Pyrazole compound and pharmaceutical use thereof

Abstract

To provide a pyrazole compound having SGLT1 inhibitory action, or a pharmaceutical composition comprising the same, and its pharmaceutical use.SOLUTION: The present invention provides a compound represented by the general formula [Ib] in the figure, or a pharmaceutically acceptable salt thereof. [In the formula, each symbol is as described in the specification.]SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pyrazole compound having SGLT1 inhibitory activity or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and medical use thereof. [Background technology]

[0002] SGLT1(Na + Sodium-glucose cotransporter 1 (SGLT1) is known to be responsible for most of the absorption of glucose and galactose in the small intestine, and it has been reported that glucose and galactose absorption is poor in patients with a deficiency in human SGLT1. Furthermore, it has been confirmed that the expression of SGLT1 in the small intestine is increased in diabetic patients, and it is believed that the increased glucose absorption in diabetic patients is due to the high expression of SGLT1 in the small intestine.

[0003] From these findings, SGLT1 inhibitors are expected to normalize blood glucose levels by inhibiting the absorption of sugar from the small intestine, and are considered to be effective against diabetic complications accompanying diabetes and hyperglycemia, specifically retinopathy, nephropathy, and neuropathy, known as microangiopathy, as well as cerebrovascular disease, ischemic heart disease, and lower limb obliterative arteriosclerosis, known as macroangiopathy. They are also considered to be effective against obesity by suppressing the inflow of sugar into the body (Non-Patent Documents 1 and 2).

[0004] In addition, SGLT1 is expressed in cardiac myocytes. Glucose uptake into cardiac myocytes is usually carried out by GLUT1 and GLUT4 (Glucose Transporter Type 4), and it is known that SGLT1 plays a small role. However, it has been reported that SGLT1 expression is induced in the cardiac myocytes of mice that have been introduced with a mutant gene of PRKAG2 (gamma (gamma)2 subunit of AMPK (AMP-Activated Protein Kinase)), which is the causative gene of familial hypertrophic cardiomyopathy (glycogen storage cardiomyopathy), and mice that have been treated with myocardial ischemia, and that SGLT1 contributes to glucose uptake into cardiac myocytes in these pathological conditions. It is believed that glucose taken up by SGLT1 accumulates excessively in cardiac myocytes or is metabolized, causing damage to the cells. In fact, it has been reported that in the former model, glycogen accumulation in the cardiac myocytes is suppressed by treatment with phlorizin, a non-selective SGLT inhibitor. Based on these findings, it is believed that SGLT1 inhibitors are effective against hypertrophic cardiomyopathy and ischemic heart disease by suppressing excessive glucose uptake into cardiomyocytes (Non-Patent Documents 3 and 4).

[0005] In cancer cells, SGLT1 is stabilized by the epidermal growth factor receptor (EPR, a surface protein found on many cancer cells). Transporters of glucose, lactate, amino acids, etc. are involved in the supply of nutrients to cancer cells, and it is known that SGLT1 and GLUT1 in particular constantly supply glucose to cancer cells with regard to glucose transport. If glucose is not supplied for a long period of time, the cells are destroyed through autophagy. Based on these findings, it is believed that SGLT1 inhibitors exert their anticancer effects by suppressing the supply of glucose to cancer cells (Non-patent Documents 5 and 6).

[0006] Since carbohydrates in the diet are broken down into monosaccharides in the digestive tract and absorbed in the upper part of the digestive tract, most of the sugar does not reach the lower digestive tract. However, when taking drugs that delay or inhibit sugar absorption or ingesting large amounts of indigestible polysaccharides, undigested sugars remain in the lower digestive tract, and the undigested sugars remaining in the lower digestive tract cause osmotic diarrhea. SGLT1 inhibitors increase the amount of monosaccharides in the lower gastrointestinal tract by inhibiting sugar absorption, which is why they are thought to be effective against constipation. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Am J Physiol Gastrointest Liver Physiol. 2002; 282(2):G241-8 [Non-Patent Document 2] Nature. 1991; 350(6316):354-6 [Non-Patent Document 3] J Mol Cell Cardiol. 2010; 49(4):683-92 [Non-Patent Document 4] Cardiovasc Res. 2009; 84(1):111-8 [Non-Patent Document 5] Cancer Cell. 2008, 13: 385-93 [Non-Patent Document 6] Pharmacol Ther. 2009, 121: 29-40 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a pyrazole compound or a pharma- ceutical acceptable salt thereof that has an SGLT1 inhibitory activity and is useful as a medicament, and a pharmaceutical composition containing the same. [Means for solving the problem]

[0009] The present invention is as follows. Item 1: A compound represented by the following general formula [I] or a pharma- ceutically acceptable salt thereof: [ka] [In the formula, The ring Cy is (1) C 6-10 Aryl, (2) C 3-8 cycloalkyl, or (3) C 3-8 is cycloalkenyl, n1 is 0, 1, 2, 3 or 4; R 1 teeth, (1) a halogen atom, (2) a hydroxy group, (3) a carboxy group, (4) C 1-6 Alkyl groups, (5) C 1-6 Alkoxy groups, (6) C 3-6 Cycloalkyl groups, (7) HaroC 1-6 Alkyl groups, (8) Hydroxy C 1-6 Alkyl groups, (9) C 1-6 Alkoxy C 1-6 Alkyl groups, (10) HaroC 1-6 an alkoxy group, or (11) Carboxy C 1-6 is an alkoxy group, However, when n1 is 2, 3, or 4, each R 1 may be the same or different, R 2 teeth, (1) C 1-8 Alkyl groups, (2) C 3-8 Cycloalkyl C 1-6 Alkyl groups, (3) C 6-10 Aryl C 1-6Alkyl groups, (4) Saturated heterocycle C 1-6 an alkyl group (the saturated heterocycle is a 5- or 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); (5) C 3-8 Cycloalkyl groups, (6) HaroC 1-6 Alkyl groups, (7) C 1-6 Alkoxy C 1-6 Alkyl groups, (8) HaroC 3-8 Cycloalkyl groups, (9) C 6-10 Aryl group (C 6-10 The aryl group is (a) a halogen atom, (b)C 1-6 Alkyl groups, (c)C 1-6 Alkoxy groups, and (d) Carboxy C 1-6 alkoxy groups), or (10) A saturated heterocyclic group (the saturated heterocyclic ring is a 5- or 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 4 C 1-6 may be substituted with an alkyl group, n2 is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; R 3 teeth, (1) C 1-6 an alkyl group, or (2) Hydroxy C 1-6 is an alkyl group, However, when n2 is 2, 3, or 4, each R 3 may be the same or different, X a teeth, (1) Combination, or (2)NR 4 (The R 4 teeth (a) a hydrogen atom, or (b)C1-6 alkyl group), X b teeth, (1) NH, or (2) an oxygen atom; However, X a NR 4 When X b is not an oxygen atom].

[0010] Section 2:X b Item 2. The compound according to item 1, or a pharma- ceutically acceptable salt thereof, wherein is NH.

[0011] Term 3: Ring Cy is C 6-10 Item 3. The compound according to any one of items 1 and 2, wherein R is aryl, or a pharma- ceutically acceptable salt thereof.

[0012] Item 4: The compound according to item 3, wherein ring Cy is phenyl, or a pharma- ceutically acceptable salt thereof.

[0013] Section 5:R 1 but, (1) a halogen atom, (2) C 1-6 Alkyl groups, (3) C 1-6 Alkoxy groups, (4) HaroC 1-6 Alkyl groups, (5) C 1-6 Alkoxy C 1-6 an alkyl group, or (6) HaroC 1-6 is an alkoxy group, However, when n1 is 2, 3, or 4, each R 1 and may be the same or different, the compound according to any one of items 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0014] Section 6:R 2 But, C 6-10 Aryl group (C 6-10 The aryl group is (a) a halogen atom, (b)C 1-6 Alkyl groups, (c)C 1-6Alkoxy groups, and (d) Carboxy C 1-6 6. The compound according to any one of items 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein R is an aryl group, R is an aryl group, and R is an aryl group.

[0015] Section 7:R 2 However, a phenyl group (the phenyl group is (a) a halogen atom, (b)C 1-6 Alkyl groups, (c)C 1-6 Alkoxy groups, and (d) Carboxy C 1-6 Item 7. The compound according to item 6, wherein the aryl group is aryl, and .... Item 7. The compound according to item 6, wherein the aryl group is aryl, and the aryl group is aryl.

[0016] Item 8: A pharmaceutical composition comprising the compound according to any one of items 1 to 7 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0017] Item 9: An SGLT1 inhibitor comprising the compound according to any one of items 1 to 7 or a pharma- ceutically acceptable salt thereof.

[0018] Item 10: An agent for treating or preventing diabetes, comprising the compound according to any one of items 1 to 7 or a pharma- ceutically acceptable salt thereof.

[0019] Item 11: The therapeutic or preventive agent according to Item 10, wherein the diabetes is type II diabetes.

[0020] Item 12: A method for inhibiting SGLT1, comprising administering a pharma- ceutically effective amount of the compound according to any one of items 1 to 7 or a pharma- ceutical acceptable salt thereof to a mammal.

[0021] Item 13: A method for treating or preventing diabetes, which comprises administering a pharma- ceutically effective amount of the compound according to any one of items 1 to 7 or a pharma- ceutical acceptable salt thereof to a mammal.

[0022] Item 14: The method according to Item 13, wherein the diabetes is type II diabetes.

[0023] Item 15: Use of the compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 7 for the manufacture of an SGLT1 inhibitor.

[0024] Item 16: Use of the compound according to any one of items 1 to 7 or a pharma- ceutically acceptable salt thereof for the production of an agent for treating or preventing diabetes.

[0025] Item 17: The use according to Item 16, wherein the diabetes is type II diabetes.

[0026] Item 18: A commercial kit comprising (a) a pharmaceutical composition comprising, as an active ingredient, a compound according to any one of items 1 to 7 or a pharma- ceutical acceptable salt thereof, and (b) a package insert for the pharmaceutical composition, which explains that the pharmaceutical composition can be or should be used for the treatment or prevention of type II diabetes.

[0027] Item 19: A commercial package comprising (a) a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of items 1 to 7 or a pharma- ceutical acceptable salt thereof, and (b) a package insert for the pharmaceutical composition, which describes that the pharmaceutical composition can be or should be used for the treatment or prevention of type II diabetes.

[0028] Item 20: A compound represented by the following general formula [Ib] or a pharma- ceutically acceptable salt thereof: [ka] [In the formula, The ring Cy is (1) C 6-10 Aryl, (2) C 3-8 cycloalkyl, or (3) C 3-8 is cycloalkenyl, n1 is 0, 1, 2, 3 or 4; R 1a teeth, (1) a halogen atom, (2) a hydroxy group, (3) a carboxy group, (4) C 1-6 Alkyl groups, (5) C 2-8 Alkenyl groups, (6) C 2-8 Alkynyl groups, (7) C 1-6 Alkoxy groups, (8) C 3-6 Cycloalkyl groups, (9) HaroC 1-6 Alkyl groups, (10) Hydroxy C 1-6 Alkyl groups, (11) C 1-6 Alkoxy C 1-6 Alkyl groups, (12) HaroC 1-6 Alkoxy C 1-6 Alkyl groups, (13) C 1-6 Alkylsulfonyl C 1-6 Alkyl groups, (14) HaroC 1-6 Alkylsulfonyl C 1-6 Alkyl groups, (15) HaroC 1-6 Alkylamino C 1-6 Alkyl groups, (16)C 3-6 Cycloalkyl C 2-6 Alkynyl groups, (17) HaroC 1-6 Alkoxy groups, (18) Carboxy C 1-6 Alkoxy groups, (19)C 1-6 Alkylsulfanyl groups, (20)C 1-6 Alkylsulfonyl groups, (21) HaroC 1-6 Alkylsulfonyl groups, (22)C 1-8 Alkylcarbonyl groups, (23)C 1-6 Alkyloxycarbonyl group, Equation (24): [ka] (In the formula, R 5 teeth, (a) a hydrogen atom, or (b)C 1-6 is an alkyl group, R 6 teeth, (a)C 1-6 an alkyl group, or (b) Halo C 1-6 is an alkyl group) is a group represented by (25) Saturated heterocycle C 1-6 an alkyl group (wherein the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); or (26) Saturated heterocyclic oxy C 1-6 an alkyl group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); However, when n1 is 2, 3, or 4, each R 1a may be the same or different, R 2a teeth, (1) C 1-8 Alkyl groups, (2) C 3-8 Cycloalkyl C 1-6 Alkyl groups, (3) C 6-10 Aryl C 1-6 Alkyl groups, (4) Saturated heterocycle C 1-6 an alkyl group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); (5) C 3-8 Cycloalkyl groups, (6) HaroC 1-6 Alkyl groups, (7) C 1-6 Alkoxy C 1-6 Alkyl groups, (8) HaroC 3-8 Cycloalkyl groups, (9) C 6-10 Aryl group (C 6-10 The aryl group is (a) a halogen atom, (b) a hydroxy group, (c)C 1-6 Alkyl groups, (d) C 2-8 Alkenyl groups, (e)C 2-6 Alkynyl groups, (f)C 1-6 Alkoxy group (g) Halo C 1-6 Alkyl groups, (h)C 1-6 Alkoxy C 1-6 Alkyl groups, (i) Halo C 1-6 Alkoxy groups, (j) Hydroxy C 1-6 Alkoxy groups, (k)C 1-6 Alkoxy C 1-6 Alkoxy groups, (l) Carboxy C 1-6 Alkoxy groups, (m)C 6-10 Aryl C 1-6 Alkoxy groups, (n)C 1-6 Alkyl Sulfanyl C 1-6 Alkoxy groups, (o)C 1-6 Alkylsulfonyl C 1-6 Alkoxy groups, (p)C 6-10 Aryl C 1-6 Alkoxy C 1-6 Alkoxy groups, (q) Saturated heterocycle C 1-6 An alkoxy group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 2 C 1-6 may be substituted with an alkyl group, (r) a saturated heterocyclic oxy group (the saturated heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom), (s)C 3-8 cycloalkyloxy groups, (t)C 1-6 alkoxycarbonyloxy groups, and (u)C 1-6 alkylsulfonyl groups), or (10) A saturated heterocyclic group (the saturated heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 4 C 1-6 may be substituted with an alkyl group, Ring Cy a teeth, {Formula (1): [ka] (In the formula, m2 is 1, 2 or 3; m3 is 1, 2 or 3; n3 is 1 or 2) A group represented by the formula: (2) Formula: [ka] (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or greater.) A group represented by the formula: (3) Formula: [ka] (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or greater.) A group represented by the formula: Equation (4): [ka] (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or greater.) A group represented by the formula: Equation (5): [ka] (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or greater.) A group represented by the formula: Equation (6): [ka] (In the formula, m8 is 1 or 2; m9 is 1 or 2) or Equation (7): [ka] (In the formula, m8 is 1 or 2; m9 is 1 or 2) is a group represented by n2 is 0, 1, 2, 3 or 4; R 3a teeth, (1) a hydroxy group, (2) C 1-6 an alkyl group, or (3) Hydroxy C 1-6 is an alkyl group, However, when n2 is 2, 3, or 4, each R 3a may be the same or different. R 3b teeth, (1) a hydroxy group, (2) C 1-6 Alkyl group (R 3b Together with the carbon adjacent to the carbon to which it is bonded, C 3-6 may form a cycloalkyl group), or (3) Hydroxy C 1-6 an alkyl group; or (4) Two R’s 3b When they are bonded to the same carbon atom, together with the carbon to which they are bonded, C 3-6 A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R 3b may be the same or different. R 4b teeth, (1) a hydrogen atom, (2) C 1-6 Alkyl groups, (3) Carboxy C 1-6 Alkyl groups, (4) HaroC 1-6 an alkyl group, or (5) C 1-6 Alkoxy C 1-6 alkyl group} [is].

[0029] Term 21: Ring Cy a but, {Formula (1): [ka] (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or greater.) A group represented by the formula: (2) Formula: [ka] (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or greater.) A group represented by the formula: (3) Formula: [ka] (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or greater.) A group represented by the formula: Equation (4): [ka] (In the formula, m8 is 1 or 2; m9 is 1 or 2) or Equation (5): [ka] (In the formula, m8 is 1 or 2; m9 is 1 or 2) is a group represented by n2 is 0, 1, 2, 3 or 4; R 3a teeth, (1) a hydroxy group, (2) C 1-6 an alkyl group, or (3) Hydroxy C 1-6 is an alkyl group, However, when n2 is 2, 3, or 4, each R 3a may be the same or different. R 3b teeth, (1) a hydroxy group, (2) C 1-6 Alkyl group (R 3b Together with the carbon adjacent to the carbon to which it is bonded, C 3-6 may form a cycloalkyl group), or (3) Hydroxy C 1-6 an alkyl group; or (4) Two R’s 3b When they are bonded to the same carbon atom, together with the carbon to which they are bonded, C 3-6 A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R 3b may be the same or different. R 4b teeth, (1) a hydrogen atom, (2) C 1-6 Alkyl groups, (3) Carboxy C 1-6 Alkyl groups, (4) HaroC 1-6 an alkyl group, or (5) C 1-6 Alkoxy C 1-6 alkyl group} Item 21. The compound according to item 20, or a pharma- ceutically acceptable salt thereof, wherein:

[0030] Term 22: Ring Cy a but, {Formula (1): [ka] (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or greater.) A group represented by the formula: (2) Formula: [ka] (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or greater.) A group represented by the formula: n2 is 0, 1, 2, 3 or 4; R3a teeth, (1) a hydroxy group, (2) C 1-6 an alkyl group, or (3) Hydroxy C 1-6 is an alkyl group, However, when n2 is 2, 3, or 4, each R 3a may be the same or different. R 3b teeth, (1) a hydroxy group, (2) C 1-6 Alkyl group (R 3b Together with the carbon adjacent to the carbon to which it is bonded, C 3-6 may form a cycloalkyl group), or (3) Hydroxy C 1-6 an alkyl group; or (4) Two R’s 3b When they are bonded to the same carbon atom, together with the carbon to which they are bonded, C 3-6 A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R 3b may be the same or different. R 4b teeth, (1) a hydrogen atom, (2) C 1-6 Alkyl groups, (3) Carboxy C 1-6 Alkyl groups, (4) HaroC 1-6 an alkyl group, or (5) C 1-6 Alkoxy C 1-6 alkyl group} Item 21. The compound according to item 20, or a pharma- ceutically acceptable salt thereof, wherein:

[0031] Term 23: Ring Cy a but, {Formula (1): [ka] (In the formula, n2 is 0, 1, 2, 3 or 4. or (2) Formula: [ka] (In the formula, where n2 is 0 or 1. is a group represented by R 3a teeth, (1) a hydroxy group, (2) C 1-6 an alkyl group, or (3) Hydroxy C 1-6 is an alkyl group, R 3b teeth, (1) a hydroxy group, (2) C 1-6 Alkyl group (R 3b Together with the carbon adjacent to the carbon to which it is bonded, C 3-6 may form a cycloalkyl group), or (3) Hydroxy C 1-6 an alkyl group; or (4) Two R’s 3b When they are bonded to the same carbon atom, together with the carbon to which they are bonded, C 3-6 A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R 3b may be the same or different. R 4b teeth, (1) a hydrogen atom, (2) C 1-6 Alkyl groups, (3) Carboxy C 1-6 Alkyl groups, (4) HaroC 1-6 an alkyl group, or (5) C 1-6 Alkoxy C 1-6 alkyl group} Item 21. The compound according to item 20, or a pharma- ceutically acceptable salt thereof, wherein:

[0032] Term 24: Ring Cy is C 6-10 24. The compound according to any one of items 20 to 23, wherein R is aryl, or a pharma- ceutically acceptable salt thereof.

[0033] Item 25: The compound according to item 24, or a pharma- ceutically acceptable salt thereof, wherein ring Cy is phenyl.

[0034] Section 26:R1 a but, (1) a halogen atom, (2) C 1-6 Alkyl groups, (3) C 1-6 Alkoxy groups, (4) HaroC 1-6 Alkyl groups, (5) C 1-6 Alkoxy C 1-6 Alkyl groups, (6) HaroC 1-6 Alkoxy C 1-6 an alkyl group, or (7) HaroC 1-6 is an alkoxy group, However, when n1 is 2, 3, or 4, each R1 a and may be the same or different, the compound according to any one of items 20 to 25, or a pharma- ceutically acceptable salt thereof.

[0035] Section 27:R 2a But, C 6-10 Aryl group (C 6-10 The aryl group is (a) a halogen atom, (b)C 1-6 Alkyl groups, (c)C 1-6 Alkoxy groups, and (d) Carboxy C 1-6 27. The compound according to any one of items 20 to 26, or a pharma- ceutically acceptable salt thereof, wherein R is an aryl group, R is an aryl group, and R is an aryl group.

[0036] Section 28:R2a However, a phenyl group (the phenyl group is (a) a halogen atom, (b)C 1-6 Alkyl groups, (c)C 1-6 Alkoxy groups, and (d) Carboxy C 1-6 Item 28. The compound according to item 27, or a pharma- ceutically acceptable salt thereof, wherein R is an aryl group, R is an aryl group, and R is an aryl group.

[0037] Item 29: The following chemical structure: [ka] TIFF2025039641000021.tif241104 TIFF2025039641000022.tif242106 TIFF2025039641000023.tif206109 Item 21. The compound according to item 20, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0038] Item 30: A pharmaceutical composition comprising the compound according to any one of items 20 to 29 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0039] Item 31: An SGLT1 inhibitor comprising the compound according to any one of items 20 to 29 or a pharma- ceutically acceptable salt thereof.

[0040] Item 32: An agent for treating or preventing diabetes, comprising the compound according to any one of items 20 to 29 or a pharma- ceutically acceptable salt thereof.

[0041] Item 33: The therapeutic or preventive agent according to Item 32, wherein the diabetes is type II diabetes.

[0042] Item 34: A method for inhibiting SGLT1, comprising administering a pharma- ceutically effective amount of the compound according to any one of items 20 to 29 or a pharma- ceutical acceptable salt thereof to a mammal.

[0043] Item 35: A method for treating or preventing diabetes, which comprises administering a pharma- ceutically effective amount of the compound according to any one of items 20 to 29 or a pharma- ceutically acceptable salt thereof to a mammal.

[0044] Item 36: The method of Item 35, wherein the diabetes is type II diabetes.

[0045] Item 37: Use of the compound or a pharma- ceutically acceptable salt thereof according to any one of items 20 to 29 for the manufacture of an SGLT1 inhibitor.

[0046] Item 38: Use of the compound according to any one of items 20 to 29 or a pharma- ceutically acceptable salt thereof for the manufacture of an agent for treating or preventing diabetes.

[0047] Item 39: The use according to Item 38, wherein the diabetes is type II diabetes.

[0048] Item 40: A commercial kit comprising (a) a pharmaceutical composition comprising, as an active ingredient, a compound according to any one of items 20 to 29 or a pharma- ceutical acceptable salt thereof, and (b) a package insert for the pharmaceutical composition, which describes that the pharmaceutical composition can be or should be used for the treatment or prevention of type II diabetes.

[0049] Item 41: A commercial package comprising (a) a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of items 20 to 29 or a pharma- ceutical acceptable salt thereof, and (b) a package insert for the pharmaceutical composition, which describes that the pharmaceutical composition can be or should be used for the treatment or prevention of type II diabetes. Effect of the Invention

[0050] The pyrazole compound or a pharma- ceutical acceptable salt thereof of the present invention has an SGLT1 inhibitory action, and is therefore useful for the treatment and / or prevention of diabetes, obesity, diabetic complications (e.g., retinopathy, nephropathy, and neuropathy, known as microangiopathy, and cerebrovascular disease, ischemic heart disease, and obliterative arteriosclerosis of the lower extremities, known as macroangiopathy), hypertrophic cardiomyopathy, ischemic heart disease, cancer, and constipation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The terms used in this specification are defined as follows. The term "optionally substituted" includes both cases where the substitutable positions of the target group are substituted and cases where the target group is not substituted (unsubstituted). Here, "unsubstituted" refers to cases where all substitutable positions of the target group are hydrogen atoms. For example, "1 to 4 C 1-6 The term "may be substituted with an alkyl group" means that the substitutable positions of the target group are each selected from 1 to 4 C 1-6 The alkyl group may be substituted or unsubstituted (unsubstituted), and each substituent may be the same or different. Unless otherwise indicated, the description of each group also applies when that group is a part or substituent of another group.

[0052] The "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like. A fluorine atom or a chlorine atom is preferred.

[0053] "C 1-8 The term "alkyl" group means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. 1-6 The term "alkyl" group refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 2-methylpropyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Preferably, C 1-6 It is an alkyl group. More preferably, it is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isopentyl, 2-methylpropyl, 1,1-dimethylpropyl, hexyl, or 3,3-dimethylbutyl. Particularly preferably, it is methyl, ethyl, propyl, n-butyl, or isopentyl.

[0054] "C 2-8 The term "alkenyl" refers to a straight or branched hydrocarbon group having 2 to 8 carbon atoms and at least one double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethylvinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethylvinyl, 1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-isopropylvinyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-methyl-1-pentenyl, 3,3-dimethylbutenyl (i.e., 3,3-dimethylbut-1-enyl), and the like. Preferably, C 2-6 It is an alkenyl group. More preferred are 1-propenyl, 2-methyl-1-propenyl, and 3,3-dimethylbut-1-enyl.

[0055] "C2-6 The term "alkynyl" refers to a linear or branched hydrocarbon group having 2 to 6 carbon atoms and at least one triple bond. 2-8 The term "alkynyl group" refers to a linear or branched hydrocarbon group having 2 to 8 carbon atoms and at least one triple bond. Specific examples include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 1-ethylethynyl, 3,3-dimethylbutynyl (i.e., 3,3-dimethylbut-1-ynyl), and the like. Preferably, C 2-6 It is an alkynyl group. More preferably, it is 3,3-dimethylbut-1-ynyl.

[0056] "C 1-6 The term "alkoxy" means a straight or branched chain alkoxy group having 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy, hexyloxy, and the like. Preferably, C 1-4 It is an alkoxy group. More preferred are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, isopentyloxy (i.e., 3-methylbutoxy), neopentyloxy (i.e., 2,2-dimethylpropoxy), 1,1-dimethylpropoxy, and 3,3-dimethylbutoxy.

[0057] "C 6-10 The term "aryl" refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. Such groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferably it is phenyl.

[0058] "C 3-8 The term "cycloalkyl" group means a monocyclic saturated hydrocarbon group having 3 to 8 carbon atoms. 3-6 The term "cycloalkyl group" refers to a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Such groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, C 3-7 It is a cycloalkyl group, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0059] "C 3-8 The term "cycloalkenyl group" refers to a monocyclic unsaturated hydrocarbon group having 3 to 8 carbon atoms and containing one or more double bonds. Such groups include, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Preferably, C 3-6 It is a cycloalkenyl group. More preferably, it is cyclohexenyl. Particularly preferably, it is 1-cyclohexenyl.

[0060] The term "saturated heterocyclic" group refers to a group having, in addition to carbon atoms, 1 to 2 heteroatoms selected from nitrogen atoms, oxygen atoms, or sulfur atoms, and having 4 to 6, preferably 5 to 6, atoms constituting the ring. Examples of such groups include pyrrolidinyl, pyrrolidino (1-pyrrolidinyl, etc.), piperidinyl, piperidino (1-piperidinyl, etc.), morpholinyl, morpholino (4-morpholinyl, etc.), thiomorpholinyl, thiomorpholino (4-thiomorpholinyl, etc.), piperazinyl, piperazino (1-piperazinyl, etc.), tetrahydropyranyl ((R)-tetrahydropyran-3-yl, (S)-tetrahydropyran-3-yl, etc.), tetrahydrofuranyl ((R)-tetrahydrofuran-3-yl, (S)-tetrahydrofuran-3-yl, etc.), oxetanyl, and the like. Preferred are saturated heterocyclic groups having one heteroatom selected from a nitrogen atom or an oxygen atom other than carbon atoms and having 5 to 6 atoms constituting the ring. More preferred are tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl. Particularly preferred are (R)-tetrahydropyran-3-yl, (S)-tetrahydropyran-3-yl, 4-tetrahydropyranyl, (R)-tetrahydrofuran-3-yl, (S)-tetrahydrofuran-3-yl, oxetan-3-yl, and 1-pyrrolidinyl.

[0061] "Haro C 1-6 An "alkyl" group is a "C 1-6 The term "alkyl" refers to a group in which an "alkyl group" is substituted with 1 to 13 "halogen atoms" as defined above. When multiple halogen atoms are substituted, the halogen atoms may be the same or different. A group in which 1 to 6 "halogen atoms" are substituted is preferred. A group in which 1 to 6 fluorine atoms are substituted is more preferred. Examples of such groups include 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethyl, and the like. Preferably, halo C 1-4 It is an alkyl group. More preferably, it is 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl, trifluoromethyl, 2,2,2-trifluoroethyl, or 3,3,3-trifluoropropyl.

[0062] "Hydroxy C 1-6 An "alkyl" group is a "C 1-6 The term "alkyl" refers to a group in which a hydroxy group is mono- or di-substituted on an "alkyl" group. Preferably, the group is mono-substituted with a hydroxy group. Examples of such groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 1-hydroxy-2,2-dimethylpropyl, 4-hydroxybutyl, 1-hydroxy-2,2-dimethylbutyl, 5-hydroxypentyl, and 6-hydroxyhexyl. Preferably, hydroxy C 1-4 It is an alkyl group. More preferably, it is hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxy-2,2-dimethylpropyl, or 1-hydroxy-2,2-dimethylbutyl.

[0063] "C 1-6 Alkoxy C 1-6 An "alkyl" group is a "C 1-6 The "C" alkyl group is defined as above. 1-6 "Alkoxy" means a mono- or di-substituted group. 1-6 When the alkoxy group is di-substituted, each C 1-6 The alkoxy groups may be the same or different. Examples of such groups include methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, isobutoxymethyl, tert-butoxymethyl, (R)-sec-butoxymethyl, (S)-sec-butoxymethyl, 2-methoxyethyl, (R)-1-propoxyethyl, (S)-1-propoxyethyl, 1-ethylpropoxymethyl, 1-methoxy-1-methylethyl, 1,2-dimethoxyethyl, 2,2-dimethylpropoxymethyl, 2-methoxy-1,1-dimethylethyl, 1-methyl-1-propoxy-ethyl, 2-isopropoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2,3-diethoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 5-ethoxypentyl, 6-methoxyhexyl, 6-ethoxyhexyl, pentyloxymethyl, and hexyloxymethyl. Preferably, C 1-4 Alkoxy C 1-3It is an alkyl group. More preferred are methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, isobutoxymethyl, 1-methoxy-1-methylethyl, 2-isopropoxyethyl, tert-butoxymethyl, (R)-sec-butoxymethyl, (S)-sec-butoxymethyl, 1-ethylpropoxymethyl, (R)-1-propoxyethyl, (S)-1-propoxyethyl, 1-ethoxy-1-methylethyl, 1-methoxy-1-methylethyl, 2,2-dimethylpropoxymethyl, 2-methoxy-1,1-dimethylethyl, and 1-methyl-1-propoxyethyl.

[0064] "C 3-8 Cycloalkyl C 1-6 An "alkyl" group is a "C 1-6 The "C" alkyl group is defined as above. 3-8 "Cycloalkyl" means a mono- or di-substituted group. 3-8 If the cycloalkyl group is di-substituted, each C 3-8 The cycloalkyl groups may be the same or different. Examples of such groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 2-cyclooctylethyl, 3-cyclopropylpropyl, 3,3-dicyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 2-cyclohexylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl, 3-cyclooctylpropyl, 4-cyclopropylbutylpropyl, and 5-cyclopropylbutylpropyl. Examples of cyclohexyl include cyclobutylmethyl, 4-cyclopentylbutyl, 4-cyclohexylbutyl, 4-cycloheptylbutyl, 4-cyclooctylbutyl, 5-cyclopropylpentyl, 5-cyclobutylpentyl, 3-cyclopentylpentyl, 5-cyclopentylpentyl, 5-cyclohexylpentyl, 5-cycloheptylpentyl, 5-cyclooctylpentyl, 6-cyclopropylhexyl, 6-cyclobutylhexyl, 6-cyclopentylhexyl, 6-cyclohexylhexyl, 6-cycloheptylhexyl, and 6-cyclooctylhexyl. Preferably, C 3-6 Cycloalkyl C 1-3 It is an alkyl group. More preferably, it is cyclohexylmethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl.

[0065] "C 3-6 Cycloalkyl C 2-6 An alkynyl group is defined as an alkynyl group as above. 2-6 The alkynyl group may have the above-defined "C 3-6 "Cycloalkyl" means a mono- or di-substituted group. 3-6 If the cycloalkyl group is di-substituted, each C 3-6 The cycloalkyl groups may be the same or different. 3-6 Cycloalkyl group monosubstituted C 2-6 It is an alkynyl group. Examples of such groups include cyclopropylethynyl, cyclobutylethynyl, cyclopentylethynyl, cyclohexylethynyl, cyclopropyl-1-propynyl, and the like. Preferably, C 3-6 Cycloalkyl C 2-4 Alkynyl. More preferably, it is cyclopropylethynyl.

[0066] "C 6-10 Aryl C 1-6 An "alkyl" group is a "C 1-6 The "C" alkyl group is defined as above. 6-10 "Aryl" means a mono- or di-substituted group. 6-10 If the aryl group is disubstituted, each C 6-10 The aryl groups may be the same or different. Examples of such groups include benzyl, naphthylmethyl, 1-phenylethyl, 2-phenylethyl, 2-naphthylethyl, 3,3-diphenylpropyl, and the like. Preferably, C 6-10 Aryl C 1-3 It is an alkyl group. More preferably, it is benzyl or 2-phenylethyl.

[0067] "Saturated heterocycle C 1-6 An "alkyl" group is a "C 1-6 The term "alkyl" refers to a group in which an "alkyl group" is mono- or di-substituted with a "saturated heterocyclic" group as defined above. When the saturated heterocyclic groups are di-substituted, each saturated heterocyclic group may be the same or different. Examples of such groups include (1-pyrrolidinyl)methyl (i.e., pyrrolidin-1-ylmethyl), (1-piperidinyl)methyl, (4-morpholinyl)methyl, (4-thiomorpholinyl)methyl, (1-piperazinyl)methyl, (4-tetrahydropyranyl)methyl, 2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl, 2-(4-morpholinyl)ethyl, 2-(4-thiomorpholinyl)ethyl, 2-(1-piperazinyl)ethyl, 2-(4-tetrahydropyranyl)ethyl, 2-(4-tetrahydropyranyl)propyl, and the like. Preferably, the saturated heterocycle C 1-3It is an alkyl group. More preferably, it is (4-tetrahydropyranyl)methyl, pyrrolidin-1-ylmethyl, 2-(1-pyrrolidinyl)ethyl, or 2-(4-tetrahydropyranyl)ethyl.

[0068] "Haro C 1-6 An "alkoxy" group is defined as "C 1-6 The term "alkoxy" refers to a group in which an "alkoxy group" is substituted with 1 to 13 "halogen atoms" as defined above. When multiple halogen atoms are substituted, the halogen atoms may be the same or different. A group in which 1 to 6 "halogen atoms" are substituted is preferred. A group in which 1 to 6 fluorine atoms are substituted is more preferred. Examples of such groups include fluoromethoxy, chloromethoxy, bromomethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 4-chlorobutoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 1,1-difluoro-2-methylpropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, pentafluoroethoxy, 2,2,2-trifluoro-1-trifluoromethyl-ethoxy, and the like. Preferably, halo C 1-4 Another preferred group is a haloC group, where the halogen is one to three fluorine atoms. 1-6 It is an alkoxy group. More preferred are trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, and 2,2,2-trifluoro-1-trifluoromethyl-ethoxy.

[0069] "Hydroxy C 1-6 An "alkoxy" group is defined as "C 1-6 The term "alkoxy" refers to a group in which a hydroxy group is mono- or di-substituted on the alkoxy group. Preferably, the hydroxy group is mono-substituted. Examples of such groups include hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxy-1-methylethoxy, 1,2-dihydroxyethoxy, 3-hydroxypropoxy, 1-hydroxy-2,2-dimethylpropoxy, 4-hydroxybutoxy, 1-hydroxy-2,2-dimethylbutoxy, 5-hydroxypentyloxy, and 6-hydroxyhexyloxy. Preferably, hydroxy C 1-4 It is an alkoxy group, more preferably 2-hydroxyethoxy.

[0070] "Carboxy C 1-6 An "alkoxy" group is defined as "C 1-6 The term "alkoxy" refers to a group in which a carboxy group is mono- or di-substituted on the alkoxy group. Preferably, the alkoxy group is mono-substituted with a carboxy group. Examples of such groups include carboxymethoxy, 2-carboxyethoxy, 3-carboxypropoxy, 2-carboxy-1-methylethoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, and the like. Preferably, carboxy C 1-4 It is an alkoxy group, and more preferably a carboxymethoxy group.

[0071] "C 1-6 Alkoxy C 1-6 An "alkoxy" group is defined as "C 1-6 The "alkoxy" group has the above definition "C 1-6 "Alkoxy" means a mono- or di-substituted group. 1-6 When the alkoxy group is di-substituted, each C 1-6 The alkoxy groups may be the same or different. Examples of such groups include methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy, (R)-sec-butoxymethoxy, (S)-sec-butoxymethoxy, 2-methoxyethoxy, (R)-1-propoxyethoxy, (S)-1-propoxyethoxy, 1-ethylpropoxyethoxy, 1-methoxy-1-methylethoxy, 1,2-dimethoxyethoxy, 2,2-dimethylpropoxy, and the like. Examples of the methoxyalkyl group include 2-methoxymethoxy, 2-methoxy-1,1-dimethylethoxy, 1-methyl-1-propoxyethoxy, 2-isopropoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2,3-diethoxypropoxy, 4-methoxybutoxy, 5-methoxypentyloxy, 5-ethoxypentyloxy, 6-methoxyhexyloxy, 6-ethoxyhexyloxy, pentyloxymethoxy, and hexyloxymethoxy. Preferably, C 1-3 Alkoxy C 2-4 It is an alkoxy group, more preferably 2-methoxyethoxy.

[0072] "C 6-10 Aryl C 1-6 An "alkoxy" group is defined as "C 1-6 The "alkoxy" group is defined as "C 6-10 "Aryl" means a mono- or di-substituted group. 6-10 If the aryl group is disubstituted, each C 6-10 The aryl groups may be the same or different. Examples of such groups include benzyloxy, naphthylmethyloxy, 1-phenylethyloxy, 2-phenylethyloxy, 2-naphthylethyloxy, 3,3-diphenylpropoxy, and the like. Preferably, C 6-10 Aryl C 1-3 It is preferably an alkyl group. More preferably, it is preferably benzyloxy.

[0073] "Haro C 1-6 Alkoxy C 1-6 An "alkyl" group is a "C 1-6 The "haloC" group is defined as above.1-6 "Alkoxy" means a mono- or di-substituted group. 1-6 When the alkoxy group is di-substituted, each haloC 1-6 The alkoxy groups may be the same or different. Examples of such groups include fluoromethoxymethyl, chloromethoxymethyl, bromomethoxymethyl, 2-fluoroethoxymethyl, 2-chloroethoxymethyl, 2-bromoethoxymethyl, 3-fluoropropoxymethyl, 3-chloropropoxymethyl, 4-fluorobutoxymethyl, 4-chlorobutoxymethyl, 1,1-difluoroethoxymethyl, 2,2-difluoroethoxymethyl, 1,1-difluoropropoxymethyl, 2,2-difluoropropoxymethyl, 3,3-difluoropropoxymethyl, 1,1-difluoro-2- Methylpropoxymethyl, trifluoromethoxymethyl, 2,3-bistrifluoromethoxypropyl, 2,2,2-trifluoroethoxymethyl, 3,3,3-trifluoropropoxymethyl, 4,4,4-trifluorobutoxymethyl, pentafluoroethoxymethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl, 1-(trifluoromethoxy)ethyl, 1-methyl-2,3-bistrifluoromethoxypropyl, 1-(2,2,2-trifluoroethoxy)ethyl, 1-(3,3,3-trifluoropropoxymethyl, 1-(4,4,4-trifluorobutoxy)ethyl, 1-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)ethyl, 2-(trifluoromethoxy)ethyl, 2-(2,2,2-trifluoroethoxy)ethyl, 2-(3,3,3-trifluoropropoxy)ethyl, 2-(4,4,4-trifluorobutoxy)ethyl, 2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)ethyl, 1-methyl-1-(trifluoromethoxy)ethyl, 1-methyl-1-(2,2,2-trifluoro oroethoxy)ethyl, 1-methyl-1-(3,3,3-trifluoropropoxy)ethyl, 1-methyl-1-(4,4,4-trifluorobutoxy)ethyl, 1-methyl-1-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)ethyl, (R)-2,2,2-trifluoro-1-methylethoxymethyl, (S)-2,2,2-trifluoro-1-methylethoxymethyl, 2,2,2-trifluoro-1,1-dimethyl-ethoxymethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl, 2,2,Examples of the 2-trifluoro-1-methyl-1-trifluoromethyl-ethoxymethyl include 3,3,3-trifluoro-2-(trifluoromethyl)propoxymethyl, 4,4,4-trifluoro-3-(trifluoromethyl)butoxymethyl, 1,1-dimethyl-3,3,3-trifluoropropoxymethyl, 2,2-dimethyl-3,3,3-trifluoropropoxymethyl, 4,4,4-trifluoro-3-(trifluoromethyl)butoxymethyl, 1,1-dimethyl-4,4,4-trifluorobutoxymethyl, 2,2-dimethyl-4,4,4-trifluorobutoxymethyl, 3-methyl-4,4,4-trifluoro-3-(trifluoromethyl)butoxymethyl, and 2-methyl-3,3,3-trifluoro-2-trifluoromethyl-propoxymethyl. Preferably, halo C 1-4 Alkoxy C 1-3 It is an alkyl group. More preferred are trifluoromethoxymethyl, 2,2,2-trifluoroethoxymethyl, 3,3,3-trifluoropropoxymethyl, (R)-2,2,2-trifluoro-1-methylethoxymethyl, (S)-2,2,2-trifluoro-1-methylethoxymethyl, 2,2,2-trifluoro-1,1-dimethyl-ethoxymethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl, and 2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethoxymethyl.

[0074] "Haro C 3-8 A "cycloalkyl" group is a "C 3-8 The term "cycloalkyl" refers to a group in which 1 to 15 "halogen atoms" as defined above are substituted on a "cycloalkyl" group. Preferably, the group is substituted with 1 to 2 "halogen atoms". When multiple halogen atoms are substituted, the respective halogen atoms may be the same or different. Examples of such groups include 2-fluorocyclopropyl, 2-chlorocyclopropyl, 3-fluorocyclobutyl, 3-chlorocyclobutyl, 3-fluorocyclopentyl, 3-chlorocyclopentyl, 4-fluorocyclohexyl, 4-fluorocycloheptyl, 5-fluorocyclooctyl, 2,2-difluorocyclopropyl, 2,2-dichlorocyclopropyl, 3,3-difluorocyclobutyl, 3,3-dichlorocyclobutyl, 3,3-difluorocyclopentyl, 3,3-dichlorocyclopentyl, 4,4-difluorocyclohexyl, and 4,4-dichlorocyclohexyl. Preferably, halo C 3-6 Another preferred group is haloC, where the halogen is 1 to 3 fluorine atoms. 3-8 It is a cycloalkyl group. More preferably, it is 4,4-difluorocyclohexyl.

[0075] "C 1-6 An "alkylsulfanyl" group is defined as "C 1-6 It means a sulfanyl group substituted with an "alkyl" group. Examples of such groups include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, 1,1-dimethylpropylsulfanyl, 2,2-dimethylpropylsulfanyl, hexylsulfanyl, and the like. Preferably it is isobutylsulfanyl.

[0076] "C 1-6 An "alkylsulfonyl" group is defined as "C 1-6 It means a sulfonyl group substituted with an "alkyl" group. Examples of such groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl (i.e., propane-2-sulfonyl), n-butylsulfonyl, isobutylsulfonyl (i.e., 2-methylpropane-1-sulfonyl), sec-butylsulfonyl, tert-butylsulfonyl (i.e., 2-methyl-propane-2-sulfonyl), pentylsulfonyl, 1,1-dimethylpropylsulfonyl, hexylsulfonyl, 2,2-dimethylpropylsulfonyl (i.e., 2,2-dimethylpropane-1-sulfonyl), and the like. Preferred are propane-2-sulfonyl, 2-methylpropane-1-sulfonyl, 2-methyl-propane-2-sulfonyl, and 2,2-dimethylpropane-1-sulfonyl.

[0077] "Haro C 1-6 An "alkylsulfonyl" group is a "haloC" group as defined above. 1-6 It means a sulfonyl group substituted with an "alkyl" group. Examples of such groups include 2-fluoroethanesulfonyl, 2-chloroethanesulfonyl, 2-bromoethanesulfonyl, 3-fluoropropanesulfonyl, 3-chloropropanesulfonyl, 4-fluorobutanesulfonyl, 4-chlorobutanesulfonyl, 1,1-difluoroethanesulfonyl, 1,1-difluoropropanesulfonyl, 1,1-difluoro-2-methylpropanesulfonyl, trifluoromethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, 3,3,3-trifluoropropanesulfonyl, 4,4,4-trifluorobutanesulfonyl, pentafluoroethanesulfonyl, and 2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonyl. Preferred are 2,2,2-trifluoroethanesulfonyl and 3,3,3-trifluoropropanesulfonyl.

[0078] "C 1-8 An "alkylcarbonyl" group is a "C 1-8 It means a carbonyl group substituted with an "alkyl" group. Examples of such groups include acetyl, propionyl, 2,2-dimethylpropionyl, butyryl, 3-methylbutyryl, 2,2-dimethylbutyryl, pentanoyl, 4-methylpentanoyl, 3,4-dimethylpentanoyl, heptanoyl, and nonanoyl. Preferred are 2,2-dimethylbutyryl and 2,2-dimethylpropionyl.

[0079] "C 1-6 An "alkyloxycarbonyl" group is a "C 1-6 It means a carbonyl group substituted with an "alkoxy" group. Examples of such groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1,1-dimethylpropoxycarbonyl, neopentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 1-ethylpropoxycarbonyl, and hexyloxycarbonyl.

[0080] "C 1-6 The "alkoxycarbonyloxy" group is defined as "C 1-6 "Alkoxy" means a carbonyloxy group substituted with an "alkoxy" group. Examples of such groups include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, isopentyloxycarbonyloxy, 2-methylbutoxycarbonyloxy, 1,1-dimethylpropoxycarbonyloxy, neopentyloxycarbonyloxy, 3,3-dimethylbutoxycarbonyloxy, 1-ethylpropoxycarbonyloxy, and hexyloxycarbonyloxy. Preferably, C 1-4It is an alkoxycarbonyloxy group, more preferably a tert-butoxycarbonyloxy group. Preferably it is tert-butoxycarbonyl.

[0081] "C 1-6 Alkylsulfonyl C 1-6 An "alkyl" group is a "C 1-6 The "C" alkyl group is defined as above. 1-6 "Alkylsulfonyl" means a mono- or di-substituted group. 1-6 When the alkylsulfonyl group is disubstituted, each C 1-6 The alkylsulfonyl groups may be the same or different. 1-6 The alkylsulfonyl group is a mono-substituted group. Examples of such groups include methylsulfonylmethyl, ethylsulfonylmethyl (i.e., ethanesulfonylmethyl), propylsulfonylmethyl, isopropylsulfonylmethyl (i.e., propane-2-sulfonylmethyl), n-butylsulfonylmethyl, isobutylsulfonylmethyl (i.e., 2-methylpropane-1-sulfonylmethyl), sec-butylsulfonylmethyl, tert-butylsulfonylmethyl (i.e., 2-methyl-propane-2-sulfonylmethyl), pentylsulfonylmethyl, 1,1-dimethylpropylsulfonylmethyl, and hexylsulfonylmethyl. , 2,2-dimethylpropylsulfonylmethyl (i.e., 2,2-dimethylpropane-1-sulfonylmethyl), 1-ethylsulfonyl-ethyl (i.e., 1-ethanesulfonyl-ethyl), 1-isopropylsulfonyl-ethyl (i.e., 1-(propane-2-sulfonyl)-ethyl), 2-ethylsulfonyl-ethyl (i.e., 2-ethanesulfonyl-ethyl), 2-isopropylsulfonyl-ethyl (i.e., 2-(propane-2-sulfonyl)-ethyl), 2,3-bismethanesulfonylpropyl, 2,3-bismethanesulfonyl-1-methylpropyl, and the like. Preferably, C 1-4 Alkylsulfonyl C 1-3It is an alkyl group. More preferably, it is ethanesulfonylmethyl or propane-2-sulfonylmethyl.

[0082] "Haro C 1-6 Alkylsulfonyl C 1-6 An "alkyl" group is a "C 1-6 The "haloC" group is defined as above. 1-6 The alkylsulfonyl group is a mono- or di-substituted group. 1-6 When the alkylsulfonyl group is disubstituted, each haloC 1-6 The alkylsulfonyl groups may be the same or different. Preferably, the alkylsulfonyl groups are haloC 1-6 The alkylsulfonyl group is a mono-substituted group. Examples of such groups include 2-fluoroethanesulfonylmethyl, 2-chloroethanesulfonylmethyl, 2-bromoethanesulfonylmethyl, 3-fluoropropanesulfonylmethyl, 3-chloropropanesulfonylmethyl, 4-fluorobutanesulfonylmethyl, 4-chlorobutanesulfonylmethyl, 1,1-difluoroethanesulfonylmethyl, 1,1-difluoropropanesulfonylmethyl, 1,1-difluoro-2-methylpropanesulfonylmethyl, trifluoromethanesulfonylmethyl, 2,2, 2-Trifluoroethanesulfonylmethyl, 3,3,3-trifluoropropanesulfonylmethyl, 4,4,4-trifluorobutanesulfonylmethyl, pentafluoroethanesulfonylmethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonylmethyl, 1-trifluoromethanesulfonyl-ethyl, 1-(2,2,2-trifluoroethanesulfonyl)-ethyl, 1-(3,3,3-trifluoropropanesulfonyl)-ethyl, 1-(4,4,4-trifluorobutanesulfonyl) -ethyl, 1-(2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonyl)-ethyl, 2-trifluoromethanesulfonyl-ethyl, 2-(2,2,2-trifluoroethanesulfonyl)-ethyl, 2-(3,3,3-trifluoropropanesulfonyl)-ethyl, 2-(4,4,4-trifluorobutanesulfonyl)-ethyl, 2-(2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonyl)-ethyl, 1-methyl-1-trifluoromethanesulfonyl-ethyl, 1-methyl Examples of such fluoroalkyl substances include 1-methyl-1-(2,2,2-trifluoroethanesulfonyl)-ethyl, 1-methyl-1-(3,3,3-trifluoropropanesulfonyl)-ethyl, 1-methyl-1-(4,4,4-trifluorobutanesulfonyl)-ethyl, 1-methyl-1-(2,2,2-trifluoro-1-trifluoromethyl-ethanesulfonyl)-ethyl, 2,3-bis(2,2,2-trifluoroethanesulfonyl)propyl, and 1-methyl-2,3-bis(2,2,2-trifluoroethanesulfonyl)propyl. Preferably, halo C 1-4 Alkylsulfonyl C 1-3It is an alkyl group. Preferably, it is 2,2,2-trifluoroethanesulfonylmethyl.

[0083] "C 1-6 Alkyl Sulfanyl C 1-6 An "alkoxy" group is defined as "C 1-6 The "alkoxy" group is defined as "C 1-6 "Alkylsulfanyl" means a mono- or di-substituted group. 1-6 When the alkylsulfanyl group is disubstituted, each C 1-6 The alkylsulfanyl groups may be the same or different. 1-6 The alkylsulfanyl group is a mono-substituted group. Examples of such groups include 2-methylsulfanylethoxy, 2-ethylsulfanylethoxy, 2-propylsulfanylethoxy, 2-isopropylsulfanylethoxy, 2-n-butylsulfanylethoxy, 2-isobutylsulfanylethoxy, 2-sec-butylsulfanylethoxy, 2-tert-butylsulfanylethoxy, 2-pentylsulfanylethoxy, 2-(1,1-dimethylpropylsulfanylethoxy), 2-(2,2-dimethylpropylsulfanylethoxy), 2-hexylsulfanylethoxy, 3-methylsulfanylethoxy, 3-ethylsulfanylethoxy, 3-propylsulfanylethoxy, and 3-isopropylsulfanylethoxy. , 3-n-butylsulfanylpropoxy, 3-isobutylsulfanylpropoxy, 3-sec-butylsulfanylpropoxy, 3-tert-butylsulfanylpropoxy, 3-pentylsulfanylpropoxy, 3-(1,1-dimethylpropylsulfanyl)propoxy, 3-(2,2-dimethylpropylsulfanyl)propoxy, 3-hexylsulfanylpropoxy, 2-methyl-3-methylsulfanyl-propoxy, 2-methyl-3-isopropylsulfanyl-propoxy, 2-methyl-3-(2,2-dimethylpropylsulfanyl)-propoxy, 2,3-bismethylsulfanylpropoxy, 1-methyl-2,3-bismethylsulfanylpropoxy, and the like. Preferably, C 1-3Alkyl Sulfanyl C 2-4 Alkoxy is more preferred. More preferred is 3-methylsulfanylpropoxy.

[0084] "C 1-6 Alkylsulfonyl C 1-6 An "alkoxy" group is defined as "C 1-6 The "alkoxy" group is defined as "C 1-6 "Alkylsulfonyl" means a mono- or di-substituted group. 1-6 When the alkylsulfonyl group is disubstituted, each C 1-6 The alkylsulfonyl groups may be the same or different. 1-6 The alkylsulfonyl group is a mono-substituted group. Examples of such groups include 2-methylsulfonylethoxy, 2-ethylsulfonylethoxy, 2-propylsulfonylethoxy, 2-isopropylsulfonylethoxy, 2-n-butylsulfonylethoxy, 2-isobutylsulfonylethoxy, 2-sec-butylsulfonylethoxy, 2-tert-butylsulfonylethoxy, 2-pentylsulfonylethoxy, 2-(1,1-dimethylpropylsulfonyl)ethoxy, 2-(2,2-dimethylpropylsulfonyl)ethoxy, 2-hexylsulfonylethoxy, 3-methylsulfonylpropoxy, 3-ethylsulfonylpropoxy, 3-propylsulfonylpropoxy, and 3-isopropylsulfonylpropoxy. , 3-n-butylsulfonylpropoxy, 3-isobutylsulfonylpropoxy, 3-sec-butylsulfonylpropoxy, 3-tert-butylsulfonylpropoxy, 3-pentylsulfonylpropoxy, 3-(1,1-dimethylpropylsulfonyl)propoxy, 3-(2,2-dimethylpropylsulfonyl)propoxy, 3-hexylsulfonylpropoxy, 2-methyl-3-methylsulfonylpropoxy, 2-methyl-3-isopropylsulfonylpropoxy, 2-methyl-3-(2,2-dimethylpropylsulfonyl)-propoxy, 2,3-bismethylsulfonylpropoxy, 1-methyl-2,3-bismethylsulfonylpropoxy, and the like. Preferably, C 1-3 Alkylsulfonyl C2-4 Alkoxy is more preferably 3-methanesulfonylpropoxy.

[0085] "Haro C 1-6 Alkylamino C 1-6 An "alkyl" group is a "C 1-6 The "haloC" group is defined above. 1-6 The amino group is preferably a mono- or di-substituted group with a haloC group. 1-6 An amino group mono-substituted with an alkyl group is a mono-substituted group. Examples of the group include 2-fluoroethylaminomethyl, 2-chloroethylaminomethyl, 2-bromoethylaminomethyl, 3-fluoropropylaminomethyl, 3-chloropropylaminomethyl, 4-fluorobutylaminomethyl, 4-chlorobutylaminomethyl, 1,1-difluoroethylaminomethyl, 1,1-difluoropropylaminomethyl, 1,1-difluoro-2-methylpropylaminomethyl, 2,2,2-trifluoroethylaminomethyl, 3,3,3-trifluoropropylaminomethyl, 4,4,4-trifluorobutylaminomethyl, 2,2,3,3,3-pentafluoropropylaminomethyl, 1-(2,2,2-trifluoroethylamino)-ethyl, 2-(2,2,2-trifluoroethylamino)-ethyl, 1-methyl-1-(2,2,2-trifluoroethylamino)-ethyl, and bis-(2,2,2-trifluoroethyl)aminomethyl. Preferably, halo C 1-3 Alkylamino C 1-3 It is an alkyl group. More preferably, it is 2,2,2-trifluoroethylaminomethyl.

[0086] "C 3-8 "Cycloalkyloxy" groups include, for example, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like. Preferably, C 3-6 It is a cycloalkyloxy group. More preferably, it is a cyclopentyloxy or cyclobutoxy group.

[0087] The term "saturated heterocycle-oxy" group refers to a group formed by bonding an oxygen atom to a chemically permissible carbon atom in the above-defined "saturated heterocycle" group. Examples of such groups include oxetan-3-yloxy, tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, (S)-tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, (R)-tetrahydropyran-3-yloxy, (S)-tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy, tetrahydrothiopyran-4-yloxy, and the like. Preferred is oxetan-3-yloxy.

[0088] "Saturated heterocyclic oxy C 1-6 An "alkyl" group is a "C 1-6 "Saturated heterocyclic oxy" means a group in which an "alkyl" group is mono- or di-substituted with the above-defined "saturated heterocyclic oxy" group. When the saturated heterocyclic oxy group is di-substituted, each saturated heterocyclic oxy group may be the same or different. Examples of the group include oxetan-3-yloxymethyl, tetrahydrofuran-3-yloxymethyl, (R)-tetrahydrofuran-3-yloxymethyl, (S)-tetrahydrofuran-3-yloxymethyl, tetrahydropyran-3-yloxymethyl, (R)-tetrahydropyran-3-yloxymethyl, (S)-tetrahydropyran-3-yloxymethyl, tetrahydropyran-4-yloxymethyl, pyrrolidin-3-yloxymethyl, piperidin-3-yloxymethyl, piperidin-4-yloxymethyl, tetrahydrothiopyran-4-yloxymethyl, 1-(oxetan-3-yloxy)-ethyl, 1-(tetrahydropyran-4-yloxy)-ethyl, 2-(oxetan-3-yloxy)-ethyl, 2-(tetrahydropyran-4-yloxy)-ethyl, and the like. Preferably, the saturated heterocyclic oxy C 1-3It is an alkyl group. More preferably, it is oxetan-3-yloxymethyl, (R)-tetrahydrofuran-3-yloxymethyl, (S)-tetrahydrofuran-3-yloxymethyl, (R)-tetrahydropyran-3-yloxymethyl, (S)-tetrahydropyran-3-yloxymethyl, or tetrahydropyran-4-yloxymethyl.

[0089] "Saturated heterocycle C 1-6 An "alkoxy" group is defined as "C 1-6 "Alkoxy" refers to a group in which an "alkoxy" group is mono- or di-substituted with a "saturated heterocyclic" group as defined above. When the saturated heterocyclic group is di-substituted, each saturated heterocyclic group may be the same or different. Examples of such groups include (3-pyrrolidinyl)methoxy (i.e., pyrrolidin-3-ylmethoxy), (4-piperidinyl)methoxy, oxetan-3-ylmethoxy, (4-tetrahydropyranyl)methoxy, 2-(1-pyrrolidinyl)ethoxy, 2-(1-piperidinyl)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(4-thiomorpholinyl)ethoxy, 2-(1-piperazinyl)ethoxy, 2-oxetan-3-ylethoxy, 2-(4-tetrahydropyranyl)ethoxy, 2-(4-tetrahydropyranyl)propoxy, and the like. Preferably, the saturated heterocycle C 1-3 It is an alkoxy group. More preferably, it is oxetan-3-ylmethoxy.

[0090] "C 6-10 Aryl C 1-6 Alkoxy C 1-6 An "alkoxy" group is defined as "C 1-6 The "alkoxy" group is defined as "C 6-10 Aryl C 1-6 "Alkoxy" means a mono- or di-substituted group. 6-10 Aryl C 1-6 When the alkoxy group is di-substituted, each C 6-10 Aryl C 1-6 The alkoxy groups may be the same or different. Examples of such groups include 2-benzyloxyethoxy, 2-naphthylmethyloxyethoxy, 2-(1-phenylethyloxy)-ethoxy, 2-(2-phenylethyloxy)-ethoxy, 2-(2-naphthylethyloxy)-ethoxy, 2-(3,3-diphenylpropoxy)-ethoxy, 3-benzyloxypropoxy, 3-naphthylmethyloxypropoxy, 3-(1-phenylethyloxy)-propoxy, 3-(2-phenylethyloxy)-propoxy, 3-(2-naphthylethyloxy)-propoxy, 3-(3,3-diphenylpropoxy)-propoxy, 3-benzyloxy-2-methylpropoxy, and 2,3-bisbenzyloxypropoxy. Preferably, C 6-10 Aryl C 1-3 Alkyl C 1-3 It is an alkoxy group. More preferably, it is 2-benzyloxyethoxy.

[0091] "-(CH 2 ) m -X a -(C=O)-" in X a When is a "bond", it is "-(CH 2 ) m -(C=O)-".

[0092] In general formula [I], R 3 may be substituted on a carbon atom in the heterocycle to the extent that is chemically permissible, but is not substituted on a heteroatom.

[0093] In general formula [Ib], ring Cy a R on the seven heterocycles represented by the formula 3a and R 3b may be substituted on a carbon atom in the heterocycle to the extent that is chemically permissible, but is not substituted on a heteroatom.

[0094] Ring Cy a but formula: [ka] And "The two R's 3b When they are bonded to the same carbon atom, together with the carbon to which they are bonded, C 3-6 The term "may form a cycloalkyl group" means, for example, [ka] Examples include:

[0095] Ring Cy a but formula: [ka] And R 3b C 1-6 In the case of an alkyl group, "R 3b Together with the carbon adjacent to the carbon to which it is bonded, C 3-6 The term "may form a cycloalkyl group" means, for example, [ka] Examples include:

[0096] Preferred embodiments of each group in the compound represented by the general formula [I] (hereinafter also referred to as the "compound of the present invention") are explained below.

[0097] A preferred embodiment of the ring Cy is 6-10 It is aryl. Preferred examples of the ring Cy include phenyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclohexenyl, and the like. More preferably, the ring Cy is phenyl. Preferred examples of n1 include 1, 2, 3, and 4. More preferably, n1 is 1.

[0098] R 1 A preferred embodiment of the (1) a halogen atom, (2) a hydroxy group, (3) a carboxy group, (4) C 1-5 Alkyl groups, (5) C 1-4 Alkoxy groups, (6) C 3-6 Cycloalkyl groups, (7) HaroC 1-4 Alkyl groups, (8) Hydroxy C 1-4 Alkyl groups, (9) C 1-4 Alkoxy C 1-3 Alkyl groups, (10) HaroC 1-4 an alkoxy group, or (11) Carboxy C 1-4 is an alkoxy group, However, when n1 is 2, 3, or 4, each R 1 may be the same or different.

[0099] R 1 Another preferred embodiment of the (1) a halogen atom, (2) C 1-6 Alkyl groups, (3) C 1-6 Alkoxy groups, (4) HaroC 1-6 Alkyl groups, (5) C 1-6 Alkoxy C 1-6 an alkyl group, or (6) HaroC 1-6 is an alkoxy group, However, when n1 is 2, 3, or 4, each R 1 may be the same or different.

[0100] R 1Preferred specific examples of are fluoro, chloro, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1,1-dimethylpropyl, ethoxy, cyclopropyl, trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl, hydroxymethyl, 1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, carboxymethoxy, and the like.

[0101] R 2 A preferred embodiment of the (1) C 1-6 Alkyl groups, (2) C 3-6 Cycloalkyl C 1-3 Alkyl groups, (3) C 6-10 Aryl C 1-3 Alkyl groups, (4) Saturated heterocycle C 1-3 an alkyl group (the saturated heterocycle is a 5- or 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); (5) C 3-7 Cycloalkyl groups, (6) HaroC 1-4 an alkyl group, wherein the halo is 1 to 3 fluorine atoms; (7) C 1-4 Alkoxy C 1-3 Alkyl groups, (8) HaroC 3-8 cycloalkyl groups, wherein the halo is 1 to 3 fluorine atoms; (9) a phenyl group, (a) a halogen atom, (b)C 1-3 Alkyl groups, (c)C 1-3 Alkoxy groups, and (d) Carboxy C 1-3 alkoxy groups), or (10) Saturated heterocyclic group (the saturated heterocyclic ring is a 5- or 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 4 C 1-3 (which may be substituted with an alkyl group) It is.

[0102] R 2 Another preferred embodiment of the present invention is 6-10 Aryl group (C 6-10 The aryl group is (a) a halogen atom, (b)C 1-6 Alkyl groups, (c)C 1-6 Alkoxy groups, and (d) Carboxy C 1-6 may be substituted with 1 to 4 substituents selected from alkoxy groups. It is.

[0103] Preferred R 2 Specific examples of the aryl group include ethyl, propyl, isopropyl, 2-methylpropyl, tert-butyl, 3-methylbutyl, 3,3-dimethylbutyl, hexyl, cyclohexylmethyl, cyclohexylethyl, benzyl, 2-phenylethyl, 4-tetrahydropyranylmethyl, 2-(4-tetrahydropyranyl)ethyl, 2-(1-pyrrolidinyl)ethyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, 2-isopropoxyethyl, 2-cyclo Pentylethyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-4-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-carboxymethoxyphenyl, 4-tetrahydropyranyl, 2,6-dimethyl-4-tetrahydropyranyl, and the like. More preferred R2 is a phenyl group.

[0104] Preferred examples of n2 are 0, 1 or 2. More preferably, n2 is 0 or 1.

[0105] Preferred examples of m are 0, 1 or 2.

[0106] R 3 Preferred examples of the radical are methyl, ethyl or 2-hydroxyethyl.

[0107] X a Preferred examples of are a bond, NH or N-methyl. More preferred X a is a bond.

[0108] X b A preferred example of is NH.

[0109] R 4 A preferred example of is a hydrogen atom or methyl.

[0110] Preferred embodiments for each group of the compound represented by the general formula [Ib] (hereinafter also referred to as "the compound of the present invention") are explained below.

[0111] A preferred embodiment of the ring Cy is 6-10 It is aryl. Preferred examples of the ring Cy include phenyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclohexenyl, and the like. More preferably, the ring Cy is phenyl. Preferred examples of n1 include 1, 2, 3, and 4. More preferably, n1 is 1 or 2.

[0112] R 1a A preferred embodiment of the (1) Halogen atoms (2) C 1-6 Alkyl groups, (3) C1-6 Alkoxy groups, (4) C 3-6 Cycloalkyl groups, (5) Haro C 1-6 Alkyl groups, (6) Hydroxy C 1-6 Alkyl groups, (7) C 1-6 Alkoxy C 1-6 Alkyl groups, (8) HaroC 1-6 Alkoxy C 1-6 Alkyl groups, (9) C 1-6 Alkylsulfonyl C 1-6 Alkyl groups, (10) HaroC 1-6 Alkylamino C 1-6 Alkyl groups, (11) HaroC 1-6 Alkoxy groups, (12) Carboxy C 1-6 Alkoxy groups, (13) Saturated heterocycle C 1-6 an alkyl group (wherein the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); or (14) Saturated heterocyclic oxy C 1-6 an alkyl group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); However, when n1 is 2, 3, or 4, each R 1a may be the same or different.

[0113] R 1a Another preferred embodiment of the (1) a halogen atom, (2) C 1-6 Alkyl groups, (3) C 1-6 Alkoxy groups, (4) HaroC 1-6 Alkyl groups, (5) C 1-6 Alkoxy C 1-6 Alkyl groups, (6) HaroC1-6 an alkoxy group, or (7) HaroC 1-6 Alkoxy group C 1-6 is an alkyl group, However, when n1 is 2, 3, or 4, each R 1a may be the same or different.

[0114] R 1a Another preferred embodiment of the (1) a halogen atom, (2) C 1-6 Alkyl groups, (3) Haro C 1-6 an alkoxy group, or (4) HaroC 1-6 Alkoxy group C 1-6 is an alkyl group, However, when n1 is 2, 3, or 4, each R 1a may be the same or different.

[0115] R 1aPreferred specific examples of the aryl group include chloro, fluoro, hydroxy, carboxy, methyl, ethyl, n-butyl, tert-butyl, propyl, isopropyl, 1,1-dimethylpropyl, 2-methylpropyl, 3,3-dimethylbut-1-enyl, 3,3-dimethylbut-1-ynyl, ethoxy, propoxy, 1,1-dimethylpropoxy, 2,2-dimethylpropoxy, isopropoxy, butoxy, isobutoxy, 3,3-dimethylbutoxy, tert-butoxy, 3-methylbutoxy, cyclopropyl, trifluoro. fluoromethyl, 1,1-difluoroethyl, 1,1-difluoro-2-methylpropyl, 1,1-difluoropropyl, hydroxymethyl, 1-hydroxy-1-methylethyl, 1-hydroxy-2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylbutyl, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, isobutoxymethyl, tert-butoxymethyl, (R)-sec-butoxymethyl, (S)-sec-butoxymethyl, 1-ethylpropoxymethyl, (R)-1-propoxymethyl, propoxyethyl, (S)-1-propoxyethyl, 1-ethoxy-1-methylethyl, 1-methoxy-1-methylethyl, 2,2-dimethylpropoxymethyl, 2-methoxy-1,1-dimethylethyl, 1-methyl-1-propoxyethyl, trifluoromethoxymethyl, 2,2,2-trifluoroethoxymethyl, 3,3,3-trifluoropropoxymethyl, (R)-2,2,2-trifluoro-1-methylethoxymethyl, (S)-2,2,2-trifluoro-1-methylethoxymethyl, 2,2,2-trifluoro-1-methylethoxymethyl, Trifluoro-1,1-dimethyl-ethoxymethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl, 2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethoxymethyl, ethanesulfonylmethyl, propane-2-sulfonylmethyl, 2,2,2-trifluoroethanesulfonylmethyl, 2,2,2-trifluoroethylaminomethyl, cyclopropylethynyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-Trifluorobutoxy, carboxymethoxy, isobutylsulfanyl, propane-2-sulfonyl, 2-methylpropane-1-sulfonyl, 2-methyl-propane-2-sulfonyl, 2,2-dimethylpropane-1-sulfonyl, 2,2,2-trifluoroethanesulfonyl, 3,3,3-trifluoropropanesulfonyl, 2,2-dimethylbutyryl, 2,2-dimethylpropionyl, tert-butoxycarbonyl, propylcarbamoyl, isopropylcarba moyl, methylpropylcarbamoyl, 2,2,2-trifluoroethylcarbamoyl, isopropylmethylcarbamoyl, pyrrolidin-1-ylmethyl, (R)-tetrahydrofuran-3-yloxymethyl, (S)-tetrahydrofuran-3-yloxymethyl, (R)-tetrahydropyran-3-yloxymethyl, (S)-tetrahydropyran-3-yloxymethyl, oxetan-3-yloxymethyl, tetrahydropyran-4-yloxymethyl, and the like.

[0116] R 1a More preferred examples include n-butyl, trifluoromethoxy, 2,2,2-trifluoroethoxymethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl, (R)-2,2,2-trifluoro-1-methylethoxymethyl, (S)-2,2,2-trifluoro-1-methylethoxymethyl, 2,2,2-trifluoro-1,1-dimethyl-ethoxymethyl, and the like.

[0117] R 2a A preferred embodiment of the (1) C 6-10 Aryl group (C 6-10 The aryl group is (a) a halogen atom, (b) a hydroxy group, (c)C 1-6 Alkyl groups, (d) C 2-8 Alkenyl groups, (e)C 2-6 Alkynyl groups, (f)C 1-6 Alkoxy group (g) Halo C 1-6Alkyl groups, (h)C 1-6 Alkoxy C 1-6 Alkyl groups, (i) Halo C 1-6 Alkoxy groups, (j) Hydroxy C 1-6 Alkoxy groups, (k)C 1-6 Alkoxy C 1-6 Alkoxy groups, (l) Carboxy C 1-6 Alkoxy groups, (m)C 6-10 Aryl C 1-6 Alkoxy groups, (n)C 1-6 Alkyl Sulfanyl C 1-6 Alkoxy groups, (o)C 1-6 Alkylsulfonyl C 1-6 Alkoxy groups, (p)C 6-10 Aryl C 1-6 Alkoxy C 1-6 Alkoxy groups, (q) Saturated heterocycle C 1-6 An alkoxy group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 2 C 1-6 may be substituted with an alkyl group, (r) a saturated heterocyclic oxy group (the saturated heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom), (s)C 3-8 cycloalkyloxy groups, (t)C 1-6 alkoxycarbonyloxy groups, and (u)C 1-6 alkylsulfonyl groups), or (2) A saturated heterocyclic group (the saturated heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 4 C 1-6 (which may be substituted with an alkyl group) It is.

[0118] R 2aPreferred specific examples of the aryl group include ethyl, propyl, isopropyl, 2-methylpropyl, tert-butyl, 3-methylbutyl, 3,3-dimethylbutyl, hexyl, cyclohexylmethyl, cyclohexylethyl, benzyl, 2-cyclopentylethyl, 2-phenylethyl, 4-tetrahydropyranylmethyl, 2-(4-tetrahydropyranyl)ethyl, 2-(1-pyrrolidinyl)ethyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2-isopropyl, 1,2-difluorophenyl ... propyloxyethyl, 4,4-difluorocyclohexyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 5-chloro-2-fluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2,5-dimethyl Phenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3-isobutylphenyl, 3-(3,3-dimethyl-butyl)phenyl, 3-tert-butylphenyl, 3-(2-methylpropenyl)-phenyl, ((E)-3-propenyl)-phenyl, 3-(3,3-dimethylbut-1-ynyl)-phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2 -ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 3-propoxyphenyl, 4-propoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 3-isobutoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methoxymethyl-phenyl, 3-isopropoxymethyl-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 4-(2,2,2-trifluoro-ethoxy)-phenyl, 4-(3,3,3-trifluoro-propoxy)-phenyl, 3-(2,2,2-trifluoro-ethoxy)-phenyl, 3-(2-hydroxyethoxy)-phenyl, 3-(2-methoxyethoxy)-phenyl, 3-carboxymethoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 3-(3-methylsulfanylpropoxy)-phenyl, 3-(3-methanesulfonylpropoxy)-phenyl, 3-(2-benzyloxyethoxy)-phenyl, 3-(3-methyloxetan-3-ylmethoxy)-phenyl, 3-(oxetan-3-yloxy)-phenyl, 3-cyclopentyloxyphenyl, 3-cyclobutoxyphenyl, 3-tert-butoxycarbonyloxy-phenyl, 3-methanesulfonyl-phenyl, 4-tetrahydropyranyl, 2,6-dimethyl-4-tetrahydropyranyl, 4-fluoro-2-methyl-phenyl, 4-fluoro-3- (2-hydroxyethoxy)-phenyl, 4-fluoro-3-(2-methoxyethoxy)-phenyl, 2-fluoro-3-(2-methoxyethoxy)-phenyl, 2-fluoro-5-(2-methoxyethoxy)-phenyl, 2-fluoro-3-(2-methoxyethoxy)-phenyl, 2-fluoro-3-methoxy-phenyl, 4-fluoro-3-methoxy-phenyl, 2-fluoro-5-methoxy-phenyl, 3-fluoro-5-methoxy-phenyl, 3-ethoxy-4-fluoro-phenyl, 3-ethoxy-2-fluoro-phenyl, 5-ethoxy-2-fluoro-phenyl, 3-ethoxy-5-fluoro-phenyl, 4-fluoro-3-isopropoxy-phenyl, 2-fluoro-5-isopropoxy-phenyl, 3-fluoro-5-isopropoxy-phenyl, 2-fluoro-3-isopropoxy-phenyl, 4-fluoro-3-propoxy-phenyl, etc.

[0119] R 2a More preferred examples of the aryl group include phenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, and 4-fluorophenyl.

[0120] Preferred examples of n2 are 0, 1 or 2. More preferably, n2 is 0 or 1.

[0121] A preferred embodiment of m2 is 1 or 2. A preferred embodiment of m3 is 1 or 2. However, the sum of m2 and m3 is 3 or 4.

[0122] A preferred embodiment of m4 is 1 or 2. Preferred examples of m5 are 0, 1 or 2. However, the sum of m4 and m5 is 2, 3, or 4.

[0123] A preferred example of m6 is 0 or 1. Preferred examples of m7 are 0, 1, or 2. However, the sum of m6 and m7 is 1 or 2.

[0124] A preferred example of m8 is 1. A preferred example of m9 is 1.

[0125] Ring Cy a A preferred embodiment of the compound is [ka] TIFF2025039641000029.tif156162 TIFF2025039641000030.tif230162 The file is TIFF2025039641000031.tif26162.

[0126] Ring Cy a Another preferred embodiment of the compound is [ka] TIFF2025039641000033.tif228162 The file is TIFF2025039641000034.tif26162.

[0127] Ring Cya A more preferred embodiment of the compound is [ka] TIFF2025039641000036.tif180162 It is.

[0128] R 3a Preferred examples of are hydroxy, methyl, ethyl or 2-hydroxyethyl.

[0129] R 3a A more preferred example of is methyl.

[0130] R 3b Preferred specific examples of are hydroxy, methyl, ethyl, 2-hydroxyethyl, a cyclopropyl group formed by two methyl groups bonded to the same carbon and the carbon to which they are bonded, or a cyclopropyl group formed by two methyl groups bonded to adjacent carbons together.

[0131] R 3b A more preferred example of is methyl.

[0132] R 4b Preferred examples of the group include a hydrogen atom, methyl, ethyl, propyl, isopropyl, carboxymethyl, 2,2,2-trifluoroethyl, and 2-methoxyethyl.

[0133] R 4b A more preferred example of is a hydrogen atom.

[0134] A preferred embodiment of the compound of the present invention is a compound represented by the formula [I], in which ring Cy is phenyl, n1 is 1, 2, 3 or 4, and X b is a compound of general formula [II]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0135] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [I], ring Cy is phenyl, n1 is 1, 2, 3 or 4, n2 is 0, m is 1, and X a is a bond and X b is a compound of the general formula [III]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0136] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [I], ring Cy is phenyl, n1 is 1, 2, 3 or 4, n2 is 1, m is 1, and X a is a bond and X b is a compound of general formula [IV]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0137] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [I], ring Cy is phenyl, n1 is 1, 2, 3 or 4, n2 is 0, m is 2, and X a is a bond and X b is a compound of the general formula [V]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0138] In a preferred embodiment of the compound of the present invention, in the general formula [Ib], the ring Cy is phenyl, and the ring Cy a is the formula: [ka] The general formula [VI] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0139] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [Ib], ring Cy is phenyl, and ring Cy a is the formula: [ka] The general formula [VII] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0140] Another preferred embodiment of the compound of the present invention is a compound represented by the formula [Ib], wherein ring Cy is phenyl, and ring Cy a is the formula: [ka] The general formula [VIII] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0141] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [Ib], ring Cy is phenyl, and ring Cy a is the formula: [ka] The general formula [IX] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0142] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [Ib], ring Cy is phenyl, and ring Cy a is the formula: [ka] The general formula [X] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0143] In a preferred embodiment of the compound of the present invention, in the general formula [Ib], the ring Cy is phenyl, and the ring Cy a is the formula: [ka] The general formula [XI] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0144] In a preferred embodiment of the compound of the present invention, in the general formula [Ib], the ring Cy is phenyl, and the ring Cy a is the formula: [ka] The general formula [XII] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0145] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [Ib], ring Cy is phenyl, and ring Cy a is the formula: [ka] The general formula [XIII] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0146] Another preferred embodiment of the compound of the present invention is a compound in which, in the general formula [Ib], ring Cy is phenyl, and ring Cy a is the formula: [ka] The general formula [XIV] is: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0147] A preferred embodiment of the compound of the present invention is represented by the general formula [XV]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0148] A preferred embodiment of the compound of the present invention is represented by the general formula [XVI]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0149] Another preferred embodiment of the compound of the present invention is represented by the general formula [XVII]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0150] A preferred embodiment of the compound of the present invention is represented by the general formula [XVIII]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0151] Another preferred embodiment of the compound of the present invention is represented by the general formula [XIX]: [ka] [In the formula, n1′ is 0, 1, 2 or 3, and the other symbols are as defined above.] It is a compound represented by the formula:

[0152] The "pharmaceutical acceptable salt" of the compound of the present invention may be any salt that forms a non-toxic salt with the compound of the present invention, and examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids, etc.

[0153] Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like. Examples of salts with organic acids include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0154] Examples of salts with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts. Examples of salts with organic bases include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, and the like. Examples of salts with amino acids include salts with lysine, arginine, aspartic acid, glutamic acid, and the like.

[0155] According to a known method, the compound of the present invention can be reacted with an inorganic base, an organic base, an inorganic acid, an organic acid or an amino acid to obtain each salt.

[0156] In the compound of the present invention, various "isomers" exist. For example, there are E and Z isomers as geometric isomers. When asymmetric carbon atoms exist, the compound of the present invention exists as enantiomers and diastereomers as stereoisomers based on these. When axial asymmetry exists, there exist stereoisomers based on these. In some cases, the compound of the present invention may exist in tautomer form. Therefore, the scope of the present invention includes all these isomers and their mixtures.

[0157] In addition, the compound represented by the general formula [I] and [Ib] or a pharma- ceutical acceptable salt thereof may be in the form of a "solvate". The term "solvate" means a compound represented by the general formula [I] and [Ib] or a pharma- ceutical acceptable salt thereof in which a solvent molecule is coordinated. The solvate is preferably a pharma- ceutical acceptable solvate. Examples of such solvates include hydrates, ethanol solvates, and dimethylsulfoxide solvates of the compound represented by the general formula [I] and [Ib] or a pharma- ceutical acceptable salt thereof. Specifically, the compound represented by the general formula [I] and [Ib] may be a hemihydrate, monohydrate, dihydrate, or monoethanol solvate, or a monohydrate or 2 / 3 ethanol solvate of the sodium salt of the compound represented by the general formula [I] and [Ib]. The solvate can be obtained according to a known method.

[0158] The compounds of the present invention may also contain isotopes (e.g., 2 H, 3 H, 14 C. 35 It may be labeled with S, etc. The compound of the present invention or a pharma- ceutically acceptable salt thereof is preferably a substantially purified compound of the present invention or a pharma- ceutically acceptable salt thereof, more preferably a compound of the present invention or a pharma- ceutically acceptable salt thereof purified to a purity of 80% or more.

[0159] In the present invention, prodrugs of the compounds represented by the general formulae [I] and [Ib] can also be useful drugs. The term "prodrug" refers to a derivative of the compound of the present invention that has a chemically or metabolically decomposable group and that, after administration to a living body, is restored to the original compound by, for example, hydrolysis, solvolysis, or decomposition under physiological conditions to show the original pharmacological effect, and includes complexes and salts that are not based on covalent bonds. Prodrugs are used, for example, to improve absorption in oral administration or to target the target site. Examples of the modification site for forming a prodrug include highly reactive functional groups in the compound of the present invention, such as a hydroxyl group, a carboxyl group, and an amino group.

[0160] Specific examples of the modifying group for a hydroxyl group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, a fumaryl group, etc. Also included are sodium salts of a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group, etc.

[0161] Specific examples of the modifying group for a carboxy group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, a 1-(acetyloxy)ethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a 1-(isopropyloxycarbonyloxy)ethyl group, a 1-(cyclohexyloxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a phenyl group, an o-tolyl group, a morpholinoethyl group, a N,N-diethylcarbamoylmethyl group, and a phthalidyl group.

[0162] Specific examples of the modifying group for an amino group include a tert-butyl group, a docosanoyl group, a pivaloylmethyloxy group, an alanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a 3-methylthio-1-(acetylamino)propylcarbonyl group, a 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, a tetrahydrofuranyl group, and a pyrrolidylmethyl group.

[0163] The compound of the present invention or a pharma- ceutical acceptable salt thereof has an SGLT1 inhibitory action, and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating SGLT1 activity, such as diabetes, obesity, diabetic complications (e.g., retinopathy, nephropathy, and neuropathy, known as microangiopathy, and cerebrovascular disease, ischemic heart disease, and obliterative arteriosclerosis of the lower limbs, known as macroangiopathy), hypertrophic cardiomyopathy, ischemic heart disease, cancer, and constipation. Diabetes is preferably type II diabetes.

[0164] "Inhibition of SGLT1" means inhibiting the function of SGLT1 to eliminate or weaken its activity, for example, means inhibiting the function of SGLT1 based on the conditions of the test example described below. "Inhibition of SGLT1" is preferably "inhibition of human SGLT1". "SGLT1 inhibitor" is preferably "human SGLT1 inhibitor".

[0165] "Treatment" means alleviating or curing a condition or disease and / or its attendant symptoms. "Prevention" refers to a method of delaying or preventing the onset of a condition or disease and / or its attendant symptoms, a method of preventing a patient from acquiring a condition or disease, or a method of reducing a patient's risk of acquiring a condition or disease.

[0166] The pharmaceutical composition of the present invention is produced by appropriately mixing the compound of the present invention or a pharma- ceutical acceptable salt thereof with at least one or more pharma- ceutical acceptable carriers, etc. in an appropriate amount according to a method known in the technical field of pharmaceutical preparations. The content of the compound of the present invention or a pharma- ceutical acceptable salt thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight based on the total pharmaceutical composition.

[0167] Examples of "pharmaceutical compositions" 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.

[0168] The "pharmaceutical acceptable carrier" includes various organic or inorganic carrier substances commonly used as pharmaceutical ingredients, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid preparations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. are used as necessary.

[0169] 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 the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like. Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like. The "fluidizing agent" includes, for example, light anhydrous silicic acid, magnesium stearate, and the like. Examples of the "lubricant" include magnesium stearate, calcium stearate, talc, and the like.

[0170] Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate, and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like. Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, etc. An example of the "soothing agent" is benzyl alcohol.

[0171] Examples of the "preservative" include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include, for example, sodium sulfite, ascorbic acid, and the like. Examples of "colorants" include food dyes (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, and the like. Examples of "sweetening agents" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

[0172] The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, topically, rectally, intravenously, etc.) in a pharmacologic effective amount to mammals other than humans (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans. The "pharmacologic effective amount" varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when orally administered to an adult patient (body weight: about 60 kg) suffering from diabetes (type II diabetes, etc.) is usually in the range of about 1 mg to 1 g per day of the compound of the present invention or a pharmacologic acceptable salt thereof as an active ingredient. These amounts can be administered once or in divided doses.

[0173] Also useful are kits (such as administration, treatment and / or prevention kits), packages (such as packaging materials) and pharmaceutical sets (and / or containers) that contain a pharmaceutical composition containing the compound of the present invention or a pharma- ceutical acceptable salt thereof as an active ingredient or active agent, and a package insert for the pharmaceutical composition, which describes that the pharmaceutical composition can or should be used for treatment and / or prevention. Such kits, packages and pharmaceutical sets may include one or more containers filled with one or more active ingredients and other drugs or drugs (or ingredients) for the pharmaceutical composition. Examples of such kits, packages and pharmaceutical sets include commercial kits and commercial packages that are appropriately directed to the treatment and / or prevention of a target disease. Package inserts included in such kits, packages and pharmaceutical sets include notices in the form mandated by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, and which indicate the approval of the governmental agency for 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 to employ appropriate administration steps, or may include structures configured to achieve more preferable medical treatment and / or prevention, including treatment and / or prevention of a target disease.

[0174] The compound of the present invention or a pharma- ceutically acceptable salt thereof can be used in combination (hereinafter also referred to as "combination") with one or more other drugs (hereinafter also referred to as "combined drugs") in a manner generally used in the pharmaceutical field.

[0175] The administration time of the compound of the present invention or a pharma- ceutical acceptable salt thereof and the concomitant drug is not limited, and they may be administered to the subject as a combination drug, or both preparations may be administered simultaneously or at a certain interval. The pharmaceutical composition of the present invention may also be used as a medicament characterized by being a kit consisting of the pharmaceutical composition of the present invention and the concomitant drug. The dosage of the concomitant drug may be selected appropriately according to the subject, disease, symptoms, dosage form, administration route, administration time, combination, etc., as long as it is in accordance with the dosage used in clinical practice. The administration form of the concomitant drug is not particularly limited, and it is sufficient that the compound of the present invention or a salt thereof is combined with the concomitant drug.

[0176] Concomitant medications include, for example: (1) An agent for treating and / or preventing dyslipidemia, (2) an agent for treating and / or preventing obesity, (3) a therapeutic and / or preventive agent for diabetes, (4) An agent for treating and / or preventing diabetic complications, (5) an agent for treating and / or preventing hypertension, Among these, one or more drugs can be used in combination with the compound of the present invention or a pharma- ceutically acceptable salt thereof.

[0177] Next, an example of a method for producing the compound used in carrying out the present invention will be described, but the method for producing the compound of the present invention or a pharma- ceutically acceptable salt thereof is not limited to this. Even if not described in the production methods below, efficient production may be achieved by using various techniques, such as introducing a protecting group into a functional group as necessary and then deprotecting it in a later step; subjecting a functional group to each step as a precursor and converting it into a desired functional group at an appropriate stage; changing the order of each production method and step; or appropriately using a reagent other than the exemplified reagents in order to promote the progress of the reaction.

[0178] In each step, the post-reaction treatment may be carried out by a commonly used method, and the isolation and purification may be carried out, as necessary, by appropriately selecting and combining commonly used methods such as crystallization, recrystallization, distillation, liquid separation, silica gel column chromatography, preparative HPLC, etc. In some cases, the product may proceed to the next step without isolation and purification.

[0179] [Manufacturing method 1] Methods for producing the compound represented by the general formula [I] are exemplified by the following Production Methods 1-1 and 1-2. Manufacturing method 1-1 [ka] [wherein each symbol has the same meaning as defined above] (1st step) Compound [I] can be obtained by reacting compound [1] or a salt thereof with compound [2] in a solvent in the presence of a condensing agent and an additive. As the condensing agent, 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), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, or the like is preferred. The additives are preferably 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), etc. In some cases, 4-dimethylaminopyridine, etc. may be added as an additive. The solvent is preferably a halogenated hydrocarbon solvent such as chloroform; an ether solvent such as tetrahydrofuran; a polar solvent such as pyridine, acetonitrile, or N,N-dimethylformamide; or a mixed solvent thereof. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C. When a salt of compound [1] is used, the reaction may be carried out in the presence of a base such as an organic base, e.g., triethylamine; or an alkali metal salt, e.g., sodium carbonate. Compound [I] can also be obtained by first converting compound [2] to an acid chloride or the like and then reacting it with compound [1] in the presence of a base. Compound [2] may be a commercially available product or may be obtained by the following Production Method 3 or a conventional method.

[0180] Manufacturing method 1-2 [ka] [In the formula, P N1 is a protecting group for the amino group, and P N1 is preferably a tert-butoxycarbonyl group. The other symbols are as defined above.] (1st step) Compound [4] can be obtained by reacting compound [1] or a salt thereof with compound [3] in a solvent in the presence of a condensing agent and an additive. As the condensing agent, 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), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, or the like is preferred. The additives are preferably 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), etc. In some cases, 4-dimethylaminopyridine, etc. may be added as an additive. The solvent is preferably a halogenated hydrocarbon solvent such as chloroform; an ether solvent such as tetrahydrofuran; a polar solvent such as pyridine, acetonitrile, or N,N-dimethylformamide; or a mixed solvent thereof. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C. When a salt of compound [1] is used, the reaction may be carried out in the presence of a base such as an organic base, eg, triethylamine, or an alkali metal salt, eg, sodium carbonate. Compound [4] can also be obtained by first converting compound [3] to an acid chloride or the like and then reacting it with compound [1] in the presence of a base. Compound [3] may be commercially available or may be obtained by conventional methods.

[0181] (2nd process) Compound [4] P N1 The compound [5] or a salt thereof can be obtained by removing the protective group by a conventional deprotection reaction. N1 Depending on the type of P, the appropriate conditions may be used. For example, N1 When is a tert-butoxycarbonyl group, compound [5] or a salt thereof can be obtained by treating compound [4] in a solvent under acidic conditions at room temperature. Compound [5] can be isolated as a salt or as a free form after neutralization. The solvent is preferably an alcohol solvent such as ethanol; an ether solvent such as 1,4-dioxane; an ester solvent such as ethyl acetate; a halogenated hydrocarbon solvent such as chloroform; or a mixed solvent of these. The acid used in the reaction is preferably hydrochloric acid or trifluoroacetic acid.

[0182] (3rd step) Compound [Ia] can be obtained by converting the diamino group of compound [5] or a salt thereof into a urea group in a solvent. Reagents used in the reaction include, for example, diethyl carbonate, diethyl pyrocarbonate, 1,1'-carbonyldiimidazole (CDI), chloroformate, and the like, with 1,1'-carbonyldiimidazole (CDI) being preferred. As the solvent, for example, halogenated hydrocarbon solvents such as chloroform; ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; polar solvents such as pyridine, acetonitrile, and N,N-dimethylformamide; or mixed solvents thereof are preferable. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C. When a salt of compound [5] is used, the reaction may be carried out in the presence of a base such as an organic base, e.g., triethylamine; or an alkali metal salt, e.g., sodium carbonate.

[0183] When compound [I] or compound [Ia] has an enantiomer or a geometric isomer, the reaction may be carried out using a commercially available optically active compound or a single diastereomeric compound, or a compound obtained by a conventional method. In addition, the optically active or single diastereomeric form of compound [I] or compound [Ia] may be obtained by performing separation and purification in the manufacturing process as appropriate. Examples of the compound to be separated and purified include compound [I] or compound [Ia]. Examples of the method for separation and purification include column chromatography, preparative HPLC, and the like.

[0184] The method for producing the compound represented by the general formula [Ib] is exemplified by the following Production Method 1-3. Manufacturing method 1-3 [ka] [wherein each symbol has the same meaning as defined above] (1st step) Compound [Ib] or a salt thereof can be obtained in the same manner as in the first step of Production Method 1-1. Compound [2d] or a salt thereof may be commercially available, or may be obtained by the following Production Method 3 or a conventional method. When compound [Ib] has an enantiomer or a geometric isomer, the reaction may be carried out using a commercially available optically active compound or a single diastereomeric compound, or a compound obtained by a conventional method. In addition, an optically active or single diastereomeric form of compound [Ib] may be obtained by performing separation and purification in the manufacturing process as appropriate. Compounds to be separated and purified include compound [Ib], etc. Examples of the method for separation and purification include column chromatography, preparative HPLC, etc.

[0185] [Manufacturing method 2] Methods for producing the compound [1] are exemplified by the following Production Methods 2-1 to 2-3. Manufacturing method 2-1 [ka] [wherein each symbol has the same meaning as defined above] (1st step) Compound [9] can be obtained by subjecting compound [8] to Wittig reaction or Horner-Wadsworth-Emmons reaction in a solvent in the presence of a base. The reagent used in the Wittig reaction is preferably cyanomethyltriphenylphosphonium chloride, and the reagent used in the Horner-Wadsworth-Emmons reaction is preferably diethyl cyanomethylphosphonate. Examples of the base include organic bases such as triethylamine; and alkali metal salts such as sodium hydride, potassium tert-butoxide, sodium carbonate, and lithium hexadisilazide (LiHMDS), with potassium tert-butoxide being preferred. As the solvent, for example, an ether solvent such as tetrahydrofuran; a hydrocarbon solvent such as toluene; a polar solvent such as N,N-dimethylformamide; or a mixed solvent thereof is preferable. The reaction temperature is usually about -78 to 100°C, preferably about 0 to 40°C. Compound [8] may be commercially available or may be obtained by conventional methods.

[0186] (2nd process) Compound [9] and compound

[10] or a salt thereof can be reacted in a solvent in the presence of a base to obtain compound

[11] or a salt thereof. Examples of the base used in the reaction include organic bases such as triethylamine; alkali metal salts such as sodium hydride, sodium ethoxide, potassium tert-butoxide, sodium carbonate, and lithium hexadisilazide (LiHMDS), and preferably sodium ethoxide. As the solvent, for example, an alcohol solvent such as ethanol; an ether solvent such as tetrahydrofuran; a hydrocarbon solvent such as toluene; a polar solvent such as N,N-dimethylformamide; or a mixed solvent thereof is preferable. The reaction temperature is usually about 0 to 150°C, preferably about 20 to 100°C. Compound

[10] or a salt thereof may be commercially available or may be obtained by a conventional method.

[0187] (3rd step) Compound [1] or a salt thereof can be obtained by reacting compound

[11] or a salt thereof in a solvent in the presence of an oxidizing agent. The oxidizing agent is preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), p-chloranil, Oxone (registered trademark), manganese dioxide, activated carbon, oxygen gas, or the like. As the solvent, for example, an ether solvent such as dioxane; a polar solvent such as N,N-dimethylformamide; a hydrocarbon solvent such as toluene; a halogenated hydrocarbon solvent such as chloroform; or a mixed solvent of these is preferable. The reaction temperature is usually about 0 to 150°C, preferably about 20 to 150°C.

[0188] Manufacturing method 2-2 [ka] [In the formula, P N2 is a hydrogen atom or a protecting group for an amino group, and preferably two PN2 together with their attached nitrogen atoms to form 2,5-dimethylpyrrole. 1 is a leaving group, preferably a bromine atom or an iodine atom. The other symbols are as defined above.] (1st step) Compound

[13] or a salt thereof can be obtained in the same manner as in the third step of the production method 2-1. Compound

[12] or a salt thereof may be commercially available or may be obtained by a conventional method.

[0189] (2nd process) P to the amino group of compound

[13] or its salt N2 By introducing P by a conventional protection reaction, compound

[14] can be obtained. N2 Depending on the type of P, appropriate conditions may be used. For example, N2 When these are combined with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole, it can be reacted with 2,5-hexanedione under acidic conditions in a solvent to give compound

[14] . The acid used in the reaction includes, for example, concentrated hydrochloric acid, concentrated sulfuric acid, amidosulfuric acid, p-toluenesulfonic acid, acetic acid, etc., and is preferably acetic acid. The solvent is preferably, for example, an alcohol solvent such as ethanol, an ether solvent such as tetrahydrofuran, a hydrocarbon solvent such as toluene, a polar solvent such as N,N-dimethylformamide, a halogenated hydrocarbon solvent such as dichloroethane, or a mixture of these solvents. An organic acid such as acetic acid may also be used as the solvent. The reaction temperature is usually about 0 to 150°C, preferably about 20 to 120°C.

[0190] (3rd step) Compound

[15] is prepared by reacting compound

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

[15] can be obtained by iodination in a solvent in the presence of a base. The base used in the reaction includes, for example, n-butyllithium, lithium hexamethyldisilazide, lithium tetramethylpiperidide, etc., and is preferably n-butyllithium. Examples of the iodinating agent include iodine, iodine monochloride, N-iodosuccinimide, 1-chloro-2-iodoethane, and the like, and preferably iodine. As the solvent, for example, an ether solvent such as tetrahydrofuran; a hydrocarbon solvent such as toluene; or a mixed solvent thereof is preferable. The reaction temperature is usually about -100 to 40°C, preferably about -78 to 20°C.

[0191] (4th step) Compound

[16] or a salt thereof is a compound

[15] P N2 The deprotection reaction can be carried out by removing P N2 Depending on the type of P, the appropriate conditions can be used. For example, N2 When the nitrogen atoms to which they are attached form 2,5-dimethylpyrrole, compound

[16] or a salt thereof can be obtained by treating compound

[15] with hydroxylamine in a solvent. Compound

[16] can be isolated as a salt or as a free form after neutralization. The solvent is preferably an alcoholic solvent such as ethanol; water; or a mixed solvent thereof. The reaction temperature is usually about 40 to 150°C, preferably about 80 to 130°C.

[0192] (5th step) Compound [1] or a salt thereof can be obtained by subjecting compound

[16] or a salt thereof and compound

[17] to Suzuki coupling reaction. For example, compound [1] or a salt thereof can be obtained by reacting compound

[16] or a salt thereof with compound

[17] in a solvent under heating in the presence of a base and a palladium catalyst. Examples of the palladium catalyst used in the reaction include tetrakis(triphenylphosphine)palladium, (bis(diphenylphosphine)ferrocene)palladium dichloride-methylene chloride complex and the like. The base used in the reaction includes potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine and the like. Preferred solvents 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. Compound

[17] may be commercially available or may be obtained by a conventional method. Alternatively, the reaction in this step may be carried out using a boronic acid ester. Compound [1a] can be obtained in the same manner as in Production Method 2-2, except that compound [12a] is used instead of compound

[12] and compound [17a] is used instead of compound

[17] . [ka] [In the formula, compound [17a] is a boronic acid ester. The other symbols are as defined above.] Compound [12a] or a salt thereof may be commercially available or may be obtained by a conventional method. Compound [17a] may be commercially available or may be obtained by a conventional method. Alternatively, the reaction in this step may be carried out using a boronic acid. The reagents used to obtain compound [17a] include the following reagents. For example, the ring Cy is R 1a C substituted with a leaving group (preferably a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, or a trifluoromethanesulfonyloxy group) other than 6-10In the case of an aryl group, examples of the reaction product include palladium catalysts such as palladium acetate, palladium chloride, and tris(dibenzylideneacetone)dipalladium; organic phosphorus compounds such as 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; boron compounds such as bis(pinacolato)diboron; and bases such as potassium acetate, sodium carbonate, and potassium carbonate. For example, the ring Cy is R 1a C with no substituents other than 6-10 In the case of aryl groups, examples include iridium reagents such as di-μ-methoxobis(1,5-cyclo)(octadiene)diiridium; bipyridine compounds such as 4,4′-di-tert-butyl-2,2′-bipyridine and 4,4′-dimethoxy-2,2′-bipyridine; and boron compounds such as bis(pinacolato)diboron.

[0193] Manufacturing method 2-3 [ka] [In the formula, P N2 is a hydrogen atom or a protecting group for an amino group, and preferably two P N2 together with their attached nitrogen atoms to form 2,5-dimethylpyrrole. 1 is a leaving group, preferably a bromine atom or an iodine atom. 2 is a leaving group, preferably a chlorine atom, a bromine atom, an iodine atom, a dihydroxyboryl group, a p-toluenesulfonyloxy group, or a methanesulfonyloxy group. The other symbols are as defined above.] (1st step) Compound

[19] can be obtained in the same manner as in the second step of Production Method 2-2.

[0194] (2nd process) Compound

[14] can be obtained by reacting compound

[19] with compound

[20] in a solvent. For example, R 2 C 1-8 Alkyl group or C 3-8 is a cycloalkyl group, L 2 When is a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, or a methanesulfonyloxy group, compound

[14] can be obtained by reacting compound

[19] with compound

[20] in a solvent in the presence of a base. Examples of the base used in the reaction include potassium hydroxide, potassium carbonate, sodium ethoxide, potassium tert-butoxide, sodium hydride and the like, and preferably sodium hydride. As the solvent, for example, an ether solvent such as tetrahydrofuran; a polar solvent such as N,N-dimethylformamide; an alcohol solvent such as ethanol; or a mixed solvent thereof is preferable. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 80°C. For example, R 2 C 6-10 is an aryl group, L 2 When is a bromine atom or an iodine atom, compound

[14] can be obtained by reacting compound

[19] with compound

[20] in a solvent in the presence of a metal reagent, a ligand and a base. Examples of the metal reagent used in the reaction include copper(I) iodide, copper(I) oxide, cobalt(II) chloride, manganese(II) chloride, iron(III) chloride, etc., and preferably copper(I) oxide. Examples of the ligand used in the reaction include salicylaldoxime, trans-1,2-cyclohexanediamine, 8-quinolinol, 1,10-phenanthroline, L-proline, and the like, with 8-quinolinol being preferred. Examples of the base used in the reaction include potassium hydroxide, tripotassium phosphate, potassium carbonate, cesium carbonate, sodium tert-butoxide and the like, and preferably cesium carbonate. As the solvent, for example, a hydrocarbon solvent such as toluene or xylene; a polar solvent such as acetonitrile or N,N-dimethylformamide; or a mixed solvent thereof is preferable. The reaction temperature is usually about 20 to 150°C, preferably about 80 to 130°C. For example, R 2 C 6-10 is an aryl group, L 2 When is a dihydroxyboryl group, compound

[14] can be obtained by reacting compound

[19] with compound

[20] in a solvent in the presence of a copper reagent and a base under air at room temperature. The copper reagent used in the reaction is preferably copper(II) acetate or copper(I) oxide. The base used in the reaction is preferably an organic base such as pyridine or triethylamine. As the solvent, for example, an alcohol solvent such as methanol or ethanol; a halogenated hydrocarbon solvent such as dichloromethane or chloroform; or a mixed solvent thereof is preferable. Compound

[20] may be commercially available or may be obtained by conventional methods.

[0195] (3rd step) Compound

[15] can be obtained in the same manner as in the third step of production method 2-2.

[0196] (4th step) Compound

[16] or a salt thereof can be obtained in the same manner as in the fourth step of the production method 2-2.

[0197] (5th step) Compound [1] or a salt thereof can be obtained in the same manner as in the fifth step of the production method 2-2. Compound [1a] can be obtained in the same manner as in Production Method 2-3 by using compound [20a] instead of compound

[20] and compound [17a] instead of compound

[17] . [ka] [wherein each symbol has the same meaning as defined above] Compound [20a] or a salt thereof may be commercially available or may be obtained by a conventional method. The reaction of this step may be carried out using a boronic acid instead of compound [17a].

[0198] [Manufacturing method 3] Methods for producing the compound [2] are exemplified below as Production Methods 3-1 to 3-3. Manufacturing method 3-1 [ka] [In the formula, P C1 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. N3 is a protecting group for an amino group, preferably a 2,4-dimethoxybenzyl group. The carbon atom marked with * may be R 3 Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[23] can be obtained by reacting compound

[21] with compound

[22] in a solvent. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an alcohol solvent such as methanol or ethanol; or a mixed solvent thereof. The reaction temperature is usually about 20 to 150°C, preferably about 80 to 130°C. Compound

[21] may be commercially available or may be obtained by the following auxiliary step 1 or a conventional method. Compound

[22] may be commercially available or may be obtained by a conventional method.

[0199] Auxiliary process 1 [ka] [In the formula, P C1 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. m1 is 0, 1, 2, or 3. 3is a leaving group, preferably a bromine atom. The carbon atom marked with * may be replaced by R 3 Each of the other symbols has the same meaning as defined above.] (Auxiliary process 1-1) Compound

[25] L 3 By introducing L, compound

[26] can be obtained. For example, 3 When is a bromine atom, compound

[26] can be obtained by bromination in a solvent in the presence of a radical reaction initiator. The radical reaction initiator is preferably azobisisobutyronitrile (AIBN). The brominating agent is preferably N-bromosuccinimide (NBS). The solvent is preferably a halogenated hydrocarbon solvent such as dichloromethane or carbon tetrachloride. The reaction temperature is usually about 20 to 130°C, preferably about 40 to 100°C. Compound

[25] may be commercially available or may be obtained by conventional methods.

[0200] (Auxiliary process 1-2) Compound

[26] contains R 3 For example, compound [21a] can be obtained by reacting with a Grignard reagent in a solvent in the presence of an additive. The additive is preferably hexamethylphosphoric acid triamide (HMPA). As the solvent, for example, an ether solvent such as diethyl ether or tetrahydrofuran; a polar solvent such as N,N-dimethylformamide; or a mixed solvent thereof is preferable. The reaction temperature is usually about -78 to 40°C, preferably about -20 to 25°C. The Grignard reagent used in the reaction may be a commercially available product or may be obtained by a conventional method.

[0201] (2nd process) Compound

[24] or a salt thereof is a compound

[23] PC1 The deprotection reaction can be carried out by removing P C1 Depending on the type of P, the appropriate conditions may be used. For example, C1 When is a methyl group, compound

[23] can be hydrolyzed in a solvent in the presence of a base to give compound

[24] or a salt thereof. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, etc., and preferably sodium hydroxide. The solvent is preferably, for example, an alcohol solvent such as methanol; an ether solvent such as tetrahydrofuran; water; or a mixed solvent thereof. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C.

[0202] (3rd step) Compound [2a] or a salt thereof is a compound

[24] or a salt thereof N3 The deprotection reaction can be carried out by removing P N3 Depending on the type of P, the appropriate conditions may be used. For example, N3 When is a 2,4-dimethoxybenzyl group, compound [2a] or a salt thereof can be obtained by treating with an acid in a solvent in the presence of an additive. Examples of the acid include methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and the like, and preferably trifluoroacetic acid. Examples of the additive include anisole, triethylsilane, and the like, with anisole being preferred. The solvent is preferably, for example, a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene, water, or a mixture thereof. An organic acid such as trifluoroacetic acid may be used as the solvent itself. The reaction temperature is usually about 0 to 130°C, preferably about 25 to 80°C. When compound [2a] has geometric isomers, a single diastereomeric form can be obtained by performing separation and purification during the manufacturing process as appropriate. Compound

[23] and the like can be used as a compound to be separated and purified. Examples of the method for separation and purification include column chromatography and preparative HPLC. Compound

[23] may also be subjected to basic conditions to increase the diastereomeric excess of the preferred configuration, and then separated and purified. In addition, the enantiomer derived from the asymmetric carbon atom at the α-position of the carboxyl group of compound [2a] can be separated and purified as a single diastereomer by introducing a chiral auxiliary to obtain its optically active form. For example, as shown in auxiliary step 2 in the figure below, compounds [2a_chiral_1] and [2a_chiral_2] can be obtained by using (R)-4-benzyl-2-oxazolidinone as a chiral auxiliary for compound

[24] or a salt thereof.

[0203] Auxiliary process 2 [ka] [In the formula, the carbon atom marked with * may be R within a chemically permissible range. 3 Each of the other symbols has the same meaning as defined above.] (Auxiliary process 2-1) Compound [27_chiral_1] and compound [27_chiral_2] can be obtained by reacting compound

[24] or its salt with (R)-4-benzyl-2-oxazolidinone in a solvent in the presence of a condensing agent and an additive. At this stage, compound [27_chiral_1] and compound [27_chiral_2] can be separated and purified by silica gel column chromatography. The condensing agent is preferably dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), or the like. The additive is preferably 4-dimethylaminopyridine or the like. The solvent is preferably a halogenated hydrocarbon solvent such as chloroform. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C. In addition, compound [27_chiral_1] and compound [27_chiral_2] can also be obtained by first converting compound

[24] to an acid chloride or the like and then reacting it with (R)-4-benzyl-2-oxazolidinone in the presence of a base.

[0204] (Auxiliary process 2-2) Compound [24_chiral_1] or a salt thereof (or compound [24_chiral_2] or a salt thereof) can be obtained by reacting compound [27_chiral_1] (or compound [27_chiral_2]) in a solvent in the presence of a base and hydrogen peroxide. The base used in the reaction includes, for example, sodium hydroxide, lithium hydroxide, etc., and is preferably lithium hydroxide. The solvent is preferably, for example, an ether solvent such as tetrahydrofuran; water; or a mixed solvent thereof. The reaction temperature is usually about 0 to 50°C, preferably about 0 to 25°C.

[0205] (Auxiliary process 2-3) The compound [2a_chiral_1] or a salt thereof (or compound [2a_chiral_2] or a salt thereof) can be obtained in the same manner as in the third step of the production method 3-1.

[0206] Manufacturing method 3-2 [ka] [In the formula, the carbon atom marked with * may be R within a chemically permissible range. 3 Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[28] or a salt thereof can be treated with bromine in a solvent, and then with a base to obtain compound

[29] or a salt thereof. Examples of the base include potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, triethylamine, etc., and preferably sodium hydrogen carbonate or sodium carbonate. As the solvent, for example, halogenated hydrocarbon solvents such as dichloromethane and carbon tetrachloride; water, etc. are preferable. The reaction temperature is usually about 0 to 100°C, preferably about 25 to 80°C. Compound

[28] or a salt thereof may be commercially available or may be obtained by a conventional method.

[0207] (2nd process) Compound [2b] or a salt thereof can be obtained by subjecting compound

[29] or a salt thereof to catalytic reduction treatment in a solvent in the presence of a metal catalyst under a hydrogen atmosphere. Examples of the metal catalyst include palladium on carbon, rhodium supported on alumina, Raney nickel, Adams' catalyst, and the like, with palladium on carbon being preferred. As the solvent, for example, an alcohol solvent such as methanol or ethanol; an ether solvent such as tetrahydrofuran; an ester solvent such as ethyl acetate; water; or a mixed solvent thereof is preferable. The reaction temperature is usually about 25 to 80°C, preferably about 25 to 50°C.

[0208] Manufacturing method 3-3 [ka] [In the formula, P N4 is a protecting group for an amino group, preferably a benzyloxycarbonyl group. C3 R is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. 4a is C 1-6 It is an alkyl group. 4 is a leaving group, preferably a halogen atom. The carbon atom marked with * may be replaced by R 3 Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[30] or a salt thereof can be subjected to a Hofmann rearrangement reaction in a solvent in the presence of a base and bromine, followed by an intramolecular cyclization reaction to obtain compound

[31] or a salt thereof. Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, etc., and preferably sodium hydroxide. As the solvent, for example, an alcohol solvent such as methanol or ethanol; an ether solvent such as 1,4-dioxane; water; or a mixed solvent thereof is preferable. The reaction temperature is usually about -78 to 100°C, preferably about -40 to 80°C. Compound

[30] or a salt thereof may be commercially available or may be obtained by a conventional method.

[0209] (2nd process) Compound

[32] is a compound

[31] or a salt thereof having a carboxyl group thereof substituted with P. C3 can be obtained by introducing P C3 Depending on the type of P, suitable conditions may be used. For example, C3 When is a tert-butyl group, compound

[31] can be converted in advance to an acid chloride or the like in a solvent, and then reacted with tert-butyl alcohol in the presence of a base to obtain compound

[32] . Reagents used in the reaction include, for example, thionyl chloride, oxalyl chloride, phosphorus oxychloride and the like, preferably phosphorus oxychloride. Examples of the base include organic amines such as triethylamine and pyridine; alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and the like, with pyridine being preferred. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an ether solvent such as tetrahydrofuran; a halogenated hydrocarbon solvent such as chloroform; or a mixed solvent thereof. The reaction temperature is usually about 0 to 130°C, preferably about 25 to 80°C.

[0210] (3rd step) Compound

[34] is prepared by reacting the P of compound

[32] in a solvent in the presence of a base. N4 After rearrangement, R 4a can be obtained by introducing The base is preferably sodium hydride. The solvent is preferably, for example, an ether solvent such as tetrahydrofuran; a polar solvent such as N,N-dimethylformamide; or a mixed solvent thereof. The reaction temperature is usually about 0 to 80°C, preferably about 0 to 25°C. Compound

[33] may be commercially available or may be obtained by conventional methods.

[0211] (4th step) Compound

[35] is the P of compound

[34] . N4 The deprotection reaction can be carried out by removing P N4 Depending on the type of P, the appropriate conditions may be used. For example, N4 When is a benzyloxycarbonyl group, compound

[34] can be subjected to catalytic reduction in a solvent in the presence of a palladium catalyst under a hydrogen atmosphere to give compound

[35] . Examples of the palladium catalyst include palladium on carbon, palladium (II) hydroxide, and the like, and preferably palladium on carbon. The solvent is preferably an alcohol solvent such as methanol; an ether solvent such as tetrahydrofuran; an ester solvent such as ethyl acetate; or a mixture of these solvents. The reaction temperature is usually about 25 to 80°C, preferably about 25 to 50°C.

[0212] (5th step) Compound [2c] or a salt thereof is a compound

[35] P C3 The deprotection reaction can be carried out by removing P C3 Depending on the type of P, the appropriate conditions may be used. For example, C3When is a tert-butyl group, compound

[35] can be treated in a solvent under acidic conditions to give compound [2c]. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc., and preferably trifluoroacetic acid. As the solvent, for example, an ether solvent such as 1,4-dioxane; a halogenated hydrocarbon solvent such as chloroform; an ester solvent such as ethyl acetate; an alcohol solvent such as methanol; water; or a mixed solvent thereof is preferable. The reaction temperature is usually about 0 to 80°C, preferably about 0 to 40°C. When compound [2c] has enantiomers, the reaction may be carried out using a commercially available optically active compound or a compound obtained therefrom by a conventional method.

[0213] Manufacturing method 3-4 [ka] [In the formula, the carbon atom marked with * may be R within a chemically permissible range. 3a Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[37] or a salt thereof can be obtained in the same manner as in Step 1 of Production Method 3-3. Compound

[36] or a salt thereof may be commercially available or may be obtained by a conventional method. (2nd process) Compound [2d] or a salt thereof can be obtained in the same manner as in the fourth step of production method 3-3. When compound [2d] has enantiomers, the reaction may be carried out using a commercially available optically active compound or a compound obtained therefrom by a conventional method.

[0214] Manufacturing method 3-5 [ka] [In the formula, P N5is a protecting group for an amino group, preferably a benzyloxycarbonyl group. The carbon atom marked with * may be replaced by R 3a Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[38] or a salt thereof can be reacted in a solvent in the presence of a base to obtain compound [2e] or a salt thereof. Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, etc., and preferably sodium hydroxide. As the solvent, for example, an alcohol solvent such as methanol or ethanol; an ether solvent such as 1,4-dioxane; water; or a mixed solvent thereof is preferable. The reaction temperature is usually about 0 to 100°C, preferably about 25 to 50°C. Compound

[38] or a salt thereof may be commercially available or may be obtained by a conventional method. When the compound [2e] has enantiomers, the reaction may be carried out using a commercially available optically active compound or a compound obtained therefrom by a conventional method.

[0215] Manufacturing method 3-6 [ka] [In the formula, P C4 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. The carbon atom marked with * may be replaced by R within a chemically permissible range. 3a Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[39] or a salt thereof can be subjected to a Curtius rearrangement reaction in a solvent, followed by an intramolecular cyclization reaction to obtain compound

[40] . The reagent used in the reaction includes, for example, diphenylphosphoryl azide. As the solvent, for example, a hydrocarbon solvent such as toluene; an alcohol solvent such as ethanol or tert-butanol; an ether solvent such as 1,4-dioxane; or a mixed solvent thereof is preferable. The reaction temperature is usually about 40 to 140°C, preferably about 80 to 120°C. Compound

[39] or a salt thereof may be commercially available or may be obtained by a conventional method.

[0216] (2nd process) Compound [2e] or a salt thereof is P of compound

[40] C4 The deprotection reaction can be carried out by removing P C4 Depending on the type of P, the appropriate conditions may be used. For example, C4 When is a benzyl group, compound

[40] can be subjected to catalytic reduction in a solvent in the presence of a palladium catalyst under a hydrogen atmosphere to obtain compound [2e] or a salt thereof. Examples of the palladium catalyst include palladium on carbon, palladium (II) hydroxide, and the like, and preferably palladium on carbon. The solvent is preferably an alcohol solvent such as methanol; an ether solvent such as tetrahydrofuran; an ester solvent such as ethyl acetate; or a mixture of these solvents. The reaction temperature is usually about 25 to 80°C, preferably about 25 to 50°C. When the compound [2e] has enantiomers, the reaction may be carried out using a commercially available optically active compound or a compound obtained therefrom by a conventional method.

[0217] Manufacturing method 3-7 [ka] [In the formula, P C5 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. The carbon atom marked with * may be replaced by R within a chemically permissible range. 3a Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[42] can be obtained by reacting compound

[41] with compound

[22] in a solvent. Compound

[22] itself may be used as the solvent. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an alcohol solvent such as methanol or ethanol; or a mixed solvent thereof. The reaction temperature is usually about 20 to 150°C, preferably about 80 to 130°C. Compound

[41] may be commercially available or may be obtained by conventional methods. Compound

[22] may be commercially available or may be obtained by conventional methods.

[0218] (2nd process) Compound

[43] can be obtained by converting the amino group and hydroxy group of compound

[42] into a carbamate group in a solvent. Reagents used in the reaction include, for example, diethyl carbonate, diethyl pyrocarbonate, 1,1'-carbonyldiimidazole (CDI), chloroformate, and the like, with 1,1'-carbonyldiimidazole (CDI) being preferred. As the solvent, for example, halogenated hydrocarbon solvents such as chloroform; ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; polar solvents such as pyridine, acetonitrile, and N,N-dimethylformamide; or mixed solvents thereof are preferable. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C.

[0219] (3rd step) Compound [2f] or a salt thereof is a compound

[43] P N3 and P C5 The deprotection reaction can be carried out by removing P N3 and P C5 Depending on the type of P, the appropriate conditions may be used. For example, N3 is a 2,4-dimethoxybenzyl group, and P C5When is a tert-butyl group, compound [2f] or a salt thereof can be obtained by treating with an acid in a solvent in the presence of an additive. Examples of the acid include methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and the like, and preferably trifluoroacetic acid. Examples of the additive include anisole, triethylsilane, and the like, with anisole being preferred. The solvent is preferably, for example, a halogenated hydrocarbon solvent such as dichloromethane, a hydrocarbon solvent such as toluene, water, or a mixture thereof. An organic acid such as trifluoroacetic acid may be used as the solvent itself. The reaction temperature is usually about 0 to 130° C., preferably about 25 to 80° C.

[0220] Manufacturing method 3-8 [ka] [In the formula, P C6 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. 6 is a leaving group, preferably a chlorine atom or a bromine atom. The carbon atom marked with * may be replaced by R 3a Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[45] can be obtained by reacting compound

[44] with compound

[22] in a solvent. Compound

[22] itself may be used as the solvent. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an alcohol solvent such as ethanol or tert-butanol; a polar solvent such as acetonitrile or N,N-dimethylformamide; or a mixed solvent thereof. The reaction temperature is usually about 20 to 150°C, preferably about 80 to 130°C. Compound

[44] may be commercially available or may be obtained by conventional methods.

[0221] (2nd process) Compound

[47] can be obtained by reacting compound

[45] with compound

[46] in a solvent in the presence of a base. Examples of the base include organic amines such as triethylamine and pyridine; alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and the like, with triethylamine being preferred. As the solvent, for example, a hydrocarbon solvent such as toluene; an ether solvent such as tetrahydrofuran; a halogenated hydrocarbon solvent such as chloroform; a polar solvent such as acetonitrile; or a mixed solvent thereof is preferable. The reaction temperature is usually about -20 to 130°C, preferably about 0 to 80°C. Compound

[48] may be commercially available or may be obtained by conventional methods.

[0222] (3rd step) Compound

[48] can be obtained by reacting compound

[47] in a solvent in the presence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; potassium tert-butoxide, sodium hydride, and the like, with potassium tert-butoxide being preferred. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an ether solvent such as tetrahydrofuran; an alcohol solvent such as tert-butanol; a polar solvent such as N,N-dimethylformamide; or a mixed solvent thereof. The reaction temperature is usually about 0 to 130°C, preferably about 25 to 80°C.

[0223] (4th step) Compound

[59] or a salt thereof can be obtained in the same manner as in the second step of Production Method 3-1.

[0224] (5th step) The compound [2g] or a salt thereof can be obtained in the same manner as in the third step of the production method 3-1. In addition, the enantiomer derived from the asymmetric carbon atom at the α-position of the carboxy group of compound [2g] can be obtained in the same manner as in auxiliary step 2 of production method 3-1.

[0225] Manufacturing method 3-9 [ka] [In the formula, P C7 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. C8 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. C9 is a protecting group for a carboxy group, preferably a methyl group, an ethyl group, a tert-butyl group, or a benzyl group. N6 is a protecting group for an amino group, preferably a tert-butoxycarbonyl group. N7 is a protecting group for an amino group, preferably a benzyloxycarbonyl group. 7 is a leaving group, preferably a chlorine atom or a bromine atom. The carbon atom marked with * may be replaced by R 3a Each of the other symbols has the same meaning as defined above.] (1st step) Compound

[52] or a salt thereof can be obtained by reacting compound

[50] or a salt thereof with compound

[51] in a solvent in the presence of a base. Examples of the base include organic amines such as triethylamine and pyridine; alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and the like, with potassium carbonate being preferred. As the solvent, for example, a hydrocarbon solvent such as toluene; an ether solvent such as tetrahydrofuran; a halogenated hydrocarbon solvent such as chloroform; a polar solvent such as acetonitrile; or a mixed solvent thereof is preferable. The reaction temperature is usually about 0 to 130°C, preferably about 25 to 80°C. Compound

[50] or a salt thereof may be commercially available or may be obtained by a conventional method. Compound

[51] may be commercially available or may be obtained by conventional methods.

[0226] (2nd process) Compound

[53] or a salt thereof is a compound

[52] or a salt thereof having P C8 The deprotection reaction can be carried out by removing P C8 Depending on the type of P, the appropriate conditions may be used. For example, C3 When is a tert-butyl group, the compound

[53] or a salt thereof can be obtained in the same manner as in the fifth step of the production method 3-3.

[0227] (3rd step) Compound

[54] or a salt thereof is a compound

[53] or a salt thereof having a P N6 can be obtained by introducing P N6 Depending on the type of P, suitable conditions may be used. For example, N6 When is a tert-butoxycarbonyl group, the compound

[54] or a salt thereof can be obtained by reacting with di-tert-butyl dicarbonate in a solvent in the presence of a base. Examples of the base include organic amines such as triethylamine and pyridine; alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and the like, with triethylamine being preferred. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an ether solvent such as tetrahydrofuran; a halogenated hydrocarbon solvent such as chloroform; a polar solvent such as acetonitrile; water; or a mixed solvent thereof. The reaction temperature is usually about 0 to 130°C, preferably about 25 to 50°C.

[0228] (4th step) Compound

[54] or a salt thereof can be subjected to Curtius rearrangement reaction in a solvent in the presence of an alcohol to obtain compound

[55] . The reagent used in the reaction includes, for example, diphenylphosphoryl azide. The alcohol used in the reaction includes, for example, benzyl alcohol, tert-butanol, etc., and is preferably benzyl alcohol. The solvent is preferably, for example, a hydrocarbon solvent such as toluene; an ether solvent such as 1,4-dioxane; or a mixed solvent thereof. The reaction temperature is usually about 25 to 140°C, preferably about 80 to 120°C.

[0229] (5th step) Compound

[56] or a salt thereof is a compound

[55] P N7 and P C9 The deprotection reaction can be carried out by removing P N7 and P C9 Depending on the type of P, the appropriate conditions may be used. For example, N7 is a benzyloxycarbonyl group, and P C9 When is a benzyl group, compound

[58] or a salt thereof can be obtained by subjecting compound

[57] to catalytic reduction in a solvent in the presence of a metal catalyst under a hydrogen atmosphere. Examples of the metal catalyst include palladium on carbon, palladium black, palladium (II) hydroxide, and the like, with palladium on carbon being preferred. As the solvent, for example, an alcohol solvent such as methanol or ethanol; an ether solvent such as tetrahydrofuran; an ester solvent such as ethyl acetate; water; or a mixed solvent thereof is preferable. The reaction temperature is usually about 25 to 80°C, preferably about 25 to 50°C.

[0230] (6th step) Compound

[57] can be obtained by reacting compound

[56] or a salt thereof in a solvent in the presence of a condensing agent and an additive. As the condensing agent, 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), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, or the like is preferred. The additives are preferably 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), etc. In some cases, 4-dimethylaminopyridine, etc. may be added as an additive. The solvent is preferably a halogenated hydrocarbon solvent such as chloroform; an ether solvent such as tetrahydrofuran; a polar solvent such as pyridine, acetonitrile, or N,N-dimethylformamide; or a mixed solvent thereof. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C. When an acid salt of compound

[56] 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.

[0231] (7th step) Compound [2h] or a salt thereof is P of compound

[57] C7 The deprotection reaction can be carried out by removing P C7 Depending on the type of P, the appropriate conditions may be used. For example, C7 When is a methyl group, compound

[57] can be hydrolyzed in a solvent in the presence of a base to obtain compound [2h] or a salt thereof. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and preferably sodium hydroxide. The solvent is preferably, for example, an alcohol solvent such as methanol; an ether solvent such as tetrahydrofuran; water; or a mixed solvent thereof. The reaction temperature is usually about 0 to 100°C, preferably about 0 to 40°C. When the compound [2h] has enantiomers, the reaction may be carried out using a commercially available optically active compound or a compound obtained therefrom by a conventional method. When compound [2h] or a salt thereof is used, it is subjected to a reaction similar to that in Production Method 1-3, and then P N6 The compound [Ib] or a salt thereof can be obtained by removing the compound [Ib] by a conventional deprotection reaction. N6 Depending on the type of P, the appropriate conditions may be used. For example, N6 When is a tert-butoxycarbonyl group, compound [Ib] or a salt thereof can be obtained in the same manner as in the second step of the production method 1-2. EXAMPLES

[0232] The preparation of the compound of the present invention or a pharma- ceutical acceptable salt thereof will be specifically explained by way of examples, but the present invention is not limited to these examples. In the present examples, some stereochemical notations in the chemical structural formulas of the compounds are omitted.

[0233] The measuring apparatus and conditions used in this example are shown below. HPLC analysis conditions 1 Method for preparing solution A: 2.34 g of sodium dihydrogen phosphate dihydrate was dissolved in 3000 ml of water, and the pH was adjusted to 2.6 with 1.02 ml of phosphoric acid. Measurement equipment: HPLC system Shimadzu Corporation High performance liquid chromatograph Prominence Column: Daicel CHIRALPAK AD-3R 4.6mmφ×150mm Column temperature: 40℃ Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH 2.6), (Solution B) acetonitrile Liquid A:B ratio was constant at 60:40 and the solution was pumped for 12 minutes. Flow rate: 0.5ml / min Detection: UV (220 nm) HPLC analysis conditions 2 Method for preparing solution A: 2.34 g of sodium dihydrogen phosphate dihydrate was dissolved in 3000 ml of water, and the pH was adjusted to 2.6 with 1.02 ml of phosphoric acid. Measurement equipment: HPLC system Shimadzu Corporation High performance liquid chromatograph Prominence Column: Daicel CHIRALPAK AD-3R 4.6mmφ×150mm Column temperature: 40℃ Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH 2.6), (Solution B) acetonitrile Liquid A: Liquid B = 50:50, constant flow for 12 minutes Flow rate: 0.5ml / min Detection: UV (220 nm) HPLC analysis conditions 3 Measurement equipment: HPLC system Shimadzu Corporation High performance liquid chromatograph Prominence Column: Daicel CHIRALCEL OD 4.6mmφ×250mm Column temperature: 40℃ Mobile phase: (Liquid A) n-hexane, (Liquid B) 2-propanol Liquid A:B = 10:90 constant for 30 minutes Flow rate: 0.3ml / min Detection: UV (254 nm)

[0234] NMR was performed at 400 MHz.

[0235] [Production Example 1]: Synthesis of 4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] (1)(Z)-2-Bromomethyl-2-butenedicarboxylic acid dimethyl ester [ka] To a solution of (Z)-2-methyl-2-butenedicarboxylic acid dimethyl ester (15.3 g) in carbon tetrachloride (300 ml), N-bromosuccinimide (25.8 g) and 2,2'-azobis(isobutyronitrile) (319 mg) were added, and the mixture was stirred for 36 hours under heating and reflux. After cooling to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 18 / 1) to obtain the title compound (19.6 g). 1 H-NMR (CDCl 3 ) δ: 3.83 (s, 3H), 3.88 (s, 3H), 4.72 (s, 2H), 6.84 (s, 1H).

[0236] (2) 2-Methyl-3-methylene succinic acid dimethyl ester [ka] To a solution of (Z)-2-bromomethyl-2-butenedicarboxylic acid dimethyl ester (19.3 g) and hexamethylphosphoric triamide (70 ml) in diethyl ether (200 ml), methylmagnesium bromide (1.12 M tetrahydrofuran solution, 100 ml) was added dropwise at -20°C over 1 hour, and the mixture was stirred for another 1 hour. 6 M aqueous hydrochloric acid solution (18 ml) and saturated aqueous ammonium chloride solution (100 ml) were added to the reaction mixture, and the mixture was warmed to room temperature, and then extracted with diethyl ether (200 ml). The organic layer obtained was washed twice with water and once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (developing solvent: n-hexane / chloroform = 1 / 1 to 0 / 1) to obtain the title compound (9.92 g). 1 H-NMR (CDCl 3 ) δ: 1.38 (d, 3H, J = 7.2 Hz), 3.62 (q, 1H, J = 7.2 Hz), 3.69 (s, 3H), 3.77 (s, 3H), 5.72 (s, 1H), 6.34 (s, 1H).

[0237] (3) Mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester [ka] 2,4-Dimethoxybenzylamine (9.72g) was added to a solution of 2-methyl-3-methylenesuccinic acid dimethyl ester (9.81g) in toluene (100ml) and stirred for 3 days under heating and reflux. After cooling to room temperature, the reaction solution was purified by silica gel column chromatography (developing solvent: n-hexane / chloroform = 1 / 1 to 0 / 1) to obtain the title compound (14.2g). 1 H-NMR (CDCl 3 ) Cis δ: 1.13 (d, 3H, J = 7.5 Hz), 2.75-2.86 (m, 1H), 3.22-3.34 (m, 2H), 3.48-3.56 (m, 1H), 3.69 (s, 3H), 3.80 (bs, 6H), 4.41 (d, Trans-isomer δ: 1.30 (d, 3H, J = 6.6 Hz), 2.66-2.80 (m, 2H), 3.31-3.43 (m, 2H), 3.71 (s, 3H), 3.80 (s, 6H), 4.41 (d, 1H, J = 14.4 Hz), 4.45 (d, 1H, J = 14.4 Hz), 6.41-6.47 (m, 2H), 7.10-7.15 (m, 1H).

[0238] (4) (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] Sodium methoxide (about 5M methanol solution, 28ml) was added to a mixture (14.2g) of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester in methanol (150ml), and the mixture was stirred at room temperature for 16 hours, and then heated to 55°C and stirred for 3 hours. Sodium methoxide (about 5M methanol solution, 10ml) was added to the reaction solution, and the mixture was further stirred at 55°C for 2 hours. After cooling the reaction solution to room temperature, water (50ml) was added and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to remove methanol. 2M aqueous hydrochloric acid solution (105ml) was added to the obtained residue, and the mixture was extracted with ethyl acetate (300ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound (14.0 g). 1 H-NMR (CDCl 3 ) δ: 1.32 (d, 3H, J = 6.6 Hz), 2.69-2.84 (m, 2H), 3.35-3.46 (m, 2H), 3.80 (s, 6H), 4.43 (s, 2H), 6.41-6.47 (m, 2H), 7.10-7.15 (m, 1H).

[0239] (5) Optically active form of (R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone [ka] (R)-4-benzyl-2-oxazolidinone (8.15g), WSC·HCl (9.70g), and 4-dimethylaminopyridine (2.81g) were added in sequence to a solution of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid crude product (14.0g) in chloroform (60ml), and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4 / 1 to 1 / 3) to obtain the title compound (low polarity component 11.4g, high polarity component 10.1g). 1 H-NMR (CDCl 3 ) Low polar component δ: 1.31 (d, 3H, J = 7.3 Hz), 2.77-2.85 (m, 1H), 2.94-3.03 (m, 1H), 3.19-3.30 (m, 2H), 3.51-3.58 (m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.96-4.03 (m, 1H), 4.19-4.23 (m, 2H), 4.41 (d, 1H, J = 15.8 Hz), 4.49 (d, 1H, J = 15.8 Hz), 4.63-4.70 (m, 1H), 6.42-6.46 (m, 2H), 7.10-7.21 (m, 3H), 7.27-7.37 (m, 3H). Highly polar component δ: 1.26 (d, 3H, J = 7.3 Hz), 2.67-2.75 (m, 1H), 2.97-3.08 (m, 1H), 3.15-3.24 (m, 1H), 3.63-3.93 (m, 8H), 4.17-4.28 (m, 3H), 4.36-4.56 (m, 2H), 4.63-4.73 (m, 1H), 6.39-6.56 (m, 2H), 7.11-7.21 (m, 3H), 7.27-7.39 (m, 3H).

[0240] (6) Optically active form of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] A 30% by weight aqueous hydrogen peroxide solution (7.0 ml) was added dropwise to a solution of lithium hydroxide monohydrate (1.26 g) in water (30 ml) under ice cooling, and the mixture was stirred for 10 minutes. After adding 30 ml of tetrahydrofuran to this reaction solution, a solution of the low polar component (11.4 g) of (R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone in tetrahydrofuran (90 ml) was added dropwise, and the mixture was stirred for another hour. A solution of sodium hydrogen sulfite (7.18 g) in water (50 ml) was added dropwise to this reaction solution, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 1 / 1 to 1 / 2, chloroform / methanol = 5 / 1) to obtain a crude product of the title compound (8.11 g). When this solid was analyzed under HPLC analysis condition 1, the main component was an isomer with a short retention time. Short retention isomer (retention time 5.7 min) Longer retention time isomer (retention time 6.5 min) The title compound can also be obtained by the following method.

[0241] (6)-(1) Optically active form of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid and diastereomeric salt of (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol [ka] (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (1.0 g), (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (434 mg), acetonitrile (10 ml) and water (0.9 ml) were mixed and dissolved by stirring under heating and reflux. The mixed solution was stirred at 50° C. for 6 hours and then stirred at room temperature overnight. The solid precipitated from the mixed solution was collected by filtration, washed with acetonitrile (6 ml) and dried under reduced pressure to obtain solid 1 (572 mg) of the title compound. When solid 1 was analyzed under HPLC analysis condition 1, the isomer with a short retention time was the main component. Short retention isomer (retention time 5.7 min) Longer retention time isomer (retention time 6.5 min) 1 H-NMR (DMSO-D 6 ) δ: 1.11 (d, 3H, J = 7.3 Hz), 2.43-2.53 (m, 1H), 2.55-2.64 (m, 1H), 2.85-2.92 (m, 1H), 3.14-3.22 (m, 2H), 3.27 (dd, 1H, J = 9.3, 9.3 Hz), 3.38 (dd, 1H, J = 11.3, 4.8 Hz), 3.73 (s, 3H), 3.76 (s, 3H), 4.19 (d, 1H, J = 14.5 Hz), 4.29 (d, 1H, J = 14.5 Hz), 4.73 (d, 1H, J = 6.0 Hz), 6.46 (dd, 1H, J = 8.1, 2.4 Hz), 6.54 (d, 1H, J = 2.4 Hz), 6.97 (d, 1H, J = 8.1 Hz), 7.61 (d, 2H, J = 8.5 Hz), 8.19 (d, 2H, J = 8.5 Hz). In addition, solid 1 was recrystallized from methyl isobutyl ketone, and the obtained crystals were subjected to X-ray crystallography. The crystals were found to be a 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]

[0242] (6)-(2)(3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [ka] A diastereomeric salt (10.0 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 was mixed with ethyl acetate (38 ml), potassium hydrogen sulfate (2.4 g) and water (38 ml) and stirred at room temperature for 30 minutes. The organic layer was separated, and the separated aqueous layer was extracted twice with ethyl acetate (15 ml). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 2-propanol (2.2 ml) and diisopropyl ether (45 ml) were added to the obtained residue and stirred. Insoluble matter was collected by filtration, washed with a small amount of diisopropyl ether, and dried under reduced pressure to obtain the title compound (4.3 g). When this solid was analyzed under HPLC analysis condition 1, the isomer with a short retention time was the main component. Short retention isomer (retention time 5.7 min) Longer retention time isomer (retention time 6.5 min)

[0243] (7) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid [ka] Anisole (3.76 ml) and trifluoroacetic acid (40 ml) were added to the crude product of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (8.11 g), and the mixture was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diisopropyl ether was added to the resulting residue and the mixture was stirred. The insoluble matter was filtered off and dried under reduced pressure to obtain the crude product of the title compound (2.23 g). Ethanol (8 ml) was added to the resulting solid, which was dissolved under heating and refluxing, and then stirred at room temperature. The solid precipitated from this mixture was filtered off, washed with a small amount of cooled ethanol, and dried under reduced pressure to obtain the title compound (1.36 g). 1 H-NMR (DMSO-D 6 ) δ: 1.10 (d, 3H, J = 7.3 Hz), 2.40 (dq, 1H, J = 9.0, 7.3 Hz), 2.83 (ddd, 1H, J = 9.0, 8.6, 7.6 Hz), 3.22 (dd, 1H, J = 10.0, 7.6 Hz), 3.37 (dd, 1H, J = 10.0, 8.6 Hz), 7.66 (s, 1H), 12.58 (s, 1H). In addition, the highly polar component (10.1 g) of (R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone was subjected to the same reaction and post-treatment to obtain (3S,4S)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (1.53 g), which is an optical isomer of the title compound. 1 H-NMR (DMSO-D 6 ) δ: 1.10 (d, 3H, J = 7.3 Hz), 2.40 (dq, 1H, J = 9.0, 7.3 Hz), 2.83 (ddd, 1H, J = 9.0, 8.6, 7.6 Hz), 3.22 (dd, 1H, J = 10.0, 7.6 Hz), 3.37 (dd, 1H, J = 10.0, 8.6 Hz), 7.66 (s, 1H), 12.58 (s, 1H). [ka]

[0244] [Production Example 2]: Synthesis of Example 1 ((3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [1-phenyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-yl]amide) [ka] (1) 1-Phenyl-1H-pyrazol-3-ylamine [ka] 1-Phenyl-4,5-dihydro-1H-pyrazol-3-ylamine (50.0 g) in N,N-dimethylformamide (150 ml) and 1,4-dioxane (500 ml) was added with 3,4,5,6-tetrachloro-1,4-benzoquinone (84.0 g) over 20 minutes under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. 2M aqueous sodium hydroxide solution (400 ml) was added to the reaction mixture under ice cooling over 25 minutes, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration through Celite, and the mixture was eluted with ethyl acetate (250 ml x 3), and the filtrate was extracted with ethyl acetate (300 ml). The obtained organic layer was washed successively with water (300 ml) and saturated aqueous sodium chloride solution (300 ml). The separated aqueous layer was extracted twice with ethyl acetate (300 ml). To the combined organic layer, anhydrous sodium sulfate (50 g) and silica gel (50 g) were added and stirred at room temperature for 1 hour. This mixture was filtered through celite with silica gel (100 g) and eluted with ethyl acetate (250 ml x 3). The filtrate was concentrated, and diisopropyl ether (500 ml) was added to the resulting residue and stirred at room temperature. Insoluble matter was filtered off, washed twice with diisopropyl ether (100 ml), and dried under reduced pressure to obtain the title compound (12.2 g). 1 H-NMR (CDCl 3) δ: 3.81 (br s, 2H), 5.85 (d, 1H, J = 2.4 Hz), 7.16-7.19 (m, 1H), 7.38-7.40 (m, 2H), 7.55-7.57 (m, 2H), 7.69 (d, 1H, J = 2.4 Hz).

[0245] (2) 3-(2,5-dimethylpyrrol-1-yl)-1-phenyl-1H-pyrazole [ka] 2,5-hexanedione (25 ml) was added to a solution of 1-phenyl-1H-pyrazol-3-ylamine (32.7 g) in acetic acid (330 ml) and stirred under heating and reflux for 3 hours. After cooling the reaction solution to room temperature, the acetic acid was concentrated under reduced pressure, and toluene (100 ml) was added and concentrated. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate 100 / 1 to 20 / 1) to obtain the title compound (41.8 g). 1 H-NMR (CDCl 3 ) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.39 (d, 1H, J = 2.4 Hz), 7.29-7.31 (m, 1H), 7.46-7.48 (m, 2H), 7.72-7.73 (m, 2H), 7.98 (d, 1H, J = 2.4 Hz).

[0246] (3) 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1-phenyl-1H-pyrazole [ka] To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-phenyl-1H-pyrazole (14.6 g) in tetrahydrofuran (80 ml) cooled to -78 ° C, n-butyllithium (1.6 M n-hexane solution, 24 ml) was added dropwise over 5 minutes, and the mixture was stirred for 1 hour. To this mixture, a solution of iodine (15.7 g) in tetrahydrofuran (30 ml) was added dropwise over 10 minutes, and the mixture was stirred for another 1.5 hours. To this mixture, water (5 ml) and a saturated aqueous sodium hydrogen sulfite solution (30 ml) were added in sequence, and the mixture was heated to 0 ° C, and then water (150 ml) was added and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water and a small amount of methanol, and dried under reduced pressure to obtain the title compound (13.0 g). 1 H-NMR (CDCl 3 ) δ: 2.19 (s, 6H), 5.88 (s, 2H), 6.55 (s, 1H), 7.44-7.53 (m, 3H), 7.57-7.60 (m, 2H).

[0247] (4) 5-Iodo-1-phenyl-1H-pyrazol-3-ylamine [ka] Hydroxylammonium chloride (46.6 g) and triethylamine (9.3 ml) were added in sequence to a solution of 3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1-phenyl-1H-pyrazole (12.2 g) in ethanol / water (2 / 1, 180 ml), and the mixture was stirred at 95° C. for 72 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 8M aqueous sodium hydroxide solution (80 ml) was added to the resulting residue, which was then extracted with ethyl acetate (50 ml). The organic layer was washed with water and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=3 / 1) to obtain the title compound (9.1 g). 1 H-NMR (CDCl 3) δ: 3.77 (br s, 2H), 6.01 (s, 1H), 7.35-7.51 (m, 5H).

[0248] (5) 1-Phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine [ka] 3-(trifluoromethoxy)phenylboronic acid (481 mg), 2M aqueous sodium carbonate solution (6 ml), tricyclohexylphosphine (119 mg), and palladium acetate (48 mg) were added in sequence to a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (605 mg) in ethylene glycol dimethyl ether (12 ml), and the mixture was stirred under heating and reflux for 2 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by filtration through Celite. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2 / 1) to obtain the title compound (298 mg). 1 H-NMR (CDCl 3 ) δ: 3.79 (br s, 2H), 5.95 (s, 1H), 7.04 (s, 1H), 7.13-7.34 (m, 8H).

[0249] (6) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid [1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide [ka] A solution of 1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (79 mg) in N,N-dimethylformamide (0.8 ml) was added to the solution of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (46 mg) synthesized in Preparation 1, HOBt·H 2 O (57 mg), WSC·HCl (71 mg) were added successively and stirred at room temperature for 2 hours. Water and saturated aqueous sodium bicarbonate were added to this reaction solution, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to give the title compound (63 mg). 1 H-NMR (DMSO-D 6 ) δ: 1.08 (d, 3H, J = 7.3 Hz), 2.55 (ddd, 1H, J = 9.3, 8.8, 8.8 Hz), 3.04 (dq, 1H, J = 9.3, 7.3 Hz), 3.23 (dd, 1H, J = 8.8, 8.8 Hz), 3.45 (dd, 1H, J = 8.8, 8.8 Hz), 7.03 (s, 1H), 7.09 (s, 1H), 7.26 (t, 2H, J = 6.7 Hz), 7.35-7.45 (m, 5H), 7.52 (t, 1H, J = 8.0 Hz), 7.68 (s, 1H), 10.99 (s, 1H).

[0250] (7) Crystal of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide The title compound was dissolved in ethyl acetate by heating at 90°C, and then recrystallized by adding heptane at the same temperature to obtain crystals of the title compound. The crystals were also suspended in water at 100°C to obtain other crystals of the title compound.

[0251] [Production Example 3]: Synthesis of Example 2 ((3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide) [ka] (1) Mixture of (E)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile and (Z)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile [ka] To a suspension of (cyanomethyl)triphenylphosphonium chloride (2.89g) in tetrahydrofuran (10ml), potassium tert-butoxide (942mg) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To this reaction solution, 3-trifluoromethoxybenzaldehyde (1.33g) was added under ice cooling, and the mixture was stirred at room temperature overnight. To this reaction solution, n-hexane (20ml) was added, and the insoluble matter was removed by filtration through Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (1.28g). 1 H-NMR (CDCl 3 ) (E)-body δ: 5.92 (1H, d, J = 16.8 Hz), 7.27-7.49 (5H, m). (Z)-body δ: 5.55 (1H, d, J = 12.0 Hz), 7.12 (1H, d, J = 12.0 Hz), 7.35-7.52 (2H, m), 7.60 (1H, s), 7.79 (1H, d, J = 8.0 Hz).

[0252] (2) 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine [ka] 4-Fluorophenylhydrazine hydrochloride (979 mg) and sodium ethoxide (20% by weight ethanol solution, 5.0 ml) were added in order to a solution of a mixture (1.28 g) of (E)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile and (Z)-3-(3-(trifluoromethoxy)phenyl)acrylonitrile in ethanol (13 ml), and the mixture was stirred overnight under heating and reflux. After concentrating the reaction solution under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in order, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2 / 1 to 1 / 1) to obtain the title compound (1.29 g). 1 H-NMR (CDCl 3 ) δ: 2.79 (dd, 1H, J = 16.3, 8.8 Hz), 3.41 (dd, 1H, J = 16.3, 11.0 Hz), 3.98 (s, 2H), 4.83 (dd, 1H, J = 11.0, 8.8 Hz), 6.72-6.87 (m, 4H), 7.14 (d, 1H, J = 7.9 Hz), 7.25 (s, 1H), 7.32 (d, 1H, J = 7.7 Hz), 7.38 (dd, 1H, J = 7.9, 7.7 Hz).

[0253] (3) 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine [ka] Activated carbon (pH 5-8, 0.64 g) was added to a solution of 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-1H-pyrazol-3-ylamine (1.29 g) in toluene (10 ml), and the mixture was stirred for 2 hours under heating and refluxing in an oxygen atmosphere. After cooling to room temperature, the activated carbon was removed by filtration through Celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and a diisopropyl ether / n-hexane mixed solvent was added to the resulting residue, and the mixture was stirred at room temperature. Insoluble matter was collected by filtration and dried under reduced pressure to obtain the title compound (652 mg). 1 H-NMR (CDCl 3 ) δ: 3.78 (bs, 1H), 5.95 (s, 1H), 6.97-7.05 (m, 3H), 7.13-7.21 (m, 4H), 7.334 (t, 1H, J = 8.0 Hz).

[0254] (4) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid [1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide [ka] 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl) A solution of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (50 mg) synthesized in Production Example 1, HOBt·H 2 O (61 mg) and WSC·HCl (77 mg) were added and stirred at room temperature for 2 hours. To this mixture, water and saturated aqueous sodium bicarbonate were added and extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to give the title compound (80 mg). 1H-NMR (DMSO-D6) δ: 1.08 (d, 3H, J = 7.1 Hz), 2.54 (dq, 1H, J = 9.3, 7.1 Hz), 3.04 (ddd, 1H, J = 9.3, 9.2, 8.4 Hz), 3.23 (dd, 1H, J = 9.2, 8.6 Hz), 3.44 (dd, 1H, J = 8.6, 8.4 Hz), 7.03 (s, 1H), 7.11 (s, 1H), 7.25-7.38 (m, 6H), 7.53 (dd, 1H, J = 8.2, 7.9 Hz), 7.68 (s, 1H), 10.98 (s, 1H).

[0255] [Production Example 4]: Synthesis of Example 3 ((3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide) [ka] (1) 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole [ka] 2,5-hexanedione (148 ml) was added to a solution of 3-aminopyrazole (100 g) in acetic acid (1000 ml) and stirred under heating and reflux for 2.4 hours. The reaction solution was cooled to room temperature, water (1000 ml) was added, and the precipitated solid was filtered. The obtained solid was washed with water (1000 ml) and dried under reduced pressure to obtain the title compound (183 g). 1 H-NMR (DMSO-D 6 ) δ: 2.00 (s, 6H), 5.74 (s, 2H), 6.27 (d, 1H, J = 2.1 Hz), 7.84 (d, 1H, J = 2.1 Hz), 12.90 (s, 1H).

[0256] (2) 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazole [ka] Cesium carbonate (27.4 g), 8-quinolinol (1.2 g), copper(I) oxide (0.6 g), and 1-fluoro-3-iodobenzene (7.4 ml) were added in sequence to a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (6.8 g) in N-methyl-2-pyrrolidone (68 ml), and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, toluene (80 ml) was added, and the mixture was filtered through Celite. 1M aqueous sodium hydroxide solution (80 ml) was added to the filtrate, and the mixture was extracted with toluene. The organic layer obtained was washed with water and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=9 / 1) to obtain the title compound (10.4 g). 1 H-NMR (CDCl 3 ) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.41 (d, 1H, J = 2.6 Hz), 6.97-7.02 (m, 1H), 7.39-7.45 (m, 1H), 7.48-7.49 (m, 1H), 7.49-7.52 (m, 1H), 7.97 (d, 1H, J = 2.6 Hz).

[0257] (3) 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-5-iodo-1H-pyrazole [ka] To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-1H-pyrazole (10.4 g) in tetrahydrofuran (100 ml) cooled to -78°C, n-butyllithium (1.6 M n-hexane solution, 31 ml) was added dropwise over 10 minutes, and the mixture was stirred for 30 minutes. To this mixture, a solution of iodine (12.4 g) in tetrahydrofuran (20 ml) was added dropwise over 10 minutes, and the mixture was stirred for another 30 minutes. To this mixture, a 20% by weight aqueous solution of sodium thiosulfate and a saturated aqueous solution of ammonium were added in sequence, and the mixture was warmed to room temperature and extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained residue, a mixed solvent of n-hexane / ethyl acetate (2 / 1) was added, and the mixture was stirred. Insoluble matter was collected by filtration and dried under reduced pressure to obtain the title compound (4.5 g). 1 H-NMR (CDCl 3 ) δ: 2.19 (s, 6H), 5.88 (s, 2H), 6.56 (s, 1H), 7.15-7.19 (m, 1H), 7.35-7.37 (m, 1H), 7.41-7.50 (m, 2H).

[0258] (4) 1-(3-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine [ka] Hydroxylammonium chloride (16.3 g) and triethylamine (3.3 ml) were added in sequence to a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-5-iodo-1H-pyrazole (4.5 g) in ethanol / water (2 / 1, 81 ml), and the mixture was stirred at 95° C. for 17 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. An 8M aqueous solution of sodium hydroxide was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=2 / 1) to obtain the title compound (3.2 g). 1 H-NMR (CDCl 3 ) δ: 3.78 (br s, 2H), 6.03 (s, 1H), 7.05-7.09 (m, 1H), 7.26-7.29 (m, 1H), 7.32-7.43 (m, 2H).

[0259] (5) 1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine [ka] 3-(trifluoromethoxy)phenylboronic acid (197 mg), 2M aqueous sodium carbonate solution (2.5 ml), tricyclohexylphosphine (49 mg), and palladium acetate (20 mg) were added in sequence to a solution of 1-(3-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (263 mg) in ethylene glycol dimethyl ether (5 ml), and the mixture was stirred under heating and reflux for 2 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by filtration through Celite. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2 / 1) to obtain the title compound (234 mg). 1 H-NMR (CDCl 3 ) δ: 3.82 (br s, 2H), 5.96 (s, 1H), 6.92-7.02 (m, 3H), 7.05-7.07 (m, 1H), 7.17-7.38 (m, 4H).

[0260] (6) (3R,4R)-4-Methyl-5-oxopyrrolidine-3-carboxylic acid [1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl]amide [ka] A solution of 1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (68 mg) in N,N-dimethylformamide (0.7 ml) was added to the solution of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (38 mg) synthesized in Preparation 1, HOBt·H 2 O (46 mg), WSC·HCl (58 mg) were added successively and stirred at room temperature for 2 hours. Water and saturated aqueous sodium bicarbonate were added to this reaction solution, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to give the title compound (33 mg). 1 H-NMR (DMSO-D 6 ) δ: 1.08 (d, 3H, J = 7.3 Hz), 2.54 (dq, 1H, J = 9.3, 7.3 Hz), 3.04 (ddd, 1H, J = 9.3, 8.9, 8.5 Hz), 3.23 (dd, 1H, J = 8.9, 8.7 Hz), 3.45 (dd, 1H, J = 8.7, 8.5 Hz), 7.04 (s, 1H), 7.05-7.07 (m, 1H), 7.14-7.18 (m, 2H), 7.22-7.26 (m, 1H), 7.39-7.48 (m, 3H), 7.56 (t, 1H, J = 8.0 Hz), 7.68 (s, 1H), 11.03 (s, 1H).

[0261] [Production Example 5]: Synthesis of (R)- and (S)-5-oxopyrrolidine-3-carboxylic acid [ka] (1) 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid [ka] A solution of 2,4-dimethoxybenzylamine (84.0 g) in toluene (100 ml) was added to a solution of itaconic acid (65.3 g) in toluene (400 ml), and the mixture was stirred under heating and reflux for 15 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diethyl ether (600 ml) was added to the resulting residue, and the mixture was stirred. The precipitated solid was collected by filtration, washed with diethyl ether and a small amount of ethyl acetate, and then dried under reduced pressure to obtain the title compound (127 g). 1 H-NMR (CDCl 3 ) δ: 2.66-2.82 (m, 2H), 3.20 (dt, 1H, J = 17.3, 7.6 Hz), 3.49-3.53 (m, 2H), 3.80 (s, 6H), 4.40 (d, 1H, J = 14.6 Hz), 4.46 (d, 1H, J = 14.6 Hz), 6.42-6.47 (m, 2H), 7.14 (t, 1H, J = 4.5 Hz).

[0262] (2) Optically active form of (R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone [ka] To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (31.7 g) in chloroform (300 ml), (R)-4-benzyl-2-oxazolidinone (20.0 g), WSC·HCl (23.8 g), and 4-dimethylaminopyridine (6.90 g) were added in this order under ice cooling, and the mixture was stirred for 15 minutes, warmed to room temperature, and stirred for 18 hours. The reaction mixture was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 1 to 1 / 9) to obtain the title compound (low polarity component 26.4 g, high polarity component 13.3 g). 1 H-NMR (CDCl 3) Low-polarity component δ: 2.72 - 2.83 (m, 3H), 3.27 (dd, 1H, J = 13.4, 3.5 Hz), 3.46 - 3.57 (m, 2H), 3.80 (s, 3H), 3.80 (s, 3H), 4.15 - 4.29 (m, 3H), 4.40 - 4.48 (m, 2H), 4.61 - 4.69 (m, 1H), 6.42 - 6.47 (m, 2H), 7.12 - 7.21 (m, 3H), 7.27 - 7.37 (m, 3H). High-polarity component δ: 2.62 - 2.72 (m, 2H), 2.86 (dd, 1H, J = 16.9, 5.8 Hz), 3.17 (dd, 1H, J = 13.4, 3.2 Hz), 3.40 (dd, 1H, J = 10.4, 5.1 Hz), 3.66 (dd, 1H, J = 10.4, 8.8 Hz), 3.72 (s, 3H), 3.81 (s, 3H), 4.16 - 4.26 (m, 3H), 4.40 (d, 1H, J = 14.6 Hz), 4.50 (d, 1H, J = 14.6 Hz), 4.61 - 4.69 (m, 1H), 6.40 - 6.45 (m, 2H), 7.11 - 7.17 (m, 3H), 7.27 - 7.34 (m, 3H).

[0263] (3) Optically active form of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid [Chemical formula] A 30% by weight aqueous hydrogen peroxide solution (17.5 ml) was added dropwise to a solution of lithium hydroxide monohydrate (3.29 g) in water (50 ml) while cooling with an ice-sodium chloride bath, and the mixture was stirred for 15 minutes. Tetrahydrofuran (30 ml) was added to the reaction solution, and then a solution of the low polar component (26.4 g) of (R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone in tetrahydrofuran (150 ml) was added dropwise, and the mixture was stirred for another hour. A solution of sodium hydrogen sulfite (18.7 g) in water (60 ml) was slowly added to the reaction solution, the bath was removed, and the mixture was allowed to cool to room temperature, and then the mixture was extracted with ethyl acetate (100 ml). The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 1 / 1 to 1 / 2, chloroform / methanol = 5 / 1) to give the title compound (14.3 g). When this solid was analyzed under HPLC analysis condition 2, the main component was an isomer with a short retention time. Short retention isomer (retention time 4.1 min) Longer retention time isomer (retention time 4.6 min) 1 H-NMR (CDCl 3 ) δ: 2.66-2.82 (m, 2H), 3.20 (dt, 1H, J = 17.3, 7.6 Hz), 3.49-3.53 (m, 2H), 3.80 (s, 6H), 4.40 (d, 1H, J = 14.6 Hz), 4.46 (d, 1H, J = 14.6 Hz), 6.42-6.47 (m, 2H), 7.14 (t, 1H, J = 4.5 Hz).

[0264] (4) Optically active form of 5-oxopyrrolidine-3-carboxylic acid [ka] Anisole (8.4 ml) and trifluoroacetic acid (100 ml) were added to the optically active 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (14.3 g), and the mixture was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diisopropyl ether (100 ml) was added to the resulting residue, and the mixture was stirred at room temperature. Insoluble matter was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain the title compound (4.96 g). 1 H-NMR (DMSO-D 6 ) δ: 2.26-2.40 (m, 2H), 3.18-3.28 (m, 1H), 3.30-3.35 (m, 1H), 3.40-3.47 (m, 1H), 7.64 (s, 1H), 12.58 (s, 1H); [α] D 25 +37 (c 0.10, CH 3 OH). By comparing the specific rotation with that in the literature (Tetrahedron: Asymmetry 12 (2001) 3241-3249), the obtained compound was found to be (R)-5-oxopyrrolidine-3-carboxylic acid. [ka] In addition, the highly polar component of (R)-4-benzyl-3-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone was subjected to a similar reaction and post-treatment to obtain the optical isomer, (S)-5-oxopyrrolidine-3-carboxylic acid (2.83 g). 1 H-NMR (DMSO-D 6 ) δ: 2.26-2.40 (m, 2H), 3.18-3.28 (m, 1H), 3.30-3.35 (m, 1H), 3.40-3.47 (m, 1H), 7.64 (s, 1H), 12.58 (s, 1H); [α] D 25 -40 (c 0.10, CH 3 OH). [ka]

[0265] [Production Example 6]: Synthesis of Example 4 ((R)-5-oxopyrrolidine-3-carboxylic acid [1-phenyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-yl]amide) [ka] (1) (R)-5-Oxopyrrolidine-3-carboxylic acid [1-phenyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazol-3-yl]amide [ka] A solution of 1-phenyl-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (40 mg) synthesized in the same manner as in Production Example 2 in N,N-dimethylformamide (0.3 ml) was added to a solution of (R)-5-oxopyrrolidine-3-carboxylic acid (24 mg) synthesized in Production Example 5, HOBt·H 2 O (29 mg), WSC·HCl (36 mg) were added in that order, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, and the mixture was stirred. Insoluble matter was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (45 mg). 1 H-NMR (DMSO-D 6 ) δ: 2.35-2.42 (m, 2H), 3.31-3.54 (m, 3H), 7.01 (s, 1H), 7.08 (s, 1H), 7.22-7.28 (m, 2H), 7.32-7.46 (m, 5H), 7.52 (t, 1H, J = 8.0 Hz), 7.64 (s, 1H), 10.90 (s, 1H).

[0266] [Production Example 7]: Synthesis of optically active 6-oxopiperidine-3-carboxylic acid [ka] (1) 2-Methylenepentanedioic acid dimethyl ester [ka] A solution of 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo(3,3,3)undecane (4.62g) in tetrahydrofuran (20ml) was added dropwise to a solution of methyl acrylate (40.5ml) in tetrahydrofuran (180ml) at room temperature, and the mixture was stirred overnight. This reaction solution was concentrated under reduced pressure, and diisopropyl ether, n-hexane and chloroform were added to the resulting residue, and the mixture was concentrated under reduced pressure again. Diisopropyl ether was added to the precipitated solid, and the mixture was stirred, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=9 / 1 to 4 / 1) to obtain the title compound (19.2g). 1 H-NMR (CDCl 3 ) δ: 2.53 (td, 2H, J = 7.6, 1.3 Hz), 2.65 (t, 2H, J = 7.6 Hz), 3.67 (s, 3H), 3.76 (s, 3H), 5.61 (q, 1H, J = 1.3 Hz), 6.20 (d, 1H, J = 1.3 Hz).

[0267] (2) 1-(2,4-Dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid methyl ester [ka] 2,4-Dimethoxybenzylamine (16.6 ml) was added to a solution of 2-methylenepentanedioic acid dimethyl ester (19.2 g) in toluene (195 ml) and the mixture was stirred for 3 days under heating and reflux. After cooling to room temperature, the reaction solution was washed with 1M aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (26.8 g) as a crude product. 1 H-NMR (CDCl 3) δ: 1.93-2.05 (m, 1H), 2.08-2.17 (m, 1H), 2.40-2.50 (m, 1H), 2.52-2.62 (m, 1H), 2.74-2.83 (m, 1H), 3.45 (d, 2H, J = 7.4 Hz), 3.68 (s, 3H), 3.81 (s, 3H), 3.81 (s, 3H), 4.54 (d, 1H, J = 14.6 Hz), 4.62 (d, 1H, J = 14.6 Hz), 6.44-6.48 (m, 2H), 7.15-7.19 (m, 1H).

[0268] (3) 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid [ka] A 1M aqueous solution of sodium hydroxide (174 ml) was added to a solution of the crude 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid methyl ester (26.8 g) in methanol / tetrahydrofuran (1 / 1, 174 ml) at room temperature and stirred overnight. A 1M aqueous solution of hydrochloric acid (174 ml) was added to the reaction solution and stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (15.1 g). 1 H-NMR (DMSO-D 6 ) δ: 1.77-1.90 (m, 1H), 1.95-2.06 (m, 1H), 2.25-2.41 (m, 2H), 2.75-2.86 (m, 1H), 3.31 (d, 2H, J = 7.1 Hz), 3.74 (s, 3H), 3.78 (s, 3H), 4.34 (d, 1H, J = 15.2 Hz), 4.43 (d, 1H, J = 15.2 Hz), 6.47 (dd, 1H, J = 8.4, 2.4 Hz), 6.56 (d, 1H, J = 2.4 Hz), 7.00 (d, 1H, J = 8.4 Hz), 12.56 (br s, 1H).

[0269] (4) Optically active form of 5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one [ka] To a solution of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid (3.39 g) in chloroform (15 ml), (R)-4-benzyl-2-oxazolidinone (2.04 g), WSC·HCl (2.44 g), and 4-dimethylaminopyridine (706 mg) were added at room temperature and stirred overnight. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate = 4 / 1 to 1 / 1) to obtain the title compound (low polarity component 3.37 g, high polarity component 2.72 g). 1 H-NMR (CDCl 3 ) Low polar component δ: 1.91-2.02 (m, 1H), 2.14-2.24 (m, 1H), 2.50-2.66 (m, 2H), 2.73-2.81 (m, 1H), 3.18-3.25 (m, 1H), 3.34-3.41 (m, 1H), 3.51-3.60 (m, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 3.84-3.93 (m, 1H), 4.05-4.20 (m, 2H), 4.53-4.65 (m, 3H), 6.42-6.47 (m, 2H), 7.14-7.38 (m, 6H). Highly polar component 1 H-NMR (CDCl 3 ) δ: 1.92-2.14 (m, 2H), 2.47-2.67 (m, 3H), 3.14-3.23 (m, 1H), 3.44-3.59 (m, 2H), 3.77 (s, 3H), 3.81 (s, 3H), 3.91-4.01 (m, 1H), 4.14-4.26 (m, 2H), 4.54-4.68 (m, 3H), 6.42-6.49 (m, 2H), 7.15-7.21 (m, 3H), 7.25-7.35 (m, 3H).

[0270] (5) Optically active form of 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid [ka] To a solution of lithium hydroxide monohydrate (316 mg) in water (10 ml), 30% by weight hydrogen peroxide (1.8 ml) was added dropwise under ice cooling, and the mixture was stirred for 10 minutes. Tetrahydrofuran (10 ml) was added to this reaction solution, and then a solution of the low polar component (3.37 g) of 5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one in tetrahydrofuran (20 ml) was added dropwise, and the mixture was stirred for another 1 hour. An aqueous solution of sodium hydrogen sulfite (1.81 g) was added dropwise to this reaction solution, and the mixture was warmed to room temperature and stirred for 30 minutes. This mixture was extracted with ethyl acetate, and the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred at room temperature. Insoluble matter was collected by filtration and dried under reduced pressure to obtain the title compound (1.36 g). When this solid was analyzed under HPLC analysis condition 2, the isomer with a short retention time was found to be the main component. Short retention isomer (retention time 4.5 min) Longer retention isomer (retention time 6.6 min).

[0271] (6) Optically active form of 6-oxopiperidine-3-carboxylic acid [ka] Anisole (758 μl) and trifluoroacetic acid (10 ml) were added to the optically active 1-(2,4-dimethoxybenzyl)-6-oxopiperidine-3-carboxylic acid (1.36 g), and the mixture was stirred at 80° C. for 6 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Diisopropyl ether was added to the resulting residue, and the mixture was stirred at room temperature. Insoluble matter was collected by filtration and dried under reduced pressure to obtain the title compound (628 mg). 1 H-NMR (DMSO-D 6) δ: 1.75-1.88 (m, 1H), 1.91-2.01 (m, 1H), 2.11-2.24 (m, 2H), 2.66-2.73 (m, 1H), 3.21-3.32 (m, 2H), 7.45 (s, 1H), 12.51 (br s, 1H). The highly polar component (2.72 g) of 5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one was subjected to the same reaction and post-treatment to give the optical isomer (485 mg) of the title compound. 1 H-NMR (DMSO-D 6 ) δ: 1.75-1.88 (m, 1H), 1.91-2.01 (m, 1H), 2.11-2.24 (m, 2H), 2.66-2.73 (m, 1H), 3.21-3.32 (m, 2H), 7.45 (s, 1H), 12.51 (br s, 1H).

[0272] [Production Example 8]: Synthesis of optically active substance of Example 5 (6-oxopiperidine-3-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide) [ka] (1) 1-Bromo-3-propylbenzene [ka] Triethylsilane (94 ml) was added dropwise to a solution of 3-bromopropiophenone (25 g) in trifluoroacetic acid (250 ml) under ice cooling over 20 minutes, and the mixture was stirred for another 20 minutes. The reaction solution was heated to 80° C. and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and toluene was added, followed by concentration under reduced pressure again. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane) to obtain the title compound (16.6 g). 1 H-NMR (CDCl 3) δ: 0.95 (t, 3H, J = 7.4 Hz), 1.64 (tq, 2H, J = 7.7, 7.4 Hz), 2.57 (t, 2H, J = 7.7 Hz), 7.08-7.13 (m, 1H), 7.13-7.18 (m, 1H), 7.30-7.35 (m, 2H).

[0273] (2) 3-Propylbenzaldehyde [ka] To a solution of 1-bromo-3-propylbenzene (16.6 g) in tetrahydrofuran (83 ml) cooled to -78°C, n-butyllithium (2.66 M n-hexane solution, 34 ml) was added dropwise over 9 minutes, and the mixture was stirred for 1 hour. To this reaction solution, N,N-dimethylformamide (7.7 ml) was added dropwise over 6 minutes, and the mixture was stirred for another 20 minutes. To this reaction solution, 4 M hydrochloric acid / 1,4-dioxane solution (23 ml) was added dropwise over 5 minutes, and the mixture was warmed to room temperature and stirred. To this mixture, water (83 ml) was added, followed by 6 M aqueous hydrochloric acid (12 ml), and then extracted with n-hexane (80 ml). The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (14.0 g) of the title compound. 1 H-NMR (CDCl 3 ) δ: 0.95 (t,3H, J = 7.3 Hz), 1.68 (tq, 2H, J = 7.7, 7.3 Hz), 2.67 (t, 2H, J = 7.7 Hz), 7.42-7.47 (m, 2H), 7.67-7.72 (m, 2H), 9.98-10.01 (m, 1H).

[0274] (3) Mixture of (E)-3-(3-propylphenyl)acrylonitrile and (Z)-3-(3-propylphenyl)acrylonitrile [ka] To a suspension of (cyanomethyl)triphenylphosphonium chloride (34g) in tetrahydrofuran (110ml), potassium tert-butoxide (13g) was added in portions under ice cooling, and the mixture was stirred at room temperature for 1 hour. To this reaction solution, a solution of crude 3-propylbenzaldehyde (14.0g) in tetrahydrofuran (30ml) was added dropwise over 7 minutes under ice cooling, and the mixture was stirred overnight at room temperature. n-Hexane (280ml) was added, and the mixture was stirred under ice cooling for 1 hour, after which the insoluble matter was removed by filtration through Celite and eluted with n-hexane (840ml). The filtrate was concentrated, and a mixed solvent of n-hexane / ethyl acetate (5 / 1, 120ml) was added to the residue, and the mixture was stirred. The insoluble matter was removed by filtration through Celite, and the mixture was eluted with a mixed solvent of n-hexane / ethyl acetate (10 / 1). The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 0 to 25 / 1) to obtain the title compound (11.4 g). 1 H-NMR (CDCl 3 ) (E)-body δ: 0.95 (t, 3H, J = 7.5 Hz), 1.65 (tq, 2H, J = 7.7, 7.5 Hz), 2.60 (t, 2H, J = 7.7 Hz), 5.87 (d, 1H, J = 16.5 Hz), 7.22-7.41 (m, 5H). (Z)-body δ: 0.95 (t, 3H, J = 7.5 Hz), 1.67 (tq, 2H, J = 7.7, 7.5 Hz), 2.64 (t, 2H, J = 7.7 Hz), 5.42 (d, 1H, J = 12.1 Hz), 7.11 (d, 1H, J = 12.1 Hz), 7.23-7.42 (m, 2H), 7.58-7.66 (m, 2H).

[0275] (4) 1-Phenyl-5-(3-propylphenyl)-4,5-dihydro-1H-pyrazol-3-ylamine [ka] Phenylhydrazine (6.4 ml) was added dropwise to a solution of sodium ethoxide (20% by weight in ethanol, 31 ml) in ethanol (66 ml) at room temperature, and the mixture was stirred for 40 minutes. A solution of a mixture of (E)-3-(3-propylphenyl)acrylonitrile and (Z)-3-(3-propylphenyl)acrylonitrile (11.1 g) in ethanol (33 ml) was added dropwise to the reaction solution, and the mixture was stirred overnight under heating and reflux. The reaction solution was cooled to room temperature, and water (30 ml) was added. Then, the pH of the reaction solution was adjusted to 7 by adding a 6M aqueous hydrochloric acid solution under ice cooling. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Toluene was added to the resulting residue, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Toluene was added to the resulting residue, and the mixture was concentrated under reduced pressure again to obtain a crude product of the title compound (18.6 g). 1 H-NMR (CDCl 3 ) δ: 0.91 (t, 3H, J = 7.5 Hz), 1.61 (tq, 2H, J = 7.7, 7.5 Hz), 2.56 (t, 2H, J = 7.7 Hz), 2.78 (dd, 1H, J = 16.3, 8.5 Hz), 3.41 (dd, 1H, J = 16.3, 11.3 Hz), 3.96 (s, 2H), 4.90 (dd, 1H, J = 11.3, 8.5 Hz), 6.67-6.72 (m, 1H), 6.80-6.87 (m, 2H), 7.02-7.37 (m, 6H).

[0276] (5) 1-Phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine [ka] Activated carbon (pH 5-8, 9.29 g) was added to a solution of crude 1-phenyl-5-(3-propylphenyl)-4,5-dihydro-1H-pyrazol-3-ylamine (18.6 g) in toluene (185 ml), and the mixture was stirred overnight under heating and refluxing in an oxygen atmosphere. After cooling the reaction solution to room temperature, the activated carbon was removed by filtration through Celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in toluene (185 ml), and new activated carbon (pH 5-8, 9.29 g) was added, and the mixture was stirred overnight under heating and refluxing in an oxygen atmosphere. After cooling the reaction solution to room temperature, the activated carbon was removed by filtration through Celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4 / 1-1 / 1) to obtain the title compound (8.68 g). 1 H-NMR (CDCl 3 ) δ: 0.82 (t, 3H, J = 7.3 Hz), 1.49 (tq, 2H, J = 7.6, 7.3 Hz), 2.47 (t, 2H, J = 7.6 Hz), 3.75 (s, 2H), 5.90 (s, 1H), 6.96-7.00 (m, 1H), 7.02-7.12 (m, 2H), 7.15-7.30 (m, 6H).

[0277] (6) Optically active form of 6-oxopiperidine-3-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide [ka] A solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (56 mg) in tetrahydrofuran (1.5 ml) was added with the optically active form of 6-oxopiperidine-3-carboxylic acid (derived from the low polarity component of 5-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one) (43 mg) synthesized in Preparation 7, HOBt·H 2O (46 mg) and WSC·HCl (58 mg) were added in that order, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to give the title compound (50 mg). 1 H-NMR (DMSO-D 6 ) δ: 0.77 (t, 3H, J = 7.3 Hz), 1.44 (tq, 2H, J = 7.5, 7.3 Hz), 1.83-2.03 (m, 2H), 2.12-2.30 (m, 2H), 2.46 (t, 2H, J = 7.5 Hz), 2.84 (tt, 1H, J = 10.7, 3.6 Hz), 3.24-3.31 (m, 2H), 6.89 (s, 1H), 7.00 (s, 1H), 7.06 (d, 1H, J = 7.7 Hz), 7.17 (d, 1H, J = 7.7 Hz), 7.19-7.43 (m, 6H), 7.51 (s, 1H), 10.83 (s, 1H).

[0278] [Production Example 9]: Synthesis of (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid and (S)-3-methyl-2-oxoimidazolidine-4-carboxylic acid [ka] (1)(R)-2-Oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester [ka] To a solution of sodium hydroxide (743 mg) in water (15 ml), bromine (318 μl) was added dropwise over 30 minutes under ice cooling. ZD-asparagine (1.5 g) was added to this reaction solution, which was then heated to 55° C. and stirred for 3 hours. This reaction solution was cooled to room temperature and washed twice with diethyl ether (15 ml). 6M aqueous hydrochloric acid was added dropwise to the resulting aqueous layer until the pH reached 1. This mixture was left to stand overnight at 4° C. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (1.1 g). 1 H-NMR (DMSO-D 6 ) δ: 3.22 (dd, 1H, J = 10.0, 3.3 Hz), 3.65 (dd, 1H, J = 10.0, 10.2 Hz), 4.68 (dd, 1H, J = 10.2, 3.3 Hz), 5.16 (d, 1H, J = 14.8 Hz), 5.19 (d, 1H, J = 14.8 Hz), 7.29-7.39 (m, 5H), 7.57 (s, 1H), 13.25 (br s, 1H).

[0279] (2)(R)-2-Oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester 5-tert-butyl ester [ka] To a solution of (R)-2-oxo-imidazolidine-1,5-dicarboxylic acid 1-benzyl ester (534 mg) in chloroform (2.6 ml), pyridine (1.0 ml) and tert-butyl alcohol (1.5 ml) were added in sequence at room temperature and stirred. The reaction solution was ice-cooled, phosphorus oxychloride (0.23 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was ice-cooled, 20 wt% aqueous sodium acetate solution (20 ml) was added, and chloroform (5 ml) was added at room temperature and stirred for 30 minutes. The mixture was extracted with chloroform, and the resulting organic layer was washed with 0.1 M aqueous hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product (467 mg) of the title compound. 1 H-NMR (CDCl 3 ) δ: 1.39 (s, 9H), 3.38 (dd, 1H, J = 9.8, 3.3 Hz), 3.71 (dd, 1H, J = 9.8, 9.8 Hz), 4.62 (dd, 1H, J = 9.8, 3.3 Hz), 5.24 (d, 1H, J = 12.6 Hz), 5.29 (d, 1H, J = 12.6 Hz), 6.00 (br s, 1H), 7.28-7.41 (m, 5H).

[0280] (3)(R)-3-Methyl-2-oxoimidazolidine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester [ka] Sodium hydride (42 mg) was added to a solution of the crude product (318 mg) of (R)-2-oxo-imidazolidine-1,5-dicarboxylic acid 1-benzyl ester 5-tert-butyl ester in N,N-dimethylformamide (3 ml) under ice cooling, and the mixture was stirred for 40 minutes. After adding methyl iodide (309 μl) to the reaction solution, the mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was ice-cooled, and water and ethyl acetate were added and stirred. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1) to obtain the title compound (167 mg). 1 H-NMR (CDCl 3 ) δ: 1.48 (s, 9H), 2.91 (s, 3H), 3.81-3.85 (m, 1H), 3.96-4.02 (m, 2H), 5.27 (d, 1H, J = 13.1 Hz), 5.30 (d, 1H, J = 13.1 Hz), 7.29-7.45 (m, 5H).

[0281] (4)(R)-3-Methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester [ka] To a solution of (R)-3-methyl-2-oxoimidazolidine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (167 mg) in methanol (1.7 ml), 10% by weight palladium on carbon was added at room temperature and stirred under 1 atm hydrogen for 15 hours. Under a nitrogen atmosphere, the reaction solution was filtered through Celite and eluted with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (94 mg). 1 H-NMR (CDCl 3 ) δ: 1.50 (s, 9H), 2.86 (s, 3H), 3.41-3.46 (m, 1H), 3.62-3.67 (m, 1H), 4.05 (dd, 1H, J = 9.8, 6.1 Hz), 4.38 (br s, 1H).

[0282] (5) (R)-3-Methyl-2-oxoimidazolidine-4-carboxylic acid [ka] Trifluoroacetic acid (1 ml) was added to a solution of (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester (94 mg) in chloroform (2 ml) at room temperature and stirred for 3 hours. This reaction solution was concentrated under reduced pressure, and toluene (3 ml) was added and concentrated again. Diethyl ether (0.5 ml) was added to the resulting residue at room temperature and stirred. Then, n-hexane (2 ml) was added and stirred further. Insoluble matter was collected by filtration and dried under reduced pressure to obtain the title compound (52 mg). 1 H-NMR (DMSO-D 6) δ: 2.66 (s, 3H), 3.18 (dd, 1H, J = 9.2, 5.7 Hz), 3.51 (dd, 1H, J = 9.2, 9.9 Hz), 4.12 (dd, 1H, J = 9.9, 5.7 Hz), 6.42 (br s, 1H), 12.99 (br s, 1H). In addition, ZL-asparagine was subjected to the same reaction and post-treatment to obtain (S)-3-methyl-2-oxoimidazolidine-4-carboxylic acid (686 mg), which is an optical isomer of the title compound. 1 H-NMR (DMSO-D 6 ) δ: 2.66 (s, 3H), 3.18 (dd, 1H, J = 9.2, 5.7 Hz), 3.51 (dd, 1H, J = 9.2, 9.9 Hz), 4.12 (dd, 1H, J = 9.9, 5.7 Hz), 6.42 (br s, 1H), 12.99 (br s, 1H). [ka]

[0283] [Production Example 10]: Synthesis of Example 6 ((R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide) [ka] (1) (R)-3-Methyl-2-oxoimidazolidine-4-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide [ka] A solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (56 mg) synthesized in the same manner as in Production Example 8 in N,N-dimethylformamide (0.6 ml) was added to a solution of (R)-3-methyl-2-oxoimidazolidine-4-carboxylic acid (38 mg) synthesized in Production Example 9, HOBt·H2 O (46 mg), WSC·HCl (58 mg) were added successively and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and water were added to this reaction solution, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to give the title compound (40 mg). 1 H-NMR (DMSO-D 6 ) δ: 0.77 (t, 3H, J = 7.3 Hz), 1.44 (tq, 2H, J = 7.5, 7.3 Hz), 2.46 (t, 3H, J = 7.5 Hz), 2.64 (s, 3H), 3.21 (dd, 1H, J = 8.8, 6.3 Hz), 3.54 (dd, 1H, J = 9.4, 8.8 Hz), 4.28 (dd, 1H, J = 9.4, 6.3 Hz), 6.44 (s, 1H), 6.92 (s, 1H), 7.01 (s, 1H), 7.08 (d, 1H, J = 7.0 Hz), 7.17 (d, 1H, J = 7.0 Hz), 7.20-7.44 (m, 6H), 11.02 (s, 1H).

[0284] [Production Example 11]: Synthesis of 5-oxotetrahydrofuran-3-carboxylic acid [ka] (1) Sodium 5-oxo-2,5-dihydrofuran-3-carboxylate [ka] Bromine (10.3 ml) was added dropwise to a solution of itaconic acid (26.0 g) in water (35 ml) at room temperature while controlling the temperature of the reaction solution to 45° C. or less, and then the mixture was stirred at 30° C. for 15 minutes. Sodium hydrogen carbonate (33.6 g) was added in portions to the reaction solution, and the temperature was raised to 55° C. A solution of sodium carbonate (10.6 g) in water (15 ml) was added dropwise to the reaction solution, and the mixture was stirred for 20 minutes. The reaction solution was ice-cooled and stirred for 1 hour. The precipitated solid was collected by filtration, washed with cold water and ethanol, and then dried under reduced pressure to obtain the title compound (16.8 g). 1 H-NMR (DMSO-d 6 ) δ: 4.83 (d, 2H, J = 2.0 Hz), 5.93-5.95 (m, 1H).

[0285] (2) 5-Oxotetrahydrofuran-3-carboxylic acid [ka] 10% by weight palladium on carbon (30 mg) was added to a solution of sodium 5-oxo-2,5-dihydrofuran-3-carboxylate (150 mg) in water (3 ml), and the mixture was stirred at room temperature under 1 atm hydrogen for 18 hours. Under a nitrogen atmosphere, an appropriate amount of Amberlite IR-120 was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes, and then filtered through Celite. The filtrate was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue, which was then dried over sodium sulfate and concentrated under reduced pressure again to give the title compound (83 mg). 1 H-NMR (DMSO-d 6 ) δ: 2.64 (dd, 1H, J = 17.6, 6.2 Hz), 2.75 (dd, 1H, J = 17.6, 9.4 Hz), 3.39-3.49 (m, 1H), 4.34 (dd, 1H, J = 8.8, 5.4 Hz), 4.44 (dd, 1H, J = 8.8, 8.2 Hz), 12.82 (br s, 1H).

[0286] [Production Example 12]: Synthesis of Example 7 (5-oxotetrahydrofuran-3-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide) [ka] (1) 5-Oxotetrahydrofuran-3-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide [ka] The 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (109 mg) synthesized in the same manner as in Production Example 8 was dissolved in N,N-dimethylformamide / tetrahydrofuran (1 / 1, 2 ml) and the 5-oxotetrahydrofuran-3-carboxylic acid (82 mg) synthesized in Production Example 11, HOBt·H 2 O (96 mg), WSC·HCl (121 mg) were added in that order, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to give the title compound (96 mg). 1 H-NMR (DMSO-D 6 ) δ: 0.77 (t, 3H, J = 7.3 Hz), 1.38-1.50 (m, 2H), 2.46 (t, 2H, J = 7.5 Hz), 2.69 (dd, 1H, J = 17.4, 5.9 Hz), 2.81 (dd, 1H, J = 17.4, 9.0 Hz), 3.56-3.65 (m, 1H), 4.34 (dd, 1H, J = 8.8, 5.0 Hz), 4.47-4.55 (m, 1H), 6.89 (s, 1H), 7.00 (s, 1H), 7.07 (d, 1H, J = 7.5 Hz), 7.17 (d, 1H, J = 7.1 Hz), 7.20-7.30 (3H, m), 7.31-7.43 (3H, m), 11.00 (s, 1H).

[0287] [Production Example 13]: Synthesis of Example 8 ((R)-2-oxoimidazolidine-4-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide) [ka] (1)(R)-2,3-bis-tert-butoxycarbonylaminopropionic acid [ka] To a solution of di-tert-butyl dicarbonate (513 mg) in 1,4-dioxane (4 ml), N-Boc-(R)-2,3-diaminopropionic acid (400 mg) was added at room temperature, stirred for 20 minutes, then heated to 50°C and stirred for 20 minutes. After cooling to room temperature again, triethylamine (546 μl) was added and stirred for 2 hours. Water and a 10% by weight aqueous solution of citric acid were added to this reaction solution, and it was extracted with ethyl acetate. The obtained organic layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / ethanol = 1 / 0 to 10 / 1) to obtain the title compound (557 mg). 1 H-NMR (DMSO-D 6 ) δ: 1.37 (s, 9H), 1.38 (s, 9H), 3.23 (dd, 2H, J = 6.2, 6.0 Hz), 3.99 (dt, 1H, J = 8.2, 6.2 Hz), 6.78 (t, 1H, J = 6.0 Hz), 6.86 (d, 1H, J = 8.2 Hz), 12.52 (br s, 1H).

[0288] (2) {(R)-2-tert-butoxycarbonylamino-2-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester [ka] A solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (177 mg) synthesized in the same manner as in Preparation Example 8 in DMF (1.8 ml) was added to (R)-2,3-bis-tert-butoxycarbonylaminopropionic acid (292 mg), HOBt·H 2 O (147 mg) and WSC·HCl (184 mg) were added and stirred at room temperature for 2 hours. Water and saturated aqueous sodium bicarbonate were added to this reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2 / 1) to give the title compound (329 mg). 1 H-NMR (CDCl 3 ) δ: 0.83 (t, 3H, J = 7.3 Hz), 1.45 (s, 9H), 1.48 (s, 9H), 1.50 (tq, 2H, J = 7.3, 7.5 Hz), 2.49 (t, 2H, J = 7.5 Hz), 3.61-3.64 (br m, 2H), 4.38-4.41 (br m, 1H), 5.06 (br s, 1H), 5.94 (br s, 1H), 7.01 (s, 1H), 7.05-7.35 (m, 9H), 8.94 (br s, 1H).

[0289] (3)(R)-2,3-Diamino-N-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]-propionamide dihydrochloride [ka] To a solution of {(R)-2-tert-butoxycarbonylamino-2-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (328 mg) in 1,4-dioxane (3 ml), 4M hydrochloric acid / 1,4-dioxane solution (3 ml) was added at room temperature and stirred for 2 hours. After concentrating the reaction solution, n-hexane (4 ml) was added and stirred. Insoluble matter was collected by filtration, washed with n-hexane, and dried under reduced pressure to obtain the title compound (181 mg). 1 H-NMR (DMSO-D 6 ) δ: 0.77 (t, 3H, J = 7.3 Hz), 1.44 (tq, 2H, J = 7.5, 7.3 Hz), 2.46 (t, 2H, J = 7.5 Hz), 3.41-3.46 (m, 2H), 3.57 (s, 1H), 4.38-4.41 (m, 1H), 6.91 (s, 1H), 7.11-7.31 (m, 9H), 8.56 (br s, 4H).

[0290] (4) (R)-2-Oxoimidazolidine-4-carboxylic acid [1-phenyl-5-(3-propyl-phenyl)-1H-pyrazol-3-yl]amide [ka] To a solution of (R)-2,3-diamino-N-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]-propionamide dihydrochloride (181 mg) in N,N-dimethylformamide (3 ml), 1,1'-carbonyldiimidazole (67 mg) and triethylamine (116 μl) were added at room temperature and stirred for 16 hours. Water was added to this reaction solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1) to obtain the title compound (76 mg). 1H-NMR (DMSO-D 6 ) δ: 0.77 (t, 3H, J = 7.4 Hz), 1.44 (tq, 2H, J = 7.5, 7.4 Hz), 2.46 (t, 2H, J = 7.5 Hz), 3.35 (dd, 1H, J = 9.4, 5.6 Hz), 3.59 (dd, 1H, J = 9.4, 9.4 Hz), 4.32 (dd, 1H, J = 9.4, 5.6 Hz), 6.34 (s, 1H), 6.61 (s, 1H), 6.90 (s, 1H), 7.00 (s, 1H), 7.06-7.41 (m, 8H), 10.71 (s, 1H).

[0291] [Production Example 14]: Synthesis of (S)-5-oxopyrrolidine-3-carboxylic acid [ka] (1) (S)-4-benzyl-3-[(S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone [ka] To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (20 g) obtained in the same manner as in Production Example 5 in chloroform (200 ml), (S)-4-benzyl-2-oxazolidinone (15.2 g), WSC·HCl (16.4 g), and 4-(dimethylamino)pyridine (4.4 g) were added in that order at room temperature and stirred for 3 hours. This reaction solution was washed with a 5% by weight aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 1 to 1 / 3), azeotropically dried with toluene, and dried under reduced pressure to obtain the title compound (17.2 g). 1 H-NMR (CDCl 3) δ: 2.72-2.83 (m, 3H), 3.27 (dd, 1H, J = 13.4, 3.5 Hz), 3.46-3.57 (m, 2H), 3.80 (s, 3H), 3.80 (s, 3H), 4.15-4.29 (m, 3H), 4.40-4.48 (m, 2H), 4.61-4.69 (m, 1H), 6.42-6.47 (m, 2H), 7.12-7.21 (m, 3H), 7.27-7.37 (m, 3H).

[0292] (2) (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid [ka] A 30% by weight aqueous hydrogen peroxide solution (11 ml) was added dropwise to a solution of lithium hydroxide monohydrate (2.0 g) in water (45 ml) while cooling with an ice-sodium chloride bath, and the mixture was stirred for 15 minutes. Tetrahydrofuran (36 ml) was added to the reaction solution, and then a solution of (S)-4-benzyl-3-[(S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone (17.2 g) in tetrahydrofuran (144 ml) was added dropwise, and the mixture was stirred for another 20 minutes. A 10% by weight aqueous sodium hydrogen sulfite solution (131 ml) was slowly added to the reaction solution, the bath was removed, and the mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (180 ml). The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (developing solvent: ethyl acetate to chloroform / methanol = 9 / 1). Diisopropyl ether (13.4 ml) was added to the obtained purified product (6.7 g) and stirred at 70° C., then cooled to 0° C. and stirred. The solid was filtered from this suspension and dried under reduced pressure to obtain the title compound (5.5 g). This solid was analyzed under HPLC analysis condition 1, and it was confirmed that the isomer with a long retention time was the main component. Short retention isomer (retention time 4.7 min) Longer retention time isomer (retention time 5.4 min) 1 H-NMR (CDCl 3 ) δ: 2.66-2.82 (m, 2H), 3.20 (dt, 1H, J = 17.3, 7.6 Hz), 3.49-3.53 (m, 2H), 3.80 (s, 6H), 4.40 (d, 1H, J = 14.6 Hz), 4.46 (d, 1H, J = 14.6 Hz), 6.42-6.47 (m, 2H), 7.14 (t, 1H, J = 4.5 Hz).

[0293] (3) (S)-5-Oxopyrrolidine-3-carboxylic acid [ka] Anisole (3.1 ml) and trifluoroacetic acid (26.5 ml) were added to (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (5.3 g) at room temperature, and the mixture was stirred under heating and reflux for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and then azeotropically dried with toluene. Diisopropyl ether (53 ml) was added to the resulting residue, and the mixture was stirred at room temperature. The solid was filtered from the suspension, washed with diisopropyl ether, and dried under reduced pressure to obtain the title compound (2.4 g). 1 H-NMR (DMSO-D 6 ) δ: 2.26-2.40 (m, 2H), 3.18-3.28 (m, 1H), 3.30-3.35 (m, 1H), 3.40-3.47 (m, 1H), 7.64 (s, 1H), 12.58 (s, 1H).

[0294] [Production Example 15]: Synthesis of Example 235 ((S)-5-oxopyrrolidine-3-carboxylic acid {5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide) [ka] (1) 1-Fluoro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene [ka] Under an argon atmosphere, a suspension of sodium hydride (76 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0°C, and a solution of (R)-1,1,1-trifluoropropan-2-ol (219 mg) in N,N-dimethylformamide (2.0 ml) was added and stirred for 25 minutes. Then, a solution of 1-bromomethyl-3-fluorobenzene (297 mg) in N,N-dimethylformamide (2.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 9 / 1) to obtain the title compound (242 mg). 1 H-NMR (CDCl 3 ) δ: 1.35 (d, 3H, J = 6.47 Hz), 3.84 (qq, 1H, J = 6.47, 9.40 Hz), 4.63 (d, 1H, J = 12.00Hz), 4.76 (d, 1H, J = 12.00 Hz), 6.98-7.03 (m, 1H), 7.06-7.12 (m, 2H), 7.29-7.35 (m, 1H).

[0295] (2) 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ka] Under an argon atmosphere, bis-pinacolatodiboron (202 mg), 4,4'-di-tert-butyl-2,2'-dipyridyl (10 mg), and di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (12 mg) were added in sequence to a solution of 1-fluoro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene (159 mg) in tetrahydrofuran (3.0 ml) at room temperature, and the mixture was stirred for 16 hours under heating and reflux. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added, the mixture was filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 85 / 15) to obtain the title compound (49 mg). 1 H-NMR (CDCl 3 ) δ: 1.35 (m, 15H), 3.83 (qq, 1H, J = 6.47, 9.40 Hz), 4.62 (d, 1H, J = 12.00Hz), 4.75 (d, 1H, J = 12.00 Hz), 7.19 (d, 1H, J = 9.60 Hz), 7.43 (d, 1H, J = 9.60 Hz), 7.49 (s, 1H).

[0296] (3) 5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine [ka] 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (49 mg), 1,2-dimethoxyethane (1.0 ml) solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (36 mg) obtained in the same manner as in Production Example 2, 2M aqueous sodium carbonate solution (0.5 ml), tricyclohexylphosphine (7.3 mg), and palladium (II) acetate (3.0 mg) were added in sequence at room temperature, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution and ethyl acetate were added, filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the separated organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol=9 / 1) to obtain the title compound (37 mg).

[0297] (4) (S)-5-Oxopyrrolidine-3-carboxylic acid {5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide [ka] To a solution of 5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (37 mg) in N,N-dimethylacetamide (1.0 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (16 mg) obtained in Production Example 14 and WSC·HCl (23 mg) were added in that order at room temperature, and the mixture was stirred for 5.2 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. This solid was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid, and the mixture was stirred. The solid was collected by filtration from this suspension and dried under reduced pressure to obtain the title compound (20 mg). 1H-NMR (DMSO-D6) δ: 1.18 (d, 3H, J = 6.5 Hz), 2.36-2.38 (m, 2H), 3.32-3.33 (m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.10 (qq, 1H, J = 6.5, 9.4 Hz), 4.57 (d, 1H, J = 12.7 Hz), 4.61 (d, 1H, J = 12.7 Hz), 6.96-3.98 (m, 2H), 7.09 (s, 1H), 7.15-7.18 (m, 1H), 7.25-7.27 (m, 2H), 7.35-7.44 (m, 3H), 7.63 (s, 1H), 10.88 (s, 1H).

[0298] [Production Example 16]: Synthesis of Example 236 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 1-(4-chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole [ka] Under an argon atmosphere, cesium carbonate (12.37 g), 8-quinolinol (0.55 g), copper oxide (I) (0.27 g), and 1-chloro-4-iodobenzene (6.79 g) were added in sequence at room temperature to a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (3.06 g) obtained in the same manner as in Production Example 4 in N-methylpyrrolidone (31 ml), and the mixture was stirred at 110° C. for 2 hours. After cooling the reaction mixture to room temperature, toluene (30 ml) was added, the mixture was filtered through Celite, and the mixture was eluted with toluene. The filtrate was washed with 1N aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 9 / 1) to obtain the title compound (4.98 g). 1 H-NMR (CDCl 3 ) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.40 (d, 1H, J = 2.65 Hz), 7.43 (d, 2H, J = 8.82 Hz), 7.66 (d, 2H, J = 8.82 Hz), 7.94 (d, 1H, J = 2.65 Hz).

[0299] (2) 1-(4-chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1H-pyrazole [ka] Under an argon atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-chlorophenyl)-1H-pyrazole (4.98 g) in tetrahydrofuran (40 ml) was cooled to -78°C, n-butyllithium (13.7 ml, 1.6 M n-hexane solution) was added dropwise, and the mixture was stirred for 30 minutes. A solution of iodine (5.58 g) in tetrahydrofuran (10 ml) was added dropwise to the reaction solution, and the mixture was stirred for 30 minutes. A 20% by weight aqueous solution of sodium sulfite and a saturated aqueous solution of ammonium chloride were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. A mixed solvent of ethyl acetate / n-hexane = 1 / 2 was added to the obtained solid residue, and the mixture was stirred. The solid was collected by filtration from this suspension and dried under reduced pressure to obtain the title compound (4.19 g). 1 H-NMR (CDCl 3 ) δ: 2.18 (s, 6H), 5.88 (s, 2H), 6.55 (s, 1H), 7.47 (d, 2H, J = 9.04 Hz), 7.55 (d, 2H, J = 9.04 Hz).

[0300] (3) 1-(4-chlorophenyl)-5-iodo-1H-pyrazole-3-ylamine [ka] Hydroxylammonium chloride (14.64 g) and triethylamine (2.9 ml) were added to a suspension of 1-(4-chlorophenyl)-3-(2,5-dimethylpyrrol-1-yl)-5-iodo-1H-pyrazole (4.19 g) in ethanol / water (2 / 1, 72 ml) at room temperature, and the mixture was stirred at 95° C. for 86 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 8M aqueous sodium hydroxide solution was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=2 / 1) to obtain the title compound (1.87 g). 1 H-NMR (CDCl 3 ) δ: 3.77 (br s, 2H), 6.01 (s, 1H), 7.39-7.50 (m, 4H).

[0301] (4) 1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] Under an argon atmosphere, 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (46 mg) obtained in the same manner as in Production Example 15, 2M aqueous sodium carbonate solution (0.35 ml), tricyclohexylphosphine (6.1 mg), and palladium(II) acetate (2.5 mg) were added in that order at room temperature to a solution of 1-(4-chlorophenyl)-5-iodo-1H-pyrazol-3-ylamine (35 mg) in 1,2-dimethoxyethane (0.7 ml), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and eluted with ethyl acetate. The filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate 1 / 1) to obtain the title compound.

[0302] (5) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.110 mol) obtained in the previous step in N,N-dimethylacetamide (0.5 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) obtained in Production Example 14 and WSC·HCl (32 mg) were added in that order at room temperature and stirred for 0.5 hours. Water was added to this reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1) to obtain the title compound (18 mg). 1 H-NMR (DMSO-D6) δ: 1.20 (d, 3H, J = 6.5 Hz), 2.38-2.40 (m, 2H), 3.33-3.35 (m, 1H), 3.40-3.44 (m, 1H), 3.48-3.51 (m, 1H), 4.10-4.15 (m, 1H), 4.63 (s, 2H), 6.99 (s, 1H), 7.06 (s, 1H), 7.08 (d, 1H, J = 9.3 Hz), 7.19 (d, 1H, J = 9.3 Hz), 7.27 (dd, 2H, J = 6.6, 2.0 Hz), 7.48 (dd, 2H, J = 6.6, 2.0 Hz), 7.63 (s, 1H), 10.91 (s, 1H).

[0303] [Production Example 17]: Synthesis of Example 237 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-1H-pyrazole [ka] 1-Fluoro-2-iodobenzene (1.08 ml), copper oxide (I) (89 mg), 8-quinolinol (180 mg), and cesium carbonate (4.04 g) were added in sequence at room temperature to a solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (1.00 g) obtained in the same manner as in Production Example 4 in N-methylpyrrolidone (10 ml), and the mixture was stirred at 110° C. for 3 hours. After cooling the reaction mixture to room temperature, toluene was added and the mixture was filtered through Celite. The filtrate was washed with 2N aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (1.19 g).

[0304] (2) 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-5-iodo-1H-pyrazole [ka] Under a nitrogen atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-1H-pyrazole (1.19 g) in tetrahydrofuran (10 ml) was cooled to -78°C, n-butyllithium (3.5 ml, 1.6 M n-hexane solution) was added dropwise, and the mixture was stirred for 30 minutes. A solution of iodine (1.42 g) in tetrahydrofuran (5 ml) was added dropwise to the reaction solution, and the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium sulfite and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. A mixed solvent of n-hexane / ethyl acetate (=6 / 1) was added to the obtained solid residue, and the mixture was stirred. The solid was collected by filtration from the suspension and dried under reduced pressure to obtain the title compound (1.23 g).

[0305] (3) 1-(2-fluorophenyl)-5-iodo-1H-pyrazole-3-ylamine [ka] Hydroxylammonium chloride (4.47 g) and triethylamine (0.9 ml) were added to a mixture of 3-(2,5-dimethylpyrrol-1-yl)-1-(2-fluorophenyl)-5-iodo-1H-pyrazole (1.23 g) in ethanol / water (2 / 1, 18 ml) at room temperature, and the mixture was stirred at 90° C. for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. An 8M aqueous solution of sodium hydroxide was added to the residue obtained, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4 / 1 to 1 / 1) to obtain the title compound (0.61 g). 1 H-NMR (CDCl 3 ) δ: 3.76 (br s, 2H), 6.03(s, 1H), 7.19-7.25 (m, 2H), 7.38-7.46 (m, 2H).

[0306] (4) 1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] 1-(2-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg) in 1,4-dioxane (0.4 ml) was added with 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (52 mg) obtained in the same manner as in Production Example 15, palladium(II) acetate (3 mg), tricyclohexylphosphine (7 mg), and 2M potassium carbonate aqueous solution (0.2 ml) in that order at room temperature, and the mixture was stirred at 105° C. for 4 hours. After removing the aqueous layer of the reaction mixture, the mixture was filtered through silica gel (5 g) and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate 1 / 1) to obtain the title compound.

[0307] (5) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(2-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) obtained in the previous step in dimethylformamide (0.5 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) obtained in Production Example 14 and WSC·HCl (29 mg) were added in that order at room temperature and stirred for 3 hours. Water was added to this reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a residue, which was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1). Water and a small amount of methanol were added to the obtained solid, and the mixture was stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (32 mg). 1 H-NMR (CDCl 3) δ: 1.29 (d, 3H, J = 6.4 Hz), 2.59 (dd, 1H, J = 17.2, 9.6 Hz), 2.78 (dd, 1H, J = 17.2, 8.8 Hz), 3.29-3.40 (m, 1H), 3.60 (dd, 1H, J = 9.2 Hz), 3.67-3.80 (m, 2H), 4.52 (d, 1H, J = 12.0 Hz), 4.63 (d, 1H, J = 12.0 Hz), 6.08 (s, 1H), 6.85 (dt, 1H, J = 9.6, 2.0 Hz), 6.98-7.04 (m, 2H), 7.09-7.17 (m, 2H), 7.22 (t, 1H, J = 8.0 Hz), 7.34-7.22 (m, 2H), 8.69 (s, 1H).

[0308] [Production Example 18]: Synthesis of Example 238 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazole [ka] Pyridine (0.50 ml) was added to a chloroform (5 ml) solution of 3-(2,5-dimethylpyrrol-1-yl)-1H-pyrazole (500 mg), 4-fluorophenylboronic acid (651 mg), and copper(II) acetate (563 mg) obtained in the same manner as in Production Example 4 at room temperature, and the mixture was stirred for 40 hours. The reaction solution was filtered through silica gel and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=9 / 1) to obtain the title compound (599 mg). 1 H-NMR (CDCl3 ) δ: 2.19 (s, 6H), 5.90 (s, 2H), 6.39 (d, 1H, J = 2.56 Hz), 7.15-7.17 (m, 2H), 7.67-7.70 (m, 2H), 7.91 (d, 1H, J = 2.56 Hz).

[0309] (2) 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-5-iodo-1H-pyrazole [ka] Under an argon atmosphere, a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-1H-pyrazole (599 mg) in tetrahydrofuran (4 ml) was cooled to -78°C, n-butyllithium (1.8 ml, 1.6 M n-hexane solution) was added dropwise, and the mixture was stirred for 30 minutes. A solution of iodine (715 mg) in tetrahydrofuran (2 ml) was added dropwise to the reaction mixture, and the mixture was stirred for another 30 minutes. A saturated aqueous solution of sodium sulfite was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. A mixed solvent of ethyl acetate / n-hexane (=1 / 5) was added to the obtained solid residue, and the mixture was stirred. The solid was collected by filtration from the suspension and dried under reduced pressure to obtain the title compound (625 mg). 1 H-NMR (CDCl 3 ) δ: 2.18 (s, 6H), 5.88 (s, 2H), 6.54 (s, 1H), 7.18-7.20 (m, 2H), 7.54-7.57 (m, 2H).

[0310] (3) 1-(4-fluorophenyl)-5-iodo-1H-pyrazole-3-ylamine [ka] Hydroxylammonium chloride (2.28 g) and triethylamine (0.46 ml) were added to a suspension of 3-(2,5-dimethylpyrrol-1-yl)-1-(4-fluorophenyl)-5-iodo-1H-pyrazole (625 mg) in ethanol / water (2 / 1, 12.5 ml) at room temperature, and the mixture was stirred at 95° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. An 8M aqueous solution of sodium hydroxide was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1) to give the title compound (318 mg). 1 H-NMR (CDCl 3 ) δ: 3.75 (br s, 2H), 6.00 (s, 1H), 7.11-7.15 (m, 2H), 7.44-7.47 (m, 2H).

[0311] (4) (R)-3-[1,1,1-trifluoropropane-2-yloxy]phenylboronic acid [ka] A solution of (R)-1,1,1-trifluoropropan-2-ol (212 mg) in N,N-dimethylformamide (1.5 ml) was cooled to 0° C., and sodium hydride (74 mg, 60% by weight oil dispersion) and 3-(bromomethyl)phenylboronic acid (100 mg) were added in that order, followed by stirring at room temperature for 2 hours. Water and 1M aqueous hydrochloric acid were added to this reaction mixture, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (147 mg).

[0312] (5) 1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (70 mg) in 1,2-dimethoxyethane (0.7 ml), (R)-3-[1,1,1-trifluoropropane-2-yloxy]phenylboronic acid (104 mg), 2M aqueous sodium carbonate solution (0.35 ml), tricyclohexylphosphine (13.0 mg), and palladium(II) acetate (5.2 mg) were added in sequence at room temperature, and the mixture was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1) to obtain the title compound (52 mg). 1 H-NMR (CDCl 3 ) δ: 1.28 (d, 3H, J = 6.51 Hz), 3.74-3.80 (m, 2H), 3.76-3.78 (m, 1H), 4.56 (d, 1H, J = 11.86 Hz), 4.66 (d, 1H, J = 11.86 Hz), 5.92 (s, 1H), 6.96-6.99 (m, 2H), 7.15-7.21 (m, 4H), 7.29-7.29 (m, 2H).

[0313] (6) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (52 mg) in N,N-dimethylacetamide (0.5 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (20 mg) obtained in the same manner as in Production Example 5 and WSC·HCl (40 mg) were added in that order at room temperature and stirred for 0.5 hours. Water was added to this reaction mixture, and the precipitated solid was collected by filtration. This solid was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (37 mg). 1 H-NMR (DMSO-D6) δ: 1.20 (d, 3H, J = 6.5 Hz), 2.38-2.39 (m, 2H), 3.33-3.34 (m, 1H), 3.39-3.43 (m, 1H), 3.49-3.51 (m, 1H), 4.09-4.11 (m, 1H), 4.59 (d, 1H, J = 12.1 Hz), 4.63 (d, 1H, J = 12.1 Hz), 6.92 (s, 1H), 7.18-7.39 (m, 8H), 7.63 (s, 1H), 10.85 (s, 1H).

[0314] [Production Example 19]: Synthesis of Example 239 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg) obtained in Production Example 18 in 1,4-dioxane (0.4 ml), 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (52 mg) obtained in the same manner as in Production Example 15, palladium(II) acetate (3 mg), tricyclohexylphosphine (7 mg), and 2M potassium carbonate aqueous solution (0.2 ml) were added in that order at room temperature, and the mixture was stirred at 105° C. for 4 hours. After removing the aqueous layer of this reaction mixture, the mixture was filtered through silica gel (5 g) and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate 1 / 1) to obtain the title compound.

[0315] (2) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) obtained in the previous step in dimethylformamide (0.5 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) obtained in the same manner as in Production Example 14 and WSC·HCl (29 mg) were added in that order at room temperature and stirred for 3 hours. Water was added to this reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a residue, which was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1). Water and a small amount of methanol were added to the obtained solid, and the mixture was stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (31 mg). 1 H-NMR (CDCl 3) δ: 1.31 (d, 3H, J = 6.4 Hz), 2.61 (dd, 1H, J = 16.8, 9.6 Hz), 2.78 (dd, 1H, J = 16.8, 8.4 Hz), 3.31-3.42 (m, 1H), 3.61 (t, 1H, J = 8.8 Hz), 3.67-3.83 (m, 2H), 4.55 (d, 1H, J = 12.0 Hz), 4.65 (d, 1H, J = 12.0 Hz), 6.04 (s, 1H), 6.85 (d, 1H, J = 9.2 Hz), 6.98-7.10 (m, 5H), 7.19-7.25 (m, 2H), 8.48 (s, 1H).

[0316] [Production Example 20]: Synthesis of (R)-2-oxoimidazolidine-4-carboxylic acid [ka] (1)(R)-2-Oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester [ka] Bromine (6.60 ml) was added dropwise to 1M aqueous sodium hydroxide solution (124 ml) under ice cooling, followed by the addition of (R)-2-benzyloxycarbonylaminosuccinamic acid (10.0 g), and the mixture was stirred at 55° C. for 3 hours. The reaction solution was cooled to room temperature, washed twice with diethyl ether, and then 6M aqueous hydrochloric acid solution (21 ml) was added. The reaction mixture was left to stand at 4° C. for 3 days, and the precipitated solid was collected by filtration to obtain the title compound (6.16 g). 1 H-NMR (DMSO-D 6 ) δ: 3.19-3.22 (m, 1H), 3.63 (dd, 1H, J = 10.2, 5.0 Hz), 4.67 (dd, 1H, J = 10.2, 3.3 Hz), 5.14-5.18 (m, 2H), 7.28-7.40 (m, 5H), 7.56 (s, 1H), 13.24 (br s, 1H).

[0317] (2) (R)-2-Oxoimidazolidine-4-carboxylic acid [ka] Under a nitrogen atmosphere, 10% by weight palladium on carbon (161 mg) was added to a solution of (R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester (1.61 g) in methanol / tetrahydrofuran (4 / 1, 20 ml) at room temperature, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 24 hours. After the mixture was placed under a nitrogen atmosphere, the palladium on carbon in the reaction solution was filtered off through Celite, and the filtrate was concentrated under reduced pressure. Diisopropyl ether and n-hexane were added to the resulting residue, and the mixture was stirred. The solid was collected from the suspension by filtration and dried under reduced pressure to obtain the title compound (565 mg). 1 H-NMR (DMSO-D 6 ) δ: 3.27 (ddd, 1H, J = 9.8, 4.8, 0.8 Hz), 3.54 (dd, 1H, J = 9.8, 9.8 Hz), 4.10 (dd, 1H, J = 9.8, 4.8 Hz), 6.24 (s, 1H), 6.56 (s, 1H), 12.83 (br s, 1H).

[0318] [Production Example 21]: Synthesis of Example 240 ((R)-2-oxoimidazolidine-4-carboxylic acid {1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (84 mg) obtained in the same manner as in Production Example 18 in 1,4-dioxane (1.0 ml), 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (106 mg) obtained in the same manner as in Production Example 15, palladium(II) acetate (7 mg), tricyclohexylphosphine (17 mg), and 2M potassium carbonate aqueous solution (0.5 ml) were added in sequence at room temperature, and the mixture was stirred at 105° C. for 2 hours. The reaction mixture was cooled to room temperature, the aqueous layer was removed, and then the mixture was filtered through silica gel (5 g) and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate 3 / 2) to obtain the title compound.

[0319] (2) (R)-2-Oxoimidazolidine-4-carboxylic acid {1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a chloroform (1 ml) solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (approximately 0.277 mmol) obtained in the previous step, (R)-2-oxoimidazolidine-4-carboxylic acid (40 mg) and WSC·HCl (64 mg) were added in that order at room temperature and stirred for 3 hours. This reaction mixture was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (56 mg). 1 H-NMR (DMSO-D 6) δ: 1.20 (d, 3H, J = 6.0 Hz), 3.35 (dd, 1H, J = 8.6, 6.2 Hz), 3.58 (dd, 1H, J = 9.3, 8.6 Hz), 4.12 (tq, 1H, J = 9.7, 6.0 Hz), 4.31 (dd, 1H, J = 9.3, 6.2 Hz), 4.60 (d, 1H, J = 12.5 Hz), 4.63 (d, 1H, J = 12.5 Hz), 6.33 (s, 1H), 6.59 (s, 1H), 6.98 (s, 1H), 7.02-7.07 (m, 2H), 7.18 (d, 1H, J = 9.6 Hz), 7.23-7.35 (m, 4H), , 10.72 (s, 1H).

[0320] [Production Example 22]: Synthesis of Example 241 ((S)-5-oxopyrrolidine-3-carboxylic acid {5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide) [ka] (1) 1-Chloro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene [ka] Under an argon atmosphere, a suspension of sodium hydride (77 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0°C, and a solution of (R)-1,1,1-trifluoropropan-2-ol (213 mg) in N,N-dimethylformamide (2.0 ml) was added and stirred for 15 minutes. Then, a solution of 1-bromomethyl-3-chlorobenzene (311 mg) in N,N-dimethylformamide (2.0 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 19 / 1) to obtain the title compound (307 mg). 1 H-NMR (CDCl 3 ) δ: 1.35 (d, 3H, J = 6.47 Hz), 3.84 (qq, 1H, J = 6.47, 9.40 Hz), 4.62(d, 1H, J = 12.00Hz), 4.73(d, 1H, J = 12.00 Hz), 7.21-7.24 (m, 1H), 7.27-7.30 (m, 2H), 7.34 (s 1H).

[0321] (2) 2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl[1,3,2]dioxaborolane [ka] Under an argon atmosphere, bis-pinacolatodiboron (362 mg), 4,4'-di-tert-butyl-2,2'-dipyridyl (18 mg), and di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (22 mg) were added in sequence to a solution of 1-chloro-3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)benzene (307 mg) in tetrahydrofuran (6.0 ml) at room temperature, and the mixture was heated to reflux for 13 hours. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer obtained was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 9 / 1) to obtain the title compound (374 mg). 1 H-NMR (CDCl 3 ) δ: 1.35 (m, 15H), 3.83 (qq, 1H, J = 6.47, 9.40 Hz), 4.59 (d, 1H, J = 12.00Hz), 4.73 (d, 1H, J = 12.00 Hz), 7.46 (s, 1H), 7.59 (d, 1H, J = 9.60 Hz), 7.72 (s, 1H).

[0322] (3) 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine [ka] Under an argon atmosphere, 2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (269 mg) was added with a 1,2-dimethoxyethane (2.0 ml) solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (181 mg) obtained in the same manner as in Production Example 2, 2M aqueous sodium carbonate solution (1.0 ml), tricyclohexylphosphine (36 mg), and palladium (II) acetate (15 mg) in that order at room temperature, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, followed by filtration through Celite and elution with ethyl acetate. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate=3 / 7) to obtain the title compound (196 mg).

[0323] (4) (S)-5-Oxopyrrolidine-3-carboxylic acid {5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide [ka] To a solution of 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (79 mg) in N,N-dimethylacetamide (1.0 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (31 mg) obtained in the same manner as in Production Example 14 and WSC·HCl (47 mg) were added in that order at room temperature and stirred overnight. Water was added to this reaction mixture, and the precipitated solid was collected by filtration. This solid was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (60 mg). 1 H-NMR (DMSO-D6) δ: 1.18 (d, 3H, J = 6.5 Hz), 2.36-2.38 (m, 2H), 3.32-3.33 (m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.10 (qq, 1H, J = 6.5, 9.4 Hz), 4.57 (d, 1H, J = 12.7 Hz), 4.61 (d, 1H, J = 12.7 Hz), 6.98 (s, 1H), 7.19-7.20 (m, 2H), 7.25-7.27 (m, 2H), 7.35-7.45 (m, 4H), 7.63 (s, 1H), 10.88 (s, 1H).

[0324] [Production Example 23]: Synthesis of Example 242 ((S)-5-oxopyrrolidine-3-carboxylic acid {5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-yl}amide) [ka] (1) 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-ylamine [ka] 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (50 mg) obtained in the same manner as in Production Example 18 was dissolved in 1,2-dimethoxyethane (0.5 ml), and 2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (72 mg) obtained in the same manner as in Production Example 22, 2M aqueous sodium carbonate solution (0.25 ml), tricyclohexylphosphine (9.3 mg), and palladium(II) acetate (3.7 mg) were added in that order at room temperature, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1) to obtain the title compound (79 mg). 1 H-NMR (CDCl 3 ) δ: 1.29 (d, 3H, J = 6.47 Hz), 3.75 (qq, 1H, J = 6.47, 9.40 Hz), 3.78 (br s, 2H), 4.50 (d, 1H, J = 12.02 Hz), 4.61 (d, 1H, J = 12.02 Hz), 5.93 (s, 1H), 6.99-7.02 (m, 3H), 7.18-7.20 (m, 3H), 7.26-7.28 (m, 1H).

[0325] (2) (S)-5-Oxopyrrolidine-3-carboxylic acid {5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-yl}amide [ka] To a solution of 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-ylamine (79 mg) in chloroform (0.4 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) obtained in the same manner as in Production Example 14 and WSC·HCl (47 mg) were added in that order at room temperature and stirred for 2 hours. This reaction mixture was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (43 mg). 1 H-NMR (DMSO-D6) δ: 1.18 (d, 3H, J = 6.5 Hz), 2.36-2.38 (m, 2H), 3.32-3.33 (m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.10 (qq, 1H, J = 6.5, 9.4 Hz), 4.57 (d, 1H, J = 12.7 Hz), 4.61 (d, 1H, J = 12.7 Hz), 6.97 (s, 1H), 7.13 (s, 1H), 7.23-7.32 (m, 5H), 7.37 (s, 1H), 7.61 (s, 1H), 10.86 (s, 1H). .

[0326] [Production Example 24]: Example 243 Synthesis of (S)-5-oxopyrrolidine-3-carboxylic acid {5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide [ka] (1) 1-Chloro-3-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)benzene [ka] Under an argon atmosphere, 1,1,1-trifluoro-2-methylpropan-2-ol (320 μL) was added dropwise to a suspension of sodium hydride (126 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (5 ml) cooled to 0°C, and the mixture was stirred for 15 minutes. 1-Bromomethyl-3-chlorobenzene (320 μL) was added dropwise to this reaction mixture, and the mixture was stirred for 3 hours. Water was added to this reaction mixture, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 40 / 1) to obtain the title compound (389 mg). 1 H-NMR (CDCl 3 ) δ: 1.45 (s, 6H), 4.50 (s, 2H), 7.15-7.30 (m, 3H), 7.34 (s, 1H).

[0327] (2) 2-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ka] Under an argon atmosphere, bis-pinacolatodiboron (430 mg), 4,4'-di-tert-butyl-2,2'-dipyridyl (21 mg), and di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (29 mg) were added in sequence to a solution of 1-chloro-3-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)benzene (389 mg) in tetrahydrofuran (4 ml) at room temperature, and the mixture was heated under reflux for 13 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 100 / 1 to 20 / 1) to obtain the title compound (481 mg). 1 H-NMR (CDCl 3 ) δ: 1.34 (s, 12H), 1.44 (s, 6H), 4.57 (s, 2H), 7.45 (s, 1H), 7.57 (s, 1H), 7.69 (s, 1H).

[0328] (3) 5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine [ka] Under an argon atmosphere, 2-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (64 mg), palladium(II) acetate (3 mg), tricyclohexylphosphine (8 mg), and 2M aqueous sodium carbonate solution (0.5 ml) were added to a 1,2-dimethoxyethane (1.0 ml) solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (40 mg) obtained in the same manner as in Production Example 2 at room temperature, and the mixture was stirred at 100° C. for 13 hours. After cooling the reaction mixture to room temperature, the title compound (62 mg) was obtained by purifying the mixture by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate 3 / 2 to 1 / 1). 1 H-NMR (CDCl 3 ) δ: 1.35 (s, 6H), 3.77 (br s, 2H), 4.46 (s, 2H), 5.93 (s, 1H), 7.00 (s, 1H), 7.15 (s, 1H), 7.20-7.26 (m, 4H), 7.28-7.33 (m, 2H).

[0329] (4) (S)-5-Oxopyrrolidine-3-carboxylic acid {5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-yl}amide [ka] Under an argon atmosphere, to a solution of 5-[3-chloro-5-(2,2,2-trifluoro-1,1-dimethylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (62 mg) in N,N-dimethylacetamide (1 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) obtained in the same manner as in Production Example 14 and WSC·HCl (40 mg) were added in that order at room temperature and stirred for 1 hour. Water was added to this reaction mixture, and it was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid, and it was stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (35 mg). 1 H-NMR (DMSO-D 6 ) δ: 1.32 (s, 6H), 2.37-2.42 (m, 2H), 3.33-3.53 (m, 3H), 4.53 (s, 2H), 6.98 (s, 1H), 7.16 (s, 1H), 7.19 (s, 1H), 7.23-7.28 (m, 2H), 7.33-7.45 (m, 4H), 7.63 (s, 1H), 10.89 (s, 1H).

[0330] [Production Example 25]: Synthesis of Example 244 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 2-(3-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ka] To a solution of 3-(bromomethyl)phenylboronic acid (3.13 g) in ethyl acetate (45 ml), pinacol (1.72 g) and anhydrous magnesium sulfate (15 g) were added successively at room temperature, and the mixture was stirred for 8 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.43 g). 1 H-NMR (CDCl 3 ) δ: 1.33 (s, 12H), 4.49 (s, 2H), 7.31-7.37 (m, 1H), 7.46-7.50 (m, 1H), 7.70-7.74 (m, 1H), 7.79-7.82 (m, 1H).

[0331] (2) 4,4,5,5-tetramethyl-2-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-[1,3,2]dioxaborolane [ka] Under argon flow, at 0°C, (R)-1,1,1-trifluoropropan-2-ol (3.32 g) was dissolved in N,N-dimethylformamide (43 ml). Sodium hydride (1.16 g, 60 wt% oil dispersion) was added in portions and stirred for 20 minutes. Then, 2-(3-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.32 g) was added, and the mixture was stirred overnight at room temperature. Water and 2M aqueous hydrochloric acid were added to the reaction mixture in that order, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 19 / 1) to obtain the title compound (3.43 g). 1 H-NMR (CDCl 3) δ: 1.31 (d, 3H, J = 6.6 Hz), 1.35 (s, 12H), 3.77-3.89 (m, 1H), 4.62 (d, 1H, J = 11.7 Hz), 4.76 (d, 1H, J = 11.7 Hz), 7.35-7.43 (m, 1H), 7.46-7.54 (m, 1H), 7.71-7.81 (m, 2H).

[0332] (3) 1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] To a solution of 11-(4-chlorophenyl)-5-iodo-1H-pyrazol-3-ylamine (40 mg) obtained in Production Example 16 in 1,4-dioxane (0.4 ml), 4,4,5,5-tetramethyl-2-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl)-[1,3,2]dioxaborolane (50 mg), palladium(II) acetate (3 mg), tricyclohexylphosphine (7 mg), and 2M potassium carbonate aqueous solution (0.2 ml) were added in that order at room temperature, and the mixture was stirred at 105° C. for 4 hours. After removing the aqueous layer of this reaction mixture, the organic layer was filtered through silica gel (5 g) and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1) to obtain the title compound.

[0333] (4) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) obtained in the previous step in N,N-dimethylformamide (1 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) obtained in the same manner as in Production Example 14 and WSC·HCl (29 mg) were added in that order at room temperature and stirred for 3 hours. Water was added to this reaction mixture, and it was extracted with ethyl acetate. The organic layer obtained was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1). Water and a small amount of methanol were added to the obtained solid, and it was stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (33 mg). 1 H-NMR (CDCl 3 ) δ: 1.29 (d, 3H, J = 6.8 Hz), 2.61 (dd, 1H, J = 17.2, 9.6 Hz), 2.78 (dd, 1H, J = 17.2, 8.8 Hz), 3.30-3.40 (m, 1H), 3.61 (t, 1H, J = 8.8 Hz), 3.68-3.82 (m, 2H), 4.57 (d, 1H, J = 12.0 Hz), 4.68 (d, 1H, J = 12.0 Hz), 5.90 (s, 1H), 7.04 (s, 1H), 7.15-7.20 (m, 3H) , 7.24 (br s, 1H), 7.28-7.35 (m, 4H), 8.38 (s, 1H).

[0334] [Production Example 26]: Synthesis of Example 245 ((R)-2-oxoimidazolidine-4-carboxylic acid [5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-yl]amide) [ka] 1-Bromo-3-butylbenzene [ka] Under a nitrogen stream, n-propylmagnesium bromide (60 ml, 2M tetrahydrofuran solution) and lithium cuprate tetrachloride (5 ml, 0.1M tetrahydrofuran solution) were added dropwise to a solution of 1-bromo-3-bromomethylbenzene (25 g) in tetrahydrofuran (200 ml) at -78°C. The reaction mixture was then stirred at 0°C for 2 hours. A saturated aqueous ammonium chloride solution (100 ml) and water (100 ml) were added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (200 ml). The resulting aqueous layer was extracted again with ethyl acetate (100 ml), and the combined organic layer was washed with a saturated aqueous sodium chloride solution (100 ml) and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 100 / 1) to obtain the title compound (8.5 g). 1 H-NMR (CDCl 3 ) δ: 0.91 (t, 3H, J = 7.4 Hz), 1.31-1.35 (m, 2H), 1.55-1.59 (m, 2H), 2.56 (t, 2H, J = 7.8 Hz), 7.06-7.13 (m, 2H), 7.27-7.32 (m, 2H).

[0335] (2) 2-(3-butylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ka] Under an argon atmosphere, bis-pinacolatodiboron (1.97 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct (287 mg), and potassium acetate (2.07 g) were added to a solution of 1-bromo-3-butylbenzene (1.44 g) in 1,4-dioxane (15 ml) at room temperature, and the mixture was stirred at 80°C for 15 hours. The mixture was cooled to room temperature, and insoluble matter was removed by filtration through Celite. The filtrate was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30 / 1 to 10 / 1) to give the title compound (1.37 g). 1 H-NMR (CDCl 3 ) δ: 0.92 (t, 3H, J = 7.3 Hz), 1.31-1.41 (m, 14H), 1.59-1.61 (m, 2H), 2.61 (t, 2H, J = 7.9 Hz), 7.24-7.30 (m, 2H), 7.59-7.65 (m, 2H).

[0336] (3) 5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-ylamine [ka] To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (1.00 g) obtained in the same manner as in Production Example 2 in 1,2-dimethoxyethane (20 ml), 2-(3-butylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.37 g), 2M aqueous sodium carbonate solution (10 ml), tricyclohexylphosphine (197 mg), and palladium acetate (79 mg) were added in that order at room temperature, and the mixture was stirred under heating and reflux for 3 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution was added, after which the insoluble matter was filtered off through Celite. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2 / 1 to 2 / 3) to obtain the title compound (880 mg). 1 H-NMR (CDCl 3 ) δ: 0.85 (t, 3H, J = 7.3 Hz), 1.17-1.27 (m, 2H), 1.40-1.47 (m, 2H), 2.49 (t, 2H, J = 7.6 Hz), 3.75 (br s, 2H), 5.90 (s, 1H), 6.97 (s, 1H), 7.02-7.12 (m, 2H), 7.13-7.29 (m, 6H).

[0337] (4) (R)-2-Oxoimidazolidine-4-carboxylic acid [5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-yl]amide [ka] To a solution of 5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-ylamine (40 mg) in N,N-dimethylformamide (0.4 ml), (R)-2-oxoimidazolidine-4-carboxylic acid (21 mg) obtained in the same manner as in Production Example 20, HATU (63 mg), and diisopropylethylamine (29 μL) were added in that order at room temperature and stirred for 2 hours. Water was added to this reaction mixture, and it was extracted with ethyl acetate. The organic layer obtained was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel thin layer chromatography (developing solvent: n-hexane / acetone = 1 / 5). Diisopropyl ether was added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (12 mg). 1 H-NMR (DMSO-D6) δ: 0.82 (t, 3H, J = 7.4 Hz), 1.15 (tq, 2H, J = 7.4 Hz, 7.4Hz), 1.39 (tt, 2H, J = 7.4 Hz, 7.4Hz), 2.48 (t, 2H, J = 7.4 Hz), 3.36 (dd, 1H, J = 9.2 Hz, 5.6Hz), 3.59 (dd, 1H, J = 9.2 Hz, 9.2Hz), 4.32 (dd, 1H, J = 9.2 Hz, 5.6Hz), 6.33 (s, 1H), 6.60 (s, 1H), 6.90 (s, 1H), 6.98 (s, 1H), 7.09 (d, 1H, J = 7.6 Hz), 7.17 (d, 1H, J = 7.6 Hz), 7.20-7.30 (m, 3H), 7.32-7.43 (m, 3H), 10.70 (s, 1H). .

[0338] [Production Example 27]: Synthesis of Example 246 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 3-(1,1,1,3,3,3-hexafluoropropane-2-yloxy)phenylboronic acid [ka] A suspension of sodium hydride (149 mg, 60 wt% oil dispersion) in N,N-dimethylformamide (3.0 ml) was cooled to 0°C, (R)-1,1,1,3,3,3-hexafluoropropan-2-ol (392 mg) was added, and the mixture was stirred for 15 minutes. Then, 3-(bromomethyl)phenylboronic acid (200 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water and 1M aqueous hydrochloric acid were added to the reaction mixture in that order, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound (1.0 g).

[0339] (2) 1-Phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] 3-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)phenylboronic acid (1.0 g) was added with a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (180 mg) obtained in the same manner as in Production Example 2 in 1,2-dimethoxyethane (2.0 ml), 2M aqueous sodium carbonate solution (1.0 ml), tricyclohexylphosphine (35 mg), and palladium (II) acetate (18 mg) at room temperature in that order, and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate=3 / 7) to obtain the title compound (151 mg).

[0340] (3) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethylethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-phenyl-5-[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (78 mg) in N,N-dimethylacetamide (1.0 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (29 mg) obtained in the same manner as in Production Example 5 and WSC·HCl (44 mg) were added in that order at room temperature and stirred overnight. Water was added to this reaction mixture, and the precipitated solid was filtered off. The obtained solid was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was filtered from this suspension and dried under reduced pressure to obtain the title compound (54 mg). 1 H-NMR (DMSO-D 6 ) δ: 2.36-2.38 (m, 2H), 3.32-3.33 (m, 1H), 3.37-3.41 (m, 1H), 3.46-3.49 (m, 1H), 4.85 (m, 2H), 5.53-5.59 (m, 1H), 6.94 (s, 1H), 7.17-7.18 (m, 1H), 7.22-7.24 (m, 2H), 7.34- 7.41 (m, 6H), 7.63 (s, 1H), 10.88 (s, 1H).

[0341] [Production Example 28]: Synthesis of Example 247 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 1-Bromo-3-(2,2,2-trifluoroethoxymethyl)benzene [ka] Under a nitrogen atmosphere, a suspension of sodium hydride (352 mg, 60 wt % oil dispersion) in tetrahydrofuran (10 ml) was cooled to 0°C, 2,2,2-trifluoroethanol (0.63 ml) was added, and the mixture was stirred for 5 minutes. Then, 3-bromobenzyl bromide (2.00 g) was added, and the mixture was stirred under heating and reflux for 1 hour. The reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 10 / 1) to obtain the title compound (2.05 g). 1 H-NMR (CDCl 3 ) δ: 3.84 (q, 2H, J = 8.68 Hz), 4.65 (s, 2H), 7.22-7.28 (m, 2H), 7.45-7.47 (m, 1H), 7.49-7.51 (m, 1H).

[0342] (2) 4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane [ka] Under argon atmosphere, bis-pinacolatodiboron (2.12 g), potassium acetate (2.24 g), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct (310 mg) were added to a solution of 1-bromo-3-(2,2,2-trifluoroethoxymethyl)benzene (2.05 g) in 1,4-dioxane (21 ml) at room temperature, and the mixture was stirred at 80°C for 19 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 1) to give the title compound (1.69 g). 1 H-NMR (CDCl 3 ) δ: 1.35 (s, 12H), 3.81 (q, 2H, J = 8.67 Hz), 4.68 (s, 2H), 7.38-7.40 (m, 1H), 7.47-7.48 (m, 1H), 7.76-7.78 (m, 2H).

[0343] (3) 1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] Under an argon atmosphere, 4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-[1,3,2]dioxaborolane (80 mg), 2M aqueous sodium carbonate solution (0.35 ml), tricyclohexylphosphine (13.0 mg), and palladium(II) acetate (5.2 mg) were added to a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (70 mg) obtained in Production Example 18 in 1,2-dimethoxyethane (0.7 ml) at room temperature, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=1 / 1) to obtain the title compound (43 mg). 1 H-NMR (CDCl 3 ) δ: 3.74 (q, 2H, J = 8.61 Hz), 3.77 (br s, 2H), 4.60 (s, 2H), 5.93 (s, 1H), 6.97-6.99 (m, 2H), 7.16-7.21 (m, 4H), 7.29-7.31 (m, 2H).

[0344] (4) (S)-5-Oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (43 mg) in N,N-dimethylacetamide (0.4 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) obtained in the same manner as in Production Example 5 and WSC·HCl (34 mg) were added in that order at room temperature and stirred for 0.5 hours. Water was added to this reaction mixture, and the precipitated solid was collected by filtration. This solid was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (26 mg). 1 H-NMR (DMSO-D6) δ: 2.38-2.40 (m, 2H), 3.32-3.35 (m, 1H), 3.40-3.45 (m, 1H), 3.48-3.52 (m, 1H), 3.98 (q, 2H, J = 9.3 Hz), 4.61 (s, 2H), 6.93 (s, 1H), 7.18-7.40 (m, 8H), 7.63 (s, 1H), 10.86 (s, 1H). .

[0345] [Production Example 29]: Synthesis of Example 248 ((S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 1-Chloro-3-fluoro-5-(2,2,2-trifluoroethoxymethyl)benzene [ka] Trifluoroethanol (1.08 ml) was added dropwise to a suspension of sodium hydride (601 mg, 60 wt % oil dispersion) in dimethylformamide (13 ml) at 0°C under an argon stream, and the mixture was stirred for 15 minutes. A solution of 1-chloro-3-fluoro-5-chloromethylbenzene (2.23 g) in dimethylformamide (9 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of n-hexane / ethyl acetate = 1 / 1. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 9 / 1) to obtain the title compound (2.85 g). 1 H-NMR (CDCl 3 ) δ: 3.87 (q, 2H, J = 8.8 Hz), 4.64 (s, 2H), 6.97 (d, 1H, J = 8.8 Hz), 7.05 (dt, 1H, J = 8.8, 2.4 Hz), 7.13 (br s, 1H).

[0346] (2) 2-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane [ka] Under an argon atmosphere, bis-pinacolatodiboron (3.41 g), potassium acetate (3.33 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (521 mg), and tris(dibenzylideneacetone)dipalladium(0) (253 mg) were added to a solution of 1-chloro-3-fluoro-5-(2,2,2-trifluoroethoxymethyl)benzene (2.65 g) in 1,4-dioxane (60 ml) in that order at room temperature, and the mixture was stirred under heating and reflux for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 19 / 1). The resulting crude product was suspended in n-hexane, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (2.71 g). 1 H-NMR (CDCl 3 ) δ: 1.35 (s, 12H), 3.83 (q, 2H, J = 8.8 Hz), 4.67 (s, 2H), 7.18 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 8.8, 2.4 Hz), 7.50 (br s, 1H).

[0347] (3) 1-(4-chlorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine [ka] To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg) obtained in Production Example 18 in 1,4-dioxane (0.4 ml), 2-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (50 mg), palladium(II) acetate (3 mg), tricyclohexylphosphine (7 mg), and 2M potassium carbonate aqueous solution (0.2 ml) were added in that order at room temperature, and the mixture was stirred at 105° C. for 4 hours. After removing the aqueous layer of the reaction mixture, the mixture was filtered through a silica gel (5 g) and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: n-hexane / ethyl acetate 1 / 1) to obtain the title compound.

[0348] (4) Synthesis of (S)-5-oxopyrrolidine-3-carboxylic acid {1-(4-fluorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide [ka] To a solution of 1-(4-chlorophenyl)-5-[3-fluoro-5-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) obtained in the previous step in N,N-dimethylformamide (0.5 ml), (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) obtained in the same manner as in Production Example 14 and WSC·HCl (29 mg) were added in that order at room temperature and stirred for 3 hours. Water was added to this reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 10 / 1). Water and a small amount of methanol were added to the obtained solid and stirred. The solid was collected from this suspension by filtration and dried under reduced pressure to obtain the title compound (33 mg). 1 H-NMR (CDCl 3) δ: 2.61 (dd, 1H, J = 17.2, 9.6 Hz), 2.78 (dd, 1H, J = 17.2, 8.8 Hz), 3.32-3.42 (m, 1H), 3.61 (t, 1H, J = 8.8 Hz ), 3.71 (dd, 1H, J = 9.6, 7.2 Hz), 3.79 (q, 2H, J = 8.8 Hz), 4.59 (s, 2H), 6.04 (s, 1H), 6.89 (d, 1H, J = 9.2 Hz), 6.99-7.10 (m, 5H), 7.19-7.24 (m, 2H), 8.48 (s, 1H).

[0349] [Production Example 30]: Synthesis of Example 249 (4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide) [ka] (1) 2-(tert-butyldimethylsilanyloxymethyl)-2-propen-1-ol [ka] Under an argon atmosphere, 2-methylene-1,3-propanediol (1 ml) and tert-butyldimethylchlorosilane (2.22 g) were added in sequence to a suspension of sodium hydride (490 mg, 60 wt % oil dispersion) in tetrahydrofuran (10 ml) at 0°C, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 3 / 1) to obtain the title compound (1.62 g). 1 H-NMR (CDCl 3) δ: 0.09 (s, 6H), 0.91 (s, 9H), 1.96 (t, 1H, J = 3.09 Hz), 4.18 (d, 2H, J = 3.09 Hz), 4.25 (s, 2H), 5.08 (d, 1H, J = 1.32 Hz), 5.10 (d, 1H, J = 1.32 Hz).

[0350] (2) [2-(tert-butyldimethylsilanyloxymethyl)allyl]-(2,4-dimethoxybenzyl)amine [ka] At 0°C, triethylamine (2.2ml) and methanesulfonyl chloride (0.73ml) were added in sequence to a solution of 2-(tert-butyldimethylsilanyloxymethyl)-2-propen-1-ol (1.58g) in chloroform (16ml), and the mixture was stirred for 2 hours. Triethylamine (1.2ml) and 2,4-dimethoxybenzylamine (1.3ml) were added in sequence to the reaction solution, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the organic layer was separated and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 1) to obtain the title compound (1.14g). 1 H-NMR (CDCl 3 ) δ: 0.07 (s, 6H), 0.91 (s, 9H), 3.21 (s, 2H), 3.69 (s, 2H), 3.80 (s, 6H), 4.18 (s, 2H), 5.02 (s, 1H), 5.13 (s, 1H), 6.41-6.45 (m, 2H), 7.12 (d, 1H, J = 7.91 Hz).

[0351] (3)(E)-2-(2-Tosylhydrazono)acetic acid [ka] Glyoxylic acid monohydrate (644 mg) was added to water (7 ml), and the resulting suspension was heated to 65° C. to dissolve it, and a 2.5 M aqueous hydrochloric acid solution (4.2 ml) of p-toluenehydrazide (1.30 g) was added and stirred for 15 minutes. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain the title compound (1.42 g). 1 H-NMR (CDCl 3 ) δ: 2.46 (s, 3H), 7.14 (s, 1H), 7.38 (d, 2H, J = 8.14 Hz), 7.83 (d, 2H, J = 8.14 Hz), 8.46 (s, 1H).

[0352] (4) Diazoacetic acid 2,5-dioxopyrrolidin-1-yl ester [ka] Under an argon atmosphere, N-hydroxysuccinimide (677 mg) and dicyclohexylcarbodiimide (1.21 g) were added successively to a solution of (E)-2-(2-tosylhydrazono)acetic acid (1.42 g) in 1,4-dioxane (14 ml) at room temperature, and the mixture was stirred for 17 hours. The reaction mixture was filtered through Celite and eluted with 1,4-dioxane. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / diethyl ether = 1 / 3) to give the title compound (579 mg). 1 H-NMR (CDCl 3 ) δ: 2.85 (s, 4H), 5.11 (s, 1H).

[0353] (5) N-[2-(tert-butyldimethylsilanyloxymethyl)allyl]-2-diazo-N-(2,4-dimethoxybenzyl)acetamide [ka] To a solution of [2-(tert-butyldimethylsilanyloxymethyl)allyl]-(2,4-dimethoxybenzyl)amine (384 mg) in chloroform (3.8 ml), triethylamine (0.23 ml) and diazoacetic acid 2,5-dioxopyrrolidin-1-yl ester (200 mg) were added at room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=4 / 1) to give the title compound (223 mg). 1 H-NMR (CDCl 3 ) δ: 0.06 (s, 6H), 0.90 (s, 9H), 3.79 (s, 3H), 3.80 (s, 3H), 3.88-3.91 (m, 2H), 4.08 (s, 2H), 4.93 (s, 1H), 5.04 (s, 1H), 5.18 (s, 1H), 6.43-6.47 (m, 3H).

[0354] (6) 5-(tert-butyldimethylsilanyloxymethyl)-3-(2,4-dimethoxybenzyl)-3-azabicyclo[3.1.0]hexan-2-one [ka] Under an argon atmosphere, rhodium(II) acetate dimer dihydrate (2.4 mg) was added to a solution of N-[2-(tert-butyldimethylsilanyloxymethyl)allyl]-2-diazo-N-(2,4-dimethoxybenzyl)acetamide (43 mg) in benzotrifluoride (0.4 ml) at room temperature, and the mixture was stirred for 24 hours at 50° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=2 / 1) to obtain the title compound (14.2 mg). 1 H-NMR (CDCl 3) δ: 0.01 (s, 6H), 0.72 (dd, 1H, J = 4.42, 3.61 Hz), 0.85 (s, 9H), 1.11 (dd, 1H, J = 8.84, 4.42 Hz), 1.81 (dd, 1H, J = 8.84, 3.61 Hz), 3.16 (d, 1H, J = 10.47 Hz), 3.36 (d, 1H, J = 10.47 Hz), 3.62 (d, 1H, J = 10.70 Hz), 3.70 (d, 1H, J = 10.70 Hz), 3.79 (s, 3H), 3.79 (s, 3H), 4.25 (d, 1H, J = 14.65 Hz), 4.38 (d, 1H, J = 14.65 Hz), 6.40-6.44 (m, 2H), 7.06-7.09 (m, 1H).

[0355] (7) 3-(2,4-Dimethoxybenzyl)-5-hydroxymethyl-3-azabicyclo[3.1.0]hexan-2-one [ka] To a solution of 5-(tert-butyldimethylsilanyloxymethyl)-3-(2,4-dimethoxybenzyl)-3-azabicyclo[3.1.0]hexan-2-one (14.2 mg) in tetrahydrofuran (0.3 ml), n-butylammonium fluoride (54 μl, 1.0 M tetrahydrofuran solution) was added at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate only to chloroform / methanol = 9 / 1) to obtain the title compound (9.2 mg). 1 H-NMR (CDCl 3) δ: 0.77 (dd, 1H, J = 4.84, 3.43 Hz), 1.12 (dd, 1H, J = 8.87, 4.84 Hz), 1.85 (dd, 1H, J = 8.87, 3.43 Hz), 3.23 (d, 1H, J = 10.07 Hz), 3.45 (d, 1H, J = 10.07 Hz), 3.66 (d, 1H, J = 11.69 Hz), 3.70 (d, 1H, J = 11.69 Hz), 3.79 (s, 3H), 3.79 (s, 3H), 4.21 (d, 1H, J = 14.51 Hz), 4.43 (d, 1H, J = 14.51 Hz), 6.41-6.44 (m, 2H), 7.07-7.10 (m, 1H).

[0356] (8) 3-(2,4-Dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carbaldehyde [ka] Under an argon atmosphere, triethylamine (23 μl) and sulfur trioxide-pyridine complex (10.6 mg) were added to a solution of 3-(2,4-dimethoxybenzyl)-5-hydroxymethyl-3-azabicyclo[3.1.0]hexan-2-one (9.2 mg) in dimethyl sulfoxide / chloroform (2 / 1, 135 μl) at room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product of the title compound (10.8 mg).

[0357] (9) 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid [ka] Sodium dihydrogen phosphate dihydrate (20.2 mg) was added to a solution of 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carbaldehyde (10.8 mg) in tert-butanol / tetrahydrofuran / water (4 / 3 / 1, 0.5 ml) at room temperature under an argon atmosphere. The reaction mixture was cooled to 0°C, and 2-methyl-2-butene (18 μl) and sodium chlorite (9.0 mg) were added in sequence, followed by stirring at room temperature for 24 hours. The reaction mixture was cooled to 0°C, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 9 / 1) to obtain the title compound (3.7 mg). 1 H-NMR (CDCl 3 ) δ: 0.69-0.71 (m, 1H), 1.68-1.71 (m, 1H), 2.25-2.28 (m, 1H), 3.11 (d, 1H, J = 11.28 Hz), 3.49 (s, 1H), 3.71 (s, 3H), 3.73 (s, 3H), 3.75 (d, 1H, J = 11.28 Hz), 3.98 (d, 1H, J = 13.30 Hz), 4.42 (d, 1H, J = 13.30 Hz), 6.33-6.38 (m, 2H), 6.95-6.98 (m, 1H).

[0358] (10) 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide [ka] 1-Phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (3.5mg) obtained in the same manner as in Production Method 2-2 was dissolved in N,N-dimethylformamide (0.5ml), and 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (3.7mg) and WSC·HCl (3.6mg) were added in sequence at room temperature and stirred for 14 hours. Diisopropylethylamine (3.3μl) and HATU (7.3mg) were added to this reaction mixture and stirred at room temperature for another 72 hours. Water was added to this reaction mixture and it was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (6.3mg).

[0359] (11) 4-Oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide [ka] Anisole (2 μl) and trifluoroacetic acid (0.5 ml) were added to 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid [1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide (6.3 mg) at room temperature, and the mixture was stirred for 3 hours at 80° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol=9 / 1) to obtain the title compound (0.3 mg). 1H-NMR (CDCl3) δ: 0.83-0.88 (m, 4H), 1.22-1.28 (m, 3H), 1.95 (dd, 1H, J = 9.3, 4.8 Hz), 2.49 (t, 2H, J = 8.5 Hz), 3.60 (d, 1H, J = 10.1 Hz), 4.01 (d, 1H, J = 10.1 Hz), 5.14 (s, 1H), 6.99 (s, 1H), 7.04-7.34 (m, 9H), 7.83 (s, 1H). .

[0360] [Production Example 31]: Synthesis of Example 250 (4-oxo-5-azabispiro[2.4]heptane-7-carboxylic acid {1-phenyl-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-yl}amide) [ka] (1) 1-Acetylcyclopropanecarboxylic acid methyl ester [ka] Potassium carbonate (11.54 g) and 1,2-dibromoethane (2.4 ml) were added successively to a solution of methyl acetoacetate (3 ml) in acetone (30 ml) at room temperature, and the mixture was stirred for 17 hours at 65° C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate=10 / 1) to obtain the title compound (2.17 g). 1 H-NMR (CDCl 3 ) δ: 1.48 (s, 4H), 2.47 (s, 3H), 3.75 (s, 3H).

[0361] (2) 1-(1-trifluoromethanesulfonyloxyvinyl)cyclopropanecarboxylic acid methyl ester [ka] Under an argon atmosphere, at 0°C, n-butyllithium (10.4 ml, 1.6M n-hexane solution) was added to a solution of diisopropylamine (2.37 ml) in tetrahydrofuran (11 ml), and the mixture was stirred for 0.5 hours. At -78°C, a solution of 1-acetylcyclopropanecarboxylic acid methyl ester (2.17 g) in tetrahydrofuran (11 ml) was added, and the mixture was stirred for 0.5 hours. Next, N-phenylbis(trifluoromethanesulfonimide) (6.00 g) was added, and the mixture was stirred for 0.5 hours, and then stirred at 0°C for an additional 1 hour. Water was added to this reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (4.36 g).

[0362] (3) 1-(1-methoxycarbonylvinyl)cyclopropanecarboxylic acid methyl ester [ka] Triethylamine (6.4 ml) and bis(triphenylphosphine)palladium(II) dichloride (1.07 g) were added in sequence at room temperature to a mixed solution of 1-(1-trifluoromethanesulfonyloxyvinyl)cyclopropanecarboxylate (4.36 g) obtained in the previous step in N,N-dimethylformamide / methanol (1 / 2, 66 ml), and the atmosphere in the reaction vessel was replaced with carbon monoxide at normal pressure. After stirring this reaction solution at 50°C for 18 hours, it was cooled to room temperature and the atmosphere in the reaction vessel was replaced with nitrogen. Water and ethyl acetate were added to this reaction mixture, filtered through Celite, and eluted with ethyl acetate. The filtrate was extracted with ethyl acetate, and the separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 8 / 1) to obtain the title compound (720 mg). 1 H-NMR (CDCl 3) δ: 1.03 (dd, 2H, J = 7.33, 4.07 Hz), 1.51 (dd, 2H, J = 7.33, 4.07 Hz), 3.65 (s, 3H), 3.78 (s, 3H), 5.64 (d, 1H, J = 0.93 Hz), 6.31 (d, 1H, J = 0.93 Hz).

[0363] (4) 5-(2,4-Dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid methyl ester [ka] To a solution of 1-(1-methoxycarbonylvinyl)cyclopropanecarboxylate (720 mg) in toluene (3.6 ml), 2,4-dimethoxybenzylamine (587 μl) was added at room temperature, and the mixture was stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=1 / 1) to give the title compound (567 mg). 1 H-NMR (CDCl 3 ) δ: 0.81-0.84 (m, 2H), 1.09-1.12 (m, 1H), 1.22-1.28 (m, 1H), 3.10 (dd, 1H, J = 8.84, 5.23 Hz), 3.48 (dd, 1H, J = 10.00, 8.84 Hz), 3.66 (dd, 1H, J = 10.00, 5.23 Hz), 3.67 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 4.45 (d, 1H, J = 14.77 Hz), 4.51 (d, 1H, J = ...

Claims

1. A compound represented by the following general formula [Ib] or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, Ring Cy is (1) C ６－１０ Aryl, (2) C ３－８ cycloalkyl, or (3) C ３－８ is cycloalkenyl, n1 is 0, 1, 2, 3 or 4; R １ａ teeth, (1) a halogen atom, (2) a hydroxy group, (3) a carboxy group, (4) C １－６ Alkyl groups, (5) C ２-８ Alkenyl groups, (6) C ２-８ Alkynyl groups, (7) C １－６ Alkoxy groups, (8) C ３－６ Cycloalkyl groups, (9) Halo C １－６ Alkyl groups, (10) Hydroxy C １－６ Alkyl groups, (11) C １－６ Alkoxy C １－６ Alkyl groups, (12) Halo C １-６ Alkoxy C １-６ Alkyl groups, (13) C １-６ Alkylsulfonyl C １-６ Alkyl groups, (14) Halo C １-６ Alkylsulfonyl C １-６ Alkyl groups, (15) Halo C １-６ Alkylamino C １-６ Alkyl groups, (16) C ３-６ Cycloalkyl C ２-６ Alkynyl groups, (17) Haro C １－６ Alkoxy groups, (18) Carboxy C １－６ Alkoxy groups, (19) C １-６ Alkylsulfanyl groups, (20) C １-６ Alkylsulfonyl groups, (21) Haro C １-６ Alkylsulfonyl groups, (22) C １-8 Alkylcarbonyl groups, (23) C １-６ Alkyloxycarbonyl group, (24) Formula: 【Chemistry 2】 (In the formula, R ５ teeth, (a) a hydrogen atom, or (b) C １-６ is an alkyl group, R ６ teeth, (a) C １-６ an alkyl group, or (b) Halo C １-６ is an alkyl group) is a group represented by (25) saturated heterocycle C １-６ an alkyl group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); or (26) saturated heterocyclic oxy C １-６ an alkyl group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); However, when n1 is 2, 3, or 4, each R １a may be the same or different, R ２ａ teeth, (1) C １－８ Alkyl groups, (2) C ３－８ Cycloalkyl C １－６ Alkyl groups, (3) C ６－１０ Aryl C １－６ Alkyl groups, (4) Saturated heterocycle C １－６ an alkyl group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom); (5) C ３－８ Cycloalkyl groups, (6) Halo C １－６ Alkyl groups, (7) C １－６ Alkoxy C １－６ Alkyl groups, (8) Halo C ３－８ Cycloalkyl groups, (9) C ６－１０ Aryl group (the C ６－１０ The aryl group is (a) a halogen atom, (b) a hydroxy group, (c) C １－６ Alkyl groups, (d) C ２-８ Alkenyl groups, (e) C ２-６ Alkynyl groups, (f) C １－６ Alkoxy group (g) Halo C １-６ Alkyl groups, (h) C １-６ Alkoxy C １-６ Alkyl groups, (i) Halo C １-６ Alkoxy groups, (j) Hydroxy C １-６ Alkoxy groups, (k) C １-６ Alkoxy C １-６ Alkoxy groups, (l) Carboxy C １－６ Alkoxy groups, (m) C ６－１０ Aryl C １-６ Alkoxy groups, (n) C １-６ Alkylsulfanyl C １-６ Alkoxy groups, (o)C １-６ Alkylsulfonyl C １-６ Alkoxy groups, (p) C ６－１０ Aryl C １-６ Alkoxy C １-６ Alkoxy groups, (q) saturated heterocycle C １-６ An alkoxy group (the saturated heterocycle is a 4- to 6-membered saturated heterocycle having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 2 C １－６ may be substituted with an alkyl group); (r) a saturated heterocyclic oxy group (the saturated heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom), (s) C ３－８ cycloalkyloxy groups, (t) C １-６ alkoxycarbonyloxy groups, and (u)C １-６ alkylsulfonyl groups), or (10) A saturated heterocyclic group (the saturated heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and having 1 to 4 C １－６ may be substituted with an alkyl group); Ring Cy ａ teeth, {Formula (1): 【Chemistry 3】 (In the formula, m2 is 1, 2 or 3; m3 is 1, 2 or 3; n3 is 1 or 2. A group represented by the formula: (2) Formula: 【Chemistry 4】 (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or more. A group represented by the formula: (3) Formula: 【Chemistry 5】 (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or more. A group represented by the formula: (4) Formula: 【Chemistry 6】 (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or more. A group represented by the formula: (5) Formula: 【Chemistry 7】 (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or more. A group represented by the formula: (6) Formula: 【Chemistry 8】 (In the formula, m8 is 1 or 2; m9 is 1 or 2. or (7) Formula: 【Chemistry 9】 (In the formula, m8 is 1 or 2; m9 is 1 or 2. is a group represented by n2 is 0, 1, 2, 3 or 4; R ３ａ teeth, (1) a hydroxy group, (2) C １－６ an alkyl group, or (3) Hydroxy C １－６ is an alkyl group, However, when n2 is 2, 3, or 4, each R ３ａ may be the same or different. R ３ｂ teeth, (1) a hydroxy group, (2) C １－６ Alkyl group (R ３ｂ Together with the carbon adjacent to the carbon to which it is bonded, C ３－６ may form a cycloalkyl group), or (3) Hydroxy C １－６ an alkyl group; or (4) Two R’s ３ｂ When bonded to the same carbon, together with the carbon to which they are bonded, C ３－６ A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R ３ｂ may be the same or different. R ４ｂ teeth, (1) a hydrogen atom, (2) C １－６ Alkyl groups, (3) Carboxy C １－６ Alkyl groups, (4) Halo C １－６ an alkyl group, or (5) C １－６ Alkoxy C １－６ is an alkyl group. is.]

2. Ring Cy ａ but, {Formula (1): 【Chemistry 10】 (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or more. A group represented by the formula: (2) Formula: 【Chemistry 11】 (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or more. A group represented by the formula: (3) Formula: 【Chemistry 12】 (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or more. A group represented by the formula: (4) Formula: 【Chemistry 13】 (In the formula, m8 is 1 or 2; m9 is 1 or 2. or (5) Formula: 【Chemistry 14】 (In the formula, m8 is 1 or 2; m9 is 1 or 2. is a group represented by n2 is 0, 1, 2, 3 or 4; R ３ａ teeth, (1) a hydroxy group, (2) C １－６ an alkyl group, or (3) Hydroxy C １－６ is an alkyl group, However, when n2 is 2, 3, or 4, each R ３ａ may be the same or different. R ３ｂ teeth, (1) a hydroxy group, (2) C １－６ Alkyl group (R ３ｂ Together with the carbon adjacent to the carbon to which it is bonded, C ３－６ may form a cycloalkyl group), or (3) Hydroxy C １－６ an alkyl group; or (4) Two R’s ３ｂ When bonded to the same carbon, together with the carbon to which they are bonded, C ３－６ A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R ３ｂ may be the same or different. R ４ｂ teeth, (1) a hydrogen atom, (2) C １－６ Alkyl groups, (3) Carboxy C １－６ Alkyl groups, (4) Halo C １－６ an alkyl group, or (5) C １－６ Alkoxy C １－６ is an alkyl group.

2. The compound according to claim 1, wherein:

3. Ring Cy ａ but, {Formula (1): 【Chemistry 15】 (In the formula, m4 is 0, 1, 2 or 3; m5 is 0, 1 or 2; However, the sum of m4 and m5 is 1 or more. A group represented by the formula: (2) Formula: 【Chemistry 16】 (In the formula, m6 is 0, 1 or 2; m7 is 0, 1 or 2; However, the sum of m6 and m7 is 1 or more. A group represented by the formula: n2 is 0, 1, 2, 3 or 4; R ３ａ teeth, (1) a hydroxy group, (2) C １－６ an alkyl group, or (3) Hydroxy C １－６ is an alkyl group, However, when n2 is 2, 3, or 4, each R ３ａ may be the same or different. R ３ｂ teeth, (1) a hydroxy group, (2) C １－６ Alkyl group (R ３ｂ Together with the carbon adjacent to the carbon to which it is bonded, C ３－６ may form a cycloalkyl group), or (3) Hydroxy C １－６ an alkyl group; or (4) Two R’s ３ｂ When bonded to the same carbon, together with the carbon to which they are bonded, C ３－６ A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R ３ｂ may be the same or different. R ４ｂ teeth, (1) a hydrogen atom, (2) C １－６ Alkyl groups, (3) Carboxy C １－６ Alkyl groups, (4) Halo C １－６ an alkyl group, or (5) C １－６ Alkoxy C １－６ is an alkyl group.

2. The compound according to claim 1, wherein:

4. Ring Cy ａ but, {Formula (1): 【Chemistry 17】 (In the formula, n2 is 0, 1, 2, 3 or 4. or (2) Formula: 【Chemistry 18】 (In the formula, where n2 is 0 or 1. is a group represented by R ３ａ teeth, (1) a hydroxy group, (2) C １－６ an alkyl group, or (3) Hydroxy C １－６ is an alkyl group, R ３ｂ teeth, (1) a hydroxy group, (2) C １－６ Alkyl group (R ３ｂ Together with the carbon adjacent to the carbon to which it is bonded, C ３－６ may form a cycloalkyl group), or (3) Hydroxy C １－６ an alkyl group; or (4) Two R’s ３ｂ When bonded to the same carbon, together with the carbon to which they are bonded, C ３－６ A cycloalkyl group may be formed. However, when n2 is 2, 3, or 4, each R ３ｂ may be the same or different. R ４ｂ teeth, (1) a hydrogen atom, (2) C １－６ Alkyl groups, (3) Carboxy C １－６ Alkyl groups, (4) Halo C １－６ an alkyl group, or (5) C １－６ Alkoxy C １－６ is an alkyl group.

2. The compound according to claim 1, wherein:

5. Ring Cy is C ６－１０ 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, which is aryl.

6. 6. The compound according to claim 5, or a pharma- ceutically acceptable salt thereof, wherein ring Cy is phenyl.

7. R1 ａ but, (1) a halogen atom, (2) C １－６ Alkyl groups, (3) C １－６ Alkoxy groups, (4) Halo C １－６ Alkyl groups, (5) C １－６ Alkoxy C １－６ Alkyl groups, (6) Halo C １-６ Alkoxy C １-６ an alkyl group, or (7) Haro C １－６ is an alkoxy group, However, when n1 is 2, 3 or 4, each R1 ａ and may be the same or different, the compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. R ２ａ But, C ６－１０ Aryl group (the C ６－１０ The aryl group is (a) a halogen atom, (b) C １－６ Alkyl groups, (c) C １－６ Alkoxy groups, and (d) Carboxy C １－６ 8. The compound according to claim 1, wherein the aryl group is aryl, and the aryl group is aryl; and the aryl group is aryl.

9. R ２ａ However, a phenyl group (the phenyl group is (a) a halogen atom, (b) C １－６ Alkyl groups, (c) C １－６ Alkoxy groups, and (d) Carboxy C １－６ 9. The compound according to claim 8, wherein the aryl group is aryl, and the aryl group is aryl; and the aryl group is aryl.

10. The chemical structure is as follows: 【Chemistry 19】 【change】 【change】 【change】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, selected from:

11. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

12. 11. An SGLT1 inhibitor comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

13. 11. A therapeutic or prophylactic agent for diabetes, comprising the compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof.

14. The therapeutic or preventive agent according to claim 13, wherein the diabetes is type II diabetes.

15. 13. A method for inhibiting SGLT1, comprising administering to a mammal a pharma- ceutical effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt thereof.

16. 11. A method for treating or preventing diabetes mellitus, which comprises administering to a mammal a pharma- ceutical effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt thereof.

17. 17. The method of claim 16, wherein the diabetes is type II diabetes.

18. 13. Use of a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt thereof for the manufacture of an SGLT1 inhibitor.

19. 13. Use of the compound according to any one of claims 1 to 10 or a pharma- ceutical acceptable salt thereof for the manufacture of an agent for treating or preventing diabetes.

20. 20. The use according to claim 19, wherein the diabetes is type II diabetes.

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