Method for treating or preventing chronic kidney disease

Abstract

One aim of the present invention is to treat or prevent chronic kidney disease. Provided is a treatment or prophylactic pharmaceutical composition for chronic kidney disease, that contains an SGLT1-inhibiting compound or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for treating or preventing chronic kidney disease, which contains an SGLT1-inhibiting compound or a pharmaceutically acceptable salt thereof, and a method for treating or preventing chronic kidney disease, which comprises administering an SGLT1-inhibiting compound or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Chronic kidney disease (CKD) is a condition characterized by kidney damage or decreased kidney function that persists for more than three months and is generally diagnosed based on glomerular filtration rate (GFR). Diabetic nephropathy is known to be one of the diseases included in CKD.

[0003] SGLT1, one of the SGLT subtypes, is known to be responsible for the majority of glucose and galactose absorption in the small intestine, and it has been reported that SGLT1 deficiency in humans results in impaired glucose and galactose absorption. Furthermore, it has been confirmed that small intestinal SGLT1 expression is increased in diabetic patients, and it is thought that the increased glucose absorption in diabetic patients is due to this high expression of small intestinal SGLT1.

[0004] Based on these findings, SGLT1 inhibitors are expected to normalize blood glucose levels by inhibiting sugar absorption from the small intestine, and are thought to be effective in treating diabetes and diabetic complications associated with hyperglycemia (Non-Patent Documents 1 and 2). There have been no examples of SGLT1 inhibitors being used to treat chronic kidney disease (e.g., diabetic nephropathy) in humans. [Prior art documents] [Non-patent literature]

[0005] [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 Summary of the Invention

[0006] Provided are a pharmaceutical composition for treating or preventing chronic kidney disease, which contains an SGLT1-inhibiting compound or a pharmaceutically acceptable salt thereof, and a method for treating or preventing chronic kidney disease, which comprises administering an SGLT1-inhibiting compound or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0007] [Figure 1] Figure 1 shows that the compound of Example 1 (hereinafter also referred to as Compound 1) significantly reduced blood glucose levels in SD rats subjected to glucose loading in an OGTT compared to the vehicle. * in the figure indicates p<0.05 compared to the vehicle. [Figure 2] Figure 2 shows that among the administered compounds, only Compound 1 significantly reduced the blood glucose level in glucose-loaded SD rats in an OGTT compared to the vehicle. ** in the figure indicates p<0.05 compared to the vehicle. [Figure 3] 3 shows the GFR in Test Example 5. In the figure, * indicates p<0.05 relative to the SD rat vehicle-administered group, # indicates p<0.05 relative to the SDT fatty rat vehicle-administered group, and ## indicates p<0.01 relative to the SDT fatty rat vehicle-administered group. [Figure 4] FIG. 4 shows that the amount of urinary protein (mg / mgCr) in 5 / 6 nephrectomized rats was lower in the Compound 1 group than in the Vehicle group. [Figure 5] Figure 5 shows that the creatinine clearance (mL / min) in 5 / 6 nephrectomized rats was significantly higher in the Compound 1 group than in the Vehicle group. ## in the figure indicates p<0.01 compared to the Vehicle group (Student's test). [Figure 6]Figure 6 shows that the urea nitrogen concentration (mg / dL) in 5 / 6 nephrectomized rats was significantly lower in the Compound 1 group than in the Vehicle group, and significantly higher in the Vehicle group than in the Sham group. # indicates p<0.05 compared to the Vehicle group (Aspin-Welch test), and ** indicates p<0.01 compared to the Sham group (Student test). DETAILED DESCRIPTION OF THE INVENTION

[0008] Some specific embodiments are exemplified below. [Section 1] A pharmaceutical composition for treating or preventing chronic kidney disease, comprising a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

[0009] [Section 2] Formula [I]: [ka] [In the formula, R 1 is hydrogen or halogen, R 2 is C 1-6 Alkyl or haloC 1-6 is alkyl, R 3 teeth (1)C 1-6 Alkyl, (2) Haro C 1-6 Alkyl, (3)R 3A pyridyl substituted with, or (4)R 3B pyrazinyl, pyrimidinyl or pyridazinyl, optionally substituted by R 3A is cyano, halogen or haloC 1-3 is alkyl, R 3B is halogen, hydroxy, C 1-3 Alkyl, HaloC 1-3 Alkyl, C 1-3 Alkoxy or -N(R 4 )(R5 ) and R 4 and R 5 are each independently hydrogen or C 1-3 alkyl] A pharmaceutical composition for treating or preventing chronic kidney disease, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] [Section 3] The compound that inhibits SGLT1 or the compound of formula [I] is any one of formulas [II] to [V]: [ka] Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is

[0011] [Section 4] The compound that inhibits SGLT1 or the compound of formula [I] is represented by formula [II]: [ka] Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the compound is

[0012] [Section 5] A method for treating or preventing chronic kidney disease, comprising administering to a subject a therapeutically effective amount of a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

[0013] [Section 6] A compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof for treating or preventing chronic kidney disease.

[0014] [Section 7] Use of a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing chronic kidney disease.

[0015] The compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof (hereinafter also referred to as SGLT1 inhibitor) may be any substance that inhibits SGLT1, and may be a low molecular weight compound, a nucleic acid, a polypeptide, a protein, an antibody, a vaccine, etc. In one embodiment, the SGLT1 inhibitor is a substance that has the function of normalizing blood glucose levels by inhibiting the absorption of sugar from organs such as the small intestine and myocardium. In another embodiment, the SGLT1 inhibitor can suppress glomerular hyperfiltration associated with obesity or hyperglycemia by normalizing blood glucose levels. In yet another embodiment, the SGLT1 inhibitor is represented by formula [I]: [ka] wherein each symbol has the same meaning as defined above. or a pharmaceutically acceptable salt thereof. In yet another embodiment, the SGLT1 inhibitor is a substance whose metabolites are not mutagenic. Here, a substance that is not mutagenic means, for example, a substance that does not exhibit reverse mutation induction ability under the conditions of Test Example 4 described below. In yet another embodiment, the SGLT1 inhibitor is a human SGLT1 inhibitor.

[0016] In substructures: [ka] The double wavy line indicates the binding site of the structure.

[0017] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine.

[0018] "C 1-3 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1-3 "Alkyl" includes methyl, ethyl, n-propyl, and isopropyl.

[0019] "C 1-6 "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6"Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.

[0020] "Haro C 1-3 "Alkyl" refers to the above "C alkyl" substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-3 "Alkyl" means "haloC 1-3 "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.

[0021] "Fluoro C 1-3 "Alkyl" refers to the above "C alkyl" substituted with 1 to 5 fluorines. 1-3 "Alkyl" means "Fluoro C 1-3 "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.

[0022] "Haro C 1-6 "Alkyl" refers to the above "C alkyl" substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-6 "Alkyl" means "haloC 1-6"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.

[0023] "Fluoro C 1-6 "Alkyl" refers to the above "C alkyl" substituted with 1 to 5 fluorines. 1-6 "Alkyl" means "Fluoro C 1-6 "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.

[0024] "C 1-3 "Alkoxy" refers to the above "C 1-3 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-3 "Alkoxy" includes methoxy, ethoxy, n-propoxy, and isopropoxy.

[0025] "Pyridyl" means any of the following formulae: [ka]

[0026] "Pyrazinyl" refers to the following formula: [ka]

[0027] "Pyrimidinyl" means any of the following formulae: [ka]

[0028] "Pyridazinyl" means any of the following formulae: [ka]

[0029] The term "substituted" includes any chemically permissible substitution. For example, "R 3A "Pyridyl substituted with" means any of the following formulae: [ka]

[0030] Each of the substituents of the compound of formula [I] includes the specific embodiments exemplified below, and combinations of the specific embodiments of each of these substituents are also included in the compound of formula [I].

[0031] In some embodiments, R 1 is halogen. In another embodiment, R 1 is fluorine.

[0032] In some embodiments, R 2 is C 1-6 Alkyl or Fluoro C 1-6 In another embodiment, R 2 is C 1-6 In yet another embodiment, R 2 Fluoro-C 1-3 It is alkyl.

[0033] In some embodiments, R 3 teeth (1) Haro C 1-6 Alkyl, (2)R 3A pyridyl substituted with, or (3)R3B and pyrazinyl or pyrimidinyl, optionally substituted by In another embodiment, R 3 Halo C 1-6 is selected from the group consisting of alkyl and formula [H1] to [H14] In yet another embodiment, R 3 Halo C 1-6 Alkyl, formula [H2] or [H8]. [ka]

[0034] In some embodiments, R 3A is a halogen or haloC 1-3 In another embodiment, R 3A is fluorine or fluoro C 1-3 It is alkyl.

[0035] In some embodiments, R 3B is a halogen or haloC 1-3 In another embodiment, R 3B Fluoro C 1-3 It is alkyl.

[0036] In some embodiments, R 4 and R 5 are each independently, C 1-3 It is alkyl.

[0037] In some embodiments, the compound of formula [I] has formula [II] or [III]: [ka] 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 the compound of formula [III], i.e., a compound of formula [VI]: [ka] is a compound of

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (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). According to a method known per se, the compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base to obtain a pharmaceutically acceptable salt thereof.

[0039] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Preferred examples include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric 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, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, and lactobionic acid. , malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferred examples include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 2-hydroxy-1-ethanesulfonic acid.

[0040] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium, and preferably salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases 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 used.

[0041] The active ingredients of SGLT1 inhibitors (e.g., the compound of formula [I] or a pharmaceutically acceptable salt thereof) and SGLT2 inhibitors may exist as solvates. A solvate is, for example, a compound of formula [I] or a pharmaceutically acceptable salt thereof in which solvent molecules are coordinated. The solvate may be any pharmaceutically acceptable solvate, including hydrates, ethanolates, and dimethyl sulfoxide solvates of the compound of formula [I] or a pharmaceutically acceptable salt thereof. Specific examples include the hemihydrate, monohydrate, dihydrate, or monoethanolate of the compound of formula [I], or the monohydrate of the sodium salt or 2 / 3 ethanolate of the dihydrochloride salt of the compound of formula [I]. These solvates can be obtained according to known methods. For example, the compound of formula [III] can exist as a monohydrate, as shown in the following formula [VI]. [ka]

[0042] The compound of formula [I] may contain isotopes ( 2 H, 3 H, 14 C. 35 It may be labeled with (e.g., S).

[0043] The compound of formula [I] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of formula [I] or a pharmaceutically acceptable salt thereof, more preferably a compound of formula [I] or a pharmaceutically acceptable salt thereof purified to a purity of 80% or more.

[0044] Inhibiting SGLT1 means inhibiting the function of SGLT1 to eliminate or attenuate its activity, for example, under the conditions of Test Example 1 described below. Preferably, human SGLT1 is inhibited. The inhibition of SGLT1 function or elimination or attenuation of SGLT1 activity is preferably performed for clinical applications in humans.

[0045] The SGLT2 inhibitor may be any substance that inhibits SGLT2, and may be a low molecular weight compound, a nucleic acid, a polypeptide, a protein, an antibody, a vaccine, etc. In one embodiment, the SGLT2 inhibitor is a substance that has the function of lowering blood glucose levels by inhibiting the reuptake of glucose from urine and increasing the amount of sugar excreted in urine.

[0046] Inhibiting SGLT2 means inhibiting the function of SGLT2 to eliminate or attenuate its activity. Preferably, it means inhibiting human SGLT2. The inhibition of SGLT2 function or elimination or attenuation of SGLT2 activity is preferably performed for clinical applications in humans.

[0047] As used herein, SGLT2 inhibitors include, for example, glycoside compounds or salts thereof, or solvates thereof. Here, a glycoside compound is a compound in which a sugar or a sugar derivative is bound to an aglycone 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: [ka] wherein Y is O or S and the glycosidic bond is formed with the carbon atom at position 1.

[0048] As used herein, SGLT2 inhibitors include, for example, the following: For convenience, common names will be used throughout the specification. [Table 1] [Table 2-1] [Table 2-2]

[0049] SGLT1 inhibitors (e.g., the compound of formula [I] or a pharmaceutically acceptable salt thereof) suppress an increase in GFR and have renal protective effects, and therefore may be useful in the treatment and / or prevention of chronic kidney disease.

[0050] Chronic kidney disease refers to a condition in which renal damage or decreased renal function persists for three months or more, and is classified into pre-nephropathy (stage 1, G1), early nephropathy (stage 2, G2), overt nephropathy (stage 3, G3a and G3b), renal failure (stage 4, G4), and dialysis therapy (stage 5, G5) according to the severity measured using glomerular filtration rate (GFR). In one embodiment, chronic kidney disease is chronic kidney disease accompanied by hypertension, obesity, hyperglycemia, dyslipidemia, hyperuricemia, or immune system or inflammatory disease.

[0051] In one embodiment, the chronic kidney disease is chronic kidney disease associated with hyperglycemia. In another embodiment, the chronic kidney disease is diabetic kidney disease or diabetic nephropathy. In yet another embodiment, the chronic kidney disease is diabetic kidney disease.

[0052] In one embodiment, the chronic kidney disease is chronic kidney disease without hyperglycemia. In another embodiment, the chronic kidney disease is chronic kidney disease without a disease selected from the group consisting of diabetic kidney disease and diabetic nephropathy. In some embodiments, the chronic kidney disease without hyperglycemia is chronic kidney disease associated with hypertension, obesity, dyslipidemia, hyperuricemia, or immune system or inflammatory disease. In certain embodiments, the chronic kidney disease associated with an immune system or inflammatory disease is a chronic kidney disease associated with a disease selected from the group consisting of chronic tubulointerstitial nephropathy, focal segmental glomerulosclerosis, idiopathic crescentic glomerulonephritis, IgA nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, amyloidosis, anti-GBM antibody disease (Goodpasture's syndrome), granulomatosis with polyangiitis, hemolytic uremic syndrome, mixed cryoglobulinemia, post-infectious glomerulonephritis, systemic lupus erythematosus, autosomal dominant interstitial kidney disease (medullary cystic kidney disease), hereditary nephritis (Alport syndrome), nail-patella syndrome, and polycystic kidney disease.

[0053] In some embodiments, the chronic kidney disease is chronic kidney disease excluding diabetic complications associated with hyperglycemia.

[0054] In certain embodiments, an SGLT1 inhibitor may be used to treat and / or prevent chronic kidney disease by administering it to a subject in combination with an SGLT2 inhibitor.

[0055] In another aspect, there is provided a pharmaceutical agent for treating or preventing chronic kidney disease containing an SGLT1 inhibitor, characterized by using an SGLT1 inhibitor in combination with an SGLT2 inhibitor.

[0056] In yet another aspect, there is provided a pharmaceutical agent for treating or preventing chronic kidney disease containing an SGLT2 inhibitor, characterized in that an SGLT1 inhibitor and an SGLT2 inhibitor are used in combination.

[0057] In yet another aspect, there is provided a pharmaceutical agent for treating or preventing chronic kidney disease, comprising an SGLT1 inhibitor, which is administered to a subject undergoing treatment with an SGLT2 inhibitor.

[0058] In yet another aspect, there is provided a pharmaceutical agent for treating or preventing chronic kidney disease, comprising an SGLT2 inhibitor, which is administered to a subject undergoing treatment with an SGLT1 inhibitor.

[0059] As used herein, "combination" refers to, for example, administering an SGLT1 inhibitor and an SGLT2 inhibitor to a subject in any order. Because each drug has a different mechanism of action, their combination can provide additive or synergistic therapeutic or preventive effects. In some embodiments, the combination may involve using multiple drugs with different mechanisms of action, thereby reducing the dosage of each drug compared to administering a single drug alone and reducing side effects specific to each drug. Examples of side effects include hypoglycemia, weight gain, dehydration, polyuria, and frequent urination. In some embodiments, the SGLT1 inhibitor and the SGLT2 inhibitor may be administered to a subject simultaneously, sequentially, or at a fixed interval (e.g., within 30 minutes, 1 hour, 2 hours, or 4 hours), together, or separately, in any order. When administering one drug to a subject, the active ingredient contained in the first drug administered can be present in the subject's body in a therapeutically effective amount. In another embodiment, the SGLT1 inhibitor and the SGLT2 inhibitor may be administered to a subject as a single combination drug. The administration ratio and compounding ratio of these drugs may be appropriately selected depending on the subject, administration route, target disease, symptoms, severity of disease, and combinations thereof. For example, when the subject is a human, 0.01 to 1000 parts by weight of the SGLT2 inhibitor can be used per 1 part by weight of the SGLT1 inhibitor.

[0060] 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.

[0061] 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.

[0062] In some embodiments, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor may include, for example: A compound of formula [I] and dapagliflozin, A compound of formula [I] and ipragliflozin, A compound of formula [I] and tofogliflozin, A compound of formula [I] and empagliflozin, A compound of formula [I] and canagliflozin, and Compound of formula [I] and luseogliflozin This includes the use of a combination of

[0063] In another embodiment, the combination of an SGLT1 inhibitor and an SGLT2 inhibitor includes: A compound of formula [II] and dapagliflozin, A compound of formula [II] and ipragliflozin, A compound of formula [II] and tofogliflozin, A compound of formula [II] and empagliflozin, A compound of formula [II] and canagliflozin, and Compound of formula [II] and luseogliflozin This includes the use of a combination of

[0064] As used herein, the term "drug" refers to an SGLT1 inhibitor or an SGLT2 inhibitor. Administering a drug to a subject receiving treatment with another drug is one aspect of combination use, and includes, for example, administering a drug to a subject while the active ingredient contained in the previously administered drug is present in the subject's body in a therapeutically effective amount.

[0065] In this specification, the therapeutically effective amount can be varied as appropriate depending on the subject of administration, the administration route, the target disease, symptoms, the severity of the disease, and a combination thereof. When orally administered to a human (body weight 60 kg), the lower limit of the therapeutically effective amount can be, 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, and the upper limit of the therapeutically effective amount can be, 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.

[0066] As used herein, the frequency of administration of each drug, medicament, and pharmaceutical composition may be once, twice, three times, or more times per day.

[0067] As used herein, "treatment" includes alleviating symptoms, preventing aggravation, maintaining remission, preventing relapse, and preventing recurrence. For example, treatment of chronic kidney disease includes restoring and improving renal function and restoring GFR to within the normal range (e.g., GFR≧90). As used herein, prevention includes suppressing the onset of symptoms. For example, prevention of chronic kidney disease includes maintaining renal function and maintaining or bringing GFR close to the normal range (e.g., GFR≧90).

[0068] As used herein, renal protection refers to the process of slowing or halting the rate of progression of renal function decline due to the underlying disease (for example, slowing or preventing the decline in GFR), which inhibits progression to end-stage renal failure and can prevent transition to dialysis or kidney transplantation.

[0069] In one embodiment, a nephroprotective agent is provided that contains a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof.

[0070] In another embodiment, the compound of formula [I]: [ka] wherein each symbol has the same meaning as defined above. or a pharmaceutically acceptable salt thereof.

[0071] In yet another embodiment, the compound of formula [II]: [ka] The present invention provides a renal protective agent comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

[0072] In yet another embodiment, the compound of formula [II]: [ka] or a pharmaceutically acceptable salt thereof.

[0073] In yet another embodiment, the compound of formula [II]: [ka] and a pharmaceutical composition for treating or preventing diabetic nephropathy, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0074] In yet another aspect, there is provided a pharmaceutical composition for treating or preventing chronic kidney disease, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

[0075] The pharmaceutical composition herein may be prepared by appropriately mixing a therapeutically effective amount of each contained drug with at least one or more pharmaceutically acceptable carriers, etc., according to a method known in the technical field of pharmaceutical formulations. The content of each drug in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0076] In this specification, dosage forms of each drug, medicament, and pharmaceutical composition include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0077] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be added as necessary.

[0078] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of disintegrants include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and crystalline cellulose. Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate. Lubricants include magnesium stearate, calcium stearate, talc, and the like. Examples of the solvent include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. Examples of solubilizing agents include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate. Suspending agents include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate. Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, and D-mannitol. Buffering agents include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate. Examples of soothing agents include benzyl alcohol. Examples of bases 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, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more thereof. Preservatives include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid. Antioxidants include sodium sulfite and ascorbic acid. Examples of coloring agents include food dyes (such as Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), and β-carotene. Sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0079] Each drug, medicament, and pharmaceutical composition herein can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to humans and non-human mammals (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). The dosage varies depending on the subject, disease, symptoms, dosage form, administration route, etc. For example, the oral dosage for an adult patient (60 kg body weight) is typically in the range of about 0.01 mg to about 1 g per day of the active ingredient of each drug. These amounts can be administered once or in divided doses. In one embodiment, each drug may be formulated into a separate pharmaceutical composition and administered to a subject in any order via different administration routes. In another embodiment, the dosage of each drug may be reduced by the combination of drugs compared to when each drug is administered alone, and the oral dosage for an adult patient (60 kg body weight) may be in the range of about 0.01 mg to 1000 mg per day.

[0080] In some embodiments, kits (e.g., administration, treatment, and / or prevention kits), packages (e.g., wrapping), and pharmaceutical sets (and / or containers) may be provided that include an SGLT1 inhibitor, optionally an SGLT2 inhibitor, and written material describing how these agents can or should be used for treatment and / or prevention. Such kits, packages, and pharmaceutical sets may include one or more containers filled with an SGLT1 inhibitor, optionally an SGLT2 inhibitor, and / or other pharmaceutical or drug (or ingredient). Examples of such kits, packages, and pharmaceutical sets include commercial kits, commercial packages, and commercial pharmaceutical sets appropriately directed to the treatment and / or prevention of a target disease. The written material included in such kits, packages, and pharmaceutical sets may include notices or inserts in the form required by a governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, indicating the agency's approval of the manufacture, use, or sale of the product for administration to humans. The above kits, packages, and pharmaceutical sets include packaged products, and may also include structures configured for appropriate administration steps, or structures configured to achieve more desirable medical treatment and / or prevention, including treatment and / or prevention of a target disease.

[0081] [General manufacturing method] A general method for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof is exemplified below. However, the method for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof is not limited to the general method. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases can be used to proceed to the next step without isolation and / or purification. In this specification, room temperature refers to a temperature in an uncontrolled state, and in one embodiment, it is 1°C to 40°C.

[0082] [General Process A] Compound of formula [I-1] or a pharmaceutically acceptable salt thereof R3 R 3A pyridyl substituted with, or R 3B The compound of formula [I], which is pyrazinyl, pyrimidinyl or pyridazinyl optionally substituted by, or a pharmaceutically acceptable salt thereof, can be obtained, for example, by the process shown below. [ka] [In the formula, R 1 and R 2 is as defined above, R 31 is R 3A pyridyl substituted with, or R 3B pyrazinyl, pyrimidinyl or pyridazinyl, optionally substituted by R 3A and R 3B is as defined above, X 1A and X 1B are each independently a halogen, but in step 1, X 1A X is better 1B It is more reactive than R 1 If is halogen, R 1 and X 1A are preferably the same halogen; A 4 is n-butyl, A 7 is C 1-4 alkyl or benzyl; A 12 is tert-butyl or benzyl]

[0083] (Process A1) The compound of formula [3] can be obtained by reacting the compound of formula [1] with the compound of formula [2] in a solvent in the presence of a base. 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'-dimethylpropyleneurea. A preferred solvent is 1,3-dimethyl-2-imidazolidinone. Examples of the base include cesium carbonate and sodium hydride, and a preferred base is sodium hydride. The reaction temperature is, for example, 60 to 170°C, preferably 100 to 140°C. The compounds of formula [1] and formula [2] are either commercially available products or may be prepared by known methods. Alternatively, R 2 When is trifluoromethyl, the compound of formula [3] may be commercially available.

[0084] (Process A2) The compound of formula [5] can be obtained by subjecting the compound of formula [3] and the compound of formula [4] to the Mizoroki-Heck reaction. For example, the compound of formula [5] can be obtained by reacting the compound of formula [3] with the compound of formula [4] in a solvent in the presence of a palladium catalyst and a base. 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. 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. The base may be, for example, an organic base such as triethylamine, etc. A preferred base is triethylamine. The reaction temperature is, for example, 80 to 150°C, preferably 100 to 140°C. The compound of formula [4] is commercially available or may be prepared by known methods.

[0085] (Process A3) The compound of formula [6] is a compound of formula [5] -C(=CH2)OA 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. 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. Acids include, for example, hydrochloric acid and trifluoroacetic acid, with hydrochloric acid being the preferred acid. The reaction temperature is, for example, 20°C to 50°C, preferably room temperature.

[0086] (Process A4) The compound of formula [8] can be obtained by reacting the compound of formula [6] with the compound of formula [7] in a solvent in the presence of a base. 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. Examples of bases 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. The reaction temperature is, for example, from −78° C. to 110° C., preferably from 0° C. to room temperature. The compound of formula [7] is commercially available or may be prepared by known methods.

[0087] (Process A5) The compound of formula

[10] can be obtained by reacting the compound of formula [8] with the compound of formula [9] in a solvent in the presence of an acid. Examples of the solvent include ether solvents such as tetrahydrofuran; alcohol solvents such as methanol and ethanol; and hydrocarbon solvents such as toluene. 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 may be used as solvents. The reaction temperature is, for example, 20°C to 130°C, preferably 80°C to 110°C. The compound of formula [9] is commercially available or may be prepared by known methods, or may be obtained by the general method B described below.

[0088] (Process A6) The compound of formula

[11] is -A of the compound of formula

[10] 7 The elimination reaction can be carried out by removing the A 7 The conditions should be appropriate depending on the type of A. 7 When is ethyl, the compound of formula

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

[10] in a solvent in the presence of a base. Examples of the solvent include alcoholic solvents such as methanol and ethanol, ethereal solvents such as tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of two or more selected from the group consisting of methanol, tetrahydrofuran, and water. Examples of the base include lithium hydroxide, sodium hydroxide, and potassium hydroxide. A preferred base is sodium hydroxide. The reaction temperature is, for example, 0°C to 100°C, preferably room temperature to 40°C.

[0089] (Process A7) The compound of formula

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

[11] and the compound of formula

[12] to a Curtius rearrangement reaction. 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 it with the compound of formula

[12] . 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. Preferred solvents are toluene or a mixed solvent of toluene and the compound of formula

[12] . An example of the azidating agent is diphenylphosphoryl azide. Examples of the base include organic bases such as triethylamine, N,N-diisopropylethylamine, etc. A preferred base is triethylamine. The reaction temperature is, for example, 65 to 130°C, preferably 90 to 110°C. Compounds of formula

[12] are commercially available or may be prepared by known methods.

[0090] (Process A8) The compound of formula

[14] is reacted with the compound of formula

[13] -C(=O)OA in a solvent. 12 The elimination reaction can be carried out by removing the A 12 The conditions should be appropriate depending on the type of A. 12 When is tert-butyl, the compound of formula

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

[13] in a solvent in the presence of an acid. 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 mixtures thereof. A preferred solvent is 1,4-dioxane. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. A preferred acid is hydrochloric acid. These acids may be used as a solvent. The reaction temperature is, for example, 0° C. to 60° C., preferably 0° C. to room temperature.

[0091] (Process A9) The compound of formula [I-1] can be obtained by condensation reaction of a compound of formula

[14] and a compound of formula

[15] in a solvent. 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. A preferred solvent is pyridine. 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-methylpropyl)methyl] ... Examples of suitable condensing agents include {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). The reaction temperature is, for example, 0° C. to 100° C., preferably room temperature. The compound of formula

[15] can be obtained, for example, by the method of General Production Method E described below.

[0092] [General manufacturing method B] Manufacturing method B1 The compound of formula [9] can be obtained, for example, by the following method. [ka] [In the formula, R 31 is as defined above, X 16 is a halogen] The compound of formula [9] can be obtained by reacting the compound of formula

[16] with hydrazine monohydrate in a solvent. Examples of solvents 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. The reaction temperature is, for example, from room temperature to 140°C, preferably from 60°C to 100°C. Compounds of formula

[16] are commercially available or may be prepared by known methods.

[0093] Manufacturing method B2 The compound of formula [9] also has R 31 R 3A When the pyridyl is substituted with the following, it can be obtained, for example, by the following process. [ka] [In the formula, R 31 is R 3A pyridyl substituted with R 3A are as defined above] The compound of formula [9] can be obtained by diazotizing the compound of formula

[17] in a solvent in the presence of an acid, followed by reduction. An example of the solvent is water. An example of the diazotizing agent is sodium nitrite. Examples of the acid include hydrochloric acid and sulfuric acid, and the preferred acid is hydrochloric acid. Examples of reducing agents include tin(II) chloride and sodium sulfite, and a preferred reducing agent is tin(II) chloride. The reaction temperature for diazotization is, for example, -20°C to 5°C, preferably -5°C to 0°C. The reaction temperature for the reduction is, for example, from −5° C. to room temperature, preferably from 0° C. to room temperature. Compounds of formula

[17] are commercially available or may be prepared by known methods.

[0094] Manufacturing method B3 Alternatively, the compound of formula [9] may also be R 31 (1)R 3A or (2) R 3B When the pyrimidinyl is an optionally substituted pyrimidinyl, it can be obtained, for example, by the process shown below. [ka] [In the formula, R 31 (1)R 3A or (2) R 3B pyrimidinyl optionally substituted with R 3A , R 3B and X 16 is as defined above, A 19 is tert-butoxycarbonyl or benzyloxycarbonyl]

[0095] (Process B3-1) The compound of formula

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

[16] with a base and a boric acid ester in a solvent. Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. The preferred solvent is tetrahydrofuran. Examples of the base include n-butyllithium and isopropylmagnesium bromide, and a preferred base is n-butyllithium. Examples of borate esters include triisopropyl borate and trimethyl borate, with triisopropyl borate being preferred. The reaction temperature is, for example, from -78°C to room temperature, preferably from -78°C to 0°C. Compounds of formula

[16] are commercially available or may be prepared by known methods.

[0096] (Process B3-2) The compound of formula

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

[18] with the compound of formula

[19] in a solvent in the presence of a copper catalyst. Examples of the solvent include ether solvents such as tetrahydrofuran, and alcohol solvents such as methanol. A preferred solvent is methanol. The copper catalyst includes, for example, copper(II) acetate. The reaction temperature is, for example, from room temperature to 100°C, preferably from 45°C to 65°C.

[0097] (Process B3-3) The compound of formula [9] is reacted with the compound of formula

[20] in a solvent. 19 The elimination reaction can be carried out by removing the A 19 The conditions should be appropriate depending on the type of A. 19 When is tert-butoxycarbonyl, the compound of formula [9] can be obtained by reacting the compound of formula

[20] in a solvent in the presence of an acid. 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 mixtures thereof. A preferred solvent is 1,4-dioxane. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. A preferred acid is hydrochloric acid. The reaction temperature is, for example, 0° C. to 60° C., preferably 0° C. to room temperature.

[0098] [General Process C] Compound of formula [I-2] or a pharmaceutically acceptable salt thereof R 3 C 1-6 Alkyl or haloC 1-6 The compound of formula [I] or a pharmaceutically acceptable salt thereof, which is alkyl, can be obtained, for example, by any of the following processes. Manufacturing method C1 [ka] [In the formula, R 1 and R 2 is as defined above, R 32 is C 1-6 Alkyl or haloC 1-6 alkyl]

[0099] (Process 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. 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-oxo-2-methylpropyl)methyl] ... Examples include {benzotriazol-1-yloxy)tripyrrolidinophosphonium}-4-methylmorpholinium chloride n-hydrate (DMT-MM), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, and propylphosphonic anhydride. Examples of additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine, and 1-methylimidazole. 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. The reaction temperature is, for example, 0°C to 100°C. When a salt of the compound of formula

[21] is used, the reaction may be carried out in the presence of a base, such as an organic base such as triethylamine, or an alkali metal salt such as sodium carbonate.

[0100] 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 it with the compound of formula

[21] in the presence of a base. Examples of halogenating agents used in the reaction include oxalyl chloride and thionyl chloride, with oxalyl chloride being preferred. Examples of the base used in the reaction include organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine, etc., and alkali metal salts such as sodium bicarbonate, sodium carbonate, etc. A preferred base is pyridine. 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 of these with water. A preferred solvent is chloroform. The reaction temperature is, for example, 0°C to 80°C, preferably 0°C to 60°C. In the production of the carboxylic acid halide, N,N-dimethylformamide may be added as an additive.

[0101] Manufacturing method C2 [ka] [In the formula, R 1 , R 2 and R 32 is as defined above, P N1 is a protecting group for the amino group. N1 is a 2,4-dimethoxybenzyl group.

[0102] (Process C2-1) The compound of formula

[23] can be produced from a compound of formula

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

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

[0103] (Process C2-2) The compound of formula [I-2] or a salt thereof is a compound of formula

[23] N1 The deprotection reaction can be carried out by removing P N1 The process may be carried out under suitable conditions depending on the type of material. For example, P N1When is a 2,4-dimethoxybenzyl group, the compound of formula [I-2] or a salt thereof can be produced by reacting it with an acid in a solvent in the presence of an additive. Examples of the acid include methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid, with trifluoroacetic acid being preferred. Examples of additives include anisole and triethylsilane, with anisole being preferred. Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, hydrocarbon solvents such as toluene, water, and mixtures thereof. Organic acids such as trifluoroacetic acid may also be used as the solvent. The reaction temperature is, for example, 0°C to 130°C, preferably 25°C to 80°C. In this step, when an acid is used, the compound represented by formula

[24] : [ka] [In the formula, R 1 and R 32 are as defined above] The compound of formula [I-2] or a salt thereof can be obtained by converting the hydroxyl group of the compound of formula

[24] or a salt thereof to C 1-6 Alkyl-O or Halo-C 1-6 It can be produced by converting it into an alkyl-O group. For example, R 1 is fluorine and R 2 is tert-butyl, and R 32 The compound of formula [I-2], in which is trifluoromethyl (i.e., the compound of formula [II]), or a salt thereof, can be produced by reacting the compound of formula

[24] or a salt thereof with di-tert-butyl dicarbonate in the presence of magnesium perchlorate. Examples of the solvent include halogenated hydrocarbon solvents such as chloroform, and ether solvents such as tetrahydrofuran, with chloroform being the preferred solvent. The reaction temperature is, for example, 0°C to 100°C, preferably room temperature to 70°C.

[0104] [General manufacturing method D] The compound of formula

[21] can be produced by the following method. Manufacturing method D1 [ka] [In the formula, R 1 , R 2 and R 32 is as defined above, L 1 is a leaving group. Preferred L 1 is chlorine, bromine, or iodine. P N2 are each independently an amine protecting group. Preferably, two P N2 together with their attached nitrogens to form 2,5-dimethylpyrrole.]

[0105] (Process D1-1) The compound of formula

[26] can be prepared by adding P to the amino group of the compound of formula

[25] or a salt thereof by a known method. N2 The introduction of a protecting group can be carried out by introducing P N2 For example, two P N2 When these are taken together with their attached nitrogen to form 2,5-dimethylpyrrole, the compound of formula

[26] can be prepared by reacting the compound of formula

[25] with 2,5-hexanedione in a solvent under acidic conditions. Examples of the acid used in the reaction include concentrated hydrochloric acid, concentrated sulfuric acid, amidosulfuric acid, p-toluenesulfonic acid, and acetic acid. A preferred acid is acetic acid. 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 may also be used as the solvent. The reaction temperature is, for example, from room temperature to 150°C, preferably from 80°C to 140°C.

[0106] (Process D1-2) The compound of formula

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

[26] by known methods. For example, R 32 When is trifluoromethyl, it can be produced by a method comprising: a step (a) of reacting a compound of formula

[26] with dibromodifluoromethane in a solvent in the presence of a base and a catalyst; and a step (b) of fluorinating the compound in a solvent in the presence of tetramethylammonium fluoride or silver tetrafluoroborate(I). Examples of the base used in step (a) include sodium hydride and potassium tert-butoxide, with sodium hydride being preferred. Examples of the catalyst used in step (a) include tetrabutylammonium bromide and zinc, with tetrabutylammonium bromide being the preferred catalyst. Examples of the solvent used in step (a) include ether solvents such as tetrahydrofuran and polar solvents such as N,N-dimethylformamide, etc. The preferred solvent is N,N-dimethylformamide. The reaction temperature in step (a) is, for example, 0°C to 40°C, preferably 0°C to room temperature. When tetramethylammonium fluoride is used, examples of the solvent used in step (b) include ether solvents such as 1,4-dioxane and polar solvents such as sulfolane. A preferred solvent is sulfolane. When silver(I) tetrafluoroborate is used, examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane. A preferred solvent is dichloromethane. The reaction temperature in step (b) is, for example, 80° C. to 180° C., preferably 100° C. to 140° C. when tetramethylammonium fluoride is used. When silver(I) tetrafluoroborate is used, the reaction temperature is, for example, −78° C. to 50° C., preferably −78° C. to room temperature.

[0107] (Process D1-3) The compound of formula

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

[27] with L in a solvent in the presence of a base. 1 For example, L 1 When is iodine, the compound of formula

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

[27] in a solvent in the presence of a base. Examples of the base used in the reaction include n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium tetramethylpiperidide. A preferred base is n-butyllithium. Examples of the iodinating agent include iodine, iodine monochloride, N-iodosuccinimide, and 1-chloro-2-iodoethane. The preferred iodinating agent is iodine. Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from -100°C to 40°C, preferably from -78°C to 20°C.

[0108] (Process D1-4) The compound of formula

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

[28] N2 The deprotection reaction can be carried out by removing P N2 For example, two P N2 When these groups are taken together with the nitrogen to which they are attached to form 2,5-dimethylpyrrole, a compound of formula

[29] or a salt thereof can be prepared by reacting a compound of formula

[28] with hydroxylamine in a solvent. 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. The reaction temperature is, for example, 40 to 150°C, preferably 80 to 130°C. Hydroxylamine hydrochloride may be used instead of hydroxylamine, and in that 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.

[0109] (Process 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 and a compound of formula

[30] to Suzuki coupling reaction. 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. Examples of palladium catalysts used in the reaction include 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 with tricyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. A preferred palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct. Examples of the base used in the reaction include tripotassium phosphate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, and triethylamine. Preferred bases are tripotassium phosphate, cesium carbonate, and sodium carbonate. 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 of these with water. Preferred solvents are 1,2-dimethoxyethane, toluene, dimethyl sulfoxide, and mixed solvents of these with water. The reaction temperature is, for example, 20°C to 150°C, preferably 80°C to 130°C.

[0110] The compound of formula

[30] can be prepared according to a known method. The reaction of step D1-5 may be carried out using a corresponding boronic acid ester instead of the compound of formula

[30] . For example, the boronic acid ester

[33] can be prepared by the following method. Manufacturing method D2 [ka] [In the formula, R 1 and R 2 is as defined above, R 6 is a fluorine or hydroxyl group. L 2 is a leaving group. Preferred L 2 is chlorine, bromine, iodine, p-toluenesulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy. B(OR 7 )2 is a boronic acid ester. 7 are, for example, each independently methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl; or OR 7 may combine with their attached boron to form a cyclic boronic ester. 7 ) 2 is a pinacol boronic acid ester.

[0111] (Process D2-1) The compound of formula

[32] can be prepared by reacting R 1 This reaction can be carried out according to known methods. R 1 When is fluorine, the compound of formula

[32] can be produced, 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. R 1 When is a hydroxyl group, the compound of formula

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

[0112] (Process D2-2) The compound of formula

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

[32] with a boron compound in a solvent in the presence of a palladium catalyst, an organophosphorus compound and a base. Examples of the palladium catalyst include palladium(II) acetate, palladium(II) chloride, and tris(dibenzylideneacetone)dipalladium(0). Examples of organic phosphorus compounds 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. Instead of the palladium catalyst and the organophosphorus compound, 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. Examples of the base include potassium acetate, sodium carbonate, cesium carbonate, and potassium carbonate, and the preferred base is potassium acetate. An example of the boron compound is bis(pinacolato)diboron. Examples of the solvent include ether solvents such as 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, etc.; hydrocarbon solvents such as toluene, etc.; and polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, etc. The preferred solvent is dimethyl sulfoxide. The reaction temperature is, for example, from room temperature to 150°C, preferably from 70°C to 110°C.

[0113] [General Method E] The compound of formula

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

[22] or a salt thereof can be produced by the following production method. Manufacturing method E1 [ka] [In the formula, P N1 is as defined above, P E1 and P E2 are each independently a protecting group for carboxy. E1 and P E2 are each independently methyl, ethyl, tert-butyl, or benzyl. R 8 are each independently methoxy or ethoxy. L 3 is a leaving group. Preferred L 3 is bromine or chlorine.]

[0114] (Process E1-1) The compound of formula

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

[34] with the compound of formula

[35] in a solvent in the presence of a base. 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. 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. The reaction temperature is, for example, from -78°C to 100°C, preferably from 0°C to 70°C.

[0115] (Process E1-2) The compound of formula

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

[36] with formaldehyde (preferably an aqueous formaldehyde solution) in a solvent in the presence of a base. 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. 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. The reaction temperature is, for example, from -78°C to 100°C, preferably from 0°C to 70°C.

[0116] (Process E1-3) The compound of formula

[39] can be produced by reacting compound

[37] with compound

[38] in a solvent. 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. The reaction temperature is, for example, 20°C to 150°C, preferably 80°C to 130°C.

[0117] (Process E1-4) Compound

[40] or a salt thereof is a compound

[39] P E1 The deprotection reaction can be carried out by removing P E1 Depending on the type of material, it can be carried out under appropriate conditions. For example, E1 When is ethyl, compound

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

[39] in a solvent in the presence of a base. Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium ethoxide. A preferred base is sodium ethoxide. Examples of the solvent include alcoholic solvents such as ethanol, etheric solvents such as tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of ethanol and water. The reaction temperature is, for example, 0°C to 100°C, preferably 0°C to 40°C.

[0118] (Process E1-5) The compound of formula

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

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

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

[22] or a salt thereof can be obtained by separating it as a diastereomeric salt with a basic optical resolution agent, and then decomposing this salt with an acid. An example of a basic optical resolution agent is (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. Examples of solvents used for derivatization into diastereomeric salts include alcoholic solvents such as 2-propanol, ethereal solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and mixed solvents of these with water. Preferred solvents are acetonitrile, 1,2-dimethoxyethane, or mixed solvents of these with water. The optical purity of this diastereomeric salt can be increased by recrystallization. Examples of solvents used for recrystallization include ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and mixtures of these with water. A preferred solvent is a mixture of acetonitrile and water. Examples of acids that can be used to resolve diastereomeric salts include hydrochloric acid, sulfuric acid, and potassium hydrogen sulfate, with hydrochloric acid being preferred. Examples of solvents that can be used for decomposing 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.

[0119] (Process E1-6) The compound of formula

[15] or a salt thereof is P of the compound of formula

[22] or a salt thereof. N1 The deprotection reaction can be carried out by removing P N1 The process can be carried out under suitable conditions depending on the type of P. N1 When is a 2,4-dimethoxybenzyl group, the compound of formula

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

[0120] The meanings of the abbreviations used in this specification are as follows: DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide THF: tetrahydrofuran CPME: Cyclopentyl methyl ether WSC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0121] The present invention will be explained below by way of examples of production, working examples, reference examples, test examples and formulation examples.

[0122] 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. Unless otherwise specified, measurements were performed using a 400 MHz NMR instrument. 1 The symbols in the H-NMR spectrum have the following meanings: s: singlet d: doublet t: triplet q:quartet dd: double doublet ddd: double double doublet brs: broad singlet m: multiplet J: Coupling constant

[0123] [Production Example 1] Production of 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0124] (Step 1) Preparation of 1-bromo-3-(tert-butoxy)-5-fluorobenzene [ka] Under an argon atmosphere, 3-bromo-5-fluorophenol (500 mg) was added to di-tert-butyl dicarbonate (1.14 g) and magnesium perchlorate (58 mg) sequentially at room temperature. The reaction mixture was stirred at 50°C for 1 hour and 20 minutes. Di-tert-butyl dicarbonate was added to the reaction mixture at 50°C. The reaction mixture was stirred at 50°C for 1 hour, then at 65°C for 1 hour, and then 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 and ethyl acetate (1 / 1) was added. The reaction mixture was washed sequentially with 3N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 0 to 20 / 1) to give the title compound (437 mg) in 68% yield. 1 H-NMR (CDCl3) δ: 1.35 (s, 9H), 6.62-6.66 (m, 1H), 6.92-6.98 (m, 2H).

[0125] (Step 2) Preparation of 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 1-bromo-3-(tert-butoxy)-5-fluorobenzene (437 mg) obtained in Step 1 in DMSO (5 mL) was added potassium acetate (434 mg), bis(pinacolato)diboron (898 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (144 mg) sequentially under an argon atmosphere at room temperature. The reaction mixture was stirred at 90°C for 2.5 hours. The reaction mixture was cooled to room temperature. To this reaction mixture was added a n-hexane / ethyl acetate (1 / 1) mixture and water sequentially. The reaction mixture was stirred at room temperature for 50 minutes and then allowed to stand overnight. To this reaction mixture was added a n-hexane / ethyl acetate (1 / 1) mixture, water, silica gel, and Celite sequentially. After stirring, the reaction mixture was filtered to remove insoluble material, which was then washed with a n-hexane / ethyl acetate (1 / 1) mixture. The filtrate was extracted with a 1 / 1 mixture of n-hexane and ethyl acetate. The organic layer was washed twice with water and then with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin-layer chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to give the title compound (443 mg) in an 85% yield. 1 H-NMR (CDCl3) δ: 1.33 (s, 12H), 1.36 (s, 9H), 6.77-6.82 (m, 1H), 7.18-7.23 (m, 2H).

[0126] [Production Example 2] Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka]

[0127] (Step 1) Preparation of 2-methyl-3-methylenesuccinic acid diethyl ester [ka] Under a nitrogen atmosphere, potassium tert-butoxide (180 g) was added to THF (2.55 L) at room temperature. Triethyl phosphonoacetate (314 g) was added dropwise to this mixture over 13 minutes under ice-cooling. The dropping funnel used was washed with THF (511 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred under ice-cooling for 2 hours and 9 minutes. Ethyl 2-bromopropionate (247 g) was added dropwise to this reaction mixture over 20 minutes under ice-cooling. The dropping funnel used was washed with THF (79 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 22 hours and 45 minutes. Potassium carbonate (188 g) was added to this reaction mixture over 1 minute under ice-cooling. 37 wt % aqueous formaldehyde solution (152 mL) was added dropwise to this reaction mixture over 10 minutes under ice-cooling. The reaction mixture was stirred at room temperature for 19 hours and 44 minutes. Water (1.57 L) was added to this reaction mixture over 1 minute at room temperature. 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 resulting 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 removed by filtration. A similar reaction was separately performed using triethyl phosphonoacetate (300 g). The filtrate obtained was combined with the filtrate obtained above to give a toluene solution (approximately 921 mL) of the title compound (equivalent to 2.66 mol). The obtained toluene solution of the title compound was used in the next step as a 100% yield. The production of the title compound was confirmed by HPLC analysis. The HPLC measurement equipment and conditions are as follows: Measurement equipment: HPLC system Shimadzu Corporation High-Performance Liquid Chromatograph Prominence Measurement conditions: Column: Kinetex C18: 2.6 μm, 50 mm x 2.1 mm (Phenomenex) Column temperature: 40℃ Flow rate: 0.4mL / min. Analysis time: 10min. Detection wavelength: UV (220 nm) Mobile phase: (Liquid A) water, (Liquid B) acetonitrile Mobile phase delivery: The mixture ratio of solution A and solution B (solution A / solution B (volume %)) was maintained at 80 / 20 from 0 to 0.01 minutes after injection, then changed linearly from 80 / 20 to 10 / 90 from 0.01 to 7 minutes, maintained at 10 / 90 from 7 to 8 minutes, then changed linearly from 10 / 90 to 80 / 20 from 8 to 9 minutes, and maintained at 80 / 20 from 9 to 10 minutes. The retention time of the title compound under the above HPLC measurement conditions was about 3.7 minutes.

[0128] (Step 2) Preparation 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 [ka] To a toluene solution (approximately 921 mL) of 2-methyl-3-methylenesuccinic acid diethyl ester (equivalent to 2.66 mol) obtained in Step 1, 2,4-dimethoxybenzylamine (468 g) was added dropwise over 2 minutes at room temperature 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 to an internal temperature of approximately 15°C. 2N hydrochloric acid (1.33 L) was added dropwise to the reaction mixture and stirred. The reaction mixture was separated into layers. The aqueous layer was extracted with toluene (150 mL). The resulting organic layers were combined, washed with a mixture of saturated brine and water (600 mL, saturated brine / water = 1 / 1), dried over sodium sulfate (120 g), concentrated, and dried under reduced pressure at room temperature overnight to obtain the crude title compound (790 g; cis / trans = approximately 1 / 1, containing 5.5 wt% toluene). The production of the title compound was confirmed by HPLC analysis. The HPLC measurement equipment and conditions are as follows: Measurement equipment: HPLC system Shimadzu Corporation High-Performance Liquid Chromatograph Prominence Measurement conditions: Column: Atlantis T3: 5 μm, 150 mm x 4.6 mm (Waters) Column temperature: 40℃ Flow rate: 1.15mL / min. Analysis time: 18min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH = 2.6), (Solution B) acetonitrile Mobile phase delivery: The mixture ratio of solution A and solution B (solution A / solution B (vol %)) was maintained at 60 / 40 from 0 to 0.5 minutes after injection, then changed linearly from 60 / 40 to 10 / 90 from 0.5 to 8 minutes, maintained at 10 / 90 from 8 to 12.5 minutes, then changed linearly from 10 / 90 to 60 / 40 from 12.5 to 13.5 minutes, and maintained at 60 / 40 from 13.5 to 18 minutes. Under the above HPLC measurement conditions, the retention time of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester was approximately 6.6 minutes, and the retention time of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester was approximately 6.9 minutes.

[0129] (Step 3) Preparation of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] To the crude 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 (790 g, containing 5.5 wt % toluene) obtained in Step 2, ethanol (1.15 L) was added at room temperature under a nitrogen stream. Sodium ethoxide (20 wt % ethanol solution, 1.15 L) was added dropwise to the reaction mixture over 31 minutes at room temperature. 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 mixture was separated (organic layer 1). CPME (1.8 L) was added to the aqueous layer, and the mixture was separated (organic layer 2). 1.8 L of the 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 this mixture under ice-cooling, and the mixture was stirred for approximately 10 minutes. Water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% aqueous sodium hydrogen sulfate solution (300 mL), and ethanol (300 mL) were sequentially added to the mixture under ice-cooling. The mixture was stirred overnight at room temperature. Ethyl acetate (600 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (600 mL). The resulting organic layers (excluding organic layer 1 and organic layer 2) were combined and washed with a mixture 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 mixture was filtered through Celite, and insoluble matter was removed by filtration. The insoluble matter was washed with ethyl acetate (3 L). The resulting filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to give the title compound as a crude product (561 g). Separately, the organic layers 1 and 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 mixture under ice cooling. Ethyl acetate (300 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The resulting organic layers of ethyl acetate were combined and washed with a mixture 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 the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and insoluble matter was removed by filtration. The insoluble matter was washed with ethyl acetate (750 mL). The resulting filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain the crude product of the title compound (87.3 g). To a mixture of this crude product and the crude product of the title compound obtained above, CPME (3 L) was added under a nitrogen stream. The mixture was stirred at 120°C. The mixture was stirred for 17 hours and 34 minutes and then gradually cooled to room temperature. The mixture was ice-cooled and stirred at an internal temperature of approximately 1°C for 3 hours. The precipitate was collected by filtration and washed with chilled CPME (900 mL). The precipitate was dried under reduced pressure at 50°C overnight to give the title compound (585 g) in a 75% yield over the three steps. The formation of the title compound was confirmed by HPLC analysis and NMR. The HPLC measurement equipment and conditions were the same as in Step 2. The retention time of the title compound under these HPLC measurement conditions was about 3.1 minutes. 1 H-NMR (CDCl3) δ: 1.33 (d, 3H, J = 6.5 Hz), 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).

[0130] (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 [ka] 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 mixture was stirred at 85°C. To this mixture, (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (254 g) was added over 14 minutes at 85°C. The reaction mixture was stirred at 90°C for 2 hours and 48 minutes. The reaction mixture was stirred overnight and then cooled to room temperature. The precipitate was collected by filtration and washed with acetonitrile (2.4 L). The precipitate was dried for 8.5 hours at room temperature and atmospheric pressure to obtain crude crystals of the title compound (516 g). To the crude crystals, acetonitrile (2.5 L) and water (0.5 L) were added at room temperature under a nitrogen stream. This mixture was stirred at 100°C for 1 hour and 14 minutes. Acetonitrile (1.5 L) was added dropwise to this mixture at 100°C over 1 hour and 7 minutes. This mixture was stirred at 100°C for 10 minutes. This mixture was stirred for 21 hours and 10 minutes and then cooled to room temperature. This mixture was stirred under ice cooling for 3 hours and 54 minutes. The precipitate was collected by filtration and washed with acetonitrile (1.5 L). This precipitate was dried for 4 hours at room temperature and atmospheric pressure to obtain the title compound (448 g, 99.8% de) in 45% yield. The production of the title compound was confirmed by HPLC analysis. The HPLC measurement equipment and conditions are shown below. Measurement equipment: HPLC system Shimadzu Corporation High-Performance Liquid Chromatograph Prominence Measurement conditions: Column: CHIRAL PAK AD-3R: 3 μm, 150 mm x 4.6 mm (Daicel) Column temperature: 40℃ Flow rate: 0.50mL / min. Analysis time: 10min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH = 2.6), (Solution B) acetonitrile Mobile phase delivery: The mixture ratio of solution A and solution B (solution A / solution B (vol %)) was maintained at 60 / 40. Under the above HPLC measurement conditions, the retention time of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid was approximately 5.6 minutes, and the retention time of (3S,4S)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid was approximately 6.5 minutes. The stereostructure of the title compound was determined by X-ray crystallography of the single crystal obtained by recrystallization from methyl isobutyl ketone. The diastereomeric excess was determined by the HPLC area percentage of the measurement results ((3R,4R) isomer / (3S,4S) isomer=99.886% / 0.114%).

[0131] (Step 5) Preparation of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] Ethyl acetate (1.8 L) and water (1.34 L) were added 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 at room temperature. 6N hydrochloric acid (168 mL) was added dropwise to this mixture over 16 minutes at room temperature. The mixture was separated into layers. The aqueous layer was extracted three times with ethyl acetate (450 mL). The combined organic layers were washed sequentially with 2N hydrochloric acid (224 mL) and saturated brine (224 mL), 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 give the title compound (254 g) in 98% yield. 1H-NMR (DMSO-D6) δ: 1.15 (d, 3H, J = 7.2 Hz), 2.50-2.58 (m, 1H), 2.73-2.83 (m, 1H), 3.18-3.25 (m, 1H), 3.30-3.38 (m, 1H), 3.75 (s, 3H), 3.77 (s, 3H), 4.19-4.35 (m, 2H), 6.48 (dd, 1H, J = 8.4, 2.3 Hz), 6.56 (d, 1H, J = 2.3 Hz), 7.00 (d, 1H, J = 8.4 Hz), 12.61 (br s, 1H).

[0132] [Production Example 3] Production of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka]

[0133] (Step 1) Preparation of 2-methyl-3-methylenesuccinic acid diethyl ester [ka] Under a nitrogen stream, potassium tert-butoxide (180 g) was added to THF (2.55 L) at room temperature. Triethyl phosphonoacetate (314 g) was added dropwise to this mixture over 13 minutes under ice-cooling. The dropping funnel used was washed with THF (511 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred under ice-cooling for 2 hours and 9 minutes. Ethyl 2-bromopropionate (247 g) was added dropwise to this reaction mixture over 20 minutes under ice-cooling. The dropping funnel used was washed with THF (79 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 22 hours and 45 minutes. Potassium carbonate (188 g) was added to this reaction mixture over 1 minute under ice-cooling. 37 wt % aqueous formaldehyde solution (152 mL) was added dropwise to this reaction mixture over 10 minutes under ice-cooling. The reaction mixture was stirred at room temperature for 19 hours and 44 minutes. Water (1.57 L) was added to this reaction mixture over 1 minute at room temperature. 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 resulting 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 removed by filtration. A similar reaction was separately performed using triethyl phosphonoacetate (300 g). The filtrate obtained was combined with the filtrate obtained above to give a toluene solution (approximately 921 mL) of the title compound (equivalent to 2.66 mol). The obtained toluene solution of the title compound was used in the next step as a 100% yield. The production of the title compound was confirmed by HPLC analysis. The HPLC measurement equipment and conditions are shown below. Measurement equipment: HPLC system Shimadzu Corporation High-Performance Liquid Chromatograph Prominence Measurement conditions: Column: Kinetex C18: 2.6 μm, 50 mm x 2.1 mm (Phenomenex) Column temperature: 40℃ Flow rate: 0.4mL / min. Analysis time: 10min. Detection wavelength: UV (220 nm) Mobile phase: (Liquid A) water, (Liquid B) acetonitrile Mobile phase delivery: The mixture ratio of solution A and solution B (solution A / solution B (volume %)) was maintained at 80 / 20 from 0 to 0.01 minutes after injection, then changed linearly from 80 / 20 to 10 / 90 from 0.01 to 7 minutes, maintained at 10 / 90 from 7 to 8 minutes, then changed linearly from 10 / 90 to 80 / 20 from 8 to 9 minutes, and maintained at 80 / 20 from 9 to 10 minutes. The retention time of the title compound under the above HPLC measurement conditions was about 3.7 minutes.

[0134] (Step 2) Preparation 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 [ka] To a toluene solution (approximately 921 mL) of 2-methyl-3-methylenesuccinic acid diethyl ester (equivalent to 2.66 mol) obtained in Step 1, 2,4-dimethoxybenzylamine (468 g) was added dropwise over 2 minutes at room temperature 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 to an internal temperature of approximately 15°C. 2N hydrochloric acid (1.33 L) was added dropwise to the reaction mixture and stirred. The reaction mixture was separated into layers. The aqueous layer was extracted with toluene (150 mL). The resulting organic layers were combined, washed with a mixture of saturated brine and water (600 mL, saturated brine / water = 1 / 1), dried over sodium sulfate (120 g), concentrated, and dried under reduced pressure at room temperature overnight to obtain the crude title compound (790 g; cis / trans = approximately 1 / 1, containing 5.5 wt% toluene). The production of the title compound was confirmed by HPLC analysis. The HPLC measurement equipment and conditions are shown below. Measurement equipment: HPLC system Shimadzu Corporation High-Performance Liquid Chromatograph Prominence Measurement conditions: Column: Atlantis T3: 5 μm, 150 mm x 4.6 mm (Waters) Column temperature: 40℃ Flow rate: 1.15mL / min. Analysis time: 18min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH = 2.6), (Solution B) acetonitrile Mobile phase delivery: The mixture ratio of solution A and solution B (solution A / solution B (vol %)) was maintained at 60 / 40 from 0 to 0.5 minutes after injection, then changed linearly from 60 / 40 to 10 / 90 from 0.5 to 8 minutes, maintained at 10 / 90 from 8 to 12.5 minutes, then changed linearly from 10 / 90 to 60 / 40 from 12.5 to 13.5 minutes, and maintained at 60 / 40 from 13.5 to 18 minutes. Under the above HPLC measurement conditions, the retention time of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester was approximately 6.6 minutes, and the retention time of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester was approximately 6.9 minutes.

[0135] (Step 3) Preparation of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] To the crude 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 (790 g, containing 5.5 wt % toluene) obtained in Step 2, ethanol (1.15 L) was added at room temperature under a nitrogen stream. Sodium ethoxide (20 wt % ethanol solution, 1.15 L) was added dropwise to the reaction mixture over 31 minutes at room temperature. 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 mixture was separated (organic layer 1). CPME (1.8 L) was added to the aqueous layer, and the mixture was separated (organic layer 2). 1.8 L of the 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 this mixture under ice-cooling, and the mixture was stirred for approximately 10 minutes. Water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% aqueous sodium hydrogen sulfate solution (300 mL), and ethanol (300 mL) were sequentially added to the mixture under ice-cooling. The mixture was stirred overnight at room temperature. Ethyl acetate (600 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (600 mL). The resulting organic layers (excluding organic layer 1 and organic layer 2) were combined and washed with a mixture 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 mixture was filtered through Celite, and insoluble matter was removed by filtration. The insoluble matter was washed with ethyl acetate (3 L). The resulting filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to give the title compound as a crude product (561 g). Separately, the organic layers 1 and 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 mixture under ice cooling. Ethyl acetate (300 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The resulting organic layers of ethyl acetate were combined and washed with a mixture 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 the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and insoluble matter was removed by filtration. The insoluble matter was washed with ethyl acetate (750 mL). The resulting filtrates were combined, concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain the crude product of the title compound (87.3 g). To a mixture of this crude product and the crude product of the title compound obtained above, CPME (3 L) was added under a nitrogen stream. The mixture was stirred at 120°C. The mixture was stirred for 17 hours and 34 minutes and then gradually cooled to room temperature. The mixture was ice-cooled and stirred at an internal temperature of approximately 1°C for 3 hours. The precipitate was collected by filtration and washed with chilled CPME (900 mL). The precipitate was dried under reduced pressure at 50°C overnight to give the title compound (585 g) in a 75% yield over the three steps. The formation of the title compound was confirmed by HPLC analysis and NMR. The HPLC measurement equipment and conditions were the same as in Step 2. The retention time of the title compound under these HPLC measurement conditions was about 3.1 minutes. 1 H-NMR (CDCl3) δ: 1.33 (d, 3H, J = 6.5 Hz), 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).

[0136] (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 [ka] 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 mixture was stirred at 85°C. To this mixture, (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (254 g) was added over 14 minutes at 85°C. The reaction mixture was stirred at 90°C for 2 hours and 48 minutes. The reaction mixture was stirred overnight and then cooled to room temperature. The precipitate was collected by filtration and washed with acetonitrile (2.4 L). The precipitate was dried for 8.5 hours at room temperature and atmospheric pressure to obtain crude crystals of the title compound (516 g). To the crude crystals, acetonitrile (2.5 L) and water (0.5 L) were added at room temperature under a nitrogen stream. This mixture was stirred at 100°C for 1 hour and 14 minutes. Acetonitrile (1.5 L) was added dropwise to this mixture at 100°C over 1 hour and 7 minutes. This mixture was stirred at 100°C for 10 minutes. This mixture was stirred for 21 hours and 10 minutes and then cooled to room temperature. This mixture was stirred under ice cooling for 3 hours and 54 minutes. The precipitate was collected by filtration and washed with acetonitrile (1.5 L). This precipitate was dried for 4 hours at room temperature and atmospheric pressure to obtain the title compound (448 g, 99.8% de) in 45% yield. The production of the title compound was confirmed by HPLC analysis. The HPLC measurement equipment and conditions are as follows: Measurement equipment: HPLC system Shimadzu Corporation High-Performance Liquid Chromatograph Prominence Measurement conditions: Column: CHIRAL PAK AD-3R: 3 μm, 150 mm x 4.6 mm (Daicel) Column temperature: 40℃ Flow rate: 0.50mL / min. Analysis time: 10min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH = 2.6), (Solution B) acetonitrile Mobile phase delivery: The mixture ratio of solution A and solution B (solution A / solution B (vol %)) was maintained at 60 / 40. Under the above HPLC measurement conditions, the retention time of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid was approximately 5.6 minutes, and the retention time of (3S,4S)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid was approximately 6.5 minutes. The stereostructure of the title compound was determined by X-ray crystallography of the single crystal obtained by recrystallization from methyl isobutyl ketone. The diastereomeric excess was determined by the HPLC area percentage of the measurement results ((3R,4R) isomer / (3S,4S) isomer=99.886% / 0.114%).

[0137] (Step 5) Preparation of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] Ethyl acetate (1.8 L) and water (1.34 L) were added 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 at room temperature. 6N hydrochloric acid (168 mL) was added dropwise to this mixture over 16 minutes at room temperature. The mixture was separated into layers. The aqueous layer was extracted three times with ethyl acetate (450 mL). The combined organic layers were washed sequentially with 2N hydrochloric acid (224 mL) and saturated brine (224 mL), 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 give the title compound (254 g) in 98% yield. 1H-NMR (DMSO-D6) δ: 1.15 (d, 3H, J = 7.2 Hz), 2.50-2.58 (m, 1H), 2.73-2.83 (m, 1H), 3.18-3.25 (m, 1H), 3.30-3.38 (m, 1H), 3.75 (s, 3H), 3.77 (s, 3H), 4.19-4.35 (m, 2H), 6.48 (dd, 1H, J = 8.4, 2.3 Hz), 6.56 (d, 1H, J = 2.3 Hz), 7.00 (d, 1H, J = 8.4 Hz), 12.61 (br s, 1H).

[0138] (Step 6) Preparation of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] 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 same compound (33 g) obtained in the same manner as in 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 the mixture was concentrated. The residue was allowed to stand overnight at room temperature. Toluene (287 mL) was added to the residue, and the mixture was 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 mixture was collected by filtration and washed with diisopropyl ether (431 mL). This solid was dried at room temperature and atmospheric pressure to obtain the title compound (137 g) in a yield of 98%. 1H-NMR (DMSO-D6) δ: 1.10 (d, 3H, J = 7.2 Hz), 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).

[0139] [Production Example 4] Production of 3-hydrazine-5-(trifluoromethyl)pyridine [ka]

[0140] (Step 1) Preparation of 3-fluoro-5-hydrazinylpyridine [ka] To a solution of 5-fluoropyridin-3-amine (1.5 g) in 6N hydrochloric acid (15 mL) was added dropwise a solution of sodium nitrite (0.923 g) in water (7.5 mL) over 2 minutes at 0°C. The reaction mixture was stirred at 0°C for 1 hour and 7 minutes. To this reaction mixture, a suspension of tin(II) chloride (6.34 g) in 6N hydrochloric acid (15 mL) was added dropwise over 3 minutes at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 23 hours. To this reaction mixture, 8N aqueous sodium hydroxide solution (approximately 34 mL) was added dropwise at 0°C. The mixture was stirred at 0°C. The mixture was extracted eight times with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. To the resulting residue was added a mixture of methyl tert-butyl ether (6 mL) and n-hexane (36 mL) at room temperature. The suspension was stirred at room temperature. The solid was collected by filtration from the suspension and washed with n-hexane. This solid was dried under reduced pressure at 60°C to give the title compound (965.8 mg) in a yield of 57%. 1H-NMR (CDCl3) δ: 3.64 (br s, 2H), 5.41 (br s, 1H), 6.99 (dt, 1H, J = 10.8, 2.5 Hz), 7.89 (d, 1H, J = 2.5 Hz), 7.97-7.99 (m, 1H).

[0141] [Production Example 5] Production of 3-hydrazine-5-(trifluoromethyl)pyridine [ka]

[0142] (Step 1) Preparation of 3-hydrazine-5-(trifluoromethyl)pyridine [ka] To a solution of 5-(trifluoromethyl)pyridin-3-amine (3 g) in 6N hydrochloric acid (30 mL) was added dropwise a solution of sodium nitrite (1.277 g) in water (15 mL) over 2 minutes at 0°C. The reaction mixture was stirred at 0°C for 1 hour. To this reaction mixture was added a suspension of tin(II) chloride (8.77 g) in 6N hydrochloric acid (30 mL) over 3 minutes at 0°C. The reaction mixture was stirred at 0°C for 28 minutes and then at room temperature for 20 hours and 9 minutes. To this reaction mixture was added dropwise 8N aqueous sodium hydroxide solution (approximately 68 mL) at 0°C. The mixture was stirred at 0°C. The mixture was extracted three times with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. To the resulting residue was added seed crystals of the title compound, which had been synthesized separately in the same manner as in this step. To this mixture was added a mixture of diisopropyl ether (2 mL) and n-hexane (30 mL) at room temperature. The suspension was stirred at room temperature. The solid was collected by filtration and washed with n-hexane. The solid was dried under reduced pressure at room temperature to obtain the title compound (2.8464 g) in 87% yield. 1H-NMR (CDCl3) δ: 3.69 (br s, 2H), 5.49 (br s, 1H), 7.43-7.45 (m, 1H), 8.28-8.30 (m, 1H), 8.34 (d, 1H, J = 2.8 Hz).

[0143] The seed crystals of the title compound used in step 1 were obtained by purifying the residue obtained by the same reaction as in this step by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1).

[0144] [Production Example 6] Production of 5-hydrazineyl-2-(trifluoromethyl)pyrimidine [ka]

[0145] (Step 1) Preparation of 5-hydrazineyl-2-(trifluoromethyl)pyrimidine [ka] 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 shield, the reaction mixture was stirred at 95°C for 22 hours. The reaction mixture was cooled to room temperature. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted five times with ethyl acetate. The resulting 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 collected by filtration and washed with a mixture of n-hexane / ethyl acetate (3 / 1). The solid was dried under reduced pressure at room temperature to give the title compound (647 mg) in 41% yield. 1 H-NMR (DMSO-D6) δ: 4.43 (br s, 2H), 7.94 (br s, 1H), 8.33 (s, 2H).

[0146] 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 [ka]

[0147] (Step 1) Preparation of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole [ka] Acetic acid (1 L) was added to 1H-pyrazol-3-amine (100 g) at room temperature and stirred for 5 minutes. 2,5-hexanedione (148 mL) was added to this mixture at room temperature and stirred for 5 minutes. This reaction mixture was stirred at 120°C for 2.5 hours and cooled to room temperature. Water (1 L) was added to this reaction mixture at room temperature. This reaction mixture was stirred at room temperature for 50 minutes. The precipitated solid was collected by filtration and washed with water (1 L). The obtained wet solid was dried at room temperature under normal pressure overnight and then dried under reduced pressure at 65°C for 3 days and 8.5 hours to obtain the title compound (172.47 g) in 89% yield. 1 H-NMR (CDCl3) δ: 2.11 (s, 6H), 5.90 (s, 2H), 6.25 (d, 1H, J = 2.4 Hz), 7.51 (d, 1H, J = 2.4 Hz).

[0148] (Step 2) Preparation 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 [ka] Under an argon atmosphere, DMF (100 mL) was added to sodium hydride (14.9 g) with ice-cooling. A suspension of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (40 g) obtained in Step 1 in DMF (150 mL) was added dropwise to this mixture over 20 minutes with ice-cooling. The dropping funnel used was washed with DMF (50 mL), and the washings were added to the reaction mixture. This reaction mixture was stirred with water for 1.5 hours. Tetrabutylammonium bromide (0.80 g) was added to this reaction mixture with ice-cooling. This reaction mixture was stirred with ice-cooling for 15 minutes. A solution of dibromodifluoromethane (45 mL) in DMF (50 mL) was added dropwise to this reaction mixture with ice-cooling over 15 minutes. This reaction mixture was stirred with water for 2 hours and 10 minutes. To this reaction mixture, dibromodifluoromethane (20 mL) was added dropwise under water cooling under an argon atmosphere. This reaction mixture was stirred under water cooling for 40 minutes and then allowed to stand overnight. To this reaction mixture, saturated aqueous ammonium chloride solution (200 mL) was added under ice cooling. Ethyl acetate and water were added to this reaction mixture. This reaction mixture was filtered through Celite and separated into layers. The aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined, and saturated brine was added thereto. This mixture was filtered through Celite and separated into layers. The aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined, dried over sodium sulfate, and concentrated. Toluene (250 mL) was added to this residue, and the mixture was concentrated. This process was repeated. Ethyl acetate (approximately 150 mL) was added to this residue, and insoluble matter was removed by filtration. This insoluble matter was washed with ethyl acetate. The obtained filtrates were combined and concentrated. The residue was dried under reduced pressure at room temperature for 10 minutes with stirring. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30 / 1 to 20 / 1) to obtain the title compound (40.6 g, containing 3.7 wt% hexane, 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole:1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole = approximately 3:1) in 54% yield. 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).

[0149] (Step 3) Preparation 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 [ka] To a solution of a mixture of 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (40.6 g, containing 3.7 wt% hexane) obtained in Step 2 in sulfolane (400 mL), tetramethylammonium fluoride (13.0 g) was added at room temperature under an argon stream. The reaction mixture was stirred at 100°C for 1 hour. Additional tetramethylammonium fluoride (9.4 g) was added to the reaction mixture at 100°C. The reaction mixture was stirred at 100°C for 1 hour and 15 minutes. Additional tetramethylammonium fluoride (10 g) was added to the reaction mixture 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 then cooled to room temperature. Water (400 mL) and saturated aqueous sodium bicarbonate solution (200 mL) were added slowly to the reaction mixture under ice cooling. A mixture of n-hexane and ethyl acetate (2 / 3) (400 mL) was added to the reaction mixture. The reaction mixture was filtered through Celite and separated into layers. The organic layer was washed with saturated brine. The resulting aqueous layers were combined and extracted with a mixture of n-hexane and ethyl acetate (2 / 3) (300 mL). The organic layer was washed with saturated brine. The resulting organic layers were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30 / 1 to 25 / 1) to obtain the title compound (21.85 g, containing 24.4 wt% n-hexane, 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole:5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole = approximately 6:1) in 51% yield. 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, 0.86H, J = 2.8 Hz), 6.42 (d, 0.14H, J = 1.6 Hz), 7.83 (d, 0.14H, J = 1.6 Hz), 7.87 (d, 0.86H, J = 2.8 Hz).

[0150] (Step 4) Preparation of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-(trifluoromethyl)-1H-pyrazole [ka] To a solution of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole (21.85 g, containing 24.4 wt% n-hexane) obtained in Step 3 in THF (180 mL), a solution of n-butyllithium in n-hexane (1.55 M, 51.1 mL) was added dropwise over 5 minutes at −70° C. under an argon atmosphere. The reaction mixture was stirred at −70° C. for 25 minutes. To the reaction mixture was added dropwise a solution of iodine (18.3 g) in THF (50 mL) over 5 minutes at −70° C. 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. To this reaction mixture, additional iodine (0.90 g) was added 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 sequentially at -70°C. The reaction mixture was stirred at room temperature and separated into layers. The organic layer was washed sequentially with 10 wt% aqueous sodium hydrogen sulfite solution (250 mL) and saturated brine (150 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 1 to 30 / 1). Fractions containing the title compound were collected and concentrated. n-Hexane was added to the residue. The residue was concentrated until the weight of the residue reached 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 collected by filtration, washed with n-hexane (30 mL), and dried under reduced pressure to give the title compound (17.14 g) in a 67% yield. The filtrate was concentrated, and the residue was crystallized from n-hexane to give the title compound (1.63 g) in a 6.4% yield. 1 H-NMR (CDCl3) δ: 2.15 (s, 6H), 5.88 (s, 2H), 6.60 (s, 1H).

[0151] (Step 5) Preparation of 5-iodo-1-(trifluoromethyl)-1H-pyrazol-3-amine [ka] To the 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-(trifluoromethyl)-1H-pyrazole (18.77 g) obtained in Step 4, a mixture of ethanol and water (ethanol / water = 2 / 1, 480 mL), hydroxylamine hydrochloride (73.5 g), and triethylamine (14.7 mL) were added sequentially 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 the ethanol was distilled off. To the reaction mixture was slowly added a solution of sodium hydroxide (42.3 g) in water (130 mL) under ice cooling, followed by the addition of ethyl acetate (200 mL). The reaction mixture was stirred and then separated. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were 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 insoluble matter was removed by filtration. The filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1 to 3 / 1) to give the title compound (16.27 g, containing 14 wt% ethyl acetate) in a 96% yield. 1 H-NMR (CDCl3) δ: 3.93 (br s, 2H), 6.09 (s, 1H).

[0152] (Step 6) Preparation of 5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-amine [ka] To a solution of 5-iodo-1-(trifluoromethyl)-1H-pyrazol-3-amine (80 mg, containing 14% by weight of ethyl acetate) obtained in Step 5 in toluene (3 mL) was added 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127 mg) obtained in Step 2 of Production Example 1, palladium(II) acetate (6.5 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (20 mg) in that order under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 4 minutes. To the reaction mixture was added 2 M aqueous potassium phosphate solution (1.5 mL) 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 saturated aqueous sodium bicarbonate 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 successively with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated. This residue was combined with a portion (15 mg) of the title compound obtained separately in the same manner as in this step using 5-iodo-1-(trifluoromethyl)-1H-pyrazol-3-amine (70 mg, containing 14% by weight of ethyl acetate) obtained in Step 5. The resulting mixture was purified by silica gel thin-layer chromatography (developing solvent: n-hexane / ethyl acetate = 3 / 1) to give the title compound (108 mg). 1 H-NMR (CDCl3) δ: 1.36 (s, 9H), 3.93 (br s, 2H), 5.83 (s, 1H), 6.75-6.85 (m, 3H).

[0153] (Step 7) Preparation of (3R,4R)—N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxamide [ka] Under an argon atmosphere, DMF (1 μL) and oxalyl chloride (33 μL) were sequentially added to a chloroform (0.55 mL) solution of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (55 mg) obtained in the same manner as in Step 5 of Production Example 2 under ice-cooling. The reaction mixture was stirred under ice-cooling for 50 minutes. The reaction mixture was concentrated and dried under reduced pressure. Under an argon atmosphere, chloroform (0.4 mL) and 5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-amine (40 mg) obtained in Step 6 were sequentially added to the residue under ice-cooling. Pyridine (50 μL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 minutes and at room temperature for 35 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at room temperature, and the mixture was 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 (eluent: n-hexane / ethyl acetate = 1 / 1) to give the title compound (60 mg) in 80% yield. The production of the title compound was confirmed by thin layer chromatography (eluent: n-hexane / ethyl acetate = 2 / 1, Rf value: 0.19).

[0154] (Step 8) Preparation of (3R,4R)—N-(5-(3-fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [ka] To the (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 solution of sodium bicarbonate was added to the residue, and the mixture was 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 (developing solvent: chloroform / ethyl acetate=1 / 1) to give the title compound (29.9 mg) in a 76% yield. 1 H-NMR (DMSO-d6) δ: 1.06 (d, 3H, J = 7.2 Hz), 2.50-2.53 (m, 1H), 2.96-3.04 (m, 1H), 3.17-3.23 (m, 1H), 3.40-3.46 (m, 1H), 6.67-6.81 (m, 3H), 6.96 (s, 1H), 7.67 (s, 1H), 10.34 (s, 1H), 11.26 (s, 1H).

[0155] (Step 9) Preparation of (3R,4R)—N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [ka] To (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 sequentially at room temperature. The reaction mixture was stirred at 55° C. for 0.5 hours. To this reaction mixture, magnesium perchlorate was added at 55° C. The reaction mixture was stirred at 55° C. for 1 hour and 10 minutes. To this reaction mixture, further magnesium perchlorate was added 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 sequentially with 1N hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol=15 / 1) to give the title compound (19.2 mg) in a yield of 56%.

[0156] (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 to this mixed solution at 65°C over 2 minutes. This mixed solution was stirred at 65°C for 10 minutes. This mixed solution was stirred over 2 hours until the temperature reached 25°C. This mixed solution was further stirred at room temperature for 2 hours. The solid precipitated from this mixed solution was collected by filtration. The obtained solid was washed with ethanol / water (=1 / 1) and dried under reduced pressure at 60°C to obtain crystals of the title compound (87.8 mg) in 88% yield.

[0157] [Example 2] Synthesis of (3R,4R)-N-(5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [ka]

[0158] (Step 1) Preparation of 1-bromo-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene [ka] To a solution of 1-bromo-3,5-difluorobenzene (5.97 mL) in 1,3-dimethyl-2-imidazolidinone (10 mL) was added sodium hydride (4.14 g) at room temperature under a nitrogen stream. 1,1,1-trifluoro-2-methylpropan-2-ol (8 mL) was added dropwise to this mixture under water cooling. 1,3-Dimethyl-2-imidazolidinone (2 mL) was added dropwise to this reaction mixture at room temperature. 1,1,1-trifluoro-2-methylpropan-2-ol (3.16 mL) was added dropwise to this reaction mixture at room temperature. The dropwise addition of all of 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 this reaction mixture under ice cooling. The mixture was extracted three times with n-hexane. The resulting organic layers were combined, washed three times with water, washed with saturated brine, dried over sodium sulfate, and concentrated under a reduced pressure of 140 mmHg at 35° C. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (8.31 g; containing 12 wt% n-hexane) in a 47% yield. 1 H-NMR (DMSO-D6) δ: 1.46 (s, 6H), 7.08 (dt, 1H, J = 10.2, 2.1 Hz), 7.18 (s, 1H), 7.39-7.45 (m, 1H).

[0159] (Step 2) Preparation of 1-(1-butoxyvinyl)-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene [ka] To a solution of 1-bromo-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene (2.86 g; containing 12 wt% n-hexane) obtained in Step 1 and the same compound (10.2 g; containing 12 wt% n-hexane) obtained in the same manner as in Step 1 in ethylene glycol (69 mL) was added 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) 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 Celite. The filtrate was extracted twice with n-hexane. The resulting organic layers were combined, washed twice with water and with saturated brine, dried over magnesium sulfate, and concentrated under a reduced pressure of 140 mmHg at 35° C. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5) to give the title compound (6.39 g; containing 15 wt% n-hexane) in a 44% yield. 1 H-NMR (DMSO-D6) δ: 0.95 (t, 3H, J = 7.3 Hz), 1.40-1.51 (m, 2H), 1.44 (s, 6H), 1.69-1.76 (m, 2H), 3.84 (t, 2H, J = 6.3 Hz), 4.39 (d, 1H, J = 3.0 Hz), 4.90 (d, 1H, J = 3.0 Hz), 6.96-7.01 (m, 1H), 7.12 (s, 1H), 7.24-7.29 (m, 1H).

[0160] (Step 3) Preparation of 1-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)ethan-1-one [ka] To a solution of 1-(1-butoxyvinyl)-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene (6.39 g; containing 15 wt. % n-hexane) obtained in Step 2 in THF (25 mL) was added 2N hydrochloric acid (12.71 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour and 10 minutes. Under ice-cooling, 2N aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to 12. The mixture was extracted twice with n-hexane. The combined organic layers were washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure of 120 mmHg at 35°C. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give the title compound (4.09 g; containing 6 wt. % n-hexane) in 86% yield. 1 H-NMR (DMSO-D6) δ: 1.47 (s, 6H), 2.60 (s, 3H), 7.32 (dt, 1H, J = 9.7, 2.3 Hz), 7.42-7.43 (m, 1H), 7.58-7.62 (m, 1H).

[0161] (Step 4) Preparation of ethyl 4-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-2,4-dioxobutanoate [ka] To a solution of 1-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)ethan-1-one (4.09 g; containing 6 wt% n-hexane) obtained in Step 3 in THF (38.4 mL) was added diethyl oxalate (2.171 mL) under an argon atmosphere. Lithium tert-butoxide (1.396 g) was added to this mixture at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and 10 minutes. 1N hydrochloric acid was added to this reaction mixture under ice cooling to adjust the pH to 1. Water was added to this mixture, and the mixture was 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 give the title compound (5.53 g; containing 4 wt% diethyl oxalate and 6 wt% ethyl acetate) in 94% yield. 1 H-NMR (CDCl3) δ: 1.42 (t, 3H, J = 7.5 Hz), 1.50 (s, 6H), 4.42 (q, 2H, J = 7.5 Hz), 6.97 (s, 1H), 7.01 (dt, 1H, J = 9.3, 2.2 Hz), 7.42-7.45 (m, 1H), 7.48 (dt, 1H, J = 8.8, 2.2 Hz), 15.02 (br s, 1H).

[0162] (Step 5) Preparation of ethyl 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylate [ka] To a solution of ethyl 4-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-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) was added 5-hydrazineyl-2-(trifluoromethyl)pyrimidine (242 mg) obtained in Step 1 of Production Example 6 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 three times with toluene. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 75 / 25 to 0 / 100) to obtain a crude product of the title compound. A mixture of n-hexane / ethyl acetate (20 / 1) was added to the crude product at room temperature. The suspension was stirred at room temperature. The solid was collected from this 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 = 7.1 Hz), 4.38 (q, 2H, J = 7.1 Hz), 6.83-6.84 (m, 1H), 7.13 (dt, 1H, J = 10.0, 2.3 Hz), 7.31-7.35 (m, 1H), 7.39 (s, 1H), 9.12 (s, 2H).

[0163] (Step 6) Preparation of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid [ka] To a solution of ethyl 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-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) was added 2N aqueous sodium hydroxide solution (1.068 mL) at room temperature. Methanol (4 mL) was added to this reaction mixture at room temperature. This reaction mixture was stirred at room temperature for 25 hours and 30 minutes. To this reaction mixture was added 1N hydrochloric acid under ice cooling to adjust the pH to 1. Water was added to this mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layers were combined, washed twice with saturated brine, and dried over sodium sulfate. This organic layer was concentrated to give the title compound (504 mg) in 99% yield. 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).

[0164] (Step 7) Preparation of tert-butyl (5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)carbamate [ka] To a mixture of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid (495 mg) obtained in Step 6 and 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. To the reaction mixture, tert-butanol (4.26 mL) was added 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 (developing solvent: n-hexane / ethyl acetate = 99 / 1 to 50 / 50) to give the title compound (315 mg) in a 55% yield. 1 H-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).

[0165] (Step 8) Preparation of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-amine [ka] To the tert-butyl (5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)carbamate (315 mg) obtained in Step 7, a 4N hydrochloric acid / 1,4-dioxane solution (1.575 mL) was added at 0°C under an argon atmosphere. This reaction mixture was stirred at 0°C for 10 minutes and then at room temperature for 27 hours and 40 minutes. This reaction mixture was concentrated. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. This residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain a solid. A mixture of n-hexane / ethyl acetate (10 / 1) was added to the solid at room temperature. This suspension was stirred at room temperature. The solid was collected from this suspension by filtration and washed with a mixture of n-hexane / ethyl acetate (10 / 1). The obtained solid was dried under reduced pressure at room temperature to give 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, 2.3 Hz), 7.21-7.26 (m, 1H), 8.76 (s, 2H).

[0166] (Step 9) Preparation of (3R,4R)—N-(5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [ka] To a solution of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-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 Production Example 3 in pyridine (1 mL), WSC·HCl (28.2 mg) was added at room temperature under an argon atmosphere. This reaction mixture was stirred at room temperature for 29 hours. This reaction mixture was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed twice with 1N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, 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 give the title compound (69 mg; containing 4% by weight of ethyl acetate and 1% by weight of n-hexane) in a yield of 86%. 1 H-NMR (DMSO-D6) δ: 1.09 (d, 3H, J = 7.2 Hz), 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, 2.3 Hz), 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

[0167] [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 [ka]

[0168] (Step 1) Preparation of benzyl 4-(3-fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutanoate [ka] Under an argon atmosphere, lithium tert-butoxide (1.982 g) was added to a solution of 1-(3-fluoro-5-(trifluoromethoxy)phenyl)ethan-1-one (5 g) and dibenzyl oxalate (6.69 g) in THF (50 mL) under ice-cooling. This reaction mixture was stirred under ice-cooling for 1 hour. To this reaction mixture, 2N hydrochloric acid (12.5 mL), ethyl acetate, and water were added under ice-cooling. This mixture was separated into layers. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. This organic layer was concentrated to obtain a crude product of the title compound (11.7 g).

[0169] (Step 2) Preparation of benzyl 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate [ka] To a solution of the crude benzyl 4-(3-fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutanoate (800 mg) obtained in Step 1 in acetic acid (6 mL), 3-fluoro-5-hydrazinylpyridine (218 mg) obtained in Production Example 4, Step 1, was added at room temperature under an argon atmosphere. 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 the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 90 / 10 to 69 / 31) to give the title compound (589.5 mg) in a 79% yield over two steps. 1H-NMR (CDCl3) δ: 5.44 (s, 2H), 6.83-6.86 (m, 1H), 6.93 (ddd, 1H, J = 8.4, 2.3, 1.6 Hz), 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, 1.8 Hz), 8.32 (d, 1H, J = 1.8 Hz), 8.53 (d, 1H, J = 2.5 Hz).

[0170] (Step 3) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid [ka] To a solution of benzyl 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate (589.5 mg) obtained in Step 2 in ethyl acetate (5.90 mL) was added 5% by weight palladium on carbon (88 mg) at room temperature under an argon atmosphere. This reaction mixture was stirred at room temperature under a hydrogen atmosphere at 1 atmosphere pressure for 2 hours. After the mixture was placed under a nitrogen atmosphere, the palladium on carbon in the reaction mixture was filtered off through Celite. The Celite used was washed with a mixture of ethyl acetate / methanol (9 / 1). The obtained filtrates were combined and concentrated. Toluene was added to the residue, and the mixture was concentrated. The residue was dried under reduced pressure at room temperature to give the title compound (425.9 mg) in 89% yield. 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, 1.5 Hz), 7.47-7.52 (m, 1H), 7.96 (ddd, 1H, J = 9.2, 2.5, 2.1 Hz), 8.44-8.47 (m, 1H), 8.73 (d, 1H, J = 2.5 Hz), 13.23 (br s, 1H).

[0171] (Step 4) Preparation of tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)carbamate [ka] To a solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid (425.9 mg) obtained in Step 3 and triethylamine (0.370 mL) in tert-butanol (4.26 mL) / toluene (8.52 mL), diphenylphosphoryl azide (0.286 mL) was added at room temperature under an argon atmosphere. This reaction mixture was stirred at 110°C for 14 hours and 50 minutes. This reaction mixture was cooled to room temperature and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The resulting 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. This suspension was stirred at room temperature. Insoluble matter was collected by filtration and washed with a mixture of n-hexane / ethyl acetate (1 / 1). The resulting 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 give the title compound (207.4 mg) in a yield of 41%. 1 H-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, 1.5 Hz), 7.44-7.49 (m, 1H), 7.73 (ddd, 1H, J = 9.5, 2.5, 2.1 Hz), 8.32-8.34 (m, 1H), 8.61 (d, 1H, J = 2.3 Hz), 10.05 (br s, 1H).

[0172] (Step 5) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-amine [ka] 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. This reaction mixture was stirred at room temperature for 22 hours and 40 minutes. Water was added to this reaction mixture at 0°C. 8N aqueous sodium hydroxide solution (approximately 3.36 mL) was added dropwise to this mixture at 0°C. Saturated aqueous sodium bicarbonate solution was added to this mixture at 0°C. This 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 (developing solvent: n-hexane / ethyl acetate = 64 / 36 to 43 / 57) to obtain a solid. n-Hexane was added to this solid at room temperature. This suspension was stirred at room temperature. The solid was collected by filtration from this suspension and washed with n-hexane. The obtained solid was dried under reduced pressure at 60°C to give 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, 1.4 Hz), 6.96-7.00 (m, 1H), 7.43 (dt, 1H, J = 9.2, 2.5 Hz), 8.20-8.22 (m, 1H), 8.36 (d, 1H, J = 2.5 Hz).

[0173] (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 [ka] To a solution of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-amine (38 mg; containing 0.21 wt % 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 in pyridine (0.380 mL) was added WSC·HCl (24.5 mg) at room temperature under an argon atmosphere. This reaction mixture was stirred at room temperature for 2 hours and 54 minutes. To this reaction mixture was added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (18 mg) obtained in the same manner as in Step 6 of Production Example 3 and WSC·HCl (25 mg). This reaction mixture was stirred at room temperature overnight. To this reaction mixture was added 10 wt % aqueous citric acid solution at room temperature, followed by extraction with ethyl acetate. The resulting 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 (developing solvent: ethyl acetate / methanol = 97 / 3) to obtain the title compound. A mixture of n-hexane / ethyl acetate was added to the title compound at room temperature. The resulting suspension was stirred at room temperature. The solid was filtered from the suspension and washed with n-hexane. The resulting solid was dried under reduced pressure at 70 °C to obtain the title compound (46.6 mg; containing 3.5 wt% n-hexane) in 87% yield.

[0174] [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 [ka] 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 form a solution. The solution was cooled to room temperature. Water (1.2 mL) was added dropwise to the solution at room temperature, and the mixture was stirred for 4 hours. The precipitated solid was collected by filtration and washed with an ethanol / water (= 1 / 2) mixture. The obtained solid was dried under reduced pressure at 40° C. to give the title compound (192 mg) in 92% yield. elemental analysis Calculated values: C 50.51 wt%, H 3.63 wt%, N 14.02 wt% Actual measurements: C 50.61wt%, H 3.46wt%, N 13.95wt%

[0175] [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 [ka]

[0176] (Step 1) Preparation of benzyl 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylate [ka] To a solution of the crude benzyl 4-(3-fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutanoate (800 mg) obtained in Step 1 of Example 3 in acetic acid (6 mL) was added 3-hydrazineyl-5-(trifluoromethyl)pyridine (304 mg) obtained in Step 1 of Production Example 5 at room temperature under an argon atmosphere. 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 the mixture was concentrated. This procedure was repeated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 97 / 3 to 70 / 30) to give the title compound (640 mg) in 78% yield over two steps. 1 H-NMR (CDCl3) δ: 5.45 (s, 2H), 6.80-6.83 (m, 1H), 6.94 (ddd, 1H, J = 8.3, 2.3, 1.6 Hz), 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 = 2.5 Hz), 8.88-8.92 (m, 1H).

[0177] (Step 2) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid [ka] To a solution of benzyl 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylate (640 mg) obtained in Step 1 in ethyl acetate (6.4 mL) was added 5 wt% palladium on carbon (32 mg) at room temperature. This reaction mixture was stirred under a hydrogen atmosphere at 1 atmosphere pressure for 2 hours. After the mixture was placed under a nitrogen atmosphere, THF was added to the reaction mixture. The palladium on carbon in the reaction mixture was removed by filtration through Celite. The Celite used was washed with THF. The obtained filtrates were combined and concentrated. n-Hexane was added to the residue, and the mixture was concentrated. This process was repeated. The residue was dried under reduced pressure at room temperature to give the title compound (525 mg) as a crude product.

[0178] (Step 3) Preparation of tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)carbamate [ka] To a solution of the crude 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (525 mg) obtained in Step 2 and triethylamine (0.403 mL) in tert-butanol (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 (eluent: n-hexane / ethyl acetate = 97 / 3 to 70 / 30) to give the title compound (420 mg) in 68% yield over two steps. The formation of the title compound was confirmed by thin-layer chromatography (eluent: n-hexane / ethyl acetate = 4 / 1, Rf value: 0.46).

[0179] (Step 4) Preparation of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-amine [ka] To the 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. This reaction mixture was stirred at room temperature for 1 hour and 30 minutes. This reaction mixture was concentrated. Toluene was added to the residue, and the mixture was concentrated. This procedure was repeated. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. This mixture was separated into layers. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 92 / 8 to 20 / 80) to obtain the title compound (313 mg) in a 93% yield. 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, 1.3 Hz), 6.97-7.02 (m, 1H), 7.87-7.90 (m, 1H), 8.57 (d, 1H, J = 2.4 Hz), 8.71-8.74 (m, 1H).

[0180] (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 [ka] To a 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 Production Example 3 in pyridine (1 mL), WSC·HCl (31.1 mg) was added at room temperature. This reaction mixture was stirred at room temperature for 15 hours and 30 minutes. Water and ethyl acetate were added to this reaction mixture at room temperature. This mixture was separated into layers. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. Toluene was added to this residue, and the mixture was concentrated. This procedure was repeated. The residue was purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate) to give the title compound (75 mg) in 96% yield.

[0181] The compounds of other Examples were obtained by the same methods as those in the above General Methods, Preparations, and Examples, or by using other known methods as necessary. The structural formulas and physical property data of the compounds of Examples 1 to 40 are shown in the following table.

[0182] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0183] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8]

[0184] [Reference example] Compounds A to H shown in the table below were obtained based on the description in WO 2013 / 031922. [Table 5-1] [Table 5-2]

[0185] 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 table below were obtained based on the above examples and the description in WO 2013 / 031922. [Table 6-1] [Table 6-2]

[0186] [Test Example 1] Evaluation of SGLT1 inhibitory activity SGLT1 inhibitory activity (IC 50 The value) is the labeled form of α-methyl-D-glucopyranoside ( 14 The amount of C-AMG taken up into the cells was calculated. 1) Construction of human SGLT1 expression plasmid Using pCMV6-hSGLT1 (OriGene) as a template, a DNA fragment containing human SGLT1 was amplified by polymerase chain reaction (PCR). An NheI recognition sequence was inserted before the Kozac consensus sequence derived from the vector, and a stop codon TAG and a SalI recognition sequence were inserted immediately after the protein coding region of human SGLT1. The purified DNA fragment was digested with restriction enzymes NheI and SalI and then ligated with pcDNA3.1(+) digested with NheI and XhoI to construct the human SGLT1 expression plasmid, pcDNA-hSGLT1. The nucleotide sequence of the human SGLT1 inserted into the vector was identical to the protein coding region of the human SGLT1 sequence registered in GenBank (Accession number NM_000343), and the sequence at the junction with the vector was also as expected.

[0187] 2) Establishment of a cell line stably expressing human SGLT1 The human SGLT expression plasmid pcDNA-hSGLT1 was transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen), and drug-resistant cell lines were selected in the presence of G418 (Nacalai Tesque). 14 C-AMG uptake and the effect of phlorizin, an SGLT inhibitor 14 The cell line with the highest C-AMG uptake ratio (S / B ratio) was selected as a human SGLT1 stable expressing cell line.

[0188] 3) Evaluation of SGLT1 inhibitory activity Human SGLT1 stable expressing cell line was treated with BioCoat TM Poly-D-Lysine 96-well plate with lid (Becton, Dickinson and Company) 4 Cells / well were seeded and cultured overnight at 37°C, 5% CO2. The medium was replaced 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, pH 7.4), and the plate was left standing at 37°C, 5% CO2 for 20 minutes. After removing the Na(-)buffer, 40 μL / well of 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, pH 7.4) containing BSA was added. Furthermore, 8 kBq of 14 40 μL / well of Na(+) buffer containing C-AMG and 2 mM AMG was added and mixed. For the blank, 40 μL / well of Na(-) buffer containing BSA was added, and 8 kBq of 14C-AMG and 2 mM AMG in Na(-) buffer were added at 40 μL / well and mixed. After incubation at 37°C and 5% CO2 for 1 hour, the cells were washed twice with 100 μL / well of ice-cold wash buffer (100 mM AMG, 140 mM choline chloride, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4) to stop the reaction. Cell lysates were prepared by adding 50 μL / well of 0.2 N NaOH solution. 14 To evaluate the C-AMG uptake, the entire cell lysate was transferred to an OptiPlate96 (Perkin-Elmer) containing 100 μL / well of MicroScint-40 (Perkin-Elmer), and analyzed using a TOPCOUNT NXT (Perkin-Elmer). 14 The CPM of C was measured. The data was calculated by subtracting the average CPM of the blank wells from the average CPM of the wells treated with each treatment. The inhibition rate of each concentration of the test compound was calculated using the following formula: [(AB) / A] x 100 (where A represents the data for the solvent control and B represents the data for the test compound treatment). IC of test compound 50 The value (50% inhibitory concentration) was calculated from the two concentrations that sandwiched the 50% inhibition rate 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 table below.

[0189] [Table 7]

[0190] [Test Example 2] OGTT (Oral Glucose Tolerance Test) Male SD rats (8 weeks old, Charles River Japan, Inc.) (six rats per group) were fasted for approximately 4 hours and orally administered 5 mL / kg of vehicle (0.5% methylcellulose solution) or Compound 1 (1, 3, or 10 mg / kg) suspended in 0.5% methylcellulose solution. 16 hours later, a glucose load was performed by orally administering 5 mL / kg of a 0.4 g / mL glucose solution. Blood samples were taken from the tail vein immediately before the glucose load, and 30, 60, and 120 minutes after the load. Blood glucose levels were measured using an automatic biochemical analyzer (Hitachi, Model 7180). 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 blood glucose levels up to 120 minutes after glucose loading in the compound-treated group compared to the vehicle group. Statistical analysis was performed using Steel's multiple test. The significance level was set at 5% on both sides. As a result, Compound 1 significantly reduced blood glucose levels after glucose loading compared to the vehicle.

[0191] [Test Example 3] OGTT (Oral Glucose Tolerance Test) Male SD rats (8 weeks old, Charles River Japan, Inc.) (5 rats per group) were fasted for approximately 4 hours and orally administered 5 mL / kg of vehicle (0.5% methylcellulose solution) or Compound 1, Compound A, or Compound B (3 mg / kg each) suspended in 0.5% methylcellulose solution. 16 hours later, a glucose load was performed by orally administering 5 mL / kg of a 0.4 g / mL glucose solution. Blood samples were taken from the tail vein immediately before the glucose load, and 30, 60, and 120 minutes after the load. Blood glucose levels were measured using an automatic biochemical analyzer (Hitachi, Model 7180). The results are shown in Figure 2. The data represent the mean ± standard deviation of the ratio (% of Vehicle) of the area under the curve (ΔAUC) of blood glucose levels up to 120 minutes after glucose loading in the compound-treated group compared to the vehicle group. Statistical analysis was performed using Dunnett's multiple group test. The significance level was set at 5% on both sides. As a result, Compound 1 significantly reduced blood glucose levels after glucose loading compared to the vehicle.

[0192] [Test Example 4] Ames test (reverse mutation test) Metabolites 1, 3, and 5, and metabolites C to H were tested as follows. The purpose of this study was to evaluate the ability of each metabolite to induce reverse mutations in standard strains of Salmonella typhimurium (TA98, TA1537, TA100, and TA1535) and Escherichia coli (WP2uvrA) in the presence or absence of a rat liver metabolic activation system (S9 mix). In this test, dimethyl sulfoxide (DMSO, 100 μL / plate) was used as a solvent. Tests were performed using the preincubation method in the presence or absence of S9 mix. In tests without S9 mix, sodium phosphate buffer (pH 7.4) was added. 0.5 mL of S9 mix or 0.5 mL of 0.1 mol / L sodium phosphate buffer (pH 7.4) and 0.1 mL of bacterial culture were added to test tubes containing 0.1 mL of negative control substance (DMSO only), metabolites, or positive control substances. This mixture was preincubated at 37°C for 20 minutes with shaking. After preincubation, 2 mL of top agar was added, and the mixture was vortex-mixed and plated. Two plates were used for each treatment. Each plate was incubated at 37±1°C for at least 48 hours, and the revertant colonies were counted. The average number of revertant colonies per treatment plate was then calculated. Growth inhibition due to the antibacterial activity of the test compound and the presence or absence of test compound precipitation were observed with the naked eye or a stereomicroscope. Results were considered positive if the mean number of revertant colonies showed a dose-dependent increase of more than twofold over the negative control at one or more doses. Evaluation was based on mean values ​​without statistical comparison.

[0193] 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 mutations in any of the test strains, whereas metabolites C to H showed the ability to induce reverse mutations in at least one test strain in the presence and / or absence of S9 mix. Details are explained below. Metabolite C showed reverse mutation-inducing activity in the test strains TA98 in the presence of S9 mix and TA100 in the presence of S9 mix. Metabolite D showed reverse mutation-inducing activity in the test strains TA98 and TA1537 in the presence of S9 mix. Metabolite E showed reverse mutation induction in the test strains TA98, TA1537, TA100 and TA1535 in the presence of S9 mix, and in the test strain TA1537 in the absence of S9 mix. Metabolite F showed reverse mutation induction ability in the test strains TA98, TA1537, and TA100 in the presence of S9 mix, and in the test strain WP2uvrA in the absence of S9 mix. Metabolite G showed reverse mutation induction in the test strain TA100 in the presence of S9 mix and in the test strain TA1535 in the absence of S9 mix. Metabolite H showed reverse mutation-inducing activity in the test strains TA98, TA1537, and TA100 in the presence of S9 mix.

[0194] [Table 8]

[0195] [Table 9]

[0196] [Table 10]

[0197] [Table 11]

[0198] [Table 12]

[0199] [Table 13]

[0200]

Table 14

[0201]

Table 15

[0202] Table 16

[0203]

Table 17

[0204] Table 18

[0205]

Table 19

[0206] Table 20

[0207] Table 21

[0208] Table 22

[0209] Table 23

[0210] [Table 24]

[0211] [Table 25]

[0212] [Table 26]

[0213] [Table 27]

[0214] [Table 28]

[0215] [Test Example 5] Evaluation of renal protective effect Male SDT fatty rats (7 weeks old, CLEA Japan, Inc.) were orally administered vehicle (0.5% methylcellulose solution), compound 1 (2 mg / kg), or dapagliflozin (0.3 mg / kg) once daily. Male SD rats (7 weeks old, CLEA Japan, Inc.) served as normal controls and were orally administered vehicle once daily. After 16 weeks of administration, GFR (mL / min / 100 g B.W.) was measured using a transdermal GFR monitor (MediBeacon). Statistical analysis was performed using a Student's test between the SD rat vehicle-administered group and the SDT fatty rat vehicle-administered group. Dunnett's multigroup test was used to test the efficacy of compound 1 and dapagliflozin against the vehicle in SDT fatty rats. The significance level was set at 5% on both sides. As a result, compound 1 inhibited the increase in GFR. The results are shown in Figure 3.

[0216] [Test Example 6] Renal protection evaluation 2 Seven-week-old male Wistar rats (Japan SLC) were anesthetized with isoflurane, and two-thirds of the left kidney was removed. One week later, the right kidney was completely removed to produce 5 / 6 nephrectomized rats. From 9 weeks of age, oral administration of compound 1 (2 mg / kg / day) was initiated in the diet. Male Wistar rats of the same age served as a sham group as normal controls. Blood and urine samples were collected 16, 30, and 69 days after the start of administration, and urinary protein, creatinine clearance, and urea nitrogen concentrations (mg / dL) were measured. The compound 1 group showed lower urinary protein levels than the vehicle group. Creatinine clearance was significantly higher in the compound 1 group than in the vehicle group. Statistical analysis was performed using a Student's test between the vehicle and compound 1 groups. The urea nitrogen concentration in the vehicle group was significantly higher than that in the sham group, and the compound 1 group was significantly lower than that in the vehicle group. Statistical analysis was performed using the Student test or Aspin-Welch test. The results are shown in Figures 4 to 6.

[0217] [Formulation example] Examples of formulations of the compound of formula [I] include, but are not limited to, the following formulations. Formulation Example 1 (Capsule Production) (1)Compound 1 30mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg Components (1), (2), (3) and (4) are mixed and filled into a gelatin capsule.

[0218] Formulation Example 2 (Tablet Production) (1) Compound 1 10g (2) Lactose 50g (3) 15g corn starch (4) Carmellose calcium 44g (5) Magnesium stearate 1g The total amount of components (1), (2), and (3) and 30 g of component (4) are kneaded with water, vacuum dried, and then sized. 14 g of component (4) and 1 g of component (5) are mixed with this sized powder and compressed into tablets using a tablet press. 1,000 tablets containing 10 mg of compound 1 per tablet are thus obtained. [Industrial Applicability]

[0219] Compounds that inhibit SGLT1 or pharmaceutically acceptable salts thereof are expected to have renal protective effects and thus be useful in the treatment or prevention of chronic kidney disease.

Claims

1. A pharmaceutical composition for treating or preventing chronic kidney disease, comprising a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof, wherein the compound that inhibits SGLT1 is represented by the formula [II]: 【Chemical 1】 A pharmaceutical composition comprising the compound of formula (I).

2. Use of a compound that inhibits SGLT1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing chronic kidney disease, wherein the compound that inhibits SGLT1 is a compound of formula [II]: 【Chemistry 2】 is a compound of, use.

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