KR102179406B1 - Novel indazole derivatives, and use thereof - Google Patents

Abstract

The present invention provides a novel indazole derivative, or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for the prevention or treatment of DYRK1A (Dual-specificity tyrosine phosphorylation-regulated kinase 1a) or DYRK1B-related diseases comprising the same as an active ingredient.

Description

Novel indazole derivatives, and use thereof

The present invention provides a novel indazole derivative, or a pharmaceutically acceptable salt thereof; And it relates to a pharmaceutical composition for the prevention or treatment of DYRK1A (Dual-specificity tyrosine phosphorylation-regulated kinase 1a) or DYRK1B-related diseases comprising the same as an active ingredient.

DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) is a family of enzymes capable of phosphorylation using both aromatic tyrosine as well as aliphatic amino acid residues serine and threonine as substrates. In the case of self-phosphorylation, tyrosine phosphorylation-regulated kinase It functions as a phosphorylating enzyme, and in cells, it functions as a "proline-directed" phosphorylation enzyme for serine and threonine. There are a total of five known DYRK family members, DYRK1A, DYRK1B, DYRK2, DYRK3 and DYRK4, and classify DYRK1A and DYRK1B as Class I, and DYRK2, DYRK3 and DYRK4 as Class II.

Among them, DYRK1A is known to be associated with neurodegenerative diseases. The DYRK1A gene is located in the Down syndrome critical region (DSCR) of trisomy of chromosome 21, which is the cause of Down syndrome. It is known that overexpression of DYRK1A alone in mice causes neurological symptoms such as Down syndrome, and DYRK1A expression is known to increase in the brain of patients with Down syndrome and model mice with Down syndrome. In addition, beta-amyloid (Aβ) accumulation and abnormal phosphorylation of tau protein are known to be the cause of Alzheimer's disease, and it is also known that DYRK1A is involved in the relaying of Aβ expression to abnormal phosphorylation of tau protein in Alzheimer's disease patients. .

DYRK1B is associated with malignant tumors, for example, the expression of DYRK1B is elevated in pancreatic cancer tissues, and DYRK1B is overexpressed in rhabdomyosarcoma. In addition, DYRK1B is also known to be activated by a stress response pathway, function as a checkpoint kinase, and repair tumor cells by stopping damaged tumor cells in a dormant state.

On the other hand, these DYRK1A and DYRK1B expressions are very low in normal cells excluding skeletal muscle, and it was confirmed that they have little effect on normal tissues as a result of knockout experiments.Inhibitors of these kinases can prevent or treat diseases caused by these kinases. In addition, it can be expected that side effects can be minimized.

Republic of Korea Patent Publication No. 10-2010-0044859

In designing and developing a novel therapeutic agent for cancer diseases or neurodegenerative diseases, the present inventors have made intensive research efforts to discover small molecule compounds that can minimize side effects. As a result, the derivatives represented by the following formula 1 have low expression in normal cells. It was confirmed that the activity of DYRK1A and/or DYRK1B, a kinase that has little effect on normal tissues, can be inhibited or regulated, and the present invention was completed:

[Formula 1]

In one embodiment, the present invention provides a compound represented by Formula 1 below, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

R ₁ and R ₂ are each independently unsubstituted or C _6- substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl, hydroxy, C _1-4 alkoxy, amino, nitro and aryloxy. ₁₀ aryl or C _4-10 heteroaryl,

n is an integer of 0 or 1,

When n is 1, R ₃ is hydrogen, C _1-6 hydroxyalkyl, C _1-6 thiohydroxyalkyl, C _1-6 aminoalkyl, (C _1-4 alkoxycarbonyl)-(C _1-4 Alkyl), (aminocarbonyl)-(C _1-4 alkyl) or C _1-4 carboxyalkyl.

For example, the compound represented by Formula 1 may be a compound wherein R ₁ and R ₂ are each independently unsubstituted or substituted phenyl, pyridinyl, pyrimidinyl, thiophenyl, pyrazolyl, or indolyl.

For example, in the compound represented by Formula 1, R ₁ is phenyl or bromophenyl, R ₂ is phenyl, chlorophenyl, methylphenyl, phenyloxyphenyl, hydroxyphenyl, methoxyphenyl, pyridinyl or thiophenyl, and R ₃ may be a compound which is hydrogen, hydroxyethyl, methoxycarbonylmethyl or carboxymethyl.

Specifically, it may be the following compound.

1) 3-benzamido-N-phenyl-1H-indazole-5-carboxamide;

2) 3-benzamido-N-(m-tolyl)-1H-indazole-5-carboxamide;

3) 3-benzamido-N-(3-chlorophenyl)-1H-indazole-5-carboxamide;

4) 3-benzamido-N-(4-phenoxyphenyl)-1H-indazole-5-carboxamide;

5) 3-benzamido-N-benzyl-1H-indazole-5-carboxamide;

6) 3-benzamido-N-(3-chlorobenzyl)-1H-indazole-5-carboxamide;

7) 3-benzamido-N-(4-chlorobenzyl)-1H-indazole-5-carboxamide;

8) 3-benzamido-N-(2-chlorobenzyl)-1H-indazole-5-carboxamide;

9) 3-benzamido-N-(4-hydroxybenzyl)-1H-indazole-5-carboxamide;

10) 3-benzamido-N-(4-methoxybenzyl)-1H-indazole-5-carboxamide;

11) 3-Benzamido-N-(pyridin-3-ylmethyl)-1H-indazole-5-carboxamide;

12) 3-benzamido-N-(pyridin-4-ylmethyl)-1H-indazole-5-carboxamide;

13) 3-Benzamido-N-(3-hydroxyphenyl)-1H-indazole-5-carboxamide;

14) 3-benzamido-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide;

15) Methyl 3-(3-benzamido-1H-indazole-5-carboxamido)-3-phenylpropanoate;

16) N-benzyl-3-(4-bromobenzamido)-1H-indazole-5-carboxamide;

17) N-Benzyl-3-(3-bromobenzamido)-1H-indazole-5-carboxamide; or

18) N-Benzyl-3-(2-bromobenzamido)-1H-indazole-5-carboxamide

In another aspect, the present invention provides a first step of reacting a compound represented by the following formula (3) with 3-amino-1H-indazole-5-carboxylic acid represented by the following formula (2); And a second step of reacting the compound obtained from the first step with an amine containing a C _6-10 aryl group or a C _4-10 heteroaryl group represented by Formula 4 below. The manufacturing method is provided:

[Formula 2]

[Formula 3]

[Formula 4]

In the above formula,

X is halogen,

R ₁ and R ₂ are each independently an unsubstituted, or a halogen, C _1-4 alkyl, hydroxy, C _{1- 4} alkoxy, amino, nitro, and aryloxy-substituted C with one or more substituents selected from the group consisting of _{6- 10} aryl or C _4-10 heteroaryl,

n is an integer of 0 or 1,

When n is 1, R ₃ is hydrogen, C _1-6 hydroxyalkyl, C _1-6 thiohydroxyalkyl, C _1-6 aminoalkyl, (C _1-4 alkoxycarbonyl)-(C _1-4 Alkyl), (aminocarbonyl)-(C _1-4 alkyl) or C _1-4 carboxyalkyl.

Specifically, X may be chloro.

In the manufacturing method of the present invention, the first step may be a step of converting an amine group into an amido group (-NHC(O)R) by reacting with an amine group bound to a pyrazole by adding an acyl halide. have. Specifically, the reaction may be carried out by adding benzoyl chloride to a 3-amino-1H-indazole-5-carboxylic acid solution dissolved in an organic solvent. The reaction may be carried out by stirring for 30 minutes to 2 hours, but is not limited thereto.

In the manufacturing method of the present invention, the second step may be a step of converting a carboxyl group into an amino group (-C(O)NHR) by reacting a carboxyl group substituted with phenyl with an amine group by adding an amine. The reaction can be carried out by using a carbodiimide such as EDC-HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) as a catalyst. Specifically, it may be reacted by adding aniline and EDC-HCl to 3-benzamido-1H-indazole-5-carboxylic acid dissolved in an organic solvent. The reaction may be carried out by stirring at room temperature for 10 to 15 hours, but is not limited thereto.

Further, prior to the first step, a step of performing an intramolecular cyclization reaction by reacting 3-cyano-4-fluorobenzoic acid represented by the following Formula 5 with hydrazine may be further included.

[Formula 5]

Specifically, the step may be a step of forming a pyrazole ring in which an amine group is substituted by performing a cyclization reaction between a cyano derivative and hydrazine. In this case, as the organic solvent that can be used, methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), and the like may be freely selected and used, and the reaction is not limited as long as the reaction is performed.

In another aspect, the present invention comprises an amine containing a C _6-10 aryl group or a C _4-10 heteroaryl group represented by the following formula (4) and 3-cyano-4-fluorobenzoic acid represented by the following formula (5). A first step of reacting; A second step of performing an intramolecular cyclization reaction by reacting the compound obtained from the first step with hydrazine; And a third step of reacting the compound obtained from the second step with the compound represented by the following formula (3), and provides a method for preparing the compound represented by the formula (1):

[Formula 3]

[Formula 4]

[Formula 5]

In the above formula,

X, n, R ₁ , R ₂ and R ₃ are the same as defined above.

The first step may be a step of converting an amino group (-C(O)NHR) by reacting a carboxyl group with an amine group, and the second step is a cyclization reaction between a cyano derivative and hydrazine to form a pyrazole ring. It may be a step to do. The third step may be a step of converting into an amido group (-NHC(O)R) by reacting with an amine group by adding an acyl halide.

The reaction mechanism and reaction conditions for each step are the same as previously described.

Depending on the specific structure of the compound, it can be prepared using one of the two production methods described above.

The present invention includes a tautomer of the compound represented by Chemical Formula 1. The term "tautomer" may mean a structural isomer of an organic compound capable of interconverting. The conversion reaction of the tautomer may mainly be a result of proton relocation.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As the salt, an acid value formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" of the present invention is a concentration that is relatively non-toxic and harmless to patients, and side effects caused by this salt do not degrade the beneficial efficacy of the compound represented by formula (1). Means any organic or inorganic addition salt.

Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess acid aqueous solution, and precipitating this salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.

At this time, organic acids and inorganic acids can be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid can be used as organic acids. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , Not limited to these.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, the metal salt is particularly suitable for preparing sodium, potassium, or calcium salts, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be manufactured through a method.

The salt of the indazole derivative of the present invention is a pharmaceutically acceptable salt, and any salt of an indazole derivative exhibiting inhibitory activity against DYRK1A and/or DYRK1B equivalent to the indazole derivative compound can be used without limitation.

In another aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of DYRK1A or DYRK1B-related diseases comprising the compound represented by Formula 1, its tautomer, or a pharmaceutically acceptable salt thereof as an active ingredient. .

For example, since the compound of the present invention can inhibit DYRK1A, DYRK1B or both, it can be used for the prevention or treatment of diseases that overexpress them.

The term "prevention" of the present invention means any action that inhibits or delays the occurrence, spread, and recurrence of DYRK1A or DYRK1B related diseases by administration of the composition of the present invention, and "treatment" refers to the administration of the composition of the present invention It refers to any action in which the symptoms of a disease are improved or beneficially changed.

The composition of the present invention can prevent or treat DYRK1A or DYRK1B related diseases by inhibiting the activity of DYRK1A and/or DYRK1B by regulating cell death, proliferation and/or metastasis, and thus caused by abnormalities in DYRK1A and/or DYRK1B activity. It can be usefully used in the prevention or treatment of disease.

For example, non-limiting examples of DYRK1A-related diseases that can be prevented or treated with the composition of the present invention include autosomal dominant early onset coronary artery disease, juvenile-onset truncal obesity. , Severe hypertension, type II diabetes mellitus, Down syndrome, Alzheimer's disease and Autism spectrum disorder, non-limiting examples of DYRK1B related diseases Is a variety of cancer diseases such as ovarian cancer, osteosarcoma, pancreatic cancer, lung cancer, colon cancer, rhabdomyosarcoma, and cervical cancer. And metabolic syndrome.

Preferably, the pharmaceutical composition according to the present invention contains a compound represented by Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient in 0.1 to 75% by weight based on the total weight of the composition, more preferably May contain 1 to 50% by weight.

The composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and powders, granules, tablets, capsules, suspensions, emulsions, syrups, according to a conventional method for each purpose of use, It can be formulated and used in various forms such as oral formulations such as aerosols and injections of sterile injection solutions, and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. In addition, the composition of the present invention may further include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Is formulated by mixing. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Oral liquid preparations may include suspensions, liquid solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. I can.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspensions are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectables such as ethyl oleate.

Esters and the like can be used. The base for suppositories is Withepsol, Macrogol, and Tween61. Cacao butter, laurin paper, glycerogelatin, and the like may be used. Meanwhile, the injection may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents, and preservatives.

The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the health condition of the patient, The type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field. I can. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and body weight of the patient, and is generally 1 to 100 mg, preferably 5 to 60 mg per kg of body weight daily or every other day or 1 It can be administered in 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the dosage amount is not limited by any method.

The present invention also includes the step of administering a compound represented by Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof, for preventing or treating DYRK1A or DYRK1B-related diseases in an individual. Provides a way.

The term "individual" of the present invention refers to monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, rabbits, including humans who have or may develop DYRK1A or DYRK1B-related diseases. Or it means all animals including guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. In addition, since the pharmaceutical composition of the present invention can be sensitized to an existing anticancer chemotherapy or a target anticancer agent, it can exhibit a synergistic effect by administering it in parallel with an existing therapeutic agent.

The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration, but are not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to target cells. Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drop injections and the like. Injectables include aqueous solvents such as physiological saline solution and ring gel solution, non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., oleic acid ethyl, etc.), alcohols (e.g. ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be prepared by using, and stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, and for inhibiting the growth of microorganisms. Pharmaceutical carriers such as preservatives (eg, mercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.

The term "therapeutically effective amount" used in combination with an active ingredient in the present invention refers to an amount of an indazole derivative compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof effective for preventing or treating a target disease.

The pharmaceutical composition of the present invention is used for the prevention or treatment of each known disease other than an indazole derivative compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, depending on the type of disease to be prevented or treated. It may further include known drugs. For example, when used for the prevention or treatment of DYRK1A or DYRK1B-related diseases, in addition to an indazole derivative compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, a known anticancer agent may be additionally included. It can be combined with other known treatments for treatment. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapy, immunotherapy, and the like.

Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include mechloethamine, chlorambucil, phenylalanine, mustard, and cyclophospha as DNA alkylating agents. Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin ( cisplatin) and carboplatin; Anti-cancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicama. Plicamycin, mitomycin C and bleomycin; And plant alkaloids as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan And iridotecan, but are not limited thereto.

Since the novel indazole derivatives of the present invention can inhibit DYRK1A and/or DYRK1B, they can be usefully used in the treatment or prevention of diseases caused by overexpression or excessive activity of tankyase.

Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

Example 1: 3 - Benz Amido -N-phenyl-1H- Indazole -5- Carboxamide (3- benzamido -N-phenyl-1H-indazole-5-carboxamide; KS- 40010) of Produce

3-benzamido-N-phenyl-1H-indazole-5-carboxamide was prepared in the same manner as in Scheme 1 below.

[Scheme 1]

Reaction reagents and conditions: (a) Copper(I) cyanide, NMP, 170℃, 24 h, (b) KH ₂ PO ₄ , hydrogen peroxide (30% in water), ACN, H ₂ O, rt, 3 h, (c) hydrazine monohydrate, ethanol, reflux, 3 h, (d) benzoyl chloride, pyridine, rt, 3 h (e) NH ₂ -R, EDC-HCl, DMAP, DMF, rt, 12 h

1-1. 2- Fluoro -5- Of formylbenzonitrile (compound 1) Manufacturing-Step (a)

3-Bromo-4-fluorobenzaldehyde (500 mg, 2.5 mmol) and Copper(I) cyanide (246 mg, 2.75 mmol, 1.1 eq.) were dissolved in NMP (1.5 mL) and heated to 170°C. Stir for 24 hours. After the reaction was completed, the mixture was cooled at room temperature, copper was removed through a Celite filter, and the organic layer was washed with H ₂ O (15 mL). After washing with brine once more, the organic layer was dried over MgSO ₄ and concentrated under reduced pressure in vacuo. Purified by silica gel column chromatography to obtain the title compound in a yield of 52%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.99 (s, 1H), 8.20-8.14 (m, 2H), 7.42 (t, 1H, J = 8.4 Hz).

1-2. 3- Cyano -4- Of fluorobenzoic acid (compound 2) Manufacturing-Step (b)

Compound 1 (180 mg, 1.21 mmol) was dissolved in ACN (2 mL) and then KH ₂ PO ₄ (99 mg, 0.73 mmol, 0.6 eq.) dissolved in H ₂ O (1 mL) and hydrogen peroxide (30% in water) ) (0.23 mL) was added. The mixture was adjusted to 0° C., and NaClO ₂ (241 mg in 2 mL of water, 80% technical grade) was slowly added. After stirring until oxygen production stops, Na ₂ SO ₃ (190 mL in 0.6 mL of water) was added and stirred at room temperature for 2 hours. After adding 1N HCl to the obtained residue, it was extracted several times with EA. The combined organic layer was washed with water and brine, dried over MgSO _4, and concentrated under reduced pressure in vacuo to give the title compound in a yield of 98%.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.44-8.34 (m, 2H), 7.36 (t, 1H, J = 8.6 Hz).

¹ H-NMR (300 MHz, DMSO) δ 13.60 (s, 1H), 8.41 (dd, 1H, J = 6.3, 2.1 Hz), 8.32-8.26 (m, 1H), 7.66 (t, 1H, J = 9.0 Hz)

1-3. 3-amino-1H- Indazole -5- Of carboxylic acid (compound 3) Manufacturing-Step (c)

Compound 2 (180 mg, 1.09 mmol) was dissolved in ethanol (1 mL), and then hydrazine monohydrate (0.16 mL, 3.27 mmol, 3.0 eq.) was added. The mixture was stirred at reflux for 3 hours, cooled at room temperature, concentrated under reduced pressure to remove ethanol, and then H ₂ O (9 mL) and 1N NaOH (0.9 mL) were added, followed by washing with EA. The obtained water layer was adjusted to pH 3 with 2N HCl, and then stirred at room temperature for 1 hour. The resulting precipitate was filtered to give the title compound in a yield of 73%.

¹ H-NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 8.47 (s, 1H), 7.78 (dd, 1H, J = 8.8, 1.5 Hz), 7.24 (d, 1H, J = 8.8 Hz) , 5.65 (s, 2H)

1-4. 3- Benz Amido -1H- Indazole -5- Of carboxylic acid (compound 4) Manufacturing-Step (d)

After dissolving compound 3 (150 mg, 0.85 mmol) in pyridine (3 mL), benzoyl chloride (0.1 mL, 0.85 mmol, 1.0 eq.) was added and stirred for 1 hour. The reaction mixture was extracted with EA and 1N HCl, and the combined organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure in vacuo. After making a precipitate by adding MC, it was filtered to obtain the title compound in a yield of 84%.

1-5. 3- Benz Amido -N-phenyl-1H- Indazole -5- Carboxamide Manufacturing-Step (e)

Compound 4 (100 mg, 0.36 mmol) was dissolved in DMF (2 mL), followed by DMAP (9 mg, 0.07 mmol, 0.2 eq.), aniline (0.54 mmol, 1.5 eq.), EDC-HCl (138 mg, 0.72 mmol, 2.0 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours, extracted with EA and water, and washed with sodium hydrogen carbonate. Thereafter, the organic layer was dried over MgSO ₄ , concentrated under reduced pressure in vacuo, and purified by silica gel column chromatography to obtain the title compound in a yield of 40%.

¹ H-NMR (300 MHz, DMSO) δ 13.09 (s, 1H), 10.94 (s, 1H), 10.25 (s, 1H), 8.44 (s, 1H), 8.11 (d, 2H, J = 6.9 Hz) , 7.96 (d, 1H, J = 8.8 Hz), 7.76 (d, 2H, J = 8.2 Hz), 7.64-7.53 (m, 4H), 7.33 (t, 2H, J = 7.9 Hz), 7.08 (t, 1H, J = 7.4 Hz)

Example 2: 3 - Benz Amido -N-(m- Tolyl )-1H- Indazole -5- Carboxamide (3-benzamido- N-(m-tolyl)-1H-indazole-5-carboxamide; KS-40009) manufacturing

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with m-toluidine.

¹ H-NMR (300 MHz, DMSO) δ 13.09 (s, 1H), 10.93 (s, 1H), 10.16 (s, 1H), 8.42 (s, 1H), 8.11 (d, 2H, J = 7.0 Hz) , 7.96 (d, 1H, J = 7.4 Hz), 7.59-7.56 (m, 6H), 7.21 (t, 1H, J = 7.7 Hz), 6.90 (d, 1H, J = 7.5 Hz), 2.30 (s, 3H)

Example 3: 3 - Benz Amido -N-(3- Chlorophenyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(3-chlorophenyl)-1H-indazole-5-carboxamide; KS-40011) manufacturing

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with 3-chloroaniline.

¹ H-NMR (300 MHz, DMSO) δ 13.12 (s, 1H), 10.95 (s, 1H), 10.41 (s, 1H), 8.44 (s, 1H), 8.12-8.06 (m, 3H), 7.62- 7.54 (m, 6H), 7.37 (t, 1H, J = 8.3 Hz), 7.14 (d, 1H, J = 8.0 Hz)

Example 4: 3 - Benz Amido -N-(4- Phenoxyphenyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(4-phenoxyphenyl)-1H-indazole-5-carboxamide; KS-40014) manufacturing

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with 4-phenoxyaniline.

¹ H-NMR (300 MHz, DMSO) δ 13.09 (s, 1H), 10.93 (s, 1H), 10.28 (s, 1H), 8.44 (s, 1H), 8.11 (d, 2H, J = 7.2 Hz) , 7.97 (d, 1H, J = 8.8 Hz), 7.78 (d, 2H, J = 8.9 Hz), 7.64-7.53 (m, 4H), 7.37 (t, 2H, J = 7.9 Hz), 7.10 (t, 1H, J = 7.3 Hz), 7.01 (t, 4H, J = 9.7 Hz)

Example 5: 3 - Benz Amido -N- benzyl -1H- Indazole -5- Carboxamide (3- benzamido -N-benzyl-1H-indazole-5-carboxamide; KS-40015)

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with phenylmethanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.86 (s, 1H), 9.03 (t, 1H, J = 5.8 Hz), 8.35 (s, 1H), 8.09 (d, 2H, J = 7.1 Hz), 7.93 (d, 1H, 8.8 Hz), 7.65-7.52 (m, 4H), 7.32-7.21 (m, 5H), 4.48 (d, 2H, J = 5.9 Hz)

Example 6: 3 - Benz Amido -N-(3- Chlorobenzyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(3-chlorobenzyl)-1H-indazole-5-carboxamide; KS- 40016) of Produce

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with (3-chlorophenyl) methanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 10.87 (s, 1H), 9.05 (t, 1H, J = 5.9 Hz), 8.34 (s, 1H), 8.09 (d, 2H, J = 7.3 Hz), 7.92 (d, 1H, 8.8 Hz), 7.66-7.53 (m, 4H), 7.38-7.30 (m, 4H), 4.48 (d, 2H, J = 5.6 Hz)

Example 7: 3 - Benz Amido -N-(4- Chlorobenzyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(4-chlorobenzyl)-1H-indazole-5-carboxamide; KS- 40017) of Produce

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with (4-chlorophenyl) methanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.05 (s, 1H), 10.88 (s, 1H), 9.07 (t, 1H, J = 5.8 Hz), 8.35 (s, 1H), 8.09 (d, 2H, J = 7.3 Hz), 7.92 (d, 1H, 8.8 Hz), 7.65-7.53 (m, 4H), 7.39-7.31 (m, 4H), 4.46 (d, 2H, J = 5.9 Hz)

Example 8: 3 - Benz Amido -N-(2- Chlorobenzyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(2-chlorobenzyl)-1H-indazole-5-carboxamide; KS-40018) manufacture

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with (2-chlorophenyl) methanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.06 (s, 1H), 10.88 (s, 1H), 9.04 (t, 1H, J = 5.8 Hz), 8.39 (s, 1H), 8.09 (d, 2H, J = 7.2 Hz), 7.95 (d, 1H, 9.2 Hz), 7.63-7.53 (m, 4H), 7.45 (d, 1H, J =8.6 Hz), 7.33-7.28 (m, 3H), 4.55 (d, 2H, J = 5.8 Hz)

Example 9: 3 - Benz Amido -N-(4- Hydroxybenzyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(4-hydroxybenzyl)-1H-indazole-5-carboxamide; KS-40028) manufacture

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with 4-(aminomethyl)phenol.

¹ H-NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.85 (s, 1H), 9.27 (s, 1H), 8.91 (t, 1H, J = 5.8 Hz), 8.33 (s, 1H) , 8.09 (d, 2H, J = 7.4 Hz), 7.91 (d, 1H, 8.6 Hz), 7.63-7.51 (m, 4H), 7.11 (d, 2H, J = 8.3 Hz), 6.69 (d, 2H, J = 8.3 Hz), 4.36 (d, 2H, J = 5.8 Hz)

Example 10: 3 - Benz Amido -N-(4-methoxybenzyl)-1H- Indazole -5- Carboxamide (3- benzamido-N-(4-methoxybenzyl)-1H-indazole-5-carboxamide; KS-40029)

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with (4-methoxyphenyl) methanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 10.84 (s, 1H), 8.94 (t, 1H, J = 5.9 Hz), 8.32 (s, 1H), 8.09 (d, 2H, J = 7.1 Hz), 7.90 (d, 1H, 8.8 Hz), 7.63-7.51 (m, 4H), 7.24 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 4.40 (d, 2H, J = 5.9 Hz), 3.71 (s, 3H)

Example 11: 3 - Benz Amido -N-(pyridin-3- Monomethyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(pyridin-3-ylmethyl)-1H-indazole-5-carboxamide; KS-40030)

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with pyridin-3-ylmethanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 10.86 (s, 1H), 9.06 (t, 1H, J = 5.9 Hz), 8.54 (d, 1H, J = 1.7 Hz), 8.44 (dd, 1H, J = 4.7, 1.5 Hz), 8.34 (s, 1H), 8.09 (d, 2H, 7.0 Hz), 7.91 (dd, 1H, J = 8.9, 1.5 Hz), 7.71 (d, 1H, J = 7.9 Hz), 7.65-7.53 (m, 4H), 7.36-7.32 (m, 1H), 4.50 (d, 2H, J = 5.9 Hz)

Example 12: 3 - Benz Amido -N-(pyridin-4- Monomethyl )-1H- Indazole -5- Carboxamide (3-benzamido-N- (pyridin-4-ylmethyl)-1H-indazole-5-carboxamide; KS- 40044) of Produce

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with pyridin-4-ylmethanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.06 (s, 1H), 10.88 (s, 1H), 9.10 (t, 1H, J = 5.9 Hz), 8.49 (d, 2H, J = 5.4 Hz), 8.37 (s, 1H), 8.09 (d, 2H, 7.7 Hz), 7.93 (d, 1H, J = 9.0 Hz), 7.63-7.55 (m, 4H), 7.29 (d, 2H, J = 5.5 Hz), 4.50 (d, 2H, J = 5.6 Hz)

Example 13: 3 - Benz Amido -N-(3- Hydroxyphenyl )-1H- Indazole -5- Carboxamide (3- benzamido-N-(3-hydroxyphenyl)-1H-indazole-5-carboxamide; KS-40051)

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with 3-aminophenol.

¹ H-NMR (300 MHz, DMSO) δ 13.08 (s, 1H), 10.92 (s, 1H), 10.11 (s, 1H), 9.36 (s, 1H), 8.42 (s, 1H), 8.11 (d, 2H, J = 7.0 Hz), 7.95 (dd, 1H, J = 8.9, 1.5 Hz), 7.64-7.57 (m, 4H), 7.34 (s, 1H), 7.16-7.07 (m, 2H), 6.49 (d , 1H, J = 7.7 Hz)

Example 14: 3 - Benz Amido -N-( Thiophene -2- Monomethyl )-1H- Indazole -5- Carbox Army De(3-benzamido-N-(thiophen-2-ylmethyl)-1H-indazole-5-carboxamide; KS- 40052) of Produce

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with thiophene-2-ylmethanamine.

¹ H-NMR (300 MHz, DMSO) δ 13.04 (s, 1H), 10.86 (s, 1H), 9.11 (s, 1H), 8.32 (s, 1H), 8.09 (d, 2H, J = 7.0 Hz) , 7.90 (d, 1H, J = 8.6 Hz), 7.63-7.52 (m, 4H), 7.36 (d, 1H, J = 4.0 Hz), 6.99 (s, 1H), 6.96-6.93 (m, 1H), 4.62 (d, 2H, J = 5.9 Hz)

Example 15: methyl 3-(3- Benz Amido -1H- Indazole -5- Carboxamido )-3- Phenylpropanoate (methyl 3-(3- benzamido -1H- indazole -5- carboxamido )-3-phenylpropanoate; KS-40045)

The title compound was synthesized by reacting in the same manner as in Example 1, except that aniline was replaced with methyl 3-amino-3-phenylpropanoate.

¹ H-NMR (300 MHz, DMSO) δ 9.03 (d, 1H, J = 8.3 Hz), 8.45 (s, 1H), 8.39 (d, 1H, J = 8.7 Hz), 8.08 (d, 1H, J = 9.1 Hz), 7.95 (d, 2H, J = 7.5 Hz), 7.61-7.23 (m, 8H), 6.62 (s, 1H), 5.56-5.48 (m, 1H), 3.58 (s, 3H), 3.07- 2.87 (m, 2H)

Example 16: N- benzyl -3-(4- BromoBenz Amido )-1H- Indazole -5- Carboxamide Preparation of (N-benzyl-3-(4-bromobenzamido)-1H-indazole-5-carboxamide; KS-40041)

N-benzyl-3-(4-bromobenzamido)-1H-indazole-5-carboxamide was prepared in the same manner as in Scheme 2 below.

[Scheme 2]

Reaction reagents and conditions: (a) benzyl amine, EDC-HCl, DMAP, DMF, rt, 12 h, (b) hydrazine monohydrate, ethanol, reflux, 3 h, (c) R-benzoyl chloride, pyridine, rt, 3 h

16-1. N- benzyl -3- Cyano -4- Of fluorobenzamide (compound 6) Manufacturing-Step (a)

Compound 2 (2.2 g, 13.32 mmol) was dissolved in DMF (25 mL), followed by DMAP (325 mg, 2.66 mmol, 0.2 eq.), benzyl amine (2.18 mL, 19.98 mmol, 1.5 eq.), EDC-HCl (5.11 g, 26.64 mmol, 2.0 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours, extracted with EA and water, and washed with sodium hydrogen carbonate. Thereafter, the organic layer was dried over MgSO ₄ , concentrated under reduced pressure in vacuo, and purified by silica gel column chromatography to obtain the title compound in a yield of 76%.

¹ H-NMR (300 MHz, DMSO) δ 9.22 (t, 1H, J = 5.6 Hz), 8.42 (dd, 1H, J = 6.2, 2.3 Hz), 8.30-8.25 (m, 1H), 7.66 (t, 1H, J = 9.0 Hz), 7.33 (d, 4H, J = 4.4 Hz), 7.29-7.22 (m, 1H), 4.49 (d, 2H, J = 5.9 Hz)

16-2. 3-amino-N- benzyl -1H- Indazole -5- Of carboxamide (compound 7) Manufacturing-Step (b)

Compound 6 (2.56 g, 10.07 mmol) was dissolved in ethanol (40 mL), and then hydrazine monohydrate (1.48 mL, 30.21 mmol, 3.0 eq.) was added. The mixture was stirred at reflux for 3 hours, cooled at room temperature, concentrated under reduced pressure to remove ethanol, and the resulting precipitate was filtered to obtain the title compound in a yield of 69%.

¹ H-NMR (300 MHz, DMSO) δ 11.61 (s, 1H), 8.82 (t, 1H, J = 6.0 Hz), 8.34 (s, 1H), 7.76 (dd, 1H, J = 8.8, 1.5 Hz) , 7.34-7.20 (m, 6H), 5.47 (s, 2H), 4.49 (d, 2H, J = 6.0 Hz)

16-3. N- benzyl -3-(4- BromoBenz Amido )-1H- Indazole -5- Carboxamide (KS-40041) Preparation of-step (c)

After compound 7 (100 mg, 0.38 mmol) was dissolved in pyridine (1.3 mL), 4-bromobenzoyl chloride (0.38 mmol, 1.0 eq.) was added and stirred for 3 hours. The reaction mixture was extracted with EA and 1N HCl, and the combined organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure in vacuo. Purified by silica gel column chromatography to obtain the title compound in a yield of 67%.

¹ H-NMR (300 MHz, DMSO) δ 13.06 (s, 1H), 10.97 (s, 1H), 9.02 (s, 1H), 8.35 (s, 1H), 8.03 (d, 2H, J = 8.3 Hz) , 7.92 (d, 1H, J = 8.8 Hz), 7.77 (d, 2H, J = 8.3 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.32-7.22 (m, 5H), 4.48 (d, 2H, J = 6.0 Hz)

Example 17: N- benzyl -3-(3- BromoBenz Amido )-1H- Indazole -5- Carboxamide (N-benzyl-3-(3-bromobenzamido)-1H-indazole-5-carboxamide; KS-40042)

The title compound was synthesized by reacting in the same manner as in Example 16, except that 4-bromobenzoyl chloride was replaced with 3-bromobenzoyl chloride.

¹ H-NMR (300 MHz, DMSO) δ 13.06 (s, 1H), 10.99 (s, 1H), 9.01 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 8.08 (d, 1H, J = 7.4 Hz), 7.93 (d, 1H, J = 8.5 Hz), 7.84 (d, 1H, J = 9.0 Hz), 7.54 (d, 2H, J = 8.3 Hz), 7.32-7.21 (m, 5H), 4.49 (d, 2H, J = 6.0 Hz)

Example 18: N- benzyl -3-(2- BromoBenz Amido )-1H- Indazole -5- Carboxamide (N-benzyl-3-(2-bromobenzamido)-1H-indazole-5-carboxamide; KS-40043)

The title compound was synthesized by reacting in the same manner as in Example 16, except that 4-bromobenzoyl chloride was replaced with 2-bromobenzoyl chloride.

¹ H-NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 10.97 (s, 1H), 9.01 (s, 1H), 8.48 (s, 1H), 7.90 (d, 1H, J = 8.0 Hz) , 7.75 (d, 1H, J = 7.9 Hz), 7.65 (d, 1H, J = 7.0 Hz), 7.54-7.45 (m, 3H), 7.34-7.25 (m, 5H), 4.50 (d, 2H, J) = 6.0 Hz)

Experimental example One: In vitro (in vitro) DYRK1B Kinase inhibitory activity assay

The ability of the compounds prepared in Examples to inhibit human DYRK1B kinase activity in vitro was evaluated by LanthaScreen™ Eu Kinase Binding Assay (Invitrogen).

The experiment was performed using Invitrogen's human DYRK1B kinase. Put 5 μl of the drug diluted in Kinase Buffer A (Invitrogen) into a 348-well plate, add 5 μl of human DYRK1B kinase and antibody mixture (Invitrogen) and 5 μl of tracer solution (Invitrogen) in sequence. It was reacted at room temperature for hours. After the reaction, Invitrogen's LanthaScreen™ Eu Kinase Binding Assay was measured according to the attached method. Kinase Buffer A was added to the control group instead of the diluted drug, and Kinase Buffer A was added to the background group instead of the diluted drug and tracer solution. The method of calculating the degree of inhibition (%) is as follows.

1.Ratio = fluorescence value measured at 665 nm/fluorescence value measured at 620 nm × 104

2. Standardized value = ratio of drug-ratio of background group

3. Inhibition (%) = 100-(Standardized value of drug/Standardized value of control group × 100)

Using the degree of inhibition (%) according to the concentration, the DYRK1B kinase inhibitory effect of the test compound was calculated as an IC ₅₀ value, and is shown in Table 1 below.

Compound code % Inhibition at 5 μM IC ₅₀ (nM) KS-40009 87 413 KS-40010 93 100 KS-40011 59 775 KS-40014 38 KS-40015 96 26 KS-40016 97 8 KS-40017 93 62 KS-40018 96 44 KS-40028 95 128 KS-40029 93 185 KS-40030 98 52 KS-40042 95 56 KS-40043 97 72 KS-40044 83 335 KS-40045 26

Claims (12)

A compound represented by the following Formula 1, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is phenyl or bromophenyl,
R ₂ is unsubstituted or phenyl or pyridinyl substituted with one or more substituents selected from the group consisting of chloro, methyl, hydroxy, methoxy and phenyloxy,
n is an integer of 0 or 1,
When n is 1 R ₃ is hydrogen.
The method of claim 1,
R ₂ is phenyl, chlorophenyl or pyridinyl, and n is 1, a tautomer or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₂ is a compound wherein R ₂ is phenyl, chlorophenyl, methylphenyl, hydroxyphenyl, methoxyphenyl, or pyridinyl, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The compound is
1) 3-benzamido-N-phenyl-1H-indazole-5-carboxamide;
2) 3-benzamido-N-(m-tolyl)-1H-indazole-5-carboxamide;
3) 3-benzamido-N-(3-chlorophenyl)-1H-indazole-5-carboxamide;
4) 3-benzamido-N-(4-phenoxyphenyl)-1H-indazole-5-carboxamide;
5) 3-benzamido-N-benzyl-1H-indazole-5-carboxamide;
6) 3-benzamido-N-(3-chlorobenzyl)-1H-indazole-5-carboxamide;
7) 3-benzamido-N-(4-chlorobenzyl)-1H-indazole-5-carboxamide;
8) 3-benzamido-N-(2-chlorobenzyl)-1H-indazole-5-carboxamide;
9) 3-benzamido-N-(4-hydroxybenzyl)-1H-indazole-5-carboxamide;
10) 3-benzamido-N-(4-methoxybenzyl)-1H-indazole-5-carboxamide;
11) 3-Benzamido-N-(pyridin-3-ylmethyl)-1H-indazole-5-carboxamide;
12) 3-benzamido-N-(pyridin-4-ylmethyl)-1H-indazole-5-carboxamide;
13) 3-Benzamido-N-(3-hydroxyphenyl)-1H-indazole-5-carboxamide;
16) N-benzyl-3-(4-bromobenzamido)-1H-indazole-5-carboxamide;
17) N-Benzyl-3-(3-bromobenzamido)-1H-indazole-5-carboxamide; or
18) N-Benzyl-3-(2-bromobenzamido)-1H-indazole-5-carboxamide phosphorus
A compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
A first step of reacting a compound represented by the following formula (3) with 3-amino-1H-indazole-5-carboxylic acid represented by the following formula (2); And
A method for preparing the compound of any one of claims 1 to 4, comprising a second step of reacting the compound obtained from the first step with an amine containing phenyl or pyridinyl represented by the following Formula 4:
[Formula 2]

[Formula 3]

[Formula 4]

In the above formula,
X is halogen,
R ₁ is phenyl or bromophenyl,
R ₂ is unsubstituted or phenyl or pyridinyl substituted with one or more substituents selected from the group consisting of chloro, methyl, hydroxy, methoxy and phenyloxy,
n is an integer of 0 or 1,
When n is 1 R ₃ is hydrogen.
The method of claim 5,
X is chloroin production method.
The method of claim 5, further comprising performing an intramolecular cyclization reaction by reacting 3-cyano-4-fluorobenzoic acid represented by the following formula (5) with hydrazine before the first step.
[Formula 5]

A first step of reacting an amine containing phenyl or pyridinyl represented by the following Formula 4 with 3-cyano-4-fluorobenzoic acid represented by the following Formula 5;
A second step of performing an intramolecular cyclization reaction by reacting the compound obtained from the first step with hydrazine; And
A method for preparing the compound of any one of claims 1 to 4, comprising a third step of reacting the compound obtained from the second step with a compound represented by the following formula (3):
[Formula 3]

[Formula 4]

[Formula 5]

In the above formula,
X, n, R ₁ , R ₂ and R ₃ are the same as defined in claim 5.
As a pharmaceutical composition for the treatment or prevention of DYRK1A or DYRK1B-related diseases comprising the compound according to any one of claims 1 to 4, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
DYRK1A or DYRK1B-related diseases include ovarian cancer, osteosarcoma, pancreatic cancer, lung cancer, colon cancer, rhabdomyosarcoma, cervical cancer, and Metabolic syndrome, autosomal dominant early onset coronary artery disease, juvenile-onset truncal obesity, severe hypertension, type 2 diabetes mellitus II diabetes mellitus), Down syndrome, Alzheimer's disease, or Autism spectrum disorder.
The method of claim 9,
A pharmaceutical composition that inhibits DYRK1A, DYRK1B or both.
delete The method of claim 9,
A pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent or excipient.