Condensed tricyclic compound and pharmaceutical use thereof

Abstract

To provide a compound having PDHK inhibitory activity that is useful for the treatment or prevention of diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, or chronic kidney disease.SOLUTION: A compound of formula [I-a] or a pharmaceutically acceptable salt thereof, wherein the symbols in the formula have the same meanings as defined in the specification.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a fused tricyclic compound and its pharmaceutical use. More specifically, the present invention relates to a fused tricyclic compound or a pharmaceutically acceptable salt thereof having pyruvate dehydrogenase kinase (hereinafter abbreviated as PDHK) inhibitory activity, a pharmaceutical composition containing the compound, and a therapeutic or preventive agent for diabetes (e.g., type 1 diabetes, type 2 diabetes), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications (e.g., diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataracts), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, or chronic kidney disease. [Background technology]

[0002] Energy-consuming reactions in tissues, such as biosynthesis, active transport, and muscle contraction, are fueled by the hydrolysis of adenosine triphosphate (ATP). ATP is produced by the oxidation of energy-rich metabolic fuels such as glucose or free fatty acids. In oxidative tissues such as muscle, the majority of ATP is derived from acetyl-CoA, which enters the citric acid cycle. Acetyl-CoA is produced by the oxidation of glucose via glycolysis or the β-oxidation of free fatty acids. The key enzyme regulating acetyl-CoA production from glucose is pyruvate dehydrogenase (PDH). PDH catalyzes the oxidation of pyruvate to acetyl-CoA and carbon dioxide, while simultaneously reducing nicotinamide adenine dinucleotide (NAD) to NADH (e.g., Non-Patent Documents 1 and 2).

[0003] PDH is a multienzyme complex consisting of three enzyme components (E1, E2, and E3) and several subunits located in the mitochondrial matrix. E1, E2, and E3 decarboxylate pyruvate, generate acetyl-CoA, and reduce NAD to generate NADH, respectively. PDH is bound to two types of enzymes that play a regulatory role. One is PDHK, a protein kinase specific for PDH. Its role is to inactivate the E1α subunit of the PDH complex by phosphorylating it. The other is PDH phosphatase, a specific protein phosphatase that activates PDH by dephosphorylating the E1α subunit. The proportion of active (dephosphorylated) PDH is determined by the balance between kinase activity and phosphatase activity. Kinase activity is regulated by the relative concentrations of metabolic substrates. For example, kinase activity is activated by increases in the ratios of NADH / NAD, acetyl-CoA / CoA, and ATP / adenosine diphosphate (ADP), and is inhibited by pyruvate (e.g., Non-Patent Document 3).

[0004] Four types of PDHK isozymes have been identified in mammalian tissues. Among them, PDHK2 is expressed in a wide range of tissues, including the liver, skeletal muscle, and adipose tissue, which are involved in glucose metabolism. Furthermore, PDHK2 is relatively sensitive to activation by increases in NADH / NAD and acetyl-CoA / CoA and to inhibition by pyruvate, suggesting its involvement in short-term glucose metabolism regulation (e.g., Non-Patent Document 4).

[0005] PDHK1 is also highly expressed in cardiac muscle, skeletal muscle, pancreatic β cells, etc. Furthermore, under ischemic conditions, PDHK1 expression is induced via activation of hypoxia-inducible factor (HIF) 1. Therefore, it is suggested that it is involved in ischemic diseases and cancer diseases (for example, Non-Patent Document 5).

[0006] In diseases such as insulin-dependent (type 1) diabetes and non-insulin-dependent (type 2) diabetes, lipid oxidation is enhanced and glucose utilization is simultaneously reduced. This reduced glucose utilization contributes to hyperglycemia. PDH activity is reduced in conditions with reduced oxidative glucose metabolism, such as type 1 and type 2 diabetes and obesity, suggesting that reduced PDH activity is involved in reduced glucose utilization in type 1 and type 2 diabetes (e.g., Non-Patent Documents 6 and 7). In addition, gluconeogenesis in the liver is enhanced in type 1 and type 2 diabetes, which is also a factor in hyperglycemia. Decreased PDH activity increases pyruvate, resulting in increased utilization of lactate as a gluconeogenesis substrate in the liver. This suggests that decreased PDH activity may be involved in the enhancement of gluconeogenesis in type 1 and type 2 diabetes (e.g., Non-Patent Documents 8 and 9). Activation of PDH by PDHK inhibition is thought to increase the glucose oxidation rate, which is expected to improve hyperglycemia in type 1 and type 2 diabetes by enhancing glucose utilization in the body and suppressing hepatic gluconeogenesis (e.g., Non-Patent Documents 10, 11, and 12). Another factor involved in diabetes is impaired insulin secretion, which is known to involve reduced PDH activity and induction of PDHK1, 2, and 4 in pancreatic β cells (eg, Non-Patent Documents 13 and 14). Furthermore, persistent hyperglycemia due to diabetes is known to cause complications such as diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy. Thiamine and α-lipoic acid contribute to the activation of PDH as coenzymes. These, as well as thiamine derivatives and α-lipoic acid derivatives, have been shown to have promising effects in the treatment of diabetic complications. Therefore, activation of PDH is expected to improve diabetic complications (e.g., Non-Patent Documents 15 and 16).

[0007] Under ischemic conditions, limited oxygen supply reduces both glucose and fatty acid oxidation, leading to a decrease in the amount of ATP produced by oxidative phosphorylation in tissues. In the absence of sufficient oxygen, anaerobic glycolysis is promoted in an attempt to maintain ATP levels. This results in increased lactate and a decrease in intracellular pH. Cells consume energy to maintain ionic homeostasis, but abnormally low ATP levels and osmotic collapse of the cells result in cell death. Additionally, adenosine monophosphate-activated kinase, activated under ischemic conditions, inactivates acetyl-CoA carboxylase by phosphorylation. A decrease in tissue malonyl-CoA levels increases carnitine palmitoyltransferase-I activity, promoting the transport of acyl-CoA into mitochondria, favoring fatty acid oxidation over glucose oxidation. Glucose oxidation produces more ATP per oxygen molecule consumed than fatty acid oxidation. Therefore, under ischemic conditions, shifting energy metabolism toward glucose oxidation by activating PDH may improve the ability to maintain ATP levels (e.g., Non-Patent Document 17). Furthermore, activation of PDH leads to the oxidation of pyruvate produced through glycolysis, resulting in a decrease in lactate production, which is thought to result in a net decrease in proton load in ischemic tissue. Therefore, activation of PDH by PDHK inhibition is expected to have a protective effect in ischemic diseases, such as myocardial ischemia (e.g., Non-Patent Documents 18 and 19).

[0008] Drugs that activate PDH by inhibiting PDHK are thought to enhance pyruvate metabolism and thereby reduce lactate production, and are therefore thought to be useful in the treatment of hyperlactemia, such as mitochondrial disease, mitochondrial encephalomyopathy, or sepsis (e.g., Non-Patent Document 20).

[0009] In cancer cells, the expression of PDHK1 or 2 is elevated. ATP production by oxidative phosphorylation in mitochondria is reduced, while ATP production via anaerobic glycolysis in the cytoplasm is increased. Activation of PDH by PDHK inhibition is expected to enhance oxidative phosphorylation in mitochondria, leading to increased production of reactive oxygen species and inducing apoptosis in cancer cells. Therefore, activation of PDH by PDHK inhibition is thought to be useful for the treatment of cancer diseases (e.g., Non-Patent Document 21).

[0010] Pulmonary hypertension is a disease characterized by increased pulmonary arterial cell proliferation, resulting in partial narrowing of the pulmonary arteries, leading to elevated blood pressure. Activation of PDH in pulmonary arterial cells in pulmonary hypertension is expected to promote mitochondrial oxidative phosphorylation and increase the production of reactive oxygen species, thereby inducing apoptosis of pulmonary arterial cells. Therefore, PDH activation by PDHK inhibition is thought to be useful in the treatment of pulmonary hypertension, such as pulmonary arterial hypertension (e.g., Non-Patent Document 22).

[0011] In Alzheimer's disease, energy production and glucose metabolism in the cerebrum are reduced, and PDH activity is also reduced. Decreased PDH activity leads to reduced acetyl-CoA production. Acetyl-CoA is used to produce ATP in the electron transport system via the citric acid cycle. Acetyl-CoA is also a raw material for synthesizing acetylcholine, a neurotransmitter. Therefore, decreased brain PDH activity in Alzheimer's disease is thought to cause neuronal cell death due to reduced ATP production. Furthermore, in cholinergic neurons, the synthesis of acetylcholine, a neurotransmitter, is suppressed, leading to memory loss and other problems. Activating brain PDH in Alzheimer's disease is expected to enhance energy production and acetylcholine synthesis. Therefore, PDH activation by PDHK inhibition is thought to be useful in the treatment of Alzheimer's disease (e.g., Non-Patent Documents 23 and 24).

[0012] Vascular dementia is broadly classified into large vessel disease and small vessel disease. In the large vessel disease, cerebral infarction, including ischemia-reperfusion, is a cause, leading to increased pyruvate and lactate levels due to decreased PDH activity in the brain, and decreased energy production, which induces neuronal death. In the small vessel disease, white matter lesions due to cerebral hypoperfusion are thought to be a cause, leading to chronic decreased glucose metabolism and cognitive impairment. Activation of cerebral PDH in vascular dementia is expected to reduce lactate levels and increase energy production in the large vessel disease, and to enhance glucose metabolism in the small vessel disease. Therefore, activation of PDH by PDHK inhibitors is thought to be useful in the treatment of vascular dementia (e.g., Non-Patent Documents 28, 29, 30).

[0013] Dichloroacetic acid, a drug with PDH activating activity, has been shown to have promising effects in the treatment of diabetes, myocardial ischemia, myocardial infarction, angina pectoris, heart failure, hyperlactatemia, cerebral ischemia, stroke, peripheral arterial disease, chronic obstructive pulmonary disease, cancer, and pulmonary hypertension (e.g., Non-Patent Documents 10, 18, 20, 22, 25, 26, 27). It has been shown that compounds with PDHK inhibitory activity have a neuroprotective effect against retinal ischemia-reperfusion injury (Non-Patent Document 31). Retinal ischemic injury is involved in diseases such as glaucoma, diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. Furthermore, it has been shown that compounds with PDHK inhibitory activity reduce the severity of disease in disease model animals exhibiting chronic kidney disease-like renal damage and decreased renal function (Patent Document 1).

[0014] Based on these findings, PDHK inhibitors are considered to be useful for the treatment or prevention of diseases associated with impaired glucose utilization, such as diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, and diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.). Furthermore, PDHK inhibitors are also useful for the treatment or prevention of diseases in which the supply of energy substrates to tissues is limited, such as heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, and atherosclerosis. PDHK inhibitors are believed to be useful in the treatment or prevention of peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease. Furthermore, PDHK inhibitors are believed to be useful in the treatment or prevention of mitochondrial diseases, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, etc.

[0015] Therefore, PDHK inhibitors are considered to be useful for the treatment or prevention of diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataracts, etc.), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, or chronic kidney disease. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] International Publication No. 2020 / 054734 [Non-patent literature]

[0017] [Non-Patent Document 1] Reed LJ, Hackert ML. Structure-function relationships in dihydrolipoamide acyltransferases. J Biol Chem. 1990 Jun 5;265(16):8971-4. [Non-patent document 2] Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J. 1990 Nov;4(14):3224-33. [Non-patent document 3] Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab. 2003 May;284(5):E855-62. [Non-patent document 4] Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998 Jan 1;329 (Pt 1):191-6. [Non-patent document 5] Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006 Mar;3(3):177-85. [Non-patent document 6] Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005 Dec;115(12):3587-93.

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[0018] The present invention is as follows. [1] A compound of formula [Ia], or a pharmaceutically acceptable salt thereof:

[0019] [ka]

[0020] [In the formula, The dotted bond is a single or double bond, X 1 , X 2 , X 3 and X 4 are each independently C or N, and Y 1 and Y 2 are each independently C, N, or O (wherein X 2 , X 3 , X 4 , Y 1 or Y 2 The total number of N and O as R A is C 1-4 is alkyl, R B teeth, (1) halogen, (2) Cyano, (3) hydroxy, (4) oxo, (5)-COR 1 {where R 1 teeth (A) hydrogen, (B) -OH, (C)-NR 2 R 3 (where R 2 and R 3 are each independently hydrogen or C 1-4 alkyl), or (D) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, wherein the saturated heterocyclyl is optionally substituted with one or two halogens; (6) C 1-8 Alkyl {wherein the C 1-8 Alkyl is (A) halogen, (B) hydroxy, (C) phenyl optionally substituted with halogen; (D) Halo C 1-4 pyridyl optionally substituted with alkyl, and (E)-OR 4 (where R 4 teeth, (a)C 1-4 Alkyl, (b) phenyl optionally substituted with halogen, or (c)C 1-4 benzyl optionally substituted with alkoxy and optionally substituted with 1 to 8 substituents independently selected from the group consisting of: (7) C 1-8 Alkoxy {wherein the C 1-8 Alkoxy is (A) halogen, (B) cyano, (C) hydroxy, (D) C optionally substituted with 1 to 3 halogens 1-4 Alkoxy, (E)C 1-4 alkylsulfonyl, (F) Cyano and Cyano C 1-4 C optionally substituted with one substituent selected from the group consisting of alkyl3-6 cycloalkyl, (G) phenyl optionally substituted with cyano; (H)-COCy 1 (where Cy 1 is a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, which may be substituted with one or two halogens, and (I) a 4- to 6-membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the saturated heterocyclyl is (a)C 1-4 Alkyl, (b) oxo, (c)C 1-4 alkylcarbonyl, (d) benzoyl optionally substituted with halogen, and (e)C 1-4 Alkyl sulfonyl and wherein the saturated heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 1-4 When substituted with alkyl, two C 1-4 Alkyl groups may be joined to each other to form a bridged ring together with the atoms to which they are attached. and optionally substituted with 1 to 8 substituents independently selected from the group consisting of: (8)-Cy 2 {where Cy 2 teeth, (A)C 3-6 Cycloalkyl (wherein the C 3-6 Cycloalkyl is (a) halogens, (b)C 1-4 Alkyl, (c) Halo C 1-4 alkyl, and (d) Phenyl optionally substituted with halogen and optionally substituted with one or two substituents independently selected from the group consisting of: (B) Halogen, Halo C 1-4 Alkyl, and C 1-4 Independently from the group consisting of alkoxy phenyl, optionally substituted with one or two substituents selected from the following: (C) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom or one oxygen atom, wherein the saturated heterocyclyl is (a) a phenyl optionally substituted with halogen and (b) C 1-4 alkylcarbonyl)}, or (9)-OCy 3 {where Cy 3 teeth (A) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom or one oxygen atom (wherein the saturated heterocyclyl is (a) benzoyl optionally substituted with halogen and (b) C 1-4 alkylcarbonyl), or (B) 6-membered heteroaryl having 1 or 2 nitrogen atoms, wherein the heteroaryl is cyano, haloC 1-4 Alkyl, and C 3-6 cycloalkyl)}, m is 0 or 1, n is 0, 1, or 2, and when n is 2, each R B may be the same or different.]

[0021] [2] Formula [Ib]:

[0022] [ka]

[0023] (In the formula, each symbol has the same meaning as in [1].) or a pharmaceutically acceptable salt thereof.

[0024] [3] Formula [Ic]:

[0025] [ka]

[0026] (In the formula, each symbol has the same meaning as in [1].) or a pharmaceutically acceptable salt thereof.

[0027] [4] The compound according to any one of [1] to [3], wherein n is 1, or a pharmaceutically acceptable salt thereof.

[0028] [5] Expression [Id]:

[0029] [ka]

[0030] (In the formula, the symbols have the same meanings as in [1].) or a pharmaceutically acceptable salt thereof.

[0031] [6] Formula [Ie]:

[0032] [ka]

[0033] (In the formula, the symbols have the same meanings as in [1].) or a pharmaceutically acceptable salt thereof.

[0034] [7] R B but, (1)C 1-8 Alkyl {wherein the C 1-8 Alkyl is (A) halogen, (B) hydroxy, (C) phenyl optionally substituted with halogen; (D) Halo C 1-4 pyridyl optionally substituted with alkyl, and (E)-OR 4 (where R 4 teeth, (a)C 1-4 Alkyl, (b) phenyl optionally substituted with halogen, or (c)C 1-4 benzyl optionally substituted with alkoxy and optionally substituted with 1 to 8 substituents independently selected from the group consisting of: (2) C 1-8 Alkoxy {wherein the C 1-8 Alkoxy is (A) halogen, (B) cyano, (C) hydroxy, (D) C optionally substituted with 1 to 3 halogens 1-4 Alkoxy, (E)C 1-4 alkylsulfonyl, (F) Cyano and Cyano C 1-4 C optionally substituted with one substituent selected from the group consisting of alkyl 3-6 cycloalkyl, (G) phenyl optionally substituted with cyano; (H)-COCy 1 (where Cy 1 is a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, which may be substituted with one or two halogens, and (I) a 4- to 6-membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the saturated heterocyclyl is (a)C 1-4 Alkyl, (b) oxo, (c)C 1-4 alkylcarbonyl, (d) benzoyl optionally substituted with halogen, and (e)C 1-4Alkyl sulfonyl and the saturated heterocyclic group may be substituted with 1 to 4 substituents independently selected from the group consisting of Two C 1-4 When substituted with alkyl, two C 1-4 Alkyl groups may be joined to each other to form a bridged ring together with the atoms to which they are attached. The compound according to any one of [1] to [6], or a pharmaceutically acceptable salt thereof, wherein:

[0035] [8] The following formula:

[0036] [ka]

[0037] or a pharmaceutically acceptable salt thereof.

[0038] [9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0039]

[10] A PDHK inhibitor comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0040]

[11] A PDHK2 inhibitor comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0041]

[12] A therapeutic or preventive agent for diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy or chronic kidney disease, comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0042]

[13] The method for treating or preventing diabetes according to

[12] , wherein the diabetes is type 1 diabetes or type 2 diabetes. Antiseptic.

[0043]

[14] The therapeutic or preventive agent according to

[12] , wherein the vascular dementia is large vessel disease type or small vessel disease type vascular dementia.

[0044]

[15] The therapeutic or preventive agent according to

[12] , wherein the heart failure is acute heart failure or chronic heart failure.

[0045]

[16] The therapeutic or preventive agent according to

[12] , wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0046]

[17] A method for inhibiting PDHK, comprising administering a therapeutically effective amount of the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof to a mammal.

[0047]

[18] A method for treating or preventing a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease, comprising administering a therapeutically effective amount of the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof to a mammal.

[0048]

[19] The method according to

[18] , wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0049]

[20] The method according to

[18] , wherein the vascular dementia is large vessel disease type or small vessel disease type vascular dementia.

[0050]

[21] The method according to

[18] , wherein the heart failure is acute heart failure or chronic heart failure.

[0051]

[22] The method according to

[18] , wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0052]

[23] Use of the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof for the manufacture of a PDHK inhibitor.

[0053]

[24] Use of the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.

[0054]

[25] The use according to

[24] , wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0055]

[26] The use according to

[24] , wherein the vascular dementia is large vessel disease type or small vessel disease type vascular dementia.

[0056]

[27] The use according to

[24] , wherein the heart failure is acute heart failure or chronic heart failure.

[0057]

[28] The use according to

[24] , wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0058]

[29] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of diabetes mellitus, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.

[0059]

[30] The compound or a pharmaceutically acceptable salt thereof according to

[29] , wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0060]

[31] The compound or a pharmaceutically acceptable salt thereof according to

[29] , wherein the vascular dementia is large vessel disease type or small vessel disease type vascular dementia.

[0061]

[32] The compound or a pharmaceutically acceptable salt thereof according to

[29] , wherein the heart failure is acute heart failure or chronic heart failure.

[0062]

[33] The compound or a pharmaceutically acceptable salt thereof according to

[29] , wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0063]

[34] A method for inhibiting PDHK2, comprising administering a therapeutically effective amount of the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof to a mammal.

[0064]

[35] A commercial package comprising the pharmaceutical composition according to [9] and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.

[0065]

[36] A kit comprising the pharmaceutical composition according to [9] and a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease. DETAILED DESCRIPTION OF THE INVENTION

[0066] The definitions of terms used in the present invention are as follows.

[0067] "Halogen" is fluoro, chloro, bromo or iodo. As "halogen", fluoro or chloro is preferred.

[0068] "C 1-4 "Alkyl" means a straight or branched chain alkyl having 1 to 4 carbon atoms, and butyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl "C 1-4 As the "alkyl", methyl is preferred.

[0069] "C 1-8 The term "alkyl" means a straight or branched chain alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, 1-methyl-1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methyl-1-propylbutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like.

[0070] "C 1-4 "Alkylcarbonyl" refers to a group in which the alkyl moiety is defined as "C 1-4 "Alkyl" means alkyl-carbonyl, including acetyl, propanoyl, butanoyl, 2-methyl propanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, and 2,2-dimethylpropanoyl. 1-4 The "alkylcarbonyl" is preferably acetyl.

[0071] "C 1-4 "Alkylsulfonyl" refers to a group in which the alkyl moiety is defined as "C 1-4 alkyl-sulfonyl, methanesulfonyl, ethylsulfonyl, propylsulfonyl, sulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. 1-4 Alkyl sulfonyl " is preferably methanesulfonyl.

[0072] "Haro C 1-4 "Alkyl" means a straight or branched alkyl having 1 to 4 carbon atoms substituted with 1 to 5 "halogens" as defined above. When an alkyl is substituted with multiple halogens, the halogens may be the same or different. 1-4 Examples of "alkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoro-1-methylethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl, and the like. 1-4 "Alkyl" includes C substituted with 1 to 3 fluoro groups. 1-4 Alkyl is preferred, and trifluoromethyl is more preferred.

[0073] "Cyano C 1-4"Alkyl" means a "C" as defined above substituted with one cyano. 1-4 For example, cyanomethyl, 2-cyanoethyl, 1-cyano-1-methylethyl, 3-cyano Examples include 4-cyanopropyl, 4-cyanobutyl, and the like.

[0074] "C 1-4 "Alkoxy" refers to a group in which the alkyl portion is defined as "C 1-4 alkyl-oxy, which is "alkyl" and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, Examples include isobutoxy, sec-butoxy, and tert-butoxy. 1-4 "Alkoxy" Of these, methoxy is preferred.

[0075] "C 1-8 "Alkoxy" means a group in which the alkyl portion is defined as "C 1-8 For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, Examples thereof include neopentyloxy, 1,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 1,2,2-trimethylpropyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, and 2-ethylbutyloxy.

[0076] "C 3-6 "Cycloalkyl" means a 3- to 6-membered monocyclic hydrocarbon ring group, including cyclopro Examples include cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 As the "cycloalkyl", cyclopropyl is preferred.

[0077] "4- to 6-membered saturated heterocyclyl having one nitrogen atom" refers to a 4- to 6-membered monocyclic saturated heterocyclic group having one nitrogen atom in addition to carbon atoms. Examples of the saturated heterocyclyl include azetidinyl, pyrrolidinyl, and piperidinyl.

[0078] "4- to 6-membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom" refers to a 4- to 6-membered monocyclic saturated heterocyclic group having, in addition to carbon atoms, 1 or 2 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Examples of the saturated heterocyclyl include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, isothiazolidinyl, and the like, and preferably oxetanyl, tetrahydrofuranyl, piperidinyl, tetrahydrothiopyranyl, and isothiazolidinyl.

[0079] "Saturated heterocyclyl has two C 1-4 When substituted with alkyl, two C 1-4 The phrase "alkyls may be bonded to each other to form a bridged ring together with the atoms to which they are attached" means that, for example, the saturated heterocyclyl is the following group:

[0080] [ka]

[0081] "4- to 6-membered saturated heterocyclyl having one nitrogen atom or oxygen atom" means a 4- to 6-membered monocyclic saturated heterocyclic group having, in addition to carbon atoms, one heteroatom independently selected from the group consisting of nitrogen atoms and oxygen atoms. Examples of the saturated heterocyclyl include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, etc., and preferably oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, and piperidinyl.

[0082] "6-membered heteroaryl having 1 or 2 nitrogen atoms" means a 6-membered monocyclic heteroaryl having 1 or 2 nitrogen atoms in addition to carbon atoms. Examples of the heteroaryl include pyridyl, pyrimidinyl, and pyrazinyl.

[0083] Preferred embodiments of the compound of formula [Ia] are described below. One preferred embodiment of formula [Ia] is formula [I-a1]:

[0084] [ka]

[0085] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0086] Another preferred embodiment of formula [Ia] is formula [I-a2]:

[0087] [ka]

[0088] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0089] Another preferred embodiment of formula [Ia] is formula [I-a3]:

[0090] [ka]

[0091] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0092] Another preferred embodiment of formula [Ia] is formula [I-a4]:

[0093] [ka]

[0094] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0095] Another preferred embodiment of formula [Ia] is formula [I-a5]:

[0096] [ka]

[0097] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0098] Another preferred embodiment of formula [Ia] is formula [I-a6]:

[0099] [ka]

[0100] (In the formula, R B1 and R B2 are each independently R in formula [Ia] B is synonymous with; The other symbols have the same meanings as in formula [Ia]. It is a compound represented by the formula:

[0101] Another preferred embodiment of formula [Ia] is formula [I-a7]:

[0102] [ka]

[0103] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0104] Another preferred embodiment of formula [Ia] is formula [I-a8]:

[0105] [ka]

[0106] (In the formula, each symbol has the same meaning as in formula [Ia] above.) It is a compound represented by the formula:

[0107] Another preferred embodiment of formula [Ia] is formula [I-a10]:

[0108] [ka]

[0109] (In the formula, the symbols have the same meanings as in formula [Ia] above.) It is a compound represented by the formula:

[0110] In the above formulas [Ia] and [I-a1] to [I-a8], R A is preferably methyl. In the above formulae [Ia], [I-a1] and [I-a3], n is preferably 1.

[0111] The term "pharmaceutically acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, etc. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977), (b) Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use ” (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). A compound of formula [Ia] and an inorganic acid, an organic acid, an inorganic base or an organic salt according to a method known per se. By reacting the groups, pharmaceutically acceptable salts thereof can be obtained. The pharmaceutically acceptable salt of the compound of formula [Ia] is used in an amount of 1 / 2 molecule, 1 / 2 molecule, or 1 / 2 molecule per molecule of the compound of formula [Ia]. It may be formed with one or more molecules of an acid or base.

[0112] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, and Hydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid Acid, mandelic acid, methanesulfonic acid, methyl sulfate, methyl nitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, urea Examples include salts with undecanoic acid, aspartic acid or glutamic acid.

[0113] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium. Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0114] Preferred embodiments of the "pharmaceutically acceptable salt" are as follows. Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. 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, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid. Examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium or zinc. Salts with organic bases include tris(hydroxymethyl)methylamine, N-methylglucan, Examples include salts with amine or lysine.

[0115] The compound of formula [Ia] or a pharmaceutically acceptable salt thereof may exist as a solvate. "Solvate" refers to a compound of formula [Ia] or a pharmaceutically acceptable salt thereof in which solvent molecules are present. The solvate is preferably a pharmaceutically acceptable solvate, and may be a hydrate, an ethanol solvate, a dihydrate, or the like of the compound of formula [Ia] or a pharmaceutically acceptable salt thereof. methyl sulfoxide solvate and the like. Specifically, the compound of formula [Ia] may be a hemihydrate, monohydrate, dihydrate or monoethanolate, or a monohydrate or dihydrate of the hydrochloride of the compound of formula [Ia]. The solvates can be obtained according to known methods.

[0116] The compound of formula [Ia] may have stereoisomers that should be recognized as cis / trans isomers. In this case, the compound of formula [Ia] may be a cis-isomer, a trans-isomer, or a combination of a cis-isomer and a trans-isomer. It may exist as a mixture of isomers. The compounds of formula [Ia] may exist as tautomers, and in that case, the compounds of formula [Ia] may exist as an individual tautomer or a mixture of tautomers. The compound of formula [Ia] may have one or more asymmetric carbon atoms. In this case, the compound of formula [Ia] may be a single enantiomer, a single diastereomer, or a mixture of enantiomers. It may exist as a mixture of diastereomers or diastereomers. The compounds of formula [Ia] may exist as atropisomers, in which case the compounds of formula [Ia] may exist as individual atropisomers or as a mixture of atropisomers. The compound of formula [Ia] may simultaneously contain multiple structural features that give rise to the above isomers. In addition, the compound of formula [Ia] may contain the above isomers in any ratio. In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned possible isomers unless otherwise noted.

[0117] The diastereomeric mixture can be separated by conventional methods such as chromatography or crystallization. Therefore, each diastereomer can be separated, and each diastereomer can also be produced by using a stereochemically pure starting material or by a synthetic method using a stereoselective reaction.

[0118] Separation of individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a substantially pure enantiomer, known as a chiral auxiliary, by standard methods such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by cleavage and removal of the added chiral auxiliary. A mixture of enantiomers can also be separated directly by chromatographic techniques using chiral stationary phases, which are well known in the art. Alternatively, one enantiomer can be obtained by stereoselective synthesis (asymmetric synthesis) using substantially pure optically active starting materials or prochiral intermediates using chiral auxiliaries and asymmetric catalysts. It can also be obtained by performing induction.

[0119] The absolute configuration can be determined by X-ray crystallography of crystalline products or intermediates. In this case, crystalline products or intermediates may be used which have been derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0120] The compound of formula [Ia] may be isotopic ( 2 H, 3 H, 14 C. 35 It may be labeled with (e.g., S).

[0121] The compound of formula [Ia] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of formula [Ia] or a pharmaceutically acceptable salt thereof, more preferably a compound of formula [Ia] or a pharmaceutically acceptable salt thereof purified to a purity of 80% or more.

[0122] The pharmaceutical composition of the present invention can be prepared by compounding a compound of formula [Ia] according to a method known in the technical field of pharmaceutical formulation. The compound or a pharmaceutically acceptable salt thereof is mixed with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared by appropriately mixing the compounds of formula [Ia] and the compounds of formula [Ia] in an appropriate amount. The content of the compound or a pharmaceutically acceptable salt thereof varies depending on the dosage form, dosage amount, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0123] The compound of formula [Ia] or a pharmaceutically acceptable salt thereof may be administered in the form of a tablet, a capsule, a granule, or the like. Examples of the preparation include oral preparations such as tablets, powders, lozenges, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0124] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed.

[0125] 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. Disintegrants include carmellose, carmellose calcium, and carmellose sodium. Examples of suitable cellulose acetate preparations include cellulose acetate, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose. Examples of "binders" include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of the "fluidizing agent" include light anhydrous silicic acid, magnesium stearate, and the like. "Lubricants" include magnesium stearate, calcium stearate, talc, and the like. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. "Solubilizing agents" include propylene glycol, D-mannitol, and benzoate. Examples of suitable solvents include ethanol, triethanolamine, sodium carbonate, and sodium citrate. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, glycerin monostearate and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. "Buffers" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like. "Soothing agents" include benzyl alcohol. Examples of "bases" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macrogol 200 to 600, etc.), and two or more of these. The above combinations are included. Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include sodium sulfite, ascorbic acid, and the like. "Coloring agents" include food dyes (such as Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), β-carotene, and the like. "Sweetening agents" include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and the like.

[0126] The pharmaceutical composition of the present invention can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans. The dosage varies depending on the subject, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when administered orally to an adult patient is usually in the range of about 0.01 mg to 1 g per day of the compound of formula [Ia], which is the active ingredient. These amounts can be administered in one or several divided doses. It is possible.

[0127] The compound of formula [Ia] or a pharmaceutically acceptable salt thereof has a PDHK inhibitory activity and is therefore useful in the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating PDHK activity. Examples of various diseases or conditions that can be expected to be improved by regulating PDHK activity include diabetes (type 1 diabetes, type 2 diabetes), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataracts), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension (pulmonary arterial hypertension), Alzheimer's disease, vascular dementia (large vessel disease type or small vessel disease type vascular dementia), glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.

[0128] Symptoms of Alzheimer's disease include cognitive decline, psychiatric symptoms, and behavioral disturbances.

[0129] The term "inhibiting PDHK" means that the activity of PDHK is eliminated or attenuated by inhibiting its function. For example, the function of PDHK is inhibited under the conditions of Test Example 1 described below. "Inhibiting PDHK" preferably means "inhibiting human PDHK." Furthermore, "inhibiting PDHK" preferably means "inhibiting PDHK2." The term "PDHK inhibitor" refers to a substance that binds to PDHK and inhibits the function of PDHK. A preferred "PDHK inhibitor" is a "human PDHK inhibitor." Furthermore, a preferred "PDHK inhibitor" is a "PDHK2 inhibitor."

[0130] As used herein, "treatment" includes alleviation of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence. As used herein, "prevention" means suppressing the onset of symptoms.

[0131] In this specification, the presentation of preferred aspects and options of the compounds, methods, uses and compositions of the present invention also includes the presentation of combinations of such preferred aspects and options, provided that these are combinable and not inconsistent.

[0132] The method for producing the compound of formula [Ia] or a pharmaceutically acceptable salt thereof is explained below. However, the method for producing the compound of formula [Ia] or a pharmaceutically acceptable salt thereof is as follows: It is not limited to the manufacturing method. The compounds obtained in each step can be isolated or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they may proceed to the next step without isolation or purification. When the reaction carried out in each step is an anhydrous reaction, it is preferable to carry out the reaction under an inert gas atmosphere such as argon or nitrogen.

[0133] [Manufacturing method 1] The compound of formula [I-a1] can be obtained by Production Method 1 shown in the following scheme.

[0134] [ka]

[0135] (In the formula, R 11 is C 1-4 is alkyl; The other symbols have the same meanings as in formula [Ia].

[0136] Process 1-1 Compound [A2] can be obtained by reducing the ester group of compound [A1]. For example, compound [A2] can be obtained by reacting compound [A1] with a reducing agent in a solvent at -40°C to room temperature. can be obtained. Reducing agents include lithium aluminum hydride, diisobutylaluminum hydride, and lithium borohydride. Solvents include tetrahydrofuran, diethyl ether and cyclopentyl methyl ether. Compound [A1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0137] Process 1-2 Compound [A3] can be obtained by oxidation of the hydroxy group of compound [A2]. For example, compound [A3] can be obtained by reacting compound [A2] with an oxidizing agent in a solvent at ice-cooling to room temperature. Oxidizing agents include manganese dioxide, Dess-Martin periodinane, and sulfur trioxide-pyridine complex. Solvents include tetrahydrofuran, dimethoxyethane, toluene, dimethylsulfoxide, chloroform, and dichloromethane.

[0138] Process 1-3 Compound [A5] can be obtained by the imination reaction of compound [A3] and compound [A4], followed by a cyclization reaction using p-toluenesulfonylmethyl isocyanide. For example, compound [A3] and compound [A4] are subjected to the imination reaction in a solvent at room temperature to 60°C. The product is then reacted with p-toluenesulfonylmethyl isocyanide in a solvent in the presence of a base, under ice-cooling to room temperature, to obtain compound [A5]. Solvents for the imination reaction include methanol and dimethylformamide. The base includes potassium carbonate. The solvent for the cyclization reaction may be dimethoxyethane. Compounds [A3] and [A4] may be commercially available products, or may be obtained by appropriately converting commercially available products by methods well known to those skilled in the art.

[0139] Process 1-4 Compound [A6] can be obtained by intramolecular Mitsunobu reaction of compound [A5]. For example, compound [A5] can be reacted with phosphine and azodicarboxylic acid diester in a solvent at room temperature to 100°C. By reacting this, compound [A6] can be obtained. Phosphines include trioctylphosphine, tributylphosphine and triphenylphosphine. Azodicarboxylic acid diesters include diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate. Solvents include toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

[0140] Process 1-5 Compound [A7] is obtained by reacting compound [A6] with N-methoxy-N-methylacetamide. For example, compound [A6] can be reacted with N-methyl-N ... By reacting with methylacetamide, compound [A7] can be obtained. . Bases include n-butyllithium and lithium diisopropylamide. Solvents include cyclopentyl methyl ether, tetrahydrofuran, and toluene.

[0141] Process 1-6 Compound [I-a1] can be obtained by reacting compound [A7] with (trifluoromethyl)trimethylsilane. For example, compound [I-a1] can be obtained by reacting compound [A7] with (trifluoromethyl)trimethylsilane in a solvent in the presence of an additive under ice-cooling to room temperature. Additives include tetra-n-butylammonium fluoride, lithium acetate, and potassium carbonate. and cesium fluoride. Solvents include tetrahydrofuran, dimethylformamide, and dimethylacetamide. R of compound [A7] A The steric hindrance of the aryl group causes the reaction to proceed diastereoselectively. The configuration of compound [I-a1] can be estimated from this reaction mechanism and confirmed by X-ray crystal structure analysis. Cut.

[0142] [Manufacturing method 2] The compound of formula [I-a2] can be obtained by Production Method 2 shown in the following scheme: .

[0143] [ka]

[0144] (In the formula, R 12 is C 1-4 is alkyl; Pr 2 is a protecting group for an amino group such as tert-butoxycarbonyl; Z 2 is R B C(O)O- or chloro; The other symbols have the same meanings as in formula [Ia].

[0145] Process 2-1 Compound [B3] can be obtained by the Mitsunobu reaction of compound [B1] and compound [B2]. For example, compound [B1] can be reacted with compound [B2], phosphine, and azodiamine in a solvent at room temperature to 100°C. By reacting with a carboxylic acid diester, compound [B3] can be obtained. Phosphines include trioctylphosphine, tributylphosphine and triphenylphosphine. Azodicarboxylic acid diesters include diisopropyl azodicarboxylate and azodic acid. Examples thereof include di-tert-butyl carboxylate. Solvents include toluene and tetrahydrofuran. Compound [B1] and compound [B2] may be commercially available products, or may be obtained by appropriately converting commercially available products by methods well known to those skilled in the art.

[0146] Process 2-2 Compound [B4] can be obtained by deprotecting the amino group of compound [B3]. 2 When is tert-butoxycarbonyl, compound [B4] can be obtained by treating compound [B3] with an acid in a solvent at ice-cooling to room temperature. Compound [B4] may be obtained as a salt with the acid used in this reaction. Acids include trifluoroacetic acid and hydrochloric acid. Solvents include tetrahydrofuran and ethyl acetate.

[0147] Process 2-3 Compound [B5] can be obtained by lactamization of compound [B4]. For example, compound [B5] can be obtained by reacting compound [B4] with a base in a solvent at ice-cooling to room temperature. The base includes sodium bicarbonate. Solvents include methanol and water.

[0148] Process 2-4 Compound [B6] can be obtained by reacting compound [B5] with a sulfur reagent. For example, compound [B6] can be obtained by reacting compound [B5] with a sulfur reagent in a solvent at room temperature to 110°C. ] can be obtained. The sulfur reagent includes Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide). Solvents include toluene and pyridine.

[0149] Process 2-5 Compound [B8] can be obtained by a cyclization reaction using compound [B6] and compound [B7]. For example, compound [B8] can be obtained by reacting compound [B6] with compound [B7] in a solvent at 100 to 200°C. A microwave device may be used if necessary. Solvents include n-butanol and N-methylpyrrolidone. Compound [B7] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0150] Steps 2-6 and 2-7 Compound [B8] can also be obtained by methylating compound [B6] to obtain compound [B9], and then reacting compound [B9] with compound [B7]. Methylation of compound [B6] can be carried out, for example, by reacting compound [B6] with a methylating agent in a solvent at ice-cooling to room temperature. Compound [B9] may also be obtained as a salt such as a hydrogen iodide salt. Methylating agents include methyl iodide. Solvents include dimethylformamide and acetone. The reaction of compound [B9] with compound [B7] can be carried out, for example, by the same procedure as in step 2-5. can. Compound [B7] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0151] Steps 2-8 and 2-9 Compound [B8] can also be obtained by reacting compound [B6] with hydrazine to obtain compound [B10], and then reacting compound [B10] with compound [B11]. The reaction of compound [B6] with hydrazine can be carried out, for example, by reacting compound [B6] with hydrazine in a solvent at room temperature to 80°C. Solvents include ethanol and isopropanol. The reaction of compound [B10] with compound [B11] is carried out by dissolving compound [B10] in a solvent in the presence of an acid and cooling it on ice. This can be carried out by reacting with compound [B11] from below at room temperature. The acid includes trifluoroacetic acid. The solvent may be chloroform. Compound [B11] may be a commercially available product, or a commercially available product may be appropriately modified by a method well known to those skilled in the art. It may be obtained by converting it.

[0152] Process 2-10 Compound [B12] can be obtained by the reaction of compound [B8] with N-methoxy-N-methylacetamide. For example, compound [B12] can be obtained by the same procedure as in step 1-5.

[0153] Process 2-11 The reaction of compound [B12] with (trifluoromethyl)trimethylsilane gives compound [I-a2] For example, compound [I-a2] can be obtained by the same procedure as in step 1-6. can be done.

[0154] [Manufacturing method 3] The compound of formula [I-a3] can be obtained by Production Method 3 shown in the following scheme: .

[0155] [ka]

[0156] (In the formula, R 13 is C 1-4 is alkyl; Z 3 is a leaving group such as bromo, iodo, trifluoromethanesulfonyloxy, etc.; Z 4 is a leaving group such as chloro, bromo, methanesulfonyloxy, etc.; The other symbols have the same meanings as in formula [Ia].

[0157] Process 3-1 Compound [C2] can be obtained by reducing the carbonyl group of compound [C1]. For example, compound [C2] can be obtained by reacting compound [C1] with a reducing agent in a solvent at ice-cooling to room temperature. The reducing agent includes sodium borohydride. Solvents include tetrahydrofuran and methanol. Compound [C1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0158] Process 3-2 The hydroxy group of compound [C2] can be converted into a leaving group to give compound [C3]. For example, Z 4 When is methanesulfonyloxy, compound [C2] can be reacted with methanesulfonic anhydride in a solvent in the presence of a base under ice-cooling to obtain compound [C3]. The base includes triethylamine. Solvents include tetrahydrofuran, chloroform and dichloromethane.

[0159] Process 3-3 Compound [C5] can be obtained by reacting compound [C3] with compound [C4]. For example, compound [C5] can be obtained by reacting compound [C3] with compound [C4] in a solvent in the presence of a base at room temperature to 80°C. The base includes cesium carbonate. The solvent may be dimethylformamide. Compound [C4] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0160] Process 3-4 Compound [C6] can be obtained by an intramolecular cyclization reaction of compound [C5]. For example, compound [C5] can be reacted in a solvent in the presence of a metal catalyst, a ligand, and a base at 120°C to obtain compound [C6]. This gives compound [C6]. The metal catalyst includes palladium(II) acetate. Ligands include di-1-adamantyl-n-butylphosphine and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl. The base includes potassium carbonate. The solvent may be dimethylacetamide.

[0161] Process 3-5 Compound [C7] can be obtained by hydrolysis of the ester group of compound [C6]. For example, compound [C7] can be obtained by treating compound [C6] with an alkali in a solvent at ice-cooling to 60°C. Alkalis include lithium hydroxide and sodium hydroxide. Solvents include methanol, ethanol and water.

[0162] Process 3-6 Compound [C8] can be obtained by the amidation reaction of compound [C7] with N,O-dimethylhydroxylamine. For example, compound [C8] can be obtained by reacting compound [C7] with N,O-dimethylhydroxylamine in a solvent in the presence of a base and a condensing agent at ice-cooling to room temperature. Bases include diisopropylethylamine and triethylamine. The condensing agent includes HATU. The solvent may be dimethylformamide.

[0163] Process 3-7 Compound [C9] can be obtained by the reaction of compound [C8] with methylmagnesium halide. For example, compound [C8] can be reacted with methylmagnesium halide in a solvent at 0°C to room temperature. By reacting this, compound [C9] can be obtained. Methyl magnesium halides include methyl magnesium bromide. Solvents include tetrahydrofuran and diethyl ether.

[0164] Process 3-8 Compound [C10] is obtained by the reaction of compound [C9] with (trifluoromethyl)trimethylsilane. For example, compound [C10] can be obtained by the same procedure as in step 1-6.

[0165] Process 3-9 Compound [C10] can be purified by chiral column chromatography to obtain compound [I-a3]. The configuration of compound [I-a3] can be determined, for example, by X-ray crystallography.

[0166] [Manufacturing method 4] The compound of formula [I-a4] can be obtained by Production Method 4 shown in the following scheme: .

[0167] [ka]

[0168] (In the formula, R 14 and R 15 are each independently C 1-4 is alkyl; Z 5 is C 1-4 is alkoxy or chloro; The other symbols have the same meanings as in formula [Ia].

[0169] Process 4-1 Compound [D2] can be obtained by reducing the carbonyl group of compound [D1]. For example, compound [D2] can be obtained by reacting compound [D1] with a reducing agent in a solvent at -78°C to room temperature. can be obtained. The reducing agent includes sodium borohydride. Solvents include methanol and tetrahydrofuran. Compound [D1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0170] Process 4-2 Compound [D4] can be obtained by the Mitsunobu reaction of compound [D2] and compound [D3]. For example, compound [D4] can be obtained by the same procedure as in step 2-1. Compound [D3] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0171] Process 4-3 Compound [D5] can be obtained by intramolecular Claisen condensation of compound [D4]. For example, Compound [D4] is treated with a base in a solvent at room temperature to 110°C to give compound [D5]. can be obtained. The base includes potassium tert-butoxide. Solvents include toluene and tetrahydrofuran.

[0172] Process 4-4 Compound [D6] can be obtained by decarboxylation of the ester group of compound [D5]. For example, compound [D6] can be obtained by treating compound [D5] with an acid or sodium chloride in a solvent at 100 to 160°C. The acid includes hydrochloric acid. Solvents include water and dimethyl sulfoxide.

[0173] Steps 4-5 and 4-6 Compound [D6] can be reacted with compound [D7] to obtain compound [D8], which can then be cyclized with hydroxylamine to obtain compound [D9]. Compound [D8] can be obtained, for example, by reacting compound [D6] with compound [D7] in a solvent in the presence of a base at 0 to 70°C. This can be obtained by: Bases include sodium hydride and lithium bis(trimethylsilyl)amide. The solvent may be tetrahydrofuran. Compound [D7] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art. Compound [D9] can be prepared, for example, by reacting compound [D8] with hydroxylamine in a solvent at 70 to 110°C. If necessary, an acid may be used. The acid may be concentrated sulfuric acid. Solvents include acetic acid and methanol.

[0174] Process 4-7 Compound [D10] can be obtained by reacting compound [D9] with N-methoxy-N-methylacetamide. For example, compound [D10] can be obtained by the same procedure as in step 1-5.

[0175] Process 4-8 Compound [D11] can be obtained by reacting compound [D10] with (trifluoromethyl)trimethylsilane. For example, compound [D11] can be obtained by the same procedure as in step 1-6.

[0176] Process 4-9 Compound [D11] can be purified by chiral column chromatography to obtain compound [I-a4]. The configuration of compound [I-a4] can be determined, for example, by X-ray crystallography.

[0177] [Manufacturing method 4-a] In step 4-6 of production method 4, a compound of the formula:

[0178] [ka]

[0179] Compound [D12] represented by the formula: can be obtained by carrying out the same reactions as in steps 4-7 to 4-9 using compound [D12].

[0180] [ka]

[0181] The compound [I-a16] can be obtained by the following stereochemistry: It can be determined by X-ray crystallography.

[0182] [Manufacturing method 5] The compound of formula [I-a5] can be obtained by Production Method 5 shown in the following scheme: .

[0183] [ka]

[0184] (In the formula, each symbol has the same meaning as in formula [Ia] above.)

[0185] Process 5-1 By reacting compound [D6] with tert-butoxybis(dimethylamino)methane, For example, compound [E1] can be obtained by reacting compound [D6] with tert-butoxybis(dimethylamino)methane in a solvent at room temperature to 110°C. The solvent may be dioxane.

[0186] Process 5-2 Compound [E3] can be obtained by a cyclization reaction between compound [E1] and compound [E2]. For example, compound [E3] can be obtained by reacting compound [E1] with compound [E2] in a solvent in the presence of a base at room temperature to 78°C. The base includes sodium ethoxide. The solvent may be ethanol. Compound [E2] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0187] Process 5-3 Compound [E4] can be obtained by the reaction of compound [E3] with N-methoxy-N-methylacetamide. For example, compound [E4] can be obtained by the same procedure as in step 1-5.

[0188] Process 5-4 Compound [E5] can be obtained by reacting compound [E4] with (trifluoromethyl)trimethylsilane. For example, compound [E5] can be obtained by the same procedure as in step 1-6. do.

[0189] Process 5-5 Compound [E5] can be purified by chiral column chromatography to obtain compound [I-a5]. The configuration of compound [I-a5] can be determined by, for example, X-ray crystal structure analysis. It can be determined.

[0190] [Manufacturing method 6] The compound of formula [I-a6] can be obtained by Production Method 6 shown in the following scheme: .

[0191] [ka]

[0192] (In the formula, R B1 and RB2 are each independently R in formula [Ia] B is synonymous with; Z 6 is C 1-4 is alkoxy or chloro; The other symbols have the same meanings as in formula [Ia].

[0193] Process 6-1 Compound [F2] can be obtained by the reaction of compound [D6] with compound [F1]. For example, compound [F2] can be obtained by the same procedure as in step 4-5. Compound [F1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0194] Process 6-2 Compound [F4] can be obtained by pyrazole cyclization between compound [F2] and compound [F3]. For example, compound [F2] is reacted with compound [F3] in a solvent at room temperature to 100°C. This gives the compound [F4]. Solvents include acetic acid and ethanol. Compound [F3] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0195] Process 6-3 Compound [F5] can be obtained by the reaction of compound [F4] with N-methoxy-N-methylacetamide. For example, compound [F5] can be obtained by the same procedure as in step 1-5.

[0196] Process 6-4 Compound [F6] can be obtained by reacting compound [F5] with (trifluoromethyl)trimethylsilane. For example, compound [F6] can be obtained by the same procedure as in step 1-6. do.

[0197] Process 6-5 Compound [F6] can be purified by chiral column chromatography to obtain compound [I-a6]. The configuration of compound [I-a6] can be determined by, for example, X-ray crystal structure analysis. It can be determined.

[0198] [Manufacturing method 7] The compound of formula [I-a7] can be obtained by Production Method 7 shown in the following scheme: .

[0199] [ka]

[0200] (Wherein, Pr 6 is a protecting group for pyrazole, such as p-methoxybenzyl; The other symbols have the same meanings as in formula [Ia].

[0201] Process 7-1 Compound [G1] can be obtained by pyrazole cyclization of compound [D8] with hydrazine. For example, compound [G1] can be obtained by the same procedure as in step 6-2.

[0202] Process 7-2 Compound [G2] can be obtained by introducing a protecting group into the pyrazole of compound [G1]. For example, Pr 6 When is a p-methoxybenzyl group, compound [G1] is reacted in a solvent in the presence of a base, Compound [G2] can be obtained by reacting with p-methoxybenzyl chloride under ice-cooling or at room temperature. 6 is attached to either of the two nitrogen atoms of pyrazole. They may also be combined. The solvent may be tetrahydrofuran. The base includes sodium hydride.

[0203] Process 7-3 Compound [G3] can be obtained by the reaction of compound [G2] with N-methoxy-N-methylacetamide. For example, compound [G3] can be obtained by the same procedure as in step 1-5.

[0204] Process 7-4 Compound [G4] can be obtained by reacting compound [G3] with (trifluoromethyl)trimethylsilane. For example, compound [G4] can be obtained by the same procedure as in step 1-6. do.

[0205] Process 7-5 Compound [G5] can be obtained by deprotecting the pyrazole of compound [G4]. 6 When is a p-methoxybenzyl group, compound [G4] is treated with an acid in a solvent at 60 to 80°C. By treating the compound [G5], compound [G5] can be obtained. The acid includes trifluoroacetic acid. The solvent may be dichloromethane.

[0206] Process 7-6 Compound [G5] can be purified by chiral column chromatography to obtain compound [I-a7]. The configuration of compound [I-a7] can be determined by, for example, X-ray crystal structure analysis. It can be determined.

[0207] [Manufacturing method 8] The compound of formula [I-a8] can be obtained by Production Method 8 shown in the following scheme: .

[0208] [ka]

[0209] (In the formula, R 18 is C 1-4 is alkyl; Pr 7 and Pr8 are protecting groups for amino groups such as tert-butoxycarbonyl; The other symbols have the same meanings as in formula [Ia].

[0210] Process 8-1 Compound [H3] can be obtained by reacting (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Compound H1) with Compound [H2]. For example, Compound [H3] can be obtained by reacting Compound H1 with Compound [H2] in a solvent in the presence of a condensing agent at ice-cooling to room temperature. Condensing agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate. Solvents include acetonitrile and dimethylformamide. The compound [H2] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0211] Process 8-2 By deprotecting compound [H3], (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanehydrazine (compound H4) can be obtained. For example, Pr 7 When is tert-butoxycarbonyl, compound [H3] can be treated with an acid in a solvent under ice-cooling to room temperature to obtain compound H4. Compound H4 may be obtained as a salt with the acid used in this reaction. Acids include trifluoroacetic acid and hydrochloric acid. Solvents include tetrahydrofuran, ethyl acetate and chloroform.

[0212] Process 8-3 Compound [H7] can be obtained by the Mitsunobu reaction of compound [H5] and compound [H6]. For example, compound [H7] can be obtained by the same procedure as in step 2-1. Compound [H5] and compound [H6] may be commercially available products, or may be obtained by appropriately converting commercially available products by methods well known to those skilled in the art.

[0213] Process 8-4 Compound [H8] can be obtained by deprotecting the amino group of compound [H7] and lactamizing it. The deprotection of the amino group can be carried out, for example, by the same procedure as in step 2-2. The tamylation can be carried out, for example, by the same procedure as in step 2-3.

[0214] Process 8-5 Compound [H9] can be obtained by reacting compound [H8] with a sulfur reagent. For example, compound [H9] can be obtained by the same procedure as in step 2-4.

[0215] Process 8-6 Compound [H10] can be obtained by methylation of compound [H9]. For example, compound [H10] can be obtained by the same procedure as in step 2-6.

[0216] Process 8-7 Compound [H10] can be cyclized with compound H4 to give compound [I-a8]. For example, compound [H10] can be reacted with compound H4 in a solvent in the presence of an acid at 60°C to 120°C to obtain compound [I-a8]. The acid includes acetic acid. Solvents include isopropanol and water.

[0217] [Manufacturing method 9] In the preparation methods 1 to 8, the desired R B For example, compounds [I-a10] to [I-a15] can be obtained by converting compound [I-a9] obtained by any of Production Methods 1 to 8 using Production Method 9 shown in the following scheme.

[0218] [ka]

[0219] (Wherein, Pr 9 is a protecting group for a hydroxy group, such as p-methoxybenzyl; R 19 and R 20 are each independently hydrogen or C 1-4 is alkyl; The other symbols have the same meanings as in formula [Ia].

[0220] Process 9-1 Compound [I-a10] can be obtained by deprotecting the hydroxy group of compound [I-a9]. For example, compound [I-a9] can be treated with an acid in a solvent at room temperature to give compound [I-a10]. The acid includes trifluoroacetic acid. The solvent may be dichloromethane.

[0221] Process 9-2 Compound [I-a11] can be obtained by oxidizing the hydroxy group of compound [I-a10]. For example, compound [I-a11] can be obtained by the same procedure as in step 1-2.

[0222] Process 9-3 Compound [I-a12] can be obtained by oxidizing the hydroxy group of compound [I-a10]. For example, compound [I-a12] can be obtained by reacting compound [I-a10] with an oxidizing agent in a solvent at room temperature. The oxidizing agent includes potassium permanganate. The solvent may be acetone.

[0223] Process 9-4 Compound [I-a12] and HNR 19 R 20For example, compound [I-a12] can be amidated with HNR in a solvent in the presence of a base and a condensing agent under ice-cooling to room temperature. 19 R 20 The compound [I-a13] can be obtained by reacting the compound [I-a14] with the compound [I-a15]. Bases include diisopropylethylamine and triethylamine. The condensing agent includes HATU. The solvent may be dimethylformamide. In this process, HNR 19 R 20 R 19 and R 20 When both are hydrogen, compound [I-a14] can be obtained.

[0224] Process 9-5 Compound [I-a15] can be obtained by cyanation of compound [I-a14]. For example, compound [I-a14] can be reacted with an acid anhydride in a solvent in the presence of a base under ice-cooling to room temperature to obtain compound [I-a15]. By this, the compound [I-a15] can be obtained. The base includes pyridine. Acid anhydrides include trifluoroacetic anhydride. The solvent may be 1,4-dioxane. [Manufacturing method 10] The compound of formula [I-a10] can be obtained by Production Method 10 shown in the following scheme. do.

[0225] [ka]

[0226] (In the formula, R 19 is C 1-4 is alkyl; R 20 are hydrogen, halogen, C 1-4 is alkyl or nitro; Pr 9 is a protecting group for pyrazoles, such as 2-tetrahydropyranyl; X 5 is a leaving group such as chloro, bromo, methanesulfonyloxy, etc.; The other symbols have the same meanings as in formula [Ia].

[0227] Process 10-1 Compound [J2] can be obtained by reacting compound [J1] with hydrazine. For example, compound [J2] can be obtained by reacting compound [J1] with hydrazine in a solvent at room temperature. If necessary, the reaction can be carried out in the presence of an acid. Solvents include acetonitrile, toluene and ethanol. The acid includes acetic acid. Compound [J1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0228] Process 10-2 Compound [J3] can be obtained by introducing a protecting group into the pyrazole of compound [J2]. For example, Pr 9 When is a 2-tetrahydropyranyl group, compound [J2] is reacted in a solvent in the presence of an acid. The compound [J3] can be obtained by reacting the compound [J3] with 3,4-dihydro-2H-pyran at room temperature. Solvents include acetonitrile and N,N-dimethylformamide. Acids include pyridinium p-toluenesulfonate and p-toluenesulfonic acid.

[0229] Process 10-3 Compound [J5] can be obtained by reacting compound [J3] with compound [J4]. For example, compound [J5] can be obtained by reacting compound [J3] with compound [J4] in a solvent in the presence of a base at room temperature. Solvents include N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, toluene, isopropyl acetate, tetrahydrofuran, and dimethyl sulfoxide. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium tert-butoxide, potassium acetate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and N,N-diisopropylethylamine. Compound [J4] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0230] Process 10-4 After hydrolysis of the ester of compound [J5], compound [J6] can be obtained by amidation with N,O-dimethylhydroxylamine. For example, compound [J5] can be reacted with an alkali in a solvent to hydrolyze the ester, and then reacted with N,O-dimethylhydroxylamine in the presence of a condensing agent at room temperature to obtain compound [J6]. The alkali includes sodium hydroxide. The condensing agent may be a combination of WSC·HCl and HOBt. The solvent may be 1,2-dimethoxyethane.

[0231] Process 10-5 Compound [J7] can be obtained by reduction of compound [J6]. For example, compound [J7] can be obtained by reacting compound [J6] with a reducing agent in a solvent under ice-cooling. The reducing agent includes sodium bis(2-methoxyethoxy)aluminum hydride. Solvents include toluene and 1,2-dimethoxyethane.

[0232] Process 10-6 Compound [J8] can be obtained by deprotecting the pyrazole protecting group of compound [J7]. For example, Pr 9When is a 2-tetrahydropyranyl group, compound [J7] is reacted with an acid in a solvent at room temperature. By treating the compound [J8], the compound [J8] can be obtained. Acids include hydrochloric acid, methanesulfonic acid, sulfuric acid, and phosphoric acid. The solvent may be 1,2-dimethoxyethane.

[0233] Process 10-7 Compound [J9] can be obtained by the reaction of compound [J8] with compound [A4]. For example, compound [J9] can be obtained by the same procedure as in step 1-3.

[0234] Process 10-8 Compound [J10] can be obtained by intramolecular Mitsunobu reaction of compound [J9]. For example, Compound [J10] can be obtained by the same procedure as in step 1-4. Compound [J10] can be obtained by the same procedure as in step 1-4. It may also be obtained as a salt with an acid such as

[0235] Process 10-9 Compound [J10] is reacted with N-methoxy-N-methylacetamide to give compound [J11]. For example, compound [J11] can be obtained by the same procedure as in step 1-5.

[0236] Process 10-10 Compound [J12] can be obtained by deprotecting compound [J11]. For example, compound [J12] can be obtained by treating compound [J11] with an acid at room temperature to 50°C. Compound [J12] may be obtained as a salt with the acid used. The acid may be concentrated hydrochloric acid.

[0237] Process 10-11 The reaction of compound [J12] with diethyl (bromodifluoromethyl)phosphonate yields the compound For example, compound [J12] can be reacted with diethyl (bromodifluoromethyl)phosphonate in a solvent in the presence of a base at room temperature to obtain compound [J13]. Solvents include acetonitrile, 1,2-dimethoxyethane and tetrahydrofuran. Bases include potassium hydroxide, lithium hydroxide and tetrabutylammonium hydroxide.

[0238] Process 10-12 Compound [I-a10] can be obtained by reacting compound [J13] with (trifluoromethyl)trimethylsilane. For example, compound [I-a10] can be obtained by the same procedure as in step 1-6. R of compound [J13] A The group acts as a steric hindrance, and the reaction proceeds diastereoselectively. The configuration of compound [I-a10] can be deduced from this reaction mechanism and confirmed by X-ray crystal structure analysis. [Example]

[0239] Next, the compound of formula [Ia] of the present invention or a pharmaceutically acceptable salt thereof can be produced by the following method. However, the compound of formula [Ia] or its pharmaceutically acceptable salts may be used in combination with other compounds. The method for producing the acceptable salt is not limited to these production examples. Unless otherwise specified, % indicates % by weight. Ratios shown in mixed solvents indicate volume ratios unless otherwise specified. In the examples, the abbreviations are as follows. DMSO: dimethyl sulfoxide M: mol / L N: Regulation HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate WSC·HCl:1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt·H2O:1-Hydroxybenzotriazole monohydrate 1 The following abbreviations are used to represent the H-NMR measurement results. s: singlet, d: doublet, dd: double doublet, dt: double triplet le triplet), t: triplet, q: quartet artet), dq: double quartet, m: multi multiplet, brs: broad singlet glet), brm: broad multiplet, J : Coupling constant, Hz: Hertz z) 1 H-NMR spectra were measured in CDCl3 or DMSO-D6 using tetramethylsilane as an internal standard, and all δ values ​​are expressed in ppm.

[0240] Manufacturing Example 1 Synthesis of (R)-2-((S)-9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropan-2-ol (Compound of Example 23)

[0241] 1st process Ethyl 3-(benzyloxy)-1H-pyrazole-5-carboxylate

[0242] [ka]

[0243] Ethyl 3-hydroxy-1H-pyrazole-5-carboxylate (10 g) was mixed with tetrahydrofuran (100 ml). Benzyl alcohol (7.99 ml) and triphenylphosphine (18.48 g) were added to this mixture. Diisopropyl azodicarboxylate (13.7 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (70 ml) and hexane (140 ml) were added, followed by stirring at room temperature. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 92:8 to hexane:ethyl acetate = 47:53) to give the title compound (20 g) as a crude product. This crude product was carried on to the next step without further purification.

[0244] 2nd process (3-(benzyloxy)-1H-pyrazol-5-yl)methanol

[0245] [ka]

[0246] The crude product (19 g) of ethyl 3-(benzyloxy)-1H-pyrazole-5-carboxylate obtained in the previous step was dissolved in cyclopentyl methyl ether (70 ml). Under ice-cooling, this solution was added dropwise to a solution of lithium borohydride (4.17 g) in cyclopentyl methyl ether (150 ml). The reaction mixture was stirred at 0°C for 5 minutes. Under ice-cooling, a solution of methanol (8 ml) in cyclopentyl methyl ether (50 ml), methanol (8 ml), and methanol (8 ml) were added dropwise in that order. The mixture was stirred at 0°C for 10 minutes. A saturated aqueous solution of ammonium chloride and a 1N aqueous solution of hydrochloric acid were added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 16:84 to ethyl acetate, then ethyl acetate:methanol = 82:18) to give the title compound (8.2 g). 1 H-NMR (400 MHz, CDCl3) 4.66 (s, 2H), 5.19 (s, 2H), 5.64 (s, 1H), 7.26 - 7.47 (m, 5H)

[0247] 3rd process 3-(benzyloxy)-1H-pyrazole-5-carbaldehyde

[0248] [ka]

[0249] The (3-(benzyloxy)-1H-pyrazol-5-yl)methanol (8.2 g) obtained in the previous step was dissolved in 1,2-dimethoxyethane (164 ml). Manganese dioxide (41 g) was added at room temperature, and the mixture was stirred at 80°C for 1.5 hours. After cooling, the mixture was filtered through Celite. The solution was concentrated under reduced pressure to give the title compound as a crude product (5.4 g), which was used in the next step without further purification.

[0250] 4th step (S)-2-(5-(3-(benzyloxy)-1H-pyrazol-5-yl)-1H-imidazol-1-yl)propan-1-ol

[0251] [ka]

[0252] 3-(benzyloxy)-1H-pyrazole-5-carbaldehyde obtained in the previous step The crude product (5.4 g) of the above was mixed with methanol (54 ml). (S)-2-aminopropan-1-ol (2 g) was added at room temperature, and the mixture was stirred overnight at room temperature. Under ice-cooling, 1,2-dimethoxyethane (164 ml), p-toluenesulfonylmethyl isocyanide (7.82 g), and potassium carbonate (11.07 g) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 25:75 to ethyl acetate, then ethyl acetate:methanol = 60:40) to give the crude product (4.1 g) of the title compound.

[0253] 5th step (S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine

[0254] [ka]

[0255] The crude (S)-2-(5-(3-(benzyloxy)-1H-pyrazol-5-yl)-1H-imidazol-1-yl)propan-1-ol product (4.1 g) obtained in the previous step and triphenylphosphine (4.69 g) were mixed in tetrahydrofuran (123 ml). Di-tert-butyl azodicarboxylate (4.11 g) was added under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:hexane = 25:75 to ethyl acetate, then ethyl acetate:methanol = 60:40) to obtain the title compound (2.98 g). 1H-NMR (400 MHz, CDCl3) 1.64 (d, J=6.70Hz, 3H), 3.97 (dd, J=12.95, 8.09Hz, 1H), 4.31 (dd, J=12.95, 4.39Hz, 1H), 4.54 - 4.65 (m, 1H), 5.21 (s, 2H), 5.86 (s, 1H), 7.26 (s, 1H), 7.29 - 7.49 (m, 5H), 7.59 (s, 1H)

[0256] 6th step (S)-1-(9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0257] [ka]

[0258] (S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine (2.98 g) obtained in the previous step was mixed with tetrahydrofuran (29.8 ml). This mixture was cooled to -78°C, and a 2M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (13.29 ml) was added dropwise. The mixture was stirred at -78°C for 30 minutes. N-methoxy-N-methylacetamide (5.25 ml) was added to the mixture, and the mixture was stirred at -78°C for 1 hour. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and the precipitated solid was collected by filtration. The filtrate was separated and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate / hexane = 1 / 1 (10 ml) was added to the resulting residue, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration. This was combined with the solid collected earlier, mixed with ethyl acetate, and concentrated to obtain the title compound (2 g). 1H-NMR (400 MHz, CDCl3) 1.44 (d, J=6.58Hz, 3H), 2.69 (s, 3H), 4.19 (dd, J=13.45, 1.20Hz, 1H), 4.29 (dd, J=13.45, 4.63Hz, 1H), 5.24 (s, 2H), 5.75 - 5.84 (m, 1H), 5.98 (s, 1H), 7.32 - 7.50 (m, 6H)

[0259] 7th step (R)-2-((S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropan-2-ol

[0260] [ka]

[0261] (S)-1-(9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one (2 g) obtained in the previous step was mixed with tetrahydrofuran (29.8 ml). Cesium fluoride (0.195 g) was added to this mixture under ice cooling, and then (trifluoromethyl)trimethylsilyl To the resulting mixture was added dropwise ethanol (1.088 ml). The reaction mixture was stirred at room temperature for 20 minutes. Methanol (24.84 ml) and potassium carbonate (1.065 g) were added under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure, followed by addition of water and extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 12:88 to 4:96) to give the title compound (2.2 g). 1H-NMR (400 MHz, DMSO-D6) 1.28 (d, J=6.70Hz, 3H), 1.80 (s, 3H), 4.12 - 4.24 (m, 2H), 5.15 (s, 2H), 5.27 - 5.36 (m, 1H), 6.04 (s, 1H), 7.23 (s, 1H), 7.28 (s, 1H), 7.29 - 7.46 (m, 5H)

[0262] 8th process (S)-5-Methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-9-ol

[0263] [ka]

[0264] (R)-2-((S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropan-2-ol (2.2 g) obtained in the previous step and 10% palladium on carbon (0.44 g) were mixed in ethanol (44 g). The mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. The crude product was purified by column chromatography (ethyl acetate:hexane = 16:84 to ethyl acetate, then ethyl acetate:methanol = 80:20). Ethyl acetate (6 ml) and hexane (6 ml) were added successively to the crude product, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain the title compound (1.82 g). The configuration of the title compound was confirmed by X-ray crystal structure analysis. It was decided. 1H-NMR (400 MHz, DMSO-D6) 1.28 (d, J=6.58Hz, 3H), 1.81 (s, 3H), 4.07 - 4.11 (m, 2H), 5.23 - 5.36 (m, 1H), 5.75 (s, 1H), 7.20 (s, 1H), 7.26 (brs, 1H), 9.89 (brs, 1H)

[0265] 9th step (R)-2-((S)-9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropan-2-ol

[0266] [ka]

[0267] (S)-5-Methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-9-ol (1 g) obtained in the previous step, potassium carbonate (0.914 g), and sodium chlorodifluoroacetate (1.009 g) were mixed in dimethylformamide (6 ml) and stirred at 100°C for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 88:12 to ethyl acetate). Ethyl acetate / hexane = 1 / 2 (1.5 ml) was added to the crude product, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (0.315 g). 1H-NMR (400 MHz, DMSO-D6) 1.27 (d, J=6.70Hz, 3H), 1.81 (s, 3H), 4.20 - 4.30 (m, 2H), 5.31 - 5.40 (m, 1H), 6.31 (s, 1H), 7.27 (t, J=73.29Hz, 1H), 7.31 (s, 1H), 7.32 (s, 1H)

[0268] Manufacturing Example 2 Synthesis of (R)-1,1,1-trifluoro-2-((S)-9-(2-hydroxy-2-methylpropoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)propan-2-ol (Compound of Example 52)

[0269] 1st process Methyl 2-(((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-9-yl)oxy)acetate

[0270] [ka]

[0271] (S)-5-Methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-9-ol (0.5 g) and potassium carbonate (0.288 g) were mixed in dimethylformamide (5 ml). Methyl bromoacetate (0.154 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified sequentially by silica gel chromatography (hexane:ethyl acetate = 88:12 to ethyl acetate) and amino silica gel chromatography (ethyl acetate:hexane = 12:88 to ethyl acetate, followed by ethyl acetate:methanol = 90:10) to give the title compound (0.411 g). 1 H-NMR (400 MHz, DMSO-D6) 1.26 (d, J=6.47Hz, 3H), 1.80 (s, 3H), 3.67 (s, 3H), 4.08 - 4.21 (m, 2H), 4.78 (s, 2H), 5.24 - 5.36 (m, 1H), 6.03 (s, 1H), 7.25 (s, 1H), 7.27 (s, 1H)

[0272] 2nd process (R)-1,1,1-trifluoro-2-((S)-9-(2-hydroxy-2-methylpropoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)propan-2-ol

[0273] [ka]

[0274] Methyl 2-(((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-9-yl)oxy)acetate (0.411 g) obtained in the previous step was mixed with tetrahydrofuran (2 ml). Under ice-cooling, 1.08 M methylmagnesium bromide / tetrahydrofuran solution (4 ml) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 88:12 to ethyl acetate) and amino silica gel chromatography (ethyl acetate:hexane = 24:76 to ethyl acetate). Ethyl acetate (0.7 ml) and hexane (1.4 ml) were added successively to the obtained crude product, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (0.251 g). 1 H-NMR (400 MHz, DMSO-D6) 1.16 (s, 6H), 1.27 (d, J=6.47Hz, 3H), 1.80 (s, 3H), 3.82 (s, 2H), 4.09 - 4.19 (m, 2H), 4.57 (s, 1H), 5.25 - 5.36 (m, 1H), 5.98 (s, 1H), 7.22 (s, 1H), 7.26 (s, 1H)

[0275] Manufacturing Example 3 Synthesis of (R)-1,1,1-trifluoro-2-((S)-6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazin-8-yl)propan-2-ol (Compound of Example 2)

[0276] 1st process Methyl (S)-1-(1-((tert-butoxycarbonyl)amino)propane-2 -yl)-1H-imidazole-5-carboxylate

[0277] [ka]

[0278] Methyl 1H-imidazole-5-carboxylate (250g), tert-butyl (R)-(2-Hydroxypropyl)carbamate (521 g) and trioctylphosphine (1505 ml) were mixed in toluene (1750 ml). The reaction solution was heated to 80°C, and then 40% diisopropyl azodicarboxylate / toluene solution (1599 ml) was added dropwise. The reaction solution was stirred at 80°C for 1 hour. The mixture was extracted twice with a 1N aqueous potassium hydrogen sulfate solution. The aqueous layer was washed with ethyl acetate:hexane (1:1). Under ice cooling, 1.4 M aqueous sodium carbonate solution (1 L) was added portionwise to the aqueous layer, and the mixture was extracted twice with ethyl acetate. Sodium sulfate and silica gel were added, and the mixture was stirred at room temperature for 30 minutes. The sodium sulfate and silica gel were removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (250 ml) was added to the resulting residue, and the mixture was stirred at 80°C for 10 minutes. Hexane (1750 ml) was slowly added, and the mixture was stirred while being allowed to cool to room temperature. The precipitated solid was collected by filtration to give the title compound (432.4 g). 1 H-NMR (400 MHz, CDCl3) 1.39 (s, 9H), 1.54 (d, J=6.88Hz, 3H), 3.48 (t, J=6.28Hz, 2H), 3.85 (s, 3H), 4.63 (brs, 1H), 5.17 - 5.32 (m, 1H), 7.72 - 7.77 (m, 2H)

[0279] 2nd process Methyl (S)-1-(1-aminopropan-2-yl)-1H-imidazole-5-carboxylate dihydrochloride

[0280] [ka]

[0281] Methyl (S)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-imidazole-5-carboxylate (432.4 g) obtained in the previous step was mixed with ethyl acetate (865 ml). Under ice-cooling, 4N hydrochloric acid / ethyl acetate (1526 ml) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. Under ice-cooling, 4N hydrochloric acid / ethyl acetate (382 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Under ice-cooling, 4N hydrochloric acid / ethyl acetate (38.2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Precipitation The solid was collected by filtration to give the title compound (388.89 g). 1 H-NMR (400 MHz, DMSO-D6) 1.51 (d, J=6.94Hz, 3H), 3.20 - 3.36 (m, 1H), 3.42 - 3.57 (m, 1H), 3.85 (d, J=4.62Hz, 3H), 5.29 - 5.43 (m, 1H), 8.09 (s, 1H), 8.21 (brs, 3H), 8.95 (s, 1H)

[0282] 3rd process (S)-5-Methyl-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one

[0283] [ka]

[0284] Methyl (S)-1-(1-aminopropan-2-yl)-1H-imidazole-5-carboxylate dihydrochloride (388.89 g) obtained in the previous step was mixed with methanol (1944 ml) and water (117 ml). Sodium carbonate (644 g) was added to this mixture, and the mixture was stirred at 90°C for 2 hours. Tetrahydrofuran (1944 ml) was added at room temperature, and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. Toluene was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (278.65 g). 1H-NMR (400 MHz, DMSO-D6) 1.46 (d, J=6.28Hz, 3H), 3.19 - 3.28 (m, 1H), 3.46 - 3.58 (m, 1H), 4.37 - 4.48 (m, 1H), 7.45 (s, 1H), 7.83 - 7.94 (m, 2H)

[0285] 4th step (S)-5-Methyl-6,7-dihydroimidazo[1,5-a]pyrazine-8(5H)-thione

[0286] [ka]

[0287] (S)-5-Methyl-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one (62.2 g) was mixed with toluene (600 ml) and pyridine (200 ml). Lawesson's reagent (50 g) was added to this mixture, and the mixture was stirred at 110 °C overnight. After cooling, the mixture was decanted and the resulting gum was washed with toluene. Methanol (187 ml) was added to the resulting gum, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (39.9 g). The title compound (20.7 g) was further obtained by the same method. 1 H-NMR (400 MHz, DMSO-D6) 1.43 (d, J=6.47Hz, 3H), 3.23 - 3.31 (m, 1H), 3.58 (dt, J=13.56, 4.10Hz, 1H), 4.39 - 4.52 (m, 1H), 7.61 (s, 1H), 7.96 (s, 1H), 10.03 (brs, 1H)

[0288] 5th step (S)-6-Methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazine

[0289] [ka]

[0290] (S)-5-methyl-6,7-dihydroimidazo[1,5-a]pyrazine-8(5H)-thione (3 g) obtained in the previous step was mixed with isopropyl alcohol (30 ml). Hydrazine hydrate (2.62 ml) was added at room temperature, and the mixture was stirred at 80°C for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure and azeotroped once with ethanol and twice with toluene. The resulting residue was added to Trifluoroacetic acid (23.68 ml) and trifluoroacetic anhydride (12.65 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotroped twice with toluene. The resulting residue was purified by aminosilica gel column chromatography (ethyl acetate:hexane = 75:25 to ethyl acetate, then ethyl acetate:methanol = 80:20) to give the title compound (3.96 g). 1 H-NMR (400 MHz, DMSO-D6) 1.57 (d, J=6.58Hz, 3H), 4.26 (dd, J=13.15, 8.67Hz, 1H), 4.64 (dd, J=13.15, 4.48Hz, 1H), 4.74 - 4.85 (m, 1H), 7.72 (s, 1H), 8.13 (s, 1H)

[0291] 6th step (S)-1-(6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazin-8-yl)ethan-1-one

[0292] [ka]

[0293] (S)-6-Methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazine (3.96 g) obtained in the previous step was mixed with tetrahydrofuran (80 ml). This mixture was cooled to -78 °C, and 2 M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (24.67 ml) was added dropwise. The mixture was stirred at -78 °C for 30 minutes. N-Methoxy-N-methylacetamide (5.25 ml) was added to the mixture, and the mixture was stirred at -78 °C for 35 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then warmed to room temperature and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 12:88 to ethyl acetate). Toluene (12 ml) was added to the obtained crude product, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain the title compound (2.04 g). 1 H-NMR (400 MHz, DMSO-D6) 1.27 (d, J=6.70Hz, 3H), 2.63 (s, 3H), 4.49 - 4.61 (m, 2H), 5.66 - 5.78 (m, 1H), 7.94 (s, 1H)

[0294] 7th step (R)-1,1,1-trifluoro-2-((S)-6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazin-8-yl)propan-2-ol

[0295] [ka]

[0296] (S)-1-(6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazin-8-yl)ethan-1-one (2.04 g) obtained in the previous step was mixed with tetrahydrofuran (40.8 ml). The resulting mixture was combined. Under ice-cooling, cesium fluoride (0.217 g) and (trifluoromethyl)trimethylsilane (2.111 ml) were added, and the mixture was stirred at 0°C for 25 minutes. Under ice-cooling, methanol (24.48 ml) and potassium carbonate (1.186 g) were added, and the mixture was stirred at room temperature for 1 hour. Silica gel (40 ml) was added to the reaction mixture, which was then filtered through a pad of silica gel (20 ml). The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 16:84 to ethyl acetate). Toluene (20 ml) and ethyl acetate (4 ml) were added to the resulting crude product, and the mixture was stirred at 80°C. The precipitated solid was collected by filtration. Ethyl acetate (6 ml) and hexane (4 ml) were added to the resulting solid, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (1.171 g). The stereochemistry of the title compound was determined by X-ray crystallography. 1 H-NMR (400 MHz, DMSO-D6) 1.28 (d, J=6.47Hz, 3H), 1.86 (s, 3H), 4.48 (dd, J=13.64, 3.93Hz, 1H), 4.55 (d, J=13.64Hz, 1H), 5.45 - 5.51 (m, 1H), 7.49 (s, 1H), 7.75 (s, 1H)

[0297] Production Example 4 Synthesis of 1,1,1-trifluoro-2-(5-methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)propan-2-ol (Compound of Example 1)

[0298] 1st process 1-(2-bromophenyl)propan-2-ol

[0299] [ka]

[0300] 1-(2-Bromophenyl)propan-2-one (2 g) was mixed with methanol (10 ml). Sodium borohydride (0.533 g) was added to this mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 95:5 to 60:40) to give the title compound (1.937 g). 1 H-NMR (400 MHz, CDCl3) 1.27 (d, J=6.01Hz, 3H), 1.46 (d, J=3.93Hz, 1H), 2.83 (dd, J=13.52, 7.98Hz, 1H), 2.96 (dd, J=13.52, 4.74Hz, 1H), 4.07 - 4.19 (m, 1H), 7.04 - 7.13 (m, 1H), 7.21 - 7.28 (m, 2H), 7.54 (d, J=8.09Hz, 1H)

[0301] 2nd process 1-(2-Bromophenyl)propan-2-yl methanesulfonate

[0302] [ka]

[0303] Methanesulfonic anhydride (2.11 g) was mixed with dichloromethane (10 ml). To this mixture, 1-(2-bromophenyl)propan-2-ol (1.737 g) obtained in the previous step and triethylamine (3.38 ml) were added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (hexane:ethyl acetate=95:5 to 60:40) to give the title compound (2.142 g). 1 H-NMR (400 MHz, CDCl3) 1.51 (d, J=6.24Hz, 3H), 2.50 (s, 3H), 3.00 - 3.14 (m, 2H), 4.94 - 5.06 (m, 1H), 7.08 - 7.17 (m, 1H), 7.23 - 7.30 (m, 2H), 7.56 (d, J=7.86Hz, 1H)

[0304] 3rd process Ethyl 1-(1-(2-bromophenyl)propan-2-yl)-1H-imidazole-2-carboxylate

[0305] [ka]

[0306] Ethyl 1H-imidazole-2-carboxylate (3.54 g) and cesium carbonate (3.29 g) were mixed in dimethylformamide (11.85 ml). The reaction solution was heated to 80°C, and 1-(2-bromophenyl)propan-2-yl methanesulfonate (1.54 g) obtained in the previous step was added and stirred overnight. Water was added to the reaction mixture, followed by extraction twice with ethyl acetate. The organic layer was washed three times with water and once with saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 88:12 to ethyl acetate) to give the title compound (0.383 g). 1H-NMR (400 MHz, CDCl3) 1.33 (t, J=7.17Hz, 3H), 1.54 (d, J=6.94Hz, 3H), 3.04 (dd, J=13.64, 7.86Hz, 1H), 3.27 (dd, J=13.64, 6.24Hz, 1H), 4.27 (q, J=7.17Hz, 2H), 5.74 - 5.86 (m, 1H), 6.87 (dd, J=7.51, 1.73Hz, 1H), 7.04 (td, J=7.63, 1.70Hz, 1H), 7.12 (td, J=7.46, 1.31Hz, 1H), 7.17 (s, 1H), 7.50 (dd, J=7.98, 1.27Hz, 1H)

[0307] 4th step Ethyl 5-methyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxylate

[0308] [ka]

[0309] Ethyl 1-(1-(2-bromophenyl)propan-2-yl)-1H-imidazole-2-carboxylate (383 mg) obtained in the previous step, palladium(II) acetate (74.3 mg), potassium carbonate (305 mg), and di-1-adamantyl-n-butylphosphine (178 mg) were mixed with dimethylacetamide (3.7 ml). Under an argon atmosphere, this mixture was stirred at 120°C for 7 hours. Water was added under ice-cooling, and the precipitated solid was collected by filtration. The filtrate was extracted twice with ethyl acetate. The organic layer was washed twice with water and once with a saturated aqueous sodium chloride solution, and then dried over sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. The resulting residue and the collected solid were each purified by silica gel chromatography (hexane:ethyl acetate = 88:12 to ethyl acetate) to give the title compound. (145 mg) was obtained. 1H-NMR (400 MHz, CDCl3) 1.26 (d, J=6.70Hz, 3H), 1.44 (t, J=7.05Hz, 3H), 2.84 (d, J=15.95Hz, 1H), 3.36 (dd, J=15.95, 6.24Hz, 1H), 4.35 - 4.50 (m, 2H), 5.59 - 5.69 (m, 1H), 7.23 - 7.33 (m, 3H), 7.49 (s, 1H), 7.59 (d, J=6.94Hz, 1H)

[0310] 5th step N-Methoxy-N,5-dimethyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide

[0311] [ka]

[0312] Ethyl 5-methyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxylate (82.4 mg) obtained in the previous step was mixed with ethanol (1.6 ml). Under ice-cooling, 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and azeotroped with toluene. The resulting residue was mixed with dimethylformamide. Under ice-cooling, N,O-dimethylhydroxylamine hydrochloride (94 mg), HATU (183 mg), and diisopropylethylamine (0.253 ml) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 88:12 to ethyl acetate) to give the title compound (80 mg). 1H-NMR (400 MHz, CDCl3) 1.29 (d, J=6.58Hz, 3H), 2.82 (dd, J=15.84, 1.49Hz, 1H), 3.35 (dd, J=15.84, 5.98Hz, 1H), 3.61 (s, 3H), 3.89 (s, 3H), 5.38 - 5.50 (m, 1H), 7.11 - 7.34 (m, 3H), 7.43 (s, 1H), 7.59 (d, J=7.47Hz, 1H)

[0313] 6th step 1-(5-methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)ethan-1-one

[0314] [ka]

[0315] Tetrahydrofuran (2 ml) was mixed with N-methoxy-N,5-dimethyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide (80 mg) obtained in the previous step. 1 M methylmagnesium bromide / tetrahydrofuran solution (0.59 ml) was added dropwise to this mixture under ice-cooling, and the mixture was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was warmed to room temperature and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 12:88 to ethyl acetate) to obtain the title compound (46.3 ml). g) was obtained. 1 H-NMR (400 MHz, CDCl3) 1.24 (d, J=6.70Hz, 3H), 2.68 (s, 3H), 2.82 (dd, J=15.95, 1.39Hz, 1H), 3.33 (dd, J=15.95, 6.47Hz, 1H), 5.61 - 5.73 (m, 1H), 7.23 - 7.33 (m, 3H), 7.48 (s, 1H), 7.57 - 7.64 (m, 1H)

[0316] 7th step 1,1,1-trifluoro-2-(5-methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)propan-2-ol

[0317] [ka]

[0318] 1-(5-Methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)ethan-1-one (46.3 mg) obtained in the previous step was mixed with dimethylformamide (1 ml). Under ice-cooling, cesium fluoride (7.42 mg) and (trifluoromethyl)trimethylsilane (54.1 μl) were added, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, methanol (0.332 ml) and potassium carbonate (40.5 mg) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed twice with water and once with a saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified sequentially by silica gel column chromatography (hexane:ethyl acetate=12:88 to ethyl acetate) and thin-layer silica gel chromatography (hexane:ethyl acetate=2:1) ​​to give the title compound (50.8 mg) as a racemate. 1 H-NMR (400 MHz, CDCl3) 1.21 (d, J=6.47Hz, 3H), 1.95 (s, 3H), 2.77 (dd, J=15.49, 1.62Hz, 1H), 3.28 (dd, J=15.49, 5.32Hz, 1H), 3.52 (s, 1H), 5.10 - 5.20 (m, 1H), 7.17 - 7.30 (m, 5H), 7.33 (s, 1H), 7.54 (d, J=7.40Hz, 1H)

[0319] Production Example 5 Synthesis of 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol (Compound of Example 34) and 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol (Compound of Example 35)

[0320] 1st process Methyl 4-hydroxypentanoate

[0321] [ka]

[0322] Methyl 4-oxopentanoate (14 g) was mixed with methanol (112 ml). The mixture was cooled to -78°C, sodium borohydride (4.07 g) was added, and the mixture was stirred at -50°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then acetic acid was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=12:88 to ethyl acetate) to give the title compound as a crude product (11.15 g). This crude product was used in the next step without further purification.

[0323] 2nd process Methyl 1-(5-methoxy-5-oxopentan-2-yl)-1H-imidazole-5-carboxylate

[0324] [ka]

[0325] Methyl 1H-imidazole-5-carboxylate (3 g) was mixed with toluene (24 ml). To this mixture was added the crude methyl 4-hydroxypentanoate (4.85 g) obtained in the previous step and trioctylphosphine (10.58 g). The mixture was heated to 80°C, and diisopropyl azodicarboxylate (5.77 g) was added dropwise, followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate:hexane = 50:50 to ethyl acetate, then ethyl acetate:methanol = 90:10) to obtain the title compound (2.6 g). 1 H-NMR (400 MHz, CDCl3) 1.52 (d, J=6.94Hz, 3H), 2.05 - 2.35 (m, 4H), 3.63 (s, 3H), 3.83 (s, 3H), 5.17 - 5.30 (m, 1H), 7.70 - 7.74 (m, 2H)

[0326] 3rd process Methyl 5-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylate

[0327] [ka]

[0328] Tetrahydrofuran (45 ml) was mixed with methyl 1-(5-methoxy-5-oxopentan-2-yl)-1H-imidazole-5-carboxylate (1.48 g) obtained in the previous step. Potassium tert-butoxide (0.76 g) was added to this mixture, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to this reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (1.04 g). This crude product was used in the next step without further purification.

[0329] 4th step 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one

[0330] [ka]

[0331] The crude product (1 g) of methyl 5-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylate obtained in the previous step was mixed with dimethyl sulfoxide (6.82 ml). Sodium chloride (0.421 g) and water (1.73 ml) were added to this mixture, and the mixture was stirred at 160°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove water, and then purified twice by cation exchange column chromatography (methanol to 1N ammonia / methanol solution) to obtain the title compound (0.714 g). 1 H-NMR (400 MHz, DMSO-D6) 1.54 (d, J=6.70Hz, 3H), 1.86 - 2.02 (m, 1H), 2.16 - 2.28 (m, 1H), 2.52 - 2.59 (m, 2H), 4.35 - 4.50 (m, 1H), 7.63 (d, J=0.69Hz, 1H), 8.05 (s, 1H)

[0332] 5th step 7-(Cyclopropanecarbonyl)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one

[0333] [ka]

[0334] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one (100 mg) obtained in the previous step was mixed with tetrahydrofuran (1.5 ml). To this mixture, 1.1 M lithium bis(trimethylsilyl)amide / n-hexane solution (0.908 ml) was added dropwise under ice cooling, and the mixture was stirred for 40 minutes. Cyclopropanecarbonyl chloride (77 mg) was added to the reaction mixture, and the mixture was stirred at 0°C for 5 minutes and at room temperature for 25 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate to ethyl acetate:methanol = 90:10) to obtain the crude product of the title compound (91.1 mg). This crude product was carried on to the next step without further purification.

[0335] 6th step Mixture of 3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridine and 3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridine

[0336] [ka]

[0337] 7-(Cyclopropanecarbonyl)-5-methyl-6,7-dihydroxide obtained in the previous step The crude product of roimidazo[1,5-a]pyridin-8(5H)-one (90 mg) was mixed with acetic acid (0.9 ml). Hydroxylamine hydrochloride (86 mg) was added to the mixture, and the mixture was stirred at 90°C for 40 minutes. After cooling to room temperature, sulfuric acid (81 mg) was added to the reaction mixture, and the mixture was stirred at 100°C for 2 hours and at 110°C for 4 hours. After cooling to room temperature, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After removing the magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified sequentially by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol = 90:10) and preparative thin-layer chromatography (ethyl acetate:methanol = 90:10) to give the crude product of the title compound (45.2 mg). This crude product was carried on to the next step without further purification.

[0338] 7th step Mixture of 1-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)ethan-1-one and 1-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)ethan-1-one

[0339] [ka]

[0340] The crude products (43.2 mg) of 3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridine and 3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridine obtained in the previous step were mixed with tetrahydrofuran (0.864 ml). This mixture was cooled to -78 °C, and 2 M lithium diisopropylamide solution (0.251 ml) was added dropwise. The mixture was stirred at -78 °C for 40 minutes. N-Methoxy-N-methylacetamide (62.1 mg) was added to the mixture, and the mixture was stirred at -78 °C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then warmed to room temperature and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25 to 50:50) to give the title compound (18.8 mg) as a crude product, which was used in the next step without further purification.

[0341] 8th process 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol (compound of Example 34) and 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol (compound of Example 35)

[0342] [ka]

[0343] The crude products (17 mg) of 1-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)ethan-1-one and 1-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)ethan-1-one obtained in the previous step were mixed with tetrahydrofuran (0.34 ml). Under ice-cooling, cesium fluoride (7.42 mg) and (trifluoromethyl)trimethylsilane (54.1 μl) were added and stirred at room temperature for 1 hour. Under ice-cooling, methanol (0.332 ml) and potassium carbonate (40.5 mg) were added and stirred for 1.5 hours while warming to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the layers were separated. The organic layer was purified by silica gel column chromatography (hexane:ethyl acetate=12:88 to ethyl acetate) to give the compound of Example 34 (5.2 mg) and the compound of Example 35 (8.4 mg), each as a racemate. The structure of the isoxazole moiety was determined by NMR. 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol 1 H-NMR (400 MHz, CDCl3) 1.02 - 1.04 (m, 4H), 1.30 (d, J=3.29Hz, 3H), 2.00 (s, 3H), 2.63 - 2.67 (m, 1H), 3.05 - 3.11 (m, 1H), 3.33 - 3.37 (m, 1H), 5.30 - 5.36 (m, 1H), 7.41 (s, 1H) 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol 1H-NMR (400 MHz, CDCl3) 1.06 - 1.16 (m, 4H), 1.31 (d, J=6.58Hz, 3H), 1.85 (s, 3H), 2.79 (dd, J=15.55, 1.79Hz, 1H), 2.96 - 3.02 (m, 1H), 3.87 - 4.04 (m, 1H), 5.42 - 5.44 (m, 1H), 7.60 (s, 1H)

[0344] Manufacturing Example 6 Synthesis of 1,1,1-trifluoro-2-(6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-8-yl)propan-2-ol (Compound of Example 6)

[0345] 1st process 7-((dimethylamino)methylene)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one

[0346] [ka]

[0347] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one (250 mg) was mixed with 1,4-dioxane (1.25 ml). To the mixture was added 435 mg of thoxybis(dimethylamino)methane, and the mixture was stirred at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product of the title compound. This crude product was used in the next step without further purification.

[0348] 2nd process 6-Methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidine

[0349] [ka]

[0350] The crude product of 7-((dimethylamino)methylene)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one obtained in the previous step was mixed with ethanol (0.95 ml). Trifluoroacetamidine (142 mg) was added to this mixture, and the mixture was stirred at room temperature for 15 minutes. Sodium ethoxide (86 mg) was added to this mixture, and the mixture was stirred overnight under reflux. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride solution was added, followed by extraction twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 to 60:40) to give the title compound (172.6 mg). 1 H-NMR (400 MHz, CDCl3) 1.62 (d, J=6.47Hz, 3H), 2.94 (dd, J=16.18, 8.32Hz, 1H), 3.25 (dd, J=16.18, 5.09Hz, 1H), 4.44 - 4.58 (m, 1H), 7.76 (s, 1H), 8.00 (s, 1H),8.64 (s, 1H)

[0351] 3rd process 1-(6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-8-yl)ethan-1-one

[0352] [ka]

[0353] 6-Methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidine (50 mg) obtained in the previous step was mixed with tetrahydrofuran (0.5 ml). This mixture was cooled to -78°C, and 2M lithium diisopropylamide solution (0.118 ml) was added dropwise. The mixture was stirred at -78°C for 1 hour. N-Methoxy-N-methylacetamide (40.6 mg) was added to the mixture, and the mixture was stirred at -78°C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was warmed to room temperature and extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then diluted with sodium sulfate. The mixture was dried over ice. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=12:88 to ethyl acetate) to give the title compound (17.2 mg). 1 H-NMR (400 MHz, CDCl3) 1.30 (d, J=6.70Hz, 3H), 3.00 (dd, J=16.30, 1.16Hz, 1H), 3.38 (dd, J=16.30, 6.59Hz, 1H), 5.77 - 5.86 (m, 1H), 8.04 (s, 1H), 8.74 (s, 1H)

[0354] 4th step 1,1,1-trifluoro-2-(6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-8-yl)propan-2-ol

[0355] [ka]

[0356] 1-(6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-8-yl)ethan-1-one (17.2 mg) obtained in the previous step was mixed with tetrahydrofuran (0.172 ml). To this mixture, cesium fluoride (1.764 mg) and (trifluoromethyl)trimethylsilane (16.51 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To this mixture, (trifluoromethyl)trimethylsilane (16.51 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. To this mixture, (trifluoromethyl)trimethylsilane (16.51 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. To this reaction mixture, methanol (0.103 ml) and potassium carbonate (9.63 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer silica gel chromatography (hexane:ethyl acetate=1:1). Ethyl acetate / hexane=1:1 was added to the resulting crude product, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain the title compound (7.1 mg) as a racemate. 1 H-NMR (400 MHz, DMSO-D6) 1.20 (d, J=6.47Hz, 3H), 1.84 (s, 3H), 3.14 (d, J=16.41Hz, 1H), 3.23 (dd, J=16.41, 5.32Hz, 1H), 5.34 - 5.44 (m, 1H), 7.40 (s, 1H), 7.81 (s, 1H), 8.92 (s, 1H)

[0357] Manufacturing Example 7 Synthesis of 2-(1,5-dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol (Compound of Example 24)

[0358] 1st process 1,5-Dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine

[0359] [ka]

[0360] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one (150 mg) was mixed with tetrahydrofuran (1.5 ml). Ethyl trifluoroacetate (312 mg) was added to this mixture. Sodium hydride (88 mg) was added to this mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes, followed by stirring at 60°C for 1 hour. After cooling to room temperature, methylhydrazine (138 mg) and ethanol (1.5 ml) were added to the reaction mixture. The reaction mixture was stirred at 95°C for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with acetic acid. To the resulting residue, acetic acid (1.5 ml) and methylhydrazine (138 mg) were added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, followed by addition of saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate twice. The organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5 to 60:40) to give the title compound (170.4 mg). The substitution position of the methyl group in the pyrazole moiety was determined by two-dimensional NMR. 1 H-NMR (400 MHz, DMSO-D6) 1.44 (d, J=6.47Hz, 3H), 2.72 (dd, J=15.95, 7.86Hz, 1H), 3.09 (dd, J=15.95, 5.55Hz, 1H), 4.01 (s, 3H), 4.41 - 4.52 (m, 1H), 7.46 (s, 1H), 7.96 (s, 1H)

[0361] 2nd process 1-(1,5-dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one

[0362] [ka]

[0363] 1,5-Dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine (170.4 mg) obtained in the previous step was mixed with tetrahydrofuran (5.112 ml). This mixture was cooled to -78 °C, and 2 M lithium diisopropylamide solution (0.831 ml) was added dropwise. The mixture was stirred at -78 °C for 30 minutes. N-Methoxy-N-methylacetamide (206 mg) was added to the mixture, and the mixture was stirred at -78 °C for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then warmed to room temperature and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 12:88 to ethyl acetate) to give the title compound (150 mg).

[0364] 3rd process 2-(1,5-dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropan-2-ol

[0365] [ka]

[0366] 1-(1,5-Dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one (150 mg) obtained in the previous step was mixed with tetrahydrofuran (1.5 ml). To this mixture, cesium fluoride (1.764 mg) and (trifluoromethyl)trimethylsilane (143 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. To this mixture, (trifluoromethyl)trimethylsilane (143 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. To this reaction mixture, methanol (0.103 ml) and potassium carbonate (9.63 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=12:88 to ethyl acetate) to give the title compound (127.7 mg) as a racemic mixture. 1 H-NMR (400 MHz, DMSO-D6) 1.16 (d, J=6.58Hz, 3H), 1.84 (s, 3H), 2.90 (d, J=16.14Hz, 1H), 2.97 (dd, J=16.14, 5.38Hz, 1H), 4.04 (s, 3H), 5.32 - 5.43 (m, 1H), 7.27 (s, 1H), 7.46 (s, 1H)

[0367] Manufacturing Example 8 Synthesis of 1,1,1-trifluoro-2-(5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)propan-2-ol (Compound of Example 50)

[0368] 1st process 5-Methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine

[0369] [ka]

[0370] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one (200 mg) was mixed with tetrahydrofuran (8 ml). Ethyl trifluoroacetate (227 mg) was added to this mixture. Sodium hydride (80 mg) was added to this mixture, and the mixture was stirred at room temperature for 1 hour and then at 70°C for 1.5 hours. After cooling to room temperature, ethyl trifluoroacetate (37.8 mg) was added to the reaction mixture, and the mixture was stirred at 70°C for 30 minutes. After cooling to room temperature, acetic acid (80 mg) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Acetic acid (2 ml), hydrazine monohydrate (233 mg), and sulfuric acid (261 mg) were added to the resulting residue, and the mixture was stirred at 100°C for 2 hours. The reaction mixture was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol = 80:20) to obtain the crude title compound (316.8 mg). This crude product was carried to the next step without further purification.

[0371] 2nd process Mixture of 1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine and 2-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine

[0372] [ka]

[0373] The crude product (82 mg) of 5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine obtained in the previous step was mixed with dimethylformamide (0.82 ml). Under ice-cooling, sodium hydride (16.25 mg) was added to this mixture, and the mixture was stirred for 30 minutes. Under ice-cooling, 4-methoxybenzyl chloride (58.3 mg) was added to this reaction mixture, and the mixture was stirred overnight at room temperature. 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 and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 12:88 to ethyl acetate) to give the crude product (67.1 mg) of the title compound. This crude product was carried on to the next step without further purification.

[0374] 3rd process 1-(1-(4-Methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one and 1-(2-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one Mixture of (fluoromethyl)-4,5-dihydro-2H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one

[0375] [ka]

[0376] The crude products (61.1 mg) of 1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine and 2-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine obtained in the previous step were mixed with tetrahydrofuran (0.611 ml). The mixture was cooled to -78°C, and 2M lithium diisopropylamide solution (0.211 ml) was added dropwise. The mixture was stirred at -78°C for 45 minutes. N-methoxy-N-methylacetamide was added to the mixture. After adding hexane (52.2 mg) and stirring at -78°C for 40 minutes, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was warmed to room temperature and separated. The organic layer was purified by silica gel column chromatography (hexane:ethyl acetate = 20:80 to ethyl acetate) to obtain a crude product of the title compound (48 mg). This crude product was carried on to the next step without further purification.

[0377] 4th step Mixture of 1,1,1-trifluoro-2-(1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)propan-2-ol and 1,1,1-trifluoro-2-(2-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-2H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)propan-2-ol

[0378] [ka]

[0379] The 1-(1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one obtained in the previous step and 1-(2-(4-methoxybenzyl)-5 The crude product (45mM) of 4,5-dihydro-2H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one g) was mixed with tetrahydrofuran (0.9 ml). Cesium fluoride (5.07 mg) and (trifluoromethyl)trimethylsilane (47.5 mg) were added to this mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Methanol (0.45 ml) and potassium carbonate (77 mg) were added to this reaction mixture under ice-cooling, and the mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to this mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer silica gel chromatography (hexane:ethyl acetate=50:50) to give the crude product of the title compound (11.8 mg). This crude product was used in the next step without further purification. We moved forward.

[0380] 5th step 1,1,1-trifluoro-2-(5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)propan-2-ol

[0381] [ka]

[0382] The crude product (11.5 mg) of 1,1,1-trifluoro-2-(1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)propan-2-ol and 1,1,1-trifluoro-2-(2-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-2H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)propan-2-ol obtained in the previous step was mixed with dichloromethane (0.46 ml). Trifluoroacetic acid (0.0467 ml) was added to this mixture, and the mixture was stirred at room temperature for 2 days and at 60 ° C. for 2 hours. Trifluoroacetic acid (0.3 ml) was added to this mixture, which was then stirred at 70°C for 2 hours and at 80°C overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added. Ethyl acetate was extracted twice, and the organic layer was dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer silica gel chromatography (hexane:ethyl acetate = 1:2) to give the title compound (6.5 mg) as a racemate. 1 H-NMR (400 MHz, DMSO-D6) 1.17 (d, J=6.58Hz, 3H), 1.84 (s, 3H), 2.87 - 3.02 (m, 2H), 3.41 - 3.48 (m, 2H), 5.30 - 5.45 (m, 1H), 7.23 (s, 1H), 14.06 (s, 1H)

[0383] Manufacturing Example 9 Synthesis of (R)-1,1,1-trifluoro-2-((S)-5-methyl-9-(trifluoromethyl)-5,6-dihydropyrazolo[1,5-a][1,2,4]triazolo[3,4-c]pyrazin-3-yl)propan-2-ol (Compound of Example 13)

[0384] 1st process tert-Butyl (R)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)hydrazine-1-carboxylate

[0385] [ka]

[0386] tert-Butoxycarbonylhydrazine (1.17 g) was dissolved in acetonitrile (15 ml ) and mixed. (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1 g) was added to this mixture. Under ice-cooling, 1-hydroxybenzotriazole monohydrate (0.581 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.455 g) were added to this mixture, and the mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was washed successively with 0.5 N hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration. After removal of the solvent, the filtrate was concentrated under reduced pressure to give the title compound (1.66 g). 1 H-NMR (400 MHz, DMSO-D6) 1.27 - 1.42 (m, 9H), 1.46 (s, 3H), 6.99 (s, 1H), 8.31 (s, 0.25H), 8.76 (s, 0.75H), 9.64 - 9.96 (m, 1H)

[0387] 2nd process (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanehydrazide

[0388] [ka]

[0389] The tert-butyl (R)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)hydrazine-1-carboxylate (0.6 g) obtained in the previous step was mixed with ethyl acetate (1.114 ml). Trifluoroacetic acid (2.78 ml) was added to this mixture under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and then purified by cation exchange column chromatography (methanol to 1N ammonia / methanol solution) to give the title compound (155.8 mg). 1 H-NMR (400 MHz, DMSO-D6) 1.44 (s, 3H), 4.32 (s, 2H), 6.82 (s, 1H), 9.28 (brs, 1H)

[0390] 3rd process Methyl (S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0391] [ka]

[0392] Methyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (200 mg), N-(tert-butoxycarbonyl)-L-alaninol (271 mg), and triphenylphosphine (405 mg) were mixed in tetrahydrofuran (2 ml). This mixture was heated to 80°C, and diisopropyl azodicarboxylate (0.3 ml) was added dropwise. The reaction mixture was stirred at 80°C for 2 hours and then at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 92:8 to 44:66) to afford the title compound (388.9 mg). 1 H-NMR (400 MHz, CDCl3) 1.18 (d, J=6.70Hz, 3H), 1.31 (s, 9H), 3.90 (s, 3H), 4.14 - 4.29 (m, 1H), 4.37 - 4.52 (m, 1H), 4.55 - 4.79 (m, 2H), 7.06 (s, 1H)

[0393] 4th step (S)-6-Methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0394] [ka]

[0395] Methyl (S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (362 mg) obtained in the previous step was mixed with chloroform (2 ml). Trifluoroacetic acid (2 ml) was added to this mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. Methanol (3.62 ml) and sodium carbonate (437 mg) were added to the obtained residue, and the mixture was stirred at room temperature for 3 hours. Water was added to this reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain the title compound (193.4 mg). 1 H-NMR (400 MHz, DMSO-D6) 1.22 (d, J=6.47Hz, 3H), 3.97 - 4.16 (m, 2H), 4.49 (dd, J=12.60, 4.05Hz, 1H), 7.17 (s, 1H), 8.50 (s, 1H)

[0396] 5th step (S)-6-Methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-thione

[0397] [ka]

[0398] (S)-6-Methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (193.4 mg) obtained in the previous step was mixed with tetrahydrofuran (3.868 ml). 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (250 mg) was added to this mixture and stirred at 70 °C for 7 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 92:8 to 44:66) to give the title compound (199.8 mg). 1 H-NMR (400 MHz, CDCl3) 1.47 (d, J=6.47Hz, 3H), 4.03 - 4.23 (m, 2H), 4.48 (dd, J=12.25, 3.47Hz, 1H), 7.29 (s, 1H), 7.62 (brs, 1H)

[0399] 6th step (S)-6-Methyl-4-(methylthio)-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine hydroiodide

[0400] [ka]

[0401] (S)-6-Methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-thione (80 mg) obtained in the previous step was mixed with acetone (0.8 ml). Methyl iodide (57.9 mg) was added to this mixture under ice-cooling, and the mixture was stirred at room temperature overnight. Methyl iodide (57.9 mg) was added to this mixture under ice-cooling, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (128 mg) as a crude product. This crude product was carried on to the next step without further purification.

[0402] 7th step (R)-1,1,1-trifluoro-2-((S)-5-methyl-9-(trifluoromethyl)-5,6-dihydropyrazolo[1,5-a][1,2,4]triazolo[3,4-c]pyrazin-3-yl)propan-2-ol

[0403] [ka]

[0404] The crude (S)-6-methyl-4-(methylthio)-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine hydroiodide (128 mg) obtained in the previous step and (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanehydrazide (61 mg) obtained in the second step were mixed in isopropanol (1 mL). Acetic acid (0.039 mL) was added to this mixture, and the mixture was stirred at 100°C for 1.5 hours. After cooling to room temperature, sodium acetate (56 mg) and water (0.256 mL) were added to the reaction mixture, and the mixture was stirred at 100°C overnight. The reaction mixture was purified sequentially by cation exchange column chromatography (methanol) and silica gel column chromatography (hexane:ethyl acetate = 88:12, then ethyl acetate) to afford the title compound (32.2 mg). 1 H-NMR (400 MHz, DMSO-D6) 1.30 (d, J=6.58Hz, 3H), 1.91 (s, 3H), 4.62 (d, J=13.75Hz, 1H), 4.70 (dd, J=13.75, 4.04Hz, 1H), 5.31 - 5.42 (m, 1H), 7.47 (s, 1H), 7.71 (s, 1H)

[0405] Manufacturing Example 10 Synthesis of (R)-2-((S)-9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropan-2-ol (Compound of Example 23)

[0406] 1st process Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate

[0407] [ka]

[0408] Diethyl acetylenedicarboxylate (250 ml) was mixed with acetonitrile (797 ml). Under ice-cooling, hydrazine monohydrate (80 ml) and acetic acid (17.9 ml) were added dropwise in that order, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was stirred under ice-cooling for 2 hours, and the precipitated solid was collected by filtration to obtain the title compound (156.71 g). 1 H-NMR (400 MHz, DMSO-D6) 1.26 (t, J=7.05Hz, 3H), 3.94 - 4.53 (m, 2H), 5.39 - 6.26 (m, 1H), 9.47 - 11.36 (brm, 1H), 12.73 (s, 1H)

[0409] 2nd process Ethyl 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0410] [ka]

[0411] Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (300 g) obtained in the previous step was mixed with acetonitrile (720 ml). Pyridinium p-toluenesulfonate (24.14 g) was added at room temperature. 3,4-Dihydro-2H-pyran (170 g) was added dropwise to this mixture, which was then stirred at room temperature for 2 days. The reaction mixture was stirred under ice cooling for 2 hours, and the precipitated solid was collected by filtration to give the title compound (410 g). 1H-NMR (400 MHz, DMSO-D6) 1.25 (t, J=7.05Hz, 3H), 1.42 - 1.77 (m, 4H), 1.88 - 1.99 (m, 1H), 2.12 - 2.26 (m, 1H), 3.49 - 3.61 (m, 1H), 3.85 - 3.94 (m, 1H), 4.13 - 4.29 (m, 2H), 5.27 - 5.35 (m, 1H), 5.73 (s, 1H), 11.63 (s, 1H)

[0412] 3rd process Ethyl 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

[0413] [ka]

[0414] Ethyl 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (205 g) obtained in the previous step was mixed with N-methylpyrrolidone (615 ml). Under ice-cooling, potassium carbonate (142 g) was added, followed by dropwise addition of benzyl bromide (175 g) and stirring at room temperature for 2 hours. Acetic acid (25.6 g) was added dropwise to this mixture and stirred overnight at room temperature. Water (1.23 L) was added to this reaction mixture, followed by extraction with isopropyl acetate (2.05 L). The organic layer was washed twice with 10% aqueous sodium chloride solution (1.025 L) and concentrated under reduced pressure. The resulting residue was azeotroped with isopropyl acetate (2.05 L). Isopropyl acetate (615 ml) was added to the resulting solid, and the mixture was heated and stirred at 55°C until dissolution occurred. The solution was gradually cooled to 40°C and seeded with seed crystals. To the resulting suspension, n-heptane (2.46 L) was added dropwise, and the mixture was gradually cooled to room temperature and stirred at room temperature for 2 hours. After stirring for 2 hours under ice-cooling, the precipitated solid was collected by filtration to give the title compound (235.15 g). 1H-NMR (400 MHz, DMSO-D6) 1.26 (t, J=7.05Hz, 3H), 1.45 - 1.56 (m, 2H), 1.57 - 1.80 (m, 2H), 1.89 - 2.00 (m, 1H), 2.11 - 2.26 (m, 1H), 3.52 - 3.62 (m, 1H), 3.84 - 3.92 (m, 1H), 4.19 - 4.28 (m, 2H), 5.19 - 5.31 (m, 2H), 5.35 - 5.42 (m, 1H), 6.22 (s, 1H), 7.30 - 7.51 (m, 5H) In this step, crystals of the title compound can be obtained without using seed crystals.

[0415] 4th step 5-(Benzyloxy)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide

[0416] [ka]

[0417] Ethyl 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (235.15 g) obtained in the previous step was mixed with 1,2-dimethoxyethane (941 ml). 2N aqueous sodium hydroxide solution (428 ml) was added dropwise to this mixture, and the mixture was stirred at room temperature for 3.5 hours. Under ice cooling, N-methoxy-N-methylamine hydrochloride (83 g) and HOBt·HO (21.8 g) were added to the mixture, followed by the addition of WSC·HCl (164 g) in four portions, and the mixture was stirred overnight at room temperature. 5% aqueous sodium bicarbonate solution (941 ml) was added to the reaction mixture, and the mixture was extracted with toluene (1411 ml). The organic layer was washed with 5% aqueous sodium chloride solution (941 ml) and concentrated under reduced pressure. The resulting residue was azeotroped with toluene (2.35 L). Toluene was added to the resulting residue to prepare a solution of the title compound containing toluene in an amount five times the weight of the raw material.

[0418] 5th step 5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde

[0419] [ka]

[0420] To the toluene solution of 5-(benzyloxy)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide obtained in the previous step, a 70% sodium bis(2-methoxyethoxy)aluminum hydride solution (141 ml) was added dropwise under ice cooling, and the mixture was stirred for 2.5 hours. To this reaction mixture, a solution of isopropanol (54.8 ml) and toluene (118 ml) was added dropwise under water cooling. The mixture was warmed to room temperature, and Rochelle salt (201 g) in water (941 ml) was added and stirred for 1 hour. The solution was separated, and the organic layer was washed twice with 5% aqueous sodium chloride solution (941 ml) and concentrated under reduced pressure. The resulting residue was solvent-exchanged with 1,2-dimethoxyethane (2.35 L). 1,2-Dimethoxyethane was added to the resulting residue to prepare a solution of the title compound containing 1,2-dimethoxyethane in an amount 13 times the weight of the starting material.

[0421] 6th step 5-(benzyloxy)-1H-pyrazole-3-carbaldehyde

[0422] [ka]

[0423] To the solution of 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde obtained in the previous step in 1,2-dimethoxyethane was added 1N hydrochloric acid (1423 ml) under ice cooling, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration to give the title compound (132.04 g). 1H-NMR (400 MHz, DMSO-D6) 5.18 (s, 2H), 6.36 (s, 1H), 7.26 - 7.49 (m, 5H), 9.70 (s, 1H), 13.34 (brs, 1H)

[0424] 7th step (S)-2-(5-(3-(benzyloxy)-1H-pyrazol-5-yl)-1H-imidazol-1-yl)propan-1-ol

[0425] [ka]

[0426] 5-(benzyloxy)-1H-pyrazole-3-carbaldehyde (261.97 g) obtained in the previous step was mixed with dimethylformamide (1040 ml). (S)-2-aminopropan-1-ol (102 g) was added at room temperature and stirred overnight at room temperature. Potassium carbonate (358 g) was added to this mixture, followed by p-toluenesulfonylmethyl isocyanide (304 g) in three portions and stirring overnight at room temperature. Potassium tert-butoxide (72.7 g) was added to this reaction mixture and stirred overnight at room temperature. 2-Methyltetrahydrofuran (1572 ml) and KC floc (W-300G, Nippon Paper Industries Co., Ltd., 131 g) were added to this reaction mixture and the mixture was filtered using KC floc as an auxiliary. 2-Methyltetrahydrofuran (1572 ml) was added to the filtered residue, stirred at room temperature, and filtered. The filtrates were combined and washed three times with 10% aqueous sodium chloride solution (1048 ml). The first aqueous layer was extracted with 2-methyltetrahydrofuran (2620 ml) and washed three times with 10% aqueous sodium chloride solution (1048 ml). The combined organic layers were concentrated under reduced pressure and azeotroped sequentially with toluene and 2-methyltetrahydrofuran. 2-Methyltetrahydrofuran was added to the resulting residue to prepare a solution of the title compound containing 2-methyltetrahydrofuran in an amount four times the weight of the starting material.

[0427] 8th process (S)-9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine hydrochloride

[0428] [ka]

[0429] Triphenylphosphine (408 g) was added to the (S)-2-(5-(3-(benzyloxy)-1H-pyrazol-5-yl)-1H-imidazol-1-yl)propan-1-ol / 2-methyltetrahydrofuran solution obtained in the previous step. A 40% diisopropyl azodicarboxylate / toluene solution (763 ml) was added dropwise while heating at 73°C, and the mixture was stirred for 1 hour. A 2N hydrochloric acid / ethanol solution (842 ml) was added dropwise while heating at 60°C, and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration to obtain the title compound (244.13 g). 1 H-NMR (400 MHz, DMSO-D6) 1.59 (d, J=6.47Hz, 3H), 4.05 - 4.19 (m, 1H), 4.43 - 4.53 (m, 1H), 4.85 - 4.99 (m, 1H), 5.19 (s, 2H), 6.23 (s, 1H), 7.26 - 7.48 (m, 5H), 8.01 (d, J=1.16Hz, 1H), 9.29 (s, 1H)

[0430] 9th step (S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine

[0431] [ka]

[0432] (S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine hydrochloride (224 g) obtained in the previous step was mixed with 2-methyltetrahydrofuran (896 ml) and water (448 ml). 4N aqueous sodium hydroxide solution (194 ml) was added to this mixture and stirred for 1 hour. The solution was separated, and the organic layer was washed with 20% aqueous sodium chloride solution (896 ml) and concentrated under reduced pressure. The resulting residue was azeotropically distilled with toluene (1 L) and tetrahydrofuran (1.1 L) sequentially. Tetrahydrofuran was added to the resulting residue to prepare a solution of the title compound containing 5.4 times the amount of tetrahydrofuran as the starting material.

[0433] 10th step (S)-1-(9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0434] [ka]

[0435] While cooling to −78° C., the (S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine / tetrahydrofuran obtained in the previous step was 1M lithium diisopropylamide / hexane-tetrahydrofuran solution (634 ml) was added dropwise to the tetrahydrofuran solution and stirred for 1 hour. N-methoxy-N-methylacetamide (173 ml) was added to this mixture and stirred at -78°C for 1.5 hours. A lithium diisopropylamide / hexane-tetrahydrofuran solution (667 ml) was added dropwise and stirred for 2.5 hours. This reaction mixture was added dropwise to an acetic acid (405 ml) / ethanol (672 ml) solution cooled to 0°C. The precipitated solid was collected by filtration. The obtained solid was mixed with ethanol / water = 1 / 2 (2016 ml) and stirred at room temperature. The precipitated solid was collected by filtration to obtain the title compound (205.85 g). 1H-NMR (400 MHz, CDCl3) 1.44 (d, J=6.58Hz, 3H), 2.69 (s, 3H), 4.19 (dd, J=13.45, 1.20Hz, 1H), 4.29 (dd, J=13.45, 4.63Hz, 1H), 5.24 (s, 2H), 5.75 - 5.84 (m, 1H), 5.98 (s, 1H), 7.32 - 7.50 (m, 6H)

[0436] 11th step (S)-1-(9-hydroxy-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0437] [ka]

[0438] (S)-1-(9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one (205.7 g) obtained in the previous step was mixed with concentrated hydrochloric acid (563 ml). This mixture was stirred overnight at 48°C and then at room temperature. The reaction mixture was washed with toluene (1.029 L). The resulting aqueous layer was diluted with ethanol (206 ml) and water (411 ml), and then 4N aqueous sodium hydroxide solution (1276 ml) and 10% aqueous trisodium citrate solution (1076 ml) were added. After stirring for 2 hours under ice-cooling, the precipitated solid was collected by filtration to give the title compound (144.84 g). 1 H-NMR (400 MHz, DMSO-D6) 1.28 (d, J=6.73Hz, 3H), 2.57 (s, 3H), 4.12 (d, J=13.46Hz, 1H), 4.22 (dd, J=13.46, 4.49Hz, 1H), 5.53 - 5.65 (m, 1H), 5.94 (s, 1H), 7.48 (s, 1H), 10.04 (s, 1H)

[0439] 12th step (S)-1-(9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0440] [ka]

[0441] (S)-1-(9-hydroxy-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one (1 g) obtained in the previous step was mixed with acetonitrile (10 ml). To this mixture was added 8M aqueous potassium hydroxide solution (168 ml). To this mixture was added dropwise diethyl (bromodifluoromethyl)phosphonate (1.533 ml) under ice cooling, and the mixture was stirred for 1 hour under water cooling. This reaction mixture was then cooled at room temperature. Water (20 ml) and ethyl acetate (20 ml) were added to the mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give the title compound (561 mg). 1 H-NMR (400 MHz, DMSO-D6) 1.27 (d, J=6.70Hz, 3H), 2.58 (s, 3H), 4.25 - 4.43 (m, 2H), 5.59 - 5.69 (m, 1H), 6.50 (s, 1H), 7.30 (t, J=73.06Hz, 1H), 7.57 (s, 1H)

[0442] 13th step (R)-2-((S)-9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropan-2-ol

[0443] [ka]

[0444] (S)-1-(9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one (561 mg) obtained in the previous step was mixed with tetrahydrofuran (5.6 ml). Cesium fluoride (0.06 g) was added to this mixture. Under ice-cooling, (trifluoromethyl)trimethyl Silane (0.587 ml) was added dropwise and stirred at room temperature for 1.5 hours. Methanol (3.366 ml) and potassium carbonate (0.33 g) were added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:3 to 1:1) to give the title compound (529 mg). 1 H-NMR (400 MHz, DMSO-D6) 1.27 (d, J=6.70Hz, 3H), 1.81 (s, 3H), 4.20 - 4.30 (m, 2H), 5.31 - 5.40 (m, 1H), 6.31 (s, 1H), 7.27 (t, J=73.29Hz, 1H), 7.31 (s, 1H), 7.32 (s, 1H)

[0445] The compounds of Examples 1 to 103 were obtained by the same methods as those of Production Methods 1 to 10 and Production Examples 1 to 10, and by using other known methods as necessary. The structural formulas and physical property data of the example compounds are shown in the table below. Remarks in the table indicate the following meanings.

[0446] 1 (Examples 1, 3, 5, 6, 24, 25, 34, 35 and 50) Racemic 2 (Example 26) Mixture of two diastereomers 3 (Example 97) The cyclopropane moiety has a trans configuration and is a mixture of two diastereomers.

[0447] Table 1-1

[0448] Table 1-2

[0449] Table 1-3

[0450] Table 1-4

[0451] Table 1-5

[0452] Table 1-6

[0453] Table 1-7

[0454] Table 1-8

[0455] Table 1-9

[0456] Table 1-10

[0457] Table 1-11

[0458] Table 1-12

[0459] Table 1-13

[0460] Table 1-14

[0461] Table 1-15

[0462] Table 1-16

[0463] Table 1-17

[0464] Table 1-18

[0465] Table 1-19

[0466] Table 1-20

[0467] Table 1-21

[0468] [Table 1-22]

[0469] [Table 1-23]

[0470] [Table 1-24]

[0471] Test Example 1 (PDHK2 activity inhibitory effect) For human PDHK2 (hPDHK2, NCBI Reference Database Accession number NM_002611.4), a FLAG-Tag sequence was added to the N-terminus by polymerase chain reaction (PCR) based on the hPDHK2 cDNA clone (pReceiver-M01 / PDK2-GeneCopoeia). Modified hPDHK2 cDNA was prepared and inserted into the pET-17b vector (Merck KGaA The recombinant construct was ligated into the NdeI / EcoRI site of the nucleotide sequence ... The recombinant clones were identified, their plasmid DNA was isolated, and subjected to DNA sequence analysis. One clone with the predicted nucleic acid sequence was selected for expression work.

[0472] To express hPDHK2 activity, the pET17b vector containing the modified hPDHK2 cDNA was transformed into Escherichia coli strain BL21(DE3) (Merck KGaA, Cat. No. 69450-4). E. coli was grown at 30°C until it reached an optical density of 0.6 (600 nmol / L). Protein expression was induced by the addition of 500 μmol / L isopropyl-β-thiogalactopyranoside. E. coli was cultured at 20°C for 17–18 h and then harvested by centrifugation. The collected E. coli was resuspended in suspension buffer (20 mmol / L HEPES-NaOH, 500 mmol / L sodium chloride, 1% ethylene glycol, 0.1% Pluronic® F-68 (pH 8.0), cOmplete, EDTA-free (Roche) (pH 8.0)) and then disrupted using a Microfluidizer M-110H (Mizuho Industries Co., Ltd.). After removing the precipitate by centrifugation, the supernatant was passed through DDDDK-tagged Protein Purification Gel (MBL, type The DDDDK-tagged Protein PUR was washed with washing buffer (20 mmol / L HEPES-NaOH, 500 mmol / L sodium chloride, 1% ethylene glycol, 0.1% Pluronic F-68 (pH 8.0)). After washing the IFICATION GEL, the bound protein was eluted with elution buffer 1 (20 mmol / L HEPES-NaOH, 100 μg / mL peptide (amino acid sequence DYKDDDDK) (SEQ ID NO: 1), 500 mmol / L sodium chloride, 1% ethylene glycol, 0.1% Pluronic F-68 (pH 8.0)). The eluted fractions containing the FLAG-tagged protein were pooled and concentrated by ultrafiltration, and then loaded onto a gel filtration column (HiLoad 26 / 60 Superdex 200 (GE Healthcare)). Add elution buffer 2 (20 mmol / L) Elution was performed with HEPES-NaOH, 150 mmol / L sodium chloride, 0.5 mmol / L ethylenediaminetetraacetic acid (EDTA), 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0). The eluted fractions were pooled and stored at -80°C.

[0473] PDH (porcine heart PDH complex, Sigma P7032) and 0.5 μg / mL hPDHK2 were mixed in assay buffer (50 mmol / L 3-morpholinopropanesulfonic acid (pH 7.0), 20 mmol / L dipotassium hydrogen phosphate, 60 mmol / L potassium chloride, 2 mmol / L magnesium chloride, 0.4 mmol / L EDTA, 0.2% poloxamer, 2 mmol / L dithiothreitol) to a final PDH concentration of 0.025 U / mL, and the mixture was incubated overnight at 4°C to prepare a PDH / hPDHK2 complex solution. PDH was mixed with the assay buffer to a final concentration of 0.025 U / mL, and the mixture was incubated at 4°C overnight to prepare a PDH solution. Test compounds were diluted in DMSO. To measure the inhibitory effect of test compounds on PDHK activity in the PDH / hPDHK2 complex solution, 20 μL of PDH / hPDHK2 complex solution, 1.5 μL of test compound, and 8.5 μL of 1.06 μmol / L ATP (diluted with assay buffer) were added to a 384-well microplate (Greiner Bio-One 781801), and the PDHK reaction was carried out at room temperature for 45 minutes (test compound wells). 1.5 μL of DMSO was added to control wells instead of the test compound. 1.5 μL of DMSO was added to blank wells instead of the test compound, and PDH solution was added instead of the PDH / hPDHK2 complex solution. To measure the inhibitory effect of test compounds on PDHK activity inherent in the PDH solution, the test compound was added to blank + test compound wells, and PDH solution was added instead of the PDH / hPDHK2 complex solution.

[0474] Subsequently, 10 μL of substrate (5 mmol / L sodium pyruvate, 5 mmol / L coenzyme A, 12 mmol / L NAD, 5 mmol / L thiamine pyrophosphate, diluted with assay buffer) was added, and the mixture was incubated at room temperature for 90 minutes to measure the residual PDH activity.

[0475] The absorbance at 340 nm in each well was measured using a microplate reader to detect NADH produced by the PDH reaction. The PDH activity in each well was calculated from the change in absorbance before and after the PDH reaction. The PDH activity of the test compound-treated sample was calculated using the formula {PDH activity in the test compound well - (blank + PDH activity in the test compound well - PDH activity in the blank well)}. The hPDHK2 inhibition rate (%) of the test compound was calculated using the formula [{(PDH activity in the test compound-treated sample - PDH activity in the control well) / (PDH activity in the blank well - PDH activity in the control well)} x 100]. IC 50 The values ​​were calculated by logistic regression based on the test compound concentration and the hPDHK2 inhibition rate (%).

[0476] The results are shown in the table below. IC 50 When a value could not be calculated, the value indicated was the inhibition rate at the lowest or highest concentration of the test compound in that assay. For example, the compound of Example 12 showed a 35% hPDHK2 inhibition rate at 0.1 μM.

[0477] [Table 2-1]

[0478] [Table 2-2]

[0479] [Table 2-3]

[0480] [Table 2-4]

[0481] Examples of the formulation of the present invention include the following formulations: However, the present invention is not limited to these formulation examples.

[0482] Formulation Example 1: Capsule production 1) 30 mg of the compound of Example 1 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0483] Formulation Example 2: Tablet manufacturing 1) 10 g of the compound of Example 1 2) Lactose 50 g 3) 15g corn starch 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amount of 1), 2), and 3) and 30 g of 4) are mixed with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and compressed into tablets using a tablet press. 1,000 tablets containing 10 mg of the compound of Example 1 are thus obtained.

[0484] Formulation Example 3: Manufacture of injections 1) 5 mg of the compound of Example 1 2) D-mannitol 5 g 3) 100 mL of distilled water 3) is prepared by dissolving 1) and 2) and fills an injection container, seals it, and then sterilizes it. [Industrial Applicability]

[0485] The compound of formula [Ia] or a pharmaceutically acceptable salt thereof has PDHK inhibitory activity, and therefore, Diabetic diseases (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetes) and mitochondrial encephalomyopathy, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, or chronic kidney disease.

Claims

1. A compound of formula [Ia], or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, The dotted bond is a single or double bond, X １ , X ２ , X ３ and X ４ are each independently C or N, and Y １ and Y ２ are each independently C, N or O (wherein X ２ , X ３ , X ４ , Y １ or Y ２ the total number of N and O as R Ａ is C １－４ is alkyl, R Ｂ teeth, (1) halogen, (2) cyano, (3) hydroxy, (4) oxo, (5) -COR １ {where R １ teeth (A) hydrogen, (B) —OH, (C)-NR ２ R ３ (where R ２ and R ３ are each independently hydrogen or C １－４ alkyl), or (D) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, wherein the saturated heterocyclyl is optionally substituted with one or two halogens; (6) C １－８ alkyl {wherein the C １－８ Alkyl is (A) a halogen, (B) hydroxy, (C) phenyl optionally substituted with halogen; (D) Halo C １－４ pyridyl optionally substituted with alkyl, and (E)-OR ４ (where R ４ teeth, (a) C １－４ Alkyl, (b) phenyl optionally substituted with halogen, or (c) C １－４ benzyl optionally substituted with alkoxy and optionally substituted with 1 to 8 substituents independently selected from the group consisting of: (7) C １－８ Alkoxy {wherein the C １－８ Alkoxy is (A) a halogen, (B) cyano, (C) hydroxy, (D) C optionally substituted with 1 to 3 halogens １－４ Alkoxy, (E) C １－４ alkylsulfonyl, (F) Cyano and Cyano C １－４ C optionally substituted with one substituent selected from the group consisting of alkyl ３－６ cycloalkyl, (G) phenyl optionally substituted with cyano; (H)-COCy １ (where Cy １ is a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, which saturated heterocyclyl may be substituted with one or two halogens, and (I) a 4- to 6-membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the saturated heterocyclyl is (a) C １－４ Alkyl, (b) oxo, (c) C １－４ alkylcarbonyl, (d) benzoyl optionally substituted with halogen, and (e) C １－４ Alkyl sulfonyl and wherein the saturated heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: １－４ When substituted with alkyl, two C １－４ Alkyl groups may be joined to each other to form a bridged ring together with the atoms to which they are attached. and optionally substituted with 1 to 8 substituents independently selected from the group consisting of: (8)-Cy ２ {where Cy ２ teeth, (A) C ３－６ Cycloalkyl (wherein the C ３－６ Cycloalkyl is (a) a halogen, (b) C １－４ Alkyl, (c) Halo C １－４ alkyl, and (d) phenyl optionally substituted with halogen and optionally substituted with one or two substituents independently selected from the group consisting of: (B) Halogen, HaloC １－４ Alkyl, and C １－4 Independently from the group consisting of alkoxy phenyl, optionally substituted with one or two substituents selected from the following: (C) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom or one oxygen atom, wherein the saturated heterocyclyl is (a) a phenyl optionally substituted with halogen and (b) C １－４ alkylcarbonyl); or (9)-OCy ３ {where Cy ３ teeth (A) a 4- to 6-membered saturated heterocyclyl having one nitrogen atom or one oxygen atom, wherein the saturated heterocyclyl is (a) benzoyl optionally substituted with halogen and (b) C １－４ alkylcarbonyl), or (B) a 6-membered heteroaryl having 1 or 2 nitrogen atoms, wherein the heteroaryl is cyano, haloC １－４ Alkyl, and C ３－６ cycloalkyl); m is 0 or 1; n is 0, 1 or 2, and when n is 2, each R Ｂ may be the same or different.

2. Formula [Ib]: 【Chemistry 2】 (In the formula, each symbol has the same meaning as in claim 1.) or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts.

3. Formula [Ic]: 【Transformation 3】 (In the formula, each symbol has the same meaning as in claim 1.) 3. The compound of claim 1 or 2, wherein the compound is: or a pharmaceutically acceptable salt thereof.

4. 4. The compound according to any one of claims 1 to 3, wherein n is 1, or a pharmaceutically acceptable salt thereof.

5. Formula [Id]: 【Chemistry 4】 (In the formula, the symbols have the same meanings as in claim 1.) 5. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

6. Formula [Ie]: 【Transformation 5】 (In the formula, the symbols have the same meanings as in claim 1.) 5. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

7. R Ｂ but, (1) C １－８ alkyl {wherein the C １－８ Alkyl is (A) a halogen, (B) hydroxy, (C) phenyl optionally substituted with halogen; (D) Halo C １－４ pyridyl optionally substituted with alkyl, and (E)-OR ４ (where R ４ teeth, (a) C １－４ Alkyl, (b) phenyl optionally substituted with halogen, or (c) C １－４ benzyl optionally substituted with alkoxy and optionally substituted with 1 to 8 substituents independently selected from the group consisting of: (2) C １－８ Alkoxy {wherein the C １－８ Alkoxy is (A) a halogen, (B) cyano, (C) hydroxy, (D) C optionally substituted with 1 to 3 halogens １－４ Alkoxy, (E) C １－４ alkylsulfonyl, (F) Cyano and Cyano C １－４ C optionally substituted with one substituent selected from the group consisting of alkyl ３－６ cycloalkyl, (G) phenyl optionally substituted with cyano; (H)-COCy １ (where Cy １ is a 4- to 6-membered saturated heterocyclyl having one nitrogen atom, which saturated heterocyclyl may be substituted with one or two halogens, and (I) a 4- to 6-membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the saturated heterocyclyl is (a) C １－４ Alkyl, (b) oxo, (c) C １－４ alkylcarbonyl, (d) benzoyl optionally substituted with halogen, and (e) C １－４ Alkyl sulfonyl and wherein the saturated heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: １－４ When substituted with alkyl, two C １－４ Alkyl groups may be joined to each other to form a bridged ring together with the atoms to which they are attached.

7. The compound of claim 1, wherein R is an integer from 1 to 6; and R is an integer from 1 to 8 ...

8. The following formula: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

9. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A PDHK inhibitor comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. A PDHK2 inhibitor comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

12. 9. A therapeutic or preventive agent for diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy or chronic kidney disease, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

13. The therapeutic or preventive agent according to claim 12, wherein the diabetes is type 1 diabetes or type 2 diabetes.

14. The therapeutic or preventive agent according to claim 12, wherein the vascular dementia is large vessel disease type or small vessel disease type vascular dementia.

15. The therapeutic or prophylactic agent according to claim 12, wherein the heart failure is acute heart failure or chronic heart failure.

16. The therapeutic or prophylactic agent according to claim 12, wherein the pulmonary hypertension is pulmonary arterial hypertension.

17. 10. A method of inhibiting PDHK, comprising administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

18. A method for treating or preventing a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof to a mammal.

19. 19. The method of claim 18, wherein the diabetes is type 1 diabetes or type 2 diabetes.

20. 19. The method of claim 18, wherein the vascular dementia is large vessel or small vessel vascular dementia.

21. 19. The method of claim 18, wherein the heart failure is acute heart failure or chronic heart failure.

22. 19. The method of claim 18, wherein the pulmonary hypertension is pulmonary arterial hypertension.

23. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a PDHK inhibitor.

24. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.

25. 25. The use according to claim 24, wherein the diabetes is type 1 diabetes or type 2 diabetes.

26. 25. The use according to claim 24, wherein the vascular dementia is large vessel or small vessel vascular dementia.

27. 25. The use according to claim 24, wherein the heart failure is acute heart failure or chronic heart failure.

28. 25. The use according to claim 24, wherein the pulmonary hypertension is pulmonary arterial hypertension.

29. 9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of diabetes mellitus, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.

30. 30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the diabetes is type 1 diabetes or type 2 diabetes.

31. 30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein the vascular dementia is large vessel disease type or small vessel disease type vascular dementia.

32. 30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the heart failure is acute heart failure or chronic heart failure.

33. 30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the pulmonary hypertension is pulmonary arterial hypertension.

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