Condensed tricyclic compound and its medical use

Abstract

The present invention provides compounds having PDHK inhibitory activity and can be used to treat or prevent diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, 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, cerebral 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. The present invention relates to a compound of formula [I-a] or a pharmaceutically acceptable salt thereof: #imgabs0# wherein each symbol is as defined in the specification.

Description

Technical Field

[0001] The present invention relates to a fused tricyclic compound and its medical 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 them, and a therapeutic or preventive agent containing them for diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, 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 artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral 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, etc. Background Art

[0002] In tissues, for reactions using energy such as biosynthesis, active transport, muscle contraction, etc., energy is provided by the hydrolysis of adenosine triphosphate (ATP). ATP is produced by the oxidation of metabolic fuels, which produce a large amount of energy, such as glucose and free fatty acids. In oxidative tissues such as muscles, ATP is mainly produced by acetyl-CoA entering the citric acid cycle. Acetyl-CoA is produced by the oxidation of glucose or the beta oxidation of free fatty acids by the glycolytic pathway. An enzyme that plays a key role in controlling the production of acetyl-CoA from glucose is pyruvate dehydrogenase (hereinafter abbreviated as PDH). PDH catalyzes the reduction of nicotinamide adenine dinucleotide (NAD) to NADH, while oxidizing pyruvate to acetyl-CoA and carbon dioxide (e.g., non-patent literature 1, 2).

[0003] PDH is a multienzyme complex composed of three enzyme components (E1, E2, and E3) and some subunits located in the mitochondrial matrix. E1, E2, and E3 are responsible for decarboxylation from pyruvate, generation of acetyl-CoA, and reduction of NAD to NADH, respectively.

[0004] Two types of enzymes with regulatory functions bind to PDH. One is PDHK, which is a protein kinase specific for PDH. Its function is to inactivate the E1α subunit of the PDH complex by phosphorylation. The other is PDH phosphatase, which is a specific protein phosphatase that activates PDH by dephosphorylation of the E1α subunit. The proportion of PDH in its active (dephosphorylated) state 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 NADH / NAD, acetyl-CoA / CoA, and ATP / adenosine diphosphate (ADP) ratios, and is inhibited by pyruvate (e.g., Non-Patent Document 3).

[0005] In mammalian tissues, four PDHK isozymes have been identified. Specifically, PDHK2 is expressed in a wide range of tissues, including the liver, skeletal muscle, and adipose tissue, which are involved in glucose metabolism. In addition, since PDHK2 exhibits relatively high sensitivity to activation caused by increased NADH / NAD or acetyl-CoA / CoA and inhibition caused by pyruvate, it is proposed to be involved in short-term regulation of glucose metabolism (e.g., Non-Patent Document 4).

[0006] In addition, PDHK1 is abundantly expressed in cardiac muscle, skeletal muscle, pancreatic β cells, etc. Furthermore, since the expression of PDHK1 is induced by the activation of hypoxia-inducible factor (HIF) 1 under ischemic conditions, it is proposed to be involved in ischemic diseases and cancerous diseases (eg, Non-Patent Document 5).

[0007] In diseases such as insulin-dependent (type 1) diabetes, non-insulin-dependent (type 2) diabetes, etc., lipid oxidation is promoted and glucose utilization is reduced. This reduction in glucose utilization is one of the factors leading to hyperglycemia. When oxidative glucose metabolism is reduced in type 1 and type 2 diabetes and obesity, PDH activity is also reduced. This indicates that reduced PDH activity is related to reduced glucose utilization in type 1 and type 2 diabetes (e.g., non-patent literature 6, 7).

[0008] In contrast, hepatic gluconeogenesis is enhanced in type 1 and type 2 diabetes, which is also a factor leading to hyperglycemia. Reduced PDH activity increases pyruvate concentration, which in turn increases the availability of lactate as a substrate for hepatic gluconeogenesis. This suggests that reduced PDH activity may be associated with enhanced gluconeogenesis in type 1 and type 2 diabetes (e.g., Non-Patent Literature 8, 9).

[0009] When PDH is activated by inhibition of PDHK, it is believed that the glucose oxidation rate increases, thereby promoting glucose utilization in the body and inhibiting hepatic gluconeogenesis, thereby being expected to improve hyperglycemia in type 1 and type 2 diabetes (eg, non-patent documents 10, 11, 12).

[0010] Another factor contributing to diabetes is impaired insulin secretion, which is known to be associated with reduced PDH activity and induction of PDHK1, 2, and 4 in pancreatic β cells (eg, Non-Patent Documents 13, 14).

[0011] In addition, it is known that persistent hyperglycemia caused by diabetes can cause complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, etc. Thiamine and α-lipoic acid promote the activation of PDH as coenzymes. Thiamine and α-lipoic acid, or thiamine derivatives and α-lipoic acid derivatives have been shown to have a good effect on the treatment of diabetic complications. Therefore, the activation of PDH is expected to improve diabetic complications (e.g., Non-Patent Literature 15, 16).

[0012] Under ischemic conditions, limited oxygen supply can reduce the oxidation of glucose and fatty acids, and reduce the amount of ATP produced by oxidative phosphorylation in tissues. In the absence of sufficient oxygen, ATP levels are maintained by promoting anaerobic glycolysis. Therefore, lactic acid increases, and intracellular pH decreases. Even if cells attempt to maintain the steady state of ions by energy consumption, abnormally low ATP levels and damaged cell osmotic pressures can also lead to cell death. In addition, the adenosine monophosphate activated kinase activated under ischemic conditions inactivates acetyl-CoA carboxylase by phosphorylation. The level of total malonyl-CoA in tissues decreases, and carnitine palmitoyl transferase-I activity therefore increases, and fatty acid oxidation is superior to glucose oxidation by allowing acyl-CoA to be transported to mitochondria. Compared with the oxidation of fatty acids, the oxidation of glucose can produce more ATP per molecule of oxygen. Therefore, under ischemic conditions, when energy metabolism becomes glucose oxidation dominant by the activation of PDH, the ability to maintain ATP levels is considered to be enhanced (for example, non-patent literature 17).

[0013] In addition, since the activation of PDH causes the oxidation of pyruvic acid produced by glycolysis and reduces the production of lactic acid, it is believed that the net proton load in ischemic tissue is reduced. Therefore, the activation of PDH by the inhibition of PDHK is expected to play a protective role in ischemic diseases such as myocardial ischemia (e.g., non-patent literature 18, 19).

[0014] Drugs that activate PDH by inhibiting PDHK are thought to reduce lactate production because they promote pyruvate metabolism. Therefore, such drugs are expected to be used to treat hyperlactatemia such as mitochondrial diseases, mitochondrial encephalomyopathy and sepsis (e.g., Non-Patent Document 20).

[0015] In cancer cells, the expression of PDHK1 or 2 increases. In addition, in cancer cells, the ATP produced by oxidative phosphorylation in mitochondria decreases, and the ATP produced by anaerobic glycolysis in the cytoplasm increases. Activating PDH by inhibiting PDHK is expected to promote oxidative phosphorylation in mitochondria and increase the production of reactive oxygen species, which will induce apoptosis of cancer cells. Therefore, activating PDH by PDHK inhibition can be used to treat cancerous diseases (e.g., non-patent literature 21).

[0016] Pulmonary hypertension is characterized by hypertension caused by partial stenosis of the pulmonary artery, which is due to cell proliferation promoted in the pulmonary artery. Therefore, in pulmonary hypertension, the activation of PDH in pulmonary artery cells is expected to promote oxidative phosphorylation in mitochondria, increase the production of reactive oxygen species, and induce apoptosis of pulmonary artery cells. Therefore, activating PDH by PDHK inhibition is considered to be useful for treating pulmonary hypertension, for example, pulmonary arterial hypertension (e.g., non-patent literature 22).

[0017] Energy generation and glucose metabolism in the brain decrease in Alzheimer's disease, and PDH activity also decreases. When PDH activity decreases, the generation of acetyl-CoA decreases. Acetyl-CoA is used for ATP production in the electron transport system through the citric acid cycle. Acetyl-CoA is also the starting material for synthesizing acetylcholine, which is one of the neurotransmitters. Therefore, the brain PDH activity reduced in Alzheimer's disease is considered to cause neuronal cell death due to reduced ATP generation. In addition, it is believed that the synthesis of acetylcholine (which is a transmitter of cholinergic nerves) is inhibited, thereby inducing memory decline, etc. The activation of PDH in the brain is expected to improve energy generation and acetylcholine synthesis in Alzheimer's disease. Therefore, activating PDH by the inhibition of PDHK is considered to be useful for treating Alzheimer's disease (e.g., non-patent literature 23, 24).

[0018] Vascular dementia is a disease that is roughly divided into large vessel type and small vessel type. In large vessel type, cerebral infarction including ischemia-reperfusion is a factor, and neuronal cell death is induced by the increase of pyruvic acid and lactic acid values ​​and the reduction of energy production, and the increase of pyruvic acid and lactic acid values ​​is due to the reduction of PDH activity in the brain. In small vessel type, white matter damage caused by cerebral hypoperfusion is a factor, and it is considered that the chronic decline of glucose metabolism causes cognitive dysfunction. When PDH in the brain is activated in vascular dementia, it is expected that lactic acid values, etc. are reduced and the increase of energy production in large vessel type, and it is expected that the glucose metabolism promoted in small vessel type. Therefore, the activation of PDH by PDHK inhibitor is considered to be useful for treating vascular dementia (e.g., non-patent literature 28,29,30).

[0019] It has been demonstrated that dichloroacetic acid, which is a drug having a PDH activating effect, provides good effects in the treatment of diabetes, myocardial ischemia, myocardial infarction, angina pectoris, heart failure, hyperlactatemia, cerebral ischemia, cerebral stroke, peripheral arterial disease, chronic obstructive pulmonary disease, cancerous diseases and pulmonary hypertension (e.g., Non-Patent Documents 10, 18, 20, 22, 25, 26, 27).

[0020] It has been demonstrated that compounds having PDHK inhibitory effects have a neuroprotective effect on retinal ischemia-reperfusion injury (Non-patent Document 31). Retinal ischemic injury is involved in diseases such as glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, and the like.

[0021] It has also been demonstrated that compounds having a PDHK inhibitory effect reduce the severity of the disease in disease model animals showing chronic kidney disease-like renal impairment and reduced renal function (Patent Document 1).

[0022] According to the aforementioned discovery, PDHK inhibitors are considered to be useful for treating or preventing diseases associated with glucose utilization disorders, such as diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataracts, etc.). In addition, PDHK inhibitors are considered to be useful for treating or preventing diseases caused by the limited energy matrix supply to tissues, such as heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral stroke, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy and chronic kidney disease. In addition, PDHK inhibitors are considered to be useful for treating or preventing mitochondrial diseases, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, etc.

[0023] Therefore, PDHK inhibitors are believed to be useful for treating or preventing diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, 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 artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral 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.

[0024] Literature List

[0025] Patent Literature

[0026] Patent Document 1: WO 2020 / 054734

[0027] Non-patent literature

[0028] Non-patent literature 1: Reed LJ, Hackert ML. Structure-function relationships of indihydrolipoamide acyltransferases. J Biol Chem. 1990 June 5; 265(16):8971-4.

[0029] Non-patent literature 2: Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J. 1990 November; 4(14):3224-33.

[0030] Non-patent literature 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.

[0031] 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 pyruvatedehydrogenase complex. Biochem J. 1998 January 1; 329 (Pt 1): 191-6.

[0032] Non-patent literature 5: Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: ametabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006 March; 3(3):177-85.

[0033] Non-patent literature 6: Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N et al. Reduced mitochondrial density and increased IRS-1 serinephosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005 Dec;115(12):3587-93.

[0034] Non-patent literature 7: Caterson ID, Fuller SJ, Randle PJ. Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvatedehydrogenase complex activity in starved and alloxan-diabetic rats. Biochem J. 1982 Oct 15; 208(1):53-60.

[0035] Non-patent literature 8: Boden G, Chen X, Stein TP. Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. Am JPhysiol Endocrinol Metab. 2001 January; 280(1):E23-30.

[0036] Non-patent literature 9: Shangraw RE, Fisher DM. Pharmacokinetics and pharmacological dynamics of dichloroacetate in patients with cirrhosis. Clin Pharmacol Ther. 1999 Oct; 66(4):380-90.

[0037] Non-patent literature 10: Stacpoole PW, Moore GW, Kornhauser DM. Metabolism effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med. 1978 Mar 9; 298(10):526-30.

[0038] Non-patent literature 11: Mayers RM, Leighton B, Kilgour E. PDH kinaseinhibitors: a novel therapy for Type II diabetes Biochem Soc Trans. 2005 Apr;33(Pt 2):367-70.

[0039] Non-patent literature 12: Jeoung NH, Rahimi Y, Wu P, Lee WN, Harris RA. Fasting induces ketoacidosis and hypothermia in PDHK2 / PDHK4-double-knockout mice. Biochem J. 2012 May 1; 443(3):829-39.

[0040] Non-patent literature 13: Zhou YP, Berggren PO, Grill V. A fatty acid-induceddecrease in pyruvate dehydrogenase activity is an importantdeterminant of beta-cell dysfunction in the obese diabetic db / db mouse. Diabetes. 1996 May;45(5):580-6.

[0041] Non-patent literature 14: Xu J, Han J, Epstein PN, Liu YQ. Regulation of PDK mRNA by high fatty acid and glucose in pancreatic islets. BiochemBiophys ResCommun. 2006.6.9; 344(3):827-33.

[0042] Non-patent literature 15: Benfotiamine. Monograph. Altern Med Rev. 2006 Sep;11(3):238-42.

[0043] Non-patent literature 16: Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoicAcid and diabetic neuropathy. Rev Diabet Stud. 2009 Winter; 6(4):230-6.

[0044] Non-patent literature 17: Ussher JR, Lopaschuk GD. The malonyl CoA axis as a potential target for treating ischaemic heart disease. Cardiovasc Res. 2008 Jul 15; 79(2):259-68.

[0045] Non-patent literature 18: Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol. 1988 Jan 1; 61(1):65-70.

[0046] Non-patent literature 19: Taniguchi M, Wilson C, Hunter CA, Pehowich DJ,Clanachan AS, Lopaschuk GD. Dichloroacetate improves cardiacefficiency afterischemia independent of changes in mitochondrial proton leak. Am J PhysiolHeart Circ Physiol. 2001 April; 280(4):H1762-9.

[0047] Non-patent literature 20: Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol. 2003 July; 43(7):683-91.

[0048] Non-patent literature 21: Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R et al. A mitochondria-K+ channel axis is suppressed incancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007 Jan;11(1):37-51.

[0049] Non-patent document 22: McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004 Oct 15; 95(8):830-40.

[0050] Non-patent literature 23: Saxena U. Bioenergetics breakdown in Alzheimer's disease: targets for new therapies. Int J Physiol Pathophysiol Pharmacol. 2011; 3(2):133-9.

[0051] Non-patent literature 24: Stacpoole PW. The pyruvate dehydrogenase complex as atherapeutic target for age-related diseases. AgingCell. 2012 Jun; 11(3):371-7.

[0052] Non-patent literature 25: Marangos PJ, Turkel CC, Dziewanowska ZE, Fox AW. Dichloroacetate and cerebral ischaemia therapeutics. Expert Opin Investig Drugs. 1999 April; 8(4):373-82.

[0053] Non-patent literature 26: Calvert LD, Shelley R, Singh SJ, Greenhaff PL, BankartJ, Morgan MD et al. Dichloroacetateenhances performance and reduces bloodlactate during maximal cycle exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 May 15; 177(10):1090-4.

[0054] Non-patent literature 27: Flavin DF. Non-Hodgkin's Lymphoma Reversal with Dichloroacetate. J Oncol. Hindawi Publishing Corporation Journal of Oncology Volume 2010, Article ID 414726, 4 pages, doi:10.1155 / 2010 / 414726.

[0055] Non-patent literature 28: Froelich L, Goetz ME, Weinmueller M, Youdim MB, BarthN, Dirr A, Gsell W, Jellinger K, Beckmann H, Riederer P. (r)-,but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia. J Neural Transm(Vienna). March 2004; 111(3):295-310

[0056] Non-patent literature 29: Parnetti L, Reboldi GP, Gallai V. Cerebrospinal fluid pyruvate levels in Alzheimer's disease and vascular dementia. Neurology. 2000 Feb 8; 54(3):735-7.

[0057] Non-patent literature 30: Pascual B, Prieto E, Arbizu J, Marti-Climent J, Olier J, Masdeu JC. Brain glucose metabolism in vascular whitematter disease with dementia: differentiation from Alzheimer disease. Stroke. 2010 Dec; 41(12):2889-93.

[0058] Non-patent literature 31: Sato K, Mochida S, Tomimoto D, Konuma T, Kiyota N, Tsuda S, Shiga Y, Omodaka K, Nakazawa T. A pyruvatedehydrogenase kinaseinhibitor prevents retinal cell death and improves energy metabolism in ratretinas after ischemia / reperfusion injury. Experimental eyeresearch 2020 April; 193: 107997. SUMMARY OF THE INVENTION

[0060] The present invention is as follows.

[0061] [1] A compound of formula [Ia] or a pharmaceutically acceptable salt thereof:

[0062]

[0063] in

[0064] The bonds in dotted form are single or double bonds.

[0065] X 1 , X 2 , X 3 and X 4 are independently C or N, Y 1 and Y 2 Each independently is C, N or O (wherein X 2 , X 3 , X 4 , Y 1 or Y 2 The total number of N and O is 0-3),

[0066] R A It is C 1-4 alkyl,

[0067] R B yes

[0068] (1) Halogen,

[0069] (2) cyano group,

[0070] (3) hydroxyl group,

[0071] (4) Oxo,

[0072] (5) -COR 1 {where R 1 yes

[0073] (A) Hydrogen,

[0074] (B) -OH,

[0075] (C) -NR 2 R 3 (where R 2 and R 3 are independently hydrogen or C 1-4 alkyl), or

[0076] (D) a 4-6 membered saturated heterocyclic group having one nitrogen atom (wherein the saturated heterocyclic group is optionally substituted by 1 or 2 halogens)},

[0077] (6) C 1-8 Alkyl {wherein the C 1-8 The alkyl group is optionally substituted with 1 to 8 substituents independently selected from

[0078] (A) halogen,

[0079] (B) hydroxyl group,

[0080] (C) phenyl optionally substituted by halogen,

[0081] (D) optionally halogenated C 1-4 an alkyl-substituted pyridyl group, and

[0082] (E) -OR 4 (where R 4 yes

[0083] (a) C 1-4 alkyl,

[0084] (b) phenyl optionally substituted by halogen, or

[0085] (c) optionally C 1-4alkoxy-substituted benzyl)},

[0086] (7) C 1-8 Alkoxy {wherein the C 1-8 The alkoxy group is optionally substituted with 1-8 substituents independently selected from

[0087] (A) halogen,

[0088] (B) cyano,

[0089] (C) hydroxyl group,

[0090] (D) C optionally substituted by 1 to 3 halogens 1-4 Alkoxy,

[0091] (E) C 1-4 Alkylsulfonyl,

[0092] (F) C optionally substituted with one substituent 3-6 Cycloalkyl, the substituent is selected from cyano and cyanoC 1-4 alkyl,

[0093] (G) phenyl optionally substituted by cyano,

[0094] (H)-COCy 1 (Among which Cy 1 is a 4-6 membered saturated heterocyclic group having one nitrogen atom, and the saturated heterocyclic group is optionally substituted by 1 or 2 halogens), and

[0095] (I) a 4-6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom (wherein the saturated heterocyclic group is optionally substituted by 1 to 4 substituents independently selected from

[0096] (a) C 1-4 alkyl,

[0097] (b) oxo,

[0098] (c) C 1-4 Alkylcarbonyl,

[0099] (d) benzoyl optionally substituted by halogen, and

[0100] (e) C 1-4 Alkylsulfonyl,

[0101] When the saturated heterocyclic group is replaced by two C 1-4 When alkyl is substituted, the two C 1-4 The alkyl groups are optionally bonded to each other to form a bridged ring together with the atoms to which they are bonded)},

[0102] (8) -Cy 2 {where Cy 2 yes

[0103] (A) C 3-6 Cycloalkyl (wherein the C 3-6 The cycloalkyl group is optionally substituted with 1 or 2 substituents independently selected from

[0104] (a) halogen,

[0105] (b) C 1-4 alkyl,

[0106] (c) Halogenated C 1-4 Alkyl, and

[0107] (d) phenyl optionally substituted by halogen),

[0108] (B) phenyl optionally substituted by 1 or 2 substituents independently selected from halogen, halogenated C 1-4 Alkyl and C 1-4 Alkoxy, or

[0109] (C) a 4-6 membered saturated heterocyclic group having one nitrogen atom or oxygen atom (wherein the saturated heterocyclic group is optionally substituted by a substituent selected from (a) phenyl optionally substituted by halogen and (b) C 1-4 alkylcarbonyl)}, or

[0110] (9) -OCy 3 {where Cy 3 yes

[0111] (A) a 4-6 membered saturated heterocyclic group having one nitrogen atom or oxygen atom (wherein the saturated heterocyclic group is optionally substituted by a substituent selected from (a) a benzoyl group optionally substituted by a halogen group and (b) a 1-4 alkylcarbonyl), or

[0112] (B) a 6-membered heteroaryl group having 1 or 2 nitrogen atoms (wherein the heteroaryl group is optionally substituted by 1 or 2 substituents independently selected from cyano, halo 1-4 Alkyl and C 3-6 Cycloalkyl)},

[0113] m is 0 or 1, and

[0114] n is 0, 1, or 2. When n is 2, each R B Can be the same or different.

[0115] [2] The compound of [1] or a pharmaceutically acceptable salt thereof, which is a compound of formula [Ib] or a pharmaceutically acceptable salt thereof:

[0116]

[0117] where each symbol is as defined in [1].

[0118] [3] The compound of [1] or [2] or a pharmaceutically acceptable salt thereof, which is a compound of formula [Ic] or a pharmaceutically acceptable salt thereof:

[0119]

[0120] where each symbol is as defined in [1].

[0121] [4] The compound of any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0122] [5] The compound of any one of [1] to [4] or a pharmaceutically acceptable salt thereof, which is a compound of formula [Id] or a pharmaceutically acceptable salt thereof:

[0123]

[0124] where the symbols are as defined in [1].

[0125] [6] The compound of any one of [1] to [4] or a pharmaceutically acceptable salt thereof, which is a compound of formula [Ie] or a pharmaceutically acceptable salt thereof:

[0126]

[0127] where the symbols are as defined in [1].

[0128] [7] The compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein R B yes

[0129] (1) C 1-8 Alkyl {wherein the C 1-8 The alkyl group is optionally substituted with 1 to 8 substituents independently selected from

[0130] (A) halogen,

[0131] (B) hydroxyl group,

[0132] (C) phenyl optionally substituted by halogen,

[0133] (D) optionally halogenated C 1-4 an alkyl-substituted pyridyl group, and

[0134] (E) -OR 4 (where R 4yes

[0135] (a) C 1-4 alkyl,

[0136] (b) phenyl optionally substituted by halogen, or

[0137] (c) optionally C 1-4 alkoxy-substituted benzyl)}, or

[0138] (2) C 1-8 Alkoxy {wherein the C 1-8 The alkoxy group is optionally substituted with 1-8 substituents independently selected from

[0139] (A) halogen,

[0140] (B) cyano,

[0141] (C) hydroxyl group,

[0142] (D) C optionally substituted by 1 to 3 halogens 1-4 Alkoxy,

[0143] (E) C 1-4 Alkylsulfonyl,

[0144] (F) C optionally substituted with one substituent 3-6 Cycloalkyl, the substituent is selected from cyano and cyanoC 1-4 alkyl,

[0145] (G) phenyl optionally substituted by cyano,

[0146] (H)-COCy 1 (Among which Cy 1 is a 4-6 membered saturated heterocyclic group having one nitrogen atom, and the saturated heterocyclic group is optionally substituted by 1 or 2 halogens), and

[0147] (I) a 4-6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom (wherein the saturated heterocyclic group is optionally substituted by 1 to 4 substituents independently selected from

[0148] (a) C 1-4 alkyl,

[0149] (b) oxo,

[0150] (c) C 1-4 Alkylcarbonyl,

[0151] (d) benzoyl optionally substituted by halogen, and

[0152] (e) C 1-4Alkylsulfonyl,

[0153] When the saturated heterocyclic group is replaced by two C 1-4 When alkyl is substituted, the two C 1-4 The alkyl groups are optionally bonded to each other to form a bridged ring together with the atoms to which they are bonded).

[0154] [8] A compound selected from the following formula or a pharmaceutically acceptable salt thereof:

[0155]

[0156] [9] A pharmaceutical composition comprising the compound of any one of [1] to [8] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0157]

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

[0158]

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

[0159]

[12] An agent for treating or preventing 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, cerebral 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, the agent comprising a compound of any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0160]

[13] The agent of

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

[0161]

[14] The agent of

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

[0162]

[15] The agent of

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

[0163]

[16] The agent of

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

[0164]

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

[0165]

[18] A method for treating or preventing 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, cerebral 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, the method comprising administering to a mammal a therapeutically effective amount of a compound of any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0166]

[19] The method of

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

[0167]

[20] The method of

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

[0168]

[21] The method of

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

[0169]

[22] The method of

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

[0170]

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

[0171]

[24] Use of a compound of any one of [1] to [8] or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing 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, cerebral 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.

[0172]

[25] The use of

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

[0173]

[26] The use of

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

[0174]

[27] The use of

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

[0175]

[28] The use of

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

[0176]

[29] A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [8] for use in treating or preventing 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, cerebral 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.

[0177]

[30] The compound of

[29] or a pharmaceutically acceptable salt thereof, wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0178]

[31] The compound of

[29] or a pharmaceutically acceptable salt thereof, wherein the vascular dementia is large vessel type vascular dementia or small vessel type vascular dementia.

[0179]

[32] The compound of

[29] or a pharmaceutically acceptable salt thereof, wherein the heart failure is acute heart failure or chronic heart failure.

[0180]

[33] The compound of

[29] or a pharmaceutically acceptable salt thereof, wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0181]

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

[0182]

[35] A commercial package comprising the pharmaceutical composition of [9] and written materials related thereto, wherein the written materials explain that the pharmaceutical composition can be used to treat or prevent 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, cerebral 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.

[0183]

[36] A kit comprising the pharmaceutical composition of [9] and written materials related thereto, wherein the written materials indicate that the pharmaceutical composition can be used to treat or prevent 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, cerebral 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.

[0184] Description of the implementation plan

[0185] Definitions of terms used in the present invention are as follows.

[0186] "Halogen" is fluorine, chlorine, bromine or iodine. As "halogen", fluorine or chlorine is preferred.

[0187] “C 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. As "C 1-4 Alkyl", methyl is preferred.

[0188] “C 1-8 The term "alkyl" refers to a straight or branched alkyl group having 1 to 8 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, 1-ethyl-propyl, 1-methyl-1-ethyl-propyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methyl-1-propyl-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

[0189] “C 1-4 "Alkylcarbonyl" refers to a "C 1-4 As the "C alkyl" alkyl-carbonyl group, for example, acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, 2-methylbutyryl and 2,2-dimethylpropionyl are included. 1-4 Alkylcarbonyl", acetyl is preferred.

[0190] “C 1-4 "Alkylsulfonyl" refers to a "C 1-4 The alkyl-sulfonyl group as “C 2-4” includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. 1-4 "alkylsulfonyl", methylsulfonyl is preferred.

[0191] "Halogenated C 1-4 "Alkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms and substituted by 1 to 5 "halogens" as defined above. When the alkyl group is substituted by multiple halogens, the halogens may be the same or different. "Halo C 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. As "halogenated C 1-4 Alkyl", C substituted by 1-3 fluorine 1-4 An alkyl group is preferred, and a trifluoromethyl group is more preferred.

[0192] "Cyano C 1-4 "Alkyl" refers to the above-defined "C 1-4 Examples include cyanomethyl, 2-cyanoethyl, 1-cyano-1-methylethyl, 3-cyanopropyl, 4-cyanobutyl and the like.

[0193] “C 1-4 "Alkoxy" refers to a "C 1-4 As "C alkyl" alkyl-oxy, and include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. 1-4 "Alkoxy", methoxy are preferred.

[0194] “C 1-8 "Alkoxy" refers to a "C 1-8Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,2,2-trimethylpropoxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy and the like.

[0195] “C 3-6 "Cycloalkyl" refers to a 3-6 membered monocyclic hydrocarbon ring group, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As "C 3-6 Cycloalkyl", cyclopropyl is preferred.

[0196] The "4- to 6-membered saturated heterocyclic group 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 heterocyclic group include azetidinyl, pyrrolidinyl and piperidinyl.

[0197] "A 4-6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom" refers to a 4-6 membered monocyclic saturated heterocyclic group having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. Examples of saturated heterocyclic groups include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrothiopyranyl, isothiazolidinyl and the like, and oxetanyl, tetrahydrofuranyl, piperidinyl, tetrahydrothiopyranyl and isothiazolidinyl are preferred.

[0198] "When a saturated heterocyclic group is replaced by two C 1-4 When alkyl is substituted, the two C 1-4 "Alkyl groups are optionally bonded to each other to form a bridged ring together with the atoms to which they are bonded" means, for example, that the saturated heterocyclic group is the following group:

[0199] .

[0200] "A 4-6-membered saturated heterocyclic group having one nitrogen atom or oxygen atom" refers to a 4-6-membered monocyclic saturated heterocyclic group having one heteroatom independently selected from nitrogen atoms and oxygen atoms in addition to carbon atoms. Examples of saturated heterocyclic groups include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, and the like, and oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, and piperidinyl are preferred.

[0201] The "6-membered heteroaryl group having 1 or 2 nitrogen atoms" refers to a 6-membered monocyclic heteroaryl group having 1 or 2 nitrogen atoms in addition to carbon atoms. Examples of the heteroaryl group include pyridyl, pyrimidinyl and pyrazinyl.

[0202] Preferred embodiments of the compound of formula [Ia] are described below.

[0203] One of the preferred embodiments of the compound of formula [Ia] is a compound represented by formula [I-a1]:

[0204]

[0205] wherein each symbol is as defined in the aforementioned formula [Ia].

[0206] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a2]:

[0207]

[0208] wherein each symbol is as defined in the aforementioned formula [Ia].

[0209] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a3]:

[0210]

[0211] wherein each symbol is as defined in the aforementioned formula [Ia].

[0212] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a4]:

[0213]

[0214] wherein each symbol is as defined in the aforementioned formula [Ia].

[0215] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a5]:

[0216]

[0217] wherein each symbol is as defined in the aforementioned formula [Ia].

[0218] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a6]:

[0219]

[0220] Where R B1 and R B2 Each independently is as in the above formula [Ia] for R B and other symbols are as defined in the aforementioned formula [Ia].

[0221] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a7]:

[0222]

[0223] wherein each symbol is as defined in the aforementioned formula [Ia].

[0224] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a8]:

[0225]

[0226] wherein each symbol is as defined in the aforementioned formula [Ia].

[0227] One of other preferred embodiments of formula [Ia] is a compound represented by formula [I-a10]:

[0228]

[0229] wherein the symbols are as defined in the aforementioned formula [Ia].

[0230] In the above formulas [Ia] and [I-a1] to [I-a8], R A Preferred is methyl.

[0231] In the above-mentioned formulas [Ia], [I-a1] and [I-a3], n is preferably 1.

[0232] "Pharmaceutically acceptable salts" may be any salts known in the art that are not excessively toxic. Specifically, salts formed with inorganic acids, salts formed with organic acids, salts formed with inorganic bases, salts formed with organic bases, etc. may be mentioned. Various forms of pharmaceutically acceptable salts are well known in the art, and, for example, they are described in the following references:

[0233] (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977),

[0234] (b) Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002).

[0235] (c) Paulekuhn et al., J. Med. Chem., 50, pp. 6665-6672 (2007).

[0236] The pharmaceutically acceptable salt of the compound of formula [Ia] can be obtained by reacting the compound with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se. Each molecule of the compound of formula [Ia] can form a pharmaceutically acceptable salt of the compound of formula [Ia] with half a molecule, one molecule, or two or more molecules of an acid or base.

[0237] Examples of the salt with an inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid.

[0238] Examples of salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydrous methylene 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, glycolyl arsanilic acid, hexylresoronic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid , malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclicacid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid and glutamic acid.

[0239] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium.

[0240] Examples of the salt with an organic base include a salt with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine.

[0241] Preferred embodiments of the "pharmaceutically acceptable salt" are described below.

[0242] Examples of the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid.

[0243] Examples of the salt with an organic acid 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.

[0244] Examples of the salt with an inorganic base include salts with sodium, potassium, calcium, magnesium and zinc.

[0245] Examples of the salt with an organic base include salts with tris(hydroxymethyl)methylamine, N-methylglucamine and lysine.

[0246] The compound of formula [Ia] or a pharmaceutically acceptable salt thereof may exist as a solvate. The term "solvate" refers to a compound of formula [Ia] or a pharmaceutically acceptable salt thereof to which a solvent molecule is bound, and also includes hydrates. Such solvates are preferably pharmaceutically acceptable solvates, and include, for example, hydrates, ethanol solvates, dimethyl sulfoxide solvates, and the like of the compound of formula [Ia] or a pharmaceutically acceptable salt thereof.

[0247] Specific examples include a hemihydrate, monohydrate, dihydrate or mono(ethanol)solvate of the compound of formula [Ia], or a monohydrate of the hydrochloride of the compound of formula [Ia], a dihydrate of the hydrochloride of the compound of formula [Ia], etc. Such a solvate can be produced according to a conventional method.

[0248] The compound of formula [Ia] may exist as stereoisomers, which should be identified as cis / trans isomers. In this case, the compound of formula [Ia] may exist as a cis isomer, a trans isomer, or a mixture of a cis isomer and a trans isomer.

[0249] The compound of formula [Ia] may exist as a tautomer. In this case, the compound of formula [Ia] may exist as a single tautomer or a mixture of tautomers.

[0250] The compound of formula [Ia] may contain one or more asymmetric carbons. In this case, the compound of formula [Ia] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0251] The compound of formula [Ia] may exist as an atropisomer. In this case, the compound of formula [Ia] may exist as a single atropisomer or a mixture of atropisomers.

[0252] The compound of formula [Ia] may contain a plurality of structural features that give rise to the above isomers. In addition, the compound of formula [Ia] may contain the above isomers in any ratio.

[0253] In the absence of other references such as comments etc., the formulae, chemical structures and compound names (without specifying their stereochemistry) indicated in the present specification include all the above-mentioned isomers that may exist.

[0254] Diastereomeric mixtures can be separated into each diastereomer by conventional methods such as chromatography, crystallization, etc. In addition, each diastereomer can also be formed by using stereochemically single starting materials or by synthetic methods using stereoselective reactions.

[0255] Enantiomeric mixtures can be separated into each individual enantiomer by methods well known in the art.

[0256] For example, a mixture of enantiomers can be reacted with a substantially pure enantiomer, known as a chiral auxiliary, to form a mixture of diastereomers, which can then be separated into diastereomers of enhanced isomeric ratio or substantially pure single diastereomers by conventional methods such as fractional crystallization or chromatography. The added chiral auxiliary can be removed from the separated diastereomers by a cleavage reaction to produce the desired enantiomer.

[0257] In addition, mixtures of enantiomers of a compound may be separated directly by chromatographic methods using chiral solid phases well known in the art. Alternatively, one of the enantiomers may be obtained by stereoselective synthesis (asymmetric induction) using substantially pure optically active starting materials or prochiral intermediates using chiral auxiliary agents or asymmetric catalysts.

[0258] The absolute stereo configuration can be determined based on X-ray crystallographic analysis of the resulting crystalline product or intermediate. In this case, the resulting crystalline product or intermediate derivatized with a reagent having an asymmetric center of known stereo configuration can be used, if necessary.

[0259] Isotopes ( 2 H. 3 H. 14 C. 35 The compound of formula [Ia] is labeled with S, etc.

[0260] 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. Further preferably, it is a compound of formula [Ia] or a pharmaceutically acceptable salt thereof purified to a purity of not less than 80%.

[0261] The pharmaceutical composition of the present invention can be prepared by appropriately mixing a suitable amount of a compound of formula [Ia] or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier according to methods known in the art of drug preparation. The content of the compound of formula [Ia] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies with the dosage form, dosage, etc. For example, the content is 0.1-100% by weight of the entire composition.

[0262] The dosage form of the compound of formula [Ia] or a pharmaceutically acceptable salt thereof includes oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions, or parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.

[0263] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances conventionally used as formulation materials, and include excipients, disintegrants, binders, fluidizers, lubricants, etc. (for solid preparations), and solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. (for liquid preparations), and bases, emulsifiers, wetting agents, tranquilizers, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, fillers, solubilizers, suspending agents, etc. (for semi-solid preparations). In addition, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may also be used when necessary.

[0264] Examples of the "excipient" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, crystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic and the like.

[0265] Examples of the "disintegrant" include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.

[0266] Examples of the "binder" include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, sodium carboxymethyl cellulose, gum arabic and the like.

[0267] Examples of the "fluidizer" include light anhydrous silicic acid, magnesium stearate and the like.

[0268] Examples of the "lubricant" include magnesium stearate, calcium stearate, talc and the like.

[0269] Examples of the "solvent" include purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and the like.

[0270] Examples of the "solubilizer" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.

[0271] Examples of the "suspending agent" include benzalkonium chloride, carboxymethylcellulose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like.

[0272] Examples of the "isotonic agent" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.

[0273] Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.

[0274] Examples of "soothing agents" include benzyl alcohol and the like.

[0275] Examples of the “base” include water, animal and plant oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, water-absorbing ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, etc.), propylene glycol, polyethylene glycol (polyethylene glycol 200-600, etc.), and combinations of two or more thereof.

[0276] Examples of the "preservative" include ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.

[0277] Examples of the "antioxidant" include sodium sulfite, ascorbic acid and the like.

[0278] Examples of the "colorant" include food coloring (eg, food coloring red 2 or 3, food coloring yellow 4 or 5, etc.), β-carotene, and the like.

[0279] Examples of the "sweeteners" include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.

[0280] The pharmaceutical composition of the present invention can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to mammals other than humans (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.) and humans. The dosage varies according to the subject of administration, disease, symptoms, dosage form, route of administration, etc. For example, based on the compound of formula [Ia] as the active ingredient, the daily dose administered orally to an adult patient is generally in the range of about 0.01 mg to 1 g. This amount can be administered in one to several portions.

[0281] The compound of formula [Ia] or its pharmaceutically acceptable salt has PDHK inhibitory effect, and can be used for treating and / or preventing various diseases or conditions expected to be improved by controlling PDHK activity. Examples of various diseases or conditions expected to be improved by controlling PDHK activity include diseases such as diabetes (type 1 diabetes, type 2 diabetes), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, 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 artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension (pulmonary hypertension), Alzheimer's disease, vascular dementia (large vessel type or small vessel type vascular dementia), glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, chronic kidney disease, etc.

[0282] Symptoms of Alzheimer's disease include cognitive impairment, psychological symptoms, and behavioral disorders.

[0283] "Inhibiting PDHK" means eliminating or weakening the activity of PDHK by inhibiting the function of PDHK. For example, it means inhibiting the function of PDHK based on the conditions in Experimental Example 1 described below. "Inhibiting PDHK" preferably inhibits human PDHK. "Inhibiting PDHK" preferably "inhibits PDHK2".

[0284] "PDHK inhibitor" refers to a substance that binds to PDHK and inhibits the function of PDHK. As a "PDHK inhibitor", a "human PDHK inhibitor" is preferred. As a "PDHK inhibitor", an "inhibitor of PDHK2" is preferred.

[0285] In this specification, "treatment" also includes improving symptoms, preventing severity, maintaining remission, preventing worsening, and further preventing recurrence.

[0286] In the present specification, "inhibit" or "prevent" means to inhibit the onset of symptoms.

[0287] In the present specification, presentation of preferred embodiments and options of the compounds, methods, uses and compositions of the present invention also includes combinations of preferred embodiments and options as long as they can be combined and there is no inconsistency.

[0288] The method for preparing the compound of formula [Ia] or a pharmaceutically acceptable salt thereof is explained below. However, the method for preparing the compound of formula [Ia] or a pharmaceutically acceptable salt thereof is not limited to such a preparation method.

[0289] When necessary, the compound obtained in each step can be separated or purified by conventional methods such as distillation, recrystallization, column chromatography, etc. In some cases, the next step can be carried out without separation or purification. When the reaction to be carried out in each step is an anhydrous reaction, the reaction is preferably carried out in an inert gas atmosphere such as argon, nitrogen, etc.

[0290] [Preparation method 1]

[0291] The compound of formula [I-a1] can be obtained by the production method 1 shown in the following scheme.

[0292]

[0293] Where R 11 It is C 1-4 an alkyl group; and each other symbol is as defined in the aforementioned formula [Ia].

[0294] Step 1-1

[0295] 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.

[0296] Examples of the reducing agent include lithium aluminum hydride, diisobutylaluminum hydride, and lithium borohydride.

[0297] Examples of the solvent include tetrahydrofuran, diethyl ether and cyclopentyl methyl ether.

[0298] The compound [A1] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0299] Step 1-2

[0300] Compound [A3] can be obtained by oxidizing the hydroxyl group of compound [A2]. For example, compound [A3] can be obtained by reacting compound [A2] with an oxidizing agent in a solvent under ice cooling to room temperature.

[0301] Examples of the oxidizing agent include manganese dioxide, Dess-Martin periodinane, and sulfur trioxide-pyridine complex.

[0302] Examples of the solvent include tetrahydrofuran, dimethoxyethane, toluene, dimethyl sulfoxide, chloroform and dichloromethane.

[0303] Steps 1-3

[0304] Compound [A5] can be obtained by an imidization reaction of compound [A3] and compound [A4] and a cyclization reaction using p-toluenesulfonylmethyl isocyanide. For example, the imidization reaction of compound [A3] and compound [A4] is carried out in a solvent at room temperature to 60°C. Then, the obtained product is reacted with p-toluenesulfonylmethyl isocyanide in a solvent in the presence of a base under ice cooling to room temperature to produce compound [A5].

[0305] Examples of the solvent for the imination reaction include methanol and dimethylformamide.

[0306] Examples of the base include potassium carbonate.

[0307] Examples of the solvent for the cyclization reaction include dimethoxyethane.

[0308] 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.

[0309] Steps 1-4

[0310] Compound [A6] can be obtained by intramolecular Mitsunobu reaction of compound [A5]. For example, compound [A6] can be obtained by reacting compound [A5] with phosphine and azodicarboxylic acid diester in a solvent at room temperature to 100°C.

[0311] Examples of the phosphine include trioctylphosphine, tributylphosphine and triphenylphosphine.

[0312] Examples of the azodicarboxylic acid diesters include diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate.

[0313] Examples of the solvent include toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

[0314] Steps 1-5

[0315] Compound [A7] can be obtained by reacting compound [A6] with N-methoxy-N-methylacetamide. For example, compound [A7] can be obtained by reacting compound [A6] with N-methoxy-N-methylacetamide in a solvent at -78°C to room temperature in the presence of a base.

[0316] Examples of the base include n-butyllithium and lithium diisopropylamide.

[0317] Examples of the solvent include cyclopentyl methyl ether, tetrahydrofuran and toluene.

[0318] Steps 1-6

[0319] Compound [A7] can be reacted with (trifluoromethyl)trimethylsilane to obtain compound [I-a1]. For example, compound [A7] can be reacted with (trifluoromethyl)trimethylsilane in a solvent in the presence of an additive under ice cooling to room temperature to obtain compound [I-a1].

[0320] Examples of the additive include tetra-n-butylammonium fluoride, lithium acetate, potassium carbonate and cesium fluoride.

[0321] Examples of the solvent include tetrahydrofuran, dimethylformamide and dimethylacetamide.

[0322] R of compound [A7] A The group becomes sterically hindered, and the reaction proceeds in a diastereoselective manner. The steric configuration of compound [I-a1] can be assumed from the reaction mechanism and can be confirmed by X-ray crystal structure analysis.

[0323] [Preparation method 2]

[0324] The compound of formula [I-a2] can be obtained by the production method 2 shown in the following scheme.

[0325]

[0326] Where R 12 It is C 1-4 alkyl;

[0327] Pr 2 is an amino protecting group such as tert-butoxycarbonyl;

[0328] Z 2 YesR B C(O)O- or chlorine; and

[0329] Each other symbol is as defined in the aforementioned formula [Ia].

[0330] Step 2-1

[0331] Compound [B3] can be obtained by Mitsunobu reaction of compound [B1] and compound [B2]. For example, compound [B3] can be obtained by reacting compound [B1] with compound [B2], phosphine and azodicarboxylic acid diester in a solvent at room temperature to 100°C.

[0332] Examples of the phosphine include trioctylphosphine, tributylphosphine and triphenylphosphine.

[0333] Examples of the azodicarboxylic acid diesters include diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate.

[0334] Examples of the solvent include toluene and tetrahydrofuran.

[0335] 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 of ordinary skill in the art.

[0336] Step 2-2

[0337] By deprotecting the amino group of compound [B3], compound [B4] can be obtained. 2 When it is a tert-butoxycarbonyl group, compound [B4] can be obtained by treating compound [B3] with an acid in a solvent under ice cooling to room temperature. Compound [B4] can be obtained in the form of a salt with the acid used in the reaction.

[0338] Examples of the acid include trifluoroacetic acid and hydrochloric acid.

[0339] Examples of the solvent include tetrahydrofuran and ethyl acetate.

[0340] Steps 2-3

[0341] Compound [B5] can be obtained by lactamizing compound [B4]. For example, compound [B5] can be obtained by reacting compound [B4] with a base in a solvent under ice cooling to room temperature.

[0342] Examples of the base include sodium bicarbonate.

[0343] Examples of the solvent include methanol and water.

[0344] Steps 2-4

[0345] 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.

[0346] Examples of the sulfur reagent include Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphatane-2,4-disulfide).

[0347] Examples of the solvent include toluene and pyridine.

[0348] Steps 2-5

[0349] Compound [B8] can be obtained by cyclization reaction of compound [B6] and compound [B7]. For example, compound [B8] can be obtained by reacting compound [B6] and compound [B7] in a solvent at 100°C to 200°C. If necessary, a microwave device can also be used.

[0350] Examples of the solvent include n-butanol and N-methylpyrrolidone.

[0351] Compound [B7] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0352] Steps 2-6 and 2-7

[0353] Compound [B8] can also be obtained by methylating compound [B6] to obtain compound [B9], and then reacting compound [B9] with compound [B7]. For example, compound [B6] can be methylated by reacting compound [B6] with a methylating agent in a solvent under ice cooling to room temperature. Compound [B9] can also be obtained as a salt such as hydroiodide.

[0354] Examples of the methylating agent include methyl iodide.

[0355] Examples of the solvent include dimethylformamide and acetone.

[0356] For example, the reaction of compound [B9] and compound [B7] can be carried out by an operation similar to that in step 2-5.

[0357] Compound [B7] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0358] Steps 2-8 and 2-9

[0359] Compound [B8] can also be obtained by reacting compound [B6] with hydrazine to obtain compound [B10], and then reacting compound [B10] with compound [B11]. For example, the reaction of compound [B6] and hydrazine can be carried out by reacting compound [B6] with hydrazine in a solvent at room temperature to 80°C.

[0360] Examples of the solvent include ethanol and isopropanol.

[0361] The reaction of compound [B10] and compound [B11] can be carried out by reacting compound [B10] with compound [B11] in a solvent in the presence of an acid under ice cooling to room temperature.

[0362] Examples of the acid include trifluoroacetic acid.

[0363] Examples of the solvent include chloroform.

[0364] The compound [B11] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0365] Steps 2-10

[0366] Compound [B12] can be obtained by reacting compound [B8] with N-methoxy-N-methylacetamide. For example, compound [B12] can be obtained by an operation similar to that in step 1-5.

[0367] Steps 2-11

[0368] Compound [I-a2] can be obtained by reacting compound [B12] with (trifluoromethyl)trimethylsilane. For example, compound [I-a2] can be obtained by an operation similar to that in step 1-6.

[0369] [Preparation method 3]

[0370] The compound of formula [I-a3] can be obtained by the production method 3 shown in the following scheme.

[0371]

[0372] Where R 13 It is C 1-4 alkyl;

[0373] Z 3 is a leaving group such as bromine, iodine, trifluoromethanesulfonyloxy, etc.;

[0374] Z 4 is a leaving group such as chloro, bromo, methanesulfonyloxy, etc.; and

[0375] Each other symbol is as defined in the aforementioned formula [Ia].

[0376] Step 3-1

[0377] 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 under ice cooling to room temperature.

[0378] Examples of the reducing agent include sodium borohydride.

[0379] Examples of the solvent include tetrahydrofuran and methanol.

[0380] The compound [C1] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0381] Step 3-2

[0382] By converting the hydroxyl group of compound [C2] into a leaving group, compound [C3] can be obtained. 4In the case of a methanesulfonyloxy group, compound [C3] can be obtained by reacting compound [C2] with methanesulfonic anhydride in a solvent in the presence of a base under ice cooling.

[0383] Examples of the base include triethylamine.

[0384] Examples of the solvent include tetrahydrofuran, chloroform and dichloromethane.

[0385] Step 3-3

[0386] 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.

[0387] Examples of the base include cesium carbonate.

[0388] Examples of the solvent include dimethylformamide.

[0389] Compound [C4] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0390] Steps 3-4

[0391] Compound [C6] can be obtained by intramolecular cyclization of compound [C5]. For example, compound [C6] can be obtained by reacting compound [C5] at 120°C in a solvent in the presence of a metal catalyst, a ligand and a base.

[0392] Examples of metal catalysts include palladium (II) acetate.

[0393] Examples of the ligand include di-1-adamantyl-n-butylphosphine and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl.

[0394] Examples of the base include potassium carbonate.

[0395] Examples of the solvent include dimethylacetamide.

[0396] Steps 3-5

[0397] 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 a base in a solvent under ice cooling to 60°C.

[0398] Examples of the base include lithium hydroxide and sodium hydroxide.

[0399] Examples of the solvent include methanol, ethanol and water.

[0400] Steps 3-6

[0401] Compound [C8] can be obtained by an amidation reaction of compound [C7] and 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 under ice cooling to room temperature.

[0402] Examples of the base include diisopropylethylamine and triethylamine.

[0403] Examples of the condensing agent include HATU.

[0404] Examples of the solvent include dimethylformamide.

[0405] Steps 3-7

[0406] Compound [C9] can be obtained by reacting compound [C8] with methylmagnesium halide. For example, compound [C9] can be obtained by reacting compound [C8] with methylmagnesium halide in a solvent at 0°C to room temperature.

[0407] Examples of the methylmagnesium halide include methylmagnesium bromide.

[0408] Examples of the solvent include tetrahydrofuran and diethyl ether.

[0409] Steps 3-8

[0410] Compound [C10] can be obtained by reacting compound [C9] with (trifluoromethyl)trimethylsilane. For example, compound [C10] can be obtained by an operation similar to that in step 1-6.

[0411] Steps 3-9

[0412] Compound [I-a3] can be obtained by purifying compound [C10] using chiral column chromatography. For example, the spatial configuration of compound [I-a3] can be determined by X-ray crystal structure analysis.

[0413] [Preparation method 4]

[0414] The compound of formula [I-a4] can be obtained by the production method 4 shown in the following scheme.

[0415]

[0416] Where R 14 and R 15 Each is independently C 1-4 alkyl;

[0417] Z 5 It is C 1-4 alkoxy or chlorine; and

[0418] Each other symbol is as defined in the aforementioned formula [Ia].

[0419] Step 4-1

[0420] 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.

[0421] Examples of the reducing agent include sodium borohydride.

[0422] Examples of the solvent include methanol and tetrahydrofuran.

[0423] The compound [D1] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0424] Step 4-2

[0425] Compound [D4] can be obtained by Mitsunobu reaction of compound [D2] and compound [D3]. For example, compound [D4] can be obtained by a similar operation to that in step 2-1.

[0426] The compound [D3] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0427] Step 4-3

[0428] Compound [D5] can be obtained by intramolecular Claisen condensation of compound [D4]. For example, compound [D5] can be obtained by treating compound [D4] with a base in a solvent at room temperature to 110°C.

[0429] Examples of the base include potassium tert-butoxide.

[0430] Examples of the solvent include toluene and tetrahydrofuran.

[0431] Step 4-4

[0432] Compound [D6] can be obtained by decarboxylating 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°C to 160°C.

[0433] Examples of the acid include hydrochloric acid.

[0434] Examples of the solvent include water and dimethyl sulfoxide.

[0435] Steps 4-5 and 4-6

[0436] Compound [D9] can be obtained by reacting compound [D6] with compound [D7] to produce compound [D8], and subjecting compound [D8] and hydroxylamine to a cyclization reaction. For example, compound [D8] can be obtained by reacting compound [D6] with compound [D7] in a solvent in the presence of a base at 0°C to 70°C.

[0437] Examples of the base include sodium hydride and lithium bis(trimethylsilyl)amide.

[0438] Examples of the solvent include tetrahydrofuran.

[0439] Compound [D7] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0440] For example, compound [D9] can be obtained by reacting compound [D8] with hydroxylamine in a solvent at 70°C to 110°C and, if necessary, using an acid.

[0441] Examples of the acid include concentrated sulfuric acid.

[0442] Examples of the solvent include acetic acid and methanol.

[0443] Steps 4-7

[0444] Compound [D10] can be obtained by reacting compound [D9] with N-methoxy-N-methylacetamide. For example, compound [D10] can be obtained by an operation similar to that in step 1-5.

[0445] Steps 4-8

[0446] Compound [D11] can be obtained by reacting compound [D10] with (trifluoromethyl)trimethylsilane. For example, compound [D11] can be obtained by an operation similar to that in step 1-6.

[0447] Steps 4-9

[0448] Compound [I-a4] can be obtained by purifying compound [D11] by chiral column chromatography. For example, the spatial configuration of compound [I-a4] can be determined by X-ray crystal structure analysis.

[0449] [Preparation method 4-a]

[0450] In step 4-6 of production method 4, compound [D12] represented by the following formula can be obtained together with compound [D9]:

[0451] .

[0452] By reactions similar to those in Step 4-7 to Step 4-9 and using Compound [D12], Compound [I-a16] represented by the following formula can be obtained:

[0453] .

[0454] For example, the spatial configuration of compound [I-a16] can be determined by X-ray crystal structure analysis.

[0455] [Preparation method 5]

[0456] The compound of formula [I-a5] can be obtained by the production method 5 shown in the following scheme.

[0457]

[0458] wherein each symbol is as defined in the aforementioned formula [Ia].

[0459] Step 5-1

[0460] Compound [E1] can be obtained 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.

[0461] Examples of the solvent include dioxane.

[0462] Step 5-2

[0463] Compound [E3] can be obtained by cyclization reaction of 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.

[0464] Examples of the base include sodium ethoxide.

[0465] Examples of the solvent include ethanol.

[0466] The compound [E2] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0467] Step 5-3

[0468] Compound [E4] can be obtained by reacting compound [E3] with N-methoxy-N-methylacetamide. For example, compound [E4] can be obtained by an operation similar to that in step 1-5.

[0469] Step 5-4

[0470] Compound [E5] can be obtained by reacting compound [E4] with (trifluoromethyl)trimethylsilane. For example, compound [E5] can be obtained by an operation similar to that in step 1-6.

[0471] Step 5-5

[0472] Compound [I-a5] can be obtained by purifying compound [E5] by chiral column chromatography. For example, the spatial configuration of compound [I-a5] can be determined by X-ray crystal structure analysis.

[0473] [Preparation method 6]

[0474] The compound of formula [I-a6] can be obtained by the production method 6 shown in the following scheme.

[0475]

[0476] Where R B1 and R B2 Each independently is as in the above formula [Ia] for R B defined;

[0477] Z 6 It is C 1-4 alkoxy or chlorine; and

[0478] Each other symbol is as defined in the aforementioned formula [Ia].

[0479] Step 6-1

[0480] Compound [F2] can be obtained by reacting compound [D6] with compound [F1]. For example, compound [F2] can be obtained by an operation similar to that in step 4-5.

[0481] The compound [F1] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0482] Step 6-2

[0483] Compound [F4] can be obtained by pyrazole cyclization reaction of compound [F2] and compound [F3]. For example, compound [F4] can be obtained by reacting compound [F2] and compound [F3] in a solvent at room temperature to 100°C.

[0484] Examples of the solvent include acetic acid and ethanol.

[0485] Compound [F3] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0486] Step 6-3

[0487] Compound [F5] can be obtained by reacting compound [F4] with N-methoxy-N-methylacetamide. For example, compound [F5] can be obtained by an operation similar to that in step 1-5.

[0488] Step 6-4

[0489] Compound [F6] can be obtained by reacting compound [F5] with (trifluoromethyl)trimethylsilane. For example, compound [F6] can be obtained by an operation similar to that in step 1-6.

[0490] Step 6-5

[0491] Compound [I-a6] can be obtained by purifying compound [F6] by chiral column chromatography. For example, the spatial configuration of compound [I-a6] can be determined by X-ray crystal structure analysis.

[0492] [Preparation method 7]

[0493] The compound of formula [I-a7] can be obtained by the production method 7 shown in the following scheme.

[0494]

[0495] Among them, Pr 6 is a pyrazole-protecting group such as p-methoxybenzyl and the like; and

[0496] Each other symbol is as defined in the aforementioned formula [Ia].

[0497] Step 7-1

[0498] Compound [G1] can be obtained by pyrazole cyclization reaction of compound [D8] and hydrazine. For example, compound [G1] can be obtained by an operation similar to that in step 6-2.

[0499] Step 7-2

[0500] By introducing a protecting group into the pyrazole of compound [G1], compound [G2] can be obtained. 6 When it is a p-methoxybenzyl group, compound [G2] can be obtained by reacting compound [G1] with p-methoxybenzyl chloride in a solvent in the presence of a base under ice cooling to room temperature. 6 It may be bonded to either of the two nitrogen atoms of the pyrazole.

[0501] Examples of the solvent include tetrahydrofuran.

[0502] Examples of the base include sodium hydride.

[0503] Step 7-3

[0504] Compound [G3] can be obtained by reacting compound [G2] with N-methoxy-N-methylacetamide. For example, compound [G3] can be obtained by an operation similar to that in step 1-5.

[0505] Step 7-4

[0506] Compound [G4] can be obtained by reacting compound [G3] with (trifluoromethyl)trimethylsilane. For example, compound [G4] can be obtained by an operation similar to that in step 1-6.

[0507] Step 7-5

[0508] Compound [G5] can be obtained by deprotecting the pyrazole of compound [G4]. 6 In the case of a p-methoxybenzyl group, compound [G5] can be obtained by treating compound [G4] with an acid in a solvent at 60°C to 80°C.

[0509] Examples of the acid include trifluoroacetic acid.

[0510] Examples of the solvent include dichloromethane.

[0511] Step 7-6

[0512] Compound [I-a7] can be obtained by purifying compound [G5] by chiral column chromatography. For example, the spatial configuration of compound [I-a7] can be determined by X-ray crystal structure analysis.

[0513] [Preparation method 8]

[0514] The compound of formula [I-a8] can be obtained by the production method 8 shown in the following scheme.

[0515]

[0516] Where R 18 It is C 1-4 alkyl;

[0517] Pr 7 and Pr 8 Each is an amino protecting group such as tert-butoxycarbonyl and the like; and

[0518] Each other symbol is as defined in the aforementioned formula [Ia].

[0519] Step 8-1

[0520] 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 under ice cooling to room temperature.

[0521] Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate.

[0522] Examples of the solvent include acetonitrile and dimethylformamide.

[0523] The compound [H2] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0524] Step 8-2

[0525] By deprotecting compound [H3], (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoylhydrazide (compound H4) can be obtained. 7 In the case of a tert-butoxycarbonyl group, compound H4 can be obtained by treating compound [H3] with an acid in a solvent under ice cooling to room temperature. Compound H4 can be obtained in the form of a salt with the acid used in the reaction.

[0526] Examples of the acid include trifluoroacetic acid and hydrochloric acid.

[0527] Examples of the solvent include tetrahydrofuran, ethyl acetate and chloroform.

[0528] Step 8-3

[0529] Compound [H7] can be obtained by Mitsunobu reaction of compound [H5] and compound [H6]. For example, compound [H7] can be obtained by a similar operation to that in step 2-1.

[0530] 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 of ordinary skill in the art.

[0531] Step 8-4

[0532] Compound [H8] can be obtained by deprotection of the amino group of compound [H7] and lactamization. For example, deprotection of the amino group can be performed by an operation similar to that in step 2-2. For example, lactamization can be performed by an operation similar to that in step 2-3.

[0533] Step 8-5

[0534] Compound [H9] can be obtained by reacting compound [H8] with a sulfur reagent. For example, compound [H9] can be obtained by an operation similar to that in step 2-4.

[0535] Step 8-6

[0536] Compound [H10] can be obtained by methylating compound [H9]. For example, compound [H10] can be obtained by an operation similar to that in step 2-6.

[0537] Step 8-7

[0538] Compound [I-a8] can be obtained by cyclization reaction of compound [H10] and compound H4. For example, compound [I-a8] can be obtained by reacting compound [H10] with compound H4 in a solvent in the presence of an acid at 60°C to 120°C.

[0539] Examples of the acid include acetic acid.

[0540] Examples of solvents include isopropyl alcohol and water.

[0541] [Preparation method 9]

[0542] By converting the functional groups at appropriate stages in Preparation Methods 1-8, the desired R B For example, by the production method 9 shown in the following scheme, compounds [I-a10] to [I-a15] can be obtained by converting the compound [I-a9] obtained in any one of the production methods 1 to 8.

[0543]

[0544] Among them, Pr 9 is a hydroxy protecting group such as p-methoxybenzyl;

[0545] R 19 and R 20 are independently hydrogen or C 1-4 alkyl; and

[0546] Each other symbol is as defined in the aforementioned formula [Ia].

[0547] Step 9-1

[0548] Compound [I-a10] can be obtained by deprotecting the hydroxyl group of compound [I-a9]. For example, compound [I-a10] can be obtained by treating compound [I-a9] with an acid in a solvent at room temperature.

[0549] Examples of the acid include trifluoroacetic acid.

[0550] Examples of the solvent include dichloromethane.

[0551] Step 9-2

[0552] Compound [I-a11] can be obtained by oxidation of the hydroxyl group of compound [I-a10]. For example, compound [I-a11] can be obtained by an operation similar to that in step 1-2.

[0553] Step 9-3

[0554] Compound [I-a12] can be obtained by oxidizing the hydroxyl 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.

[0555] Examples of the oxidizing agent include potassium permanganate.

[0556] Examples of the solvent include acetone.

[0557] Step 9-4

[0558] By compound [I-a12] and HNR 19 R 20 Compound [I-a13] can be obtained by amidation. For example, by reacting compound [I-a12] with HNR in a solvent in the presence of a base and a condensing agent under ice cooling to room temperature. 19 R 20 Reaction can give compound [I-a13].

[0559] Examples of the base include diisopropylethylamine and triethylamine.

[0560] Examples of the condensing agent include HATU.

[0561] Examples of the solvent include dimethylformamide.

[0562] When HNR 19 R 20 R 19 and R 20 When each is hydrogen, compound [I-a14] can be obtained.

[0563] Step 9-5

[0564] Compound [I-a15] can be obtained by cyanation reaction of compound [I-a14]. For example, compound [I-a15] can be obtained by reacting compound [I-a14] with an acid anhydride in a solvent in the presence of a base under ice cooling to room temperature.

[0565] Examples of the base include pyridine.

[0566] Examples of the acid anhydride include trifluoroacetic anhydride.

[0567] Examples of the solvent include 1,4-dioxane.

[0568] [Preparation method 10]

[0569] The compound of formula [I-a10] can be obtained by the production method 10 shown in the following scheme.

[0570]

[0571] Where R 19 It is C 1-4 alkyl;

[0572] R 20 It is hydrogen, halogen, C 1-4 Alkyl or nitro;

[0573] Pr 9 is a pyrazole protecting group such as 2-tetrahydropyranyl;

[0574] X 5 is a leaving group such as chloro, bromo, methanesulfonyloxy, etc.; and

[0575] Each other symbol is as defined in the aforementioned formula [Ia].

[0576] Step 10-1

[0577] 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.

[0578] Examples of the solvent include acetonitrile, toluene and ethanol.

[0579] Examples of the acid include acetic acid.

[0580] Compound [J1] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0581] Step 10-2

[0582] By introducing a protecting group into the pyrazole of compound [J2], compound [J3] can be obtained. 9 When it is 2-tetrahydropyranyl, compound [J3] can be obtained by reacting compound [J2] with 3,4-dihydro-2H-pyran in a solvent in the presence of an acid at room temperature.

[0583] Examples of the solvent include acetonitrile and N,N-dimethylformamide.

[0584] Examples of the acid include pyridinium p-toluenesulfonate and p-toluenesulfonic acid.

[0585] Step 10-3

[0586] 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.

[0587] Examples of the solvent include N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, toluene, isopropyl acetate, tetrahydrofuran and dimethyl sulfoxide.

[0588] 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), N,N-diisopropylethylamine.

[0589] Compound [J4] may be a commercially available product, or can be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.

[0590] Step 10-4

[0591] Compound [J6] can be obtained by hydrolyzing the ester of compound [J5] and then subjecting it to an amidation reaction with N,O-dimethylhydroxylamine. For example, compound [J6] can be obtained by reacting compound [J5] with a base in a solvent to hydrolyze the ester and reacting the obtained compound with N,O-dimethylhydroxylamine at room temperature in the presence of a condensing agent.

[0592] Examples of the base include sodium hydroxide.

[0593] Examples of the condensing agent include a combination of WSC-HCl and HOBt.

[0594] Examples of the solvent include 1,2-dimethoxyethane.

[0595] Step 10-5

[0596] Compound [J7] can be obtained by reducing compound [J6]. For example, compound [J7] can be obtained by reacting compound [J6] with a reducing agent in a solvent under ice cooling.

[0597] Examples of the reducing agent include sodium bis(2-methoxyethoxy)aluminum hydride.

[0598] Examples of the solvent include toluene and 1,2-dimethoxyethane.

[0599] Step 10-6

[0600] By deprotecting the pyrazole protecting group of compound [J7], compound [J8] can be obtained. 9 When it is 2-tetrahydropyranyl, compound [J8] can be obtained by treating compound [J7] with an acid in a solvent at room temperature.

[0601] Examples of the acid include hydrochloric acid, methanesulfonic acid, sulfuric acid, and phosphoric acid.

[0602] Examples of the solvent include 1,2-dimethoxyethane.

[0603] Step 10-7

[0604] Compound [J9] can be obtained by reacting compound [J8] with compound [A4]. For example, compound [J9] can be obtained by a similar operation to that in step 1-3.

[0605] Step 10-8

[0606] Compound [J10] can be obtained by intramolecular Mitsunobu reaction of compound [J9]. For example, compound [J10] can be obtained by an operation similar to that in step 1-4. Compound [J10] can be obtained in the form of a salt with an acid such as hydrochloric acid.

[0607] Step 10-9

[0608] Compound [J11] can be obtained by reacting compound [J10] with N-methoxy-N-methylacetamide. For example, compound [J11] can be obtained by a similar operation to that in step 1-5.

[0609] Step 10-10

[0610] 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] can be obtained in the form of a salt with the acid used.

[0611] Examples of the acid include concentrated hydrochloric acid.

[0612] Steps 10-11

[0613] Compound [J13] can be obtained by reacting compound [J12] with diethyl (bromodifluoromethyl)phosphonate. For example, compound [J13] can be obtained by reacting compound [J12] with diethyl (bromodifluoromethyl)phosphonate in a solvent in the presence of a base at room temperature.

[0614] Examples of the solvent include acetonitrile, 1,2-dimethoxyethane and tetrahydrofuran.

[0615] Examples of the base include potassium hydroxide, lithium hydroxide and tetrabutylammonium hydroxide.

[0616] Steps 10-12

[0617] Compound [I-a10] can be obtained by reacting compound [J13] with (trifluoromethyl)trimethylsilane. For example, compound [I-a10] can be obtained by an operation similar to that in step 1-6. A The group becomes sterically hindered, and the reaction proceeds in a diastereoselective manner. The steric configuration of compound [I-a10] can be assumed from the reaction mechanism and can be confirmed by X-ray crystal structure analysis. Example

[0618] The preparation method of the compound of formula [Ia] or its pharmaceutically acceptable salt of the present invention is specifically explained by the following preparation examples. However, the preparation method of the compound of formula [Ia] or its pharmaceutically acceptable salt is not limited to the preparation examples.

[0619] Unless otherwise specified, % indicates weight %. Unless otherwise specified, the ratio of mixed solvents is a volume mixing ratio.

[0620] In the Examples, the abbreviations have the following meanings.

[0621] DMSO: dimethyl sulfoxide

[0622] M: mol / L

[0623] N: equivalent concentration

[0624] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0625] WSC-HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0626] HOBt-H2O: 1-Hydroxybenzotriazole monohydrate.

[0627] Use the following abbreviations to indicate 1 H-NMR measurement results.

[0628] s: singlet, d: doublet, dd: doublet of doublet, dt: doublet of triplet, t: triplet, q: quartet, dq: doublet of quartet, m: multiplet, brs: broad singlet, brm: broad multiplet, J: coupling constant, Hz: Hertz.

[0629] Measured in CDCl3 or DMSO-D6 using tetramethylsilane as internal standard 1 H-NMR spectra, and all δ values ​​are shown in ppm.

[0630] Preparation Example 1

[0631] 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-trifluoropropane-2-ol (Compound of Example 23)

[0632] Step 1

[0633] 3-(Benzyloxy)-1H-pyrazole-5-carboxylic acid ethyl ester

[0634]

[0635] 3-hydroxy-1H-pyrazole-5-ethyl formate (10 g) is mixed with tetrahydrofuran (100 ml). Benzyl alcohol (7.99 ml) and triphenylphosphine (18.48 g) are added to the mixture. Under ice cooling, diisopropyl azodicarboxylate (13.7 ml) is added dropwise, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, ethyl acetate (70 ml) and hexane (140 ml) are added, and the mixture is stirred at room temperature. The precipitated solid is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate=92:8 to hexane: ethyl acetate=47:53) to obtain the title compound (20 g) as a crude product. The crude product is used for the next step without further purification.

[0636] Step 2

[0637] (3-(Benzyloxy)-1H-pyrazol-5-yl)methanol

[0638]

[0639] The crude product (19 g) of 3-(benzyloxy)-1H-pyrazole-5-carboxylic acid ethyl ester obtained in the previous step was dissolved in cyclopentyl methyl ether (70 ml). Under ice cooling, the 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 min. 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 one after another. The mixture was stirred at 0 ° C for 10 min. Saturated aqueous ammonium chloride solution and 1N aqueous hydrochloric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 16: 84 to ethyl acetate, thereafter ethyl acetate: methanol = 82: 18) to obtain the title compound (8.2 g).

[0640] 1 H-NMR (400 MHz, CDCl3) 4.66 (s, 2H), 5.19 (s, 2H), 5.64 (s, 1H), 7.26- 7.47 (m, 5H).

[0641] Step 3

[0642] 3-(Benzyloxy)-1H-pyrazole-5-carbaldehyde

[0643]

[0644] 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, and the filtrate was concentrated under reduced pressure to give the title compound (5.4 g) as a crude product. The crude product was used in the next step without further purification.

[0645] Step 4

[0646] (S)-2-(5-(3-(Benzyloxy)-1H-pyrazol-5-yl)-1H-imidazol-1-yl)propan-1-ol

[0647]

[0648] The crude product (5.4 g) of 3-(benzyloxy)-1H-pyrazole-5-carboxaldehyde obtained in the previous step is mixed with methanol (54ml). (S)-2-aminopropane-1-ol (2 g) is added at room temperature, and the mixture is stirred at room temperature overnight. Under ice cooling, 1,2-dimethoxyethane (164 mL), p-toluenesulfonylmethyl isocyanide (7.82 g) and potassium carbonate (11.07g) are added, and the mixture is stirred at room temperature overnight. The reaction mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure. Water is added to the obtained residue, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75 to ethyl acetate, thereafter ethyl acetate: methanol = 60: 40) to obtain the title compound (4.1 g) as a crude product.

[0649] Step 5

[0650] (S)-9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine

[0651]

[0652] The crude product (4.1 g) of (S)-2-(5-(3-(benzyloxy)-1H-pyrazole-5-yl)-1H-imidazole-1-yl)propane-1-ol obtained in the previous step and triphenylphosphine (4.69 g) are mixed with tetrahydrofuran (123 ml). Under ice cooling, di-tert-butyl azodicarboxylate (4.11 g) is added, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: hexane=25:75 to ethyl acetate, thereafter ethyl acetate: methanol=60:40) to obtain the title compound (2.98 g).

[0653] 1 H-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).

[0654] Step 6

[0655] (S)-1-(9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0656]

[0657] The (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). The mixture was cooled to -78 ° C, and 2M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (13.29 ml) was added dropwise. The mixture was stirred at -78 ° C for 30 min. N-methoxy-N-methylacetamide (5.25 mL) was added to the mixture, and the mixture was stirred at -78 ° C for 1 hour. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the precipitated solid was collected by filtration. The filtrate was distributed, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. Ethyl acetate / hexane=1 / 1 (10 mL) was added to the obtained residue, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, combined with the solid collected earlier by filtration, mixed with ethyl acetate, and concentrated to give the title compound (2 g).

[0658] 1 H-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).

[0659] Step 7

[0660] (R)-2-((S)-9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropane-2-ol

[0661]

[0662] The (S)-1-(9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-3-yl)ethane-1-one (2 g) obtained in the previous step was mixed with tetrahydrofuran (29.8 ml). Under ice cooling, cesium fluoride (0.195 g) was added to the mixture, and (trifluoromethyl)trimethylsilane (1.088 ml) was added dropwise. The reaction mixture was stirred at room temperature for 20 min. Under ice cooling, methanol (24.84 ml) and potassium carbonate (1.065 g) were added, and the mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=12:88 to 4:96) to give the title compound (2.2 g).

[0663] 1 H-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).

[0664] Step 8

[0665] (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

[0666]

[0667] The (R)-2-((S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-3-yl)-1,1,1-trifluoropropane-2-ol (2.2 g) obtained in the previous step and 10% carbon-supported palladium (0.44 g) were mixed with ethanol (44 g). Under a hydrogen atmosphere, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 16: 84 to ethyl acetate, thereafter ethyl acetate: methanol = 80: 20). Ethyl acetate (6 ml) and hexane (6 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 obtain the title compound (1.82 g). The spatial configuration of the title compound was determined by X-ray crystal structure analysis.

[0668] 1 H-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).

[0669] Step 9

[0670] (R)-2-((S)-9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropane-2-ol

[0671]

[0672] The (S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropane-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-9-ol (1 g), potassium carbonate (0.914 g) and sodium chlorodifluoroacetate (1.009 g) obtained in the previous step were mixed with dimethylformamide (6 mL), and the mixture was stirred at 100°C for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained 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 obtained 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).

[0673] 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).

[0674] Preparation Example 2

[0675] 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)

[0676] Step 1

[0677] 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

[0678]

[0679] (S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropane-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-9-ol (0.5 g) and potassium carbonate (0.288 g) were mixed with dimethylformamide (5 ml). Under ice cooling, methyl bromoacetate (0.154 ml) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution in succession and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified 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, thereafter ethyl acetate: methanol = 90: 10) to obtain the title compound (0.411 g).

[0680] 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).

[0681] Step 2

[0682] (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

[0683]

[0684] The 2-(((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropane-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-9-yl)oxy)acetic acid methyl ester (0.411 g) obtained in the previous step was mixed with tetrahydrofuran (2 ml). Under ice cooling, 1.08M methylmagnesium bromide / tetrahydrofuran solution (4 ml) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained 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). To the obtained crude product were successively added ethyl acetate (0.7 ml) and hexane (1.4 mL), and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (0.251 g).

[0685] 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).

[0686] Preparation Example 3

[0687] 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)

[0688] Step 1

[0689] (S)-1-(1-((tert-Butyloxycarbonyl)amino)propan-2-yl)-1H-imidazole-5-carboxylic acid methyl ester

[0690]

[0691] 1H-imidazole-5-carboxylic acid methyl ester (250 g), (R)-(2-hydroxypropyl) carbamic acid tert-butyl ester (521 g) and trioctylphosphine (1505 ml) were mixed with toluene (1750 ml). The reaction solution was heated to 80°C, and 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 1N potassium hydrogen sulfate aqueous solution. The water layer was washed with ethyl acetate: hexane = 1:1. Under ice cooling, 1.4M sodium carbonate aqueous solution (1L) was added in small portions to the water 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 min. Sodium sulfate and silica gel were filtered out, and the filtrate was concentrated under reduced pressure. Ethyl acetate (250mL) was added to the obtained residue, and the mixture was stirred at 80°C for 10 min. Hexane (1750 ml) was slowly added, and the mixture was stirred while it was cooled to room temperature.The precipitated solid was collected by filtration to give the title compound (432.4 g).

[0692] 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).

[0693] Step 2

[0694] (S)-1-(1-Aminopropan-2-yl)-1H-imidazole-5-carboxylic acid methyl ester dihydrochloride

[0695]

[0696] The (S)-1-(1-((tert-butoxycarbonyl)amino)propane-2-yl)-1H-imidazole-5-methyl formate (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. The precipitated solid was collected by filtration to obtain the title compound (388.89 g).

[0697] 1H-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).

[0698] Step 3

[0699] (S)-5-Methyl-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one

[0700]

[0701] The (S)-1-(1-aminopropane-2-yl)-1H-imidazole-5-methyl formate dihydrochloride (388.89 g) obtained in the previous step is mixed with methanol (1944 ml) and water (117 ml). Sodium carbonate (644 g) is added to the mixture, and the mixture is stirred at 90 ° C for 2 hours. Tetrahydrofuran (1944 ml) is added at room temperature, and the reaction mixture is filtered through diatomite. The filtrate is concentrated under reduced pressure and azeotroped 2 times with toluene. Toluene is added to the residue obtained, and the mixture is stirred at room temperature for 1 hour. The precipitated solid is collected by filtration to obtain the title compound (278.65 g).

[0702] 1 H-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).

[0703] Step 4

[0704] (S)-5-Methyl-6,7-dihydroimidazo[1,5-a]pyrazine-8(5H)-thione

[0705]

[0706] (S)-5-methyl-6,7-dihydroimidazo[1,5-a]pyrazine-8(5H)-one (62.2 g) was mixed with toluene (600 ml) and pyridine (200 ml). Lawesson's reagent (50 g) was added to the mixture, and the mixture was stirred at 110°C overnight. After cooling, the solvent was decanted, and the gum-like substance was washed with toluene. Methanol (187 mL) was added to the obtained gum-like substance, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to obtain the title compound (39.9 g). The title compound (20.7 g) was obtained by a similar method.

[0707] 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).

[0708] Step 5

[0709] (S)-6-Methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazine

[0710]

[0711] The (S)-5-methyl-6,7-dihydroimidazo[1,5-a]pyrazine-8(5H)-thione (3g) obtained in the previous step was mixed with isopropanol (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. Trifluoroacetic acid (23.68ml) and trifluoroacetic anhydride (12.65 mL) were added to the obtained residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotroped 2 times with toluene. The obtained residue was purified by amino silica gel column chromatography (ethyl acetate: hexane = 75: 25 to ethyl acetate, thereafter ethyl acetate: methanol = 80: 20) to obtain the title compound (3.96 g).

[0712] 1H-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).

[0713] Step 6

[0714] (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

[0715]

[0716] The (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). The mixture was cooled to -78 ° C, and 2M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (24.67 ml) was added dropwise. The mixture was stirred at -78 ° C for 30 min. N-methoxy-N-methylacetamide (5.25 mL) was added to the mixture, and the mixture was stirred at -78 ° C for 35 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was warmed to room temperature and extracted with ethyl acetate twice. The organic layer was washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 12: 88 to ethyl acetate). To the obtained crude product was added toluene (12 mL), and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (2.04 g).

[0717] 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).

[0718] Step 7

[0719] (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

[0720]

[0721] The (S)-1-(6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a][1,2,4]triazolo[3,4-c]pyrazine-8-yl)ethane-1-one (2.04 g) obtained in the previous step was mixed with tetrahydrofuran (40.8 ml). 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 min. 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, the mixture was filtered through a silica gel (20 ml) pad, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 16:84 to ethyl acetate). Toluene (20 ml) and ethyl acetate (4 mL) are added to the crude product obtained, and the mixture is stirred at 80 ° C. The precipitated solid is collected by filtration. Ethyl acetate (6 ml) and hexane (4 mL) are added to the solid obtained, and the mixture is stirred at room temperature. The precipitated solid is collected by filtration to obtain the title compound (1.171 g). The spatial configuration of the title compound is determined by X-ray crystal structure analysis.

[0722] 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).

[0723] Preparation Example 4

[0724] 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)

[0725] Step 1

[0726] 1-(2-Bromophenyl)propan-2-ol

[0727]

[0728] 1-(2-bromophenyl)propane-2-one (2 g) is mixed with methanol (10 ml). Under ice cooling, sodium borohydride (0.533 g) is added to the mixture, and the mixture is stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate 2 times. The organic layer is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel chromatography (hexane: ethyl acetate=95:5 to 60:40) to obtain the title compound (1.937 g).

[0729] 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).

[0730] Step 2

[0731] 1-(2-Bromophenyl)propan-2-yl methanesulfonate

[0732]

[0733] Methanesulfonic anhydride (2.11 g) and dichloromethane (10 ml) were mixed. Under ice cooling, 1-(2-bromophenyl)propane-2-ol (1.737 g) and triethylamine (3.38 mL) obtained in the previous step were added to the mixture, 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 obtain the title compound (2.142 g).

[0734] 1H-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).

[0735] Step 3

[0736] 1-(1-(2-bromophenyl)propan-2-yl)-1H-imidazole-2-carboxylic acid ethyl ester

[0737]

[0738] 1H-imidazole-2-ethyl formate (3.54 g) and cesium carbonate (3.29 g) are mixed with dimethylformamide (11.85 ml).The reaction solution is heated to 80 ° C, the methanesulfonic acid 1- (2-bromophenyl) propane-2-yl ester (1.54 g) obtained in the previous step is added, and the mixture is stirred overnight. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate 2 times. The organic layer is washed with water 3 times and saturated sodium chloride aqueous solution 1 time in succession, and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel chromatography (hexane: ethyl acetate = 88: 12 to ethyl acetate) to obtain the title compound (0.383 g).

[0739] 1 H-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, 1.27 Hz, 1H).

[0740] Step 4

[0741] Ethyl 5-methyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxylate

[0742]

[0743] The 1-(1-(2-bromophenyl)propane-2-yl)-1H-imidazole-2-formic acid ethyl ester (383 mg), palladium acetate (II) (74.3 mg), potassium carbonate (305 mg) and di-1-adamantyl-n-butylphosphine (178 mg) obtained in the previous step are mixed with dimethylacetamide (3.7 ml). Under an argon atmosphere, the mixture is stirred at 120 ° C for 7 hours. Under ice cooling, water is added, and the precipitated solid is collected by filtration. The filtrate is extracted with ethyl acetate 2 times. The organic layer is washed with water 2 times and with saturated sodium chloride aqueous solution 1 time in succession, and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue and the solid collected by filtration are each purified by silica gel chromatography (hexane: ethyl acetate=88:12 to ethyl acetate) to obtain the title compound (145 mg).

[0744] 1 H-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).

[0745] Step 5

[0746] N-Methoxy-N,5-dimethyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide

[0747]

[0748] The 5-methyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxylic acid ethyl ester (82.4 mg) obtained in the previous step was mixed with ethanol (1.6 ml). Under ice cooling, 2N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and azeotroped with toluene. The obtained 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. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with water and saturated sodium chloride aqueous solution in succession and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 88: 12 to ethyl acetate) to obtain the title compound (80 mg).

[0749] 1 H-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).

[0750] Step 6

[0751] 1-(5-Methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)ethan-1-one

[0752]

[0753] The N-methoxy-N,5-dimethyl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide (80 mg) obtained in the previous step was mixed with tetrahydrofuran (2 ml). Under ice cooling, 1M methylmagnesium bromide / tetrahydrofuran solution (0.59 mL) was added dropwise to the mixture, and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride solution 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 saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 12:88 to ethyl acetate) to obtain the title compound (46.3 mg).

[0754] 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).

[0755] Step 7

[0756] 1,1,1-Trifluoro-2-(5-methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)propan-2-ol

[0757]

[0758] 1-(5-methyl-5,6-dihydroimidazo[5,1-a]isoquinolin-3-yl)ethane-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 min. 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 min. 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 twice and with saturated aqueous sodium chloride solution once, and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified successively 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.

[0759] 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).

[0760] Preparation Example 5

[0761] Synthesis of 2-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)-1,1,1-trifluoropropane-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-trifluoropropane-2-ol (Compound of Example 35)

[0762] Step 1

[0763] 4-Hydroxyvalerate Methyl ester

[0764]

[0765] 4-oxopentanoic acid methyl ester (14 g) is mixed with methanol (112 ml). The mixture is cooled to -78 ° C, sodium borohydride (4.07 g) is added, and the mixture is stirred at -50 ° C for 2 hours. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel chromatography (hexane: ethyl acetate=12:88 to ethyl acetate) to obtain the title compound (11.15 g) as a crude product. The crude product is used for the next step without further purification.

[0766] Step 2

[0767] 1-(5-methoxy-5-oxopentan-2-yl)-1H-imidazole-5-carboxylic acid methyl ester

[0768]

[0769] Mix 1H-imidazole-5-methyl formate (3 g) and toluene (24 ml). Add 4-hydroxypentanoic acid methyl ester (4.85 g) and trioctylphosphine (10.58 g) obtained as crude product in the previous step into the mixture. The mixture is heated to 80 ° C, diisopropyl azodicarboxylate (5.77 g) is added dropwise, and the mixture is stirred for 3 hours. The reaction mixture is concentrated under reduced pressure, and purified by silica gel chromatography (ethyl acetate: hexane = 50: 50 to ethyl acetate, thereafter ethyl acetate: methanol = 90: 10) to obtain the title compound (2.6 g).

[0770] 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).

[0771] Step 3

[0772] 5-Methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylic acid methyl ester

[0773]

[0774] The 1-(5-methoxy-5-oxopentane-2-yl)-1H-imidazole-5-methyl formate (1.48 g) obtained in the previous step is mixed with tetrahydrofuran (45 ml). Potassium tert-butoxide (0.76 g) is added to the mixture, and the mixture is stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate 2 times. The organic layer is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure to obtain the title compound (1.04 g) as a crude product. The crude product is used for the next step without further purification.

[0775] Step 4

[0776] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one

[0777]

[0778] The crude product (1 g) of 5-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylic acid methyl ester 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 the mixture, and the mixture was stirred at 160° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to evaporate water, and purified twice by cation exchange column chromatography (methanol to 1N ammonia / methanol solution) to obtain the title compound (0.714 g).

[0779] 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).

[0780] Step 5

[0781] 7-(Cyclopropanecarbonyl)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one

[0782]

[0783] The 5-methyl-6,7-dihydroimidazo[1,5-a]pyridine-8(5H)-one (100 mg) obtained in the previous step was mixed with tetrahydrofuran (1.5 ml). Under ice cooling, 1.1M bis(trimethylsilyl) lithium amide / n-hexane solution (0.908 mL) was added dropwise to the mixture, and the mixture was stirred for 40 min. Cyclopropanecarbonyl chloride (77 mg) was added to the reaction mixture, and the mixture was stirred at 0 ° C for 5 min and at room temperature for 25 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Magnesium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate to ethyl acetate: methanol = 90: 10) to obtain the title compound (91.1 mg) as a crude product. The crude product was used in the next step without further purification.

[0784] Step 6

[0785] 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

[0786]

[0787] The crude product (90 mg) of 7-(cyclopropanecarbonyl)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridine-8(5H)-one obtained in the previous step 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 min. 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 solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Magnesium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified successively by silica gel chromatography (ethyl acetate to ethyl acetate: methanol = 90: 10) and preparative thin layer chromatography (ethyl acetate: methanol = 90: 10) to obtain the title compound (45.2 mg) as a crude product. The crude product was used in the next step without further purification.

[0788] Step 7

[0789] 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

[0790]

[0791] The crude product (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 was mixed with tetrahydrofuran (0.864 ml). The mixture was cooled to -78°C, and 2M lithium diisopropylamide solution (0.251 ml) was added dropwise. The mixture was stirred at -78°C for 40 min. N-methoxy-N-methylacetamide (62.1 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, and the mixture was warmed to room temperature and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Magnesium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained 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. The crude product was used in the next step without further purification.

[0792] Step 8

[0793] 2-(3-Cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)-1,1,1-trifluoropropane-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-trifluoropropane-2-ol (compound of Example 35)

[0794]

[0795] The crude product (17 mg) of 1-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)ethane-1-one and 1-(3-cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)ethane-1-one obtained in the previous step was mixed with tetrahydrofuran (0.34 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 1 hour. Under ice cooling, methanol (0.332 ml) and potassium carbonate (40.5 mg) were added, and the mixture was stirred for 1.5 hours while warming to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was partitioned, and the organic layer was purified by silica gel column chromatography (hexane: ethyl acetate = 12:88 to ethyl acetate) to produce 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.

[0796] 2-(3-Cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[5,4-c]pyridin-7-yl)-1,1,1-trifluoropropane-2-ol

[0797] 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).

[0798] 2-(3-Cyclopropyl-5-methyl-4,5-dihydroimidazo[1,5-a]isoxazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropane-2-ol

[0799] 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).

[0800] Preparation Example 6

[0801] 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)

[0802] Step 1

[0803] 7-((Dimethylamino)methylene)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridin-8(5H)-one

[0804]

[0805] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridine-8(5H)-one (250 mg) was mixed with 1,4-dioxane (1.25 ml). Tert-butoxybis(dimethylamino)methane (435 mg) was added to the mixture, and the mixture was stirred at 110°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a crude product. The crude product was used in the next step without further purification.

[0806] Step 2

[0807] 6-Methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidine

[0808]

[0809] The crude product of 7-((dimethylamino)methylene)-5-methyl-6,7-dihydroimidazo[1,5-a]pyridine-8(5H)-one obtained in the previous step was mixed with ethanol (0.95 ml). Trifluoroacetamidine (142 mg) was added to the mixture, and the mixture was stirred at room temperature for 15 min. Sodium ethoxide (86 mg) was added to the mixture, and the mixture was heated and stirred under reflux overnight. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate 2 times. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 to 60: 40) to obtain the title compound (172.6 mg).

[0810] 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),

[0811] 8.64 (s, 1H).

[0812] Step 3

[0813] 1-(6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-8-yl)ethan-1-one

[0814]

[0815] The 6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidine (50 mg) obtained in the previous step is mixed with tetrahydrofuran (0.5 ml). The mixture is cooled to -78 ° C, and 2M lithium diisopropylamide solution (0.118 ml) is added dropwise. The mixture is stirred at -78 ° C for 1 hour. N-methoxy-N-methylacetamide (40.6 mg) is added to the mixture, and the mixture is stirred at -78 ° C for 1 hour. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is warmed to room temperature and extracted with ethyl acetate 2 times. The organic layer is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate=12:88 to ethyl acetate) to obtain the title compound (17.2 mg).

[0816] 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).

[0817] Step 4

[0818] 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

[0819]

[0820] 1-(6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-8-yl)ethane-1-one (17.2 mg) obtained in the previous step was mixed with tetrahydrofuran (0.172 ml). Under ice cooling, cesium fluoride (1.764 mg) and (trifluoromethyl)trimethylsilane (16.51 mg) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, (trifluoromethyl)trimethylsilane (16.51 mg) was added to the mixture, and the mixture was stirred at room temperature for 20 min. Under ice cooling, (trifluoromethyl)trimethylsilane (16.51 mg) was added to the mixture, and the mixture was stirred at room temperature for 20 min. Under ice cooling, methanol (0.103 ml) and potassium carbonate (9.63 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. In the mixture, add saturated aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate 2 times.The organic layer is washed with water and saturated aqueous sodium chloride solution in succession and dried over sodium sulfate.Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate=1:1).Ethyl acetate / hexane=1 / 1 is added to the crude product obtained, and the mixture is stirred at room temperature.The precipitated solid is collected by filtration to obtain the title compound (7.1 mg) as a racemate.

[0821] 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).

[0822] Preparation Example 7

[0823] 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-trifluoropropane-2-ol (Compound of Example 24)

[0824] Step 1

[0825] 1,5-Dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine

[0826]

[0827] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridine-8(5H)-one (150 mg) was mixed with tetrahydrofuran (1.5 ml). Ethyl trifluoroacetate (312 mg) was added to the mixture. Under ice cooling, sodium hydride (88 mg) was added to the mixture, and the mixture was stirred at room temperature for 10 min and 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. Acetic acid (1.5 ml) and methylhydrazine (138 mg) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and dried over sodium sulfate. Sodium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained 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.

[0828] 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).

[0829] Step 2

[0830] 1-(1,5-dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one

[0831]

[0832] 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 is mixed with tetrahydrofuran (5.112 ml). The mixture is cooled to -78 ° C, and 2M lithium diisopropylamide solution (0.831 ml) is added dropwise. The mixture is stirred at -78 ° C for 30 min. N-methoxy-N-methylacetamide (206 mg) is added to the mixture, and the mixture is stirred at -78 ° C for 1 hour. Saturated aqueous ammonium chloride solution is added to the reaction mixture, and the mixture is warmed to room temperature and extracted with ethyl acetate 2 times. The organic layer is washed with saturated sodium chloride aqueous solution and dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 12: 88 to ethyl acetate) to obtain the title compound (150 mg).

[0833] Step 3

[0834] 2-(1,5-dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)-1,1,1-trifluoropropane-2-ol

[0835]

[0836] 1-(1,5-dimethyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethane-1-one (150 mg) obtained in the previous step was mixed with tetrahydrofuran (1.5 ml). Under ice cooling, cesium fluoride (1.764 mg) and (trifluoromethyl)trimethylsilane (143 mg) were added to the mixture, and the mixture was stirred at room temperature for 45 min. Under ice cooling, (trifluoromethyl)trimethylsilane (143 mg) was added to the mixture, and the mixture was stirred at room temperature for 15 min. Under ice cooling, methanol (0.103 ml) and potassium carbonate (9.63 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained 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 racemate.

[0837] 1H-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).

[0838] Preparation Example 8

[0839] 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)

[0840] Step 1

[0841] 5-Methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridine

[0842]

[0843] 5-Methyl-6,7-dihydroimidazo[1,5-a]pyridine-8(5H)-one (200 mg) was mixed with tetrahydrofuran (8 ml). Ethyl trifluoroacetate (227 mg) was added to the mixture. Sodium hydride (80 mg) was added to the mixture, and the mixture was stirred at room temperature for 1 hour and 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 min. 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 obtained 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 title compound (316.8 mg) as a crude product. The crude product was used in the next step without further purification.

[0844] Step 2

[0845] 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

[0846]

[0847] 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 the mixture, and the mixture was stirred for 30 min. Under ice cooling, 4-methoxybenzyl chloride (58.3 mg) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Magnesium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 12: 88 to ethyl acetate) to obtain the title compound (67.1 mg) as a crude product. The crude product was used in the next step without further purification.

[0848] Step 3

[0849] Mixture of 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-2H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethan-1-one

[0850]

[0851] The crude product (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 was mixed with tetrahydrofuran (0.611 ml). The mixture was cooled to -78°C, and a 2M lithium diisopropylamide solution (0.211 ml) was added dropwise. The mixture was stirred at -78°C for 45 min. N-methoxy-N-methylacetamide (52.2 mg) was added to the mixture, and the mixture was stirred at -78°C for 40 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was warmed to room temperature and partitioned. The organic layer was purified by silica gel column chromatography (hexane:ethyl acetate = 20:80 to ethyl acetate) to give the title compound (48 mg) as a crude product. The crude product was used in the next step without further purification.

[0852] Step 4

[0853] 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

[0854]

[0855] The crude product (45 mg) of 1-(1-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethane-1-one and 1-(2-(4-methoxybenzyl)-5-methyl-3-(trifluoromethyl)-4,5-dihydro-2H-imidazo[1,5-a]pyrazolo[3,4-c]pyridin-7-yl)ethane-1-one obtained in the previous step was mixed with tetrahydrofuran (0.9 ml). Under ice cooling, cesium fluoride (5.07 mg) and (trifluoromethyl)trimethylsilane (47.5 mg) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. Under ice cooling, methanol (0.45 ml) and potassium carbonate (77 mg) were added to the reaction mixture, and the mixture was stirred for 2 hours. In the mixture, add saturated aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate.The organic layer is dried over magnesium sulfate.Magnesium sulfate is filtered out, and the filtrate is concentrated under reduced pressure.The obtained residue is purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate=50:50) to obtain the title compound (11.8 mg) as a crude product.The crude product is used for the next step without further purification.

[0856] Step 5

[0857] 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

[0858]

[0859] The crude products (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 were mixed with dichloromethane (0.46 ml). Trifluoroacetic acid (0.0467 mL) was added to the 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 the mixture, and the mixture was 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 sodium bicarbonate aqueous solution were added. The mixture was extracted with ethyl acetate twice, and the organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 1: 2) to obtain the title compound (6.5 mg) as a racemate.

[0860] 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).

[0861] Preparation Example 9

[0862] 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)

[0863] Step 1

[0864] (R)-tert-Butyl 2-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)hydrazine-1-carboxylate

[0865]

[0866] Tert-butoxycarbonyl hydrazine (1.17 g) is mixed with acetonitrile (15 ml). (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (1 g) is added to the mixture. Under ice cooling, 1-hydroxybenzotriazole monohydrate (0.581 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.455 g) are added to the mixture, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the obtained residue, and the mixture is washed with 0.5N hydrochloric acid and saturated sodium bicarbonate aqueous solution in succession. The organic layer is dried over sodium sulfate. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure to obtain the title compound (1.66g).

[0867] 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).

[0868] Step 2

[0869] (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoylhydrazide

[0870]

[0871] The (R)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)hydrazine-1-tert-butyl formate (0.6 g) obtained in the previous step was mixed with ethyl acetate (1.114 ml). Under ice cooling, trifluoroacetic acid (2.78 mL) was added to the mixture, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and purified by cation exchange column chromatography (methanol to 1N ammonia / methanol solution) to obtain the title compound (155.8 mg).

[0872] 1 H-NMR (400 MHz, DMSO-D6) 1.44 (s, 3H), 4.32 (s, 2H), 6.82 (s, 1H), 9.28 (brs, 1H).

[0873] Step 3

[0874] (S)-1-(2-((tert-Butoxycarbonyl)amino)propyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid methyl ester

[0875]

[0876] 3-(Trifluoromethyl)-1H-pyrazole-5-methyl formate (200 mg), N-(tert-butoxycarbonyl)-L-aminopropanol (271 mg) and triphenylphosphine (405 mg) are mixed with tetrahydrofuran (2 ml). The mixture is heated to 80 ° C, and diisopropyl azodicarboxylate (0.3 ml) is added dropwise. The reaction mixture is stirred at 80 ° C for 2 hours and stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate=92:8 to 44:66) to obtain the title compound (388.9 mg).

[0877] 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).

[0878] Step 4

[0879] (S)-6-Methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0880]

[0881] The (S)-1-(2-((tert-butoxycarbonyl)amino)propyl)-3-(trifluoromethyl)-1H-pyrazole-5-methyl formate (362 mg) obtained in the previous step was mixed with chloroform (2 ml). Under ice cooling, trifluoroacetic acid (2 mL) was added to the mixture, 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 the reaction mixture, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration to obtain the title compound (193.4 mg).

[0882] 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).

[0883] Step 5

[0884] (S)-6-Methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-thione

[0885]

[0886] The (S)-6-methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-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-dithiadiphosphatane-2,4-disulfide (250 mg) was added to the mixture, and the mixture was stirred at 70 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 92: 8 to 44: 66) to obtain the title compound (199.8 mg).

[0887] 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).

[0888] Step 6

[0889] (S)-6-Methyl-4-(methylthio)-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine hydroiodide

[0890]

[0891] The (S)-6-methyl-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-thione (80 mg) obtained in the previous step is mixed with acetone (0.8 ml). Under ice cooling, iodomethane (57.9 mg) is added to the mixture, and the mixture is stirred at room temperature overnight. Under ice cooling, iodomethane (57.9 mg) is added to the mixture, and the mixture is stirred at room temperature for 7 hours. The reaction mixture is concentrated under reduced pressure to obtain the title compound (128 mg) as a crude product. The crude product is used for the next step without further purification.

[0892] Step 7

[0893] (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

[0894]

[0895] The crude product (128 mg) of (S)-6-methyl-4-(methylthio)-2-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine hydroiodide obtained in the previous step and (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoylhydrazide (61 mg) obtained in step 2 were mixed with isopropanol (1 ml). Acetic acid (0.039 mL) was added to the mixture, and the mixture was stirred at 100°C for 1.5 hours. The mixture was cooled 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 by cation exchange column chromatography (methanol) and silica gel column chromatography (hexane: ethyl acetate = 88:12 to ethyl acetate) in succession to obtain the title compound (32.2 mg).

[0896] 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).

[0897] Preparation Example 10

[0898] 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-trifluoropropane-2-ol (Compound of Example 23)

[0899] Step 1

[0900] 5-Hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester

[0901]

[0902] 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 succession, 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).

[0903] 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).

[0904] Step 2

[0905] 5-Hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester

[0906]

[0907] The 5-hydroxy-1H-pyrazole-3-ethyl carboxylate (300 g) obtained in the previous step is mixed with acetonitrile (720 ml). Pyridinium p-toluenesulfonate (24.14 g) is added at room temperature. 3,4-dihydro-2H-pyrans (170 g) is added dropwise to the mixture, and the mixture is stirred at room temperature for 2 days. The reaction mixture is stirred for 2 hours under ice cooling, and the precipitated solid is collected by filtration to obtain the title compound (410 g).

[0908] 1 H-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).

[0909] Step 3

[0910] 5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester

[0911]

[0912] The 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (205g) obtained in the previous step was mixed with N-methylpyrrolidone (615 ml). Under water cooling, potassium carbonate (142 g) was added, benzyl bromide (175 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Acetic acid (25.6 g) was added dropwise to the mixture, and the mixture was stirred at room temperature overnight. Water (1.23 L) was added to the reaction mixture, and the mixture was extracted with isopropyl acetate (2.05 L). The organic layer was washed twice with 10% sodium chloride aqueous solution (1.025 L) and concentrated under reduced pressure. The obtained residue was azeotroped with isopropyl acetate (2.05L). Isopropyl acetate (615 mL) was added to the obtained solid, and the mixture was heated and stirred at 55°C to dissolve the solid. The solution was cooled to 40°C and seeded. To the obtained suspension was added n-heptane (2.46 L) dropwise, and the mixture was cooled to room temperature and stirred at room temperature for 2 hr.The mixture was stirred under ice-cooling for 2 hr, and the precipitated solid was collected by filtration to give the title compound (235.15 g).

[0913] 1 H-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).

[0914] In this step, crystals of the title compound can be obtained without using seed crystals.

[0915] Step 4

[0916] 5-(Benzyloxy)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide

[0917]

[0918] The 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (235.15 g) obtained in the previous step was mixed with 1,2-dimethoxyethane (941 ml). A 2N aqueous sodium hydroxide solution (428 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 3.5 hours. Under water cooling, N-methoxy-N-methylamine hydrochloride (83 g) and HOBt-H2O (21.8 g) were added to the mixture, WSC-HCl (164 g) was added in 4 portions, and the mixture was stirred at room temperature overnight. A 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 a 5% aqueous sodium chloride solution (941 mL) and concentrated under reduced pressure. The obtained residue was azeotroped with toluene (2.35 L). Toluene was added to the obtained residue to prepare a solution of the title compound containing toluene in an amount 5 times the weight of the starting material.

[0919] Step 5

[0920] 5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde

[0921]

[0922] Under ice cooling, 70% bis(2-methoxyethoxy) sodium aluminum hydride / toluene solution (141 mL) was added dropwise to the 5-(benzyloxy)-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide / toluene solution obtained in the previous step, and the mixture was stirred for 2.5 hours. Under water cooling, isopropanol (54.8 ml) / toluene (118 ml) solution was added dropwise to the reaction mixture. The mixture was warmed to room temperature, Rochelle salt (201 g) / water (941 ml) was added, and the mixture was stirred for 1 hour. The solution was distributed, and the organic layer was washed twice with 5% sodium chloride aqueous solution (941 ml) and concentrated under reduced pressure. The obtained residue was solvent replaced with 1,2-dimethoxyethane (2.35 L). To the obtained residue was added 1,2-dimethoxyethane to prepare a solution of the title compound containing 1,2-dimethoxyethane in an amount 13 times the weight of the starting material.

[0923] Step 6

[0924] 5-(Benzyloxy)-1H-pyrazole-3-carbaldehyde

[0925]

[0926] To the 5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde / 1,2-dimethoxyethane solution obtained in the previous step 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 obtain the title compound (132.04 g).

[0927] 1 H-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).

[0928] Step 7

[0929] (S)-2-(5-(3-(Benzyloxy)-1H-pyrazol-5-yl)-1H-imidazol-1-yl)propan-1-ol

[0930]

[0931] The 5-(benzyloxy)-1H-pyrazole-3-carboxaldehyde (261.97 g) obtained in the previous step is mixed with dimethylformamide (1040 ml). (S)-2-aminopropane-1-ol (102 g) is added at room temperature, and the mixture is stirred at room temperature overnight. Potassium carbonate (358 g) is added to the mixture, and p-toluenesulfonylmethyl isonitrile (304 g) is added and is stirred at room temperature overnight. Potassium tert-butoxide (72.7 g) is added to the reaction mixture, and the mixture is stirred at room temperature overnight. 2-methyltetrahydrofuran (1572 ml) and KC FLOCK (W-300G, Nippon PaperIndustries Co., Ltd., 131 g) are added to the reaction mixture, and the mixture is filtered using KC FLOCK as an auxiliary agent. 2-methyltetrahydrofuran (1572 mL) is added to the filtrate, and the mixture is stirred and filtered at room temperature. The filtrates are combined and washed 3 times with 10% sodium chloride aqueous solution (1048 ml). The first aqueous layer is extracted with 2-methyltetrahydrofuran (2620 ml) and washed 3 times with 10% sodium chloride aqueous solution (1048 ml). The organic layers are combined, concentrated under reduced pressure, and azeotroped with toluene and 2-methyltetrahydrofuran in succession. In the residue obtained, 2-methyltetrahydrofuran is added to prepare a solution of the title compound, which contains 4 times the weight of the starting material 2-methyltetrahydrofuran.

[0932] Step 8

[0933] (S)-9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine hydrochloride

[0934]

[0935] The (S)-2-(5-(3-(benzyloxy)-1H-pyrazol-5-yl)-1H-imidazole-1-yl)propane-1-ol / 2-methyltetrahydrofuran solution obtained in the previous step was mixed with triphenylphosphine (408 g). Under heating at 73° C., 40% diisopropyl azodicarboxylate / toluene solution (763 ml) was added dropwise, and the mixture was stirred for 1 hour. Under heating at 60° C., 2N hydrochloric acid / ethanol solution (842 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration to obtain the title compound (244.13 g).

[0936] 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).

[0937] Step 9

[0938] (S)-9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine

[0939]

[0940] The (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 sodium hydroxide aqueous solution (194 mL) was added to the mixture, and the mixture was stirred for 1 hour. The solution was distributed, and the organic layer was washed with 20% sodium chloride aqueous solution (896 ml) and concentrated under reduced pressure. The obtained residue was azeotroped with toluene (1 L) and tetrahydrofuran (1.1 L) in succession. Tetrahydrofuran was added to the obtained residue to prepare a solution of the title compound, which contained 5.4 times the weight of the starting material.

[0941] Step 10

[0942] (S)-1-(9-(Benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0943]

[0944] Under -78 ° C cooling, 1M lithium diisopropylamide / hexane-tetrahydrofuran solution (634 mL) was added dropwise to the (S)-9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine / tetrahydrofuran solution obtained in the previous step, and the mixture was stirred for 1 hour. N-methoxy-N-methylacetamide (173 mL) was added to the mixture, and the mixture was stirred at -78 ° C for 1.5 hours. 1M lithium diisopropylamide / hexane-tetrahydrofuran solution (667 mL) was added dropwise to the mixture, and the mixture was stirred for 2.5 hours. The 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 the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound (205.85 g).

[0945] 1 H-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).

[0946] Step 11

[0947] (S)-1-(9-Hydroxy-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0948]

[0949] The (S)-1-(9-(benzyloxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-3-yl)ethane-1-one (205.7 g) obtained in the previous step was mixed with concentrated hydrochloric acid (563 ml). The mixture was stirred at 48°C overnight and then at room temperature overnight. The reaction mixture was washed with toluene (1.029 L). The obtained aqueous layer was diluted with ethanol (206 ml) and water (411 mL), and 4N aqueous sodium hydroxide solution (1276 ml) and 10% trisodium citrate aqueous solution (1076 ml) were added. After stirring for 2 hours under ice cooling, the precipitated solid was collected by filtration to obtain the title compound (144.84 g).

[0950] 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).

[0951] Step 12

[0952] (S)-1-(9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)ethan-1-one

[0953]

[0954] The (S)-1-(9-hydroxy-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-3-yl)ethane-1-one (1 g) obtained in the previous step was mixed with acetonitrile (10 ml). 8M potassium hydroxide aqueous solution (168 ml) was added to the mixture. Under ice cooling, diethyl (bromodifluoromethyl)phosphonate (1.533 mL) was added dropwise to the mixture, and the mixture was stirred under water cooling for 1 hour. Water (20 ml) and ethyl acetate (20 ml) were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate twice. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to obtain the title compound (561 mg).

[0955] 1H-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).

[0956] Step 13

[0957] (R)-2-((S)-9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazin-3-yl)-1,1,1-trifluoropropane-2-ol

[0958]

[0959] The (S)-1-(9-(difluoromethoxy)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazolo[5,1-c]pyrazine-3-yl)ethane-1-one (561 mg) obtained in the previous step was mixed with tetrahydrofuran (5.6 ml). Cesium fluoride (0.06 g) was added to the mixture. Under ice cooling, (trifluoromethyl)trimethylsilane (0.587 ml) was added dropwise, and the mixture was 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 the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to obtain the title compound (529 mg).

[0960] 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).

[0961] According to the methods similar to the above-mentioned preparation methods 1 to 10 and the preparation examples 1-10 or other known methods as necessary, the compounds of examples 1-103 are obtained. The structural formulas and performance data of the example compounds are shown in the following table. The notes in the table show the following contents.

[0962] 1 (Examples 1, 3, 5, 6, 24, 25, 34, 35 and 50)

[0963] Racemate

[0964] 2 (Example 26)

[0965] A mixture of two diastereomers

[0966] 3 (Example 97)

[0967] The spatial configuration of the cyclopropane part is trans, and it is a mixture of two diastereomers.

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992] Experimental Example 1

[0993] (Inhibition of PDHK2 activity)

[0994] In the case of human PDHK2 (hPDHK2, NCBI reference database accession number NM_002611.4), a modified hPDHK2 cDNA was prepared by polymerase chain reaction (PCR), wherein the FLAG-tag sequence was added to the N-terminus of the hPDHK2 cDNA clone (pReceiver-M01 / PDK2-GeneCopoeia) as a substrate and ligated to the NdeI / EcoRI site of the pET-17b vector (Merck KGaA, catalog number 69663-3). The recombinant construct was transformed into Escherichia coli DH5α. The recombinant clones were identified, plasmid DNA was isolated and DNA sequence analysis was performed. A clone with the expected nucleic acid sequence was selected for expression work.

[0995] To express hPDHK2 activity, E. coli strain BL21 (DE3) cells (Merck KGaA, catalog number 69450-4) were transformed with the pET17b vector containing the modified hPDHK2 cDNA. E. coli was grown at 30°C to an optical density of 0.6 (600 nmol / L). Protein expression was induced by adding 500 μmol / L isopropyl-β-thiogalactopyranoside. E. coli was cultured at 20°C for 17-18 hours and harvested by centrifugation. The harvested E. coli was resuspended in a suspension buffer (20 mmol / L HEPES-NaOH, 500 mmol / L sodium chloride, 1% ethylene glycol, 0.1% Pluronic (registered trademark) F-68 (pH 8.0), cOmplete, EDTA-free (Roche) (pH 8.0)) and disrupted by a microfluidizer M-110H (MIZUHO INDUSTRIAL CO., LTD.). The precipitate was removed by centrifugation, and the supernatant was added to a DDDDK-labeled protein purification gel (MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Code No. 3329). The DDDDK-labeled protein purification gel was washed with wash buffer (20 mmol / L HEPES-NaOH, 500 mmol / L sodium chloride, 1% ethylene glycol, 0.1% Pluronic F-68 (pH 8.0)), and 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 combined, concentrated by ultrafiltration, added to a gel filtration column (HiLoad26 / 60 Superdex 200 (GE Healthcare Life Sciences, Code No. 17-1070-01)), and eluted with elution buffer 2 (20 mmol / L HEPES-NaOH, 150 mmol / L sodium chloride, 0.5 mmol / L ethylenediaminetetraacetic acid (EDTA), 1% ethylene glycol, 0.1% Pluronic F-68 (pH 8.0)). The eluted fractions were combined and stored at -80°C.

[0996] 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 potassium 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 give a final concentration of PDH of 0.025 U / mL, and the mixture was incubated overnight at 4°C to obtain a PDH / hPDHK2 complex solution.

[0997] PDH was mixed with an assay buffer so that the final concentration was 0.025 U / mL, and the mixture was incubated at 4°C overnight to prepare a PDH solution.

[0998] The test compound was diluted with DMSO. To measure the inhibitory effect of the test compound on PDHK activity in the PDH / hPDHK2 complex solution, the PDH / hPDHK2 complex solution (20 μL), the test compound (1.5 μL) and 1.06 μmol / L ATP (diluted with assay buffer) (8.5 μL) were added to a 384-well microplate (Greiner Bio-One 781801) and the PDHK reaction was carried out at room temperature for 45 min (test compound wells). DMSO (1.5 μL) was added to the control wells instead of the test compound. In addition, DMSO (1.5 μL) was added to the blank wells instead of the test compound, and the PDH solution was added instead of the PDH / hPDHK2 complex solution. To measure the inhibitory effect of the test compound on the intrinsic PDHK activity in the PDH solution, the test compound was added, and the PDH solution was added to the blank + test compound wells instead of the PDH / hPDHK2 complex solution.

[0999] Then, 10 μL of substrate (5 mmol / L sodium pyruvate, 5 mmol / L CoA, 12 mmol / L NAD, 5 mmol / L thiamine pyrophosphate, diluted in assay buffer) was added, the mixture was incubated at room temperature for 90 min, and the residual PDH activity was measured.

[1000] The absorbance of each well at 340 nm was measured using a microplate reader to detect NADH produced by the PDH reaction. The PDH activity of each well was calculated from the change in absorbance before and after the PDH reaction. The PDH activity of the sample treated with the test compound was calculated by the formula {PDH activity of the test compound well - (PDH activity of the blank + test compound well - PDH activity of the blank well)}. The hPDHK2 inhibition rate (%) of the test compound was calculated by the formula [{(PDH activity of the sample treated with the test compound - PDH activity of the control well) / (PDH activity of the blank well - PDH activity of the control well)} × 100]. Based on the test compound concentration and the hPDHK2 inhibition rate (%), the IC was calculated according to the logistic regression method 50 value.

[1001] The results are shown in the table below. 50 When the value is , the inhibition rate at the lowest or highest concentration of the test compound in the assay is shown. For example, the compound of Example 12 showed 35% hPDHK2 inhibition at 0.1 μM.

[1002]

[1003]

[1004]

[1005]

[1006] As formulation examples of the present invention, the following formulations can be mentioned. However, the present invention is not limited to these formulation examples.

[1007] Formulation Example 1: Preparation of Capsules

[1008] 1) 30 mg of the compound of Example 1

[1009] 2) Crystalline cellulose 10 mg

[1010] 3) Lactose 19 mg

[1011] 4) Magnesium stearate 1 mg

[1012] 1), 2), 3) and 4) are mixed and filled into gelatin capsules.

[1013] Formulation Example 2: Preparation of Tablets

[1014] 1) 10 g of the compound of Example 1

[1015] 2) Lactose 50 g

[1016] 3) Corn starch 15 g

[1017] 4) Carboxymethylcellulose calcium 44 g

[1018] 5) Magnesium stearate 1 g

[1019] The total amount of 1), 2), 3) and 30 g of 4) was kneaded with water, vacuum dried, and sieved. The sieved powder was mixed with 14 g of 4) and 1 g of 5), and the mixture was punched with a tablet press. In this way, 1000 tablets were obtained, each containing 10 mg of the compound of Example 1.

[1020] Preparation Example 3: Preparation of injection

[1021] 1) 5 mg of the compound of Example 1

[1022] 2) D-mannitol 5 g

[1023] 3) 100 mL distilled water

[1024] 1) and 2) are dissolved in 3), and the solution is filled into a container for injection, sealed and sterilized.

[1025] Industrial Applicability

[1026] Since the compound of formula [Ia] or a pharmaceutically acceptable salt thereof has PDHK inhibitory activity, it can be used as an active ingredient of a drug for treating or preventing diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, 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, cerebral stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia (large vessel type or small vessel type vascular dementia), glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy or chronic kidney disease. Sequence Listing <110> JAPAN TOBACCO INC. <120> Condensed tricyclic compound and its medical use <130> 093110 <150> JP 2020-036931 <151> 2020-03-04 <150> JP 2021-001452 <151> 2021-01-07 <160> 1 <170> PatentIn Version 3.5 <210> 1 <211> 8 <212> PRT <213> Artificial sequence <220> <223> FLAG-Tag <400> 1 Asp Tyr Lys Asp Asp Asp Asp Lys 1 5

Claims

1. A compound of formula [Ic] or a pharmaceutically acceptable salt thereof: in X 3 C or N, Y 1 and Y 2 are independently C, N or O, wherein X 3 , Y 1 or Y 2 The total number of N and O is 0-3, R B yes (1) Halogen, (2) cyano group, (3) hydroxyl group, (4) Oxo, (5)-COR 1 , where R 1 yes (A) Hydrogen, (B)-OH, (C)-NR 2 R 3 , where R 2 and R 3 are independently hydrogen or C 1-4 Alkyl, or (D) a 4-6 membered saturated heterocyclic group having one nitrogen atom, wherein the saturated heterocyclic group is optionally substituted by 1 or 2 halogens, (6)C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted with 1 to 8 substituents independently selected from (A) halogen, (B) hydroxyl group, (C) phenyl optionally substituted by halogen, (D) optionally halogenated C 1-4 an alkyl-substituted pyridyl group, and (E)-OR 4 , where R 4 yes (a)C 1-4 alkyl, (b) phenyl optionally substituted by halogen, or (c) optionally C 1-4 Alkoxy substituted benzyl, (7)C 1-8 Alkoxy, wherein the C 1-8 The alkoxy group is optionally substituted with 1-8 substituents independently selected from (A) halogen, (B) cyano, (C) hydroxyl group, (D) C optionally substituted by 1 to 3 halogens 1-4 Alkoxy, (E)C 1-4 Alkylsulfonyl, (F) C optionally substituted with one substituent 3-6 Cycloalkyl, the substituent is selected from cyano and cyanoC 1-4 alkyl, (G) phenyl optionally substituted by cyano, (H)-COCy 1 , where Cy 1 is a 4-6 membered saturated heterocyclic group having one nitrogen atom, and the saturated heterocyclic group is optionally substituted by 1 or 2 halogens, and (I) a 4-6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the saturated heterocyclic group is optionally substituted by 1-4 substituents independently selected from (a)C 1-4 alkyl, (b) oxo, (c)C 1-4 Alkylcarbonyl, (d) benzoyl optionally substituted by halogen, and (e)C 1-4 Alkylsulfonyl, When the saturated heterocyclic group is replaced by two C 1-4 When alkyl is substituted, the two C 1-4 The alkyl groups are optionally bonded to each other to form a bridged ring together with the atoms to which they are bonded, (8)-Cy 2 , where Cy 2 yes (A)C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally substituted with 1 or 2 substituents independently selected from (a) halogen, (b)C 1-4 alkyl, (c) Halogenated C 1-4 Alkyl, and (d) phenyl optionally substituted by halogen, (B) phenyl optionally substituted by 1 or 2 substituents independently selected from halogen, halogenated C 1-4 Alkyl and C 1-4 Alkoxy, or (C) a 4-6 membered saturated heterocyclic group having one nitrogen atom or oxygen atom, wherein the saturated heterocyclic group is optionally substituted by a substituent selected from (a) phenyl optionally substituted by halogen and (b) C 1-4 Alkylcarbonyl, or (9)-OCy 3 , where Cy 3 yes (A) a 4-6 membered saturated heterocyclic group having one nitrogen atom or oxygen atom, wherein the saturated heterocyclic group is optionally substituted by a substituent selected from (a) a benzoyl group optionally substituted by halogen and (b) C 1-4 Alkylcarbonyl, or (B) a 6-membered heteroaryl group having 1 or 2 nitrogen atoms, wherein the heteroaryl group is optionally substituted by 1 or 2 substituents independently selected from cyano, halo 1-4 Alkyl and C 3-6 a cycloalkyl group, and n is 0, 1, or 2. When n is 2, each R B Same or different.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound of formula [Id] or a pharmaceutically acceptable salt thereof: Where R B As defined in claim 1.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound of formula [Ie] or a pharmaceutically acceptable salt thereof: Where R B As defined in claim 1.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R B yes (1)C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted with 1 to 8 substituents independently selected from (A) halogen, (B) hydroxyl group, (C) phenyl optionally substituted by halogen, (D) optionally halogenated C 1-4 an alkyl-substituted pyridyl group, and (E)-OR 4 , where R 4 yes (a)C 1-4 alkyl, (b) phenyl optionally substituted by halogen, or (c) optionally C 1-4 Alkoxy substituted benzyl, or (2)C 1-8 Alkoxy, wherein the C 1-8 The alkoxy group is optionally substituted with 1 to 8 substituents independently selected from (A) halogen, (B) cyano, (C) hydroxyl group, (D) C optionally substituted by 1 to 3 halogens 1-4 Alkoxy, (E)C 1-4 Alkylsulfonyl, (F) C optionally substituted with one substituent 3-6 Cycloalkyl, the substituent is selected from cyano and cyanoC 1-4 alkyl, (G) phenyl optionally substituted by cyano, (H)-COCy 1 , where Cy 1 is a 4-6 membered saturated heterocyclic group having one nitrogen atom, and the saturated heterocyclic group is optionally substituted by 1 or 2 halogens, and (I) a 4-6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the saturated heterocyclic group is optionally substituted by 1-4 substituents independently selected from (a)C 1-4 alkyl, (b) oxo, (c)C 1-4 Alkylcarbonyl, (d) benzoyl optionally substituted by halogen, and (e)C 1-4 Alkylsulfonyl, When the saturated heterocyclic group is replaced by two C 1-4 When alkyl is substituted, the two C 1-4 Alkyl groups are optionally bonded to each other to form a bridged ring together with the atoms to which they are bonded.

6. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

7. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

8. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

9. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

10. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

11. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

12. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

13. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

14. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

15. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. A PDHK inhibitor comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

18. The PDHK inhibitor of claim 17, wherein the PDHK inhibitor is a PDHK2 inhibitor.

19. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a PDHK inhibitor.

20. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease selected from diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral stroke, mitochondrial disease, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy and chronic kidney disease.

21. The use according to claim 20, wherein the diabetes is type 1 diabetes or type 2 diabetes.

22. The use according to claim 20, wherein the vascular dementia is vascular dementia of the large vessel type or vascular dementia of the small vessel type.

23. The use according to claim 20, wherein the heart failure is acute heart failure or chronic heart failure.

24. The use according to claim 20, wherein the pulmonary hypertension is pulmonary arterial hypertension.

25. The use according to claim 20, wherein the disease is diabetic retinopathy.

26. The use according to claim 20, wherein the disease is atherosclerosis.

27. The use according to claim 20, wherein the disease is mitochondrial encephalomyopathy.

Images