz, 1H), 3.74(s, 3H), 1.37(s, 6H), 1.29(d, J=6.8Hz, 6H)

[0725]

[0726] 1.48 Synthesis of chemical formula 1-48 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-nitrophenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0727] The chromene-benzimidazole derivative of chemical formula 1-48 was synthesized as follows.

[0728] [Chemical Formula 1-48]

[0729]

[0730] Compound 1-48 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-nitrophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0731] Yield 78%

[0732] 1 H NMR (400 MHz, DMSO-d6) δ 13.12(bs, 1H), 9.29(bs, 1H), 8.40(m, 4H), 8.13(s, 1H), 8.03(bs, 1H), 7.86(d, J=8.8Hz, 1H), 7.61(m, 1H), 7.06(m, 1H), 6.58(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0733]

[0734] 1.49 Synthesis of chemical formula 1-49 (1-(2-(2,5-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0735] The chromene-benzimidazole derivative of chemical formula 1-49 was synthesized as follows.

[0736] [Chemical Formula 1-49]

[0737]

[0738] Compound 1-49 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,5-difluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0739] Yield 80%

[0740] 1 H NMR (400 MHz, DMSO-d6) δ 12.56(bs, 1H), 9.27(bs, 1H), 8.12(s, 1H), 8.04(s, 1H), 7.96(m, 1H), 7.87(d, J=8.8Hz, 1H), 7.61(d, J=8.8Hz, 1H), 7.50(m, 1H), 7.42(m, 1H), 7.08(d, J=8.8Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0741]

[0742] 1.50 Synthesis of chemical formula 1-50 (1-(2-(2,3-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0743] The chromene-benzimidazole derivative of chemical formula 1-50 was synthesized as follows.

[0744] [Chemical Formula 1-50]

[0745]

[0746] Compound 1-50 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,3-difluorophenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0747] Yield 77%

[0748] 1 H NMR (400 MHz, DMSO-d6) δ 12.58(bs, 1H), 9.29(bs, 1H), 8.14(s, 1H), 8.04(s, 1H), 7.97(m, 1H), 7.87(d, J=9.2Hz, 1H), 7.62(m, 2H), 7.41(m, 1H), 7.07(d, J=8.8Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0749]

[0750] 1.51 Synthesis of chemical formula 1-51 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-phenoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0751] The chromene-benzimidazole derivative of chemical formula 1-51 was synthesized as follows.

[0752] [Chemical Formula 1-51]

[0753]

[0754] Compound 1-51 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-phenoxyphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0755] Yield 77%

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 12.76(bs, 1H), 9.24(bs, 1H), 8.11(s, 1H), 7.98(s, 1H), 7.83(m, 2H), 7.68(s, 1H), 7.58(m, 2H), 7.43(m, 2H), 7.22(m, 1H), 7.12(m, 3H), 6.98(d, J=9.2Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0757]

[0758] 1.52 Synthesis of chemical formula 1-52 (1-(2-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0759] The chromene-benzimidazole derivative of chemical formula 1-52 was synthesized as follows.

[0760] [Chemical Formula 1-52]

[0761]

[0762] Compound 1-52 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0763] Yield 73%

[0764] 1 H NMR (400 MHz, DMSO-d6) δ 12.86(bs, 1H), 9.25(bs, 1H), 8.26(m, 2H), 8.12(bs, 1H), 8.01(s, 1H), 7.88(m, 3H), 7.79(d, J=7.2Hz, 2H), 7.58(m, 3H), 7.49(m, 1H), 7.00(d, J=7.2Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 1.37(s, 6H)

[0765]

[0766] 1.53 Synthesis of chemical formula 1-53 (1-(2-(4-isobutylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0767] The chromene-benzimidazole derivative of chemical formula 1-53 was synthesized as follows.

[0768] [Chemical Formula 1-53]

[0769]

[0770] Compound 1-53 was obtained by reacting 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-isobutylphenyl)-1H-benzo[d]imidazol-5-amine according to the method of Example 1-7.

[0771] Yield 79%

[0772] 1H NMR (400 MHz, DMSO-d6) δ 12.70(bs, 1H), 9.22(bs, 1H), 9.10-8.02(m, 4H), 7.86(m, 1H), 7.54(d, J=8.8Hz, 1H), 7.33(d, J=8.0Hz, 2H), 6.97(d, J=8.8Hz, 1H), 6.55(t, 2H), 5.84(d, J=10.0Hz, 1H), 3.74(s, 3H), 2.52(d, J=8.0, Hz, 2H), 1.91(m, 1H), 1.37(s, 6H), 0.91(d, J=6.4Hz, 6H)

[0773]

[0774] Example 2. Measurement of anticancer activity and confirmation of mechanism of action of chromene-benzimidazole derivatives.

[0775] 2.1 Cell viability screening of chromene-benzimidazole derivatives

[0776] MDA-MB-231, a human triple-negative breast cancer (TNBC) cell line (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.

[0777] The above cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), streptomycin-penicillin (100 U / mL), and Fungizone (0.625 ㎍ / mL) at 5% CO2 and 37°C.

[0778] The human breast cancer cell lines MDA-MB-231 and JIMT-1 were treated with the chromene-benzimidazole derivatives of Chemical Formulas 1-1 to 1-53 at various concentrations of 0, 1, and 5 μM, respectively, for 72 hours, and then cell viability was measured using the MTS assay technique. In the MTS assay, cells were allowed to attach to a 96-well plate for 24 hours, treated with the chromene-benzimidazole derivatives for 72 hours, and then color was developed with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) for 4 hours, and then the absorbance was measured at 490 nm using a Spectramax Plus384 microplate analyzer.

[0779] The measurement results are shown in Figures 1 to 6. As a result, it was confirmed that most of the chromene-benzimidazole derivatives of the chemical formulas 1-1 to 1-53 inhibited cell viability in a concentration-dependent manner in the human breast cancer cell lines MDA-MB-231 and JIMT-1.

[0780]

[0781] 2.2 Confirmation of the apoptotic effect of chromene-benzimidazole derivatives

[0782] Triple-negative breast cancer cell lines MDA-MB-231 and BT549 were treated with chromene-benzimidazole derivative compound (1-1) at various concentrations (0, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 20, and 40 μM) for 72 hours. The concentration-dependent inhibition of cell viability (MTS assay) and the IC50 values ​​according to cell viability inhibition were confirmed, and these are shown in Fig. 7 (a) and (b). In the case of the compound of chemical formula 1-1, the IC50 values ​​were 5.659 μM and 8.491 μM in MDA-MB-231 and BT549, respectively.

[0783] After treatment of MDA-MB-231 and BT549 cell lines with compound 1-1 at various concentrations (0, 5, 10, and 20 μM) for 72 hours, morphological changes in cells were observed using an optical microscope, and the results are shown in Fig. 7 (c). It was confirmed that cell death was induced in a concentration-dependent manner.

[0784] The degree of cell death of MDA-MB-231 and BT549 cells by the compound of chemical formula 1-1 was confirmed by flow cytometry through Annexin V / PI staining, and is shown in (d) of Fig. 7. It was confirmed that early and late apoptosis were induced in both cancer cells.

[0785]

[0786] 2.3 Confirmation of the mechanism of action of chromene-benzimidazole derivatives

[0787] The chromene-benzimidazole derivative of the present invention is designed to bind strongly to the C-terminal domain of Hsp90, as described above, and simultaneously bind between tubulin polymers to inhibit polymerization. To verify this dual-targeting effect, the following experiments were conducted.

[0788] In order to evaluate the inhibitory ability of Hsp90 C-terminal domain, the binding affinity between compound 1-1, C-terminal Hsp90 inhibitor Novobiocin, and N-terminal inhibitor Onalespib and C recombinant protein was analyzed to evaluate the inhibitory ability of Hsp90 C-terminal activity. The experimental results are shown in Fig. 8 (a). It was confirmed that the compound of chemical formula 1-1 of the present invention has a significantly superior inhibitory ability by reducing C-terminal HSP90 activity by more than half compared to the existing Novobiocine.

[0789] In addition, after treatment of triple-negative breast cancer cell line MDA-MB-231 with the compound of chemical formula 1-1 at various concentrations (0, 5, 10, and 20 μM) for 72 hours, a decrease in protein expression and phosphorylation of STAT3, c-MET, ERK, and AKT, known as client proteins of HSP90, was confirmed using the Western blot technique, and this is shown in (b) of Figure 8.

[0790] Next, after treating the MDA-MB-231 cell line with the compound of chemical formula 1-1 at various concentrations (0, 5, 10, and 20 μM) for 72 hours, the degradation of tubulin and the expression of apoptosis-related proteins were confirmed by Western blot, and this is shown in (c) of Figure 8. It was confirmed that the compound of the present invention can inhibit tubulin polymerization reaction.

[0791] Finally, after treatment of the BT549 cell line with the compound of chemical formula 1-1 at various concentrations (0, 5, 10, and 20 μM) for 72 hours, propidium iodide staining was performed, and the DNA content of cancer cells was analyzed using flow cytometry to confirm the G2 / M phase cell cycle arrest of the chromene-benzimidazole derivative, which is shown in (d) of Fig. 8.

[0792]

[0793] Example 3. Screening of effective substances of chromene-benzimidazole derivatives and confirmation of anticancer activity by cancer type.

[0794] 3.1 Derivation of effective substances from chromene-benzimidazole derivatives

[0795] Triple-negative breast cancer cell lines MDA-MB-231 and JIMT-1 were treated with chromene-benzimidazole derivative compounds (1-13, 1-19, and 1-22) at various concentrations (0, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2, and 5 μM) for 72 hours. The detailed treatment conditions were as described in Example 2.1. Concentration-dependent inhibition of cell viability (MTS assay) and IC50 values ​​according to cell viability inhibition were confirmed and are shown in Fig. 9. It was confirmed that the IC50 values ​​for compounds 1-13, 1-19, and 1-22 of the present invention were excellent, being 0.154, 1.06, and 0.276 μM, respectively.

[0796] Next, to confirm the targeting ability of compounds 1-13 and 1-22, the following experiment was conducted. After treating the MDA-MB-231 cell line with compounds 1-22 and 1-13 at a concentration of 0.5 μM for 72 hours, morphological changes in the cells were observed using an optical microscope, and the microscopic images are shown in Fig. 10 (a). Typical morphological changes of cell cycle arrest and apoptosis were confirmed. In addition, after treatment with compounds 1-22 and 1-13 at a concentration of 0.5 μM for 72 hours in MDA-MB-231, the expression of HSP90 chaperon complex (HSP90, HSP70, HSP27, HSF-1), HSP90 substrate proteins (EGFR, AKT, JAK2, STAT3), Tubulin targeting ability (Tubulin, mitotic marker p-His H3), and apoptosis-related factors (cleaved caspase-7, Survivin, Mcl-1) proteins was confirmed using Western blot technique, and this is shown in Fig. 10 (b).

[0797]

[0798] 3.2 Confirmation of anticancer activity of chromene-benzimidazole derivatives by cancer type

[0799] After treatment with chromene-benzimidazole derivative compounds 1-22 at various concentrations (0, 0.1, 0.5, 1, 5, and 10 μM) for 72 hours in hematological cancer cell line HL-60, liver cancer cell line HepG2, lung cancer cell line H1299, colon cancer cell line HCT116, and ovarian cancer cell line SKOV3, concentration-dependent inhibition of cell viability (MTS assay) and IC50 values ​​according to cell viability inhibition were confirmed, which are shown in Fig. 11. The same experiment was performed for compounds 1-13, and the results are shown in Fig. 12. Both compounds were confirmed to effectively inhibit cell viability in cancer cell lines other than breast cancer.

[0800]

[0801] 3.3 Derivation of additional effective substances from chromene-benzimidazole derivatives

[0802] After treatment of triple-negative breast cancer cell line MDA-MB-231 with chromene-benzimidazole derivative compounds (1-9, 1-10, 1-11, 1-15, 1-16, and 1-17) at various concentrations (0, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2, and 5 μM) for 72 hours, concentration-dependent inhibition of cell viability (MTS assay) and IC50 values ​​according to inhibition of cell viability were confirmed, and these results are shown in Figure 13. For compounds 1-9, 1-10, 1-11, 1-15, 1-16, and 1-17, very good IC50 values ​​of 0.273, 0.829, 0.335, 0.452, 0.96, and 0.586 μM were confirmed, respectively.

[0803]

[0804] Comparative Example 1. Comparative Experiment with Compounds of Similar Structure

[0805] A comparative experiment was conducted with the following reference compounds in prior literature that have structural similarity to the compound of the present invention.

[0806] [Comparative Experimental Compounds]

[0807]

[0808] The Ref. compound is a compound in which chromene and benzimidazole are combined, similar to the present invention, but there is a difference in that the 5-carbon of benzimidazole in the present invention is linked to chromene through urea, whereas the 2-carbon of benzimidazole in the Ref. compound is linked to chromene through an imine. After treating MDA-MB-231 and JIMT-1 cell lines with the chromene-benzimidazole derivative compounds (1-19 and 1-22) of the present invention or the Ref. compound at various concentrations (0, 2, 5, and 10 μM) for 72 hours, the effects on cell viability were compared using the MTS assay technique, and the results are shown in Fig. 14. Unlike the chromene-benzimidazole derivative of the present invention, the Ref. compound known in the prior art did not inhibit cell viability at all in both cancer cells.

[0809]

[0810] Although the embodiments described above have been described with limited drawings, those skilled in the art will appreciate that various technical modifications and variations can be applied based on the above. For example, appropriate results can still be achieved even if the described techniques are performed in a different order than described, and / or components of the described systems, structures, devices, circuits, etc. are combined or combined in a different manner than described, or are replaced or substituted with other components or equivalents.

[0811] Therefore, other implementations, other embodiments, and equivalents to the claims also fall within the scope of the claims described below.

Claims

1. A chromene-benzimidazole derivative represented by the following [chemical formula 1] or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 is hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl group of C1-C6, substituted or unsubstituted C3-C 20 Cycloalkyl group, substituted or unsubstituted C3-C 20 Heterocycloalkyl group, substituted or unsubstituted C3-C 20 Aryl group and substituted or unsubstituted C3-C 20 Any one selected from the group consisting of heteroaryl groups, If the above straight-chain or branched alkyl group is substituted, it is substituted with halogen, When the above cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group is substituted, straight or branched C1-C6 alkyl, C1-C 10 of Substituted with at least one selected from the group consisting of cycloalkyl, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl.

2. In paragraph 1, In the above [chemical formula 1], R 1 The substituted or unsubstituted straight-chain or branched C1-C6 alkyl group is a substituted or unsubstituted methyl group, and when the methyl group is substituted, it is substituted with a halogen, R 1 Substituted or unsubstituted C3-C 20 The cycloalkyl group of is an unsubstituted cyclohexyl group, R 1 Substituted or unsubstituted C3-C 20 The heterocycloalkyl group is a methylpiperazine group, R 1 Substituted or unsubstituted C3-C 20 The aryl group of is a substituted or unsubstituted phenyl group, and when the phenyl group is substituted, it is a straight or branched C1-C6 alkyl, C1-C 10 of Substituted with at least one selected from the group consisting of cycloalkyl, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl, R 1 Substituted or unsubstituted C3-C 20 A chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein the heteroaryl group is any one selected from the group consisting of a pyridyl group, a thiophenyl group, and a thiazolyl group.

3. In paragraph 1, In the above [chemical formula 1], R 1 is a substituted or unsubstituted phenyl group, A chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof, wherein the phenyl group is substituted with at least one selected from the group consisting of methyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, F, Cl, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, methoxy, pentoxy, N,N-dimethylamino, N,N-diethylamino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl.

4. In paragraph 1, The chromene-benzimidazole derivative represented by the above [chemical formula 1] is characterized in that it is any one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] [Chemical Formula 1-5] [Chemical Formula 1-6] [Chemical Formula 1-7] [Chemical Formula 1-8] [Chemical Formula 1-9] [Chemical Formula 1-10] [Chemical Formula 1-11] [Chemical Formula 1-12] [Chemical Formula 1-13] [Chemical Formula 1-14] [Chemical Formula 1-15] [Chemical Formula 1-16] [Chemical Formula 1-17] [Chemical Formula 1-18] [Chemical Formula 1-19] [Chemical Formula 1-20] [Chemical Formula 1-21] [Chemical Formula 1-22] [Chemical Formula 1-23] [Chemical Formula 1-24] [Chemical Formula 1-25] [Chemical Formula 1-26] [Chemical Formula 1-27] [Chemical Formula 1-28] [Chemical Formula 1-29] [Chemical Formula 1-30] [Chemical Formula 1-31] [Chemical Formula 1-32] [Chemical Formula 1-33] [Chemical Formula 1-34] [Chemical Formula 1-35] [Chemical Formula 1-36] [Chemical Formula 1-37] [Chemical Formula 1-38] [Chemical Formula 1-39] [Chemical Formula 1-40] [Chemical Formula 1-41] [Chemical Formula 1-42] [Chemical Formula 1-43] [Chemical Formula 1-44] [Chemical Formula 1-45] [Chemical Formula 1-46] [Chemical Formula 1-47] [Chemical Formula 1-48] [Chemical Formula 1-49] [Chemical Formula 1-50] [Chemical Formula 1-51] [Chemical Formula 1-52] and [Chemical Formula 1-53] .

5. In paragraph 1, The chromene-benzimidazole derivative represented by the above [chemical formula 1] is characterized in that it is any one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1-1] [Chemical Formula 1-9] [Chemical Formula 1-10] [Chemical Formula 1-11] [Chemical Formula 1-13] [Chemical Formula 1-15] [Chemical Formula 1-16] [Chemical Formula 1-17] [Chemical Formula 1-19] and [Chemical Formula 1-22] .

6. In paragraph 1, A chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof, characterized in that the chromene-benzimidazole derivative has both an effect of inhibiting tubulin polymerization and an effect of inhibiting the C-terminal domain of Hsp90.

7. In paragraph 1, A pharmaceutically acceptable salt of the chromene-benzimidazole derivative, characterized in that the pharmaceutically acceptable salt of the chromene-benzimidazole derivative is at least one selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

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

9. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the pharmaceutical composition induces apoptosis by arresting the cancer cell cycle.

10. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the pharmaceutical composition induces denaturation and decomposition of an oncoprotein.

11. In paragraph 8, A pharmaceutical composition for preventing or treating cancer, characterized in that the cancer is at least one selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, large intestine 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 preventing or treating cancer, characterized in that the cancer is triple-negative breast cancer.

Images