Novel indazole derivative or pharmaceutically acceptable salt thereof, and use thereof

Abstract

The present invention relates to an indazole derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing, treating or ameliorating cancer, comprising the derivative or the salt thereof as an active ingredient. The indazole derivative of the present invention is intended to form strong binding with a C-terminal domain of Hsp90 and does not affect a composite structure of Hsp90 and HSF-1, thereby not inducing activation of HSF-1 or expression of an Hsp gene, thereby effectively promoting apoptosis of cancer cells, and thus can be used for preventing, treating or improving cancer.

Description

Technical Field

[0001] The present invention relates to a novel indazole derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a composition comprising the indazole derivative as an active ingredient for preventing, treating or improving cancer. Background Art

[0002] Breast cancer has been on the rise in Korea and overseas since the 1990s, and since the beginning of the 21st century, breast cancer has become the most common cancer among women, with the highest incidence and mortality rates. HER2-positive breast cancer is a type of cancer that overexpresses HER2 (human epidermal growth factor receptor 2), a membrane protein receptor present on the cancer cell membrane. Among all breast cancer patients, 20-30% have HER2-positive breast cancer, which has a worse prognosis than HER2-negative patients, resulting in a significantly lower survival rate and extremely low responsiveness to commonly used cytotoxic anticancer drugs.

[0003] Targeted therapies for HER2-positive breast cancer include the monoclonal antibody trastuzumab (trade name: Herceptin), Pertuzumab (trade name: Perjet) and T-DM1 (trade name: There are many drugs that can treat HER2-positive breast cancer, such as trastuzumab and trastuzumab, but their high prices have brought a heavy financial burden to patients. In particular, trastuzumab is mainly used as a first-line treatment for patients with HER2-positive breast cancer, but about 40-50% of patients show primary drug resistance during initial treatment, and even among patients with good initial responses, about 90% of patients develop secondary drug resistance within a year. This drug resistance is the main cause of recurrence and metastasis, and is a key factor in reducing patient survival rates.

[0004] In addition, triple-negative breast cancer (ER-, PR-, HER2-) patients account for 10-15% of all breast cancer patients. They lack hormone receptors (ER (estrogen receptor), PR (progesterone receptor)) and HER2 protein, so they cannot benefit from hormone therapy or HER2-targeted therapy. Currently, the standard treatment for triple-negative breast cancer completely relies on general cytotoxic anticancer drugs (Taxene or Anthracycline). Due to the lack of mature targeted therapy, the treatment strategies for other subtypes are less diverse than those for breast cancer. More seriously, most patients relapse within 2-3 years after surgery or chemotherapy and are prone to metastasis to other organs such as the lungs, liver, brain, and bones, thus affecting the survival rate of patients.

[0005] The 5-year overall survival rate of patients diagnosed with stage-III is less than 55%, and the 5-year overall survival rate of advanced-stage metastatic patients is very low, less than 30%. Most of these patients will eventually die within a few years, which is a very serious disease.

[0006] Hsp90 inhibitors are potential chemotherapeutic drugs for angiogenesis-related diseases, especially for HER2, which is one of the main client proteins of Hsp90, and its kinase activity is directly regulated by Hsp90. Therefore, Hsp90 inhibition can directly inhibit the activation of p95HER2 and HER2 / HER3 dimerization, which are the main causes of drug resistance. Therefore, Hsp90 inhibitors can be used as upstream targeted drugs for HER2 and thus have high value as drugs to overcome drug resistance.

[0007] However, most Hsp90 inhibitors in current clinical trials inhibit the N-terminal Hsp90, and most of them fail or are aborted due to serious side effects such as lack of pharmacological activity, toxicity, induction of heat shock response, etc.

[0008] Thus, the inventors of the present invention confirmed that a novel indazole derivative or a pharmaceutically acceptable salt thereof has a strong binding ability to the C-terminal of Hsp90, thereby inhibiting the activity of Hsp90, inhibiting the growth and proliferation of cancer cells, and inducing effective apoptosis, thus completing the present invention. Summary of the Invention

[0009] Technical Problem to be Solved

[0010] The object of the present invention is to provide an indazole derivative or a pharmaceutically acceptable salt thereof.

[0011] In addition, another object of the present invention is to provide a composition for preventing, treating or ameliorating cancer, which comprises the indazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0012] In addition, another object of the present invention is to provide a method for preparing the indazole derivative or a pharmaceutically acceptable salt thereof.

[0013] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by ordinary technicians in this field through the following description.

[0014] Technical methods to solve problems

[0015] In order to solve the above problems, the present invention provides an indazole derivative represented by the following [Chemical Formula 1], a racemate, an isomer, a solvate or a pharmaceutically acceptable salt thereof:

[0016] [Chemical formula 1]

[0017]

[0018] Wherein in the chemical formula 1,

[0019] A is

[0020] B is

[0021] R 1 and R 2 are the same as or different from each other and are hydrogen or C 1 -C 6 Chain alkyl;

[0022] R 3 and R 4 are the same as or different from each other and are hydrogen or C 1 -C 6 A chain alkyl group in which one or more hydrogen atoms of the alkyl group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10 Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, replace;

[0023] R 5is a halogen group or C 1 -C 6 Alkoxy;

[0024] R 6 and R 7 The same or different from each other, respectively C 1 -C 6 Chain alkyl;

[0025] R 8 NR 10 C(O)R 11 , OR 12 , C 5 -C 10 heteroaryl or tetrahydropyranylamino;

[0026] R 9 For hydrogen, C 1 -C 6 Alkoxy or C 5 -C 10 Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or replaced by C 1 -C 6 Chain alkyl substitution;

[0027] R 10 and R 11 The same or different from each other, respectively C 1 -C 6 Chain alkyl or C 5 -C 10 aryl, wherein the alkyl group is unsubstituted or substituted with methylpiperazinyl;

[0028] R 12 C 5 -C 10 Aryl or C 5 -C 10 benzyl, wherein the benzyl group is unsubstituted or substituted with a halogen group;

[0029] It can be a single bond or a double bond.

[0030] In one embodiment of the present invention, the heterocycloalkyl group may be morpholino, piperidinyl, piperazinyl, pyrrolidinyl, etc., but is not limited thereto. The heteroaryl group may be pyridinyl, pyrimidinyl, pyrazinyl, furyl, thiophenyl, oxazolyl, benzimidazolyl, indolyl, etc., preferably pyridinyl, but is not limited thereto.

[0031] In another embodiment of the present invention, the R 3 and R 4 The same or different from each other, respectively, may be hydrogen, methyl,

[0032] and combinations thereof, but are not limited thereto.

[0033] In another embodiment of the present invention, the indazole derivative represented by [Chemical Formula 1] may be any one or more selected from the group consisting of compounds represented by the following chemical formulas, but is not limited thereto:

[0034] (1) 5-Methoxy-2,2-dimethyl-N-(3-methyl-1H-indazol-6-yl)-2H-chromene-6-carboxamid (Chemical Formula 1-1, 6a);

[0035] (2) N-(1,3-dimethyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-2, 6b);

[0036] (3) 5-Methoxy-N-(1-(2-methoxyethyl)-3-methyl-1H-indazol-6-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-3, 6c);

[0037] (4) 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-morpholinoethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-4, 6d);

[0038] (5) 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(pyridin-3-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-5, 6e);

[0039] (6) 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(pyridin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-6, 6f);

[0040] (7) 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-7, 11k);

[0041] (8) 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-8, 111);

[0042] (9) 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(3-(1-methylpiperidin-4-yl)propyl)-1H-isoindol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-9, 11m);

[0043] (10) 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (chemical formula 1-10, 11n);

[0044] (11) N-(1-(2-(1-(but-2-ynoyl)piperidin-4-yl)ethyl)-3-methyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-11, 11o);

[0045] (12) N-(1-(2-(1-acryloylpiperidin-4-yl)ethyl)-3-methyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-12, 11p);

[0046] (13) 5-methoxy-2,2-dimethyl-N-(1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-13, 12k);

[0047] (14) N-(1H-indazol-3-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-14, 18a);

[0048] (15) 5-Methoxy-N,2,2-trimethyl-N-(1-methyl-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-15, 18b);

[0049] (16) 5-Methoxy-N-(1-(2-methoxyethyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-16, 18c);

[0050] (17) 5-Methoxy-N-(1-(3-methoxypropyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-17, 18d);

[0051] (18) 5-Methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-18, 18e);

[0052] (19) 5-Methoxy-2,2-dimethyl-N-(1-(2-(methylamino)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-19, 191);

[0053] (20) 5-Methoxy-2,2-dimethyl-N-(1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-20, 18 g);

[0054] (21) 5-Methoxy-2,2-dimethyl-N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-21, 18h);

[0055] (22) 5-Methoxy-2,2-dimethyl-N-(1-(2-morpholinoethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-22, 18i);

[0056] (23) 5-Methoxy-2,2-dimethyl-N-(1-(2-(pyridin-3-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-23, 18j);

[0057] (24) 5-Methoxy-2,2-dimethyl-N-(1-(2-(pyridin-4-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-24, 18k);

[0058] (25) 5-Methoxy-N-(1-(2-methoxyethyl)-1H-indazol-3-yl)-N,2,2-trimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-25, 20c);

[0059] (26) 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)chroman-6-carboxamide (chemical formula 1-26, 34);

[0060] (27) 5-ethoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (5-ethoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide) (Chemical Formula 1-27, 35);

[0061] (28) 2,2-diethyl-5-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (chemical formula 1-28, 36);

[0062] (29) 5-fluoro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (5-fluoro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide) (Chemical Formulas 1-29, 37);

[0063] (30) 5-chloro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (5-chloro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide) (Chemical Formulas 1-30, 38);

[0064] (31) N-methyl-N-(4-((3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)carbamoyl)phenyl)benzamide (Chemical Formula 1-31, 42a);

[0065] (32) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)benzamide (Chemical Formula 1-32, 42b);

[0066] (33) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (Chemical Formulas 1-33, 46);

[0067] (34) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-4-yl)benzamide (Chemical Formula 1-34, 50a);

[0068] (35) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-3-yl)benzamide (Chemical Formula 1-35, 50b);

[0069] (36) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-4-yl)benzamide (Chemical Formula 1-36, 50c);

[0070] (37) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-3-yl)benzamide (Chemical Formula 1-37, 50d);

[0071] (38) 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-4-yl)benzamide (Chemical Formula 1-38, 50e);

[0072] (39) 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-3-yl)benzamide (Chemical Formula 1-39, 50f);

[0073] (40) 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-4-yl)benzamide (chemical formula 1-40, 50 g);

[0074] (41) 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-3-yl)benzamide (Chemical Formula 1-41, 50h);

[0075] (42) N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-phenoxybenzamide (Chemical Formula 1-42, 57a);

[0076] (43) 4-(benzyloxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-43, 57b);

[0077] (44) 4-((4-fluorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-44, 57c);

[0078] (45) 4-((3-fluorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-45, 57d);

[0079] (46) 4-((4-chlorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-46, 57e);

[0080] (47) 4-((3-chlorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-47, 57f);

[0081] (48) 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-phenoxybenzamide (Chemical Formula 1-48, 57g);

[0082] (49) 4-(benzyloxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-49, 57h);

[0083] (50) 4-((3-fluorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-50, 57i);

[0084] (51) 4-((4-fluorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-51, 57j);

[0085] (52) 4-((3-Chlorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-52, 57k); and

[0086] (53) 4-((4-Chlorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (1-53, 571).

[0087] In another embodiment of the present invention, the pharmaceutically acceptable salt of the indazole derivative may be any one or more selected from the group consisting of hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartrate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt and combinations thereof, but is not limited thereto.

[0088] In addition, the present invention also provides a pharmaceutical composition for preventing or treating cancer, which comprises the indazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0089] In one embodiment of the present invention, the indazole derivatives can be used as Hsp90 inhibitors to inhibit the growth and proliferation of cancer cells and induce cell apoptosis.

[0090] In another embodiment of the present invention, the cancer can be any one or more selected from 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, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, thymic cancer, urethral cancer, bronchial cancer and a combination thereof, preferably breast cancer, more preferably HER-2 positive breast cancer or triple negative breast cancer, but not limited thereto.

[0091] In another embodiment of the present invention, the pharmaceutical composition may further include: the indazole derivative or a pharmaceutically acceptable salt thereof; and any one or more additional components selected from the group consisting of pharmaceutically acceptable carriers, excipients, diluents, stabilizers and preservatives, but the types of additional components are not limited thereto.

[0092] In another embodiment of the present invention, the pharmaceutical composition may further include: the indazole derivative or a pharmaceutically acceptable salt thereof; and an anticancer agent.

[0093] In another embodiment of the present invention, the anticancer agent can be any one or more selected from the group consisting of paclitaxel, docetaxel, doxorubicin, sorafenib, vemurafenib, irinotecan, cisplatin, radium 223 chloride (alpharadin), mitoxantrone, cyclophosphamide, vinblastine, carboplatin, dactinomycin-D, etoposide, teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), 5-fluorouracil, busulfan, chlorambucil, melphalan, nitrogen mustard, nitrosourea drugs and combinations thereof, but is not limited thereto.

[0094] In another embodiment of the present invention, the pharmaceutical composition may have any one or more dosage forms selected from the group consisting of powder, granules, tablets, capsules and injections, but is not limited thereto.

[0095] In addition, the present invention provides a method for preventing or treating cancer, comprising administering the indazole derivative or a pharmaceutically acceptable salt thereof to a subject.

[0096] In addition, the present invention provides use of the indazole derivative or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating cancer.

[0097] Furthermore, the present invention provides a cosmetic composition for preventing or ameliorating cancer, comprising the indazole derivative or a cosmetically acceptable salt thereof as an active ingredient.

[0098] In addition, the present invention provides a food composition for preventing or improving cancer, which comprises the indazole derivative or a food-acceptable salt thereof as an active ingredient.

[0099] In addition, the present invention provides a feed composition for preventing or treating cancer, which comprises the indazole derivative or a feed-acceptable salt thereof as an active ingredient.

[0100] In addition, the present invention also provides a method for preparing an indazole derivative represented by [Chemical Formula 1] or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound represented by the following [Chemical Formula 2] or [Chemical Formula 3] with a compound represented by [Chemical Formula 4] or [Chemical Formula 5]:

[0101] [Chemical formula 1]

[0102]

[0103] [Chemical formula 2]

[0104]

[0105] [Chemical formula 3]

[0106]

[0107] [Chemical formula 4]

[0108]

[0109] [Chemical formula 5]

[0110]

[0111] Wherein in the chemical formula 1,

[0112] A is

[0113] B is

[0114] R 1 is hydrogen or C 1 -C 6 Chain alkyl;

[0115] Wherein in the chemical formula 1 and the chemical formula 2,

[0116] R 2 is hydrogen or C 1 -C 6 Chain alkyl;

[0117] R 3 is hydrogen or C 1 -C 6 A chain alkyl group, wherein one or more hydrogen atoms of the alkyl group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10 Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, replace;

[0118] Wherein in the chemical formula 1 and the chemical formula 3,

[0119] R 4 is hydrogen or C 1 -C 6 Chain alkyl;

[0120] One or more hydrogen atoms of the alkyl group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, replace;

[0121] Wherein in the chemical formula 1 and the chemical formula 4,

[0122] R 5 is hydrogen or C 1 -C 6 Chain alkyl;

[0123] R 6 and R 7 The same or different from each other, respectively C 1 -C 6 Chain alkyl;

[0124] Wherein in the chemical formula 1 and the chemical formula 5,

[0125] R 8 NR 10 C(O)R 11 , OR 12 , C 5 -C 10 heteroaryl or tetrahydropyranylamino;

[0126] R 9 For hydrogen, C 1 -C 6 Alkoxy or C 5 -C 10 Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or replaced by C 1 -C 6 Chain alkyl substitution;

[0127] R 10 and R 11 The same or different from each other, respectively C 1 -C 6 Chain alkyl or C 5 -C 10 aryl, wherein the alkyl group is unsubstituted or substituted with methylpiperazinyl;

[0128] R 12 C 5 -C 10 Aryl or C 5 -C 10 Benzyl, wherein the benzyl is unsubstituted or substituted with a halogen group.

[0129] In one embodiment of the present invention, the compound represented by the chemical formula 2 may be any one or more selected from the group consisting of compounds represented by the following chemical formulas, but is not limited thereto:

[0130] (1) 3-Methyl-1H-indazol-6-amine (Chemical Formula 2-1, 5a);

[0131] (2) 1,3-Dimethyl-1H-indazol-6-amine (Chemical Formula 2-2,5b);

[0132] (3) 1-(2-Methoxyethyl)-3-methyl-1H-indazol-6-amine (Chemical Formula 2-3, 5c);

[0133] (4) 3-Methyl-1-(2-morpholinoethyl)-1H-indazol-6-amine (Chemical Formula 2-4, 5d);

[0134] (5) 3-Methyl-1-(2-(pyridin-3-yl)ethyl)-1H-indazol-6-amine (Chemical Formula 2-5, 5e);

[0135] (6) 3-Methyl-1-(2-(pyridin-4-yl)ethyl)-1H-indazol-6-amine (Chemical Formula 2-6, 5f);

[0136] (7) 3-Methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-amine (Chemical Formula 2-7, 9k);

[0137] (8) 3-Methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-6-amine (Chemical Formula 2-8, 91);

[0138] (9) 3-methyl-1-(3-(1-methylpiperidin-4-yl)propyl)-1H-indazol-6-amine (Chemical Formula 2-9, 9m);

[0139] (10) 3-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-indazol-6-amine (Chemical Formula 2-10, 9n); and

[0140] (11) 1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-amine (Chemical Formula 2-11, 10k).

[0141] In one embodiment of the present invention, the compound represented by the [Chemical Formula 3] may be any one or more selected from the group consisting of compounds represented by the following chemical formulas, but is not limited thereto:

[0142] (1) 1-Methyl-1H-indazol-3-amine (Chemical Formula 3-1, 17b);

[0143] (2) 1-(2-Methoxyethyl)-1H-indazol-3-amine (Chemical Formula 3-2, 17c);

[0144] (3) 1-(3-Methoxypropyl)-1H-indazol-3-amine (Chemical Formula 3-3, 17d);

[0145] (4) 1-(2-(2-Methoxyethoxy)ethyl)-1H-indazol-3-amine (Chemical Formula 3-4, 17e);

[0146] (5) 1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-3-amine (Chemical Formula 3-5, 17g);

[0147] (6) 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-3-amine (Chemical Formula 3-6, 17h);

[0148] (7) 1-(2-Morpholinoethyl)-1H-indazol-3-amine (Chemical Formula 3-7, 17i);

[0149] (8) 1-(2-(Pyridin-3-yl)ethyl)-1H-indazol-3-amine (Chemical Formula 3-8, 17j); and

[0150] (9) 1-(2-(Pyridin-4-yl)ethyl)-1H-indazol-3-amine (Chemical Formula 3-9, 17k).

[0151] In one embodiment of the present invention, the compound represented by the chemical formula 4 may be any one or more selected from the group consisting of compounds represented by the following chemical formulas, but is not limited thereto:

[0152] (1) 5-methoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (Chemical Formula 4-1, 29);

[0153] (2) 5-ethoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (Chemical Formula 4-2, 30);

[0154] (3) 2,2-diethyl-5-methoxy-2H-chromene-6-carboxylic acid (Chemical Formula 4-3, 31);

[0155] (4) 5-fluoro-2,2-dimethyl-2H-chromene-6-carboxylic acid (Chemical Formula 4-4, 32); and

[0156] (5) 5-chloro-2,2-dimethyl-2H-chromene-6-carboxylic acid (Chemical Formula 4-5, 33).

[0157] In one embodiment of the present invention, the compound represented by the chemical formula 5 may be any one or more selected from the group consisting of compounds represented by the following chemical formulas, but is not limited thereto:

[0158] (1) 4-(N-methylbenzamido)benzoic acid (Chemical Formula 5-1, 41a);

[0159] (2) 4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)benzoic acid (Chemical Formula 5-2, 41b);

[0160] (3) 3-(pyridin-4-yl)benzoic acid (Chemical Formula 5-3, 49a);

[0161] (4) 3-(pyridin-3-yl)benzoic acid (Chemical Formula 5-4, 49b);

[0162] (5) 4-(pyridin-4-yl)benzoic acid (Chemical Formula 5-5, 49c);

[0163] (6) 4-(pyridin-3-yl)benzoic acid (Chemical Formula 5-6, 49d);

[0164] (7) 2-methoxy-3-(pyridin-4-yl)benzoic acid (Chemical Formula 5-7, 49e);

[0165] (8) 2-methoxy-3-(pyridin-3-yl)benzoic acid (Chemical Formula 5-8, 49f);

[0166] (9) 2-methoxy-4-(pyridin-4-yl)benzoic acid (chemical formula 5-9, 49 g);

[0167] (10) 2-methoxy-4-(pyridin-3-yl)benzoic acid (chemical formula 5-10, 49h);

[0168] (11) 4-phenoxybenzoic acid (Chemical Formula 5-11, 56a);

[0169] (12) 4-(benzyloxy)benzoic acid (Chemical Formula 5-12, 56b);

[0170] (13) 4-((4-fluorobenzyl)oxy)benzoic acid (Chemical Formula 5-13, 56c);

[0171] (14) 4-((3-fluorobenzyl)oxy)benzoic acid (Chemical Formula 5-14, 56d);

[0172] (15) 4-((4-chlorobenzyl)oxy)benzoic acid (Chemical Formula 5-15, 56e);

[0173] (16) 4-((3-chlorobenzyl)oxy)benzoic acid (chemical formula 5-16, 56f);

[0174] (17) 2-methoxy-4-phenoxybenzoic acid (chemical formula 5-17, 56g);

[0175] (18) 4-(benzyloxy)-2-methoxybenzoic acid (chemical formula 5-11, 56h);

[0176] (19) 4-((3-fluorobenzyl)oxy)-2-methoxybenzoic acid (chemical formula 5-11, 56i);

[0177] (20) 4-((4-fluorobenzyl)oxy)-2-methoxybenzoic acid (chemical formula 5-11, 56j);

[0178] (21) 4-((3-Chlorobenzyl)oxy)-2-methoxybenzoic acid (chemical formula 5-11, 56k); and

[0179] (22) 4-((4-Chlorobenzyl)oxy)-2-methoxybenzoic acid (chemical formula 5-11, 56l).

[0180] In another embodiment of the present invention, the reaction can be carried out by adding the compound represented by the [chemical formula 2] or [chemical formula 3] to a mixture of the compound represented by the [chemical formula 4] or [chemical formula 5], hydroxybenzotriazole (HOBt), triethylamine (Et 3 N), and EDC·HCl, and at this time, the solvent can be dichloromethane (DCM), but is not limited thereto.

[0181] In another embodiment of the present invention, it may further include steps such as extracting the organic compound after the reaction, washing, drying, and concentrating in vacuo.

[0182] Effects of the Invention

[0183] The present invention relates to an indazole derivative or a pharmaceutically acceptable salt thereof, and a composition for preventing, treating or improving cancer comprising the derivative or the salt thereof as an active ingredient. The indazole derivative of the present invention does not affect the complex structure of Hsp90 and HSF-1, and thus does not induce the activation of HSF-1 or the expression of Hsp genes, thereby effectively promoting the death of cancer cells, and thus can be used to prevent, treat or improve cancer.

[0184] The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art through the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0185] Figure 1 The cell survival rates after treatment of the indazole derivatives of the present invention (corresponding to Chemical Formula 1-1 to Chemical Formula 1-13) in JIMT-1 and MDA-MB-231 cell lines are shown.

[0186] Figure 2 The cell survival rates after treatment of the indazole derivatives of the present invention (corresponding to Chemical Formulas 1-14 to 1-25) in JIMT-1 and MDA-MB-231 cell lines are shown.

[0187] Figure 3 The cell survival rates after treatment of the indazole derivatives of the present invention (corresponding to Chemical Formula 1-26 to Chemical Formula 1-41) in JIMT-1 and MDA-MB-231 cell lines are shown.

[0188] Figure 4 The cell survival rates after treatment of the indazole derivatives of the present invention (corresponding to Chemical Formula 1-42 to Chemical Formula 1-53) in JIMT-1 and MDA-MB-231 cell lines are shown.

[0189] Figure 5 The anticancer effect of compound 18c (chemical formula 1-16) in breast cancer cell lines is shown, wherein, Figure 5 A shows that the cell viability in BT474, JIMT-1 and MDA-MB-231 decreased in a concentration-dependent manner; Figure 5 B shows the degree of apoptosis of cancer cells confirmed by flow cytometry; Figure 5 C shows the expression of apoptosis-related proteins confirmed by western blotting.

[0190] Figure 6 The anticancer effect of compound 11k (chemical formula 1-7) in breast cancer cell lines is shown, wherein: Figure 6A shows that the cell viability in BT474, JIMT-1 and MDA-MB-231 decreased in a concentration-dependent manner; Figure 6 B shows the degree of apoptosis of cancer cells confirmed by flow cytometry; Figure 6 C shows the expression of apoptosis-related proteins confirmed by Western blotting.

[0191] Figure 7 It was shown that compound 11m (Chemical Formula 1-9), compound 11n (Chemical Formula 1-10) and compound 12k (Chemical Formula 1-13) decreased the cell viability in JIMT-1 and MDA-MB-231 cell lines in a concentration-dependent manner.

[0192] Figure 8 The anticancer effect of compound 38 (chemical formula 1-30) in breast cancer cell lines is shown, wherein, Figure 8 A shows that the survival rate of MDA-MB-231 cells decreased in a concentration-dependent manner; Figure 8 B shows that the viability of BT549 cells decreased in a concentration-dependent manner; Figure 8 C shows that the survival rate of 4T1 cells decreased in a concentration-dependent manner; Figure 8 D shows the changes in cell morphology; Figure 8 E shows cell apoptosis.

[0193] Fig. 9 Show Fig. 9 Compound 18c (Chemical Formula 1-16) in A and Fig. 9 The expression measurement results of Hsp90 client proteins of compound 11k in B (Chemical Formula 1-7).

[0194] Fig.10 The anticancer effect of compound 18c (chemical formula 1-16) in vivo is shown, wherein, Fig.10 A shows the changes in tumor volume when compound 18c was treated; Fig.10 B shows the changes in tumor weight and size when compound 18c was treated; Fig.10 C shows the changes in body weight when compound 18c was treated; Fig.10 D shows the results of examining the histomorphological changes of other organs (liver, kidney and lung) when compound 18c was treated; Fig.10 E shows the results of examining whether liver and kidney functions were abnormal when compound 18c was treated.

[0195] Fig.11 The anticancer effect of compound 11k (Chemical Formula 1-7) in vivo is shown, wherein: Fig.11 A shows the changes in tumor volume when compound 11k is treated; Fig.11 B shows the changes in tumor weight and size when compound 11k is treated; Fig.11 C shows the changes in body weight when compound 11k is treated; Fig.11 D shows the results of examining the histomorphological changes of other organs (liver, kidney and lung) when compound 18c was treated; Fig.11 E shows the results of examining whether liver and kidney functions were abnormal when compound 18c was treated.

[0196] Fig.12 The cell survival rates after treatment of compound 11k (Chemical Formula 1-7) with leukemia cell line (HL-60), liver cancer cell line (HepG2), colon cancer cell line (HCT116), prostate cancer cell line (Du145), ovarian cancer cell line (SKOV3) and non-small cell lung cancer cell line (NCI-H1299 and A549) are shown.

[0197] Fig.13 The combination index (CI) according to the combined treatment concentration of compound 11k (Chemical Formula 1-7) and paclitaxel is shown.

[0198] Fig.14 The in vivo anticancer effect of the combined use of compound 11k (chemical formula 1-7) and paclitaxel is shown, wherein: Fig.14 A shows the changes in tumor volume when the drug is combined; Fig.14 B shows the changes in tumor weight when the drug is combined; Fig.14 C shows the changes in tumor size when the drug is combined; Fig.14 D shows the change in body weight when the drug is used in combination; Fig.14 E shows the evaluation of hepatotoxicity and nephrotoxicity when the drugs are used in combination.

[0199] Fig.15 The cell survival rate after treatment of the indazole derivatives of the present invention and the chromene (Benzopyran) derivatives of the previous invention (KR10-23045320) in BT474 cell line is shown.

[0200] Fig.16 The cell survival rates after treatment of the indazole derivatives of the present invention and the chromene derivatives of the previous invention (KR10-23045320) in JIMT-1 cell line are shown.

[0201] Fig.17 The cell survival rates after treatment of the indazole derivatives of the present invention and the chromene derivatives of the previous invention (KR10-23045320) in the MDA-MB-231 cell line are shown. DETAILED DESCRIPTION

[0202] The present inventors have studied indazole derivatives or pharmaceutically acceptable salts thereof and confirmed the anticancer activity of the derivatives, thereby completing the present invention.

[0203] More specifically, it was confirmed that the indazole derivatives inhibit cancer cell growth and proliferation by inhibiting Hsp90, induce cell apoptosis, and exhibit cytotoxicity, especially specifically inhibit tumor growth, and do not affect normal organs.

[0204] Based on the above results, the present invention provides an indazole derivative represented by the following [Chemical Formula 1], a racemate, an isomer, a solvate or a pharmaceutically acceptable salt thereof.

[0205] [Chemical formula 1]

[0206] Wherein in the chemical formula 1,

[0207]

[0208] A is B is R 1 and R 2 are the same as or different from each other and are hydrogen or C 1 -C 6 Chain alkyl; R 3 and R 4 are the same as or different from each other and are hydrogen or C 1 -C 6 A chain alkyl group, wherein the alkyl

[0209] One or more hydrogen atoms of the group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10 Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, Replacement; R 5 is a halogen group or C 1 -C 6 Alkoxy; R 6 and R 7 The same or different from each other, respectively C 1 -C 6 Chain alkyl; R 8 NR 10 C(O)R 11 , OR 12 , C5 -C 10 Heteroaryl or tetrahydropyranylamino; R 9 For hydrogen, C 1 -C 6 Alkoxy or C 5 -C 10 Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or replaced by C 1 -C 6 Chain alkyl substitution; R 10 and R 11 The same or different from each other, respectively C 1 -C 6 Chain alkyl or C 5 -C 10 Aryl, wherein the alkyl group is unsubstituted or substituted with methylpiperazinyl; R 12 C 5 -C 10 Aryl or C 5 -C 10 benzyl, wherein the benzyl group is unsubstituted or substituted with a halogen group; It can be a single bond or a double bond.

[0210] In the present invention, the term "substitution" refers to a reaction in which an atom or an atomic group included in a molecule of a compound is substituted with another atom or an atomic group.

[0211] In the present invention, the term "chain alkyl" refers to a group derived from a straight or branched saturated aliphatic hydrocarbon having a specific number of carbon atoms and at least one atomic valence. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, and the like.

[0212] In the present invention, the term "cycloalkyl" is also called cyclic alkyl, which refers to a monovalent group having one or more saturated rings and all atoms on the rings are carbon. Examples of such cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl.

[0213] In the present invention, the term "heterocycloalkyl" refers to a saturated or unsaturated (but non-aromatic) cyclic hydrocarbon (cyclohydrocarbon), which may be selectively unsubstituted, monosubstituted or polysubstituted, and at least one heteroatom selected from N, O or S in its structure.

[0214] In the present invention, the term "aryl" refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms with a single ring (such as phenyl) or multiple condensed rings (such as naphthyl). Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0215] In the present invention, the term "heteroaryl" refers to a single ring or multiple condensed rings, wherein at least one of the atoms constituting the ring carries a N, O or S heteroatom.

[0216] In the present invention, the term "alkoxy" refers to an atomic group CnH2n+1O- formed by the combination of an oxygen atom and an alkyl group. Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy or butoxy.

[0217] In the present invention, the term "halogen group" may be an element belonging to Group 17 of the periodic table, such as fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0218] In the present invention, "pharmaceutically acceptable salt" refers to a dosage form of a compound, wherein the compound does not cause severe irritation to the organism to which it is applied, and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt can be obtained by reacting the compound of the present invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid; tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutyric acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. In addition, the compound of the present invention can also be obtained by reacting with a base to form an alkali metal salt such as an ammonium salt, sodium salt or potassium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; an amino acid salt such as arginine, lysine and the like.

[0219] Furthermore, the indazole derivative or a pharmaceutically acceptable salt thereof includes not only pharmaceutically acceptable salts but also all salts, hydrates and solvates which can be prepared by conventional methods.

[0220] In addition, the present invention can provide a pharmaceutical composition for preventing and treating cancer, which comprises the derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0221] In the present invention, the term "prevention" refers to any action to inhibit or delay the occurrence, spread or recurrence of cancer by administering the composition of the present invention; "treatment" refers to any action to improve or beneficially change the symptoms of the disease by administering the composition of the present invention.

[0222] In the present invention, the term "pharmaceutical composition" refers to a preparation for preventing or treating the disease, which can be prepared according to conventional methods and used in various forms. For example, it can be prepared into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can also be prepared into external preparations, suppositories, sterile injections, etc.

[0223] In the present invention, "included as an active ingredient" means that the amount of the ingredient included is necessary or sufficient to achieve the desired biological effect. In practical applications, the amount of the active ingredient can be determined based on the amount of the target disease to be treated and not causing other toxicity, and may vary depending on the disease or condition to be treated, the form of the composition to be administered, the body shape of the subject, or the severity of the disease or condition. Those skilled in the art can determine the effective amount of a single composition based on experience without excessive experiments.

[0224] In addition, the pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers in addition to the above-mentioned active ingredients according to each dosage form.

[0225] The pharmaceutically acceptable carrier can be physiological saline, sterile water, Ringer's solution, buffered physiological saline, glucose solution, maltodextrin solution, glycerol, ethanol and a mixture of more than one of the above components, and other conventional additives such as antioxidants, buffers, antibacterial agents, etc. can also be added as needed. In addition, injection forms such as aqueous solutions, suspensions, emulsions, etc., as well as pills, capsules, granules or tablets can also be prepared by adding diluents, dispersants, surfactants, adhesives, lubricants, etc. In addition, it can be preferably formulated according to each disease or component using appropriate methods in the art or the methods disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA).

[0226] The composition 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" of the present invention refers to a dose that is sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects. The effective dosage level can be determined based on factors such as the patient's health status, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment cycle, and other factors well known in the medical field (including combined or simultaneous medication).

[0227] In addition, the present invention may also provide a method for preventing or treating cancer, comprising the step of administering the indazole derivative or a pharmaceutically acceptable salt thereof to an individual.

[0228] In the present invention, the term "individual" refers to a mammal that needs to prevent, treat and / or diagnose the disease, such as livestock, humans, etc., but is not limited thereto, and is preferably a human.

[0229] In the present invention, the term "administration" refers to providing a predetermined substance to a patient by any appropriate method. The pharmaceutical composition of the present invention can be formulated into various forms for application to an individual, and a typical formulation for parenteral administration is an injection form, preferably an isotonic aqueous solution or suspension. The injection form can be prepared according to techniques known in the art using a suitable dispersant or wetting agent and a suspending agent. For example, each component can be dissolved in physiological saline or a buffer solution and formulated into an injection form. In addition, oral dosage forms include, for example, ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, and flakes, etc., which, in addition to active ingredients, may also include diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silicon dioxide, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). The tablet may include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, and may also include additional disintegrants such as starch, agar, alginic acid or its sodium salt as needed; absorbents; colorants; flavoring agents and / or sweeteners. The preparation may be prepared by conventional mixing, granulation or coating methods.

[0230] In addition, the pharmaceutical composition of the present invention may also include preservatives, moisturizers, emulsifiers, auxiliary agents such as salts or buffers for controlling osmotic pressure, and other substances with therapeutic effects, and can be prepared according to conventional methods.

[0231] The pharmaceutical composition of the present invention can be administered by various routes, including oral, transdermal, subcutaneous, intravenous or intramuscular injection, and the dosage of the active ingredient can be appropriately selected according to various factors, such as the route of administration, the age, sex, body weight or severity of the patient, etc. In addition, the composition of the present invention can be administered in combination with known compounds that can enhance the desired effect.

[0232] The pharmaceutical composition of the present invention can be administered to humans and animals orally or parenterally, such as intravenous injection, subcutaneous injection, intranasal injection or intraperitoneal injection. Oral administration also includes sublingual administration. Parenteral administration includes injection methods such as subcutaneous injection, intramuscular injection, intravenous injection and drip method.

[0233] In the pharmaceutical composition of the present invention, the total effective amount of the indazole derivative or a pharmaceutically acceptable salt thereof according to the present invention can be administered to a patient as a single dose, or can be administered to a patient in multiple doses over a longer period of time through a fractionated treatment protocol. The pharmaceutical composition of the present invention can change the content of the active ingredient according to the severity of the disease, but can be repeatedly administered multiple times a day, usually based on an effective dose of 100 μg to 3,000 mg per administration for an adult, but is not limited to this content, and in addition to the route of administration and the number of treatments, the concentration of the indazole derivative or a pharmaceutically acceptable salt thereof can also be determined as an effective dose for the patient by considering various factors, such as the patient's age, weight, health status, gender, severity of the disease, diet, excretion rate, etc.

[0234] In addition, as long as the pharmaceutical composition of the present invention can exert the effect of the present invention, its dosage form, route of administration and method of administration are not particularly limited. In addition to the indazole derivative or its pharmaceutically acceptable salt as an active ingredient, the pharmaceutical composition of the present invention may also include known drugs, and may be used in combination with other known treatment methods to treat these diseases. As a non-limiting example, it can be administered in combination with a known anticancer agent, and the anticancer agent may be paclitaxel, docetaxel, doxorubicin, sorafenib, vemurafenib, irinotecan, cisplatin, radium 223 chloride (alpharadin), mitoxantrone, cyclophosphamide, vinblastine, carboplatin, actinomycin-D, etoposide, teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), 5-fluorouracil, busulfan, chlorambucil, melphalan, nitrogen mustard, nitrosourea drugs, etc., but is not limited thereto.

[0235] In addition, the present invention also provides a cosmetic composition for preventing or improving cancer, which comprises the indazole derivative or a cosmetically acceptable salt thereof as an active ingredient.

[0236] In the present invention, the term "improvement" refers to all actions that at least reduce parameters related to the disease being treated (such as the degree of symptoms) or improve the disease condition.

[0237] The cosmetic composition, for example, comprises the indazole derivative or a cosmetically acceptable salt thereof as an active ingredient, and can be prepared together with a dermatologically acceptable excipient into the form of a basic cosmetic composition (toner, cream, essence, cleansing foam and cleansing water and other cleansing agents, facial mask, body oil), a color cosmetic composition (foundation, lipstick, mascara, primer), a hair composition (shampoo, conditioner, hair conditioner, hair spray) and a soap, etc.

[0238] The excipients may include, for example, skin softeners, skin penetration enhancers, colorants, fragrances, emulsifiers, thickeners and solvents, and more specifically, may include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, anhydrous skim milk, glycerol, propylene, ethylene glycol, water, ethanol, etc., but are not limited thereto.

[0239] In addition, the present invention also provides a food composition for preventing or improving cancer, which comprises the indazole derivative or a food-acceptable salt thereof as an active ingredient.

[0240] The food composition includes, for example, the indazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient. When the indazole derivative is used as an additive of the food composition, it can be directly added or used together with other foods or food ingredients, and can be appropriately used according to a conventional method. Generally, when manufacturing food or beverages, the composition of the present invention is added in an amount of less than 15% by weight based on raw materials, preferably less than 10% by weight. However, in the case of long-term intake for the purpose of health and hygiene or health management, it can be less than the above range, and since there is no problem in terms of safety, the active ingredient can also be used in an amount higher than the above range. That is, the mixed amount of the active ingredient can be appropriately determined according to various purposes of use such as prevention, health care or treatment.

[0241] The dosage form of the food composition can be in the form of powder, granules, pills, tablets, capsules, or any general food or beverage.

[0242] The food of the present invention can be manufactured by the method commonly used in the art, and can be manufactured by adding the raw materials and ingredients commonly used in the art during the manufacturing process. Specifically, it can include protein, carbohydrates, fat, nutrients, flavoring agents and flavor enhancers, and the examples of the carbohydrates include but are not limited to glucose, fructose, maltose, sucrose, oligosaccharides, dextrin, cyclodextrin, xylitol, sorbitol, erythritol, saccharin or synthetic flavor enhancers.

[0243] In addition, the present invention also provides a feed composition for preventing or improving cancer, which comprises the indazole derivative or a feed-acceptable salt thereof as an active ingredient.

[0244] The feed composition includes, for example, the indazole derivative or a feed-acceptable salt thereof as an active ingredient. In the present invention, the term "feed" refers to any natural or artificial feed, diet, etc. or a component of the above diet for livestock to ingest and digest or suitable for livestock. The feed may include feed additives or supplementary feed.

[0245] The type of the feed is not particularly limited, and feed commonly used in the relevant technical field can be used. Non-limiting examples of the above feed include plant feeds, such as grains, roots, food processing byproducts, algae, fibers, pharmaceutical byproducts, fats, starches, coarse powders or grain byproducts; animal feeds, such as proteins, inorganic substances, fats, minerals, oils, single-cell proteins, zooplankton or food. These can be used alone or in combination of two or more.

[0246] The terms used in the embodiments are for descriptive purposes only and should not be considered as limiting. In the absence of special instructions in the content, singular expressions include plural meanings. In this specification, the terms "including" or "having" are used to express the presence of features, numbers, steps, operations, constituent elements, accessories or combinations thereof recorded in the specification, and do not exclude the presence of one or more other features, numbers, steps, operations, constituent elements, accessories or combinations thereof, or additional functions.

[0247] In the absence of other definitions, all terms used herein, including technical or scientific terms, have the common meanings understood by those of ordinary skill in the art. Commonly used terms that are the same as dictionary definitions should be understood to have meanings consistent with the common content of the relevant technology and should not be overly idealized or interpreted as formal meanings unless explicitly mentioned in this application.

[0248] In the description of the components of the embodiments, terms such as first, second, A, B, (a), (B) may be used. These terms are only used to distinguish one constituent element from another constituent element, and the nature, sequence or order of the element is not limited by these terms. When a constituent element is described as being "connected", "coupled" or "in contact with" another constituent element, it should be understood that the constituent element can be directly connected or in contact with the other constituent element, and it can also be understood that the other constituent element is "connected", "coupled" or "in contact with" each constituent element.

[0249] Hereinafter, the embodiments will be described in detail with reference to the accompanying drawings. However, various changes can be made to the embodiments, and the scope of the present invention is not limited or defined by these embodiments. All variations, equivalents or substitutes of the embodiments are included in the scope of rights.

[0250] Furthermore, in the process of describing with reference to the accompanying drawings, regardless of the figure numerals, the same constituent elements are given the same figure numerals, and repeated descriptions thereof are omitted. In the process of describing the embodiments, when it is determined that the detailed description of the related known technology will unnecessarily confuse the embodiments, the detailed description thereof will be omitted.

[0251] The present invention may be modified in various ways and have various embodiments, and therefore specific embodiments are shown in the drawings and described in detail in the following detailed description. However, this is not meant to limit the present invention to specific embodiments, but it should be understood that it includes all modifications, equivalents or substitutes included in the spirit and technical scope of the present invention. In describing the present invention, when it is judged that the specific description of the relevant known technology will unnecessarily confuse the subject matter of the present invention, its detailed description will be omitted.

[0252] Example 1. General preparation method

[0253] Example 1.1. N-alkylation reaction of indazole (Procedure A)

[0254] Method I: Alkyl halide (1.1 eq.) was added to DMF 6-nitroindazole (1.0 eq.) and Cs 2 CO 3 (1.5 equivalents) was added to a mixture and stirred at room temperature to 60°C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added, and extracted twice with ethyl acetate. The organic layer was collected, washed three times with water, and MgSO 4 Dry and concentrate in vacuo.The residue is purified by silica gel column chromatography to give the desired product.

[0255] Method II: DIAP (diisopropyl azodicarboxylate, 1.1 equivalent) was added to 6-nitroindazole (1.0 equivalent), Ph 3 P (1.1 equivalents) and 2-substituted ethanol (1.1 equivalents) were added to a mixture and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was concentrated and removed in vacuo, and the residue was purified by silica gel column chromatography to obtain the desired product.

[0256] Method III: 1,3-dibromoethane or 1,3-dibromopropane (1.2 eq.) was added to 3-methyl-6-nitroindazole (1.0 eq.) and Cs in DMF at 0 °C. 2 CO 3 (1.5 equivalents) was added to the mixture. The reaction mixture was stirred at room temperature for 18 hours and then quenched with water. The reaction mixture was extracted with ethyl acetate and washed with water. MgSO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0257] Example 1.2, Hydrogenation reaction (Procedure B)

[0258] 10% Pd / C is added to a solution of starting material (1.0 equivalent) in MeOH-THF or MeOH co-solution, degassed and refilled with hydrogen. The mixture is stirred at room temperature for 2-4 hours. After the reaction is complete, the reaction mixture is filtered through diatomite and washed twice with MeOH. The filtrate is concentrated under vacuum, and the residue is purified by silica gel chromatography to obtain the target product.

[0259] Example 1.3, Amide coupling reaction (Procedure C)

[0260] Method I: At room temperature, RNH 2 (1.0 equiv) was added to a solution of carboxylic acid (1.1 equiv), HOBt (1.5 equiv), triethylamine (2.0 equiv) and EDC·HCl (1.5 equiv) in DCM and reacted for 15 hours. After the reaction was completed, the organic compound was extracted with ethyl acetate and washed with water several times. The combined organic layer was washed with brine and MgSO 4 It was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0261] Method II: RNH in THF 2 or R 1 R 2 NH (1.0 eq.) was added to 2 M NaOH (aq.), stirred at room temperature, and then acid chloride (1.2 eq.) was added dropwise and stirred at room temperature for 2 hours. After removing the solvent, the mixture was acidified with 1 M HCl (aq.). The organic compound was extracted with ethyl acetate, washed with water, and washed with Na 2 SO 4 Dry and concentrate in vacuo. The residue is purified by silica gel column chromatography to give the desired product.

[0262] Method III: SOCl 2 (0.5 mL) was added to a mixture of carboxylic acid (1.0 eq.) and catalytic amount of DMF in DCM and stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed, the reaction mixture was dissolved in DCM, and amine (1.0 eq.) and Et 3 N (2.0 eq.) After one hour at room temperature, the crude mixture was purified by silica gel column chromatography to give the desired product.

[0263] Example 1.4, Boc deprotection (Procedure D)

[0264] TFA (20.0 eq) was added dropwise to a solution of the Boc-protected compound in DCM at 0 °C and the mixture was stirred at room temperature for 2 - 4 h. The solvent was removed and the residue was purified by silica gel column chromatography to afford the target product.

[0265] Example 1.5, Reductive amination reaction (Procedure E)

[0266] Method I: Acetic acid (5.0 eq) was added to a mixture of a primary aromatic amine (1.0 eq) and a ketone or aldehyde (1.0 eq) in MeOH, then NaBH 3 CN (3.0 eq) was added and the mixture was stirred at 40 °C. After 16 h, the reaction mixture was basified with NaHCO 3 (aq), then extracted with DCM. The organic layers were concentrated in vacuo and purified by silica gel column chromatography to afford the target product.

[0267] Method II: TFA (0.1 mL) was added to a solution of an amine (1.0 eq) and tetrahydro-4H-pyran-4-one (5.0 eq) in DCM (2 mL), then NaBH(OAc) 3 (5.0 eq) was added and the mixture was stirred at room temperature for 18 h. The mixture was neutralized with 10% K 2 CO 3 (aq), extracted with DCM and washed with water. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo, and purified by fractional chromatography to afford the target product.

[0268] Example 1.6, Preparation of piperidine derivatives (Procedure F)

[0269] Method I: 2-(Piperidin-4-yl)ethyl-substituted intermediate (1.0 eq) was added to a mixture of EDC·HCl (1.5 eq), but-2-ynoic acid (2.0 eq), Et 3 N (2.0 eq) and HOBt (1.5 eq) in DCM. After stirring for 15 h, the mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the target product.

[0270] Method II: Et 3N (2.0 equiv) was added to a mixture of 2-(piperidin-4-yl)ethyl substituted intermediate (1.0 equiv) in DCM, followed by acryloyloxy chloride (2.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate, and washed with brine. MgSO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0271] Example 1.7. Preparation of piperazine derivatives (Procedure G)

[0272] N-Methylpiperazine (3.0 equiv.) was added to 2-bromoethyl or 2-bromopropylindazole in acetonitrile and stirred at room temperature for 15 h. The reaction mixture was diluted with DCM, washed twice with water, and washed with MgSO 4 Dry and concentrate in vacuo. The residue is purified by silica gel column chromatography to obtain the desired product.

[0273] Example 1.8. O-Alkylation of Phenol (Procedure H)

[0274] Method I: ROH (1.0 eq.), RX (1.5 eq.) and K in DMF (4 mL) were stirred at 40 °C. 2 CO 3 The mixture of (2.0 equivalents) was stirred for 3 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and washed with water. 2 SO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0275] Method II: Alkyl halide (2.0 eq.) was added to a solution of ROH (1.0 eq.) and 20% NaOH (aq., 10 eq.) in EtOH. The reaction mixture was stirred at reflux for 18 h. After the reaction was complete, the solvent was removed, the residue was acidified with 1 M HCl (aq.), and extracted with ethyl acetate. The organic layer was washed with water and washed with anhydrous Na 2 SO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0276] Method III: At room temperature, 2 CO 3(2.0 equiv.), KI (2.0 equiv.), CuI (0.05 equiv.) and RX (1.1 equiv.) were added to a solution of ROH (1.0 equiv.) in DMF (2 mL) and reacted for 15 h. The mixture was extracted with ethyl acetate and washed with water. 2 SO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0277] Example 1.9. Preparation of 2,2-dialkyl-2H-chromene (Procedure I)

[0278] Method I (intramolecular cyclization): A solution of the starting material in o-xylene (2 mL) was heated at 180°C for 1 hour. The solvent was evaporated and the residue was extracted with ethyl acetate and washed with water. 2 SO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0279] Method II (intermolecular cyclization): 3-Methyl-2-butenol (2.0 equiv.), anhydrous calcium chloride (1.0 equiv.) and triethylamine (2.0 equiv.) were added to a solution of the phenol derivative (1.0 equiv.) in ethanol and refluxed for 2 h. The solvent was removed and the residue was diluted, extracted with ethyl acetate and washed with MgSO 4 Dry and concentrate in vacuo. The residue is purified by silica gel column chromatography to give the desired product.

[0280] Example 1.10, Pinnick oxidation reaction (Procedure J)

[0281] At 0 °C, aldehyde (1.0 equivalent), 30% H 2 O 2 (1.0 eq.) and NaH 2 PO 4 (0.2 equivalent) was added to the mixture of NaClO 2 (1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with water, extracted with ethyl acetate, and washed with MgSO 4 The residue was purified by silica gel column chromatography to obtain the target product.

[0282] Example 1.11, Hydrolysis reaction (Procedure K)

[0283] To EtOH (4 mL) and H 2To a solution of the nitrile derivative (1.0 equiv) in 2H2O (1 mL) was added NaOH (10.0 equiv). The reaction mixture was stirred at 120 °C (in a sealed tube) for 3 h. The mixture was acidified with 2N HCl (aq), extracted with ethyl acetate, and washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The residue is purified by silica gel column chromatography to give the desired product.

[0284] Example 1.12, Suzuki Coupling Reaction (Procedure L)

[0285] EtOH: HO 2 O (1:1) or BuOH:H 2 Boric acid (1.0 equivalent), RBr (1.0 equivalent), K 2 CO 3 (3.0 equivalent) and Pd(PPh 3 ) 4 The mixture of (0.05 eq.) was stirred at 90°C or 110°C. The solvent was evaporated, the crude mixture was dissolved in water and filtered through celite. The filtrate was acidified to pH 3 with formic acid and extracted with ethyl acetate. 2 SO 4 The organic layer was dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product.

[0286] Example 1.13, benzyl deprotection (Procedure M)

[0287] 1-Chloroethyl chloroformate (1.0 equiv) was added to a solution of RBn in DCM and refluxed for 1 h. 3 (aq) was reacted, extracted with DCM, and washed with MgSO 4 Dry and concentrate in vacuo. The residue is purified by silica gel column chromatography to give the desired product.

[0288] Example 1.14, Phthalimide Deprotection (Procedure N)

[0289] To a solution of RPhth (1.0 eq.) in EtOH was added hydrazine hydrate (5.0 eq.) and stirred at room temperature for 15 hours. The solid residue was filtered and the filtrate was concentrated in vacuo. The residue was used in the next step without purification.

[0290] Example 2, Preparation of 6-aminoindazole derivatives

[0291] The preparation method of 6-aminoindazole derivatives is shown in the following reaction formula 1. In this case, (a) [Method A] RX, Cs 2 CO 3 , DMF, room temperature, 15 hours; [Method B] ROH, DEAD, Ph 3 P, THF, room temperature, 15 hours; (b) H 2 , 10% Pd / C, THF-MeOH, room temperature, 2 hours; (c) 29, EDC·HCl, HOBt, Et 3 N, DCM, room temperature, 15 hours; (d) TFA, DCM, room temperature, 3 hours; (e) for 7k, 8k and 7m, [Method A] (i) (HCHO) n 、ZnCl 2 , MC, (ii) NaBH 4 ; For 7l, 7n, [Method B] 1-methylpiperazine, K 2 CO 3 , CH 3 CN, 70°C, 3 hours; (f) for 11o, [Method A] RCl, Et 3 N, MC, 0°C to room temperature, 3 hours; for 11p, [Method B] RCOOH, EDC·HCl, HOBt, Et 3 N, MC, room temperature, 15 hours.

[0292] [Reaction 1]

[0293]

[0294] Example 2.1. Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-1, 6a)

[0295] Example 2.1.1. Preparation of 3-Methyl-1H-indazol-6-amine (5a)

[0296] Using Procedure B, compound 5a was prepared from compound 1 as a red solid in 98% yield. 1 H NMR (500 MHz, CDCl 3 ) δ7.33 (d, J=8.55Hz, 1H), 6.54 (d, J=1.40Hz, 1H), 6.49 (dd, J=8.55, 1.65Hz, 1H), 3.36 (brs, 2H), 2.39 (s, 3H).

[0297] Example 2.1.2. Preparation of 5-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (24)

[0298] Compound 24 was prepared as a pale yellow oil in 60% yield from compound 21 using Procedure I - Procedure II and Procedure A - Method I with iodomethane. 1 H NMR (400 MHz, CDCl 3 ) δ10.16 (s, 1H), 7.64 (d, J=8.6Hz, 1H), 6.64 (d, J=8.5Hz, 1H), 6.59 (d, J=10.0Hz, 1H), 5.68 (d, J=10.1Hz, 1H), 3.89 (s, 3H), 1.45 (s, 6H).

[0299] Example 2.1.3. Preparation of 5-methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (29)

[0300] Using Procedure J, compound 29 was prepared from compound 24 as a white solid in 69% yield. 1 H NMR (400 MHz, CDCl 3 ) δ10.61 (br s, 1H), 7.90 (d, J = 8.7Hz, 1H), 6.69 (d, J = 8.7Hz, 1H), 6.53 (d, J = 10.0Hz, 1H), 5.73 (d, J = 10.1Hz, 1H), 3.94 (s, 3H), 1.46 (s, 6H).

[0301] Example 2.1.4. Preparation of 5-Methoxy-2,2-dimethyl-N-(3-methyl-1H-indazol-6-yl)-2H-chromene-6-carboxamide (6a)

[0302] Using Procedure C - Method I, compound 6a was prepared as a white solid in 81% yield from compound 5a and compound 29 as described. mp 244-245°C. 1 H NMR (500 MHz, CDCl 3)δ9.95 (s, 1H), 8.34 (s, 1H), 7.98 (d, J = 8.65Hz, 1H), 7.60 (d, J = 8.60Hz, 1H), 7.07 (d, J = 8.50Hz, 1H), 6.72 (d, J = 8 .70Hz, 1H), 6.59 (d, J=10.0Hz, 1H), 5.72 (d, J=10.0Hz, 1H), 3.89 (s, 1H), 2.61 (s, 3H), 1.46 (s, 6H).ESI-MS[M+H] + 364.

[0303] Example 2.2, Preparation of N-(1,3-dimethyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-2, 6b)

[0304] Example 2.2.1. Preparation of 1,3-dimethyl-6-nitro-1H-indazole (3b) Using Procedure A-Method I, compound 3b was prepared from compound 1 and iodoethane as a yellow solid with a yield of 62%. 1 H NMR (300 MHz, CDCl 3 ) δ8.58 (dd, J=1.83, 0.75Hz, 1H), 7.81 (dd, J=9.15, 2.01Hz, 1H), 7.63 (dd, J=9.15, 0.57Hz, 1H), 4.16 (s, 3H), 2.56 (s, 3H).

[0305] Example 2.2.2 Preparation of 1,3-dimethyl-1H-indazole-6-amine (1,3-Dimethyl-1H-indazole-amine) (5b)

[0306] Using Procedure B, compound 5b was prepared from compound 3b as a reddish solid in 92% yield. 1 H NMR (300 MHz, CDCl 3 ) δ7.37 (d, J=8.22Hz, 1H), 5.22-6.50 (m, 2H), 3.96 (s, 3H), 3.85 (brs, 2H), 2.46 (s, 3H).

[0307] Example 2.2.3. Preparation of N-(1,3-dimethyl-1H-indazole-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (6b)

[0308] Using Procedure C - Method I, compound 6b was prepared as a white solid in 87% yield from 29 prepared according to compound 5b and Example 2.1.3. mp 166-1s 67°C. 1 H NMR (400 MHz, CDCl 3 )δ9.90 (s, 1H), 8.31 (d, J = 1.28Hz, 1H), 7.98 (d, J = 8.64Hz, 1H), 7.95 (d, J = 8.48Hz, 1H), 6.86 (dd, J = 8.56, 1.68Hz, 1H), 6.72 (d, J =8.68Hz, 1H), 6.59 (d, J = 10.0Hz, 1H), 5.72 (d, J = 10.0Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 2.50 (s, 3H), 1.46 (s, 6H).ESI-MS[M+H] + 378.

[0309] Example 2.3, Preparation of 5-methoxy-N-(1-(2-methoxyethyl)-3-methyl-1H-indazol-6-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-3, 6c)

[0310] Example 2.3.1. Preparation of 1-(2-Methoxyethyl)-3-methyl-6-nitro-1H-indazole (3c)

[0311] Using Procedure A - Method I, compound 3c was prepared from compound 1 and 2-bromoethyl methyl ether as a yellow solid in 42% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.39 (d, J=2.0Hz, 1H), 7.95 (dd, J=8.4, 1.6Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 4.54 (t, J=5.6Hz, 2H), 3.81 (t, J=5.2Hz, 2H), 3.29 (s, 3H), 2.60 (s, 3H).

[0312] Example 2.3.2, Preparation of 1-(2-Methoxyethyl)-3-methyl-1H-indazole-6-amine (5c)

[0313] Using Procedure B, compound 5c was prepared from compound 3c as a reddish solid in 95% yield. 1 H NMR (400 MHz, CDCl 3 ) δ7.37 (d, J=8.0Hz, 1H), 6.54-6.50 (m, 2H), 4.32 (t, J=6.0Hz, 2H), 3.82 (brs, 2H), 3.76 (t, J=6.0Hz, 2H), 3.30 (s, 3H), 2.47 (s, 3H).

[0314] Example 2.3.3. Preparation of 5-Methoxy-N-(1-(2-methoxyethyl)-3-methyl-1H-indazole-6-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (6c)

[0315] Using Procedure C - Method I, compound 6c was prepared as a white solid in 73% yield from 29 prepared according to compound 5c and Example 2.1.3. mp 113-114 °C. 1 H NMR (400 MHz, CDCl 3 )δ9.92 (s, 1H), 8.31 (d, J = 1.2Hz, 1H), 7.98 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 6.93 (dd, J = 8.8, 2.0Hz, 1H), 6.73 (d, J = 8.4Hz, 1H), 6.60 (d, J =9.6Hz, 1H), 5.73 (d, J = 10Hz, 1H), 4.48 (t, J = 5.6Hz, 2H), 3.90 (s, 3H), 3. 82(t, J=5.2Hz, 2H), 3.32(s, 3H), 2.54(s, 3H), 1.47(s, 6H).ESI-MS[M+H] + 422.

[0316] Example 2.4, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-morpholinoethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-4, 6d)

[0317] Example 2.4.1. Preparation of 4-(2-(3-Methyl-6-nitro-1H-indazol-1-yl)ethyl)morpholine (3d)

[0318] Using Procedure A - Method II, compound 3d was prepared from compound 1 and 4-(2-hydroxyethyl)morpholine as a yellow solid in 61% yield.

[0319] 1 H NMR (400 MHz, CDCl 3 )δ8.38 (d, J=2.0Hz, 1H), 7.95 (dd, J=8.8, 2.0Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 4.4 9 (t, J=6.0Hz, 1H), 3.64 (br, 4H), 2.84 (t-like, 2H), 2.59 (s, 2H), 2.50 (br, 4H).

[0320] Example 2.4.2. Preparation of 3-Methyl-1-(2-morpholinoethyl)-1H-indazole-6-amine (5d)

[0321] Using Procedure B, compound 5d was prepared from compound 3d as a brown solid in 91% yield. 1 H NMR (500 MHz, CDCl 3 )δ7.38 (d, J=9.2Hz, 1H), 6.53-6.50 (m, 2H), 4.34 (t, J=6.8Hz, 2H), 3.85 (brs, 1H), 3.72 (t, J=4.0Hz, 4H), 2.85 (br, 2H), 2.55 (br, 4H), 2.46 (s, 3H).

[0322] Example 2.4.3. Preparation of 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-morpholinoethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (6d)

[0323] Using Procedure C - Method I, compound 6d was prepared as a white solid in 88% yield from 29 prepared according to compound 5d and Example 2.1.3. mp 89-90°C. 1 H NMR (400 MHz, CDCl 3 )δ9.93 (s, 1H), 8.36 (d, J = 0.8Hz, 1H), 7.96 (d, J = 4.4Hz, 1H), 7.52 (d, J = 8.4H z, 1H), 8.65 (dd, J=8.8, 1.2Hz, 1H), 6.71 (d, J=8.8Hz, 1H), 6.58 (d, J=10.0Hz, 1H), 5.71 (d, J=10.0Hz, 1H), 4.42 (t, J=7.2Hz, 2H), 3.90 (s, 3H), 3.67 (t, J=4. 4Hz, 4H), 2.84 (t, J=7.6Hz, 2H), 2.53-2.51 (m, 6H), 1.45 (s, 6H).ESI-MS[M+H] + 477.

[0324] Example 2.5, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(pyridin-3-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-5, 6e)

[0325] Example 2.5.1. Preparation of 3-Methyl-6-nitro-1-(2-(pyridin-3-yl)ethyl)-1H-indazole (3e)

[0326] Compound 3e was prepared as a yellow solid in 73% yield from compound 1 and 2-(pyridin-3-yl)ethanol using Procedure A - Method II. 1 H NMR (400 MHz, CDCl 3)δ8.41 (dd, J=5.2, 2.0Hz, 1H), 8.25 (d, J=2.0Hz, 1H), 7.98 (d, J=2.0Hz, 1H), 7.91 (dd, J=9.2, 2.0Hz, 1H), 7.70 (d, J=9. 2Hz, 1H), 7.55-7.43 (1H, mix), 7.16 (dd, J=8.0, 4.8Hz, 1H), 4.59 (t, J=7.2Hz, 2H), 3.24 (t, J=7.2Hz, 2H), 2.61 (s, 3H).

[0327] Example 2.5.2. Preparation of 3-Methyl-1-(2-(pyridin-3-yl)ethyl)-1H-indazole-6-amine (5e)

[0328] Using Procedure B, compound 5e was prepared from compound 3e as a brown solid in 92% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.43 (d, J=4.8Hz, 1H), 8.42 (s, 1H), 7.37 (d, J=8.4Hz, 1H), 7.35 (dt, J=7.6, 2.0Hz, 1H), 7.12 (dd, J=7.6, 4.8Hz, 1H), 6.4 8 (dd, J=8.8, 1.6Hz, 1H), 6.25 (d, J=1.6Hz, 1H), 4.35 (t, J=7.2Hz, 2H), 7.38 (brs, 2H), 3.15 (t, J=7.2Hz, 2H), 2.48 (s, 3H).

[0329] Example 2.5.3. Preparation of 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(pyridin-3-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (6e)

[0330] Using Procedure C - Method I, compound 6e was prepared as a white solid in 80% yield from 29 prepared according to compound 5e and Example 2.1.3. mp 119-120 °C. 1 H NMR (400 MHz, CDCl 3)δ9.91 (s, 1H), 8.42 (dd, J = 5.2, 2.0Hz, 1H), 8.38 (d, J = 1.6Hz, 1H), 8.21 (d, J = 0.8Hz, 1H), 7.97 (d , J=8.8, 1H), 7.54 (d, J=8.0Hz, 1H), 4.48 (dt, J=7.6, 1.6Hz, 1H), 7.17 (dd, J=7.6, 5.6Hz, 1H), 6.8 6 (dd, J=8.8, 1.6Hz, 1H), 6.73 (d, J=8.8Hz, 1H), 6.60 (d, J=10.0Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 4 .16 (t, J=7.2Hz, 2H), 3.90 (s, 3H), 3.22 (t, J=7.6Hz, 2H), 2.54 (s, 3H), 1.47 (s, 6H).ESI-MS[M+H] + 469.

[0331] Example 2.6, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(pyridin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-6, 6f)

[0332] Example 2.6.1. Preparation of 3-Methyl-6-nitro-1-(2-(pyridin-4-yl)ethyl)-1H-indazole (3f)

[0333] Using Procedure A - Method II, compound 3f was prepared from compound 1 and 2-(pyridin-4-yl)ethanol as a yellow solid in 67% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.44 (dd, J=4.8, 1.6Hz, 2H), 8.08 (d, J=1.6Hz, 1H), 7.93 (dd, J=8.4, 1.6Hz, 1H), 7.71 (d, J= 8.8Hz, 1H), 7.02 (d, J=6.0Hz, 2H), 4.61 (t, J=7.2Hz, 2H), 3.24 (t, J=6.8Hz, 2H), 2.61 (s, 3H).

[0334] Example 2.6.2. Preparation of 3-Methyl-1-(2-(pyridin-4-yl)ethyl)-1H-indazole-6-amine (5f)

[0335] Using Procedure B, compound 5f was prepared from compound 3f as a red solid in 90% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.45 (dd, J=4.8, 2.0Hz, 2H), 7.38 (d, J=8.4Hz, 1H), 7.05 (d, J=6.0Hz, 2H), 6.50 (dd, J=8.8, 2.0Hz , 1H), 6.28 (d, J=1.2Hz, 1H), 4.37 (t, J=7.2Hz, 2H), 3.79 (s, 2H), 3.14 (t, J=7.6Hz, 2H), 2.48 (s, 3H).

[0336] Example 2.6.3. Preparation of 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(pyridin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (6f)

[0337] Using Procedure C - Method I, compound 6f was prepared as a white solid in 89% yield from 29 prepared according to compound 5f and Example 2.1.3. mp 150-151 °C. 1 H NMR (400 MHz, CDCl 3 )δ9.91 (s, 1H), 8.44 (d, J = 4.8Hz, 2H), 7.97 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.09 (d, J=5.6, 2H), 6.83 (dd, J=8.8, 2.0Hz, 1H), 6.73 (d, J=8.0Hz, 1H), 6.60 (d, J=10.0Hz, 1H), 5.73 (d, J=10.0Hz, 1H), 4.54 (t, J=7.6Hz, 2H), 3.90(s, 3H), 3.21(t, J=8.0Hz, 2H), 2.54(s, 3H), 1.47(s, 6H).ESI-MS[M+H] + 469.

[0338] Example 2.7, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-7, 11k)

[0339] Example 2.7.1. Preparation of tert-butyl 4-(2-(3-methyl-6-nitro-1H-indazol-1-yl)ethyl)piperidine-1-carboxylate (3 g)

[0340] Using Procedure A - Method I, Compound 3g was prepared as a yellow solid in 63% yield from Compound 1 and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate. 1 H NMR (400 MHz, CDCl 3 )δ8.65 (dd, J=1.9, 0.7Hz, 2H), 7.86 (dd, J=8.8, 1.9Hz, 1H), 4.47 (t, J=7.2Hz, 2H), 3.92-3.81 (m, 2H), 2.67-2.53 (m, 2H ), 2.51 (s, 3H), 1.73 (q, J=7.1Hz, 2H), 1.68-1.62 (m, 2H), 1.44-1.36 (m, 1H), 1.34 (s, 9H), 1.01 (qd, J=12.2, 4.2Hz, 2H).

[0341] Example 2.7.2, Preparation of 3-Methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-6-nitro-1H-indazole (7k)

[0342] Using Procedure D and Procedure E - Method I, compound 7k was prepared from compound 3g as a yellow solid in 84% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.27 (d, J=1.6Hz, 1H), 7.95 (dd, J=9.2, 2.0Hz, 1H), 7.72 (d, J=8.8Hz, 1H), 4.39 (t, J=7.2Hz, 2H), 2.83 (d, J=11.6Hz, 2H), 2.5 9 (s, 3H), 2.46 (s, 3H), 2.24 (s, 3H), 1.89-1.84 (m, 4H), 1.73 (d, J=12.8Hz, 2H), 1.35 (qd, J=12.4, 3.6Hz, 2H), 1.29-1.21 (m, 1H).

[0343] Preparation of Example 2.7.3, 3-Methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-amine (9k)

[0344] Using Procedure B, compound 9k as a brown solid was prepared from compound 7k with a yield of 98%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J = 8.8 Hz, 1H), 6.50 (dd, J = 8.0, 2.0 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 4.16 (t, J = 7.2, 2H), 3.83 (s, 2H), 2.79 (d, J = 11.6 Hz, 2H), 2.46 (s, 3H), 2.22 (s, 3H), 1.88 - 1.70 (m, 6H), 1.36 - 1.20 (m, 3H).

[0345] Preparation of Example 2.7.4, 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (11k)

[0346] Using Procedure C - Method I, compound 11k as a white solid was prepared from 29 prepared according to compound 9k and Example 2.1.3 with a yield of 83%. mp 103 - 104 °C. 1 H NMR (400 MHz, CDCl 3)δ9.44 (s, 1H), 8.33 (d, J = 1.2Hz, 1H), 7.98 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 6.85 (dd, J = 8.4, 1.6Hz, 1H), 6.73 (d, J = 8.8Hz, 1H), 6.60 (d, J = 9.6Hz, 1H), 5.73 (d, J = 10.0Hz, 1H), 4.32 (t, J =7.6Hz, 2H), 3.90 (s, 3H), 2.90 (d, J = 9.6Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.98 (t, J = 11.2Hz, 2 H), 1.86 (q, J=7.2Hz, 2H), 1.79 (d, J=12.8Hz, 2H), 1.46 (s, 6H), 1.46-1.32 (m, 3H).ESI-MS[M+H] + 491.

[0347] Example 2.8, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-8, 111)

[0348] Example 2.8.1. Preparation of 1-(2-bromoethyl)-3-methyl-6-nitro-1H-indazole (3i)

[0349] Compound 3i was prepared as a colorless oil in 49% yield from compound 1 and 1,2-dibromoethane using Procedure A - Method III. 1 HNMR (400 MHz, CDCl 3 ) δ8.39 (d, J=1.6Hz, 1H), 7.95 (dd, J=8.8, 2.0Hz, 1H), 4.72 (t, J=6.4Hz, 2H), 3.75 (t, J=6.4Hz, 2H), 2.59 (s, 3H).

[0350] Example 2.8.2, Preparation of 3-Methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-6-nitro-1H-indazole (71)

[0351] Using Procedure G, compound 71 was prepared from compound 3i as a pale yellow solid in 97% yield. 1H NMR (400 MHz, CDCl 3 )δ8.39 (d, J=1.6Hz, 1H), 7.95 (dd, J=8.4, 1.6Hz, 1H), 7.70 (d, J=9.2Hz, 1H), 4.48 (t, J=6 .8, 2H), 2.83 (t, J=6.4Hz, 2H), 2.59 (s, 3H), 2.54 (brs, 4H), 2.40 (brs, 4H), 2.25 (s, 3H).

[0352] Example 2.8.3. Preparation of 3-Methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-6-amine (91)

[0353] Using Procedure B, compound 91 was prepared from compound 71 as a brown solid in 94% yield. 1 H NMR (400 MHz, CDCl 3 )δ7.37 (d, J=8.0Hz, 1H), 6.52-6.48 (m, 2H), 4.29 (t, J=7.60Hz, 2H), 3.83 (s, 2H ), 2.80 (t, J=6.0Hz, 2H), 2.57 (br, 4H), 2.47 (s, 3H), 2.43 (br, 4H), 2.27 (s, 3H).

[0354] Example 2.8.4. Preparation of 5-Methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (111)

[0355] Using Procedure C - Method I, compound 111 was prepared as a white solid in 78% yield from 29 prepared as described for compound 91 and Example 2.1.3. mp 90-91°C. 1 H NMR (400 MHz, CDCl 3) δ9.93 (s, 1H), 8.36 (s, 1H), 7.96 (d, J = 4.8Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 6.85 (dd, J = 8.4, 1.2Hz, 1H), 6.73 (d, J = 8.8Hz, 1H), 6.60 ( d, J=10.4Hz, 1H), 5.73 (d, J=10.0Hz, 1H), 4.16 (t, J=6.8Hz, 2H), 2.66 (br, 8H), 2.52 (s, 3H), 2.36 (s, 3H), 1.46 (s, 6H).ESI-MS[M+H] + 490.

[0356] Example 2.9, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(3-(1-methylpiperidin-4-yl)propyl)-1H-isoindol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-9, 11m)

[0357] Example 2.9.1. Preparation of tert-butyl 4-(2-(3-methyl-6-nitro-1H-indazol-1-yl)propyl)piperidine-1-carboxylate (3h)

[0358] Compound 3h was prepared as a yellow solid in 67% yield from compound 1 and tert-butyl 4-(3-bromopropyl)piperidine-1-carboxylate using Procedure A - Method I. 1 H NMR (400 MHz, CDCl 3 )δ8.28 (d, J=1.8Hz, 1H), 7.96 (dd, J=8.8, 1.9Hz,

[0359] 1H), 7.73 (d, J=8.9Hz, 1H), 4.36 (t, J=7.2Hz, 2H), 4.04 (d, J=13.1Hz, 2H), 2.66-2 .59(m, 5H), 1.99-1.90(m, 2H), 1.63-1.60(m, 2H), 1.42(s, 9H), 1.40-1.33(m, 1H),

[0360] 1.29-1.23 (m, 2H), 1.10-0.98 (m, 2H).

[0361] Example 2.9.2, Preparation of 3-methyl-1-(3-(1-methylpiperidin-4-yl)propyl)-6-nitro-1H-indazole (7m)

[0362] Compound 7m was prepared as a yellow solid in 84% yield from compound 3h using Procedure D and Procedure E - Method I. 1 H NMR (400MHz, MeOD) δ8.48 (dd, J=1.9, 0.7Hz, 1H), 7.93 (dd, J=8.8, 1.9Hz, 1H), 7.86 (dd, J=8.9, 0.7Hz, 1H), 4.42 (t, J=6.9, 2H ), 2.86-2.79(m, 2H), 2.57(s, 3H), 2.23(s, 3H), 2.03-1.94(m, 2H), 1.94-1.86(m, 2H), 1.68-1.62(m, 2H), 1.24-1.09(m, 5H).

[0363] Example 2.9.3, Preparation of 3-methyl-1-(3-(1-methylpiperidin-4-yl)propyl)-1H-indazol-6-amine (9m)

[0364] Using Procedure B, compound 9m was prepared from compound 7m as a light red solid in 91% yield. 1 H NMR (400 MHz, DMSO-d 6 )δ7.24 (d, J=8.5Hz, 1H), 6.39 (dd, J=8.5, 1.7Hz, 1H), 6.35 (d, J=1.7Hz, 1H), 5.21 (s, 2H), 3.98 (t, J=7.0Hz, 2H), 2. 64 (dt, J=11.3, 3.2Hz, 2H), 2.27 (s, 3H), 2.05 (s, 3H), 1.76-1.65 (m, 4H), 1.51 (d, J=11.6Hz, 2H), 1.17-0.96 (m, 5H).

[0365] Example 2.9.4. Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(3-(1-methylpiperidin-4-yl)propyl)-1H-isoindol-6-yl)-2H-chromene-6-carboxamide (11m)

[0366] Using Procedure C - Method I, compound 11m was prepared as a white solid in 89% yield from 29 prepared as described for compound 9m and Example 2.1.3. mp 62-63°C. 1 H NMR (400 MHz, CDCl 3 )δ9.95 (s, 1H), 8.35 (d, J = 1.7Hz, 1H), 7.97 (d, J = 8.7Hz, 1H), 7.55 (d, J = 8.5Hz, 1H), 6.84 (dd , J=8.6, 1.7Hz, 1H), 6.73 (d, J=8.6Hz, 1H), 6.60 (d, J=10.0Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 4. 27(t, J=7.2Hz, 2H), 3.91(s, 9H), 3.05-2.84(m, 2H), 2.53(s, 3H), 2.35(s, 3H), 2.16-2.02(m , 2H), 1.91 (p, J=7.3Hz, 2H), 1.73-1.67 (m, 2H), 1.47 (s, 6H), 1.42-1.25 (m, 5H).FAB-MS[M+H] + 503.

[0367] Example 2.10, Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-10, 11n)

[0368] Example 2.10.1. Preparation of 1-(3-bromopropyl)-3-methyl-6-nitro-1H-indazole (3j)

[0369] Compound 3j was prepared as a colorless oil in 45% yield from compound 1 and 1,3-dibromopropane using Procedure A - Method III. 1 HNMR (400 MHz, CDCl3 )δ8.40 (d, J=1.6Hz, 1H), 7.97 (dd, J=8.8, 1.8Hz, 1H), 7.73 (d, J=8.8Hz, 1H), 4. 55 (t, J=6.4Hz, 2H), 3.34 (t, J=6.2Hz, 2H), 2.60 (s, 3H), 2.50 (p, J=6.3Hz, 2H).

[0370] Example 2.10.2. Preparation of 3-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-6-nitro-1H-indazole (7n)

[0371] Using Procedure G, compound 7n was prepared from compound 3j as a colorless oil in 91% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.44 (d, J=1.9Hz, 1H), 7.94 (dd, J=8.8, 1.9Hz, 1H), 7.70 (d, J=8.9Hz, 1H), 4.46 (t, J=6.3Hz, 2H), 2.59 (s, 3H), 2.70-2.25 (m, 8H), 2.32 (s, 3H), 2.21 (t, J=6.5Hz, 2H), 2.08 (p, J=6.4Hz, 3H).

[0372] Example 2.10.3. Preparation of 3-methyl-1-(3-(4-methylpiperidin-1-yl)propyl)-1H-indazol-6-amine (9n)

[0373] Using Procedure B, compound 9n was prepared from compound 7n as a light red solid in 96% yield. 1 H NMR (400 MHz, DMSO-d 6 )δ7.24 (d, J=8.5Hz, 1H), 6.40 (dd, J=8.5, 1.7Hz, 1H), 6.35 (d, J=1.3Hz, 1H), 5.20 (s, 2H), 4.03 ( t, J=6.9Hz, 2H), 2.45-2.12 (m, 11H), 2.15 (t, J=7.0Hz, 2H), 2.10 (s, 3H), 1.82 (p, J=6.9Hz, 2H).

[0374] Example 2.10.4. Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(3-(4-methylpiperazin-1-yl)propyl)-1H-indazole-6-yl)-2H-chromene-6-carboxamide (11n)

[0375] Compound 11n was prepared as a white solid in 57% yield from 29 prepared as described for compound 9n and Example 2.1.3 using Procedure C - Method I. mp 88-89°C. 1 H NMR (400 MHz, DMSO-d 6 )δ10.21 (s, 1H), 8.16 (s, 1H), 7.57 (d, J = 8.6Hz, 1H), 7.40 (d, J = 8.5Hz, 1H), 7.17 ( dd, J=8.6, 1.7Hz, 1H), 6.64 (d, J=8.5Hz, 1H), 6.58 (d, J=10.0Hz, 1H), 5.84 (d, J=10 .0Hz, 1H), 4.22 (t, J=6.7Hz, 2H), 3.76 (s, 3H), 2.40 (s, 3H), 2.50-2.02 (m, 8H), 2. 15(t, J=6.8Hz, 2H), 2.07(s, 3H), 1.89(p, J=6.9Hz, 2H), 1.38(s, 6H).FAB-MS[M+H] + 504.

[0376] Example 2.11, Preparation of N-(1-(2-(1-(but-2-ynyl)piperidin-4-yl)ethyl)-3-methyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-11, 11o)

[0377] Example 2.11.1. Preparation of tert-butyl 4-(2-(6-amino-3-methyl-1H-indazol-1-yl)ethyl)piperidine-1-carboxylate (5 g)

[0378] Using Procedure B, compound 5 g was prepared as a white solid in 99% yield from 3 g prepared according to Example 2.7.1. 1H NMR (400 MHz, CDCl 3 )δ7.40 (d, J=8.6Hz, 1H), 6.56 (dd, J=8.5, 1.8Hz, 1H), 6.50 (d, J=1.8Hz, 1H), 4.19 (t, J=7.4Hz, 2H), 4.13-3.98 (m, 2H ), 2.70-2.61 (m, 2H), 2.47 (s, 3H), 1.79 (q, J=7.2Hz, 2H), 1.73-1.66 (m, 2H), 1.45-1.37 (m, 10H), 1.20-1.09 (m, 2H).

[0379] Example 2.11.2. Preparation of tert-butyl 4-(2-(6-(5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamido)-3-methyl-1H-indazol-1-yl)ethyl)piperidine-1-carboxylate (6 g)

[0380] Using Procedure C - Method II, compound 6g was prepared from compound 5g as a white solid in 53% yield. 1 HNMR (400 MHz, CDCl 3 ) δ10.00 (s, 1H), 8.41 (s, 1H), 7.98 (d, J = 8.6Hz, 1H), 7.59 (d, J = 8.6Hz, 1H), 6.88 (dd, J=8.5, 1.7Hz, 1H), 6.74 (d, J=8.7Hz, 1H), 6.60 (d, J=9.9Hz, 1H), 5.74 (d, J=1 0.3Hz, 1H), 4.41 (t, J=7.5Hz, 2H), 4.10-4.02 (m, 2H), 3.91 (s, 3H), 2.71-2.62 (m, 2H), 2.59(m, 3H), 1.88(q, J=7.0Hz, 2H), 1.78-1.70(m, 2H), 1.47(s, 6H), 1.43(s,

[0381] 10H), 1.22-1.12 (m, 2H).

[0382] Example 2.11.3. Preparation of N-(1-(2-(1-(but-2-ynoyl)piperidin-4-yl)ethyl)-3-methyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide) (11o)

[0383] Compound 11o was prepared from compound 6g as a white solid in 26% yield using Procedure D and Procedure F - Method I. mp 71-72°C. 1 H NMR (400 MHz, CDCl 3 )δ9.96 (s, 1H), 7.98 (d, J = 8.6Hz, 1H), 7.56 (d, J = 8.5Hz,

[0384] 1H), 6.84 (dd, J=8.6, 1.6Hz, 1H), 6.74 (d, J=8.7Hz, 1H), 6.60 (d, J=10.0Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 4.56-4.45 (m, 1H), 4.41-4.29 (m, 3H), 3.91 (s, 3 H), 3.04-2.95 (m, 1H), 2.63-2.56 (m, 1H), 2.55 (s, 3H), 1.99 (s, 3H), 1.94-1 .71(m, 4H), 1.63-1.51(m, 1H), 1.47(s, 6H), 1.24-1.10(m, 2H).FAB-MS[M+H] + 541.

[0385] Example 2.12, Preparation of N-(1-(2-(1-acryloylpiperidin-4-yl)ethyl)-3-methyl-1H-indazol-6-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-12, 11p)

[0386] Compound 11p was prepared as a white solid in 65% yield from 6 g prepared according to Example 2.11.2 using Procedure D and Procedure F - Method II. mp 69-70 °C. 1 H NMR (400 MHz, CDCl 3) δ9.98 (s, 1H), 8.40 (d, J = 1.3Hz, 1H), 7.98 (d, J = 8.7Hz, 1H), 7.56 (d, J = 8. 5Hz, 1H), 6.84 (dd, J=8.6, 1.7Hz, 1H), 6.74 (dd, J=8.7, 0.8Hz, 1H), 6.64-6. 52 (m, 2H), 6.23 (dd, J=16.9, 2.0Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 5.64 (dd, J =10.6, 2.0Hz, 1H), 4.67-4.56(m, 1H), 4.37(t, J=7.3Hz, 2H), 4.01-3.94(m,

[0387] 1H), 3.91 (s, 3H), 3.07-2.94 (m, 1H), 2.64-2.56 (m, 1H), 2.55 (s, 3H), 1.90-1 .80(m, 4H), 1.58-1.53(m, 1H), 1.47(s, 6H), 1.23-1.15(m, 2H).FAB-MS[M+H] + 529.

[0388] Example 2.13, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-13, 12k)

[0389] Example 2.13.1. Preparation of tert-butyl 4-(2-(6-nitro-1H-indazol-1-yl)ethyl)piperidine-1-carboxylate (4 g)

[0390] Using Procedure A - Method I, Compound 4g was prepared as a yellow solid in 47% yield from Compound 2 and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate. 1 H NMR (400 MHz, CDCl 3)δ8.35 (s, 1H), 8.10 (s, 1H), 8.01 (dd, J=8.9, 2.0Hz, 1H), 7.83 (dd, J=8.8, 1.4Hz, 1H), 4.50 (t, J=6.4Hz, 2H), 4.14-4 .01 (m, 2H), 2.73-2.56 (m, 2H), 1.91 (q, J=7.0, 6.6Hz, 2H), 1.47-1.41 (m, 10H), 1.79-1.68 (m, 2H), 1.27-1.12 (m, 2H).

[0391] Example 2.13.2. Preparation of 1-(2-(1-methylpiperidin-4-yl)ethyl)-6-nitro-1H-indazole (8k)

[0392] Compound 8k was prepared from compound 4g as a yellow solid in 58% yield using Procedure D and Procedure E - Method I. 1 H NMR (400 MHz, CDCl 3 )δ8.36-8.35 (m, 1H), 8.10 (d, J = 1.0Hz, 1H), 8.01 (dd, J = 8.8, 1.9Hz,

[0393] 1H), 7.83 (dd, J=8.9, 0.7Hz, 1H), 4.50 (t, J=7.2Hz, 2H), 3.03-2.85 (m, 2H), 2.35 (s, 3H), 2.08 -2.02 (m, 2H), 1.94 (q, J=7.0Hz, 2H), 1.83-1.75 (m, 2H), 1.58-1.47 (m, 5H), 1.35-1.25 (m, 1H).

[0394] Example 2.13.3. Preparation of 1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-amine (10k)

[0395] Using Procedure B, compound 10k was prepared from compound 8k as a light red solid in 92% yield. 1 H NMR (401 MHz, CDCl 3)δ7.77 (d, J=0.9Hz, 1H), 7.46 (dd, J=8.6, 0.7Hz, 1H), 6.55 (dd, J=8.5, 1.8Hz, 1H), 6.51 (dt, J=1.8, 0.9Hz, 1H), 4.25 (t, J=7.2Hz, 2H), 3.86 (s, 2H), 2.94-2.84 (m, 2H), 2.29 (s, 3H), 1.99-1.93 (m, 2H), 1.83 (q, J=6.9Hz, 2H), 1.79-1.71 (m, 2H), 1.48-1.36 (m, 2H), 1.32-1.21 (m, 1H).

[0396] Example 2.13.4. Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (12k)

[0397] Compound 12k was prepared as a white solid in 52% yield from 29 prepared according to compound 10k and Example 2.1.3 using Procedure C - Method I. mp 78-79°C. 1 H NMR (400 MHz, CDCl 3 )δ9.96 (s, 1H), 8.43 (s, 1H), 7.98 (d, J = 8.7Hz, 1H), 7.90 (d, J = 0.9Hz, 1H), 7.63 (d, J = 8.5Hz, 1H) , 6.88 (dd, J=8.6, 1.7Hz, 1H), 6.74 (d, J=8.7Hz, 1H), 6.60 (d, J=10.0Hz, 1H), 5.73 (d, J=10.0Hz, 1 H), 4.41 (t, J=7.3Hz, 2H), 3.90 (s, 3H), 2.90-2.84 (m, 2H), 2.27 (s, 3H), 1.97-1.91 (m, 2H), 1.91- 1.86(m, 2H), 1.81-1.75(m, 2H), 1.47(s, 6H), 1.43-1.33(m, 2H), 1.33-1.25(m, 1H).FAB-MS[M+H] + 475.

[0398] Example 3, Preparation of 3-aminoindazole derivatives

[0399] The preparation method of 3-aminoindazole derivatives is shown in the following reaction formula 2. In this case, (a) N 2 H 4 .H 2 O, t-BuOH, reflux, 18 hours; (b) phthalic anhydride, 1,4-dioxane, reflux, 15 hours; (c) alkyl halide, Cs 2 CO 3 , DMF, 60°C, 4 hours; (d) N 2 H 4 .H 2 O, EtOH, room temperature, 15 hours; (e) for 17k, 4-vinylpyridine, K 3 PO 4 , H 2 O, microwave 180℃, 20 minutes; (f) i) 29, (COCl) 2 , DMF, THF, room temperature, 2 hours; ii) amine, TEA, DCM, room temperature, 1 hour or -20°C, 4 hours; (g) ACE-Cl, DCM, -5°C, 2 hours; (h) NaH, THF, CH 3 I. 0°C to room temperature, 4 hours.

[0400] [Reaction 2]

[0401]

[0402] Example 3.1. Preparation of N-(1H-indazol-3-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-14, 18a)

[0403] Example 3.1.1. Preparation of 1H-indazol-3-amine (14)

[0404] A mixture of 2-fluoroaniline (1.0 equiv.) and hydrazine monohydrate (1.05 equiv.) in t-BuOH was heated and refluxed overnight. After the reaction was complete, t-BuOH was removed under low pressure. Water was added to the residue, filtered, and washed with water. The filtrate was collected and extracted twice with ethyl acetate. The organic layer was washed with water and MgSO 4 Dry and concentrate. The solids were combined and stored for the next step (86%).

[0405] 1 H NMR (400 MHz, CD 3 OD) δ7.56 (d, J=7.04Hz, 1H), 7.36-7.26 (m, 2H), 6.98 (ddd, J=7.92, 5.84, 1.88Hz, 1H).

[0406] Example 3.1.2, Preparation of 2-(1H-indazol-3-yl)isoindoline-1,3-dione (15)

[0407] To the solution of compound 14 was added a stoichiometric amount of phthalimide in 1,4-dioxane. The mixture was heated and refluxed overnight. The mixture was then evaporated under vacuum and the residual solid was collected, washed with hexane, and dried to give an off-white solid (yield 89%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.05-7.99 (m, 2H), 7.83-7.80 (m, 2H), 7.55 (d, J = 8.2Hz, 1H), 7.48-7.44 (m, 2H), 7.21-7.18 (m, 1H).

[0408] Example 3.1.3. Preparation of N-(1H-indazol-3-yl)-5-methoxy-2,2-dimethyl-2H-chromene-6-carboxamide (18a)

[0409] Using Procedure C - Method I, compound 18a was prepared as a white solid in 86% yield from compound 15 and 29 prepared according to Example 2.1.3. mp 222-223 °C. 1 H NMR (400 MHz, CDCl 3 ) δ10.31 (s, 1H), 8.08 (d, J = 8.28Hz, 1H), 8.01 (d, J = 8.72Hz, 1H), 7.48 (d, J = 8.44Hz, 1H), 7.42 (t, J = 7.88Hz, 1H), 7.18 (t, J = 7.64Hz, 1H), 6.71 (d, J=8.68Hz, 1H), 6.60 (d, J=10.0Hz, 1H), 5.71 (d, J=10.0Hz, 1H), 3.91 (s, 3H), 1.47 (s, 6H).ESI-MS[M+H] + 350.

[0410] Example 3.2, Preparation of 5-methoxy-N,2,2-trimethyl-N-(1-methyl-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-15, 18b)

[0411] Example 3.2.1. Preparation of 2-(1-Methyl-1H-indazol-3-yl)isoindoline-1,3-dione (16b)

[0412] Using Procedure A - Method I, compound 16b was prepared as a white solid in 51% yield from 15 prepared according to Example 3.1.2 and iodomethane. 1 H NMR (500 MHz, CDCl 3 )δ8.00-7.98 (m, 2H), 7.82-7.80 (m, 2H), 7.54 (d, J=8.28Hz, 1H), 7.44-7.43 (m, 2H), 7.20-7.17 (m, 1H), 4.13 (s, 3H).

[0413] Example 3.2.2. Preparation of 1-Methyl-1H-indazol-3-amine (17b)

[0414] Using Procedure N, compound 17b was prepared from compound 16b as a brown solid in 87% yield. 1 H NMR (400 MHz, CDCl 3 )δ7.50 (m, J=8.4, 1H), 7.34-7.27 (m, 2H), 7.00 (m, 1H), 4.07 (brs, 2H), 3.91 (s, 3H).

[0415] Example 3.2.3. Preparation of 5-Methoxy-N,2,2-trimethyl-N-(1-methyl-1H-indazol-3-yl)-2H-chromene-6-carboxamide (18b)

[0416] Using Procedure C - Method I, compound 18b was prepared as a white solid in 92% yield from 29 prepared according to compound 17b and Example 2.1.3. mp 103-104°C. 1 H NMR (400 MHz, CDCl 3) δ10.10 (s, 1H), 8.07 (d, J = 8.25Hz, 1H), 8.03 (d, J = 8.65Hz, 1H), 7.38 (t, J = 7.85Hz, 1H), 7.29 (d, J = 8.55Hz, 1H), 7.13 (t, J = 7.35Hz , 1H), 6.72 (d, J=8.70Hz, 1H), 6.60 (d, J=10.05Hz, 1H), 5.71 (d, J=10.0Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 1.46 (s, 6H).ESI-MS[M+H] + 364.

[0417] Example 3.3, Preparation of 5-methoxy-N-(1-(2-methoxyethyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-16, 18c)

[0418] Example 3.3.1. Preparation of 2-(1-Methoxyethyl-1H-indazol-3-yl)isoindoline-1,3-dione (16c)

[0419] Using Procedure A - Method I, compound 16c was prepared as a white solid in 67% yield from 15 prepared according to Example 3.1.2 and 2-bromoethyl methyl ether. 1 H NMR (400 MHz, CDCl 3 )δ8.03-7.98 (m, 2H), 7.84-7.80 (m, 2H), 7.53 (dd, J=9.2, 0.8Hz, 2H), 7.42 (td, J=7.6, 1.2Hz , 1H), 7.18 (td, J=8.0, 0.8Hz, 1H), 4.60 (t, J=5.6Hz, 2H), 3.87 (t, J=5.6Hz, 2H), 3.31 (s, 3H).

[0420] Example 3.3.2. Preparation of 1-(2-Methoxyethyl)-1H-indazol-3-amine (17c)

[0421] Using Procedure N, compound 17c was prepared from compound 16c as a brown solid in 75% yield. 1 H NMR (400 MHz, CDCl 3)δ7.51 (dt, J=8.4, 0.8Hz, 1H), 7.35-7.26 (m, 2H), 7.00 (ddd, J=8.0, 6.4, 0.8Hz , 1H), 4.31 (t, J=5.2Hz, 2H), 4.03 (brs, 2H), 3.75 (t, J=5.6Hz, 2H), 3.29 (s, 3H).

[0422] Example 3.3.3. Preparation of 5-Methoxy-N-(1-(2-methoxyethyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (18c)

[0423] Using Procedure C - Method I, compound 18c was prepared as a white solid in 76% yield from 29 prepared as described for compound 17c and Example 2.1.3. mp 92-93°C. 1 H NMR (400 MHz, CDCl 3 ) δ10.07 (s, 1H), 8.06 (d, J = 8.8Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.40-7.35 (m, 2H), 7.12 (ddd, J = 8.4, 6.0, 2.0Hz, 1H), 6.72 (d, J = 8.4Hz, 1H), 6.6 1 (d, J=10.4Hz, 1H), 5.72 (d, J=10.0Hz, 1H), 4.47 (t, J=5.6Hz, 2H), 3.95 (s, 3H), 3.81 (t, J=5.6Hz, 2H), 3.30 (s, 3H), 1.50 (s, 6H).ESI-MS[M+H] + 408.

[0424] Example 3.4, Preparation of 5-methoxy-N-(1-(3-methoxypropyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-17, 18d)

[0425] Example 3.4.1. Preparation of 2-(1-(3-Methoxypropyl)-1H-indazol-3-yl)isoindoline-1,3-dione (16d)

[0426] Using Procedure A - Method I, compound 16d was prepared as a white solid in 42% yield from 15 prepared according to Example 3.1.2 and 3-bromopropyl methyl ether. 1 H NMR (400 MHz, CDCl 3 )δ7.99 (dd, J=5.6, 2.8 Hz, 2H), 7.82 (dd, J=5.6, 3.2 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.20-7.16 (m, 1H), 4.55 (t, J=7.2 Hz, 2H), 3.33 (t, J=6.0 Hz, 2H), 3.31 (s, 3H), 2.21 (quintet, J=6.0 Hz, 2H).

[0427] Example 3.4.2, Preparation of 1-(3-Methoxypropyl)-1H-indazol-3-amine (17d)

[0428] Using Procedure N, compound 17d was prepared from compound 16d as a brown solid in 71% yield. 1 H NMR (400 MHz, CDCl 3 )δ7.49 (d, J=8.4 Hz, 1H), 7.32-7.28 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.98-6.95 (m, 1H), 4.22 (t, J=6.4 Hz, 2H), 4.10 (brs, 2H), 3.24 (s, 3H), 3.24 (t, J=6.0 Hz, 2H), 2.05 (quintet, J=6.0 Hz, 2H).

[0429] Example 3.4.3. Preparation of 5-Methoxy-N-(1-(2-Methoxypropyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (18d)

[0430] Using Procedure C - Method I, compound 18d was prepared as a white solid in 65% yield from 29 prepared as described for compound 17d and Example 2.1.3. mp 95-97°C. 1 H NMR (400 MHz, CDCl 3)δ10.09 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.37-7.36 (m, 2H), 7.15-7.09 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 10.0 Hz, 1H), 5.71 (d, J = 10.0 Hz, 1H), 4.40 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.29 (s, 3H), 3.29 (t, J = 5.6 Hz, 2H), 2.14 (quintet, J = 6.0 Hz, 2H), 1.47 (s, 6H).ESI-MS [M+H] + 422.

[0431] Example 3.5, 5-methoxy-N-(1-(2-(2-methoxyethoxy)ethyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-

[0432] Preparation of 6-formamide (chemical formula 1-18, 18e)

[0433] Example 3.5.1. Preparation of 2-(1-(2-(2-Methoxyethoxy)ethyl)-1H-indazol-3-yl)isoindoline-1,3-dione (16e)

[0434] Using Procedure A - Method I, compound 16e was prepared as a white solid in 34% yield from 15 prepared according to Example 3.1.2 and 1-bromo-2-(2-methoxyethoxy)ethane. 1 H NMR (400 MHz, CDCl 3 )δ8.01-7.97 (m, 2H), 7.84-7.80 (m, 2H), 7.56 (d, J=6.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.41 (t, J=8.8Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 4.62 (t, J=6.0Hz, 2H), 3.97 (t, J=6.0Hz, 2H), 3.55-3.52 (m, 2H), 3.43-3.41 (m, 2H), 3.29 (s, 3H).

[0435] Example 3.5.2. Preparation of 1-(2-(2-Methoxyethoxy)ethyl)-1H-indazol-3-amine (17e)

[0436] Using Procedure N, compound 17e was prepared from compound 16e as a brown solid in 67% yield. 1 H NMR (400 MHz, CDCl 3 )δ7.51-7.49(m, 1H), 7.34-7.29(m, 2H), 7.01-7.92(m, 1H), 4.33(t, J=6.0Hz, 2H), 3.83 (t, J=6.4Hz, 2H), 3.51-3.49 (m, 2H), 3.42-3.38 (m, 2H), 3.29 (s, 3H).

[0437] Example 3.5.3. Preparation of 5-Methoxy-N-(1-(2-(2-Methoxyethoxy)ethyl)-1H-indazol-3-yl)-2,2-dimethyl-2H-chromene-6-carboxamide (18e)

[0438] Using Procedure C - Method I, compound 18e was prepared as a white solid in 64% yield from 29 prepared according to compound 17e and Example 2.1.3. mp 104-105°C. 1 H NMR (400 MHz, CDCl 3 ) δ10.09 (s, 1H), 8.05 (d, J = 8.0Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.42 (d, J = 8.4Hz, 1H) , 7.36 (t, J=6.3Hz, 1H), 7.12 (t, J=7.2Hz, 1H), 6.72 (d, J=8.4Hz, 1H), 6.61 (d, J=10.0 Hz, 1H), 5.72 (d, J=10.4Hz, 1H), 4.49 (t, J=6.0Hz, 2H), 3.95 (s, 3H), 3.91 (t, J=6.0H z, 2H), 3.54-3.52 (m, 2H), 3.44-3.41 (m, 2H), 3.31 (s, 3H), 1.47 (s, 6H).ESI-MS[M+H] + 452.

[0439] Example 3.6, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(methylamino)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-19, 191)

[0440] Compound 191 was prepared from compound 18f as a white solid in 56% yield using Procedure M. mp 92-93 °C. 1 H NMR (400 MHz, CDCl 3 ) δ10.08 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.95 (d, J = 8.8Hz, 1H), 7.36-7.32 (m, 1H), 7.10-7.06 (m, 1H), 6.69 (d, J = 8.4Hz, 1H), 6.59 (d, J = 10.0Hz, 1H), 5.71 (d, J=10.0Hz, 1H), 4.52 (t, J=6.0Hz, 2H), 3.92 (s, 3H), 3.19 (t, J=5.6Hz, 2H), 2.51 (s, 3H), 1.46 (s, 6H).ESI-MS[M+H] + 407.

[0441] Example 3.7, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-20, 18 g)

[0442] Compound 18g was prepared as a white solid from compound 17g and 29 prepared according to Example 2.1.3 using Procedure C - Method I. mp 97-98°C. 1 H NMR (400 MHz, CDCl 3 )δ10.08(s, 1H), 8.08(d, J=8.0Hz, 1H), 8.03(d, 8.8Hz, 1H), 7.39-7.35(m, 1H), 7.29(d, J=8.4Hz, 1H), 7.14-7.10(m, 1H), 6.72(d, J=8.8Hz, 1H), 6.61(d, J=10.0Hz, 1H), 7.72(d, J=10.4Hz, 1H), 4.32 (t, J=7.2Hz, 2H), 3.94 (s, 3H), 2.83 (d, J=11.6Hz, 2H), 2.25 (s, 3H), 1.91-1.82(m, 4H), 1.75(d, J=12.0Hz, 2H), 1.48(s, 6H), 1.42-1.26(m, 3H).ESI-MS[M+H] + 475.

[0443] Example 3.8, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-21, 18h)

[0444] Compound 18h ​​was prepared as a white solid from compound 17h and 29 prepared according to Example 2.1.3 using Procedure C - Method I. mp 102-103 °C. 1 H NMR (400 MHz, CDCl 3 )δ10.08 (s, 1H), 8.06 (d, J=8.0Hz, 1H), 8.02 (dd, 8.8, 2.8Hz, 1H), 7.38-7.32 (m, 2H), 7.11 (t, J=6.8Hz, 1H), 6.60 (d, J=10Hz, 1H), 5.71 (d , J=10.4Hz, 1H), 4.42 (t, J=6.8Hz, 2H), 3.94 (s, 3H), 2.86 (t, J=6.4Hz, 2H), 2.58-2.41 (brm, 8H), 2.28 (s, 3H), 1.46 (s, 6H).ESI-MS[M+H] + 476.

[0445] Example 3.9, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-morpholinylethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-22, 18i)

[0446] Example 3.9.1. Preparation of 2-(1-(2-Morpholinoethyl)-1H-indazol-3-yl)isoindoline-1,3-dione (16i)

[0447] Using Procedure A - Method I, compound 16i was prepared as a white solid in 61% yield from 15 prepared according to Example 3.1.2 and 4-(2-bromoethyl)morpholine. 1 H NMR (400 MHz, CDCl 3 )δ8.02-7.95(m, 2H), 7.85-7.80(m, 2H), 7.54(d, J=8.0Hz, 1H), 7.51(br, 1H), 7.44(t, J=8 .4Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 4.61 (br, 2H), 3.71 (br, 4H), 2.98 (br, 2H), 2.56 (br, 4H).

[0448] Example 3.9.2, Preparation of 1-(2-Morpholinoethyl)-1H-indazol-3-amine (17i)

[0449] Using Procedure N, compound 17i was prepared from compound 16i as a brown solid in 71% yield. 1 H NMR (400 MHz, CDCl 3 )δ7.51 (d, J=5.6Hz, 1H), 7.34 (t, J=7.2Hz, 1H), 7.27 (d-like, 1H), 7.02 (t, J=7. 6Hz, 1H), 4.33 (br, 2H), 4.04 (br, 2H), 3.70 (br, 4H), 2.85 (br, 2H), 2.55 (br, 4H).

[0450] Example 3.9.3. Preparation of 5-Methoxy-2,2-dimethyl-N-(1-(2-morpholinoethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (18i)

[0451] Compound 18i was prepared as a white solid in 85% yield from compound 17i and 29 prepared according to Example 2.1.3 using Procedure C - Method I. mp 84-85°C. 1 H NMR (400 MHz, CDCl 3 )δ10.09 (s, 1H), 8.07 (d, J = 8.0Hz, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.39-7.33 ( m, 2H), 7.14-7.10 (m, 1H), 6.71 (d, J=9.2Hz, 1H), 6.59 (d, J=9.6Hz, 1H), 5.7 1 (d, J=10.4Hz, 1H), 4.43 (t, J=6.8Hz, 2H), 3.94 (s, 3H), 3.67 (t, J=4.4Hz, 4 H), 2.85 (t, J=7.2Hz, 2H), 2.52 (t, J=4.0Hz, 4H), 1.46 (s, 6H).ESI-MS[M+H] + 463.

[0452] Example 3.10, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(pyridin-3-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-23, 18j)

[0453] Example 3.10.1. Preparation of 2-(1-(2-(Pyridin-3-yl)ethyl)-1H-indazol-3-yl)isoindoline-1,3-dione (16j)

[0454] Using Procedure A - Method I, compound 16j was prepared as a white solid in 67% yield from 15 prepared according to Example 3.1.2 and 2-(pyridin-3-yl)ethyl 4-methylbenzenesulfonate. 1 H NMR (400 MHz, CDCl 3 )δ8.49 (d, J=1.6Hz, 1H), 8.42 (d, J=3.6Hz, 1H), 8.03-7.99 (m, 2H), 7.86-7.81 (m, 2H), 7.52 (d, J=8.4Hz, 1H), 7.36-7.31 (m, 2H), 7.21 (d, J=6.0Hz, 1H), 7.15 (t, J=7.2Hz, 1H), 7.09 (dd, J=7.6, 5.2Hz, 1H), 4.64 (t, J=6.8Hz, 2H), 3.30 (t, J=7.2Hz, 2H).

[0455] Example 3.10.2, Preparation of 1-(2-(Pyridin-3-yl)ethyl)-1H-indazol-3-amine (17j)

[0456] Using Procedure N, compound 17j was prepared from compound 16j as a brown solid in 87% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.41-8.38 (m, 2H), 7.49 (d, J=8.0Hz, 1H), 7.32 (dt, J=7.6, 2.0Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 7.08 ( dd, J=7.6, 4.4Hz, 1H), 6.98-6.95 (m, 2H), 4.34 (t, J=7.6Hz, 2H), 4.08 (brs, 2H), 3.13 (t, J=6.8Hz, 2H).

[0457] Example 3.10.3. Preparation of 5-Methoxy-2,2-dimethyl-N-(1-(2-(pyridin-3-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (18j)

[0458] Using Procedure C - Method I, compound 18j was prepared as a white solid in 89% yield from 29 prepared as described for compound 17j and Example 2.1.3. 1 H NMR (400 MHz, CDCl 3 ) δ10.12 (s, 1H), 8.46 (s, 1H), 8.43 (d, J = 4.0Hz, 1H), 8.08 (d, J = 8.0Hz, 1H), 8.04 (d, J=8.8Hz, 1H), 7.34 (dt-like, J=7.6Hz, 1H), 7.32-7.28 (m, 1H), 7.13-7.08 (m , 3H), 7.73 (d, J=8.4Hz, 1H), 6.62 (d, J=10.4Hz, 1H), 5.73 (d, J=9.6Hz, 1H), 4.51 (t, J=6.8Hz, 2H), 3.96 (s, 3H), 3.22 (t, J=7.2Hz, 2H), 1.47 (s, 6H).ESI-MS[M+H] + 455.

[0459] Example 3.11, Preparation of 5-methoxy-2,2-dimethyl-N-(1-(2-(pyridin-4-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-24, 18k)

[0460] Example 3.11.1. Preparation of 1-(2-(pyridin-4-yl)ethyl)-1H-indazol-3-amine (17k)

[0461] A mixture of 3-aminoindazole (1.0 equiv.), potassium phosphate (2.0 equiv.), 4-vinylpyridine (1.5 equiv.), and TBAB (20 mol%) was placed in a glass microwave vial with a magnetic stir bar. The vial was placed in a microwave oven at 180°C for 20 minutes. After the reaction was complete, the mixture was cooled to room temperature and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and MgSO 4The residue was dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate / n-hexane (1 / 2) as eluent to obtain an off-white solid in a yield of 56%. 1 H NMR (400 MHz, CD 3 OD) δ 8.41 (br, 2H), 7.49 (d, J=8.0Hz, 1H), 7.25-7.21 (m, 1H), 7.08-6.95 (m, 3H), 4.35 (t, J=7.2Hz, 2H), 3.11 (t, J=7.2Hz, 2H).

[0462] Example 3.11.2. Preparation of 5-Methoxy-2,2-dimethyl-N-(1-(2-(pyridin-4-yl)ethyl)-1H-indazol-3-yl)-2H-chromene-6-carboxamide (18k)

[0463] Compound 18k was prepared as a white solid in 93% yield from 29 prepared as described for compound 17k and Example 2.1.3 using Procedure C - Method I. mp 68-69°C. 1 H NMR (400 MHz, CDCl 3 ) δ10.11 (s, 1H), 8.46 (br, 2H), 8.08 (d, J = 8.0Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.30 (t, J = 8.4Hz, 1H), 7.13-7.05 (m, 4H), 6.72 (d, J = 8.8Hz, 1H), 6.61 (d, J=10.4Hz, 1H), 5.72 (d, J=10.4Hz, 1H), 4.52 (t, J=7.2Hz, 2H), 3.94 (s, 3H), 3.17 (t, J=6.8Hz, 2H), 1.47 (s, 6H).ESI-MS[M+H] + 455.

[0464] Example 3.12, Preparation of 5-methoxy-N-(1-(2-methoxyethyl)-1H-indazol-3-yl)-N,2,2-trimethyl-2H-chromene-6-carboxamide (Chemical Formula 1-25, 20c)

[0465] Compound 18c was prepared from 17c prepared according to Example 3.3.2 and 29 prepared according to Example 2.1.3 using Procedure C - Method I. NaH (1.1 eq.) was added to a solution of compound 18c in anhydrous THF at 0°C under nitrogen. The mixture was stirred and iodomethane (3.0 eq.) was added in one portion. After removing the ice bath, the mixture was stirred at room temperature for another 4 hours. The reaction product was then quenched with water, extracted with ethyl acetate, and washed with MgSO 4 Drying, concentration, and purification by silica gel column chromatography using ethyl acetate / hexane (1 / 1) as eluent gave compound 20c (white solid, yield 94%). mp 78-79°C. 1 H NMR (400 MHz, CDCl 3 )δ7.56 (d, J=8.4Hz, 1H), 7.43 (d, J=7.6Hz, 1H), 7.31 (t, J=7.2Hz, 1H), 7.0 1 (t, J=8.0Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 6.39 (d, J=8.0Hz, 1H), 6.16 (d, J =10.0Hz, 1H), 5.60 (d, J = 10.0Hz, 1H), 4.29 (t, J = 5.6Hz, 2H), 3.85 (s, 3H), 3.54(t, J=5.6Hz, 2H), 3.50(s, 6H), 3.07(s, 3H), 1.25(s, 6H).ESI-MS[M+H] + 422.

[0466] Example 4. Preparation of 2-chromene-6-carboxylic acid derivatives

[0467] The preparation method of 2-chromene-6-carboxylic acid derivatives is shown in the following reaction formula 3. In this case, (a) [Method A] 3-methyl-2-butenal, CaCl 2 , Et 3 N, EtOH, reflux, 2 hours; [Method B] (i) R 2 C(OH)CCH,conc.HCl,CuCl,Cu,CaCl 2 , 0℃, 1 hour, (ii) CuI, K 2 CO 3 , KI, DMF, room temperature, 15 hours, (iii) o-xylene, 180°C, 1 hour; (b) for 24, 25, RI, K 2 CO 3 , DMF, 40°C, 3 hours; (c) for 29-32, [Method A] 27% H 2 O 2 (aq), NaClO 2 、NaH2 PO 4 , CH 3 CN, 0°C, 2 hours; for 33, [Method B] NaO, EtOH, H 2 O, 120°C, 2 hours; (d) 9k, EDC.HCl, HOBt, Et 3 N, MC, room temperature, 15 hours; (e) H 2 , 10% Pd / C, MeOH, room temperature, 3 hours.

[0468] [Reaction 3]

[0469]

[0470] Example 4.1. Preparation of 5-methoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)chromene-6-carboxamide (Chemical Formula 1-26, 34)

[0471] Compound 34 was prepared as a white solid in 99% yield from 11k prepared according to Example 2.7.4 using Procedure B. mp 74-75 °C. 1 H NMR (400 MHz, CDCl 3 )δ9.91 (s, 1H), 8.34 (d, J = 1.7Hz, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.5Hz, 1H), 6 .85 (dd, J=8.5, 1.7Hz, 1H), 6.73 (d, J=8.8Hz, 1H), 4.32 (t, J=7.4Hz, 2H), 3.89 (s, 3H), 2.95-2.87(m, 2H), 2.81(t, J=6.7Hz, 2H), 2.53(s, 3H), 2.30(s, 3H), 2.03-1.92(m, 2H ), 1.91-1.75(m, 6H), 1.46-1.39(m, 2H), 1.36(s, 6H), 1.34-1.30(m, 1H).FAB-MS[M+H] + 491.

[0472] Example 4.2, Preparation of 5-ethoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-27, 35)

[0473] Example 4.2.1. Preparation of 5-ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde (25)

[0474] Compound 25 was prepared as a pale yellow oil in 63% yield from compound 21 using Procedure I - Procedure II and Procedure A - Method I with iodomethane. 1 H NMR (400 MHz, CDCl 3 )δ10.17 (s, 1H), 7.65 (d, J = 8.6Hz, 1H), 6.63 (d, J = 8.6Hz,

[0475] 1H), 6.57 (dd, J=10.0, 0.8Hz, 1H), 5.66 (d, J=10.0Hz, 1H), 4.03 (q, J=7.0Hz, 2H),

[0476] 1.45 (s, 6H), 1.43 (t, J=7.1Hz, 3H).

[0477] Example 4.2.2 Preparation of 5-ethoxy-2,2-dimethyl-2H-chromene-6-carboxylic acid (30)

[0478] Using Procedure J, compound 30 was prepared from compound 25 as a white solid in 55% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.46 (s, 1H), 7.53 (d, J=8.6Hz, 1H), 6.58-6.52 (m, 2H), 5.78 (d, J=10.0Hz, 1H), 3.87 (q, J=7.0Hz, 2H), 1.35 (s, 6H), 1.26 (t, J=7.0Hz, 3H).

[0479] Example 4.2.3. Preparation of 5-ethoxy-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (35)

[0480] Using Procedure C - Procedure I, compound 35 was prepared as a white solid in 30% yield from 9k prepared according to compound 30 and Example 2.7.3. mp 72-73°C. 1 H NMR (400 MHz, CDCl 3 ) δ10.04 (s, 1H), 7.96 (d, J = 8.7Hz, 1H), 7.55 (d, J = 8.5Hz, 1H), 6.84 (dd, J = 8.5, 1.8Hz, 1H), 6.7 2(d, J=8.7Hz, 1H), 6.57 (d, J=10.0Hz, 1H), 5.72 (d, J=10.0Hz, 1H), 4.32 (t, J=7.3Hz, 2H), 4.04 (q, J=7.1Hz, 2H), 3.05-2.95 (m, 2H), 2.52 (s, 3H), 2.36 (s, 3H), 2.17-2.06 (m, 2H), 1.87 (q, J=7 .1Hz, 2H), 1.84-1.77(m, 2H), 1.54-1.47(m, 5H), 1.46(s, 6H), 1.39-1.31(m, 1H).FAB-MS[M+H] + 503.

[0481] Example 4.3, Preparation of 2,2-diethyl-5-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-28, 36)

[0482] Example 4.3.1. Preparation of 2,2-diethyl-5-methoxy-2H-chromene-6-carbaldehyde (26)

[0483] Compound 26 was prepared as a colorless oil in 41% yield from 3-chloro-3-ethylpent-1-yne and compound 21 using Procedure H - Procedure III, Procedure I - Method I and Procedure A - Method A. 1 HNMR (400 MHz, CDCl 3 ) δ10.14 (s, 1H), 7.63 (d, J = 8.6Hz, 1H), 6.69 (d, J = 10.2Hz, 1H), 6.62 (d, J = 8.6Hz, 1 H), 5.53 (d, J=10.3Hz, 1H), 3.88 (s, 3H), 1.86-1.57 (m, 4H), 0.93 (t, J=7.5Hz, 6H).

[0484] Example 4.3.2. Preparation of 2,2-diethyl-5-methoxy-2H-chromene-6-carboxylic acid (31)

[0485] Using Procedure J, compound 31 was prepared from compound 26 as a white solid in 67% yield. 1 H NMR (400 MHz, CDCl 3 ) δ10.73 (s, 1H), 7.88 (d, J = 8.7Hz, 1H), 6.68 (dd, J = 8.7, 0.8Hz, 1H), 6.63 (dd, J = 10.2, 0. 8Hz, 1H), 5.59 (d, J=10.3Hz, 1H), 3.93 (s, 3H), 1.85-1.60 (m, 4H), 0.93 (t, J=7.5Hz, 6H).

[0486] Example 4.3.3. Preparation of 2,2-diethyl-5-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (36)

[0487] Using Procedure C - Procedure I, compound 36 was prepared as a white solid in 53% yield from 9k prepared according to compound 31 and Example 2.7.3. mp 66-67°C. 1 H NMR (400 MHz, DMSO-d 6 )δ10.21 (s, 1H), 8.14 (s, 1H), 7.58 (d, J = 8.7Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.19 (dd, J = 8.7, 1.7Hz, 1H), 6.69 (d, J = 10.3Hz,

[0488] 1H), 6.62 (dd, J=8.5, 0.7Hz, 1H), 5.71 (d, J=10.3Hz, 1H), 4.23 (t, J=7.1Hz, 2H), 3.74 (s, 3H), 2.94-2.80 (m, 2H), 2.4 0(s, 3H), 2.28(s, 3H), 2.21-2.01(m, 2H), 1.77-1.55(m, 8H), 1.29-1.18(m, 3H), 0.85(t, J=7.4Hz, 6H).FAB-MS[M+H] + 517.

[0489] Example 4.4, 5-fluoro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-

[0490] Preparation of chromene-6-carboxamide (chemical formula 1-29, 37)

[0491] Example 4.4.1. Preparation of 5-fluoro-2,2-dimethyl-2H-chromene-6-carbaldehyde (27)

[0492] Compound 27 was prepared as a colorless oil in 21% yield from 3-chloro-3-methylbut-1-yne and compound 22 using Procedure H - Procedure III and Procedure I - Method I. 1 H NMR (400 MHz, CDCl 3 )δ10.16(d, J=0.8Hz,

[0493] 1H), 7.63 (dd, J=8.6, 7.9Hz, 1H), 6.64 (dd, J=8.6, 0.9Hz, 1H), 6.57 (dd, J=10.1, 0.8Hz, 1H), 5.70 (d, J=10.1Hz, 1H), 1.47 (s, 6H).

[0494] Example 4.4.2. Preparation of 5-fluoro-2,2-dimethyl-2H-chromene-6-carboxylic acid (32)

[0495] Using Procedure J, compound 32 was prepared from compound 27 as a white solid in 27% yield. 1 H NMR (400 MHz, DMSO-d 6) δ7.57 (t, J=8.6Hz, 1H), 6.61 (d, J=8.6Hz, 1H), 6.52 (d, J=10.1Hz, 1H), 5.85 (d, J=10.0Hz, 1H), 1.37 (s, 6H).

[0496] Example 4.4.3. Preparation of 5-fluoro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (37)

[0497] Using Procedure C - Procedure I, compound 37 was prepared as a white solid in 40% yield from 9k prepared according to compound 32 and Example 2.7.3. mp 69-70°C. 1 H NMR (400 MHz, DMSO-d 6 ) δ10.32 (s, 1H), 8.11 (s, 1H), 7.59 (d, J = 8.8Hz, 1H), 7.43 (t, J = 8.4Hz, 1H), 7.18 ( dd, J=8.7, 1.6Hz, 1H), 6.71 (d, J=8.5Hz, 1H), 6.58 (d, J=10.0Hz, 1H), 5.92 (d, J=1 0.0Hz, 1H), 4.23 (t, J=7.1Hz, 2H), 3.03-2.84 (m, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2 .26-2.02(m, 2H), 1.79-1.65(m, 4H), 1.40(s, 6H), 1.30-1.20(m, 3H).FAB-MS[M+H] + 477.

[0498] Example 4.5, Preparation of 5-chloro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (Chemical Formula 1-30, 38)

[0499] Example 4.5.1. Preparation of 5-chloro-2,2-dimethyl-2H-chromene-6-carbonitrile (28)

[0500] Compound 28 was prepared as a white oil in 50% yield from 3-chloro-3-methylbut-1-yne and compound 23 using Procedure H - Procedure III and Procedure I - Method I. 1 H NMR (400 MHz, CDCl 3 ) δ7.38 (d, J=8.5Hz, 1H), 6.72 (d, J=8.5Hz, 1H), 6.66 (d, J=10.2Hz, 1H), 5.80 (d, J=10.2Hz, 1H), 1.45 (s, 6H).

[0501] Example 4.5.2. Preparation of 5-chloro-2,2-dimethyl-2H-chromene-6-carboxylic acid (33)

[0502] Compound 33 was prepared as a white solid in 87% yield from compound 28 using Procedure K. Procedure K, white solid, yield 87%. 1 H NMR (400 MHz, DMSO-d 6 ) δ13.03 (br s, 1H), 7.55 (d, J = 8.5Hz, 1H), 6.76 (d, J = 8.6Hz, 1H), 6.70 (d, J = 10.2Hz, 1H), 5.95 (d, J = 10.1Hz, 1H), 1.37 (s, 6H).

[0503] Example 4.5.3. Preparation of 5-chloro-2,2-dimethyl-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-2H-chromene-6-carboxamide (38)

[0504] Using Procedure C - Procedure I, compound 38 was prepared as a white solid in 35% yield from 9k prepared according to compound 33 and Example 2.7.3. mp 146-147°C. 1 H NMR (400 MHz, DMSO-d 6)δ 10.50 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.7, 1.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 10.1 Hz, 1H), 5.99 (d, J = 10.1 Hz, 1H), 4.21 (t, J = 7.2 Hz, 2H), 2.70 - 2.62 (m, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.74 - 1.62 (m, 6H), 1.39 (s, 6H), 1.17 - 1.10 (m, 3H). FAB-MS [M+H] + 493。

[0505] Example 5. Preparation of 4-methylaminobenzamide derivatives

[0506] The preparation method of 4-methylaminobenzamide derivatives is shown in the following Reaction Formula 4. At this time, (a) BnBr, K 2 CO 3 , DMF, room temperature, 18 h; (b) RCl, Et 3 N, MC, room temperature, 3 h; (c) H 2 , Pd / C, MeOH, room temperature, 3 h; (d) BzCl, NaOH, THF, H 2 O, room temperature, 2 h; (e) 9k, EDC·HCl, HOBt, Et 3 N, MC, room temperature, 15 h.

[0507] [Reaction Formula 4]

[0508]

[0509] Example 5.1. Preparation of N-methyl-N-(4-((3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)carbamoyl)phenyl)benzamide (Chemical Formula 1-31, 42a)

[0510] Example 5.1.1. Preparation of 4-(N-methylbenzamido)benzoic acid (4-(N-methylbenzamido)benzoic acid) (41a)

[0511] Using Procedure C - Method II, a white solid compound 41a was prepared from compound 39 and benzoyl chloride with a yield of 36%. 1 H NMR (400 MHz, CDCl 3)δ7.94 (d, J=8.6Hz, 2H), 7.32-7.25 (m, 3H), 7.18 (t, J=7.5Hz, 2H), 7.10 (d, J=8.6Hz, 2H), 3.53 (s, 3H).

[0512] Example 5.1.2. Preparation of N-methyl-N-(4-((3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)carbamoyl)phenyl)benzamide (42a)

[0513] Using Procedure C - Procedure I, compound 42a was prepared as a white solid in 33% yield from 9k prepared according to compound 41a and Example 2.7.3. mp 201-202°C. 1 H NMR (400 MHz, CDCl 3 )δ8.17-8.08(m, 2H), 7.79-7.73(m, 2H), 7.53(d, J=8.4Hz, 1H), 7.32-7.24( m, 3H), 7.21-7.16 (m, 2H), 7.12 (d, J=8.5Hz, 2H), 6.92 (dd, J=8.6, 1.7Hz, 1H) , 4.27(t, J=7.5Hz, 2H), 3.51(s, 3H), 2.90-2.76(m, 2H), 2.51(s, 3H), 2.26(s , 3H), 1.92-1.77(m, 4H), 1.76-1.69(m, 2H), 1.38-1.26(m, 3H).FAB-MS[M+H] + 510.

[0514] Example 5.2, Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)benzamide (Chemical Formula 1-32, 42b)

[0515] Example 5.2.1. Preparation of Benzyl 4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)benzoate (40b)

[0516] Using Procedure H-Method I, compound 39 and benzyl bromide were acylated with chloroacetyl chloride and then reacted in MC in the presence of Et 3 In the presence of N, 1-methylpiperazine was used to replace the residue, thereby preparing compound 40b as a white solid with a yield of 62%. 1 HNMR (400 MHz, CDCl 3 )δ8.11 (d, J=8.4Hz, 2H), 7.48-7.33 (m, 5H), 7.28 (d, J=8.6Hz, 2H), 5.37 (s, 2H), 3.28 (s, 3H), 2.96 (s, 2H), 2.70-2.37 (m, 8H), 2.32 (s, 3H).

[0517] Example 5.2.2 Preparation of 4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)benzoic acid (41b)

[0518] Using Procedure B, compound 41b was prepared from compound 40b as a light yellow solid in 97% yield. 1 HNMR (400MHz, MeOD) δ7.99 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 3.26 (s, 3H), 3.03 (s, 2H), 2.96-2.79 (m, 4H), 2.74-2.43 (m, 7H).

[0519] Example 5.2.3. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)benzamide (42b)

[0520] Using Procedure C - Method III, compound 42b was prepared as a white solid in 18% yield from 9k prepared according to compound 41b and Example 2.7.3. mp 52-53°C. 1 H NMR (400 MHz, DMSO-d 6) δ10.36 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 8.3Hz, 2H), 7.61 (d, J = 9.0Hz, 1H), 7.47 (d, J = 8.3Hz, 2H), 7.34 (dd, J = 8.7, 1.6Hz,

[0521] 1H), 4.23 (t, J=7.3Hz, 2H), 3.21 (s, 3H), 2.98 (s, 2H), 2.69-2.63 (m, 2H), 2.41 (s, 3H), 2.38-2. 10(m, 8H), 2.06(s, 3H), 1.74-1.66(m, 4H), 1.66-1.62(m, 2H), 1.17-1.12(m, 3H).FAB-MS[M+H] + 546.

[0522] Example 6. Preparation of 2,4-disubstituted benzamide amine derivatives

[0523] The preparation method of 2,4-disubstituted benzamide amine derivatives is shown in the following reaction formula 5. In this case, (a) Boc 2 O, DMAP, t-BuOH, MC, room temperature, 20 hours; (b) 1-methylpiperidine, room temperature, 12 hours; (c) TFA, MC, room temperature, 3 hours; (d) (i) SOCl 2 , MC, DMF, room temperature, 2 hours; (ii) 9k, Et 3 N, MC, room temperature, 1 hour; (e) H 2 , 10% Pd / C, methanol, room temperature, 3 hours; (f) tetrahydro-4H-pyran-4-one, NaBH(OAc) 3 , TFA, MC, room temperature, 18 hours.

[0524] [Reaction 5]

[0525]

[0526] Example 6.1. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (Chemical Formula 1-33, 46)

[0527] Example 6.1.1. Preparation of tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitrobenzoate (44)

[0528] Compound 43 (1.0 equivalent) was dissolved in a mixture of t-BuOH (2 mL) and MC (2 mL). Then (Boc) was added to the mixture. 2 O (2.0 equiv.) and 4-(N,N-dimethylamino)pyridine (0.3 equiv.). The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated to dryness, the residue was diluted with acetic acid, and washed with 1 M HCl and water. The organic layer was concentrated to anhydrous Na 2 SO 4 The mixture was dried and evaporated to dryness. 1-Methylpiperazine (2 mL) was added to the residue. The mixture was stirred at room temperature for 12 hours. Afterwards, water (20 mL) was added to the solution and stirred for 12 hours at room temperature. The solid was filtered, washed with water and dried at 40°C to obtain a yellow solid, which was then deprotected in MC (2 mL) with TFA (2 mL) to obtain compound 44 as a yellow solid with a yield of 68% (TFA salt). 1 H NMR (400MHz, MeOD) δ7.82 (d, J=8.8Hz, 1H), 7.28 (d, J=2.5Hz, 1H), 7.18 (dd, J=8.8, 2.6Hz, 1H), 3.69-3.09 (m, 8H), 2.94 (s, 3H).

[0529] Example 6.1.2. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(4-methylpiperazin-1-yl)-2-nitrobenzamide (45)

[0530] Using Procedure C - Method III, compound 45 was prepared as a yellow solid in 52% yield from 9k prepared as described for compound 44 and Example 2.7.3. 1 H NMR (400 MHz, DMSO-d 6)δ10.36 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 8.3Hz, 2H), 7.61 (d, J = 9.0Hz, 1H) , 7.47 (d, J=8.3Hz, 2H), 7.34 (dd, J=8.7, 1.6Hz, 1H), 4.23 (t, J=7.3Hz, 2H) , 3.21(s, 3H), 2.98(s, 2H), 2.69-2.63(m, 2H), 2.41(s, 3H), 2.38-2.10(m, 8H), 2.06(s, 3H), 1.74-1.66(m, 4H), 1.66-1.62(m, 2H), 1.17-1.12(m, 3H).

[0531] Example 6.1.3. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(4-methylpiperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide (46)

[0532] Compound 46 was prepared from compound 45 as a white solid in 34% yield using Procedure B and Procedure E - Method II. mp 123-124°C. 1 H NMR (400 MHz, CDCl 3 )δ7.93 (d, J=7.4Hz, 1H), 7.90 (d, J=1.7Hz, 1H), 7.84 (s,

[0533] 1H), 7.53 (d, J=8.5Hz, 1H), 7.43 (d, J=8.9Hz, 1H), 6.89 (dd, J=8.6, 1.7Hz, 1H), 6.21 (dd, J=8.9, 2.3Hz, 1H), 6.10 ( d, J=2.3Hz, 1H), 4.29 (t, J=7.4Hz, 2H), 3.99 (dt, J=11.9, 4.0Hz, 2H), 3.64-3.49 (m, 3H), 3.29 (t, J=5.1Hz, 4H), 2.9 0-2.82 (m, 2H), 2.55 (t, J=5.1Hz, 4H), 2.52 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H), 2.08-2.00 (m, 2H), 1.98-1.89 (m, 2H ), 1.84(q, J=7.0Hz, 2H), 1.80-1.72(m, 2H), 1.70-1.56(m, 2H), 1.46-1.33(m, 2H), 1.32-1.25(m, 1H).FAB-MS[M+H] + 574.

[0534] Example 7. Preparation of pyridylbenzamide derivatives

[0535] The preparation method of pyridylbenzamide derivatives is shown in the following reaction formula 6. At this time, (a) [Method A] occasionally bromopyridine,

[0536] Pd(PPh 3 ) 4 , K 2 CO 3 , EtOH, H 2 O, 90°C, 18 hours, [Method B] occasionally pyridine boronic acid, Pd(PPh 3 ) 4 ,K 2 CO 3 , n-BuOH, H 2 O, 110℃, 18 hours; (b) 9k, EDC·HCl, HOBt, Et 3 N, MC, room temperature, 15 hours.

[0537] [Reaction 6]

[0538]

[0539] Example 7.1. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-4-yl)benzamide (Chemical Formula 1-34, 50a)

[0540] Example 7.1.1. Preparation of 3-(pyridin-4-yl)benzoic acid (49a)

[0541] Compound 49a was prepared in 73% yield as a white solid by treatment of EtOH from 3-carboxyphenylboronic acid and 4-bromopyridine using Procedure L. 1 H NMR (401 MHz, DMSO-d 6 )δ8.63 (dd, J=4.6, 1.6Hz, 2H), 8.25 (t, J=1.8Hz, 1H), 8.05-7.97 (m, 2H), 7.72 (dd, J=4.6, 1.7Hz, 2H), 7.63 (t, J=7.8Hz, 1H).

[0542] Example 7.1.2. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-4-yl)benzamide (50a)

[0543] Using Procedure C - Method I, compound 50a was prepared as a white solid in 41% yield from compound 49a and 9k prepared according to Example 2.7.3. mp 57-58°C. 1 H NMR (400 MHz, CDCl 3 )δ8.72-8.58 (m, 2H), 8.49 (m, 2H), 8.49 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.96 (d, J=7.8Hz, 1H), 7 .80 (d, J=7.9Hz, 1H), 7.61 (t, J=7.7Hz, 1H), 7.57 (d, J=8.6Hz, 1H), 7.52 (d, J=6.2Hz, 2H), 7.04 (dd , J=8.6, 1.7Hz, 1H), 4.29 (t, J=7.5Hz, 2H), 2.89-2.81 (m, 2H), 2.53 (s, 3H), 2.26 (s, 3H), 1.98-1.8 9(m, 2H), 1.88-1.81(m, 2H), 1.78-1.70(m, 2H), 1.44-1.33(m, 2H), 1.32-1.27(m, 1H).FAB-MS[M+H] + 454.

[0544] Example 7.2, Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-3-yl)benzamide (Chemical Formula 1-35, 50b)

[0545] Example 7.2.1. Preparation of 3-(pyridin-3-yl)benzoic acid (49b)

[0546] Using procedure L, the 3-bromophenylboronic acid and 3-bromopyridine were prepared in HO. 2 Compound 49b was prepared as a white solid in 67% yield by treating EtOH with DMF. 1 H NMR (400 MHz, DMSO-d 6 )δ8.88 (d, J=2.6Hz, 1H), 8.57 (dd, J=4.7, 1.6Hz, 1H), 8.17 (t, J=1.9Hz, 1H), 8.09 (dt, J =8.0, 2.0Hz, 1H), 7.99-7.89 (m, 2H), 7.60 (t, J=7.8Hz, 1H), 7.48 (dd, J=7.9, 4.7Hz, 1H).

[0547] Example 7.2.2. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-3-yl)benzamide (50b)

[0548] Using Procedure C - Method I, compound 50b was prepared as a white solid in 60% yield from 9k prepared according to compound 49b and Example 2.7.3. mp 56-57°C. 1 H NMR (400 MHz, CDCl 3)δ8.83 (s, 1H), 8.59 (d, J = 4.9Hz, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.11 (t, J = 1.8Hz, 1H ), 7.94-7.84(m, 2H), 7.74-7.70(m, 1H), 7.61-7.50(m, 2H), 7.35(dd, J=7.9, 4.8Hz, 1 H), 7.02 (dd, J=8.6, 1.7Hz, 1H), 4.28 (t, J=7.5Hz, 2H), 2.86-2.77 (m, 2H), 2.52 (s, 3H ), 2.22(s, 3H), 1.95-1.79(m, 4H), 1.76-1.68(m, 2H), 1.40-1.25(m, 3H).FAB-MS[M+H] + 454.

[0549] Example 7.3, Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-4-yl)benzamide (Chemical Formula 1-36, 50c)

[0550] Example 7.3.1. Preparation of 4-(pyridin-4-yl)benzoic acid (49c)

[0551] Using procedure L, the 4-carboxyphenylboronic acid and 4-bromopyridine were prepared in HO. 2 Compound 49c was prepared as a white solid in 83% yield by treating EtOH with DMF. 1 H NMR (400 MHz, DMSO-d 6 ) δ8.64 (dd, J=4.6, 1.7Hz, 2H), 8.03 (d, J=8.4Hz, 2H), 7.90 (d, J=8.4Hz, 2H), 7.73 (dd, J=4.3, 1.6Hz, 2H).

[0552] Example 7.3.2. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-4-yl)benzamide (50c)

[0553] Using Procedure C - Method I, compound 50c was prepared as a white solid in 41% yield from compound 49c and 9k prepared according to Example 2.7.3. mp 156-157°C. 1 H NMR (400 MHz, CDCl 3 )δ8.70 (d, J=5.5Hz, 2H), 8.23-8.20 (m, 2H), 8.03 (d, J=8.4Hz, 2H), 7.75 (d, J=8.5Hz, 2 H), 7.58 (d, J=8.5Hz, 1H), 7.53 (dd, J=4.7, 1.5Hz, 2H), 6.98 (dd, J=8.5, 1.7Hz, 1H), 4.3 1(t, J=7.5Hz, 2H), 2.89-2.80(m, 2H), 2.54(s, 3H), 2.26(s, 3H), 1.97-1.89(m, 2H), 1. 88-1.82(m, 2H), 1.78-1.72(m, 2H), 1.43-1.33(m, 2H), 1.31-1.26(m, 1H).FAB-MS[M+H] + 454.

[0554] Example 7.4, Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-3-yl)benzamide (Chemical Formula 1-37, 50d)

[0555] Example 7.4.1. Preparation of 4-(pyridin-3-yl)benzoic acid (49d)

[0556] Using procedure L, the reaction mixture was prepared from 4-carboxyphenylboronic acid and 3-bromopyridine in solvent HO. 2 Compound 49d was prepared as a white solid in 44% yield by treatment of EtOH in 0. 1 H NMR (400 MHz, DMSO-d 6 )δ8.92 (d, J=2.4Hz, 1H), 8.58 (dd, J=4.8, 1.6Hz, 1H), 8.1 (dt, J=8.0, 2.0Hz, 1 H), 8.01 (d, J=8.3Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.49 (dd, J=8.0, 4.8Hz, 1H).

[0557] Example 7.4.2. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-3-yl)benzamide (50d)

[0558] Compound 50d was prepared as a white solid in 35% yield from compound 49d and 9k prepared according to Example 2.7.3 using Procedure C - Method I. mp 71-72°C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 1H), 8.64 (d, J = 4.8Hz, 1H), 8.28 (s, 1H), 8.21 (d, J = 1.7Hz, 1H), 8.02 (d, J = 8.1Hz, 2H), 7. 91 (d, J=8.0Hz, 1H), 7.70 (d, J=8.1Hz, 2H), 7.58 (d, J=8.5Hz, 1H), 7.40 (dd, J=7.9, 4.8Hz, 1H), 7.01 ( dd, J=8.6, 1.8Hz, 1H), 4.31 (t, J=7.4Hz, 2H), 2.97-2.85 (m, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 2.03-1. 94(m, 2H), 1.91-1.84(m, 2H), 1.78-1.73(m, 2H), 1.48-1.36(m, 2H), 1.34-1.28(m, 1H).FAB-MS[M+H] + 454.

[0559] Example 7.5, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-4-yl)benzamide (Chemical Formula 1-38, 50e)

[0560] Example 7.5.1. Preparation of 2-methoxy-3-(pyridin-4-yl)benzoic acid (49e)

[0561] Using procedure L, the precipitate was prepared from 3-bromo-2-methoxybenzoic acid and 3-pyridylboronic acid in solvent HO. 2 Compound 49e was prepared as a white solid in 55% yield by treating BuOH in 2% O. 1H NMR (400MHz, MeOD) δ8.68-8.49 (m, 2H), 7.82 (dd, J=7.8, 1.8Hz, 1H), 7.65 (d, J =5.1Hz, 2H), 7.57 (dd, J=7.7, 1.7Hz, 1H), 7.29 (t, J=7.7Hz, 1H), 3.53 (s, 3H).

[0562] Example 7.5.2, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-4-yl)benzamide (50e)

[0563] Using Procedure C - Method I, compound 50e was prepared as a white solid in 14% yield from compound 49e and 9k prepared according to Example 2.7.3. mp 147-148°C. 1 H NMR (400 MHz, CDCl 3 ) δ10.10 (s, 1H), 8.94-8.54 (m, 2H), 8.35 (d, J = 1.7Hz, 1H), 8.28 (dd, J = 7.9, 1.8Hz, 1H), 7.61-7.50 (m, 4H), 7.41 (t, J=7.7Hz, 1H), 6.90 (dd, J=8.6, 1.7Hz, 1H), 4.34 (t, J=7.3Hz, 2H), 3.56 (s, 3H), 3.03-2.86 (m, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 2.14-1.98 (m, 2H), 1.88 (q, J=7.0Hz, 2H), 1.85-1.77(m, 2H), 1.55-1.41(m, 2H), 1.38-1.29(m, 1H).FAB-MS[M+H] + 484.

[0564] Example 7.6, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-3-yl)benzamide (Chemical Formula 1-39, 50f)

[0565] Example 7.6.1. Preparation of 2-methoxy-3-(pyridin-3-yl)benzoic acid (49f)

[0566] Using procedure L, the precipitate was prepared from 3-bromo-2-methoxybenzoic acid and 3-pyridylboronic acid in solvent HO. 2 Compound 49f was prepared as a white solid in 36% yield by treating BtOH in 0. 1 H NMR (401MHz, MeOD) δ8.71 (d, J=2.3Hz, 1H), 8.53 (dd, J=4.9, 1.6Hz, 1H), 8.04 (dt, J=7.9, 1.9Hz, 1H), 7.82 (dd , J=7.8, 1.8Hz, 1H), 7.56 (dd, J=7.6, 1.8Hz, 1H), 7.52 (dd, J=7.9, 5.0Hz, 1H), 7.34-7.26 (m, 1H), 3.50 (s, 3H).

[0567] Example 7.6.2, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-3-(pyridin-3-yl)benzamide (50f)

[0568] Using Procedure C - Method I, compound 50f was prepared as a white solid in 56% yield from compound 49f and 9k prepared according to Example 2.7.3. mp 105-106°C. 1 H NMR (400 MHz, CDCl 3)δ10.13 (s, 1H), 9.01-8.77 (m, 1H), 8.77-8.55 (m, 1H), 8.35 (d, J = 1.7Hz, 1H), 8.26 (dd, J = 7.8, 1.8Hz, 1H), 7.95 (dt, J=7.9, 1.9Hz, 1H), 7.57 (d, J=8.5Hz, 1H), 7.53 (dd, J=7.6, 1.8Hz, 1H), 7.48-7.37 (m, 2H), 6.90 (dd , J=8.5, 1.7Hz, 1H), 4.34 (t, J=7.4Hz, 2H), 3.54 (s, 3H), 2.99-2.88 (m, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 2.09 -1.95(m, 2H), 1.88(q, J=7.0Hz, 2H), 1.84-1.77(m, 2H), 1.52-1.40(m, 2H), 1.38-1.27(m, 1H).FAB-MS[M+H] + 484.

[0569] Example 7.7, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-4-yl)benzamide (Chemical Formula 1-40, 50 g)

[0570] Example 7.7.1. Preparation of 2-methoxy-4-(pyridin-4-yl)benzoic acid (49 g)

[0571] Using procedure L, the precipitate was prepared from 4-bromo-2-methoxybenzoic acid and 4-pyridylboronic acid in solvent HO. 2 O to prepare compound 49g as a white solid with a yield of 74%. 1 H NMR (400 MHz, DMSO-d 6 ) δ8.63 (dd, J=4.5, 1.6Hz, 2H), 7.75 (dd, J=4.4, 1.7Hz, 2H), 7.69 (d, J=7.9Hz, 1H), 7.41 (d, J=1.6Hz, 1H), 7.36 (dd, J=7.9, 1.7Hz, 1H), 3.89 (s, 3H).

[0572] Example 7.7.2, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-4-yl)benzamide (50 g)

[0573] Using Procedure C - Method I, compound 50g was prepared as a white solid in 42% yield from 9k prepared according to compound 49g and Example 2.7.3. mp 138-139°C. 1 H NMR (400 MHz, CDCl 3 )δ10.01 (s, 1H), 8.71 (d, J = 4.9Hz, 2H), 8.41 (d, J = 8.1Hz, 1H), 8.36 (d, J = 1.7Hz, 1H), 7.55 (d, J = 8.5Hz, 1H), 7.53 (d, J=6.1Hz, 2H), 7.41 (dd, J=8.2, 1.6Hz, 1H), 7.25 (d, J=1.2Hz, 1H), 6.85 (dd, J =8.6, 1.7Hz, 1H), 4.33 (t, J = 7.4Hz, 2H), 4.18 (s, 3H), 2.90-2.84 (m, 2H), 2.53 (s, 3H), 2.26 (s, 3 H), 1.97-1.90 (m, 2H), 1.86 (q, J=6.7Hz, 2H), 1.82-1.75 (m, 2H), 1.43-1.32 (m, 3H).FAB-MS[M+H] + 484.

[0574] Example 7.8, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-3-yl)benzamide (Chemical Formula 1-41, 50h)

[0575] Example 7.8.1. Preparation of 2-methoxy-4-(pyridin-3-yl)benzoic acid (49h)

[0576] Using procedure L, the precipitate was prepared from 4-bromo-2-methoxybenzoic acid and 3-pyridylboronic acid in solvent HO. 2 Compound 49h was prepared as a white solid in 57% yield by treatment of EtOH in 0. 1H NMR (400 MHz, DMSO-d 6 )δ8.94 (d, J=2.3Hz, 1H), 8.58 (dd, J=4.8, 1.6Hz, 2H), 8.13 (dt, J=8.0, 2.0Hz, 1H), 7.71 (d, J=7.9Hz , 1H), 7.48 (dd, J=8.0, 4.8Hz, 1H), 7.38 (d, J=1.4Hz, 1H), 7.31 (dd, J=8.0, 1.6Hz, 1H), 3.89 (s, 3H).

[0577] Example 7.8.2, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-(pyridin-3-yl)benzamide (50h)

[0578] Using Procedure C - Method I, compound 50h was prepared as a white solid in 39% yield from compound 49h and 9k prepared according to Example 2.7.3. mp 149-150°C. 1 H NMR (400 MHz, CDCl 3 )δ10.02 (s, 1H), 8.96-8.78 (m, 1H), 8.73-8.60 (m, 1H), 8.40 (d, J = 8.1Hz, 1H), 8.36 (d, J = 1.6Hz, 1H), 7.92 (dt, J = 8 .0, 1.8Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.41 (dd, J=8.0, 4.8Hz, 1H), 7.36 (dd, J=8.1, 1.6Hz, 1H), 7.22 (d, J=1.7Hz, 1H), 6.85 (dd, J=8.6, 1.7Hz, 1H), 4.33 (t, J=7.4Hz, 2H), 4.17 (s, 3H), 2.98-2.89 (m, 2H), 2.53 (s, 3H), 2.31 (s, 3H) , 2.07-1.98(m, 2H), 1.87(q, J=6.9Hz, 2H), 1.83-1.75(m, 2H), 1.50-1.38(m, 2H), 1.35-1.27(m, 1H).FAB-MS[M+H] + 484.

[0579] Example 8. Preparation of phenoxy and benzyloxybenzamide derivatives

[0580] The preparation method of phenoxy and benzyloxy derivatives is shown in the following reaction formula 7. In this case, (a) phenol, K 2 CO 3 , DMF, 140°C, 6 hours; (b) R 2 Br, K 2 CO 3 , DMF, 40°C, 3 hours; (c) [Method A] NaOH, EtOH, water, 120°C, 3 hours,

[0581] [Method B] NaClO 2 、NaH 2 PO 4 , H 2 27% H in O 2 O 2 , acetonitrile, 0°C to room temperature, 2 hours; (d) 9k, EDC·HCl, HOBt, Et 3 N, MC, room temperature, 15 hours.

[0582] [Reaction 7]

[0583]

[0584] Example 8.1. Preparation of N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-phenoxybenzamide (Chemical Formula 1-42, 57a)

[0585] Using Procedure C - Method I, compound 57a was prepared as a white solid in 67% yield from 9k prepared according to compound 56a and Example 2.7.3. mp 136-137°C. 1 H NMR (400 MHz, CDCl 3 )δ8.20(d, J=1.8Hz, 1H), 7.89(s, 1H), 7.87(d, J=8.8Hz, 2H), 7.57(d, J=8.5Hz, 1H), 7.40(dd, J=8.6, 7.4Hz, 2H), 7.22-7.17(m, 1H), 7.09-7.04(m, 4H), 6.90(dd , J=8.6, 1.7Hz, 1H), 4.31 (t, J=7.5Hz, 2H), 2.87-2.76 (m, 2H), 2.54 (s, 3H), 2.2 3(s, 3H), 1.94-1.82(m, 4H), 1.79-1.72(m, 2H), 1.39-1.28(m, 3H).FAB-MS[M+H] + 469.

[0586] Example 8.2, Preparation of 4-(Benzyloxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-43, 57b)

[0587] Using Procedure C - Method I, compound 57b was prepared as a white solid in 73% yield from 9k prepared according to compound 56b and Example 2.7.3. mp 150-151 °C. 1 H NMR (400 MHz, CDCl 3 )δ8.16 (d, J=1.9Hz, 1H), 8.01 (s, 1H), 7.88 (d, J=8.8Hz, 2H), 7.56 (d, J=8.5Hz, 1H), 7. 46-7.32 (m, 5H), 7.06 (d, J=8.6Hz, 2H), 6.96 (dd, J=8.5, 1.7Hz, 1H), 5.14 (s, 2H), 4.31 ( t, J=7.1Hz, 2H), 3.09-3.00 (m, 2H), 2.53 (s, 3H), 2.41 (s, 3H), 2.24-2.21 (m, 2H), 1.89 ( q, J=7.0Hz, 2H), 1.84-1.78(m, 2H), 1.63-1.52(m, 2H), 1.38-1.31(m, 1H).FAB-MS[M+H] + 483.

[0588] Example 8.3, Preparation of 4-((4-fluorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-44, 57c)

[0589] Compound 57c was prepared as a white solid in 27% yield from compound 56c and 9k prepared according to Example 2.7.3 using Procedure C - Method I. mp 149-150°C. 1 H NMR (400 MHz, CDCl 3)δ8.19 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 8.6Hz, 2H), 7.56 (d, J = 8.5Hz, 1H), 7 .41 (dd, J=8.4, 5.3Hz, 2H), 7.12-7.02 (m, 4H), 6.90 (dd, J=8.5, 1.7Hz, 1H), 5.09(s, 2H), 4.31(t, J=7.5Hz, 2H), 2.90-2.80(m, 2H), 2.53(s, 3H), 2.24(s , 3H), 1.90-1.80(m, 4H), 1.77-1.70(m, 2H), 1.38-1.29(m, 3H).FAB-MS[M+H] + 501.

[0590] Example 8.4. Preparation of 4-((3-fluorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-45, 57d)

[0591] Compound 57d was prepared as a white solid in 38% yield from 9k prepared according to compound 56d and Example 2.7.3 using Procedure C - Method I. mp 144-145°C. 1 H NMR (400 MHz, CDCl 3 )δ8.19 (d, J=1.7Hz, 1H), 7.89 (s, 1H), 7.87 (d, J=8.7Hz, 2H), 7.56 (d, J=8.5Hz, 1H), 7.36 (dd d, J=7.9, 7.9, 5.7Hz, 1H), 7.20 (ddd, J=7.5, 1.1, 1.1Hz, 1H), 7.18-7.14 (m, 1H), 7.08-7.00 (m , 3H), 6.90 (dd, J=8.6, 1.8Hz, 1H), 5.13 (s, 2H), 4.31 (t, J=7.4Hz, 2H), 2.88-2.81 (m, 2H), 2.5 3(s, 3H), 2.24(s, 3H), 1.92-1.83(m, 4H), 1.76-1.73(m, 2H), 1.41-1.28(m, 3H).FAB-MS[M+H] + 501.

[0592] Example 8.5, Preparation of 4-((4-chlorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-46, 57e)

[0593] Compound 57e was prepared as a white solid in 24% yield from compound 56e and 9k prepared according to Example 2.7.3 using Procedure C - Method I. mp 148-149°C. 1 H NMR (400 MHz, CDCl 3 )δ8.18 (d, J=1.7Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=8.6Hz, 2H), 7.55 (d, J=8.5H z, 1H), 7.40-7.34 (m, 4H), 7.03 (d, J=8.7Hz, 2H), 6.91 (dd, J=8.5, 1.7Hz, 1H) , 5.09 (s, 2H), 4.30 (t, J=7.3Hz, 2H), 2.93-2.78 (m, 2H), 2.53 (s, 3H), 2.24 (s , 3H), 1.93-1.80(m, 4H), 1.79-1.71(m, 2H), 1.41-1.28(m, 3H).FAB-MS[M+H] + 517.

[0594] Example 8.6, Preparation of 4-((3-chlorobenzyl)oxy)-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-47, 57f)

[0595] Compound 57f was prepared as a white solid in 53% yield from compound 56f and 9k prepared according to Example 2.7.3 using Procedure C - Method I. mp 136-137 °C. 1 H NMR (400 MHz, CDCl 3 )δ8.19 (d, J=1.7Hz, 1H), 7.91 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.56 (d, J=8.5Hz, 1H ), 7.44 (t, J=2.1Hz, 1H), 7.34-7.29 (m, 3H), 7.05 (d, J=8.8Hz, 2H), 6.90 (dd, J=8.5 , 1.7Hz, 1H), 5.11 (s, 2H), 4.31 (t, J=7.4Hz, 2H), 2.88-2.78 (m, 2H), 2.53 (s, 3H), 2 .24(s, 3H), 1.92-1.84(m, 4H), 1.77-1.72(m, 2H), 1.40-1.27(m, 3H).FAB-MS[M+H] + 517.

[0596] Example 8.7, Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-phenoxybenzamide (Chemical Formula 1-48, 57 g)

[0597] Example 8.7.1. Preparation of 2-methoxy-4-phenoxybenzonitrile (53)

[0598] Compound 51 (1.0 equivalent), phenol (1.5 equivalent) and K 2 CO 3 The mixture of (2.0 equivalents) was heated at 140 ° C in DMF (4 mL) for 6 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purified by silica gel column chromatography (n-hexane (Hex): ethyl acetate (EA) = 10: 1), thereby preparing compound 53 as a white solid, with a yield of 95%. 1 H NMR (400 MHz, CDCl 3 )δ7.45 (d, J=8.6Hz, 1H), 7.40 (dd, J=8.5, 7.4Hz, 2H), 7.24-7.19 (m, 1H), 7.06 (dd, J=8.6, 1.2Hz, 2H), 6.56 (d, J=2.2Hz, 1H), 6.48 (dd, J=8.6, 2.2Hz, 1H), 3.85 (s, 3H).

[0599] Example 8.7.2, Preparation of 2-methoxy-4-phenoxybenzoic acid (56 g)

[0600] Using Procedure K, compound 56g was prepared from compound 53 as a white solid in 88% yield. 1 H NMR (400 MHz, CDCl 3 )δ10.49(br s, 1H), 8.10 (d, J=8.7Hz, 1H), 7.47-7.37 (m, 2H), 7.24-7.20 (m, 1H), 7.12-7 .03 (m, 2H), 6.65 (d, J=2.2Hz, 1H), 6.60 (dd, J=8.8, 2.2Hz, 1H), 4.00 (s, 3H).

[0601] Example 8.7.3. Preparation of 2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)-4-phenoxybenzamide (57 g)

[0602] Using Procedure C - Method I, compound 57g was prepared as a white solid in 57% yield from compound 56g and 9k prepared according to Example 2.7.3. mp 84-85°C. 1 H NMR (400 MHz, CDCl 3 ) δ9.91 (s, 1H), 8.34 (d, J = 1.6Hz, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.5Hz, 1H), 7.40 (dd, J = 8. 5, 7.4Hz, 2H), 7.24-7.17 (m, 1H), 7.09 (dd, J=8.6, 1.1Hz, 2H), 6.82 (dd, J=8.5, 1.7Hz, 1H), 6.70 (d , J=2.2Hz, 1H), 6.65 (dd, J=8.7, 2.2Hz, 1H), 4.31 (t, J=7.5Hz, 2H), 4.03 (s, 3H), 2.86-2.79 (m, 2H) , 2.53(s, 3H), 2.23(s, 3H), 1.91-1.82(m, 4H), 1.79-1.75(m, 2H), 1.40-1.27(m, 3H).FAB-MS[M+H] + 499.

[0603] Example 8.8, 4-(Benzyloxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)

[0604] Preparation of benzamide (chemical formula 1-49, 57h)

[0605] Example 8.8.1. Preparation of 4-(benzyloxy)-2-methoxybenzaldehyde (55h)

[0606] Compound 55h was prepared from compound 54 and benzyl bromide as a white solid in 85% yield using Procedure H - Method I. 1 H NMR (400 MHz, CDCl 3)δ10.28 (d, J=0.7Hz, 1H), 7.80 (d, J=8.6Hz, 1H), 7.44-7.32 (m, 5H), 6.61 (d dd, J=8.7, 2.3, 0.8Hz, 1H), 6.52 (d, J=2.2Hz, 1H), 5.12 (s, 2H), 3.87 (s, 3H).

[0607] Example 8.8.2, Preparation of 4-(benzyloxy)-2-methoxybenzoic acid (56h)

[0608] Compound 56h was prepared from compound 55h as a white solid in 70% yield using Procedure J. 1 H NMR (400 MHz, CDCl 3 ) δ10.50 (br s, 1H), 8.13 (d, J = 8.8Hz, 1H), 7.44-7.34 (m, 5H), 6.71 (dd, J = 8.8, 2.3Hz, 1H), 6.61 (d, J = 2.3Hz, 1H), 5.12 (s, 2H), 4.01 (s, 3H).

[0609] Example 8.8.3. Preparation of 4-(benzyloxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (57h)

[0610] Using Procedure C - Method I, compound 57h was prepared as a white solid in 66% yield from 9k prepared according to compound 56h and Example 2.7.3. mp 123-124°C. 1 H NMR (400 MHz, CDCl 3)δ9.92 (s, 1H), 8.35 (s, 1H), 8.26 (d, J = 8.7Hz, 1H), 7.53 (d, J = 8.5Hz, 1H), 7.46-7.33 (m, 5H), 6 .81 (dd, J=8.6, 1.7Hz, 1H), 6.75 (dd, J=8.8, 2.3Hz, 1H), 6.63 (d, J=2.2Hz, 1H), 5.13 (s, 2H), 4.3 2(t, J=7.4Hz, 2H), 4.04(s, 3H), 2.98-2.88(m, 2H), 2.53(s, 3H), 2.31(s, 3H), 2.05-1.95(m, 2H ), 1.87(q, J=7.1Hz, 2H), 1.83-1.76(m, 2H), 1.50-1.39(m, 2H), 1.36-1.26(m, 1H).FAB-MS[M+H] + 513.

[0611] Example 8.9, Preparation of 4-((3-fluorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-50, 57i)

[0612] Example 8.9.1. Preparation of 4-((3-fluorobenzyl)oxy)-2-methoxybenzaldehyde (55i)

[0613] Compound 55i was prepared from compound 54 and 3-fluorobenzyl bromide as a white solid in 82% yield using Procedure H - Method I. 1 H NMR (400 MHz, DMSO-D 6 )δ10.14 (d, J=0.7Hz, 1H), 7.63 (d, J=8.7Hz, 1H), 7.48-7.37 (m, 1H), 7.32-7.26 (m, 2H), 7.20-7 .11 (m, 1H), 6.77 (d, J=2.3Hz, 1H), 6.70 (ddd, J=8.7, 2.2, 0.8Hz, 1H), 5.22 (s, 2H), 3.86 (s, 3H).

[0614] Example 8.9.2. Preparation of 4-((3-fluorobenzyl)oxy)-2-methoxybenzoic acid (56i)

[0615] Using Procedure J, compound 56i was prepared from compound 55i as a white solid in 90% yield. 1 H NMR (400 MHz, CDCl 3 )δ10.46(br s, 1H), 8.14 (d, J = 8.8Hz, 1H), 7.37 (td, J = 8.0, 5.8Hz, 1H), 7.18 (d, J = 7.6Hz, 1H), 7.14 (dt, J = 9.5, 2.1Hz, 1H ), 7.04 (td, J=8.3, 2.3Hz, 1H), 6.69 (dd, J=8.8, 2.3Hz, 1H), 6.61 (d, J=2.3Hz, 1H), 5.12 (s, 2H), 4.03 (s, 3H).

[0616] Example 8.9.3. Preparation of 4-((3-fluorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (57i)

[0617] Using Procedure C - Method I, compound 57i was prepared as a white solid in 49% yield from compound 56i and 9k prepared according to Example 2.7.3. mp 145-146°C. 1 H NMR (400 MHz, CDCl 3)δ9.91 (s, 1H), 8.34 (d, J = 1.3Hz, 1H), 8.26 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.5Hz, 1H), 7.37 (td, J = 8.0, 5.8Hz, 1H), 7.20 (dt, J=7.6, 1.2Hz, 1H), 7.17 (dt, J=9.6, 2.2Hz, 1H), 7.04 (ddt, J=8.7, 7.9, 1.6Hz, 1H), 6.81 (dd, J=8.5, 1.7Hz, 1H), 6.72 (dd, J= 8.8, 2.3Hz, 1H), 6.64 (d, J=2.3Hz, 1H), 5.13 (s, 2H), 4.32 (t, J=7.3Hz, 2H), 4.06 (s, 3H), 3.02-2.88 (m, 2H), 2.53 (s, 3H), 2. 35(s, 3H), 2.14-1.99(m, 2H), 1.87(q, J=7.1Hz, 2H), 1.84-1.78(m, 2H), 1.56-1.45(m, 2H), 1.38-1.29(m, 1H).FAB-MS[M+H] + 531.

[0618] Example 8.10, Preparation of 4-((4-fluorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-51, 57j)

[0619] Example 8.10.1. Preparation of 4-((4-fluorobenzyl)oxy)-2-methoxybenzaldehyde (55j)

[0620] Compound 55j was prepared as a white solid in 75% yield from compound 54 and 4-fluorobenzyl bromide using Procedure H - Method I. 1 H NMR (400 MHz, CDCl 3 )δ10.28 (s, 1H), 7.80 (d, J=8.7Hz, 1H), 7.40 (dd, J=8.2, 5.3Hz, 2H), 7.08 (t, J=8.7H z, 2H), 6.60 (dd, J=8.7, 2.1Hz, 1H), 6.51 (d, J=2.2Hz, 1H), 5.07 (s, 2H), 3.88 (s, 3H).

[0621] Example 8.10.2. Preparation of 4-((4-fluorobenzyl)oxy)-2-methoxybenzoic acid (56j)

[0622] Using Procedure J, compound 56j was prepared from compound 55j as a white solid in 90% yield. 1 H NMR (400 MHz, CDCl 3 )δ10.46(br s, 1H), 8.14 (d, J=8.8Hz, 1H), 7.40 (dd, J=8.5, 5.4Hz, 2H), 7.09 (t, J=8.6Hz, 2H ), 6.70 (dd, J=8.8, 2.3Hz, 1H), 6.60 (d, J=2.3Hz, 1H), 5.08 (s, 2H), 4.02 (s, 3H).

[0623] Example 8.10.3. Preparation of 4-((4-fluorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (57j)

[0624] Using Procedure C - Method I, compound 57j was prepared as a white solid in 41% yield from 9k prepared according to compound 56j and Example 2.7.3. mp 126-127°C. 1 H NMR (400 MHz, CDCl 3)δ9.91 (s, 1H), 8.34 (d, J=1.0Hz, 1H), 8.26 (d, J=8.8Hz, 1H), 7.53 (dd, J=8.5, 0.7Hz, 1H), 7.42 (dd, J=8. 7, 5.3Hz, 2H), 7.09 (t, J=8.7Hz, 2H), 6.81 (dd, J=8.5, 1.7Hz, 1H), 6.73 (dd, J=8.8, 2.3Hz, 1H), 6.62 (d, J= 2.3Hz, 1H), 5.09 (s, 2H), 4.33 (t, J=7.2Hz, 2H), 4.05 (s, 3H), 3.10-2.92 (m, 2H), 2.53 (s, 3H), 2.39 (s, 3H ), 2.39(s, 3H), 2.21-2.08(m, 2H), 1.92-1.80(m, 4H), 1.61-1.50(m, 2H), 1.39-1.28(m, 1H).FAB-MS[M+H] + 531.

[0625] Example 8.11, Preparation of 4-((3-chlorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (Chemical Formula 1-52, 57k)

[0626] Example 8.11.1. Preparation of 4-((3-chlorobenzyl)oxy)-2-methoxybenzaldehyde (55k)

[0627] Compound 55k was prepared from compound 54 and 3-chlorobenzyl bromide as a white solid in 88% yield using Procedure H - Method I. 1 H NMR (400 MHz, CDCl 3 )δ10.29 (d, J=0.7Hz, 1H), 7.81 (d, J=8.6Hz, 1H), 7.46-7.41 (m, 1H), 7.34-7.27 (m, 3H), 6.59 (dd, J=8.7, 2.2Hz, 1H), 6.52 (d, J=2.2Hz, 1H), 5.09 (s, 2H), 3.89 (s, 3H).

[0628] Example 8.11.2. Preparation of 4-((3-chlorobenzyl)oxy)-2-methoxybenzoic acid (56k)

[0629] Compound 56k was prepared from compound 55k as a white solid in 94% yield using Procedure J. 1 H NMR (400 MHz, CDCl 3 )δ10.44(br s, 1H), 8.14 (d, J=8.8Hz, 1H), 7.44-7.41 (m, 1H), 7.35-7.27 (m, 3H), 6.69 (dd, J=8.8, 2.3Hz, 1H), 6.61 (d, J=2.3Hz, 1H), 5.09 (s, 2H), 4.03 (s, 3H).

[0630] Example 8.11.3. Preparation of 4-((3-chlorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (57k)

[0631] Compound 57k was prepared as a white solid in 62% yield from compound 56k and 9k prepared according to Example 2.7.3 using Procedure C - Method I. mp 152-153 °C. 1 H NMR (400 MHz, CDCl 3 )δ9.91 (s, 1H), 8.33 (d, J = 1.6Hz, 1H), 8.26 (d, J = 8.8Hz, 1H), 7.53 (dd, J = 8.5, 0.7Hz, 1H), 7.47-7. 44 (m, 1H), 7.34-7.30 (m, 3H), 6.81 (dd, J=8.6, 1.7Hz, 1H), 6.72 (dd, J=8.8, 2.3Hz, 1H), 6.64 (d, J= 2.3Hz, 1H), 5.10 (s, 2H), 4.33 (t, J=7.1Hz, 2H), 4.06 (s, 3H), 3.10-2.94 (m, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 2.26-2.09 (m, 2H), 1.91-1.81 (m, 4H), 1.63-1.50 (m, 2H), 1.38-1.29 (m, 1H).FAB-MS[M+H] + 547.

[0632] Example 8.12, Preparation of 4-((4-chlorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (1-53,571)

[0633] Example 8.12.1. Preparation of 4-((4-chlorobenzyl)oxy)-2-methoxybenzaldehyde (551)

[0634] Compound 551 was prepared as a white solid in 90% yield from compound 54 and 4-chlorobenzyl bromide using Procedure H - Method I. 1 H NMR (400 MHz, CDCl 3 ) δ10.28 (d, J=0.7Hz, 1H), 7.80 (d, J=8.6Hz, 1H), 7.41-7.32 (m, 4H), 6.58 (dd, J=8.7, 2.2Hz, 1H), 6.51 (d, J=2.2Hz, 1H), 5.08 (s, 2H), 3.88 (s, 3H).

[0635] Example 8.12.2 Preparation of 4-((4-chlorobenzyl)oxy)-2-methoxybenzoic acid (561)

[0636] Using Procedure J, compound 561 was prepared from compound 551 as a white solid in 90% yield. 1 H NMR (400 MHz, CDCl 3 )δ10.45 (br s, 1H), 8.13 (d, J=8.8Hz, 1H), 7.43-7.30 (m, 4H), 6.69 (dd, J=8.8, 2.3Hz, 1H), 6.59 (d, J=2.3Hz, 1H), 5.08 (s, 2H), 4.02 (s, 3H).

[0637] Example 8.12.3. Preparation of 4-((4-chlorobenzyl)oxy)-2-methoxy-N-(3-methyl-1-(2-(1-methylpiperidin-4-yl)ethyl)-1H-indazol-6-yl)benzamide (571)

[0638] Using Procedure C - Method I, compound 571 was prepared as a white solid in 55% yield from 9k prepared according to compound 56k and Example 2.7.3. mp 134-135°C. 1 H NMR (400 MHz, CDCl 3 )δ9.90 (s, 1H), 8.33 (d, J = 1.6Hz, 1H), 8.25 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.5, 1H), 7.41-7.3 4 (m, 4H), 6.81 (dd, J=8.4, 1.7Hz, 1H), 6.72 (dd, J=8.8, 2.3Hz, 1H), 6.62 (d, J=2.3Hz, 1H), 5 .09(s, 2H), 4.33(t, J=7.0Hz, 2H), 4.05(s, 3H), 3.21-2.96(m, 2H), 2.52(s, 3H), 2.44(s, 3H ), 2.34-2.11(m, 2H), 1.93-1.81(m, 4H), 1.71-1.52(m, 2H), 1.41-1.29(m, 1H).FAB-MS[M+H] + 547.

[0639] Experimental Example 1: Screening of cell survival rate in breast cancer cells

[0640] The HER2 positive breast cancer (HER2+BC) cell line JIMT-1 (cell seeding number: 1.0 (JIMT) × 10 4 cells / well (confluence ≤ 30%)) and triple-negative breast cancer (TNBC, triple-negative breast cancer) cell line MDA-MB-231 (cell seeding number: 1.0 (M231) × 10 4 cells / well (confluence ≤ 30%)).

[0641] The cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) or Eagle's minimum essential medium (MEM) containing 10% fetal bovine serum (FBS), streptomycin-penicillin (100 U / ml) and Fungizone (0.625 μg / ml) at 5% CO. 2 , and was carried out at 37°C.

[0642] The JIMT-1 cell line and the MDA-MB-231 cell line were treated with the indazole derivatives of the present invention (Chemical Formula 1-1 to Chemical Formula 1-53) at a concentration of 10 μM for 72 hours, and then the cell survival rate was measured using the MTS detection technique. At this time, the control group was treated with DMSO as an untreated group (0 μM) of the indazole derivatives of the present invention.

[0643] Specifically, the cells were attached to a 96-well plate for 24 hours, treated with the indazole derivative for 72 hours, and developed with MTS for 4 hours. Then, the absorbance was measured at 490 nm using a Spectramax Plus 384 microplate analyzer. The results are shown in FIG. Figures 1 to 4 At this time, the difference between the control group and the experimental group was verified by unpaired Students t-test (*p<0.01; DMSO control group vs indazole series).

[0644] The results showed that most of the indazole derivatives inhibited the cell viability in JIMT-1 cell line and MDA-MB-231 cell line compared with the control group ( Figures 1 to 4 ).

[0645] Experimental Example 2: Evaluation of anticancer effects in vitro

[0646] Experimental Example 2.1: Confirmation of cell viability by concentration

[0647] The HER2-positive breast cancer cell line BT474, which is sensitive to trastuzumab, was used (cell seeding number: 2.0 (JIMT) × 10 4 cells / well (confluence ≤ 30%), JIMT-1 resistant to trastuzumab (cell seeding number: 1.0 (JIMT) × 10 4 cells / well (confluence ≤ 30%), and triple-negative breast cancer cell line MDA-MB-231 (cell seeding number: 1.0 (M231) × 10 4 cells / well (confluence ≤ 30%)).

[0648] The BT474, JIMT-1 and MDA-MB-231 cell lines were treated with compound 18c (Chemical Formula 1-16) and compound 11k (Chemical Formula 1-7) at concentrations of 0 (DMSO), 0.1, 0.5, 1, 5, 10 and 20 μM for 72 hours, and then the cell viability was measured using the MTS assay described in Experimental Example 1. At this time, three cell viability experiments were performed independently, and the experimental results were verified by one-way analysis of variance (One-Way Anova) and Bonferroni post-hoc test (Bonferroni post-hoc test) (*p<0.01; DMSO control group vs. compound 18c or compound 11k).

[0649] The results showed that in all three breast cancer cell lines, cell viability was significantly reduced in a concentration-dependent manner. Specifically, the IC 50 The values ​​were 4.976μM (BT474), 4.602μM (JIMT-1), 6.838μM (MDA-MB-231) ( Figure 5 A), IC of compound 11k 50 The values ​​were 8.477 μM (BT474), 4.056 μM (JIMT-1), and 2.686 μM (MDA-MB-231), respectively, showing very low values ​​( Figure 6 A).

[0650] In addition, the JIMT-1 and MDA-MB-231 cell lines were treated with compound 11m (Chemical Formula 1-9), compound 11n (Chemical Formula 1-10), and compound 12k (Chemical Formula 1-13) at concentrations of 0 (DMSO), 0.1, 1, 5, 10, and 20 μM, respectively, for 72 hours, and then the cell viability was measured.

[0651] The results showed that the three compounds all reduced cell viability in a concentration-dependent manner. Specifically, the IC 50 The values ​​were 2.104 (JIMT-1) and 1.50 (MDA-MB-231), respectively. The IC 50 The values ​​were 3.276 μM (JIMT-1) and 3.65 μM (MDA-MB-231), respectively. The IC 50 The values ​​were 5.559 μM (JIMT-1) and 2.05 μM (MDA-MB-231), both showing very low values ​​( Figure 7 ).

[0652] Meanwhile, triple negative breast cancer cell lines MDA-MB-231 and BT549, and mouse breast cancer cell line 4T1 were treated with compound 38 (Chemical Formula 1-30) at concentrations of 0 (DMSO), 0.1, 0.5, 1, 2, 5, 10, and 20 μM for 72 hours, and then the cell survival rate was measured.

[0653] The results showed that, similar to compound 18c (Chemical Formula 1-16) and compound 11k (Chemical Formula 1-7), cell viability decreased in a concentration-dependent manner, with IC 50 The values ​​were also low, 3.67 μM (MDA-MB-231), 4.84 μM (BT549) and 1.21 μM (4T1) ( Figure 8 A to Figure 8 C).

[0654] Experimental Example 2.2: Confirmation of cell cycle arrest and apoptosis

[0655] DNA content was analyzed by flow cytometry, thus measuring the degree of death of cancer cells by the indazole derivatives of the present invention. Compound 18c (chemical formula 1-16) and compound 11k (chemical formula 1-7) were treated with 0 (DMSO), 5 and 10 μM concentrations for 72 hours, and then the above cells were harvested, and then fixed with 95% ethanol containing 0.5% Tween-20 (Tween) for 24 hours, and stained with propidium iodide (PI, 50 μg / mL) and ribonuclease (50 μg / mL) for 30 minutes. Afterwards, the degree of death of cancer cells was analyzed using flow cytometry.

[0656] Generally, the cell cycle is divided into G1 (cell growth phase) - S (cell replication phase) - G2 / M (cell division phase) according to the intracellular DNA content. When apoptosis is induced, DNA fragmentation occurs, and the DNA content in each cell is significantly less than that in the G1 phase. The result of such apoptosis is manifested as a sub-G1 region in the cell cycle. The sub-G1 ratio of the indazole derivatives of the present invention is expressed as a numerical value, such as Figure 5 B and Figure 6 As shown in B.

[0657] The results showed that the compound 18c (Chemical Formula 1-16) and the compound 11k (Chemical Formula 1-7) significantly induced cell apoptosis (sub-G1 population) in BT474 and JIMT-1 breast cancer cell lines and blocked the G2 / M phase of the cell cycle.

[0658] At the same time, the triple-negative breast cancer cell lines MDA-MB-231 and BT549 were treated with compound 38 (chemical formula 1-30), and then the type of cell death was confirmed by Annexin V / PI staining. The results showed that early and late apoptosis of cancer cells ( Figure 8 E).

[0659] Experimental Example 2.3: Confirmation of expression of proteins related to apoptosis

[0660] In order to investigate the apoptotic mechanism of compound 18c (Chemical Formula 1-16) and compound 11k (Chemical Formula 1-7), activation of apoptosis-related factors, caspase family members, was confirmed by Western blotting.

[0661] For western blotting, the control group (DMSO), compound 18c and compound 11k were treated at a concentration of 10 μM for 72 hours, and then BT-474 and JIMT-1 cell lines were lysed in a lysis buffer (lysis buffer; 30 mM NaCl, 0.5% Triton X-100, 50 mM Tris-HCl; pH 7.4) containing phosphatase and protease inhibitors, and the proteins present in the supernatant were harvested. At this time, the protein concentration was determined using a Bradford protein assay kit, and an average of 30 μg of protein was extracted from each experimental group and electrophoresed onto a nitrocellulose membrane after SDS-polyacrylamide gel (8-15%) electrophoresis. The membrane was reacted with primary antibodies [PRO PARP (1:1000), cleaved PARP (1:2000), cleaved caspase-3 (1:1000), cleaved caspase-7 (1:1000), β-actin (1:5000)] diluted with 5% bovine serum albumin (BSA) at 4°C for 24 hours, and then reacted with secondary antibody horseradish peroxidase (HRP)-conjugated rabbit IgG (1:3000) at room temperature for 2 hours. The signal intensity of the above proteins was confirmed using an enhanced chemiluminescence kit and X-ray film for color development.

[0662] like Figure 5 C and Figure 6As shown in Figure C, the amount of cleaved caspase-3 and cleaved caspase-7 in BT474 and JIMT-1 cell lines was confirmed by Western blotting, and the results confirmed that the amount of protein in the compound 18c and compound 11k treatment groups was significantly increased compared with the control group. For the DNA repair factor PARP (Poly (ADP-ribose) polymerase), which is a substrate of caspase-3, the increase in cleaved PARP (89kDa) indicates that it is cleaved under the activation of caspase-3 induced by the treatment of compound 18c and compound 11k. This shows that the apoptosis induced by the indazole derivatives of the present invention is related to caspase activation.

[0663] Experimental Example 2.4: Confirmation of cell morphology changes

[0664] MDA-MB-231 and BT549 cell lines were treated with compound 38 (Chemical Formula 1-30) at concentrations of 0 (DMSO), 5, and 10 μM for 72 hours, and then the changes in cell morphology were observed by phase contrast microscopy to evaluate drug-induced cytotoxicity. Photos were taken at 200x magnification using a phase contrast microscope. Figure 8 As shown in D.

[0665] When treated with compound 38 (chemical formula 1-30), both MDA-MB-231 and BT549 cell lines showed morphological changes, in which the cytoplasm shrank and most of the cells were in a floating state due to cytotoxicity ( Figure 8 D).

[0666] Experimental Example 2.5: Study on the expression of Hsp90 client proteins

[0667] Western blotting was used to study whether Hsp90 inhibitor compound 18c (chemical formula 1-16) and compound 11k (chemical formula 1-7) could downregulate the expression and activity (phosphorylation) of Hsp90 representative client proteins HER2 and HER3 in BT474 and JIMT-1 cell lines. In addition, the expression of Akt, MEK, ERK, Bcl-2, Cyclin D1 and Survivin, which are key factors for cell survival and are Hsp90 client proteins, was also studied. The method for performing the Western blotting method is the same as that of the above-mentioned Experimental Example 2.3.

[0668] The primary antibodies used for the western blotting method were [HER2 (1:5000), phospho-HER2 (Tyr1221 / 1222, 1:1000), HER3 (1:2000), phospho-HER3 (Tyr1289, 1:2000), Akt (1:2000), MEK (1:2000), ERK (1:2000), phospho-ERK (Thr202 / Tyr204, 1:2000), Bcl-2 (1:2000), cyclin D1 (1:3000), survivin (1:1000)] and were diluted in 5% bovine serum albumin (BSA) before use.

[0669] When compound 18c and compound 11k were treated at a concentration of 10 μM for 72 hours, it was confirmed that the expression of HER2 and HER3 in BT474 and JIMT-1 cell lines was reduced, and the expression of activated phosphorylated-HER2 and phosphorylated-HER3 was also significantly reduced. In addition, it was confirmed that both compounds inhibited the expression of cell proliferation factors Akt, MEK, ERK, Bcl-2, cyclin D1, and survivin ( Fig. 9 ).

[0670] Experimental Example 3: Evaluation of in vivo anticancer effect

[0671] Experimental Example 3.1. Tumor Growth Confirmation

[0672] The following experiments were performed in an in vivo environment using an animal model (xenograft mouse model) transplanted with JIMT-1 breast cancer cell line.

[0673] Specifically, 6-week-old mice (Balb / c nude mice) were purchased and raised in an environment with free access to food and water. After acclimation for more than 7 days, tumor cells were transplanted. JIMT-1 breast cancer cells were inoculated at 3×10 6 The cells were injected subcutaneously into the breast tissue at a density of 10 cells / mL. 3 The indazole derivatives of the present invention were intraperitoneally injected, and the growth of the tumor was measured. The experimental groups were treated with 30 mg / kg of compound 18c (Chemical Formula 1-16) or 20 mg / kg of compound 11k (Chemical Formula 1-7), and the tumor volume, tumor weight, body weight, etc. were measured every 3 to 4 days from the start to the end of the administration.

[0674] The results showed that compared with the control group, the tumor volume of the compound 18c and compound 11k treatment groups ( Fig.10 A and Fig.11 A) and weight ( Fig.10 B and Fig.11In particular, it was found by visual observation that the tumor size of the control group continued to increase, but in the indazole derivative-treated group of the present invention, the tumor size was reduced by more than half. At this time, it can be seen that the body weight was maintained, indicating that only tumor growth was specifically inhibited without causing serious toxic effects due to administration ( Fig.10 C and Fig.11 C).

[0675] Experimental Example 3.2: Toxicity Confirmation

[0676] In order to confirm whether the treatment with the indazole derivatives of the present invention affects normal organs, toxicity analysis was performed.

[0677] First, after the mouse model was sacrificed, the liver, kidney and lung tissues were fixed in 4% paraformaldehyde for 24 hours, washed in PBS buffer, and then embedded in paraffin. The tissue samples were sliced ​​and stained with H&E (hematoxylin and eosin).

[0678] In addition, blood was collected from the mouse models to confirm the levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) proteins, which can predict liver toxicity, and BUN (blood urea nitrogen) measurement, which is associated with kidney toxicity, was performed.

[0679] The results showed that the degree of functional abnormalities in liver, kidney and lung tissues was similar to that in the control group ( Fig.10 D. Fig.10 E. Fig.11 D and Fig.11 This indicates that the indazole derivatives of the present invention only affect tumors and do not affect normal cells.

[0680] Experimental Example 4: Confirmation of anticancer activity against other cancer cell lines

[0681] In addition to the breast cancer cell line, the leukemia cell line HL-60, the liver cancer cell line HepG2, the colorectal cancer cell line HCT116, the prostate cancer cell line Du145, the ovarian cancer cell line SKOV3, the non-small cell lung cancer cell line NCI-H1299 and the A549 cell line were treated with compound 11k (chemical formula 1-7) at concentrations of 0 (DMSO), 0.1, 0.5, 1, 2, 5, 10 and 20 μM, respectively, for 72 hours, and then the cell survival rate was measured using the MTS assay technique described in Experimental Example 1. At this time, the difference between the control group and the experimental group was verified by unpaired Students t-tests (*p<0.01; DMSO control vs. compound 11k).

[0682] The results show that the indazole derivatives of the present invention have excellent cell survival rate inhibition effects not only on breast cancer but also on other cancer cell lines ( Fig.12 ).

[0683] Experimental Example 5: Combination therapy with paclitaxel

[0684] Experimental Example 5.1: Confirmation of synergistic effect in vitro

[0685] The experiment used BT474, a HER2-positive breast cancer cell line sensitive to trastuzumab (cell inoculation number: 2.4 (BT474) × 10 4 cells / well (confluence ≥ 50%)) and trastuzumab-resistant JIMT-1 (cell seeding number: 1.0 (JIMT-1) × 10 4 cells / well (confluence ≥ 30%)).

[0686] Compound 11k (Chemical Formula 1-7) and representative anticancer drug paclitaxel were co-administered to the above-mentioned BT474 and JIMT-1 cell lines. At this time, compound 11k was treated at a concentration of 0 (DMSO) and 2.5 μM, and paclitaxel was treated at a concentration of 0 (DMSO), 0.01, 0.05, and 0.1 μM for 72 hours, and then the cell survival rate was measured. In addition, the combination index (CI) according to the concentration of the combined treatment of compound 11k and paclitaxel was used to calculate the synergistic effect during the combined treatment.

[0687] The results showed that when compound 11k was combined with paclitaxel, the cell survival rate was further reduced, and a very strong synergistic effect was confirmed in the JIMT-1 cell line ( Fig.13 ).

[0688] Experimental Example 5.2: Confirmation of in vivo synergistic effect

[0689] As described in Experimental Example 3, a xenograft mouse model transplanted with JIMT-1 breast cancer cell line was prepared, and the tumor volume, tumor weight, body weight, etc. were measured when compound 11k and paclitaxel were treated alone or in combination with compound 11k and paclitaxel.

[0690] The results showed that compared with the control group, the group treated with compound 11k or paclitaxel alone, the tumor volume ( Fig.14 A) and tumor weight ( Fig.14 In addition, it was confirmed that the tumor size was also significantly reduced ( Fig.14Specifically, the tumor volume of each group was measured 40 days after administration, and the results were as follows: the control group was 1246.91 mm 3 ; The compound 11k and paclitaxel alone treatment groups were 786.392 mm 3 and 813.356mm 3 ; The group treated with compound 11k and paclitaxel was 451.915 mm 3 , which showed a good synergistic effect. Similarly, the tumor weight measured after tumor resection was: 761.667 mg for the control group; 500 mg for the group treated with compound 11k alone; 488.333 mg for the group treated with paclitaxel alone; and 298.333 mg for the group treated with compound 11k and paclitaxel in combination. At this time, the body weights of the group treated with compound 11k alone, the group treated with paclitaxel alone, and the group treated with compound 11k and paclitaxel in combination remained unchanged ( Fig.14 D).

[0691] In addition, blood was collected from the mouse model to measure AST and ALT levels, and BUN was determined. The results showed that the compound 11k alone treatment group, the paclitaxel alone treatment group, and the compound 11k and paclitaxel combined treatment group all showed levels similar to those of the control group ( Fig.14 E).

[0692] This means that when the indazole derivatives of the present invention are administered in combination with paclitaxel, a representative anticancer drug, this can specifically inhibit tumor growth only and affect only tumors without affecting normal cells.

[0693] Experimental Example 6: Comparison with the Prior Art (KR 10-2304532)

[0694] The cell viability of the benzopyran derivatives of the prior invention (KR 10-2304532) and the indazole derivatives of the present invention was compared in BT474, JIMT-1 and MDA-MB-231 cell lines (Table 1). At this time, the benzopyran derivatives and indazole derivatives were treated at a concentration of 10 μM for 72 hours, respectively, and then the cell viability was measured.

[0695] [Table 1]

[0696]

[0697]

[0698] The results show that even though they have similar substituents, the indazole derivatives of the present invention exhibit a more excellent cell survival inhibitory effect ( Figures 15 to 17 ).

[0699] In summary, the embodiments are described through limited drawings, and a person skilled in the art can make various changes and modifications based on the description. For example, the described techniques are performed in a different order from the described method, and / or the described systems, structures, devices, circuits and other components are combined or combined in a different form from the described method, or replaced or substituted by other components or equivalents, and appropriate results can also be obtained.

[0700] Therefore, other embodiments, other examples and equivalents of the claims are all within the scope of the claims of the present invention.

Claims

1. An indazole derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof: [Chemical formula 1] Wherein in the chemical formula 1, A is B is R 1 and R 2 are the same as or different from each other and are hydrogen or C 1 -C 6 Chain alkyl; R 3 and R 4 are the same as or different from each other and are hydrogen or C 1 -C 6 A chain alkyl group in which one or more hydrogen atoms of the alkyl group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10 Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, replace; R 5 is a halogen group or C 1 -C 6 Alkoxy; R 6 and R 7 The same or different from each other, respectively C 1 -C 6 Chain alkyl; R 8 NR 10 C(O)R 11 , OR 12 , C 5 -C 10 heteroaryl or tetrahydropyranylamino; R 9 For hydrogen, C 1 -C 6 Alkoxy or C 5 -C 10 Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or replaced by C 1 -C 6 Chain alkyl substitution; R 10 and R 11 The same or different from each other, respectively C 1 -C 6 Chain alkyl or C 5 -C 10 aryl, wherein the alkyl group is unsubstituted or substituted with methylpiperazinyl; R 12 C 5 -C 10 Aryl or C 5 -C 10 benzyl, wherein the benzyl group is unsubstituted or substituted with a halogen group; It is a single bond or a double bond.

2. The indazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that The indazole derivative represented by [Chemical Formula 1] is any one or more selected from the group consisting of compounds represented by the following chemical formulas: [Chemical formula 1-1] [Chemical formula 1-2] [Chemical formula 1-3] [Chemical formula 1-4] [Chemical formula 1-5] [Chemical formula 1-6] [Chemical formula 1-7] [Chemical formula 1-8] [Chemical formula 1-9] [Chemical formula 1-10] [Chemical formula 1-11] [Chemical formula 1-12] [Chemical formula 1-13] [Chemical formula 1-14] [Chemical formula 1-15] [Chemical formula 1-16] [Chemical formula 1-17] [Chemical formula 1-18] [Chemical formula 1-19] [Chemical formula 1-20] [Chemical formula 1-21] [Chemical formula 1-22] [Chemical formula 1-23] [Chemical formula 1-24] [Chemical formula 1-25] [Chemical formula 1-26] [Chemical formula 1-27] [Chemical formula 1-28] [Chemical formula 1-29] [Chemical formula 1-30] [Chemical formula 1-31] [Chemical formula 1-32] [Chemical formula 1-33] [Chemical formula 1-34] [Chemical formula 1-35] [Chemical formula 1-36] [Chemical formula 1-37] [Chemical formula 1-38] [Chemical formula 1-39] [Chemical formula 1-40] [Chemical formula 1-41] [Chemical formula 1-42] [Chemical formula 1-43] [Chemical formula 1-44] [Chemical formula 1-45] [Chemical formula 1-46] [Chemical formula 1-47] [Chemical formula 1-48] [Chemical formula 1-49] [Chemical formula 1-50] [Chemical formula 1-51] [Chemical formula 1-52] And [Chemical Formula 1-53] 3. A pharmaceutical composition for preventing or treating cancer, comprising an indazole derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical formula 1] Wherein in the chemical formula 1, A is B is R 1 and R 2 are the same as or different from each other and are hydrogen or C 1 -C 6 Chain alkyl; R 3 and R 4 are the same as or different from each other and are hydrogen or C 1 -C 6 A chain alkyl group in which one or more hydrogen atoms of the alkyl group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10 Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, replace; R 5 is a halogen group or C 1 -C 6 Alkoxy; R 6 and R 7 The same or different from each other, respectively C 1 -C 6 Chain alkyl; R 8 NR 10 C(O)R 11 , OR 12 , C 5 -C 10 heteroaryl or tetrahydropyranylamino; R 9 For hydrogen, C 1 -C 6 Alkoxy or C 5 -C 10 Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or replaced by C 1 -C 6 Chain alkyl substitution; R 10 and R 11 The same or different from each other, respectively C 1 -C 6 Chain alkyl or C 5 -C 10 aryl, wherein the alkyl group is unsubstituted or substituted with methylpiperazinyl; R 12 C 5 -C 10 Aryl or C 5 -C 10 benzyl, wherein the benzyl group is unsubstituted or substituted with a halogen group; It is a single bond or a double bond.

4. The pharmaceutical composition for preventing or treating cancer according to claim 3, It is characterized in that The indazole derivatives induce cell apoptosis by inhibiting Hsp90.

5. The pharmaceutical composition for preventing or treating cancer according to claim 3, It is characterized in that The cancer is any one or more selected from the group consisting of skin cancer, breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain tumor, colon cancer, rectal cancer, colorectal cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, thymus cancer, urethral cancer, bronchial cancer and combinations thereof.

6. The pharmaceutical composition for preventing or treating cancer according to claim 3, It is characterized in that The pharmaceutical composition further comprises: The indazole derivative or a pharmaceutically acceptable salt thereof; and Any one or more additional components selected from the group consisting of pharmaceutically acceptable carriers, excipients, diluents, stabilizers and preservatives.

7. The pharmaceutical composition for preventing or treating cancer according to claim 3, It is characterized in that The pharmaceutical composition further comprises: The indazole derivative or a pharmaceutically acceptable salt thereof; and Anticancer agent.

8. The pharmaceutical composition for preventing or treating cancer according to claim 7, It is characterized in that The anticancer agent is any one or more selected from the group consisting of paclitaxel, docetaxel, doxorubicin, sorafenib, vemurafenib, irinotecan, cisplatin, radium 223 chloride (alpharadin), mitoxantrone, cyclophosphamide, vinblastine, carboplatin, dactinomycin-D, etoposide, teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), 5-fluorouracil, busulfan, chlorambucil, melphalan, nitrogen mustard, nitrosourea drugs and combinations thereof.

9. The pharmaceutical composition for preventing or treating cancer according to claim 3, It is characterized in that The pharmaceutical composition has any one or more dosage forms selected from the group consisting of powder, granules, tablets, capsules and injections.

10. A method for preparing an indazole derivative represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound represented by the following [Chemical Formula 2] or [Chemical Formula 3] with a compound represented by [Chemical Formula 4] or [Chemical Formula 5]: [Chemical formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] [Chemical formula 5] Wherein in the chemical formula 1, A is B is R 1 is hydrogen or C 1 -C 6 Chain alkyl; Wherein in the chemical formula 1 and the chemical formula 2, R 2 is hydrogen or C 1 -C 6 Chain alkyl; R 3 is hydrogen or C 1 -C 6 A chain alkyl group, wherein one or more hydrogen atoms of the alkyl group are not replaced or replaced by C 1 -C 6 Alkoxy, C 5 -C 10 Heterocycloalkyl or C 5 -C 10 Heteroaryl substituted, wherein the alkoxy group is unsubstituted or replaced by C 1 -C 6 Alkoxy is substituted, the heterocycloalkyl is unsubstituted or is replaced by C 1 -C 6 Chain alkyl, replace; Wherein in the chemical formula 1 and the chemical formula 4, R 5 is hydrogen or C 1 -C 6 Chain alkyl; R 6 and R 7 The same or different from each other, respectively C 1 -C 6 Chain alkyl; Wherein in the chemical formula 1 and the chemical formula 5, R 8 NR 10 C(O)R 11 , OR 12 , C 5 -C 10 heteroaryl or tetrahydropyranylamino; R 9 For hydrogen, C 1 -C 6 Alkoxy or C 5 -C 10 Heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or replaced by C 1 -C 6 Chain alkyl substitution; R 10 and R 11 The same or different from each other, respectively C 1 -C 6 Chain alkyl or C 5 -C 10 aryl, wherein the alkyl group is unsubstituted or substituted with methylpiperazinyl; R 12 C 5 -C 10 Aryl or C 5 -C 10 Benzyl, wherein the benzyl is unsubstituted or substituted with a halogen group.

11. The method for preparing the indazole derivative or a pharmaceutically acceptable salt thereof according to claim 10, It is characterized in that The compound represented by the above-mentioned [Chemical Formula 2] is any one or more selected from the group consisting of compounds represented by the following chemical formulas: [Chemical formula 2-1] [Chemical formula 2-2] [Chemical formula 2-3] [Chemical formula 2-4] [Chemical formula 2-5] [Chemical formula 2-6] [Chemical formula 2-7] [Chemical formula 2-8] [Chemical formula 2-9] [Chemical formula 2-10] And [Chemical Formula 2-11] 12. The method for preparing the indazole derivative or the pharmaceutically acceptable salt thereof according to claim 10, It is characterized in that The compound represented by the above-mentioned [Chemical Formula 3] is any one or more selected from the group consisting of compounds represented by the following chemical formulas: [Chemical formula 3-1] [Chemical formula 3-2] [Chemical formula 3-3] [Chemical formula 3-4] [Chemical formula 3-5] [Chemical formula 3-6] [Chemical formula 3-7] [Chemical formula 3-8] as well as [Chemical formula 3-9] 13. The method for preparing the indazole derivative or a pharmaceutically acceptable salt thereof according to claim 10, It is characterized in that The compound represented by the above-mentioned [Chemical Formula 4] is any one or more selected from the group consisting of compounds represented by the following chemical formulas: [Chemical formula 4-1] [Chemical formula 4-2] [Chemical formula 4-3] [Chemical formula 4-4] as well as [Chemical formula 4-5] 14. The method for preparing the indazole derivative or a pharmaceutically acceptable salt thereof according to claim 10, It is characterized in that The compound represented by the above-mentioned [Chemical Formula 5] is any one or more selected from the group consisting of compounds represented by the following chemical formulas: [Chemical Formula 5-1] [Chemical formula 5-2] [Chemical formula 5-3] [Chemical formula 5-4] [Chemical formula 5-5] [Chemical formula 5-6] [Chemical formula 5-7] [Chemical formula 5-8] [Chemical formula 5-9] [Chemical formula 5-10] [Chemical formula 5-11] [Chemical formula 5-12] [Chemical formula 5-13] [Chemical formula 5-14] [Chemical formula 5-15] [Chemical formula 5-16] [Chemical formula 5-17] [Chemical formula 5-18] [Chemical formula 5-19] [Chemical formula 5-20] [Chemical formula 5-21] as well as [Chemical formula 5-22] 15. The method for preparing the indazole derivative or the pharmaceutically acceptable salt thereof according to claim 10, It is characterized in that By adding the compound represented by the [Chemical Formula 2] or [Chemical Formula 3] to the compound represented by the [Chemical Formula 4] or [Chemical Formula 5], hydroxybenzotriazole (HOBt), triethylamine (Et 3 N) and EDC·HCl mixture to carry out the reaction.

Images