RU2789670C2 - Nitrogen-containing heterocyclic amide and its use for medical purposes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a compound of the formula [I-a] or the formula [II] or its pharmaceutically acceptable salt, where a dotted line bond is a single bond or a double bond, X¹ is a carbon atom, a nitrogen atom, or an oxygen atom, X² is a carbon atom or a nitrogen atom, R^1a is C_1-4 alkyl or C_1-4 alkyl carbonyl, R² is halogen, cyano group, or C_1-4 alkyl, m is 0 or 1, n is 0, 1, or 2, if n is 2, all R² are the same or different, A¹, A², A³, A⁴, A⁵, A⁶, and A⁷ are all independently selected from a group including a carbon atom, a nitrogen atom, and an oxygen atom, A⁸ is selected from a group including a carbon atom and a nitrogen atom, and the total number of nitrogen atoms and oxygen atoms contained in the structural formula of a fragment (a) is 0, 1, 2, or 3, t is 0 or 1, r is 0, 1, or 2, and the sum of t and r is 1 or 2, w is 0 or 1, R³ and R⁴, all independently, are hydrogen or C_1-4 alkyl; Cy¹ is (1) (i) C_4-6 cycloalkyl or (ii) 4-6-element saturated or partially saturated heterocyclyl containing one nitrogen atom, C_4-6 cycloalkyl and saturated or partially saturated heterocyclyl is optionally substituted with one substitute independently selected from a group including C_1-4 alkyl and an oxo group, or (2) (i) phenyl or (ii) 5- or 6-element heteroaryl containing 1, 2, or 3 heteroatoms independently selected from a group including a nitrogen atom and an oxygen atom, phenyl and heteroaryl are optionally substituted with 1 or 2 substitutes independently selected from a group including halogen, cyano group, carboxy group, C_1-4 alkyl, halogen-C_1-4 alkyl, and C_3-6 cycloalkyl; Cy² is (1) (i) C_3-6 cycloalkyl or (ii) 4-6-element saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from a group including a nitrogen atom and an oxygen atom, and C_3-6 cycloalkyl and saturated heterocyclyl are optionally substituted with 1 or 2 substitutes independently selected from a group including halogen, hydroxy group, and C_1-4 alkyl, or (2) (i) phenyl or (ii) 5- or 6-element heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, and phenyl and heteroaryl are optionally substituted with 1 or 2 substitutes independently selected from a group including halogen, cyano group, C_1-4 alkyl, C_1-4 alkoxy group, and C_1-4 alkyl sulfonyl, and v is 0 or 1. The invention also relates to a pharmaceutical composition having an inhibitory effect on the activity of PDHK1 and 2, containing effective amount of a compound, according to the invention, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. Compounds, according to the invention, are intended for use in the treatment of diseases associated with an inhibitory effect on the activity of PDHK1 and 2.

EFFECT: nitrogen-containing heterocyclic amide, which has an inhibitory effect on pyruvate dehydrogenase kinase (PDHK 1 and 2).

,

,

46 cl, 26 tbl, 140 ex

Description

The field of technology to which the invention belongs

[0001]

The present invention relates to a nitrogen-containing heterocyclic amide and its use in pharmaceuticals. More specifically, the present invention relates to a nitrogen-containing heterocyclic amide or a pharmaceutically acceptable salt thereof having an inhibitory effect on pyruvate dehydrogenase kinase (hereinafter abbreviated as PDHK), to a pharmaceutical composition containing the same, containing the therapeutic or prophylactic agent for the treatment of diabetes (diabetes type 1, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.), heart failure (acute cardiac 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 apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer or pulmonary hypertension or Alzheimer's disease, and the like.

State of the art

[0002]

In tissue, for energy-using reactions such as biosynthesis, active transport, muscle contraction, and the like, energy is supplied by hydrolysis of adenosine triphosphate (ATP). ATP is formed by the oxidation of metabolic fuels that provide a lot of energy, such as glucose and free fatty acids. In oxidative tissues such as muscle, ATP is mainly formed from acetyl-CoA, which enters the citric acid cycle. Acetyl-CoA is formed by the oxidation of glucose by the glycolytic pathway or the (free fatty acid oxidation) pathway. The enzyme that plays a major role in regulating the production of acetyl-CoA from glucose is pyruvate dehydrogenase (abbreviated hereinafter as PDH). (NAD) to NADH, simultaneously with the oxidation of pyruvic acid to acetyl-CoA and carbon dioxide (eg, non-patent documents 1, 2).

[0003]

PDH is a polyenzymatic complex consisting of three enzyme components (E1, E2, and E3) and a number of subunits localized in the mitochondrial matrix. E1, E2, and E3 are responsible for the decarboxylation of pyruvic acid, production of acetyl-CoA, and reduction of NAD to NADH, respectively.

Two classes of enzymes with a regulatory function bind to PDH. One is PDHK, which is a protein kinase with specificity for PDH. Its role is to inactivate the E1 subunit (PDH complex by phosphorylation. Another 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 of kinase activity and phosphatase activity. Kinase activity is regulated with using the relative concentration of metabolic substrates For example, kinase activity is activated by increasing the ratios of NADH/NAD, acetyl-CoA/CoA, and ATP/adenosine diphosphate (ADP) and inhibited by pyruvic acid (eg, non-patent document 3).

[0004]

Four types of PDHK isozymes have been identified in mammalian tissues. In particular, PDHK2 is expressed in a wide range of tissues, including the liver, skeletal muscle, and adipose tissues involved in glucose metabolism. In addition, since PDHK2 exhibits a relatively high sensitivity to activation by increasing NADH/NAD or acetyl-CoA/CoA and inhibition by pyruvic acid, it is expected to be involved in the short-term regulation of glucose metabolism (eg, Non-Patent Document 4).

[0005]

In addition, PDHK1 is highly expressed in cardiac muscle, skeletal muscle, pancreatic β-cells, etc. In addition, since PDHK1 expression is induced by activation of hypoxia-inducible factor (HIF) 1 in the ischemic state, it is assumed to be involved in ischemic diseases and cancers (eg, non-patent document 5).

[0006]

In diseases such as non-insulin dependent (type 1) diabetes, non-insulin dependent (type 2) diabetes, and the like, lipid oxidation is promoted by simultaneous reduction with glucose. This recovery with the use of glucose is one of the factors that cause hyperglycemia. When oxidative glucose metabolism is reduced in type 1 and type 2 diabetes and obesity, PDH activity is also reduced. This suggests the involvement of reduced PDH activity in reduced glucose utilization in type 1 diabetes and type 2 diabetes (eg Non-Patent Documents 6, 7).

On the contrary, hepatic gluconeogenesis is increased in type 1 diabetes and type 2 diabetes, which becomes one factor causing hyperglycemia. Reduced PDH activity leads to a decrease in the concentration of pyruvic acid, which in turn increases the availability of lactic acid as a substrate for hepatic gluconeogenesis. This suggests a possible involvement of reduced PDH activity in enhanced gluconeogenesis in type 1 diabetes and type 2 diabetes (eg Non-Patent Documents 8, 9).

If PDH is activated by inhibiting PDHK, the rate of glucose oxidation is said to increase. As a result, it is promoted by the use of glucose in the body and hepatic gluconeogenesis is suppressed, as a result of which the course of hyperglycemia in type 1 diabetes and type 2 diabetes is expected to improve (for example, non-patent documents 10 , 11, 12).

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

In addition, prolonged hyperglycemia due to diabetes is known to cause complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, and the like. Thiamine and α-lipoic acid contribute to 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 promising effect in the treatment of diabetic complications. Thus, PDH activation is expected to improve the course of complications in diabetes (eg, non-patent documents 15, 16).

[0007]

In ischemic pathological conditions, limited oxygen supply reduces the oxidation of both glucose and fatty acid and reduces the amount of ATP produced by oxidative phosphorylation in tissues. In the absence of sufficient oxygen, the ATP content is maintained by promoted anaerobic glycolysis. As a result, the content of lactic acid increases and intracellular pH decreases. Even if cells try to maintain ion homeostasis through energy consumption, abnormally low ATP and disturbed cellular osmolality lead to cell death. In addition, an activating adenosine monophosphate kinase activated in an ischemic state inactivates acetyl-CoA carboxylase by phosphorylation. The total content of malonyl-CoA in the tissue decreases, therefore, the activity of carnitine palmitoyltransferase-I increases and fatty acid oxidation becomes more favorable than glucose oxidation due to the possibility of transfer of acyl-CoA to mitochondria. Glucose oxidation is allowed and more ATP per oxygen molecule is required than fatty acid oxidation. Therefore, in ischemic pathological conditions, if glucose oxidation dominated by PDH activation becomes energy metabolism, the ability to maintain ATP content is said to be increased (for example, non-patent document 17) .

In addition, since PDH activation causes the oxidation of pyruvic acid formed by glycolysis and reduces the production of lactic acid, the total number of protons in ischemic tissues is considered to be reduced. Accordingly, PDH activation by PDHK inhibition is expected to act in a protective manner in ischemic diseases such as myocardial ischemia (eg, Non-Patent Documents 18, 19).

[0008]

A drug that activates PDH by inhibiting PDHK is thought to decrease lactate production because it promotes pyruvate metabolism. Therefore, such a drug is presumably useful for treating hyperlactacidemia such as mitochondrial disease, mitochondrial encephalopathy, and sepsis (eg, Non-Patent Document 20).

[0009]

In cancer cells, the expression of PDHK1 or 2 is increased. In cancer cells, in addition, ATP production is reduced by oxidative phosphorylation in mitochondria and ATP production is increased by anaerobic glycolysis in the cytoplasm. Activation of PDH by inhibition of PDHK presumably promotes oxidative phosphorylation in mitochondria and increases active oxygen supply, which induces apoptosis in cancer cells. Therefore, activation of PDH by inhibition of PDHK is applicable to cancer treatment (eg, Non-Patent Document 21).

[0010]

Pulmonary hypertension is characterized by high blood pressure caused by partial narrowing of the pulmonary artery due to promoted cell proliferation taking place in it. Therefore, in pulmonary hypertension, it is assumed that PDH activation in pulmonary artery cells promotes oxidative phosphorylation in mitochondria, increases active oxygen supply, and induces apoptosis of pulmonary artery cells. Therefore, activation of PDH by inhibition of PDHK is considered useful for the treatment of pulmonary hypertension, such as pulmonary arterial hypertension (eg, Non-Patent Document 22).

[0011]

Energy production and glucose metabolism in the brain are reduced in Alzheimer's disease and PDH activity is also reduced. If the activity of PDH decreases, then the formation of acetyl CoA decreases. Acetyl CoA is used to generate ATP in the electron transport system via the citric acid cycle. Acetyl CoA is also a precursor for the synthesis of acetylcholine, which is one of the neurotransmitters. Therefore, it is believed that reduced PDH activity in the brain in Alzheimer's disease leads to neuronal cell death due to reduced ATP production. Furthermore, the synthesis of acetylcholine, which is a cholinergic nerve transmitter, is believed to be inhibited and induce memory impairment and the like. PDH activation in the brain is hypothesized to increase energy production and acetylcholine synthesis in Alzheimer's disease. Therefore, activation of PDH by inhibition of PDHK is considered useful for the treatment of Alzheimer's disease (eg, non-patent documents 23, 24).

[0012]

Dichloroacetic acid, which is a PDH activating drug, has been shown to provide promising effects for the treatment of diabetes, myocardial ischemia, myocardial infarction, angina pectoris, heart failure, hyperlactacidemia, cerebral ischemia, cerebral apoplexy, peripheral artery disease, chronic obstructive pulmonary disease , cancer, and pulmonary hypertension (eg, non-patent documents 10, 18, 20, 22, 25, 26, 27).

[0013]

It follows from the above data that a PDHK inhibitor is considered useful for the treatment or prevention of diseases associated with impaired glucose utilization, such as diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia , hyperlactacidemia, complications of diabetes (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataracts, etc.). In addition, the PDHK inhibitor is considered useful for the treatment or prevention of diseases caused by limited supply of energy substrates 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 and cerebral apoplexy. In addition, the PDHK inhibitor is considered useful for the treatment or prevention of mitochondrial disease, mitochondrial encephalopathy, cancer, pulmonary hypertension, and the like.

[0014]

Therefore, a PDHK inhibitor is considered useful for treating or preventing diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, pulmonary hypertension, or Alzheimer's disease.

List of documents

Non-Patent Documents

[0015]

non-patent document1: Reed LJ, Hackert ML. Structure-function relationships in dihydrolipoamide acyltransferases. J Biol Chem. 1990 Jun 5; 265(16):8971-4.

non-patent document2: Patel MS, Roche TE. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J. 1990 Nov; 4(14):3224-33.

non-patent document3: 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. May 2003; 284 (5): E855-62.

non-patent document4: Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998 Jan 1; 329(Pt 1):191-6.

non-patent document5: Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006 Mar; 3(3):177-85.

non-patent document6: Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. Dec 2005; 115(12):3587-93.

non-patent document7: Caterson ID, Fuller SJ, Randle PJ. Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in starved and alloxan-diabetic rats. Biochem J. 1982 Oct 15; 208(1):53-60.

non-patent document8: Boden G, Chen X, Stein TP. Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2001 Jan; 280(1):E23-30.

non-patent document9: Shangraw RE, Fisher DM. Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis. Clin Pharmacol Ther. 1999 Oct; 66(4):380-90.

non-patent document10: Stacpoole PW, Moore GW, Kornhauser DM. Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. NEngl J Med. 1978 Mar 9; 298(10):526-30.

non-patent document11: Mayers RM, Leighton B, Kilgour E. PDH kinase inhibitors: anovel therapy for Type II diabetes? Biochem Soc Trans. 2005 Apr; 33(Pt 2):367-70.

non-patent document12: 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.

non-patent document13: Zhou YP, Berggren PO, Grill V. A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse. diabetes. May 1996; 45 (5): 580-6.

non-patent document14: Xu J, Han J, Epstein PN, Liu YQ. Regulation of PDK mRNA by high fatty acid and glucose in pancreatic islets. Biochem Biophys Res Commun. 2006 Jun 9; 344(3):827-33.

non-patent document15: Benfotiamine. Monograph. Altern Med Rev. 2006 Sep; 11(3):238-42.

non-patent document16: Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic Acid and diabetic neuropathy. Rev Diabet Stud. 2009 Winter; 6(4):230-6.

non-patent document17: 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.

non-patent document18: Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, StacpoolePW, Pepine CJ. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol. 1988 Jan 1; 61(1):65-70.

non-patent document19: Taniguchi M, Wilson C, Hunter CA, Pehowich DJ, Clanachan AS, Lopaschuk GD. Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak. Am J Physiol Heart Circ Physiol. 2001 Apr; 280(4):H1762-9.

non-patent document20: Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clinic Pharmacol. 2003 Jul; 43(7):683-91.

non-patent document21: Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, et al. A mitochondria-K+channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell.2007 Jan; 11(1):37-51.

non-patent document22: 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.

non-patent document23: Saxena U. Bioenergetics breakdown in Alzheimer’s disease: targets for new therapies. Int J Physiol Pathophysiol Pharmacol. 2011; 3(2):133-9.

non-patent document24: Stacpoole PW. The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. aging cell. Jun 2012; 11(3):371-7.

non-patent document25: Marangos PJ, Turkel CC, Dziewanowska ZE, Fox AW. Dichloroacetate and cerebral ischaemia therapeutics. Expert Opin Investig Drugs. 1999 APR; 8(4):373-82.

non-patent document26: Calvert LD, Shelley R, Singh SJ, Greenhaff PL, Bankart J, Morgan MD, et al. Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 May 15; 177(10):1090-4.

non-patent document27: 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.

The essence of the invention

[0016]

The present invention includes the following.

[0017]

[1] A compound of formula [I-a] or formula [11], or a pharmaceutically acceptable salt thereof:

[0018]

[0019]

[0020]

Where

a bond in the form of a dotted line means a single bond or a double bond,

X ¹ means a carbon atom, a nitrogen atom or an oxygen atom,

X ² means a carbon atom or a nitrogen atom,

R ^1a means C _1-4 alkyl or C _1-4 alkylcarbonyl,

R ² means halogen, cyano or C _1-4 alkyl,

m is 0 or 1,

n is 0, 1 or 2, if n is 2, all R ² are the same or different,

A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ and A ⁷ are all independently selected from the group consisting of a carbon atom, a nitrogen atom and an oxygen atom, A ⁸ is selected from the group consisting of a carbon atom and a nitrogen atom, and the total number of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment:

[0021]

[0022]

is 0, 1, 2 or 3,

t is 0 or 1,

r is 0, 1 or 2 and the sum of t and r is 1 or 2,

w is 0 or 1,

R ³ and R ⁴ are all independently hydrogen or C _1-4 alkyl,

Cy ¹ means

(1) (i) C _4-6 cycloalkyl or (ii) 4- to 6-membered saturated or partially saturated heterocyclyl containing one nitrogen atom, C _4-6 cycloalkyl and saturated or partially saturated heterocyclyl optionally substituted with one substituent independently selected from the group consisting of C _1-4 alkyl and an oxo group, or

(2) (i) phenyl or (ii) 5- or 6-membered heteroaryl containing 1, 2 or 3 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom, phenyl and heteroaryl are optionally substituted with 1 or 2 substituents, independently selected from the group consisting of halogen, cyano, carboxy, C _1-4 alkyl, halo-C _1-4 alkyl and C _3-6 cycloalkyl,

Cy ² means

(1) (i) C _3-6 cycloalkyl or (ii) 4- to 6-membered saturated heterocyclyl containing 1 or 2 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom, and C _3-6 cycloalkyl and saturated heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy and C _1-4 alkyl, or

(2) (i) phenyl, or (ii) 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 nitrogen atoms, and phenyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, cyano , C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylsulfonyl, and

v is 0 or 1.

[0023]

[2] The compound of [1], wherein X ¹ is a carbon atom and X ² is a nitrogen atom, or a pharmaceutically acceptable salt thereof.

[0024]

[3] The compound according to paragraph [1] or [2], where in the formula [I-a] the total number of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment:

[0025]

[0026]

where each symbol is as defined in paragraph [1], is 2, or a pharmaceutically acceptable salt thereof.

[0027]

[4] A compound according to any one of paragraphs [1] to [3], which is a compound of formula [I-b]:

[0028]

[0029]

where each symbol is as defined in paragraph [1] or a pharmaceutically acceptable salt thereof.

[0030]

[5] The compound of [1], wherein v is 0, or a pharmaceutically acceptable salt thereof.

[0031]

[6] A compound according to [1] or [5], wherein Cy ¹ is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom, and the heteroaryl is optionally substituted 1 or 2 substituents independently selected from the group consisting of halo, cyano, C _1-4 alkyl, halo-C _1-4 alkyl and C _3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0032]

[7] The connection according to any of paragraphs [1], [5] and [6], where Cy ² means

(1) C _3-6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, hydroxy and C _1-4 alkyl, or

(2) phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylsulfonyl, or a pharmaceutically acceptable salt thereof.

[0033]

[8] A compound selected from the following formulas:

[0034]

[0035]

or a pharmaceutically acceptable salt thereof.

[0036]

[9] A compound selected from the following formulas:

[0037]

.

.

[0038]

[10] A pharmaceutical composition comprising a compound according to any one of paragraphs [1] - [9] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0039]

[11] A PDHK inhibitor comprising a compound according to any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof.

[0040]

[12] A PDHK1 inhibitor comprising a compound according to any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof.

[0041]

[13] A PDHK2 inhibitor comprising a compound according to any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof.

[0042]

[14] An agent for treating or preventing diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer or pulmonary hypertension, the agent comprises a compound according to any one of paragraphs [1] - [9] or a pharmaceutically acceptable salt thereof.

[0043]

[15] The agent of [14], wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0044]

[16] The agent of [14], wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract.

[0045]

[17] The remedy of [14], wherein the heart failure is acute heart failure or chronic heart failure.

[0046]

[18] The remedy of [14], wherein pulmonary hypertension is pulmonary arterial hypertension.

[0047]

[19] A method for inhibiting PDHK, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof.

[0048]

[20] A method for treating or preventing a disease selected from the group including diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, diabetic complication, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, disease peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer and pulmonary hypertension, the method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs [1] - [9] or its pharmaceutically acceptable salt.

[0049]

[21] The method of [20], wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0050]

[22] The method of [20], wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, and cataract.

[0051]

[23] The method of [20], wherein the heart failure is acute heart failure or chronic heart failure.

[0052]

[24] The method of [20], wherein the pulmonary hypertension is pulmonary arterial hypertension.

[0053]

[25] The use of a compound according to any of paragraphs [1] - [9] or a pharmaceutically acceptable salt thereof for the production of a PDHK inhibitor.

[0054]

[26] The use of a compound according to any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof for the preparation of an agent for the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complication in diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension .

[0055]

[27] The use of [26], wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0056]

[28] The use of [26], wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract.

[0057]

[29] The use of [26], wherein the heart failure is acute heart failure or chronic heart failure.

[0058]

[30] The use of [26], wherein pulmonary hypertension is pulmonary arterial hypertension.

[0059]

[31] The compound according to any one of paragraphs [1] - [9] or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, a complication of diabetes , heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension.

[0060]

[32] The compound or pharmaceutically acceptable salt thereof according to [31], wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0061]

[33] The compound or pharmaceutically acceptable salt thereof according to [31], wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract.

[0062]

[34] The compound or pharmaceutically acceptable salt thereof according to [31], wherein the heart failure is acute heart failure or chronic heart failure.

[0063]

[35] The compound or pharmaceutically acceptable salt thereof according to [31], wherein pulmonary hypertension is pulmonary arterial hypertension.

[0064]

[36] A sales package including the pharmaceutical composition of paragraph [10] and related printed material, the printed material indicates that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group including diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer and pulmonary hypertension.

[0065]

[37] A kit comprising the pharmaceutical composition of [10] and its associated printed material, the printed material indicates 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, hyperlactacidemia, complication of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer and pulmonary hypertension.

[0066]

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

[0067]

[0068]

Where

R ¹ means C _1-4 alkyl,

R ² means halogen, cyano or C _1-4 alkyl,

m is 0 or 1,

n is 0, 1 or 2, if n is 2, all R ² are the same or different,

A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ and A ⁷ are all independently selected from the group consisting of a carbon atom, a nitrogen atom and an oxygen atom, A ⁸ is selected from the group consisting of a carbon atom and a nitrogen atom, and the total number of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment:

[0069]

[0070]

is 0, 1 or 2,

a bond in the form of a dotted line means a single bond or a double bond,

t is 0 or 1,

u is 0 or 1 and the sum of t and u is 1 or 2, and

w is 0 or 1.

[0071]

[39] Compound according to paragraph [38], where the total number of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment:

[0072]

[0073]

where each symbol is as defined in paragraph [38], equal to 2, or a pharmaceutically acceptable salt thereof.

[0074]

[40] Compound according to paragraph [38], in which the structural formula of the fragment is:

[0075]

[0076]

where each symbol is as defined in paragraph [38], is the formula:

[0077]

[0078]

where each symbol is as defined in paragraph [38] or a pharmaceutically acceptable salt thereof.

[0079]

[41] A compound selected from the following formulae:

[0080]

[0081]

or a pharmaceutically acceptable salt thereof.

[0082]

[42] A pharmaceutical composition comprising a compound according to any of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof.

[0083]

[43] A PDHK inhibitor, comprising a compound according to any one of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof.

[0084]

[44] A PDHK1 inhibitor comprising a compound according to any one of paragraphs [38] to [41] or a pharmaceutically acceptable salt thereof.

[0085]

[45] A PDHK2 inhibitor, comprising a compound according to any one of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof.

[0086]

[46] A lactic acid reducing agent, comprising a compound according to any one of paragraphs [38] to [41] or a pharmaceutically acceptable salt thereof.

[0087]

[47] An agent for the treatment or prevention of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer or pulmonary hypertension, the agent comprises a compound according to any of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof.

[0088]

[48] The agent of [47], wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0089]

[49] The agent of [47], wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract.

[0090]

[50] The agent of [47], wherein the heart failure is acute heart failure or chronic heart failure.

[0091]

[51] The remedy of [47], wherein pulmonary hypertension is pulmonary arterial hypertension.

[0092]

[52] A method for inhibiting PDHK, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof.

[0093]

[53] A method for treating or preventing a disease selected from the group including diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, diabetic complication, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, disease peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension, the method comprises administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs [38] - [41] or its pharmaceutically acceptable salt.

[0094]

[54] The use of a compound according to any of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof for the production of a PDHK inhibitor.

[0095]

[55] The use of a compound according to any one of [38] to [41] or a pharmaceutically acceptable salt thereof for the preparation of an agent for the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complication in diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension .

[0096]

[56] A compound according to any one of paragraphs [38] - [41] or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, a complication of diabetes , heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension.

[0097]

[57] A compound or pharmaceutically acceptable salt thereof according to [56], wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0098]

[58] The compound or pharmaceutically acceptable salt thereof according to [56], wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract.

[0099]

[59] The compound or pharmaceutically acceptable salt thereof according to [56], wherein the heart failure is acute heart failure or chronic heart failure.

[0100]

[60] The compound or pharmaceutically acceptable salt thereof according to [56], wherein pulmonary hypertension is pulmonary arterial hypertension.

[0101]

[61] A sales package including the pharmaceutical composition of paragraph [42] and related printed material, the printed material indicates that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group including diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer and pulmonary hypertension.

[0102]

[62] A kit comprising the pharmaceutical composition of [42] and its associated printed material, the printed material indicates 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, hyperlactacidemia, complication of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer and pulmonary hypertension.

Description of Embodiments

[0103]

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

[0104]

In the following formula [I-a]:

[0105]

[0106]

where each character is as defined for the above formula [I-a],

this means that R ^1a binds to A ¹ , A ² or A ³ and R ² binds to A ⁴ , A ⁵ , A ⁶ or A ⁷ . If n is 2, the two R ² may be associated with the same atom selected from the group consisting of A ⁴ , A ⁵ , A ⁶ and A ⁷ or may be associated with different atoms.

[0107]

The wavy line below:

[0108]

[0109]

in the fragment structure denotes the attachment position.

[0110]

In the structural formula of the fragment:

[0111]

[0112]

where each character is as defined for the above formula [I-a],

"a bond in the form of a dotted line means a single bond or a double bond" means that the two rings fused in the above formula are all a saturated ring, a partially saturated ring, or an aromatic ring.

[0113]

Examples of a group described by the structural formula of a fragment:

[0114]

[0115]

in the formula [I-a], include the following groups.

[0116]

[0117]

[0118]

In the following formula [1]:

[0119]

[0120]

where each symbol is as defined for the above formula [1],

this means that R ¹ is associated with A ¹ , A ² or A ³ and R ² is associated with A ⁴ , A ⁵ , A ⁶ or A ⁷ . If n is 2, the two R ² may be associated with the same atom selected from the group consisting of A ⁴ , A ⁵ , A ⁶ and A ⁷ or may be associated with different atoms.

[0121]

In the structural formula of the fragment:

[0122]

[0123]

where each symbol is as defined for the above formula [1],

"a bond in the form of a dotted line means a single bond or a double bond" means that the two rings fused in the above formula are all a saturated ring, a partially saturated ring, or an aromatic ring.

[0124]

Examples of a group described by the structural formula of a fragment:

[0125]

[0126]

where each symbol is as defined for the above formula [1], include the following groups.

[0127]

[0128]

In the formula [11], the structural formula of the fragment is:

[0129]

[0130]

where each symbol is as defined for the above formula [11], indicates a group in which Cy ¹ and Cy ² are linked to each other by a single bond. Examples of the group described by the structural formula of the fragment include the following groups.

[0131]

[0132]

"Halogen" means fluorine, chlorine, bromine or iodine. As "halogen", fluorine or chlorine is preferred.

[0133]

"C _1-4 alkyl" means straight chain or branched chain alkyl 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.

[0134]

"Halo-C _1-4 alkyl" means straight chain or branched chain alkyl containing from 1 to 4 carbon atoms and substituted with 1 to 5 "halogens" as defined above. When alkyl is substituted with more than one halogen, the halogens may be the same or different. Examples of "halo-C _1-4 alkyl" include fluoromethyl, trifluoromethyl, and the like. As "halo-C _1-4 alkyl", C _1-4 alkyl substituted with 1-3 fluorine atoms is preferred.

[0135]

"C _1-4 alkoxy" means an alkyloxy group in which the alkyl moiety is "C _1-4 alkyl" as defined above, and includes, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. . As the "C _1-4 alkoxy group", a methoxy group is preferred.

[0136]

"C _1-4 alkylcarbonyl" means an alkyl carbonyl wherein the alkyl moiety is "C _1-4 alkyl" as defined above and includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl and 2,2-dimethylpropanoyl. As "C _1-4 alkylcarbonyl", acetyl is preferred.

[0137]

"C _1-4 alkylsulfonyl" means an alkylsulfonyl wherein the alkyl moiety is "C _1-4 alkyl" as defined above and includes, for example, methanesulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl . As "C _1-4 alkylsulfonyl", methanesulfonyl is preferred.

[0138]

"C _3-6 cycloalkyl" means a 3- to 6-membered monocyclic hydrocarbon ring group and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As "C _3-6 cycloalkyl", cyclopropyl is preferred.

[0139]

"C _4-6 cycloalkyl" means a 4- to 6-membered monocyclic hydrocarbon ring group and includes, for example, cyclobutyl, cyclopentyl and cyclohexyl.

[0140]

"4- to 6-Membered saturated or partially saturated heterocyclyl containing one nitrogen atom" means a monocyclic heterocyclic group containing one secondary or tertiary amino group in the ring, where the heterocyclic group is saturated or partially saturated. Examples of heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, 1,2-dihydropyridyl and the like. Azetidinyl, pyrrolidinyl or 1,2-dihydropyridyl is preferred.

[0141]

"5- or 6-membered heteroaryl containing 1, 2 or 3 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom" means a 5- or 6-membered monocyclic heteroaryl containing, in addition to a carbon atom, 1, 2 or 3 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom. As heteroaryl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl and the like can be mentioned. pyrazolyl or pyridyl.

[0142]

"4- to 6-membered saturated heterocyclyl containing 1 or 2 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom" means a 4- to 6-membered monocyclic saturated heterocyclic group containing, in addition to a carbon atom, 1 or 2 heterotoms independently selected from the group consisting of a nitrogen atom and an oxygen atom. As the heterocyclyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like can be mentioned. Tetrahydropyranyl, piperidinyl or piperazinyl is preferred.

[0143]

"5- or 6-membered heteroaryl containing 1, 2, 3 or 4 nitrogen atoms" means a 5- or 6-membered monocyclic heteroaryl containing 1, 2, 3 or 4 nitrogen atoms in addition to the carbon atom. As heteroaryl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl and the like can be mentioned. Pyrazolyl, tetrazolyl or pyridyl is preferred.

[0144]

A preferred embodiment of a compound of formula [I-a] or formula [11] is described below.

A preferred embodiment of R ^1a is methyl.

A preferred embodiment of R ² is halo or cyano.

The preferred embodiment m is 0.

The preferred embodiment n is 1.

The preferred embodiment t is 0.

The preferred embodiment r is 1.

The preferred embodiment w is 1.

[0145]

A preferred embodiment of the combination of X ¹ and X ² (X ¹ , X ² ) is (carbon atom, nitrogen atom), (oxygen atom, carbon atom) or (nitrogen atom, nitrogen atom).

[0146]

A preferred embodiment of a compound of formula [I-a] is a compound having the structural formula [I-c]:

[0147]

[0148]

where the symbols in the formula are as defined in the definition of the above formula [I-a].

[0149]

Another preferred embodiment of a compound of formula [I-a] is a compound having the structural formula [I-d]:

[0150]

[0151]

where the symbols in the formula are as defined in the definition of the above formula [I-a].

[0152]

Another preferred embodiment of the compound of formula [I-a] is a compound having the structural formula [1]:

[0153]

[0154]

where the symbols in the formula are as defined in the definition of the above formula [1].

In the formula [1] R ¹ preferably means C _1-4 alkyl, the total number of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment:

[0155]

[0156]

preferably 0, 1 or 2, more preferably 2, and u preferably 0 or 1.

In the formula [1], the preferred embodiment of the structural formula of the fragment is:

[0157]

[0158]

is the formula:

[0159]

[0160]

where A ¹ , A ² and A ³ are all independently selected from the group consisting of a carbon atom, a nitrogen atom and an oxygen atom, the total number of nitrogen atoms and oxygen atoms contained in the above formula is 0, 1 or 2,

a bond in the form of a dotted line means a single bond or a double bond,

t is 0 or 1, and

u is 0 or 1, and the sum of t and u is 1 or 2.

[0161]

A preferred embodiment of a compound of formula [11] is a compound having the structural formula [II-a]:

[0162]

[0163]

where R ⁵ means halogen or C _1-4 alkyl;

x is 0 or 1,

the Cy ^2-a ring is (i) phenyl or (ii) 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 nitrogen atoms, and phenyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from the group, comprising halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylsulfonyl; And

other symbols are as defined in the definition of the above formula [11].

[0164]

Another preferred embodiment of a compound of formula [11] is a compound having the structural formula [II-b]:

[0165]

[0166]

where R ⁶ means halogen, C _1-4 alkyl or cyclopropyl;

y is 0, 1, or 2, if y is 2, each R ⁶ is independently selected; And

other symbols are as defined in the definition of the above formula [11].

[0167]

Another preferred embodiment of a compound of formula [11] is a compound having the structural formula [II-g]:

[0168]

[0169]

where the symbols in the formula are as defined in the definition of the above formula [11].

[0170]

Another preferred embodiment of a compound of formula [11] is a compound having the structural formula [II-h]:

[0171]

[0172]

where the symbols in the formula are as defined in the definition of the above formula [11].

[0173]

Another preferred embodiment of a compound of formula [11] is a compound having the structural formula [II-i]:

[0174]

[0175]

Where the symbols in the formula are such as determined in the determination of the above formula [11].

In formula [II-g], formula [II-h], and formula [II-i], v is 0 in the preferred embodiment.

[0176]

A "pharmaceutically acceptable salt" can be any salt without excessive toxicity known in the art. In particular, salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and the like can be mentioned. Various forms of pharmaceutically acceptable salts are well known in the art and, for example, they are described in the following publications:

(a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977),

(b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),

(c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).

A pharmaceutically acceptable salt of a compound of formula [I-a] or formula [11] can be obtained by reacting the compound with an inorganic acid, an organic acid, an inorganic base, or an organic base in a conventional manner. A pharmaceutically acceptable salt of a compound of formula [I-a] or formula [11] can be prepared with half a molecule, one molecule, or two or more acid or base molecules, based on a molecule of a compound of formula [I-a] or formula [11].

[0177]

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

Examples of the organic acid salt include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium ethylenediaminetetraacetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxynaphthoic 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 Othe, oleic acid, oxalic acid, pamomic acid, pantothenic acid, pectic acid, picrinic acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, amber acid, tanninic acid, wine acid, teenic acid, thythocyanic acid, trifto -ore acid, triftooscinic acid, trifteric acid, and triftoosmic acid. P-deoluol usphonic acid, undecanic acid, asparaginic acid and glutamic acid.

[0178]

Examples of the inorganic base salt include the lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium salt.

Examples of the organic base salt include the salt with arecoline, betaine, choline, clemisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine.

[0179]

A preferred embodiment of the "pharmaceutically acceptable salt" is as described below.

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

Examples of the organic acid salt include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-hydroxy-1-ethanesulfonic acid.

Examples of the inorganic base salt include sodium, potassium, calcium, magnesium and zinc salts.

Examples of salt with an organic base include salts with tris (hydroxymethyl) with methymilamin, N-methylhlyukomin and lysine.

[0180]

A compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof may exist as a solvate. The term "solvat" refers to the connection of the formula [i-a] or formula [11] or its pharmaceutically acceptable salt, with which the solvent molecule is associated and also includes hydrates. Such solvates preferably are pharmaceutically acceptable solvates and include, for example, a hydrate, a solvate with ethanol, a solvat with dimethyl sulfoxide, etc. Formula [i-a] or formulas [11] or its pharmaceutically acceptable salt.

Specific examples include the hemihydrate, monohydrate, dihydrate or mono(ethanol) solvate of the compound of formula [I-a] or formula [11], or the hydrochloride monohydrate of the compound of formula [I-a] or formula [11], its hydrochloride dihydrate, and the like. Such solvates can be prepared by conventional methods.

[0181]

A compound of formula [I-a] or formula [11] may exist as a stereoisomer, which should be considered a cis/trans isomer. In this case, the compound of formula [I-a] or formula [11] may exist as a cis isomer, a trans isomer, or a mixture of a cis isomer and a trans isomer.

The compound of formula [I-a] or formula [11] may exist as a tautomer. In this case, the compound of formula [I-a] or formula [11] may exist as a single tautomer or as a mixture of tautomers.

The compound of formula [I-a] or formula [11] may contain one or more asymmetric carbon atoms. In this case, the compound of formula [I-a] or formula [11] may exist as a single enantiomer, a single diastereoisomer, a mixture of enantiomers, or a mixture of diastereoisomers.

The compound of formula [I-a] or formula [11] may exist as an atropisomer. In this case, the compound of formula [I-a] or formula [11] may exist as a single atropisomer or as a mixture of atropisomers.

A compound of formula [I-a] or formula [11] can simultaneously have multiple structural characteristics that lead to the formation of the above isomers. In addition, the compound of formula [I-a] or formula [11] may contain the above isomers in any ratio.

Unless otherwise referenced, such as a note or the like, the formulas, chemical structures, and compound names given herein without indication of stereochemical configuration include all of the above isomers that may exist.

[0182]

A mixture of diastereoisomers can be separated into individual diastereoisomers by conventional techniques such as chromatography, crystallization, and the like. In addition, each diastereoisomer can also be obtained by using a stereochemically unambiguous starting material or by a synthetic method using a stereoselective reaction.

[0183]

A mixture of enantiomers can be separated into individual enantiomers by methods well known in the art.

For example, a mixture of enantiomers can be reacted with a substantially pure enantiomer known to be a chiral auxiliary to obtain a mixture of diastereoisomers, from which the diastereoisomer can then be isolated at an increased isomer ratio, or the substantially pure individual diastereoisomer can be isolated by a conventional procedure such as as fractional crystallization or chromatography. The added chiral auxiliary can be removed from the isolated diastereoisomer by a cleavage reaction to obtain the desired enantiomer.

In addition, a mixture of enantiomers of a compound can also be directly resolved by chromatography using a chiral solid phase well known in the art. Alternatively, one of the enantiomers can also be obtained by using a substantially optically pure starting material or stereoselective synthesis (asymmetric induction) of a prochiral intermediate using a chiral auxiliary or an asymmetric catalyst.

[0184]

The absolute stereochemical configuration can be determined from the crystal X-ray diffraction analysis of the resulting crystalline product or intermediate. In this case, if necessary, the resulting crystalline product or an intermediate derivatized with a reagent containing an asymmetric center with a known stereochemical configuration can be used.

[0185]

The compound of formula [Ia] or formula [11] can be provided with an isotopic label ( ² H, ³ H, ¹⁴ C, ³⁵ S, etc.).

[0186]

The compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof. It is also preferred if it is a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof, which is purified to a purity of at least 80%.

[0187]

The pharmaceutical composition of the present invention can be prepared by mixing an appropriate amount of a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof with at least one type of pharmaceutically acceptable carrier, according to a method known in the pharmaceutical art. The content of the compound of formula [I-a] or formula [11] or its pharmaceutically acceptable salt in the pharmaceutical composition varies depending on the dosage form, dose, etc. It is equal to, for example, from 0.1 to 100 wt.% of the entire composition.

[0188]

The dosage form of a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof includes an oral preparation such as a tablet, capsule, granule, powder, lozenge, syrup, emulsion and suspension, or a parenteral preparation such as an external preparation, suppository, preparation for injection, eye drops, nasal preparation and lung preparation.

[0189]

Examples of a "pharmaceutically acceptable carrier" include various organic or inorganic carrier materials commonly used as formulation materials and include an excipient, a disintegrant, a binder, a fluidizer, a lubricant, and the like. for solid preparations and solvent, solubilizing agent, suspending agent, isotonic agent, buffer agent, soothing agent, etc. for liquid preparations and base, emulsifier, wetting agent, stabilizer, stabilizing agent, dispersing agent, plasticizer, pH regulator, stimulant absorbents, gelling agent, preservative, bulking agent, dissolving agent, solubilizing agents, suspending agent, and the like for semi-liquid dosage forms. In addition, if necessary, additives such as a preservative, an antioxidant, a coloring agent, a sweetener, and the like can also be used.

[0190]

Examples of "inert filler" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low substituted hydroxypropyl cellulose, gum arabic, and the like.

Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, crystalline cellulose, and the like.

Examples of the "binder" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.

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

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

Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate, and the like.

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

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

Examples of the "calming agent" include benzyl alcohol and the like.

Examples of "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, and etc.), higher fatty acid and its ester, wax, higher alcohol, polyhydric alcohol, hydrocarbons (white liquid paraffin, liquid paraffin, paraffin, etc.), hydrophilic liquid paraffin, purified lanolin, water-absorbing ointment containing water lanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivative (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymer (carboxyvinyl polymer, sodium polyacrylate, poly(vinyl alcohol) , polyvinylpyrrolidone, and the like), propylene glycol, macrogol (macrogol 200-600, etc.), and a combination of two or more types thereof.

Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.

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

Examples of the "coloring agent" include food colors (eg, Food Color Red No. 2 or 3, Food Color yellow No. 4 or 5, etc.), β-carotene, and the like.

Examples of the "sweetener" include sodium saccharinate, dipotassium glycyrrhizinate, aspartame, and the like.

[0191]

The pharmaceutical composition of the present invention can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to non-human mammals (e.g. mice, rats, hamsters, guinea pigs, rabbits, cats , dogs, pigs, ruminants, horses, sheep, monkeys, etc.) and humans. The dose varies depending on the subject of administration, disease, symptom, dosage form, route of administration, and the like. For example, a daily dose for oral administration to an adult patient is typically in the range of about 0.01 mg to about 1 g, based on the compound of formula [I-a] or formula [11] as the active ingredient. This amount can be administered in one or more portions.

[0192]

The compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof has an inhibitory effect on PDHK and is useful for the treatment and/or prevention of various diseases or conditions that are supposed to be improved by regulation of PDHK activity. Examples of various diseases or conditions that are believed to be improved by regulation of PDHK activity include diseases such as diabetes (type 1 diabetes, type 2 diabetes), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes (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 brain, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, pulmonary hypertension (pulmonary arterial hypertension), Alzheimer's disease, and the like.

[0193]

"PDHK inhibition" means the elimination or reduction of PDHK activity by inhibiting its function. For example, it means inhibition of its function as PDHK based on the conditions indicated in Experimental Example 1 below. In "PDHK inhibition", human PDHK is preferably inhibited. In "PDHK inhibition", "PDHK1 and PDHK2" are preferably inhibited.

"PDHK inhibitor" means a substance that binds to PDHK and inhibits the function of PDHK. As the "PDHK inhibitor", "human PDHK inhibitor" is preferable. As "PDHK inhibitor", "PDHK1 and 2 inhibitor" is preferable.

[0194]

As used herein, "treatment" also includes amelioration of symptoms, reduction in severity, maintenance of remission, prevention of relapse, and furthermore prevention of relapse.

As used herein, "prevention" or "prophylaxis" means the suppression of symptoms.

[0195]

The pharmaceutical composition of the present invention may be used in combination with one or more other drugs (hereinafter also referred to as a concomitant drug) in a manner commonly used in medicine (hereinafter referred to as co-administration).

[0196]

The period of administration of a drug containing a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof and a concomitant drug is not limited, and they can be administered to the excipient as a combined preparation, or both drugs can be administered simultaneously or at predetermined intervals. In addition, the pharmaceutical composition of the present invention and the concomitant drug can be used as a medicine in the form of a kit. The dose of the concomitant drug is similar to the clinically used dose and can be appropriately selected according to the subject of administration, disease, symptom, dosage form, route of administration, time of administration, combination, and the like. and only it needs to be combined with a drug containing a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof.

[0197]

Examples of the concomitant drug include therapeutic agents and/or prophylactic agents for diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, 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 apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, pulmonary hypertension or Alzheimer's disease, and the like, and one or more of these agents and a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof can be used put in combination.

[0198]

In the present description, the presentation of preferred embodiments and variants of the connection, method, use and composition of the present invention also includes combinations of preferred embodiments and options, if they can be combined and they are not incompatible.

[0199]

Procedures for preparing a compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof are described below. However, the production method of the compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof is not limited to such production methods.

The compound obtained in each step can be isolated or purified, if necessary, by conventional techniques such as distillation, recrystallization, column chromatography, and the like. In some cases, the next step can be carried out without isolation or purification. If the reaction to be carried out in each step is carried out in an anhydrous environment, it is preferably carried out in an atmosphere of inert gas, argon, nitrogen, or the like.

[0200]

[Production Method 1]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride can be obtained by the method of obtaining 1, shown in the following scheme.

[0201]

[0202]

Stage 1-1

tert-Butyl-(S)-(1-(benzylamino)propan-2-yl)carbamate (compound A2) can be prepared by benzylation of the amino group of tert-butyl-(S)-(1-aminopropan-2-yl)carbamate (compound A1 ). For example, compound A2 can be prepared by reacting compound A1 with benzaldehyde in a solvent at room temperature to 80°C, followed by reaction with a reducing agent under ice cooling. In addition, compound A2 can also be obtained by reacting compound A1 with benzaldehyde, followed by catalytic reduction in the presence of a platinum catalyst at room temperature under a hydrogen atmosphere.

Examples of the reducing agent include sodium borohydride.

Examples of the platinum catalyst include platinum on carbon.

Examples of the solvent include ethanol, tetrahydrofuran and toluene.

[0203]

Stage 1-2

tert-Butyl-(S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate (compound A3) can be prepared by reacting compound A2 with 2-chloroacetyl chloride. For example, compound A3 can be prepared by reacting compound A2 with 2-chloroacetyl chloride in a solvent in the presence of a base under ice-cooling to room temperature conditions.

Examples of the base include sodium hydrogen carbonate and triethylamine.

Examples of the solvent include ethyl acetate, tetrahydrofuran and toluene.

[0204]

Stage 1-3

tert-Butyl-(S)-4-benzyl-2-methyl-5-oxopiperazine-1-carboxylate (compound A4) can be obtained by intramolecular cyclization reaction of compound A3. For example, compound A4 can be prepared by treating compound A3 with a base in a solvent from ice-cooling to room temperature.

Examples of the base include sodium hydride and potassium t-butoxide.

Examples of the solvent include tetrahydrofuran, dimethylformamide and cyclopentylmethyl ether.

[0205]

Stage 1-4

tert-Butyl-(2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylate (compound A5) can be prepared by alkylation of compound A4 and benzylchloromethyl ether. For example, compound A5 can be prepared by reacting compound A4 with benzylchloromethyl ether in a solvent in the presence of a base at -78°C to -40°C.

Examples of the base include lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.

Examples of the solvent include tetrahydrofuran and diethyl ether.

The methyl group at position 2 of compound A4 becomes sterically hindered and the reaction proceeds diastereoselectively. Based on this reaction mechanism, the stereochemical configuration of compound A5 can be proposed.

[0206]

Stage 1-5

(3S,5S)-1-Benzyl-3-((benzyloxy)methyl)-5-methylpiperazin-2-one (compound A6) can be obtained by removing the tert-butoxycarbonyl group of compound A5. For example, compound A6 can be prepared by reacting compound A5 with an acid in a solvent under ice-cooling to room temperature conditions.

Examples of the acid include hydrochloric acid and trifluoroacetic acid.

Examples of the solvent include ethyl acetate, chloroform, methanol and 1,4-dioxane.

[0207]

Stage 1-6

(3R,5S)-1-Benzyl-3-((benzyloxy)methyl)-5-methylpiperazine (compound A7) can be obtained by removing the oxo group of compound A6 by reduction. For example, compound A7 can be prepared by reacting compound A6 with a reducing agent in a solvent at 40°C to 70°C.

Examples of the reducing agent include lithium aluminum hydride, aluminum isobutyl hydride, borane, and alan.

Examples of the solvent include tetrahydrofuran and diethyl ether.

[0208]

Stage 1-7

2-((2R,6S)-4-Benzyl-2-((benzyloxy)methyl)-6-methylpiperazin-1-yl)-2-oxoethyl acetate (compound A8) can be prepared by acylation of compound A7 with acetoxyacetyl chloride. For example, compound A8 can be prepared by reacting compound A7 with acetoxyacetyl chloride in a solvent in the presence of a base under conditions ranging from ice-cooling to room temperature.

Examples of the base include triethylamine and sodium hydrogen carbonate.

Examples of the solvent include tetrahydrofuran, ethyl acetate and toluene.

[0209]

Stage 1-8

tert-Butyl-(3R,5S)-4-(2-acetoxyacetyl)-3-(hydroxymethyl)-5-methylpiperazine-1-carboxylate (compound A9) can be obtained by removing the two benzyl groups of compound A8, followed by protection of the nitrogen atom of the piperazine rings. For example, compound A9 can be prepared by catalytically reducing compound A8 in a solvent under hydrogen atmosphere in the presence of a palladium catalyst and di-tert-butyl dicarbonate at room temperature.

Examples of the palladium catalyst include palladium hydroxide on carbon.

Examples of the solvent include ethanol, methanol and ethyl acetate.

[0210]

Stage 1-9

tert-Butyl-(3R,5S)-4-(2-acetoxyacetyl)-3-formyl-5-methylpiperazine-1-carboxylate (compound A10) can be obtained by oxidation of the hydroxy group of compound A9. For example, compound A10 can be prepared by reacting compound A9 with an oxidizing reagent in a solvent under ice-cooling to room temperature conditions.

Examples of the oxidizing agent include the combination of 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) and diacetoxyiodobenzene, sulfur trioxide pyridine complex, and Dess-Martin periodinane.

Examples of the solvent include chloroform, dichloromethane, acetonitrile and dimethyl sulfoxide.

[0211]

Stage 1-10

tert-Butyl-(S)-3-(1-acetoxymethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (compound A11) can be obtained by cyclization reaction with using compound A10 and ammonium reagent. For example, compound A11 can be prepared by heating compound A10 and an ammonium reagent in a solvent at 70°C to 110°C.

Examples of the ammonium reagent include ammonium acetate.

Examples of the solvent include acetic acid, toluene, and cyclopentyl methyl ether.

[0212]

Stage 1-11

tert-Butyl-(S)-3-(1-hydroxymethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (compound A12) can be obtained by removing the acetyl group connections A11. For example, compound A12 can be prepared by treating compound A11 with a base in a solvent from ice-cooling to room temperature.

Examples of the base include potassium carbonate and sodium hydroxide.

Examples of the solvent include methanol and tetrahydrofuran and a mixture of these solvents and water.

[0213]

Stage 1-12

tert-Butyl-(S)-3-formyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (compound A13) can be obtained by oxidation of the hydroxy group of compound A12. For example, compound A13 can be prepared by reacting compound A12 with an oxidizing agent in a solvent at room temperature to 80°C.

Examples of the oxidizing agent include manganese dioxide and Dess-Martin periodinane.

Examples of the solvent include tetrahydrofuran and chloroform.

[0214]

Stage 1-13

tert-Butyl-(5S)-3-(1-hydroxyethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (compound A14) can be obtained by the reaction of compound A13 with methyl magnesium halide. For example, compound A14 can be prepared by reacting compound A13 with methylmagnesium halide in a solvent under ice-cooling to room temperature conditions.

Examples of methyl magnesium halide include methyl magnesium bromide.

Examples of the solvent include tetrahydrofuran and diethyl ether.

[0215]

Stage 1-14

tert-Butyl-(S)-3-acetyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (compound A15) can be obtained by oxidation of the hydroxy group of compound A14. For example, compound A15 can be prepared by reacting compound A14 with an oxidizing agent in a solvent at room temperature to 90°C.

Examples of the oxidizing agent include manganese dioxide and Dess-Martin periodinane.

Examples of the solvent include tetrahydrofuran and chloroform.

[0216]

Stage 1-15

Treret-butyl- (s) -5-methyl-3-((r) -1,1-trifthor-2-hydroxypropan-2-l) -5.6-dihydromidazo [1.5-a] pyrazin- 7 (8H) -carboxylate (connection A16) can be obtained by the reaction of the A15 C (triformethyl) trimethylilane. For example, the A16 connection can be obtained by the A15 C connection reaction (triformethyl) with trimethylilane in the solvent in the presence of an additive under conditions from ice cooling to room temperature.

Examples of the additive include ammonium tetra-n-butyl fluoride, lithium acetate, potassium carbonate and cesium fluoride.

Examples of the solvent include tetrahydrofuran, dimethylformamide and methanol.

The methyl group at position 5 of compound A15 becomes sterically hindered and the reaction proceeds diastereoselectively. Based on this reaction mechanism, a stereochemical configuration of the A16 compound can be proposed.

[0217]

Stage 1-16

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-ol It can be obtained by removing the third-butotoxicarbonal group A16 with acid. For example, (R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2 -LDIGIRDHLORID (connection A17) can be obtained by processing the compound A16 by chloristoric acid in the solvent under conditions from cooling with ice to room temperature.

Examples of the acid include hydrochloric acid and trifluoroacetic acid.

Examples of the solvent include chloroform, 1,4-dioxane, methanol and ethyl acetate.

The free base form can also be obtained by treating compound A17 with alkali.

[0218]

[Production method 2]

The compound of formula [1] can be obtained according to the method of obtaining 2, shown in the following scheme.

[0219]

[0220]

where each symbol is as defined for the above formula [1].

[0221]

Stage 2-1

The compound [1] can be obtained by the amydging reaction of the compound A17 by the connection [31]. For example, compound [1] can be prepared by reacting compound A17 with compound [31] in a solvent in the presence of a base and a condensing agent under ice-cooling to room temperature conditions.

Examples of the base include diisopropylethylamine and triethylamine.

Examples of the condensing reagent include a 1-ethyl-3- (3-deimethylaminopropil) combination (WSC.HCl) and 1-hydroxybenzotriazole (HOBT), and O- (7-Azabenzotriazole-1-Il) -n, N, N ', N' N'-tetramethyluronium hexafluorophosphate (HATU).

Examples of the solvent include dimethylformamide, acetonitrile and chloroform.

Connection [31] can be available on sale by the product or it can be obtained by corresponding to turn the product available into sale according to the methodology, well known to specialists with general training in this field of technology.

[0222]

Stage 2-2

Compound [32] can be obtained by chlorination of the carboxy group of compound [31]. For example, the compound [32] can be obtained by processing the connection [31] with the chlorinating reagent in the solvent under conditions from cooling with ice up to 60 ° C. A catalytic amount of dimethylformamide can also be added to the reaction mixture as an additive.

Examples of the chlorinating agent include oxalyl chloride and thionyl chloride.

Examples of the solvent include chloroform and tetrahydrofuran.

[0223]

Stage 2-3

The compound [1] can be obtained by the amydging reaction of the compound A17 by the connection [32]. For example, the compound [1] can be obtained by reaction of the A17 connection with the connection [32] in the solvent in the presence of the base under conditions from cooling ice to room temperature.

Examples of the base include triethylamine.

Examples of the solvent include chloroform.

[0224]

[Production method 3]

The compound of formula [I-a] or formula [11] can be obtained according to the preparation method 3 shown in the following scheme.

[0225]

[0226]

[0227]

where each symbol is as defined for the above formula [I-a] or formula [11].

[0228]

Stage 3-A

Compound [I-a] can be obtained by the amidation reaction of compound [17] with compound [2]. For example, compound [I-a] can be obtained by reacting compound [17] with compound [2] in a solvent in the presence of a base and a condensing agent under ice-cooling to room temperature conditions.

Examples of the base include diisopropylethylamine and triethylamine.

Examples of the condensing reagent include a 1-ethyl-3- (3-deimethylaminopropil) combination (WSC.HCl) and 1-hydroxybenzotriazole (HOBT), and O- (7-Azabenzotriazole-1-Il) -n, N, N ', N' N'-tetramethyluronium hexafluorophosphate (HATU).

Examples of the solvent include dimethylformamide, acetonitrile and chloroform.

The compound [17] can be salt such as hydrochloride, dihydochloride, etc. The compound [17] can be obtained in accordance with an example of obtaining 1, 12 or 13, described below, or by a methodology, well known to specialists with general training in this field of technology.

Compound [2] may be a commercially available product, or it may be obtained by appropriate conversion of a commercially available product according to a procedure well known to those of ordinary skill in the art.

[0229]

Stage 3-B

Compound [3] can be obtained by chlorination of the carboxy group of compound [2]. For example, compound [3] can be obtained by treating compound [2] with a chlorinating agent in a solvent under conditions ranging from ice-cooling to 60°C. A catalytic amount of dimethylformamide can also be added to the reaction mixture as an additive.

Examples of the chlorinating agent include oxalyl chloride and thionyl chloride.

Examples of the solvent include chloroform and tetrahydrofuran.

[0230]

Stage 3-C

Compound [I-a] can be obtained by the amidation reaction of compound [17] with compound [3]. For example, compound [I-a] can be obtained by reacting compound [17] with compound [3] in a solvent in the presence of a base under ice-cooling to room temperature conditions.

Examples of the base include diisopropylethylamine and triethylamine.

Examples of the solvent include dichloromethane and chloroform.

[0231]

Stage 3-D

Compound [11] can be obtained by the amidation reaction of compound [17] with compound [4]. For example, compound [11] can be obtained by reacting compound [17] with compound [4] according to Step 3-A.

Connection [4] can be available on sale by the product or it can be obtained by the corresponding transformation of the product available in the sale by a methodology, well known to specialists with general training in this field of technology.

[0232]

Stage 3-e

Compound [5] can be obtained by chlorination of the carboxy group of compound [4]. For example, compound [5] can be obtained by reacting compound [4] with a chlorinating agent according to Step 3-B.

[0233]

Stage 3-F

Compound [11] can be obtained by the amidation reaction of compound [17] with compound [5]. For example, compound [11] can be obtained by reacting compound [17] with compound [5] according to Step 3-C.

[0234]

In Production Method 3, if the compound [17] is compound A17 having the formula:

[0235]

,

,

[0236]

Compound A17 can be prepared by the above Preparation Method 1.

[Production Method 4]

In Production Method 3, if the compound [17] is the compound B17 having the formula:

[0237]

[0238]

connection B17 can be obtained according to the method of obtaining 4, shown in the following scheme.

[0239]

[0240]

Stage 4-A

(3R,7aS)-3-Phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (compound B2) can be obtained by the cyclization reaction of (S)-5-(hydroxymethyl)pyrrolidin-2-one (compound B1) and benzaldehyde. For example, compound B2 can be obtained by reacting compound B1 with benzaldehyde in a solvent in the presence of an acid at a temperature of 80°C to 150°C.

Examples of the acid include p-toluenesulfonic acid.

Examples of the solvent include toluene and benzene.

[0241]

Stage 4-B

(3R,6S,7aS)-6-Methyl-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (compound B3) can be obtained by methylation of compound B2. For example, compound B3 can be prepared by reacting compound B2 with a methylating reagent in a solvent in the presence of a base at -78°C to -50°C.

Examples of the base include lithium diisopropylamide and lithium bis(trimethylsilyl)amide.

Examples of the methylating reagent include methyl iodide.

Examples of the solvent include tetrahydrofuran.

[0242]

Stage 4-C

(3R,6R,7aS)-6-Methyl-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (compound B4) can be obtained by isomerization of compound B3. For example, compound B4 can be prepared by reacting compound B3 with a base in a solvent at -78°C to -50°C followed by reaction with water at -20°C to 10°C.

Examples of the base include lithium diisopropylamide and lithium bis(trimethylsilyl)amide.

Examples of the solvent include tetrahydrofuran.

[0243]

Stage 4-D

((2S,4R)-1-Benzyl-4-methylpyrrolidin-2-yl)methanol (compound B5) can be prepared by reducing compound B4. For example, compound B5 can be prepared by reacting compound B4 with a reducing agent in a solvent under conditions ranging from ice-cooling to 80°C.

Examples of the reducing agent include lithium aluminum hydride and borane-tetrahydrofuran complex.

Examples of the solvent include tetrahydrofuran.

[0244]

Stage 4-E

(3R,5R)-1-Benzyl-5-methylpiperidin-3-ol (compound B6) can be obtained by converting the hydroxy group of compound B5 into a leaving group, followed by an intramolecular cyclization reaction and a subsequent ring-opening reaction.

Conversion to a leaving group can be carried out, for example, by reacting compound B5 with trifluoroacetic anhydride at -78°C to room temperature. Intramolecular cyclization can be carried out, for example, by heating the product of the above reaction in a solvent in the presence of a base at a temperature of from 50°C to 90°C. The ring-opening reaction can be carried out by, for example, reacting the product obtained from the above cyclization reaction with an alkali in a solvent under ice-cooling to room temperature conditions.

Examples of the base include triethylamine.

Examples of alkali include sodium hydroxide.

Examples of the solvent include tetrahydrofuran and a mixed solvent of tetrahydrofuran and water.

[0245]

Stage 4-F

(R)-1-Benzyl-5-methylpiperidin-3-one (compound B7) can be obtained by oxidizing the hydroxy group of compound B6. For example, compound B7 can be prepared by reacting compound B6 with an oxidizing agent in a solvent in the presence of a base at -78°C to room temperature.

Examples of the oxidizing agent include a combination of oxalyl chloride and dimethyl sulfoxide, and a combination of a sulfur trioxide complex with pyridine and dimethyl sulfoxide.

Examples of the base include triethylamine.

Examples of the solvent include dichloromethane and chloroform.

[0246]

Stage 4-G

(4R)-6-Benzyl-7a-hydroxy-4-methyl-3a,4,5,6,7,7a-hexahydroisoxazolo[5,4-c]pyridine-3-carboxylic acid ethyl ester (compound B8) can be obtained by cyclization reaction of compound B7 and ethyl chloro(hydroxyimino)acetate. For example, compound B8 can be prepared by reacting base-treated compound B7 with base-treated ethyl chloro(hydroxyimino)acetate in a solvent at -78°C to room temperature.

Examples of the base include lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.

Examples of the solvent include tetrahydrofuran.

[0247]

Stage 4-H

(R)-6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxylic acid ethyl ester (compound B9) can be obtained by converting the hydroxy group of compound B8 into a leaving group followed by an elimination reaction. When the leaving group is a mesyloxy group, compound B9 can be prepared by reacting compound B8 with methanesulfonyl chloride in a solvent in the presence of a base under ice-cooling.

Examples of the base include triethylamine.

Examples of the solvent include tetrahydrofuran and toluene.

[0248]

Stage 4-I

(R)-6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxylic acid (compound B10) can be obtained by hydrolysis of the ester of compound B9. For example, compound B10 can be prepared by reacting compound B9 with an alkali in a solvent under ice-cooling to room temperature conditions.

Examples of the alkali include sodium hydroxide, potassium carbonate and lithium hydroxide.

Examples of the solvent include methanol and tetrahydrofuran and a mixture of these solvents and water.

[0249]

Stage 4-J

(R)-6-Benzyl-N-methoxy-N,4-dimethyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxamide (compound B11) can be obtained by the amidation reaction of compound B10 N, O-dimethylhydroxylamine. For example, compound B11 can be prepared by reacting compound B10 with N,O-dimethylhydroxylamine in a solvent in the presence of a base and a condensing agent under ice-cooling to room temperature conditions.

Examples of the base include diisopropylethylamine and triethylamine.

Examples of the condensing agent include HATU.

Examples of the solvent include dimethylformamide.

[0250]

Stage 4-K

(R)-1-(6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)ethan-1-one (compound B12) can be obtained by the reaction compound B11 with methylmagnesium halide. For example, compound B12 can be prepared by reacting compound B11 with methylmagnesium halide in a solvent at 0°C to room temperature.

Examples of methyl magnesium halide include methyl magnesium bromide.

Examples of the solvent include tetrahydrofuran and diethyl ether.

[0251]

Stage 4-L

(R)-2-((R)-6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)-1,1,1-trifluoropropan- 2-ol (compound B13) can be obtained by reacting compound B12 with (trifluoromethyl)trimethylsilane. For example, compound B13 can be prepared by reacting compound B12 with (trifluoromethyl)trimethylsilane in a solvent in the presence of an additive at -78°C to room temperature.

Examples of the additive include ammonium tetra-n-butyl fluoride, lithium acetate, potassium carbonate and cesium fluoride.

Examples of the solvent include tetrahydrofuran, dimethylformamide and methanol.

The methyl group at position 4 of compound B12 becomes sterically hindered and the reaction proceeds diastereoselectively. Based on this reaction mechanism, the stereochemical configuration of compound B13 can be proposed.

[0252]

Stage 4-M

(9H-Fluoren-9-yl)methyl (R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4,7-dihydroisooxazolo[5, 4-c]pyridine-6(5H)-carboxylate (compound B14) can be prepared by reacting compound B13 with 9-fluorenylmethyl chloroformate. For example, compound B14 can be prepared by reacting compound B13 with 9-fluorenylmethyl chloroformate in a solvent under ice-cooling to room temperature conditions.

Examples of the solvent include chloroform and toluene.

[0253]

Stage 4-N

(R)-1,1,1-Trifluoro-2-((R)-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)propan-2-ol (compound B17) can be obtained by removing the protective group of the compound B14. For example, compound B17 can be prepared by reacting compound B14 with a secondary amine in a solvent under ice-cooling to room temperature conditions.

Examples of the secondary amine include diethylamine and piperidine.

Examples of the solvent include acetonitrile and dimethylformamide.

[0254]

[Production method 5]

In Production Method 3, if the compound [17] is a C17 compound having the formula:

[0255]

,

,

[0256]

compound C17 can be obtained according to the method of obtaining 5, shown in the following scheme.

[0257]

[0258]

Stage 5-A

tert-Butyl-(R)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)hydrazine-1-carboxylate (compound C2) can be obtained by the reaction (R)-3,3,3- trifluoro-2-hydroxy-2-methylpropanoic acid (compound C1) with tert-butylcarbazate. For example, Compound C2 can be prepared by reacting Compound C1 with t-butylcarbazate in a solvent in the presence of a condensing agent under ice-cooling to room temperature conditions.

Examples of the condensing agent include the combination of WSC.HCl and HOBt, and HATU.

Examples of the solvent include acetonitrile and dimethylformamide.

[0259]

Stage 5-B

(R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanehydrazide (Compound C3) can be prepared by removing the tert-butoxycarbonyl group of Compound C2 with an acid. For example, compound C3 can be prepared by treating compound C2 with an acid in a solvent from ice-cooling to room temperature.

Examples of the acid include hydrochloric acid and trifluoroacetic acid.

Examples of the solvent include chloroform, 1,4-dioxane, methanol and ethyl acetate.

[0260]

Stage 5-C

(S)-(2-((tert-butoxycarbonyl)amino)propyl)glycine methyl ester (compound C5) can be obtained by the reductive amination reaction of tert-butyl-(S)-(1-oxopropan-2-yl)carbamate (compound C4) with glycine methyl ester. For example, compound C5 can be prepared by reacting compound C4 with glycine methyl ester in a solvent in the presence of a base and a reducing agent under ice-cooling to room temperature conditions.

Examples of the base include diisopropylethylamine and sodium acetate.

Examples of the reducing agent include sodium triacetoxyborohydride.

Examples of the solvent include chloroform and dichloromethane.

[0261]

Stage 5-D

tert-Butyl-(S)-3-methyl-5-oxopiperazine-1-carboxylate (compound C6) can be obtained by removing the tert-butoxycarbonyl group of compound C5, intramolecular cyclization and protection of the amino group.

The tert-butoxycarbonyl group can be removed, for example, by reacting the C5 compound with an acid in a solvent under conditions ranging from ice-cooling to room temperature. Examples of the acid include hydrochloric acid and trifluoroacetic acid. Examples of the solvent include chloroform, 1,4-dioxane, methanol and ethyl acetate.

Intramolecular cyclization can be carried out by, for example, heating the above obtained product without a protective group in a solvent in the presence of a base at a temperature of from room temperature to 80°C. Examples of the base include sodium acetate. Examples of the solvent include methanol.

Protection of the amino group, if, for example, the protecting group is t-butoxycarbonyl group, can be carried out by reacting the product obtained from the above cyclization reaction with di-t-butyl dicarbonate in a solvent in the presence of a base under conditions ranging from ice-cooling to room temperature. Examples of the base include triethylamine. Examples of the solvent include chloroform.

[0262]

Stage 5-E

tert-Butyl-(S)-3-methyl-5-thiooxopiperazine-1-carboxylate (compound C7) can be obtained by converting the oxo group of compound C6 into a thioxo group. For example, compound C7 can be prepared by reacting compound C6 with a sulphurizing agent in a solvent at 50°C to 80°C.

Examples of the sulphurizing agent include the Lavesson reagent.

Examples of the solvent include tetrahydrofuran.

[0263]

Stage 5-F

tert-Butyl-(S)-3-methyl-5-(methylthio)-3,6-dihydropyrazine-1(2H)-carboxylate (compound C8) can be obtained by methylation of compound C7. For example, compound C8 can be prepared by reacting compound C7 with a methylating agent in a solvent under conditions ranging from ice-cooling to 50°C.

Examples of the methylating reagent include methyl iodide.

Examples of the solvent include acetone and acetonitrile.

Compound C8 can be obtained as a salt. For example, compound C8 hydroiodide can be prepared by reacting compound C7 with methyl iodide.

[0264]

Stage 5-G

tert-Butyl-(S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo [4,3-a]pyrazine-7(8H)-carboxylate (compound C9) can be obtained by cyclization of compound C3 with compound C8. For example, compound C9 can be prepared by reacting compound C3 with compound C8 in a solvent in the presence of an acid.

Examples of the acid include acetic acid.

Examples of the solvent include water and isopropanol, and a mixed solvent formed therefrom.

[0265]

Stage 5-H

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine-3 -yl)propan-2-oldihydrochloride (compound C17) can be obtained by removing the tert-butoxycarbonyl group of compound C9 with acid. For example, compound C17 can be prepared by treating compound C9 with an acid in a solvent under conditions ranging from ice-cooling to 70°C.

Examples of the acid include hydrochloric acid and trifluoroacetic acid.

Examples of the solvent include chloroform, 1,4-dioxane, methanol and ethyl acetate.

The form of a free base can also be obtained by processing the connection C17 by alkali.

[0266]

[Obtaining Method 6-1]

If the compound of the formula [11] is a compound [II-D], described by the formula:

[0267]

[0268]

where R ¹¹ means C _1-4 alkyl;

R ¹² means hydrogen or C _1-4 alkyl; And

other symbols are as defined for the above formula [11],

The compound [II-D] can be obtained according to the method of obtaining 6-1, given in the following scheme.

[0269]

[0270]

where R ¹³ means C _1-4 alkyl; And

other characters are as defined for the above formula [II-d].

[0271]

Stage 6-1-A

Compound [7] can be obtained by the pyrazole cyclization reaction using compound [6]. For example, compound [7] can be obtained by reacting compound [6] with dialkyl oxalate R ¹³ O ₂ CCO ₂ R ¹³ in a solvent in the presence of a base and an alcohol under conditions ranging from ice-cooling to 50°C and its reaction with hydrazine in the presence of an acid under conditions from ice cooling to 50°C. The dialkyl oxalate reaction intermediate can also be isolated and reacted with hydrazine.

Examples of the dialkyl oxalate include diethyl oxalate.

Examples of the base include sodium ethoxide, sodium hydrid and bis (trimethylilil) amide lithium.

Examples of the solvent include tetrahydrofuran.

Examples of the acid include acetic acid.

Connection [6] can be available on sale by the product or it can be obtained by the corresponding transformation of the product available in the sale by a methodology, well known to specialists with general training in this field of technology.

[0272]

Stage 6-1-B

A mixture of compounds [8-d] and [8-e] can be obtained by alkylation of the pyrazole ring of compound [7]. For example, compounds [8-d] and [8-e] can be prepared by reacting compound [7] with a C _1-4 alkyl halide in a solvent in the presence of a base under ice-cooling to room temperature conditions.

Examples of the base include sodium hydride and potassium carbonate.

Examples of the solvent include dimethylformamide.

Examples of C _1-4 alkyl halide include methyl iodide.

The position of the alkyl group in the pirazol ring can be presumed by NMR for the connection, disclosed, for example, in the next publication. Schmidt, Andreas, et al. "New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid Nigellicine". The Journal of Organic Chemistry 68.15 (2003): 5977-5982.

[0273]

Stage 6-1-C

Connection [9] can be obtained by hydrolysis of the complex compound group [8-D]. For example, the connection [9] can be obtained by processing the connection [8-D] with the alkali in the solvent under conditions from cooling with ice up to 60 ° C.

Examples of the alkali include sodium hydroxide, potassium carbonate and lithium hydroxide.

Examples of solvent include methanol and tetrahydrofuran and a mixture of these solvents and water.

[0274]

Stage 6-1-D

The compound [II-D] can be obtained by reaction of amydging the compound [17] in the methodology of obtaining 3 and compound [9]. For example, compound [II-d] can be prepared by reacting compound [17] with compound [9] in Preparation 3, Step 3-A.

[0275]

[Obtaining Method 6-2]

Connection [II-E], in which the compound of the formula [11] has a structure described by the formula:

[0276]

[0277]

where each character is as defined above,

It can be obtained by introducing a compound [8-E] obtained according to the methodology of obtaining 6-1, stage 6-1-b, in the reaction of stage 6-1-C and stage 6-1-D.

[0278]

[Production method 7]

If the compound of formula [11] is the compound [II-f] described by the formula:

[0279]

[0280]

where the ring Cy ^2-a means (i) phenyl or (ii) 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 nitrogen atoms, phenyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylsulfonyl; And

all other symbols are as defined for the above formula [11],

the compound [II-f] can be obtained according to the preparation method 7 shown in the following scheme.

[0281]

[0282]

where Hal means chlorine, bromine or iodine;

R ¹⁴ means C _1-4 alkyl;

R ¹⁵ is independently hydrogen or C _1-4 alkyl, one of R ¹⁵ may be linked to the other R ¹⁵ to form a ring; And

other characters are as defined for the above formula [11] or [II-f].

[0283]

Stage 7-A

Compound [12] can be prepared by Suzuki coupling of compound [10] with compound [11]. For example, compound [12] can be obtained by reacting compound [10] with compound [11] in a solvent in the presence of a base and a palladium catalyst at room temperature to 70°C.

Examples of the base include potassium carbonate and tripotassium phosphate.

Examples of the palladium catalyst include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

Examples of the solvent include dimethylacetamide, toluene and methanol.

Compound [10] may be a commercially available product, or it may be obtained by appropriate conversion of a commercially available product according to a procedure well known to those of ordinary skill in the art.

Compound [11] may be a commercially available product, or it may be obtained by appropriate conversion of a commercially available product according to a procedure well known to those of ordinary skill in the art.

[0284]

Stage 7-B

Compound [13] can be obtained by hydrolysis of the ester group of compound [12]. For example, compound [13] can be obtained by treating compound [12] with an alkali in a solvent under conditions ranging from ice-cooling to 60°C.

Examples of the alkali include sodium hydroxide, potassium carbonate and lithium hydroxide.

Examples of the solvent include methanol and tetrahydrofuran and a mixture of these solvents and water.

[0285]

Stage 7-C

Compound [II-f] can be obtained by the amidation reaction of compound [17] in Preparation Method 3 and compound [13]. For example, compound [II-f] can be prepared by reacting compound [17] with compound [13] in Preparation Method 3, Step 3-A.

Examples

[0286]

The method for obtaining the compound of formula [I-a] or formula [11] or its pharmaceutically acceptable salt proposed in the present invention is specifically explained using the following production examples. However, the method for preparing the compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof is not limited to preparation examples.

Unless otherwise indicated, % means wt.%. Unless otherwise indicated, the ratio of the components in the mixed solvent is by volume.

In the examples, the abbreviations have the following meanings.

DMSO: dimethyl sulfoxide

M: mol/l

HATU: O-(7-azabenzotriazol-1-yl)-N, N,N',N'-tetramethyluronium hexafluorophosphate

Measurement results with ¹ H-NMR are described using the following abbreviations:

s: singlet, d: doublet, dd: doublet, dt: double triplet, t: triplet, q: quartet, dq: double quartet, m: multiplet, brs: wide singlet, brm: wide multiplet, J: spin constant spin interaction, Hz: Hz

The ¹ H-NMR spectrum was measured in CDCl ₃ or DMSO-D ₆ using tetramethylsilane as an internal standard and all values (given in ppm).

[0287]

Production Example 1 Synthesis of (R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propane -2-oldihydrochloride

[0288]

Stage 1

tert-butyl-(S)-(1-(benzylamino)propan-2-yl)carbamate

[0289]

[0290]

tert-Butyl-(S)-(1-aminopropan-2-yl)carbamate (3.60 g) and benzaldehyde (2.64 ml) were mixed with ethanol (50 ml). This mixture was stirred at 60° C. for 1 hour. Under ice-cooling, sodium borohydride (1.51 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. When ice cooling, the saturated aqueous solution of ammonium chloride and 1 n. hydrochloric acid was successively added to the reaction mixture until pH=9. The reaction mixture was concentrated at reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to chloroform:methanol=25:1) to give the title compound (4.47 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.01 (d, J=6.45Hz, 3H), 1.38 (s, 9H), 1.99 (brs, 1H), 2.36 -2.48(m, 2H), 3.54-3.57(brm, 1H), 3.66(s, 2H), 6.57(brs, 1H), 7.19-7.30(m , 5H)

[0291]

Stage 2

tert-butyl-(S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate

[0292]

[0293]

tert-Butyl-(S)-(1-(benzylamino)propan-2-yl)carbamate (6.75 g) was mixed with saturated aqueous sodium hydrogen carbonate solution (60 ml) and ethyl acetate (60 ml). Under ice-cooling, 2-chloroacetyl chloride (4.06 ml) was added to the mixture, and the mixture was stirred for 50 minutes. The organic layer was partitioned and washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (9.41 g) as a crude product.

[0294]

Stage 3

tert-butyl-(S)-4-benzyl-2-methyl-5-oxopiperazine-1-carboxylate

[0295]

[0296]

The crude product (9.4 g) tert-butyl-(S)-(1-(N-benzyl-2-chloroacetamido)propan-2-yl)carbamate obtained in the previous step was mixed with tetrahydrofuran (45 ml) and dimethylformamide (45 ml). When cooling with ice, 60 wt./WEA.% Sodium hydrid (2.6 g). This mixture was mixed at room temperature for 30 minutes. Under ice-cooling, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 3:2) to give the title compound (7.07 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.06 (d, J=6.70Hz, 3H), 1.44 (s, 9H), 2.92 (dd, J=12.25, 1, 85Hz, 1H), 3.50 (dd, J=12.25, 4.39Hz, 1H), 3.84 (d, J=18.50Hz, 1H), 4.34-4.38 (m, 3H ), 4.83 (d, J=14.57Hz, 1H), 7.15-7.34 (m, 5H)

[0297]

Stage 4

tert-butyl-(2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylate

[0298]

[0299]

tert-Butyl-(S)-4-benzyl-2-methyl-5-oxopiperazine-1-carboxylate (6.46 g) obtained in the previous step was mixed with tetrahydrofuran (85 ml). Under an argon atmosphere, a 1.1 M solution of lithium bis(trimethylsilyl)amide/tetrahydrofuran (21.2 ml) was added dropwise to this mixture at -78°C. The reaction mixture was stirred at -78°C for 1 h and benzylchloromethyl ether (7.3 ml) was added dropwise. The reaction mixture was stirred at -78°C for 1 h. hydrochloric acid (20 ml) at -20°C and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:1) to give the title compound (6.80 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.01 (d, J=6.47Hz, 3H), 1.41 (s, 9H), 1.61 (t, J=5.90Hz, 1H) , 2.77 (d, J=12.48Hz, 1H), 3.86-3.91 (m, 2H), 4.40 (brs, 1H), 4.50-4.53 (m, 2H) , 4.69 (d, J=5.78Hz, 2H), 4.78-4.81 (m, 1H), 7.19-7.36 (m, 10H)

[0300]

Stage 5

(3S,5S)-1-benzyl-3-((benzyloxy)methyl)-5-methylpiperazin-2-one

[0301]

[0302]

tert-Butyl-(2S,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methyl-3-oxopiperazine-1-carboxylate (6.80 g) obtained in the previous step was stirred with ethyl acetate ( 70 ml). When cooled by ice, 4 N. was added to this mixture. A solution of chloristoric acid/ethyl acetate (35 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=10:1) to give the title compound (4.99 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.05 (d, J=6.47Hz, 3H), 2.95 (dd, J=11.56, 8.79Hz, 1H), 3.07 ( dd, J=11.68, 3.81Hz, 1H), 3.27-3.29 (m, 1H), 3.78-3.95 (m, 3H), 4.40 (d, J=14 .80Hz, 1H), 4.57 (q, J=11.71Hz, 2H), 4.74 (d, J=14.57Hz, 1H), 7.15-7.36 (m, 10H)

[0303]

Stage 6

(3R,5S)-1-benzyl-3-((benzyloxy)methyl)-5-methylpiperazine

[0304]

[0305]

Lithium alumohydride (1.75 g) was mixed with tetrahydrofuran (100 ml). Under ice-cooling, to this mixture was added dropwise a solution of (3S,5S)-1-benzyl-3-((benzyloxy)methyl)-5-methylpiperazin-2-one (4.99 g) obtained in the previous step in tetrahydrofuran (60 ml). The reaction mixture was stirred at 70° C. for 1.5 h. Under ice-cooling, water (1.75 ml), 4N was added dropwise to the reaction mixture successively. Aqueous solution of sodium hydroxide (1.75 ml) and water (5.25 ml). Sodium sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound (6.31 g) as a crude product.

[0306]

Stage 7

2-((2R,6S)-4-benzyl-2-((benzyloxy)methyl)-6-methylpiperazin-1-yl)-2-oxoethyl acetate

[0307]

[0308]

The crude product (6.3 g) of (3R,5S)-1-benzyl-3-((benzyloxy)methyl)-5-methylpiperazine obtained in the previous step, tetrahydrofuran (50 ml) and triethylamine (4.3 ml) were mixed . Under ice-cooling, acetoxyacetyl chloride (1.82 ml) was added dropwise to this mixture. The reaction mixture was mixed at room temperature for 50 minutes. Under ice-cooling, a saturated ammonium chloride aqueous solution was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 3:2) to give the title compound (5.71 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.43 (d, J=6.36Hz, 3H), 2.16 (s, 3H), 2.19 (brs, 1H), 2.61-2 .63 (m, 3H), 3.40 (d, J=13.20Hz, 1H), 3.56 (d, J=13.20Hz, 1H), 3.70-3.78 (m, 4H) , 4.50 (dd, J=21.64, 11.86Hz, 2H), 4.71 (d, J=14.18Hz, 1H), 4.80 (d, J=14.43Hz, 1H), 7.24-7.35(m, 10H)

[0309]

Stage 8

tert-butyl-(3R,5S)-4-(2-acetoxyacetyl)-3-(hydroxymethyl)-5-methylpiperazine-1-carboxylate

[0310]

[0311]

2-((2R,6S)-4-Benzyl-2-((benzyloxy)methyl)-6-methylpiperazin-1-yl)-2-oxoethyl acetate (5.71 g) obtained in the previous step, ethanol (60 ml) and di-tret-butyldicarbonate (3.35 g). To this mixture was added 20 wt./wt.% palladium hydroxide on carbon (2.9 g) and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to hexane:acetone=1:1) to give the title compound (4.40 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.35 (d, J=10.64Hz, 3H), 1.48 (s, 9H), 2.18 (s, 3H), 2.83 (brs , 1H), 3.35-3.41 (m, 1H), 3.55 (dd, J=13.69, 3.91Hz, 1H), 3.74-3.79 (m, 4H), 4 .11-4.13(m, 2H), 4.72-4.75(m, 2H)

[0312]

Stage 9

Treret-butyl- (3r, 5s) -4- (2-acceaciacetile) -3-formil-5-methylpiperin-1-carboxylate

[0313]

[0314]

tert-Butyl-(3R,5S)-4-(2-acetoxyacetyl)-3-(hydroxymethyl)-5-methylpiperazine-1-carboxylate (4.40 g) obtained in the previous step was stirred with chloroform (44 ml) . Under ice-cooling, Dess-Martin periodinan (7.4 g) was added to this mixture. The reaction mixture was stirred at room temperature for 40 minutes. Under ice-cooling, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (4.97 g) as a crude product.

[0315]

Stage 10

tert-Butyl-(S)-3-(1-acetoxymethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate

[0316]

[0317]

The crude product (4.97 g) tert-butyl-(3R,5S)-4-(2-acetoxyacetyl)-3-formyl-5-methylpiperazine-1-carboxylate obtained in the previous step was mixed with acetic acid (53 ml) and ammonium acetate (4.11 g). The reaction mixture was stirred at 90° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene. A saturated sodium hydrogencarbonate aqueous solution was added to the obtained residue under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to hexane:acetone=1:1) to give the title compound (2.98 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.38 (d, J=6.70Hz, 3H), 1.49 (s, 9H), 2.08 (s, 3H), 3.26, ( brs, 1H), 4.26-4.45(m, 3H), 5.09-5.17(m, 3H), 6.83(s, 1H)

[0318]

Stage 11

tert-Butyl-(S)-3-(1-hydroxymethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate

[0319]

[0320]

tert-Butyl-(S)-3-(1-acetoxymethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (2.98 g) obtained in the previous stage, mixed with methanol (30 ml). Under ice-cooling, potassium carbonate (0.133 g) was added to this mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:acetone=1:2 to chloroform:methanol=15:1) to give the title compound (2.60 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.43 (d, J=6.47Hz, 3H), 1.48 (s, 9H), 3.15-3.39 (m, 1H), 4 .13-4.20(m, 2H), 4.53(brs, 1H), 4.61(s, 2H), 4.81-5.13(m, 1H), 6.67(s, 1H )

[0321]

Stage 12

tert-butyl-(S)-3-formyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate

[0322]

[0323]

tert-Butyl-(S)-3-(1-hydroxymethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (2.40 g) obtained in the previous stage, mixed with tetrahydrofuran (40 ml). Manganese dioxide (3.0 g) was added to this mixture at room temperature, and the mixture was stirred at 70° C. for 2.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.34 g) as a crude product.

[0324]

Stage 13

tert-Butyl-(5S)-3-(1-hydroxyethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate

[0325]

[0326]

The crude product (2.34 g) tert-butyl-(S)-3-formyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate obtained in the previous step, mixed with tetrahydrofuran (30 ml). Under an argon atmosphere, a 3.0M methylmagnesium bromide/diethyl ether solution (4.1 ml) was added dropwise to this mixture at 0°C. The reaction mixture was stirred at room temperature for 50 minutes. A saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution were added to the reaction mixture under ice-cooling. The reaction mixture was extracted with a mixture of chloroform:methanol=20:1. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to chloroform:methanol=15:1) to give the title compound (2.40 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.44 (d, J=6.24Hz, 3H), 1.49 (s, 9H), 1.63 (d, J=4.62Hz, 3H) , 3.12-3.36 (m, 1H), 4.02-4.73 (m, 3H), 4.77-5.07 (m, 2H), 6.74 (s, 1H)

[0327]

Stage 14

tert-Butyl-(S)-3-acetyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate

[0328]

[0329]

tert-Butyl-(5S)-3-(1-hydroxyethyl)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (2.40 g) obtained in the previous stage, and manganese dioxide (2.4 g) was mixed with tetrahydrofuran (35 ml). The reaction mixture was stirred at 80° C. for 3.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 2:3) to give the title compound (1.84 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.40 (d, J=6.36Hz, 3H), 1.53 (s, 9H), 2.65 (s, 3H), 3.25-3 .27 (m, 1H), 4.10-4.30 (m, 2H), 5.05-5.21 (m, 2H), 6.99 (s, 1H)

[0330]

Stage 15

tert-Butyl-(S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin- 7(8H)-carboxylate

[0331]

[0332]

tert-Butyl-(S)-3-acetyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (1.84 g) obtained in the previous stage, and fluoride cesium (0.15 g) was mixed with tetrahydrofuran (25 ml). Under ice-cooling, (trifluoromethyl)trimethylsilane (1.95 ml) was added to this mixture. The reaction mixture was stirred at room temperature for 1 hour. Under ice-cooling, methanol (8 ml) and 1.5 M aqueous potassium carbonate solution (13 ml) were added to the reaction mixture. The reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. Ethyl acetate:hexane=1:2 was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (1.65 g). The resulting compound was analyzed using a chiral column, and it was found that the retention time of the resulting title compound was 13.4 minutes and the optical purity was >99.9%. Conditions for analysis using a chiral column are described below.

measuring device; HPLC system Shimadzu Corporation high performance liquid chromatograph

column; Daicel CHIRALPAK IC 4.6mmφ×250mm

column temperature; 40°C

mobile phase; hexane:ethanol=19:1

flow rate; 0.5 ml/min

detection; UV (220 nm)

¹ H-NMR (400 MHz, CDCl ₃ ) (1.41 (d, J=6.60Hz, 3H), 1.53 (s, 9H), 1.94 (s, 3H), 3.23 (dd , J=37.78, 13.08Hz, 1H), 3.47 (d, J=22.99Hz, 1H), 4.10 (dd, J=43.53, 17.06Hz, 1H), 4, 51 (d, J=16.14Hz, 1H), 4.75 (t, J=17.85Hz, 1H), 4.98 (brs, 1H), 6.85 (s, 1H)

[0333]

Stage 16

(R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride

[0334]

[0335]

tert-Butyl-(S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin- 7(8H)-carboxylate (1.60 g) obtained in the previous step was mixed with methanol (6 ml). Under ice-cooling, 4N hydrochloric acid was added to this mixture. hydrochloric acid/ethyl acetate solution (11.8 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (1.49 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.56 (d, J=7.63Hz, 3H), 1.86 (s, 3H), 3.28 (brs, 1H), 3.56 (d, J=13.18Hz, 1H), 4.38-4.44(m, 2H), 5.19(brs, 1H), 7.25(s, 1H), 7.77(brs, 1H ), 9.86 (brs, 1H), 10.49 (brs, 1H)

[0336]

Preparation Example 2Synthesis of (2,3-dihydro-1H-inden-2-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl) -5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (compound of Example 3)

[0337]

Stage 1

2,3-dihydro-1H-indene-2-carbonyl chloride

[0338]

[0339]

2,3-Dihydro-1H-indene-2-carboxylic acid (6.4 mg) was stirred with chloroform (0.5 ml). Under ice cooling, oxalyl chloride (15.2 μl) and a catalytic amount of dimethylformamide were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to give the title compound as the crude product.

[0340]

Stage 2

(2,3-dihydro-1H-inden-2-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5, 6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0341]

[0342]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (13.3 mg) and the crude product 2,3-dihydro-1H-indene-2-carbonyl chloride obtained in the previous step were mixed with chloroform (0.5 ml). Triethylamine (15.2 μl) was added to this mixture at room temperature, and the mixture was stirred for 1.5 hours. Under ice-cooling, a small amount of methanol was added to the reaction mixture to stop the reaction. The reaction mixture was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (13.9 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.41-1.50 (m, 3H), 1.96-1.97 (m, 3H), 3.12-3.65 (m, 7H) , 3.99-5.08 (m, 4H), 6.91 (s, 1H), 7.16-7.21 (m, 4H)

[0343]

Preparation Example 3 Synthesis of 2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile (compound of Example 4) its salts and its hydrate, and 1-methyl-3-((S)-5-methyl-3 -((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-indazole- 6-carbonitrile (compound of example 5)

[0344]

Stage 1

6-cyano-2-methyl-2H-indazole-3-carboxylic acid methyl ester and 6-cyano-1-methyl-1H-indazole-3-carboxylic acid methyl ester

[0345]

[0346]

6-Cyano-2H-indazole-3-carboxylic acid (100 mg) and potassium carbonate (220 mg) were mixed with dimethylformamide (3 ml). Under ice-cooling, methyl iodide (82.5 μl) was added to this mixture. The reaction mixture was stirred at room temperature overnight. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give 6-cyano-2-methyl-2H-indazole-3-carboxylic acid methyl ester (42.9 mg) as less polar compound.

¹ H-NMR (400 MHz, CDCl ₃ ) (4.05 (s, 3H), 4.55 (s, 3H), 7.41 (dd, J=8.79, 0.92Hz, 1H), 8 .11 (d, J=8.79Hz, 1H), 8.18 (s, 1H)

In addition, 6-cyano-1-methyl-1H-indazole-3-carboxylic acid methyl ester (46.1 mg) was obtained as a more polar compound.

¹ H-NMR (400 MHz, CDCl ₃ ) (4.05 (s, 3H), 4.22 (s, 3H), 7.53 (d, J=8.55Hz, 1H), 7.85 (s , 1H), 8.34 (d, J=8.32Hz, 1H)

The structure of each isomer was determined by comparing the ¹ H-NMR spectrum of each isomer and analogues with known structures.

[0347]

Stage 2-1

6-cyano-2-methyl-2H-indazole-3-carboxylic acid

[0348]

[0349]

6-cyano-2-methyl-2H-indazole-3-carboxylic acid methyl ester (42.9 mg) obtained in the previous step was mixed with tetrahydrofuran (2 ml) and methanol (1 ml). Under ice-cooling, 2N hydrochloric acid was added to this mixture. aqueous sodium hydroxide solution (150 µl). The reaction mixture was stirred at room temperature for 3 hours. aqueous sodium hydroxide solution (50 μl) and the mixture was further stirred at room temperature for 30 minutes. Under ice-cooling, 1 N sodium hydroxide was added to the reaction mixture. hydrochloric acid (800 μl) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (37.8 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (4.47 (s, 3H), 7.52 (dd, J=8.67, 1.27Hz, 1H), 8.12 (dd, J= 8.79, 0.92Hz, 1H), 8.48(s, 1H), 13.96(brs, 1H)

[0350]

Stage 3-1

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

[0351]

[0352]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (35.4 mg) and 6-cyano-2-methyl-2H-indazole-3-carboxylic acid (21.7 mg) obtained in the previous step were mixed with dimethylformamide (1 ml). Under ice-cooling, diisopropylethylamine (54.9 μl) and HATU (41.1 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated sodium hydrogen carbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (29.5 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.25-1.47 (m, 3H), 1.75 (s, 3H), 3.26-3.37 (m, 1H), 3 .67 (brs, 1H), 4.22 (s, 3H), 4.76-5.16 (m, 3H), 6.62-6.89 (m, 1H), 7.03-7.10 (m, 1H), 7.42 (s, 1H), 7.91 (brs, 1H), 8.43 (s, 1H)

[0353]

Step 4-1 Synthesis of hydrochloride dihydrate, hydrochloride, sulfate, 0.5 sulfate, p-toluenesulfonate, methanesulfonate, phosphate and tartrate 2-methyl-3-((S)-5-methyl-3-((R)-1,1 ,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

[0354]

2-Methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile (50.0 mg) was mixed with tert-butyl alcohol (0.5 ml) and water (0.05 ml). To this mixture was added concentrated hydrochloric acid (0.023 ml) and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration to give 2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5 hydrochloride dihydrate, 6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile (36.9 mg). Based on the measurement of chloride ion by ion chromatography, the resulting compound was presumably considered to be monohydrochloride. In addition, according to the measurement of the decrease in mass, constituting 2 eq. of water compared to the free form when the temperature was raised in TG-DTA (thermogravimetry-differential thermal analysis) and it was presumed to be a dihydrate by powder x-ray structure analysis.

[0355]

In the same way, 2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile obtained in the previous step was treated according to the usual method and obtained hydrochloride, sulfate, 0.5 sulfate, p-toluenesulfonate, methanesulfonate, phosphate and tartrate, respectively.

[0356]

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo hydrochloride dihydrate [1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.34-1.55 (m, 3H), 1.91 (s, 3H), 3.51-3.79 (m, 1H), 4 .24 (s, 3H), 4.68-5.29 (m, 4H), 7.30-7.45 (m, 2H), 7.89-7.91 (m, 2H), 8.45 (s, 1H)

[0357]

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[ hydrochloride 1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.34-1.55 (m, 3H), 1.92 (s, 3H), 3.48-3.78 (m, 1H), 4 .24 (s, 3H), 4.70-4.89 (m, 2H), 5.09-5.19 (m, 2H), 7.22-7.45 (m, 2H), 7.89 -7.91(m, 2H), 8.45(s, 1H)

[0358]

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[] sulfate 1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.33-1.55 (m, 3H), 1.89 (s, 3H), 3.50-3.79 (m, 2H), 4 .24 (s, 3H), 4.85-4.89 (m, 1H), 5.10-5.20 (m, 2H), 7.26-7.68 (m, 2H), 7.88 -7.91(m, 2H), 8.46(s, 1H)

[0359]

0.5 sulfate 2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8 -tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

(400 MHz, DMSO-d ₆ ) 1.29-1.51 (m, 3H), 1.84 (s, 3H), 3.47-3.75 (m, 1H), 4.23 (s, 3H), 4.88-5.15 (m, 4H), 7.04-7.34 (m, 1H), 7.43-7.46 (m, 1H), 7.60 (brs, 1H) , 7.87-7.89 (m, 1H), 8.45 (s, 1H)

[0360]

p-toluenesulfonate 2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

(400 MHz, DMSO-d ₆ ) 1.33-1.54 (m, 3H), 1.88 (s, 3H), 2.27 (s, 3H), 3.50-3.80 (m, 1H), 4.24 (s, 3H), 4.90-5.18 (m, 4H), 7.10 (dd, J=8.44, 0.58Hz, 2H), 7.45-7, 47(m, 4H), 8.03-8.31(m, 3H)

[0361]

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[] methanesulfonate 1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.33-1.54 (m, 3H), 1.88 (s, 3H), 2.32 (s, 3H), 3.50-3 .78 (m, 1H), 4.24 (s, 3H), 4.70-4.88 (m, 2H), 5.05-5.26 (m, 2H), 7.20-7.54 (m, 2H), 7.83-7.91 (m, 2H), 8.45 (s, 1H)

[0362]

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[phosphate] 1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.26-1.48 (m, 3H), 1.76 (s, 3H), 3.36-3.65 (m, 1H), 4 .22 (s, 3H), 4.63-4.77 (m, 2H), 4.88-5.16 (m, 2H), 6.62-6.89 (m, 1H), 7.06 (brs, 1H), 7.42(s, 1H), 7.89(s, 1H), 8.43(s, 1H)

[0363]

2-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[tartrate] 1,5-a]pyrazine-7-carbonyl)-2H-indazole-6-carbonitrile

¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.26-1.48 (m, 3H), 1.76 (s, 3H), 3.40-3.69 (m, 1H), 4, 22 (s, 3H), 4.29 (s, 2H), 4.76-5.16 (m, 5H), 6.62-6.89 (m, 1H), 7.03-7.10 ( m, 1H), 7.42(s, 1H), 7.89(s, 1H), 8.43(s, 1H), 12.64(brs, 2H)

[0364]

Stage 2-2

6-cyano-1-methyl-1H-indazole-3-carboxylic acid

[0365]

[0366]

6-Cyano-1-methyl-1H-indazole-3-carboxylic acid The methyl ester (46.1 mg) obtained in step 1 was mixed with tetrahydrofuran (5 ml) and methanol (2 ml). Under ice-cooling, 2N hydrochloric acid was added to this mixture. aqueous sodium hydroxide solution (160 μl). The reaction mixture was stirred at room temperature for 3 hours. aqueous sodium hydroxide solution (160 μl) and the mixture was further stirred at room temperature for 30 minutes. Under ice-cooling, 1 N sodium hydroxide was added to the reaction mixture. hydrochloric acid (1.3 ml) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (41.8 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (4.21 (s, 3H), 7.63 (dd, J=8.44, 1.27Hz, 1H), 8.21 (d, J= 8.55Hz, 1H), 8.52(s, 1H), 13.29(s, 1H)

[0367]

Stage 3-2

1-methyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-7-carbonyl)-1H-indazole-6-carbonitrile

[0368]

[0369]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (35.4 mg) and 6-cyano-1-methyl-1H-indazole-3-carboxylic acid (21.7 mg) obtained in the previous step were mixed with dimethylformamide (1 ml). Under ice-cooling, diisopropylethylamine (54.9 μl) and HATU (41.1 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated sodium hydrogen carbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (32.3 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.37-1.42 (m, 3H), 1.78 (s, 3H), 3.26-3.63 (m, 1H), 4 .21-4.24 (m, 3H), 4.84-5.39 (m, 4H), 6.77-6.87 (m, 1H), 7.08-7.09 (m, 1H) , 7.60 (d, J=8.52Hz, 1H), 8.22 (d, J=8.37Hz, 1H), 8.52-8.54 (m, 1H)

[0370]

Preparation Example 4 2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (5,6-difluoro-1-methyl-1H-indazol-3-yl)((S )-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl ) methanone (compounds of examples 9 and 10)

[0371]

Stage 1

5,6-Difluoro-2-methyl-2H-indazole-3-carboxylic acid methyl ester and 5,6-difluoro-1-methyl-1H-indazole-3-carboxylic acid methyl ester

[0372]

[0373]

5,6-Difluoro-2H-indazole-3-carboxylic acid (500 mg) and potassium carbonate (1046 mg) were mixed with dimethylformamide (5 ml). Under ice-cooling, methyl iodide (394 μl) was added to this mixture. The reaction mixture was stirred at room temperature overnight. Under ice-cooling, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 3:2) to give 5,6-difluoro-2-methyl-2H-indazole-3-carboxylic acid methyl ester (202 mg) as less polar compound.

¹ H-NMR (400 MHz, CDCl ₃ ) (4.04 (s, 3H), 4.48 (s, 3H), 7.48 (dd, J=10.02, 7.03Hz, 1H), 7 .73 (dd, J=10.16, 7.77Hz, 1H)

In addition, 5,6-difluoro-1-methyl-1H-indazole-3-carboxylic acid methyl ester (259 mg) was obtained as a more polar compound.

¹ H-NMR (400 MHz, CDCl ₃ ) (4.03 (s, 3H), 4.14 (s, 3H), 7.24 (dd, J=9.42, 6.13Hz, 1H), 7 .98 (dd, J=9.72, 7.62Hz, 1H)

The structure of each isomer was determined by comparing the ¹ H-NMR spectrum of each isomer and analogues with known structures.

[0374]

Stage 2-1

5,6-difluoro-2-methyl-2H-indazole-3-carboxylic acid

[0375]

[0376]

5,6-Difluoro-2-methyl-2H-indazole-3-carboxylic acid methyl ester (202 mg) obtained in the previous step was mixed with tetrahydrofuran (2 ml) and methanol (2 ml). To this mixture at room temperature was added 2 N. aqueous sodium hydroxide solution (671 μl). The reaction mixture was stirred at room temperature for 3 hours. Under ice-cooling, 1N sodium chloride was added to the reaction mixture. hydrochloric acid (1.8 ml) and water. The mixture was stirred at room temperature for 30 minutes and the precipitated solid was collected by filtration to give the title compound (171 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (4.39 (s, 3H), 7.79-7.84 (m, 2H), 13.88 (brs, 1H)

[0377]

(5,6-difluoro-2-methyl-2H-indazol-3-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl )-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0378]

[0379]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (70.0 mg) and 5,6-difluoro-2-methyl-2H-indazole-3-carboxylic acid (53.3 mg) obtained in the previous step were mixed with dimethylformamide (675 μl). Under ice-cooling, diisopropylethylamine (146 μl) and HATU (96 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was purified by SCX column chromatography (methanol to 1N ammonia/methanol). The resulting crude product was purified by silica gel column chromatography (hexane:acetone=5:1 to 1:4) to give the title compound (69.0 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.24-1.45 (m, 3H), 1.75 (s, 3H), 3.29-3.35 (m, 1H), 3 .70 (brs, 1H), 4.13 (s, 3H), 4.72-5.16 (m, 3H), 6.64-6.88 (m, 1H), 7.03-7.08 (m, 1H), 7.75-7.78 (m, 2H)

[0380]

Stage 2-2

5,6-difluoro-1-methyl-1H-indazole-3-carboxylic acid

[0381]

[0382]

5,6-Difluoro-1-methyl-1H-indazole-3-carboxylic acid methyl ester (259 mg) obtained in step 1 was mixed with tetrahydrofuran (4 ml) and methanol (4 ml). To this mixture at room temperature was added 2 N. aqueous sodium hydroxide solution (857 μl). The reaction mixture was stirred at room temperature for 4 hours. Under ice-cooling, 1N sodium chloride was added to the reaction mixture. hydrochloric acid (2.3 ml) and water. The mixture was stirred at room temperature for 30 minutes and the precipitated solid was collected by filtration to give the title compound (238 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (4.12 (d, J=6.47Hz, 3H), 7.89 (dd, J=10.06, 7.74Hz, 1H), 8, 00 (dd, J=10.63, 6.70Hz, 1H), 13.18 (s, 1H)

[0383]

Stage 3-2

(5,6-difluoro-1-methyl-1H-indazol-3-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl )-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0384]

[0385]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (70.0 mg) and 5,6-difluoro-1-methyl-1H-indazole-3-carboxylic acid (53.3 mg) obtained in the previous step were mixed with dimethylformamide (675 μl). Under ice-cooling, diisopropylethylamine (146 μl) and HATU (96 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was purified by SCX column chromatography (methanol to 1N ammonia/methanol). The resulting crude product was purified by silica gel column chromatography (hexane:acetone=5:1 to 1:4) to give the title compound (78.2 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.35-1.39 (m, 3H), 1.77 (s, 3H), 3.25-3.57 (m, 1H), 4 .11-4.14 (m, 3H), 4.90-5.35 (m, 4H), 6.77-6.84 (m, 1H), 7.06-7.07 (m, 1H) , 7.95-7.99 (m, 2H)

[0386]

Preparation Example 5Synthesis of (2,2-difluorobenzo[d][1,3]dioxol-5-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropane -2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (compound of Example 11)

[0387]

[0388]

2,2-Difluorobenzo[d][1,3]dioxole-5-carboxylic acid (55.0 mg), diisopropylethylamine (146 μl) and HATU (96.0 mg) were mixed with dimethylformamide (1 ml). Under ice-cooling, (R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- yl)propan-2-oldihydrochloride (70.0 mg) and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated sodium hydrogen carbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:acetone=9:1 to 1:4) to give the title compound (80.7 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.26-1.40 (m, 3H), 1.75 (s, 3H), 3.15-5.04 (m, 5H), 6 .65-6.84 (m, 1H), 7.05 (s, 1H), 7.33-7.35 (m, 1H), 7.50 (d, J=8.09Hz, 1H), 7 .57 (brs, 1H)

[0389]

Preparation Example 6 Synthesis of 6-(1-methyl-5-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7 ,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-pyrazol-3-yl)nicotinonitrile (compound of Example 73)

[0390]

Stage 1

6-acetylnicotinonitrile

[0391]

[0392]

2-Chloro-5-cyanopyridine (1.5 g) and dichlorobis(triphenylphosphine)palladium(II) (760 mg) were mixed with toluene (15 ml). Tributyl(1-ethoxyvinyl)tin (4.4 ml) was added to this mixture at room temperature under argon. The reaction mixture was stirred at 130° C. for 2 hours. hydrochloric acid (4 ml) and the mixture was stirred at room temperature for 1 hour. aqueous sodium hydroxide solution (4 ml) and saturated aqueous sodium hydrogen carbonate solution to adjust pH=9. Under ice-cooling, an aqueous potassium fluoride solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with an aqueous potassium fluoride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 3:2) to give the title compound (1.3 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (2.73 (s, 3H), 8.09-8.14 (m, 2H), 8.94 (s, 1H)

[0393]

Stage 2

ethyl 3-(5-cyanopyridin-2-yl)-1H-pyrazole-5-carboxylate

[0394]

[0395]

6-Acetylnicotinonitrile (731 mg) obtained in the previous step was mixed with tetrahydrofuran (7 ml). Under ice-cooling, diethyl oxalate (812 μl), ethanol (29.2 μl) and 60 w/w% sodium hydride (220 mg) were added to this mixture. The reaction mixture was stirred at room temperature for 2 hours. Hydrazine monohydrate (267 µl) and acetic acid (630 µl) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (182 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.43 (t, J=7.17Hz, 3H), 4.44 (q, J=7.08Hz, 2H), 7.45 (s, 1H) , 7.98-8.03 (m, 2H), 8.88 (d, J=1.49Hz, 1H)

[0396]

Stage 3

3-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

[0397]

[0398]

Ethyl 3-(5-cyanopyridin-2-yl)-1H-pyrazole-5-carboxylate (182 mg) obtained in the previous step was mixed with dimethylformamide (2 ml). Under ice-cooling, 60 w/w% sodium hydride (36 mg) and methyl iodide (140 μl) were added to this mixture. The reaction mixture was stirred at room temperature for 1 hour. Under ice-cooling, acetic acid (51.5 μl) was added to the reaction mixture. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:2) to give the title compound (86.2 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.39 (t, J=7.17Hz, 3H), 4.26 (s, 3H), 4.37 (q, J=7.17Hz, 2H) , 7.50 (s, 1H), 7.95-8.07 (m, 2H), 8.86 (d, J=2.08Hz, 1H)

[0399]

Stage 4

3-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0400]

[0401]

3-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (86.2 mg) obtained in the previous step was mixed with tetrahydrofuran (1.6 ml) and water ( 0.4 ml). Under ice-cooling, lithium hydroxide monohydrate (16.9 mg) was added to this mixture. The reaction mixture was stirred at room temperature for 30 minutes. Under ice-cooling, 1 N sodium hydroxide was added to the reaction mixture. hydrochloric acid (403 μl) and water (10 ml) and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (70.5 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (4.19 (d, J=0.60Hz, 3H), 7.39 (s, 1H), 8.09 (d, J=8.37Hz, 1H), 8.34 (dd, J=8.37, 2.09Hz, 1H), 9.04-9.54 (m, 1H), 13.64 (brs, 1H)

[0402]

Stage 5

6-(1-methyl-5-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-pyrazol-3-yl)nicotinonitrile

[0403]

[0404]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (60.0 mg) and 3-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (41.1 mg) obtained in the previous step were mixed with dimethylformamide (0.5 ml). Under ice-cooling, diisopropylethylamine (91.4 μl) and HATU (68.4 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated sodium hydrogen carbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. Ethyl acetate:hexane=1:1 was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (70.9 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.32, 1.42 (d, J=6.47, 3H), 1.76 (s, 3H), 3.21-3.68 ( m, 1H), 3.97-5.09 (m, 7H), 6.72-7.36 (m, 3H), 8.09 (d, J=8.20Hz, 1H), 8.33 ( dd, J=8.20, 1.85Hz, 1H), 9.02(s, 1H)

[0405]

Preparation Example 7Synthesis of (3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (compound of Example 16) and its hydrochloride

[0406]

[0407]

(R) -1,1,1-trifthor-2-((s) -5-methyl-5,6,7,8-tetrahydromidaso [1.5-a] pirazin-3-il) propane-2-oldigloride (60 mg) and 3- (4-florfenil) -1-methyl-1h-pyrazol-5-carbonic acid (46.5 mg) was mixed with dimethylformamamamam (0.4 ml). When cooling with ice, diizopropileylamine (107 μl) and Hatu (80.2 mg) was added to this mixture. The reaction mixture was stirred at room temperature overnight. Ethylcetate was added to the reaction mixture at room temperature. The reaction mixture was sequentially washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (ethyl acetate) to give the title compound (76.2 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.31-1.47 (m, 3H), 1.78 (s, 3H), 3.19-3.69 (m, 1H), 3 .92 (s, 3H), 4.03-4.56 (m, 1H), 4.68-5.16 (m, 3H), 6.74, 6.87 (s, 1H), 7.01 -7.31(m, 4H), 7.82-7.91(m, 2H)

[0408]

(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2 -yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methanone hydrochloride

[0409]

[0410]

(3-(4-Fluorophenyl)-1-methyl-1H-pyrazol-5-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2 -yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone obtained in the previous step was treated in the usual manner to give the hydrochloride.

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.43-1.50 (m, 3H), 1.93 (s, 3H), 3.37-3.74 (m, 1H), 3 .90 (s, 3H), 4.13-5.30 (m, 4H), 7.00-7.54 (m, 4H), 7.84-8.00 (m, 3H)

[0411]

Preparation Example 8 Synthesis of 4-(1-cyclopropyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7 ,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-pyrazol-5-yl)benzonitrile (compound of Example 53)

[0412]

Stage 1

(Z)-4-(4-cyanophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester

[0413]

[0414]

4-Acetylbenzonitrile (1.00 g) and diethyl oxalate (1.21 ml) were mixed with acetonitrile (8 ml). Under ice-cooling, sodium tert-butoxide (1.32 g) was added to this mixture. The reaction mixture was stirred at room temperature overnight. Under ice-cooling, water was added to the reaction mixture, and the mixture was washed twice with diethyl ether. When cooled with ice 1 N. hydrochloric acid was added to the aqueous layer until the pH was adjusted to about 4. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (1.02 g) as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) (1.41 (t, J=7.17Hz, 4H), 4.40 (q, J=7.17Hz, 2H), 7.05 (s, 1H) , 7.78-7.80 (m, 2H), 8.06-8.08 (m, 2H)

[0415]

Stage 2

5-(4-cyanophenyl)-1-cyclopropyl-1H-pyrazole-3-carboxylic acid Ethyl ester

[0416]

[0417]

(Z)-4-(4-cyanophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester (400 mg) obtained in the previous step and cyclopropylhydrazine hydrochloride (177 mg) were mixed with ethanol (8 ml). The reaction mixture was stirred at room temperature for 1.5 h and at 60°C for 6 h. Under ice-cooling, cyclopropylhydrazine hydrochloride (177 mg) was added to the reaction mixture, and the mixture was stirred at 60°C for 1 h. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. The reaction mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. Sulfate sodium filtered and the filtrate was concentrated at reduced pressure. The resulting residue was cleaned with column chromatography on silica gel (hexane: ethylacetate = 1: 1) and thin -layer chromatography on silica gel (chloroform: methanol = 20: 1) and received the desired compound (213 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.04-1.05 (m, 2H), 1.20-1.20 (m, 2H), 1.38 (t, J=7.05Hz, 3H), 3.60-3.64 (m, 1H), 4.40 (q, J=7.17Hz, 3H), 6.91 (s, 1H), 7.70-7.71 (m, 2H), 7.76-7.77 (m, 2H)

[0418]

Stage 3

5-(4-cyanophenyl)-1-cyclopropyl-1H-pyrazole-3-carboxylic acid

[0419]

[0420]

5-(4-cyanophenyl)-1-cyclopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (38.5 mg) obtained in the previous step was mixed with tetrahydrofuran (400 μl) and methanol (400 μl). Under ice-cooling, 2N hydrochloric acid was added to this mixture. aqueous sodium hydroxide solution (137 µl). The reaction mixture was stirred at room temperature for 2 hours. hydrochloric acid (46 μl). The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to give the title compound (43.9 mg) as a crude product.

[0421]

Stage 4

4-(1-cyclopropyl-3-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-pyrazol-5-yl)benzonitrile

[0422]

[0423]

5- (4-cyanophenil) -1-cyclopropil-1h-pirazol-3-carbonic acid (43.9 mg), obtained at the previous stage, was mixed with dimethylformamamamam (0.4 ml). Diisopropylethylamine (88.4 μl), HATU (51.9 mg) and (R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6, 7.8-tetrahydromidaso [1.5-a] pirazin-3-il) propane-2-oldigidloride (48.8 mg) and the mixture was mixed at room temperature during the night. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was cleaned with thin -layer chromatography on silica gel (chloroform: methanol = 10: 1) and received the desired compound (55.9 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (0.98-1.24 (m, 4H), 1.46-1.47 (m, 3H), 1.95 (s, 3H), 3.26 -3.66 (m, 2H), 3.98-5.61 (m, 5H), 6.81-6.90 (m, 1H), 7.67-7.80 (m, 4H)

[0424]

Preparation Example 9Synthesis of 4-(4-chloro-1-methyl-5-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5 ,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-pyrazol-3-yl)benzonitrile (compound of Example 40)

[0425]

Stage 1

3-(4-cyanophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0426]

[0427]

(Z)-4-(4-cyanophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester (600 mg) and hydrazine monohydrate (119 μl) were mixed with ethanol (9 ml). Under ice-cooling, acetic acid (140 μl) was added to this mixture. The reaction mixture was mixed at room temperature during the night and at a temperature of 50 ° C for 4.5 hours. The reaction mixture was concentrated at reduced pressure, ethanol and hexane were added to the resulting balance and the mixture was mixed at room temperature for 1 hour. The precipitated solid substance collected by filtration to give the title compound (462 mg).

[0428]

Stage 2

3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

[0429]

[0430]

3-(4-cyanophenyl)-1H-pyrazole-5-carboxylic acid ethyl ester (241 mg) obtained in the previous step was mixed with dimethylformamide (2.5 ml). When cooling with ice, 60 wt. The reaction mixture was mixed at room temperature for 1 hour. When ice is cooled to the reaction mixture, a saturated aqueous solution of ammonium was added and the mixture was extracted by ethylacetate. The organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate. Sulfate sodium filtered and the filtrate was concentrated at reduced pressure. The resulting residue was cleaned with colonial chromatography on silica gel (hexane: ethyl acetate = 3: 7) and received the desired compound (201 mg).

[0431]

Stage 3

4-Chloro-3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

[0432]

[0433]

3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (50.0 mg) obtained in the previous step was stirred with acetonitrile (750 μl). Under ice-cooling, N-chlorosuccinimide (52.3 mg) and trifluoroacetic acid (33.0 μl) were added to this mixture. The reaction mixture was stirred at room temperature overnight. Chloroform was added to the reaction mixture at room temperature (750 μl) and the mixture was mixed at room temperature during the night and at a temperature of 70 ° C for 6 hours. The reaction mixture was concentrated at low pressure and ethylaceta was added to the resulting residue. The reaction mixture was washed successively with an aqueous saturated sodium sulfite solution, an aqueous saturated sodium hydrogen carbonate solution, and an aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (61.8 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.45 (t, J=7.03Hz, 3H), 4.21 (s, 3H), 4.45 (q, J=7.17Hz, 2H) , 7.72 (d, J=8.67Hz, 2H), 8.05 (d, J=8.97Hz, 2H)

[0434]

Stage 4

4-chloro-3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0435]

[0436]

4-Chloro-3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (38.5 mg) obtained in the previous step was mixed with tetrahydrofuran (400 µl) and methanol (400 µl ). Under ice-cooling, 2N hydrochloric acid was added to this mixture. aqueous sodium hydroxide solution (137 µl). The reaction mixture was stirred at room temperature for 6 hours. hydrochloric acid (46 μl). The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to give the title compound (49.3 mg) as a crude product.

[0437]

Stage 5

4-(4-chloro-1-methyl-5-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5.6, 7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1H-pyrazol-3-yl)benzonitrile

[0438]

[0439]

The crude product (42.1 mg) 4-chloro-3-(4-cyanophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid obtained in the previous step was mixed with dimethylformamide (400 μl). Diisopropylethylamine (86.5 µl), HATU (51.9 mg) and (R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6, 7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (48.8 mg) and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (chloroform:methanol=12:1) to give the title compound (46.4 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.33-1.57 (m, 3H), 1.94 (s, 3H), 3.38-3.96 (m, 6H), 4.61 -5.29 (m, 3H), 6.80, 6.94 (s, 1H), 7.71 (d, J=8.55Hz, 2H), 8.03 (d, J=8.32Hz, 2H)

[0440]

Production Example 10Synthesis of (2-(4-fluorophenyl)pyridin-4-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)- 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (Example 48) and its hydrochloride

[0441]

Stage 1

2-(4-fluorophenyl)isonicotinoyl chloride

[0442]

[0443]

2-(4-Fluorophenyl)isonicotinic acid (34 mg) was stirred with chloroform (1.2 ml). Under ice cooling, oxalyl chloride (26 μl) and a catalytic amount of dimethylformamide were added. Tetrahydrofuran (1 ml) was added to the reaction mixture, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to give the title compound as the crude product.

[0444]

Stage 2

(2-(4-fluorophenyl)pyridin-4-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5.6 -dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0445]

[0446]

The crude product 2-(4-fluorophenyl)isonicotinoyl chloride obtained in the previous step was stirred with chloroform (1.0 ml). Under ice-cooling, (R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- yl)propan-2-oldihydrochloride (39 mg) and triethylamine (67 μl). The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated ammonium chloride aqueous solution, water, and saturated sodium chloride aqueous solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give the title compound (14.3 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.28-1.46 (m, 3H), 1.75 (s, 3H), 3.19-5.11 (m, 5H), 6 .65-6.87 (m, 1H), 7.03-7.09 (m, 1H), 7.29-7.35 (m, 2H), 7.37-7.43 (m, 1H) , 8.01-8.02 (m, 1H), 8.18-8.21 (m, 2H), 8.75-8.76 (m, 1H)

[0447]

Stage 3

(2-(4-fluorophenyl)pyridin-4-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5.6 -dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone hydrochloride

[0448]

[0449]

(2-(4-Fluorophenyl)pyridin-4-yl)((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5.6 -dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone obtained in the previous step was treated in the usual manner to give the hydrochloride.

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.41, 1.55 (d, J=6.47Hz, 3H), 1.97 (s, 3H), 3.34-5.28 ( m, 5H), 7.31-7.66 (m, 4H), 8.03, 8.10 (s, 1H), 8.18-8.26 (m, 3H), 8.79-8, 80(m, 1H)

[0450]

Preparation Example 11 Synthesis of 4-(5-fluoro-4-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7 ,8-Tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)pyridin-2-yl)benzonitrile (Example 68)

[0451]

Stage 1

2-Bromo-5-fluoroisonicotinic acid methyl ester

[0452]

[0453]

2-Bromo-5-fluoroisonicotinic acid (1.1 g) was mixed with toluene (15 ml) and methanol (5 ml). To this mixture was added a 2M trimethylsilyldiazomethane/hexane solution at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (1.17 g) as a crude product.

[0454]

Stage 2

2-(4-cyanophenyl)-5-fluoroisonicotinic acid methyl ester

[0455]

[0456]

The crude product 2-bromo-5-fluoroisonicotinic acid methyl ester (234 mg) obtained in the previous step, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (229 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14 mg) and potassium carbonate (415 mg) were mixed with toluene (3 ml) and methanol (2 ml). The reaction mixture was stirred at 65° C. for 2 hours. hydrochloric acid to adjust pH=7. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1). The eluate was concentrated and hexane was added to the resulting residue. The precipitated solid was collected by filtration to give the title compound (152 mg).

[0457]

Stage 3

2-(4-cyanophenyl)-5-fluoroisonicotinic acid

[0458]

[0459]

2-(4-cyanophenyl)-5-fluoroisonicotinic acid methyl ester (43 mg) obtained in the previous step was mixed with tetrahydrofuran (1 ml) and methanol (0.3 ml). To this mixture at room temperature was added 2 N. aqueous sodium hydroxide solution (140 μl). The reaction mixture was stirred at room temperature overnight. Under ice-cooling, 6N hydrochloric acid was added to the reaction mixture. hydrochloric acid (47 µl). The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to give the title compound as the crude product.

[0460]

Stage 4

4-(5-fluoro-4-((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)pyridin-2-yl)benzonitrile

[0461]

[0462]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propan-2-oldihydrochloride (45 mg) and the crude product 2-(4-cyanophenyl)-5-fluoroisonicotinic acid obtained in the previous step were mixed with dimethylformamide (1 ml). Under ice cooling, diisopropylethylamine (96 μl) and HATU (64 mg) were added to this mixture. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture at room temperature. The reaction mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (chloroform:methanol=9:1) to give the title compound (59.4 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.29-1.44 (m, 3H), 1.75 (s, 3H), 3.23-5.12 (m, 5H), 6 .64-6.88 (m, 1H), 7.06-7.11 (m, 1H), 7.96-7.99 (m, 2H), 8.25-8.32 (m, 3H) , 8.85-8.86 (m, 1H)

[0463]

Preparation Example 12Synthesis of (3-cyclopropyl-1H-pyrazol-5-yl)((R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4 ,7-dihydroisooxazolo[5,4-c]pyridin-6(5H)-yl)methanone (Example 111)

[0464]

Stage 1

(3R,7aS)-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one

[0465]

[0466]

(S)-5-(Hydroxymethyl)pyrrolidin-2-one (50 g), benzaldehyde (69.1 g) and p-toluenesulfonic acid hydrate were mixed with toluene (300 ml). The reaction mixture was stirred overnight at 130° C. while removing water using a Dean-Stark apparatus. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 1:1) to give the title compound (45.8 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.92-1.95 (m, 1H), 2.33-2.41 (m, 1H), 2.52-2.57 (m, 1H) , 2.80 (dt, J=18.34, 8.67Hz, 1H), 3.48 (t, J=7.98Hz, 1H), 4.10-4.17 (m, 1H), 4, 22 (dd, J=7.86, 6.24Hz, 1H), 6.32 (s, 1H), 7.30-7.35 (m, 3H), 7.42-7.44 (m, 2H )

[0467]

Stage 2

(3R,6S,7aS)-6-methyl-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one

[0468]

[0469]

Diisopropylamine (13.2 ml) was mixed with tetrahydrofuran (50 ml). To this solution was added dropwise a 1.6 M n-butyllithium/hexane solution (57.8 ml) under ice-cooling. The reaction mixture was cooled to -78°C and a solution of (3R,7aS)-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (17.4 g) obtained in the previous stage, in tetrahydrofuran (50 ml). The reaction mixture was stirred at -78°C for 30 min and methyl iodide (5.86 ml) was added dropwise at -78°C. The reaction mixture was stirred at -78° C. for 1 hour, and a saturated ammonium chloride aqueous solution and water were added dropwise. The reaction mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (11.3 g).

¹ H-NMR (400 MHz, CDCl ₃ ) 1.23 (d, J=6.01Hz, 3H), 1.50-1.53 (m, 1H), 2.58-2.62 (m, 1H ), 2.90-2.97 (m, 1H), 3.51 (d, J=7.74Hz, 1H), 4.08 (s, 1H), 4.22 (dd, J=8.21 , 6.36Hz, 1H), 6.32(s, 1H), 7.31-7.35(m, 3H), 7.42-7.44(m, 2H)

[0470]

Stage 3

(3R,6R,7aS)-6-methyl-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one

[0471]

[0472]

A 2.0M solution of lithium diisopropylamide/tetrahydrofuran/heptane/ethylbenzene (97.9 ml) was mixed with tetrahydrofuran (180 ml). A solution of (3R,6S,7aS)-6-methyl-3-phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (30.4 d) in tetrahydrofuran (120 ml). The mixture was stirred at -78° C. for 30 min and tetrahydrofuran/water (60 ml/30 ml) was added. Water (200 ml) was added to the reaction mixture at 0°C, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed successively with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (34.8 g) as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) (1.34 (d, J=7.40Hz, 3H), 1.94-2.01 (m, 1H), 2.15-2.22 (m, 1H), 2.70-2.74 (m, 1H), 3.41 (t, J=8.32Hz, 1H), 4.08 (s, 1H), 4.21 (t, J=7, 17Hz, 1H), 6.30(s, 1H), 7.30-7.37(m, 3H), 7.43-7.44(m, 2H)

[0473]

Stage 4

((2S,4R)-1-benzyl-4-methylpyrrolidin-2-yl)methanol

[0474]

[0475]

To a 2.5M solution of lithium aluminum hydride/tetrahydrofuran (73.6 ml) was added dropwise under ice-cooling a solution of the crude product (30.8 g) of (3R,6R,7aS)-6-methyl-3-phenyltetrahydro-3H,5H- pyrrolo[1,2-c]oxazol-5-one obtained in the previous step in tetrahydrofuran (110 ml). This reaction mixture was stirred at 80° C. for 2 hours. Water (7 ml), 4N was added dropwise slowly to the reaction mixture under ice-cooling. aqueous sodium hydroxide solution (7 ml) and water (21 ml). The reaction mixture was stirred at room temperature for 1 hour, sodium sulfate was added and the mixture was kept at room temperature overnight. This mixture was filtered through celite and the solid was washed successively with ethyl acetate (100 ml) and tetrahydrofuran (400 ml). The filtrate was concentrated under reduced pressure and azeotropically distilled with toluene to give the title compound (32.5 g) as a crude product.

¹ H-NMR (400 MHz, CDCl ₃ ) 0.94 (d, J=6.47Hz, 3H), 1.50-1.55 (m, 1H), 1.94-1.98 (m, 2H ), 2.10-2.12 (m, 1H), 2.80 (s, 1H), 3.01 (dd, J=7.51, 3.76Hz, 1H), 3.34-3.37 (m, 2H), 3.61 (dd, J=10.75, 3.35Hz, 1H), 3.92 (d, J=12.95Hz, 1H), 7.15-7.32 (m, 5H)

[0476]

Stage 5

(3R,5R)-1-benzyl-5-methylpiperidin-3-ol

[0477]

[0478]

The crude product (32.5 g) ((2S,4R)-1-benzyl-4-methylpyrrolidin-2-yl)methanol obtained in the previous step was mixed with tetrahydrofuran (200 ml). Trifluoroacetic anhydride (23.6 ml) was added to this mixture at -78°C. The reaction mixture was stirred at room temperature for 1 hour. Triethylamine (78.9 ml) was added to the reaction mixture at -78°C. The reaction mixture was stirred at 80° C. for 6 hours. an aqueous solution of sodium hydroxide (234 ml) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (25.4 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (0.82 (d, J=6.70Hz, 3H), 0.99-1.06 (m, 1H), 1.81-1.84 (m, 1H), 1.96-2.00 (m, 1H), 2.09 (dd, J=11.21, 1.50Hz, 1H), 2.77 (dt, J=11.02, 2.02Hz , 1H), 2.83-2.85 (m, 2H), 3.49 (s, 2H), 3.85 (brs, 1H), 7.22-7.32 (m, 5H)

[0479]

Stage 6

(R)-1-benzyl-5-methylpiperidin-3-one

[0480]

[0481]

(3R,5R)-1-Benzyl-5-methylpiperidin-3-ol (25.2 g) obtained in the previous step, triethylamine (49.8 g) and dimethyl sulfoxide (48.0 g) were mixed with chloroform (180 ml ). Sulfur trioxide-pyridine complex (43.1 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Under ice-cooling, water (150 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and the mixture was extracted 4 times with ethyl acetate. The combined organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give the title compound (20.6 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (0.97 (d, J=6.24Hz, 3H), 1.95 (dd, J=15.14, 9.83Hz, 1H), 2.08- 2.16 (m, 2H), 2.44-2.49 (m, 1H), 2.76 (d, J=14.33Hz, 1H), 2.85-2.86 (m, 1H), 3.15 (dt, J=14.33, 1.50Hz, 1H), 3.57 (d, J=5.45Hz, 2H), 7.23-7.33 (m, 5H)

[0482]

Stage 7

(4R)-6-Benzyl-7a-hydroxy-4-methyl-3a,4,5,6,7,7a-hexahydroisoxazolo[5,4-c]pyridine-3-carboxylic acid ethyl ester

[0483]

[0484]

Ethyl 2-chloro-2-(hydroxyimino)acetate (16.4 g) was mixed with tetrahydrofuran (150 ml). To this solution, a 1.1M lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (108 ml) was added dropwise at -78°C to obtain a nitrile oxide solution. To another reaction vessel, a 1.1 M solution of lithium bis(trimethylsilyl)amide/tetrahydrofuran (90.0 ml) was added. To this solution was added a solution of (R)-1-benzyl-5-methylpiperidin-3-one (18.3 g) obtained in the previous step in tetrahydrofuran (140 ml) at -78°C. This reaction mixture was added dropwise via cannula to the above nitrile oxide solution cooled to -78°C. This reaction mixture was stirred at -78°C for 30 min and it was allowed to warm to 10°C for 1.5 h. hydrochloric acid (150 ml). Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture to adjust the pH to about 8. This mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (22.4 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.09 (d, J=6.70Hz, 3H), 1.37 (t, J=7.17Hz, 3H), 1.59-1.66 ( m, 1H), 1.79 (t, J=11.44Hz, 1H), 2.37-2.40 (brm, 1H), 2.71-2.76 (m, 3H), 3.33 ( dd, J=12.60, 1.50Hz, 1H), 3.58-3.63 (m, 2H), 4.36 (ddd, J=14.28, 7.11, 1.10Hz, 2H) , 7.23-7.31 (m, 5H)

[0485]

Stage 8

(R)-6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxylic acid ethyl ester

[0486]

[0487]

(4R)-6-Benzyl-7a-hydroxy-4-methyl-3a,4,5,6,7,7a-hexahydroisoxazolo[5,4-c]pyridine-3-carboxylic acid ethyl ester (22.4 g) obtained in the previous step, and triethylamine (39.2 ml) was mixed with tetrahydrofuran (200 ml). Under ice-cooling, methanesulfonyl chloride (10.9 ml) was added dropwise to this mixture, and the mixture was stirred for 1 hour. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (19.0 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.26 (d, J=6.70Hz, 3H), 1.40 (t, J=7.17Hz, 3H), 2.61 (m, 2H) , 3.03 (brs, 1H), 3.40 (d, J=15.72Hz, 1H), 3.71-3.77 (m, 3H), 4.42 (q, J=7.09Hz, 2H), 7.27-7.34 (m, 5H)

[0488]

Stage 9

(R)-6-benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxylic acid

[0489]

[0490]

(R)-6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxylic acid ethyl ester (19.0 g) obtained in the previous step was mixed with tetrahydrofuran (95 ml) and methanol (95 ml). Under ice-cooling, 2N hydrochloric acid was added dropwise to this mixture. aqueous sodium hydroxide solution (44.9 ml). The reaction mixture was stirred at room temperature for 2 hours. hydrochloric acid (15.0 ml). This reaction mixture was concentrated under reduced pressure to give the title compound as the crude product.

[0491]

Stage 10

(R)-6-benzyl-N-methoxy-N,4-dimethyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxamide

[0492]

[0493]

The crude product (R)-6-benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxylic acid from the previous step and N,O-dimethylhydroxylamine hydrochloride (9 .39 g) was mixed with dimethylformamide (190 ml). Under ice-cooling, diisopropylethylamine (33.5 ml) and HATU (29.3 g) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated sodium hydrogen carbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (19.3 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.14 (d, J=6.70Hz, 3H), 2.39 (dd, J=11.56, 6.01Hz, 1H), 2.78 ( dd, J=11.79, 4.62Hz, 1H), 2.99 (brs, 1H), 3.37 (brs, 3H), 3.55-3.63 (m, 2H), 3.70- 3.73(m, 5H), 7.29-7.32(m, 5H)

[0494]

Stage 11

(R)-1-(6-benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)ethan-1-one

[0495]

[0496]

(R)-6-Benzyl-N-methoxy-N,4-dimethyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridine-3-carboxamide (19.3 g) obtained in the previous step , mixed with tetrahydrofuran (100 ml). Under cooling with 3.0 M ice, a methylmagnesium bromide/diethyl ether solution (30.6 ml) was added dropwise to this mixture. The reaction mixture was stirred at room temperature for 1 hour. Under ice-cooling, a saturated aqueous ammonium chloride solution (100 ml) was slowly added to the reaction mixture. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (15.7 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.23 (d, J=5.66Hz, 3H), 2.54-2.65 (m, 2H), 2.54 (s, 3H), 3 .03 (d, J=6.47Hz, 1H), 3.39 (d, J=15.26Hz, 1H), 3.68-3.77 (m, 3H), 7.26-7.39 ( m, 5H)

[0497]

Stage 12

(R)-2-((R)-6-benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)-1,1,1-trifluoropropan- 2-ol

[0498]

[0499]

(R)-1-(6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)ethan-1-one (15.5 g) obtained in the previous step, mixed with tetrahydrofuran (150 ml). Under ice-cooling, cesium fluoride (1.71 g) was added to this mixture, and (trifluoromethyl)trimethylsilane (12.5 ml) was added dropwise. The reaction mixture was stirred under ice-cooling for 1 hour. Under ice-cooling, methanol (150 ml) and potassium carbonate (11.7 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. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give the title compound (10.3 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.30 (d, J=6.94Hz, 3H), 1.83 (s, 3H), 2.52 (dd, J=11.56, 3, 70Hz, 1H), 2.67 (dd, J=11.68, 2.66Hz, 1H), 2.84 (s, 1H), 2.89 (brs, 1H), 3.28 (d, J= 15.72Hz, 1H), 3.72(dd, J=15.95, 13.18Hz, 2H), 3.83(d, J=15.49Hz, 1H), 7.25-7.37(m , 5H)

[0500]

Stage 13

(9H-fluoren-9-yl)methyl (R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4,7-dihydroisooxazolo[5, 4-c]pyridine-6(5H)-carboxylate

[0501]

[0502]

(R)-2-((R)-6-Benzyl-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)-1,1,1-trifluoropropan- 2-ol (10.3 g) obtained in the previous step was stirred with chloroform (150 ml). Under ice-cooling, 9-fluorenylmethyl chloroformate (9.3 g) was added to this mixture, and the mixture was stirred at room temperature for 5 hours. This reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (9.9 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (0.96, 1.12 (m, 3H), 1.84 (s, 3H), 2.80-2.98 (m, 3H), 3.84 -4.15(m, 3H), 4.55-4.58(m, 2H), 4.81-5.05(m, 1H), 7.33-7.37(m, 4H), 7 .56 (d, J=7.40Hz, 2H), 7.76 (d, J=7.40Hz, 2H)

[0503]

Stage 14

(R)-1,1,1-trifluoro-2-((R)-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)propan-2-ol

[0504]

[0505]

(9H-Fluoren-9-yl)methyl (R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4,7-dihydroisooxazolo[5, 4-c]pyridine-6(5H)-carboxylate (9.9 g) obtained in the previous step was stirred with acetonitrile (200 ml). Under ice-cooling, diethylamine (32.3 ml) was added to this mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with methanol. The resulting residue was purified by SCX column chromatography (methanol to 1N ammonia/methanol) and further purified by silica gel column chromatography (hexane:ethyl acetate=1:2). Ethyl acetate (10 ml) and hexane (10 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (3.91 g).

¹ H-NMR (400 MHz, CDCl ₃ ) (1.27 (d, J=6.88Hz, 3H), 1.86 (s, 3H), 2.91-2.93 (m, 3H), 3 .93-4.01 (m, 2H)

[0506]

Stage 15

(3-cyclopropyl-1H-pyrazol-5-yl)((R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4,7- dihydroisooxazolo[5,4-c]pyridin-6(5H)-yl)methanone

[0507]

[0508]

(R)-1,1,1-Trifluoro-2-((R)-4-methyl-4,5,6,7-tetrahydroisooxazolo[5,4-c]pyridin-3-yl)propan-2-ol (90 mg) obtained in the previous step and 3-cyclopropyl-1H-pyrazole-5-carboxylic acid (61 mg) were mixed with dimethylformamide (675 μl). Under ice-cooling, diisopropylethylamine (87 μl) and HATU (151 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. Chloroform and diethyl ether were added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration to give the title compound (119 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (0.68-0.72 (m, 2H), 0.90-0.97 (m, 2H), 1.11-1.17 (m, 3H), 1.71 (s, 3H), 1.88-1.95 (m, 1H), 2.95-3.10 (m, 1.5H), 3.34-3.46 (m, 0.5H), 4.24-4.54 (m, 1H), 4.61-4.97 (m, 1H), 5.18-5.30 (m, 0.5H), 5.76- 5.91(m, 0.5H), 6.22-6.35(m, 1H), 7.09(s, 1H), 13.01(s, 1H)

[0509]

Preparation Example 13 Synthesis of ((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo [4,3-a]pyrazin-7(8H)-yl)(1-methyl-3-phenyl-1H-pyrazol-5-yl)methanone (Example 122)

[0510]

Stage 1

tert-butyl-(R)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)hydrazine-1-carboxylate

[0511]

[0512]

(R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (4.74 g), tert-butylcarbazate (5.55 g) and 1-hydroxybenzotriazole monohydrate were mixed with acetonitrile (50 ml). Under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.75 g) was added and the mixture was stirred at room temperature overnight. This mixture was concentrated under reduced pressure. Ethyl acetate and 0.5N were added. hydrochloric acid and the layers were separated. The organic layer was washed successively with water, an aqueous saturated sodium hydrogen carbonate solution, and an aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (9.18 g) as a crude product.

[0513]

Stage 2

(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanehydrazide

[0514]

[0515]

The crude product (4.74 g) tert-butyl-(R)-2-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)hydrazine-1-carboxylate obtained in the previous step was stirred with ethyl acetate ( 40 ml). Under ice-cooling, 4N hydrochloric acid was added to this mixture. hydrochloric acid/ethyl acetate solution (40 ml) and the mixture was stirred at room temperature overnight. This mixture was concentrated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1 to 9:1) to give the title compound (4.10 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.45 (s, 3H), 4.34 (brs, 2H), 6.85 (brs, 1H), 9.30 (brs, 1H)

[0516]

Stage 3

(S)-(2-((tert-butoxycarbonyl)amino)propyl)glycine Methyl ester

[0517]

[0518]

tert-Butyl-(S)-(1-oxopropan-2-yl)carbamate (5.2 g) and glycine hydrochloride methyl ester (7.53 g) were mixed with chloroform (100 ml). Under ice-cooling, diisopropylethylamine (7.75 ml) and sodium triacetoxyborohydride (9.93 g) were added. This mixture was stirred at room temperature overnight. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the layers were separated. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to chloroform:methanol=20:1) to give the title compound (8.44 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (0.99 (d, J=6.60Hz, 3H), 1.37 (s, 9H), 1.95 (brs, 1H), 2.39 -2.48(m, 2H), 3.48(brs, 1H), 3.61-3.62(m, 4H), 6.56(brs, 1H)

[0519]

Stage 4

tert-butyl-(S)-3-methyl-5-oxopiperazine-1-carboxylate

[0520]

[0521]

(S)-(2-((tert-butoxycarbonyl)amino)propyl)glycine methyl ester (8.4 g) obtained in the previous step was mixed with methanol (80 ml). To this mixture at room temperature was added 4N. hydrochloric acid/1,4-dioxane solution (23 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Methanol (90 ml) and sodium acetate (7.4 g) were added to the resulting residue, and the mixture was stirred at 70° C. for 4 hours. The reaction mixture was filtered at room temperature, and the filtrate was concentrated under reduced pressure and azeotropically distilled with toluene. Chloroform (100 ml), triethylamine (5.0 ml) and di-t-butyl dicarbonate were added to the resulting residue, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered at room temperature, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate:methanol=20:1). Ethyl acetate (8 ml) and hexane (35 ml) were added to the resulting solid, and the mixture was stirred at room temperature for 1 hour. This mixture was collected by filtration to give the title compound (3.13 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.04 (d, J=6.47Hz, 3H), 1.39 (s, 9H), 3.00 (brs, 1H), 3.43 (brs, 1H), 3.61 (brs, 1H), 3.75-3.83 (m, 2H), 8.03 (brs, 1H)

[0522]

Stage 5

tert-butyl-(S)-3-methyl-5-thiooxopiperazine-1-carboxylate

[0523]

[0524]

tert-Butyl-(S)-3-methyl-5-oxopiperazine-1-carboxylate (3.1 g) obtained in the previous step and Lawesson's reagent (4.14 g) were mixed with tetrahydrofuran (50 ml). This mixture was stirred at 75° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 3:2) to give the title compound (2.69 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.26 (d, J=6.47Hz, 3H), 1.46 (s, 9H), 2.98 (brs, 1H), 3.65 (brs, 1H), 3.99 (brs, 1H), 4.34 (d, J=19.88Hz, 1H), 4.67 (d, J=20.11Hz, 1H), 8.25 (brs , 1H)

[0525]

Stage 6

tert-Butyl-(S)-3-methyl-5-(methylthio)-3,6-dihydropyrazine-1(2H)-carboxylate hydroiodide

[0526]

[0527]

tert-Butyl-(S)-3-methyl-5-thiooxopiperazine-1-carboxylate (2.68 g) obtained in the previous step was mixed with acetone (50 ml). To this mixture was added iodomethane (3.63 ml) and the mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound as the crude product.

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.23 (d, J=6.47Hz, 3H), 1.42 (s, 9H), 2.62 (s, 3H), 3.26 (brs, 1H), 3.67 (dd, J=13.41, 4.16Hz, 1H), 3.87-3.89 (m, 1H), 4.52 (brs, 2H)

[0528]

Stage 7

tert-Butyl-(S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo [4,3-a]pyrazine-7(8H)-carboxylate

[0529]

[0530]

The crude product of tert-butyl-(S)-3-methyl-5-(methylthio)-3,6-dihydropyrazine-1(2H)-carboxylate hydroiodide from the previous step and (R)-3,3,3- trifluoro-2-hydroxy-2-methylpropanehydrazide (2.01 g) obtained in step 2 was mixed with 2-propanol (80 ml) and water (15 ml). To this mixture was added acetic acid (1.33 ml) and the mixture was stirred at 100° C. overnight. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:9 to ethyl acetate). Diethyl ether and hexane were added to the resulting solid, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give the title compound (1.30 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.32 (d, J=5.78Hz, 3H), 1.43 (s, 9H), 1.82 (s, 3H), 3.12 -3.30 (m, 1H), 4.05 (d, J=38.15Hz, 1H), 4.44 (dd, J=43.70, 17.11Hz, 1H), 4.80 (s, 1H), 4.96(d, J=16.88Hz, 1H), 7.42(s, 1H)

[0531]

Stage 8

(R)-1,1,1-trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine-3 -yl)propan-2-oldihydrochloride

[0532]

[0533]

tert-Butyl-(S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo [4,3-a]pyrazine-7(8H)-carboxylate (1.3 g) obtained in the previous step was mixed with methanol (2 ml) and ethyl acetate (2 ml). Under ice-cooling, 4N hydrochloric acid was added to this mixture. hydrochloric acid/ethyl acetate solution (5.0 ml) and the mixture was stirred at room temperature for 1 h and additionally at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue were added methanol, ethyl acetate and diethyl ether. The precipitated solid was collected by filtration to give the title compound (1.08 g).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.60 (d, J=6.70Hz, 3H), 1.84 (s, 3H), 3.42 (dd, J=14.10, 6.94Hz, 1H), 3.57 (d, J=12.48Hz, 1H), 4.45 (d, J=16.18Hz, 1H), 4.58 (d, J=15.95Hz, 1H ), 4.97-4.98 (m, 1H), 7.64 (brs, 2H), 9.93 (brs, 1H), 10.81 (brs, 1H)

[0534]

Stage 9

((S)-5-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6-dihydro-[1,2,4]triazolo[4, 3-a]pyrazin-7(8H)-yl)(1-methyl-3-phenyl-1H-pyrazol-5-yl)methanone

[0535]

[0536]

(R)-1,1,1-Trifluoro-2-((S)-5-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine-3 -yl)propan-2-oldihydrochloride (39 mg) obtained in the previous step and 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid (29.1 mg) were mixed with dimethylformamide (0.6 ml) . Under ice-cooling, diisopropylethylamine (83 μl) and HATU (55 mg) were added to this mixture, and the mixture was stirred at room temperature overnight. Under ice-cooling, a saturated sodium hydrogen carbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to chloroform:methanol=20:1). Ethyl acetate and hexane were added to the resulting solid, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give the title compound (41.7 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) (1.34-1.46 (m, 3H), 1.83 (s, 3H), 3.26-3.38 (m, 0.5H) , 3.64-3.77(m, 0.5H), 3.91(s, 3H), 4.10-4.22(m, 0.5H), 4.60-4.75(m, 1H), 4.85-5.06 (m, 1.5H), 5.18-5.32 (m, 1H), 6.93-7.02 (m, 0.5H), 7.19- 7.27 (m, 0.5H), 7.32 (tt, J=7.40, 1.46Hz, 1H), 7.42 (t, J=7.63Hz, 2H), 7.48 (s , 1H), 7.80-7.86 (m, 2H)

[0537]

Compounds of examples 1-123 were obtained according to methods similar to the above methods of preparation 1-6 and examples of preparation 1-13, or, if necessary, according to other known methods. Structural formulas and characteristics of the compounds of examples are given in the following tables.

[0538]

[Table 1-1] Example Structure ¹ H-NMR Weight M+1 Weight M-1 1

(400 MHz, DMSO-d ₆ ) δ: 1.25-1.47 (m, 3H), 1.77 (s, 3H), 3.26-3.40 (m, 1 H), 3.74 (brs, 1H), 4.17(s, 3H), 4.77-4.91(m, 2H), 5.14-5.17(m, 1H), 6.67-6.89( m, 1H), 7.05(s, 1H), 7.23-7.25(m, 1H), 7.48(brs, 1H), 7.80(brs, 1H) 426 424 2

(400 MHz, CDCl ₃ ) δ: 1.49-1.51 (m, 3H), 1.96 (s, 3H), 3.39-3.76 (m, 1 H), 3.63 (brs , 1H), 4.76-4.84(m, 1H), 5.24-5.53(m, 3H), 6.92-6.94(m, 1H), 7.22-7 .28 (m, 1H), 7.48 -7.54 (m, 1H), 7.60-7.62 (m, 1H) 413 411 3

(400 MHz, CDCl3) δ: 1.41-1.50 (m, 3H), 1.96-1.97 (m, 3H), 3.12-3.65 (m, 7H), 3.99 -5.08(m, 4H), 6.91(s, 1H), 7.16-7.21(m, 4H) 394 392 4

(400 MHz, DMSO-d ₆ ) δ: 1.25-1.47 (m, 3H), 1.75 (s, 3H), 3.26-3.37 (m, 1 H), 3.67 (brs, 1H), 4.22(s, 3H), 4.76-5.16(m, 3H), 6.62-6.89(m, 1H), 7.03-7.10( m, 1H), 7.42(s, 1H), 7.91(brs, 1H), 8.43(s, 1H) 433 431 5

(400 MHz, DMSO-d ₆ ) δ: 1.37-1.42 (m, 3H), 1.78 (s, 3H), 3.26-3.63 (m, 1 H), 4.21 -4.24 (m, 3H), 4.84 -5.39 (m, 4H), 6.77-6.87 (m, 1H), 7.08-7.09 (m, 1H) , 7.60 (d, J=8.52Hz, 1H), 8.22 (d, J=8.37Hz, 1H), 8.52-8.54 (m, 1H) 433 431 6

(400 MHz, DMSO-d ₆ ) δ: 1.26-1.41 (m, 3H), 1.75-1.76 (m, 3H), 3.33-5.15 (m, 5H), 4.08-4.11(m, 3H), 6.69-6.81(m, 1H), 7.01-7.09(m, 1H), 7.33-7.36(m, 1H ) 444 442

[0539]

[Table 1-2] Example Structure ¹ H-NMR Weight M+1 Weight M-1 7

(400 MHz, DMSO-d ₆ ) δ: 1.29-1.41 (m, 3H), 1.76 (s, 3H), 3.30-5.10 (m, 5H), 4.06- 4.16(m, 3H), 6.64-6.84(m, 1H), 7.05-7.10(m, 1H), 7.55-7.56(m, 1H) 444 488 (M-1+46) 8

(400 MHz, DMSO-d ₆ ) δ: 1.38 (d, J=6.47Hz, 3H), 1.77 (s, 3H), 3.55 (brs, 1 H), 4.42 (d , J=12.72Hz, 1H), 4.97-5.07(m, 3H), 6.82(s, 1H), 7.09(s, 1H), 7.56-7.61 (m, 1H), 7.82 (dd, J=9.94, 5.32Hz, 1H), 8.26 (s, 1H), 9.11-9.12 (m, 1H) 412 410 9

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.45 (m, 3H), 1.75 (s, 3H), 3.29-3.35 (m, 1 H), 3.70 (brs, 1H), 4.13(s, 3H), 4.72-5.16(m, 3H), 6.64-6.88(m, 1H), 7.03-7.08 (m, 1H), 7.75-7.78 (m, 2H) 444 442 10

(400 MHz, DMSO-d ₆ ) δ: 1.35-1.39 (m, 3H), 1.77 (s, 3H), 3.25-3.57 (m, 1H), 4.11- 4.14(m, 3H), 4.90-5.35(m, 4H), 6.77-6.84(m, 1H), 7.06-7.07(m, 1H), 7.95-7.99(m, 2H) 444 442 eleven

(400 MHz, DMSO-d ₆ ) δ: 1.26-1.40 (m, 3H), 1.75 (s, 3H), 3.15-5.04 (m, 5H), 6.65- 6.84 (m, 1H), 7.05 (s, 1 H), 7.33-7.35 (m, 1 H), 7.50 (d, J=8.09Hz, 1 H), 7 .57 (brs, 1 H) 434 432 12

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.31 (m, 3H), 1.77 (s, 3H), 3.44-3.69 (m, 2H), 4.20 ( s, 3H), 4.71-4.87(m, 3H), 6.79(brs, 1H), 7.05(s, 1H), 7.30(d, J=8.80Hz, 1H), 7.65(d, J=8.80Hz, 1H), 7.88(s, 1H), 8.45(s, 1H) 408 406

[0540]

[Table 1-3] Example Structure ¹ H-NMR Weight M+1 Weight M-1 13

(400 MHz, DMSO-d ₆ ) δ: 1.39 (d, J=6.47Hz, 3H), 1.77 (s, 3H), 3.69 (brs, 1 H), 4.55-5 .01 (m, 4H), 6.83 (brs, 1H), 7.09 (s, 1H), 7.34 (t, J=7.17Hz, 1H), 7.44-7.49 (m, 1H), 7.51 (brs, 1H), 7.69 (d, J=8.32Hz, 1H), 7.77 (d, J=7.63Hz, 1H) 394 392 14

(400 MHz, CDCl ₃ ) δ: 0.68-0.78 (m, 2H), 0.90-0.97 (m, 2H), 1.35-1.49 (m, 3H), 1, 86-1.98(m, 1H), 1.96(s, 3H), 2.93-3.39(m, 0.7H), 3.54-3.65(m, 0.4H) , 3.91 (s, 3H), 4.02-4.17 (m, 0.6H), 4.54-4.76 (m, 0.3H), 4.72 (d, J=17, 73Hz, 1H), 4.94-5.14(m, 2H), 5.95-6.16(m, 1H), 6.77-6.99(m, 1H) 398 396 15

(400 MHz, DMSO-d ₆ ) δ: 1.35-1.39 (m, 3H), 1.77 (s, 3H), 3.21-3.25 (m, 1H), 3.62- 5.09(m, 5H), 3.92(s, 3H), 6.72-6.86(m, 1H), 7.07-7.15(m, 2H), 7.31(t , J=7.40Hz, 1H), 7.41 (t, J=7.40Hz, 2H), 7.81 (d, J=7.17Hz, 2H) 434 432 16

(400 MHz, DMSO-d ₆ ) δ: 1.31-1.47 (m, 3H), 1.78 (s, 3H), 3.19-3.69 (m, 1H), 3.92 ( s, 3H), 4.03-4.56 (m, 1H), 4.68-5.16 (m, 3H), 6.74, 6.87 (s, 1H), 7.01-7, 31 (m, 4H), 7.82-7.91 (m, 2H) 452 450 17

(400 MHz, DMSO-d ₆ ) δ: 1.29-1.41 (m, 3H), 1.78 (s, 3H), 3.16-3.93 (m, 2H), 4.55- 5.13 (m, 3H), 6.71-6.89 (m, 1H), 7.11 (s, 1H), 7.41-7.52 (m, 2H), 7.59-7, 72(m, 2H), 8.05-8.18(m, 1H) 506 504 18

(400 MHz, DMSO-d ₆ ) δ: 0.68-0.74 (m, 2H), 0.95-1.02 (m, 2H), 1.20-1.43 (m, 3H), 1.75 (s, 3H), 1.92-1.99 (m, 1H), 3.10-3.31 (m, 0.5H), 3.43-3.58 (m, 0.6H ), 3.65-3.78 (m, 0.6H), 4.39-5.06 (m, 3.3H), 6.58-6.86 (m, 1H), 7.03 (s , 1H), 7.14 (d, J=8.09Hz, 2H), 7.33 (d, J=7.40Hz, 2H) 394 392

[0541]

[Table 1-4] Example Structure ¹ H-NMR Mass m+1 Mass M-1 19

(400 MHz, CDCl ₃ ) δ: 1.00-1.01 (m, 4H), 1.37, 1.50 (d, J=6.47Hz, 3H), 1.93 (s, 3H), 1.97-1.98 (m, 1H), 3.42-3.77 (m, 2H), 3.83 (s, 3H), 4.03-5.20 (m, 4H), 6, 81, 6.92 (s, 1H) 423 421 20

(400 MHz, DMSO-d ₆ ) δ: 1.27-1.42 (m, 3H), 1.57-1.68 (m, 2H), 1.73-1.83 (m, 2H), 1.76 (s, 3H), 2.75-2.85 (m, 1H), 3.13-3.24 (m, 0.4H), 3.40 (t, J=10.87Hz, 2H ), 3.51-3.61(m, 0.6H), 3.79(s, 3H), 3.84-3.92(m, 2H), 3.93-4.01(m, 0 .6H), 4.39-4.52(m, 0.4H), 4.60-4.94(m, 2H), 4.96-5.10(m, 1H), 6.36-6 .58 (m, 1H), 6.70-6.85 (m, 1H), 7.07 (s, 1H) 442 440 21

(400 MHz, CDCl3) δ: 0.99-1.02 (m, 2H), 1.09-1.13 (m, 2H), 1.43-1.45 (m, 3H), 1.93 (s, 3H), 2.05-2.10 (m, 1H), 3.28-3.63 (m, 1H), 3.66-5.33 (m, 5H), 6.28 (s , 1H), 6.83, 6.90 (s, 1H) 385 383 22

(400 MHz, DMSO-d ₆ ) δ: 0.73-0.94 (m, 4H), 1.23-1.43 (m, 3H), 1.75 (s, 3H), 1.78- 1.87(m, 1H), 3.22-3.33(m, 0.6H), 3.49-3.80(m, 4.1H), 4.44-4.78(m, 1 .8H), 4.88-5.10(m, 1.5H), 6.74(s, 0.4H), 6.84(s, 0.6H), 7.06-7.10(m , 1H) 432 430 23

(400 MHz, DMSO-d ₆ ) δ: 0.96-1.09 (m, 4H), 1.31 (d, J=6.85Hz, 1.8H), 1.39 (d, J=6 ,36Hz, 1.2H), 1.77(s, 3H), 2.32-2.38(m, 1H), 3.20-3.25(m, 0.4H), 3.38- 3.44(m, 0.6H), 3.98-4.03(m, 0.6H), 4.51-4.55(m, 0.4H), 4.62-4.68(m , 1H), 4.82-4.99 (m, 1.6H), 5.03-5.09 (m, 0.4H), 6.68 (s, 0.4H), 6.84 (s , 0.6H), 7.06-7.09(m, 1H), 7.47-7.53(m, 1H), 7.73-7.80(m, 1H) 413 411 24

(400 MHz, DMSO-d ₆ ) δ: 0.87-1.01 (m, 4H), 1.32 (d, J=6.58Hz, 3H), 1.77 (s, 3H), 2, 45-2.60 (m, 1H), 3.27-3.39 (m, 3H), 4.56-5.07 (m, 3H), 6.41 (d, J=9.27Hz, 1H ), 6.79 (s, 1H), 7.07 (s, 1H), 7.49-7.58 (m, 1H), 7.80 (s, 1H) 411 455 (M-1+46)

[0542]

[Table 1-5] Example Structure ¹ H-NMR Weight M+1 Weight M-1 25

(400 MHz, CDCl ₃ ) δ: 1.46-1.48 (m, 3H), 1.95 (s, 3H), 3.35-3.66 (m, 1H), 3.78 (brs, 1H), 3.86 (s, 3H), 4.67-5.42 (m, 4H), 6.78-6.92 (m, 2H), 6.97-7.01 (m, 2H) , 7.72-7.74 (m, 2H) 451 495 (M-1+46) 26

(400 MHz, CDCl3) δ: 1.47-1.49 (m, 3H), 1.95 (s, 3H), 3.35-3.69 (m, 1H), 3.82 (brs, 1H ), 4.68-5.42(m, 4H), 6.87-6.91(m, 2H), 7.18-7.20(m, 2H), 7.77-7.82(m , 2H) 439 437 27

(400 MHz, DMSO-d ₆ ) δ: 0.59-1.02 (m, 4H), 1.26-1.32 (m, 2H), 1.36-1.46 (m, 1H), 1.70-1.99(m, 1H), 1.76(s, 3H), 3.15-3.26(m, 0.4H), 3.39-3.49(m, 1.2H ), 4.31-5.10 (m, 3.4H), 6.67-6.87 (m, 2H), 6.98-7.11 (m, 2H), 7.19-7.32 (m, 1H) 412 410 28

(400 MHz, DMSO-d ₆ ) δ: 0.83-0.94 (m, 2H), 1.12-1.17 (m, 2H), 1.26 (d, J=6.11Hz, 2H ), 1.42 (d, J=7.09Hz, 1H), 1.76 (s, 3H), 2.17-2.26 (m, 1H), 3.15-3.22 (m, 0 .4H), 3.46-3.56(m, 1.3H), 4.48-4.65(m, 1.7H), 4.86-4.95(m, 1.3H), 5 .03-5.10(m, 0.3H), 6.66(s, 0.4H), 6.85(s, 0.6H), 7.04-7.16(m, 2H), 7 .36-7.43 (m, 1H), 7.86 (d, J=7.58Hz, 1H) 419 417 29

(400 MHz, DMSO-d ₆ ) δ: 0.57-1.13 (m, 8H), 1.26-1.43 (m, 3H), 1.77 (s, 3H), 1.81- 1.91 (m, 1H), 3.14-3.90 (m, 3H), 4.49-5.13 (m, 3H), 6.14-6.33 (m, 1H), 6, 70-6.87 (m, 1H), 7.08 (s, 1H) (400 MHz, DMSO-d ₆ ) δ: 0.92-1.02 (m, 4H), 1.21-1.44 (m, 3H), 1.75 (s, 3H), 2.11-2.18 (m, 1H), 3.12 - 424 422 thirty

3.25(m, 0.4H), 3.52-3.76(m, 1.2H), 4.43-5.09(m, 3.4H), 6.63-6.86(m , 1H), 7.05 (s, 1H), 7.38 (d, J=8.09Hz, 1H), 7.70-7.80 (m, 1H), 8.48 (brs, 1H) 395 393

[0543]

[Table 1-6] Example Structure ¹ H-NMR Weight M+1 Weight M-1 31

(400 MHz, CDCl3) δ: 1.43 (brs, 3H), 1.95 (s, 3H), 3.49-3.67 (m, 2H), 4.07 (s, 3H), 4, 10-5.06 (m, 4H), 6.95 (s, 2H), 7.68 (d, J=8.55Hz, 2H), 7.88 (d, J=7.63Hz, 2H) 459 457 32

(400 MHz, DMSO-d ₆ ) δ: 0.84-1.17 (m, 4H), 1.27-1.46 (m, 3H), 1.77 (s, 3H), 3.20- 3.61 (m, 1H), 3.75-5.12 (m, 5H), 6.48-6.89 (m, 2H), 7.09 (s, 1H), 7.44-7, 51 (m, 1H), 384 382 33

(400 MHz, CDCl3) δ: 1.43-1.51 (m, 3H), 1.95 (s, 3H), 3.24-4.37 (m, 5H), 4.66-5.67 (m, 4H), 6.83-6.95 (m, 2H), 7.56 (d, J=8.09Hz, 2H), 7.78 (d, J=8.09Hz, 2H) 459 457 34

(400 MHz, DMSO-d6) δ: 1.34-1.41 (m, 3H), 1.78 (s, 3H), 3.14-3.24 (m, 1H), 3.56-4 .11 (m, 1H), 4.55-5.12 (m, 3H), 6.75-6.87 (m, 1H), 7.05-7.23 (m, 2H), 7, 27-7.35(m, 2H), 7.64-7.65(m, 2H), 13.72(brs, 1H) 438 436 35

(400 MHz, CDCl3) δ: 1.17-1.38 (m, 7H), 1.95 (s, 3H), 3.27-4.03 (m, 4H), 4.85-5.01 (m, 3H), 6.70-6.90 (m, 2H), 7.66 (d, J=8.32Hz, 2H), 7.86 (d, J=7.63Hz, 2H) 485 464 36

(400 MHz, DMSO-d ₆ ) δ: 0.64-0.98 (m, 4H), 1.24-1.38 (m, 3H), 1.77 (s, 3H), 1.87- 2.00(m, 1H), 3.18-5.35(m, 7H), 6.51-6.88(m, 2H), 7.09(s, 1H) 466 464

[0544]

[Table 1-7] Example Structure ¹ H-NMR Weight M+1 Weight M-1 37

(400 MHz, DMSO-d ₆ ) δ: 0.70-0.76 (m, 2H), 0.98-1.05 (m, 2H), 1.34 (d, J=6.60Hz, 3H ), 1.77 (s, 3H), 1.99-2.07 (m, 1H), 3.13-3.52 (m, 1H), 4.49-5.41 (m, 6H), 6.33-6.37(m, 1H), 6.70-6.82(m, 1H), 7.07(s, 1H) 466 464 38

(400 MHz, DMSO-d ₆ ) δ: 1.34 (d, J=6.01 Hz, 2H), 1.44 (d, J=6.01 Hz, 1H), 1.76 (s, 3H ), 3.24-3.32(m, 0.3H), 3.50-3.55(m, 0.6H), 4.08-4.13(m, 0.6H), 4.56 -4.61 (m, 0.4H), 4.69 (d, J=17.80Hz, 0.6H), 4.78 (d, J=16.41Hz, 0.4H), 4.91- 5.03(m, 1.7H), 5.07-5.13(m, 0.4H), 6.67(s, 0.4H), 6.85(s, 0.6H), 7, 01-7.10 (m, 1H), 7.30-7.36 (m, 2H), 7.57-7.63 (m, 1H), 8.00-8.19 (m, 4H) 449 447 39

(400 MHz, DMSO-d ₆ ) δ: 1.02 (d, J=6.01Hz, 1.5H), 1.10 (d, J=6.01Hz, 1.5H), 1.72 (s , 3H), 3.02-3.13(m, 1H), 3.41-3.45(m, 0.5H), 4.27-4.43(m, 1.5H), 4.52 (d, J=17.34Hz, 0.5H), 4.70-4.76 (m, 0.5H), 4.81-4.87 (m, 0.5H), 4.92-4, 99 (m, 0.5H), 6.61 (s, 0.5H), 6.79 (s, 0.5H), 7.00 (d, J=8.55Hz, 1H), 7.20- 7.30 (m, 2H), 7.44-7.51 (m, 2H), 7.56-7.62 (m, 1H), 7.92-7.96 (m, 1H), 8, 60-8.66(m, 1H) 449 447 40

(400 MHz, CDCl ₃ ) δ: 1.33-1.57 (m, 3H), 1.94 (s, 3H), 3.38-3.96 (m, 6H), 4.61-5, 29 (m, 3H), 6.80, 6.94 (s, 1H), 7.71 (d, J=8.55Hz, 2H), 8.03 (d, J=8.32Hz, 2H) 493 491 41

(400 MHz, CDCl3) δ: 1.45, 1.52 (d, J=6.47Hz, 3H), 1.94 (s, 3H), 3.31, 3.67 (d, J=10, 40Hz, 1H), 3.82, 3.88 (s, 3H), 4.32-5.15 (m, 5H), 6.79, 6.92 (s, 1H), 7.58 (d, J=8.44Hz, 2H), 7.83 (d, J=8.44Hz, 2H) 493 537 (M-1+46)

[0545]

[Table 1-8] Example Structure ¹ H-NMR Weight M+1 Weight M-1 42

(400 MHz, DMSO-d ₆ ) δ: 1.33 (d, J=6.01 Hz, 1.8H), 1.42 (d, J=6.47Hz, 1.2H), 1.76 ( s, 3H), 3.20-3.29(m, 0.4H), 3.49-3.55(m, 0.6H), 4.09-4.15(m, 0.6H), 4.56-4.78(m, 1.4H), 4.92-5.03(m, 1.6H), 5.05-5.11(m, 0.4H), 6.67(s , 0.4H), 6.85 (s, 0.6H), 7.02-7.09 (m, 1H), 7.33-7.40 (m, 2H), 7.75 (t, J =7.74Hz, 1H), 7.82-7.89(m, 2H), 8.21-8.26(m, 1H), 8.92-8.95(m, 1H) 449 447 43

(400 MHz, DMSO-d ₆ ) δ: 1.35 (d, J=6.36Hz, 1.8H), 1.46 (d, J=6.60Hz, 1.2H), 1.78 (s , 3H), 3.26-3.32(m, 0.4H), 3.52-3.58(m, 0.6H), 4.08-4.13(m, 0.6H), 4 .58-4.83(m, 1.4H), 4.93-5.05(m, 1.6H), 5.08-5.15(m, 0.4H), 6.68(s, 0.4H), 6.87(s, 0.6H), 7.05(s, 0.6H), 7.10(s, 0.4H), 7.68-7.74(m, 1H) , 7.97-8.01 (m, 2H), 8.10-8.15 (m, 1H), 8.20-8.34 (m, 3H) 456 454 44

(400 MHz, DMSO-d ₆ ) δ: 1.33-1.47 (m, 3H), 1.78 (s, 3H), 3.24 (s, 3H), 3.25-3.69 ( m, 1H), 3.97 (s, 3H), 4.05-4.55 (m, 1H), 4.70-5.16 (m, 3H), 6.72-6.90 (m, 1H), 7.08-7.42(m, 2H), 7.94-8.00(m, 2H), 8.07-8.13(m, 2H) 512 510 45

(400 MHz, DMSO-d ₆ ) δ: 1.35 (d, J=5.87Hz, 1.8H), 1.44 (d, J=6.60Hz, 1.2H), 1.78 (s , 3H), 3.24-3.30 (m, 0.4H), 3.51-3.56 (m, 0.6H), 4.07-4.12 (m, 0.6H), 4 .57-4.79(m, 1.4H), 4.93-5.04(m, 1.6H), 5.07-5.13(m, 0.4H), 6.68(s, 0.4H), 6.87 (s, 0.6H), 7.05-7.10 (m, 1H), 7.81 (t, J=8.19Hz, 1H), 7.99-8, 06 (m, 4H), 8.34-8.38 (m, 1H), 9.02-9.06 (m, 1H) 456 454 46

(400 MHz, DMSO-d ₆ ) δ: 1.41 (d, J=6.36 Hz, 3H), 1.79 (s, 3H), 2.40-2.43 (m, 3H), 3 .61-4.70 (m, 3H), 4.91-5.33 (m, 2H), 6.85 (br s, 1H), 7.11 (s, 1H), 8.01-8, 27 (m, 4H), 460 458

[0546]

[Table 1-9] Example Structure ¹ H-NMR Weight M+1 Weight M-1 47

(400 MHz, DMSO-d ₆ ) δ: 1.30-1.48 (m, 3H), 1.78 (s, 3H), 3.21-3.68 (m, 1H), 3.94 ( s, 3H), 3.99-4.56 (m, 1H), 4.66-5.16 (m, 3H), 6.71-7.11 (m, 3H), 7.15-7, 22 (m, 1H), 7.31-7.41 (m, 1H), 7.93-8.01 (m, 1H) 470 468 48

(400 MHz, DMSO-D ₆ ) Δ: 1.28-1.46 (M, 3H), 1.75 (S, 3H), 3.19-5,11 (M, 5H), 6.65- 6.87 (m, 1H), 7.03-7.09 (m, 1H), 7.29-7.35 (m, 2H), 7.37-7.43 (m, 1H), 8 .01-8.02 (m, 1H), 8.18-8.21 (m, 2H), 8.75-8.76 (m, 1H) 449 447 49

(400 MHz, DMSO-D ₆ ) Δ: 1.26-1.47 (M, 3H), 1.75 (S, 3H), 3.19-3,29 (M, 0.4H), 3, 3, 3, 52-3.62 (m, 0.6h), 3.71-3.79 (m, 0.6H), 4.52-4.72 (M, 1.7H), 4.91-5.10 (m, 1.7H), 6.65 (brs, 0.4H), 6.85 (brs, 0.6H), 7.00-7.08 (m, 1H), 7.38 (dd, J =7.28, 4.97Hz, 1H), 7.49-7.54 (m, 1H), 7.59 (t, J=7.51Hz, 1H), 7.89 (td, J=7, 74, 1.77Hz, 1H), 8.02 (d, J=7.63Hz, 1H), 8.15 (s, 1H), 8.19 (d, J=8.32Hz, 1H), 8, 67 (d, J=4.86Hz, 1H) 431 429 50

(400 MHz, CDCl ₃ ) δ: 1.30-1.51 (m, 3H), 1.94 (s, 3H), 3.25-3.78 (m, 1H), 4.08 (s, 3H), 4.48-5.29 (m, 5H), 6.73-7.00 (m, 2H), 7.36-7.54 (m, 2H), 8.18 (t, J= 7.74Hz, 1H) 477 475 51

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.45 (m, 3H), 1.63-1.74 (m, 1H), 1.77 (s, 3H), 1.90- 2.00 (m, 1H), 2.24-2.44 (m, 4H), 3.15-3.78 (m, 2H), 4.55-5.08 (m, 3H), 5 .59 (s, 1H), 6.64-6.87 (m, 1H), 7.05 (s, 1H), 7.44 (d, J=7.63 Hz, 2H), 7.57 ( d, J=8.09Hz, 2H), 424 468 (M-1+46)

[0547]

[Table 1-10] Example Structure ¹ H-NMR Weight M+1 Weight M-1 52

(400 MHz, DMSO-d ₆ ) δ: 1.23-1.47 (m, 3H), 1.71-1.93 (m, 11H), 3.49-3.80 (m, 1H), 4.46-5.08 (m, 4H), 6.63-6.89 (m, 1H), 7.05 (br s, 1H), 7.41 (d, J=7.58 Hz, 2H ), 7.55 (d, J=8.07 Hz, 2H), 438 436 53

(400 MHz, CDCl ₃ ) δ: 0.98-1.24 (m, 4H), 1.46-1.47 (m, 3H), 1.95 (s, 3H), 3.26-3, 66 (m, 2H), 3.98-5.61 (m, 5H), 6.81-6.90 (m, 1H), 7.67-7.80 (m, 4H) 485 529 (M-1+46) 54

(400 MHz, DMSO-D ₆ ) Δ: 1.30-1.45 (M, 3H), 1.75 (S, 3H), 3.19-5,11 (M, 5H), 6.65- 6.87 (m, 1H), 7.04-7.09 (m, 1H), 7.54-7.59 (m, 1H), 7.70-7.75 (m, 1H), 7. 91-8.04(m, 3H), 8.83-8.86(m, 1H) 474 472 55

(400 MHz, DMSO-d ₆ ) δ: 1.33 (d, J=6.47Hz, 1.8H), 1.43 (d, J=6.47Hz, 1.2H), 1.76 (s , 3H), 3.22-3.28 (m, 0.4H), 3.48-3.53 (m, 0.6H), 3.98-4.04 (m, 0.6H), 4 .56-4.61(m, 0.4H), 4.66-4.73(m, 1H), 4.84-5.01(m, 1.6H), 5.05-5.11( m, 0.4H), 6.66(s, 0.4H), 6.85(s, 0.6H), 7.02-7.08(m, 1H), 7.33-7.39( m, 2H), 7.82-7.86 (m, 1H), 7.90-7.96 (m, 3H), 8.65-8.69 (m, 1H) 449 447 56

(400 mhz, DMSO-D ₆ ) Δ: 1.31 (D, J = 4,86HZ, 1.8H), 1.45 (D, J = 6.01 HZ, 1.2H), 1.76 ( s, 3H), 3.19-3.28 (m, 0.4H), 3.63-3.71 (m, 0.6H), 3.85-3.92 (m, 0.6H), 4,48-4.55 (m, 0.4h), 4.68-5.00 (M, 2.6H), 5.07-5.15 (M, 0.4H), 6.66 (S , 0.4H), 6.87(s, 0.6H), 7.07(s, 1H), 7.53-7.60(m, 3H), 8.41-8.46(m, 2H ), 9.02 -9.08 (m, 2H) 432 430

[0548]

[Table 1-11] Example Structure ¹ H-NMR Weight M+1 Weight M-1 57

(400 mhz, DMSO -D ₆ ) PA: 1.33 (D, J = 7.09HZ, 3H), 1.77 (S, 3H), 4,11 -4.28 (M, 1H), 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 57-4.76 (m, 1 h), 4,86-4.94 (m, 1H), 4,98-5.05 (m, 1H), 6.55 (D, J = 9.29HZ, 1H), 6.78 (s, 1H), 7.08 (s, 1H), 7.08 (s, 1H), 7.34-7.40 (m, 2H), 7.51-7.57 (m, 2H), 7.66 (dd, J=9.66, 2.81Hz, 1H), 7.97 (s, 1H) 465 463 58

(400 MHz, DMSO-D ₆ ) Δ: 1.26-1.46 (M, 3H), 1.77 (S, 3H), 3.19-3.31 (M, 0.4H), 3, 3, 3, 54-3.64 (m, 0.6h), 3.73-3.85 (M, 0.6H), 4.51-4.77 (M, 1.8H), 4.89-5.11 (M, 1.6H), 6.67 (S, 0.4H), 6.85 (S, 0.6H), 7.06 (S, 1H), 7.52 (DD, J = 10.88 , 8.44hz, 1H), 7.66-7.75 (M, 1H), 8.06 (D, J = 8.07HZ, 1H), 8,10 (DD, J = 7.46, 2, 2, 08HZ, 1H), 8.46 (DD, J = 8.31, 2.20HZ, 1H), 9.17-9.18 (M, 1H) 474 472 59

(400 MHz, DMSO-d ₆ ) δ: 1.34 (d, J=6.36Hz, 2H), 1.46 (d, J=6.36Hz, 1H), 1.77 (s, 3H), 2.37 (d, J=5.38Hz, 3H), 3.23-3.30 (m, 0.4H), 3.53-3.56 (m, 1.2H), 4.50-4 .79 (m, 1.8H), 4.92-5.03 (m, 1.2H), 5.08-5.14 (m, 0.4H), 6.70 (s, 0.4H) , 6.88 (s, 0.6H), 7.05-7.13 (m, 1H), 7.72-7.78 (m, 1H), 7.87 (d, J=6.11Hz, 1H), 7.96-8.03(m, 2H), 8.58(s, 0.6H), 8.65(s, 0.4H) 488 486 60

(400 MHz, CDCl ₃ ) δ: 1.36, 1.43 (d, J=6.30Hz, 3H), 1.81-1.95 (m, 9H), 2.21-2.25 (m , 2H), 2.58-2.66 (m, 1H), 3.07 (d, J=10.63Hz, 0.5H), 3.58-3.89 (m, 1H), 4.17 -4.19 (m, 1H), 4.64 (d, J=17.11Hz, 1H), 4.75 (t, J=15.72Hz, 1H), 4.90 (d, J=15, 26Hz, 0.5H), 5.13-5.19(m, 1H), 5.37-5.59(m, 1H), 6.24(s, 1H), 6.85(s, 1H) , 7.41(s, 1H), 7.49(s, 1H) 426 424 61

(400 MHz, DMSO-D ₆ ) Δ: 1.35-1.43 (M, 3H), 1.76 (S, 3H), 3.22-5,11 (M, 5H), 3.95 ( S, 3H), 6.69-6.86 (M, 1H), 7.08-7.23 (M, 2H), 7.65-7.70 (M, 1H), 7.91-7, 98(m, 2H) 477 521 (M-1+46)

[0549]

[Table 1-12] Example Structure ¹ H-NMR Weight M+1 Weight M-1 62

(400 MHz, DMSO-d ₆ ) δ: 1.29-1.43 (m, 3H), 1.75 (s, 3H), 3.20-5.10 (m, 5H), 6.64- 6.86 (m, 1H), 7.04-7.08 (m, 1H), 7.53-7.60 (m, 1H), 7.83-7.92 (m, 2H), 8, 03 (dd, J=11.10, 1.39Hz, 1H), 8.14 (t, J=7.98Hz, 1H), 8.86-8.89 (m, 1H) 474 472 63

(400 MHz, DMSO-d ₆ ) δ: 1.28-1.43 (m, 3H), 1.75 (s, 3H), 2.37-2.39 (m, 3H), 3.18- 5.10 (m, 5H), 6.67-6.85 (m, 1H), 7.04-7.08 (m, 1H), 7.46-7.53 (m, 1H), 7. 61-7.68 (m, 2H), 7.77 (d, J=7.86Hz, 1H), 7.83 (s, 1H), 8.80-8.82 (m, 1H) 470 468 64

(400 MHz, DMSO-D ₆ ) Δ: 1.22-1.45 (M, 3H), 1.75 (S, 3H), 3.15-3,27 (M, 0.3H), 3, 3, 3, 50-3.61(m, 0.6H), 3.72-3.82(m, 0.6H), 3.76(s, 3H), 4.43-5.09(m, 3.5H ), 6.45 (s, 1H), 6.63-6.87 (m, 1H), 7.05 (s, 1H), 7.45-7.54 (m, 2H), 7.55- 7.72(m, 2H) 452 450 65

(400 MHz, DMSO-d ₆ ) δ: 1.33-1.46 (m, 3H), 1.77 (s, 3H), 2.16-2.24 (m, 3H), 3.19- 5.13 (m, 5H), 6.69-6.89 (m, 1H), 7.06-7.12 (m, 1H), 7.31-7.42 (m, 1H), 7. 78-7.82(m, 2H), 7.95-7.98(m, 2H), 8.59-8.64(m, 1H) 470 514 (M-1+46) 66

(400 MHz, CDCl ₃ ) δ: 1.35-1.51 (m, 3H), 1.94 (s, 3H), 3.32-3.72 (m, 2H), 4.08 (s, 3H), 4.17-5.16 (m, 4H), 6.95-6.97 (m, 2H), 7.69-7.95 (m, 2H), 8.54 (s, 1H) 469 464

[0550]

[Table 1-13] Example Structure ¹ H-NMR Weight M+1 Weight M-1 67

(400 MHz, DMSO-d ₆ ) δ: 1.28-1.47 (m, 3H), 1.75 (s, 3H), 3.19-5.12 (m, 5H), 6.64- 6.87 (m, 1H), 7.04-7.10 (m, 1H), 7.48-7.53 (m, 1H), 7.96-7.99 (m, 2H), 8, 16-8.17(m, 1H), 8.31-8.36(m, 2H), 8.82-8.84(m, 1H) 456 454 68

(400 MHz, DMSO-d ₆ ) δ: 1.29-1.44 (m, 3H), 1.75 (s, 3H), 3.23-5.12 (m, 5H), 6.64- 6.88 (m, 1H), 7.06-7.11 (m, 1H), 7.96-7.99 (m, 2H), 8.25-8.32 (m, 3H), 8. 85-8.86(m, 1H) 474 472 69

(400 MHz, DMSO-d ₆ ) δ: 1.25-1.45 (m, 3H), 1.75 (s, 3H), 3.16-3.27 (m, 0.4H), 3, 56-3.64 (m, 0.6H), 3.72-3.81 (m, 0.6H), 4.47-5.09 (m, 3.4H), 6.61-6.87 (m, 1H), 7.05 (s, 1H), 7.54 (t, J=9.25Hz, 1H), 7.71-7.83 (m, 2H), 8.63 (dd, J =8.44, 2.89Hz, 1H), 9.05 (d, J=2.77Hz, 1H) 492 490 70

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.44 (m, 3H), 1.75 (s, 3H), 3.17-3.31 (m, 0.4H), 3, 50-3.61 (m, 0.6H), 3.72-3.82 (m, 0.6H), 4.48-5.08 (m, 3.4H), 6.62-6.87 (m, 1H), 7.04 (s, 1H), 7.45 (dd, J=11.21, 8.44Hz, 1H), 7.57-7.64 (m, 1H), 7.84 -7.94 (m, 2H), 7.99 (dd, J=7.51, 2.20Hz, 1H), 8.72 (d, J=3.01Hz, 1H) 467 465 71

(400 MHz, DMSO-d ₆ ) δ: 1.28-1.48 (m, 3H), 1.77 (s, 3H), 3.19-3.29 (m, 0.4H), 3, 59-3.67 (m, 0.6H), 3.73-3.80 (m, 0.6H), 4.52-4.58 (m, 0.4H), 4.67-4.79 (m, 1.4H), 4.90-5.01 (m, 1.2H), 5.06-5.13 (m, 0.4H), 6.68 (s, 0.4H), 6 .87 (s, 0.6H), 7.06-7.11 (m, 1H), 7.85-7.95 (m, 2H), 8.07 (d, J=9.78Hz, 1H) , 8.14-8.22(m, 1H), 8.75-8.81(m, 1H), 8.93(s, 1H) 474 472

[0551]

[Table 1-14] Example Structure ¹ H-NMR Weight M+1 Weight M-1 72

(400 MHz, DMSO-d ₆ ) δ: 1.28-1.46 (m, 3H), 1.76 (s, 3H), 3.19-3.27 (m, 0.4H), 3, 61-3.81(m, 1.2H), 4.51-4.58(m, 0.4H), 4.68-5.13(m, 3H), 6.64(s, 0.4H ), 6.86 (s, 0.6H), 7.06 (s, 1H), 7.75 (td, J=8.55, 2.85Hz, 1H), 7.79-7.86 (m , 1H), 8.06 (dd, J=8.55, 2.54Hz, 1H), 8.15-8.24 (m, 1H), 8.77-8.82 (m, 1H), 8 .87(s, 1H) 474 472 73

(400 MHz, DMSO-d ₆ ) δ: 1.32, 1.42 (d, J=6.47, 3H), 1.76 (s, 3H), 3.21-3.68 (m, 1H ), 3.97-5.09 (m, 7H), 6.72-7.36 (m, 3H), 8.09 (d, J=8.20Hz, 1H), 8.33 (dd, J =8.20, 1.85Hz, 1H), 9.02(s, 1H) 460 458 74

(400 MHz, CDCl ₃ ) δ: 1.46-1.50 (m, 3H), 1.96 (s, 3H), 3.36-3.77 (m, 2H), 4.65-5, 20 (m, 4H), 6.57 (s, 1H), 6.82-7.02 (m, 1H), 7.47 (d, J=7.40Hz, 1H), 7.80 (d, J=1.39Hz, 1H), 7.86(d, J=8.09Hz, 1H), 7.92(s, 1H), 8.23(d, J=2.31Hz, 1H) 445 443 75

(400 MHz, DMSO-d ₆ ) δ: 1.32-1.48 (m, 3H), 1.78 (s, 3H), 2.52-2.59 (m, 3H), 3.20- 3.69 (m, 1H), 3.96 (s, 3H), 4.03-4.56 (m, 1H), 4.66-5.16 (m, 3H), 6.73, 6, 87 (s, 1H), 6.95-7.19 (m, 2H), 7.69-7.87 (m, 3H) 473 471 76

(400 MHz, DMSO-d ₆ ) δ: 1.23-1.47 (m, 3H), 1.72-1.81 (m, 3H), 2.12-2.26 (m, 3H), 3.15-3.89 (m, 5H), 4.56-5.17 (m, 3H), 6.73, 6.88 (s, 1H), 7.08, 7.12 (s, 1H ), 7.85-7.94 (m, 4H) 473 471

[0552]

[Table 1-15] Example Structure ¹ H-NMR Mass m+1 Mass M-1 77

(400 MHz, DMSO-d ₆ ) δ: 1.29 (d, J=6.01 Hz, 1.8H), 1.43 (d, J=6.01 Hz, 1.2H), 1.75 (s, 3H), 3.18-3.26 (m, 0.4H), 3.53-3.59 (m, 0.6H), 3.65-3.71 (m, 0.6H) , 4.51-4.56(m, 0.4H), 4.63-4.69(m, 1.4H), 4.90-4.97(m, 1.2H), 5.04- 5.10 (m, 0.4H), 6.65 (s, 0.4H), 6.85 (s, 0.6H), 7.02-7.09 (m, 1H), 7.71 ( dd, J=15.49, 8.32Hz, 1H), 7.93-8.04 (m, 3H), 8.08 (d, J=7.63Hz, 1H), 8.76 (d, J =3.01Hz, 1H) 474 472 78

(400 MHz, DMSO-d ₆ ) δ: 1.30-1.42 (m, 3H), 1.75 (s, 3H), 3.22-5.10 (m, 5H), 6.64- 6.87 (m, 1H), 7.05-7.10 (m, 1H), 7.57-7.65 (m, 1H), 7.99-8.02 (m, 2H), 8, 09-8.13(m, 2H), 8.67-8.71(m, 1H) 474 472 79

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.47 (m, 3H), 1.75 (s, 3H), 3.20-3.32 (m, 0.4H), 3, 54-3.62(m, 0.6H), 3.69-3.77(m, 0.6H), 4.52-4.70(m, 1.7H), 4.90-5.11 (m, 1.7H), 6.64 (s, 0.4H), 6.85 (s, 0.6H), 7.01-7.08 (m, 1H), 7.58-7.67 (m, 2H), 8.23-8.25 (m, 1H), 8.26-8.30 (m, 2H), 8.41 (dd, J=8.44, 2.20Hz, 1H) , 9.11 (dd, J=2.20, 0.81Hz, 1H) 456 454 80

(400 MHz, DMSO-d ₆ ) δ: 1.27-1.48 (m, 3H), 1.76 (s, 3H), 3.18-3.26 (m, 0.4H), 3, 60-3.67 (m, 0.6H), 3.73-3.79 (m, 0.6H), 4.50-4.58 (m, 0.4H), 4.66-4.78 (m, 1.4H), 4.88-5.12 (m, 1.6H), 6.66 (s, 0.4H), 6.86 (s, 0.6H), 7.02-7 .09 (m, 1H), 7.35 (t, J=8.79Hz, 2H), 7.82-7.88 (m, 2H), 8.15-8.20 (m, 1H), 8 .63-8.68 (m, 1H), 8.98 (d, J=2.08Hz, 1H) 449 447 81

(400 MHz, DMSO-d ₆ ) δ: 1.33, 1.44 (d, J=5.98, 3H), 1.78 (s, 3H), 3.22-3.68 (m, 1H ), 3.95 (s, 3H), 4.02-5.03 (m, 4H), 6.74-7.22 (m, 3H), 7.80 (td, J=8.67, 2 .09Hz, 1H), 7.98-8.01(m, 1H), 8.59(s, 1H) 453 451

[0553]

[Table 1-16] Example Structure ¹ H-NMR Mass m+1 Mass M-1 82

(400 MHz, DMSO-d ₆ ) δ: 1.22-1.47 (m, 3H), 1.75 (s, 3H), 3.14-3.28 (m, 0.4H), 3, 52-3.63(m, 0.6H), 3.72-3.82(m, 0.6H), 4.45-5.10(m, 3.4H), 6.64-6.86 (m, 1H), 7.05 (s, 1H), 7.51 (t, J=9.25Hz, 1H), 7.60-7.73 (m, 3H), 8.56 (dd , J=4.74, 1.04Hz, 1H), 8.72 (d, J=2.08Hz, 1H) 467 465 83

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.47 (m, 3H), 1.75 (s, 3H), 3.15-3.25 (m, 0.4H), 3, 56-3.65 (m, 0.6H), 3.74-3.81 (m, 0.6H), 4.46-5.10 (m, 3.4H), 6.65-6.87 (m, 1H), 7.05 (s, 1H), 7.49 (dd, J=10.63, 8.55Hz, 1H), 7.59-7.65 (m, 1H), 7.75-7.80 (m, 1H), 7.99-8.06 (m, 1 H), 8.64 (d, J=3.01Hz, 1 H), 8.69 (brs, 1 h) 467 465 84

(400 MHz, DMSO-d ₆ ) δ: 1.25-1.45 (m, 3H), 1.75 (s, 3H), 3.16-3.26 (m, 0.4H), 3, 57-3.65(m, 0.6H), 3.74-3.82(m, 0.6H), 4.47-5.10(m, 3.4H), 6.63-6.86 (m, 1H), 7.06 (s, 1H), 7.58 (t, J=9.25Hz, 1H), 7.71-7.82 (m, 3H), 8.96 ( d, J=5.32Hz, 1H), 9.17 (d, J=0.69Hz, 1H) 474 472 85

(400 MHz, CDCl ₃ ) δ: 1.22-1.26 (m, 3H), 1.94 (s, 3H), 2.94-3.66 (m, 2H), 4.61-5, 11 (m, 4H), 6.77-6.96 (m, 1H), 7.48-7.50 (m, 1H), 7.73 (s, 1H), 7.86-7, 87(m, 2H), 8.21(s, 1H) 479 477 86

(400 MHz, DMSO-d ₆ ) δ: 1.30-1.44 (m, 3H), 1.75 (s, 3H), 3.22-5.11 (m, 5H), 6.65- 6.88 (m, 1H), 7.05-7.11 (m, 1H), 7.29-7.35 (m, 2H), 8.11-8.17 (m, 3H), 8 .77-8.78 (m, 1H) 467 465 87

(400 MHz, DMSO-d ₆ ) δ: 1.30-1.42 (m, 3H), 1.75 (s, 3H), 3.23-5.10 (m, 5H), 6.65- 6.86(m, 1H), 7.05-7.10(m, 1H), 7.34-7.39(m, 2H), 7.48-7.56(m, 1H), 7.95-8.02(m, 2H), 8.61-8.64(m, 1H) 467 465

[0554]

[Table 1-17] Example Structure ¹ H-NMR Weight M+1 Weight M-1 88

(400 MHz, DMSO-d6) δ: 1.31-1.45 (m, 3H), 1.77 (s, 3H), 3.20-5.11 (m, 5H), 6.66-6 .87(m, 1H), 7.06-7.11(m, 1H), 7.24-7.29(m, 1H), 7.39-7.53(m, 2H), 7 .78-7.82(m, 1H), 8.01-8.07(m, 1H), 8.82-8.85(m, 1H) 467 465 89

(400 MHz, CDCl ₃ ) δ: 1.37-1.44 (m, 3H), 1.68-1.79 (m, 7H), 1.94 (s, 3H), 2.22-2, 25 (m, 2H), 2.60 (d, J=34.22Hz, 1H), 3.05-3.90 (m, 2H), 4.62-4.92 (m, 3H), 5, 07-5.11(m, 1H), 6.88(s, 1H), 7.39(s, 1H), 7.41(s, 1H) 460 458 90

(400 MHz, DMSO-d ₆ ) δ: 1.26-1.36 (m, 3H), 1.62 (s, 3H), 1.77 (s, 3H), 3.03-5.08 ( m, 9H), 6.47 (dd, J=9.02, 3.47Hz, 1H), 6.79 (s, 1H), 7.05-7.10 (brm, 1H), 7, 50 (td, J=8.79, 3.01Hz, 1H), 8.05 (d, J=3.01Hz, 1H) 442 440 91

(400 MHz, DMSO-d ₆ ) δ: 1.27-1.34 (m, 3H), 1.51 (s, 3H), 1.77 (s, 3H), 2.29-2.32 ( m, 2H), 2.58-2.59 (m, 2H), 2.99-5.04 (m, 10H), 6.75-6.79 (brm, 1H), 7.05-7, 10 (brm, 1H) 437 435 92

(400 MHz, DMSO-d ₆ ) δ: 1.22-1.41 (m, 3H), 1.76 (s, 3H), 2.05-2.34 (m, 2H), 2.91- 3.86 (m, 6H), 4.15-5.12 (m, 4H), 6.54-6.60 (m, 1H), 6.74-6.79 (m, 1H), 7 .04-7.10 (m, 1H), 7.80 (dt, J=8.86, 1.85Hz, 1H), 8.45 (t, J=1.85Hz, 1H) 449 493 (M-1+46) 93

(400 MHz, DMSO-d ₆ ) δ: 1.28 (s, 3H), 1.75 (s, 3H), 2.21 (s, 3H), 2.43 (t, J=4.97Hz, 4H), 3.21 (t, J=4.97Hz, 4H), 3.32-3.60 (m, 1H), 3.80-4.20 (m, 1H), 4.50-4 .68(m, 1H), 4.77-4.90(m, 1H), 4.91-5.02(m, 1H), 6.76(s, 1H), 6.95(d , J=8.79Hz, 2H), 7.03(s, 1H), 7.34(d, J=8.79Hz, 2H) 452 450

[0555]

[Table 1-18] Example Structure ¹ H-NMR Weight M+1 Weight M-1 94

(400 MHz, CDCl3) δ: 1.13-1.23 (m, 4H), 1.39-1.44 (m, 3H), 1.94 (s, 3H), 2.27-2.33 (m, 1H), 3.40-3.47 (m, 1H), 3.71 (d, J=18.26Hz, 1H), 4.71-5.06 (m, 3H), 6, 79-6.95(m, 1H), 8.66(s, 2H) 396 394 95

(400 MHz, DMSO-d ₆ ) δ: 1.24-1.44 (m, 3H), 1.75 (s, 3H), 1.88-2.06 (m, 4H), 3.11- 3.78 (m, 6H), 4.45-5.10 (m, 3H), 6.62-6.86 (m, 2H), 6.92-6.97 (m, 1H), 7 .01-7.09(m, 1H), 8.17-8.23(m, 1H) 474 518 (M-1+46) 96

(400 MHz, DMSO-d ₆ ) δ: 0.88-1.02 (m, 4H), 1.23-1.46 (m, 3H), 1.75 (s, 3H), 2.08- 2.20(m, 1H), 3.14-5.11(m, 5H), 6.65-6.86(m, 1H), 7.01-7.09(m, 1H), 7.11-7.20(m, 1H), 7.30-7.39(m, 1H), 8.45-8.52(m, 1H) 395 393 97

(400 MHz, DMSO-d ₆ ) δ: 1.00-1.08 (m, 3H), 1.72 (s, 3H), 3.09-3.17 (m, 1H), 3.50 -4.97 (m, 4H), 6.60 -6.80 (m, 1H), 7.02 (d, J=4.39Hz, 1H), 7.27-7.35 (m, 2H ), 7.53-7.56 (m, 2H), 9.03 (d, J=9.25Hz, 1H), 9.27 (d, J=13.41 Hz, 1H) 450 448 98

(400 MHz, DMSO-d ₆ ) δ: 0.90-1.12 (m, 4H), 1.23-1.48 (m, 3H), 1.76 (s, 3H), 2.21- 2.34 (m, 1H), 3.15-3.66 (m, 2H), 4.45-5.15 (m, 3H), 6.65-6.89 (m, 1H), 7 .02-7.11 (m, 1H), 7.63-7.74 (m, 2H) 463 461 99

(400 MHz, CDCl3) δ: 1.20-1.29 (m, 3H), 1.86 (s, 3H), 2.79 (s, 1H), 3.02-3.15 (m, 1.6H), 3.35-3.43(m, 0.4H), 4.22-4.38(m, 2.6H), 4.60-4.72(m, 1H), 5 .02-5.11 (m, 0.6H), 5.08 (t, J=7.98Hz, 2H), 5.42-5.51 (m, 0.4H), 5.84-5, 99(m, 1.4H) 387 385

[0556]

[Table 1-19] Example Structure ¹ H-NMR Weight M+1 Weight M-1 100

(400 MHz, CDCl ₃ ) δ: 1.18-1.30 (m, 3H), 1.85 (s, 3H), 2.59-2.66 (m, 2H), 2.88-2, 97 (m, 3H), 3.03-3.15 (m, 1.5H), 3.34-3.44 (m, 0.5H), 4.11-4.20 (m, 2H), 4.21-4.31(m, 0.5H), 4.59-4.75(m, 1H), 5.08-5.17(m, 0.5H), 5.43-5.53 (m, 0.5H), 5.92-6.03 (m, 0.5H), 6.45-6.52 (m, 1H) 385 383 101

(400 MHz, CDCl3) δ: 1.25-1.34 (m, 3H), 1.86 (s, 3H), 2.93 (s, 1H), 3.08-3.51 (m, 2H), 4.32-5.17(m, 2H), 5.62-5.97(m, 1H), 7.26-7.30(m, 1H), 7.42-7.46( m, 1H), 7.52 (d, J=8.55Hz, 1H), 8.20 (brs, 1H), 10.33 (brs, 1H) 395 393 102

(400 MHz, DMSO-d ₆ ) δ: 1.06-1.21 (m, 3H), 1.72 (s, 3H), 2.89-5.49 (m, 5H), 7.14- 7.17 (m, 2H), 7.44 (dd, J=8.32, 6.94Hz, 1H), 7.66 (d, J=8.32Hz, 1H), 7.98 (brs, 1H ), 13.33(s, 1H) 395 393 103

(400 MHz, DMSO-d ₆ ) δ: 0.96 (s, 6H), 1.11-1.18 (m, 3H), 1.45 (t, J=6.24Hz, 2H), 1, 72 (s, 3H), 2.38 (s, 2H), 2.45-2.56 (m, 2H), 2.95-3.44 (m, 2H), 4.29-4.55 ( m, 1H), 4.64-4.86 (m, 1H), 5.27-5.86 (m, 1H), 7.10-7.12 (brm, 1H), 12.73-12, 77 (brm, 1H) 427 425 104

(400 MHz, DMSO-d ₆ ) δ: 1.08-1.29 (m, 3H), 1.72 (s, 3H), 3.00-3.60 (m, 2H), 4.35- 6.05 (m, 3H), 7.08-7.14 (m, 1H), 7.33 (td, J=9.07, 2.47Hz, 1H), 7.63-7.74 (m , 2H), 13.78(s, 1H) 413 411 105

(400 MHz, CDCl3) δ: 1.02-1.22 (m, 3H), 1.85 (s, 3H), 2.71-2.87 (m, 2H), 2.97-3.02 (m, 3H), 3.20-3.35 (m, 1H), 3.42-3.77 (m, 1H), 4.17-5.12 (m, 3H), 5.31-5 .61 (m, 1H), 6.97 (d, J=7.40Hz, 1H), 7.10-7.21 (m, 3H) 410 468 (M-1+60)

[0557]

[Table 1-20] Example Structure ¹ H-NMR Weight M+1 Weight M-1 106

(400 MHz, CDCl ₃ ) δ: 0.35, 1.23 (d, J=6.70Hz, 3H), 1.78, 1.82 (s, 3H), 2.36, 2.44 (s , 3H), 2.46-3.05 (m, 5H), 3.15-3.30 (m, 2H), 4.19-4.66 (m, 2H), 5.10-5.95 (m, 1H), 7.09 -7.17 (m, 4H) 424 482 (M-1+60) 107

(400 MHz, CDCl3) δ: 1.16-1.26 (m, 3H), 1.85 (s, 3H), 2.19 (s, 3H), 2.83-3.75 (m, 5H ), 4.01-4.91 (m, 3H), 5.14-5.42 (m, 1H), 6.25-6.45 (m, 1H), 7.03-7.14 ( m, 4H) 452 450 108

(400 MHz, CDCl3) δ: 0.69-0.75 (m, 2H), 0.88-0.94 (m, 2H), 1.23 (s, 3H), 1.88 (s, 3H ), 1.88-1.94 (m, 1H), 3.10-3.34 (m, 3H), 3.87 (s, 3H), 4.02-5.47 (m, 2H), 6.05(s, 1H) 399 457 (M-1+60) 109

(400 MHz, CDCl3) δ: 0.99 (brs, 2H), 1.23-1.27 (m, 5H), 1.88 (s, 3H), 3.10-3.89 (m, 5H ), 4.36-5.53(m, 2H), 6.35(s, 1H), 7.44(s, 1H) 385 443 (M-1+60) 110

(400 MHz, CDCl3) δ: 1.12-1.22 (m, 7H), 1.86-1.88 (m, 3H), 3.09-4.27 (m, 4H), 4.68 -4.76 (m, 1H), 5.11 -6.01 (m, 2H), 6.71-6.74 (m, 1H), 7.47 (s, 1H) 385 443 (M-1+60) 111

(400 MHz, DMSO-d ₆ ) δ: 0.68-0.72 (m, 2H), 0.90-0.97 (m, 2H), 1.11-1.17 (m, 3H), 1.71(s, 3H), 1.88-1.95(m, 1H), 2.95-3.10(m, 1.5H), 3.34-3.46(m, 0.5H ), 4.24-4.54 (m, 1H), 4.61-4.97 (m, 1H), 5.18-5.30 (m, 0.5H), 5.76-5.91 (m, 0.5H), 6.22-6.35 (m, 1H), 7.09 (s, 1H), 13.01 (s, 1H) 385 383

[0558]

[Table 1-21] Example Structure ¹ H-NMR Weight M+1 Weight M-1 112

(400 MHz, DMSO-d ₆ ) δ: 0.84-0.90 (m, 2H), 0.94-1.02 (m, 2H), 1.04-1.11 (m, 1.7H ), 1.17-1.21(m, 1.3H), 1.71(s, 3H), 1.84-1.93(m, 1H), 2.90-3.13(m, 1 .5H), 3.36-3.46(m, 0.6H), 3.89-4.05(m, 0.5H), 4.34-4.52(m, 1H), 4.57 -4.67 (m, 0.4H), 4.89-5.02 (m, 0.4H), 5.33 (d, J=16.41Hz, 0.6H), 7.07-7, 13(m, 1H), 13.13(s, 1H) 419 417 113

(400 MHz, DMSO-d ₆ ) δ: 0.64-0.69 (m, 2H), 0.84-0.89 (m, 2H), 1.06-1.26 (m, 3H), 1.72(s, 3H), 1.84-1.91(m, 1H), 2.96-3.14(m, 1.5H), 3.38-3.51(m, 0.5H ), 3.73 (s, 3H), 3.79-3.91 (m, 0.5H), 4.29-5.38 (m, 2.5H), 6.16-6.38 (m , 1H), 7.14(s, 1H) 399 397 114

(400 MHz, DMSO-d ₆ ) δ: 0.99-1.17 (m, 7H), 1.73 (s, 3H), 3.00-5.36 (m, 6H), 7.15 ( s, 1H), 7.28(m, 1H) 410 408 115

(400 MHz, DMSO-d ₆ ) δ: 1.00-1.25 (m, 7H), 1.68-1.75 (m, 3H), 2.30-2.36 (m, 1H), 3.03-3.55(m, 2H), 4.42-5.63(m, 3H), 7.15(s, 1H) 387 445 (M-1+60) and 385 116

(400 MHz, DMSO-d ₆ ) δ: 0.46-1.68 (m, 16H), 2.33-4.49 (m, 6H), 6.58-7.20 (m, 3H), 7.66-7.75(m, 1H), 12.81(brs, 1H) 481 479 117

(400 MHz, CDCl ₃ ) δ: 1.04-1.06 (m, 4H), 1.10-1.31 (m, 3H), 1.88 (s, 3H), 1.98-2, 02 (m, 1H), 2.86-2.91 (m, 1H), 3.12-3.23 (m, 1H), 3.70-3.73 (m, 1H), 3.83 ( s, 3H), 4.37 -5.72 (m, 2H) 424 422

[0559]

[Table 1-22] Example Structure ¹ H-NMR Weight M+1 Weight M-1 118

(400 MHz, CDCl ₃ ) δ: 0.73-0.77 (m, 2H), 0.94-0.98 (m, 2H), 1.24-1.26 (m, 3H), 1, 44 (s, 3H), 1.87 (s, 3H), 3.13-3.49 (m, 2H), 3.85 (s, 3H), 4.15-5.47 (m, 3H) , 6.13(s, 1H) 413 471 (M-1+60) 119

(400 MHz, CDCl3) δ: 0.76-0.85 (m, 4H), 1.24-1.29 (m, 3H), 1.33 (s, 3H), 1.86-1.87 (m, 3H), 3.08-3.39 (m, 2H), 3.77-3.84 (m, 1H), 3.93 (s, 3H), 4.22-5.99 (m , 3H), 6.49-6.52 (m, 1H) 413 471 (M-1+60) 120

(400 MHz, DMSO-d ₆ ) δ: 0.46-0.64 (m, 3H), 1.48 (s, 3H), 1.56 (s, 3H), 1.66 (s, 3H) , 2.77-2.92 (m, 2H), 3.87-4.86 (m, 3H), 7.04 (s, 1H), 7.35 (d, J=8.40Hz, 2H) , 7.97 (d, J=8.40Hz, 2H) 465 463 121

(400 MHz, DMSO-d ₆ ) δ: 0.76-0.79 (m, 4H), 1.16 (d, J=6.94Hz, 3H), 1.73 (s, 3H), 1, 98 (ddd, J=14.28, 7.34, 4.33Hz, 1H), 3.01-5.12 (m, 5H), 3.74 (s, 3H), 7.10 (s, 1H ), 7.85(s, 1H) 399 795(2M-1) 122

(400 MHz, DMSO-d ₆ ) δ: 1.34-1.46 (m, 3H), 1.83 (s, 3H), 3.26-3.38 (m, 0.5H), 3, 64-3.77 (m, 0.5H), 3.91 (s, 3H), 4.10-4.22 (m, 0.5H), 4.60-4.75 (m, 1H), 4.85-5.06(m, 1.5H), 5.18-5.32(m, 1H), 6.93-7.02(m, 0.5H), 7.19-7.27 (m, 0.5H), 7.32 (tt, J=7.40, 1.46Hz, 1H), 7.42 (t, J=7.63Hz, 2H), 7.48 (s, 1H) , 7.80-7.86 (m, 2H) 435 433 123

(400 MHz, DMSO-d ₆ ) δ: 0.65-0.71 (m, 2H), 0.84-0.90 (m, 2H), 1.29-1.42 (m, 3H), 1.81-1.93(m, 1H), 1.84(s, 3H), 3.24-3.34(m, 0.6H), 3.57-3.70(m, 0, 5H), 3.76 (s, 3H), 4.00-4.12 (m, 0.4H), 4.55-4.70 (m, 0.9H), 4.83-4.95 ( m, 1.6H), 5.05-5.30(m, 1H), 6.18-6.50(m, 1H), 7.48(s, 1H) 399 397

[0560]

Experimental Example 1: Inhibitory effect on PDHK activity in vitro

The inhibitory effect on PDHK activity was assessed indirectly by determining the residual PDH activity after PDHK reaction in the presence of the test compound.

[0561]

(Inhibitory effect on PDHK1 activity)

In the case of human PDHK1 (hPDHK1, NCBI Reference Database Accession number NM_002610.3), a 1.3 kb fragment. (bp) encoding this protein was isolated from human liver cDNA by polymerase chain reaction (PCR). A modified hPDHK1 cDNA with a FLAG-Tag sequence added to the N-terminus was obtained by PCR and ligated to the NdeI/EcoRI site of the pET-17b vector (Merck MGaA, model number 69663-3). The recombinant construct was converted into Escherichia coli DH5((TOYOBO, model number DNA-903). Recombinant clones were identified and plasmid DNA was isolated and DNA sequence analysis was performed. One clone that had the expected nucleic acid sequence was selected for expression.

[0562]

To express hPDHK1 activity, Escherichia coli BL21(DE3) (Merck KGaA, model number 69450-4) cells were transformed with the pET17b vector containing the modified hPDHK1 cDNA. Escherichia coli were grown to an optical density of 0.6 (600 nmol/l) at 30°C. Protein expression was induced by adding 500 μmol/l isopropyl-β-thiogalactopyranoside. Escherichia coli were grown at 20°C for 17-18 hours and harvested by centrifugation.

[0563]

The harvested Escherichia coli was resuspended in suspension buffer (20 mmol/L N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid-sodium hydroxide (HEPES-NaOH), 500 mmol/L sodium chloride, 1% ethylene glycol and 0.1% polyoxyethylene-polyoxypropylene block copolymer (Pluronic F-68), cOmplete without EDTA (pH 8.0)) and destroyed with an M-110H microfluidizer (MIZUHO INDUSTRIAL CO., LTD.) or by sonication. The pellet was removed by centrifugation and the supernatant was added to a protein purification gel labeled DDDDK (MBL, model number 3329). Protein purification gel labeled with DDDDK 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 bound protein was eluted with eluting 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)).

[0564]

Eluted fractions containing FLAG protein were pooled, concentrated by ultrafiltration, loaded onto a gel filtration column (HiLoad 26/60 Superdex 200 (GE Healthcare, model number 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 pooled and stored at -80°C.

[0565]

0.025 U/mL PDH (PDH porcine heart complex, Sigma P7032) and 0.5 µg/mL hPDHK1 were mixed in assay buffer (50 mmol/L 3-morpholinopropane sulfonic 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) and the mixture was incubated at 4°C overnight to obtain a solution of the PDH complex /hPDHK1. In 0.025 U/ml assay buffer, PDH was mixed and incubated at 4° C. overnight to prepare a PDH solution.

[0566]

Test compounds were diluted with dimethyl sulfoxide (DMSO). To determine the inhibitory effect of a test compound on PDHK activity in PDH/hPDHK1 complex solution, PDH/hPDHK1 complex solution (20 µl), test compound (1.5 µl) and 0.353 µmol/L ATP (diluted in assay buffer) (8, 5 µl) were placed in a 384-well microplate (Greiner Bio-One 781801) and the PDHK reaction was carried out at room temperature for 45 min (test compound well). DMSO (1.5 μl) was added to control wells in place of test compound. In addition, DMSO (1.5 μl) was added to blank wells in place of test compound and PDH solution was added in place of PDH/hPDHK1 complex solution. To determine the inhibitory effect of the test compound on the activity of PDHK contained in the PDH solution, the test compound was added and the PDH solution instead of the PDH/hPDHK1 complex solution was added to the blank well+well with the test compound.

[0567]

Then 10 µl of substrates (5 mmol/l sodium pyruvate, 5 mmol/l coenzyme A, 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 determined.

[0568]

The absorbance for each well at 340 nm was measured with a microplate reader to detect NADH generated by the PDH reaction. PDH activity in each well was calculated from changes in absorbance before and after the PDH reaction. The PDH activity of the test compound treated sample was calculated using the formula {PDH activity for test compound well - (PDH activity for blank well+test compound well - PDH activity for blank well)}. The degree of inhibition of hPDHK1 (%) by the test compound was calculated by the formula wells)}×100]. The IC ₅₀ value was calculated by the method of logistic regression based on the concentration of the test compound and the degree of hPDHK1 inhibition (%).

[0569]

(Inhibitory effect on PDHK2 activity)

In the case of human PDHK2 (hPDHK2, NCBI Reference Database Accession number NM_002611.4), a modified hPDHK2 cDNA where the FLAG-Tag sequence is added to the N-terminus of the hPDHK2 cDNA clone (pReceiver-M01/PDK2-GeneCopoeia) as a backbone was obtained by PCR and ligated to the NdeI/EcoRI site of the pET-17b vector. The recombinant construct was converted into Escherichia coli DH5α. Recombinant clones were identified and plasmid DNA was isolated and DNA sequence analysis was performed. One clone that had the expected nucleic acid sequence was chosen for expression.

[0570]

To express hPDHK2 activity, Escherichia coli BL21(DE3) cells were transformed with the pET17b vector containing the modified hPDHK2 cDNA. Escherichia coli were grown to an optical density of 0.6 (600 nmol/l) at 30°C. Protein expression was induced by adding 500 μmol/l isopropyl-β-thiogalactopyranoside. Escherichia coli were grown at 20°C for 17-18 hours and harvested by centrifugation. Harvested Escherichia coli was resuspended in resuspension buffer (20 mmol/L HEPES-NaOH, 500 mmol/L sodium chloride, 1% ethylene glycol, 0.1% pluronic F-68 (pH 8.0), cOmplete, no EDTA (pH 8.0)) and destroyed with a microfluidizer. The precipitate was removed by centrifugation and the supernatant was added to the protein purification gel labeled DDDDK. Protein purification gel labeled with DDDDK 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 bound protein was eluted with eluting buffer 1 (20 mmol/l HEPES-NaOH, 100 μg/ml peptide (amino acid sequence DYKDDDDK) (SEQ ID NO: 1) 500 mmol/l sodium chloride, 1% ethylene glycol, 0.1% pluronic F-68 (pH 8 ,0)). The eluted fractions containing the FLAG tagged protein were pooled, concentrated by ultrafiltration, loaded onto a gel filtration column (HiLoad 26/60 Superdex 200), 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 pooled and stored at -80°C.

[0571]

0.025 U/mL PDH and 0.5 µg/mL hPDHK2 were mixed in assay buffer (50 mmol/L 3-morpholinopropane sulfonic 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) and the mixture was incubated at 4°C overnight and received a solution of the PDH/hPDHK2 complex. In 0.025 U/ml assay buffer, PDH was mixed and incubated at 4° C. overnight to prepare a PDH solution.

Test compounds were diluted with DMSO. To determine the inhibitory effect of a test compound on PDHK activity in PDH/hPDHK2 complex solution, PDH/hPDHK2 complex solution (20 µl), test compound (1.5 µl) and 1.06 µmol/L ATP (diluted in assay buffer) ( 8.5 µl) were placed in a 384-well microplate and the PDHK reaction was carried out at room temperature for 45 min (test compound well). DMSO (1.5 μl) was added to control wells in place of test compound. In addition, DMSO (1.5 μl) was added to blank wells in place of the test compound of the complex, and PDH solution was added in place of PDH/hPDHK2 solution. To determine the inhibitory effect of the test compound on the activity of PDHK contained in the PDH solution, the test compound was added and the PDH solution instead of the PDH/hPDHK2 complex solution was added to the blank well+well with the test compound.

[0572]

Then 10 µl of substrates (5 mmol/l sodium pyruvate, 5 mmol/l coenzyme A, 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 determined.

[0573]

The absorbance for each well at 340 nm was measured with a microplate reader to detect NADH generated by the PDH reaction. PDH activity in each well was calculated from changes in absorbance before and after the PDH reaction. The PDH activity of the test compound treated sample was calculated using the formula {PDH activity for test compound well - (PDH activity for blank well+test compound well - PDH activity for blank well)}. The degree of hPDHK2 inhibition (%) by the test compound was calculated by the formula wells)}×100]. The IC ₅₀ value was calculated by the method of logistic regression based on the concentration of the test compound and the degree of hPDHK2 inhibition (%).

The results are shown in the following tables. If the IC ₅₀ value could not be calculated, then the degree of inhibition at the lowest concentration of the test compound used for the analysis is given. For example, the compound of example 5 had equal to 55% inhibition of hPDHK1 at a concentration of 3 nmol/L.

[0574]

[Table 2-1] Example No. hPDHK1 IC ₅₀ (nmol/l) hPDHK2 IC ₅₀ (nmol/l) 1 6 5 2 12 15 3 16 14 4 4 5 5 <3 (55%) 5 6 eleven eleven 7 8 10 8 49 34 9 7 eleven 10 9 13 eleven 14 15 12 8 10 13 29 36 14 <3 (68%) <3 (57%) 15 3 5 16 6 7 17 8 7 18 7 7 19 5 <3 (67%) 20 8 12 21 13 12 22 6 8 23 6 12 24 42 36 25 7 14 26 9 14 27 9 8 28 12 10 29 7 7 thirty 20 13

[0575]

[Table 2-2] Example No. hPDHK1 IC ₅₀ (nmol/l) hPDHK2 IC ₅₀ (nmol/l) 31 9 eleven 32 13 10 33 12 16 34 10 13 35 3 4 36 4 5 37 3 8 38 <3 (73%) 4 39 46 18 40 5 6 41 6 6 42 4 5 43 <3 (52%) 5 44 5 7 45 9 8 46 5 5 47 <3 (53%) 4 48 <3 (88%) <3 (81%) 49 3 3 50 4 5 51 4 6 52 4 6 53 4 8 54 <3 (53%) 5 55 <3 (54%) 4 56 10 10 57 eleven 10 58 3 4 59 4 3 60 14 9

[0576]

[Table 2-3] Example No. hPDHK1 IC ₅₀ (nmol/L) hPDHK2 IC ₅₀ (nmol/l) 61 3 5 62 3 4 63 5 7 64 5 7 65 4 5 66 4 6 67 5 7 68 4 6 69 5 8 70 3 6 71 4 7 72 7 9 73 6 7 74 6 eleven 75 6 eleven 76 6 9 77 6 9 78 4 7 79 5 8 80 3 6 81 5 7 82 5 7 83 5 eleven 84 5 eleven 85 <3 (49%) 6 86 <3 (52%) 4 87 <3 (66%) <3 (53%) 88 3 4 89 20 19 90 66 45

[0577]

[Table 2-4] Example No. hPDHK1 IC ₅₀ (nmol/L) hPDHK2 IC ₅₀ (nmol/l) 91 49 28 92 27 23 93 8 eleven 94 40 24 95 6 15 96 8 8 97 63 26 98 6 6 99 8 12 100 4 5 101 <3 (69%) 4 102 4 4 103 <3 (67%) <3 (66%) 104 4 6 105 9 8 106 <3 (61%) 4 107 5 6 108 5 6 109 <3 (53%) 5 110 7 13 111 3 6 112 3 5 113 4 5 114 5 7 115 6 8 116 17 32 117 6 8 118 4 4 119 4 5 120 5 9 121 5 5 122 5 7 123 6 12

[0578]

As an example of the preparation proposed in the present invention, the following preparations can be mentioned. However, the present invention is not limited to these formulation examples.

[0579]

Formulation Example 1: Capsule Preparation

1) connection of example 1 30 mg 2) microcrystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg

1), 2), 3) and 4) are mixed and placed in a gelatin capsule.

[0580]

Formulation Example 2: Tablet Preparation

1) connection of example 1 10 g 2) lactose 50 g 3) cornstarch 15 g 4) calcium salt of carmellose 44 g 5) magnesium stearate 1 g

The total amount of 1), 2), 3) and 30 g of 4) is mixed with water, dried in vacuum and sieved. In this way, 1000 tablets are obtained, each containing 10 mg of the compound of example 1 per tablet.

[0581]

Formulation Example 3: Preparation of a Formulation for Injection

1) connection of example 1 5 mg 2) D-mannitol 5 g 3) distilled water 100 ml

1) and 2) Dissolve in 3) and the solution is placed in an injection container, sealed and sterilized.

Industrial Application

[0582]

Since the compound of formula [I-a] or formula [11] or a pharmaceutically acceptable salt thereof has PDHK inhibitory activity, it is useful as an active ingredient of a medicament for the treatment or prevention of diabetes (type 1 diabetes, type 2 diabetes, etc.). ), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataracts, etc.), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, ischemia myocardial infarction, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, pulmonary hypertension, or Alzheimer's disease.

Claims (101)

1. A compound of formula [I-a] or formula [II] or a pharmaceutically acceptable salt thereof:

, where the bond in the form of a dotted line means a single bond or a double bond, X ¹ means a carbon atom, a nitrogen atom or an oxygen atom, X ² means a carbon atom or a nitrogen atom, R ^1a means C _1-4 alkyl or C _1-4 alkylcarbonyl, R ² means halogen, cyano or C _1-4 alkyl, m is 0 or 1, n is 0, 1 or 2, if n is 2, all R ² are the same or different, A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , and A ⁷ , are all independently selected from a group that includes an atom of carbon, a nitrogen atom and an oxygen atom, A ⁸ is selected from a group that includes a carbon and a nitrogen atom, and an atom of nitrogen, and an atom of nitrogen A full amount of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment

, is 0, 1, 2 or 3, t is 0 or 1, r is 0, 1 or 2 and the sum of t and r is 1 or 2, w is 0 or 1, R ³ and R ⁴ are all independently hydrogen or C _1-4 alkyl, Cy ¹ means (1) (I) C _4-6 Cyclicl or (II) 4-6-member saturated or partially saturated heterocyclic, containing one nitrogen atom, C _4-6 cycloilkils and saturated or partially saturated heterocylille is not necessarily replaced by one deputy, independently selected from a group containing C _1-4 alkyl and an oxo group, or (2) (I) phenyl or (II) 5- or 6-member heteroaril containing 1, 2 or 3 heterotoma, independently selected from a group, including an atom of nitrogen and oxygen atom, phenyl and heteroaril are not necessarily replaced by 1 or 2 deputies, independently selected from the group, including halogen, cyanogroup, carboxygoup, C _1-4 alkyl, halogen-C _1-4 alkyl and C _3-6 cycloalkil, Cy ² means (1) (I) C _3-6 Cyclicl or (II) 4-6-member saturated heterocyclic, containing 1 or 2 heterotoma, independently selected from the group, including the nitrogen and oxygen atom, and C _3-6 cycliclles and saturated heterocyllles It is not necessarily replaced by 1 or 2 deputies, independently selected from the group, including halogen, hydroxygoup and C _1-4 alkyl, or (2) (I) Phoenil or (II) 5- or 6-member heteroaril containing 1, 2, 3 or 4 atom of nitrogen, and phenyl and heteroaril are not necessarily replaced by 1 or 2 deputies, independently selected from the group including halogen, cyano group , C _1-4 alkyl, C _1-4 alkoxy and C _1-4 alkylsulfonyl, and v is 0 or 1. 2. The connection according to clause 1, where x ¹ means an atom of carbon and X ² means an atom of nitrogen, or its pharmaceutically acceptable salt. 3. The compound according to claim 1 or 2, where in the formula [I-a] the total number of nitrogen atoms and oxygen atoms contained in the structural formula of the fragment

, where each symbol is as defined in claim 1, equals 2, or a pharmaceutically acceptable salt thereof. 4. The connection according to any one of paragraphs. 1-3, which is a compound of formula [I-b]

, where each symbol is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1 wherein v is 0 or a pharmaceutically acceptable salt thereof. 6. Connection according to paragraph 1 or 5, where CY ¹ means 5- or 6-member heteroaril containing 1, 2 or 3 heterotoma, independently selected from the group, including an atom of nitrogen and oxygen atom, and heteroaril is not necessarily discaired by 1 or 2 deputies , independently selected from the group, including halogen, cyanogroup, C _1-4 alkyl, halogen-C _1-4 alkyl and C _3-6 cyclicl, or its pharmaceutically acceptable salt. 7. Connection according to any one of paragraphs. 1, 5 and 6, where Cy ² means (1) C _3-6 cycloal, not necessarily replaced by 1 or 2 deputies, independently selected from the group, including halogen, hydroxygoup and C _1-4 alkyl, or (2) The phenyl, not necessarily replaced by 1 or 2 deputies, independently selected from the group, including halogen, cyanogroup, C _1-4 alkyl, C _1-4 alcohoxygroup and C _1-4 alkyphonilla, or its pharmaceutically acceptable salt. 8. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 9. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 10. The compound represented by the formula

. 11. The compound represented by the formula

. 12. The compound represented by the formula

. 13. The compound represented by the formula

. 14. The compound represented by the formula

. 15. The compound represented by the formula

. 16. The compound represented by the formula

. 17. The compound represented by the formula

. 18. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 19. The compound represented by the formula

. 20. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 21. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 22. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 23. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 24. The compound represented by the formula

. 25. The compound represented by the formula

, or a pharmaceutically acceptable salt thereof. 26. Pharmaceutical composition having an inhibitory effect on the activity of PDHK1 and 2, containing an effective amount of the compound according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 27. A means for the treatment of diseases associated with inhibitory effects on the activity of PDHK1 and 2 , selected from diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications in diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial and myocardial infarction, angina praise, angina praise, angina praise, angina praise, angina praise, angina praise, and angina praise, and angina praise, anginaocardium dyslipidemia, atherosclerosis, peripheral artery diseases, intermittent chromium, chronic obstructive disease, brain ischemia, brain apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer or pulmonary hypertension, containing a compound according to any of the paragraphs. 1-25 or a pharmaceutically acceptable salt thereof. 28. The agent of claim 27 wherein the diabetes is type 1 diabetes or type 2 diabetes. 29. The agent of claim 27 wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract. 30. The agent of claim 27 wherein the heart failure is acute heart failure or chronic heart failure. 31. The agent of claim 27, wherein the pulmonary hypertension is pulmonary arterial hypertension. 32. A method for treating diseases associated with an inhibitory effect on the activity of PDHK1 and 2 selected from the group including diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, complications of diabetes, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension, the method includes administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof. 33. The method of claim 32 wherein the diabetes is type 1 diabetes or type 2 diabetes. 34. The method of claim 32, wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, and cataract. 35. The method of claim 32 wherein the heart failure is acute heart failure or chronic heart failure. 36. The method of claim 20, wherein the pulmonary hypertension is pulmonary arterial hypertension. 37. The use of a compound according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof for the preparation of an agent for treating diseases associated with an inhibitory effect on PDHK1 activity and 2 selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, a complication of diabetes, heart failure , cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension. 38. Use according to claim 37, wherein the diabetes is type 1 diabetes or type 2 diabetes. 39. Use according to claim 37 wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract. 40. Use according to claim 37, wherein the heart failure is acute heart failure or chronic heart failure. 41. Use according to claim 37 wherein pulmonary hypertension is pulmonary arterial hypertension. 42. Connection according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases associated with an inhibitory effect on PDHK1 and 2 activity selected from the group consisting of diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidemia, diabetic complication, cardiac failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, cerebral apoplexy, mitochondrial disease, mitochondrial encephalopathy, cancer, and pulmonary hypertension. 43. The compound or pharmaceutically acceptable salt thereof according to claim 42, wherein the diabetes is type 1 diabetes or type 2 diabetes. 44. The compound or pharmaceutically acceptable salt thereof according to claim 42, wherein the diabetic complication is selected from the group consisting of diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and cataract. 45. A compound or pharmaceutically acceptable salt thereof according to claim 42, wherein the heart failure is acute heart failure or chronic heart failure. 46. The compound or pharmaceutically acceptable salt thereof according to claim 42, wherein the pulmonary hypertension is pulmonary arterial hypertension.