SA515361182B1 - Pyrazole-amide compound and medicinal uses therefor - Google Patents

Abstract

A compound represented by the following formula: wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof.

Description

1 Pyrazole-amide compound and its medicinal uses

Pyrazole-amide compound and medicinal uses therefor Full description Background of the invention and a medical use thereof. More specifically, a pyrazole-amide compound (Jad) The invention provides a specification The present invention relates to a pyrazole-amide compound or a pharmaceutically acceptable salt thereof that has inhibitory activity following LAD (which will be abbreviated as dehydrogenase kinase) contains pyruvate dehydrogenase kinase; a pharmaceutical composition containing it; a preventive or therapeutic agent containing it for diabetes (PDHK 0 resistance, etc.); type 10 resistance syndrome 1; type 1 diabetes; hypertensive disease metabolic syndrome; metabolic syndrome; insulin syndrome; hyperlactacidemia; hyperlactacidemia; hyperglycemia; diabetic neuropathy; diabetic complications; complications of diabetes; diabetic nephropathy. diabetic retinopathy neuropathy 0 cardiac failure etc.); heart failure cataract diabetic nephropathy chronic cardiac acute cardiac failure myocardial ; cardiomyopathy chest myocardial infarction ischemia; atherosclerosis; Atherosclerosis dyslipidemia 0 intermittent | ; intermittent claudication peripheral arterial disease “chronic obstructive pulmonary disease”; chronic obstructive rheumatic disease claudication; mitochondrial diseases cerebral apoplexy stroke « brain ischemia mitochondrial encephalopathy » mitochondrial disease pulmonary; pulmonary hypertension; cancer encephalomyopathy 0; And the like. Alzheimer disease ull or “hypertension H1”.

a in (dal) reactions using energy Jie biosynthesis, transport dail) muscle contraction and the like; Energy is provided by the breakdown of adenosine triphosphate (ATP) ATP is produced by the oxidation of a metabolic fuel that produces a lot of energy; Such as glucose 9116056 and free fatty acids. in oxidative tissues.<idl Jie 0 muscle; ATP is produced mostly from the acetyl-Jay, CoA- acetyl ring of citric acid. Acetyl-/60 is produced by oxidation of glucose via either the sugar-free pathway or the B-type oxidation of free fatty acids. The enzyme that plays a central role in controlling the production of acetyl-060 from glucose is pyruvate dehydrogenase (abbreviated here as PDH). PDH 0 catalyzes the reductase of nicotinamide adenine dinucleotide dinucleotide (NAD) to NADH in conjunction with the oxidation of pyruvic acid to acetyl-CoA and carbon dioxide (Jb) non-patent documents 0; PDH is a multi-enzyme complex enabled by three enzymatic components (ET)2p (E35) and some Vo subunits present in the estimator matrix. 1]; E2 and 3 are responsible for the decarboxylation of pyruvic acid pyruvic acid, production of acetyl-0/8©, and reduction of NAD to “NADH”, respectively. It has selectivity towards PDH and its role is to inhibit the Ela subunit of complex 0 by phosphorylation. Through the interaction of dephosphorylation of the subunit (Ela), the proportion of PDH in its active state (phosphorus-depleted Leia) is determined by the balance of kinase activity and phosphatase activity. The kinase activity is regulated By the relative concentration of lie Metabolic substrates, Yo activates the kinase activity by increasing the ratios of NADH/NAD; Acetyl CoA/CoA- and 1 2 // adenosine 1e

Meh gla diphosphate (ADP) 806005106; The inhibition is done by pyruvic acid (eg; non-patent document?). in the tissues of mammalian organisms; is defined; Types of enzyme isotypes 0011. Specifically, PDHK2 is expressed in a wide range of tissues including liver, skeletal muscles, and adipose tissues involved in glucose metabolism. In addition to the cell where PDHK2 (gay high sensitivity to NADH/NAD daily activation or excess acetyl-CoA/CoA- and inhibition by pyruvate; implication in a low sAD regulation) of glucose metabolism is proposed ( Je) a document that is not a patent 4). Furthermore it; 00011161 is highly expressed in cardiac muscle, skeletal muscle0, pancreatic B cells, and the like. Furthermore it; where expression of 1011161 is induced by activation of hypoxia inducible factor (HIF)1 in a brain state; It is proposed to include them in ischemic diseases and cancerous diseases (eg non-patent document #). in diseases such as insulin-dependent diabetes (type 1); non-insulin-dependent diabetes 1 (type 7) and the like; Fat oxidation is accomplished by a simultaneous reduction in glucose utilization. This underutilization of glucose is one of the factors that cause hyperglycemia. When oxidative glucose metabolism is reduced in type 1 diabetes mellitus? obesity; PDH activity also decreases. It proposes inclusion of reduced PDH activity in reduced glucose utilization in type yo diabetes (eg non-patent documents 36 .1 0 to the contrary; Hepatic gluconeogenesis is enhanced in type 1 diabetes, which is also one of the factors causing hyperglycemia. reduced PDH activity day by decreasing the concentration of pyruvic acid; which in turn increases the availability of lactic acid as a substrate for gluconeogenesis in the liver. It indicates the possible implication of reduced PDH activity in enhanced gluconeogenesis in type 1 and 7 diabetes (eg; non-patent documents cA 9). When PDH is activated by inhibition

(PDHK) glucose oxidation is considered to be elevated. As a result; glucose utilization in the body is improved and gluconeogenesis in the liver is suppressed; thus development of hyperglycemia is expected in type 1 diabetes and? JE) Documentation Not patented.) 1” 1 001 Another factor leading to diabetes is impaired insulin secretion; known to be associated with reduced PDH activity © in pancreatic f cells [(¢ cells) and entry 1 1011161 f; (eg; non-patent documents (VE OT) Furthermore, persistent hyperglycemia due to diabetes is known to lead to complications Jie Diabetic neuropathy; Diabetic retinopathy; Diabetic nephropathy and the like. Thiamine and acid contribute Lipoic acid -lipoic acid a- has been shown to be involved in the activation of PDH as coenzymes Thiamine and lipoic acid -0 OR 0 derivatives of thiamine and om lipoic acid derivatives have been shown to have a promising effect on the treatment of diabetes complications. Thus, activation of PDH is expected to promote the development of complications of diabetes (eg; Documents List

Patents 11 Vo.) in ischemic conditions; The limited supply of oxygen reduces the oxidation of both glucose and fatty acid and reduces the amount of ATP produced by oxidized saul in tissues. in the absence of sufficient oxygen; 1 ATP levels are maintained by enhanced anaerobic glycolysis. as a result; Lactic acid increases and intracellular pH decreases. However, the body tries to maintain ion balance by expending energy; Normally low ATP level and disturbed cellular osmolarity lead to cell death. Furthermore it; adenosine monophosphate--activating kinase; The activator during lay) “phosphorylates and thus inhibits 0-acetyl carboxylase CoA-0/8-A/80617. Melanoyl levels -/60) in tissue are reduced; Thus, carnitine palmitoyltransferase activity is increased—and fatty acid oxidation is favored over glucose oxidation by allowing acyl-CoA-transfer into mitochondria. The oxidation of glucose is capable of producing more 8075 per oxygen molecule than the oxidation of fatty acids can do. In conditions of poverty, therefore; when it becomes too

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Energy controlled glucose oxidation by PDH activation can be considered to be the ability to conserve energy

at ATP level as optimized (Jie) Non-patent document (VY

Furthermore it; PDH activation results in the oxidation of the resulting pyruvic acid by glycolysis

glucose; and reduce lactic acid production; The net proton load is considered to be

was reduced in ischemic tissues. Thus, activation of PDH by inhibition of PDHK is expected to be

It works preventively in brain diseases, Jie lack of heart muscle, cardiac muscle ischemia

(Example; documents that are not OA patents ?91).

A drug that activates PDH by inhibiting PDHK is considered to decrease lactate production

Cua lactate improves pyruvate metabolism thus; This drug will be 0 useful in the treatment of hyperlactic acid in the blood Jie mitochondrial diseases; Encephalopathy

mitochondrial muscle and sepsis (example; non-patent document 01).

in WDA cancer; Express over 0011161 or . in cancer cells; Furthermore it; less

ATP production by phosphorylation 016108176 in mitochondria”; and increases production

ATP via anaerobic hydrolysis in cytoplasm 07710018507. Activation of PDH by Yo inhibition of PDHK is expected to enhance oxidative phosphorylation in mitochondria; It increases active oxygen production

PDH thus “activates .cancer cells, which will stimulate the programmed killing of cancer cells.” OXygen

By inhibiting PDHK it is useful in treating cancerous diseases dul ull (eg;

Document that is not patented (YY).

Pulmonary hypertension is characterized by high blood pressure ail 0 6 by the spatial narrowing of the pulmonary artery Partial narrowing of the

pulmonary artery due to enhanced cell proliferation. in hypertension

catarrhal Subsequently; It is expected that PDH will activate the pulmonary artery cell

by enhancing oxidative phosphorylation in mitochondria; increases active oxygen production »; It stimulates programmed cell killing

E1

—y— so that PDHK is beneficial by inhibiting PDH activation of the pulmonary artery. Subsequently; YY is considered for the treatment of rheumatic hypertension (eg; non-patent document) Energy production and glucose metabolism in the brain are reduced in Alzheimer's disease; Use of acetylation (PDH) when PDH activity is diminished

CoA is also acetylated .01010 acid in the electron transport system across the citric acid ring ATP © transponders saa); which is acetylcholine is a precursor to reduced cerebral acetylcholine synthesis in PDH thus; Furthermore, the activity of neurotransmitters is considered; JATP deficiency will be caused by WAN Alzheimer's disease as causing neuronal death; The cholinergic nerve may be involved in the synthesis of acetylcholine; PDH, which is the transmitter of the cholinergic nerve in the brain to improve energy production, is inhibited to trigger memory decline and the like. Activation of 0 by inhibition of PDH and acetylcholine synthesis is predicted in Alzheimer's disease. Subsequently; Activation (YE YY non-patent documents (JB) is considered to be useful for the treatment of Alzheimer's disease PDHK; which is a drug dichloroacetic acid It has been shown that myocardial dichloroacetic acid gives one effect for the treatment of Diabetes myocardial ischemia (PDH) effect includes stimulation of “angina pectoris” myocardial infarction “ischemia Vo” hyperlactacidemia; hyperlactic acid disease in the blood cardiac failure heart failure; arterial blockage cerebral apoplexy stroke brain ischemia chronic obstructive chronic obstructive pulmonary disease progressive peripheral arterial disease and hypertension cancerous disease pulmonary disease

YY Mk T YY 0 Non-patent documents (JB) Pulmonary 0 have been shown to be useful for the prevention or treatment of diseases related to PDHK of previous findings; considered to be associated with a glucose utilization disorder; for example; diabetes (type 1 diabetes; type 1 diabetes? etc.); insulin resistance syndrome; metabolic syndrome; hyperglycemia; Hyperlactic acid disease Complications of diabetes (diabetic neuropathy; diabetic retinopathy; diabetic nephropathy (all in PDHK; diabetic nephropathy; cataracts etc.). Yo e1

A —_ _ prevention or treatment of diseases caused by the limited supply of energy substrate to tissues; for example; heart failure (acute failure of the heart ¢ gad t chronic heart) ' Died myocardium (ca lal muscle ischemia) myocardial infarction; angina; high blood fats; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive rheumatoid disease; Cerebral ischemia and stroke. © hence; A PDHK inhibitor is considered to be useful for the treatment or prevention of diabetes (type 0 diabetes, type 7 diabetes, etc.); insulin resistance syndrome; metabolic syndrome; hyperglycemia ¢ hyperlactic acid disease; Complications of diabetes (diabetic neuropathy; diabetic retinopathy » Diet kidney diabetes cataracts etc. (heart failure (acute heart failure 3 chronic heart failure) 3 cardiomyopathy; myocardial ischemia 3 myocardial infarction; diphtheria A pectoris; hyperlipidemia; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease; cerebral ischemia; stroke; mitochondrial diseases; mitochondrial encephalopathy; cancer; rheumatic hypertension or Alzheimer's disease. Non-patents Reed LJ, Hackert ML Structure-function 1 : non-patent trust 1 relationships in dihydrolipoamide acyltransferases J Biol Chem 1990 Jun 5;265(16):8971-4.

Patel MS, Roche TE. Molecular biology and Y non-patent document: biochemistry of pyruvate dehydrogenase complexes. FASEB J. 1990 Nov; 4(14):3224-33. 0

Sugden MC, Holness MJ. Recent advances in Non-Patent Document?: mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab. 2003

May; 284(5): E855-62. e1

_q —_

Bowker—Kinley MM, Davis WI, Wu P, Harris RA, Non-Patent Document:

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.

Kim JW, Tchernyshev I, Semenza GL, Dang CV. :0 is not a patent dai, ©

HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006 March; 3(3):177-85.

Morino K, Petersen KF, Dufour S, Befroy, NA Frattini Non-patent document D:

J, Shatzkes N, et al. Reduced mitochondrial density and increased IRS-1 00 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005 Dec; 115(12):3587-93.

Caterson ID, Fuller SJ, Randle PJ. Effect of the fatty: 1 Non-patent document, acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in starved and alloxan -diabetic rats. Yo

Biochem J. 1982 Oct 15; 208(1):53-60.

Boden G, Chen X, Stein TP. Non-patent document A: Gluconeogenesis 10 moderately and severely hyperglycemic patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2001 Jan; 280(1):E23-30.

Shangraw RE, Fisher DM. Pharmacokinetics and Non-Patent Document 4:0 Pharmacodynamics of dichloroacetate in patients with cirrhosis.Clin

Pharmacol Ther. 1999 Oct; 66(4):380-90. E1

-1 “=

Stacpoole PW, Moore GW, Kornhauser DM. 01: A document that is not a patent

Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. N Engl J Med. 1978 Mar 9; 298(10):526-30.

Mayers RM, Leighton B, Kilgour E. PDH kinase 11: non-patent 488 inhibitors: a novel therapy for Type 11 diabetes? Biochem Soc Trans. 2005 ©

Apr; 33 (Pt 2): 367-70.

Jeoung NH, Rahimi Y, Wu P, Lee WN, Harris RA. :\Y Document is not a patent

Fasting induces ketoacidosis and hypothermia in PDHK2 /PDHK4-double- knockout mice. Biochem J. 2012 May 1; 443(3):829-39.

Zhou YP, Berggren PO, Grill V. A fatty acid—non-patent document: 11:0 induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse.

Diabetes. 1996 May; 45(5):580-6.

Xu J, Han J, Epstein PN, Liu YQ. Regulation of 16: Non-patent documents

PDK mRNA by high fatty acid and glucose in pancreatic islets. Biochem\o

Biophys Res Commune. 2006 Jun 9; 344(3):827-33.

Benfotiamine. Monograph. Alternate Med Rev. 2006: 11 document that is not a patent

Sep; 11(3):238-42.

Vallianou N, Evangelopoulos A, Koutalas P. V7 Non-patent document

Alpha lipoic acid and diabetic neuropathy. Rev Diabetes Stud. 2009 Winter; 06(4):230-6. E1

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Ussher JR, Lopaschuk GD. The malonyl CoA axis: VV non-patent document as a potential target for treating ischaemic heart disease. Cardiovasc Res. 2008 Jul 15; 79(2):259-68.

Wargovich TJ, MacDonald RG, Hill JA, Feldman YA: Non-patent document

RL, Stacpoole PW, Pepine CJ. Myocardial metabolic and hemodynamic© effects of dichloroacetate in coronary artery disease. Am J Cardiol. 1988

Jan 1; 61(1):65-70.

Taniguchi M, Wilson C, Hunter CA, Pehowich DJ, %4: Non-patent document

Clanachan AS, Lopaschuk GD. Dichloroacetate improves cardiac ischemia independent of changes in mitochondrial proton efficiency 0 leak. Am J Physiol Heart Circ Physiol. 2001 Apr; 280(4):H1762-9.

Stacpoole PW, Nagaraja NV, Hutson AD. Efficiency:¥. Not Patented 488 of dichloroacetate as a lactate—lowering drug. J Clin Pharmacol. 2003 Jul; 43(7):683-91.

Bonnet 5, Archer SL, Allalunis—Turner J, Haromy: ¥ A trust is not a patent 0

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.

McMurtry MS, Bonnet 5, Wu X, Dyck JR, Haromy : 7 Non-Patent Document

A, Hashimoto, Ka et al. Dichloroacetate prevents and reverses pulmonary 0 hypertension by inducing pulmonary artery smooth muscle cell apoptosis.

Circ Res. 2004 Oct 15; 95(8):830-40. E1

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

Stacpoole PW. The pyruvate dehydrogenase: Yf document is not a patent complex as a therapeutic target for age-related diseases. Aging Cell. © 2012 Jun; 11(3):371-7.

Non-patent document: Marangos PJ, Turkel CC, Dziewanowska ZE, Fox

AW. Dichloroacetate and cerebral ischemia therapeutics. Expert Opin

Investig Drugs. 1999 Apr; 8(4):373-82.

Calvert LD, Shelley R, Singh SJ, Greenhaff PL, Non-patent document 0

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.

Flavin DF. Non-Hodgkin's Lymphoma Reversal: YV Vo with Dichloroacetate. J Oncol. Hindawi Publishing Corporation Journal of

Oncology, Volume 2010, Article ID 414726, 4 pages doi: 10.1155/2010/414726. General Description of the Invention Ye The present invention is as follows. [1] A compound represented by the formula [1 CER!

HOE. US

co,

HG M_ a Py

Heo 8 for HG pa SY

Np Ak © NA x7

RE foxton

Fk 1 lla al or 1 is ro (Ala or pharmaceutically acceptable salt) compound represented by the formula: [Y] lo } lo}

H.C

Hye Ay 3 Hy Uncle N H.C N 3 1 Yg 3 1 “N

H,C OH : Hic OH we Lr 3 3

ALS

Foy Fo: H,0

A" OH 7 c oH 2

FF F

(ny e (taa) 1] represented by the formula ([V] [?] compound according to the above oO 1

HO LH

PUTA,

HG p 1 <n

WH

He PH;

HC A | FEN, Fa A: 0 A oA NS

Fol

A OH

Fr0

_— ¢ \ _ [£] [VY] compound represented by the formula [Ih] 1 Lv AN H, xT TNH HC | H N p « oo (Wi ne, PH J FN din ie Api HG M 0 Nga, i Pay Las Foo OH «HOD 232 FL EB {lih} [©] Compound represented by the formula IN] 3 HC BN SS NH, HE ON N 1 Wo HC - / J Hey NENT = HO ote.

FN uz Nm Me Nea Fo A oH F {ly 3[ 0 [1] A pharmaceutical composition includes the compound according to any of the above [1] to [0] or an acceptable salt Pharmaceutical Acceptable Terminator and Carrier [V] Associated PDHK includes the compound according to any of the above [1] to [*]; or a pharmaceutically acceptable salt of which [A] 0014/41 includes the compound in accordance with any of the foregoing [1] to [*]; Or a pharmaceutically acceptable salt, 10 of which is FRE

C \ — [4] PDHK2 inhibitor Including the compound in accordance with any of the above [1] to [0] or a pharmaceutically acceptable salt thereof [01] Hypoglycemic agent Including the compound in accordance with any of the above [1] to [*]; or a pharmaceutically acceptable salt of which ¢ [VV] 0 lactic acid-lowering agent includes the compound according to any of the foregoing [1] to [*]; or a pharmaceutically acceptable salt of which 3 [VY] are agents for the prevention or treatment of diabetes; insulin resistance syndrome; metabolic syndrome; Hyperglycemia Uae Excessive lactic acid in the blood » Complications of diabetes Heart failure Died heart muscle 3 Myocardial ischemia 3 Myocardial infarction; angina; high blood fats; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease”; ischemia of leal stroke; mitochondrial diseases; mitochondrial encephalopathy, cancer or rheumatic hypertension; which includes the compound according to any of the foregoing [1] to [*]; or a pharmaceutically acceptable salt of which ¢ [VY] is an agent for the prevention or treatment of diabetes; insulin resistance syndrome; metabolic syndrome; Yo disease Hyperglycemia Uae Hyperlactic acidemia ¢ Complications of diabetes Heart failure; Died cla muscle) myocardial ischemia; myocardial infarction; angina; la) p lipids in the blood; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive rheumatoid disease 3 cerebral ischemia; brain attack; mitochondrial diseases; mitochondrial encephalopathy; cancer; rheumatic hypertensive pallidum or Alzheimer's disease; which includes the compound according to any of the foregoing [1] to [*]; Yo or a pharmaceutically acceptable salt terminated [VY] the preventive or curative agent according to the above [VY] where diabetes is type 1 diabetes or type 1 diabetes for CARY

[0] The preventive or curative factor according to the above [VY] where the complications of diabetes are selected

From the group consisting of diabetic neuropathy “diabetic retinopathy” Died kidney

diabetic cataracts;

[V0] the preventive or curative factor according to the above [VY] where heart failure 5a is acute heart failure

or chronic heart failure;

[11] Pharmaceutical composition includes

(a) compound according to any of the foregoing [1] to [*]; or a pharmaceutically acceptable salt of the terminator

(b) At least one AT treatment is effective for preventing or treating a disease selected from the group

Consists of Diabetes mellitus (Type 3 Diabetes mellitus Type AF ( Insulin Resistance Syndrome) >00 Metabolic Syndrome 0 Hyperglycemia; hyperlactic acid disease in pall Complications

Diabetes (diabetic neuropathy » diabetic retinopathy » diabetic nephropathy cataracts

eye) heart failure (acute heart failure ¢ chronic heart failure) call myopathy

myocardial ischemia; myocardial infarction; angina; high blood fats; atherosclerosis;

progressive arterial occlusion; intermittent claudication chronic obstructive pulmonary disease; cerebral ischemia; stroke mitochondrial diseases; encephalopathy and mitochondrial myopathy; Cancer and high blood pressure

pathetic '

[11] Pharmaceutical composition includes

(a) compound according to any of the foregoing [1] to [*]; or a pharmaceutically acceptable salt of the terminator

(b) at least one other effective treatment for the prevention or treatment of a disease selected from the group yo consisting of diabetes mellitus (type 3 diabetes mellitus type AF (‘insulin resistance syndrome’)

Metabolic Syndrome 0 Hyperglycemia; Hyperlactic acid disease in pall complications

Diabetes (diabetic neuropathy » diabetic retinopathy » diabetic nephropathy cataracts

eye) heart failure (acute heart failure ¢ chronic heart failure) call myopathy

oy

myocardial ischemia; myocardial infarction; angina; high blood fats; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease; cerebral ischemia; brain attack; mitochondrial diseases; mitochondrial encephalopathy; cancer; hypertension (sh) and Alzheimer's disease; [VY] 1 drug combination comprising (a) the compound in accordance with any of the above [1] to [*]; or a pharmaceutically acceptable salt terminated and (b) at least one other treatment effective for the prevention or treatment of a disease selected from the group consisting of diabetes mellitus (type 3 diabetes mellitus type a) insulin resistance syndrome metabolic syndrome 0 hyperglycemia blood; hyperlactic acid disease of the pall Complications of A Diabetes (diabetic neuropathy » Ded diabetic retinopathy; diabetic nephropathy cataracts) heart failure (acute heart failure ¢ chronic heart failure) call myopathy Myocardial ischemia; myocardial infarction; angina pectoris; hyperlipidemia; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease; ischemic stroke; stroke; mitochondrial diseases; mitochondrial encephalopathy; cancer and hypertension. pneumoniae administered concomitantly, separately, or continuously. [VV] A naked combination comprising (a) the compound according to any of the above [1] to [*]; or a pharmaceutically acceptable salt of the terminator and (b) one other treatment At least effective for preventing or treating a disease selected from the group consisting of diabetes mellitus (type 3 diabetes mellitus type A) syndrome Insulin resistance 0 Metabolic syndrome Hyperglycemia; hyperlactic disease; complications of diabetes (diabetic neuropathy » Ded diabetic retinopathy; diabetic nephropathy cataracts) heart failure (acute heart failure ¢ chronic heart failure) call myopathy myocardial ischemia 3 myocardial infarction; angina; high blood fats; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease; cerebral ischemia; Stroke 1e

-m1- ischemic; mitochondrial diseases; mitochondrial encephalopathy; cancer; pulmonary hypertension and Alzheimer's disease; that are given simultaneously, separately, or continuously. [VA] Method of inhibition of PDHK in a mammal; Include administration of a therapeutically effective amount of a compound in accordance with any of the foregoing [1] to [0] or a pharmaceutically acceptable salt thereof to said mammal; [V4] © Method 0014/41 of inhibition in an organism of ‎involves administration of a therapeutically effective amount of a compound according to any of the above [1] to [0] or a pharmaceutically acceptable salt thereof to said mammal; [01] Method of Inactivation 0014/42 in a Mammalian; Include administration of a therapeutically effective amount of a compound in accordance with any of the foregoing [1] to [0] or a pharmaceutically acceptable salt thereof to said mammal; [YY] method for preventing or treating diabetes mellitus (type diabetes) type oY diabetes mellitus 0 insulin resistance; metabolic syndrome; hyperglycemia; hyperlactic acid disease in call complications of diabetes (diabetic neuropathy; diabetic retinopathy; diabetic nephropathy; cataracts); heart failure (acute heart failure; chronic heart failure); myopathy (lal myocardial ischemia; myocardial infarction; angina pectoris; hyperlipidemia; atherosclerosis; progressive arterial occlusion; intermittent claudication; Cadel's obstructive pulmonary disease); brain attack; mitochondrial diseases; mitochondrial encephalopathy; cancer or pulmonary hypertension in a mammal; It includes administering a therapeutically effective amount of the compound according to any of the above [1] to [5]; or a pharmaceutically acceptable salt thereof to the organism OSA ofl [YY] A method for preventing or treating diabetes (type 1 diabetes; type oY diabetes; insulin resistance syndrome; metabolic syndrome; hyperglycemia; hyperglycemia blood lactic acid; complications of diabetes (diabetic neuropathy; diabetic retinopathy; diabetic nephropathy; cataracts); heart failure (acute heart failure; chronic heart failure); myopathy (lal muscle ischemia). Heart; myocardial infarction; angina pectoris; hyperlipidemia; atherosclerosis; progressive arterial occlusion; intermittent claudication; obstructive pulmonary disease (Cadel) ischemia of Lal; stroke; mitochondrial diseases; mitochondrial encephalopathy; cancer; hyperthyroidism. CARY

q —_ \ _ pulmonary hypertension or Alzheimer's disease in a mammal; Include administration of a therapeutically effective amount of a compound in accordance with any of the foregoing [1] to [0] or a pharmaceutically acceptable salt thereof to said mammal; [YY] Method for reducing the blood glucose level of a cathin (oS) | Uae ¢ includes a therapeutically effective amount of compound according to any of the above [1] to [0] or a pharmaceutically acceptable salt thereof to said mammal; [YY] 5 The method of reducing the lactate level of cathin (ad) involves administering a therapeutically effective amount of the compound according to any of the above [1] to [0] or a pharmaceutically acceptable salt thereof to said mammal;

[7] Using the compound according to any of the above [1] to [5]; Or a pharmaceutically acceptable salt thereof to produce an inhibitor “PDHK [Yo] Use the compound in accordance with any of the above [1] to [0] Or a pharmaceutically acceptable salt thereof to produce an inhibitor “PDHK1 0

[17] Using the compound according to any of the above [1] to [5]; or a pharmaceutically acceptable salt thereof to produce a 2i[YY] inhibitor Use the compound in accordance with any of the foregoing [1] to [*]; or its Pharmaceutical Acceptable Salt for Producing Blood Glucose Lowering Agent [YA] V0 Use the compound in accordance with any of the above [1] to [0] or its Pharmaceutical Acceptable Salt for Producing Blood Lactate Lowering Agent; [4] Using the compound according to any of the above [1] to [*]; or a pharmaceutically acceptable salt thereof for producing a prophylactic or therapeutic agent for diabetes mellitus (type 1 diabetes; type oY diabetes; insulin resistance syndrome; metabolic syndrome; hyperglycemia; hyperlactic acidemia; 0 Complications of Diabetes (Diabetic Neuropathy » Died Retina Diabetes » ied Kidney Diabetes Cataracts) ¢ Heart failure (Acute heart failure 0 Chronic heart failure) Cardiomyopathy Myocardial ischemia Canal angina) angina pectoris high blood fats; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease”; l).

=« \ — brainstroke » stroke; mitochondrial diseases; carcinoid mitochondrial encephalopathy or rheumatic hypertension; [774] Using the compound according to any of the above [1] to [*]; or a pharmaceutically acceptable salt thereof to produce a prophylactic or therapeutic agent for diabetes mellitus (type 1 diabetes; type oY diabetes; insulin resistance syndrome 0; metabolic syndrome; hyperglycemia; hyperlactic acidosis; complications Diabetes (Diabetic Neuropathy » Died Diabetic Retina » ied Kidney Diabetes Cataracts) ¢ Heart failure (acute heart failure 0 Chronic heart failure) Cardiomyopathy 'ischemic heart' Angina pectoris hyperlipidemia, atherosclerosis, progressive arterial occlusion, intermittent claudication, chronic obstructive pulmonary disease (LA) brain; cerebral PRC; mitochondrial diseases; mitochondrial encephalopathy; cancer; Rheumatoid hypertension or Alzheimer's disease ¢ [31] Use in accordance with any of the above [YE] to [YA] in combination with at least one AT therapy effective for the prevention or treatment of a disease selected from the group for which Consists of Diabetes mellitus (type 0 diabetes mellitus type oY diabetes Insulin resistance syndrome Metabolic syndrome Hyperglycemia Yo ¢ Hyper-lactic acid disease Complications of diabetes (diabetic neuropathy Diabetic retinopathy) » Diet Kidney Diabetes Cataracts) Heart failure (acute heart failure; chronic heart failure) 3 Died heart muscle 3 Myocardial ischemia; progressive; intermittent claudication; chronic obstructive pulmonary disease (ischemia of lead); stroke; mitochondrial diseases; Encephalopathy A) and mitochondrial myopathy Cancer and rheumatic hypertension 6 and [3”] Use in accordance with any of the above [VE] to YA] in combination with at least one HAT is effective for the prevention or treatment of disease Choosing from the group consisting of Diabetes (Type 0 diabetes mellitus type oY diabetes Insulin resistance syndrome; Metabolic syndrome; Hyperglycemia  Hyperlactic acid disease; Complications of diabetes (Diabetic neuropathy; Yo Diabetic retinopathy » Diabetic nephropathy Cataract) Heart failure Acute failure of ARS

- \ \ - the heart; chronic heart failure) 3 Died heart muscle 3 Myocardial ischemia; myocardial infarction; angina; high blood lipids; atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive pulmonary disease; cerebral ischemia; brain attack; mitochondrial diseases; mitochondrial encephalopathy; cla pull Rheumatoid Hypertension and Alzheimer's Disease; and the like. EFFECT OF THE INVENTION The compound of the present invention or a pharmaceutically acceptable salt thereof inhibits the activity of 00111/6; It is useful as a curative or prophylactic agent for diabetes mellitus (type 1 diabetes; type oY diabetes mellitus; insulin resistance syndrome; metabolic syndrome hyperglycemia; hyperlactic acidosis in pall) complications of diabetes mellitus (diabetic neuropathy). » Ded Diabetic retinopathy Diabetic nephropathy Ye cataracts Heart failure (acute heart failure ¢ chronic heart failure) Call myopathy Myocardial ischemia Angina pectoris Hyperlipidemia Atherosclerosis; progressive arterial occlusion; intermittent claudication; chronic obstructive rheumatic disease; cerebral ischemia; stroke; mitochondrial diseases; mitochondrial encephalopathy; cancer; rheumatic pallid hypertension or Alzheimer's disease; and the like. Figure 1 shows the effect of test compounds on hepatic PDH activity (ratio of active liver PDH activity to total liver PDH activity) in nonfasting SD(IGS) rats (mean + sd (0). The figure shows the effect of test compounds on PDH activity in adipose tissue (the ratio of PDH activity in Yo active adipose tissue to the total PDH activity in adipose tissue (ad ipose tissue in non-fasting SD (IGS) rats (mean + standard deviation (0–3)). Description 1 for my detail: The present invention is explained in detail lad below. CARS

The compound of the present invention is a compound represented by the formula [a]: 0 HE A NH, a HO N . 0 a a p EAN f= a) NA NJ a a om PY Fg {1} JUN is 1 or ; (hereinafter also referred to as compound (1)); or a pharmaceutically acceptable salt thereof. © The compound of the present invention is a compound represented by the formula [1 He ~~ 0 NH, i.e. :. Aben 0 Ra Al OH Ai Lahsla ~~ HE Nn CHENG A WW F al OH Fr {l) Spam d= (RAFT) -7-(7-hydroxy ar T= butyl (nS -(trifluoro cyst HA (Je-;-yl]-11-pyrazole-1-yl)-7-methylpropaneamide) (hereinafter also referred to as compound (7) 0 - The compound of the present invention is a compound represented by the formula: [1!1] ATS o

Ha to NH,

HE 0 8 the HG 88 the HC em for \ or > and tb

Food Bio -9H-fluoren—4-yl]-1H-pyrazol-1-yl}-2- ((hY) (also hereinafter referred to as a compound (methylpropanamide monohydrate [IN]) The compound of the present invention is a compound represented by the formula © b uh oY NH,

HE = N 8 hy wo 8

He ETN a 5 ae \

HG oN tr l

F x Vou

FE

00 (2-{4-[(9R)-9-hydroxy-2—-(4-hydroxy-4-methylpentyloxy)-9- (trifluoromethyl) -9H-fluoren—4-yl]-1H-pyrazol-1- yl}-2- (7) (hereinafter also referred to as a compound (methylpropanamide 0) The pharmaceutically acceptable salt of the compound of the present invention can be any salt as long as it is inorganic acids; salts with “organic” acids acids Salts with amino acids and the like

— ¢ \ — Examples of salt with inorganic acid include salt with hydrochloric acid 0 nitric acid acid 01016 ; sulfuric acid » phosphoric acid - hydrobromic acid and the like. Examples of a salt with an organic acid include salts with oxalic acid ; maleic acid; citric acid fumaric acid lactic acid ¢ dll acid succinic acid; tartaric acid; acetic acid; trifluoroacetic acid 0 ; gluconic acid; ascorbic acid, methanesulfonic acid; benzenesulfonic acid « Vo p-toluenesulfonic acid and the like. Examples of a salt with an amino acid include salts with lysine, arginine, aspartic acid, glutamic acid, and the like. A pharmaceutically acceptable salt of a compound of the present invention is preferably a salt with an acid other than 1 moreover; A compound of the present invention or a pharmaceutically acceptable salt thereof may be numbered with an isotope (eg “14C 3H 355 etc.). Where the compound of the present invention is preferably a compound of the present invention or a pharmaceutically acceptable salt terminated by a compound (1) or a pharmaceutically acceptable salt of which each is essentially purified. Less than 0 oA A compound of formula [A] or a pharmaceutically acceptable salt thereof may be present as soluble The term 'soluble' refers to a compound of formula [I] or a pharmaceutically acceptable salt thereof to which a solvent molecule is attached; also includes a hydrate hydrate These solubles are preferably pharmaceutically acceptable solutes.These solubilities include soluble “ethanol” soluble dimethyl sulfoxide dihydrochloride and the like of a compound of formula [a] or a pharmaceutically acceptable salt thereof.Includes 1e ‏

E01 "Specific Examples Soluble hemihydrate hemihydrate; monohydrate « dihydrate or mono (ethanol) of compound of formula [I] or monohydrate of compound of formula [A] ]; Soluble 7/?(ethanol) of dihydrochloride thereof and the like. These solutes can be produced by conventional methods.© Examples of 'pharmaceutical composition' include oral preparations Jie tablet; capsule; granule; powder; pill;

syrup; emulsion Suspension Ma call and injection agents Jie parenteral External preparations; suppositories; injection ¢ eye drops drop 6 no; Nasal preparation » pulmonary preparation and the like.

The pharmaceutical composition of the present invention is produced according to a method known in the art for a pharmaceutical preparation; By mixing the compound of the present invention or a pharmaceutically acceptable salt thereof with an appropriate amount of at least one type of pharmaceutically acceptable carrier and the like as needed. While the content of the compound of the present invention or a pharmaceutically acceptable salt thereof in the pharmaceutical composition differs on the basis of the dosage form; dose size, etc.; He is; 1.1 lie to 96,001 by weight of the composition

yo college. Examples of a “pharmaceutically acceptable carrier” include “various organic or inorganic substances traditionally used as preparation materials”; eg; excipient; disintegrant; binder; AAA fluidizer; lubricant and similar for solid preparations; solvent cules » solubilizing agent; suspending agent » equalizing agent

isotonicity agent 00 “buffering agent; Soothing agent and the like for liquid preparations. at yy pall furthermore; Additives such as preservatives are used; antioxidant; colorant “sweetening agents” and the like.

e1

- a \ -

Examples of "excipients" include lactose; lactose sucrose «0-mannitol, D-mannitol».

Las ¢ cornstarch J giv sD corn dextrin; dextrin; Microcrystalline cellulose

microcrystalline cellulose carmellose; Carmellose Calcium

“sodium carboxymethyl starch” carmellose calcium gum reduced substituted; Arabic Gum hydroxypropylcellulose ©

arabic and the like.

Examples of “carmellose disintegrant” include carmellose calcium; carmellose sodium

croscarmellose sodium; sodium carboxymethyl starch; Croscarmellose Sodium

croscarmellose sodium; crospovidone; Hydroxypropylcellulose

Vo is low substitution; Hydroxypropyl Methyl Cellulose; Crystalline cellulose and the like. Examples of 'binder' include hydroxypropyl cellulose hydroxypropyl methylcellulose povidone crystalline cellulose sucrose ¢ dextrin starch gelatin carmellose sodium carmellose arabic etc. Examples of 'thinning agent' include light anhydrous silicic acid;

Veo magnesium stearate and the like. Examples of "lubricant" include magnesium stearate; calcium stearate; talk and the like. Examples of 'pure water' solvent include ethanol; propylene glycol; macrogol; sesame oil; corn oil; olive oil and the like.

“propylene glycol” solubilizing agents Examples include “solubilizing agents 0; ethanol; triethanolamine; benzyl benzoate; benzyl benzoate mannitol 0-mannitol sodium; sodium carbonate citrate; Sodium carbonate, triethanolamine similar. Ly citrate

E1

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

0 Examples of an “isotonic agent” include glucose; N-sorbitola5010510; sodium chloride; No-mannitol and the like. Examples of a "buffering agent" include sodium hydrogenphosphate; sodium acetate; sodium carbonate 06; Sodium citrate and the like.

0 Examples of "soothing agent" include benzyl alcohol and the like. Examples of “preservatives” include ethyl parahydroxybenzoate; chlorobutanol; benzyl alcohol; sodium dehydroacetate; sorbic acid 0, etc. Like.

Examples of 'antioxidant' include sodium sulfite; ascorbic acid and the like. Examples of 'colorant' include food coloring (eg Red Food Color No. ? or OF Yellow food color No. ; or © etc.)» 8]-B-carotene and the like. Examples of "sweetening agent" include "saccharin sodium"

Yo dipotassium glycyrrhizinate dipotassium glycyrrhizinate aspartame and the like. The pharmaceutical composition according to the present invention can be administered orally or parenterally (e.g. topical, intramuscular, subcutaneous, rectal, or

E1

A —_ \ _ intravenous etc.) of humans as well as other non-human mammals (eg mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey etc.). Dosage varies based on administering subject, disease, symptoms, dosage form, route of administration, etc. Sle The daily dose for oral administration to an adult patient (body weight: about 10 0 kg) is generally in the range of about 1 mg to 1 g; on the basis of compound (1) as the active compound. This amount may be administered in one to several portions. Where a compound of the present invention or a pharmaceutically acceptable salt thereof has an inhibitory effect on PDHK (PDHK and/or 62/00); It will be deemed beneficial to treat or prevent diseases related to (arian +0 glucose utilization , diabetes (type 3 diabetes, type Y0 diabetes, etc.); insulin resistance syndrome; metabolic syndrome; disease Hyperglycemia in all Diseases of hyper-lactic acidemia Complications of diabetes (Diabetic neuropathy Died diabetic retinopathy Diabetic nephropathy Cataracts etc.) Moreover, PDHK inhibitor is considered to be useful in Treatment or prevention of diseases in which supply of energy substrate to tissue is limited; Sli heart failure (acute heart failure chronic heart failure) cardiomyopathy myocardial ischemia Vo myocardial infarction angina pectoris gla) fat in the blood; atherosclerosis; progressive arterial occlusion; intermittent claudication, chronic obstructive pulmonary disease; Cerebral ischemia and stroke. Furthermore it; PDHK inhibitors are being considered useful for the treatment or prevention of mitochondrial diseases; mitochondrial encephalopathy; cancer; rheumatic hypertension or Alzheimer's disease; and the like. diabetes is; Se type 1 diabetes or type 7 diabetes Yo Examples of diabetes complications include diabetic neuropathy; diabetic retinopathy; Diabetic nephropathy and cataracts. Heart failure is; Ole is acute heart failure or chronic heart failure. CARY

_\q—_

The term “PDHK inhibition” means inhibition of PDHK function and excludes or attenuates activity. Preferably

PDHK inhibition is human PDHK inhibition. As a 'PDHK inhibitor' preferably PDHK Laid

human.”

[‘PDHK inhibition] means inhibition of 0014/61 function and exclusion or attenuation of activity. lie means

© Disable the function of 0011161 based on the conditions mentioned in the test example

mentioned below 1. For 'inhibition of 0011/61' human 0011/61 is preferentially inhibited.

[PDHK] Lid would preferably be 'Human Inhibitor 00011141'. More preferably is

is "0014441 linked to target human organs".

'PDHK2 inhibition' means inhibition of PDHK2 function and exclusion or attenuation of activity. lie 0 means inhibition of function of 0011/62 based on the conditions stated in the test example

mentioned below 1. For '0011/62 inhibition' human 0011/62 is preferentially inhibited. Where

'PDHK2 Laid is preferably human PDHK2 Laid'.

It is a “PDHK2-associated target human organ”.

“Lapis’ 0011” means activation of PDH in a target organ (eg liver; skeletal muscle; fatty tissue of the heart; brain) etc.; cancer or the like.

'Reduce glucose level' andl means decrease the concentration of glucose in the blood (including in serum and plasma);

Preferably to reduce a high blood glucose level; more favorably»; To reduce blood glucose level

to a normal, therapeutically effective level for humans.

'Reduce lactic acid level' means to reduce the concentration of lactic acid in the blood (including in serum A) and plasma (preferably to reduce the level of high lactic acid » more preferably to reduce the level of lactic acid

Lactic acid to reduce blood glucose to a normal, therapeutically effective level for humans.

The compound of the present invention or a pharmaceutically acceptable salt thereof may be used in combination with one or more

A combination of other treatments (hereinafter also referred to as an additional drug) according to the method used

Generally in the medical field (hereinafter referred to as combined use).

CARY

the

The period of administration of the compound of the invention (all) or a pharmaceutically acceptable salt terminated and an additional drug other than Gade

They may be administered to a subject as a combination preparation or two preparations may be administered simultaneously

or at certain intervals. Furthermore it; The pharmaceutical composition may be used according to the present invention

An additional drug may be used as a kit treatment. The dose of the additional drug is the same as the dose

© used clinically and can be appropriately selected according to the subject of administration; (papal display"; photo

dose; route of administration; time of administration; Synthesis and the like. The form of administration of the additional drug is not

are specifically restricted and do not need to be combined with the compound of the present invention or a pharmaceutically acceptable salt

Of which.

Examples of a combination drug include therapeutic and/or preventive agents for diabetes (type 0 diabetes; type 0 diabetes? etc.); insulin resistance syndrome; metabolic syndrome; Hyperglycemia in

col disease hyperlactic acidemia; Complications of diabetes (diabetic neuropathy;

diabetic retinopathy; diabetic nephropathy; cataracts); Heart failure (severe heart failure).

the heart; chronic heart failure); Myopathy (lil myocardial ischemia; myocardial infarction; diphtheria

thoracic high blood fats; atherosclerosis; progressive arterial occlusion; intermittent claudication; 1 chronic obstructive pulmonary disease; cerebral ischemia; brain attack; mitochondrial diseases; Encephalopathy

mitochondrial muscle; cancer; rheumatic hypertension or Alzheimer's disease; and the like; and one or more

of agents thereof and a compound of the present invention or a pharmaceutically acceptable salt thereof which can be

Use them in combination.

Examples of "agent for the treatment and/or prevention of diabetes" include an insulin preparation; Hypoglycaemic Agent pl Yo Sulfonylurea Metformin; retarder 000-4; Insulin resistance improving agent (eg; derivative

thiazolidinene); Auxiliary receiver 60-1 and the like.

Examples

The method of producing a compound of the present invention or a pharmaceutically acceptable salt thereof is specifically explained by examples.

However; The present invention is not limited by these examples.

CARS!

“yy Even if the description is not found in the current production method; Steps can be modified for sufficient production; such as introducing a protecting group into a functional group where the protection is removed in a next step; using a functional group as a starting material in each step; followed by conversion to a required functional group at an appropriate stage; change the order of production methods and steps; and the like. The post-reaction treatment at each step was carried out by a conventional method; Where it is possible to isolate and purify as necessary according to an appropriate method selected from traditional methods such as crystallization, recrystallization, distillation, preparative and the like; or a combination thereof. All Factors; HPLC Fractionation; Silica gel chromatographs; commercially available products and where to use without purification. Baga and solvents include Bab) Ratio 96 indicates weight percentage. They will mean the other abbreviations used in the following example. Single : 5 A double id triple :] quadruple : multiple tM wide sbr | 05 duplex binary 0 : triple duplex td binary duplex duplex 0 l : deuterated deuterated coupling constant chloroform chloroform :00003 | 0 deuterated dimethyl sulfoxide DMSO-D6: H1

— \ As 1H NMR : proton nuclear magnetic resonance : HPLC : high performance liquid chromatograph : DPPA : diphenylphosphoryl azide ITH-NMR spectrum was measured in 60013 or DMSO-D6 using Tetra © tetramethylsilane as internal standard; Values of 5 are shown in rpm. 01 (mL) phosphate buffer (pH 001) Sodium dihydrogen phosphate (7.10 g) was dissolved in water (de Tov) and adjusted to pH 001 with phosphoric acid 0 to give the buffer solution mentioned in the title. 0 HPLC ANALYSIS CONDITIONS ANALYSIS CONDITIONS 1 MEASURING DEVICE: CORPORATION SHIMADZU HPLC SYSTEM High Performance Liquid Chromatograph Age: 000-34 DAICEL CHIRALCEL 4.7 mm 001 XD mm 0° Column temperature: 6 26 C. Transition phase: (01 solution (A) ml molar phosphate buffer solution (pH Y,e) (3 (Solution 8) acetonitrile, then changing the composition of the transition phase (Solution /: Solution 8) linearly from 567 :56 to 8 over 00 minutes after which the rate is maintained at 0:80 for © minutes. Jae Yo Flow: 0,” mL/min Detection: UV (YY nm) 1e

Alnakh _ conditions of analysis? Meter: CORPORATION SHIMADZU HPLC system High Performance Liquid Chromatograph Age: 001 X Das 2.1 RH-0OJ CHIRALCEL DAICEL mm© Column temperature: 6 26 °C Phase transition: (01 (A) mM buffer solution Phosphate (pH Y,e) 3 (solution 8) acetonitrile and then change the phase transition composition (solution/:solution 8) linearly from Ver¥e to gen over 10 minutes and after and then maintained at 16:560 for 10 minutes. Yo Flow Rate: 0,” mL/min Detection: UV (YY) nm) Analysis Conditions? Measurement Device: CORPORATION SHIMADZU HPLC Chromatograph System HIGH PERFORMANCE LIQUID 0 Column: DAICEL CHIRALPAK AD-3R 2.1 mm © 001 X mm Column temperature: 66°C Phase transition: (01) solution (A) mM phosphate buffer solution (pH Y ,e ( 3 (Solution 8) acetonitrile and then changing the phase transition composition (Solution/:Solution 8) linearly from 56:56 to 8 over the course of 10 Yo minutes and then then ay on it at 86:00 for 0 minutes.Flow rate: 0.50 ml/min CARS

_ Detection: UV (YY) nm) 1 JEL Synthesis: 2-{4-[(9R)-9-hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren—4-yl]-1H-pyrazol-1-yl}-2- © methylpropanamide (compound (7) step 1 Ethyl 2°-chloro—4' -methoxybiphenyl-2-carboxylate © Rasm Tat Cl La 0 A “18 71 Ai Er.

AE + 1 A 0 CH3 _ Na CH EN J kL ee dreamer 1 1 0 I a >< 2# oH 3 Hao ed mg pal H HaC 3 oper 3 win 1 in jo argon (413) 1-bromo-7-chloro-4-methoxybenzene (££,Y) methoxybenzene g) in toluene (YY.) toluene (ml)-4,4 ,5,5)-2 ethyl T+, A) tetramethyl[1,3,2]dioxaborolan-2-yl)benzoate c); water (YTY) mL); Glin S sodium hydrogen carbonate (1,? (pa) and ¥,A) dichlorobis(triphenylphosphine)palladium(il) 10 g) added; The mixture was stirred at an ales oil temperature of 1710 °C for 1 hour. To the reaction mixture was added: «(p> 0,Y) ethyl 2—(4,4,5,5-tetramethyl[1,3,2]dioxaborolan—-2-yl)benzoate and the mixture was also stirred for 2 hours . The reaction mixture was cooled to room temperature; Toluene (100 mL) and Yoo water (mL) were added; The mixture was stirred overnight. to the reaction mixture

A: Activated carbon (7 g) has been added; The mixture was also stirred for an hour. The insoluble matter was filtered through the silite; The insoluble substance was washed with 100 (ml) toluene and 100 (ml) water. The obtained filtrate was combined to allow separation of the layers. The obtained organic layer was washed with water (Yoo ml) and then evaporated the s-acy solvent mentioned in the title (17.7 g). 1H-NMR (400MHz, DMSO-D6) 56: 7.88-7.86 (1H, m), 7.63 (1H, td, J = Hz), 7.51 (1H, td, J = 7.6, 1.4 Hz), 7.27 (1H, dd, J = 7.6, 0.9 1.4 ,1.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.06 (1H, d, J = 2.6 Hz), 6.95 (1H, dd, J = Hz), 4.01 (2H, m), 3.80 (3H, s), 0.96 (3H, t, J = 7.1 Hz).8.6 , 2.6 0 step Y 2'—Chloro—4' -methoxybiphenyl-2--carboxylic acid 0 . <0 0 n0 mk SO< of CH,CH,1V,Y) Ethyl 2°—chloro-4'-methoxybiphenyl-2-carboxylate g) was dissolved in 01 ethanol (mL); Ala); 001 N of aqueous sodium hydroxide (VO mL); The mixture was stirred at an oil bath temperature of 1100°C for an hour and a half. The reaction mixture was cooled to room temperature; Yor water (ml) and toluene (001 ml) added; The mixture was stirred overnight. To the reaction mixture activated carbon (6 g) was added; The mixture was also stirred for an hour. The insoluble matter was filtered through the silite; The insoluble material was washed with toluene (daTo) and To water (ml). The obtained YL filtrate was combined to allow separation of the layers. The obtained aqueous layer was washed with 01 (ml) toluene; The aqueous layer was acidified with concentrated hydrochloric acid (50 ml); And it was flipped

© at room temperature for one hour. The precipitated solid was collected by filtration. The obtained solid was dried for 1 hour; The drying was done under reduced pressure at 0°C overnight to give the compound mentioned in the title (0.7 5 g). 1H-NMR (400MHz, DMSO-D6) 6: 12.57 (1H, s), 7.90-7.88 (1H, m), E (1H, td, J = 7.6, 1.3 Hz), 7.49 (1H, td , J = 7.6, 1.3 Hz), 7.24 (1H, 7.60 dd,J = 17.6, 1.0 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 2.4 Hz), (1H, dd, J = 8.5, 2.4 Hz), 3.81 (3H, s). 6.95 Step 1 4-Chloro-2-methoxy-9H-fluoren-9-one 1 0 0 and one CH 0 º CH, 3 in an atmosphere of 2'—chloro-4'-methoxybiphenyl-2—carboxylic acid _l” argon sj (15.4 g) Eaton reagent (phosphorous pentoxide) added phosphorus pentoxide - methanesulfonic acid (weight ratio + (Ve) solution » YY ml) Vo and the mixture was stirred at ha in an oil bath of 100 μL for 1 hour. It was cooled The reaction mixture (Cah Fant) (Je 118 ) PR was added slowly on droplets, then the mixture was stirred an die at room temperature for 1 hour. The precipitated solid was collected by filtration; it was washed with (00 mL) water. The obtained solid was dried overnight to give the compound mentioned in the title (47.0 g). the

— 7 since 1H-NMR (400MHz, DMSO-D6) 6: 8.01 (1H, d, J = 7.4 Hz), 7.64-7.60 (2H, m), 7.36)1 td, J = 7.4, 0.9 Hz ), 7.17 (2H, dd, J = 8.4, 2.3 Hz), (3H, s).3.85 35d) ¢ 4-Chloro-2-hydroxy—-9H-fluoren-9-one © Yas Qs OH 0 CH, 0 0 in argon atmosphere” to AY, +) 4-chloro-2-methoxy—-9H-fluoren-9-one g) added (Je VY + ) N-methylpyrrolidone and pyridine hydrochloride (V ££) g). The reaction mixture was stirred at an oil bath temperature of 7000 C for ? Vo hours with water removed by Dean—Stark apparatus. Reaction mixture cooled to 0024 °C; water (JeTe) added dropwise; The mixture was stirred at room temperature for two hours. The precipitated solid was collected by filtration; Washing was done with 0.50 mL water. The obtained sald was dried for days; A mixed solvent of Ji-hexane was added; hexane ethyl acetate (hexane:ethyl acetate (Je 00 1:1); the mixture was stirred at RTV for 1 h. The solid was collected by filtration; washed with a mixed solvent of hexane and ethyl acetate (Hexane:ethyl acetate- 5800 1:11 mL).The solid obtained was dried under reduced pressure at 0 20 C for 1 hour to give the compound mentioned in heading EAT (g). 1H-NMR (400MHz, DMSO-D6) 6: 10.56 (1H, s), 7.96 (1H, d, J = 8.4 Hz), 7.61-7.57 (2H, m), 7.32 (1H, td, J = 7.4, 0.9 Hz), 6.97 (1H, d, J = 00 Hz), 6.94 (1H, d, J = 2.2 Hz).

M with step © Ethyl 4-(4-chloro-9-oxo-9H-fluoren-2-yloxy)butyrate Cl Gl a 01 What Tes! goa laas-0 7 0 ~~ 0 . 0 ¢A,7) (4-Chloro-2-hydroxy-9H-fluoren-9-one g) dissolved in N,N-Vo + (dimethylformamide o mL); °A,Y) potassium carbonate

g) and (Je YY, 0) ethyl 4-bromobutyrate ¢ was added and the mixture was stirred at 1071°C

for two hours . Then the reaction mixture was cooled to 0 ot and toluene (Yeo mL) and s was added.

ml) to allow separation of the layers. The obtained aqueous layer was extracted again

betoluene) (Je 01. laa) organic matter obtained 3 and then washed twice with 0111 Ve ml); Anhydrous sodium sulfate ALY and carbon were added

tonic (Y, 0 g); The mixture was stirred at room temperature for ½ minutes. The article has been nominated

dissolvable through cellite; The solvent was evaporated into the filtrate. to the remaining article that was done

obtained hexane (4 YY mL) was added; The mixture was stirred at 0 22°C for 10 minutes

and at room temperature for an hour. The precipitated solid was collected by filtration; VO was washed with hexane. The obtained solid was dried under reduced pressure to give the compound

Mentioned in the title (114 g). Further, the solvent was evaporated into the filtered product

get it; To the residue ethyl acetate (0 mL) and Hexane (Yo) (mL) were added; And done

Stir the mixture at room temperature for an hour. The precipitated solid was collected by

Purification; Washing was done with hexane. The obtained solid (sald) was dried under reduced Yo pressure also to give the compound mentioned in the title (7.5 g).

1H-NMR (400MHz, DMSO-D6) 6: 8.01 (1H, d, J = 7.6 Hz), 7.65-7.61

(2H, my, 7.37 (1H, t, J = 7.6 Hz), 7.17-7.14 (2H, m), 4.13-4.05 (4H,

E1

q —_ as J = 7.3 Hz), 2.02-1.95 (2H, m), 1.19 (3H, td, J = 7.2, ,a m), 2.47 (2H, Hz). 0.7 Step + Ethyl 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren-2- yloxy]butyrate © Cl 0 rol — 0 CH + ~ ~ ِ 1 otherwise.” 0 TY ~~ i! - 3" 1 ; in an argon atmosphere; dissolved: ethyl 4-(4-chloro-9-oxo-9H-fluorene-2-yloxy)butyrate (15.4 g) in tetrahydrofuran 001 ( THF) mL); and: N=(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide 00 (.4 g) was added to the reaction mixture a dropwise solution of oY, +) trimethyl(trifluoromethyl)silane was added mL) in (Je 10 (THE) at -11”C; the mixture was stirred at the same temperature for 11 minutes. Acetic acid (YY, +) acetic acid) and 1 mL were sequentially added to the reaction mixture. se of tetrabutylammonium; fluoride solution (YYY) THF/fluoride VO mL) and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated; and to the residue obtained Toluene (00 ml) and aqueous saturated sodium hydrogen carbonate (Yoo ml) were added to the Jad z layers.The organic layer that was then obtained was washed sequentially with aqueous saturated sodium hydrogen carbonate (100 ml; twice). Yo 001 mo of aqueous sodium hydroxide (ml); 001 water (ml); 1 mo of 0 001 hydrochloric acid ( hydrochloric acid mL); Water (Je 001) and saturated brine 001 (ml). To the obtained organic layer anhydrous magnesium sulfate 018908510000 and silica gel V0 (g) were added; The mixture was stirred for 10 minutes. CER!

=« ¢ — the insoluble matter is filtered out; The insoluble substance was washed sequentially with toluene (Je Yoo) and ethyl acetate Av (ml). The obtained filtrate and the leaching product were combined with toluene, As evaporation of the solvent, acy 3, the compound mentioned in the title (7 g). Also, then evaporate the solvent in the washing product, Jel acetate; To the obtained residue a silica gel© (£4 g) and a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane 1:7 001 mL) were added; The mixture was stirred at room temperature. The insoluble matter is filtered out; The insoluble substance was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane-1:7; de 001). g).1H-NMR (400MHz, DMSO-D6) 8: 8.14 (1 d, J = 7.7 Hz), 7.66 (1H, 0, 0

J = 7.5 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.42-7.38 (2H, m), 7.14 (2H, s), 4.11-4.05 (4H, m), 2.47 (2H, t, J = 7.5 Hz), 2.03-1.96 (2H, m), 1.19 (3H, td, J = 7.1, 0.8 Hz). (Absolute Conformation) 1 Determine the Absolute Conformation of (trifluoromethyl) -9H-fluoren—9-ol -9-E4-01010-2-008 in the step mentioned below No. 01 confirm that the aforementioned compound in the address obtained in this step Blue for formula (4a). The optical purity was 6.69687,1. Optical clarity was determined under HPLC analysis conditions 1. Image retention time | Retention 686 (5) 14.7 minutes; Image retention time 77.10 (R) minutes. 0 Step A 4-[(9R)-4-Chloro—9-hydroxy-9—(trifluoromethyl)-9H-fluoren-2- yloxy]butyric acid E1

-1 ;- cl 0

%e o_O, — © OH on 1) i 0 a F F Dissolved: Ethyl 4-[(9R)-4-chloro—-9-hydroxy—9—(trifluoromethyl)-9H-fluoren -2- (a > 4Y,Y) yloxylbutyrate in ethanol (Je 001) was added; 01Nm of aqueous sodium hydroxide mL was added; the mixture was stirred at 0°C overnight The reaction mixture was cooled to room temperature Yor water (ml) was added; The mixture was washed twice with 1001 (ml) toluene. The obtained hydrate was titrated with concentrated hydrochloric acid (0 pH mL); The extraction was done twice with ethyl acetate (Tov ml). The obtained ethyl acetate extract was washed sequentially with ede 001 water (twice); Brian Ve Saturated 001 (mL); Anhydrous Magnesium Sulfate and Alia Activated Carbon (4.7 g); The mixture was stirred at room temperature for 10 minutes. The insoluble matter is filtered out; The solvent was evaporated into the filtrate. To the residue obtained chloroform A (ml) was added; The mixture was heated to 0*7 M. Hexane (£00 (Je) was added dropwise; the mixture was stirred at the same temperature, Vo sad 1 minute, and at room temperature for 2 hours. Vo _ precipitated solid was collected By filtration, it was washed with a mixed solvent of hexane and chloroform 0 (hexane:chloroform < 5:1; 0 © ml), and dried under reduced pressure at 0°C for 2 hours to give the compound mentioned in the title (17.25 g 1H-NMR (400MHz, DMSO-D6) 6: 12.17 (1H, brs), 8.14 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.54 ( 1H, td, J = 7.7, 1.2 Hz), 7.42-7.30 (2H, m), 7.18-7.15 (2H, m), 4.09 (2H, t, J = 6.4 Hz), 2.41 2H, t, J = ¥.Hz), 2.00-1.93 (2H, 0 7.3 step A

Salt : (18)-1-(4-Methylphenyl)ethylamine salt of 4-[(9R)-4-chloro-9—hydroxy- (trifluoromethyl) -9H-fluoren-2-yloxy]butyric acid - 9 Cl FR 'Hy SE H CH: 3 6 cm 4 3 cH + d TNH ? ae OH Ban AA LOH 7 NH Le 2 1 M 0 NA Mk 2 HA 01 7 Mhr Fred F 0 0 P ad M 9 mm © in nitrogen atmosphere 0112098610; Dissolved: 00108 8EF©(L80|L4-0081)-1-(15) (14,9) in ethyl acetate (771 ml); added: ethyl acetate (720 ml), and 4-[(9R)-4-chloro-9-hydroxy-9- ‎VY, 0) (trifluoromethyl) -9H-fluoren—2-yloxy]butyric acid g). The reaction mixture was stirred at 10°C for two hours.” And at room temperature all night. The precipitated solid was collected by filtration; Washing was done with ethyl acetate 01 (ml). The obtained solid was dried under reduced pressure at 10°C for a period of © hours to give the compound mentioned in the heading (TAT (g). Furthermore it; : 4-[(9S)-4~-chloro-9-hydroxy-9—(trifluoromethyl)-9H-fluoren-2- yloxylbutyric 8610 Ye can be obtained from the filtrate. Optical purity gyal (Then determine the optical purity: 4-[(9R)~4-chloro-9-hydroxy-9- (trifluoromethyl) -9H-fluoren-2- yloxylbutyric 0 in analytical conditions 1 HPLC (resolution grad 6.69690:7.).0 time | image hold 1.5 (R) min; image hold time (5) ALE) +E no

1H-NMR (400MHz, DMSO-D6) 6: 8.14 (1H, d, J = 7.7 Hz), 7.66 (1H, 0)

J = 7.7 Hz), 7.53 (1H, td, J = 7.6, 1.1 Hz), 7.40 (1H, td, J = 7.6, 1.0

Hz), 7.26 (2H, d, J = 7.9 Hz), 7.16-7.10 (4H, m), 4.08 (2H, t, J = 6.5

Hz), 4.01 (1H, q, J = 6.7 Hz), 2.32 (2H, t, J = 7.3 Hz), 2.26 (3H, s), 1.98-1.91 (2H, m), 1.26 (3H, d, J = 6.7 Hz). E0 9 Step 4-[(9R)-4-Chloro—9-hydroxy-9— (trifluoromethyl) -9H-fluoren-2- yloxy]butyric acid cl 0

G.H.

Spr Sp i oH 0 HC i 5 OH 0

F

: to salt 0

To (1S)-1-(4-methylphenyljethylamine salt of 4-[(9R)-4-chloro-9- g) TAT) hydroxy -9—(trifluoromethyl)-9H-fluoren—2-yloxyJbutyric acid Ml); The mixture was stirred at To) NY hydrochloric acid 5 addition of ethyl acetate (+00 ml) minutes. Separation of seams is allowed. The organic layer was washed at room temperature for 1 ml. Yor) saturated brine (ml) and You) saturated brine were sequentially obtained with water 1 by drying the organic layer that was then obtained on anhydrous magnesium sulfate ¢ and then filtering the material

ter) unsolvable; The solvent was evaporated into the filtrate to give the compound mentioned in heading g). 1H-NMR (400MHz, DMSO-D6) 6: 12.17 (1H, brs), 8.14 (1H, d, J - 7)

Hz), 7.66 (1H, d, J = 7.5 Hz), 7.54 (1H, td, J = 7.7, 1.2 Hz), 7.42-7.30 0 (2H, my, 7.18-7.15 (2H, m), 4.09 (2H , t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.00-1.93 (2H, 0

IRS

_ _ Step 01 A911-11101606-2,9-010- (9R)—4-Chloro—9— (trifluoromethyl) cl 0) mit — from 6 oY ¢ 3 OH : p 0 OH FF F to : 4-[(9R)-4-chloro-9-hydroxy—9—(trifluoromethyl)-9H-fluoren-2- 0 (aa© +) yloxy]butyric acid (Je Yoo) N-methylpyrrolidone and pyridine hydrochloride (YA) pyridine hydrochloride g) were added; The mixture was stirred at 100"C oil bath for 2 days. The reaction mixture was cooled to room temperature; diluted with ethyl acetate (00 mL); washed twice with water. The obtained aqueous layer was extracted again with ethyl Tov acetate (ml). The organic layer was washed sequentially with water; 1 M HCl and saturated Bryan. to the layer and the mixture was stirred at room temperature. The insoluble matter was filtered through a celite. The solvent in the organic layer was evaporated obtained; hexane was added to the residue 1; the mixture was stirred at room temperature. the precipitated solid was collected by filtration; and dried under reduced pressure at room temperature. The obtained raw material was dissolved in ethyl acetate (500 mL); washed ¥ times with water; dried over anhydrous magnesium sulfate. The insoluble matter was filtered off; the solvent in the filtrate was evaporated. CER!

A_ Hexane was added to the residue » and then the mixture was stirred at room temperature. The precipitated solid was collected dang the filtration; Then drying under reduced pressure at room temperature to give 6 of the compound mentioned in the title (YV, ¢ g). 1H-NMR (400MHz, DMSO-D6) 6: 10.37 (1H, br s), 8.09 (1H, dJ=17.5 Hz), 7.63 (1H, d,J=17.5 Hz), 7.50 (1H, td , J = 7.6, 1.0 Hz), 7.36 (1H, ° td, J = 7.6, 1.0 Hz), 7.32 (1H, br s), 7.06 (1H, s), 6.91 (1H, brd, J = 0 Hz). Step a-1 Cl Cl 1) BrCH,CO,Et TMSCF PA) 1 2TBAF Ng OR pass CU on = grown FF 0 compound (100) racemic Cl CH, Cl ( mm » 0 mm ALS Jon, (TM A A (ron FA 0 FA 0 : FF “pO FF “pO OH OH compound (100AA) single crystal X-ray structural analysis

4-Chloro-2-methyl-9H-fluoren-9-one was subjected to trifluoromethylation; Jil reacted ethyl bromoacetate and hydrated to give H .[4-chloro—-2-methyl-9— (trifluoromethyl) -9H-fluorene-9-yloxylacetic acid ©) The compound was optically resolved Sg ( IR)=1-phenylethylaminealaainl Determination of the absolute configuration to be (R) by structural X-ray single crystal analysis of a salt: using (1R)-1-phenylethylamine obtained (4) (V+ step a-?

HO NH 5 | FT, he, : Ag hy TIHGE 0 as, r 1 radmo 0 9 mr kan tr DEEL OH rt yr st 8 m 1 compound (RIE) Compound (1001aa) 0-911-110160-9-0- (1111101010081)-9-E4-61610-2-00281- (9a4) (compound ))001) was synthesized from compound 100aa by acid treatment, etc. ex. step b-0 TH / iPHEL ) 1 Pd(PPh), ) 2 CH, Cl 0 B. 0 Cl a CH, yla 0 li oH FA OH FA 1 FF FF compound ( 100b).

— 7 ¢ — 4—chloro-9— (trifluoromethyl) -9H-fluorene-2,9—diol obtained in step 01 to a methyl group by the above method to give: 4-chloro-2- methyl-9—(trifluoromethyl)-9H-fluoren-9-ol (compound (100b)) (HPLC analysis using an optically activated column) then separated each of the isomers of the compound (by hand HPLC dail gs) 1 using Optically activated column (HPLC analysis conditions 9). HPLC analysis of compound (100a) confirmed that the image retention time (R) was ¢ 1 A, min and the image retention time was yt ( Then the synthesis of compound (0 ve and compound 1 “ue) b induces HPLC conditions to reach that retention time. It was considered that the absolute conformation of the isotropic carbon does not undergo transformation during the production of compound: m “0” and compound “m” 1ab according to the above. The results confirm that Ye ) obtained in 4-chloro-9- (trifluoromethyl) -9H-fluorene-2,9-diol

A(R) has an absolute conformation to 01 step 11 step (9R)-4-Chloro—-2-(3-hydroxy—3-methylbutyloxy)-9—(trifluoromethyl)-9H- fluorine-9-ol 0 0 Cl

Oy 0 0 HC CH AB HC, Of

Fay w Ty me p 0 0

Fe Fr : in a nitrogen atmosphere; This g) is dissolved in ©) (9R)—-4-chloro-9— (trifluoromethyl) -9H-fluorene-2,9-diol «(Je 00+) N,N-dimethylformamide (1,1- Dimethylformamide

m _(ax £4.7) 3-hydroxy—3-methylbutyl 1010606-4-036 and T4,0) potassium carbonate g) added; The mixture was stirred at an oil bath temperature of 17 °C overnight. To the reaction mixture a solution of: 3-hydroxy—3-methylbutyl toluene-4-sulfonate (+ .5 g) in: N,N-dimethylformamide © (© ml) was added; The mixture was also stirred at the same temperature for hours. The reaction mixture was cooled with ice; Avr (ml) water added; The mixture was extracted as Jl acetate (400 ml). The obtained organic layer was washed with 000 water (5 ml; ? times) and saturated brine (5.6 (Je). Then the obtained organic layer was dried on anhydrous sodium sulfate; the insoluble matter was filtered out; and the insoluble matter was evaporated. The residue obtained by silica gel column chromatography (a mixture of hexane and ethyl acetate) eluate solvent was eluted firstly with a mixture of (hexane:ethyl acetate) at a mixing ratio of 1:3; thereafter with the mixture at a mixing ratio of 1:7; and also with the mixture at a mixing ratio of 7:7) to give the compound mentioned in the title (£9.0g). 1H-NMR (400MHz, DMSO-D6) 6: 8.12 (1H, d, J = 7.6 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.52 (1H, td, J = 7.6, 0.9 Hz), 7.40-7.36 (2H, m), 7.15- 10 (2H, m), 4.41 (1H, s), 4.16 (2H, t, J = 7.1 Hz), 1.85 (2H, t, J = 7.1 7.13 Hz), 1.17 (6H, s).VY step Ethyl 2-{4-[(9R)-9-hydroxy-2—-(3-hydroxy-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionate 0 1e

©1113 Wonaj _CH3 Chg

Hot: B H3C.; ] 0

Cl Fe did not

Pa Non N-N with ‎#7 HC CHy | 0 La

TN co % H_hand FI 0" : R © 7 OH omg LS Ober CH3

Vd i is not counting

FF Hae and For 27 07" OH nor CH3 F goH

LY in Joe Arjun; atmosphere, (9R)—4-chloro-2-(3-hydroxy-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren-9-ol (4.5; g) in toluene (£20 mL) : 0 ethyl 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan—2-yl)-1H- tripotassium phosphate o(J— VE) g); Water ©4,Y) pyrazol-1-yl]propionate g) ¥,4) palladium acetate Palladium acetate «(pa 0¢,Y) tripotassium phosphate 2—dicyclohexylphosphino-2',6'-dimethoxybiphenyl ( SPhos) and was added for? 5 001 hours of heat in an oil bath of ia gm) and the mixture was stirred when Ye 01) was added. (Je Ye) and a half were nominated. The reaction mixture was cooled to room temperature; slog water (ml) Vor) the insoluble matter through celite; The insoluble substance was washed with toluene (ml). The obtained filtrate was combined to allow separation of the layers. The layer (00 ml) was washed. Then drying Ou (ml) and saturated Brian (Orn) & organic, which then obtained sequentially with what

ALE The organic layer obtained on anhydrous sodium sulfate; Substance other than Yo was filtered out of solution; The solvent was evaporated into the filtrate. The residue obtained was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as eluate and subsequently with Vi) with a mixture of (hexane:ethyl acetate) at a mixing rate of Ny as the solvent; beveled Also purified by (V:Y) and also with the mixture at a mixing ratio of 1:1 the mixture at the mixing rate of a silica gel chromatography column (a mixture of hexane and acetone was used as eluate solvent; eluent 0 L

- see at a mixing ratio of 1:7; And then with the mixture at (acetone) first with a mixture of (hexane: acetone) to give (V:Y) and also with the mixture at a mixing rate of 3:7 1:1 7:1 oF) 4:1 mixing rates g). 7.21 (4H, m), 7.13 (1H, brd, J = 1.6 Hz), 6.84 (1H, d, J © = 2.3 Hz), 4.38 (1H, s), 4.16-4.11 (4H, m), 1.86 ( 2H, t, J = 7.1 Hz), 1.84 (6H, s), 1.16 (6H, s), 1.13 (3H, t, J = 7.0 Hz). Step 11: 2-{4-[(9R)-9-Hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]- 1H-pyrazol-1-yl}-2-methylpropionic 0 acid

CH

CH only 3 CH; Oh

Ho] ® 0 HC at a/p yy

LJHC. GH, SeHC. CH,

HL SAREE,

A Fr: dissolved

Ethyl 2-{4-[(9R)-9-hydroxy-2—-(3-hydroxy-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl }-2-methylpropionate 01

VTA) ml); § N of aqueous sodium hydroxide (YO) g) in ethanol (TA, £ (ml)) was added; The mixture was stirred at room temperature for two and a half hours. The mixture of (Je YYY) hydrochloric acid 1 Nd hydrochloric acid reaction was cooled with ice; the organic layer Jug added to drops; The mixture was extracted with ethyl acetate (+00 ml). Done

_— \g obtained sequentially with water (Een) ml; twice) and Brian saturated (en ml). The obtained organic layer was dried on anhydrous sodium sulfate; The insoluble matter is filtered out; As the solvent was evaporated in the filter product to give the compound mentioned in the title (Yo, g). 1H-NMR (400MHz, DMSO-D6) 6:13.06 (1H, br s), 8.14 (1H, s), 7.62 (1H, s), 7.57 (1H, dd, J = 6.4, 0.6 Hz) , 7.27-7.19 (4H, m), 7.12 (1H, s), © (1H, d, J = 2.3 Hz), 4.38 (1H, s), 4.14 (2H, t, J = 7.2 Hz), 1.85 6.84 (2H, t, J = 7.2 Hz), 1.82 (3H, s), 1.81 (3H, s), 1.16 (6H, s). Step 6 1 2-{4-[( 9R)-9-Hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren—4-yl]-1H-pyrazol-1-yl}-2- 0 methylpropanamide (compound (((Y) oof? OH of NH, 1 a N—N p yr / CJ HC.

CH, 2 © HC.

CH, ap oo F a Fon OH Fe FF in nitrogen atmosphere; Dissolved: 2-{4-[(9R)-9-hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]-1H -pyrazol-1-yl}-2-methylpropionic acid 00 (717,Y) g) in no:1-dimethylformamide (£A+) N,N-dimethylformamide ml); YV,71) hydroxybenzotriazole (HOBt) 1 hydrate >(« 1-ethyl-3~(3'~dimethylaminopropyl)carbodiimide (WSC) hydrochloride YE,7 g) and %YA were added from aqueous ammonia (Je Y£,0) ¢ and the mixture was stirred

— \g at room temperature overnight. The reaction mixture was cooled with ice; (TY) elo ml) and a titer of hydrochloric acid 8610 (YY hydrochloric ml) was added to the droplets; the mixture was extracted with ethyl acetate Avo (ml). The obtained aqueous layer was extracted again Jil acetate (000 ml). The obtained organic layers were combined; washing was carried out sequentially with water (000 cde twice); aqueous saturated sodium hydrogen carbonate (500 ml); and saturated brine (5.6 (J). Then drying Aaya) organic obtained on sodium sulfate (WY) then filtered the insoluble matter; the solvent in the filtrate was evaporated to give 6 the compound mentioned in the title (ve) 1 g). 1H-NMR (400MHz, DMSO-D6) 8: 8.08 (1H, s), 7.66 (1H, s), 7.58-7.56 (1H, m), 7.32-7.30 (1H, m), 7.25-7.22 (4H, m), 7.12 (1H, br s), 6.96 0 (1H, br s), 6.87 (1H, d, J = 2.3 Hz), 4.38 (1H, s), 4.14 (2H, t, J = 7.2 Hz) , 1.85 (2H, t, J = 7.2 Hz), 1.78 (3H, s), 1.78 (3H, s), 1.17 (6H, s). Step 11 2-{4-[(9R)- 9-Hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl)-9H-fluoren—4-yl]-1H-pyrazol-1-yl}-2- 0 methylpropanamidemonohydrate (compound (((hY) CH CH H.C 3 HH, HC 3 NH, a a Ps . H20 7 Se HG.

CH, se HC.

CH, pS EN and k pS OH 2 OH 2 dissolved: CER!

-."g 2-{4-[(9R)-9-Hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl) -9H-fluoren—4-yl]- 1H-pyrazol-1-yl}-2- methylpropanamide (compound (7)) (1000 g) obtained in the previous step in ethyl acetate (Ved) (dw© water (? mL) was added, and the mixture was heated 2 0 M. To this mixture was added sequentially over drops of hexane YY (mL); and a mixed solvent of hexane ethyl acetate (hexane:ethyl acetate YO (YD mL); and the mixture was allowed to cool brought to room temperature and stirred overnight.The precipitated solid was collected by filtration;washed with a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate-<1:7; 0830 mL). That Ve was obtained under reduced pressure at room temperature overnight to give the compound mentioned in the title (, ov g; optical purity A 4 M). + Optical purity was determined under HPLC analysis conditions?. Time Image retention (6*a) 11.1 min; NMR (400MHz, DMSO-D6) 6: 8.08 (1H, s), 7.66 (1H, s), 7.58-7.56 10 (1H, m), 7.32-7.30 (1H, m), 7.25-7.22 (4H, m), 7.12 (1H, br s), 6.96 (1H, brs), 6.87 (1H, d,J = 2.3 Hz), 4.38 (1H, s), 4.14 (2H, t, J = 7.2 Hz), 1.85 (2H, t, J = 7.2 Hz ), 1.78 (3H, s), 1.78 (3H, s), 1.17 (6H, s). Elemental analysis measurement Ye The results of the elemental analysis are in good agreement with the theoretical value of the compound (7H) calculated. Calculated: “Nto JA Heed AAC except (Calculated Potential Hydrate) Exists: “(Neo ve Heed AC) Step 11 CER!

_ g 2-{4-[(9R)-9-Hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl) -9H-fluoren—4-yl]-1H- pyrazol-1-yl}-2- methylpropanamide (compound (((Y) GH CH he 3 Mh He] © NH m a H20 2 - 7 vsse HC.

CH,ve HC.

CH, ip IX SALA, OH OH FF FF to: 2-{4-[(9R)-9-hydroxy—-2-(3-hydroxy—-3-methylbutyloxy)-9- (trifluoromethyl) -9H-fluoren—4-yl]-1H-pyrazol-1-yl}-2- methylpropanamide monohydrate (compound YV,TY) ((7Y) g) obtained in In the previous step, toluene (00;? ml) was added. The reaction mixture was stirred at a 0 | bath temperature oil at 1010°C for two hours in nitrogen atmosphere with water removed by a Dean-Stark apparatus. The reaction mixture was also stirred at a temperature of an oil bath at 17°C for an hour and a half; Allow to cool to room temperature; It stirred all night. The precipitated solid was collected by filtration; Washed with 01 (ml) toluene. The obtained solid was dried under reduced pressure at room temperature for ? days; Also, it was dried under reduced pressure 1 at 1002°C for a day to give the compound mentioned in the title 70.9 (g). 1H-NMR (400MHz, DMSO-D6) 8: 8.08 (1H, s), 7.66 (1H, s), 7.58-7.56 (1H, m), 7.32-7.30 (1H, m), 7.25-7.22 (4H, m), 7.12 (1H, br s), 6.96 (1H, br s), 6.87 (1H, d, J = 2.3 Hz), 4.38 (1H, s), 4.14 (2H, t, J = 7.2 Hz), 1.85 (2H, t, J = 7.2 Hz), 1.78 (3H, s), 1.78 (3H, s), 1.17 (6H, s). IRS

Elemental analysis measurement The results of the elemental analysis are in good agreement with the theoretical value of the calculated compound (7). o Step C-0 Preparation of N-(4-tert-butylbenzyl)cinchonidium bromide Ng EN HO HO H ion Ho _ J Topo LZ pe CH, N N on Cinchonidine (V+,7) g) was dissolved in tetrahydrofuran (aa 011( 4-tert-butylbenzylbromide “(Je Y+ +)) and tetrabutylammonium 0 iodide was added tetrabutylammonium (0.11 g); the mixture was stirred at 0 L overnight. The reaction mixture was cooled to room temperature; the solid was collected by filtration; and washed with ethyl acetate (04 mL). The obtained solid (sald) was dried under reduced pressure overnight to give the compound mentioned in the title 18.5(g). 1H-NMR (400MHz, DMSO-D6) 6: 8.99 (1H, d, J = 4.4 Hz), 8.27 (1H, 0 J = 8.2 Hz), 8.11 (1H, dd, J = 8.5, 1.0 Hz ), 7.89-7.79 (2H, m), 7.78- 10 (1H, m), 7.63 (2H,d, J = 8.4 Hz), 7.59 (2H, t, J = 8.4 Hz), 6.72 7.71 (1H, d, J = 4.2 Hz), 6.57-6.51 (1H, brs), 5.67 (1H, ddd, J = 17.0, 10.4, Hz), 5.14 (1H, d, J = 17.2 Hz), 5.08 (1H, d, J = 12.6 Hz), 5.00-4.90 6.4 (2H, m), 4.30-4.18 (1H, m), 3.91 (1H, t, J = 8.7 Hz), 3.74-3.64 (1H, CARY

h — g m), 3.35-3.18 (2H, m), 2.76-2.65 (1H, m), 2.18-1.94 (3H,m), 1.90 - (1H, m), 1.40-1.22 ( 1H, m), 1.34 (9H, s). 1.78 Y—z shall Prepare N-(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide Ny EN Pp . HO 1 HO + Ho : Ho b© (oN ee - CH bz CH 2 N 3 N 3 0 CH, oH, oH os 8 added YA,©) N—(4-tert-Butylbenzyl)cinchonidium bromide >=(« AMBERLYST (trademark) Yi (strong basic ion exchange resin styrene divinylbenzene matrix ) YA, 0) g) (Jo YAY) methanol gli ; The mixture was stirred at room temperature overnight. The non-jall was then filtered through celite 3 as washed with methanol (Je 01). To the filtrate was added 4-methoxyphenol (5.8 g); the solvent was evaporated. The residue was evaporated as Do not drip 100 times Toluene (ml); Toluene Yo (ml) was added. after that; (Je Yo 0) diisopropyl ether was added dropwise; The mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration; Vo was washed with diisopropyl ether (Je 5 1) and the mixture was dried under reduced pressure at room temperature overnight to give the compound mentioned in the title (TVA (g). 1H-NMR (400MHz, DMSO-D6) 6: 8.91 (1H, d, J = 4.4 Hz), 8.17 (1H, d, J = 8.2 Hz), 8.07 (1H, d, J = 8.4 Hz) , 7.89 (1H, d, J = 4.4 Hz), 7.79 (1H, t, J = 7.6 Hz), 7.64 (1H, t, J = 7.5 Hz), 7.57-7.52 (5H, m), 6.56~ (2H, m), 6.43-6.42 (3H, m), 5.67-5.59 (1H, m), 5.28 (1H, d, J = 0 6.55 Hz), 5.12 (1H, d, J = 17.2 Hz), 4.92 (1H, d, J = 10.6 Hz), 4 12.1 1H

for g (1H, d, J = 12.1 Hz), 4.65-4.53 (1H, m), 3.80 (1H, t, J = 8.8 Hz), 3.65- (1H, m), 3.57 (3H, s) ), 3.25 (1H, t, J = 11.6 Hz), 3.10-3.07 (1H, 3.63 m), 2.67 (1H, brs), 2.07-2.02 (2H, m), 1.95 (1H, brs), 1.79 -1.76 (1H, br m), 1.33 (9H, s), 1.16-1.11 (1H, m).© Step D Preparation of 3-hydroxy-3-methylbutyl toluene-4-sulfonate H.C ENP Al me H3C CH3: 4, Al me H3C CH3 “Peace be upon me, I bin tamped sow gravel in a nitrogen atmosphere; Yer) 3-methylbutane—1,3-diol g) was dissolved in pyridine 5001 (mL); A solution of 4-methylbenzenesulfonyl chloride (+ © g) 0 in toluene (400) (Je) and acetonitrile (Je Y YO) acetonitrile was added dropwise over the course of 2 hours. The reaction mixture was stirred at room for ; hours; and toluene (ml) ov) and water (Jo YA) was added to allow separation of the layers. The obtained organic layer was washed sequentially with aqueous sulfuric acid 8010 sulfuric acid 8006015 and water (twice). The solvent was evaporated in the obtained organic layer; the residue was evaporated non-driptically with toluene (000 Jo) to give the compound mentioned in the title (270 g). 1H-NMR (CDCI3) 8: 7.81-7.76 (2H, m), 7.36-7.31 (2H, m), 4.20 (2H, td, J = 6.8, 1.6 Hz), 2.44 (3H, s), 1.85 (2H, td, J = 6.8, 1.6 Hz), 1.33 (1H, s), 1.21 (6H, s). Example Y A Yo synthesis: 1e

m g 2—-{4-[(9R)-9-hydroxy-2—(4-hydroxy—-4-methylpentyloxy)-9- (trifluoromethyl) -9H-fluoren—4-yl]-1H- pyrazol-1-yl}-2- methylpropanamide (compound )¥(( Step 1 Ethyl 4-[(9R)-4-chloro-9-hydroxy-9-(trifluoromethyl)-9H-fluoren- 2- © yloxy]butyrate Cl Cl otherwise #ha OH 8 [> 0 Ny 0 0 : z : OH e OH 0 FF F Y + +) dissolved (9R)— -4-Chloro-9—(trifluoromethyl)-9H-fluorene-2,9—diol mg) obtained in step 01 according to metal 1 in N,N-dimethylformamide (¥ Vo) Ml); potassium carbonate 185 (mg) and Veo (ethyl 4-bromobutyrate μl) added; The mixture was stirred at room temperature for 1 hour. To the reaction mixture water was added; The mixture was extracted twice with ethyl acetate. The obtained organic layer was washed sequentially with water (twice) and saturated brine. The obtained organic layer was dried on magnesium sulfate (WY) and the insoluble matter was filtered off; the solvent was evaporated in the filtrate. 15 The obtained residue was purified by silica gel column chromatography (a mixture of hexane ily acetate as eluent solvent; rinsed first with a mixture at mixing rate 51 (hexane:ethyl acetate); thereafter sequentially with mixture at mixing rate:1; and also with mixture at mixing rate (V2) to give the compound mentioned in the heading (YAY) in mg). 1H-NMR (400MHz, CDCI3) 6: 8.19 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = Hz), 7.46 (1H, td, J = 7.6, 1.0 Hz), 7.32 (1H, td, J = 7.6, 1.0 Hz), 0 7.7 (1H, brs), 6.93 (1H, d, J = 2.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.05 7.16 1 e

q — g (2H, t, J = 7.1 Hz), 2.82 (1H, s), 2.50 (2H, t, J = 7.1 Hz), 2.15-2.06 (2H, m), 1.25 (3H , t, J = 7.1 Hz). © ve oe gest , what c10) oY . 0 Sa 3 1 Fk FE in nitrogen atmosphere; Dissolved: ethyl 4-[(9R)-4-chloro-9-hydroxy-9—(trifluoromethyl)-9H-fluoren-2- Y4V) yloxy]butyrate mg) in THE (¥ ml) ; A methyllithium | solution was added 0.17 diethyl ether 7.7 M (Je) was dissolved in drops at 0°C. The reaction mixture was stirred at the same temperature for 2 hours. Water was added; the mixture was extracted with ethyl acetate ( twice).The obtained organic layer was washed sequentially with water (twice) and saturated brine.The obtained organic layer was dried on magnesium sulfate (WY) and the insoluble matter was filtered; the solvent was evaporated in the filtrate.Vo The remaining sald) obtained was purified by a silica gel column chromatography (a mixture of hexane and ethyl acetate was used as solvent eluate; first eluted with a mixture at mixing rate Yi) (hexane:ethyl acetate); thereafter with a mixture At a mixing ratio (7:1) to give the compound mentioned in the title (119 (mg). 1H-NMR (400MHz, CDCI3) &: 8.19 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = Hz), 7.47 (1H, td, J = 7.7, 1.0 Hz), 7.32 (1H, td, J = 7.7, 1.0 Hz), 0 7.7 (1H, brs), 6.93 (1H, d , J = 2.3 Hz), 4.02 (2H, t, J = 6.4 Hz), 2.82 7.17

-11 “= (1H, s), 1.92-1.85 (2H, m), 1.65-1.62 (2H, m), 1.26 (3H, s), 1.25 (3H, 5:) Step 1 Ethyl 2-{4-[(9R)-9-hydroxy-2—(4-hydroxy-4-methylpentyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1 -yl}-2-methylpropionate © CH Lm CH, OH Nh | po Ho. and Hej 0 3 m m from 7 / a sine + eo) oN hy 58 oi [2 m27 CH raz an name so oon Fy oT CH, CH, 2 001 HG CH, in an argon atmosphere; (9R)-4~chloro-2~(4-hydroxy—4-methylpentyloxy)—9— a0--911-100160-9- (trifluoromethyl) (5 5 mg) dissolved in 1 © ) 1,4-dioxane mL); ethyl 2-methyl-2-[4—(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H- (pak Y4¢) pyrazol-1-yl] propionate 0 water (+0 mL); ghd potassium phosphate (YYA) tripotassium phosphate mg); palladium acetate (4 mg); SPhos (YY) added; The mixture was stirred at 1002 m for a period of one and a half hours. The reaction mixture was cooled to room temperature; water has been added; The mixture was extracted with ethyl acetate (twice). The obtained organic layer was washed sequentially with water (twice) and saturated brine. The obtained organic Vo layer was dried on anhydrous magnesium sulfate; The insoluble matter is filtered out; The solvent was evaporated into the filtrate. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate at a mixing ratio of 0:1 (hexane:ethyl acetate) was used as eluate solvent) to give the compound mentioned in heading 718 (mg) . 1H-NMR (400MHz, CDCI3) &: 7.69 (1H, s), 7.63-7.62 (2H, m), 7.21- (4H, m), 6.81 (1H, d, J = 2.3 Hz), 4.21 (2H, q, J = 7.1 Hz), 4.04 0 7.19 IRS

h \ —_ _ (2H, t, J = 6.3 Hz), 2.82 (1H, s), 1.92 (3H, s), 1.91 (3H, s), 1.89-1.88 (2H, m) , 1.66-1.64 (2H, m), 1.26 (6H, s), 1.26-1.23 (3H, m). 35d) ¢ R)-9-Hydroxy—-2-(4-hydroxy—4- methylpentyloxy)-9-4)]-¢}-¥ (trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}~2-methylpropionic © acid M “Ren H.C CH, a NH 0 P Vi / Yeo 0 ay 0 ST 1 CE 3 3 p OH HL CH, p F Dissolved: Ethyl 2-{4-[ (9R)-9-hydroxy-2—(4-hydroxy-4-methylpentyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionate 0 (pale TVA) in Y,T ethanol (mL); has been added; titer of aqueous sodium hydroxide (YY) (μl) and the mixture was stirred at room temperature overnight. The reaction mixture was titrated with 1 M hydrochloric acid; The extraction was done with ethyl acetate (twice). The obtained organic layer was washed sequentially with water (twice) and saturated brine. The obtained organic layer Vo was dried on anhydrous magnesium sulfate; The insoluble matter is filtered out; The solvent was evaporated in the mud ill product to give the compound mentioned in heading YY (mg). 1H-NMR (400MHz, CDCI3) &: 7.73 (1H, s), 7.68 (1H, s), 7.63-7.62 J = , A (1H, m), 7.23-7.09 (4H, m) , 6.78 (1H, d, J = 2.6 Hz), 4.02 (2H, Hz), 1.93 (6H, s), 1.89-1.86 (2H, m), 1.65-1.61 (2H, m), 1.25 (6H , 6.3 Yo. (5 IRS

h \ —_ _ step © 2-{4-[(9R)-9-Hydroxy-2—-(4-hydroxy-4-methylpentyloxy)-9- (trifluoromethyl) -9H-fluoren—4 -yl]-1H-pyrazol-1-yl}-2- methylpropanamide (compound )¥() o to ob ph 0 l b 0 / oN (I) 0 but F—¢ "% "A on HC CH OH HC CH, F 3 3 F 8 A in nitrogen atmosphere; dissolved: 2—-{4-[(9R)-9-hydroxy-2—(4- hydroxy—-4-methylpentyloxy)-9- (trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}~2-methylpropionic Ad) acid mg) in «(d = 1 ( N,N-dimethylformamide ammonium chloride YA) chloride 0 mg) - 1 £A) N,N-diisopropylethylamine µl) and -1 [bis(dimethylamino)methylene] added -1H-1,2,3~triazolo[4,5-b]pyridin—1-ium 3- (oxide hexafluorophosphate (HATU) 44 mg); The mixture was stirred at room temperature overnight. To the reaction mixture water was added; The mixture was extracted with ethyl acetate (twice). The obtained organic layer was washed sequentially with diluted (twice) VO braine and saturated braine. The obtained organic layer was dried on anhydrous magnesium sulfate; The insoluble matter is filtered out; The solvent was evaporated into the filtrate. The residue obtained by thin-layer chromatography was purified from silica gel (a mixture of chloroform and methanol was used at a mixing ratio of 9:1 (chloroform : methanola 00610800 (eluate solvent) to give the compound mentioned in title £A) mg; optical purity 7.5 6.6969.). the

What was the optical clarity determined under the conditions of HPLC analysis? Image retention time 111 (R) min; Image retention time (5) 14.4 minutes. Relative optical rotation 00[H] +4-0(*97.5 ‎(Ye MeOH 0.1H-NMR (400MHz, DMSO-D6) 6): 8.07 (1H, s), 7.66 (1H, s), 7.57 -7.55 (IH, m), 7.34-7.31 (1H, m), 7.24-7.23 (3H, m), 7.18 (1H, s), 7.11 (1H, brs), 6.94 (1H, brs), 6.86 (1H, d, J = 2.3 Hz), 4.16 (1H, s), 4.03 (2H, a

J = 6.5 Hz), 1.80 (3H, s), 1.79 (3H, s), 1.80-1.75 (2H, m), 1.51-1.47 (2H, m), 1.11 (6H, s). (iii) Preparative crystallization of Jil compound 0 to compound (pale £4) (F) synthesized by the above exemplary steps to which a mixture of MeOH and water (1:7 volume ratio) was added, + ml)). after that; To this solution, a crystal (1,0 (pale) of compound (7h) was added, and the mixture was stirred at room temperature for ? days. The precipitated solid was collected by filtration to give a crystal (£1 mg) of compound (7). Preparation Compounds (a)» (b)» (c) 93 (Vo). Compound [of] compound (b), compound (c) and compound (d) were obtained; represented by the following formulas; obtained as active forms Visually according to the production method described in international order EVVEA 0101. CARY

0 l NH 1 l +] 2 ay m HO ped wh en

Ho the six 1 6.

AN wl

Foe

EN OH

F

( ) JKHJKH compound 2-(4-{(9R)-9-Hydroxy-2-[2—-(3-hydroxyadamantan—1- yl)ethoxy]-9—(trifluoromethyl)-9H-fluoren—4 -yl}-1H-pyrazol-1-yl)acetamide °

Cris

M, MN0 &

HO0

H3C Al Amsj =f) he Na Ada 3 ¢ Al 2 OH p Compound (B) (9R)—-2—(2-Hydroxy-2-methylpropoxy)—4—( 1-methyl-1H-pyrazol-4-yl)- 9— (trifluoromethyl) -9H—-fluoren-9-ol

C A — oH N > ~~ and I B HO TY Ada L : L 1 TN MN Obtain SN BAT F "OH 5H Compound (C) (9R)- 4-[1-(2-Hydroxyethyl)-1H-pyrazol-4-yl]-2-(2-hydroxy-2- methylpropoxy)-9- (trifluoromethyl) -9H-fluoren-9-ol 0 . H=C Ruy A min 3C Noy 2 36 A J FN in a has m noy F.o% Ho a F F lo} compound 2(3 —-{4-[(9R)-2-Fluoro-9-hydroxy-9—(trifluoromethyl)-9H—-fluoren—4-yl]- 1H-pyrazol-1-yl}-2-methylpropanamide JES on the formulation according to the present invention; the following preparation may be stated. However, 0 of the present invention is not restricted by these examples of formulations. Ideal formulation 1 (capsule production) 1) compound according to example 1 ( Compound Pale Vo (1) L

-??-") Microcrystalline cellulose Pale 01) 0 mg lactose ¢ (Magnesium stearate 1 mg 1); (V oY £5) is mixed and filled into a gelatin capsule. © Perfect Formula ¥ ( Producing tablet 1) compound according to example 1 (compound 01) 1 (g) 1 lactose mor 0 cornstarch yo g carmellose calcium g A 5 (magnesium stearate 1 g) The total amounts of 1 oY 1) and 10 g of ¢ ( ) are kneaded with water; As vacuum drying; As sieving. The sieved powder is mixed with VE g of 4) and 1 g of ©) and the mixture is pressed (dad gs) in a tablet making machine. In this way 01 tablets are obtained, each containing 0 mg of compound Example 1 (compound ((Y) For each tablet obtained 1 exemplary experiment: 1 Inhibitory effect of PDHK activity in vitro The inhibitory effect of PDHK activity was assessed indirectly by measuring remaining PDH activity after a kinase reaction in the presence of a test compound. (Inhibitory effect of PDHK1 activity in case of human chPDHKI 00011161) Genbank accession number ¢ (L42450.1). Yo 0.7 kb was isolated from a fragment encoding this protein from CDN A of human liver by cDNA hPDHK polymerase chain reaction (PCR) modified dua 1e.

h7__ FLAG-Tag sequence was added to the N terminus which was prepared by PCR and cloned into vector (01175-11078980). The recombinant genomic product construct was transformed into E. coli (DHS5a-TOYOBO). 25 Identification of sage recombination product clones”; DNA was isolated and subjected to DNA-sequencing analysis. A clone that was predicted to have 0 DNA was tested for expression work. to express activity 001011161; WIA E. coli cells BL2I(DE3) (Novagen) were transformed with vector 01175 containing modified hPDHK cDNA. Escherichia coli were grown to an optical density (+, Tew nanomol/L) at + lm. Then, protein expression was induced by the addition of 000 μmol/L of isopropyl-]-thiogalactopyranoside-Lm10M500A08005006/A8-111098180100. E. coli were cultured at 10°C for ½ hours and collected by centrifugation. A re-dispersed solution of Escherichia coli paste was disturbed with a micro-diluent. The FLAGγ-labeled protein was purified using a FLAG binding gel (Sigma). The gel was washed with 01 mmol/L of: N-(2-hydroxyethyl)piperazine—-N'-2 -ethanesulfonic acid-sodium 10,hydroxide (HEPES-NaOH) 80 mmol/l sodium chloride 961 « sodium chloride ethylene glycol ; and 1,700 of a bulk copolymer of polyoxyethylene—polyoxypropylene “Pluronic F-68) pH as “(A 0) binding protein elution of 2,00 mmol/L of 05-80 001 Yo μg/mL Own peptide FLAG mmol/L Sodium Chloride 901 ¢ sodium chloride ethylene glycol Silas 760.1 Pluronic F-68 (pH (Av) The eluted fragments containing the FLAG-labelled protein were transfected and dialysed against Yoo [mmol/L of Yoo (HEPES-NaOH] [01.5 mmol/L NaCl]). from CER!

“A 9611 “ethylenediamine tetraacetic acid (EDTA) ethylenediamine tetraacetic acid at OA = (pH 0.8); and preserved at Pluronic 7-68 960,1 se Sila ethylene of inhibition activity 9640 Fahd »; The concentration of enzyme 700441 was determined at the lowest specified concentration on PDH. PDH (porcine heart PDH complex, Sigma P7032) was mixed + 00 units/mL © 3 - mmol/L of (501 μg). 7000111641/ml in buffer solution 0.1 mixing mmol/L of DiI 01 7.0 (pH morpholinopropane sulfonic acid 01 mmol/L dipotassium hydrogen phosphate) ¥ mmol/L potassium chloride magnesium chloride ? mmol/L dithio Pluronic F-68 960.7 (EDTA mmol +,¢ “chloride 0”); The mixture was incubated at “C” overnight to obtain a dithiothreitol complex.PDH/hPDHK1 Dimethyl sulfoxide (DMSO) The test compounds were diluted with dimethyl sulfoxide (μL) and 7?*5,? *1,*(μl); test compound Yo) 1011/701011161 addition of complex 16 μl) to a flour plate with AO (diluted with buffer; ATP 10 μmol/L The reaction was carried out (Corning 3679 (transparent eye 22330 UV having a surface area of \u200b\u200bhalf a microliter) to 1.0) DMSO min. £ was added 0 saa At room temperature PDHK PDH was used for comparison purposes instead of the test compound. In order to determine the maximum reaction rate (µL) to sample eyes instead of the test compound in the absence of DMSO (add 0.5 hPDHK1 sodium. 0 µL of substrates)© mmol/L sodium pyruvate 10 after that; mmol/L thiamine ©NAD mmol/L VY (A mmol/L co-enzyme © » pyruvate diluted in buffer) was added. The mixture was incubated with ¢ thiamin pyrophosphate pyrophosphate The remaining .PDH was kept at room temperature for 0 min; H1 activity was measured

h q —_ _ Absorbance at TE nm before and after the PDH reaction was measured using a microplate reader to detect NADH produced by the PDH reaction. The inhibition rate 01011161 (%) for the test compound was calculated from formula [( (PDH activity of the test compound - PDH activity of the control sample) / PDH activity of the model eye - PDH activity of the control sample).] 0% of the inhibition of the activity of 55011161. Then, the results obtained by using compound a (Y), compound (Yh) and compound (7) as test compounds are explained in the following table. 1. The inhibitory effect of the activity of PDHK?2 in the case of human PDHK2 chPDHK2 (Genbank Accession No. 580040478.1); 0 cDNA hPDHK2 is modified in which a FLAG-Tag sequence was added to the no end of the (pPReceiver-MO1/PDK2-GeneCopoeia) cDNA hPDHK2 clone prepared by PCR and cloned into the L vector (PET17b— -Novagen) recombinant construct was transformed into Escherichia coli ((001150-1©070860). Recombinant clones were identified; plasmid DNA was isolated and DNA-sequencing was analyzed. Vo contained the DNA sequence predicted to trigger expression.To express chPDHK2 activity E. coli cells of strain BL2I(DE3) (Novagen) were transformed with vector 01175 containing modified cDNA 701011162.Escherichia coli were grown into optical density, + (tew nanomol/L) at 1 0 5 . Then, protein expression was stimulated by the addition of 5.0 μmol/L isopropyl—p-thiogalactopyranoside. 0 has been cultivated. Escherichia coli at 70 °C for © hours and collected by centrifugation. A re-dispersed solution of Escherichia coli paste was disturbed with a micro-diluent. The FLAG-tagged protein was purified using a FLAG-binding gel. The gel was spiked with 01 mmol/L Owe «HEPES-NaOH mmol/L NaCl; 1% ethylene glycol; and 721 Pluronic F-68 (pH ahd As “(A 0) Binding Protein 2 Yo mmol/L CER!

Vm 761 mmol/l NaCl”; FLAG 500 μg/ml Peptide 001 (HEPES-NaOH) Soaked eluted fragments (Ar (pH 7-68 Pluronic 960.1 ethylene glycol” ; and

HEPES—01 mmol/L dialysed against FLAG containing protein numbered B ethylene glycol; EDTA 961 mmol/L NaCl; +0,0 mmol/L Yor (NaOH) on assay; LOA maintained at Ar (Pluronic F-68 pH 960.,1, © hPDHK2 enzyme concentration set to Ji Concentration giving 96900 PDH inhibiting activity 0.05 units/mL of PDH +A µg/mL 01011162 was mixed in buffer (0 mmol/L) of L 3-morpholinopropanesulfonic acid (pH Yo (Vr mmol/L dipotassium hydrogen phosphate 101 " dipotassium hydrogen phosphate 0 mmol/L potassium chloride; ¥ mmol/L magnesium chloride; +f mmol/L EDTA and 960.7 Pluronic F-68?mmol/L of di(dithiothreitol) and the mixture was incubated at **C overnight to obtain complex 1011/01011162. The test compounds were diluted with DMSO. PDH/WPDHK2Y (yo complex) μl); test compound (58.9 L) and 3.5 μmol/L ATP (diluted with buffer; 4.5 μL) 0 were added to a plate flour with 976 UV-transparent eyes of half an area” PDHK reaction was performed at room temperature for £0 min. DMSO (1.0 μl) was added to the eyes Comparator instead of checksum. In order to determine the maximum rate of PDH reaction; DMSO (0.0 μl) was added to sample eyes instead of compound in the absence of .10014/62 thereafter; 01 μL of substrate © mmol/L sodium lisp © mmol/L of Co-0 coenzyme 11 (A) mmol/L (NAD) 5 © mmol/L thiamine pyrophosphate; dilution with buffer solution).The mixture was incubated at room temperature for 0 min; residual PDH activity was measured. Absorbance was measured at Viv nm before and after PDH reaction using a microplate reader to detect NADH Produced by the reaction of PDH The hPDHK2 activity rate (%) of the test compound was calculated from the formula [((PDH activity of the test compound - PDH activity of the control) H1

/ PDH activity of the model eye — PDH activity of the control sample.] Then clarify the results obtained using Compound (Y; Compound (H); Compound (7); Compound (A) » Compound (B), Compound (C) and Compound (D) as test compounds in the following table 1. TABLE 1 IC50 hPDHK2 IC50 hPDHK1 Compound (µmol/L) (µmol/L) Ideal experiment oY Ex vivo PDH activation assay Test method Test compound il was evaluated for activity PDH production on tissue was detected by an iodonitrotetrazolium violet (INT)-conjugated system to measure

PDH Lia 0 H1

Normal males to the carrier group and the compound Dawley–Sprague rats were assigned; © ml/kg) or methylcellulose from test Sle methylcellulose. vector (960.5 solution hr post-administration; rats were sterilized. Yoo test compound was administered to rats. after © or mg/kg); T+) sodium pentobarbital was injected into the intraperitoneal membrane of sodium pentobarbitol. epididymal adipose tissues, ll Liver slides and adipose tissue ©

To liver slices, 4 volumes of ice-cooled homogeneous buffer (*7.5 mol/L sucrose; © mmol/Letser) tris(hydroxymethyl)aminomethane hydrochloride (pH 7.5" 1 mmol/L) were rapidly added. L. ethylene diamine tetra acetic acid “(EDTA)ethlene diamine tetra acetic acid, and the mixture was homogenized using a homogenizer

0 - Polytron homogenizer The homogenate was centrifuged at <680 g; 4 °C for 0 min to obtain the supernatants. The supernatants were centrifuged 1 (mL) at 0,600,000 g; Then for 10 minutes to collect the sedimentation products. The precipitate was washed by (sale) suspension in homogenizer buffer (1 ml) and centrifuged in the same way. The precipitate was frozen with liquid nitrogen and stored at -<0 + 28 °C as liver mitochondrial fragments.

1 to adipose tissue; © volumes of ice-cooled buffer homogenizing solution were quickly added; The mixture was homogenized using a Polytron homogenizer. The homogenate was centrifuged at 100g; pf for 10 minutes to obtain the supernatants. The supernatants were centrifuged 1 (mL) at Tew kg; 24 m for 10 minutes to collect sedimentation products. The precipitate was washed by resuspending in homogenizing buffer (1 ml) and centrifuged by the same method. Output has been frozen

Ye precipitated with liquid nitrogen and stored at PA as mitochondrial adipose tissue fragments. Mitochondrial fragments were dissolved and resuspended in sample buffer (Yo), + 01 mol/L sucrose 686 mmol/L tris(hydroxymethyl)aminomethane hydrochloride (pH ov (V,0 mmol/L) Vy potassium chloride ml/L Triton X=) 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol

© 100)). Active PDH activity (PDHa activity) and total PDH activity (PDHt activity) were measured to assess

E1

To measure PDH activity, equal volumes of mitochondrial suspension and activation buffer solution were mixed (° A mol/L sucrose Yo mmol/L tris(hydroxymethyl)aminomethane (pH ¢) (V,0 © mmol/L potassium chloride 1 » potassium chloride ml/L Triton 26-100 4 mmol/L calcium chloride “calcium chloride 56 mmol/L © magnesium chloride 01 » magnesium chloride mmol/L sodium dichloroacetate and the mixtures were incubated at PTY for 10 minutes. Forty microliters of mitochondrial suspensions were diluted with sample buffer added to an AT microplate for measuring Activity and typical eye measurement YAY was then added μL of reaction mixture (057 mmol/L potassium phosphate buffer solution (pH 5), 1.5 mmol/L Y,A ¢ carnitine-DL 0 mmol/L 71 (NAD mmol/L thiamin 1,11 thiamin pyrophosphate mmol/L coenzyme 0.1 A ml/L 01-100 Triton 2 mmol /l magnesium chloride; YA lil fie mmol/L sodium oxamate ( to each eye; Then, 010 μL of 0 mmol/L sodium pyruvate Vo for the activity assay or water for the sample assay was incubated. The mixtures were incubated at room temperature in the shade. Absorbance was measured at 150-5001 nm; which was due to the reduction of the last electron acceptor measured; Using a microdish reader over time the change in absorbance was calculated. PDH activity was calculated by subtracting the change in absorption in a typical eye from the measurement of eye activity. The ratio of PDH activity to PDH activity was calculated and 0 was taken as an indicator of PDH activation. Results obtained using compound (7h) are illustrated; Compound (©)» Compound FL] Compound B » Compound (C) and Compound (la) as test compounds in the following table oY Figure 1 (liver) and Figure ? (adipose tissue). Furthermore it; The results obtained using compound (7) are shown in the following Table 7. Yo Table Y 1e

PDHa activity (% of PDHt activity) © hours Yo hours © hours Yo hours compound v mg h mg/7 ES PRADA mg/7 ES mg/mg 7 ES The amount of the carrier, how much aad For the transport group, the asf, the carrier, compound + 1: YoY] 01 + 11 oY ahm aga YEHVY (cY) compound + YoY] AY "| 1 for me aj + a ‎ +1 Ahlam 1 (0 Composite + Adag 10.+ 11 1 + 11.1 YoY] 1 4 Gala 0 Composite

SEY of ood YAY FEY YEVY] a +0 (b) compound

VEYA 10.11 gm+; 10.11 +111 : mah a + (z) compound + 101.11 + 11+ VEY +17 10+61 +0 8 0 =n) average 5 + No.

FRE

AG 7 - table? PDHa activity (% of PDHt activity) ~ [a as Fie sand of group | ] Video TEYA YYEVE TEVA Standard EEN S (7) Average 5 (n=3).D.+£ Experimental example ©: Effect of repeated administration of the test compound on 116/810 in the ZDF test method Fethran Zucker obese and diabetic (male; 1-week-old; CHARLES (RIVER LABORATORIES JAPAN INC.) animal model of type 7 diabetes; after being placed on a purified diet (0.4% of diet) The carrier group and the groups given the test compound were assigned no bias in plasma glucose, insulin levels, HPALC levels, and 0 body weights. Repeated oral doses of the test compound 1 (mg/kg/#mL) to ol times before −8 hours before dark.960.5 methylcellulose Al solution was administered orally in the same manner to Mice from the vector group On the VE day of administration, blood samples were collected from a vein It is located in the tail and is measured at a3 level. HbAlc (%) Statistical analysis was performed by Dunnett test. Values of v0>p+ , were considered statistically significant.

The results obtained using compound (7) and compound (7) as test compounds are shown in the following table 6. Sal; HbAlc (%) compound of the JER vector group, kg day VE from the (0 01 -) .0.0.+ 5 hug o (Dunnett) vs. the carrier group (test +, <0% p (human 8-90-90 ether-linked gene) experimental hERG cell batch cross-linking assay: JE complete Test method —(human hERG fi) 8-90-9060 Transmitted Infection has a gene associated with HEK293 using 0 cells according to the whole-cell batch cross-linking technique. Effect on hERG stream was examined (Cytomyx Limited)

BNA-)CO2 cells were incubated with Jas-infected hERGL HEK293. Cells of CO20% humidity (YY are shige) were passaged under conditions (111), TABAI ESPEC CORP. 1 cm? Contains saturated VO type collagen. The culture containers used were a sealed flask (AGC TECHNO GLASS CO., Ltd. 00-4600; 10) and a sealed culture plate of #8 ? mm containing collagen type TECHNO GLASS CO., Ltd. 60 (00-4600 00). 1 60 min.) The culture medium used was MEM-E (Eagled minimum essential medium (Nikken (Earle) salts)

1/7

BioWest, supplemented with 0% (fetal bovine serum) (biomedical laboratory

Invitrogen “NEAA) MEM Non-Essential Amino Acid Solution 01 and L.L.C. hERG Expression of the WIA Geneticin Selection Geneticin Geneticin Corporation (Corporation) from 4 0171 μg/ml cells were added as control cells.” 40810 was applied to a concentration equal to days before measuring 4 mM V to Vo on hERGS culture plate that had been infected with HEK293 © above without deal. The culture plate produced for measurement contained Geneticin stream hERG medium (Invitrogen Corporation). The highest evaluation concentration for each compound was determined from the highest concentration at which no precipitation was present in the fluid.

Y: MgCl2 mmol/L ¥,0 KCl: mmol/L 0400 Standard extracellular NaCl: 01 mM glucose: AY mmol/01 : 15085 mmol/L 08012: see? mmol/L; Ve with Tris base). as an application method; Each VE was pronounced in mol/L (adjusted to pH of a solution drawn from tube 7 having a terminal diameter of about 0.75 mm; contiguous (about ? mm) min. [de vf for cells; And it is applied to the cells The rate of excretion was about The experiment was carried out at room temperature under a phase-reversing microscope A dish of mm in which the cells were placed was prepared on the measuring device, and the fluid outside the cells was applied to a culture of length 05 Continuously measure the cells from tube 7. The measuring glass electrode was filled with a fluid inside 01 mM KCl 111 mmol/L. Cells: Potassium Gluconate (potassium gluconate) V0 (mmol/EGTA) 1 ¢ 1/-1/09: © mmol/L (1:1/09012 mol/L with Tris base) is 17.7 mmol/L (adjusted to pH 01 Conventional HEPES on cells and maintenance voltage was configured for ALIS Ye mV cell batch interlocking method applied. Under constant voltage the full cell current was amplified by an Ave amplifier and the data was uploaded «(Axon Instruments, Inc. ¢ (AXOPATCH-200B) for batch networking using software Analysis (Intermedical ©0., Ltd. (MC-P642400) on a 1H data acquisition computer (PCLAMP 9.2, Axon Instruments, Inc.).

A —_ 7 _ hERG current measurement was performed in the next two steps. In both cases WIS” the hERG current was initiated by giving the baseline voltage (maintenance voltage Av mV; previous pulse + Yo mV; 05 sec test pulse .mV mV; 0 seconds). Step (1): (1) The above base voltage was applied at 11 Hz for 2 minutes. © Step (7): The above base voltage was applied to subtract 3/5 of 9.2 pCLAMP to remove current

the leak. Then repeat this three times, taking its average as a current of 6 . After step (1); step (7) was performed (about ? minutes); The maximum tail current obtained by applying the test pulse to the hERG current obtained by the (Y) step method was taken as the current value 0546. Led follows; Operations (1) and (7) were repeated alternately until

ERG Experiment ended and current value measured (>0 min); The fluid was exchanged out of the Yo fixed three times (approximately hERG dad current) and then standardized cells were recorded instantaneously with each application fluid. The value of the 5886 stream was measured three times (approximately minutes) in the same way while perfusing a fluid application, and the obtained current value 0 after quenching the application fluid. hERG was taken by the third measurement as the current value

0 The data for each cell was converted to a relative value averaging three current values of 1,788,465 recorded at approximately 0 minutes before irrigating the application fluid (previous value) as .960000. This was measured for two cells and then averaged as a relative current (%) Relative current (%)(= xA+BY): A is the hERG current value after quenching the application fluid

Yo 8: average of three hERGs current values recorded at approximately 10 minutes before the application fluid (previous value) was quenched further; The squelch rate was calculated by the Gy DMSO group for the following formulas.

CARY

q —_ 7 _ squelch rate (%)(= 1.1 x(C+D)- Yeo ©: mean relative current (96) of the corresponding groups given test compound D: mean relative current (96) ) for the DMSO group. The results obtained using Compound (7); Compound (7) Compound (A); Compound (B)» Compound (C) and Compound (D) as test compounds are shown in the following table #. © Concentration (a) IC50 value Test compound Inhibition rate (96) (µmol/L) (µmol/L) Compound (b) 1 No N 001 7 Compound 105 Y (z) ARIA q y * Y 0 1 compound (d) ?, 4 101 ye may a): The highest evaluation concentration is initialized for each compound from the highest concentration at which there was no precipitation in the standard extracellular fluid.

A “= — experimental example ro Metabolic stability test in liver microparticle Test method Human liver microparticle (manufactured by Xenotech 10620 final concentration (after dilution); 17 mg protein/mL) was suspended in 0.01 mM of potassium phosphate buffer (pH 7.4) containing Je-dinucleotide oe J nicotinamide nicotinamide adenine phosphate 0.7 mM: dinucleotide phosphate D-glucose—-6 - 7.1 phosphate ml magnesium chloride: 7.7 ml mol glucose—-6-phosphate dehydrogenase £0 + unit/ml); And also mixed it with the test compound dissolved in MeCN/DMSO (0/40) (final concentration © micromolar). The mixture was incubated at ATV A for 0 minutes Tes min », then formic acid containing on acetonitrile (final concentration 96671 ( ; Water daly: (Acquity UPLC 015/A: SQ detector or TQ detector) The percentage of the remaining substance (%) was calculated from the obtained measurement value. 5 “The obtained results are explained Compound (oF) Compound (7) Compound (A); Compound (B)”; Compound (C) and Compound (D) as test compounds in the following Table 6. Table 6 Persistence in liver microsomes (residual 96 percent) Human Take a test inventory

— \ - BE Industrial Applicability Whereas the compound of the present invention or a pharmaceutically acceptable salt (aie) having inhibited activity (PDHKY) would be useful as an active ingredient for the treatment, prevention, or treatment of diabetes mellitus (type OV diabetes mellitus) type 1 etc.); insulin resistance syndrome; metabolic syndrome “hyperglycemia” hyperlactacidemia “complications of diabetes (diabetic neuropathy) Diabetic neuropathy; diabetic retinopathy; diabetic nephropathy; cataracts etc.); heart failure (als acute cardiac failure; chronic heart failure chronic cardiac Puel(failure 00) Progressive peripheral arterial disease, claudication Obedience | intermittent claudication “chronic obstructive pulmonary disease” “veo brain ischemia” stroke cerebral apoplexy; mitochondrial disease » mitochondrial encephalomyopathy ; cancer; pulmonary hypertension » or Alzheimer disease ull. 1 e

Claims (1)

_ A \ —_ HAMABA elements A compound represented by the formula [A]: 1. Q HE. A 3 AA HE ® A A» neo OH / H LB a . eas ) SAT 3 en / Py 1 of Nz ING for Foo Von A 3 3 F 0 or l or an acceptable salt to fish from. 1 is an n where the formula is: dad gs is a compound representative o 0 0 ' H.C HC Beer 3 SH Ham N_ H.C N_ 3 Con 3 CON ! / HyC OH HyC OH Lae s VE vo NA NA F b F =~ H ) 0 A OH A oH "2 FF FF {in {llh) [1] represented by the formula oY compound according to the claim.” In, PR St nn oo rena? Kon p F AT 2 {Il} ;. Compound of claim oF represented by the formula [lI] 1 mm NH, > 3 HC wn ON & the He OH = the ! BB H.C for Pan { Aq oH Po F as SS 1 A OH 0 0 Pa AT 8 (AAA) ° A compound represented by the formula [A!!]: CARS] ‎A ¢ —_ _ HO. dL TNH, > 83 HC nN ON J \ HC. 1 1 IN pra JESS To) clear eT HO ANT OW 4 F “ou, oS y A 98 Fr {In 11 pharmaceutical composition includes the compound according to any of Claims 1 to ©; or a pharmaceutically acceptable salt as a pharmaceutically acceptable terminator and carrier. o LV PDHK inhibitor includes the compound according to any of the claims 1 to © or a pharmaceutically acceptable salt thereof. A Inhibitor 0011141 includes the compound according to any of the claims 1 to ©; Or an acceptable salt 0 1 pharmacologist thereof. 4. Inhibitor 0011/42 includes the compound according to any of the claims 1 to ©; or a pharmaceutically acceptable salt thereof. 01.09 hypoglycemic agent includes compound according to any of claims 1 to ©; or a pharmaceutically acceptable salt thereof. CARS —Ao— include the compound according to which a lactic acid—lowering agent is a lactic acid lowering agent. 11 to ©; or a pharmaceutically acceptable salt thereof. 1 of the protective elements, resistance syndrome; Diabetes Resistant Syndrome Agent for the Prevention or Treatment of Diabetes LY; Hyperglycemia metabolic syndrome Insulin 105110 » Metabolic syndrome © hyperglycemia; Hyperlactacidemia “complications of diabetes mellitus cdiabetic complications Pel ¢ cardiac failure cardiomyopathy; myocardial ischemia; myocardial infarction » angina pectoris; High blood fats peripheral atherosclerosis; dyslipidemia 0 ; intermittent claudication; intermittent claudication arterial disease; Stroke brain ischemia chronic obstructive pulmonary disease mitochondrial disease mitochondrial encephalomyopathy mitochondrial encephalomyopathy 1 pulmonary hypertension; which includes the compound pursuant to any of the claims 1 to ©; or a pharmaceutically acceptable salt thereof. NY Preventive or curative agent according to OY protective element where diabetes is type 1 diabetes or Yoel diabetes 0 Where the complications of OY disease are selected as the preventive or curative factor according to the protective factor LV diabetes from the group consisting of diabetic neuropathy diabetic neuropathy; Diabetic retinopathy Nephropathy and cataracts Cataract retinopathy Yo where heart failure is OY deficiency The prophylactic or curative factor according to the protective element Yo e1 h — - acute cardiac failure; Or chronic heart failure. Figure (1) C * B ««< ; i i i wa : ? this is for a 1 1 ; : &EEE; to Lm since NN a - SS : 0 No To N 4 a 1! L AL J RW NAH ALA D get H { 3 : 0 3 D FACE i compound ACL aj button wa a ba jib 1 tab 1 CCIE !KBAJ AHIDI BL 0 : mg kg: no matter kg: º + h #bss {Y) form Sop 3 counting: A the: = A v SH 8 ma 1 . a jt NN = | : 1 - 7 >» 3 Bro X N L: A NO © L = 88 xX BE a. Bu a. E EE AN Sa He 1 8 N 8" Sas Bs 3 Ti | \ yl . | - A 0 N A B | A SPAREN I NE TN OE WE HR Oh His La WT Wm P ERR EE NR NRT IDNR + HOPE EE CONE PR TNE NE MRAB M: MADA AHME # ِْ 85 fag ¥ TT 1 1 LACHER Sold + Eke CARY The validity period of this patent is twenty years from the date of filing the application, provided that the annual financial fee is paid for the patent and that it is not invalid or forfeited for violating any of the provisions of the patent system, layout designs of integrated circuits, plant varieties, and industrial designs, or its executive regulations issued by King Abdulaziz City for Science and Technology; Saudi Patent Office P.O. Box TAT Riyadh 57??11 ¢ Kingdom of Saudi Arabia Email: Patents @kacst.edu.sa