Method for treating or preventing diabetes mellitus using combination drug

Abstract

One purpose is to provide treatment or prevention of diabetes, obesity, or diabetic complications. Provided are: a drug for the treatment or prophylaxis of diabetes, obesity, or diabetic complications, said drug being characterized in that an SGLT1 inhibitor is used in combination with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor; and a method for treating or preventing diabetes, obesity, or diabetic complications, characterized by administering an SGLT1 inhibitor and at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

Description

This application is a divisional application of an application with a filing date of September 3, 2020, an application number of "202080076112.9", and an invention name of "Method for treating or preventing diabetes using a combination of drugs". Technical Field

[0001] The present invention relates to a drug for treating or preventing diabetes, obesity or diabetic complications, characterized in that an SGLT1 inhibitor is used in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor; and a method for treating or preventing diabetes, obesity or diabetic complications, characterized in that an SGLT1 inhibitor is administered with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor. Background Art

[0002] SGLT1 as SGLT (Na + -Glucose cotransporter) is one of the subtypes of SGLT1, which is known to be responsible for most of the absorption of glucose and galactose in the small intestine. In patients with human SGLT1 deficiency, malabsorption of glucose and galactose has been reported. Furthermore, increased expression of SGLT1 in the small intestine has been confirmed in diabetic patients, and the hyperglycemia of glucose absorption in diabetic patients is believed to be caused by the high expression of SGLT1 in the small intestine.

[0003] Based on these insights, SGLT1 inhibitors are expected to normalize blood sugar levels by inhibiting the absorption of sugar from the small intestine, and are believed to be effective for diabetes and diabetic complications caused by hyperglycemia. In addition, they are believed to be effective for obesity by inhibiting the influx of sugar into the body (Non-Patent Documents 1 and 2).

[0004] Voglibose, commonly known as voglibose, is a drug that has obtained a manufacturing and sales license for drugs, etc. based on Article 14 of the Japanese Pharmaceutical Affairs Law (license number: 21600AMZ00368, etc.). Voglibose inhibits the disaccharide hydrolase (α-glucosidase) responsible for the decomposition of disaccharides present in the intestinal mucosa into monosaccharides, inhibits or delays the digestion and absorption of sugars in the intestine, thereby improving postprandial hyperglycemia. Its pharmacological effect is known to be effective in inhibiting the onset of type 2 diabetes in impaired glucose tolerance.

[0005] Based on these findings, it is believed that SGLT1 inhibitors are effective in suppressing the onset of type 2 diabetes in patients with impaired glucose tolerance by inhibiting the absorption of sugar from the small intestine and improving postprandial hyperglycemia.

[0006] Diabetes refers to a disease in which blood sugar levels rise due to insufficient insulin action, and continued high blood sugar levels can cause diabetic complications (e.g., retinopathy, nephropathy, and neuropathy known as microangiopathy, and cerebrovascular disease, ischemic heart disease, and lower extremity occlusive arteriosclerosis known as macroangiopathy). Other diseases associated with high blood sugar levels include obesity.

[0007] There are type 1 and type 2 diabetes. Type 1 diabetes is believed to be caused by the destruction of pancreatic β cells that secrete insulin, resulting in insufficient insulin action. Type 2 diabetes is believed to be caused by environmental factors such as overeating, lack of exercise, obesity, stress, and aging in addition to multiple genetic factors that include reduced insulin secretion and insulin resistance. In the diagnosis of diabetes, three types (normal type, borderline type, and diabetic type) are used, which are classified based on blood sugar levels. If any of the following (1) to (4) is confirmed, it is determined to be diabetic type, and there is a possibility of diabetes or diabetes (Non-patent Document 3): (1) Morning fasting blood sugar level above 126 mg / dL (2) 200 mg / dL or more in 2 hours in a 75 g OGTT (oral glucose tolerance test) (3) Blood sugar level above 200 mg / dL at any time (4) HbA1cg6.5% or above.

[0008] The OGTT used in (2) above is one of the means for diagnosing diabetes. Generally speaking, a person takes a solution containing 75g of glucose after fasting, and if the blood sugar level after a certain period of time from the glucose intake is 200mg / dL or more, it is diagnosed as diabetes (Non-patent Document 3). Therefore, OGTT is an indicator for diagnosing diabetes, and compounds that can reduce the blood sugar level of a glucose tolerance subject in OGTT are considered to be effective for diabetes.

[0009] One of the subtypes of SGLT is SGLT2, which is mainly localized in the proximal tubules of the kidneys. SGLT2 has the function of reuptake of glucose into cells in the proximal tubules, and SGLT2 inhibitors are believed to increase the amount of glucose excreted in urine by inhibiting the reuptake of glucose from urine, thereby lowering blood sugar levels.

[0010] Dapagliflozin is a representative SGLT2 inhibitor used clinically as an antidiabetic drug. It has been reported that administration of dapagliflozin to diabetic model animals and diabetic patients increases urinary glucose excretion and improves hyperglycemia.

[0011] Dipeptidyl peptidase-4 (DPP4) degrades glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin secretion-stimulating polypeptide (GIP), which are glucose-dependent insulin secretion-stimulating hormones, and renders them inactive. Based on this, DPP4 inhibitors are believed to promote glucose-dependent insulin secretion and lower blood sugar levels by inhibiting the degradation of GLP-1 and GIP.

[0012] Sitagliptin is a representative DPP4 inhibitor and is clinically used as an antidiabetic drug. It has been reported that administration of sitagliptin to diabetic model animals and diabetic patients increases blood GLP-1 and GIP concentrations and improves hyperglycemia.

[0013] Prior art literature Non-patent literature Non-patent document 1: Am J Physiol Gastrointest Liver Physiol. 2002; 282(2): G241-8 Non-patent document 2: Nature. 1991; 350(6316): 354-6 Non-patent literature 3: Diabetes Treatment Guidelines 2016-2017. Summary of the invention

[0014] Provided are a drug for treating or preventing diabetes, obesity or diabetic complications, characterized in that an SGLT1 inhibitor is used in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor; and a method for treating or preventing diabetes, obesity or diabetic complications, characterized in that an SGLT1 inhibitor is administered with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The results show that the compound of Example 1 (hereinafter also referred to as Compound 1) significantly lowered the blood glucose level of SD rats subjected to glucose loading in OGTT compared to the vehicle. * in the figure indicates p<0.05 versus the vehicle.

[0016] Figure 2 It is shown that among the administered compounds, only compound 1 significantly reduced the blood glucose level of SD rats loaded with glucose in OGTT compared with the vehicle. ** in the figure indicates p<0.05 compared with the vehicle.

[0017] Figure 3 The transition of blood sugar level in Test Example 5 is shown.

[0018] Figure 4The blood glucose level 30 minutes after glucose loading in Test Example 5 is shown. ** in the figure indicates p<0.01 relative to the vehicle, indicates p<0.01 relative to compound 1, and ## indicates p<0.01 relative to dapagliflozin.

[0019] Figure 5 It shows the blood sugar level 60 minutes after glucose loading in Test Example 5. In the figure, * indicates p<0.05 relative to the vehicle, and ** indicates p<0.01 relative to the vehicle. indicates p<0.01 relative to compound 1, and ## indicates p<0.01 relative to dapagliflozin.

[0020] Figure 6 The transition of blood sugar level in Test Example 6 is shown.

[0021] Figure 7 The blood glucose level 30 minutes after glucose loading in Test Example 6 is shown. The ** in the figure indicates p<0.01 relative to the vehicle. indicates p<0.01 relative to compound 1, and # indicates p<0.05 relative to sitagliptin.

[0022] Figure 8 The transition of the active GLP-1 concentration in plasma in Test Example 6 is shown.

[0023] Fig. 9 The concentration AUC of active GLP-1 in plasma in Test Example 6. ** in the figure indicates p<0.01 relative to the vehicle. indicates p<0.01 relative to compound 1, and ## indicates p<0.01 relative to sitagliptin. DETAILED DESCRIPTION

[0024] A number of specific embodiments are exemplified below.

[0025] [Item 1] A drug for treating or preventing diabetes, obesity or diabetic complications containing an SGLT1 inhibitor, characterized in that the SGLT1 inhibitor is used in combination with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

[0026] [Item 2] A drug for treating or preventing diabetes, obesity or diabetic complications containing at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors, characterized in that an SGLT1 inhibitor is used in combination with at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors.

[0027] [Item 3] A drug for treating or preventing diabetes, obesity or diabetic complications comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula [I] or a pharmaceutically acceptable salt thereof is used in combination with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor: [Chemistry 1] [Wherein, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 for (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B For halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl] [Item 4] A drug for the treatment or prevention of diabetes, obesity or diabetic complications comprising at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors, characterized in that a compound of formula [I] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors: [Chemistry 2] [Wherein, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R3 for (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B For halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl].

[0028] [Item 5] A drug for treating or preventing diabetes, obesity or diabetic complications, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof, [Chemistry 3] [Wherein, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 for (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B For halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl] The method is characterized in that the method is administered to a subject who has received treatment with at least one drug selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

[0029] [Item 6] A medicament for treating or preventing diabetes, obesity or diabetic complications comprising at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor, characterized in that the medicament is administered to a subject receiving treatment based on a compound of formula [I] or a pharmaceutically acceptable salt thereof: [Chemistry 4] [Wherein, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 for (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B For halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl].

[0030] [Item 7] The drug according to any one of items 1 to 6, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of the compounds of formula [II] to [V] or a pharmaceutically acceptable salt thereof: [Chemistry 5] [Item 8] The drug according to any one of items 1 to 6, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of formula [II] or a pharmaceutically acceptable salt thereof: [Chemistry 6]

[0031] [Item 9] The drug according to any one of items 1 to 6, wherein the SGLT2 inhibitor is dapagliflozin.

[0032] [Item 10] The drug according to any one of items 1 to 6, wherein the DPP4 inhibitor is sitagliptin.

[0033] [Item 11] The medicament according to any one of items 1 to 6, wherein the diabetes is type 2 diabetes.

[0034] [Item 12] The drug according to item 5 or 6, wherein the subject is a human.

[0035] [Item 13] A method for treating or preventing diabetes, obesity or diabetic complications, characterized in that a therapeutically effective amount of an SGLT1 inhibitor and a therapeutically effective amount of at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor are administered to a subject.

[0036] [Item 14] An SGLT1 inhibitor for treating or preventing diabetes, obesity or diabetic complications, characterized in that it is used in combination with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

[0037] [Item 15] At least one agent selected from SGLT2 inhibitors and DPP4 inhibitors for treating or preventing diabetes, obesity or diabetic complications, characterized in that it is used in combination with an SGLT1 inhibitor.

[0038] [Item 16] Use of an SGLT1 inhibitor in the manufacture of a medicament for the treatment or prevention of diabetes, obesity or diabetic complications for use in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor.

[0039] [Item 17] Use of at least one drug selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor in the manufacture of a medicament for the treatment or prevention of diabetes, obesity or diabetic complications for use in combination with an SGLT1 inhibitor.

[0040] [Item 18] A pharmaceutical composition for treating or preventing diabetes, obesity or diabetic complications, comprising an SGLT1 inhibitor and at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

[0041] [Item 19] A pharmaceutical composition for the treatment or prevention of diabetes, obesity or diabetic complications, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor: [Chemistry 7] [Wherein, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 for (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B For halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl].

[0042] [Item 20] The composition according to item 18 or 19, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of the compounds of formula [II] to [V] or a pharmaceutically acceptable salt thereof: [Chemistry 8] [Item 21] The composition according to item 18 or 19, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of formula [II] or a pharmaceutically acceptable salt thereof: [Chemistry 9]

[0043] SGLT1 inhibitors can be low molecular weight compounds, nucleic acids, polypeptides, proteins, antibodies, vaccines, etc. as long as they are substances that inhibit SGLT1. In a certain way, SGLT1 inhibitors are substances that have the function of normalizing blood sugar levels by inhibiting the absorption of sugar from organs such as the small intestine and myocardium. In another way, SGLT1 inhibitors are substances that inhibit the rapid rise in glucose concentration in the plasma immediately after loading glucose, for example, 0 to 30 minutes after loading glucose in OGTT, and can maintain the subsequent glucose concentration in the plasma to the same degree as or below the suppressed concentration. In another way, SGLT1 inhibitors are substances that can increase the concentration of active GLP-1 in the plasma after loading glucose in OGTT. In another way, SGLT1 inhibitors are compounds of formula [I] or their pharmaceutically acceptable salts.

[0044] [Chemistry 10] [In the formula, each symbol has the same meaning as above] In another embodiment, the SGLT1 inhibitor is a substance whose metabolites do not show mutagenicity. Here, the substance that does not show mutagenicity refers to a substance that does not show the ability to induce reverse mutation based on the conditions of Test Example 4 described later. In another embodiment, the SGLT1 inhibitor is a human SGLT1 inhibitor.

[0045] The double wavy lines below in some structures indicate the bonding sites of the structures.

[0046] [Chemistry 11] The "halogen" includes, for example, fluorine, chlorine, bromine and iodine.

[0047] “C 1-3 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1-3The term "alkyl" includes methyl, ethyl, n-propyl and isopropyl.

[0048] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 The term "alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl.

[0049] "Halogenated C 1-3 "Alkyl" refers to the above "C" substituted by 1 to 5 halogens independently selected from the above "halogen" 1-3 Alkyl." "Halo C 1-3 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl and 3,3,3-trifluoropropyl.

[0050] "Fluorine C 1-3 "Alkyl" refers to the above "C 1-3 Alkyl". "Fluoro C 1-3 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl and 3,3,3-trifluoropropyl.

[0051] "Halogenated C 1-6 "Alkyl" refers to the above "C" substituted by 1 to 5 halogens independently selected from the above "halogen" 1-6 Alkyl." "Halo C 1-6 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl.

[0052] "Fluorine C 1-6 "Alkyl" refers to the above "C 1-6 Alkyl". "Fluoro C 1-6 The term "alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl.

[0053] “C 1-3 "Alkoxy" refers to the above-mentioned "C 1-3 Alkyl" is a group bonded to an oxygen atom. 1-3 The term "alkoxy" includes methoxy, ethoxy, n-propoxy and isopropoxy.

[0054] "Pyridyl" refers to any of the following formulae.

[0055] [Chemistry 12] "Pyrazinyl" refers to the following formula.

[0056] [Chemistry 13] "Pyrimidinyl" refers to any of the following formulae.

[0057] [Chemistry 14] "Pyridazinyl" refers to any of the following formulae.

[0058] [Chemistry 15] "Substitution" includes any chemically acceptable substitution. For example, "replacement by R 3A "Substituted pyridyl" refers to any one of the following formulae.

[0059] [Chemistry 16] Each substituent of the compound of formula [I] includes the specific embodiments shown below, and embodiments obtained by combining the specific embodiments of each substituent are also included in the compound of formula [I].

[0060] In one way, R 1 In another embodiment, R 1 For fluorine.

[0061] In one way, R 2 C 1-6 Alkyl or fluorine C 1-6 In another embodiment, R 2 C 1-6 In another embodiment, R 2 Fluorine C 1-3 alkyl.

[0062] In one way, R 3 for (1) Halogenated C 1-6 alkyl, (2) R 3ASubstituted pyridyl, or (3) Optional R 3B Substituted pyrazinyl or pyrimidinyl.

[0063] In another way, R 3 Selected from halogenated C 1-6 Alkyl groups and formulas [H1] to [H14].

[0064] In yet another embodiment, R 3 Halogenated C 1-6 Alkyl, formula [H2] or [H8].

[0065] [Chemistry 17] In one way, R 3A is halogen or halogenated C 1-3 In another embodiment, R 3A Fluorine or Fluorine C 1-3 alkyl.

[0066] In one way, R 3B is halogen or halogenated C 1-3 In another embodiment, R 3B Fluorine C 1-3 alkyl.

[0067] In one way, R 4 and R 5 Each independently is C 1-3 alkyl.

[0068] In one embodiment, the compound of formula [I] is a compound of formula [II] or [III]: [Chemistry 18] In another embodiment, the compound of formula [I] is a compound of formula [II]. In yet another embodiment, the compound of formula [I] is a monohydrate of a compound of formula [III], that is, a compound of formula [VI]: [Chemistry 19] The pharmaceutically acceptable salts in this specification may be any salts as long as they are salts known in the art that are not accompanied by excessive toxicity. Specifically, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases may be cited. Various forms of pharmaceutically acceptable salts are well known in the art, for example, as described in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977), (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).

[0069] The compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se to obtain a pharmaceutically acceptable salt thereof.

[0070] Examples of the salt with an inorganic acid include a salt with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid. Preferably, a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid is used.

[0071] Examples of the salt with an organic acid include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, dehydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-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, glycollylarsanilic acid, hexylresorcinol acid, The salts of the present invention include salts of oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthalenecarboxylic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theocyanic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid or glutamic acid. Preferred examples include salts of 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 or 2-hydroxy-1-ethanesulfonic acid.

[0072] Examples of the salt with an inorganic base include a salt with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium, and preferably a salt with sodium, potassium, calcium, magnesium or zinc.

[0073] Examples of the salt with an organic base include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine are mentioned.

[0074] The active ingredients of SGLT1 inhibitors (e.g., compounds of formula [I] or pharmaceutically acceptable salts thereof), SGLT2 inhibitors, and DPP4 inhibitors sometimes exist in the form of solvates. Solvates refer to molecules coordinated with solvents on compounds of formula [I] or pharmaceutically acceptable salts thereof, for example. Solvates may be pharmaceutically acceptable solvates, and examples thereof include hydrates, ethanolates, and dimethyl sulfoxides of compounds of formula [I] or pharmaceutically acceptable salts thereof. Specifically, examples include hemihydrates, monohydrates, dihydrates, or monoethanolates of compounds of formula [I], or monohydrates of sodium salts of compounds of formula [I] or 2 / 3 ethanolates of dihydrochlorides. These solvates can be obtained by known methods. For example, compounds of formula [III] may exist in the form of monohydrates as shown in the following formula [VI].

[0075] [Chemistry 20] The compound of formula [I] may be isotopically ( 2 H. 3 H. 14 C. 35 S, etc.) mark.

[0076] The compound of formula [I] or its pharmaceutically acceptable salt is preferably a substantially purified compound of formula [I] or its pharmaceutically acceptable salt, and more preferably a compound of formula [I] or its pharmaceutically acceptable salt purified to a purity of 80% or more.

[0077] Inhibition of SGLT1 means inhibiting the function of SGLT1 so that its activity disappears or weakens, for example, inhibiting the function of SGLT1 based on the conditions of Test Example 1 described later. Preferably, human SGLT1 is inhibited. The inhibition of the function of SGLT1 or the disappearance or weakening of its activity is preferably performed in clinical applications in humans.

[0078] SGLT2 inhibitors may be any substance as long as they inhibit SGLT2, and may be low molecular weight compounds, nucleic acids, polypeptides, proteins, antibodies, vaccines, etc. In one embodiment, SGLT2 inhibitors are substances that have the function of increasing the amount of sugar excreted in urine by inhibiting the reuptake of glucose from urine, thereby lowering blood sugar levels.

[0079] Inhibition of SGLT2 means inhibiting the function of SGLT2 so that its activity disappears or weakens. Preferably, human SGLT2 is inhibited. The inhibition of the function of SGLT2 or the disappearance or weakening of its activity is preferably performed in clinical applications in humans.

[0080] The SGLT2 inhibitors in this specification include, for example, glycoside compounds or their salts or solvates. Here, glycoside compounds refer to compounds in which a sugar or a sugar derivative is bonded to an aglycon moiety via a glycosidic bond (e.g., a C-glycosidic bond or an O-glycosidic bond), and the sugar or sugar derivative has the following structure.

[0081] [Chemistry 21] [In the formula, Y is O or S, and the glycosidic bond is formed with the carbon atom at position 1] The SGLT2 inhibitors in this specification include, for example, the following substances. It should be noted that, for convenience, conventional names are used throughout this specification. [Table 1] [Table 2-1] [Table 2-2]

[0082] The DPP4 inhibitor may be any substance as long as it inhibits DPP4, and may be a low molecular weight compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. In one embodiment, the DPP4 inhibitor is a substance that has the function of promoting sugar concentration-dependent insulin secretion and lowering blood sugar level by inhibiting the decomposition of GLP-1 and GIP.

[0083] Inhibiting DPP4 means inhibiting the function of DPP4 so that its activity disappears or weakens. Preferably, human DPP4 is inhibited. The inhibition of the function of DPP4 or the disappearance or weakening of its activity is preferably performed in clinical applications in humans.

[0084] The DPP4 inhibitors in the present specification include, for example, gliptins having at least one amide group or sulfonamide group, or salts thereof, or solvates thereof.

[0085] The DPP4 inhibitors in this specification include, for example, the following substances. It should be noted that, for convenience, conventional names are used throughout this specification. [Table 3] [Table 4-1] [Table 4-2]

[0086] SGLT1 inhibitors (e.g., compounds of formula [I] or pharmaceutically acceptable salts thereof), SGLT2 inhibitors, and DPP4 inhibitors have SGLT1 inhibitory activity, SGLT2 inhibitory activity, and DPP4 inhibitory activity, respectively, and are therefore useful in the treatment and / or prevention of various diseases or conditions that are expected to be improved by regulating their activity, or various diseases or conditions that may be caused by increased blood sugar levels due to sugar absorption in the body, such as diabetes (e.g., type 1 diabetes and type 2 diabetes), obesity, and / or diabetic complications (e.g., retinopathy, nephropathy, and neuropathy known as microangiopathy, and cerebrovascular disorders, ischemic heart disease, and lower extremity occlusive arteriosclerosis known as macroangiopathy). In a certain embodiment, various diseases or conditions are diabetes, obesity, or diabetic complications. In another embodiment, various diseases or conditions are diabetes. In another embodiment, various diseases or conditions are type 1 diabetes. In another embodiment, various diseases or conditions are type 2 diabetes.

[0087] In this specification, the combination refers to the administration of an SGLT1 inhibitor (e.g., a compound of formula [I] or a pharmaceutically acceptable salt thereof) and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor to a subject in any order. Each agent has a different mechanism of action, so the combination of these agents can exert an additive or synergistic therapeutic or preventive effect on at least one disease of various diseases or states. In a certain embodiment, the combination significantly suppresses the rapid rise in the concentration of glucose in the plasma immediately after glucose loading in the OGTT, for example, 0 to 30 minutes later, compared with the single administration of each agent, and the subsequent glucose concentration in the plasma can be maintained to the same degree or less than the suppressed concentration. In another embodiment, the combination refers to the significant increase in the concentration of active GLP-1 in the plasma immediately after glucose loading in the OGTT, for example, 0 to 30 minutes later, and the subsequent concentration of active GLP-1 in the plasma can be maintained to the same degree as the rising concentration. In another mode, the combination is used by using a variety of different medicaments of action mechanism, compared with the situation of giving a kind of medicament alone, the dosage of each medicament can be reduced, and the side effects inherent in each medicament can be alleviated. In a certain mode, SGLT1 inhibitor, and the first medicament and the second medicament and / or the third medicament selected from SGLT2 inhibitor and DPP4 inhibitor can be given to the object simultaneously, continuously, or at a certain interval (for example, within 30 minutes, within 1 hour, within 2 hours, within 4 hours), together or respectively in any order. When the second medicament and / or the third medicament are given to the object, the active ingredient contained in the first medicament given initially can be given during the period of existence in the body of the object in the treatment of effective amount. In another mode, SGLT1 inhibitor, and at least one medicament selected from SGLT2 inhibitor and DPP4 inhibitor can be given to the object as a single mixture obtained by combining these medicaments. The giving ratio and the matching ratio of these medicaments can be appropriately selected according to the giving object, the giving route, the object disease, the symptom, the severity of the disease, and their combination. For example, when the subject to be administered is a human, 0.01 to 1000 parts by weight of at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor may be used relative to 1 part by weight of the SGLT1 inhibitor.

[0088] In one embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combination of a compound of formula [I] and a glycoside compound or a salt thereof or a solvate thereof.

[0089] In another embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combination of a compound of formula [II] and a glycoside compound or a salt thereof or a solvate thereof.

[0090] In one embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes The compound of formula [I] and dapagliflozin, The compound of formula [I] and ipalifloxacin, The compound of formula [I] and togliflozin, The compound of formula [I] and empagliflozin, The compound of formula [I] and canagliflozin, and A combination of a compound of formula [I] and rupagliflozin.

[0091] In another embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor comprises The compound of formula [II] and dapagliflozin, The compound of formula [II] and ipalifloxacin, The compound of formula [II] and togliflozin, The compound of formula [II] and empagliflozin, The compound of formula [II] and canagliflozin, and A combination of a compound of formula [II] and rupagliflozin.

[0092] In one embodiment, the combination of an SGLT1 inhibitor and a DPP4 inhibitor comprises the combination of a compound of formula [I] and a gliptin having at least one amide group or sulfonamide group, or a salt thereof, or a solvate thereof.

[0093] In another embodiment, the combination of an SGLT1 inhibitor and a DPP4 inhibitor comprises the combination of a compound of formula [II] and a gliptin having at least one amide group or sulfonamide group, or a salt thereof, or a solvate thereof.

[0094] In one embodiment, the combination of an SGLT1 inhibitor and a DPP4 inhibitor includes The compound of formula [I] and sitagliptin, The compound of formula [I] and saxagliptin, The compound of formula [I] and vildagliptin, The compound of formula [I] and linagliptin, The compound of formula [I] and tenegliptin, The compound of formula [I] and alogliptin, The compound of formula [I] and anagliptin, The compound of formula [I] and trelagliptin, and A combination of a compound of formula [I] and omagliptin.

[0095] In another embodiment, the combination of SGLT1 inhibitor and DPP4 inhibitor includes The compound of formula [II] and sitagliptin, The compound of formula [II] and saxagliptin, The compound of formula [II] and vildagliptin, The compound of formula [II] and linagliptin, The compound of formula [II] and tenegliptin, The compound of formula [II] and alogliptin, The compound of formula [II] and anagliptin, The compound of formula [II] and trelagliptin, and Combination use of the compound of formula [II] and omagliptin.

[0096] In one embodiment, a drug for treating or preventing diabetes, obesity or diabetic complications is provided, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 22]

[0097] In another embodiment, a drug for treating or preventing diabetes, obesity or diabetic complications comprising at least one drug selected from dapagliflozin and sitagliptin is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 23]

[0098] In yet another embodiment, a drug for treating or preventing diabetes comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 24]

[0099] In yet another embodiment, a drug for treating or preventing diabetes comprising at least one drug selected from dapagliflozin and sitagliptin is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 25] In yet another embodiment, a drug for treating or preventing type 2 diabetes comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 26]

[0100] In yet another embodiment, a drug for the treatment or prevention of type 2 diabetes comprising at least one drug selected from dapagliflozin and sitagliptin is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 27]

[0101] In yet another embodiment, a drug for treating or preventing type 2 diabetes comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof is provided, wherein the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with dapagliflozin: [Chemistry 28]

[0102] In yet another embodiment, a drug for treating or preventing type 2 diabetes containing dapagliflozin is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with dapagliflozin: [Chemistry 29]

[0103] In yet another embodiment, a drug for treating or preventing type 2 diabetes comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof is provided, wherein the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with sitagliptin: [Chemistry 30]

[0104] In yet another embodiment, a drug for treating or preventing type 2 diabetes containing sitagliptin is provided, characterized in that the compound of formula [II] or a pharmaceutically acceptable salt thereof is used in combination with sitagliptin: [Chemistry 31]

[0105] In yet another embodiment, a pharmaceutical composition for treating or preventing diabetes, obesity or diabetic complications is provided, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof, and at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 32]

[0106] In yet another embodiment, a pharmaceutical composition for treating or preventing diabetes is provided, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof, and at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 33]

[0107] In yet another embodiment, a pharmaceutical composition for treating or preventing type 2 diabetes is provided, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof, and at least one drug selected from dapagliflozin and sitagliptin: [Chemistry 34]

[0108] In yet another embodiment, a pharmaceutical composition for treating or preventing type 2 diabetes is provided, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof and dapagliflozin: [Chemistry 35]

[0109] In yet another embodiment, a pharmaceutical composition for treating or preventing type 2 diabetes is provided, comprising a compound of formula [II] or a pharmaceutically acceptable salt thereof and sitagliptin: [Chemistry 36]

[0110] In this specification, the drug refers to any one of SGLT1 inhibitors, SGLT2 inhibitors and DPP4 inhibitors. The administration of a certain drug to a subject receiving treatment based on another drug refers to a mode of combined use, including, for example, administering a certain drug to a subject while the active ingredient contained in another drug previously administered is present in the subject's body in a therapeutically effective amount.

[0111] In this specification, the effective amount of the treatment of SGLT1 inhibitor can be appropriately changed according to the severity of the subject, administration route, target disease, symptom, disease and their combination. In the case of oral administration to people (body weight 60kg), as the lower limit of the effective amount for treatment, for example, about 0.01mg, about 0.1mg, about 0.5mg, about 1mg, about 10mg, about 20mg or about 50mg can be enumerated, and as the upper limit of the effective amount for treatment, for example, about 1mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, about 200mg, about 500mg or about 1000mg can be enumerated.

[0112] In this specification, the effective amount of SGLT2 inhibitor (such as dapagliflozin) can be appropriately changed according to the subject, route of administration, target disease, symptom, severity of disease and their combination. In the case of oral administration to people (weight 60kg), as the lower limit of effective amount in treatment, for example, about 0.01mg, about 0.1mg, about 0.5mg, about 1mg, about 10mg, about 20mg or about 50mg can be cited, and as the upper limit of effective amount in treatment, for example, about 1mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, about 200mg, about 500mg or about 1000mg can be cited. In a certain way, the effective amount of SGLT2 inhibitor (such as dapagliflozin) in treatment is about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 10mg, about 12mg or about 15mg per day. In another embodiment, the therapeutically effective amount of the SGLT2 inhibitor (eg, dapagliflozin) is about 5 mg or about 10 mg per day.

[0113] The therapeutically effective amount of DPP4 inhibitors (e.g., sitagliptin) in this specification can be appropriately changed according to the subject, route of administration, subject disease, symptom, severity of the disease, and their combination. In the case of oral administration to a human (body weight 60 kg), as the lower limit of the therapeutically effective amount, for example, about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day can be cited, and as the upper limit of the therapeutically effective amount, for example, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day can be cited. In a certain embodiment, the therapeutically effective amount of a DPP4 inhibitor (e.g., sitagliptin) is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 g, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg per day. In another embodiment, the therapeutically effective amount of a DPP4 inhibitor (e.g., sitagliptin) is about 12.5 mg, about 25 mg, about 50 mg, or about 100 mg per day.

[0114] Examples of the frequency of administration of each pharmaceutical agent, drug, and pharmaceutical composition in the present specification include once, twice, three times, or more times per day.

[0115] The term "treatment" as used herein includes improvement of symptoms, prevention of aggravation of symptoms, maintenance of remission, prevention of recurrence and prevention of relapse.

[0116] In the present specification, prevention includes suppressing the onset of symptoms. For example, prevention of diabetes includes suppressing the onset of type 2 diabetes in impaired glucose tolerance.

[0117] The pharmaceutical composition in this specification can be prepared by appropriately mixing a therapeutically effective amount of each drug with at least one pharmaceutically acceptable carrier, etc., according to a method known in the technical field of pharmaceutical preparations. The content of each drug in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the entire composition.

[0118] The dosage forms of the drugs, medicines and pharmaceutical compositions in this specification include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions, and non-oral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.

[0119] As pharmaceutically acceptable carriers, various organic or inorganic carrier substances commonly used as raw materials for preparations can be cited, and excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid preparations, solvents, solubilizers, suspending agents, isotonic agents, buffers, pain-relieving agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plasticizers, pH adjusters, absorption accelerators, gelling agents, preservatives, fillers, solubilizers, solubilizers, suspending agents, etc. in semisolid preparations can be cited. Further, additives such as preservatives, antioxidants, colorants, sweeteners, etc. can be added as needed.

[0120] Examples of the excipient include lactose, saccharide, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic.

[0121] Examples of the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethyl starch sodium, cross-linked carboxymethylcellulose sodium, cross-linked povidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose.

[0122] Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, white sugar, dextrin, starch, gelatin, sodium carboxymethyl cellulose, and gum arabic.

[0123] Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate.

[0124] Examples of the lubricant include magnesium stearate, calcium stearate, and talc.

[0125] Examples of the solvent include purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, and olive oil.

[0126] Examples of the solubilizing agent include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.

[0127] Examples of the suspending agent include benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, and glycerol monostearate.

[0128] Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, and D-mannitol.

[0129] Examples of the buffer include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

[0130] Examples of the pain-relieving agent include benzyl alcohol and the like.

[0131] Examples of the base include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (white vaseline, liquid paraffin, paraffin, etc.), hydrophilic vaseline, refined lanolin, water-absorbing ointment, water-containing lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, etc.), propylene glycol, polyethylene glycol (polyethylene glycol 200 to 600, etc.), and combinations of two or more thereof.

[0132] Examples of the preservative include ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

[0133] Examples of the antioxidant include sodium sulfite and ascorbic acid.

[0134] Examples of the coloring agent include food coloring (food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), and β-carotene.

[0135] Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, and aspartame.

[0136] Each medicament, drug and pharmaceutical composition in this specification can be administered orally or non-orally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to humans and mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage varies according to the subject, disease, symptoms, dosage form, route of administration, etc. For example, the dosage for oral administration to adult patients (weight 60 kg) is generally about 0.01 mg to about 1 g per day for the active ingredient of each medicament. These amounts can be divided into one or more administrations. In a certain way, each medicament can be formulated into a separate pharmaceutical composition, or it can be administered to the subject in any order through different routes of administration. In another way, the dosage of each medicament can be reduced by combined use compared with the case of administering each medicament alone, and the dosage for oral administration to adult patients (weight 60 kg) can be about 0.01 mg to about 1000 mg per day.

[0137] In a certain embodiment, a kit (administration, treatment and / or prevention kit, etc.), a package (package, etc.), and a pharmaceutical set (and / or container) may be provided, which comprises an SGLT1 inhibitor (e.g., a compound of formula [I] or a pharmaceutically acceptable salt thereof), at least one pharmaceutical agent selected from SGLT2 inhibitors and DPP4 inhibitors, and a record that these pharmaceutical agents can be used in combination or should be used in combination for treatment and / or prevention. Such a kit, package, and pharmaceutical set may have one or more containers filled with an SGLT1 inhibitor, at least one pharmaceutical agent selected from SGLT2 inhibitors and DPP4 inhibitors, and other appropriate pharmaceutical agents or drugs (or ingredients). As examples of such a kit, package, and pharmaceutical set, commercial kits, commercial packages, and commercial pharmaceutical sets for treatment and / or prevention of appropriate target diseases may be cited. As the recorded materials included in such a kit, package and pharmaceutical set, there can be cited precautions or accompanying documents in the form indicated by the government agency for the manufacture, use or sale of controlled drugs or biological products, which are precautions or accompanying documents indicating the permission of the government agency involved in the manufacture, use or sale of products related to administration to humans. The above-mentioned kit, package and pharmaceutical set may include packaged products, and may also include structures constructed for appropriate administration steps (steps), and may also include structures constructed in a manner that can achieve more preferred medical treatment and / or prevention, such as treatment and / or prevention of target diseases.

[0138] [General manufacturing method] The general production method of the compound of formula [I] or its pharmaceutically acceptable salt is exemplified below. However, the production method of the compound of formula [I] or its pharmaceutically acceptable salt is not limited to the general production method.

[0139] The compound obtained in each step may be isolated and / or purified by a known method such as distillation, recrystallization, column chromatography, etc. as necessary, or may be transferred to the next step without isolation and / or purification in some cases.

[0140] In this specification, room temperature refers to a temperature in a state where the temperature is not controlled, and one embodiment thereof includes 1°C to 40°C.

[0141] [General Production Method A] Compound of formula [I-1] or a pharmaceutically acceptable salt thereof R 3 For R 3A substituted pyridyl, or optionally substituted by R 3B The compound of the formula [I] or a pharmaceutically acceptable salt thereof of a substituted pyrazinyl, pyrimidinyl or pyridazinyl group can be obtained, for example, by the production method shown below.

[0142] [Chemistry 37] [Wherein, R 1 and R 2 Has the same meaning as defined above, R 31 For R 3A substituted pyridyl, or optionally substituted by R 3B Substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A and R 3B Has the same meaning as defined above, X 1A and X 1B are independently halogen, in step 1, X 1A X 1B Highly reactive, R 1 In the case of halogen, R 1 and X 1A Preferably the same halogen, A 4 is n-butyl, A 7 C 1-4 Alkyl or benzyl, A 12 is tert-butyl or benzyl].

[0143] (Step A1) The compound of the formula [3] can be obtained by reacting the compound of the formula [1] with the compound of the formula [2] in a solvent in the presence of a base.

[0144] Examples of the solvent include ether solvents such as 1,2-dimethoxyethane, and polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, and N,N'-dimethylethyleneurea. A preferred solvent is 1,3-dimethyl-2-imidazolidinone.

[0145] Examples of the base include cesium carbonate and sodium hydride. A preferred base is sodium hydride.

[0146] The reaction temperature is, for example, 60°C to 170°C, and preferably 100°C to 140°C.

[0147] The compound of formula [1] and the compound of formula [2] may be commercially available or may be produced by a known method.

[0148] Or, R 2 In the case of a trifluoromethyl group, the compound of the formula [3] may be a commercially available product.

[0149] (Step A2) The compound of formula [5] can be obtained by subjecting the compound of formula [3] to a Mizoroki-Heck reaction with the compound of formula [4]. For example, the compound of formula [5] can be obtained by subjecting the compound of formula [3] to a reaction with the compound of formula [4] in a solvent in the presence of a palladium catalyst and a base.

[0150] Examples of the solvent include alcohol solvents such as ethylene glycol and polar solvents such as N,N-dimethylformamide. A preferred solvent is ethylene glycol.

[0151] Examples of the palladium catalyst include a mixture of palladium (II) acetate and 1,1'-bis(diphenylphosphino)ferrocene or 1,3-bis(diphenylphosphino)propane. A preferred palladium catalyst is a mixture of palladium (II) acetate and 1,1'-bis(diphenylphosphino)ferrocene.

[0152] Examples of the base include organic bases such as triethylamine, and a preferred base is triethylamine.

[0153] The reaction temperature is, for example, 80°C to 150°C, and preferably 100°C to 140°C.

[0154] The compound of formula [4] may be a commercially available product or may be produced by a known method.

[0155] (Step A3) The compound of formula [6] can be prepared by converting -C(=CH2)OA of the compound of formula [5] to 4 For example, the compound of formula [6] can be obtained by reacting the compound of formula [5] in a solvent in the presence of an acid.

[0156] Examples of the solvent include ketone solvents such as acetone, alcohol solvents such as ethylene glycol, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, polar solvents such as N,N-dimethylformamide, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of tetrahydrofuran and water.

[0157] Examples of the acid include hydrochloric acid and trifluoroacetic acid. A preferred acid is hydrochloric acid.

[0158] The reaction temperature is, for example, 20°C to 50°C, and preferably room temperature.

[0159] (Step A4) The compound of the formula [8] can be obtained by reacting the compound of the formula [6] with the compound of the formula [7] in a solvent in the presence of a base.

[0160] Examples of the solvent include ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; alcohol solvents such as methanol and ethanol; hydrocarbon solvents such as toluene; polar solvents such as N,N-dimethylformamide; and mixed solvents thereof. A preferred solvent is tetrahydrofuran.

[0161] Examples of the base include lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium hexamethyldisilazane and sodium hydride. A preferred base is lithium tert-butoxide.

[0162] The reaction temperature is, for example, -78°C to 110°C, and preferably 0°C to room temperature.

[0163] The compound of formula [7] may be a commercially available product or may be produced by a known method.

[0164] (Step A5) The compound of the formula

[10] can be obtained by reacting the compound of the formula [8] with the compound of the formula [9] in a solvent in the presence of an acid.

[0165] Examples of the solvent include ether solvents such as tetrahydrofuran, alcohol solvents such as methanol and ethanol, and hydrocarbon solvents such as toluene.

[0166] Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. A preferred acid is acetic acid. These acids can be used as solvents.

[0167] The reaction temperature is, for example, 20°C to 130°C, and preferably 80°C to 110°C.

[0168] The compound of formula [9] may be a commercially available product or may be produced by a known method, or may be obtained by the general production method B described below.

[0169] (Step A6) The compound of formula

[11] can be prepared by removing -A from the compound of formula

[10] . 7 The removal reaction is carried out according to A 7 The type can be carried out under appropriate conditions. For example, A 7 In the case of an ethyl group, the compound of the formula

[11] can be obtained by reacting the compound of the formula

[10] in a solvent in the presence of a base.

[0170] Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran; water; and mixed solvents thereof. A preferred solvent is a mixed solvent of two or more selected from methanol, tetrahydrofuran, and water.

[0171] Examples of the base include lithium hydroxide, sodium hydroxide and potassium hydroxide. A preferred base is sodium hydroxide.

[0172] The reaction temperature is, for example, 0°C to 100°C, and preferably room temperature to 40°C.

[0173] (Step A7) The compound of formula

[13] can be obtained by subjecting the compound of formula

[11] to a Curtius rearrangement reaction with the compound of formula

[12] . For example, the compound of formula

[13] can be obtained by reacting the compound of formula

[11] with an azidating agent in the presence of a base in a solvent, and then reacting with a compound of formula

[12] .

[0174] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; and hydrocarbon solvents such as toluene. Alternatively, the compound of formula

[12] may be used as the solvent. A preferred solvent is toluene or a mixed solvent of toluene and the compound of formula

[12] .

[0175] Examples of the azidating agent include diphenylphosphoryl azide.

[0176] Examples of the base include organic bases such as triethylamine and N,N-diisopropylethylamine. A preferred base is triethylamine.

[0177] The reaction temperature is, for example, 65°C to 130°C, and preferably 90°C to 110°C.

[0178] The compound of formula

[12] may be a commercially available product or may be produced by a known method.

[0179] (Step A8) The compound of formula

[14] can remove -C(=O)OA from the compound of formula

[13] in a solvent. 12 The removal reaction is carried out according to A12 The type can be carried out under appropriate conditions. For example, A 12 In the case of a tert-butyl group, the compound of the formula

[14] can be obtained by reacting the compound of the formula

[13] in a solvent in the presence of an acid.

[0180] Examples of the solvent include ester solvents such as ethyl acetate, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, water, and mixed solvents thereof. A preferred solvent is 1,4-dioxane.

[0181] Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. A preferred acid is hydrochloric acid. These acids can be used as solvents.

[0182] The reaction temperature is, for example, 0°C to 60°C, and preferably 0°C to room temperature.

[0183] (Step A9) The compound of formula [I-1] can be obtained by condensing a compound of formula

[14] with a compound of formula

[15] in a solvent.

[0184] Examples of the solvent include halogenated hydrocarbon solvents such as chloroform, ether solvents such as tetrahydrofuran, polar solvents such as pyridine, acetonitrile, N,N-dimethylformamide, and mixed solvents thereof. A preferred solvent is pyridine.

[0185] Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (COMU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride·n-hydrate (DMT-MM), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, and propylphosphonic anhydride. A preferred condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl).

[0186] The reaction temperature is, for example, 0°C to 100°C, and preferably room temperature.

[0187] The compound of formula

[15] can be obtained by, for example, the method of general production method E described later.

[0188] [General manufacturing method B] Manufacturing method B1 The compound of formula [9] can be obtained by, for example, the production method shown below.

[0189] [Chemistry 38] [Wherein, R 31 Has the same meaning as defined above, X 16 is halogen].

[0190] The compound of the formula [9] can be obtained by reacting the compound of the formula

[16] with hydrazine monohydrate in a solvent.

[0191] Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; alcohol solvents such as ethanol and 2-propanol; halogenated hydrocarbon solvents such as dichloromethane; polar solvents such as N,N-dimethylformamide and pyridine; water; and mixed solvents thereof. Alternatively, hydrazine monohydrate may be used as the solvent. A preferred solvent is a mixed solvent of 2-propanol and hydrazine monohydrate.

[0192] The reaction temperature is, for example, room temperature to 140°C, preferably 60°C to 100°C.

[0193] The compound of formula

[16] may be a commercially available product or may be produced by a known method.

[0194] Manufacturing method B2 The compound of formula [9] further comprises 31 For R 3A In the case of a substituted pyridyl group, it can also be obtained, for example, by the production method shown below.

[0195] [Chemistry 39] [Where R 31 For R 3A Substituted pyridyl, R 3A has the same meaning as defined above].

[0196] The compound of the formula [9] can be obtained by diazotizing and reducing the compound of the formula

[17] in a solvent in the presence of an acid.

[0197] As the solvent, water can be mentioned, for example.

[0198] As the diazotizing agent, for example, sodium nitrite can be mentioned.

[0199] Examples of the acid include hydrochloric acid and sulfuric acid. A preferred acid is hydrochloric acid.

[0200] Examples of the reducing agent include tin (II) chloride and sodium sulfite. A preferred reducing agent is tin (II) chloride.

[0201] The reaction temperature of diazotization is, for example, -20°C to 5°C, preferably -5°C to 0°C.

[0202] The reaction temperature of the reduction is, for example, -5°C to room temperature, preferably 0°C to room temperature.

[0203] The compound of formula

[17] may be a commercially available product or may be produced by a known method.

[0204] Manufacturing method B3 As another method, the compound of formula [9] further comprises R 31 For (1) by R 3A substituted pyridyl or (2) optionally substituted by R 3B In the case of a substituted pyrimidinyl group, it can also be obtained by, for example, the production method shown below.

[0205] [Chemistry 40] [Wherein, R 31 For (1) by R 3A substituted pyridyl or (2) optionally substituted by R 3B Substituted pyrimidinyl, R 3A , R 3B and X 16 Has the same meaning as defined above, A 19 is tert-butyloxycarbonyl or benzyloxycarbonyl].

[0206] (Step B3-1) The compound of the formula

[18] can be obtained by reacting the compound of the formula

[16] with a base and a boric acid ester in a solvent.

[0207] Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. A preferred solvent is tetrahydrofuran.

[0208] Examples of the base include n-butyl lithium and isopropyl magnesium bromide. A preferred base is n-butyl lithium.

[0209] Examples of the boric acid ester include triisopropyl borate and trimethyl borate. A preferred boric acid ester is triisopropyl borate.

[0210] The reaction temperature is, for example, -78°C to room temperature, preferably -78°C to 0°C.

[0211] The compound of formula

[16] may be a commercially available product or may be produced by a known method.

[0212] (Step B3-2) The compound of the formula

[20] can be obtained by reacting the compound of the formula

[18] with the compound of the formula

[19] in a solvent in the presence of a copper catalyst.

[0213] Examples of the solvent include ether solvents such as tetrahydrofuran and alcohol solvents such as methanol. A preferred solvent is methanol.

[0214] Examples of the copper catalyst include copper (II) acetate.

[0215] The reaction temperature is, for example, room temperature to 100°C, preferably 45°C to 65°C.

[0216] (Step B3-3) The compound of formula [9] can be prepared by removing -A of the compound of formula

[20] in a solvent. 19 The removal reaction is carried out according to A 19 The type can be carried out under appropriate conditions. For example, A 19 In the case of a tert-butoxycarbonyl group, the compound of the formula [9] can be obtained by reacting the compound of the formula

[20] in a solvent in the presence of an acid.

[0217] Examples of the solvent include ester solvents such as ethyl acetate, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, water, and mixed solvents thereof. A preferred solvent is 1,4-dioxane.

[0218] Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. A preferred acid is hydrochloric acid.

[0219] The reaction temperature is, for example, 0°C to 60°C, and preferably 0°C to room temperature.

[0220] [General Production Method C] Compound of formula [I-2] or its pharmaceutically acceptable salt R 3 C 1-6 Alkyl or halogenated C 1-6 The alkyl compound of the formula [I] or a pharmaceutically acceptable salt thereof can be obtained, for example, by any of the following production methods.

[0221] Manufacturing method C1 [Chemistry 41] [Wherein, R 1 and R 2 Has the same meaning as defined above, R 32 C 1-6 Alkyl or halogenated C 1-6 alkyl].

[0222] (Step C1-1) The compound of formula [I-2] can be produced by reacting a compound of formula

[21] or a salt thereof with a compound of formula

[15] or a salt thereof in a solvent in the presence of a condensing agent and an additive.

[0223] Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (COMU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride·n-hydrate (DMT-MM), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, and propylphosphonic anhydride.

[0224] Examples of the additive include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine, and 1-methylimidazole.

[0225] Examples of the solvent include halogenated hydrocarbon solvents such as chloroform; ether solvents such as tetrahydrofuran; polar solvents such as pyridine, acetonitrile, and N,N-dimethylformamide; and mixed solvents thereof.

[0226] The reaction temperature is, for example, 0°C to 100°C.

[0227] When a salt of the compound of formula

[21] is used, the reaction may be carried out in the presence of a base. Examples of the base include organic bases such as triethylamine and alkali metal salts such as sodium carbonate.

[0228] The compound of formula [I-2] can also be produced by converting the compound of formula

[15] into a carboxylic acid halide using a halogenating agent in a solvent and then reacting the resulting mixture with a compound of formula

[21] in the presence of a base.

[0229] Examples of the halogenating agent used in the reaction include oxalyl chloride and thionyl chloride. A preferred halogenating agent is oxalyl chloride.

[0230] Examples of the base used in the reaction include organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, and alkali metal salts such as sodium hydrogen carbonate and sodium carbonate. A preferred base is pyridine.

[0231] Examples of the solvent include halogenated hydrocarbon solvents such as chloroform, ether solvents such as cyclopentyl methyl ether and tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof with water. A preferred solvent is chloroform.

[0232] The reaction temperature is, for example, 0°C to 80°C, and preferably 0°C to 60°C.

[0233] In the production of the carboxylic acid halide, N,N-dimethylformamide may be added as an additive.

[0234] Manufacturing method C2 [Chemistry 42] [Wherein, R 1 , R 2 and R 32 Has the same meaning as defined above, P N1 is a protecting group for an amino group; preferably P N1 is 2,4-dimethoxybenzyl].

[0235] (Step C2-1) The compound of the formula

[23] can be produced from the compound of the formula

[21] or a salt thereof and the compound of the formula

[22] or a salt thereof according to production method C1, step C1-1.

[0236] (Step C2-2) The compound of formula [I-2] or a salt thereof can be prepared by removing the P of the compound of formula

[23] by a deprotection reaction. N1 The deprotection reaction is carried out according to P N1 The types can be implemented under appropriate conditions.

[0237] For example, P N1 In the case of 2,4-dimethoxybenzyl group, the compound of formula [I-2] or a salt thereof can be produced by reacting with an acid in a solvent in the presence of an additive.

[0238] Examples of the acid include methanesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid. A preferred acid is trifluoroacetic acid.

[0239] Examples of the additive include anisole and triethylsilane. A preferred additive is anisole.

[0240] Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, hydrocarbon solvents such as toluene, water, and mixed solvents thereof. An organic acid such as trifluoroacetic acid can be used as the solvent.

[0241] The reaction temperature is, for example, 0°C to 130°C, and preferably 25°C to 80°C.

[0242] In this step, when an acid is used, a compound of the formula

[24] or a salt thereof is obtained.

[0243] [Chemistry 43] [Where R 1 and R 32 Has the same meaning as defined above] The compound of formula [I-2] or its salt can be prepared by a known method by converting the hydroxyl group of the compound of formula

[24] or its salt into C 1-6 Alkyl-O or halo C 1-6 Alkyl-O group is used to make it.

[0244] For example, R 1 For fluorine, R 2 is tert-butyl, R 32 The trifluoromethyl compound of formula [I-2] (ie, the compound of formula [II]) or a salt thereof can be produced by reacting a compound of formula

[24] or a salt thereof with di-tert-butyl dicarbonate in the presence of magnesium perchlorate.

[0245] Examples of the solvent include halogenated hydrocarbon solvents such as chloroform and ether solvents such as tetrahydrofuran. A preferred solvent is chloroform.

[0246] The reaction temperature is, for example, 0°C to 100°C, and preferably room temperature to 70°C.

[0247] [General manufacturing method D] The compound of formula

[21] can be produced by the production method shown below.

[0248] Manufacturing method D1 [Chemistry 44] [Wherein, R 1 , R 2 and R 32 Has the same meaning as defined above, L 1 is a leaving group; preferably L1 is chlorine, bromine or iodine; P N2 Each independently is a protecting group for an amine; preferably, the two P N2 Together with the nitrogen to which they are bonded, they form 2,5-dimethylpyrrole].

[0249] (Step D1-1) The compound of formula

[26] can be prepared by a known method by introducing P into the amino group of the compound of formula

[25] or a salt thereof. N2 The introduction of the protecting group is based on P N2 The type of can be implemented under appropriate conditions. For example, 2 P N2 When the compound of the formula

[26] forms 2,5-dimethylpyrrole together with the nitrogen to which they are bonded, the compound of the formula

[25] can be produced by reacting 2,5-hexanedione in a solvent under acidic conditions.

[0250] Examples of the acid used in the reaction include concentrated hydrochloric acid, concentrated sulfuric acid, aminosulfuric acid, p-toluenesulfonic acid and acetic acid. A preferred acid is acetic acid.

[0251] Examples of the solvent include 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 mixed solvents thereof. Organic acids such as acetic acid can be used as the solvent.

[0252] The reaction temperature is, for example, room temperature to 150°C, preferably 80°C to 140°C.

[0253] (Step D1-2) The compound of formula

[27] can be prepared by alkylating or halogenating the compound of formula

[26] by a known method. 32 In the case of a trifluoromethyl group, it can be produced by a method comprising: step (a) of reacting a compound of the formula

[26] with dibromodifluoromethane in a solvent in the presence of a base and a catalyst; and step (b) of fluorinating in the presence of tetramethylammonium fluoride or silver (I) tetrafluoroborate in a solvent.

[0254] Examples of the base used in step (a) include sodium hydride and potassium tert-butoxide. A preferred base is sodium hydride.

[0255] Examples of the catalyst used in step (a) include tetrabutylammonium bromide and zinc. A preferred catalyst is tetrabutylammonium bromide.

[0256] Examples of the solvent used in step (a) include ether solvents such as tetrahydrofuran and polar solvents such as N,N-dimethylformamide. A preferred solvent is N,N-dimethylformamide.

[0257] The reaction temperature in step (a) is, for example, 0°C to 40°C, and preferably 0°C to room temperature.

[0258] As the solvent used in step (b), when tetramethylammonium fluoride is used, ether solvents such as 1,4-dioxane and polar solvents such as sulfolane can be exemplified. A preferred solvent is sulfolane. When silver (I) tetrafluoroborate is used, halogenated hydrocarbon solvents such as dichloromethane can be exemplified. A preferred solvent is dichloromethane.

[0259] The reaction temperature of step (b) is, for example, 80 to 180° C., preferably 100 to 140° C., when tetramethylammonium fluoride is used. When silver (I) tetrafluoroborate is used, it is, for example, -78 to 50° C., preferably -78 to room temperature.

[0260] (Step D1-3) The compound of formula

[28] can be prepared by introducing L into the compound of formula

[27] in a solvent in the presence of a base. 1 For example, L 1 In the case of iodine, the compound of the formula

[28] can be produced by iodinating the compound of the formula

[27] in the presence of a base in a solvent.

[0261] Examples of the base used in the reaction include n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazane, and lithium tetramethylpiperidinium. A preferred base is n-butyllithium.

[0262] Examples of the iodination agent include iodine, iodine monochloride, N-iodosuccinimide, and 1-chloro-2-iodoethane. A preferred iodination agent is iodine.

[0263] Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. A preferred solvent is tetrahydrofuran.

[0264] The reaction temperature is, for example, -100°C to 40°C, preferably -78°C to 20°C.

[0265] (Step D1-4) The compound of formula

[29] or a salt thereof can be prepared by removing the P of the compound of formula

[28] by a deprotection reaction. N2 The deprotection reaction is carried out according to P N2 The type of can be implemented under appropriate conditions. For example, 2 P N2 When forming 2,5-dimethylpyrrole together with the nitrogen to which they are bonded, the compound of the formula

[29] or a salt thereof can also be produced by reacting the compound of the formula

[28] with hydroxylamine in a solvent.

[0266] Examples of the solvent include alcoholic solvents such as ethanol, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of an alcoholic solvent and water.

[0267] The reaction temperature is, for example, 40°C to 150°C, and preferably 80°C to 130°C.

[0268] Hydroxylamine hydrochloride may be used instead of hydroxylamine. In this case, the reaction may be carried out in the presence of a base. Examples of the base include organic bases such as triethylamine and alkali metal salts such as sodium carbonate. A preferred base is triethylamine.

[0269] (Step D1-5) The compound of formula

[21] or a salt thereof can be produced by subjecting a compound of formula

[29] or a salt thereof to a Suzuki coupling reaction with a compound of formula

[30] . For example, the compound of formula

[21] or a salt thereof can be produced by reacting a compound of formula

[29] or a salt thereof with a compound of formula

[30] in a solvent in the presence of a base and a palladium catalyst.

[0270] As the palladium catalyst used in the reaction, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and a mixture of palladium(II) acetate and tricyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl can be exemplified. A preferred palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct.

[0271] Examples of the base used in the reaction include tripotassium phosphate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and triethylamine. Preferred bases are tripotassium phosphate, cesium carbonate, or sodium carbonate.

[0272] Examples of the solvent include 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 mixed solvents thereof with water. Preferred solvents are 1,2-dimethoxyethane, toluene, dimethyl sulfoxide, or mixed solvents thereof with water.

[0273] The reaction temperature is, for example, 20°C to 150°C, and preferably 80°C to 130°C.

[0274] The compound of formula

[30] can be prepared by a known method. Alternatively, the corresponding organic borates can be used in place of the compound of formula

[30] to carry out the reaction of step D1-5. For example, organic borates

[33] can be prepared by the following preparation method.

[0275] Manufacturing method D2 [Chemistry 45] [Wherein, R 1 and R 2 Has the same meaning as defined above, R 6 is fluorine or hydroxyl; L 2 is a leaving group; preferably L 2 is chlorine, bromine, iodine, p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy; B(OR 7 )2 is an organic borate; R 7 For example, each independently is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, or OR 7 Optionally, together with the boron to which they are bonded, they form a cyclic organic borate ester; preferably B(OR 7 )2 is organic boronic acid pinacol ester].

[0276] (Step D2-1) The compound of formula

[32] can be prepared by replacing R 1 This reaction can be carried out by a known method.

[0277] R 1 When it is fluorine, the compound of formula

[32] can be prepared, for example, by reacting the compound of formula

[31] with sodium tert-butoxide or potassium tert-butoxide in a solvent. Examples of the solvent include ether solvents such as tetrahydrofuran; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 100°C, preferably room temperature to 85°C.

[0278] R 1 In the case of a hydroxyl group, the compound of the formula

[32] can be produced, for example, by the method described in step C2-2 of production method C2.

[0279] (Step D2-2) The compound of the formula

[33] can be produced by reacting the compound of the formula

[32] with a boron compound in a solvent in the presence of a palladium catalyst, an organic phosphorus compound and a base.

[0280] Examples of the palladium catalyst include palladium (II) acetate, palladium (II) chloride, and tris(dibenzylideneacetone)dipalladium (0).

[0281] Examples of the organic phosphorus compound include triphenylphosphine, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.

[0282] Tetrakis(triphenylphosphine)palladium, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct, or [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) may be used instead of the palladium catalyst and the organophosphorus compound.

[0283] Examples of the base include potassium acetate, sodium carbonate, cesium carbonate and potassium carbonate. A preferred base is potassium acetate.

[0284] Examples of the boron compound include bis(pinacolato)diboron.

[0285] Examples of the solvent include ether solvents such as 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is dimethyl sulfoxide.

[0286] The reaction temperature is, for example, room temperature to 150°C, preferably 70°C to 110°C.

[0287] [General Manufacturing Method E] The compound of the formula

[15] or a salt thereof and the compound of the formula

[22] or a salt thereof can be produced by the production method shown below.

[0288] Manufacturing method E1 [Chemistry 46] [Wherein, P N1 Has the same meaning as defined above, P E1 and P E2 Each independently is a protecting group for a carboxyl group; preferably P E1 and P E2 are each independently methyl, ethyl, tert-butyl or benzyl; R 8 are each independently methoxy or ethoxy; L 3is a leaving group; preferably L 3 is bromine or chlorine].

[0289] (Step E1-1) The compound of the formula

[36] can be produced by reacting a compound of the formula

[34] with a compound of the formula

[35] in a solvent in the presence of a base.

[0290] Examples of the base used in the reaction include potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate and sodium hydride. A preferred base is potassium tert-butoxide.

[0291] Examples of the solvent include ether solvents such as tetrahydrofuran, alcohol solvents such as methanol and ethanol, and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is tetrahydrofuran.

[0292] The reaction temperature is, for example, -78°C to 100°C, preferably 0°C to 70°C.

[0293] (Step E1-2) The compound of the formula

[37] can be produced by reacting the compound of the formula

[36] with formaldehyde (preferably an aqueous formaldehyde solution) in a solvent in the presence of a base.

[0294] Examples of the base used in the reaction include potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate and sodium hydride. A preferred base is potassium carbonate.

[0295] Examples of the solvent include ether solvents such as tetrahydrofuran, alcohol solvents such as methanol and ethanol, and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is tetrahydrofuran.

[0296] The reaction temperature is, for example, -78°C to 100°C, preferably 0°C to 70°C.

[0297] (Step E1-3) The compound of the formula

[39] can be produced by reacting the compound

[37] with the compound

[38] in a solvent.

[0298] Examples of the solvent include hydrocarbon solvents such as toluene, alcohol solvents such as methanol and ethanol, and mixed solvents thereof. A preferred solvent is toluene.

[0299] The reaction temperature is, for example, 20°C to 150°C, and preferably 80°C to 130°C.

[0300] (Step E1-4) Compound

[40] or a salt thereof can be prepared by removing the P of compound

[39] by a deprotection reaction.E1 The deprotection reaction is carried out according to P E1 The types can be implemented under respective appropriate conditions. For example, P E1 In the case of an ethyl group, the compound

[40] or a salt thereof can be produced by hydrolyzing the compound

[39] in a solvent in the presence of a base.

[0301] Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide and sodium ethoxide. A preferred base is sodium ethoxide.

[0302] Examples of the solvent include alcohol solvents such as ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of ethanol and water.

[0303] The reaction temperature is, for example, 0°C to 100°C, and preferably 0°C to 40°C.

[0304] (Step E1-5) The compound of formula

[22] or its salt can be obtained by separating it from the compound of formula

[40] or its salt. The separation of the compound of formula

[22] or its salt can be carried out by a method known in the art under conditions suitable for its separation. For example, the compound of formula

[22] or its salt can be separated as a diastereoisomer salt with a basic optical resolution agent and then the salt can be decomposed with an acid to obtain it.

[0305] Examples of the basic optical resolution agent include (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

[0306] Examples of solvents for deriving diastereomeric salts include alcoholic solvents such as 2-propanol, ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and mixed solvents thereof with water. Preferred solvents are acetonitrile, 1,2-dimethoxyethane, or mixed solvents thereof with water.

[0307] The optical purity of the diastereoisomer salt can be improved by recrystallization. As the solvent used in the recrystallization, ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and mixed solvents thereof with water can be exemplified. A preferred solvent is a mixed solvent of acetonitrile and water.

[0308] Examples of the acid used for decomposing the diastereomeric salt include hydrochloric acid, sulfuric acid and potassium hydrogen sulfate. A preferred acid is hydrochloric acid.

[0309] Examples of the solvent used for decomposition of the diastereomeric salt include ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of ethyl acetate and water.

[0310] (Step E1-6) The compound of formula

[15] or its salt can be prepared by removing the P of the compound of formula

[22] or its salt by a deprotection reaction. N1 The deprotection reaction is carried out according to P N1 The types can be implemented under appropriate conditions. For example, P N1 In the case of 2,4-dimethoxybenzyl, the compound of the formula

[15] or a salt thereof can be produced according to production method C2, step C2-2. Example

[0311] Here, the meanings of the abbreviations used in this specification are as follows.

[0312] DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide THF: Tetrahydrofuran CPME: Cyclopentyl Methyl Ether WSC·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride The following is a description of the preparation examples, examples, reference examples, test examples, and formulation examples.

[0313] 1 H-NMR spectra were measured in CDCl3 or DMSO-d6 using tetramethylsilane as an internal standard, and all δ values ​​are expressed in ppm. It should be noted that, unless otherwise specified, measurements were made using a 400 MHz NMR apparatus.

[0314] 1 The symbols in the H-NMR spectrum have the following meanings.

[0315] s:singlet d: doublet t:triplet q:quartet dd: double doublet ddd: double double doublet brs: broad singlet m: multiplet (multiplet) J: coupling constant.

[0316] [Production Example 1] Production of 2-(3-(tert-Butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [Chemistry 47] (Step 1) Production of 1-bromo-3-(tert-butoxy)-5-fluorobenzene [Chemistry 48] Under an argon gas stream, di-tert-butyl dicarbonate (1.14 g) and magnesium perchlorate (58 mg) were added to 3-bromo-5-fluorophenol (500 mg) at room temperature in sequence. 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, further stirred at 65°C for 1 hour, and cooled 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 cooled to room temperature, and a mixture of n-hexane / ethyl acetate (1 / 1) was added. The reaction mixture was washed with 3N hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine in sequence, dried with sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 1 / 0 to 20 / 1), thereby obtaining the title compound (437 mg) with a yield of 68%. 1 H-NMR (CDCl3) δ: 1.35 (s, 9H), 6.62-6.66 (m, 1H), 6.92-6.98 (m, 2H).

[0317] (Step 2) Production of 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [Chemistry 49] To a DMSO (5 mL) solution of 1-bromo-3-(tert-butoxy)-5-fluorobenzene (437 mg) obtained in step 1, potassium acetate (434 mg), bis(pinacolato)diboron (898 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct (144 mg) were added in sequence at room temperature under an argon atmosphere. The reaction mixture was stirred at 90°C for 2.5 hours. The reaction mixture was cooled to room temperature. To the reaction mixture, a n-hexane / ethyl acetate (1 / 1) mixture and water were added in sequence. The reaction mixture was stirred at room temperature for 50 minutes and allowed to stand overnight. To the reaction mixture, a n-hexane / ethyl acetate (1 / 1) mixture, water, silica gel, and diatomaceous earth were added in sequence. After stirring the reaction mixture, the insoluble matter was filtered off and the insoluble matter was washed with a n-hexane / ethyl acetate (1 / 1) mixture. The filtrate was extracted with a mixture of n-hexane / ethyl acetate (1 / 1). The organic layer was washed with water twice and with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin layer chromatography (eluting solvent: n-hexane / ethyl acetate = 10 / 1) to obtain the title compound (443 mg) in a yield of 85%. 1 H-NMR (CDCl3) δ: 1.33 (s, 12H), 1.36 (s, 9H), 6.77-6.82 (m, 1H), 7.18-7.23 (m, 22H).

[0318] [Production Example 2] Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 50] (Step 1) Production of diethyl 2-methyl-3-methylenesuccinate [Chemistry 51] Under nitrogen gas flow, THF (2.55L) was added to potassium tert-butoxide (180g) at room temperature. Triethyl phosphoacetate (314g) was added dropwise to the mixed solution under ice-cold conditions for 13 minutes. The dropping funnel used was washed with THF (511mL), and the washings were added to the reaction mixture. The reaction mixture was stirred for 2 hours and 9 minutes under ice-cold conditions. Ethyl 2-bromopropionate (247g) was added dropwise to the reaction mixture under ice-cold conditions for 20 minutes. The dropping funnel used was washed with THF (79mL), 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 (188g) was added to the reaction mixture under ice-cold conditions for 1 minute. 37% by weight of formaldehyde aqueous solution (152mL) was added dropwise to the reaction mixture under ice-cold conditions for 10 minutes. 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 into layers. The aqueous layer was extracted twice with THF (200 mL). The obtained organic layers were combined and concentrated. Toluene (471 mL) and saturated brine (471 mL) were added to the residue. The reaction mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate (63 g). The sodium sulfate was filtered off. In addition, triethyl phosphoacetate (300 g) was used to react in the same manner, and the obtained filtrate was combined with the above-obtained filtrate to obtain a toluene solution (about 921 mL) of the title compound (equivalent to 2.66 mol). The toluene solution of the obtained title compound was recorded as a yield of 100% and used in the next step. The formation of the title compound was confirmed by HPLC analysis.

[0319] The HPLC measurement equipment and conditions are shown below.

[0320] Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatography Prominence Determination conditions: Column: Kinetex C18: 2.6 μm, 50 mm × 2.1 mm (Phenomenex) Column temperature: 40°C Flow rate: 0.4mL / min. Analysis time: 10 min. Detection wavelength: UV (220nm) Mobile phase: (Solution A) water, (Solution B) acetonitrile Liquid delivery of mobile phase: the mixing ratio of liquid A and liquid B (liquid A / liquid B (volume %)) was maintained at 80 / 20 from 0 minute to 0.01 minute after injection, changed linearly from 80 / 20 to 10 / 90 from 0.01 minute to 7 minutes, maintained at 10 / 90 from 7 minutes to 8 minutes, changed linearly from 10 / 90 to 80 / 20 from 8 minutes to 9 minutes, and maintained at 80 / 20 from 9 minutes to 10 minutes.

[0321] The retention time of the title compound under the above-mentioned HPLC measurement conditions was about 3.7 minutes.

[0322] (Step 2) Production of a mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester [Chemistry 52] To the toluene solution (about 921 mL) of diethyl 2-methyl-3-methylenesuccinate (equivalent to 2.66 mol) obtained in step 1, 2,4-dimethoxybenzylamine (468 g) was added dropwise at room temperature for 2 minutes under a nitrogen stream. The reaction mixture was stirred at 120°C for 5 hours and 45 minutes. The reaction mixture was allowed to stand at room temperature over the weekend. The reaction mixture was ice-cooled and the internal temperature was set to about 15°C. 2N hydrochloric acid (1.33 L) was added dropwise to the reaction mixture and stirred. The reaction mixture was separated. The aqueous layer was extracted with toluene (150 mL). The obtained organic layers were combined, washed with a mixture of saturated brine and water (600 mL, saturated brine / water = 1 / 1), dried with sodium sulfate (120 g), concentrated, and dried under reduced pressure at room temperature overnight to obtain a crude product of the title compound (790 g; cis / trans = about 1 / 1, containing 5.5% by weight of toluene). The formation of the title compound was confirmed by HPLC analysis.

[0323] The HPLC measurement equipment and conditions are shown below.

[0324] Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatography Prominence Determination conditions: Column: Atlantis T3: 5μm, 150mm×4.6mm (Waters) Column temperature: 40°C Flow rate: 1.15mL / min. Analysis time: 18 min. Detection wavelength: UV (220nm) Mobile phase: (Solution A) 10 mM sodium phosphate buffer (pH = 2.6), (Solution B) acetonitrile Liquid delivery of mobile phase: the mixing ratio of liquid A and liquid B (liquid A / liquid B (volume %)) was maintained at 60 / 40 from 0 minute to 0.5 minute after injection, changed linearly from 60 / 40 to 10 / 90 from 0.5 minute to 8 minutes, maintained at 10 / 90 from 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.

[0325] The retention time of ethyl (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate under the above HPLC measurement conditions was about 6.6 minutes, and the retention time of ethyl (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate was about 6.9 minutes.

[0326] (Step 3) Production of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 53] To the crude product of the mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester obtained in step 2 (790 g, containing 5.5% by weight of toluene), ethanol (1.15 L) was added at room temperature under a nitrogen stream. Sodium ethoxide (20% by weight ethanol solution, 1.15 L) was added dropwise to the reaction mixture at room temperature over 31 minutes. The reaction mixture was stirred at room temperature for 2 hours and 57 minutes. The reaction mixture was ice-cooled, and water (1.84 L) was added dropwise over 33 minutes. CPME (1.8 L) and toluene (1.8 L) were added to the reaction mixture at room temperature, and the layers were separated (organic layer 1). CPME (1.8 L) was added to the water layer, and the layers were separated (organic layer 2). 1.8 L of solvent was distilled off from the aqueous layer. 6N hydrochloric acid (110 mL) was added dropwise to the aqueous layer under ice cooling, and ethyl acetate (1.8 L) was added. 6N hydrochloric acid (300 mL) was added dropwise to the mixed solution under ice cooling, and the mixture was stirred for about 10 minutes. Water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% sodium hydrogen sulfate aqueous solution (300 mL), and ethanol (300 mL) were added to the mixed solution under ice cooling in sequence. The mixed solution was stirred at room temperature overnight. Ethyl acetate (600 mL) was added to the mixed solution and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (600 mL). The obtained organic layers (except organic layer 1 and organic layer 2) were combined and washed with a mixed solution of saturated brine and water (1 L, saturated brine / water = 1 / 1). Sodium sulfate (120 g) and activated carbon (30 g) were added to the organic layer and stirred at room temperature for 1 hour. The mixed solution was filtered through celite to remove insoluble matter. The insoluble matter was washed with ethyl acetate (3 L). The filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product of the title compound (561 g).

[0327] In addition, the above organic layer 1 and organic layer 2 were combined and concentrated. Toluene (450 mL) and water (450 mL) were added to the residue and the layers were separated. The aqueous layer was washed twice with toluene (450 mL). Ethyl acetate (450 mL) was added to the aqueous layer. 6N hydrochloric acid (70 mL) was added dropwise to the mixed solution under ice cooling. Ethyl acetate (300 mL) was added to the mixed solution and the layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers of the obtained ethyl acetate were combined and washed with a mixed solution of saturated brine and water (225 mL, saturated brine / water = 1 / 1). Sodium sulfate (30 g) and activated carbon (7.5 g) were added to the organic layer and stirred at room temperature for 1 hour. The mixed solution was filtered to remove insoluble matter. The insoluble matter was washed with ethyl acetate (750 mL). The obtained filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product (87.3 g) of the title compound.

[0328] To the mixture of the crude product and the crude product of the title compound obtained above, CPME (3 L) was added under a nitrogen stream. The mixed solution was stirred at 120 ° C. The mixed solution was stirred for 17 hours and 34 minutes and slowly cooled to room temperature. The mixed solution was ice-cooled and stirred for 3 hours at an internal temperature of about 1 ° C. The precipitate was filtered and washed with cold CPME (900 mL). The precipitate was dried under reduced pressure at 50 ° C overnight, thereby obtaining the title compound (585 g) with a 3-step yield of 75%. The formation of the title compound was confirmed by HPLC analysis and NMR.

[0329] The HPLC measurement equipment and conditions are the same as those in step 2. The retention time of the title compound under the present HPLC measurement conditions is about 3.1 minutes. 1 H-NMR (CDCl3) δ: 1.33 (d, 3H, J = 6.5Hz), 2.68-2.85 (m, 2H), 3.33-3.48 (m, 2H), 3.80 (s, 6H), 4.43 (s, 2H), 6.42-6.46 (m, 2H), 7.11-7.15 (m, 1H).

[0330] (Step 4) Preparation of diastereomeric salt of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid and (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol [Chemistry 54] To the (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (585 g) obtained in step 3, acetonitrile (2.9 L) was added at room temperature under a nitrogen stream. The mixed solution was stirred at 85°C. To the mixed solution, (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (254 g) was added at 85°C for 14 minutes. The reaction mixture was stirred at 90°C for 2 hours and 48 minutes. The reaction mixture was stirred overnight and cooled to room temperature. The precipitate was filtered and washed with acetonitrile (2.4 L). The precipitate was dried at room temperature and normal pressure for 8.5 hours to obtain crude crystals of the title compound (516 g). Acetonitrile (2.5 L) and water (0.5 L) were added to the crude crystals at room temperature under a nitrogen stream. The mixed solution was stirred at 100°C for 1 hour and 14 minutes. Acetonitrile (1.5 L) was added dropwise to the mixed solution at 100°C for 1 hour and 7 minutes. The mixed solution was stirred at 100°C for 10 minutes. The mixed solution was stirred for 21 hours and 10 minutes and cooled to room temperature. The mixed solution was stirred under ice cooling for 3 hours and 54 minutes. The precipitate was filtered and washed with acetonitrile (1.5 L). The precipitate was dried at room temperature and normal pressure for 4 hours, thereby obtaining the title compound (448 g, 99.8% de) with a yield of 45%. The formation of the title compound was confirmed by HPLC analysis.

[0331] The HPLC measurement equipment and conditions are shown below.

[0332] Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatography Prominence Determination conditions: Column: CHIRALPAKAD-3R: 3μm, 150mm×4.6mm (Daicel) Column temperature: 40°C Flow rate: 0.50mL / min. Analysis time: 10 min. Detection wavelength: UV (220nm) Mobile phase: (Solution A) 10 mM sodium phosphate buffer (pH = 2.6), (Solution B) acetonitrile The mobile phase was fed: the mixing ratio of solution A and solution B (solution A / solution B (volume %)) was maintained at 60 / 40.

[0333] The retention time of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid under the above HPLC measurement conditions was about 5.6 minutes, and the retention time of (3S,4S)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid was about 6.5 minutes.

[0334] The stereostructure of the title compound was determined by X-ray crystallographic analysis of a single crystal obtained by recrystallization from methyl isobutyl ketone.

[0335] The diastereomeric excess was determined by the HPLC area percentage in the present measurement results ((3R, 4R) isoform / (3S, 4S) isoform=99.886% / 0.114%).

[0336] (Step 5) Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 55] To the diastereomeric salt (448 g) of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid and (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol obtained in step 4, ethyl acetate (1.8 L) and water (1.34 L) were added at room temperature. To the mixture, 6N hydrochloric acid (168 mL) was added dropwise at room temperature over 16 minutes. The mixture was separated. The aqueous layer was extracted three times with ethyl acetate (450 mL). The obtained organic layers were combined, washed with 2N hydrochloric acid (224 mL) and saturated brine (224 mL) in that order, dried over 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 obtain the title compound (254 g) in a yield of 98%. 1 H-NMR (DMSO-D6) δ: 1.15 (d, 3H, J = 7.2Hz), 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, 2.3Hz), 6.56 (d, 1H, J=2.3Hz), 7.00 (d, 1H, J=8.4Hz), 12.61 (br s, 1H).

[0337] [Production Example 3] Production of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 56] (Step 1) Production of diethyl 2-methyl-3-methylenesuccinate [Chemistry 57] Under nitrogen gas flow, THF (2.55L) was added to potassium tert-butoxide (180g) at room temperature. Triethyl phosphoacetate (314g) was added dropwise to the mixed solution under ice-cold conditions for 13 minutes. The dropping funnel used was washed with THF (511mL), and the washings were added to the reaction mixture. The reaction mixture was stirred for 2 hours and 9 minutes under ice-cold conditions. Ethyl 2-bromopropionate (247g) was added dropwise to the reaction mixture under ice-cold conditions for 20 minutes. The dropping funnel used was washed with THF (79mL), 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 (188g) was added to the reaction mixture under ice-cold conditions for 1 minute. 37% by weight of formaldehyde solution (152mL) was added dropwise to the reaction mixture under ice-cold conditions for 10 minutes. 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 into layers. The aqueous layer was extracted twice with THF (200 mL). The obtained organic layers were combined and concentrated. Toluene (471 mL) and saturated brine (471 mL) were added to the residue. The reaction mixture was stirred and separated into layers. The organic layer was dried over sodium sulfate (63 g). The sodium sulfate was filtered off. In addition, triethyl phosphoacetate (300 g) was used to react in the same manner, and the obtained filtrate was combined with the filtrate obtained above to obtain a toluene solution (about 921 mL) of the title compound (equivalent to 2.66 mol). The toluene solution of the obtained title compound was recorded as a yield of 100% and used in the next step. The formation of the title compound was confirmed by HPLC analysis.

[0338] The HPLC measurement equipment and conditions are shown below.

[0339] Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatography Prominence Determination conditions: Column: Kinetex C18: 2.6 μm, 50 mm × 2.1 mm (Phenomenex) Column temperature: 40°C Flow rate: 0.4mL / min. Analysis time: 10 min. Detection wavelength: UV (220nm) Mobile phase: (Solution A) water, (Solution B) acetonitrile Liquid delivery of mobile phase: the mixing ratio of liquid A and liquid B (liquid A / liquid B (volume %)) was maintained at 80 / 20 from 0 minute to 0.01 minute after injection, changed linearly from 80 / 20 to 10 / 90 from 0.01 minute to 7 minutes, maintained at 10 / 90 from 7 minutes to 8 minutes, changed linearly from 10 / 90 to 80 / 20 from 8 minutes to 9 minutes, and maintained at 80 / 20 from 9 minutes to 10 minutes.

[0340] The retention time of the title compound under the above-mentioned HPLC measurement conditions was about 3.7 minutes.

[0341] (Step 2) Production of a mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester [Chemistry 58] 2,4-dimethoxybenzylamine (468 g) was added dropwise to a toluene solution (about 921 mL) of diethyl 2-methyl-3-methylenesuccinate (equivalent to 2.66 mol) obtained in step 1 under a nitrogen stream at room temperature for 2 minutes. The reaction mixture was stirred at 120°C for 5 hours and 45 minutes. The reaction mixture was allowed to stand at room temperature for a weekend. The reaction mixture was ice-cooled and the internal temperature was set to about 15°C. 2N hydrochloric acid (1.33 L) was added dropwise to the reaction mixture and stirred. The reaction mixture was separated. The aqueous layer was extracted with toluene (150 mL). The obtained organic layers were combined, washed with a mixture of saturated brine and water (600 mL, saturated brine / water = 1 / 1), dried with sodium sulfate (120 g), concentrated, and dried under reduced pressure at room temperature overnight to obtain a crude product of the title compound (790 g; cis / trans = about 1 / 1, containing 5.5% by weight of toluene). The formation of the title compound was confirmed by HPLC analysis.

[0342] The HPLC measurement equipment and conditions are shown below.

[0343] Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatography Prominence Determination conditions: Column: Atlantis T3: 5μm, 150mm×4.6mm (Waters) Column temperature: 40°C Flow rate: 1.15mL / min. Analysis time: 18 min. Detection wavelength: UV (220nm) Mobile phase: (Solution A) 10 mM sodium phosphate buffer (pH = 2.6), (Solution B) acetonitrile Liquid delivery of mobile phase: the mixing ratio of liquid A and liquid B (liquid A / liquid B (volume %)) was maintained at 60 / 40 from 0 minute to 0.5 minute after injection, changed linearly from 60 / 40 to 10 / 90 from 0.5 minute to 8 minutes, maintained at 10 / 90 from 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.

[0344] The retention time of ethyl (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate under the above HPLC measurement conditions was about 6.6 minutes, and the retention time of ethyl (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate was about 6.9 minutes.

[0345] (Step 3) Production of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 59] To the crude product of the mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester obtained in step 2 (790 g, containing 5.5% by weight of toluene), ethanol (1.15 L) was added at room temperature under a nitrogen stream. Sodium ethoxide (20% by weight ethanol solution, 1.15 L) was added dropwise to the reaction mixture at room temperature over 31 minutes. The reaction mixture was stirred at room temperature for 2 hours and 57 minutes. The reaction mixture was ice-cooled, and water (1.84 L) was added dropwise over 33 minutes. CPME (1.8 L) and toluene (1.8 L) were added to the reaction mixture at room temperature, and the layers were separated (organic layer 1). CPME (1.8 L) was added to the water layer, and the layers were separated (organic layer 2). 1.8 L of solvent was distilled off from the aqueous layer. 6N hydrochloric acid (110 mL) was added dropwise to the aqueous layer under ice cooling, and ethyl acetate (1.8 L) was added. 6N hydrochloric acid (300 mL) was added dropwise to the mixed solution under ice cooling, and the mixture was stirred for about 10 minutes. Water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% sodium hydrogen sulfate aqueous solution (300 mL), and ethanol (300 mL) were added to the mixed solution under ice cooling in sequence. The mixed solution was stirred at room temperature overnight. Ethyl acetate (600 mL) was added to the mixed solution and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (600 mL). The obtained organic layers (except organic layer 1 and organic layer 2) were combined and washed with a mixed solution of saturated brine and water (1 L, saturated brine / water = 1 / 1). Sodium sulfate (120 g) and activated carbon (30 g) were added to the organic layer and stirred at room temperature for 1 hour. The mixed solution was filtered through celite to remove insoluble matter. The insoluble matter was washed with ethyl acetate (3 L). The filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product of the title compound (561 g).

[0346] In addition, the above organic layer 1 and organic layer 2 were combined and concentrated. Toluene (450 mL) and water (450 mL) were added to the residue and the layers were separated. The aqueous layer was washed twice with toluene (450 mL). Ethyl acetate (450 mL) was added to the aqueous layer. 6N hydrochloric acid (70 mL) was added dropwise to the mixed solution under ice cooling. Ethyl acetate (300 mL) was added to the mixed solution and the layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers of the obtained ethyl acetate were combined and washed with a mixed solution of saturated brine and water (225 mL, saturated brine / water = 1 / 1). Sodium sulfate (30 g) and activated carbon (7.5 g) were added to the organic layer and stirred at room temperature for 1 hour. The mixed solution was filtered and the insoluble matter was filtered out. The insoluble matter was washed with ethyl acetate (750 mL). The obtained filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product (87.3 g) of the title compound.

[0347] To the mixture of the crude product and the crude product of the title compound obtained above, CPME (3 L) was added under a nitrogen stream. The mixed solution was stirred at 120 ° C. The mixed solution was stirred for 17 hours and 34 minutes and slowly cooled to room temperature. The mixed solution was ice-cooled and stirred for 3 hours at an internal temperature of about 1 ° C. The precipitate was filtered and washed with cold CPME (900 mL). The precipitate was dried under reduced pressure at 50 ° C overnight, thereby obtaining the title compound (585 g) with a 3-step yield of 75%. The formation of the title compound was confirmed by HPLC analysis and NMR.

[0348] The HPLC measurement equipment and conditions are the same as those in step 2. The retention time of the title compound under the present HPLC measurement conditions is about 3.1 minutes. 1 H-NMR (CDCl3) δ: 1.33 (d, 3H, J=6.5Hz), 2.68-2.85 (m, 2H), 3.33-3.48 (m, 2H), 3.80 (s, 6H), 4.43 (s, 2H), 6.42-6.46 (m, 2H), 7.11-7.15 (m, 1H).

[0349] (Step 4) Preparation of diastereomeric salt of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid and (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol [Chemistry 60] To the (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (585 g) obtained in step 3, acetonitrile (2.9 L) was added at room temperature under a nitrogen stream. The mixed solution was stirred at 85°C. To the mixed solution, (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (254 g) was added at 85°C for 14 minutes. The reaction mixture was stirred at 90°C for 2 hours and 48 minutes. The reaction mixture was stirred overnight and cooled to room temperature. The precipitate was filtered and washed with acetonitrile (2.4 L). The precipitate was dried at room temperature and normal pressure for 8.5 hours to obtain crude crystals of the title compound (516 g). Acetonitrile (2.5 L) and water (0.5 L) were added to the crude crystals at room temperature under a nitrogen stream. The mixed solution was stirred at 100°C for 1 hour and 14 minutes. Acetonitrile (1.5 L) was added dropwise to the mixed solution at 100°C for 1 hour and 7 minutes. The mixed solution was stirred at 100°C for 10 minutes. The mixed solution was stirred for 21 hours and 10 minutes and cooled to room temperature. The mixed solution was stirred under ice cooling for 3 hours and 54 minutes. The precipitate was filtered and washed with acetonitrile (1.5 L). The precipitate was dried at room temperature and normal pressure for 4 hours to obtain the title compound (448 g, 99.8% de) with a yield of 45%. The formation of the title compound was confirmed by HPLC analysis.

[0350] The HPLC measurement equipment and conditions are shown below.

[0351] Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatography Prominence Determination conditions: Column: CHIRALPAKAD-3R: 3μm, 150mm×4.6mm (Daicel) Column temperature: 40°C Flow rate: 0.50mL / min. Analysis time: 10 min. Detection wavelength: UV (220nm) Mobile phase: (Solution A) 10 mM sodium phosphate buffer (pH = 2.6), (Solution B) acetonitrile The mobile phase was fed: the mixing ratio of solution A and solution B (solution A / solution B (volume %)) was maintained at 60 / 40.

[0352] The retention time of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid under the above HPLC measurement conditions was about 5.6 minutes, and the retention time of (3S,4S)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid was about 6.5 minutes.

[0353] The stereostructure of the title compound was determined by X-ray crystallographic analysis of a single crystal obtained by recrystallization from methyl isobutyl ketone.

[0354] The diastereomeric excess was determined by the HPLC area percentage in the present measurement results ((3R, 4R) isoform / (3S, 4S) isoform=99.886% / 0.114%).

[0355] (Step 5) Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 61] To the diastereomeric salt (448 g) of (3R, 4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid and (1R, 2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol obtained in step 4, ethyl acetate (1.8 L) and water (1.34 L) were added at room temperature. To the mixture was added dropwise 6N hydrochloric acid (168 mL) at room temperature over 16 minutes. The mixture was separated. The aqueous layer was extracted three times with ethyl acetate (450 mL). The obtained organic layers were combined, washed with 2N hydrochloric acid (224 mL) and saturated brine (224 mL) in that order, dried over 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 obtain the title compound (254 g) in a yield of 98%. 1 H-NMR (DMSO-D6) δ: 1.15 (d, 3H, J = 7.2Hz), 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, 2.3Hz), 6.56 (d, 1H, J = 2.3Hz), 7.00 (d, 1H, J = 8.4Hz), 12.61 (brs, 1H).

[0356] (Step 6) Production of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemistry 62] To a mixture of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (254 g) obtained in step 5 and the compound (33 g) obtained in the same manner as step 5, a solution of anisole (160 mL) in trifluoroacetic acid (1.44 L) was added at room temperature under a nitrogen stream. The reaction mixture was stirred at 80°C for 4 hours and 4 minutes. The reaction mixture was cooled to room temperature under water cooling. The reaction mixture was concentrated. Toluene (287 mL) was added to the residue and concentrated. The residue was allowed to stand at room temperature overnight. Toluene (287 mL) was added to the residue and concentrated. Toluene (80 mL) was added to the residue at room temperature. Diisopropyl ether (2.9 L) was added to the mixture under water cooling. The mixture was stirred under water cooling. The solid precipitated from the mixed solution was collected by filtration and washed with diisopropyl ether (431 mL). The solid was dried at room temperature and normal pressure to obtain the title compound (137 g) in a yield of 98%. 1 H-NMR (DMSO-D6) δ: 1.10 (d, 3H, J = 7.2Hz), 2.35-2.44 (m, 1H), 2.79-2.87 (m, 1H), 3, 19-3.25 (m, 1H), 3.34-3.40 (m, 1H), 7.64 (s, 1H), 12.56 (s, 1H).

[0357] [Production Example 4] Production of 3-hydrazino-5-(trifluoromethyl)pyridine [Chemistry 63] (Step 1) Production of 3-fluoro-5-hydrazinopyridine [Chemistry 64] To a solution of 5-fluoropyridin-3-amine (1.5 g) in 6N hydrochloric acid (15 mL), a solution of sodium nitrite (0.923 g) in water (7.5 mL) was added dropwise at 0°C for 2 minutes. The reaction mixture was stirred at 0°C for 1 hour and 7 minutes. A suspension of 6N hydrochloric acid (15 mL) of tin (II) chloride (6.34 g) was added dropwise at 0°C for 3 minutes. The reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 23 hours. An 8N aqueous sodium hydroxide solution (about 34 mL) was added dropwise to the reaction mixture at 0°C. The mixture was stirred at 0°C. The mixture was extracted 8 times with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. A mixture of methyl tert-butyl ether (6 mL) / n-hexane (36 mL) was added to the obtained residue at room temperature. The suspension was stirred at room temperature. The solid was collected from the suspension by filtration and washed with n-hexane. The solid was dried under reduced pressure at 60°C to obtain the title compound (965.8 mg) in a yield of 57%. 1 H-NMR (CDCl3) δ: 3.64 (br s, 2H), 5.41 (br s, 1H), 6.99 (dt, 1H, J = 10.8, 2.5Hz), 7.89 (d, 1H, J = 2.5Hz), 7.97-7.99 (m, 1H).

[0358] [Production Example 5] Production of 3-hydrazino-5-(trifluoromethyl)pyridine [Chemistry 65] (Step 1) Production of 3-hydrazino-5-(trifluoromethyl)pyridine [Chemistry 66] To a solution of 5-(trifluoromethyl)pyridine-3-amine (3g) in 6N hydrochloric acid (30mL), a solution of sodium nitrite (1.277g) in water (15mL) was added dropwise at 0°C for 2 minutes. The reaction mixture was stirred at 0°C for 1 hour. A suspension of 6N hydrochloric acid (30mL) of tin (II) chloride (8.77g) was added dropwise at 0°C for 3 minutes. The reaction mixture was stirred at 0°C for 28 minutes and at room temperature for 20 hours and 9 minutes. An 8N aqueous sodium hydroxide solution (about 68mL) was added dropwise to the reaction mixture at 0°C. The mixture was stirred at 0°C. The mixture was extracted 3 times with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. Seed crystals of the title compound synthesized in the same manner as in this step were added to the obtained residue. To the mixture was added a mixture of diisopropyl ether (2 mL) / n-hexane (30 mL) at room temperature. The suspension was stirred at room temperature. A solid was filtered from the suspension and washed with n-hexane. The solid was dried under reduced pressure at room temperature to obtain the title compound (2.8464 g) in a yield of 87%. 1 H-NMR (CDCl3) δ: 3.69 (brs, 2H), 5.49 (br s, 1H), 7.43-7.45 (m, 1H), 8.28-8.30 (m, 1H), 8.34 (d, 1H, J = 2.8Hz).

[0359] The seed crystals of the title compound used in step 1 can be obtained by conducting the same reaction as in this step, and the obtained residue is purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 1).

[0360] [Production Example 6] Production of 5-hydrazino-2-(trifluoromethyl)pyrimidine [Chemistry 67] (Step 1) Production of 5-hydrazino-2-(trifluoromethyl)pyrimidine [Chemistry 68] Under an argon atmosphere, hydrazine monohydrate (4.27 mL) and 2-propanol (1 mL) were added to 5-bromo-2-(trifluoromethyl)pyrimidine (2 g). Using an explosion-proof barrier, the reaction mixture was stirred at 95 ° C for 22 hours. The reaction mixture was cooled to room temperature. Water and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and ethyl acetate was extracted 5 times. The obtained organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. A mixture of n-hexane / ethyl acetate (3 / 1) was added to the residue at room temperature. The suspension was stirred at room temperature. The solid was filtered from the suspension and washed with a mixture of n-hexane / ethyl acetate (3 / 1). The solid was dried under reduced pressure at room temperature, thereby obtaining the title compound (647 mg) with a yield of 41%. 1 H-NMR (DMSO-D6) δ: 4.43 (br s, 2H), 7.94 (br s, 1H), 8.33 (s, 2H).

[0361] [Example 1] Synthesis of (3R, 4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 69] (Step 1) Production of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole [Chemistry 70] To 1H-pyrazole-3-amine (100g) was added acetic acid (1L) at room temperature and stirred for 5 minutes. To the mixture was added 2,5-hexanedione (148mL) at room temperature and stirred for 5 minutes. The reaction mixture was stirred at 120°C for 2.5 hours and cooled to room temperature. To the reaction mixture was added water (1L) at room temperature. The reaction mixture was stirred at room temperature for 50 minutes. The precipitated solid was filtered and washed with water (1L). The obtained wet solid was dried at room temperature and normal pressure overnight, and then dried under reduced pressure at 65°C for 3 days and 8.5 hours to obtain the title compound (172.47g) with a yield of 89%. 1 H-NMR (CDCl3) δ: 2.11 (s, 6H), 5.90 (s, 2H), 6.25 (d, 1H, J = 2.4Hz), 7.51 (d, 1H, J = 2.4Hz).

[0362] (Step 2) Production of a mixture of 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole and 1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole [Chemistry 71] Under an argon gas stream, DMF (100 mL) was added to sodium hydride (14.9 g) under ice-cooling. A suspension of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (40 g) in DMF (150 mL) obtained in step 1 was added dropwise to the mixture under ice-cooling for 20 minutes. The dropping funnel used was washed with DMF (50 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred for 1.5 hours under water-cooling. Tetrabutylammonium bromide (0.80 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 15 minutes under ice-cooling. A solution of dibromodifluoromethane (45 mL) in DMF (50 mL) was added dropwise to the reaction mixture under ice-cooling for 15 minutes. The reaction mixture was stirred for 2 hours and 10 minutes under water-cooling. Dibromodifluoromethane (20mL) was added dropwise to the reaction mixture under water cooling under an argon atmosphere. The reaction mixture was stirred for 40 minutes under water cooling and then allowed to stand overnight. Saturated aqueous ammonium chloride solution (200mL) was added to the reaction mixture under ice cooling. Ethyl acetate and water were added to the reaction mixture. The reaction mixture was filtered through diatomaceous earth and separated. The water layer was extracted with ethyl acetate. The organic layers were combined and saturated saline was added thereto. The mixture was filtered through diatomaceous earth and separated. The water layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated. Toluene (250mL) was added to the residue and concentrated. The operation was performed again. Ethyl acetate (about 150mL) was added to the residue and the insoluble matter was filtered off. The insoluble matter was washed with ethyl acetate. The filtrate was combined and concentrated. The residue was dried under reduced pressure at room temperature for 10 minutes while stirring. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 30 / 1 to 20 / 1) to obtain the title compound (40.6 g, 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole:1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole = about 3:1 containing 3.7% by weight of hexane) in a yield of 54%. 1H-NMR (CDCl3) 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).

[0363] (Step 3) Production of a mixture of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole and 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole [Chemistry 72] To a solution of a mixture of 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole and 1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (40.6 g, containing 3.7% by weight of hexane) obtained in step 2 in sulfolane (400 mL), tetramethylammonium fluoride (13.0 g) was added at room temperature under an argon gas stream. The reaction mixture was stirred at 100° C. for 1 hour. To the reaction mixture was added tetramethylammonium fluoride (9.4 g) at 100° C. The reaction mixture was stirred at 100° C. for 1 hour and 15 minutes. To the reaction mixture was added tetramethylammonium fluoride (10 g) at 100° C. The reaction mixture was stirred at 100° C. for 40 minutes. Further, tetramethylammonium fluoride (5 g) was added to the reaction mixture at 100 ° C. The reaction mixture was stirred at 100 ° C for 2 hours and 5 minutes and cooled to room temperature. Water (400 mL) and saturated sodium bicarbonate aqueous solution (200 mL) were slowly added to the reaction mixture in sequence under ice cooling. A mixture of n-hexane / ethyl acetate (2 / 3) (400 mL) was added to the reaction mixture. The reaction mixture was filtered through diatomaceous earth and separated. The organic layer was washed with saturated brine. The obtained aqueous layers were combined and extracted with a mixture of n-hexane / ethyl acetate (2 / 3) (300 mL). The organic layer was washed with saturated brine. The obtained organic layers were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 30 / 1 to 25 / 1) to obtain the title compound (21.85 g, 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole:5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole = about 6:1 containing 24.4% by weight of n-hexane) with a yield of 51%. 1H-NMR (CDCl3) δ: 2.00 (s, 0.86H), 2.16 (s, 5.1H), 5.89 (s, 1.7H), 5.91 (s, 0.29H), 6.40 (d, 0.8 6H, J=2.8Hz), 6.42 (d, 0.14H, J=1.6Hz), 7.83 (d, 0.14H, J=1.6Hz), 7.87 (d, 0.86H, J=22.8Hz).

[0364] (Step 4) Preparation of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-(trifluoromethyl)-1H-pyrazole [Chemistry 73] To a THF (180 mL) solution of a mixture of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole and 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole obtained in step 3 (21.85 g, containing 24.4% by weight of n-hexane), a n-butyl lithium n-hexane solution (1.55 M, 51.1 mL) was added dropwise at -70°C for 5 minutes under an argon atmosphere. The reaction mixture was stirred at -70°C for 25 minutes. A THF (50 mL) solution of iodine (18.3 g) was added dropwise at -70°C for 5 minutes to the reaction mixture. The dropping funnel used was washed with THF (10 mL), and the washings were added to the reaction mixture. The reaction 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 0.5 hours. Water (250 mL) and ethyl acetate (250 mL) were added to the reaction mixture at -70°C in sequence. The reaction mixture was stirred at room temperature and separated into layers. The organic layer was washed with a 10% by weight aqueous sodium bisulfite solution (250 mL) and a saturated saline solution (150 mL) in sequence, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 50 / 1 to 30 / 1). The fractions containing the title compound were collected and concentrated. n-hexane was added to the residue. Concentrated to a residue weight of 27.5 g. n-hexane (20 mL) was added to the residue. The suspension was stirred at room temperature for 10 minutes. The precipitate was filtered, washed with n-hexane (30 mL), and dried under reduced pressure to obtain the title compound (17.14 g) in a yield of 67%. The filtrate was further concentrated. The residue was crystallized from n-hexane to obtain the title compound (1.63 g) in a yield of 6.4%. 1H-NMR (CDCl3) δ: 2.15 (s, 6H), 5.88 (s, 2H), 6.60 (s, 1H).

[0365] (Step 5) Preparation of 5-iodo-1-(trifluoromethyl)-1H-pyrazole-3-amine [Chemistry 74] To 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-(trifluoromethyl)-1H-pyrazole (18.77 g) obtained in step 4, a mixed solution of ethanol and water (ethanol / water=2 / 1, 480 mL), hydroxylamine hydrochloride (73.5 g), and triethylamine (14.7 mL) were added in sequence at room temperature. The reaction mixture was stirred at 100°C for 38 hours and 20 minutes. The reaction mixture was cooled to room temperature and ethanol was distilled off. A solution of sodium hydroxide (42.3 g) in water (130 mL) was slowly added to the reaction mixture under ice cooling, followed by ethyl acetate (200 mL). After stirring the reaction mixture, the layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL). The obtained organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. Ethyl acetate (30 mL) and n-hexane (30 mL) were added to the residue, and the insoluble matter was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to obtain the title compound (16.27 g, containing 14% by weight of ethyl acetate) in a yield of 96%. 1 H-NMR (CDCl3) δ: 3.93 (br s, 2H), 6.09 (s, 1H).

[0366] (Step 6) Production of 5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-amine [Chemistry 75] To the toluene (3 mL) solution of 5-iodo-1-(trifluoromethyl)-1H-pyrazole-3-amine (80 mg, containing 14% by weight of ethyl acetate) obtained in step 5, 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127 mg), palladium (II) acetate (6.5 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (20 mg) obtained in step 2 of preparation example 1 were added in sequence at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 4 minutes. A 2M potassium phosphate aqueous solution (1.5 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 90° C. for 47 minutes. The reaction mixture was cooled to room temperature. Ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction mixture. The reaction mixture was filtered through a cotton plug and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order, dried over sodium sulfate, and concentrated. The residue was combined with a portion (15 mg) of the title compound obtained in the same manner as in this step using 5-iodo-1-(trifluoromethyl)-1H-pyrazole-3-amine (70 mg, containing 14% by weight of ethyl acetate) obtained in step 5, and purified by silica gel thin layer chromatography (eluting solvent: n-hexane / ethyl acetate = 3 / 1) to obtain the title compound (108 mg). 1 H-NMR(CDCl3)8:1.36(s,9H),3.93(br s,2H),5.83(s,1H),6.75-6.85(m,3H).

[0367] (Step 7) Production 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 [Chemistry 76] Under an argon atmosphere, DMF (1 μL) and oxalyl chloride (33 μL) were added sequentially under ice-cooling to a solution of (3R, 4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (55 mg) in chloroform (0.55 mL) obtained in the same manner as in Step 5 of Production Example 2. The reaction mixture was stirred for 50 minutes under ice-cooling. The reaction mixture was concentrated and dried under reduced pressure. Chloroform (0.4 mL) and 5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazole-3-amine (40 mg) obtained in Step 6 were added to the residue under an argon atmosphere under ice-cooling. Pyridine (50 μL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 5 minutes under ice-cooling and for 35 minutes at room temperature. To the reaction mixture was added saturated sodium bicarbonate aqueous solution at room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel thin layer chromatography (eluting solvent: n-hexane / ethyl acetate = 1 / 1) to obtain the title compound (60 mg) in a yield of 80%. The formation of the title compound was confirmed by thin layer chromatography (eluting solvent: n-hexane / ethyl acetate = 2 / 1, Rf value: 0.19).

[0368] (Step 8) Preparation of (3R, 4R)-N-(5-(3-fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 77] To (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 (60 mg) obtained in step 7, anisole (58 μL) and trifluoroacetic acid (2 mL) were added at room temperature. The reaction mixture was stirred at 80°C for 1 hour and 20 minutes. The reaction mixture was concentrated. A saturated aqueous sodium bicarbonate solution was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin layer chromatography (eluting solvent: chloroform / ethyl acetate = 1 / 1) to obtain the title compound (29.9 mg) in a yield of 76%. 1H-NMR (DMSO-d6) δ: 1.06 (d, 3H, J = 7.2Hz), 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).

[0369] (Step 9) Production of (3R, 4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 78] To the (3R, 4R)-N-(5-(3-fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide (30 mg) obtained in step 8, di-tert-butyl dicarbonate, chloroform (1 mL), and magnesium perchlorate were added in sequence at room temperature. The reaction mixture was stirred at 55°C for 0.5 hours. 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. Magnesium perchlorate was further added to the reaction mixture at 55°C. The reaction mixture was stirred at 55°C for 20 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate was added. The reaction mixture was washed with 1N hydrochloric acid and saturated brine in sequence, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 15 / 1) to obtain the title compound (19.2 mg) in a yield of 56%.

[0370] (Step 10) Preparation of Crystals of (3R,4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide The title compound (100 mg) was dissolved in ethanol (0.4 mL) by stirring at 65 ° C for 8 minutes. Water (0.4 mL) was added dropwise at 65 ° C for 2 minutes. The mixed solution was stirred at 65 ° C for 10 minutes. The mixed solution was stirred for 2 hours until it reached 25 ° C. Further, the mixed solution was stirred at room temperature for 2 hours. The solid precipitated from the mixed solution was filtered out. The obtained solid was washed with ethanol / water (=1 / 1) and dried under reduced pressure at 60 ° C, thereby obtaining crystals of the title compound (87.8 mg) with a yield of 88%.

[0371] [Example 2] Synthesis of (3R, 4R)-N-(5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 79] (Step 1) Production of 1-bromo-3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)benzene [Chemistry 80] To a solution of 1-bromo-3,5-difluorobenzene (5.97 mL) in 1,3-dimethyl-2-imidazolidinone (10 mL), sodium hydride (4.14 g) was added at room temperature under a nitrogen stream. 1,1,1-trifluoro-2-methylpropane-2-ol (8 mL) was added dropwise to the mixture under water cooling. 1,3-dimethyl-2-imidazolidinone (2 mL) was added to the reaction mixture at room temperature. 1,1,1-trifluoro-2-methylpropane-2-ol (3.16 mL) was added dropwise to the reaction mixture at room temperature. The addition of all these alcohols took 45 minutes. The reaction mixture was stirred at room temperature for 20 minutes, at 80°C for 20 minutes, at 100°C for 20 minutes, and at 130°C for 20 hours and 40 minutes. Water was added to the reaction mixture under ice cooling. The mixture was extracted 3 times with n-hexane. The obtained organic layers were combined, washed with water three times, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure of 140 mmHg at 35° C. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (8.31 g; containing 12% by weight of n-hexane) in a yield of 47%. 1 H-NMR(DMSO-D6)8:1,46(s,6H),7.08(dt,1H,J=10.2,2.1Hz),7.18(s,1H),7.39-7.45(m,1H).

[0372] (Step 2) Production of 1-(1-butoxyvinyl)-3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)benzene [Chemistry 81] To a solution of 1-bromo-3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)benzene (2.86 g; containing 12 wt% of n-hexane) obtained in step 1 and the compound (10.2 g; containing 12 wt% of n-hexane) obtained in the same manner as step 1 in ethylene glycol (69 mL), butyl vinyl ether (19.77 mL), triethylamine (10.65 mL), 1,1'-bis(diphenylphosphino)ferrocene (1.271 g) and palladium (II) acetate (0.257 g) were added at room temperature. The reaction mixture was stirred at 110° C. for 19 hours under an argon atmosphere. The reaction mixture was cooled to room temperature. Water and n-hexane were added to the reaction mixture. The mixture was filtered through diatomaceous earth. The filtrate was extracted twice with n-hexane. The obtained organic layers were combined, washed twice with water, washed with saturated brine, dried over magnesium sulfate, and concentrated at 35° C. under a reduced pressure of 140 mmHg. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5) to obtain the title compound (6.39 g; containing 15% by weight of n-hexane) in a yield of 44%. 1 H-NMR (DMSO-D6) δ: 0.95 (t, 3H, J = 7.3Hz), 1.40-1.51 (m, 2H), 1.44 (s, 6H), 1.69-1.76 (m, 2H), 3.84 (t, 2H, J =6.3Hz), 4.39 (d, 1H, J = 3.0Hz), 4.90 (d, 1H, J = 3.0Hz), 6.96-7.01 (m, 1H), 7.12 (s, 1H), 7.24-7.29 (m, 1H).

[0373] (Step 3) Production of 1-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)ethan-1-one [Chemistry 82] To a THF (25 mL) solution of 1-(1-butoxyvinyl)-3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)benzene (6.39 g; containing 15% by weight of n-hexane) obtained in step 2, 2N hydrochloric acid (12.71 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour and 10 minutes. A 2N aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling to adjust the pH to 12. The mixture was extracted twice with n-hexane. The obtained organic layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated at 35°C under a reduced pressure of 120 mmHg. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15), thereby obtaining the title compound (4.09 g; containing 6% by weight of n-hexane) in a yield of 86%. 1 H-NMR (DMSO-D6) δ: 1.47 (s, 6H), 2.60 (s, 3H), 7.32 (dt, 1H, J = 9.7, 2.3Hz), 7.42-7.43 (m, 1H), 7.58-7.62 (m, 1H).

[0374] (Step 4) Preparation of ethyl 4-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-2,4-dioxobutanoate [Chemical 83] To a THF (38.4 mL) solution of 1-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)ethane-1-one (4.09 g; containing 6 wt% of n-hexane) obtained in step 3, diethyl oxalate (2.171 mL) was added under an argon atmosphere. To the mixed solution was added lithium tert-butoxide (1.396 g) at 0°C. The reaction mixture was stirred at 0°C for 3 hours and 10 minutes. 1N hydrochloric acid was added to the reaction mixture under ice cooling to a pH of 1. Water was added to the mixed solution and extracted twice with ethyl acetate. The obtained organic layer was washed twice with saturated brine and dried over sodium sulfate. The organic layer was concentrated to obtain the title compound (5.53 g; containing 4 wt% of diethyl oxalate and 6 wt% of ethyl acetate) in a yield of 94%. 1H-NMR (CDCl3) δ: 1.42 (t, 3H, J = 7.5Hz), 1.50 (s, 6H), 4.42 (q, 2H, J = 7.5Hz), 6.97 (s, 1H) , 7.01 (dt, 1H, J = 9.3, 2.2Hz), 7.42-7.45 (m, 1H), 7.48 (dt, 1H, J = 8.8, 2.2Hz), 15.02 (br s, 1H).

[0375] (Step 5) Production of ethyl 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylate [Chemistry 84] To a solution of ethyl 4-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-2,4-dioxobutanoate (500 mg; containing 4% by weight of diethyl oxalate and 6% by weight of ethyl acetate) obtained in step 4 in acetic acid (2.25 mL), 5-hydrazino-2-(trifluoromethyl)pyrimidine (242 mg) obtained in step 1 of production example 6 was added at room temperature under an argon atmosphere. The reaction mixture was stirred at 100° C. for 21 hours and 30 minutes. The reaction mixture was allowed to stand at room temperature over the weekend. The reaction mixture was concentrated. Acetic acid was azeotropically removed with toluene three times. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate=75 / 25 to 0 / 100) to obtain a crude product of the title compound. To the crude product, a mixture of n-hexane / ethyl acetate (20 / 1) was added at room temperature. The suspension was stirred at room temperature. The solid was collected from the suspension by filtration and washed with a mixture of n-hexane / ethyl acetate (20 / 1). The obtained solid was dried under reduced pressure at room temperature to obtain the title compound (541 mg) in a yield of 86%. 1 H-NMR (DMSO-D6) δ: 1.29 (s, 6H), 1.33 (t, 3H, J = 7.1Hz), 4.38 (q, 2H, J = 7.1Hz), 6.83-6. 84 (m, 1H), 7.13 (dt, 1H, J = 10.0, 2.3Hz), 7.31-7.35 (m, 1H), 7.39 (s, 1H), 9.12 (s, 2H).

[0376] (Step 6) Production of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid [Chemistry 85] To a solution of ethyl 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylate (541 mg) obtained in step 5 in THF (1.623 mL) / methanol (3.246 mL), 2N aqueous sodium hydroxide solution (1.068 mL) was added at room temperature. Methanol (4 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 25 hours and 30 minutes. 1N hydrochloric acid was added to the reaction mixture under ice cooling to a pH of 1. Water was added to the mixture, and extraction was performed twice with ethyl acetate. The obtained organic layers were combined, washed twice with saturated brine, and dried over sodium sulfate. The organic layer was concentrated to obtain the title compound (504 mg) in a yield of 99%. 1 H-NMR (DMSO-D6) δ: 1.29 (s, 6H), 6.84 (s, 1H), 7.11-7.15 (m, 1H), 7.30-7.34 (m, 2H), 9.10 (s, 2H), 13.35 (br s, 1H).

[0377] (Step 7) Production of tert-butyl (5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)carbamate [Chemistry 86] To a mixture of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid (495 mg) obtained in step 6 in toluene (4.95 mL), triethylamine (0.346 mL) and diphenylphosphoryl azide (0.267 mL) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 hour. Tert-butyl alcohol (4.26 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 100° C. for 27 hours and 15 minutes. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate=99 / 1 to 50 / 50) to obtain the title compound (315 mg) in a yield of 55%. 1H-NMR (DMSO-D6) δ: 1.32 (s, 6H), 1.48 (s, 9H), 6.85 (s, 1H), 6.92 (s, 1H), 7.09-7.14 (m, 1H), 7.27-7.31 (m, 1H), 8.90 (s, 2H), 10.18 (br s, 1H).

[0378] (Step 8) Production of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-amine [Chemistry 87] To tert-butyl (5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)carbamate (315 mg) obtained in step 7, 4N hydrochloric acid / 1,4-dioxane solution (1.575 mL) was added at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C for 10 minutes and at room temperature for 27 hours and 40 minutes. The reaction mixture was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and extraction was performed twice with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain a solid. To the solid was added a mixture of n-hexane / ethyl acetate (10 / 1) at room temperature. The suspension was stirred at room temperature. The solid was filtered from the suspension and washed with a mixture of n-hexane / ethyl acetate (10 / 1). The obtained solid was dried under reduced pressure at room temperature to obtain the title compound (224 mg) in a yield of 87%. 1 H-NMR (DMSO-D6) δ: 1.34 (s, 6H), 5.50 (br s, 2H), 6.11 (s, 1H), 6.82-6.85 (m, 1H), 7.10 (dt, 1H, J=10.1, 2.3Hz), 7.21-7.26 (m, 1H), 8.76 (s, 2H).

[0379] (Step 9) Production of (3R,4R)-N-(5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 88] To a pyridine (1 mL) solution of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-amine (60 mg) obtained in step 8 and (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (21.0 mg) obtained in the same manner as in step 6 of preparation example 3, WSC·HCl (28.2 mg) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 29 hours. The reaction mixture was concentrated. Water was added to the residue, and extraction was performed with ethyl acetate. The obtained organic layer was washed with 1N hydrochloric acid twice, washed with water, saturated sodium bicarbonate aqueous solution, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate / methanol = 50 / 1) to obtain the title compound (69 mg; containing 4 wt % of ethyl acetate and 1 wt % of n-hexane) in a yield of 86%. 1 H-NMR (DMSO-D6) δ: 1.09 (d, 3H, J = 7.2Hz), 1.32 (s, 6H), 2.50-2.59 (m, 1H), 3.03-3.11 (m, 1H), 3.20-3.27 (m, 1H), 3.43-3.50 (m, 1H), 6.85-6.87 (m, 1H), 7.13 (dt, 1H, J = 9.9, 2.3Hz), 7.17 (s, 1H), 7.27-7.32 (m, 1H), 7.68 (s, 1H), 8.95 (s, 2H), 11.20 (br s, 1H). MS(M+H)575,MS(MH)573

[0380] [Example 3] Synthesis of (3R, 4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 89] (Step 1) Preparation of 4-(3-fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutyric acid benzyl ester [Chemistry 90] Under an argon atmosphere, lithium tert-butoxide (1.982 g) was added to a solution of 1-(3-fluoro-5-(trifluoromethoxy)phenyl)ethane-1-one (5 g) and diphenylmethyl oxalate (6.69 g) in THF (50 mL) under ice-cooling. The reaction mixture was stirred for 1 hour under ice-cooling. 2N hydrochloric acid (12.5 mL), ethyl acetate and water were added to the reaction mixture under ice-cooling. The mixture was separated into layers. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The organic layer was concentrated to obtain a crude purified product (11.7 g) of the title compound.

[0381] (Step 2) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid benzyl ester [Chemistry 91] To a solution of the crude product (800 mg) of 4-(3-fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutyric acid benzyl ester obtained in step 1 in acetic acid (6 mL), 3-fluoro-5-hydrazinopyridine (218 mg) obtained in step 1 of production example 4 was added under an argon atmosphere at room temperature. The reaction mixture was stirred at 100° C. for 19 hours and 42 minutes. The reaction mixture was cooled to room temperature and concentrated. Toluene was added to the residue and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 69 / 31), thereby obtaining the title compound (589.5 mg) at a yield of 79% in step 2. 1 H-NMR (CDCl3) δ: 5.44 (s, 2H), 6.83-6.86 (m, 1H), 6.93 (ddd, 1H, J=8.4, 2.3, 1.6Hz), 6.99-7.03 (m, 1H), 7.12 (s, 1H), 7 .34-7.42 (m, 3H), 7.46-7.50 (m, 2H), 7.60 (ddd, 1H, J = 8.6, 2.5, 1.8Hz), 8.32 (d, 1H, J = 1.8Hz), 8.53 (d, 1H, J = 2.5Hz).

[0382] (Step 3) Production of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid [Chemistry 92] To the ethyl acetate (5.90 mL) solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid benzyl ester (589.5 mg) obtained in step 2, 5 wt% palladium on carbon (88 mg) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere at 1 atmosphere. After setting it to a nitrogen atmosphere, the palladium on carbon in the reaction solution was filtered off through diatomaceous earth. The diatomaceous earth used was washed with a mixture of ethyl acetate / methanol (9 / 1). The filtrate obtained was combined and concentrated. Toluene was added to the residue and concentrated. The residue was dried under reduced pressure at room temperature to obtain the title compound (425.9 mg) in a yield of 89%. 1 H-NMR (DMSO-D6) δ: 7.06-7.09 (m, 1H), 7.33 (s, 1H), 7.45 (ddd, 1H, J = 9.2, 2.4, 1.5Hz), 7.47-7.5 2 (m, 1H), 7.96 (ddd, 1H, J = 9.2, 2.5, 2.1Hz), 8.44-8.47 (m, 1H), 8.73 (d, 1H, J = 2.5Hz), 13.23 (br s, 1H).

[0383] (Step 4) Production of tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)carbamate [Chemistry 93] To a solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid (425.9 mg) and triethylamine (0.370 mL) obtained in step 3 in tert-butanol (4.26 mL) / toluene (8.52 mL), diphenylphosphoryl azide (0.286 mL) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at 110°C for 14 hours and 50 minutes. The reaction mixture was cooled to room temperature and concentrated. Water was added to the residue and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. A mixture of n-hexane / ethyl acetate (1 / 1) was added to the residue at room temperature. The suspension was stirred at room temperature. The insoluble matter was filtered off and washed with a mixture of n-hexane / ethyl acetate (1 / 1). The obtained filtrates were combined and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 90 / 10 to 69 / 31) to obtain the title compound (207.4 mg) in a yield of 41%. 1H-NMR (DMSO-D6) δ: 1.48 (s, 9H), 6.90 (s, 1H), 7.06 (s, 1H), 7.40 (ddd, 1H, J = 9.1, 2.4, 1.5Hz), 7.44- 7.49(m,1H),7.73(ddd,1H,J=9.5,2.5,2.1Hz),8.32-8.34(m,1H),8.61(d,1H,J=2.3Hz),10.05(br s,1H).

[0384] (Step 5) Production of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-amine [Chemistry 94] To tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)carbamate (207.4 mg) obtained in step 4, trifluoroacetic acid (2.07 mL) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 22 hours and 40 minutes. Water was added to the reaction mixture at 0°C. 8N aqueous sodium hydroxide solution (about 3.36 mL) was added dropwise to the mixture at 0°C. Saturated aqueous sodium bicarbonate solution was added to the mixture at 0°C. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 64 / 36 to 43 / 57) to obtain a solid. n-hexane was added to the solid at room temperature. The suspension was stirred at room temperature. The solid was collected from the suspension by filtration and washed with n-hexane. The obtained solid was dried under reduced pressure at 60°C to obtain the title compound (100.0 mg; containing 0.21% by weight of ethyl acetate) in a yield of 62%. 1 H-NMR(CDCl3)δ: 3.89(br s, 2H), 6.00 (s, 1H), 6.86-6.89 (m, 1H), 6.93 (ddd, 1H, J=8.6, 2.3, 1.4Hz), 6.96-7 .00 (m, 1H), 7.43 (dt, 1H, J = 9.2, 2.5Hz), 8.20-8.22 (m, 1H), 8.36 (d, 1H, J = 2.5Hz).

[0385] (Step 6) Preparation of ((3R, 4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 95] To a pyridine (0.380 mL) solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-amine (38 mg; containing 0.21% by weight of ethyl acetate) obtained in step 5 and (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (18.3 mg) obtained in the same manner as in step 6 of production example 3, WSC·HCl (24.5 mg) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours and 54 minutes. To the reaction mixture, (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (18 mg) and WSC·HCl (25 mg) obtained in the same manner as in step 6 of production example 3 were added at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture, a 10% by weight aqueous solution of citric acid was added at room temperature, and extraction was performed with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel thin layer chromatography (eluting solvent: ethyl acetate / methanol = 97 / 3) to obtain the title compound. A mixed solution of n-hexane / ethyl acetate was added to the title compound at room temperature. The suspension was stirred at room temperature. The solid was filtered from the suspension and washed with n-hexane. The obtained solid was dried under reduced pressure at 70°C to obtain the title compound (46.6 mg; containing 3.5% by weight of n-hexane) with a yield of 87%.

[0386] [Example 4] Preparation of ((3R,4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide monohydrate [Chemistry 96] Ethanol (0.6 mL) was added to ((3R,4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide (200 mg), and the mixture was heated at 60°C to prepare a solution. The solution was cooled to room temperature. To the solution, water (1.2 mL) was added dropwise at room temperature, and the mixture was stirred for 4 hours. The precipitated solid was collected by filtration and washed with a mixed solution of ethanol / water (=1 / 2). The obtained solid was dried under reduced pressure at 40°C to obtain the title compound (192 mg) in a yield of 92%.

[0387] Elemental analysis Calculated values: C 50.51 wt%, H 3.63 wt%, N 14.02 wt% Measured values: C 50.61wt%, H 3.46wt%, N 13.95wt%.

[0388] [Example 5] Synthesis of ((3R,4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 97] (Step 1) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid benzyl ester [Chemistry 98] To a solution of the crude product (800 mg) of 4-(3-fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutyric acid benzyl ester obtained in step 1 of example 3 in acetic acid (6 mL), 3-hydrazino-5-(trifluoromethyl)pyridine (304 mg) obtained in step 1 of preparation example 5 was added under an argon atmosphere at room temperature. The reaction mixture was stirred at 100°C for 22 hours and 30 minutes. The reaction mixture was cooled to room temperature and concentrated. Toluene was added to the residue and concentrated. This operation was performed again. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 70 / 30), thereby obtaining the title compound (640 mg) with a yield of 78% in step 2. 1 H-NMR (CDCl3) δ: 5.45 (s, 2H), 6.80-6.83 (m, 1H), 6.94 (ddd, 1H, J = 8.3, 2.3, 1.6Hz), 7.00-7.05 (m, 1H), 7.14 (s, 1H), 7.33-7.42 (m, 3H), 7.46-7.50 (m, 2H), 8.04-8.07 (m, 1H), 8.69 (d, 1H, J=2.5Hz), 8.88-8.92 (m, 1H).

[0389] (Step 2) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid [Chemical 99] To the ethyl acetate (6.4 mL) solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid benzyl ester (640 mg) obtained in step 1, 5 wt% palladium on carbon (32 mg) was added at room temperature. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere at 1 atmosphere. After being made under a nitrogen atmosphere, THF was added to the reaction mixture. The palladium on carbon in the reaction solution was filtered off through diatomaceous earth. The diatomaceous earth used was washed with THF. The obtained filtrate was combined and concentrated. n-hexane was added to the residue and concentrated. The operation was performed again. The residue was dried under reduced pressure at room temperature to obtain a crude refined product of the title compound (525 mg).

[0390] (Step 3) Production of tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)carbamate [Chemical 100] To a solution of the crude product (525 mg) of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid obtained in step 2 and triethylamine (0.403 mL) in tert-butyl alcohol (5 mL) / toluene (10 mL), diphenylphosphoryl azide (0.311 mL) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 97 / 3 to 70 / 30) to obtain the title compound (420 mg) in a yield of 68% in step 2. The formation of the title compound was confirmed by thin layer chromatography (eluting solvent: n-hexane / ethyl acetate = 4 / 1, Rf value: 0.46).

[0391] (Step 4) Production of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-amine [Chemistry 101] To tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)carbamate (420 mg) obtained in step 3, trifluoroacetic acid (3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated. Toluene was added to the residue and concentrated. The operation was performed again. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the residue. The mixed solution was layered. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 92 / 8 to 20 / 80), thereby obtaining the title compound (313 mg) in a yield of 93%. 1 H-NMR(CDCl3)δ:3,92(br s, 2H), 6.03 (s, 1H), 6.84-6.87 (m, 1H), 6.94 (ddd, 1H, J=8.4, 2.2, 1.3Hz), 6. 97-7.02(m,1H), 7.87-7.90(m,1H), 8.57(d,1H,J=2.4Hz), 8.71-8.74(m,1H).

[0392] (Step 5) Preparation of ((3R, 4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemistry 102] To a pyridine (1 mL) solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-amine (60 mg) obtained in step 4 and (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (23.3 mg) obtained in the same manner as in step 6 of preparation example 3, WSC·HCl (31.1 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 15 hours and 30 minutes. Water and ethyl acetate were added to the reaction mixture at room temperature. The mixture was separated. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. Toluene was added to the residue and concentrated. The operation was performed again. The residue was purified by silica gel thin layer chromatography (eluting solvent: ethyl acetate), thereby obtaining the title compound (75 mg) in a yield of 96%.

[0393] The compounds of other examples were obtained by the same methods as the above-mentioned general production methods, production examples and examples, and other known methods as needed. The structural formulas and physical property data of the compounds of Examples 1 to 40 are shown in the following table. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

[0394] [Reference example] Compounds A to H shown in the following table were obtained based on the description of International Publication No. 2013 / 031922. [Table 7-1] [Table 7-2]

[0395] Metabolites 1, 3 and 5 (metabolites of the compounds of Examples 1, 3 and 5) and metabolites C to H (metabolites of compounds C to H) shown in the following table were obtained based on the description of the above Examples and International Publication No. 2013 / 031922, respectively. [Table 8-1] [Table 8-2]

[0396] [Test Example 1] Evaluation of SGLT1 inhibitory activity The SGLT1 inhibitory activity (IC 50 Value) is a marker of α-methyl-D-pyranoglucoside transported by SGLT1 ( 14 The calculation was based on the intracellular uptake of C-AMG.

[0397] 1) Construction of human SGLT1 expression plasmid Using pCMV6-hSGLT1 (OriGene) as a template, NheI recognition cleavage sequence was added before the Kozac consensus sequence derived from the vector, and the termination codon TAG and SalI recognition cleavage sequence were added immediately after the protein translation region of human SGLT1, and the DNA fragment containing human SGLT1 was amplified by PCR (polymerase chain reaction). After the refined DNA fragment was digested with restriction enzymes NheI and SalI, it was linked to pcDNA3.1 (+) digested with NheI and XhoI to construct the human SGLT1 expression plasmid pcDNA-hSGLT1. The base sequence of human SGLT1 inserted into the vector is completely consistent with the protein translation region of the human SGLT1 sequence (Accession number NM_000343) registered in GenBank, and the sequence of the part connected to the vector is also in line with expectations.

[0398] 2) Establishment of a stable human SGLT1 expression cell line The human SGLT expression plasmid pcDNA-hSGLT1 was transfected into CHO-K1 cells using Lipofectamine2000 (Invitrogen), and drug-resistant cell lines were selected in the presence of G418 (Nacalai Tesque). 14 C-AMG intake and phlorizin as an SGLT inhibitor 14 The cell line with the highest C-AMG uptake ratio (S / B ratio) was selected as the human SGLT1 stable expression cell line.

[0399] 3) Evaluation of SGLT1 inhibitory activity Human SGLT1 stable expression cell line was cultured in BioCoat TM 5×10 4 Cells / well were inoculated and cultured overnight at 37°C, 5% CO2. The culture medium was exchanged with 100 μL / well of Na(-) buffer (140 mM choline chloride, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH7.4) and allowed to stand at 37°C, 5% CO2 for 20 minutes. After removing the Na(-) buffer, a test compound solution prepared using Na(+) buffer (140 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH7.4) containing BSA was added at 40 μL / well. Furthermore, 8 kBq of 14 C-AMG and 2mM AMG Na(+) buffer. To the blank, 40 μL / well of BSA-containing Na(-) buffer was added, and 40 μL / well of 8 kBq of 14 C-AMG and 2mM AMG Na(-) buffer. After standing for 1 hour at 37°C and 5% CO2, wash the cells twice with 100 μL / well of ice-cold washing buffer (100mM AMG, 140mM choline chloride, 2mM KCl, 1mM MgCl2, 1mM CaCl2, 10mM HEPES, 5mM Tris, pH7.4) to stop the reaction. Add 50 μL / well of 0.2N NaOH aqueous solution to prepare cell lysis solution. 14 In the evaluation of C-AMG uptake capacity, the whole amount of cell lysate was transferred to OptiPlate96 (Perkin-Elmer) in which MicroScint-40 (Perkin-Elmer) was dispensed at 100 μL / well and measured using TOPCOUNTNXT (Perkin-Elmer). 14 CPM of C.

[0400] The data were obtained by subtracting the average CPM of the blank wells from the average CPM of the wells subjected to each treatment. The inhibition rate of each concentration of the test compound was calculated by the following formula: [(AB) / A]×100 (where A represents the data of the solvent control, and B represents the data treated with the test compound) IC of the test compound50 The value (50% inhibition concentration) was calculated from two concentrations with an inhibition rate of 50% and the inhibition rate. This test confirmed that compound 1 has SGLT1 inhibitory activity. This test was also performed on other example compounds. The results are shown in the following table. [Table 9] Example <![CDATA[hSGLT1 IC 5( μM)]]> Example <![CDATA[hSGLT1 IC 50 (μM)]]> 2 0.0019 22 0.0012 3 0.014 23 0.0012 5 0.0086 24 0.0034 6 0.023 25 0.011 7 0.022 26 0.0053 8 0.009 27 0.0057 9 0.017 28 0.047 10 45% inhibition at 0.3 μM 29 0.03 11 0.073 30 0.0072 12 0.0012 31 0.052 13 0.0084 32 0.0027 14 0.0043 33 0.0057 15 0.0029 34 0.069 16 0.0037 35 0.0059 17 0.0061 36 0.0098 18 0.083 37 0.0046 19 0.0013 38 0.0019 20 0.029 39 0.00098 21 0.029 40 0.004

[0401] [Test Example 2] OGTT (Oral Glucose Tolerance Test) Male SD rats (8 weeks old, Charles River Co., Ltd., Japan) (6 cases in each group) that had fasted for about 4 hours were orally administered with a vehicle (0.5% methylcellulose solution) or compound 1 (1, 3 or 10 mg / kg) suspended in a 0.5% methylcellulose solution at 5 mL / kg. After 16 hours, 0.4 g / mL glucose solution was orally administered at 5 mL / kg to load glucose. Blood was collected from the tail vein immediately before, 30 minutes after, 60 minutes after, and 120 minutes after glucose loading, and blood glucose levels were measured using a biochemical automatic analyzer (HITACHI, model 7180).

[0402] The results are shown in Figure 1 The data represent the mean ± standard deviation of the ratio (% of Vehicle) of the area under the curve (ΔAUC) of the blood glucose level of the compound-administered group to 120 minutes after glucose loading relative to the vehicle group. Steel's multiple test was performed for statistical analysis. The significance level was set at 5% on both sides. As a result, compound 1 significantly reduced the blood glucose level after glucose loading compared with the vehicle.

[0403] [Test Example 3] OGTT (Oral Glucose Tolerance Test) Male SD rats (8 weeks old, Charles River Co., Ltd., Japan) (5 cases in each group) that had fasted for about 4 hours were orally administered with a solvent (0.5% methylcellulose solution) or compound 1, compound A or compound B (3 mg / kg each) suspended in a 0.5% methylcellulose solution at 5 mL / kg. After 16 hours, 0.4 g / mL of glucose solution was orally administered at 5 mL / kg to load glucose. Blood was collected from the tail vein immediately before loading glucose, 30 minutes after loading, 60 minutes after loading, and 120 minutes after loading, and blood glucose levels were measured using a biochemical automatic analyzer (HITACHI, model 7180).

[0404] The results are shown in Figure 2The data represent the mean ± standard deviation of the ratio (% of Vehicle) of the area under the curve (ΔAUC) of the blood glucose level of the compound-administered group to 120 minutes after glucose loading relative to the vehicle group. Dunnett's multiplex test was performed for statistical analysis. The significance level was set at 5% on both sides. As a result, compound 1 significantly reduced the blood glucose level after glucose loading compared with the vehicle.

[0405] [Test Example 4] Ames test (reverse mutation test) Metabolites 1, 3 and 5 and metabolites C to H were tested as described below. The purpose of this test was to evaluate the presence or absence of the reverse mutation inducing ability of the rat liver metabolic activation system (S9 mix) in standard strains of Salmonella typhimurium (TA98, TA1537, TA100 and TA1535) and Escherichia coli (WP2uvrA) for each metabolite.

[0406] In this test, dimethyl sulfoxide (DMSO, 100 μL / plate) was used as a solvent.

[0407] The experiments were performed using the pre-incubation method in the presence or absence of S9 mix. In the experiments without S9 mix, sodium phosphate buffer (pH 7.4) was added.

[0408] Add 0.5mL of S9 mix or 0.5mL of 0.1mol / L sodium phosphate buffer (pH7.4) and 0.1mL of bacterial culture solution to a test tube containing 0.1mL of negative control substance (DMSO only), metabolites or positive control substances. The mixture was pre-incubated at 37°C while shaking for 20 minutes. After pre-incubation, 2mL of upper agar was added, the mixture was mixed with a vortex mixer, and inoculated onto the plate. Two plates were used for each treatment. Each plate was incubated at 37±1°C for more than 48 hours, and the reverse mutant colonies were counted. Next, the average number of reverse mutant colonies for each treatment plate was calculated. The growth inhibition based on the antibacterial effect of the test compound and the presence or absence of precipitation of the test compound were observed with the naked eye or a stereomicroscope. When the average number of reverse mutant colonies is 1 or more and a dosage-dependent increase greater than 2 times that of the negative control is shown, the result is judged to be positive. Statistical comparison is not used, and evaluation is based on the average value.

[0409] The results of this test are shown in the table below. As a result, metabolites 1, 3, and 5 did not show the ability to induce reverse mutation in any test strain, while metabolites C to H showed the ability to induce reverse mutation in at least one test strain in the presence and / or absence of S9 mix. Specifically, the description is as follows.

[0410] Metabolite C showed the ability to induce reverse mutation in the test strains TA98 in the presence of S9 mix and TA100 in the presence of S9 mix.

[0411] Metabolite D showed the ability to induce reverse mutation in the test strains TA98 and TA1537 in the presence of S9 mix.

[0412] Metabolite E showed the ability to induce reverse mutation in the test strains of TA98, TA1537, TA100, and TA1535 in the presence of S9 mix, and in the test strain of TA1537 in the absence of S9 mix.

[0413] Metabolite F showed the ability to induce reverse mutation in the test strains of TA98, TA1537, and TA100 in the presence of S9 mix, and in the test strain of WP2uvrA in the absence of S9 mix.

[0414] Metabolite G showed the ability to induce reverse mutation in the test strain TA100 in the presence of S9 mix and in the test strain TA1535 in the absence of S9 mix.

[0415] Metabolite H showed the ability to induce reverse mutation in the test strains TA98, TA1537 and TA100 in the presence of S9 mix. [Table 10] +: S9mix exists *: Growth inhibition Separation DMSO: dimethyl sulfoxide B[a]P: Benzo[a]pyrene The number of reverse mutant colonies is the average number of each plate [Table 11] +: S9mix exists * Growth inhibition Separation --: Not tested DMSO: dimethyl sulfoxide 2AA: 2-aminoanthracene B[a]P: Benzo[a]pyrene The number of reverse mutant colonies is the average number of each plate [Table 12] +:S9mix exists *: Growth inhibition DMSO: dimethyl sulfoxide 2AA:2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 13] --: Not tested *: Growth inhibition Separation 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 reverse mutant colonies is the average number of each plate [Table 14] -: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 15] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide 9AA: 9-aminoacridine hydrochloride monohydrate SA: Sodium azide The number of reverse mutant colonies is the average number of each plate [Table 16] --: Not tested *: Growth inhibition Separation #: The state of the background bacterial colony cannot be observed due to precipitation DMSO: dimethyl sulfoxide 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 17] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide 9AA: 9-aminoacridine hydrochloride monohydrate SA: Sodium azide The number of reverse mutant colonies is the average number of each plate [Table 18] #: The result is considered positive when the average number of reverse mutant colonies shows a dosage-dependent increase of more than 2 times that of the negative control. *: Growth inhibition DMSO: dimethyl sulfoxide B[a]P: Benzo[a]pyrene The number of reverse mutant colonies is the average number of each plate [Table 19] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide 2AA: 2-aminoanthracene B[a]P: Benzo[a]pyrene The number of reverse mutant colonies is the average number of each plate [Table 20] ..: Not tested *: Growth inhibition Separation 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 reverse mutant colonies is the average number of each plate [Table 21] --: Not tested ': Growth inhibition Separation DMSO: dimethyl sulfoxide B[a]P: Benzo[a]pyrene 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 22] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide ICR-191: 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine dihydrochloride SAZ: Sodium Azide The number of reverse mutant colonies is the average number of each plate [Table 23] --: Not tested *: Growth inhibition Separation DMS0: dimethyl sulfoxide B[a]P: Benzo[a]pyrene 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 24] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide ICR-191: 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine dihydrochloride SAZ: Sodium Azide The number of reverse mutant colonies is the average number of each plate [Table 25] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide B[a]P: Benzo[a]pyrene 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 26] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(S-nitro-2-furyl) acrylamide ICR-191: 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine dihydrochloride SAZ: Sodium Azide The number of reverse mutant colonies is the average number of each plate [Table 27] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide B[a]P: Benzo[a]pyrene 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 28] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide ICR-191: 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine dihydrochloride .SAZ: Sodium Azide The number of reverse mutant colonies is the average number of each plate [Table 29] --: Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide B[a]P: Benzo[a]pyrene 2AA: 2-aminoanthracene The number of reverse mutant colonies is the average number of each plate [Table 30] Not tested *: Growth inhibition Separation DMSO: dimethyl sulfoxide AF-2:2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide ICR-191: 2-Methoxy-6-chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine dihydrochloride SAZ: Sodium Azide The number of reverse mutant colonies is the average number of each plate

[0416] [Test Example 5] Effect of combined use with SGLT2 inhibitors in OGTT (Oral Glucose Tolerance Test) Male Zucker Fatty rats (7 weeks old, Charles River Co., Ltd., Japan) that had fasted overnight were used and grouped according to blood glucose levels and body weight (8 cases in each group). After grouping, the vehicle (0.5% methylcellulose solution), compound 1 only (1 mg / kg), dapagliflozin only (3 mg / kg), or a combination of compound 1 and dapagliflozin were orally administered at 5 mL / kg. After 4 hours, 0.4 g / mL of glucose solution was orally administered at 5 mL / kg to load glucose. Blood was collected from the tail vein just before glucose was loaded, 30 minutes after loading, 60 minutes after loading, 120 minutes after loading, and 240 minutes after loading. Blood glucose levels were measured using a biochemical automatic analyzer (HITACHI, model 7180).

[0417] The results are expressed as the change in blood glucose level, the value 30 minutes after glucose loading, and the value 60 minutes after glucose loading. Statistical analysis was performed using Tukey-Kramer's multi-group test. The significance level was set at 5% on both sides. As a result, the combination of compound 1 and dapagliflozin significantly reduced blood glucose levels compared to each single agent. The results are shown in Figures 3 to 5 .

[0418] [Test Example 6] Effect of combined use with DPP4 inhibitors in OGTT (Oral Glucose Tolerance Test) Male Zucker Fatty rats (8 weeks old, Charles River Co., Ltd., Japan) that had fasted overnight were used and grouped according to blood glucose levels and body weight (8 cases in each group). After grouping, the vehicle (0.5% methylcellulose solution), compound 1 only (1 mg / kg, 4 hours before loading glucose), sitagliptin only (3 mg / kg, 30 minutes before loading glucose) or a combination of compound 1 and sitagliptin were orally administered at 5 mL / kg. Thereafter, 0.4 g / mL of glucose solution was orally administered at 5 mL / kg to load glucose. Blood was collected from the tail vein just before loading glucose, 30 minutes after loading, 60 minutes after loading, and 120 minutes after loading. Blood glucose levels were measured using a biochemical automatic analyzer (HITACHI, model 7180). Active GLP-1 was measured using a GLP-1 assay kit (IBL, #27700).

[0419] Results Regarding blood glucose levels, the transition and the value 30 minutes after glucose loading were expressed. Regarding active GLP-1, the transition and the concentration AUC were expressed. Statistical analysis Regarding the blood glucose values ​​30 minutes after glucose loading and the concentration AUC of active GLP-1, Steel Dwass's multi-group test was performed. The significance level was set to 5% on both sides. As a result, the combination of compound 1 and sitagliptin significantly reduced blood glucose levels compared to each single agent ( Figure 6 and 7 In addition, the combination of compound 1 and sitagliptin significantly increased the concentration of active GLP-1 in plasma ( Figure 8 and 9 ).

[0420] [Preparation Example] Examples of formulations of the compound of formula [I] include, but are not limited to, the following formulations.

[0421] Preparation Example 1 (Manufacture of capsules) Ingredients (1), (2), (3) and (4) are mixed and filled into gelatin capsules.

[0422] Preparation Example 2 (Manufacture of tablets) The total amount of ingredients (1), (2), and (3) and 30 g of ingredient (4) were mixed with water, vacuum dried, and then granulated. 14 g of ingredient (4) and 1 g of ingredient (5) were mixed with the granulated powder, and the mixture was compressed by a tablet press. In this way, 1000 tablets containing 10 mg of compound 1 per tablet were obtained.

[0423] Industrial Applicability The combination of an SGLT1 inhibitor and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor is expected to be useful in the treatment and / or prevention of various diseases or conditions that are expected to be improved by regulating these activities, or various diseases or conditions that may be caused by increased blood sugar levels due to sugar absorption in the body.

Claims

1. A drug for the treatment or prevention of diabetes, obesity or diabetic complications containing an SGLT1 inhibitor, characterized in that: An SGLT1 inhibitor is used in combination with at least one agent selected from the group consisting of a SGLT2 inhibitor and a DPP4 inhibitor.

2. A drug for the treatment or prevention of diabetes, obesity or diabetic complications comprising at least one drug selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor, characterized in that: An SGLT1 inhibitor is used in combination with at least one agent selected from the group consisting of a SGLT2 inhibitor and a DPP4 inhibitor.

3. A drug for treating or preventing diabetes, obesity or diabetic complications comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula [I] or a pharmaceutically acceptable salt thereof is used in combination with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor: [Chemistry 1] In the formula, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B Halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl.

4. A drug for the treatment or prevention of diabetes, obesity or diabetic complications comprising at least one drug selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor, characterized in that: Combining a compound of formula [I] or a pharmaceutically acceptable salt thereof with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor, [Chemistry 2] In the formula, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B Halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl.

5. A drug for treating or preventing diabetes, obesity or diabetic complications comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof, characterized in that: administering to a subject receiving treatment with at least one drug selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor, [Chemistry 3] In the formula, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B Halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl.

6. A drug for treating or preventing diabetes, obesity or diabetic complications comprising at least one drug selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor, characterized in that: administering to a subject receiving treatment based on a compound of formula [I] or a pharmaceutically acceptable salt thereof, [Chemistry 4] In the formula, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B Halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl.

7. The drug according to any one of claims 1 to 6, wherein The SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of any one of formulas [II] to [V] or a pharmaceutically acceptable salt thereof, [Chemistry 5] 8. The drug according to any one of claims 1 to 6, wherein The SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of formula [II] or a pharmaceutically acceptable salt thereof, [Chemistry 6] 9. The drug according to any one of claims 1 to 6, wherein The SGLT2 inhibitor is dapagliflozin.

10. The drug according to any one of claims 1 to 6, wherein The DPP4 inhibitor is sitagliptin.

11. The drug according to any one of claims 1 to 6, wherein The diabetes is type 2 diabetes.

12. The drug according to claim 5 or 6, wherein The object is a person.

13. A method for treating or preventing diabetes, obesity or diabetic complications, characterized in that: A therapeutically effective amount of an SGLT1 inhibitor and a therapeutically effective amount of at least one agent selected from a SGLT2 inhibitor and a DPP4 inhibitor are administered to a subject.

14. An SGLT1 inhibitor for treating or preventing diabetes, obesity or diabetic complications, characterized in that: Used in combination with at least one agent selected from SGLT2 inhibitors and DPP4 inhibitors.

15. At least one agent selected from SGLT2 inhibitors and DPP4 inhibitors for treating or preventing diabetes, obesity or diabetic complications, characterized in that: Combined with SGLT1 inhibitors.

16. Use of an SGLT1 inhibitor in the manufacture of a medicament for the treatment or prevention of diabetes, obesity or diabetic complications for use in combination with at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

17. Use of at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor in the manufacture of a medicament for the treatment or prevention of diabetes, obesity or diabetic complications for use in combination with an SGLT1 inhibitor.

18. A pharmaceutical composition for treating or preventing diabetes, obesity or diabetic complications, comprising an SGLT1 inhibitor and at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor.

19. A pharmaceutical composition for treating or preventing diabetes, obesity or diabetic complications, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof and at least one agent selected from the group consisting of an SGLT2 inhibitor and a DPP4 inhibitor. [Chemistry 7] In the formula, R 1 is hydrogen or a halogen, R 2 C 1-6 Alkyl or halogenated C 1-6 alkyl, R 3 (1)C 1-6 alkyl, (2) Halogenated C 1-6 alkyl, (3) R 3A Substituted pyridyl, or (4) Optional R 3B substituted pyrazinyl, pyrimidinyl or pyridazinyl, R 3A is cyano, halogen or halogenated C 1-3 alkyl, R 3B Halogen, hydroxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R 5 ), R 4 and R 5 are independently hydrogen or C 1-3 alkyl.

20. The composition according to claim 18 or 19, wherein The SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of the compounds of formula [II] to [V] or a pharmaceutically acceptable salt thereof: [Chemistry 8] 21. The composition according to claim 18 or 19, wherein The SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is a compound of formula [II] or a pharmaceutically acceptable salt thereof, [Chemistry 9]

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