WO2021045586A1 - 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridine]-5-ol 3-hydrochloride and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention provides 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridine]-5-ol 3-hydrochloride and a pharmaceutical composition comprising same. 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridine]-5-ol 3-hydrochloride according to the present invention not only has excellent stability and solubility, but can also be produced in a crystal form, and thus can be effectively used for a pharmaceutical composition.

Description

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4' -Bipyridin]-5-ol trihydrochloride and pharmaceutical composition comprising the same

The present invention is 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2 ,4'-bipyridine]-5-ol trihydrochloride and a pharmaceutical composition comprising the same. More specifically, the present invention has excellent stability and solubility, so that 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5- Methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride and a pharmaceutical composition comprising the same.

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro represented by the following formula (I) -[2,4'-Bipyridin]-5-ol is a cyclin-dependent kinase (CDK) inhibitor, which is used to treat colon cancer, lung cancer, cancer such as glioma, and degenerative brain disease such as Alzheimer's disease. It is known to be effective in [see Korean Patent Registration No. 10-1783642].

[Formula I]

However, the compound represented by Formula I has low solubility in water and acid addition salts such as tetrahydrochloride have been developed to improve this, but these acid addition salts have low stability and are difficult to obtain in a crystalline form, making them unsuitable for mass production. there was.

The inventors of the present invention are conventional 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro- [2,4'-bipyridine]-5-ol and its acid addition salts have been studied intensively to overcome the problem. As a result, 2'-amino-6-(2-amino-6-(1-isopropylpiperi) Din-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride is not only excellent in stability and solubility, but also in crystalline form. It was found that it could be manufactured, and the present invention was completed.

Therefore, the object of the present invention is 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)- excellent in stability and solubility. To provide 3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride.

Another object of the present invention is the above 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro It is to provide a pharmaceutical composition comprising ro-[2,4'-bipyridin]-5-ol trihydrochloride.

One embodiment of the present invention is 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl represented by the following formula (II). )-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride.

[Formula II]

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'- according to an embodiment of the present invention Fluoro-[2,4'-bipyridin]-5-ol trihydrochloride may be in crystalline form, and in X-ray powder diffraction analysis, I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : The diffraction angle (2θ) value of 40% or more (the intensity of the largest peak) is 6.7±0.2, 9.5±0.2, 13.1±0.2, 13.6±0.2, 14.4±0.2, 18.8±0.2, 19.3±0.2, 20.5±0.2, It can be 21.7±0.2, 22.5±0.2, 25.2±0.2 and 29.5±0.2.

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'- according to an embodiment of the present invention The crystalline form of fluoro-[2,4'-bipyridin]-5-ol trihydrochloride was determined by differential scanning calorimetry (DSC) analysis, the starting point at 144°C and the lowest point at 163°C, the starting point at 191°C, and the lowest point at 198°C, 251 It shows three endothermic peaks with a starting point at °C and a trough at 266 °C.

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'- according to an embodiment of the present invention Fluoro-[2,4'-bipyridin]-5-ol trihydrochloride is 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methyl Pyrimidine-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol was dissolved in methanol, hydrochloric acid was added, stirred, concentrated under reduced pressure, and recrystallized from water and acetone to 2 '-Amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'- A crystalline form of bipyridin]-5-ol trihydrochloride can be obtained.

In an embodiment of the present invention, the 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'- A pharmaceutical composition for inhibiting cyclin-dependent kinase (CDK) comprising fluoro-[2,4'-bipyridin]-5-ol trihydrochloride with a pharmaceutically acceptable carrier, specifically cancer or It relates to a pharmaceutical composition for the treatment or prevention of degenerative brain diseases.

In one embodiment of the present invention, the 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3' -Fluoro-[2,4'-bipyridin]-5-ol trihydrochloride inhibits CDK and induces anticancer effects through cell cycle regulation, resulting in acute lymphoblastic leukemia (ALL), chronic lymphocytic Leukemia (Chronic lymphoblastic leukemia (CLL)), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM), Hodgkin's lymphoma (Hodgkin's lymphoma), non-Hodgkin's lymphoma Hematologic cancer such as non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer, squamous cell carcinoma of the head and neck, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer , Thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, esophageal cancer, etc. can be usefully used in the treatment of solid cancer.

Further, the 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2 ,4'-bipyridine]-5-ol trihydrochloride freely passes through the blood brain barrier (BBB), such as astrocytoma, anaplastic astrocytoma, and glioblastoma. It can be effectively used to treat brain tumors such as glioma, pituitary adenoma, medulloblastoma, and meningioma, or metastatic brain tumors caused by metastasis from lung cancer, breast cancer, and melanoma. have.

In one embodiment of the present invention, the 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3' -Fluoro-[2,4'-bipyridin]-5-ol trihydrochloride not only inhibits the phosphorylation of tau protein and the production of Aβ, which is the cause of Alzheimer's disease, through CDK5 inhibition, as well as other neurodegeneration and Treatment of Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multiple system atrophy, Lou Gehrig's disease, Huntington's disease, cerebral ischemia or dementia due to cerebral hemorrhage by suppressing the associated neuroinflammation and neuronal death (Shah K et al., Mol Neurobiol. (2017) 54(3):2255-2268).

The pharmaceutical composition according to the present invention can be administered orally (e.g., ingestion or inhalation) or parenterally (e.g., injection, deposition, implantation, suppository), and the injection is, for example, intravenous , It may be a subcutaneous injection, an intramuscular injection, or an intraperitoneal injection. According to the route of administration, the pharmaceutical composition according to the present invention is formulated as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc. It can be formulated. The various types of pharmaceutical compositions according to the present invention may be prepared by known techniques using a pharmaceutically acceptable carrier commonly used in each formulation. Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffering agents, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents. , Suspending agents, stabilizers, colorants, and the like.

The pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.01 to 95% by weight of the compound of the present invention or a pharmaceutically acceptable salt thereof.

The specific dosage of the pharmaceutical composition of the present invention may vary depending on the type, weight, sex, degree of disease, judgment of a doctor, and the like of the mammal including the person to be treated. Preferably, in the case of oral administration, 0.01 to 50 mg of the active ingredient per 1 kg of body weight per day is administered, and in the case of parenteral administration, 0.01 to 10 mg of the active ingredient per 1 kg of body weight per day is administered. The total daily dosage may be administered at once or divided into several times depending on the degree of disease, judgment of a doctor, and the like.

In one embodiment of the present invention, the 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3' -Fluoro-[2,4'-bipyridin]-5-ol trihydrochloride is capecitabine, 5-fluorouracil, thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin for improved treatment. , Paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide, tamoxifen, anastrozole, letrozole, exemesteine, Fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eriburin, toremifene, goserelin, megestrol, vinblastine, bendamustine, thiotepa, bleomycin, topotecan, leuko Borine, trifluridine, tipiracil, mitomycin seed, aldesleukin, temsirolimus, everolimus, mitosantron, mechloretamine, mesotrexate, pemetrexide, trastuzumab, bevacizumab, Cetuximab, aflibercept, pertuzumab, ramucirumab, panitumumab, niborumab, nexitumumab, pembrolizumab, semiflimab, atezolizumab, abelumab, dervalumab, ipilimumab, Obinutuzumab, Ofatumumab, Erotinib, Gefitinib, Sorafenib, Lapatinib, Palboxiclip, Regorafenib, Imatinib, Sunitinib, Akcitinib, Pazopanib, Afatinib, Ceritinib , Crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and one or more anticancer agents selected from the group consisting of procarbazine, or donepezil, rivastigmine, gala Tamine, memantine, aducanumab, levodopa, carbidopa, bencerazide, bromocriptine, lopinirol, pramipexole, rotigotine, trihexifenidil, benztropine, procyclidine, ene Takaphon, selegiline, rasagiline, amantadine, rirusol, tetrabenazine, deuterate or degenerative brain disease treatment agent selected from the group consisting of actirase may be administered in combination. At this time, the administration time and dose of other drugs may vary.

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[ according to the invention 2,4'-bipyridin]-5-ol trihydrochloride is excellent in stability and solubility, and can be prepared in a crystalline form, so that it can be effectively used in pharmaceutical compositions.

Figure 1 shows 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2 It is an X-ray powder diffractogram of a crystalline form of ,4'-bipyridin]-5-ol trihydrochloride.

Figure 2 shows 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2 ,4'-bipyridine]-5-ol trihydrochloride crystal form of differential scanning calorimetry.

Figure 3 shows 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2 It is a thermogravimetric analysis diagram of the crystal form of ,4'-bipyridin]-5-ol trihydrochloride.

Figure 4 shows 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2 Dynamic vapor adsorption/desorption curve of crystalline form of ,4'-bipyridin]-5-ol trihydrochloride.

Hereinafter, the present invention will be described in more detail by examples. These examples are for illustrative purposes only, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1: 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[ Preparation of 2,4'-bipyridine]-5-ol trihydrochloride crystalline form

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4' -Bipyridin]-5-ol (56 g, 0.13 mol) was reacted with hydrochloric acid in a methanol solvent at room temperature and stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and water was added to dissolve it. Crystallization was carried out by slowly adding acetone to the solution. The resulting solid was filtered, washed with acetone and dried. The dried compound was dissolved in water and recrystallized from acetone to obtain the title compound (63 g, 90%).

¹ H NMR (600MHz, DMSO- d ₆ ) δ 8.41 (br s, 1H), 8.06-8.07 (m, 1H), 7.86-7.87 (m, 1H), 7.74 (m, 1H), 7.42 (m, 1H) ), 3.59-3.63 (m, 2H), 3.43-3.45 (m, 1H), 3.43 (m, 1H), 3.11-3.16 (m, 2H), 2.16-2.23 (m, 2H), 2.14 (s, 3H ), 1.98-2.00 (m, 2H), 1.03 (d, J = 6.6 Hz, 6H)

(1) X-ray powder diffraction analysis

X-ray powder diffraction (XRD) analysis was performed under the following conditions using an X-Pert PRO MPD (Philips, Netherlands) analyzer.

Cathode material (Kα): Cu-Kα (1.54056 Å)

Scanning range: 5° to 90°

Generator setting: 40 mA, 40 kV

Scanning speed: 1 second/step

Diver slit: 0.3°

Anti-scatter slit: 0.3°

Temperature: 20 ℃

Step size: 0.02° 2θ

Rotation: use

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[ obtained above Fig. 1 shows the XRD results of the crystal form of 2,4'-bipyridin]-5-ol trihydrochloride. In addition, peaks having a relative intensity of 30.0% or more in the XRD pattern are shown in Table 1 below.

2θ	d	I/I o (%)	2θ	d	I/I o (%)
6.7	13.2	61.7	19.9	4.5	30.4
9.5	9.3	41.9	20.5	4.3	80.4
13.1	6.8	63	21.7	4.1	46.7
13.6	6.5	41.3	22.5	3.9	56
14.4	6.1	100	22.7	3.9	36.4
16.8	5.3	34.1	24.5	3.6	32.9
18.5	4.8	36.1	25.2	3.5	41.2
18.8	4.7	57.9	29.2	3.1	31.4
19.3	4.6	79.1	29.5	3.0	66.8

2θ: diffraction angle, d: distance between crystal planes, I/I _o (%): relative intensity

(2) Differential scanning calorie analysis

Differential Scanning Calorimeter (DSC) analysis was performed at 0°C to 300°C using DSC204 F1 Phoenix (Netzsch, Germany). Samples were weighed in an amount of 5 mg to 10 mg and added to an aluminum DSC pan, and the aluminum DSC pan was sealed with a perforated aluminum lid in a non-sealing manner. Thereafter, the sample was heated from 0° C. to 300° C. at a scanning rate of 5° C./min, and the generated heat flow reaction was observed by DSC.

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[ obtained above Figure 2 shows the DSC analysis results of the 2,4'-bipyridine]-5-ol trihydrochloride crystalline form.

The crystalline form exhibited three endothermic peaks having a starting point at about 144°C and a lowest point at about 163°C, a starting point at about 191°C, and a lowest point at about 198°C, a starting point at about 251°C, and a lowest point at about 266°C.

(3) Thermogravimetric analysis

Thermogravimetric Analysis (TGA) was performed at 30° C. to 500° C. using a TG209 F1 Libra (Netzsch, Germany). The sample was weighed in an amount of 2 mg to 5 mg, and the temperature was measured directly in a vacuum state in a vertical top-loading method in which the sample can be mounted. Thereafter, the sample was heated from 30° C. to 500° C. at a rate of 10° C./min, and the heat weight calculated for exothermic and endothermic reactions occurring in the sample was observed by TGA.

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[ obtained above Fig. 3 shows the TGA results of the 2,4'-bipyridine]-5-ol trihydrochloride crystalline form.

The crystalline form was observed to have a weight change in the temperature range of 30°C to 150°C, which was identified as a weight reduction of about 6.9%.

Experimental Example 1: Long-term storage stability test

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro obtained in Example 1 -[2,4'-bipyridine]-5-ol trihydrochloride crystalline form is stored in a sealed state at 25±2 ℃, 60±5% RH, and the amount of related substances generated after the initial (0 months), 1 month, and 3 months Changes in and compound content were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 2 below.

	0 months	1 month	3 months
Individually related substances	0.06% max	0.08% max	0.09% max
Total Related Substances	0.26%	0.15%	0.35%
content	97.7%	97.6%	96.8%

As shown in Table 2 above, 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl obtained in Example 1 )-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride crystalline form has excellent stability for up to 3 months without increasing the maximum number of individual related substances among the total related substances and total related substances, and without loss of compound content. It was confirmed that it represents.

Experimental Example 2: Stability test against heat and moisture

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro obtained in Example 1 -[2,4'-bipyridine]-5-ol trihydrochloride crystalline form is stored in a sealed state under accelerated conditions of 40±2 ℃, 75±5% RH, after the initial (0 months), 1 month, 3 months Changes in the amount of related substances generated and the content of compounds were analyzed by high performance liquid chromatography (HPLC). The results are shown in Table 3 below.

	0 months	1 month	3 months
Individually related substances	0.06% max	0.10% max	0.09% max
Total Related Substances	0.26%	0.20%	0.35%
content	97.7%	97.1%	96.5%

As shown in Table 3, 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl obtained in Example 1 )-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride crystalline form is 3 months under accelerated conditions without an increase in the total related substances and the maximum individual related substances among the total related substances and without loss of the compound content. It was confirmed that it shows excellent stability until.

Experimental Example 3: Solubility Test

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro obtained in Example 1 -[2,4'-bipyridin]-5-ol trihydrochloride crystal form was subjected to a solubility test according to pH, and the results are shown in Table 4.

aqueous solution depending on pH	Solubility
0.1N HCl aqueous solution [pH 1]	It melts well.
0.01N HCl aqueous solution [pH 2]	It melts well.
0.15M acetic acid buffer [pH 4]	It melts well.
0.15M phosphate buffer [pH 6]	It melts well.
0.15M phosphate buffer [pH 8]	It melts well.

As shown in Table 4, 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl obtained in Example 1 )-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride crystalline form showed excellent solubility at pH 1 to 8.

Experimental Example 4: Hygroscopicity Test

2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro obtained in Example 1 -[2,4'-bipyridine]-5-ol trihydrochloride crystal form using a DVS-Advantage dynamic vapor adsorption device (Dynamic Vapor Sorption, Surface Measurement Systems Co., Ltd.) to change the moisture content under isothermal conditions of 25 ℃, Moisture absorption and dehumidification were repeatedly measured within the range of 0 to 95% relative humidity (RH). The adsorption and desorption behavior of moisture according to the relative humidity is shown in FIG. 4.

4, 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)- obtained in Example 1 3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride crystalline form has a change in moisture adsorption or desorption within 4.7% in the range of 80% or less relative humidity, and 95% of the relative humidity exceeds 80%. It can be seen that the change in moisture adsorption or desorption in the following section is within 21.7%. Thus, 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'- obtained in Example 1 It can be seen that the fluoro-[2,4'-bipyridin]-5-ol trihydrochloride crystalline form is a crystalline form with low hygroscopicity in the normal humidity range.

Claims (10)

1. 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro represented by the following formula (II) -[2,4'-bipyridin]-5-ol trihydrochloride:

   [Formula II]

   
2. The method of claim 1, wherein in X-ray powder diffraction analysis, I/I ₀ (I: intensity of peak at each diffraction angle, I ₀ : intensity of largest peak) is a value of diffraction angle (2θ) of 40% or more 6.7±0.2, 9.5±0.2, 13.1±0.2, 13.6±0.2, 14.4±0.2, 18.8±0.2, 19.3±0.2, 20.5±0.2, 21.7±0.2, 22.5±0.2, 25.2±0.2 and 29.5±0.2 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4' -Bipyridine]-5-ol trihydrochloride.
3. According to claim 2, In the differential scanning calorimetry (DSC) analysis, three endothermic peaks having a starting point at 144°C and a lowest point at 163°C, a starting point at 191°C, and a lowest point at 198°C, a starting point at 251°C, and a lowest point at 266°C. 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro-[ 2,4'-bipyridin]-5-ol trihydrochloride.
4. 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl according to any one of claims 1 to 3 )-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride and a pharmaceutical composition for the treatment or prevention of cancer comprising a pharmaceutically acceptable carrier.
5. The method of claim 4, wherein acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML) ), multiple myeloma (MM), Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreatic cancer, glioma, colon cancer, breast cancer , Head and neck squamous cell cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, or a pharmaceutical composition for the treatment or prevention of esophageal cancer.
6. 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl according to any one of claims 1 to 3 )-3'-fluoro-[2,4'-bipyridin]-5-ol trihydrochloride and a pharmaceutical composition for the treatment or prevention of degenerative brain diseases comprising a pharmaceutically acceptable carrier.
7. According to claim 6, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Pick's disease, Parkinson's disease, multiple system atrophy, Lou Gehrig's disease, Huntington's disease, a pharmaceutical composition for the treatment or prevention of dementia caused by cerebral ischemia or brain hemorrhage.
8. The method of claim 4, wherein 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro -[2,4'-bipyridin]-5-ol trihydrochloride with capecitabine, 5-fluorouracil, thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, Doxorubicin, vinorelbine, gemcitabine, pemetrexed, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide, tamoxifen, anastrozole, letrozole, exemestein, fulvestrant, temozolo Mide, Carmustine, Lomustine, Epirubicin, Eriburine, Toremifen, Goserelin, Megestrol, Vinblastine, Bendamustine, Thiotepa, Bleomycin, Topotecan, Leucovorin, Trifluridine, Typhi Racil, mitomycin, aldesleukin, temsirolimus, everolimus, mitosantron, mechloretamine, mesotrexate, pemetrexed, trastuzumab, bevacizumab, cetuximab, aflibercept , Pertuzumab, Ramucirumab, Panitumumab, Niborumab, Nexitumumab, Pembrolizumab, Semiplimab, Atezolizumab, Avelumab, Duvalumab, Ipilimumab, Obinutuzumab, Opatu Mumab, Erotinib, Gefitinib, Sorafenib, Lapatinib, Palbociclib, Regorafenib, Imatinib, Sunitinib, Akcitinib, Pazopanib, Afatinib, Ceritinib, Crizotinib, Osimerti A pharmaceutical composition for the treatment or prevention of cancer in which at least one anticancer agent selected from the group consisting of nip, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine is administered in combination.
9. The method of claim 6, wherein 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro -[2,4'-bipyridine]-5-ol trihydrochloride with donepezil, rivastigmine, galatamine, memantine, aducanumab, levodopa, carbidopa, bencerazide, bromocriptine, lo Pinyrol, pramipexole, rotigotine, trihexyphenidyl, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine, rirusol, tetrabenazine, dutetrabenazine and liquid A pharmaceutical composition for the treatment or prevention of degenerative brain diseases in which at least one therapeutic agent for degenerative brain diseases selected from the group consisting of tyranes is administered in combination.
10. The method of claim 4, wherein 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-fluoro -[2,4'-bipyridine]-5-ol trihydrochloride and temozolomide are administered in combination, a pharmaceutical composition for the treatment or prevention of cancer.

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