Heteroaryl derivative compounds and their uses

Abstract

The present invention relates to a fused heteroaryl derivative and its use. Since the fused heteroaryl derivative of the present invention exhibits excellent inhibitory activity against ANO6, it can be usefully used as a therapeutic agent for the thrombosis or thrombosis-related diseases.

Description

Technical Field

[0001] The present invention relates to a heteroaryl derivative compound and its pharmaceutical use. Specifically, the present invention relates to a heteroaryl derivative compound having ANO6 inhibitory activity.

Background Art

[0002] Anoctamin-6 (ANO6 / TMEM16F) is encoded by the TMEM16F gene and belongs to the anoctamin family, which is one of the transmembrane and protein families expressed in various cells. The anoctamin-6 protein is essential for the calcium ion-dependent exposure of phosphatidylserine present inside the cell membrane to the outside of the cell membrane, thereby participating in blood coagulation, bone formation, and T cell activation. In particular, when platelets are activated, anoctamin-6 exposes phosphatidylserine to activate the blood coagulation system. In addition, the external exposure of phosphatidylserine by anoctamin-6 acts as a cell activation signal in many cells and is involved in cell growth and death, playing an important role in the occurrence and progression of various diseases such as hemorrhagic diseases and cancer.

[0003] Therefore, through the development of an anoctamin-6 activity inhibitor, there is a need to develop a composition that can effectively improve or treat diseases such as thromboembolic diseases, inflammatory diseases, or cancer in which the functions of anoctamin-6 as an ion channel and phospholipid scramblase are involved.

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the present invention is to provide a heteroaryl derivative having a novel structure, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0005] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0006] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound. Specifically, a pharmaceutical composition for treating or preventing thrombosis or thrombosis-related diseases containing the heteroaryl derivative compound as an active ingredient, a use for treating or preventing thrombosis or thrombosis-related diseases using the compound, or a method for treating or preventing thrombosis or thrombosis-related diseases including the step of administering the compound is provided.

Means for Solving the Problems

[0007] To achieve the above object, a specific example of the present invention provides a heteroaryl derivative compound having a specific structure that suppresses ANO6 activity.

[0008] Heteroaryl derivative compound The present invention provides a compound represented by the following Chemical Formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Chemical Formula

[0009] According to a specific example of the present invention, the above-mentioned

Chemical formula

[0010] According to a specific example of the present invention, the above-mentioned

Chemical formula

Chemical formula

Chemical formula

[0011] According to a specific example of the present invention, L may, by way of example, be in the following range:

Chemical formula

[0012] According to a specific example of the present invention, the ring A may, by way of example, be in the following range:

Chemical formula

Chemical formula

[0013] According to a specific example of the present invention, the ring B may, by way of example, be in the following range:

Chemical formula

[0014] According to a specific example of the present invention, the Z may, by way of example, be in the following range:

Chemical formula

Chemical formula

[0015] According to a specific example of the present invention, the R e may, by way of example, be in the following range:

Chemical formula

[0016] According to a specific example of the present invention, the compound represented by the chemical formula 1 may be a compound represented by the following chemical formula 1-1:

Chemical formula

[0017] According to a specific example of the present invention, the

Chemical formula

[0018] According to a specific example of the present invention, the ring A may be in the following range: Ring A is phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered cycloalkyl {wherein one or more Hs of the phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered cycloalkyl ring may be substituted by -C 1-6 haloalkyl, -NO2, -NR a R b , -OR c , -halo, or 5- to 6-membered heterocycloalkyl [wherein one or more Hs of the 5- to 6-membered heterocycloalkyl may be substituted by -C 1-6 alkyl]}.

[0019] According to a specific example of the present invention, the L may be in the following range: L is -NR L -, -C≡C-NR L , -O-, or -S(=O)2-; R L is -H or -C 1-6 alkyl. According to a specific example of the present invention, the ring B may be in the following range: Ring B is phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl {wherein one or more Hs of the phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl ring may be substituted by -C 1-6 alkyl, -C 1-6 haloalkyl, -NO2, -NR a R b, -OR c , or may be substituted with -halo}.

[0020] According to a specific example of the present invention, the chemical formula Z may be within the following range: Z is -CN, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl {wherein one or more H atoms of the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl ring are -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -OR c , -C(=O)-R d , -(CH2)n-R e , -halo, or may be substituted with 5- to 6-membered heterocycloalkyl [at this time, one or more H atoms of the 5- to 6-membered heterocycloalkyl may be substituted with -C 1-6 alkyl], when ring B is phenyl, 6-membered heteroaryl, or 6-membered heterocycloalkyl, Z is bonded to the p-position with respect to L}.

[0021] According to a specific example of the present invention, the compound represented by the chemical formula 1 may be selected from the group consisting of the compounds listed in Table 1 below. [Table 1]

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

[0022] In the present invention, "alkyl" may mean a straight-chain or branched acyclic, cyclic, or saturated hydrocarbon to which these are bonded, unless otherwise specified. For example, "C 1-6 alkyl" may mean an alkyl containing 1 to 6 carbon atoms, "C 1-4 alkyl" may mean an alkyl containing 1 to 4 carbon atoms, "C 1-3 alkyl" may mean an alkyl containing 1 to 3 carbon atoms. Acyclic alkyl may include, but is not limited to, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary (sec)-butyl, isobutyl, or tertiary (tert)-butyl. Cyclic alkyl may be used interchangeably with "cycloalkyl" herein and may include, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0023] In the present invention, "alkoxy" may mean an alkyl ether group of -(O-alkyl), where alkyl is as defined above. For example, "C 1-6 alkoxy" may mean an alkoxy containing C 1-6 alkyl, i.e., -(O-C 1-6 alkyl), "C 1-4 alkoxy" may mean an alkoxy containing C 1-4 alkyl, i.e., -(O-C 1-4 alkyl), "C 1-3 alkoxy" may mean an alkoxy containing C 1-3 alkyl, i.e., -(O-C 1-3 alkyl). As an example, alkoxy may include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, etc.

[0024] In the present invention, "halo" may be F, Cl, Br or I.

[0025] In the present invention, "haloalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having one or more carbon atoms substituted with halo as defined in the present application. Examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, such as F, Cl, Br or I.

[0026] As used herein, "hydroxyalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH). Examples of the hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with one or more -OH.

[0027] As used herein, "aminoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR’R’’). Here, R’ and R’’ may each independently be selected from the group consisting of hydrogen, C 1-6 alkyl, and an N-protecting group (e.g., Boc), and the selected R’ and R’’ may each independently be substituted or unsubstituted.

[0028] In the present invention, "cycloalkyl" may mean a hydrocarbon ring containing no heteroatoms (such as N, O, P, P(=O), or S) in the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as cycloalkenyl. Unless otherwise specified, cycloalkyl may be a single ring or a polycyclic ring such as a spiro ring, a bridged ring, or a fused ring.

[0029] In the present invention, "heterocycloalkyl" may mean a ring containing one or more selected from N, O, P, P(=O), and S in the ring, and may be saturated or partially unsaturated. Here, when it is unsaturated, it may be referred to as heterocycloalkene. Unless otherwise specified, heterocycloalkyl may be a single ring or a multiple ring such as a spiro ring, a bridged ring or a fused ring. Further, "heterocycloalkyl having 3 to 12 atoms" may mean a heterocycloalkyl containing 3 to 12 atoms forming the ring. As an example, heterocycloalkyl may include, but is not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane, etc.

[0030] In the present invention, "arene" may mean an aromatic hydrocarbon ring. Arene may be a single ring or a multiple ring. The number of ring-forming carbon atoms of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arene include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, kinkbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. In the present specification, the residue obtained by removing one hydrogen atom from the said "arene" is called "aryl".

[0031] In the present invention, "heteroarene" is a ring containing one or more of different elements including O, N, P, Si, and S. The heteroarene may be a single ring or a multiple ring. The number of carbon atoms forming the heteroarene ring may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a structure of two or three rings. Examples of the heteroarene include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole and dibenzofuran, etc., but is not limited thereto. When the heteroarene can have a tautomer structure, it includes the tautomer. In one specific example of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene containing an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In the present specification, the residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".

[0032] In the present invention, "tautomer" means isomers that are in equilibrium with each other and whose molecular structure is converted by the movement of protons.

[0033] In the present invention, "stereoisomer" means a compound that has the same chemical formula or molecular formula but is stereochemically different. In this specification, stereoisomers include optical isomers, enantiomers, diasteromers, cis / trans isomers, rotamers, and atropisomers, and their respective isomers, racemates, and mixtures thereof are also included within the scope of the present invention. For example, since the stereochemical structure of Chemical Formula 1 of the present invention is not specified, it may include the above-mentioned stereoisomers of Chemical Formula 1. Unless otherwise specified, a solid line bond

Chemical Structure

Chemical Structure

Chemical Structure

[0034] The compounds of Chemical Formula 1 of the present invention may exist in the form of "pharmaceutically acceptable salts". As salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. The term "pharmaceutically acceptable salt" of the present invention means any and all organic or inorganic acid addition salts of the compound that have a relatively non-toxic and harmless effective concentration to the patient and do not reduce the good efficacy of the compound represented by Chemical Formula 1 due to side effects caused by this salt.

[0035] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amounts of the compound and the acid or alcohol in water are heated, and subsequently the mixture can be evaporated to dryness or the precipitated salt can be suction filtered.

[0036] At this time, as the free acid, organic acids and inorganic acids may be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid etc. may be used, and as the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, asparagine acid, ascorbic acid, carboxylic acid, vanillic acid, or hydroiodic acid etc. may be used. However, it is not limited to these.

[0037] Also, pharmaceutically acceptable metal salts can be made using a base. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving the compound in a solution of an excess of alkali metal hydroxide or alkaline earth metal hydroxide, filtering off the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, in particular, it is pharmaceutically suitable to produce sodium, potassium, or calcium salts, but it is not limited to these. Also, the corresponding silver salts can be obtained by reacting the alkali metal or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).

[0038] The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that can be present in the compound of Formula 1 above, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups may include hydrobromide, sulfate, hydrosulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelic acid, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, etc., and may be prepared by methods for producing salts known in the art.

[0039] Use of heteroaryl derivative compound The present invention provides the use of a compound represented by the following Chemical Formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0040] The Chemical Formula 1 is as defined above.

[0041] The compound represented by Chemical Formula 1 of the present invention, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against ANO6 (anoctamin-6).

[0042] According to one specific example of the present invention, since the heteroaryl derivative represented by Chemical Formula 1 exhibits excellent inhibitory activity against ANO6 (anoctamin-6), it can be usefully used for the treatment or prevention of thrombosis or thrombosis-related diseases.

[0043] In the present invention, the thrombosis or thrombosis-related disease may be one or more diseases selected from the group consisting of acute myocardial infarction; atrial fibrillation; unstable angina; chronic stable angina; transient ischemic attack; stroke; peripheral vascular disease; preeclampsia; eclampsia; deep vein thrombosis; embolism; cancer-related thrombosis; disseminated intravascular coagulation; thrombotic thrombocytopenic purpura; and thrombotic or restenotic complications occurring after an invasive procedure induced by angioplasty, carotid endarterectomy, surgery after CABG (coronary artery bypass graft), vascular transplantation, stent placement, insertion of an intravascular device or prosthesis.

[0044] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing thrombosis or thrombosis-related diseases, comprising, as an active ingredient, the compound represented by the above chemical formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof. The types of the thrombosis or thrombosis-related diseases are as mentioned above.

[0045] The pharmaceutical composition of the present invention may further contain one or more active ingredients showing the same or similar pharmaceutical effects in addition to the compound represented by the above chemical formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0046] The pharmaceutical composition of the present invention may be used at the time of clinical administration and may be manufactured so as to be administered in various dosage forms, including oral and parenteral dosage forms.

[0047] Also, according to one specific example of the present invention, there is provided a method for treating or preventing thrombosis or thrombosis-related diseases, comprising the step of administering a therapeutically effective amount of the compound represented by the above chemical formula 1, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be an animal including a human.

[0048] As used herein, the term "therapeutically effective amount" refers to the amount of the compound represented by Chemical Formula 1 that is effective for the treatment or prevention of thrombosis or thrombosis-related diseases. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the level of the effective dose can be determined according to factors such as the type and severity of the individual, age, gender, type of disease, activity of the drug, sensitivity to the drug, administration time, administration route and excretion ratio, treatment period, factors including drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered individually or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or multiply. It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects considering all the above factors, and it can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it may be used in an amount exceeding the determined dosage.

[0049] Further, according to one specific example of the present invention, the present invention provides the use of the compound represented by Chemical Formula 1, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt for use in the manufacture of a medicament for the treatment or prevention of thrombosis or thrombosis-related diseases. The compound represented by Chemical Formula 1 for the manufacture of a medicament can be mixed with acceptable adjuvants, diluents, carriers, etc., and can be manufactured as a combined preparation together with other active preparations to have a synergistic effect of the active ingredients.

[0050] Matters mentioned in the use, composition, and treatment method of the present invention are similarly applicable as long as they do not conflict with each other.

Advantages of the Invention

[0051] Since the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against ANO6, it can be usefully used for the treatment or prevention of the thrombosis or thrombosis-related diseases.

Brief Description of Drawings

[0052]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0053] Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples. However, the following production examples, examples and experimental examples are only illustrative of the present invention, and the content of the present invention is not limited thereto.

[0054] [Production Example] Production of Main Intermediate Compounds Method a. Production of amine derivative using Suzuki reaction (formula II-a)

Chemical formula

[0055] Production Example 1: Synthesis of 5-(4-methylthiophen-3-yl)pyrimidin-2-amine

Chemical formula

[0056] Production Example 2: Synthesis of 5-(pyrimidin-4-yl)pyridin-2-amine

Chemical formula

[0057] Production Example 3: Synthesis of 5-(4-fluoropyridin-2-yl)pyrimidin-2-amine

Chemical formula

[0058] Production Example 4: Synthesis of 5-(pyridin-2-yl)pyrimidin-2-amine

Chemical formula

[0059] Production Example 5: Synthesis of 4-(pyridin-2-yl)aniline

Chemical formula

[0060] Production Example 6: Synthesis of 4-(pyrimidin-5-yl)aniline

Chemical formula

[0061] Production Example 7: Synthesis of 4-(pyridin-4-yl)aniline

Chemical formula

[0062] Production Example 8: Synthesis of 6-phenylpyridazin-3-amine

Chemical Structure

[0063] Production Example 9: Synthesis of 4-(Pyridazin-3-yl)aniline

Chemical formula

[0064] Production Example 10: Synthesis of 5-(Pyridazin-3-yl)pyrimidin-2-amine

Chemical formula

[0065] Production Example 11: Synthesis of [2,5'-bipyrimidine]-2'-amine

Chemical formula

[0066] Production Example 12: Synthesis of 5-(3-Fluorophenyl)pyridin-2-amine

Chemical Structure

[0067] Production Example 13: Synthesis of 4-(Pyrimidin-4-yl)aniline

Chemical Structure

[0068] Production Example 14: Synthesis of 4-(6-fluoropyridazin-3-yl)aniline

Chemical formula

[0069] Production Example 15: Synthesis of 4-(4-(Trifluoromethyl)pyridazin-3-yl)aniline

Chemical formula

[0070] Production Example 16: Synthesis of Methyl 6-(4-aminophenyl)pyridazine-4-carboxylate [Chemical formula] Step 1: Synthesis of 6-(4-aminophenyl)pyridazine-4-carboxylic acid To a solution of methyl 6-chloropyridazine-4-carboxylate (6 g, 34.77 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (9.14 g, 41.72 mmol) in dioxane / H2O (500 mL / 100 mL) were added Cs2CO3 (33.98 g, 104.31 mmol) and Pd(dppf)Cl2 (1.26 g, 1.74 mmol), and the reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was cooled to room temperature, poured into water (500 mL), extracted with EA (80 mL × 3), the combined organic layers were washed with brine (500 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (12.1 g, crude) as a yellow solid. MS: m / z = 216 (M+1, ESI+). Step 2: Synthesis of methyl 6-(4-aminophenyl)pyridazine-4-carboxylate To a solution of 6-(4-aminophenyl)pyridazine-4-carboxylic acid (12.1 g, 56.28 mmol) in MeOH (200 ml) at 0 °C was added dropwise SOCl2 (13.39 g, 112.56 mmol), and the reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adjusted to pH 8 with an aqueous NaHCO3 solution (500 mL), extracted with EA (80 mL × 3), the combined organic layers were washed with brine (400 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (4 g, 31.05%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.72 (s, 2H), 3.95 (s, 3H). MS: m / z = 230 (M+1, ESI+).

[0071] Production Example 17: Synthesis of 4-(2-(4-Methylpiperazin-1-yl)pyrimidin-5-yl)aniline

Chemical formula

[0072] Method b. Production of carboxylic acid derivatives using Buchwald reaction (formula III-a)

Chemical formula

[0073] Production Example 18: Synthesis of 3-((5-(4-Methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid

Chemical formula

[0074] Production Example 19: Synthesis of 3 - ((5 - (pyridin - 2 - yl) pyrimidin - 2 - yl) amino) benzoic acid

Chemical Structure

[0075] Production Example 20: Synthesis of 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid

Chemical Structure

[0076] Production Example 21: Synthesis of 3 - ((4-(pyrimidin - 5 - yl)phenyl)amino)benzoic acid

Chemical formula

[0077] Production Example 22: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid [Chemical formula] Step 1: Synthesis of methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate 4-(Pyridin-4-yl)aniline (1.12 g, 6.58 mmol), methyl 3-bromobenzoate (1.56 g, 7.24 mmol), Pd2(dba)3 (0.48 g, 0.53 mmol), XPhos (0.53 g, 1.12 mmol) and Cs2CO3 (4.29 g, 18.44 mmol) were dissolved in 1,4-dioxane (33 mL), and then refluxed and stirred at 100 °C for 16 h. Pd was removed by filtration through celite and concentrated. The concentrated solution was purified by MPLC and concentrated, and then slurried with acetone and filtered to obtain the title compound as a white solid (0.79 g, 40%) as the filter cake. 1 1H NMR (400 MHz, DMSO-d6) δ 8.79 - 8.77 (m, 1H), 8.59 - 8.56 (m, 2H), 7.80 - 7.76 (m, 2H), 7.74 - 7.71 (m, 1H), 7.69 - 7.66 (m, 2H), 7.48 - 7.41 (m, 3H), 7.23 - 7.19 (m, 2H), 3.86 - 3.85 (m, 3H). Step 2: Synthesis of 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate (0.76 g, 2.5 mmol) prepared in Step 1 and LiOH·H2O (0.42 g, 10 mmol) were dissolved in H2O (8.5 mL) and THF (17 mL), and then stirred at room temperature for 40 h. After acidifying to pH 3 with 1N-HCl(aq), it was extracted with ethyl acetate and washed with brine, and then the organic layer was dried over MgSO4 and concentrated. The concentrated mixture was slurried with ethyl acetate and acetone and filtered to obtain the title compound as a yellow solid (244 mg, 34%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.99 (brs, 1H), 9.24 (s, 1H), 8.75 (s, 2H), 8.23 - 8.16 (m, 2H), 7.99 (d, J = 8.8 Hz, 2H), 7.79 (s, 1H), 7.61 - 7.40 (m, 3H), 7.26 (d, J = 42.4 Hz, 2H).

[0078] Production Example 23: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid [Chemistry] Step 1: Synthesis of methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate A solution of methyl 3-bromobenzoate (35.9 g, 167 mmol), 6-phenylpyridazin-3-amine (30.0 g, 175 mmol), BrettPhos (18.0 g, 33.4 mmol) and Cs2CO3 (136 g, 417 mmol) in 1,4-dioxane (150 mL) was degassed and purged with N2. Pd2(dba)3 (4.58 g, 5.01 mmol) was added to the mixed solution, and the mixture was refluxed and stirred at 100 °C for 6 h. After confirming the completion of the reaction by LC-MS, the reaction solution was filtered. The filter cake was dried under vacuum and slurried with THF (300 mL) and MeOH (60 mL) at 25 °C for 12 h. The suspension was filtered and the filtrate was concentrated to obtain the title compound (30.0 g, 98.3 mmol, 59%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 5.6 Hz 3H), 7.49 - 7.47 (m, 1H), 7.46 - 7.44 (m, 4H), 7.44 - 7.42 (m, 1H), 3.87 (s, 3H). Step 2: Synthesis of 3-((6-phenylpyridazin-3-yl)amino)benzoic acid Methyl 3-((6-phenylpyridazin-3-yl)amino)benzoate (20.0 g, 65.5 mmol) prepared in Step 1 and NaOH (2 M, 131 mL, 262 mmol) were dissolved in THF (100 mL) and MeOH (20 mL), and then stirred at 50 °C for 12 h. After confirming the completion of the reaction by LC-MS, the reaction solution was dried under vacuum, H2O was added, and then acidified to pH 3 with 1N-HCl(aq). The suspension was filtered with H2O and the filter cake was dried under vacuum to obtain the title compound (10.0 g, 34.3 mmol, 52%) as a yellowish-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 9.60 (s, 1H), 8.49 (s, 1H), 8.08 (t, J = 9.2 Hz, 4H), 7.55 - 7.46 (m, 5H), 7.25 (d, J = 9.2 Hz, 1H).

[0079] Production Example 24: Synthesis of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid

Chemical formula

[0080] Production Example 25: Synthesis of 3 - ((5 - (3 - fluorophenyl)pyrimidin - 2 - yl)amino)benzoic acid [Chemical formula] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate A solution of 5 - (3 - fluorophenyl)pyrimidin - 2 - amine (30.0 g, 158 mmol), methyl 3 - bromobenzoate (31.0 g, 144 mmol), XPhos (20.6 g, 43.3 mmol), and Cs2CO3 (141 g, 432 mmol) in 1,4 - dioxane (210 mL) was degassed and purged with N2. Pd2(dba)3 (3.96 g, 4.32 mmol) was added to the mixed solution, and the mixture was refluxed with stirring at 100 °C for 12 hours. After confirming the completion of the reaction by TLC, the reaction solution was diluted with H2O and the suspension was filtered with H2O. The filter cake was dried in vacuo, THF was added, and then the suspension was filtered with THF. The filtrate was purified by column chromatography to obtain the title compound (10.0 g, 22%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.93 (s, 2H), 8.49 (s, 1H), 8.05 (dd, J = 1.2 Hz, 1H), 7.67 - 7.43 (m, 5H), 7.20 (s, 1H), 3.86 (s, 3H). Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoic acid Methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzoate (10 g, 30.9 mmol) prepared in Step 1 and NaOH (2 M, 30.9 mL) were dissolved in THF (70 mL) and MeOH (50 mL), and then stirred at 50 °C for 12 hours. The completion of the reaction was confirmed by TLC. After the reaction solution was dried under vacuum and H2O was added, it was acidified to pH 1-2 with 1N-HCl(aq). The suspension was filtered with H2O and the filter cake was dried under vacuum to obtain the title compound (5.0 g, 52%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.92 (s, 2H), 8.79 (s, 1H), 8.46 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.66 - 7.50 (m, 4H), 7.42 (t, J = 9.2 Hz, 1H), 7.22 - 7.17 (m, 1H).

[0081] Production Example 26: Synthesis of 3-((5-(3-fluorophenyl)pyridin-2-yl)amino)benzoic acid

Chemical formula

[0082] Production Example 27: Synthesis of 3 - ((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid [Chemical formula] Step 1: Synthesis of methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate 4-(Pyrimidin-4-yl)aniline (1.70 g, 9.93 mmol), methyl 3-bromobenzoate (2.14 g, 9.93 mmol), BrettPhos (1.07 g, 1.99 mmol), and Cs2CO3 (8.09 g, 24.8 mmol) were dissolved in 1,4-dioxane (15 mL). The solution was degassed and purged with N2. Pd2(dba)3 (909 mg, 0.993 mmol) was added to the mixed solution, and the mixture was refluxed and stirred at 100 °C for 12 h. After confirming the completion of the reaction by TLC, the reaction solution was diluted with H2O, extracted with ethyl acetate, washed with brine, and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography to obtain the title compound (1.30 g, 43%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.91 (s, 1H), 8.74 (d, J = 5.20 Hz, 1H), 8.15 (d, J = 8.80 Hz, 2H), 7.96 (d, J = 5.20 Hz, 1H), 7.76 (s, 1H), 7.52 - 7.49 (m, 1H), 7.46 - 7.43 (m, 2H), 7.20 (d, J = 8.80 Hz, 2H), 3.85 (s, 3H). Step 2: Synthesis of 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoic acid Methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate (1.30 g, 4.26 mmol) prepared in Step 1 and KOH (478 mg, 8.52 mmol) were dissolved in H2O (5 mL) and EtOH (7 mL), and then stirred at 100 °C for 4 h. After confirming the completion of the reaction by TLC, H2O was added to the reaction solution, and then the mixture was extracted with 2-MeTHF and acidified to pH 5 - 6 with 0.5 N-HCl(aq). The mixed solution was extracted with 2-MeTHF, washed with brine, and the organic layer was dried over Na2SO4 and concentrated. The residue was slurried in CH3CN at room temperature for 12 h to obtain the title compound (1.01 g, 81%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 9.13 (s, 1H), 8.88 (s, 1H), 8.74 (d, J = 5.60 Hz, 1H), 8.15 (d, J = 8.80 Hz, 2H), 7.97 - 7.94 (m, 1H), 7.75 (s, 1H), 7.52 - 7.48 (m, 1H), 7.43 - 7.41 (m, 2H), 7.20 (d, J = 8.80 Hz, 2H).

[0083] Production Example 28: Synthesis of 3 - ((5 - (3 - fluorophenyl)pyrimidin - 2 - yl)amino)-4 - methoxybenzoic acid [Chemical formula] Step 1: Synthesis of methyl 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate 5 - (3 - fluorophenyl)pyrimidin - 2 - amine (1.13 g, 6.0 mmol), methyl 3 - chloro - 4 - methoxybenzoate (1.81 g, 9.00 mmol), XPhos (572 mg, 1.2 mmol), Cs2CO3 (3.90 g, 12.0 mmol) and Pd2(dba)3 (824 mg, 0.90 mmol) were added to 1,4 - dioxane (50 mL), and the mixture was refluxed with stirring at 100 °C for 12 hours. After confirming the completion of the reaction by LC - MS, saturated NaHCO3 solution was added to the reaction solution, and the mixture was extracted with ethyl acetate and then concentrated. The residue was purified by MPLC to obtain the title compound (1.43 g, 68%) as an orange solid. 1 1H NMR (400 MHz, DMSO) δ 8.91 (s, 2H), 8.73 (s, 1H), 8.52 (s, 1H), 7.76 - 7.59 (m, 3H), 7.56 - 7.48 (m, 1H), 7.24 - 7.17 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H). Step 2: Synthesis of 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoic acid Methyl 3 - ((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-4-methoxybenzoate (706 mg, 2.00 mmol) prepared in Step 1 and LiOH·H2O (1.68 g, 40.0 mmol) were dissolved in H2O (10 mL) and THF (20 mL), and then stirred at 60 °C for 48 h. The reaction completion was confirmed by LC-MS, and the solution was acidified to pH 2 with 1N-HCl(aq). The suspension was filtered with H2O and dried in vacuo to obtain the title compound (540 mg, 80%) as an orange solid. 1 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.80 (s, 2H), 7.92 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.61 - 7.48 (m, 4H), 7.22 - 7.15 (m, 1H), 3.56 (s, 3H).

[0084] Production Example 29: Synthesis of 3 - ((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid

Chemical Structure

[0085] Production Example 30: Synthesis of 3 - ([2,5’ - bipyrimidine] - 2’ - ylamino) benzoic acid

Chemical Structure

Chemical formula

[0086] Production Example 31: Synthesis of 3-((3-nitro-4-(pyridazin-3-yl)phenyl)amino)benzoic acid

Chemical formula

[0087] Production Example 32: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid [Chemical formula] Step 1: Synthesis of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline To a solution of 4-bromo-3-methoxyaniline (5 g, 24.74 mmol) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (9.43 g, 37.11 mmol) in dioxane (50 mL) were added KOAc (6.06 g, 61.87 mmol) and Pd(dppf)Cl2 (898 mg, 1.21 mmol), and the reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL × 3), the combined organic layers were washed with brine (300 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a yellow solid (2.4 g, 38.96%). 1 H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 7.8 Hz, 1H), 6.15 - 6.07 (m, 2H), 5.48 (s, 2H), 3.64 (d, J = 6.2 Hz, 3H), 1.22 (s, 12H). MS: m / z = 250 (M+1, ESI+). Step 2: Synthesis of 3-methoxy-4-(pyridazin-3-yl)aniline To a solution of 3-bromopyridazine (1.99 g, 12.53 mmol) and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.4 g, 9.64 mmol) in dioxane / H2O (50 mL / 10 mL) were added Cs2CO3 (6.28 g, 19.28 mmol) and Pd(dppf)Cl2 (697 mg, 0.96 mmol), and the reaction mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL × 3), the combined organic layers were washed with brine (300 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a yellow solid (1.4 g, 72.27%). MS: m / z = 202 (M+1, ESI+). Step 3: Synthesis of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate To a solution of 3-methoxy-4-(pyridazin-3-yl)aniline (1.4 g, 6.97 mmol) and methyl 3-bromobenzoate (1.95 g, 9.05 mmol) in dioxane (20 mL) were added Cs2CO3 (4.54 g, 13.94 mmol), Brettphos (697 mg, 1.30 mmol) and Pd2(dba)3 (595 mg, 0.65 mmol), and the reaction mixture was stirred at 120 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, poured into water (300 mL), extracted with EA (60 mL × 3), and the combined organic layers were washed with brine (300 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (1.1 g, 47.21%) as a pale yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ 9.08 (dd, J = 4.8, 1.6 Hz, 1H), 8.84 - 8.68 (m, 1H), 8.15 - 7.94 (m, 1H), 7.81 - 7.74 (m, 2H), 7.64 (dd, J = 8.7, 4.9 Hz, 1H), 7.51 - 7.39 (m, 3H), 6.89 - 6.81 (m, 2H), 3.86 (s, 3H), 3.82 (s, 3H). MS: m / z = 336 (M + 1, ESI+). Step 4: Synthesis of 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoic acid To a solution of methyl 3-((3-methoxy-4-(pyridazin-3-yl)phenyl)amino)benzoate (1.1 g, 3.28 mmol) in THF / H2O (20 mL / 4 mL) was added LiOH·H2O (689 mg, 16.42 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N-HCl(aq) (20 mL), extracted with EA (10 mL × 3), and the combined organic layers were washed with brine (30 mL × 3), dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (900 mg, 85.71%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 9.33 (dd, J = 4.9, 1.4 Hz, 1H), 8.68 (d, J = 8.9 Hz, 1H), 8.28 (dd, J = 8.9, 4.9 Hz, 1H), 7.79 (dd, J = 12.9, 5.5 Hz, 2H), 7.61 - 7.41 (m, 3H), 6.89 (dd, J = 6.6, 2.1 Hz, 2H). MS: m / z = 322 (M + 1, ESI+).

[0088] Production Example 33: Synthesis of 3 - ((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid [Chemical formula] Step 1: Synthesis of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine To a solution of 2-bromo-6-fluoropyridine (3 g, 17.05 mmol) and (2-aminopyrimidin-5-yl)boronic acid (2.26 g, 16.23 mmol) in dioxane / H2O (50 mL / 10 mL) were added Cs2CO3 (10.58 g, 32.46 mmol) and Pd(dppf)Cl2 (1.18 g, 1.62 mmol), and the reaction mixture was stirred at 100 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (60 mL × 3), the combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3.10 g, 92.50%) as a brown solid. MS: m / z = 191 (M + 1, ESI+). Step 2: Synthesis of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate To a solution of 5-(6-fluoropyridin-2-yl)pyrimidin-2-amine (3 g, 15.70 mmol) and methyl 3-bromobenzoate (3.39 g, 15.70 mmol) in dioxane (80 mL) were added Cs2CO3 (10.26 g, 31.40 mmol), Brettphos (847 mg, 1.57 mmol) and Pd2(dba)3 (723 mg, 1.57 mmol), and the reaction mixture was stirred at 120 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, poured into water (200 mL), extracted with EA (80 mL × 3), the combined organic layers were washed with brine (200 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (3.8 g, 71.96%) as a brown solid. 1 1H NMR (400 MHz, DMSO-d6) δ 10.22 (d, J = 24.0 Hz, 1H), 9.19 (d, J = 16.1 Hz, 2H), 8.53 - 8.41 (m, 1H), 8.15 - 8.01 (m, 2H), 7.97 (dd, J = 7.5, 2.5 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.51 - 7.40 (m, 1H), 7.18 - 7.08 (m, 1H), 3.87 (s, 3H). MS: m / z = 325 (M+1, ESI+). Step 3: Synthesis of 3-((5-(6-Fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid To a solution of methyl 3-((5-(6-fluoropyridin-2-yl)pyrimidin-2-yl)amino)benzoate (3.8 g, 11.73 mmol) in THF / H2O (50 mL / 10 mL) was added LiOH·H2O (2.46 g, 58.64 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N-HCl(aq) (80 mL), extracted with EA (40 mL × 3), the combined organic layers were washed with brine (80 mL × 3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound (3.2 g, 88.89%) as a brown solid. 11H NMR (400 MHz, DMSO-d6) δ 9.97 (d, J = 39.6 Hz, 1H), 9.22 - 9.08 (m, 2H), 8.30 (d, J = 14.8 Hz, 1H), 8.06 (q, J = 8.1 Hz, 1H), 7.99 - 7.90 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.10 (dd, J = 8.0, 2.2 Hz, 1H). MS: m / z = 311 (M+1, ESI+).

[0089] Production Example 34: Synthesis of 3-((4-(6-Fluoropyridin-2-yl)phenyl)amino)benzoic acid [Chemical formula] Step 1: Synthesis of 4-(6-Fluoropyridin-2-yl)aniline To a solution of 2-chloro-6-fluoropyridine (1 g, 7.60 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 9.12 mmol) in dioxane / H2O (50 mL / 10 mL), Cs2CO3 (4.95 g, 15.20 mmol) and Pd(dppf)Cl2 (616 mg, 0.76 mmol) were added, and the reaction mixture was stirred at 100 °C under N2 for 2 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), and then extracted with EA (60 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (1.4 g, 88.60%) as a brown solid. MS: m / z = 189 (M+1, ESI+). Step 2: Synthesis of 3-((4-(6-Fluoropyridin-2-yl)phenyl)amino)benzoate To a solution of 4-(6-fluoropyridin-2-yl)aniline (1.4 g, 7.45 mmol) and methyl 3-bromobenzoate (1.92 g, 8.94 mmol) in dioxane (30 mL) were added Cs2CO3 (4.84 g, 14.90 mmol), Brettphos (403 mg, 0.75 mmol) and Pd2(dba)3 (687 mg, 0.75 mmol), and the reaction mixture was stirred at 120 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (40 mL×3), the combined organic layers were washed with brine (100 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as a brown solid (1.1 g, 45.83%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.04 - 7.95 (m, 3H), 7.83 (dd, J = 7.6, 2.7 Hz, 1H), 7.73 (s, 1H), 7.51 - 7.39 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.01 (dd, J = 8.0, 2.8 Hz, 1H), 3.84 (d, J = 9.8 Hz, 3H). MS: m / z = 323 (M+1, ESI+). Step 3: Synthesis of 3-((4-(6-Fluoropyridin-2-yl)phenyl)amino)benzoic acid To a solution of methyl 3-((4-(6-fluoropyridin-2-yl)phenyl)amino)benzoate (1.1 g, 3.42 mmol) in THF / H2O (25 mL / 5 mL) was added LiOH·H2O (718 mg, 17.10 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N-HCl(aq) (40 mL), extracted with EA (15 mL×3), the combined organic layers were washed with brine (60 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a yellow solid (900 mg, 85.70%). 11H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.13 - 8.00 (m, 3H), 7.90 (ddd, J = 21.2, 7.6, 2.5 Hz, 1H), 7.79 (s, 1H), 7.76 - 7.63 (m, 1H), 7.57 - 7.49 (m, 1H), 7.48 - 7.38 (m, 2H), 7.28 - 7.10 (m, 2H), 7.05 (dd, J = 8.0, 2.7 Hz, 1H). MS: m / z = 309 (M+1, ESI+).

[0090] Production Example 35: Synthesis of 2-(dimethylamino)-5-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid

Chemical formula

[0091] Production Example 36: Synthesis of 4-(4-methylpiperazin-1-yl)-3-((5-(pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid

Chemical formula

[0092] Method c. Preparation of carboxylic acid derivatives using other methods (formula III-a)

Chemical formula

[0093] Production Example 37: Synthesis of (1s,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

Chemical formula

[0094] Production Example 38: Synthesis of 3-((6-Phenylpyridazin-3-yl)amino)adamantane-1-carboxylic Acid

Chemical Formula

[0095] Production Example 39: Synthesis of 3-((4-Phenylpiperazin-1-yl)methyl)benzoic Acid [Chemical formula] Step 1: Synthesis of methyl 3-((4-Phenylpiperazin-1-yl)methyl)benzoate 1-Phenylpiperazine (648 mg, 4.0 mmol), methyl 3-(bromomethyl)benzoate (458 mg, 2.0 mmol) and K2CO3 (552 mg, 4.0 mmol) were dissolved in THF (18 mL) and stirred at room temperature for 39.5 hours. After confirming the completion of the reaction by TLC, the reaction solution was concentrated. The residue was slurried with ethyl acetate and filtered, and then the filter cake was purified by MPLC to obtain the title compound (532 mg, 85%) as a white solid. MS: m / z = 311 (M + 1, ESI+). Step 2: Synthesis of 3-((4-Phenylpiperazin-1-yl)methyl)benzoic acid To a solution of methyl 3-((4-phenylpiperazin-1-yl)methyl)benzoate (310 mg, 1.0 mmol) prepared in Step 1 dissolved in MeOH (10 mL) and H2O (2 mL), LiOH·H2O (422 mg, 10.0 mmol) was added, and then the mixture was stirred at 65 °C for 2 hours. After confirming the completion of the reaction by LC-MS, it was neutralized to pH 6 with 6N-HCl(aq). The suspension was slurried with H2O and filtered to obtain the title compound (221 mg, 75%) as a white solid. MS: m / z = 297 (M + 1, ESI+).

[0096] Production Example 40: Synthesis of 3-(4-(Pyridazin-3-yl)phenoxy)benzoic Acid

Chem.

[0097] Method d. Preparation of benzimidazole derivatives using cyclization reaction (formula IV-a)

Chemical formula

[0098] Production Example 41: Synthesis of 2-(3-bromophenyl)-6-fluoro-1H-benzo[d]imidazole

Chemical formula

[0099] Production Example 42: Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)aniline [Chemical] 3-Aminobenzoic acid (411 mg, 3.0 mmol) and 4,5-dichlorobenzene-1,2-diamine (531 mg, 3.0 mmol) were dissolved in polyphosphoric acid (10 mL), and the mixture was refluxed with stirring at 200 °C for 1 h. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature and neutralized to pH 6 with 2N-NaOH(aq). The suspension was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated, and then separated by MPLC, slurried with ethyl acetate and diethyl ether, and filtered to obtain the title compound (190 mg, 68%) as a dark pink solid. 1 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.41 (t, J = 1.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.73 - 6.70 (m, 1H), 5.37 (s, 2H).

[0100] Method e. Production of amine derivatives using a steel reaction (formula II-a) [Chemical] Method e + b. Production of carboxylic acid derivatives using a steel reaction and Buchwald reaction (formula III-a) [Chemical]

[0101] Production Example 43: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid [Chemical] Step 1: Synthesis of 5-(Pyrimidin-4-yl)pyridin-2-amine To a solution of 4-(tributylstannyl)pyrimidine (4 g, 10.84 mmol) and 5-bromopyridin-2-amine (1.55 g, 7.06 mmol) in toluene (60 mL) was added Pd(PPh3)4 (1.25 g, 1.08 mmol), and the reaction mixture was stirred at 120 °C under N2 for 48 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (30 mL × 3), the combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (1.10 g, 58.9%) as a yellow solid. MS: m / z = 173 (M+1, ESI+). Step 2: Synthesis of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate To a solution of 5-(pyrimidin-4-yl)pyridin-2-amine (1 g, 5.81 mmol) and methyl 3-bromobenzoate (1.63 g, 7.56 mmol) in dioxane / DMSO (15 mL / 3 mL) were added Cs2CO3 (3.79 g, 11.62 mmol), Brettphos (936 mg, 1.74 mmol) and Pd2(dba)3 (1.59 g, 1.74 mmol), and the reaction mixture was stirred at 120 °C under N2 for 16 h. The reaction mixture was cooled to room temperature, poured into water (100 mL), extracted with EA (30 mL × 3), the combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (800 mg, 44.9%) as a pale yellow solid. MS: m / z = 307 (M+1, ESI+). Step 3: Synthesis of 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoic acid To a solution of methyl 3-((5-(pyrimidin-4-yl)pyridin-2-yl)amino)benzoate (800 mg, 2.61 mmol) in THF / H2O (10 mL / 2 mL), LiOH·H2O (547 mg, 13.04 mmol) was added, and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was acidified to pH 2 with 2N-HCl(aq) (20 mL), then extracted with EA (10 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a pale yellow solid (700 mg, 91.7%). 1 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.25 - 9.13 (m, 1H), 9.07 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 5.4 Hz, 1H), 8.48 - 8.28 (m, 3H), 8.11 - 7.96 (m, 2H), 7.54 (t, J = 10.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H). MS: m / z = 293 (M+1, ESI+).

[0102] Production Example 44: Synthesis of 3-((6-(pyridin-2-yl)pyridazin-3-yl)amino)benzoic acid

Chemical Structure

[0103] Method f. Preparation of benzimidazole derivatives using cyclization reaction (Acetic acid) (formula IV-a)

Chemical formula

[0104] Production Example 45: Synthesis of 2-(2-bromopyridin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

Chemical formula

[0105] Production Example 46: Synthesis of 2-(3-bromophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole

Chemical Structure

[0106] Method g. Preparation of benzimidazole derivatives using Mitsunobu reaction and cyclization reaction (Formular IV-b)

Chemical Structure

[0107] Production Example 47: Synthesis of 2-(2-(1H-benzo[d]imidazol-2-yl)-4-bromophenoxy)-N,N-dimethylethane-1-amine

Chemical Structure

[0108] Production Example 48: Synthesis of 2-(5-bromo-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1H-benzo[d]imidazole

Chemical Structure

[0109] Production Example 49: Synthesis of 2-(5-Bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-benzo[d]imidazole

Chemical Structure

[0110] Method h. Production of carboxylic acid derivatives using an amide coupling reaction [Chemical formula]

[0111] Production Example 50: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid [Chemical formula] Step 1: Synthesis of methyl (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylate To a solution of (1R,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.060 mL, 0.449 mmol) and 4-(pyrazin-2-yl)aniline (64 mg, 0.374 mmol) in DCM (4 mL) were added HBTU (213 mg, 0.561 mmol) and DIPEA (0.326 mL, 1.869 mmol), and the reaction mixture was stirred at room temperature for 24 hours. After washing the reaction mixture with NaHCO3(aq), it was extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was solidified using EA and hexane to obtain the title compound (100 mg, 90%) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.22 (d, J = 1.6 Hz, 1H), 8.70 - 8.66 (m, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.14 - 8.09 (m, 2H), 7.77 - 7.72 (m, 2H), 3.66 (s, 3H), 2.42 - 2.35 (m, 1H), 2.07 - 2.01 (m, 1H), 1.44 - 1.37 (m, 1H), 1.37 - 1.31 (m, 1H). Step 2: Synthesis of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid To a solution of (1R,2R)-2-((4-(pyrazin-2-yl)phenyl)carbamoyl)cyclopropane-1-carboxylic acid salt (89 mg, 0.299 mmol) in H2O / THF (1 mL / 3 mL) was added 1N NaOH (0.9 mL), and the reaction mixture was stirred at room temperature for 5 h. After acidifying the reaction mixture to pH 3 with 1N-HCl(aq), it was extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (61 mg, 71%) as a beige solid. 1 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.64 (s, 1H), 9.23 (d, J = 1.5 Hz, 1H), 8.72 - 8.66 (m, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.17 - 8.09 (m, 2H), 7.78 - 7.71 (m, 2H), 2.40 - 2.29 (m, 1H), 1.99 - 1.89 (m, 1H), 1.41 - 1.27 (m, 2H).

[0112] [Example] Production of the compound represented by Chemical Formula 1 according to the present invention Method A. Preparation by Amide Reaction and Cyclization Reaction

Chemical Structure

[0113] Example 1: Synthesis of 6-Phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine

Chemical Structure

[0114] Example 2: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine

Chemical formula

[0115] Example 5: Synthesis of 5,6-Dichloro-2-(3-((4-Phenylpiperazin-1-yl)methyl)phenyl)-1H-benzo[d]imidazole [Chemical formula] 3-((4-Phenylpiperazin-1-yl)methyl)benzoic acid (221 mg, 0.747 mmol), 4,5-Dichlorobenzene-1,2-diamine (217 mg, 0.821 mmol) and TBTU (360 mg, 1.12 mmol) were dissolved in DMF (5 mL), then DIPEA (0.260 mL, 1.49 mmol) was added and stirred at room temperature for 2.5 hours. After confirming the completion of the reaction by LC-MS, it was washed with 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, acetic acid (5 mL) was added and refluxed with stirring at 120 °C for 1.5 hours. After confirming the completion of the reaction by LC-MS, it was cooled to room temperature. It was washed with saturated NaHCO3 solution and extracted with ethyl acetate, then the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (190 mg, 43%) as a pale yellow solid.

[0116] Example 6: Synthesis of 6-Phenyl-N-(3-(6-(Trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)pyridazin-3-amine [Chemical formula] 3-((6-Phenylpyridazin-3-yl)amino)benzoic acid (73 mg, 0.25 mmol), 4-(trifluoromethoxy)benzene-1,2-diamine (48 mg, 0.25 mmol), and TBTU (160 mg, 0.5 mmol) were dissolved in DMF (5 mL), then DIPEA (0.130 mL, 0.75 mmol) was added, and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction by LC-MS, it was washed with 5% aqueous LiCl solution and extracted with ethyl acetate. The organic layer was concentrated to remove DMF, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 2 hours. After confirming the completion of the reaction by LC-MS, it was cooled to room temperature. It was washed with saturated NaHCO3 solution and extracted with ethyl acetate, and then the organic layer was dried over Na2SO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (16 mg, 14%) as a white solid.

[0117] Example 7: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine

Chemical formula

[0118] Example 11: Synthesis of N-(3-(7-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-6-phenylpyridazin-3-amine

Chemical Structure

[0119] Example 14: Synthesis of 5-phenyl-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

Chemical Structure

[0120] Example 18: Synthesis of 5-(3-Fluorophenyl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyridin-2-amine

Chemical formula

[0121] Example 20: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridin-2-yl)phenyl)aniline

Chemical Structure

[0122] Example 21: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

Chemical Structure

[0123] Example 23: Synthesis of N-(4-(Pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

Chemical Structure

[0124] Example 24: Synthesis of N-(4-(pyrimidin-4-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

Chemical Structure

[0125] Example 25: Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

Chemical Structure

[0126] Example 30: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrimidin-5-yl)phenyl)aniline

Chemical formula

[0127] Example 32: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)aniline

Chemical Structure

[0128] Example 34: Synthesis of N-((1s,4s)-4-(1H-benzo[d]imidazol-2-yl)bicyclo[2.2.1]heptan-1-yl)-6-phenylpyridazin-3-amine

Chemical Structure

[0129] Example 35: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)adamantan-1-yl)-6-phenylpyridazin-3-amine

Chemical formula

[0130] Example 38: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(3-fluorophenyl)-N-methylpyrimidin-2-amine [Chemistry] 3 - ((5 - (3 - fluorophenyl)pyrimidin - 2 - yl)(methyl)amino)benzoic acid (162 mg, 0.5 mmol), benzene - 1,2 - diamine (54 mg, 0.5 mmol) and TBTU (177 mg, 0.5 mmol) were dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction by LC - MS, the reaction solution was washed with 5% aqueous LiCl solution and extracted with ethyl acetate. Then the organic layer was concentrated to remove DMF, acetic acid (5 mL) was added and refluxed with stirring at 120 °C for 2 hours. After confirming the completion of the reaction by LC - MS, it was cooled to room temperature. After washing with saturated NaHCO3 solution and extracting with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was purified by MPLC to obtain the title compound (80 mg, 42%) as a beige solid.

[0131] Example 39: Synthesis of N-(5-(1H - benzimidazol - 2 - yl)-2 - methoxyphenyl)-5-(3 - fluorophenyl)pyrimidin - 2 - amine [Chemistry] 3 - ((5 - (3 - fluorophenyl)pyrimidin - 2 - yl)amino)-4 - methoxybenzoic acid (170 mg, 0.5 mmol), benzene - 1,2 - diamine (54 mg, 0.5 mmol) and TBTU (177 mg, 0.5 mmol) were dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added and stirred at room temperature overnight. After confirming the completion of the reaction by LC - MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and refluxed with stirring at 120 °C for 2 hours. After confirming the completion of the reaction by LC - MS, it was cooled to room temperature. After washing with saturated NaHCO3 solution and extracting with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (80 mg, 39%) as a beige solid.

[0132] Example 43: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-methylthiophen-3-yl)pyrimidin-2-amine

Chemical Structure

[0133] Example 44: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

Chemical Structure

[0134] Example 46: Synthesis of 3-(1H-imidazo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [Chemical formula] 3-((4-(Pyridazin-3-yl)phenyl)amino)benzoic acid (291 mg, 1.0 mmol), pyridine-3,4-diamine (109 mg, 1.0 mmol) and TBTU (385 mg, 1.2 mmol) were dissolved in DMF (5 mL), then DIPEA (0.348 mL, 2.0 mmol) was added and the mixture was stirred at 60 °C for 7.5 h. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 16 h. After confirming the completion of the reaction by LC-MS, it was cooled to room temperature. It was washed with saturated NaHCO3 solution and acidified to pH 2 with 1N-HCl(aq), then extracted with dichloromethane and concentrated. The concentrated solution was slurried with dichloromethane / diethyl ether / ethyl acetate and filtered to obtain the title compound (84 mg, 23%) as an off-white solid.

[0135] Example 48: Synthesis of N-(3-(1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine [Chem.] 3-((5-(Pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.34 mmol), pyridine-3,4-diamine (37 mg, 0.34 mmol), and TBTU (132 mg, 0.41 mmol) were dissolved in DMF (3.4 mL), then DIPEA (0.12 mL, 0.68 mmol) was added, and the mixture was stirred at room temperature for 21 h. After confirming the completion of the reaction by LC-MS, the mixture was concentrated to remove DMF, acetic acid (2 mL) was added, and the mixture was refluxed with stirring at 100 °C for 18 h. After confirming the completion of the reaction by LC-MS, the mixture was concentrated to remove acetic acid. The mixture was extracted with ethyl acetate and washed with brine, and then the organic layer was dried over MgSO4 and concentrated. The concentrated solution was purified by MPLC and concentrated, then slurried with a small amount of MeOH and filtered to obtain the title compound (7 mg, 5.6%) as an off-white solid as the filter cake.

[0136] Example 51: Synthesis of N-(3-(6-Fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [Chem.] 3-((5-(Pyridazin-3-yl)pyrimidin-2-yl)amino)benzoic acid (146 mg, 0.5 mmol), 4-fluorobenzene-1,2-diamine (63 mg, 0.5 mmol), and TBTU (176 mg, 0.55 mmol) were dissolved in DMF (5 mL), then DIPEA (0.174 mL, 1.0 mmol) was added, and the mixture was stirred at 60 °C for 16 h. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed with stirring at 120 °C for 19 h. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature. The mixture was washed with 1N-NaOH solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO4 and concentrated. The concentrated solution was slurried with ethyl acetate and filtered to obtain the title compound (77 mg, 40%) as a white solid.

[0137] Example 52: Synthesis of 5-(Pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

Chemical formula

[0138] Example 54: Synthesis of N-(3-(1H-imidazolo[4,5-c]pyridin-2-yl)phenyl)-6-phenylpyridazin-3-amine

Chemical formula

[0139] Example 55: Synthesis of N-(3-(6-Fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyridin-2-amine [Chemical formula] 3-((5-(Pyridazin-3-yl)pyridin-2-yl)amino)benzoic acid (100 mg, 0.34 mmol), 4-fluorobenzene-1,2-diamine (48 mg, 0.38 mmol), and TBTU (132 mg, 0.41 mmol) were dissolved in DMF (4 mL), and then DIPEA (119 μL, 0.68 mmol) was added. The mixture was stirred at room temperature for 17 hours. After confirming the completion of the reaction by LC-MS, the mixture was concentrated to remove DMF, acetic acid (4 mL) was added, and the mixture was refluxed with stirring at 110 °C for 4 hours. After confirming the completion of the reaction by LC-MS, the mixture was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered to obtain the title compound (48 mg, 37%) as a brown solid as the filter cake.

[0140] Example 58: Synthesis of N-(3-(6-Fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-[2,3'-bipyridine]-6'-amine [Chemical formula] 3-([2,3'-Bipyridin]-6'-ylamino)benzoic acid (190 mg, 0.65 mmol), 4-fluorobenzene-1,2-diamine (82 mg, 0.65 mmol) and TBTU (230 mg, 0.72 mmol) were dissolved in DMF (5 mL), then DIPEA (0.227 mL, 1.3 mmol) was added and stirred at 60 °C for 1 hour. After confirming the completion of the reaction by LC-MS, the reaction solution was concentrated, acetic acid (5 mL) was added, and the mixture was refluxed and stirred at 120 °C for 1 hour. After confirming the completion of the reaction by LC-MS, it was cooled to room temperature. It was washed with 1N-NaOH solution and extracted with ethyl acetate, and then the organic layer was dried over MgSO4 and concentrated. The concentrated solution was separated by MPLC, slurried with dichloromethane and filtered to obtain the title compound (80 mg, 32%) as a white solid.

[0141] Example 61: Synthesis of methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate [Chemical formula] 3-((4-(Pyridazin-3-yl)phenyl)amino)benzoic acid (500 mg, 1.72 mmol), methyl 3,4-diaminobenzoate (314 mg, 1.89 mmol) and TBTU (661 mg, 2.06 mmol) were dissolved in DMF (17 mL), then DIPEA (0.6 mL, 3.4 mmol) was added and stirred at room temperature for 17 hours. After confirming the completion of the reaction by LC-MS, it was concentrated to remove DMF, acetic acid (17 mL) was added, and the mixture was refluxed and stirred at 110 °C for 2 hours. After confirming the completion of the reaction by LC-MS, it was cooled to room temperature. The resulting solid was slurried with ethyl acetate and filtered, and the filter cake obtained was lyophilized to obtain the title compound (476 mg, 65%) as a yellow solid.

[0142] Example 64: Synthesis of N-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

Chemical Structure

[0143] Example 78: Synthesis of methyl 2-(3-((4-(pyrimidin-2-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate

Chemical Structure

[0144] Example 79: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-2-yl)aniline

Chemical formula

[0145] Example 91: Synthesis of 3-(1-methyl-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-3-yl)phenyl)aniline

Chemical formula

[0146] Example 200: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-6-(pyrimidin-2-yl)pyridazin-3-amine

Chemical formula

[0147] Example 213: Synthesis of 2-(3-(4-(pyridazin-3-yl)phenoxy)phenyl)-1H-benzo[d]imidazole

Chemical formula

[0148] Example 214: Synthesis of 5-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)thiazol-2-amine

Chemical formula

[0149] Example 218: Synthesis of 3-(6-bromo-1H-imidazo[4,5-c]pyridin-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

Chemical formula

[0150] Example 222: Synthesis of 3-(6-(benzyloxy)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline

Chemical formula

[0151] Example 232: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)aniline

Chemical formula

[0152] Example 234: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-3-(6-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)aniline

Chemical Structure

[0153] Example 244: Synthesis of 5-(pyridin-2-yl)-N-(3-(5-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-2-yl)phenyl)pyrimidin-2-amine [Chemical formula] A solution of 3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzoic acid (650 mg, 2.21 mmol) and T3P (850 mg, 2.67 mmol) in DMF (30 mL) was added with 6-(trifluoromethyl)pyridine-2,3-diamine (414 mg, 2.34 mmol), DIEA (863 mg, 6.68 mmol) and DMAP (134 mg, 1.11 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL), then extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-amino-6-(trifluoromethyl)pyridin-3-yl)-3-((5-(pyridin-2-yl)pyrimidin-2-yl)amino)benzamide (800 mg, crude). MS: m / z = 452 (M+1, ESI+). This crude product was dissolved in AcOH (8 mL) and stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from MeOH to obtain the title compound (330 mg, 34.23%) as a beige solid.

[0154] Example 250: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)-5-(trifluoromethyl)aniline

Chemical formula

[0155] Example 252: Synthesis of N-(4-(6-fluoropyridin-2-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

Chemical formula

[0156] Example 279: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine [Chemical formula] Step 1: Synthesis of N1-methyl-4-nitrobenzene-1,3-diamine To a solution of 5-fluoro-2-nitroaniline (5 g, 32.03 mmol) and methanamine hydrochloride (4.33 g, 64.06 mmol) in NMP (100 mL) was added DIEA (20.66 g, 160.14 mmol), and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, poured into water (500 mL), then extracted with EA (100 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (4 g, 74.77%) as a yellow solid. MS: m / z = 168 (M+1, ESI+). Step 2: Synthesis of N4-methylbenzene-1,2,4-triamine N in DCM (10 mL) 1 To a solution of 4-methyl-4-nitrobenzene-1,3-diamine (500 mg, 2.99 mmol) was added Pd / C (50 mg), and the reaction mixture was stirred at 25 °C under H for 6 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound (500 mg, crude) as a brown solid. MS: m / z=138 (M+1, ESI+). Step 3: Synthesis of N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-amine A solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (817 mg, 2.81 mmol) and HATU (1.60 g, 4.21 mmol) in DMF (20 mL) was diluted with N 4 -Methylbenzene-1,2,4-triamine (500 mg, 3.65 mmol) and DIEA (1.09 g, 8.42 mmol) were added and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (200 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over Na2SO4 and concentrated under reduced pressure to give N-(2-amino-5-(methylamino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (250 mg, crude) as a yellow solid. The crude product was dissolved in AcOH (20 mL) and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized with MeOH to give the title compound (8 mg, 0.56%) as a yellow solid.

[0157] Example 280: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazol-6-amine [ka] Step 1: Synthesis of N-benzyl-N-methyl-3,4-dinitroaniline To a solution of 4-fluoro-1,2-dinitrobenzene (10 g, 53.73 mmol) and N-methyl-1-phenylmethanamine (8.47 g, 69.85 mmol) in THF (100 mL) was added TEA (10.86 g, 107.46 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (300 mL), then extracted with EA (100 mL × 3). The combined organic layers were washed with brine (300 mL × 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (9 g, 58.44%) as a yellow solid. MS: m / z = 288 (M+1, ESI+). Step 2: Synthesis of N4-benzyl-N4-methylbenzene-1,2,4-triamine To a solution of N-benzyl-N-methyl-3,4-dinitroaniline (9 g, 31.35 mmol) in MeOH (100 mL) was added Pd / C (1 g), and the reaction mixture was stirred at 25 °C under H2 for 16 h. It was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (1.2 g, 16.9%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.31 - 7.20 (m, 5H), 6.14 (d, J = 2.4 Hz, 1H), 5.92 (dd, J = 8.4, 2.8 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 4.29 (s, 2H), 3.84 (s, 2H), 2.72 (s, 3H). MS: m / z = 228 (M+1, ESI+). Step 3: Synthesis of N-benzyl-N-methyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-amine To a solution of 3-((4-(pyridazin-3-yl)phenyl)amino)benzoic acid (1.40 g, 4.81 mmol) and T3P (2.74 g, 7.21 mmol) in DMF (20 mL) was added N 4 -benzyl-N 4-Methylbenzene-1,2,4-triamine (1.2 g, 5.28 mmol) and DIEA (1.86 g, 14.42 mmol) were added, and the reaction mixture was stirred at 50 °C for 16 h. After pouring the reaction mixture into water (200 mL), it was extracted with EA (50 mL × 3), the combined organic layers were washed with brine (200 mL × 3), dried over Na2SO4 and concentrated under reduced pressure to obtain N-(2-amino-5-(benzyl(methyl)amino)phenyl)-3-((4-(pyridazin-3-yl)phenyl)amino)benzamide (1.4 g, crude), a yellow solid. This crude product was dissolved in AcOH (20 mL) and stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from EA to obtain the title compound (36 mg, 6.8%), a slightly white solid.

[0158] Example 288: Synthesis of N-(3-(6-(2-morpholinoethoxy)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine

Chemical formula

Chemical formula

[0159] Example 303: Synthesis of N-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(thiazol-4-yl)pyrimidin-2-amine

Chemical formula

[0160] Example 158: Synthesis of (1R,2R)-2-(6-fluoro-1H-benzo[d]imidazol-2-yl)-N-(4-(pyrazin-2-yl)phenyl)cyclopropane-1-carboxamide

Chemical formula

[0161] Example 167: Synthesis of 2-(1H-benzo[d]imidazol-2-yl)-N1,N1-dimethyl-N4-(4-(pyrazin-2-yl)phenyl)benzene-1,4-diamine

Chem.

[0162] Example 176: Synthesis of N-(2-(4-methylpiperazin-1-yl)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine

Chem.

[0163] Example 328: Synthesis of 5-(pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)pyrazine-2-amine [Chemical formula] To a solution of 3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzoic acid (300 mg, 1.03 mmol) and 6-(trifluoromethyl)pyridine-3,4-diamine (182 mg, 1.13 mmol) in DMF (10 mL) were added HATU (472 mg, 1.24 mmol) and DIEA (399 mg, 3.09 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (100 mL), then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4 and concentrated under reduced pressure to give N-(5-amino-2-(trifluoromethyl)pyridin-4-yl)-3-((5-(pyridin-2-yl)pyrazin-2-yl)amino)benzamide (350 mg, crude) as a yellow solid. This crude product was dissolved in AcOH (5 mL) and stirred under microwave at 150 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was recrystallized from MeOH to give the title compound (78 mg, 16.46%) as a yellow solid.

[0164] Example 329: Synthesis of N-(3-(6-(difluoromethoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenyl)-5-(pyridin-2-yl)pyrimidin-2-amine

Chemical formula

[0165] Method B. Preparation using Buchwald reaction

Chemical formula

[0166] Example 69: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-2-yl)pyridin-2-amine

Chemical formula

[0167] Example 72: Synthesis of N-(3-(6-Fluoro-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrimidin-4-yl)pyridin-2-amine

Chemical Structure

[0168] Example 73: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(4-fluoropyridin-2-yl)pyrimidin-2-amine

Chemical Structure

[0169] Example 16: Synthesis of N-(3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

Chemical formula

[0170] Example 75: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-3-(pyrimidin-5-yl)aniline

Chem.

[0171] Example 77: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-2-phenylpyrimidin-5-amine

Chem.

[0172] Example 113: Synthesis of 6-(1-methyl-4-piperidyl)-N-[3-[6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl]phenyl]pyridazin-3-amine

Chem.

[0173] Example 261: Synthesis of N-(4-(pyridazin-3-yl)phenyl)-4-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-amine

Chem.

[0174] Example 265: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-N-(4-(6-fluoropyridazin-3-yl)phenyl)aniline

Chemical formula

[0175] Example 154: Synthesis of N-(4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)phenyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

Chemical formula

[0176] Example 168: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(dimethylamino)ethoxy)-N-(4-(pyrazin-2-yl)phenyl)aniline

Chemical Structure

[0177] Example 169: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(4-(pyrazin-2-yl)phenyl)aniline

Chemical Structure

[0178] Example 172: Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-((1-methylpiperidin-4-yl)oxy)-N-(4-(pyrazin-2-yl)phenyl)aniline

Chemical formula

[0179] Example 177: Synthesis of N-(2-((1-methylpiperidin-4-yl)oxy)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine [Chemistry] To a solution of 5-(pyridazin-3-yl)pyrimidin-2-amine (77 mg, 0.444 mmol) and 2-(3-bromo-2-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (184 mg, 0.404 mmol) in 1,4-dioxane (4 mL) were added Pd2(dba)3 (33 mg, 0.0404 mmol), BrettPhos (108 mg, 0.202 mmol) and Cs2CO3 (259 mg, 0.808 mmol), and the reaction mixture was stirred at 150 °C for 2 h in a microwave. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to afford the title compound as a yellow solid (6 mg, 16%).

[0180] Example 178: Synthesis of N-(3-((1-methylpiperidin-4-yl)oxy)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyrazin-3-yl)pyrimidin-2-amine [Chemistry] To a solution of 5-(pyridazin-3-yl)pyrimidin-2-amine (39 mg, 0.223 mmol) and 2-(3-bromo-5-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (92 mg, 0.203 mmol) in 1,4-dioxane (2 mL) were added Pd2(dba)3 (16 mg, 0.0203 mmol), BrettPhos (54 mg, 0.101 mmol) and Cs2CO3 (130 mg, 0.405 mmol), and the reaction mixture was stirred at 150 °C for 3 h in a microwave. The reaction mixture was purified by MPLC. The crude mixture was solidified using EA and hexane to afford the title compound as a pink solid (10 mg, 9%).

[0181] Example 179: Synthesis of N-(3-(2-(dimethylamino)ethoxy)-5-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)pyrimidin-2-amine

Chemical Structure

[0182] Example 311: Synthesis of 5-(5-((methylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

Chemical Structure

[0183] Example 321: Synthesis of methyl 4'-((3-(1H-benzo[d]imidazol-2-yl)phenyl)amino)-[1,1'-biphenyl]-3-carboxylate

Chemical formula

[0184] Method C. Preparation of carboxylic acid derivatives by hydrolysis reaction Example 62: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid

Chemical formula

[0185] Method D. Preparation of Amide Derivatives by Amide Coupling Reaction Example 65: Synthesis of N-isopropyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide

Chemical formula

[0186] Example 66: Synthesis of N-cyclohexyl-2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxamide

Chemical formula

[0187] Method E. Preparation by additional reaction after amide reaction and cyclization reaction

Chemical formula

[0188] Example 40: Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)phenol

Chemical formula

[0189] Example 93: Synthesis of 3-(6-(3-Methyl-1,2,4-oxadiazol-5-yl)-1H-benzo[d]imidazol-2-yl)-N-(4-(pyridazin-3-yl)phenyl)aniline [Chemical formula] To a solution of methyl 2-(3-((4-(pyridazin-3-yl)phenyl)amino)phenyl)-1H-benzo[d]imidazole-6-carboxylate (102 mg, 0.24 mmol) and N-hydroxyacetamidine (24 mg, 0.32 mmol) in DMSO (0.5 mL) was added NaOH (16 mg, 0.45 mmol), and the reaction mixture was stirred at room temperature for 49 h. After confirming the completion of the reaction by LC-MS, it was washed with brine. After extraction with 10% MeOH in DCM solution, the precipitated solid was slurried again with ethyl acetate and filtered to obtain the title compound (16 mg, 22%) as an off-white solid.

[0190] Method F. Production by other reactions [Chemical formula]

[0191] Example 122: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole [Chemical formula] Step 1: Synthesis of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 3-iodobenzaldehyde (1-1, 3 g, 12.9 mmol) in DMF (20 mL) was added 4-(trifluoromethyl)benzene-1,2-diamine (1-2, 2.06 g, 11.7 mmol) and oxone (5.03 g, 8.19 mmol). The mixture was stirred at room temperature for 2 h, then the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE:EtOAc = 10:1) to afford the title compound (1-3, 3.7 g, 81%) as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ: 13.45 (s, 1H), 8.59 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.05 - 7.75 (m, 3H), 7.56 (d, J = 6.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H). 19 19F-NMR (377 MHz, DMSO-d6): δ -58.91. Step 2: Synthesis of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole A mixture of 2-(3-iodophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-3, 1 g, 2.57 mmol), 4-bromobenzenethiol (1-4, 400 mg, 2.14 mmol), CuI (408 mg, 2.14 mmol), L-proline (246 mg, 2.14 mmol) and K3PO4 (1.36 g, 6.42 mmol) in 1,4-dioxane (10 mL) was degassed and refilled with N2 (3 times). The mixture was heated to 100 °C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EtOAc = 4:1) to afford the title compound (1-5, 1.02 g, 88%) as a white solid. MS: m / z = 449 (M+1, ESI+). Step 3: Synthesis of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(3-((4-bromophenyl)thio)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-5, 800 mg, 1.78 mmol) in CHCl3 (20 mL) was added mCPBA (645 mg, 3.75 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE:EtOAc = 4:1) to afford the title compound (1-6, 652 mg, 76%) as a white solid. 1 1H-NMR (400 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.81 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.10 (s, 0.5H), 7.98 (d, J = 8.4 Hz, 2H), 7.90 - 7.85 (m, 4H), 7.79 (d, J = 8.0 Hz, 0.5H), 7.60 - 7.55 (m, 1H). 19 19F-NMR (377 MHz, DMSO-d6): δ -58.94, -59.01. Step 4: Synthesis of 2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole A mixture of 2-(3-((4-bromophenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-6, 350 mg, 0.73 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1-7, 278 mg, 1.1 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol) and KOAc (214 mg, 2.19 mmol) in 1,4-dioxane (10 mL) was degassed and refilled with N2 (3 times). The mixture was heated at 100 °C overnight. The completion of the reaction was confirmed by LC-MS. After cooling, the product was used immediately in the next reaction. MS: m / z = 529 (M+1, ESI+). Step 5: Synthesis of 2-(3-((4-(pyridazin-3-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole A solution of 2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (1-8, 0.73 mmol) in 1,4-dioxane (10 mL) was added with 3-bromopyridazine (1-9, 139 mg, 0.87 mmol), H2O (1 mL), K2CO3 (302 mg, 2.19 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol). The mixture was degassed and refilled with N2 (3 times), and then heated at 100 °C overnight. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EtOAc = 1:2) to obtain the title compound (150 mg, 42%) as a white solid.

[0192] Example 123: Synthesis of N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)-5-(pyridazin-3-yl)-1,3,4-oxadiazol-2-amine

Chemical formula

[0193] Example 124: Synthesis of N-(4-(pyridazin-3-yl)cyclohexyl)-3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)aniline

Chemical formula

[0194] Example 125: Synthesis of 1-(Pyridazin-3-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperidin-4-amine

Chemical Structure

[0195] Example 312: Synthesis of 5-(5-((dimethylamino)methyl)pyridin-2-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)pyrimidin-2-amine

Chemical formula

[0196] Example 317: Synthesis of 6-(piperidin-4-yl)-N-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)phenyl)piperazine-3-amine

Chemical formula

[0197] The other compounds of the above Examples were produced using Methods A to F.

[0198] The chemical structural formulas, NMR, and LC-MS analysis results of the compounds of Examples 1 to 336 are summarized in Table 2 below. [Table 2] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23]

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

[0199] Experimental Example 1: Efficacy Test of Thrombosis Inhibiting Substance (Ferric Chloride-Induced Carotid Artery Thrombosis Model) 1. Experimental Materials and Equipment Isoflurane solution (Isoflurane, Hana Pharm), Iron(III) chloride (FeCl3, Sigma-Aldrich, cat.#157740), Dimethyl sulfoxide (DMSO, Sigma-Aldrich, cat.#D5879), Poly(ethylene glycol), average Mn400 (PEG400, Sigma-Aldrich, cat.#202398), Hydroxypropyl-β-cyclodextrin (HP-β-CD, TCI, cat.#H0979)

[0200] 2. Experimental Animals Eight-week-old male Sprague-Dawley rats (Orient Bio) were acclimated for two weeks before the experiment. The number of animals was confirmed upon receipt, general symptoms were observed, and body weights were measured. The test basic materials, such as the inspection certificates provided by the animal supplier, were stored. During the quarantine and acclimation periods for all animals, general symptoms were observed once a day. The animals were housed in polycarbonate cages (278W × 420L × 200H (mm)) under aseptic conditions at a temperature of (22 ± 3) °C, a relative humidity of 30 - 70%, an air change rate of 10 - 15 times / hour, and a 12-hour light / dark cycle (illuminance 150 - 300 Lux). The cages were changed once a week, and the water bottles were changed more than twice a week. The feed was solid feed for experimental animals (Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C, Envigo RMS, Inc., USA) placed in a feeder for free intake. After the final quarantine, according to the results of the ranked body weight measurements, the animals were grouped so that the average body weights of each group were distributed as uniformly as possible. The remaining animals after grouping were excluded from this test and euthanized by inhaling carbon dioxide (CO2) gas.

[0201] 3. Experimental procedures 3-1. Preparation of control substances and test substances Control substance 1 (rivaroxaban), control substance 2 (edoxaban), and the test substance were weighed in the required amounts, DMSO corresponding to 5% of the required solution was added, and sonicated for 2 minutes to confirm dissolution. Then, PEG400 corresponding to 50% was added and sonicated for 2 minutes. Subsequently, a distilled aqueous solution containing 20% HP-β-CD corresponding to 45% was added, followed by sonication for 2 minutes to completely dissolve. The test substance was prepared and used immediately before administration to the test animals.

[0202] 3-2. Preparation of the inducer (50% FeCl3 solution) The required amount of the inducer was weighed, water for injection was added, and vortexed. Then, water for injection was added to prepare the required liquid volume.

[0203] 3-3. Administration of test substance The test substance was orally administered 2 hours before thrombus induction, with a volume of 10 mL / kg and a probe for oral administration connected to a disposable syringe. The control substance was orally administered 25 minutes or 2 hours before thrombus induction, with a volume of 10 mL / kg and a probe for oral administration connected to a disposable syringe. The normal control group and negative control group were orally administered the same volume of vehicle (5% DMSO, 50% PEG400, 45% (20% HP-β-CD in distilled water)).

[0204] 3-4. Thrombus induction and measurement of vascular weight The test animals were anesthetized with Ifran solution and the carotid artery was exposed. 2 A Whatman No. 1 filter paper was placed on the carotid artery for 10 minutes. After 10 minutes, the paper was removed and the FeCl3 remaining in the blood vessel was washed with PBS. After leaving it for 20 minutes, the blood vessel was separated. 2 Whatman No. 1 filter paper from each individual was treated in the same manner. 20 minutes after removing the Whatman No. 1 filter paper, both ends of the blood vessel were tied using 4-0 silk ligatures and the blood vessel was separated. At this time, the length of the blood vessel and the length of the ligature were the same for all individuals. After removing the ligature, both ends of the blood vessel were gently touched to Kimwipes to remove any blood oozing from within the blood vessel and the weight was measured. Then, the vessel was photographed and its length was measured using the Image J program.

[0205] 3-5. End of the exam The test was completed after measuring and photographing the weight and length of the blood vessels. The test results were shown by calculating the inhibition rate (%) using the index (blood vessel weight (mg) / blood vessel length (mm)) value as follows:

number

[0206] The test results (Inhibition rate, %) of the compound administration groups in each example are presented in Figures 1 to 6, and the compounds of the examples presented in each figure are as shown in Table 3 below. [Table 3] [Table 63]

[0207] Experimental Example 2: Lact C2 assay (Measurement of the scramblase function of phosphatidylserine externalization) 1. Materials and equipment Ionomycin (Alomonelab, cat.#I-700), DAPI (Sigma-Aldrich, cat.#D8417), paraformaldehyde (Biosesang, cat.#P2031), Lionheart FX automatic fluorescence microscope (BioTek), Gen5 TM Software program (BioTek), Image J analysis software program.

[0208] 2. Cell culture Fisher rat thyroid (FRT) cells expressing human ANO6 (variant 5; GenBank accession no. NP_001191732.1) were cultured at 37 °C and 5% CO2 using DMEM / Ham’s F-12 (1:1) medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 units / mL penicillin, and 100 μg / mL streptomycin.

[0209] 3. Test method FRT cells expressing human ANO6 (variant 5) (2×10 4Cells / well) were cultured in a 96-well microplate for 24 hours. After the culture, the wells were treated with the compound dissolved in DMSO at a concentration of 1% v / v at different concentrations (50 nM, 100 nM, 1 μM) and reacted for 10 minutes. Then, ionomycin was added to each well at a final concentration of 10 μM and reacted for 10 minutes, followed by washing with 200 μL of PBS. After washing, 50 μL of Lactadherin-C2 (Lact-C2)-GFP mixed in DMEM medium was added to each well to a final concentration of 500 nM to stain phosphatidylserine and cultured at 37 °C for 10 minutes. After the reaction, the wells were washed with 200 μL of PBS and then fixed with 4% paraformaldehyde at room temperature for 5 minutes. For morphological analysis, the wells were cultured with DAPI solution for 15 minutes and then washed with PBS. The fluorescence intensity of Lact-C2-GFP bound to phosphatidylserine on the cell surface was measured using an automated fluorescence microscope. Quantitative analysis of the fluorescence intensity of Lact-C2-GFP was performed using Gen5 TM , using the Image J analysis program.

[0210] The inhibitory activity (%) of phosphatidylserine externalization by the compound was calculated by the following analysis method. After subtracting the background fluorescence value from the measured Lact-C2-GFP fluorescence value, the fluorescence values of the ionomycin non-treated group and the ionomycin-treated group in the same row where each test group was located in the 96-well microplate were calculated. To calculate the inhibitory activity (%) of the compound, the compound and ionomycin non-treated group were set as 100% inhibitory activity, and the ionomycin alone-treated group was set as 0% inhibitory activity, and the relative inhibitory activity was calculated. Repeated tests were performed 3 times to derive the results, and the average value of the results was classified according to the following ranges and shown in Table 4 below (A: >60% inhibition, B: 30 - 60% inhibition, N / A: not tested). [Table 4]

Table 64

Table 65

Table 66

Table 67

Table 68

Claims

Claim 1 A compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above chemical formula 1, Ring X is a 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl, where one or more H's of the 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl ring are -C １－６ alkyl, -benzyl, -C １－６ haloalkyl, -(CH ２ )n-R ｅ , -O-(CH ２ )n-R ｅ , or may be substituted with -halo}; Y １ or Y ４ is, independently, CR Ｙ or N; R Ｙ is -H, -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -(CH ２ )n-R ｅ , -O-(CH ２ )n-R ｅ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl {wherein one or more H of said 5- to 6-membered heteroaryl may be substituted with -C １－６ alkyl}; Ring A and Ring B are each independently aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or a multiple ring, and one or more Hs of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring are -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -(CH ２ )n-R ｅ , -O-(CH ２ )n-R ｅ , -halo, or may be substituted with a 5- to 6-membered heterocycloalkyl [wherein one or more Hs of the 5- to 6-membered heterocycloalkyl may be substituted with -C １－６ alkyl]}; L is -CH ２ -, -NR Ｌ -, -C≡C-NR Ｌ , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR Ｌ -, -NR Ｌ C(=O)-, -S-, -S(=O) ２ -, -S(=O) ２ -NR Ｌ -, or -NR Ｌ -S(=O) ２ -; R Ｌ is -H or -C １－６ alkyl; Z is -H, -C １－６ alkyl, -CN, -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein one or more H atoms of said -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring are -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -(CH ２ )n-R ｅ , -O-(CH ２ )n-R ｅ , -halo, or may be substituted with a 5- to 6-membered heterocycloalkyl [wherein one or more H atoms of said 5- to 6-membered heterocycloalkyl may be substituted with -C １－６ alkyl]}; R ａ and R ｂ each independently represents -H, -C １－６ alkyl, or -benzyl; R ｃ is -H, -C １－６ alkyl, -C １－６ haloalkyl, -(CH ２ )n-R ｅ , -benzyl, or heterocycloalkyl {wherein one or more H's of said heterocycloalkyl ring may be substituted with -C １－６ alkyl}; R ｄ is -H, -OH, -O-C １－６ alkyl, -NH ２ -, -NH-C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), -NH-C ３－６ cycloalkyl, or -NH-aryl; R ｅ is -C １－６ aminoalkyl, -NH ２ , -NH-C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl {wherein said heteroaryl, heterocycloalkyl, or heterocycloalkenyl is monocyclic or polycyclic and one or more H of said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring may be substituted with -C １－６ alkyl}; n is 0, 1, 2, 3, or 4. Claim 2 The compound represented by the above chemical formula 1 is a compound represented by the following chemical formula 1-1; 【Chemical Formula 2】 In the above chemical formula 1-1, X １ is CR １ R ２ NR ３ , O or S; X ２ is either CR ４ or N; R １ or R ４ is, independently of each other, -H or -C １－６ alkyl; Y １ or Y ４ is, independently of each other, CR Ｙ or N; R Ｙ is -H, -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl {wherein one or more H of said 5- to 6-membered heteroaryl may be substituted with -C １－６ alkyl}; Ring A and Ring B are each independently aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is a single ring or a multiple ring, and one or more Hs of the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring are -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -halo, or may be substituted with a 5- to 6-membered heterocycloalkyl [wherein one or more Hs of the 5- to 6-membered heterocycloalkyl may be substituted with -C １－６ alkyl]}; L is -CH ２ -, -NR Ｌ -, -C≡C-NR Ｌ , -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR Ｌ -, -NR Ｌ -C(=O)-, -S-, -S(=O) ２ -, -S(=O) ２ -NR Ｌ -, or -NR Ｌ -S(=O) ２ -; R Ｌ is -H or -C １－６ alkyl; Z is -H, -CN, -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl {wherein one or more H of the -C ２ alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring are -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -O-(CH ２ )n-R ｅ , -halo, or may be substituted with 5- to 6-membered heterocycloalkyl [at this time, one or more H of the 5- to 6-membered heterocycloalkyl may be substituted with -C １－６ alkyl]}; R ａ and R ｂ each independently represents -H, -C １－６ alkyl, or -benzyl; R ｃ is -H, -C １－６ alkyl, -C １－６ haloalkyl, -(CH ２ )n-R ｅ , -benzyl, or heterocycloalkyl {wherein one or more H of the heterocycloalkyl ring may be substituted with -C １－６ alkyl}; R ｄ is -H, -OH, -O-C １－６ alkyl, -NH ２ -, -NH-C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), -NH-C ３－６ cycloalkyl, or -NH-aryl; R ｅ is -NH ２ , -NH-C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), heteroaryl, heterocycloalkyl, or heterocycloalkenyl {wherein one or more Hs of said heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring may be substituted with -C １－６ alkyl}; n is 0, 1, 2, 3, or 4; The compound according to claim 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by chemical formula 1. Claim 3 X １ is NR ３ or O; X ２ is either CR ４ or N; R ３ and R ４ each independently is -H or -C １－６ alkyl; Y １ and Y ４ are each independently CR Ｙ ; Y ２ and Y ３ are each independently CR Ｙ or N {provided that when ring X １ is S, one of Y ２ and Y ３ is N, when ring X １ is O and X ２ is CR ４ one of Y ２ and Y ３ is N}; R Ｙ is -H, -C １－６ alkyl, -C １－６ haloalkyl, -CN, -NO ２ , -NR ａ R ｂ , -OR ｃ , -C(=O)-R ｄ , -S(=O) ２ -C １－６ alkyl, -halo, or 5- to 6-membered heteroaryl {wherein one or more H's of said 5- to 6-membered heteroaryl may be substituted with -C １－６ alkyl}; The compound according to claim 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by chemical formula 1. Claim 4 Ring A is phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered cycloalkyl {wherein one or more Hs of the phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered cycloalkyl ring are -C １－６ haloalkyl, -NO ２ , -NR ａ R ｂ , -OR ｃ , -halo, or may be substituted with 5- to 6-membered heterocycloalkyl [wherein one or more Hs of the 5- to 6-membered heterocycloalkyl may be substituted with -C １－６ alkyl]}; The compound according to claim 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by chemical formula 1. Claim 5 L is -NR Ｌ -, -C≡C-NR Ｌ , -O-, or -S(=O) ２ -; R Ｌ is -H or -C １－６ alkyl; The compound according to claim 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by chemical formula 1. Claim 6 Ring B is phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl {where one or more Hs of the phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl ring are -C １－６ alkyl, -C １－６ haloalkyl, -NO ２ , -NR ａ R ｂ , -OR ｃ , or may be substituted with -halo}; The compound according to claim 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by chemical formula 1. Claim 7 Z is -CN, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl {wherein one or more Hs of the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl ring are -C １－６ alkyl, -C １－６ haloalkyl, -CN, -OR ｃ -, -C(=O)-R ｄ -, -(CH ２ )n-R ｅ -, -halo, or may be substituted with 5- to 6-membered heterocycloalkyl [wherein one or more Hs of the 5- to 6-membered heterocycloalkyl may be substituted with -C １－６ alkyl], when ring B is phenyl, 6-membered heteroaryl, or 6-membered heterocycloalkyl, Z is attached to the p-position relative to L}; The compound according to claim 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by chemical formula 1. Claim 8 The compound according to claim 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the above chemical formula 1 is selected from the group consisting of the following compounds: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 Claim 9 A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 10 A pharmaceutical composition for the treatment or prevention of thrombosis or a thrombosis-related disease, comprising, as an active ingredient, the compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Claim 11 The thrombus or thrombus-related disease is one or more diseases selected from the group consisting of acute myocardial infarction; atrial fibrillation; unstable angina; chronic stable angina; transient ischemic attack; stroke; peripheral vascular disease; preeclampsia; eclampsia; deep vein thrombosis; embolism; cancer-related thrombosis; disseminated intravascular coagulation; thrombotic thrombocytopenic purpura; and thrombotic or restenotic complications occurring after an invasive procedure induced by angioplasty, carotid endarterectomy, surgery after CABG (coronary artery bypass grafting), vascular grafting, stent placement, or insertion of an intravascular device or prosthesis. The pharmaceutical composition according to claim 10.

12. Use of a compound represented by Chemical Formula 1 according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing a thrombus or thrombus-related disease.

13. A method for treating or preventing a thrombus or thrombus-related disease, comprising the step of administering a therapeutically effective amount of a compound represented by Chemical Formula 1 according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

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