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

Abstract

The present invention relates to a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the derivative as an active ingredient, the chromene-benzimidazole derivative of the present invention being activated in cancer cells, being capable of inhibiting tubulin polymerization and inhibiting a C-terminal domain of Hsp90, and being capable of preventing or treating cancer, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer comprising the derivative as an active ingredient. When the compound is administered to a subject, cancer cell cycle arrest can be caused to induce cell apoptosis and hinder the activity of protooncoprotein, and the compound can be used as a novel double-targeting anti-cancer drug to prevent or treat cancers, preferably to prevent or treat triple negative breast cancer.

Description

Technical Field

[0001] This invention relates to chromene-benzimidazole derivatives or pharmaceutically acceptable salts thereof and their uses. Background Technology

[0002] Triple-negative breast cancer (TNBC, ER-, PR-, HER2-) accounts for 10% to 15% of all breast cancer patients. These patients lack hormone receptors (ER (estrogen receptor), PR (progesterone receptor)) and the HER2 protein, and therefore cannot benefit from hormone therapy or HER2-targeted therapy. Currently, standard treatment for triple-negative breast cancer relies entirely on conventional cytotoxic anticancer drugs (taxanes or anthracyclines). Due to the lack of clearly defined targeted therapies, treatment strategies for other subtypes are very limited compared to breast cancer. More seriously, most patients experience recurrence within 2 to 3 years after surgery or chemotherapy, and the disease is prone to metastasis to other organs such as the lungs, liver, brain, and bones, reducing patient survival rates.

[0003] The 5-year overall survival rate for stage III patients is less than 55%, and the 5-year survival rate for patients with metastatic cancer (advanced stage) is less than 30%, which is extremely low. This disease is a very serious condition in which most patients will die within a few years.

[0004] Microtubules are major components of the cytoskeleton, composed of heteromeric tubulin molecules based on α and β subunits. Microtubules perform numerous cellular functions, including intracellular transport, maintaining polarity, transmitting intracellular signals, cell migration, and proliferation. During mitosis, they form spindle fibers, which facilitate chromosome separation at the cell poles after alignment at the center. If spindle fibers malfunction, cell division is inhibited, inducing apoptosis; therefore, they have attracted considerable attention as targets for anticancer drugs.

[0005] Drugs targeting microtubules can be broadly categorized into those that stabilize microtubules and those that disrupt their stability. First, microtubule stabilizers include taxane, paclitaxel (Taxol), and decetaxel, which prevent microtubule depolymerization and promote polymerization. Most microtubule stabilizers bind to taxane binding sites or overlapping sites of β-tubulin. Second, microtubule destabilizers include colchicine and vinca alkaloids, which bind to colchicine binding sites or vinca binding sites. Compared to drugs that affect microtubule polymerization, drugs targeting the microtubules themselves can be effective at lower drug concentrations, ultimately inhibiting cell mitosis. Therefore, there is a need to develop potential microtubule polymerization inhibitors as anticancer drugs.

[0006] Heat shock protein 90 (Hsp90) is one of the most abundant molecular chaperones in eukaryotic cells, promoting the folding, stabilization, activation, or formation of complexes of target proteins known as "client proteins." Hsp90 regulates the stability and activity of various kinases, transcription factors, signal transducers, and enzymes under normal and stress conditions, thereby being responsible for a variety of biological functions related to cell growth, differentiation, and survival. Furthermore, Hsp90 acts as a buffer against unstable intracellular proteins, contributing to biological evolution and stabilizing disease states. In particular, Hsp90 has attracted significant attention as a target for anticancer drugs because studies have shown that over 50 proteins associated with cancer cells, including Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, and hTERT, are client proteins of Hsp90. Inhibitors of Hsp90 activity can induce the simultaneous degradation of various oncogenic proteins by the proteasome, showing potential as anticancer drugs for treating various cancers, and positive results have been observed in clinical trials at various stages. Summary of the Invention

[0007] Technical problems to be solved

[0008] The purpose of this invention is to provide a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof.

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

[0010] However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art through the following description.

[0011] Technical methods for solving problems

[0012] To address the above problems, the present invention provides a chromene-benzimidazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof:

[0013] [Formula 1]

[0014]

[0015] in:

[0016] R 1 The free radical is selected from hydrogen, halogen, substituted or unsubstituted straight-chain or branched C1-C6 alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C3-C 20 Heterocyclic alkyl, substituted or unsubstituted C3-C 20 Aryl and substituted or unsubstituted C3-C 20 Any of the groups composed of heteroaryl groups,

[0017] If the straight-chain or branched alkyl group is substituted, it is substituted with a halogen.

[0018] If the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted, it is selected from straight-chain or branched C1-C6 alkyl, C1-C6 alkyl, or C1-C6 alkyl. 10 One or more substitutions of the group consisting of cycloalkyl, halogen, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine and benzoyl.

[0019] According to one aspect, in the aforementioned [Equation 1],

[0020] R 1 The substituted or unsubstituted straight-chain or branched C1-C6 alkyl group is a substituted or unsubstituted methyl group; if the methyl group is substituted, it is substituted by a halogen.

[0021] R 1 Substituted or unsubstituted C3-C 20 The cycloalkyl group is an unsubstituted cyclohexyl group.

[0022] R 1 Substituted or unsubstituted C3-C 20 The heterocyclic alkyl group is methylpiperazinyl.

[0023] R 1 Substituted or unsubstituted C3-C 20The aryl group is a substituted or unsubstituted phenyl group. If the phenyl group is substituted, it is selected from straight-chain or branched C1-C6 alkyl groups, C1-C6 alkyl groups, or C1-C6 alkyl groups. 10 One or more substitutions of the group consisting of cycloalkyl, halogen, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl.

[0024] R 1 Substituted or unsubstituted C3-C 20 The heteroaryl group is selected from any one of the group consisting of pyridyl, thiophene, and thiazolyl.

[0025] According to one aspect, in the aforementioned [Equation 1],

[0026] R 1 For substituted or unsubstituted phenyl groups,

[0027] If the phenyl group is substituted, it is substituted by one or more of 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, n-pentoxy, indole, methylpiperazine, and benzoyl.

[0028] According to one aspect, the chromene-benzimidazole derivative represented by [Formula 1] is selected from any of the group consisting of the following compounds:

[0029] [Equation 1-1]

[0030]

[0031] [Equation 1-2]

[0032]

[0033] [Equation 1-3]

[0034]

[0035] [Equations 1-4]

[0036]

[0037] [Equations 1-5]

[0038]

[0039] [Equations 1-6]

[0040]

[0041] [Equations 1-7]

[0042]

[0043] [Equations 1-8]

[0044]

[0045] [Equations 1-9]

[0046]

[0047] [Equation 1-10]

[0048]

[0049] [Equation 1-11]

[0050]

[0051] [Equation 1-12]

[0052]

[0053] [Equation 1-13]

[0054]

[0055] [Equation 1-14]

[0056]

[0057] [Equation 1-15]

[0058]

[0059] [Equation 1-16]

[0060]

[0061] [Equation 1-17]

[0062]

[0063] [Equation 1-18]

[0064]

[0065] [Equation 1-19]

[0066]

[0067] [Equation 1-20]

[0068]

[0069] [Equation 1-21]

[0070]

[0071] [Equation 1-22]

[0072]

[0073] [Equation 1-23]

[0074]

[0075] [Equation 1-24]

[0076]

[0077] [Equation 1-25]

[0078]

[0079] [Equation 1-26]

[0080]

[0081] [Equation 1-27]

[0082]

[0083] [Equation 1-28]

[0084]

[0085] [Equation 1-29]

[0086]

[0087] [Equation 1-30]

[0088]

[0089] [Equation 1-31]

[0090]

[0091] [Equation 1-32]

[0092]

[0093] [Equation 1-33]

[0094]

[0095] [Equation 1-34]

[0096]

[0097] [Equation 1-35]

[0098]

[0099] [Equation 1-36]

[0100]

[0101] [Equation 1-37]

[0102]

[0103] [Equation 1-38]

[0104]

[0105] [Equation 1-39]

[0106]

[0107] [Equation 1-40]

[0108]

[0109] [Equation 1-41]

[0110]

[0111] [Equation 1-42]

[0112]

[0113] [Equation 1-43]

[0114]

[0115] [Equation 1-44]

[0116]

[0117] [Equation 1-45]

[0118]

[0119] [Equation 1-46]

[0120]

[0121] [Equation 1-47]

[0122]

[0123] [Equation 1-48]

[0124]

[0125] [Equation 1-49]

[0126]

[0127] [Equation 1-50]

[0128]

[0129] [Equation 1-51]

[0130]

[0131] [Equation 1-52]

[0132] as well as;

[0133] [Equation 1-53]

[0134]

[0135] According to one aspect, the chromene-benzimidazole derivative represented by [Formula 1] is selected from any of the group consisting of the following compounds: [Formula 1-1]

[0136]

[0137] [Equations 1-9]

[0138]

[0139] [Equation 1-10]

[0140]

[0141] [Equation 1-11]

[0142]

[0143] [Equation 1-13]

[0144]

[0145] [Equation 1-15]

[0146]

[0147] [Equation 1-16]

[0148]

[0149] [Equation 1-17]

[0150]

[0151] [Equation 1-19]

[0152] as well as;

[0153] [Equation 1-22]

[0154]

[0155] According to one aspect, the chromene-benzimidazole derivative simultaneously inhibits tubulin polymerization and inhibits the C-terminal domain of Hsp9.

[0156] According to one aspect, the pharmaceutically acceptable salt of the said chromene-benzimidazole derivative is selected from one or more of the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

[0157] According to another embodiment of the present invention, a pharmaceutical composition for the prevention or treatment of cancer is provided, comprising any of the said chromene-benzimidazole derivatives or a pharmaceutically acceptable salt thereof as an active ingredient.

[0158] According to one aspect, the cancer is selected from one or more of the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, hematologic cancer, thymic cancer, urethral cancer, and bronchial cancer, preferably triple-negative breast cancer.

[0159] In addition, the present invention provides a composition for the prevention or treatment of cancer comprising the aforementioned 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 the step of administering the said chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0161] In addition, the present invention provides the use of the aforementioned chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of cancer.

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

[0163] In addition, the present invention provides the use of the aforementioned chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for diagnosing cancer.

[0164] According to one embodiment of the present invention, the pharmaceutical composition can induce cell cycle arrest in cancer cells, thereby inducing apoptosis, or it can induce denaturation and degradation of oncoproteins. Preferably, both mechanisms of action can be achieved simultaneously.

[0165] According to another embodiment of the present invention, the cancer is selected from one or more of the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic malignancies, 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, preferably breast cancer, more preferably triple-negative breast cancer.

[0166] Invention Effects

[0167] This invention relates to a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof, and compositions containing the derivative as an active ingredient for the prevention or treatment of cancer. The chromene-benzimidazole derivative of this invention is activated in cancer cells to inhibit the C-terminal domain of the Hsp90 protein while simultaneously inhibiting tubulin polymerization. Therefore, upon administration to a subject, it can block the cancer cell cycle and induce apoptosis, while also inhibiting the activity of oncoproteins, thus providing an anticancer effect while producing cytotoxicity. Therefore, the compounds of this invention and compositions containing them, as novel dual-target anticancer compositions, can be used for the prevention or treatment of cancer, preferably for the prevention or treatment of triple-negative breast cancer.

[0168] However, the technical problem to be solved by the present invention is not limited to the issues mentioned above, and other issues not mentioned will be clearly understood by those skilled in the art through the following description. Attached Figure Description

[0169] Figure 1The results of the MTS assay were shown after treating triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1 with different concentrations (0 μM, 1 μM and 5 μM) of chromene-benzimidazole derivatives (1-1 to 1-8).

[0170] Figure 2 The results of the MTS assay were shown after treating triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1 with different concentrations (0 μM, 1 μM and 5 μM) of chromene-benzimidazole derivatives (1-9 to 1-18).

[0171] Figure 3 The results of the MTS assay were shown after treating triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1 with different concentrations (0 μM, 1 μM and 5 μM) of chromene-benzimidazole derivatives (1-19 to 1-28).

[0172] Figure 4 The results of the MTS assay were shown after treating triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1 with different concentrations (0 μM, 1 μM and 5 μM) of chromene-benzimidazole derivatives (1-29 to 1-38).

[0173] Figure 5 The results of the MTS assay were shown after treating triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1 with different concentrations (0 μM, 1 μM and 5 μM) of chromene-benzimidazole derivatives (1-39 to 1-46).

[0174] Figure 6 The results of the MTS assay were shown after treating triple-negative breast cancer cell line MDA-MB-231 and HER2-positive breast cancer cell line JIMT-1 with different concentrations (0 μM, 1 μM and 5 μM) of chromene-benzimidazole derivatives (1-47 to 1-53).

[0175] Figure 7 The inhibitory effect of chromene-benzimidazole derivative (1-1) on the cell survival of triple-negative breast cancer cell lines MDA-MB-231 and BT549 was confirmed to be concentration-dependent, and it was also confirmed to induce apoptosis, both early and late.

[0176] Figure 8It was confirmed that the chromene-benzimidazole derivative binds to the C-terminal domain of Hsp90 to inhibit Hsp90 function and microtubule polymerization, thereby exerting an anti-cancer effect. It can reduce the expression and phosphorylation of STAT3, c-MET, ERK and AKT proteins in MDA-MB-231 and BT549 cell lines and induce cell cycle G2 / M phase arrest.

[0177] Figure 9 The results show that after treating triple-negative breast cancer cell lines MDA-MB-231 and JIMT-1 with different concentrations of chromone-benzimidazole derivative compounds (1-13, 1-19, 1-22), the inhibitory effect on cell viability was confirmed by the MTS method in a concentration-dependent manner, and the IC50 values ​​were also confirmed.

[0178] Figure 10 The results of optical microscopy and Western blot analysis of MDA-MB-231 cell lines treated with compounds 1-22 and 1-13 are shown. Morphological changes of cell cycle arrest and apoptosis can be observed in the results, and the expression of Hsp90 complex, Hsp90 substrate protein, tubulin targeting and apoptosis-related proteins can also be confirmed.

[0179] Figure 11 The effects of chromene-benzimidazole derivative compounds 1-22 in hematologic malignancies, liver cancer, lung cancer, colorectal cancer, and ovarian cancer cell lines are shown.

[0180] Figure 12 The effects of chromene-benzimidazole derivative compounds 1-13 in hematologic malignancies, liver cancer, lung cancer, colorectal cancer, and ovarian cancer cell lines are shown.

[0181] Figure 13 The results show that 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) confirmed that the inhibition of cell viability was concentration-dependent (MTS method), and the IC50 values ​​were also confirmed.

[0182] Figure 14 The results show a comparative evaluation of cell viability of chromene-benzimidazole derivative compounds (1-19 and 1-22) and structurally similar reference compounds in MDA-MB-231 and JIMT-1 cell lines. Detailed Implementation

[0183] The inventors have demonstrated that benzimidazole derivatives can achieve cell cycle arrest by inhibiting tubulin synthesis, thus exhibiting an anticancer effect by inhibiting cancer cell division. They have also confirmed that chromone derivatives can exert an anticancer effect by inhibiting the C-terminal domain of Hsp90. Furthermore, the inventors have demonstrated that combining benzimidazole and chromone in a single compound molecule can simultaneously activate both mechanisms of action. This leads to the invention of a novel dual-target anticancer drug, a chromone-benzimidazole derivative or a pharmaceutically acceptable salt thereof.

[0184] Based on the above results, the present invention provides a chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof represented by the following [Formula 1]:

[0185] [Formula 1]

[0186]

[0187] in:

[0188] R 1 The free radical is selected from hydrogen, halogen, substituted or unsubstituted straight-chain or branched C1-C6 alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C3-C 20 Heterocyclic alkyl, substituted or unsubstituted C3-C 20 aryl groups and substituted or unsubstituted C3-C 20 Any of the groups composed of heteroaryl groups,

[0189] If the straight-chain or branched alkyl group is substituted, it is substituted with a halogen.

[0190] If the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted, it is selected from straight-chain or branched C1-C6 alkyl, C1-C6 alkyl, or C1-C6 alkyl. 10 One or more substitutions of the group consisting of cycloalkyl, halogen, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine and benzoyl.

[0191] In this invention, the term "substitution" refers to a reaction in which one atom or group of atoms in a compound molecule is replaced by another atom or group of atoms.

[0192] In this invention, the term "chain-like" refers to a molecule with a chain-like structure. A chain-like structure is a chemical structure in which carbon atoms are connected in a chain-like manner, including straight chains and branched chains.

[0193] In this invention, the term "cyclic" refers to a ring structure formed by connecting the two ends of an organic compound skeleton.

[0194] In this invention, the term "straight-chain or branched alkyl" refers to a monovalent straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms and consisting only of carbon and hydrogen atoms.

[0195] In this invention, the term "cycloalkyl" refers to cyclic saturated hydrocarbon residues.

[0196] The alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0197] In this invention, the term "heterocyclic alkyl" generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon, which may optionally be unsubstituted, monosubstituted or polysubstituted, and has at least one heteroatom selected from N, O or S in its structure.

[0198] In this invention, the term "aryl" refers to an unsaturated aromatic ring compound having 3 to 12 carbon atoms, which has a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl). Such aryl compounds include, but are not limited to, phenyl, naphthyl, etc.

[0199] In this invention, the term "heteroaryl" refers to a monocyclic or multiple fused rings in which at least one of the atoms constituting the ring is a heteroatom having N, O, or S. Such heteroaryls include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, furanyl, etc.

[0200] In this invention, the term "alkoxy" refers to an alkyl group (-OR) bonded to oxygen. Such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc.

[0201] In this invention, "halogen" can be fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), etc.

[0202] In a preferred embodiment of the invention, the compound represented by Formula 1 is preferably one or more selected from the group consisting of the following compounds:

[0203] [Equation 1-1]

[0204]

[0205] [Equation 1-2]

[0206]

[0207] [Equation 1-3]

[0208]

[0209] [Equations 1-4]

[0210]

[0211] [Equations 1-5]

[0212]

[0213] [Equations 1-6]

[0214]

[0215] [Equations 1-7]

[0216]

[0217] [Equations 1-8]

[0218]

[0219] [Equations 1-9]

[0220]

[0221] [Equation 1-10]

[0222]

[0223] [Equation 1-11]

[0224]

[0225] [Equation 1-12]

[0226]

[0227] [Equation 1-13]

[0228]

[0229] [Equation 1-14]

[0230]

[0231] [Equation 1-15]

[0232]

[0233] [Equation 1-16]

[0234]

[0235] [Equation 1-17]

[0236]

[0237] [Equation 1-18]

[0238]

[0239] [Equation 1-19]

[0240]

[0241] [Equation 1-20]

[0242]

[0243] [Equation 1-21]

[0244]

[0245] [Equation 1-22]

[0246]

[0247] [Equation 1-23]

[0248]

[0249] [Equation 1-24]

[0250]

[0251] [Equation 1-25]

[0252]

[0253] [Equation 1-26]

[0254]

[0255] [Equation 1-27]

[0256]

[0257] [Equation 1-28]

[0258]

[0259] [Equation 1-29]

[0260]

[0261] [Equation 1-30]

[0262]

[0263] [Equation 1-31]

[0264]

[0265] [Equation 1-32]

[0266]

[0267] [Equation 1-33]

[0268]

[0269] [Equation 1-34]

[0270]

[0271] [Equation 1-35]

[0272]

[0273] [Equation 1-36]

[0274]

[0275] [Equation 1-37]

[0276]

[0277] [Equation 1-38]

[0278]

[0279] [Equation 1-39]

[0280]

[0281] [Equation 1-40]

[0282]

[0283] [Equation 1-41]

[0284]

[0285] [Equation 1-42]

[0286]

[0287] [Equation 1-43]

[0288]

[0289] [Equation 1-44]

[0290]

[0291] [Equation 1-45]

[0292]

[0293] [Equation 1-46]

[0294]

[0295] [Equation 1-47]

[0296]

[0297] [Equation 1-48]

[0298]

[0299] [Equation 1-49]

[0300]

[0301] [Equation 1-50]

[0302]

[0303] [Equation 1-51]

[0304]

[0305] [Equation 1-52]

[0306] as well as;

[0307] [Equation 1-53]

[0308]

[0309] The chromene-benzimidazole derivative or its pharmaceutically acceptable salt of the present invention has specific activity in cancer cells, inhibiting microtubule polymerization and inducing apoptosis. In addition, it can inhibit the C-terminal domain of Hsp90, thereby inhibiting the activity of proto-oncoproteins. Therefore, it can be included as an active ingredient in pharmaceutical compositions for the prevention or treatment of cancer.

[0310] In one embodiment of the present invention, the pharmaceutical composition can induce apoptosis by achieving cell cycle arrest in cancer cells, or can induce denaturation and degradation of proto-oncoproteins. Preferably, both of these mechanisms of action can be achieved.

[0311] In this invention, the term "oncoprotein" refers to a protein that regulates cell growth and division, which can promote the formation of cancer cells and the development of cancer due to gene mutations or abnormal expression regulation. Specifically, for the purposes of this invention, the oncoprotein can be a client protein of Hsp90, preferably Her2 / ErbB2, v-Src, Hif-1α, Raf-1, AKT, hTERT, ERK, p-ERK, STAT3, c-MET, etc.

[0312] In this invention, the term "pharmaceutically acceptable salt" refers to a dosage form of the compound that will not cause severe irritation to the organism administering the compound and will not impair the compound's biological activity and physical properties. Pharmaceutically acceptable salts can be prepared by reacting the compounds of this invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; and organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, decanoic acid, isobutyric acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid. Furthermore, the compounds of this invention can be prepared by reacting them with a base to form salts of alkali metals such as ammonium, sodium, and potassium salts; salts of alkaline earth metals such as calcium and magnesium salts; salts of organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, and tris(hydroxymethyl)methylamine; and salts of amino acids such as arginine and lysine.

[0313] Furthermore, the aforementioned chromene-benzimidazole derivatives or their pharmaceutically acceptable salts include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.

[0314] Furthermore, the present invention can provide a method for the prevention, treatment and / or diagnosis of cancer, comprising the step of administering the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0315] In this document, the term "prevention" refers to all actions that inhibit or delay the occurrence, spread, or recurrence of cancer by applying the compositions of the present invention; "treatment" refers to all actions that improve or benefit cancer symptoms by applying the compositions of the present invention.

[0316] In this document, the term "pharmaceutical composition" is intended for the prevention or treatment of disease and can be formulated into various forms for use according to conventional methods. For example, it can be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups, as well as into external preparations, suppositories, and sterile injections.

[0317] In this invention, "comprising as an active ingredient" means that the content of the ingredient is sufficient or necessary to achieve the desired biological effect. In practical applications, the content of the active ingredient is determined according to the purpose of treating the disease and should not cause other toxicities. For example, it can be varied based on various factors such as the disease or condition being treated, the type of composition being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art to which this invention pertains can determine the effective content of a single composition empirically without requiring extensive experimentation.

[0318] Furthermore, in addition to the active ingredients of the above-mentioned dosage forms, the pharmaceutical compositions of the present invention may also contain one or more pharmaceutically acceptable carriers.

[0319] The pharmaceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol, and at least one mixture of these components, and may further include, as needed, other common additives such as antioxidants, buffers, and antibacterial agents. Furthermore, diluents, dispersants, surfactants, binders, and lubricants may be added to formulate aqueous solutions, suspensions, emulsions, and other injectable preparations, pills, capsules, granules, or tablets. Additionally, formulations may preferably be prepared using appropriate methods in the art or using methods disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA) to suit different diseases or ingredients.

[0320] The compositions of the present invention can be administered orally or parenterally in a pharmaceutically effective amount according to the desired method. The term "pharmaceutically effective amount" in the present invention refers to a content that can adequately treat the disease without causing side effects within a reasonable benefit / risk ratio of applicable drug treatment. The level of the effective amount can be determined based on many factors as well as other factors known in the medical field. Factors to be considered may include the patient's health status, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration and excretion rate, treatment duration, and concurrently formulated or taken drugs, etc.

[0321] Furthermore, the pharmaceutical compositions of the present invention can be administered to subjects to prevent, treat, and / or diagnose cancers, including skin cancer, breast cancer, uterine cancer, esophageal cancer, gastric cancer, brain tumors, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic malignancies, 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, or bronchial cancer, preferably cancers with acidity higher than normal cells and whose cytotoxicity can be inhibited by microtubule polymerization inhibitors. Non-limiting examples include breast cancer, preferably triple-negative breast cancer, etc.

[0322] In this invention, the term "subject" can be any mammal, such as livestock or humans, that requires prevention, treatment, and / or diagnosis of cancer, without particular limitation, but is preferably human.

[0323] The pharmaceutical compositions of the present invention can be formulated into various dosage forms for administration to subjects. Representative parenteral administration formulations are injectable formulations, preferably isotonic aqueous solutions or suspensions. Injectable formulations can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. For example, the components can be dissolved in physiological saline or buffer solution to prepare an injection. Furthermore, dosage forms for oral administration include ingestible tablets, sublingual tablets, lozenges, capsules, elixirs, suspensions, syrups, and rice paper capsules, etc. These dosage forms, in addition to the active ingredient, may include diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone, and may further include disintegrants, absorbents, colorants, flavoring agents, and / or sweeteners such as starch, agar, alginate, or their sodium salts. The formulation can be prepared by conventional mixing, granulation, or coating methods.

[0324] Furthermore, the pharmaceutical composition of the present invention may also include preservatives, hydrating agents, emulsification promoters, salts or buffers for controlling osmotic pressure, and other substances that can be used for treatment, and may be formulated according to conventional methods.

[0325] The pharmaceutical compositions of the present invention can be administered via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular administration. The appropriate dosage of the active ingredient can be determined based on factors such as the route of administration, the patient's age, sex, weight, and disease severity. Furthermore, the compositions of the present invention can be used in combination with known compounds that can enhance the desired effect.

[0326] The pharmaceutical compositions according to the present invention can be administered to humans or animals via oral administration or parenteral administration, such as intravenous, subcutaneous, intranasal, or intraperitoneal administration. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as infusion methods.

[0327] In the pharmaceutical compositions of the present invention, the total effective amount of the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof can be administered to the patient via a single dose or via a fractionated treatment protocol with multiple doses over a prolonged period. The content of the active ingredient in the pharmaceutical compositions of the present invention can be varied according to the severity of the disease, but generally, based on an adult, the effective dose per administration can be from 100 μg to 3,000 mg, administered multiple times a day. However, the concentration of the chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof depends on various factors, such as the patient's age, weight, health status, sex, disease severity, diet, and excretion rate, and these factors can be taken into account when determining the patient's dosage.

[0328] Furthermore, as long as the pharmaceutical composition of the present invention achieves the effects of the present invention, there are no particular limitations on its dosage form, route of administration, or method of administration. In addition to the chromene-benzimidazole derivative or its pharmaceutically acceptable salt as the active ingredient, the pharmaceutical composition of the present invention may further include known anticancer agents and can be used in conjunction with other known treatment methods.

[0329] The terminology used in the embodiments is for illustrative purposes only and is not intended to limit the scope. Unless otherwise specified in the text, singular expressions include plural meanings. In this specification, terms such as "comprising" or "having" are used to express the presence of the features, numbers, steps, operations, constituent elements, accessories, or combinations thereof described in the specification, and do not exclude the possibility of the presence or additional addition of one or more other features, numbers, steps, operations, constituent elements, accessories, or combinations thereof.

[0330] Unless otherwise defined, all terms used herein, including technical or scientific terms, shall have their ordinary meanings as understood by one of ordinary skill in the art. Terms commonly used, such as those defined in dictionaries, shall be understood as having their meanings in the relevant technical context and shall not be interpreted as idealized or overly formalized meanings unless explicitly defined in this specification.

[0331] The exemplary embodiments will now be described in detail with reference to the accompanying drawings. However, various modifications can be made to the exemplary embodiments. This disclosure is not limited to the exemplary embodiments herein. The exemplary embodiments should be understood to include all modifications, equivalents, and alternatives thereof made within the concept and scope of this disclosure.

[0332] Furthermore, the embodiments disclosed in this specification are described in detail with reference to the accompanying drawings. Identical or similar components are assigned the same reference numerals, regardless of the reference numerals, and repetitive descriptions are omitted. Additionally, when describing the embodiments disclosed in this specification, detailed descriptions of relevant prior art will be omitted if it is determined that such detailed descriptions may obscure the main idea of ​​the embodiments disclosed in this specification.

[0333] [Example]

[0334] Example 1. Preparation of Chromene-Benzimazole Derivatives

[0335] All chemical reagents are commercially available products. 1 The H NMR spectra were recorded on a Bruker Avance III 400MHz instrument with TMS as an internal standard.

[0336] 1.1 Synthesis of Formula 1-1 (1-(2-chloro-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-chloro-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0337] The chromene-benzimidazole derivative of Formula 1-1 is synthesized using the following two methods.

[0338] [Equation 1-1]

[0339]

[0340] Method 1

[0341]

[0342] Et3N (0.05 mL, 0.5 mmol) was added dropwise to a benzene (2 mL) 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) with stirring at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then at 80 °C for 6 hours. The solvent was then removed to give the target residue (crude isocyanate). A solution was prepared by adding dry toluene (2 mL) dropwise to the residue and stirring. This solution was then slowly added dropwise to a 3 mL solution of THF containing 2-chloro-1H-benzo[d]imidazol-5-amine (36.8 mg, 0.22 mmol) as the free amine and Et3N (0.028 mL, 0.2 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solvent was then removed to obtain the target residue, which was purified by column chromatography (SiO2, MC:MeOH, 20 / 1, v / v) to give the target compound of formula 1-1 as a white solid (51 mg, 0.188 mmol). Yield: 64%.

[0343] 1 H NMR (400MHz, DMSO-d6) δ12.9(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. 6Hz, 1H), 7.05 (s, 1H), 6.56 (d, J = 9.9Hz, 1H), 6.52 (d, J = 9.9Hz, 1H), 5.82 (d, J = 9.9Hz, 1H), 3.73 (s, 3H), 1.37 (s, 6H).

[0344] Method 2

[0345] 5-Methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (0.117 g, 0.5 mmol) was dissolved in DMF (2 mL), followed by the addition of 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). The mixture was stirred in a microwave reactor at 100 °C for 2 hours. The reaction mixture was diluted with excess ethyl acetate, extracted, washed with cold water, and the solvent was removed. The oily reaction mixture was separated by silica gel column chromatography with ethyl acetate / hexane (EtOAC:Hexane, 9 / 1) to give a light brown solid of formula 1-1 (0.045 g). Yield: 50%.

[0346] 1 H NMR (400MHz, DMSO-d6) δ10.59(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).

[0347] Synthesis of Formula 1-2(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)urea).

[0348] The synthesis of the chromene-benzimidazole derivatives of formula 1-2 is as follows:

[0349] [Equation 1-2]

[0350]

[0351] Following a method similar to Method 1 in Examples 1-1, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(trifluoromethyl)-1H-1,3-benzodiazole-5-amine were reacted to give compounds 1-2. Yield: 65%.

[0352] 1 H NMR (400MHz, DMSO-d6) δ13.68(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).

[0353] Synthesis of Formula 1-3 (1-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-cyclohexyl-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0354] The synthesis of the chromene-benzimidazole derivatives of formulas 1-3 is as follows:

[0355] [Equation 1-3]

[0356]

[0357] Following a method similar to Method 1 in Examples 1-1, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-cyclohexyl-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-3. Yield: 66%.

[0358] 1H NMR (400MHz, DMSO-d6) δ11.95(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).

[0359] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-5-yl)urea).

[0360] The synthesis of the chromene-benzimidazole derivatives of formulas 1-4 is as follows:

[0361] [Equations 1-4]

[0362]

[0363] Following a method similar to Method 1 in Examples 1-1, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-4. Yield: 48%.

[0364] 1 H NMR(400MHz,DMSO-d6)δ7.78(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).

[0365] Synthesis of Formula 1-5 (1-(1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0366] The synthesis of the chromene-benzimidazole derivatives of formulas 1-5 is as follows:

[0367] [Equations 1-5]

[0368]

[0369] Following a method similar to Method 1 in Examples 1-1, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-5. Yield: 73%.

[0370] 1 H NMR (400MHz, DMSO-d6) δ12.27(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).

[0371] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(thiophen-2-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0372] The synthesis of the chromene-benzimidazole derivatives of formulas 1-6 is as follows:

[0373] [Equations 1-6]

[0374]

[0375] Following a method similar to Method 1 in Examples 1-1, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(thiophen-2-yl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-6. Yield: 52%.

[0376] 1 H NMR (400MHz, DMSO-d6) δ12.82(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).

[0377] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(thiazol-4-yl)-1H-benzo[d]imidazol-5-yl)urea)

[0378] The synthesis of the chromene-benzimidazole derivatives of formulas 1-7 is as follows:

[0379]

[0380] [Equations 1-7]

[0381] Toluene (5 mmol) of 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (0.117 g, 0.5 mmol)

[0382]

[0383] Triethylamine (0.068 g, 0.09 mL, 0.66 mmol) and diphenylphosphoazide (DPPA, 0.210 g, 0.763 mmoles, 1.5 eq) were added sequentially to a solution of 1 mL. After stirring at room temperature for 1 hour, a pre-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 stirred at 110 °C for 5 hours. The reaction mixture was cooled, the solvent was removed, and the mixture was purified by silica gel column chromatography to give pure product compounds 1-7 (0.08 g). Yield: 36%.

[0384] 1 H NMR(400MHz,DMSO-d6)δ12.80(bs,1H),9.32(s,1H),9.22(bs,1H),8.41(s,1H),8.09(s,1H),7.94-7.84(m,2 H),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).

[0385] Synthesis of formula 1-8 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-phenyl-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-phenyl-1H-benzo[d]imidazol-5-yl)urea).

[0386] The synthesis of the chromene-benzimidazole derivatives of formulas 1-8 is as follows:

[0387] [Equations 1-8]

[0388]

[0389] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-phenyl-1H-benzo[d]imidazol-5-amine were reacted, with the developing solvent being successively changed from ethyl acetate and hexane (1:1, v / v) to ethyl acetate and hexane (3:1, v / v) to obtain compounds 1-8. Yield: 72%.

[0390] 1 H NMR(400MHz,DMSO-d6)δ12.79(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).

[0391] Synthesis of formula 1-9(1-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0392] The synthesis of the chromene-benzimidazole derivatives of formulas 1-9 is as follows:

[0393] [Equations 1-9]

[0394]

[0395] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-fluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-9. Yield: 50%.

[0396] 1H NMR (400MHz, DMSO-d6) δ12.80(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).

[0397] Synthesis of formula 1-10(1-(2-(3-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(3-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0398] The synthesis of the chromene-benzimidazole derivatives of formulas 1-10 is as follows:

[0399] [Equation 1-10]

[0400]

[0401] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-fluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-10. Yield: 67%.

[0402] 1 H NMR (400MHz, DMSO-d6) δ11.82(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).

[0403] Synthesis of Formula 1-11(1-(2-(4-chlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-chlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0404] The synthesis of the chromene-benzimidazole derivatives of formula 1-11 is as follows:

[0405] [Equation 1-11]

[0406]

[0407] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-chlorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-11. Yield: 33%.

[0408] 1 H NMR (400MHz, DMSO-d6) δ12.80(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).

[0409] Synthesis of formula 1-12(1-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0410] The synthesis of the chromene-benzimidazole derivatives of formula 1-12 is as follows:

[0411] [Equation 1-12]

[0412]

[0413] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 4-(5-amino-1H-benzo[d]imidazol-2-yl)phenol were reacted to give compounds 1-12. Yield: 30%.

[0414] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),9.91(bs,1H),9.18(s,1H),8.09(s,1H),7.95(m,3H),7.86(d,J=8.8 Hz,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).

[0415] Synthesis of Formula 1-13 (1-(2-(4-cyanophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-cyanophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0416] The synthesis of the chromene-benzimidazole derivatives of formula 1-13 is as follows:

[0417] [Equation 1-13]

[0418]

[0419] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 4-(5-amino-1H-benzo[d]imidazol-2-yl)benzonitrile were reacted to give compounds 1-13. Yield: 58%.

[0420] 1H NMR (400MHz, DMSO-d6) δ13.09(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).

[0421] 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0422] The synthesis of the chromene-benzimidazole derivatives of formula 1-14 is as follows:

[0423] [Equation 1-14]

[0424]

[0425] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-14 as brown solids. Yield: 37%.

[0426] 1 H NMR (400MHz, DMSO-d6) δ13.06(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).

[0427] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(6-methoxypyridin-3-yl)-1H-benzo[d]imidazol-5-yl)urea).

[0428] The synthesis of the chromene-benzimidazole derivatives of formula 1-15 is as follows:

[0429] [Equation 1-15]

[0430]

[0431] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(6-methoxypyridin-3-yl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-15 as light brown solids. Yield: 71%.

[0432] 1 H NMR (400MHz, DMSO-d6) δ12.79(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,1 H), 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).

[0433] Synthesis of 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, 1-(2-(4-(dimethylamino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0434] The synthesis of the chromene-benzimidazole derivatives of formula 1-16 is as follows:

[0435] [Equation 1-16]

[0436]

[0437] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(dimethylamino)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-16 as light brown solids. Yield: 36%.

[0438] 1 H NMR (400MHz, DMSO-d6) δ12.36(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).

[0439] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0440] The synthesis of the chromene-benzimidazole derivatives of formula 1-17 is as follows:

[0441] [Equation 1-17]

[0442]

[0443] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-17. Yield: 23%.

[0444] 1 H NMR(400MHz,DMSO-d6)δ12.71(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).

[0445] Synthesis of 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, 1-(2-(3,5-dimethoxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0446] The synthesis of the chromene-benzimidazole derivatives of formula 1-18 is as follows:

[0447] [Equation 1-18]

[0448]

[0449] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,5-dimethoxyphenyl)-1H-benzimidazol-5-amine were reacted to obtain compounds 1-18.

[0450] Yield 57%

[0451] 1 H NMR (400MHz, DMSO-d6) δ12.71(bs,1H),9.24(bs,1H),8.11(bs,1H),8.00(s,1H),7.85(m,1H),7.57(d,J=8.4Hz,1 H),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).

[0452] Synthesis of 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, 1-(2-(2,4-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0453] The synthesis of the chromene-benzimidazole derivatives of formula 1-19 is as follows:

[0454] [Equation 1-19]

[0455]

[0456] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,4-difluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-19. Yield: 50%.

[0457] 1 H NMR (400MHz, DMSO-d6) δ12.43(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).

[0458] Synthesis of 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, 1-(2-(2,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0459] The synthesis of the chromene-benzimidazole derivatives of formula 1-20 is as follows:

[0460] [Equation 1-20]

[0461] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,4-)

[0462]

[0463] The compound was reacted with dichlorophenyl)-1H-benzo[d]imidazol-5-amine to give compounds 1-20. The yield was 53%.

[0464] 1 H NMR(400MHz,DMSO-d6)δ12.59(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),

[0465] 3.74 (s, 3H), 1.37 (s, 6H).

[0466] Synthesis of 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, 1-(2-(2,3-dichlorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0467] The synthesis of the chromene-benzimidazole derivatives of formula 1-21 is as follows:

[0468] [Equation 1-21]

[0469]

[0470] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,3-dichlorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-21.

[0471] Yield 59%

[0472] 1H NMR(400MHz,DMSO-d6)δ12.66(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).

[0473] Synthesis of formula 1-22(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(p-tolyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(p-tolyl)-1H-benzo[d]imidazol-5-yl)urea).

[0474] The synthesis of the chromene-benzimidazole derivatives of formula 1-22 is as follows:

[0475] [Equation 1-22]

[0476]

[0477] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(p-tolyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-22.

[0478] Yield 81%

[0479] 1 H NMR (400MHz, DMSO-d6) δ12.69(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).

[0480] Synthesis of Formula 1-23(1-(2-(4-isopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-isopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0481] The synthesis of the chromene-benzimidazole derivatives of formula 1-23 is as follows:

[0482] [Equation 1-23]

[0483]

[0484] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-isopropylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-23.

[0485] Yield 74%

[0486] 1 H NMR (400MHz, DMSO-d6) δ12.70(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).

[0487] Synthesis of 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, 1-(2-(4-(tert-butyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0488] The synthesis of the chromene-benzimidazole derivatives of formula 1-24 is as follows:

[0489] [Equation 1-24]

[0490]

[0491] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-tert-butylphenyl)-1H-benzimidazol-5-amine were reacted to obtain compounds 1-24.

[0492] 55% yield

[0493] 1 H NMR(400MHz,DMSO-d6)δ12.65(bs,1H),9.21(bs,1H),8.10(m,3H),7.98(s,1H),7.85(m,1H),7.57(m,3 H), 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).

[0494] Synthesis of formula 1-25(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-phenoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-phenoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0495] The synthesis of the chromene-benzimidazole derivatives of formula 1-25 is as follows:

[0496] [Equation 1-25]

[0497]

[0498] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-phenoxyphenyl)-1H-1,3-benzodiazole-5-amine were reacted to obtain compounds 1-25.

[0499] Yield 63%

[0500] 1 H NMR(400MHz,DMSO-d6)δ12.73(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).

[0501] Synthesis of 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, 1-(2-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0502] The synthesis of the chromene-benzimidazole derivatives of formula 1-26 is as follows:

[0503] [Equation 1-26]

[0504]

[0505] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-26.

[0506] 70% yield

[0507] 1 H NMR (400MHz, DMSO-d6) δ12.84(bs,1H),9.26(bs,1H),8.31(s,1H),8.12(s,2H),8.00(bs,1H),7.86(d,J=8.8H z,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).

[0508] Synthesis of 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, 1-(2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0509] The synthesis of the chromene-benzimidazole derivatives of formula 1-27 is as follows:

[0510] [Equation 1-27]

[0511]

[0512] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-27.

[0513] Yield 53%

[0514] 1 H NMR (400MHz, DMSO-d6) δ12.62(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).

[0515] 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, 1-(2-(4-(diethylamino)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0516] The synthesis of the chromene-benzimidazole derivatives of formula 1-28 is as follows:

[0517] [Equation 1-28]

[0518]

[0519] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(diethylamino)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-28.

[0520] Yield 54%

[0521] 1 H NMR (400MHz, DMSO-d6) δ12.35(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=9.2H z,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).

[0522] Synthesis of 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, 1-(2-(3,4-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0523] The synthesis of the chromene-benzimidazole derivatives of formula 1-29 is as follows:

[0524] [Equation 1-29]

[0525]

[0526] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,4-difluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-29.

[0527] Yield 57%

[0528] 1 H NMR (400MHz, DMSO-d6) δ12,84(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).

[0529] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(pentyloxy)phenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0530] The synthesis of the chromene-benzimidazole derivatives of formula 1-30 is as follows:

[0531] [Equation 1-30]

[0532]

[0533] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(pentyloxy)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-30.

[0534] 60% yield

[0535] 1H NMR (400MHz, DMSO-d6) δ12.60(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).

[0536] Synthesis of 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, 1-(2-(5-chloro-2-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0537] The synthesis of the chromene-benzimidazole derivatives of formula 1-31 is as follows:

[0538] [Equation 1-31]

[0539]

[0540] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(5-amino-1H-benzo[d]imidazol-2-yl)-4-chlorophenol were reacted to obtain compounds 1-31.

[0541] Yield 59%

[0542] 1H NMR (400MHz, DMSO-d6) δ13.26(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,1 H),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).

[0543] Synthesis of 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, 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).

[0544] The synthesis of the chromene-benzimidazole derivatives of formula 1-32 is as follows:

[0545] [Equation 1-32]

[0546]

[0547] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(1H-indol-3-yl)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-32.

[0548] Yield 38%

[0549] 1 H NMR(400MHz,DMSO-d6)δ12.28(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).

[0550] Synthesis of Formula 1-33(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-propylphenyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-propylphenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0551] The synthesis of the chromene-benzimidazole derivatives of formula 1-33 is as follows:

[0552] [Equation 1-33]

[0553]

[0554] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-propylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-33.

[0555] Yield 72%

[0556] 1 H NMR (400MHz, DMSO-d6) δ12.70(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).

[0557] 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, 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).

[0558] The synthesis of the chromene-benzimidazole derivatives of formula 1-34 is as follows:

[0559] [Equation 1-34]

[0560]

[0561] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-34.

[0562] Yield 58%

[0563] 1 H NMR (400MHz, DMSO-d6) δ12.59(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).

[0564] Synthesis of formula 1-35(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(o-tolyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(o-tolyl)-1H-benzo[d]imidazol-5-yl)urea).

[0565] The synthesis of the chromene-benzimidazole derivatives of formula 1-35 is as follows:

[0566] [Equation 1-35]

[0567]

[0568] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(o-tolyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-35.

[0569] Yield 73%

[0570] 1 H NMR (400MHz, DMSO-d6) δ12.44(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).

[0571] Synthesis of formula 1-36(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(m-tolyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(m-tolyl)-1H-benzo[d]imidazol-5-yl)urea).

[0572] The synthesis of the chromene-benzimidazole derivatives of formula 1-36 is as follows:

[0573] [Equation 1-36]

[0574]

[0575] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(m-tolyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-36.

[0576] Yield 68%

[0577] 1H NMR (400MHz, DMSO-d6) δ12.75(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).

[0578] Synthesis of Formula 1-37(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0579] The synthesis of the chromene-benzimidazole derivatives of formula 1-37 is as follows:

[0580] [Equation 1-37]

[0581]

[0582] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-methoxyphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-37.

[0583] Yield 67%

[0584] 1 H NMR (400MHz, DMSO-d6) δ12.01(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).

[0585] 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0586] The synthesis of the chromene-benzimidazole derivatives of formula 1-38 is as follows:

[0587] [Equation 1-38]

[0588]

[0589] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-38.

[0590] Yield 61%

[0591] 1 H NMR(400MHz,DMSO-d6)δ12.99(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).

[0592] Synthesis of formula 1-39(1-(2-(4-benzoylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-benzoylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0593] The synthesis of the chromene-benzimidazole derivatives of formula 1-39 is as follows:

[0594] [Equation 1-39]

[0595]

[0596] Following a method similar to that described in Examples 1-7, 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 to obtain compounds 1-39.

[0597] Yield 73%

[0598] 1 H NMR (400MHz, DMSO-d6) δ12.99(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).

[0599] Synthesis of 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, 1-(2-(3,5-bis(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0600] The synthesis of the chromene-benzimidazole derivatives of formulas 1-40 is as follows:

[0601] [Equation 1-40]

[0602]

[0603] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3,5-bis(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to give compounds 1-40.

[0604] 75% yield

[0605] 1 H NMR(400MHz,DMSO-d6)δ13.21(bs,1H),9.31(bs,1H),8.76(s,2H),8.23(s,1H),8.14(s,1H),8.05(bs,1H),7.8 7(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).

[0606] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0607] The synthesis of the chromene-benzimidazole derivatives of formula 1-41 is as follows:

[0608] [Equation 1-41]

[0609]

[0610] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 22-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-41.

[0611] Yield 69%

[0612] 1H NMR (400MHz, DMSO-d6) δ12.85(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).

[0613] Synthesis of 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, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0614] The synthesis of the chromene-benzimidazole derivatives of formula 1-42 is as follows:

[0615] [Equation 1-42]

[0616]

[0617] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-42.

[0618] Yield 66%

[0619] 1 H NMR (400MHz, DMSO-d6) δ12.92(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).

[0620] Synthesis of Formula 1-43 (1-(2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0621] The synthesis of the chromene-benzimidazole derivatives of formula 1-43 is as follows:

[0622] [Equation 1-43]

[0623]

[0624] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-cyclopropylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-43.

[0625] Yield 69%

[0626] 1 H NMR (400MHz, DMSO-d6) δ12.68(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).

[0627] Synthesis of Formula 1-44 (1-(2-(4-cyclopentylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-cyclopentylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0628] The synthesis of the chromene-benzimidazole derivatives of formula 1-44 is as follows:

[0629] [Equation 1-44]

[0630]

[0631] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-cyclopentylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-44.

[0632] Yield 71%

[0633] 1 H NMR (400MHz, DMSO-d6) δ12.70(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).

[0634] Synthesis of formula 1-45(1-(2-(4-cyclohexylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-cyclohexylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea).

[0635] The synthesis of the chromene-benzimidazole derivatives of formula 1-45 is as follows:

[0636] [Equation 1-45]

[0637]

[0638] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-cyclohexylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-45.

[0639] Yield 79%

[0640] 1 H NMR (400MHz, DMSO-d6) δ12.70(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).

[0641] Synthesis of 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, 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)

[0642] The synthesis of the chromene-benzimidazole derivatives of formula 1-46 is as follows:

[0643] [Equation 1-46]

[0644]

[0645] Following a method similar to that described in Examples 1-7, 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 were reacted to obtain compounds 1-46.

[0646] Yield 78%

[0647] 1 H NMR (400MHz, DMSO-d6) δ12.71(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),6.9 8(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).

[0648] Synthesis of Formula 1-47 (1-(2-(3-isopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(3-isopropylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0649] The synthesis of the chromene-benzimidazole derivatives of formula 1-47 is as follows:

[0650] [Equation 1-47]

[0651]

[0652] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-isopropylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-47.

[0653] Yield 79%

[0654] 1H NMR (400MHz, DMSO-d6) δ12.76(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).

[0655] Synthesis of formula 1-48(1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-nitrophenyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(4-nitrophenyl)-1H-benzo[d]imidazol-5-yl)urea).

[0656] The synthesis of the chromene-benzimidazole derivatives of formula 1-48 is as follows:

[0657] [Equation 1-48]

[0658]

[0659] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-nitrophenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-48.

[0660] Yield 78%

[0661] 1 H NMR(400MHz,DMSO-d6)δ13.12(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).

[0662] Synthesis of 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, 1-(2-(2,5-difluorophenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0663] The synthesis of the chromene-benzimidazole derivatives of formula 1-49 is as follows:

[0664] [Equation 1-49]

[0665]

[0666] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,5-difluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-49.

[0667] 80% yield

[0668] 1 H NMR (400MHz, DMSO-d6) δ12.56(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).

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

[0670] The synthesis of the chromene-benzimidazole derivatives of formula 1-50 is as follows:

[0671] [Equation 1-50]

[0672]

[0673] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(2,3-difluorophenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-50.

[0674] Yield 77%

[0675] 1 H NMR (400MHz, DMSO-d6) δ12.58(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).

[0676] Synthesis of Formula 1-51 (1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-phenoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea, 1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2-(3-phenoxyphenyl)-1H-benzo[d]imidazol-5-yl)urea)

[0677] The synthesis of the chromene-benzimidazole derivatives of formula 1-51 is as follows:

[0678] [Equation 1-51]

[0679]

[0680] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(3-phenoxyphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-51.

[0681] Yield 77%

[0682] 1 H NMR (400MHz, DMSO-d6) δ12.76(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).

[0683] Synthesis of 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, 1-(2-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0684] The synthesis of the chromene-benzimidazole derivatives of formula 1-52 is as follows:

[0685] [Equation 1-52]

[0686]

[0687] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-5-amine were reacted to obtain compounds 1-52.

[0688] Yield 73%

[0689] 1H NMR (400MHz, DMSO-d6) δ12.86(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).

[0690] Synthesis of Formula 1-53(1-(2-(4-isobutylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea, 1-(2-(4-isobutylphenyl)-1H-benzo[d]imidazol-5-yl)-3-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)urea)

[0691] The synthesis of the chromene-benzimidazole derivatives of formula 1-53 is as follows:

[0692] [Equation 1-53]

[0693] Following a method similar to that described in Examples 1-7, 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid and 2-(4-isobutylphenyl)-1H-benzo[d]imidazol-5-amine were reacted to obtain the chemical...

[0694]

[0695] Compounds 1-53.

[0696] Yield 79%

[0697] 1H NMR (400MHz, DMSO-d6) δ12.70(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).

[0698] Example 2. Determination of the anticancer activity of the chromene-benzimidazole derivative and confirmation of its mechanism of action.

[0699] 2.1 Screening of cell viability for chromene-benzimidazole derivatives

[0700] This experiment used MDA-MB-231, a human triple-negative breast cancer (TNBC) cell line (cell seeding rate: 0.8 (M231) x 10⁻⁶). 4 Cells / well (confluence ≥ 25%) and JIMT-1 as a HER2-positive breast cancer cell line (cell seeding density: 0.8 (JIMT) x 10⁻⁶). 4 Cells / pore (confluence)

[0701] ≥25%)

[0702] The cell lines were cultured at 5% CO2 and 37°C in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), streptomycin-penicillin (100 U / mL), and fungizone (0.625 μg / mL).

[0703] The human breast cancer cell lines MDA-MB-231 and JIMT-1 were treated with different concentrations (0, 1, and 5 μM) of chromene-benzimidazole derivatives of formulas 1-1 to 1-53 for 72 hours, and cell viability was measured using the MTS assay. The MTS assay method was as follows: cells were seeded in 96-well plates and adhered for 24 hours, then treated with the chromene-benzimidazole derivatives for 72 hours, and then developed with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazole) for 4 hours. The absorbance was then measured at 490 nm using a Spectramax Plus 384 microplate reader.

[0704] The measurement results are as follows Figures 1 to 6 As shown. The results confirm that the chromene-benzimidazole derivatives of formulas 1-1 to 1-53 exhibit a concentration-dependent inhibitory effect on the cell survival of human breast cancer cell lines MDA-MB-231 and JIMT-1.

[0705] 2.2 Confirmation of the apoptosis-inducing effect of chromene-benzimidazole derivatives

[0706] Treatment of triple-negative breast cancer cell lines MDA-MB-231 and BT549 with different concentrations (0, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 20, and 40 μM) of a chromene-benzimidazole derivative compound (1-1) for 72 hours revealed a concentration-dependent inhibitory effect on cell viability (MTS assay), as well as the IC50 values ​​for inhibiting cell viability. The results are as follows: Figure 7 (A) and Figure 7 As shown in (B). The IC50 values ​​of the compounds of Formula 1-1 against MDA-MB-231 and BT549 are 5.659 μM and 8.491 μM, respectively.

[0707] MDA-MB-231 and BT549 cell lines were treated with different concentrations (0, 5, 10, and 20 μM) of compound 1-1 for 72 hours, and cell morphological changes were then observed using an optical microscope. The results are as follows: Figure 7 As shown in (C), a concentration-dependent induction of apoptosis can be observed.

[0708] The degree of apoptosis induced by compound 1-1 in MDA-MB-231 and BT549 cells was confirmed by flow cytometry using Annexin V / PI staining. The results are as follows: Figure 7 As shown in (D), early and late apoptosis can be observed in both types of cancer cells.

[0709] 2.3 Confirmation of the mechanism of action of chromene-benzimidazole derivatives

[0710] As described above, the chromene-benzimidazole derivative of the present invention is designed to strongly bind to the C-terminal domain of Hsp90 and simultaneously bind between microtubule polymers to inhibit their polymerization. The following experiments were conducted to verify this dual-targeting effect.

[0711] To analyze the inhibitory effect of the C-terminal domain of Hsp90, the binding affinity of compound 1-1, the C-terminal Hsp90 inhibitor Novobiocine, and the N-terminal inhibitor Onalespib to the C-terminal recombinant protein was analyzed, thereby evaluating the inhibitory effect of Hsp90 on C-terminal activity. Experimental results are as follows: Figure 8 As shown in (A). Compared with existing Novobiocine, the compound of formula 1-1 of the present invention inhibits more than half of the activity of Hsp90 at the C-terminus, showing a significantly better inhibitory effect.

[0712] Furthermore, after treating the triple-negative breast cancer cell line MDA-MB-231 with different concentrations (0, 5, 10, and 20 μM) of compound 1-1 for 72 hours, Western blot analysis confirmed a decrease in the protein expression and phosphorylation levels of STAT3, c-MET, ERK, and AKT, which are client proteins of HSP90. The results are as follows: Figure 8 As shown in (B).

[0713] Next, after treating MDA-MB-231 cell lines with different concentrations (0, 5, 10, and 20 μM) of compound 1-1 for 72 hours, Western blot analysis confirmed the expression of microtubule degradation and apoptosis-related proteins. The results are as follows: Figure 8 As shown in (C), it can be seen that the compounds of the present invention can inhibit tubulin polymerization.

[0714] Finally, after treating BT549 cell lines with different concentrations (0, 5, 10, and 20 μM) of the compound of formula 1-1 for 72 hours, propidium iodide staining was performed, and the DNA content of cancer cells was analyzed by flow cytometry. It was observed that the chromene-benzimidazole derivative induced G2 / M phase arrest of the cell cycle, as shown in the results below. Figure 8 As shown in (D).

[0715] Example 3. Confirmation of the effective substance screening and anticancer activity of chromone-benzimidazole derivatives in different cancers.

[0716] 3.1 Derivation of the effective substances in chromene-benzimidazole derivatives

[0717] Triple-negative breast cancer cell lines MDA-MB-231 and JIMT-1 were treated with different concentrations (0, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2, and 5 μM) of chromene-benzimidazole derivatives (1-13, 1-19, and 1-22) for 72 hours. The specific treatment conditions were the same as in Example 2.1. A concentration-dependent inhibition of cell viability (MTS assay) and the IC50 value for inhibiting cell viability were observed, as shown in the following figures. Figure 9 As shown. The IC50 values ​​of compounds 1-13, 1-19 and 1-22 of the present invention are 0.154, 1.06 and 0.276 μM, respectively, exhibiting excellent inhibitory activity.

[0718] Next, the following experiments were performed to confirm the targeting ability of compounds 1-13 and 1-22. MDA-MB-231 cell lines were treated with 0.5 μM of compounds 1-22 and 1-13 for 72 hours, and cell morphological changes were observed using an optical microscope. The results are as follows: Figure 10 As shown in (A), typical morphological changes of cell cycle arrest and apoptosis were confirmed. Furthermore, after treating MDA-MB-231 cell lines with 0.5 μM compounds 1-22 and 1-13 for 72 hours, Western blotting confirmed the presence of HSP90 molecular chaperon complexes (HSP90, HSP70, HSP27, HSF-1), HSP90 substrate proteins (EGFR, AKT, JAK2, STAT3), tubulin targets (tubulin, mitotic marker p-HisH3), and apoptosis-related factors (lysing caspase-7).

[0719] The expression of (caspase-7), Survivin, and Mcl-1) was observed, and the results were as follows: Figure 10 As shown in (B).

[0720] 3.2 Confirmation of the anticancer activity of chromone-benzimidazole derivatives against different cancers.

[0721] Treatment of hematologic malignancies (HL-60), hepatocellular carcinoma (HepG2), lung cancer (H1299), colorectal cancer (HCT116), and ovarian cancer (SKOV3) cell lines with different concentrations (0, 0.1, 0.5, 1, 5, and 10 μM) for 72 hours with these compounds showed a concentration-dependent inhibitory effect on cell viability (MTS assay), as well as specific IC50 values ​​for cell viability inhibition. The same experiment was performed on compounds 1-13, with the following results: Figure 12 As shown. Besides breast cancer, both compounds effectively inhibited cell survival rates in other cancer cell lines.

[0722] 3.3 Deriving additional active substances from chromene-benzimidazole derivatives

[0723] Treatment of triple-negative breast cancer cell line MDA-MB-231 with different concentrations (0, 0.01, 0.05, 0.1, 0.25, 0.5, 1, 2, and 5 μM) of chromene-benzimidazole derivatives (1-9, 1-10, 1-11, 1-15, 1-16, and 1-17) for 72 hours revealed a concentration-dependent inhibitory effect on cell viability (MTS assay), as well as IC50 values ​​for inhibiting cell viability. The results are as follows: Figure 13 As shown, compounds 1-9, 1-10, 1-11, 1-15, 1-16 and 1-17 have IC50 values ​​of 0.273, 0.829, 0.335, 0.452, 0.96 and 0.586 μM, respectively, exhibiting excellent IC50 values.

[0724] Comparative Example 1. Experiments comparing with compounds of similar structure

[0725] Comparative experiments were conducted using the following reference compounds from prior literature with structures similar to those of the compounds of this invention.

[0726] [Comparative Experimental Compounds]

[0727]

[0728] The reference compound is a compound composed of chromone and benzimidazole, and its structure is similar to that of the compound of the present invention. However, in the compound of the present invention, the 5th carbon atom of benzimidazole is linked to the chromone via a urea group, whereas in the reference compound, the 2nd carbon atom of benzimidazole is linked to the chromone via an imine group. After treating MDA-MB-231 and JIMT-1 cell lines with different concentrations (0, 2, 5, and 10 μM) of the chromone-benzimidazole derivatives of the present invention (1-19 and 1-22) or the reference compound for 72 hours, the effect on cell viability was compared using the MTS assay. The results are as follows: Figure 14 As shown. Unlike the chromene-benzimidazole derivative of this invention, the reference compounds in previous literature did not inhibit the survival of either type of cancer cell.

[0729] The embodiments have been described above with reference to the accompanying drawings. Those skilled in the art should understand that various modifications and equivalent embodiments can be made based on these descriptions. Suitable results can also be obtained if the described techniques are performed in a different order, and / or if the constituent elements of the described systems, architectures, devices, or circuits are combined in different ways, and / or replaced or substituted by other components or their equivalents.

[0730] Therefore, other embodiments, examples, and equivalents of the claims should be interpreted as being included within the scope of protection of the claims.

Claims

1. A chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof represented by the following [Formula 1]: [Formula 1] In Equation 1: R 1 The free radical is selected from hydrogen, halogen, substituted or unsubstituted straight-chain or branched C1-C6 alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C3-C 20 Heterocyclic alkyl, substituted or unsubstituted C3-C 20 Aryl and substituted or unsubstituted C3-C 20 Any of the groups composed of heteroaryl groups, If the straight-chain or branched alkyl group is substituted, it is substituted with a halogen. If the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is substituted, it is selected from straight-chain or branched C1-C6 alkyl, C1-C6 alkyl, or C1-C6 alkyl. 10 One or more substitutions of the group consisting of cycloalkyl, halogen, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine and benzoyl.

2. The chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In the above [Equation 1], R 1 The substituted or unsubstituted straight-chain or branched C1-C6 alkyl group is a substituted or unsubstituted methyl group; if the methyl group is substituted, it is substituted by a halogen. R 1 Substituted or unsubstituted C3-C 20 The cycloalkyl group is an unsubstituted cyclohexyl group. R 1 Substituted or unsubstituted C3-C 20 The heterocyclic alkyl group is methylpiperazinyl. R 1 Substituted or unsubstituted C3-C 20 The aryl group is a substituted or unsubstituted phenyl group. If the phenyl group is substituted, it is selected from straight-chain or branched C1-C6 alkyl groups, C1-C6 alkyl groups, or C1-C6 alkyl groups. 10 One or more substitutions of the group consisting of cycloalkyl, halogen, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, amino, nitro, phenyl, phenoxy, benzoyloxymethyl, indole, methylpiperazine, and benzoyl. R 1 Substituted or unsubstituted C3-C 20 The heteroaryl group is selected from any one of the group consisting of pyridyl, thiophene, and thiazolyl.

3. The chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In the above [Equation 1], R 1 For substituted or unsubstituted phenyl groups, If the phenyl group is substituted, it is substituted by one or more of 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. The chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The chromene-benzimidazole derivative represented by [Formula 1] is selected from any one of the following groups of compounds: [Equation 1-1] [Equation 1-2] [Equation 1-3] [Equations 1-4] [Equations 1-5] [Equations 1-6] [Equations 1-7] [Equations 1-8] [Equations 1-9] [Equation 1-10] [Equation 1-11] [Equation 1-12] [Equation 1-13] [Equation 1-14] [Equation 1-15] [Equation 1-16] [Equation 1-17] [Equation 1-18] [Equation 1-19] [Equation 1-20] [Equation 1-21] [Equation 1-22] [Equation 1-23] [Equation 1-24] [Equation 1-25] [Equation 1-26] [Equation 1-27] [Equation 1-28] [Equation 1-29] [Equation 1-30] [Equation 1-31] [Equation 1-32] [Equation 1-33] [Equation 1-34] [Equation 1-35] [Equation 1-36] [Equation 1-37] [Equation 1-38] [Equation 1-39] [Equation 1-40] [Equation 1-41] [Equation 1-42] [Equation 1-43] [Equation 1-44] [Equation 1-45] [Equation 1-46] [Equation 1-47] [Equation 1-48] [Equation 1-49] [Equation 1-50] [Equation 1-51] [Equation 1-52] And; [Equation 1-53] 5. The chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The chromene-benzimidazole derivative represented by [Formula 1] is selected from any one of the following groups of compounds: [Equation 1-1] [Equations 1-9] [Equation 1-10] [Equation 1-11] [Equation 1-13] [Equation 1-15] [Equation 1-16] [Equation 1-17] [Equation 1-19] as well as; [Equation 1-22] 6. The chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The aforementioned chromene-benzimidazole derivative simultaneously inhibits microtubule polymerization and the C-terminal domain of Hsp90.

7. The chromene-benzimidazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pharmaceutically acceptable salt of the said chromene-benzimidazole derivative is selected from one or more of the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt.

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

9. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The pharmaceutical composition induces apoptosis by causing cell cycle arrest in cancer cells.

10. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The pharmaceutical composition induces the denaturation and degradation of proto-oncoproteins.

11. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The cancer mentioned is selected from one or more of the following groups: skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, hematologic malignancies, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, hematologic malignancies, thymic cancer, urethral cancer, and bronchial cancer.

12. The pharmaceutical composition for preventing or treating cancer according to claim 8, characterized in that, The cancer in question is triple-negative breast cancer.

Images