CYCLIC METHYLACTAM COMPOUND AND ITS PHARMACEUTICAL USE

Abstract

One objective hereof is to provide a cyclic methyl-lactam compound exhibiting SGLT1 inhibitory activity and useful as a drug, or a salt thereof acceptable for pharmaceutical use, a pharmaceutical composition comprising it, and its pharmaceutical use. The following compound of formula (1), or a salt acceptable for pharmaceutical use, a pharmaceutical composition comprising it, and its pharmaceutical use are provided.

Description

Description CYCLIC METHYLACTAM COMPOUND AND ITS PHARMACEUTICAL USE Technical field

[0001] The present invention relates to a cyclic compound having SGLT1 inhibitory activity or a salt acceptable for pharmaceutical use, a pharmaceutical composition comprising it, and its pharmaceutical use. Background of the technique [0002 ] SGLT1, or sodium-glucose cotransporter 1, is known to play a significant role in the absorption of glucose and galactose in the small intestine. Human patients with SGLT1 deficiency are reported to have glucose-galactose malabsorption. Furthermore, SGLT1 expression in the small intestine has been confirmed to be increased in diabetic patients, and it is believed that the increased sugar absorption in diabetic patients originates from a high presence of SGLT1 in the small intestine. IF-2019-47864117-APN-ANp#INPI Page 1 of 93

[0003] Based on current knowledge, an SGLT1 inhibitor is expected to normalize blood glucose levels by blocking glucose absorption in the small intestine. Therefore, an SGLT1 inhibitor is considered effective against diabetes and diabetic complications related to hyperglycemia. It is also considered effective against obesity by inhibiting glucose absorption in the human body (Non-Patent Literature 1 and 2).

[0004] Voglibose, a generic name, is a drug approved for manufacture and marketing under Article 14 of the Pharmaceutical Affairs Act of Japan (Approval Number: 21600AMZ00368). Voglibose improves postprandial blood glucose levels by inhibiting the disaccharidase α-glucosidase, which breaks down disaccharides in the intestinal mucosa into monosaccharides, and by inhibiting or delaying the digestion and absorption of carbohydrates in the intestinal tract. This pharmacological effect is known to be effective against late-onset type 2 diabetes associated with impaired glucose tolerance. Based on current knowledge, it is thought that inhibiting sugar absorption through the small intestine with an SGLT1 inhibitor, and consequently the IF-2019-47864117-APN-ANp#INPI Page 2 of 93 Improvement of excess blood glucose after eating, is effective against the late onset of type 2 diabetes in impaired glucose tolerance.

[0005] The presence of SGLT1 is confirmed in cardiac muscle cells. GLUT1 (Glucose Transporter Type 1) and GLUT4 (Glucose Transporter Type 4) are known to generally play a role in glucose uptake in cardiac muscle cells, and SGLT1 uptake is reduced as a consequence. However, SGLT1 expression is induced in cardiac muscle cells of mice into which mutated PRKAG2 (AMPK gamma subunit 2) genes are introduced—a gene responsible for familial hypertrophic cardiomyopathy (glycogen storage myocardosis)—or in mice that have undergone treatment for myocardial ischemia. SGLT1 is reported to contribute to glucose uptake in cardiac muscle cells in these conditions.It is thought that glucose taken up by SGLT1 is either excessively stored or metabolized within cardiac muscle cells, causing cell damage. However, the mouse model described above reports that glycogen storage in cardiac muscle cells is actually inhibited. IF-2019-47864117-APN-ANP#INPI · Page 3 of 93 for treatment with a non-selective SGLT inhibitor: the florizina. Based on current knowledge, it is thought that an SGLT1 inhibitor is effective against hypertrophic cardiomyopathy and ischemic heart disease by inhibiting the uptake of excess glucose in cardiac muscle cells (Non-Patent Literature 3 and 4).

[0006] SGLT1 is stabilized in cancer cells by epidermal growth factor receptors, which are surface proteins present on various types of cancer cells. Transporters of glucose, lactic acid, amino acids, and other substances are known to be involved in supplying nutrients to cancer cells. Specifically, regarding glucose transport, SGLT1 and GLUT1 continuously supply glucose to cancer cells. When glucose is deprived after a prolonged period, the cells are destroyed by autophagy. Based on current knowledge, it is thought that an SGLT1 inhibitor inhibits the delivery of glucose to cancer cells and exhibits anticancer activity (Non-Patent Literature 5 and 6).

[0007] Because carbohydrates break down into IF-2019-47864117-APN-ANP#INPI Page 4 of 93. Monosaccharides in the gastrointestinal tract are present in the diet and are absorbed in the upper gastrointestinal tract; many sugars never reach the lower gastrointestinal tract. However, when drugs that delay or inhibit glucose absorption are administered, or when a large amount of resistant polysaccharides is ingested, the undigested sugars are retained in the lower gastrointestinal tract, and these retained sugars cause osmotic diarrhea. An SGLT1 inhibitor inhibits glucose absorption and increases the amount of monosaccharides in the lower gastrointestinal tract. Therefore, the SGLT1 inhibitor is considered effective against constipation.

[0008] Diabetes is caused by high blood glucose levels due to insufficient insulin action, and consistently elevated blood glucose levels can lead to diabetic complications (e.g., retinopathy, nephropathy, and neuropathies, known as microangiopathies; and cerebrovascular diseases, ischemic heart disease, and obliterative arteriosclerosis of the lower limbs, known as macroangiopathies). Obesity is also among the diseases associated with high blood glucose levels. IF-2019-47864117-APN-ANp#INPI Page 5 of 93 Diabetes is classified as type 1 and type 2. Type 1 diabetes is thought to develop due to impaired insulin action caused by the destruction of insulin-secreting pancreatic beta cells, while type 2 diabetes is thought to develop due to environmental factors such as overeating, lack of exercise, obesity, and stress, as well as aging and multiple genetic factors, including decreased insulin secretion and insulin resistance. Diabetes is diagnosed using three classifications: normal type, prediabetes, and diabetes, which are based on blood glucose levels. When any of the following criteria (1) through (4) are identified, the individual is determined to be of the diabetic type and is diagnosed with diabetes or presumptive diabetes (Non-Patent Literature 7): (1) Fasting blood glucose level of 126 mg / dL or higher; (2) 200 mg / dL or more of the two-hour 75 g OGTT (glucose tolerance test) value; (3) 200 mg / dL or more of the random blood glucose level; (4) 6.5% or more of HbAlcg.

[0009] The OGTT used in point (2) above is one of IF-2019-47864117-APN-ANp#INPI Page 6 of 93. Methods for diagnosing diabetes. In general, when a human subject is administered a solution containing 75 g of glucose while fasting, and at a certain time after glucose administration, the blood glucose level is determined to be 200 mg / dL or higher, the subject is then diagnosed with diabetes (Non-Patent Literature 7). Therefore, the OGTT is a diagnostic index for diabetes, and a compound that can reduce blood glucose levels in subjects who have undergone an OGTT is considered effective against diabetes. [Non-Patent Literature]

[0010] [Non-Patent Literature 1] Am J Physiol Gastrointest Liver Physiol. 2002; 282 (2):G241-8. [Non-Patent Literature 2] Nature. 1991; 350(6316):354-6. [Non-Patent Literature 3] J Mol Cell Cardiol. 2010; 49 (4): 683-92. [Non-Patent Literature 4] Cardiovasc Res. 2009; 84(1):111-8 [Non-Patent Literature 5] Cancer Cell. 2008, 13: 38593. [Non-Patent Literature 6] Pharmacol Ther. 2009, 121: 29-40. [Non-Patent Literature 7] Treatment Guide for IF-2019-47864117-APN-ANp#INPI Page 7 of 93 Diabetes 2016-2017. Summary of the invention

[0011] A cyclic methyl-lactam compound possessing SGLT1-inhibiting activity and useful as a drug, or an acceptable salt for pharmaceutical use, is provided; a pharmaceutical composition comprising it; and its pharmaceutical use.

[0012] After exhaustive studies, the present inventors discovered a specific cyclic methyl lactam compound and achieved the present invention.

[0013] In one embodiment, a compound of Formula [I] or a salt acceptable for pharmaceutical use is provided, and its pharmaceutical use. [YO]

[0014] A compound of Formula [I] or an acceptable salt for IF-2019-47864117-APN-ANP#INPI Page 8 of 93 Pharmaceutical use compounds possess SGLT1 inhibitory activity and therefore could be useful for the treatment and / or prevention of various diseases or conditions that can be improved by regulating SGLT1 activity. A compound of Formula [I] or a salt acceptable for pharmaceutical use may also be useful for the treatment and / or prevention of various diseases or conditions that may arise due to elevated blood glucose levels. Brief description of the illustrations

[0015] [Fig. 1] Figure 1 shows that a compound from Example 1 (hereafter referred to as Compound 1) significantly reduced the blood glucose level of SD rats loaded with glucose in OGTT compared to the vehicle. [Fig. 2] Figure 2 shows that, within the test compounds, only Compound 1 significantly reduced the blood glucose level of SD rats with glucose load in OGTT compared to the vehicle. Description of the achievements

[0016] The present invention includes the embodiments illustrated as follows: IF-2019-47864117-APN-ANp#INPI Page 9 of 93 A compound of Formula [I]: Item 1. [I] an acceptable salt for pharmaceutical use. Item 2. A pharmaceutical composition comprising the compound according to item 1 or a salt thereof acceptable for pharmaceutical use and a vehicle acceptable for pharmaceutical use. Item 3. An SGLT1 inhibitor comprising the compound according to Item 1 or a salt acceptable for pharmaceutical use. Item 4. A therapeutic or preventive agent for diabetes comprising the compound according to item 1 or a salt acceptable for pharmaceutical use. Item 5. The therapeutic or preventive agent according to item 4, where the diabetes is type 2. Item 6. A method for inhibiting SGLT1 consisting of administering a therapeutically effective amount of the compound according to Item 1 or a salt acceptable for pharmaceutical use to mammals. Item 7. A method for treating or preventing diabetes that IF-2019-47864117-APN-ANP#INPI Page 10 of 93 comprises administering a therapeutically effective amount of the compound in accordance with item 1 or a salt acceptable for pharmaceutical use to mammals. Item 8. The method according to item 7, where the diabetes is type 2. Item 9. The use of the compound in accordance with item 1 or a salt thereof acceptable for pharmaceutical use for the manufacture of an SGLT1 inhibitor. Item 10. The use of the compound in accordance with item 1 or a salt thereof acceptable for pharmaceutical use for the manufacture of a therapeutic or preventive agent for diabetes. Item 11. The use in accordance with item 10, where the diabetes is type 2. Item 12. A compound in accordance with Item 1 or a salt thereof acceptable for pharmaceutical use for use in inhibiting SGLT1. Item 13. A compound in accordance with item 1 or an acceptable salt for pharmaceutical use for use in the treatment or prevention of diabetes. Item 14. The compound according to item 13 or a salt thereof acceptable for pharmaceutical use, wherein the diabetes is of type 2. Item 15. A commercial package including the composition according to item 2 and a relevant description; the description indicates that the composition may or must IF-2019-47864117-APN-ANP#INPI Page 11 of 93 to be used for the treatment and / or prevention of diabetes. Item 16. A kit comprising the composition according to item 2 and a relevant description; the description indicates that the composition can or should be used for the treatment and / or prevention of diabetes.

[0017] The term "salt acceptable for pharmaceutical use" encompasses all salts known in the art that are not associated with excessive toxicity. Such salts acceptable in pharmaceuticals specifically include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Several forms of salts acceptable for pharmaceutical use are known in the art and are described in, for example, the following references: (a) Berge et al., J. Pharm. Sci., 66, pl-19 (1977), (b) Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chern., 50, pages 6665-6672 (2007). A compound of Formula [I] can react with an inorganic acid, an organic acid, an inorganic base, or an organic base according to known methods IF-2019-47864117-APN-ANP#INPI Page 12 of 93 per se to produce the salt acceptable for corresponding pharmaceutical use.

[0018] Said inorganic acid salt comprises a salt with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Said salt preferably comprises a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Said organic acid salt comprises a salt with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphoric-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycol arsenic acid, hexylresorcinol, hydroxynaphthoic acid, 2-hydroxy-l-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, . IF-2019-47864117-APN-ANP#INPI Page 13 of 93 picric acid, propanoic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, and glutamic acid. Said salt preferably comprises a salt with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-l-ethanesulfonic acid.

[0019] Said salt with an organic base comprises a salt with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium. Said salt preferably comprises a salt with sodium, potassium, calcium, magnesium, and zinc. Said salt with an organic base comprises a salt with arecoline, betaine, choline, clemizole, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tri(hydroxymethyl)methylamine, arginine, and lysine. Said salt preferably comprises a salt with tri(hydroxymethyl)methylamine, N-methylglucamine, and lysine.

[0020] A compound of Formula [I] or a salt thereof IF-2019-47864117-APN-ANP#INPI Page 14 of 93 acceptable for pharmaceutical use may exist in its solvate form. The term “solvate” refers to a compound where the solvate molecule is coordinated with a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use, and includes a hydrate. The solvate is preferably a solvate acceptable for pharmaceutical use; and comprises, for example, a hydrate, an ethanolate, and a dimethyl sulfoxide solvate of a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use. Such solvate specifically comprises hemihydrate, monohydrate, dihydrate, and monoethanolate of a compound of Formula [I]; and a sodium salt monohydrate of a compound of Formula [I] and a 2 / 3 dihydrochloride salt ethanolate. These solvates may be obtained according to any known method.

[0021] A compound of Formula [I] can be labeled with an isotope such as 2H, 3H, 14C, and 35S.

[0022] A compound of Formula [I] or a salt thereof acceptable for pharmaceutical use is preferably a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use that is substantially purified, and more preferably a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use that has a purity of 80% or more. IF-2019-47864117-APN-ANP#INPI Page 15 of 93

[0023] A compound of Formula [I] or a salt thereof acceptable for pharmaceutical use possesses SGLT1 inhibitory activity, and may therefore be useful for the treatment and / or prevention of various diseases or conditions that may be expected to be improved by regulation of SGLT1 activity, e.g., diabetes (e.g., type 1 and type 2 diabetes), obesity, complications of diabetes (e.g., retinopathy, nephropathy, and neuropathy, which are collectively known as microangiopathies; and cerebrovascular diseases, ischemic heart disease, and obliterative arteriosclerosis of the lower limbs, which are collectively known as macroangiopathies), hypertrophic cardiomyopathy, ischemic heart disease, cancer, and constipation.

[0024] The term SGLT1 inhibition refers to the inhibition of SGLT1 function to eliminate or reduce its activity; for example, it means that SGLT1 function is inhibited based on Example Test 1 detailed later. The term SGLT1 inhibition preferentially refers to the inhibition of human SGLT1. Inhibition of function, or the elimination or reduction of activity, is preferentially carried out according to clinical indications for humans. IF-2019-47864117-APN-ANP#INPI Page 16 of 93

[0025] The term SGLT1 inhibitor can be any substance that inhibits SGLT1, and includes small molecular compounds, nucleic acids, polypeptides, proteins, antibodies, and vaccines. The term SGLT1 inhibitor preferentially refers to an SGLT1 inhibitor for humans.

[0026] A compound of Formula [I] or a salt thereof acceptable for pharmaceutical use may also prove useful in the treatment and / or prevention of various diseases or conditions that may be caused by high blood glucose levels. The term various diseases or conditions that can be caused by elevated blood glucose levels includes, for example, diabetes (e.g., type 1 and type 2 diabetes), obesity, complications of diabetes (e.g., retinopathy, nephropathy, and neuropathy, which together are known as microangiopathies; and cerebrovascular diseases, ischemic heart disease, and obliterative arteriosclerosis of the lower limbs, which together are known as macroangiopathies).

[0027] The term treatment as used in this document includes the improvement of conditions, the IF-2019-47864117-APN-ANp#INPI Page 17 of 93 prevention of aggravations, continuation of remission, prevention of exacerbation, and prevention of relapses. The term prevention as used herein includes delaying the onset of conditions. For example, diabetes prevention includes delaying the onset of type 2 diabetes in impaired glucose tolerance.

[0028] A pharmaceutical composition used herein may be prepared from a therapeutically effective amount of a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use and at least one or more vehicles acceptable for pharmaceutical use, optionally followed by mixing, in accordance with methods known in the art of medicinal preparations. The amount of a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use comprising the pharmaceutical composition varies based on a factor such as the pharmaceutical form and dosage amount and ranges, for example, from 0.1 to 100% by weight of the total amount of the composition.

[0029] A pharmaceutical form that must be formulated with a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use comprises oral preparations such IF-2019-47864117-APN-ANP#INPI Page 18 of 93 such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions; and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0030] The term “acceptable vehicle for pharmaceutical use” comprises various organic or inorganic carrier substances conventionally used for a component of a formulation. These substances include, for example, excipients, disintegrants, binders, fluidizers, and lubricants for solid preparations; solvents, solubilizing agents, suspending agents, tonicity agents, buffering agents, and soothing agents for liquid preparations; and bases, emulsifying agents, wetting agents, stabilizers, stabilizing agents, dispersing agents, plasticizers, pH adjusters, absorption promoters, gelling agents, antiseptic agents, bulking agents, solubilizers, solubilizing agents, and suspending agents for semisolid preparations. If necessary, additives such as preservatives, antioxidants, colorants, and sweeteners may be added.

[0031] IF-2019-47864117-APN-ANP#INPI Page 19 of 93 This excipient comprises, for example, lactose, fine white sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, calcium carmellose, starch carboxymethyl, low-substituted hydroxypropyl cellulose, and gum arabic. This disintegrant includes, for example, carmellose, calcium carmellose, sodium carmellose, sodium starch carboxymethyl, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and crystalline cellulose. Said binder comprises, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, providone, crystalline cellulose, fine white sugar, dextrin, corn starch, gelatin, sodium carmellose, and gum arabic. This fluidizer comprises, for example, light silicic acid and magnesium stearate. This lubricant comprises, for example, magnesium stearate, calcium stearate, and talc. This solvent comprises, for example, purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. The solubilizing agent comprises, for example, propylene glycol, d-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate. IF-2019-47864117-APN-ANP#INPI Page 20 of 93 The suspending agent comprises, for example, benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, providone, methylcellulose, and glycerol monostearate. This tonic agent comprises, for example, glucose, d-sorbitol, sodium chloride, and d-mannitol. This buffering agent comprises, for example, dibasic sodium phosphate, sodium acetate, sodium carbonate, and sodium citrate. This calming agent includes, for example, benzyl and alcohol. This base comprises, for example, water, oils of animal or vegetable origin such as olive oil, corn oil, peanut oil, sesame oil, and castor oil, lower alcohols such as ethanol, propanol, propylene glycol, 1,3-butanediol, and phenol, fatty acids and esters, waxes, higher alcohol, polyhydric alcohol, hydrocarbons such as white petrolatum, liquid paraffin, and paraffin, hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose, synthetic polymers such as carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, and IF-2019-47864117-APN-ANP#INPI Page 21 of 93 polyvinylpyrrolidone, propylene glycol, macrogol as Macrogol 200 to 600, and a combination of two or more of these elements. This preservative agent comprises, for example, ethyl para-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid. This antioxidant agent includes, for example, sodium sulfite and sorbic acid. This coloring agent comprises, for example, food colorings (for example, Red No. 2 or No. 3, Yellow No. 4, or No. 5) and β-carotene. This sweetening agent includes, for example, sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0032] A pharmaceutical composition described herein may be administered orally or parenterally (e.g., topically, rectally, intravenously, intramuscularly, and subcutaneously) to humans as well as to non-human mammals such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys. The recommended dosage varies based on the subjects to whom the composition will be administered, the diseases or conditions, the pharmaceutical forms, and the route of administration. For example, the daily dose for oral administration in an adult patient is generally in the range of approximately 0.01 IF-2019-47864117-APN-ANP#INPI Page 22 of 93 mg to 1 g of the active ingredient, i.e., a compound of Formula [I]. This dose may be administered once or several times.

[0033] Also useful are the following items: a kit, such as administration, treatment, and / or prevention kits; a package, such as packaged goods; and a medicinal set and / or case comprising a pharmaceutical composition comprising a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use as an active ingredient or active agent, and a description containing the composition indicating that the composition may or should be used for treatment and / or prevention. This medicinal kit, package, and set may comprise one or more containers filled with the pharmaceutical composition or one or more active ingredients and other drugs or medicines (or ingredients) used for the composition. Examples of such a medicinal kit, package, or set include commercial kits, commercial packages, and commercial medicinal sets for appropriate use in the treatment and / or prevention of the diseases for which it is intended.The description included in said kit, package and medicinal set includes a warning note or a leaflet in the form required by the government agency that regulates the production, use, or sale of products • IF-2019-47864117-APN-ANP#INPI. Page 23 of 93 pharmaceutical or biological products, which ensures approval by the government agency for the production, use, or sale of products related to administration to humans. The kit, package, and medicinal set may include packaged products as well as structures prepared for the appropriate administration steps to ensure the most preferable medical treatment and / or prevention, including the treatment and / or prevention of the diseases for which it is intended.

[0034] A method for preparing a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use is illustrated below. A method for preparing a compound of Formula [I] or a salt thereof acceptable for pharmaceutical use is not limited to that illustration. Each compound obtained at each step can be isolated and / or purified, if necessary, according to any of the known methods such as distillation, recrystallization, and column chromatography, or optionally, a further step can proceed without the need for isolation and / or purification. In this document, the term ambient temperature refers to a temperature that has not been controlled and is in the range of 1°C to 40°C as a realization. IF-2019-47864117-APN-ANP#INPI Page 24 of 93

[0035] [Preparation Method A] A compound of Formula [I] can be prepared according to Preparation Method Al or A2 as described in the following scheme. Preparation Method Al.

[0036] (Step Al-1) A compound of Formula [I] can be prepared by reacting a compound of Formula [I] or a salt thereof with a compound of Formula [2] or a salt thereof in the presence of a condensing agent and an additive in a solvent. The condensing agent used in the present method comprises, for example, dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSOHC1), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), O(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), {{[(l-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylamine IF-2019-47864117-APN-ANP#INPI Page 25 of 93 hexafluorophosphate (COMU), 4-(4,6-dimethoxy-l,3,5-triazine2-11)-4-methylmorpholinium chloride n-hydrate (DMT-MM), (benzotriazol-l-yloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP), diphenylphosphorylazide, and acid anhydride propylphosphonic. The additive used in the present method comprises, for example, 1-hydroxybenzotriazole (HOBt), l-hydroxy-7azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine, and 1-methylimidazole. The solvent used in the present method comprises, for example, halogenated hydrocarbon solvents such as chloroform, ether solvents such as tetrahydrofuran; polar solvents such as pyridine, acetonitrile, N,N-dimethylformamide; and a mixture of solvents including any of the aforementioned solvents. The reaction temperature of the present method is in the range of 0°C to 100°C, for example. When a salt of a compound of Formula [1] is used, the reaction can be carried out in the presence of a base; such base comprises, for example, organic bases such as triethylamine and salts of alkali metals such as sodium carbonate.

[0037] A compound of Formula [I] can also be prepared by converting a compound of Formula [2] with IF-2019-47864117-APN-ANp#INPI Page 26 of 93 a halogenating agent in the corresponding carboxylic halide in a solvent, followed by a reaction with a compound of Formula [1] in the presence of a base. The halogenating agent used in the reaction includes, for example, oxalyl chloride and thionyl chloride. The preferred halogenating agent is oxalyl chloride. The base used in the reaction includes, for example, organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine; and alkali metal salts such as sodium bicarbonate and sodium carbonate. Pyridine is the preferred base. The solvent used in the present method comprises, for example, halogenated hydrocarbon solvents such as chloroform; ether solvents such as cyclopentyl methyl ether and tetrahydrofuran; Hydrocarbon solvents such as toluene; and a mixture of solvents including any of these solvents plus water. The preferred solvent is chloroform. The reaction temperature in the present method is in the range, for example, of 0°C to 80°C, and the range of 0°C to 60°C is preferred. In the preparation of the carboxylic halide, N,N,dimethylformamide can be added as an additive.

[0038] IF-2019-47864117-APN-ANP#INPI Page 27 of 93 Preparation Method A2 A2-2H H'-NH [YO] In the scheme, pN1 is a protecting group for the amino group. PN1 is preferably a 2,4-dimethoxybenzyl group.

[0039] (Step A2-1) A compound of Formula [1] or a salt thereof can be reacted with a compound of Formula [3] or a salt thereof according to Preparation Method A1 Step A1-1 to give a compound of Formula [4].

[0040] (Step A2-2) A compound of Formula [I] or a salt thereof can be prepared by removing PN1 from a compound of Formula [4] through a deprotection reaction. This deprotection reaction can be carried out under appropriate conditions depending on PN1. IF-2019-47864117-APN-ANP#INPI Page 28 of 93 For example, when PN1 is 2,4-dimethoxybenzyl, a compound of Formula [I] or a salt thereof can be prepared by reaction with an acid in the presence of an additive in a solvent. The acid used in this method includes, for example, methanesulfonic acid, ptoluenesulfonic acid, and trifluoroacetic acid. Trifluoroacetic acid is the preferred acid. The additive used in the present method comprises, for example, anisole and triethylsilane. The preferred additive is anisole. The solvent used in the present method comprises, for example, halogenated hydrocarbon solvents such as dichloromethane, hydrocarbon solvents such as toluene, water, and a solvent mixture prepared with any of these solvents. An organic acid such as trifluoroacetic acid may also be used as the solvent. The reaction temperature here varies, for example, between 0°C and 130°C, and a range of 25°C to 80°C is preferred. When an acid is used in this step, the following compound of Formula [5] is obtained: IF-2019-47864117-APN-ANP#INPI Page 29 of 93 F [5] Or a salt thereof. A compound of Formula [I] or a salt thereof can be prepared by converting the hydroxyl group into a tert-butoxy group in a compound of Formula [5] or a salt thereof according to any of the known methods. For example, a compound of Formula [I] or a salt thereof can be prepared by reacting a compound of Formula [5] or a salt thereof with ditert-butyl dicarbonate in the presence of magnesium perchlorate. The solvent used in this method includes, for example, halogenated hydrocarbon solvents such as chloroform and ether solvents such as tetrahydrofuran. Chloroform is the preferred solvent. The reaction temperature here varies, for example, between 0°C and 100°C, and preferably from room temperature to 70°C.

[0041] [Preparation Method B] A compound of Formula [1] can be prepared from IF-2019-47864117-APN-ANP#INPI Page 30 of 93 in accordance with Preparation Method B1 as shown in the following scheme. B1 Preparation Method In this scheme, L1 is a leaving group. L1 is preferably chlorine, bromine, or iodine. PN2 is each independently an amine protecting group. The two pN2s preferentially combine with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole.

[0042] (Step Bl-1) A compound of Formula [7] or a salt thereof can be prepared by introducing PN2 into the amino group of a compound of Formula [6] or a salt thereof according to any known method. The introduction of the protecting group can be carried out under appropriate conditions depending on PN2. For example, when two PN2s combine with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole, a compound of Formula [7] can be prepared by reacting IF-2019-47864117-APN-ANP#INPI Page 31 of 93 a compound of Formula [6] with 2,5-hexanedione in a solvent under acidic conditions. The acid used in this method includes, for example, concentrated hydrochloric acid, concentrated sulfuric acid, amidosulfuric acid, ptoluenesulfonic acid, and acetic acid. Acetic acid is the preferred acid. The solvent used in the present process comprises, for example, alcohol solvents such as ethanol, ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, polar solvents such as N,N-dimethylformamide, halogenated hydrocarbon solvents such as dichloroethane, and a solvent mixture prepared with any other of these solvents. An organic acid such as acetic acid may also be used as the solvent. The reaction temperature here varies, for example, from room temperature to 150°C, and preferably from 80°C to 140°C.

[0043] (Step Bl-2) A compound of Formula [8] can be prepared by, for example, a process comprising the following steps: Step (a): reacting a compound of Formula [7] with dibromodifluoromethane in the presence of a base and a catalyst in a solvent, and IF-2019-47864117-APN-ANP#INPI Page 32 of 93 Step (b): Fluorinate the resulting product in the presence of tetramethylammonium fluoride or silver(I) tetrafluoroborate in a solvent. The base used in Step (a) comprises, for example, sodium hydride and potassium terebutoxide. The preferred base is sodium hydride. The catalyst used in Step (a) comprises, for example, tetra-n-butylammonium bromide and zinc. The preferred catalyst is tetra-n-butylammonium bromide. The solvent used in Step (a) comprises, for example, ether solvents such as tetrahydrofuran and polar solvents such as N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. The reaction temperature in Step (a) varies, for example, from 0°C to 40°C, and preferably from 0°C to room temperature. When tetramethylammonium fluoride is used in Step (b), the solvent used in that step comprises, for example, ether solvents such as 1,4-dioxane and polar solvents such as sulfolane. The preferred solvent is sulfolane. When silver(I) tetrafluoroborate is used in Step (b), the solvent used comprises, for example, halogenated hydrocarbon solvents such as dichloromethane. The preferred solvent is dichloromethane. IF-2019-47864117-APN-ANP#INPI Page 33 of 93 When tetramethylammonium fluoride is used in the In step (b), the reaction temperature varies, for example, from 80°C to 180°C, preferably from 100°C to 140°C. When silver(I) tetrafluoroborate is used in step (b), the reaction temperature varies, for example, from -78°C to 50°C, and preferably from -78°C to room temperature.

[0044] (Step B1-3) A compound of Formula [9] can be prepared by introducing L1 into a compound of Formula [8] in the presence of a base in a solvent. For example, when L1 is iodine, a compound of Formula [9] can be prepared by subjecting a compound of Formula [8] to iodination in the presence of a base in the solvent. The base used in the present method comprises, for example, n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, and lithium tetramethylpiperidide. The preferred base is n-butyllithium. The iodizing agent used in the present method includes, for example, iodine, iodine monochloride, nyodosuccinimide, and l-chloro-2-iodoethane. The preferred iodizing agent is iodine. The solvent used in the present method comprises, for example, ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and a solvent mixture prepared with IF-2019-47864117-APN-ANP#INPI Page 34 of 93 any of these solvents. The preferred solvent is tetrahydrofuran. The reaction temperature varies, for example, from 100°C to 40°C, and preferably from -78°C to 20°C. [0045 ] (Step Bl-4) A compound of Formula

[10] or a salt thereof can be prepared by removing PN2 from a compound of Formula [9] through a deprotection reaction. The deprotection reaction can be carried out under appropriate conditions depending on PN2. For example, when two PN2s combine with the nitrogen atom to which they are bonded to form 2,5-dimethylpyrrole, a compound of Formula

[10] or a salt thereof can be prepared by reacting a compound of Formula [9] with hydroxylamine in a solvent. The solvent used in the present method comprises, for example, alcohol solvents such as ethanol, water, and a solvent mixture prepared with any of these solvents. The preferred solvent is a mixture of alcohol solvents with water. The reaction temperature varies, for example, from 40°C to 150°C, and preferably from 80°C to 130°C. Hydroxylamine hydrochloride can be used instead of hydroxylamine. In that case, the reaction should IF-2019-47864117-APN-ANP#INPI Page 35 of 93. The reaction must be carried out in the presence of a base. The base used comprises, for example, organic bases such as triethylamine and alkali metal salts such as sodium carbonate. The preferred base is triethylamine.

[0046] (Step Bl-5) A compound of Formula [1] or a salt thereof can be prepared by the Suzuki coupling reaction of a compound of Formula

[10] or a salt thereof with a compound of Formula

[11] . For example, a compound of Formula [1] or a salt thereof can be prepared by reacting a compound of Formula

[10] or a salt thereof with a compound of Formula

[11] in the presence of a base and a palladium catalyst in a solvent. The palladium catalyst used in the reaction comprises, for example, tetraguis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) dichloromethane adduct, [1,1'-bis(di-tert-butylphosphine)ferrocene]dichloropalladium(II), and a mixture of palladium(II) acetate and tricyclohexylphosphine, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, or 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl. The palladium catalyst of preference is the [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) dichloromethane adduct. IF-2019-47864117-APN-ANP#INPI Page 36 of 93 The base used in the reaction includes, for example, tripotassium phosphate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, and triethylamine. The preferred base is tripotassium phosphate, cesium carbonate, or sodium carbonate. The solvent used in the present method comprises, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, 1-propanol, and 2-propanol; hydrocarbon solvents such as toluene, n-hexane, and xylene; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; and a solvent mixture prepared with any of these solvents and water. The preferred solvent is 1,2-dimethoxyethane, toluene, dimethyl sulfoxide, or a solvent mixture prepared with any of these solvents and water. The reaction temperature varies, for example, from 20°C to 150°C, and preferably from 80°C to 130°C.

[0047] A compound of Formula

[11] can be prepared according to any of the known methods. The corresponding boronic acid ester can be used instead of a compound of Formula

[11] in the reaction of step B1-5. For example, the aforementioned boronic acid ester can be prepared according to Method

[11] . IF-2019-47864117-APN-ANP#INPI Page 37 of 93 Preparation B2 described in the following scheme. B2 Preparation Method t12l

[13]

[14] In this scheme, R1 is a fluorine or hydroxyl group. L2 is a leaving group. L2 is preferably chlorine, bromine, iodine, p-toluenesulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy. B(OR2)2 is a boronic acid ester. R2 is either independently, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tere-butyl, or alternatively, OR2 can combine with boron to which it bonds to form a cyclic boronic acid ester. B(OR2)2 is preferably a pinacol ester of boronic acid.

[0048] (Step B2-1) A compound of Formula

[13] can be prepared by converting R1 into a tert-butoxy group in a compound of Formula

[12] . The reaction can be carried out according to any of the known methods. When R1 is fluorine, a compound of Formula

[13] can be prepared, for example, by reacting a compound of Formula

[12] with sodium tert-butoxide or potassium tert-butoxide in a solvent. The solvent used in the present method comprises, for example, IF-2019-47864117-APN-ANP#INPI Page 38 of 93 ether solvents such as tetrahydrofuran; and polar solvents such as N,N,dimethylformamide and dimethyl sulfoxide. The preferred solvent is N,N,dimethylformamide. The reaction temperature varies, for example, from 0°C to 100°C, and preferably from room temperature to 85°C. When R1 is a hydroxyl group, a compound of Formula

[13] can be prepared according to, for example, the method for preparing a compound of Formula [I] or a salt thereof from a compound of Formula [5] or a salt thereof, as described in Preparation Method A2 Step A2-2.

[0049] (Step B2-2) A compound of Formula

[14] can be prepared by reacting a compound of Formula

[13] with a boron compound in the presence of a palladium catalyst, an organic phosphorus compound, and a base in the solvent. The palladium catalyst comprises, for example, palladium(II) acetate, palladium(II) chloride, and tris(dibenzylideneacetone)dipalladium(O). The organic phosphorus compound comprises, for example, triphenylphosphane, tricyclohexylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, 2-dicyclohexylphosphine-2',6'dimethoxybiphenyl, 2-dicyclohexylphosphine-2',4',6' IF-2019-47864117-APN-ANP#INPI Page 39 of 93 triisopropylbiphenyl, and 2-dicyclohexylphosphine-2'-(N,N,dimethylamino)biphenyl. Instead of the palladium catalyst and the organic phosphorus compound, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)-dichloromethane adduct, or [1,1'-bis(di-tert-butylphosphine)ferrocene]dichloropalladium(II) can be used. The base includes, for example, potassium acetate, sodium carbonate, cesium carbonate, and potassium carbonate. The preferred base is potassium acetate. The boron compound comprises, for example, boron bis(pinacolate). The solvent includes, for example, ether solvents such as 1,4-dioxane, 1,4-tetrahydrofuran, and 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. The preferred solvent is dimethyl sulfoxide. The reaction temperature varies, for example, from room temperature to 150°C, and preferably from 70°C to 110°C.

[0050] [Preparation Method C] A compound of Formula [2] or a salt thereof and a compound of Formula [3] or a salt thereof can be prepared IF-2019-47864117-APN-ANp#INPI Page 40 of 93 same according to Preparation Method Cl as described in the following scheme. Preparation Method Cl In this scheme, PC1 and P<=2 are each independently a protecting group for carboxy. Preferably, PC1 and PC2 are each independently methyl, ethyl, tert-butyl, or benzyl. R3 is each independently methoxy or ethoxy. L3 is a leaving group. L3 is preferably bromine or chlorine. The other symbols have the same meanings as previously described.

[0051] (Step Cl-1) A compound of Formula

[17] can be prepared by reacting a compound of Formula

[15] with a IF-2019-47864117-APN-ANP#INPI Page 41 of 93 compound of Formula

[16] in the presence of a base in a solvent. The base used in the present method comprises, for example, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate, and sodium hydride. The preferred base is potassium tert-butoxide. The solvent includes, for example, ether solvents such as tetrahydrofuran; alcohol solvents such as methanol and ethanol; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. Tetrahydrofuran is the preferred solvent. The reaction temperature varies, for example, from 78°C to 100°C, and preferably from 0°C to 70°C

[0052] (Cl-2 step) A compound of Formula

[18] can be prepared by reacting a compound of Formula

[17] with formaldehyde (preferably a formaldehyde solution) in the presence of a base in a solvent. The base used in the reaction comprises, for example, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate, and sodium hydride. The base of IF-2019-47864117-APN-ANP#INPI Page 42 of 93, the preferred option is potassium carbonate. The solvent in this specification comprises, for example, ether solvents such as tetrahydrofuran; alcohol solvents such as methanol and ethanol; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. The preferred solvent is tetrahydrofuran. The reaction temperature varies, for example, from 78°C to 100°C, and preferably from 0°C to 70°C.

[0053] (Cl-3 Step) A compound of Formula

[20] can be prepared by reacting a compound of Formula

[18] with a compound of Formula

[19] in a solvent. The solvent in this specification comprises, for example, hydrocarbon solvents such as toluene; alcohol solvents such as methanol and ethanol; and a solvent mixture prepared with any of these solvents. The preferred solvent is toluene. The reaction temperature varies, for example, from 20°C to 150°C, and preferably from 80°C to 130°C.

[0054] (Cl-4 step) A compound of Formula

[21] or a salt thereof can be prepared by removing PC1 from a compound of Formula

[20] through a deprotection reaction. IF-2019-47864117-APN-ANp#INPI Page 43 of 93 This reaction can be carried out under appropriate conditions based on PC1. For example, when PC1 is ethyl, a compound of Formula

[21] or a salt thereof can be prepared by hydrolyzing a compound of Formula

[20] in the presence of a base in the solvent. The base used in the reaction includes, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium ethoxide. The preferred base is sodium ethoxide. The solvent comprises, for example, alcohol solvents such as ethanol, ether solvents such as tetrahydrofuran, water, and a solvent mixture prepared with any of these solvents. The preferred solvent is a solvent mixture prepared with ethanol and water. The reaction temperature varies, for example, from 0°C to 100°C, and preferably from 0°C to 40°C.

[0055] (Cl-5 step) A compound of Formula [3] or a salt thereof can be obtained by separating a compound of Formula

[21] or a salt thereof. The separation of a compound of Formula [3] or a salt thereof can be carried out under appropriate conditions according to any of the most well-known methods in the art. For example, a compound of Formula [3] or IF-2019-47864117-APN-ANP#INPI Page 44 of 93 a salt of the same by separation of a diastereomer salt with a basic optically resolving reagent, followed by treatment of the salt with an acid. The basic optical resolving reagent comprises, for example, (IR,2R)-(-)-2-amino-l-(4-nitrophenyl)-1,3-propanediol. The solvent used in the introduction of the diastereomer salt comprises, for example, alcohol solvents such as 2-propanol, ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and a solvent mixture prepared with any of these solvents and water. The preferred solvent is acetonitrile, 1,2-dimethoxyethane, or the solvent mixture prepared with any of these solvents and water. The optical purity of the diastereomeric salt can be increased by recrystallization. The solvent used in the recrystallization includes, for example, ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, or a solvent mixture prepared with any of these solvents and water. The preferred solvent is a mixture of acetonitrile and water. The acid used in the treatment of the diastereomeric salt includes, for example, hydrochloric acid, sulfuric acid, and potassium bisulfate. The acid of IF-2019-47864117-APN-ANP#INPI Page 45 of 93 preference is hydrochloric acid. The solvent used in the treatment of the diastereomeric salt comprises, for example, ether solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, water, and a solvent mixture prepared with any of these solvents. The preferred solvent is a mixture of ethyl acetate solvent and water.

[0056] (Step Cl-6) A compound of Formula [2] or a salt thereof can be prepared by removing PN1 from a compound of Formula [3] or a salt thereof through a deprotection reaction. This reaction can be carried out under appropriate conditions based on PN1. For example, when PN1 is dimethoxybenzyl, a compound of Formula [2] or a salt thereof can be prepared according to Preparation Method A2 Step A2-2. Examples

[0057] The present invention is illustrated in more detail with Preparations, Examples, Reference Examples, Test Examples, and Formulation Examples as detailed below, but is not intended to be limited to these examples. IF-2019-47864117-APN-ANP#INPI Page 46 of 93

[0058] The following are the meanings of the abbreviations used in this document. DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide THF: tetrahydrofuran. CPME: cyclopentyl methyl ether

[0059] 1H-NMR spectra were measured in CDC13o DMSO-de with tetramethylsilane for the standard internal substance, and all δ values ​​are shown in ppm. The measurement was carried out with an NMR spectrometer at 400 MHz, unless otherwise stated. Symbol references in the Examples: s: singlet d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet brs: wide singlet m: multiple J: coupling constant

[0060] [Preparation 1] Preparation of 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. IF-2019-47864117-APN-ANp#INPI Page 47 of 93

[0061] (Step 1) Preparation of l-bromo-3-(tert-butoxy)-5-fluorobenzene. 3-Bromo-5-fluorophenol (500 mg) was sequentially reacted with di-tert-butyl dicarbonate (1.14 g) and magnesium perchlorate (58 mg) at room temperature under argon flow. The reaction mixture was stirred at 50°C for 1 hour and 20 minutes. Di-tert-butyl dicarbonate was added to the reaction mixture at 50°C. The reaction mixture was stirred at 50°C for 1 hour, then stirred again at 65°C for 1 hour, and allowed to cool to room temperature. Di-tert-butyl dicarbonate was added to the reaction mixture at room temperature. The reaction mixture was stirred at 65°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and then a mixed solution of acetate was added. IF-2019-47864117-APN-ANp#INPI Page 48 of 93 hexane / ethyl (1 / 1). The reaction mixture was sequentially washed with 3N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine, then dried with sodium sulfate and concentrated. The remaining portion was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 0 to 20 / 1) to give the base compound (437 mg) in a 68% yield. x1H-NMR (CDC13) δ: 1.35 (s, 9H), 6.62-6.66 (m, 1H), 6.92-6.98 (m, 2H). [0062 ] (Step 2) Preparation of 2-(3-(tert-butoxy)-5-fluorophenyl)4,4,5,5,-tetramethyl-1-1,3,2-dioxaborolane. To a solution of l-bromo-3-(tert-butoxy)-5-fluorobenzene (437 mg) obtained in Step 1 in DMSO (5 mL), potassium acetate (434 mg), bis(pinacolate)diboron (898 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (144 mg) were sequentially added under an argon atmosphere at room temperature. The reaction mixture was mixed at IF-2019-47864117-APN-ANP#INPI Page 49 of 93 The reaction mixture was heated at room temperature for 2.5 hours. It was then cooled to room temperature. A 1:1 solution of n-hexane / ethyl acetate and water was sequentially added to the reaction mixture. The mixture was stirred at room temperature for 50 minutes and allowed to stand overnight. A 1:1 solution of n-hexane / ethyl acetate, water, silica gel, and Celite were then sequentially added to the reaction mixture. The reaction mixture was stirred, and the insoluble substances were filtered and washed with a 1:1 solution of n-hexane / ethyl acetate. The filtrate was extracted with a 1:1 solution of n-hexane / ethyl acetate. The organic layer was sequentially washed twice with water and brine, dried with sodium sulfate, and concentrated. The remaining portion was purified by silica gel thin-layer chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give the base compound (443 mg) in 85% yield. 1H-NMR (CDC13) δ: 1.33 (s, 12H), 1.36 (s, 9H), 6.77-6.82 (m, 1H), 7.18-7.23 (m, 2H).

[0063] [Preparation 2] Preparation of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid. IF-2019-47864117-APN-ANp#INPI Page 50 of 93 h3c-o

[0064] (Step 1) Preparation of diethyl 2-methyl-3-methylenesuccinate. Potassium tert-butoxide (180 g) was added to THE (2.44 L) at room temperature under a nitrogen flow. Triethyl phosphonoacetate (314 g) was added dropwise to the mixture under ice cooling for 13 minutes. The dropping funnel was washed with THE (511 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred for 2 hours and 9 minutes under ice cooling. Ethyl 2-bromopropionate (247 g) was added dropwise to the reaction mixture for 20 minutes under ice cooling. The dropping funnel was washed with THF (79 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 22 hours and 45 minutes. Potassium carbonate (188 g) was added to the reaction mixture for 1 minute under ice cooling. IF-2019-47864117-APN-ANP#INPI Page 51 of 93. Ice. 37 wt% aqueous formaldehyde solution (152 mL) was added dropwise to the reaction mixture for 10 minutes under ice cooling. The reaction mixture was stirred at room temperature for 19 hours and 44 minutes. Water (1.57 L) was added to the reaction mixture at room temperature for 1 minute. The reaction mixture was stirred at room temperature for 1 hour and 48 minutes. The reaction mixture was separated. The resulting aqueous layer was extracted twice with THF (200 mL). The resulting aqueous organic layers were combined and concentrated. Toluene (471 mL) and brine (471 mL) were added to the residues. The reaction mixture was stirred and separated. The organic layer was dried with sodium sulfate (63 g). The sodium sulfate was filtered out.Separately, a similar reaction was carried out with triethyl phosphonoacetate (300 g) to give a filtrate, which was then combined with the filtrate obtained previously to give a base compound solution (equivalent to 2.66 mol) in toluene (approximately 921 mL). The resulting base compound solution in toluene was considered capable of supporting 100% yield and was used in the next step. The generation of the base compound was confirmed by HPLC analysis. The measuring instrument and conditions for HPLC are described below. Measuring instrument: HPLC system, Shimadzu Corporation, IF-2019-47864117-APN-ANP#INPI Page 52 of 93 Prominence high-performance liquid chromatograph. Measurement conditions: Column. Kinetex C18: 2.6 pm, 50 mm x 2.1 mm (Phenomenex) Column temperature: 40°C Flow rate: 0.4 mL / min. Analysis time: 10 min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) water, (Solution B) acetonitrile. Mobile phase delivery: a mixed ratio (Solution A / Solution B) (volume %) of Solution A and Solution B of 80 / 20 was maintained from minute 0 to 0.01 after injection, changed linearly from 80 / 20 to 10 / 90 from minute 0.01 to 7 minutes, maintained at 10 / 90 for 7 minutes to 8 minutes to 9 minutes, and maintained at 80 / 20 from 9 minutes to 10 minutes. The retention time of the base compound was approximately 3.7 minutes under the measurement conditions for HPLC.

[0065] . (Step 2) Preparation of a mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate ethyl and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate ethyl. H3C-0 IF-2019-47864117-APN-ANp#INPI Page 53 of 93 To a solution of diethyl 2-methyl-3-methylenesuccinate (equivalent to 2.66 mol) obtained in Step 1 in toluene (approximately 921 mL), 2,4-dimethoxybenzylamine (468 g) was added dropwise for 2 minutes at room temperature under a nitrogen flow. The reaction mixture was stirred at 120°C for 5 hours and 45 minutes. The reaction mixture was allowed to stand for a weekend at room temperature. The reaction mixture was then cooled with ice to approximately 15°C below the internal temperature. 2N hydrochloric acid (1.33 L) was added dropwise to the reaction mixture and stirred. The reaction mixture was separated. The resulting aqueous layer was extracted with toluene (150 mL).The resulting organic layers were combined, washed with a mixed brine and water solution (600 mL; brine / water = 1 / 1), dried with sodium sulfate (120 g), concentrated, and left to dry under reduced pressure at room temperature overnight to yield a crude base compound product (790 g; cis / trans approximately 1 / 1, 5.5 wt% inclusive of toluene). Generation of the base compound was confirmed by HPLC analysis. The measuring instrument and conditions for HPLC are described below. Measuring instrument: HPLC system, Shimadzu Corporation, Prominence high-performance liquid chromatograph. Measurement conditions: IF-2019-47864117-APN-ANP#INPI Page 54 of 93 Column: Atlantis T3: 5 pm, 150 mm x 4.6 mm (Waters) Column temperature: 40°C Flow rate: 1.15 mL / min. Analysis time: 18 min. Detection wave: UV (220 nm) Mobile phase: (Solution A) 10 mM (sodium), phosphate buffer (pH = 2.6), (Solution B) acetonitrile. Mobile phase delivery: a mixed ratio (Solution A / Solution B) (volume %) of Solution A and Solution B of 60 / 40 was maintained from minute 0 to 0.5 minutes after injection, changed linearly from 60 / 40 to 10 / 90 from minute 0.5 to 8 minutes, maintained at 10 / 90 for 8 minutes to 12.5 minutes, changed linearly from 10 / 90 to 60 / 40 from 12.5 minutes to 13.5 minutes, and maintained at 60 / 40 from 13.5 minutes to 18 minutes. The retention time was approximately 6.6 minutes for (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-1,5-oxopyrrolidine-3-carboxylate and approximately 6.9 minutes for (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate under HPLC measurement conditions.

[0066] (Step 3) Preparation of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate. IF-2019-47864117-APN-ANp#INPI Page 55 of 93 To a crude mixture (790 g, inclusive of 5.5 wt% toluene) of ethyl (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate obtained in step 2, ethanol (1.15 L) was added at room temperature under a nitrogen flow. Sodium ethoxide (20 wt% of the solution in ethanol, 1.15 L) was added dropwise to the reaction mixture at room temperature for 15 minutes. The reaction mixture was stirred at room temperature for 2 hours and 57 minutes. The reaction mixture was then cooled with ice, and water (1.84 L) was added dropwise for 33 minutes. CPME (1.8 L) and toluene (1.8 L) were added to the reaction mixture at room temperature, and the mixture was separated (Organic Layer 1). CPME (1.8 L) was added to the resulting aqueous layer, and the mixture was separated (Organic Layer 2). The solvent (1.8 L) was removed from the resulting aqueous layer by evaporation.The resulting aqueous layer was treated with 6N hydrochloric acid dropwise (110 ml) by cooling with ice, and from there ethyl acetate (1.8 L) was added. The mixture was then treated with 6N hydrochloric acid dropwise (300 ml). IF-2019-47864117-APN-ANP#INPI Page 56 of 93. The mixture was cooled with ice and stirred for approximately 10 minutes. Sequentially, water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% aqueous sodium bisulfate solution (300 mL), and ethanol (300 mL) were added to the mixture by ice cooling. The mixture was stirred at room temperature overnight. Ethyl acetate (600 mL) was added to the mixture, and the mixture was separated. The resulting aqueous layer was extracted with ethyl acetate (600 mL) twice. The resulting organic layers were combined (except for Organic Layer 1 and Organic Layer 2) and washed with a brine / water mixture (1 L, brine / water = 1 / 1). Sodium sulfate (120 g) and activated carbon (30 g) were added to the resulting organic layer, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite to remove insoluble substances. The insoluble substances were washed with ethyl acetate (3 L).The resulting filtrates were combined and concentrated, and dried under reduced pressure at room temperature for 3 hours to give a crude product of the base compound (561 g). Separately, the previously mentioned Organic Layer 1 and Organic Layer 2 were combined and concentrated. Toluene (450 ml) and water (450 ml) were added to the remaining portion, and the mixture was separated. The resulting aqueous layer was washed twice with toluene (450 ml). IF-2019-47864117-APN-ANp#INPI Page 57 of 93 Ethyl acetate (450 mL) was added to the aqueous layer. 6N hydrochloric acid (70 mL) was added dropwise to the mixture via ice cooling. Ethyl acetate (300 mL) was added to the mixture, and the mixture was separated. The resulting aqueous layer was extracted with ethyl acetate (150 mL). The resulting organic layers were combined and washed with a brine / water mixture (225 mL, brine / water = 1:1). Sodium sulfate (30 g) and activated carbon (7.5 g) were added to the organic layer, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered to remove insoluble substances. The insoluble substances were washed with ethyl acetate (750 mL). The resulting filtrates were combined and concentrated, and left to dry under reduced pressure at room temperature for 3 hours to give a crude product of the base compound (87.3 g). This crude product was combined with the crude product of the previously obtained base compound, and CPME (3 L) was added under a nitrogen flow. The mixture was blended at 120°C. The mixture was slowly cooled to room temperature with blending for 17 hours and 34 minutes. The mixture was then cooled with ice and blended at approximately 1°C below the internal temperature for 3 hours. The precipitate was dried under reduced pressure at 50°C overnight to yield the base compound (585 g). IF-2019-47864117-APN-ANP#INPI Page 58 of 93 Total yield of 75% in the 3 steps. Generation of the base compound was confirmed by HPLC and NMR analysis. The instrument and measurement conditions for HPLC are the same as for Step 2. The retention time of the base compound was approximately 3.1 minutes under the measurement conditions for HPLC. δ 7.11-7.15 (m, 1H).

[0067] (Step 4) Preparation of a diastereoisomer© salt of (3R,4R)-l-(2,4-dimethoxybenzyl)-4-methyl1-5-oxopyrrolidine-3-carboxylic acid with (IR,2R)-(-)-2-amino-l-(4-nitrophenyl)-1,3-propanediol. The (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (585 g) obtained in Step 3 was treated with acetonitrile (2.9 L) at room temperature under a nitrogen flow. The mixture was stirred at 85°C. IR,2R)-(—)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (254 g) was added to the mixture for 14 minutes at 85°C. The reaction mixture was stirred at 90°C for 2 hours and 48 minutes. The reaction mixture was cooled to room temperature with overnight stirring. The precipitate was IF-2019-47864117-APN-ANp#INPI Page 59 of 93. The precipitate was filtered and washed with acetonitrile (2.4 L). The precipitate was dried under common pressure for 8.5 hours at room temperature to give a crude crystal of the base compound (516 g). Acetonitrile (2.5 L) and water (0.5 L) were added to the crude crystal at room temperature under a nitrogen flow. The mixture was stirred at 100°C for 1 hour and 14 minutes. Acetonitrile (1.5 L) was added dropwise to the mixture at 100°C for 1 hour and 7 minutes. The mixture was stirred at 100°C for 10 minutes. The mixture was cooled to room temperature with stirring for 21 hours and 10 minutes. The mixture was stirred for 3 hours and 54 minutes by ice cooling. The precipitate was collected by filtration and washed with acetonitrile (1.5 L). The precipitate was dried under ordinary pressure at room temperature for 4 hours to give the base compound (448 g, 99.8% de) in a 45% yield. The generation of the base compound was confirmed by HPLC analysis. The instrument and measurement conditions for HPLC were as follows: Measuring instrument: HPLC system, Shimadzu Corporation, Prominence high-performance liquid chromatograph.1 Measurement conditions: Column: CHIRAL PAK AD-3R: 3 pm, 150 mm x 4.6 mm (Daicel) Column temperature: 40°C IF-2019-47864117-APN-ANP#INPI Page 60 of 93 Flow rate: 0.50 mL / min. Analysis time: 10 min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) 10 mM (sodium) phosphate buffer (pH = 2.6), (Solution B) acetonitrile. Mobile phase delivery: a mixed ratio (Solution A / Solution B) (volume %) of Solution A and Solution B of 60 / 40 was maintained. The retention time was around 5.6 minutes for (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid and around 6.5 minutes for (3S,4S)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid under the measurement conditions for HPLC. The conformation of the base compound was determined by X-ray crystallography of the individual crystal obtained after recrystallization of methyl isobutyl ketone. The diastereomeric excess was determined from the HPLC area percentages in the measurement results ((3R,4R) / (3S,4S) = 99.886% / 0.114%).

[0068] (Step 5) Preparation of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid. IF-2019-47864117-APN-ANP#INPI Page 61 of 93 A diastereomeric salt of (3R,4R)-1(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid with (IR,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (448 g) obtained in Step 4 was mixed with ethyl acetate (1.8 L) and water (1.34 L) at room temperature. 6N hydrochloric acid (168 mL) was added dropwise to the mixture at room temperature for 16 minutes. The mixture was then separated. The resulting aqueous layer was extracted three times with ethyl acetate (450 mL). The resulting organic layers were combined and washed sequentially with 2N hydrochloric acid (224 mL) and brine (224 mL), then dried with sodium sulfate (90 g) and concentrated. Toluene (220 ml) was added to the residue, and the mixture was concentrated. The residue was dried under reduced pressure at room temperature to give the base compound (254 g) in 98% yield. 1H-RMN (DMSO-D6) δ: 1.15 (d, 3H, J = 7.2 Hz), 2.50-2.58 (m, 1H), 2.73-2.83 (m, 1H), 3.18-3.25 (m, 1H), 3.30-3.38 (m, 1H), 3.75 (s, 3H), 3.77 (s, 3H), 4.19-4.35 (m, 2H), 6.48 (dd, 1H, J = 8.4, 2.3 Hz), 6.56 (d, 1H, J = 2.3 Hz), 7.00 (d, 1H, J = 8.4 Hz), 12.61 (br s, 1H). .

[0069] [Ejemplo 1] Synthesis of (3R,4R)-N-(5-(3-(terc-butoxi)-5IF-2019-47864117-APN-ANP#INPI) Página 62 de 93 fluorofenil)-1-(trifluorometil)-lH-pirazol-3-il)-4-metil5-oxopyrrolidina-3-carboxamida.

[0070] (Paso 1) Preparation of 3-(2,5-dimetil-lH-pirrol-l-il)-1Hpirazol. 100 g of 1H-pyrazol-3-amine was added to 1 L of acetic acid at room temperature, and the mixture was stirred for 5 minutes. 148 mL of 2,5-hexanedione was added to the mixture at room temperature, and the mixture was stirred for 5 minutes. The reaction mixture was stirred at 120°C for 2.5 hours and cooled to room temperature. 1 L of water was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 50 minutes. The precipitated solid was collected by filtration and washed with 1 L of water. The resulting wet solid was dried under normal pressure at room temperature overnight, and then dried under reduced pressure at 65°C for 3 days and 8.5 hours. IF-2019-47864117-APN-ANp#INPI Page 63 of 93 to give the base compound (172.47 g) in 89% yield. 1H-NMR (CDC13) δ: 2.11 (s, 6H), 5.90 (s, 2H), 6.25 (d, 1H, J = 2.4 Hz), 7.51 (d, 1H, J = 2.4 Hz).

[0071] (Step 2) Preparation of a mixture of 1(bromodifluoromethyl)-3-(2,5-dimethyl-lH-pyrrol-l-yl)-1Hpyrazole and 1-(bromodifluoromethyl)-5-(2,5-dimethyl-lHpyrrol-l-yl)-lH-pyrazole. DMF (100 mL) was added to sodium hydride (14.9 g) under argon flow by ice-cooling. The 3-(2,5-dimethyl-1H-pyrrole-1-yl)-1H-pyrazole suspension (40 g) obtained in Step 1 in DMF (150 mL) was added dropwise to the mixture by ice-cooling for 20 minutes. The dropping funnel used was washed with DMF (50 mL), and the washings were added to the reaction mixture. This mixture was mixed by ice-cooling for 1.5 hours. Tetra-n-butylammonium bromide (0.80 g) was added to this mixture by ice-cooling. The reaction mixture was mixed by ice-cooling for 15 minutes. A solution of dibromodifluromethane (45 mL) in DMF (50 mL) was added dropwise to this mixture by IF-2019-47864117-APN-ANP#INPI Page 64 of 93. The reaction mixture was cooled with ice for 15 minutes. Dibromodifluoromethane (20 mL) was added dropwise to this mixture under an argon atmosphere by cooling with ice. The reaction mixture was cooled with ice for 40 minutes and then allowed to stand overnight. A saturated aqueous solution of ammonium chloride (200 mL) was added to this mixture by cooling with ice. Ethyl acetate and water were added to the reaction mixture. The reaction mixture was filtered through Celite, and the filtrate was separated. The resulting aqueous layer was extracted with ethyl acetate. The resulting organic layers were combined, and brine was added. The mixture was filtered through Celite, and the filtrate was separated. The resulting aqueous layer was extracted with ethyl acetate.The resulting organic layers were combined, then dried with sodium sulfate and concentrated. Toluene (250 mL) was added to the remaining portion, and the mixture was concentrated. This process was repeated. Ethyl acetate (approximately 150 mL) was added to the remaining portion, and the insoluble substances were filtered out and washed with ethyl acetate. The resulting filtrates were combined and concentrated. The remaining portion was dried under reduced pressure with mixing at room temperature for 10 minutes. IF-2019-47864117-APN-ANP#INPI Page 65 of 93 The remaining material was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 1 to 20 / 1) to give the base compound (40.6 g, 3.7 wt% hexane inclusive, l-(bromodifluoromethyl)-3-(2,5-dimethyl1H-pyrrole-l-yl)-1H-pyrazole:1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrole-l-yl)-1H-pyrazole = about 3:1) in a yield of 54%. XH-MRI (CDC13) δ: 2.03 (s, 1.5H), 2.18 (s, 4.5H), 5.89 (s, 1.5H), 5.91 (s, 0.5H), 6.39-6.41 (m, 1H), 7.86-7.88 (m, 1H).

[0072] (Step 3) Preparation of a mixture of 3-(2,5-dimethyl-lHpyrrol-l-yl)-l-(trifluoromethyl)-lH-pyrazole and 5-(2,5dimethyl-lH-pyrrol-l-yl)-1-(trifluoromethyl)-IH-pyrazole. Tetramethylammonium fluoride (13.0 g) was added to the solution of a mixture of l-(bromodifluoromethyl)-3-(2,5-dimethyl-lH-pyrrole-l-yl)-lH-pyrazole and 1-(bromodifluoromethyl)-5-(2,5-dimethyl-lH-pyrrole-l-yl)-lH-pyrazole (40.6 g, 3.7 wt% inclusive hexane) obtained in Step 2 in sulfolane (400 mL) at room temperature under argon flow. The reaction mixture was stirred at 100°C for 1 hour. Tetramethylammonium fluoride (9.4 g) was added to the reaction mixture at 100°C. IF-2019-47864117-APN-ANP#INPI Page 66 of 93. The mixture was heated at 100°C for 1 hour and 15 minutes. Tetramethylammonium fluoride (10 g) was added to the reaction mixture at 100°C. The reaction mixture was heated at 100°C for 40 minutes. Additionally, tetramethylammonium fluoride (5 g) was added to the reaction mixture at 100°C. The reaction mixture was heated at 100°C for 2 hours and 5 minutes, and then allowed to cool to room temperature. Water (400 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL) were added sequentially and slowly to the reaction mixture by cooling with ice. A mixed solution of n-hexane / ethyl acetate (2 / 3) (400 mL) was added to the reaction mixture. The reaction mixture was filtered with Celite, and the filtrates were separated. The resulting organic layer was washed with brine. The resulting aqueous layers were combined and extracted with a mixed solution of n-hexane / ethyl acetate (2 / 3) (300 ml). The organic layer was washed with brine.The resulting organic layers were combined, dried with sodium sulfate, and concentrated. The remaining portion was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30:1 to 25:1) to give the base compound (21.85 g, 3-(2,5-dimethyl-1H-pyrrole-1-yl)-1-(trifluoromethyl)-1H-pyrazole:5-(2,5-dimethyl-1H-pyrrole-1-yl)-1-(trifluoromethyl)-1H-pyrazole = about 6:1, 24.4 wt% n-hexane inclusive) in a 51% yield. IF-2019-47864117-APN-ANP#INPI Page 67 of 93XH-MRI (CDC13) δ: 2.00 (s, 0.86H), 2.16 (s, 5.1H), 5.89 (s, 1.7H), 5.91 (s, 0.29H), 6.40 (d, 0.86H, J = 2.8 Hz), 6.42 (d, 0.14H, J = 1.6 Hz), 7.83 (d, 0.14H, J = 1.6 Hz), 7.87 (d, 0.86H, J = 2.8 Hz).

[0073] (Step 4) Preparation of 3-(2,5-dimethyl-IH-pyrrol-1-yl)-5iodo-1-(trifluoromethyl)-lH-pyrazole. . A solution of the mixture of 3-(2,5-dimethyl-1H-pyrrole-1-yl)-5-iodo-1-(trifluoromethyl)-1H-pyrazole and 5(2,5-dimethyl-1H-pyrrole-1-yl)-1-(trifluoromethyl)-1H-pyrazole (21.85 g, 24.4 wt% n-hexane inclusive) obtained in Step 3 in THF (180 mL) was added dropwise to a solution of n-butyllithium in n-hexane (1.55 M, 51.1 mL) at -70°C for 5 minutes under an argon atmosphere. The reaction mixture was stirred at -70°C for 25 minutes. To this mixture, a solution of iodine (18.3 g) was added dropwise in THF (50 mL) at -70°C for 5 minutes. The dropping funnel used was washed with THF (10 ml), and the washings were added to the reaction mixture. This mixture was stirred at -70°C for 30 minutes. Iodine (0.90 g) was added to the reaction mixture at -70°C. The reaction mixture was stirred at -70°C for half an hour. IF-2019-47864117-APN-ANP#INPI Page 68 of 93 Water (250 mL) and ethyl acetate (250 mL) were sequentially added to the reaction mixture at -70°C. The reaction mixture was stirred at room temperature and separated. The organic layer was sequentially washed with 10 wt% aqueous sodium bisulfite solution (250 mL) and brine (150 mL), dried with sodium sulfate, and concentrated. The remaining portion was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50:1 to 30:1). The fractions containing the base compound were collected and concentrated. n-Hexane was added to the residue. The mixture was concentrated to a weight of 27.5 g. n-Hexane (20 mL) was added to the remaining residue. The suspension was stirred at room temperature for 10 minutes. The precipitate was collected by filtration, washed with n-hexane (30 ml), and dried under reduced pressure to give the base compound (17.14 g) in a 67% yield. Subsequently, the filtrate was concentrated.The remaining portion was crystallized from n-hexane to give the base compound (1.63 g) in a yield of 6.4%. 1H-NMR (CDC13) δ: 2.15 (s, 6H), 5.88 (s, 2H), 6.60 (s, 1H).

[0074] (Step 5) Preparation of 5-iodo-l-(trifluoromethyl)-1Hpyrazol-3-amine. IF-2019-47864117-APN-ANP#INPI Page 69 of 93 The 3-(2,5-dimethyl-1H-pyrrole-1-yl)-5-iodo-1(trifluoromethyl)-1H-pyrazole (18.77 g) obtained in Step 4 was sequentially mixed with a mixture of ethanol and water (ethanol / water = 2 / 1, 480 mL), hydroxyammonium chloride (73.5 g), and triethylamine (14.7 mL) at room temperature. The reaction mixture was stirred at 100°C for 38 hours and 20 minutes. This mixture was allowed to cool to room temperature, and the ethanol was removed by evaporation. A solution of sodium hydroxide (42.3 g) in water (130 mL) was slowly added to the mixture, followed by ethyl acetate (200 mL), with ice cooling. The reaction mixture was stirred and separated. The resulting aqueous layer was extracted with ethyl acetate (200 mL). The resulting organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated. Ethyl acetate (30 ml) and n-hexane (30 ml) were added to the remaining portion, and the insoluble substances were filtered out. The filtrate was then concentrated.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to give the base compound (16.27 g, 14 wt% ethyl acetate inclusive) in a yield of 96%. IF-2019-47864117-APN-ANP#INPI Page 70 of 93XH-MRI (CDC13) δ: 3.93 (br s, 2H), 6.09 (s, 1H).

[0075] (Step 6) Preparation of 5-(3-(tert-butoxy)-5-fluorophenyl)1-(trifluoromethyl)-1H-pyrazol-3-amine. To the 5-iodo-l-(trifluoromethyl)-1Hpyrazol-3-amine solution (80 mg, inclusive of 14 wt% ethyl acetate) obtained in Step 5 in toluene (3 mL), 2-(3-(tert-butoxy)-5-fluorophenyl)4,4,5,5-tetramethylol-l,3,2-dioxaborolane (127 mg) obtained in Step 2 of Preparation 1, palladium(II) acetate (6.5 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (20 mg) were sequentially added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 4 minutes. To this mixture, an aqueous solution of tripotassium phosphate (1.5 mL) was added at room temperature. The reaction mixture was stirred at 90°C for 47 minutes and allowed to cool to room temperature. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to this mixture. The mixture was then filtered through cotton and extracted with ethyl acetate. The organic layer was sequentially separated. IF-2019-47864117-APN-ANP#INPI Page 71 of 93 was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried with sodium sulfate, and concentrated. The remaining portion was combined with a portion of the base compound (15 mg) obtained separately and similarly to the present step using 5-iodo-1(t-1-ifluoromethyl)-1H-pyrazole-3-amine (70 mg, 14 wt% inclusive of ethyl acetate) obtained in Step 5, and the mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give the base compound (108 mg). ^-NMR (CDC13) δ: 1.36 (s, 9H), 3.93 (br s, 2H), 5.83 (s, 1H), 6.75-6.85 (m, 3H).

[0076] (Step 7) Preparation of (3R,4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxamide. h3c-o To the (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid solution (55 mg) obtained in a manner similar to Step 5 of Preparation 2 in chloroform (0.55 ml) DMF (1 ml) and oxalyl chloride (33 μA) were sequentially added by cooling with IF-2019-47864117-APN-ANP#INPI Page 72 of 93. The reaction mixture was mixed by ice cooling for 50 minutes. The mixture was concentrated and dried under reduced pressure. Chloroform (0.4 mL) and the 5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-amine (40 mg) obtained in Step 5 were sequentially added to the remaining portion under an argon atmosphere by ice cooling. Pyridine (50 μA) was added to the reaction mixture by ice cooling. The reaction mixture was mixed by ice cooling for 5 minutes and then at room temperature for 35 minutes. A saturated aqueous solution of sodium bicarbonate was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, and concentrated.The remaining portion was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate - 1 / 1) to give the base compound (60 mg) in 80% yield. Generation of the base compound was confirmed by thin-layer chromatography (eluent: n-hexane / ethyl acetate = 2 / 1, Rf: 0.19).

[0077] (Step 8) Preparation of (3R,4R)-N-(5-(3-fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide. IF-2019-47864117-APN-ANP#INPI Page 73 of 93 h3c-o The (3R,4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide (60 mg) obtained in Step 7 was mixed with anisole (58 μA) and trifluoroacetic acid (2 mL) at room temperature. The reaction mixture was stirred at 80 °C for 1 hour and 20 minutes. The reaction mixture was then concentrated. A saturated aqueous solution of sodium bicarbonate was added to the remaining portion, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The remaining portion was purified by silica gel thin-layer chromatography (eluent: chloroform / ethyl acetate = 1 / 1) to give the base compound (29.9 mg) in a yield of 76%. 1H-NMR (DMSO-d6) δ: 1.06 (d, 3H, J = 7.2 Hz), 2.50-2.53 (m, 1H), 2.96-3.04 (m, 1H), 3.17-3.23 (m, 1H), 3.40-3.46 (m, 1H), 6.67-6.81 (m, 3H), 6.96 (s, 1H), 7.67 (s, 1H), 10.34 (s, 1H), 11.26 (s, 1H).

[0078] (Step 9) Preparation of (3R,4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methylIF-2019-47864117-APN-ANP#INPI Page 74 of 93 5-oxopyrrolidine-3-carboxamide. To the (3R,4R)-N-(5-(3-fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-11)-4-methyl-5-oxopyrrolidine-3-carboxamide (30 mg) obtained in Step 8, di-tert-butyl dicarbonate, chloroform (1 mL), and magnesium perchlorate were sequentially added at room temperature. The reaction mixture was stirred at 55°C for half an hour. Magnesium perchlorate was added to the reaction mixture at 55°C. The reaction mixture was stirred at 55°C for 1 hour and 10 minutes, and an additional magnesium perchlorate was added at 55°C. The reaction mixture was stirred at 55°C for 20 minutes. The reaction mixture was allowed to cool to room temperature, and ethyl acetate was added. The reaction mixture was sequentially washed with 1N hydrochloric acid and brine, dried with sodium sulfate, and concentrated.The remaining portion was purified by silica gel thin-layer chromatography (eluent: chloroform / methanol = 15 / 1) to give the base compound (19.2 mg) in a yield of 56%. NMR IF-2019-47864117-APN-ANP#INPI Page 75 of 93 3.42-3.48 (m, 1H), 6.95 (s, 1H), 7.00-7.07 (m, 2H), 7.117.17 (m, 1H), 7.68 (s, 1H), 11.28 (s, 1H). MS (M+H) 443, MS (MH) 441.

[0079] (Step 10) Preparation of a crystal of (3R,4R)-N-(5-(3(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1Hpyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide. The base compound (100 mg) was mixed with ethanol (0.4 mL) at 65°C for 8 minutes and dissolved. Water was added dropwise (0.4 mL) to the mixed solution at 65°C for 2 minutes. The mixture was stirred at 65°C for 10 minutes and cooled to 25°C with stirring for 2 hours. It was then stirred at room temperature for 2 hours. The solid precipitate was collected by filtration. The resulting solid was washed with a mixed ethanol / water solution (1:1) and dried under reduced pressure at 60°C to give a crystal of base compound (87.8 mg) in an 88% yield.

[0080] [Reference example] Compound A, Compound B, and Compound C, each of which appears in the table below, were obtained in accordance with the description in WO 2013 / 031922. IF-2019-47864117-APN-A-NP#INPI Page 76 of 93

[0081] Metabolite 1 (i.e., a metabolite of Compound 1) and Metabolite C (i.e., a metabolite of Compound C), each of which appears in the table below, were obtained in accordance with Example 1 detailed above and the description in WO 2013 / 031922. h3c ch3 f h3ca; / = / o-4 Λ Metabolite 1 EF ¿ FN ^NHz IF-2019-47864117-APN-ANP#INPI Page 77 of 93

[0082] [Sample Example 1] The SGLT1 inhibitory activities of the test compounds (IC50 values) were calculated based on the amount of intracellular intake of labeled α-methyl-D-glucopyranoside (14C-AMG) transported by SGLT1. 1) Formation of human SFLT1 expression plasmid A human SGLT1 DNA fragment was amplified by PCR (Polymerase Chain Reaction) using pCMV6-hSGLT1 (OriGene) as a model. In the human SGLT1, the Nhel recognition and cleavage sequence was added to the pre-step of the vector-derived Kozak sequence, and a TAG stop codon and a Sali recognition and cleavage sequence were added to the immediate post-step of the human SGLT1 protein-transporting region. The purified DNA fragment was cleaved by the restriction enzymes Nhel and Sali, followed by ligation with pcDNA3.1(+) which was cleaved by Nhel and Xhol, thus forming a human SGLT1 expression plasmid. The human SGLT1 nucleic acid sequence inserted into a vector was completely identical. IF-2019-47864117-APN-ANP#INPI Page 78 of 93 to the protein-carrying region of the human SGLT1 sequence (Accession Number NM 000343) registered in GenBank, and the sequence of the vector-connected portion developed as expected.

[0083] 2) Establishment of cell lines that stably express human SGLT1 The human SFLT1 expression plasmid, pcDNAhSGLT1, was transfected into each CHO-K1 cell using Lipofectamine 2000 (Invitrogen) and cultured in the presence of G418 (Nacalai Tesque) to select drug-resistant cell lines. A cell line with the highest ratio (S / B ratio) of intracellular 14C-AMG uptake per cell to intracellular 14C-AMG uptake after treatment with the SGLT inhibitor phlorizin was selected as stably expressing human SGLT1 from the drug-resistant cell lines.

[0084] 3) Evaluation of SGLT1 inhibitory activity Cell lines stably expressing human SGLT1 were seeded at 5 x 104 cells / well in a 96-well BioCoat™ Poly-D-Lysine block with lid (Becton, Dickinson and Company) and cultured at 37 °C under 5% CO2 overnight. The medium was replaced with a 100 pL / well plug IF-2019-47864117-APN-ANP#INPI Page 79 of 93 Na(-) (140 mH choline chloride, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4) was added, and the mixture was then allowed to stand at 37°C under 5% CO2 for 20 minutes. After removing the Na(-) plug, 40 pL / well of a test compound solution prepared with a Na(+) plug (140 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4) containing BSA was added. Subsequently, 40 pL / well of a Na(+) plug containing 8 kBq of 14C-AMG and 2 mM AMG was added and mixed thoroughly. For the sample solution, 40 pL / well of a Na(-) plug containing BSA was added, and an additional 40 pL / well of a Na(-) plug containing 8 kBq of 14C-AMG and 2 mM AMG was added and mixed thoroughly. After incubation by standing for 1 hour at 37°C under 5% CO2, the cells were washed twice with 100 pL / well of ice-cooled wash plug (100 mM AMG, 140 mM choline chloride, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4) to complete the reaction.A cell lysate was prepared by adding 50 pL / well of 0.2N aqueous NaOH solution. In the evaluation of 14C-AMG uptake capacity, the total amount of cell lysate was transferred to OptiPlate 96 (Perkin-Elmer) with 100 pL / well of MicroScint-40 (Perkin-Elmer) administered and 14C of CPM was measured with TOPCOUNT NXT (Perkin-Elmer). The information was calculated by subtracting the average CPM value of the sample well from the average CPM value for IF-2019-47864117-APN-ANP#INPI Page 80 of 93 for each well treated. An inhibition rate was calculated for < each test compound at each concentration from the following equation: [(AB) / A] x 100 Where A is the information for a control solvent and B is the information for the treatment with each test compound. Each IC50 (50% inhibitory concentration) value was calculated for each test compound from two concentrations before and after a 50% inhibition rate and the inhibition rate. The evaluation confirmed that Compound 1 exhibits SGLT1 inhibitory activity. [0085 ] [Example Test 2] OGTT (Glucose Tolerance Test) A vehicle (0.5% methylcellulose solution) or Compound 1 (1, 3, or 10 mg / kg) suspended in a methylcellulose solution at 5 mL / kg was administered to a male SD rat that had been fasting for approximately 4 hours (8 weeks of age, Nihon Charles River KK, 6 cases for each group). After 16 hours, glucose was loaded by oral administration of a 0.4 g / mL glucose solution at 5 mL / kg. Blood samples were taken from a tail vein just before glucose loading and 30, 60, and 120 minutes post-loading; and the glucose level was measured. IF-2019-47864117-APN-ANP#INPI Page 81 of 93 blood glucose with an automatic biochemical analyzer (HITACHI, Model No. 7180). The results are shown in Figure 1. The data show the ± standard deviation values ​​of the area under the curve (ΔAUC) for blood glucose levels from the glucose load to 120 minutes for the compound-administered groups compared to the vehicle group (% of vehicle). Statistical analyses were based on Steel's multiple range test. The significance level was set at 5% (two-way). The results showed that Compound 1 significantly reduced blood glucose levels after the glucose load compared to the vehicle.

[0086] [Sample Example 3] OGTT (Glucose Tolerance Test) A vehicle (0.5% methylcellulose solution) or Compound 1, or Compound B (3 mg / kg each) suspended in a 0.5% methylcellulose solution at 5 mL / kg was administered orally to a male SD rat that had been fasting for approximately 4 hours (8 weeks of age, Nihon Charles River KK, 5 cases for each group). After 16 hours, glucose was loaded by oral administration of a 0.4 g / mL glucose solution at 5 mL / kg. The blood sample was taken from a tail vein just before the glucose load, and IF-2019-47864117-APN-ANP#INPI Page 82 of 93 30, 60, and 120 minutes after the glucose load; and the blood glucose level was measured with an automatic biochemical analyzer (HITACHI, Model No. 7180). The results are shown in Figure 2. The data show the ± standard deviation values ​​of the area under the curve (ΔAUC) for blood glucose levels from the glucose load to 120 minutes for the compound-administered groups compared to the vehicle group (% of the vehicle). Statistical analyses were based on Dunnett's multiple group test. The significance level was set at 5% (two-way). The results showed that only Compound 1 significantly reduced blood glucose levels after the glucose load compared to the vehicle.

[0087] [Sample example 4] Ames test (Reverse mutation test) In this test, Metabolite 1 and Metabolite C were measured. The objective of this test is to evaluate the potential of each metabolite to induce reverse mutations in standard strains of Salmonella typhimurium (TA98, TA1537, TA100, and TA1535) and Escherichia coli (WP2uvrA), either in the presence or absence of a rat liver metabolic activation system (S9 mixture). The solvent used in this test was IF-2019-47864117-APN-ANP#INPI Page 83 of 93 dimethyl sulfoxide (DMSO, 100 pL / plate). The test was carried out using the pre-incubation method with or without the S9 mixture. When the test was carried out without the S9 mixture, a sodium phosphate plug solution (pH 7.4) was added. 0.5 mL of either S9 mixture or 0.5 mL of 0.1 mol / L sodium phosphate plug solution (pH 7.4), and 0.1 mL of bacterial culture solution were added to test tubes containing 0.1 mL of the negative control formulation (DMSO only), the metabolite, or the positive control formulation. The mixtures were pre-incubated at 37°C for 20 minutes while being shaken. After the pre-incubation period, 2 mL of soft agar were added, and the mixtures were vortexed and plated onto plates. Two plates were used per treatment. Each plate was incubated at 37 ± 1°C for 48 hours or longer, and reverting colonies were counted. The mean number of reverting colonies was then calculated for each treatment plate. The presence or absence of growth inhibition due to any antibacterial effect of the test article and the precipitation of said article were observed using a stereomicroscope.Results were considered positive if the average number of reverting colonies showed an increase in dose dependence that doubled that of the negative control in one or more doses. The evaluation was based on... IF-2019-47864117-APN-ANP#INPI Page 84 of 93 based on average values ​​without the use of statistical comparisons. The test results are shown in the following tables (Tables 1 to 4 and Tables 5 to 7). In conclusion, Metabolite 1 did not have the potential to induce reverse mutations in any of the test bacterial strains, while Metabolite C had the potential to induce reverse mutations in the TA98 test bacterial strain with S9 mixture and the TA100 test bacterial strain with S9 mixture.

[0088] Table 1. Test Item Dose (pg / plate) Mixture S9 Number of reverting colonies TA98 TAI 00 DMSO (0.1 ml) + 36 133 Metabolite 1 2.3 + 35 120 6.9 + 31 119 21 + 35 117 62 + 28 104 185 + 16 * 78 * 556 t + 15 * 59 1667 t + 13 * 50 * 5000 t + 13 * 52 * B[a]P 5.0 + 455 1069 IF-2019-47864117-APN-ANp#INPI Page 85 of 93 +: Presence of S9 mixture *: Growth inhibition t: Precipitation DMSO: Dimethyl sulfoxide B[a]P: Benzo[a]pyrene The number of reverting colonies shows the average number on each plate.

[0001] Table 2. Test Item Dose (pg / plate) Mixture S9 Number of reverting colonies TA1537 TA1535 WP2uvrA DMSO (0.1 ml) + 13 12 25 Metabolite 1 2.3 + 11 13 31 6.9 + 10 7 31 21 + 9 6 32 62 + 6 8 40 185 + 2 * 5 * 16 * 556 + 0 * 4 * 18 * 1667 + 0 * 4 * 9 * 5000 t + 0 * 2 * 0 * 2AA 2.0 + — 223 — 10.0 + — — 818 B[a]P 5.0 + 119 — — IF-2019-47864117-APN-ANP#INPI Page 86 of 93 +: Presence of mixture S9 *: Growth inhibition t: Precipitation Not subjected to the test DMSO: Dimethyl sulfoxide 2AA: 2-Aminoanthracene B[a]P: Benzo[a]pyrene The number of reverting colonies shows the average number on each plate. [0002 ] Table 3. Test Item Dose (pg / plate) Mixture S9 Number of reverting colonies WP2uvrA DMSO (0.1 ml) + 31 Metabolite 1 6.9 + 31 12 + 28 21 + 25 36 + 34 62 + 35 107 + 25 185 + 9 * 2AA 10.0 + 740 +: Presence of S9 mixture *: Growth inhibition DMSO: Dimethyl sulfoxide 2AA: 2-Aminoanthracene IF-2019-47864117-APN-ANP#INPI Page 87 of 93 The number of reverting colonies shows the average number on each plate.

[0003] Table 4. Test Article Dose (pg / plate) Mixture S9 Number of reverting colonies TA98 TAI 5 3 7 TAI 00 TAI 5 3 5 WP2uvr A DMSO (0.1 ml) - 18 8 10 0 8 26 Metabolite 1 2.3 - 14 7 99 6 32 6.9 - 16 10 11 3 9 27 21 - 14 9 12 4 8 31 62 - 21 9 88 8 24 185 - 9 * 0 * 38 * 0 * 15 * 556 - 0 * 0 * 0 * 0 * 8 * 1667 - . 0 * 0 * 0 * 0 * 5 ★ 5000 t - 0 * 0 * 0 * 0 * 0 * AF-2 0.01 - — — 63 3 — 69 0.1 - 341 — — — — ICR-191 1.0 - — 117 0 — — — SA 0.5 - — — — 217 — Not tested*: Growth inhibition IF-2019-47864117-APN-ANp#INPI Page 88 of 93 t: Precipitation DMSO: Dimethyl sulfoxide AF-2: 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide SA: Sodium azide ICR-191: 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)aminopropylamino]acridine dihydrochloride The number of reverting colonies shows the average number on each plate.

[0004] Table 5. . Test Item Dose (pg / plate) Mixture S9 Number of reverting colonies TA98 TAI 00 DMSO (0.1 ml) + 28 117 Metabolite C 2.34 + 38 526 # 4.69 + 36 778 # 9.38 + 73 # 1210 # 18.8 + 107 # 1745 # 37.5 + 133 # 2049 # 75 + 153 # 2147 # 150 + 133 # 2043 300 + 138 * 1412 * B[a]P 5.0 + 404 1078 #: Results were considered positive if the mean number of reverting colonies showed an increase in the dose dependence that could double that of the negative control. IF-2019-47864117-APN-ANp#INPI Page 89 of 93 *: Growth inhibition DMSO: Dimethyl sulfoxide B[a]P: Benzo[a]pyrene The number of reverting colonies shows the average number on each plate.

[0005] Table 6. Test Item Dose (pg / plate) Mixture S9 Number of reverting colonies TA1537 TA1535 WP2uvrA DMSO (0.1 ml) + 6 5 21 Metabolite C 2.3 + 6 8 28 6.9 + 7 8 23 21 + 7 5 21 62 + 9 4 26 185 + 9 * 5 * 17 556 t + 4 * 4 * 8 * 1667 t + 4 * 5 * 12 * 5000 . t + 5 * 4 * 16 * 2AA 2.0 + — 250 — 10.0 + — — 685 B[a]P 5.0 + 80 — — Not subjected to the test*: Growth inhibition t: Precipitation IF-2019-47864117-APN-ANP#INPI Page 90 of 93 DMSO: Dimethyl sulfoxide 2AA: 2-Aminoanthracene B[a]P: Benzo[a]pyrene The number of reverting colonies shows the average number on each plate.

[0006] Table 7. Test Article Dose (pg / plate) Mixture S9 Number of reverting colonies TA98 TAI 5 3 7 TAI 00 TAI 5 3 5 WP2uvr A DMSO (0.1 ml) - 17 6 ​​86 6 18 Metabolite C 2.3 - 14 3 87 6 15 6.9 - 15 1 ★ 99 5 * 16 21 - 17 3 * 48 * 6 * 17 62 - 8 3 * 41 * 3 ★ 13 185 - 8 * 2 * 45 * 4 * 13 556 t - . 8 * 0 * 33 * 0 * 13 * 1667 t - 8 * 0 * 25 * 1 * 10 * 5000 t - 0 * 0 * 35 * 0 * 11 * AF-2 0.01 - -- — 54 2 — 74 0.1 - 31 7 — — — — ICR-191 1.0 - — 113 1 — — — HS 0.5 - — — — 222 — IF-2019-47864117-APN-ANP#INPI Page 91 of 93 —: Not tested *: Growth inhibition t: Precipitation DMSO: Dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide SA: Sodium azide ICR-191: 2-methoxy-6-chloro-9-[3-(2chloroethyl)-aminopropylamino]acridine dihydrochloride' The number of reverting colonies shows the average number on each plate.

[0095] [Formulation Examples] Examples of formulations for the present compound include, for example, the following formulations. However, the present invention is not intended to be limited to these examples of formulations. Formulation Example 1 (Preparation of a capsule) (1) Compound 1 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19 mg (4) Magnesium stearate 1 mg The ingredients (1), (2), (3) and (4) are mixed to fill a gelatin capsule.

[0096] Example of Formulation 2 (Preparation of a tablet) (1) Compound 1 10 g (2) Lactose 50 g (3) Corn starch 15 g (4) Calcium carboxymethylcellulose 44 g IF-2019-47864117-APN-ANP#INPI Page 92 of 93 (5) Magnesium stearate 1 g The total amount of Ingredients (1), (2), and (3), plus 30 g of Ingredient (4), are combined with water, vacuum-dried, and then granulated. The resulting granules are mixed with 14 g of Ingredient (4) and 1 g of Ingredient (5) and divided into tablets using a tablet-making machine. This process yields 1000 tablets, each containing 10 mg of Compound 1. Industrial Application

[0097] A compound of Formula [I] or a salt thereof acceptable for pharmaceutical use exhibits SGLT1 inhibitory activity and may therefore be useful in the treatment and / or prevention of various diseases or conditions that can be improved by regulating SGLT1 activity. A compound of Formula [I] or a salt thereof acceptable for pharmaceutical use may also be useful in the treatment and / or prevention of various diseases or conditions that arise due to elevated blood glucose levels. IF-2019-47864117-APN-ANP#INPI Page 93 of 93 Argentine Republic - National Executive Branch 2019 - Year of Exports Additional Signature Sheet Graphic Report Number: IF-2019-47864117-APN-ANP#INPI CITY OF BUENOS AIRES Tuesday, May 21, 2019 Reference: 20190100503 The document was imported by the GEDO system with a total of 93 page(s). Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=ELECTRONIC DOCUMENTARY MANAGEMENT - GDE, c=AR, o=GOVERNMENT SECRETARY OF MODERNIZATION, ou=ADMINISTRATIVE MODERNIZATION SECRETARY, serialNumber=CUIT 30715117564 Date: 2019.05.21 12:39:48-03'00' Mariela Flavia Gonnet Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=GEST10N DOCUMENTAL ELECTRONICA - GDE, c=AR, o=SECRETARIA DE GOBIERNO DE MODERNIZACION, ou=SECRETARIA DE MODERNIZACION ADMINISTRATIVA, serialNumber=CUIT 30715117564 Date: 2019.05.21 12:39:49-03'00'

Claims

1. A cyclic methyl-lactam compound characterized in that it has the following Formula [I]: FORMULA 1, or a pharmaceutically acceptable salt thereof. Seven claims follow.