INIBIDOR DE DIFERENCIAÇÃO E MATURAÇÃO DE MEGACARIÓCITOS

Abstract

The present invention relates to a compound of formula (I) which can selectively inhibit the differentiation from hematopoietic stem cell toward megakaryocytes.

Description

1 / 18 MEGAKARYOCYTE DIFFERENTIATION AND MATURATION INHIBITOR FIELD OF TECHNIQUE

[001] The present invention relates to an inhibitor of megakaryocyte differentiation and maturation, which comprises a derivative of 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one. In more detail, it relates to an inhibitor of platelet production (for example, a drug for the treatment of essential thrombocythemia). PREVIOUS TECHNIQUE

[002] Essential thrombocythemia (also referred to as primary thrombocythemia) is a disease characterized by high platelet counts, megakaryocyte hyperplasia, and hemorrhagic or thrombotic tendencies. Symptoms and signs include muscle weakness, headache, paresthesia, hemorrhage, and erythromelalgia with digital ischemia. The prevalence rate is approximately 0.48 per 100,000 people (Non-Patent Literature 1).

[003] Non-Patent Literature 2 classifies anagrelide, a drug for the treatment of essential thrombocythemia, as a phosphodiesterase 3 (PDE3) inhibitor. The literature suggests that the mechanism of anagrelide may be based on the interaction between PDE3A and Schlafen 12 (SLFN12), since anagrelide's action inhibits megakaryocyte differentiation, which is different from other PDE3 inhibitors. However, the literature does not reveal any results demonstrating an effect on megakaryocytes.

[004] Non-Patent Literature 1 reveals derivatives of 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one as a drug for the treatment of malignant tumors. LIST OF CITATIONS PATENTARY LITERATURE [PL 1] WO2017 / 150654 Petition 870250079785, dated 05 / 09 / 2025, p. 6 / 37 2 / 18 NON-PATENTY LITERATURE [NPL 1] Orphanet Report Series; Prevalence and incidence of rare diseases: Bibliographic data, January 2021 (www.orhpa.net) [NPL 2] Waal, L. et al., Nat. Chem. Biol. 2016; 12:102-8 SUMMARY OF THE INVENTION TECHNICAL PROBLEM

[005] The purpose of the present invention may be to provide a compound that can selectively inhibit the differentiation of hematopoietic stem cells into megakaryocytes. SOLUTION TO THE PROBLEM

[006] The present inventors have studied extensively to achieve the above purpose, and then found that a compound of Formula (I) below has a complex-building promoting action on PDE3A and SLFN12. In addition, they also found that the compound inhibits megakaryocyte differentiation without affecting the differentiation of erythroblasts and myeloid cells from hematopoietic stem cells. Based on these novel findings, the present invention has been finalized.

[007] The present invention includes the following embodiments. (1-1)

[008] A pharmaceutical composition comprising a compound of Formula (I): [Chem. 1] where R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, Petition 870250079785, dated 05 / 09 / 2025, page 7 / 37 3 / 18 or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation. (1-2)

[009] The pharmaceutical composition of (1-1), wherein the compound of Formula (I) is a compound of Formula (Ia): [Chem. 2]

[0010] The pharmaceutical composition of (1-1) or (1-2), wherein R1 and R2 are fluorine and R3 and R4 are methyl. (1-4)

[0011] The pharmaceutical composition of any one of (1-1) - (1-3), wherein the compound of Formula (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one or (R)-6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin3(2H)-one. (1-5)

[0012] The pharmaceutical composition of any of (1-1) - (1-4), wherein the symptom related to increased induction of megakaryocyte differentiation is increased platelet production. (1-6)

[0013] The pharmaceutical composition of any of (1-1) - (1-4), wherein the disease related to increased induction of megakaryocyte differentiation is essential thrombocythemia. (2-1) Petition 870250079785, dated 05 / 09 / 2025, page 8 / 37 4 / 18 Use of a compound of Formula (I): [Chem. 3] wherein R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation. (2-2)

[0014] The use of (2-1), where the compound of Formula (I) is a compound of Formula (Ia): [Chem. 4] (2-3)

[0015] The use of (2-1) or (2-2), wherein the compound of Formula (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one or (R)-6-(2,3-difluoro-4-(2-hydroxy-2methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one. (2-4)

[0016] The use of any of (2-1) - (2-3), wherein the symptom related to increased induction of megakaryocyte differentiation is increased platelet production. Petition 870250079785, dated 05 / 09 / 2025, page 9 / 37 5 / 18 (2-5)

[0017] The use of any of (2-1) - (2-3), wherein the disease related to increased induction of megakaryocyte differentiation is essential thrombocythemia. (3-1)

[0018] A method for preventing and / or treating a symptom and / or disease related to increased induction of megakaryocyte differentiation, which comprises administering an effective amount of a compound of Formula (I): [Chem. 5] wherein R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof to an individual in need thereof. (3-2)

[0019] The method of (3-1), wherein the compound of Formula (I) is a compound of Formula (Ia): [Chem. 6] (3-3)

[0020] The (3-1) or (3-2) method, wherein the compound of Formula Petition 870250079785, dated 05 / 09 / 2025, page 10 / 37 6 / 18 (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one or (R)-6-(2,3-difluoro-4-(2-hydroxy-2methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one. (3-4)

[0021] The method of any one of (3-1) - (3-3), in which the symptom related to increased induction of megakaryocyte differentiation is increased platelet production. (3-5)

[0022] The method of any one of (3-1) - (3-3), in which the disease related to increased induction of megakaryocyte differentiation is essential thrombocythemia. (4-1)

[0023] A compound of Formula (I): [Chem. 7] wherein R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation. (4-2)

[0024] The compound or a pharmaceutically acceptable salt thereof of (4-1), wherein the compound of Formula (I) is a compound of Formula (Ia): [Chem. 8] Petition 870250079785, dated 05 / 09 / 2025, p. 11 / 37 7 / 18 (4-3)

[0025] The compound or a pharmaceutically acceptable salt thereof of (4-1) or (4-2), wherein the compound of Formula (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one or (R)-6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one. (4-4)

[0026] The compound or a pharmaceutically acceptable salt thereof of any of (4-1) - (4-3), wherein the symptom related to increased induction of megakaryocyte differentiation is increased platelet production. (4-5)

[0027] The compound or a pharmaceutically acceptable salt thereof of any of (4-1) - (4-3), wherein the disease related to increased induction of megakaryocyte differentiation is essential thrombocythemia. (5-1)

[0028] Use of a compound of Formula (I): [Chem. 9] (I) wherein R1, R2, R3 and R4 are independently halogen or C1-3 halogen Petition 870250079785, dated 05 / 09 / 2025, page 12 / 37 8 / 18 kilo, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation. (5-2)

[0029] The use of (5-1), wherein the compound of Formula (I) is a compound of Formula (Ia): [Chem. 10] (5-3)

[0030] The use of (5-1) or (5-2), wherein the compound of Formula (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one or (R)-6-(2,3-difluoro-4-(2-hydroxy-2methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one. (5-4)

[0031] The use of any of (5-1) - (5-3), wherein the symptom related to increased induction of megakaryocyte differentiation is increased platelet production. (5-5)

[0032] The use of any of (5-1) - (5-3), wherein the disease related to increased induction of megakaryocyte differentiation is essential thrombocythemia. EFFECT OF THE INVENTION

[0033] The present compound or a pharmaceutically acceptable salt thereof can selectively inhibit differentiation from cells Petition 870250079785, dated 05 / 09 / 2025, page 13 / 37 9 / 18 hematopoietic stem cells in megakaryocytes, thus, it is expected to have an effect for the treatment and / or prevention of thrombocytosis, such as essential thrombocythemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 shows the electrophoresis result showing the formation of a complex between PDE3A and SLFN12 in Example 1.

[0035] Figure 2 shows the electrophoresis result showing the increase in SLFN12 protein in Example 12.

[0036] Figure 3 is a graph showing the effect of differentiation in megakaryocytes in Example 3.

[0037] Figure 4 is a graph showing the effect of differentiation in erythroid cells in Example 3.

[0038] Figure 5 is a graph showing the effect on differentiation in myeloid cells in Example 5. DESCRIPTION OF MODALITIES

[0039] The expressions and terms used here are explained in detail below.

[0040] In this report, the halogen is fluorine, chlorine, bromine, or iodine. It is preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine, and even more preferably fluorine.

[0041] In this report, C1-3 alkyl is a linear or branched alkyl having 1 to 3 carbon atoms (C1-3), and specific examples include methyl, ethyl, n-propyl and isopropyl, preferably methyl.

[0042] The individual as used here is a vertebrate, and specific examples thereof include mammals, reptiles, and birds. Examples of mammals include humans, companion animals (e.g., dogs and cats), and farm animals (e.g., cows, horses, pigs, and sheep), and preferably human beings.

[0043] Each substituent in the compound of Formula (I) in the present invention (hereinafter referred to as Compound (I)) is explained Petition 870250079785, dated 05 / 09 / 2025, page 14 / 37 10 / 18 below.

[0044] R1, R2, R3 and R4 in Compound (I) are independently halogen or C1-3 alkyl, preferably fluorine or methyl. Or R1 and R2 are halogen, preferably fluorine, and R3 and R4 are C1-3 alkyl, preferably methyl.

[0045] A specific type of Compound (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or (R)-6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one.

[0046] A specific embodiment of Compound (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin3(2H)-one.

[0047] A specific embodiment of Compound (I) is (R)-6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin3(2H)-one.

[0048] Compound (I) in the present invention includes a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt thereof may be an acidic addition salt or possibly a salt with a base depending on the types of substituents. Examples of the acid herein include organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid and lactic acid. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyl Petition 870250079785, dated 05 / 09 / 2025, p. 15 / 37 11 / 18 chlorohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picolin and choline; and ammonium salts and the like. The present compound can also form a salt with an amino acid such as lysine, arginine, aspartic acid, glutamic acid and the like.

[0049] Compound (I) of the present invention also comprises various hydrates, solvates and crystal polymorphisms of Compound (I) and salts thereof.

[0050] Compound (I) of the present invention may be in the form of a cocrystal or cocrystal salt. A cocrystal or cocrystal salt means a crystalline substance composed of two or more individual solids at room temperature, said individual solids having different physical properties (e.g., structure, melting point, heat of fusion, etc.). Such cocrystals and cocrystal salts may be prepared using known cocrystallization methods.

[0051] Compound (I) of the present invention is a known compound, which can be prepared, for example, in the manner of a method disclosed in WO 2017 / 150654.

[0052] The pharmaceutical composition comprising Compound (I) of the present invention as an active ingredient is described below.

[0053] The above pharmaceutical composition is a formulation of the present Compound (I) in the form of a general pharmaceutical composition, which is prepared with commonly used carriers, diluents and / or excipients such as fillers, bulking agents, binders, humectants, disintegrants, surfactants and lubricants (also collectively referred to herein as pharmaceutically acceptable carrier).

[0054] Such a pharmaceutical composition can be selected in various ways, depending on the therapeutic purpose, and typical examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions). Petition 870250079785, dated 05 / 09 / 2025, p. 16 / 37 12 / 18 sões, etc.).

[0055] In the preparation of oral formulations such as tablets, a wide range of known carriers can be used. Examples of carriers include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter and hydrogenated oil; Absorption enhancers such as quaternary ammonium compounds and sodium lauryl sulfate; humectants such as glycerin and starch;Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicate; lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol; and the like. In addition, flavorings, flavoring agents, sweetening agents, etc., may be added as needed.

[0056] In addition, tablets may be coated with a general coating material if necessary to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enterically coated tablets, film-coated tablets or double-layer tablets or multi-layer tablets.

[0057] In pill making, a wide range of known carriers can be used. Examples of carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin and talc; binders such as gum arabic in Petition 870250079785, dated 05 / 09 / 2025, page 17 / 37 13 / 18 powder, tragacanth powder, gelatin and ethanol; disintegrants such as laminarin and agar; and similar.

[0058] In the formation of suppositories, a wide range of known carriers can be used. Examples of carriers include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[0059] Liquids, emulsions, and suspensions prepared as injections are preferably sterilized and made isotonic to blood. Diluents used in the liquids, emulsions, and suspensions may be any known and widely used diluents, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, these preparations may comprise sodium chloride, glucose, or glycerin in sufficient quantities to prepare an isotonic solution, and may also comprise general solubilizing agents, buffers, sedatives, etc., and, in addition, if necessary, coloring agents, preservatives, etc., and / or other medications.

[0060] The amount of compound (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition is not particularly limited and may be appropriately selected from a wide range, but typically the Compound (I) or a salt thereof of the present invention is preferably contained in an amount of about 1% to about 70% of the pharmaceutical composition.

[0061] The method for administering the pharmaceutical composition of the present invention is not particularly limited, and it can be administered by a method suitable for the dosage form, the age and sex of the individual / patient (especially a human being), the disease state and other conditions. For example, it can Petition 870250079785, dated 05 / 09 / 2025, page 18 / 37 14 / 18 can be administered orally if it is in the form of a tablet, pill, liquid, suspension, emulsion, granules, or capsules. If it is an injection, it can be administered intravenously, either alone or in a mixture with a common replacement fluid such as glucose or amino acids, or it can be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally, as needed. In the case of a suppository, it can be administered rectally.

[0062] The dose of the pharmaceutical composition may be selected appropriately according to the method of administration, the age and sex of the individual / patient (especially human being), the disease state and other conditions, but normally about 0.001 to about 100 mg, preferably about 0.001 to about 50 mg per 1 kg of body weight may be administered per day in one to several portions.

[0063] The dose is affected by several conditions, and in some cases a dose below the range mentioned above may be sufficient, while in others a dose above the range mentioned above may be necessary.

[0064] The dosage of pharmaceutical compositions includes, for example, a single dose of 0.15 mg, 0.3 mg, 0.6 mg, 1 mg, 2 mg, 4 mg or 6 mg, but is not limited to these.

[0065] The frequency of administration of the above pharmaceutical composition includes, for example, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, or once every two weeks, or it may also be a combination thereof. As an example of such combination administration, the pharmaceutical composition may be administered once on the first day, then after one week, once daily for five weeks. Petition 870250079785, dated 05 / 09 / 2025, p. 19 / 37 15 / 18 consecutive days.

[0066] Compound (I) of the present invention or a pharmaceutically acceptable salt thereof selectively inhibits differentiation from hematopoietic stem cells into megakaryocytes. Compound (I) of the present invention or a pharmaceutically acceptable salt thereof is useful for the treatment and / or prevention of thrombocytosis, for example, essential thrombocythemia.

[0067] The descriptive reports of all patent and non-patent literature cited in this report are incorporated herein by reference in their entirety. Examples

[0068] The present invention is explained in more detail below by means of the following Examples, but these do not limit the present invention, and these may be modified to the extent that they do not depart from the scope of the present invention.

[0069] As the test substance, (R)-6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (Compound 1) was used. Example 1. Formation of the PDE3A and SLFN12 complex

[0070] In order to examine whether Compound 1 forms a complex between PDE3A and SLFN12, an agglutination confirmation experiment using immunoprecipitation was performed. PFSK-1 and HeLa cell lines, which express PDE3A and SLFN12, were treated with Compound 1 (1 μmol / L) for 16 hours, and then immunoprecipitated using anti-PDE3A antibody. As a result, coprecipitation with SLFN12 was confirmed, as shown in Figure 1. Example 2. Increase in SLFN12 protein

[0071] In order to examine the effect of Compound 1 on the SLFN12 protein level, Western blot analysis was performed. PFSK-1, HeLa or U-87 MG cell lines were treated with Compound 1 (1 Petition 870250079785, dated 05 / 09 / 2025, page 20 / 37 16 / 18 μmol / L) for 16 hours, and SLFN12 protein was detected in each test sample.

[0072] The result is shown in Figure 2. In test samples using PFSK-1 or HeLA that highly express PDE3A, increased SLFN12 protein levels were observed when treated with Compound 1 compared to untreated with Compound 1. On the other hand, in test samples using U-87 MG that hardly express PDE3A, no significant, Compound 1-dependent increase in SLFN12 protein level was observed. Example 3. Action of inhibiting megakaryocyte differentiation.

[0073] It was investigated whether Compound 1 inhibits the differentiation of CD34-positive cells into megakaryocytes. CD34-positive bone marrow-derived cells were cultured for 10 days in the presence and absence of Compound 1 in megakaryocyte differentiation medium (HemaTox™ Megakaryocyte Kit, STEMCELL™ Technologies) according to the kit instructions. The number of CD41-positive megakaryocytes was counted by flow cytometry and cell viability relative to the untreated cell group was calculated. The test was conducted three times using CD34-positive cells derived from different donors, and cell viability was determined with the control as 100%.

[0074] The result is shown in Figure 3. Compound 1 at concentrations of 3 nmol / L or more significantly decreased the number of CD41-positive megakaryocytes. And the 50% inhibition concentration (IC50) was 17.0 nmol / L (95% confidence interval: 10.3-23.7 nmol / L). Example 4. Action of Compound 1 for differentiation into erythroblast-like cells.

[0075] It was studied whether Compound 1 inhibits the differentiation of CD34-positive cells into erythroblasts. CD34-positive cells Petition 870250079785, dated 05 / 09 / 2025, page 21 / 37 17 / 18 CD34-derived bone marrow cells were cultured for 7 days in erythroid differentiation medium (HemaTox™ Erythroid Kit, STEMCELL™ Technologies) according to the kit instructions. The numbers of CD71-positive and CD235-positive erythroid cells were counted by flow cytometry, and cell viability relative to the untreated cell group was calculated. The test was conducted twice using CD34-positive cells derived from different donors, and cell viability was determined with controls as 100%.

[0076] The result is shown in Figure 4. Compound 1 at concentrations of 100 nmol / L or less did not affect the differentiation of hematopoietic stem cells into erythroid cells. Example 5. Action of Compound 1 for differentiation into myeloid cells.

[0077] It was investigated whether Compound 1 inhibits the differentiation of CD34-positive cells into myeloid cells. CD34-positive bone marrow-derived cells were cultured for 7 days in myeloid differentiation medium (HemaTox™ Myeloid Kit, STEMCELL™ Technologies) according to the kit instructions. The number of CD13-positive and CD15-positive myeloid cells was counted by flow cytometry, and cell viability relative to the untreated cell group was calculated. The test was conducted twice using CD34-positive cells derived from different donors, and cell viability was determined with the control as 100%.

[0078] The result is shown in Figure 5. Compound 1 at 30 nmol / L inhibited the differentiation of hematopoietic stem cells into myeloid cells, but there was no significant difference at 100 nmol / L, that is, the result showed no concentration-dependent inhibition effect of Compound 1 on differentiation. Petition 870250079785, dated 05 / 09 / 2025, page 22 / 37 18 / 18 INDUSTRIAL APPLICABILITY

[0079] The present compound or a pharmaceutically acceptable salt thereof inhibits the differentiation of hematopoietic stem cells into megakaryocytes, thus it can be used for the treatment and / or prevention of thrombocytosis, such as essential thrombocytopenia. Petition 870250079785, dated 05 / 09 / 2025, page 23 / 37

Claims

1 / 4 CLAIMS 1. Pharmaceutical composition, characterized in that it comprises a compound of Formula (I): [Chem. 1] in which R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of a symptom and / or a disease related to increased induction of megakaryocyte differentiation.

2. Pharmaceutical composition according to claim 1, characterized in that the compound of Formula (I) is a compound of Formula (Ia): [Chem. 2] 3. Pharmaceutical composition, according to claim 1, characterized in that R1 and R2 are fluorine and R3 and R4 are methyl.

4. Pharmaceutical composition, according to claim 1, characterized in that the compound of Formula (I) is 6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one or (R)-6-(2,3-difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one.

5. Pharmaceutical composition, according to any one of claims 1 to 4, characterized in that the symptom related to increased induction of megakaryocyte differentiation is increased platelet production.

6. Pharmaceutical composition, according to any one of claims 1 to 4, characterized in that the disease related to increased induction of megakaryocyte differentiation is essential thrombocythemia.

7. Use of a compound of Formula (I): [Chem. 3] characterized in that R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation.

8. Method for prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation, characterized in that it comprises administering an effective amount of a compound of Formula (I): [Chem. 4] Petition 870250079785, dated 05 / 09 / 2025, page 25 / 37 3 / 4 in which R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof to an individual in need thereof.

9. Compound of Formula (I): [Chem. 5] wherein R1, R2, R3 and R4 are independently halogen or C1-3 alkyl, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the prevention and / or treatment of a symptom and / or a disease related to increased induction of megakaryocyte differentiation.

10. Use of a compound of Formula (I): [Chem. 6] in which R1, R2, R3 and R4 are independently halogen Petition 870250079785, dated 05 / 09 / 2025, p. 26 / 37 4 / 4 or C1-3 alkyl, or a pharmaceutically acceptable salt thereof, characterized in that it is used in the manufacture of a medicament for the prevention and / or treatment of a symptom and / or disease related to increased induction of megakaryocyte differentiation. Petition 870250079785, dated 05 / 09 / 2025, p. 27 / 37

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