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Definitions

• the present invention relates to nitrogen-containing tricyclic compounds and pharmaceutical uses thereof. More specifically, a nitrogen-containing tricyclic compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactic acidemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.), heart failure ( acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, Treatment of stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy or chronic
• ATP adenosine triphosphate
• PDH pyruvate dehydrogenase
• PDH catalyzes the reduction of nicotinamide adenine dinucleotide (NAD) to NADH simultaneously with the oxidation of pyruvate to acetyl-CoA and carbon dioxide (eg, Non-Patent Documents 1 and 2).
• NAD nicotinamide adenine dinucleotide
• PDH is a multi-enzyme complex consisting of three enzymatic components (E1, E2 and E3) and several subunits localized in the mitochondrial matrix.
• E1, E2 and E3 perform decarboxylation of pyruvate, production of acetyl-CoA and reduction of NAD to produce NADH, respectively.
• PDH is bound by two enzymes that have regulatory roles. One is PDHK, a protein kinase that exhibits specificity for PDH. Its role is to phosphorylate and inactivate the E1 ⁇ subunit of the PDH complex. The other is PDH phosphatase, a specific protein phosphatase that activates PDH via dephosphorylation of the E1 ⁇ subunit.
• the proportion of PDH in the active (dephosphorylated) state is determined by the balance between kinase and phosphatase activity.
• Kinase activity is regulated by the relative concentrations of metabolic substrates. For example, kinase activity is activated by increases in NADH/NAD, acetyl CoA/CoA and ATP/adenosine diphosphate (ADP) ratios and inhibited by pyruvate (eg, Non-Patent Document 3).
• PDHK isoenzymes have been identified in mammalian tissues. Among them, PDHK2 is expressed in a wide range of tissues including liver, skeletal muscle, and adipose tissue involved in glucose metabolism. Furthermore, PDHK2 is relatively sensitive to activation by elevated NADH/NAD and acetyl-CoA/CoA and inhibition by pyruvate, suggesting that PDHK2 is involved in the regulation of short-term glucose metabolism (e.g., Non-Patent Document 4).
• PDHK1 is highly expressed in cardiac muscle, skeletal muscle, pancreatic ⁇ cells, and the like. Furthermore, PDHK1 is suggested to be involved in ischemic diseases and cancerous diseases because its expression is induced through activation of hypoxia-inducible factor (HIF) 1 in ischemic conditions (e.g., Non-Patent Document 5).
• HIF hypoxia-inducible factor
• Type 1 diabetes Diseases such as insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes result in increased lipid oxidation and concomitantly decreased glucose utilization. This reduced glucose utilization contributes to hyperglycemia.
• type 1 and type 2 diabetes hepatic gluconeogenesis is accelerated, which also contributes to hyperglycemia.
• Decreased PDH activity elevates pyruvate, resulting in increased availability of lactate as a gluconeogenic substrate in the liver.
• Non-Patent Documents 8 and 9 Activation of PDH by PDHK inhibition is thought to increase the rate of glucose oxidation.
• glucose utilization in the body is enhanced and gluconeogenesis in the liver is suppressed, which is expected to improve hyperglycemia in type 1 and type 2 diabetes (e.g., Non-Patent Document 10). , 11, 12).
• Another factor involved in diabetes is impaired insulin secretion, which is known to involve decreased PDH activity in pancreatic ⁇ -cells and induction of PDHK1, 2 and 4 (e.g., Non-Patent Document 13, 14).
• the limited oxygen supply reduces the oxidation of both glucose and fatty acids and reduces the amount of ATP produced by oxidative phosphorylation in tissues.
• anaerobic glycolysis is enhanced in an attempt to maintain ATP levels.
• the result is an increase in lactate and a decrease in intracellular pH.
• Cells expend energy to maintain ionic homeostasis, but cell death occurs as a result of abnormally low ATP levels and cellular osmotic disruption.
• ischemia-activated adenosine monophosphate-activated kinase inactivates acetyl-CoA carboxylase by phosphorylation.
• a drug that activates PDH by inhibiting PDHK is thought to reduce lactate production by enhancing pyruvate metabolism. Therefore, it is thought to be useful in the treatment of mitochondrial diseases, mitochondrial encephalomyopathy or hyperlactatemia such as sepsis (eg, Non-Patent Document 20).
• PDHK1 or 2 The expression of PDHK1 or 2 is elevated in cancer cells.
• ATP production by oxidative phosphorylation in mitochondria is reduced, and ATP production by anaerobic glycolysis in the cytoplasm is increased.
• Activation of PDH by PDHK inhibition is expected to promote oxidative phosphorylation in mitochondria and increase production of reactive oxygen species, thereby inducing apoptosis of cancer cells. Therefore, activation of PDH by PDHK inhibition is considered useful for treating cancerous diseases (eg, Non-Patent Document 21).
• pulmonary hypertension is a disease characterized by increased cell proliferation in the pulmonary artery and increased blood pressure due to partial shrinkage of the pulmonary artery.
• Activation of PDH in pulmonary artery cells in pulmonary hypertension is expected to promote oxidative phosphorylation in mitochondria and increase production of active oxygen, thereby inducing apoptosis of pulmonary artery cells. Therefore, activation of PDH by PDHK inhibition is considered useful in the treatment of pulmonary hypertension, such as pulmonary arterial hypertension (eg, Non-Patent Document 22).
• Alzheimer's disease energy production and glucose metabolism in the brain are decreased, and PDH activity is decreased. Decreased PDH activity results in decreased acetyl-CoA production.
• Acetyl-CoA is utilized for ATP production in the electron transport chain via the citric acid cycle.
• Acetyl-CoA is a raw material for synthesizing acetylcholine, which is one of neurotransmitters. Therefore, a decrease in brain PDH activity in Alzheimer's disease is thought to cause neuronal cell death due to a decrease in ATP production.
• cholinergic nerves synthesis of acetylcholine, which is a transmitter substance thereof, is suppressed, which is thought to cause deterioration of memory and the like.
• Non-Patent Documents 23, 24 Activation of brain PDH in Alzheimer's disease is expected to enhance energy production and acetylcholine synthesis. Therefore, activation of PDH by PDHK inhibition is considered useful for treatment of Alzheimer's disease (eg, Non-Patent Documents 23, 24).
• Vascular dementia is a disease that is roughly divided into macrovascular disease type and small vessel disease type.
• macrovascular disease type cerebral infarction including ischemia-reperfusion is a factor, and nerve cell death is induced by an increase in pyruvic acid and lactate levels due to decreased PDH activity in the brain and a decrease in energy production.
• small vessel disease type white matter lesions due to cerebral hypoperfusion are a factor, and it is thought that cognitive impairment is caused by chronic hypometabolism of glucose.
• Activation of PDH in the brain in vascular dementia is expected to decrease lactate levels and increase energy production in macrovascular dementia, and to enhance glucose metabolism in microvascular dementia. Therefore, activation of PDH by PDHK inhibitors is considered useful for treatment of vascular dementia (eg, Non-Patent Documents 28, 29, 30).
• Dichloroacetic acid a drug having a PDH activating action
• diabetes myocardial ischemia, myocardial infarction, angina pectoris, heart failure, hyperlactic acidemia, cerebral ischemia, stroke, peripheral arterial disease, chronic obstructive pulmonary disease
• compounds with PDHK inhibitory activity have neuroprotective effects against retinal ischemia-reperfusion injury (Non-Patent Document 31).
• Retinal ischemic injury is involved in diseases such as glaucoma, diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion.
• diseases such as glaucoma, diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion.
• a compound having a PDHK inhibitory action reduces the severity of the disease in a disease model animal exhibiting chronic kidney disease-like renal damage and decreased renal function (Patent Document 1).
• PDHK inhibitors are useful for disorders related to impaired glucose utilization, such as diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacemia, diabetes mellitus. It is thought to be beneficial for treatment or prevention of complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.).
• PDHK inhibitors are also useful in diseases in which energy substrate supply to tissues is limited, such as heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina, dyslipidemia, atheroma.
• Sclerosis peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemia It is believed to be beneficial in the treatment or prevention of bloody optic neuropathy and chronic kidney disease.
• PDHK inhibitors are believed to be beneficial in the treatment or prevention of mitochondrial diseases, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, and the like.
• PDHK inhibitors are useful for diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactic acidemia, diabetic complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, Chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion , ischemic optic neuropathy or chronic kidney disease.
• X1 , X2 , X3 , X4 , X5 , X6 and X7 are each independently C or N;
• RA is (1) C 1-6 alkyl ⁇ the C 1-6 alkyl may be substituted with one substituent selected from the group consisting of hydroxy and cyano ⁇ ; (2) haloC 1-4 alkyl, (3) -OR a
• R a is (i) C 1-6 alkyl ⁇ the C 1-6 alkyl is (a) hydroxy, (b) cyano;
• RA is (1) haloC 1-4 alkyl, (2) -OR a (R a is (i) C 1-6 alkyl ⁇ the C 1-6 alkyl is (a) hydroxy, (b) C 3-6 cycloalkyl optionally substituted with 1 cyano; and (c) 1 substitution selected from the group consisting of 4- to 6-membered saturated heterocyclyl having 1 oxygen atom.
• C3-6 cycloalkyl wherein the C3-6 cycloalkyl is from C1-6 alkyl, hydroxy, and cyano optionally substituted with 1 or 2 substituents independently selected from the group consisting of), (3) C 3-6 cycloalkyl (the C 3-6 cycloalkyl is (i) C1-4 alkyl, (ii) hydroxy, and (iii) optionally substituted with 1 or 2 substituents independently selected from the group consisting of cyano), or (4) 4 to 6 having 1 oxygen atom.
• RB is (1) a 6- to 10-membered spiroheterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms (the spiroheterocyclyl may be optionally substituted with 1 or 2 halogens); , (2) a 5- to 10-membered bridged heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, said bridged heterocyclyl being selected from halogen, cyano, and hydroxyC 1-4 alkyl; optionally substituted with 1 or 2 substituents independently selected from the group consisting of (3) a bridged C5-10 cycloalkyl (the bridged C5-10 cycloalkyl optionally substituted with one substituent selected from the group consisting of hydroxyC1-4alkyl and cyano), or (4) -OCH2Cy1 ( Cy1 is a bridged C5-10 cycloalkyl optionally substituted with one cyano). ) or a pharmaceutically acceptable salt thereof, according
• a compound selected from or a pharmaceutically acceptable salt thereof is selected from or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising the compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• a PDHK inhibitor comprising the compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
• a PDHK2 inhibitor comprising the compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
• Diabetes insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacemia, diabetes comprising the compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof
• Complications heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, Treatment or prevention of mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy or chronic kidney disease agent.
• the therapeutic or preventive agent of [10], wherein diabetes is type 1 diabetes or type 2 diabetes.
• the agent for treatment or prevention of [10], wherein the vascular dementia is macrovascular or small vessel dementia.
• the therapeutic or prophylactic agent of [10], wherein the heart failure is acute heart failure or chronic heart failure.
• the therapeutic or preventive agent of [10], wherein the pulmonary hypertension is pulmonary arterial hypertension.
• a method of inhibiting PDHK comprising administering a therapeutically effective amount of the compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof to a mammal.
• diabetes, insulin resistance syndrome comprising administering a therapeutically effective amount of the compound of any one of [1] to [6] or a pharmaceutically acceptable salt thereof to a mammal; Metabolic syndrome, hyperglycemia, hyperlactic acidemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, Chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion , ischemic optic neuropathy, and chronic
• diabetes insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactic acidemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis disease, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy , retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, and chronic kidney disease.
• Diabetes insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactic acidemia, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis disease, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, diabetic retinopathy , retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy and chronic kidney disease for use in the treatment or prevention of any one of [1] to [6] A compound as described or a pharmaceutically acceptable salt thereof.
• the compound of [27] or a pharmaceutically acceptable salt thereof, wherein the diabetes is type 1 diabetes or type 2 diabetes.
• the compound of [27] or a pharmaceutically acceptable salt thereof, wherein the vascular dementia is macrovascular or small vessel vascular dementia.
• the compound of [27] or a pharmaceutically acceptable salt thereof, wherein the heart failure is acute heart failure or chronic heart failure.
• the compound of [27] or a pharmaceutically acceptable salt thereof, wherein the pulmonary hypertension is pulmonary arterial hypertension.
• Halogen is fluoro, chloro, bromo or iodo. "Halogen” is preferably fluoro or chloro.
• C 1-4 alkyl means straight or branched chain alkyl having 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. be done. "C 1-4 alkyl” is preferably methyl or ethyl.
• C 1-6 alkyl means straight or branched alkyl having 1 to 6 carbon atoms.
• HaloC 1-4 alkyl means straight or branched alkyl having 1 to 4 carbon atoms substituted with 1 to 5 “halogens” as defined above. When the alkyl is substituted with multiple halogens, the halogens may be the same or different.
• HaloC 1-4 alkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-fluoro-1-methylethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2 -fluoro-2-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl and the like.
• haloC 1-4 alkyl C 1-4 alkyl substituted with 1 to 3 fluoro is preferred.
• Hydro C1-4 alkyl means " C1-4 alkyl” as defined above substituted with one hydroxyl group. Examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like. As “hydroxy C 1-4 alkyl”, hydroxymethyl is preferred.
• C 1-4 alkoxy means alkyl-oxy in which the alkyl moiety is "C 1-4 alkyl” as defined above, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy is included. As “C 1-4 alkoxy”, methoxy is preferable.
• C 1-4 alkoxycarbonyl means alkyl-oxy-carbonyl in which the alkyl moiety is "C 1-4 alkyl” as defined above, including methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy Carbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.
• C3-6 cycloalkyl means a 3- to 6-membered monocyclic hydrocarbon ring group, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Bridged C 5-10 cycloalkyl means a bridged cyclic saturated hydrocarbon group having 5 to 10 carbon atoms.
• a bridged cyclic saturated hydrocarbon group means a ring group in which two cycloalkyl groups share 3 or more atoms.
• “Bridged C 5-10 cycloalkyl” includes for example bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl.
• 4- to 6-membered saturated heterocyclyl having 1 oxygen atom means a 4- to 6-membered monocyclic saturated heterocyclic group having 1 oxygen atom other than a carbon atom.
• the saturated heterocyclyl includes oxetanyl, tetrahydrofuranyl, tetrahydropyranyl.
• 4- to 6-membered saturated heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms means, in addition to carbon atoms, independently from the group consisting of nitrogen and oxygen atoms It means a 4- to 6-membered monocyclic saturated heterocyclic group having 1 or 2 selected heteroatoms.
• the saturated heterocyclyl includes oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like, preferably morpholinyl.
• 6- to 10-membered saturated fused heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms means, other than carbon atoms, independently from the group consisting of nitrogen and oxygen atoms means a 6- to 10-membered fused bicyclic saturated heterocyclic group having 1 or 2 heteroatoms selected by .
• a fused bicyclic saturated heterocycle means a heterocycle in which two saturated rings share two atoms. Examples of the saturated fused heterocyclyl include the following partial structures.
• a 6- to 10-membered spiroheterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms means, in addition to carbon atoms, independently from the group consisting of nitrogen and oxygen atoms It means a 6- to 10-membered spirocyclic saturated heterocyclic group having 1 or 2 selected heteroatoms.
• a spirocyclic saturated heterocycle means a heterocycle in which two saturated rings share one atom. Examples of the spiroheterocyclyl include the following partial structures.
• “5- to 10-membered bridged heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms” means one of “bridged C 5-10 cycloalkyl” defined above or heterocyclyl in which two carbon atoms are replaced with heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms.
• Examples of the bridged heterocyclyl include the following partial structures.
• R 1 is (1) -OR a
• R a is (i) C 1-6 alkyl ⁇ the C 1-6 alkyl is (a) hydroxy, (b) cyano; (c) C1-4 alkoxy, (d) phenyl, and (e) 4- to 6-membered saturated heterocyclyl having 1 oxygen atom, optionally substituted with one substituent selected from the group consisting of], (ii) haloC 1-4 alkyl, or (iii) C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is independently selected from the group consisting of C 1-6 alkyl, hydroxy and cyano optionally substituted with 1 or 2 substituents), or (2) 4- to 6-membered saturated heterocyclyl having 1 oxygen atom, Other symbols are synonymous with the above formula [I]. ).
• R 2 is (1) C 1-6 alkyl ⁇ the C 1-6 alkyl may be substituted with one substituent selected from the group consisting of hydroxy and cyano ⁇ ; (2) haloC 1-4 alkyl, (3) C 3-6 cycloalkyl (the C 3-6 cycloalkyl is (i) C1-4 alkyl, (ii) cyano, and (iii) optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy), or (4) a bridged C 5-10 cycloalkyl (the bridged C 5-10 cycloalkyl optionally substituted with one cyano); Other symbols are synonymous with the above formula [I]. ).
• R 3 is (1) C 1-6 alkyl ⁇ the C 1-6 alkyl may be substituted with one substituent selected from the group consisting of hydroxy and cyano ⁇ ; (2) haloC 1-4 alkyl, (3) C 3-6 cycloalkyl (the C 3-6 cycloalkyl is (i) C1-4 alkyl, (ii) cyano, and (iii) optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxy), or (4) a bridged C 5-10 cycloalkyl (the bridged C 5-10 cycloalkyl optionally substituted with one cyano); Other symbols are synonymous with the above formula [I]. ).
• a compound in which m is 0 in formula [I-a] is a compound represented by formula [I-e].
• R4 is (1) C 1-6 alkyl, (2) haloC 1-4 alkyl, (3) C3-6 cycloalkyl optionally substituted with one halogen, (4) phenyl optionally substituted with one halogen, or (5) bridged C5-10 cycloalkyl (wherein said bridged C5-10 cycloalkyl is (i) C1-4 alkoxycarbonyl, (ii) hydroxyC 1-4 alkyl, and (iii) haloC 1-4 alkyl optionally substituted with one substituent selected from the group consisting of. ).
• “Pharmaceutically acceptable salt” means any salt known in the art that does not involve undue toxicity. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and the like. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).
• a compound of formula [I], formula [II] or formula [III] is reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se to obtain a pharmaceutically acceptable salt thereof. be able to.
• the compound of formula [I], formula [II] or formula [III] is 1/2 molecule, 1 molecule or 2 molecules with respect to 1 molecule of the compound of formula [I], formula [II] or formula [III] It may be formed with any of the above acids or bases.
• salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid.
• Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorucic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid
• Salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium.
• Salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine.
• Salts with inorganic acids are exemplified by salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid.
• Salts with organic acids include oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, and methanesulfone.
• Salts with acids, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid are exemplified.
• Salts with inorganic bases are exemplified by salts with sodium, potassium, calcium, magnesium or zinc.
• Examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine.
• a compound of formula [I], formula [II] or formula [III], or a pharmaceutically acceptable salt thereof may exist as a solvate.
• “Solvate” means a compound of formula [I], formula [II] or formula [III], or a pharmaceutically acceptable salt thereof, in which a solvent molecule is coordinated. subsumed.
• the solvate is preferably a pharmaceutically acceptable solvate, a compound of formula [I], formula [II] or formula [III], or a hydrate of a pharmaceutically acceptable salt thereof, an ethanolate, dimethyl sulfoxide solutes, and the like.
• the solvate can be obtained according to known methods.
• the compound of formula [I], formula [II] or formula [III] may have stereoisomers that should be recognized as cis/trans isomers. In that case, these compounds can exist as cis, trans, or a mixture of cis and trans.
• the compounds of formula [I], formula [II] or formula [III] may exist as tautomers. In that case, these compounds can exist as individual tautomers or mixtures of tautomers.
• the compounds of formula [I], formula [II] or formula [III] may have one or more asymmetric carbon atoms. These compounds may then exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.
• Compounds of formula [I], formula [II] or formula [III] may exist as atropisomers. In that case, these compounds can exist as individual atropisomers or as mixtures of atropisomers.
• the compounds of formula [I], formula [II] or formula [III] may simultaneously contain multiple structural features that give rise to the above isomers. These compounds may also contain the above isomers in any ratio. Any formula, chemical structure or compound name given herein without specifying stereochemistry includes all possible isomers of the above, unless otherwise noted.
• Diastereomeric mixtures can be separated into their respective diastereomers by commonly used methods such as chromatography and crystallization.
• the respective diastereomers can also be made by using stereochemically uniform starting materials or by synthetic methods employing stereoselective reactions.
• Separation of individual single enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, diastereomeric mixtures formed by reacting a mixture of enantiomers with a compound that is substantially pure enantiomer and is known as a chiral auxiliary, such as by fractional crystallization or chromatography. Enriched or substantially pure single diastereomers can be separated by standard methods. The separated diastereomers can be converted to the desired enantiomers by cleavage to remove the attached chiral auxiliary. Mixtures of enantiomers can also be separated directly by chromatographic methods using chiral stationary phases, well known in the art.
• either enantiomer may be synthesized by stereoselective synthesis using substantially pure, optically active starting materials, or by using chiral auxiliaries or asymmetric catalysts on prochiral intermediates (non-stereoselective synthesis). It can also be obtained by performing simultaneous induction).
• the absolute configuration can be determined by X-ray crystallography of crystalline products or intermediates. In that case, if necessary, a crystalline product or intermediate derivatized with a reagent having an asymmetric center whose configuration is known may be used.
• the compound of formula [I], formula [II] or formula [III] may be labeled with an isotope ( 2 H, 3 H, 14 C, 35 S, etc.).
• the compounds of formula [I], formula [II] or formula [III], or pharmaceutically acceptable salts thereof are preferably substantially purified compounds or pharmaceutically acceptable salts thereof. More preferably, these compounds purified to a purity of 80% or higher, or pharmaceutically acceptable salts thereof.
• the pharmaceutical composition of the present invention comprises at least one compound of formula [I], formula [II] or formula [III], or a pharmaceutically acceptable salt thereof, according to methods known in the technical field of pharmaceutical formulations. It may be produced by appropriately mixing an appropriate amount with a pharmaceutically acceptable carrier.
• the content of these compounds or pharmaceutically acceptable salts thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the entire composition.
• Dosage forms of the compounds of formula [I], formula [II] or formula [III], or pharmaceutically acceptable salts thereof include tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions.
• Oral agents such as cloudy agents, parenteral agents such as external agents, suppositories, injections, eye drops, nasal agents, and pulmonary agents can be mentioned.
• “Pharmaceutically acceptable carriers” include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid preparations, liquid preparations, etc. Solvents, solubilizers, suspending agents, tonicity agents, buffering agents, soothing agents, etc. in semi-solid preparations, emulsifiers, wetting agents, stabilizers, stabilizers, dispersing agents, plasticizers, Examples include pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizers, suspending agents and the like. Furthermore, if necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners and the like may be used.
• excipients include lactose, white sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, gum arabic and the like.
• disintegrants include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
• Binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
• fluidizing agents include light anhydrous silicic acid, magnesium stearate, and the like.
• Lubricants include magnesium stearate, calcium stearate, talc and the like.
• Solvent includes purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
• Solubilizers include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
• Sudpending agents include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate, and the like.
• Isotonic agents include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
• Buffering agents include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like.
• Salting agents include benzyl alcohol and the like.
• water, animal and vegetable oils olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.
• lower alcohols ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.
• higher Fatty acids and their esters waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, refined lanolin, water-absorbing ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic , tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (such as Macrogol 200-600
• Preservatives include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
• Antioxidants include sodium sulfite, ascorbic acid, and the like.
• Examples of the “colorant” include food dyes (food red No. 2 or 3, food yellow No. 4 or 5, etc.), ⁇ -carotene, and the like.
• Sweetening agents include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
• the pharmaceutical composition of the present invention can be administered to mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans either orally or non- It can be administered orally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.).
• the dosage varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc.
• the dosage for oral administration to adult patients is the active ingredient of formula [I], formula [II] or formula As the compound of [III], it is usually in the range of about 0.01 mg to 1 g per day. These amounts can be administered in one to several divided doses.
• the compound of formula [I], formula [II] or formula [III], or a pharmaceutically acceptable salt thereof has a PDHK inhibitory effect, it is useful for treating various diseases or conditions that can be expected to be improved by controlling PDHK activity. It is useful for therapy and/or prevention.
• Various diseases or conditions that can be expected to be improved by regulation of PDHK activity include, for example, diabetes (type 1 diabetes, type 2 diabetes), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactic acidemia, diabetic complications ( diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis , peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension (pulmonary arterial hypertension), Alzheimer's disease, vascular dementia (vascular dementia of macrovascular disease type or small vessel disease type), glaucoma, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, chronic kidney disease and the like.
• diabetes type 1 diabetes, type 2
• Symptoms of Alzheimer's disease include cognitive decline, psychiatric symptoms, and behavioral disorders.
• “Inhibiting PDHK” means eliminating or attenuating the activity of PDHK by inhibiting the function of PDHK. means. "Inhibiting PDHK” is preferably “inhibiting human PDHK”. Further, “inhibiting PDHK” is preferably “inhibiting PDHK2”.
• a “PDHK inhibitor” means a substance that binds to PDHK and inhibits the function of PDHK. The “PDHK inhibitor” is preferably a "human PDHK inhibitor”. The “PDHK inhibitor” is preferably a "PDHK2 inhibitor”.
• treatment includes improvement of symptoms, prevention of aggravation, maintenance of remission, prevention of relapse, and prevention of recurrence.
• prevention means suppression of the onset of symptoms.
• presentation of preferred embodiments and alternatives of the compounds, methods, uses and compositions of the present invention also includes presentation of combinations of the preferred embodiments and alternatives as long as they are combinable and consistent.
• a method for producing the compound of formula [I], formula [II] or formula [III] or a pharmaceutically acceptable salt thereof is described below.
• the methods for producing these compounds or their pharmaceutically acceptable salts are not limited to these production methods.
• the compound obtained in each step can be isolated or purified by known methods such as distillation, recrystallization, and column chromatography. You may proceed to When the reaction performed in each step is an anhydrous reaction, it is preferably performed in an atmosphere of an inert gas such as argon or nitrogen.
• Step 1-1 Compound A2 can be obtained by oxidation reaction of compound A1.
• compound A2 can be obtained by reacting compound A1 with iodosobenzene in the presence of tetra-n-butylammonium iodide in a solvent.
• Solvents include mixed solvents of acetonitrile and water.
• Compound A1 can be obtained according to Preparation 12 described in WO2019/151274.
• Step 1-2 Compound A3 can be obtained by reaction of compound A2 with a sulfur reagent.
• compound A3 can be obtained by reacting compound A2 with a sulfur reagent in a solvent at room temperature to 120°C.
• Sulfur reagents include Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide).
• Solvents include toluene and pyridine.
• compound [A6] can be obtained by reacting compound A4 with compound [A5].
• the reaction between compound A4 and hydrazine can be carried out, for example, by reacting compound A4 with hydrazine in a solvent at room temperature to 120°C. Solvents include ethanol and isopropanol.
• the reaction of compound A4 and compound [A5] can be carried out, for example, by reacting compound A4 with compound [A5] in a solvent in the presence of a condensing agent under ice-cooling to room temperature.
• Condensing agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole monohydrate.
• Solvents include acetonitrile and N,N-dimethylformamide.
• Compound [A5] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Compound [A6] can also be obtained by reacting the acid chloride (R A COCl) of compound [A5] with compound A4.
• compound [A6] can be obtained by reacting compound A4 with R A COCl in a solvent in the presence of a base under ice cooling to room temperature.
• Bases include diisopropylethylamine and sodium bicarbonate.
• Solvents include tetrahydrofuran and chloroform.
• a compound [I-1] can be obtained by a dehydration reaction of the compound [A6].
• compound [I-1] can be obtained by reacting compound [A6] with a dehydrating reagent in a solvent.
• Dehydrating reagents include (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent), acetic anhydride and acetic acid, trifluoroacetic anhydride and trifluoroacetic acid.
• Solvents include N-methylpyrrolidone, tetrahydrofuran, dichloromethane and toluene.
• R 10 , R 11 and R 12 are each independently C 1-4 alkyl; X 1 is a leaving group such as methanesulfonyloxy; Pr 1 is a hydroxy-protecting group such as benzyl. )
• Step 2-1 Compound [B2] can be obtained by reduction of the double bond of compound [B1].
• compound [B2] can be obtained by subjecting compound [B1] to catalytic reduction at room temperature in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
• Palladium catalysts include palladium on carbon.
• Solvents include methanol, ethanol and ethyl acetate.
• Compound [B1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 2-2 Compound [B3] can be obtained by reducing the carboxy group of compound [B2].
• compound [B3] can be obtained by reacting compound [B2] with a reducing agent in a solvent under ice-cooling to room temperature.
• a reducing agent includes borane.
• Solvents include tetrahydrofuran.
• Step 2-3 Compound [B4] can be obtained by converting the hydroxy group of compound [B3] into a leaving group.
• compound [B4] when X 1 is methanesulfonyloxy, compound [B4] can be obtained by reacting compound [B3] with methanesulfonic anhydride in a solvent in the presence of a base.
• Bases include triethylamine.
• Solvents include chloroform, dichloromethane and tetrahydrofuran.
• Step 2-4 Compound [B6] can be obtained by reacting compound [B4] and compound [B5].
• compound [B6] can be obtained by reacting compound [B4] with compound [B5] in the presence of a base in a solvent.
• Bases include potassium carbonate and cesium carbonate.
• Solvents include N,N-dimethylformamide.
• Compound [B7] can be obtained by intramolecular Claisen condensation of compound [B6].
• compound [B7] can be obtained by treating compound [B6] with a base in a solvent at room temperature to 120°C.
• Bases include potassium tert-butoxide.
• Solvents include toluene and tetrahydrofuran.
• Step 2-6 Compound [B8] can be obtained by treating compound [B7] with sodium chloride or lithium chloride at 100° C. to 160° C. in a solvent.
• Solvents include water and dimethylsulfoxide.
• Step 2-7 Compound [B10] can be obtained by reacting compound [B8] and compound [B9].
• compound [B10] can be obtained by reacting compound [B8] treated with a base with compound [B9] treated with a base at -78°C to room temperature in a solvent.
• Bases include lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.
• Solvents include tetrahydrofuran.
• Compound [B9] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 2-8 Compound [B11] can be obtained by converting the hydroxy group of compound [B10] into a leaving group, followed by an elimination reaction.
• the leaving group is methanesulfonyloxy
• the compound [B10] is reacted with methanesulfonic anhydride in a solvent in the presence of a base under ice cooling, and then heated at 40°C to 70°C to give the compound [B11] can be obtained.
• Bases include triethylamine.
• Solvents include tetrahydrofuran and toluene.
• Step 2-9 Compound [B12] can be obtained by reacting compound [B11] with methylmagnesium halide.
• compound [B12] can be obtained by reacting compound [B11] with methylmagnesium halide at -78°C to 0°C in the presence of a base in a solvent.
• Methylmagnesium halides include methylmagnesium bromide.
• Bases include triethylamine.
• Solvents include tetrahydrofuran, 2-methyltetrahydrofuran, toluene and diethyl ether.
• Compound [B13] can be obtained by reacting compound [B12] with (trifluoromethyl)trimethylsilane.
• compound [B13] can be obtained by reacting compound [B12] with (trifluoromethyl)trimethylsilane in a solvent in the presence of an additive under ice-cooling to room temperature.
• Additives include tetra-n-butylammonium fluoride, lithium acetate, potassium carbonate and cesium fluoride.
• Solvents include tetrahydrofuran, N,N-dimethylformamide and N,N-dimethylacetamide.
• the methyl group of compound [B12] becomes a steric hindrance, and the reaction proceeds diastereoselectively.
• Step 2-11 Compound B14 can be obtained by deprotection of compound [B13].
• compound B14 when Pr 1 is benzyl, compound B14 can be obtained by subjecting compound [B13] to catalytic reduction in a solvent at room temperature under a hydrogen atmosphere in the presence of a palladium catalyst.
• Palladium catalysts include palladium on carbon.
• Solvents include tetrahydrofuran and methanol.
• Compound B15 can be obtained by purifying compound B14 by chiral column chromatography.
• the configuration of compound B15 can be determined, for example, by X-ray crystallography.
• Compound B15 can also be obtained by purifying compound [B11] by chiral column chromatography and then performing the same reactions as in steps 2-9 to 2-11.
• X 2 is a leaving group such as ethanesulfonyloxy; Pr 2 is a hydroxy-protecting group such as benzyl; Other symbols have the same meanings as above.
• Step 3-1 Compound C2 can be obtained by reaction of compound C1 with tert-butyl bromoacetate.
• compound C2 can be obtained by reacting compound C1 with tert-butyl bromoacetate in a solvent at ⁇ 78° C. to room temperature in the presence of a base.
• Bases include lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide.
• Solvents include tetrahydrofuran.
• Compound C1 may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 3-2 The asymmetric auxiliary of compound C2 can be removed to give compound C3.
• compound C3 can be obtained by reacting compound C2 with an alkali and an oxidizing agent in a solvent at ice-cooled to room temperature.
• Alkali include lithium hydroxide.
• the oxidizing agent includes hydrogen peroxide water.
• Solvents include tetrahydrofuran and water.
• Step 3-3 Reduction of the carboxy group of compound C3 can provide compound C4.
• compound C4 can be obtained by reacting compound C3 with a reducing agent in a solvent under ice-cooling to room temperature.
• a reducing agent includes borane.
• Solvents include tetrahydrofuran.
• Step 3-4 Compound [C5] can be obtained by converting the hydroxy group of compound C4 into a leaving group.
• compound [C5] can be obtained by reacting compound C4 with ethanesulfonyl chloride in a solvent in the presence of a base.
• Bases include triethylamine.
• Solvents include chloroform, dichloromethane and tetrahydrofuran.
• Step 3-5 Compound [C6] can be obtained by reacting compound [C5] with compound [B5].
• compound [C6] can be obtained by an operation similar to step 2-4.
• Step 3-6 Compound [C7] can be obtained by intramolecular Claisen condensation of compound [C6].
• compound [C7] can be obtained by an operation similar to step 2-5.
• Step 3-7 Compound [C8] can be obtained by treating compound [C7] with an acid in a solvent at 80°C to 110°C.
• Acids include trifluoroacetic acid.
• Solvents include toluene.
• Step 3-8 Compound [C9] can be obtained by carrying out the same reaction as steps 2-7, 2-8 and 2-9 using compound [C8].
• Step 3-9 Compound [C10] can be obtained by reacting compound [C9] with (trifluoromethyl)trimethylsilane.
• compound [C10] can be obtained by an operation similar to step 2-10.
• the methyl group of compound [C9] becomes a steric hindrance, the reaction proceeds diastereoselectively, and compound [C10] is obtained as an optically active form.
• Step 3-10 Compound B15 can be obtained by deprotection of compound [C10].
• compound B15 when Pr2 is benzyl, compound B15 can be obtained by the same procedure as in step 2-11.
• X 3 is a leaving group such as bromo and p-toluenesulfonyloxy;
• Step 4-1 Compound [I-2] can be obtained by reacting compound B15 with compound [D1].
• compound [I-2] can be obtained by reacting compound B15 with compound [D1] in a solvent in the presence of a base at room temperature to 90°C.
• Bases include potassium carbonate and cesium carbonate.
• Solvents include N,N-dimethylformamide.
• Step 4-2 Compound I-3 can be obtained by reacting compound B15 with sodium chlorodifluoroacetate in a solvent in the presence of a base at room temperature to 100°C.
• Bases include potassium carbonate.
• Solvents include N,N-dimethylformamide.
• Step 4-3 Compound [I-4] can be obtained by Mitsunobu reaction of compound B15 and compound [D2].
• compound [I-4] can be obtained by reacting compound B15 with phosphine and azodicarboxylic acid diester in a solvent at room temperature to 100°C.
• Phosphines include trioctylphosphine, tributylphosphine and triphenylphosphine.
• Azodicarboxylic acid diesters include diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate.
• Solvents include toluene, tetrahydrofuran and 2-methyltetrahydrofuran.
• Step 4-4 Compound [D3] can be obtained by reacting compound B15 with trifluoromethanesulfonic anhydride in a solvent in the presence of a base at 0°C to room temperature.
• Bases include triethylamine.
• Solvents include dichloromethane and chloroform.
• Step 4-5 Compound [D5] can be obtained by Suzuki coupling of compound [D3] and compound [D4].
• compound [D5] can be obtained by reacting compound [D3] with compound [D4] in a solvent in the presence of a base and a palladium catalyst at room temperature to 100°C.
• Bases include potassium carbonate and tripotassium phosphate.
• Palladium catalysts include XPhos Pd G4.
• Solvents include 1,4-dioxane, water and toluene.
• Compound [D4] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 4-6 Compound [I-5] can be obtained by reduction of the double bond of compound [D5].
• compound [I-5] can be obtained by subjecting compound [D5] to catalytic reduction at room temperature in a solvent in a hydrogen atmosphere in the presence of a palladium catalyst.
• Palladium catalysts include palladium on carbon.
• Solvents include methanol, ethanol, tetrahydrofuran and ethyl acetate.
• R D is R A or p-methoxybenzyl (PMB);
• X 4 is a leaving group such as p-toluenesulfonyloxy or methanesulfonyloxy;
• Other symbols have the same meanings as in formula [I] above.
• Steps 5-1 and 5-2 Compounds [E4a] and [E4b] can be obtained by a pyrazole cyclization reaction using compound E1 and compound [E3].
• compound E1 is reacted with N,N-dimethylformamide dimethylacetal at 100°C to 120°C in a solvent, and then reacted with compound [E3] at 100°C to 200°C in the presence of an acid to give compound [E4a] and [E4b] can be obtained.
• the intermediate After isolating the intermediate compound E2, the intermediate may be reacted with compound [E3].
• a microwave device may be used if desired. The reaction may be carried out without solvent. Acids include acetic acid. Solvents include ethanol and water.
• Compounds E1 and [E3] may be commercially available products, or may be obtained by appropriately converting commercially available products by methods well known to those skilled in the art.
• Step 5-3 Compounds [E5a] and [E5b] can be obtained by carrying out the same reaction as steps 2-7 to 2-9 using compounds [E4a] and [E4b].
• Step 5-4 When RD is RA , compounds [E6a] and [E6b] can be obtained by reacting compounds [E5a] and [E5b] with (trifluoromethyl)trimethylsilane, followed by purification by column chromatography. can.
• the reaction with (trifluoromethyl)trimethylsilane can be performed by the same operation as in step 2-10.
• Step 5-5 Compounds [I-6] and [I-7] can be obtained by purifying compounds [E6a] and [E6b] by chiral column chromatography, respectively.
• the configuration of compounds [I-6] and [I-7] can be determined by, for example, X-ray crystallography.
• Step 5-6 Compounds E7a and E7b can be obtained by purifying compounds [E5a] and [E5b] by chiral column chromatography, respectively.
• the configuration of compounds E7a and E7b can be determined, for example, by X-ray crystallography.
• Step 5-7 Compound E8 can be obtained by deprotection of compound E7a or E7b.
• compound E8 can be obtained by treating compounds E7a and E7b with acid at room temperature to 100°C.
• a microwave device may be used if desired.
• a cation trapping agent may be used as necessary.
• Acids include trifluoroacetic acid.
• Cationic scavengers include anisole.
• Step 5-8 Compounds [E10a] and [E10b] can be obtained by reacting compound E8 with compound [E9].
• compounds [E10a] and [E10b] can be obtained by reacting compound E8 with compound [E9] in a solvent in the presence of a base at 80°C to 100°C.
• Additives may be added as necessary.
• Bases include potassium carbonate and cesium carbonate.
• Solvents include N,N-dimethylformamide.
• Additives include sodium iodide.
• Compound [E9] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 5-9 Compounds [I-6] and [I-7] can be obtained by carrying out the reaction of step 5-4 using compound [E10a] or [E10b].
• Step 6-1 Compound [F2] can be obtained by reduction of the ester group of compound [F1].
• compound [F2] can be obtained by reacting compound [F1] with a reducing agent in a solvent at -40°C to room temperature.
• Reducing agents include lithium aluminum hydride, diisobutylaluminum hydride and lithium borohydride.
• Solvents include tetrahydrofuran, diethyl ether and cyclopentyl methyl ether.
• Compound [F1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 6-2 Compound [F3] can be obtained by oxidation of the hydroxy group of compound [F2].
• compound [F3] can be obtained by reacting compound [F2] with an oxidizing agent in a solvent under ice-cooling to room temperature.
• Oxidizing agents include manganese dioxide, Dess-Martin periodinane and sulfur trioxide-pyridine complexes.
• Solvents include tetrahydrofuran, 1,2-dimethoxyethane, toluene, dimethylsulfoxide, chloroform and dichloromethane.
• Step 6-3 Compound [F4] can be obtained by an imination reaction of compound [F3] and (S)-2-aminopropan-1-ol and a cyclization reaction using p-toluenesulfonylmethyl isocyanide.
• compound [F3] and (S)-2-aminopropan-1-ol are allowed to react in a solvent at room temperature to 60° C. to perform an imination reaction.
• the compound [F4] can be obtained by reacting the product with p-toluenesulfonylmethyl isocyanide in a solvent in the presence of a base under ice-cooling to room temperature.
• Solvents for the imination reaction include methanol, 1,2-dimethoxyethane and N,N-dimethylformamide.
• Bases include potassium carbonate.
• Solvents for the cyclization reaction include methanol, 1,2-dimethoxyethane and N,N-dimethylformamide.
• Step 6-4 Compound [F5] can be obtained by intramolecular Mitsunobu reaction of compound [F4].
• compound [F5] can be obtained by reacting compound [F4] with phosphine and azodicarboxylic acid diester in a solvent at room temperature to 100°C.
• Phosphines include trioctylphosphine, tributylphosphine and triphenylphosphine.
• Azodicarboxylic acid diesters include diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate.
• Solvents include toluene, tetrahydrofuran and 2-methyltetrahydrofuran.
• Compound [F6] can be obtained by reacting compound [F5] with N-methoxy-N-methylacetamide.
• compound [F6] can be obtained by reacting compound [F5] with N-methoxy-N-methylacetamide in a solvent at -78°C to room temperature in the presence of a base.
• Bases include n-butyllithium and lithium diisopropylamide.
• Solvents include cyclopentyl methyl ether, tetrahydrofuran and toluene.
• Step 6-6 When RE is RB , compound [II-1] can be obtained by reacting compound [F6] with (trifluoromethyl)trimethylsilane.
• compound [II-1] can be obtained by an operation similar to step 2-10.
• the methyl group of compound [F6] becomes a steric hindrance, the reaction proceeds diastereoselectively, and compound [II-1] is obtained as an optically active form.
• Step 6-7 When X6 is nitrogen, X7 is carbon and RE is bromo attached to X7 , step 6-6 provides compound F7.
• Compound [II-2] can be obtained by reacting compound F7 with compound [F8].
• compound [II-2] can be obtained by reacting compound F7 with compound [F8] in a solvent in the presence of a base and a palladium catalyst at room temperature to 120°C.
• Bases include sodium tert-butoxide.
• Palladium catalysts include XPhos Pd G4 and RuPhos Pd G4.
• Solvents include 1,4-dioxane and toluene.
• Compound [F8] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Compound [F8] may be a salt with an acid.
• R 16 , R 17 and R 18 are each independently C 1-4 alkyl; Cy 15 is a bridged C 5-10 cycloalkylene or a 5- to 10-membered bridged heterocyclylene having 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms; Pr 3 is a hydroxy-protecting group such as 2-tetrahydropyranyl.
• Step 7-1 Compound [G2] can be obtained by reduction of the carboxy group of compound [G1].
• compound [G2] can be obtained by an operation similar to step 2-2.
• Compound [G1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 7-2 Compound [G3] can be obtained by protecting the hydroxy group of compound [G2].
• Pr 3 is 2-tetrahydropyranyl
• compound [G2] is reacted with 3,4-dihydro-2H-pyran in the presence of an acid in a solvent at ice-cooled to room temperature to give compound [G3].
• Acids include pyridinium p-toluenesulfonate.
• Solvents include acetonitrile.
• Step 7-3 Compound [G4] can be obtained by hydrolysis of the ester of compound [G3].
• compound [G4] can be obtained by treating compound [G3] with an alkali in a solvent at 80° C. under ice cooling.
• Alkalis include lithium hydroxide and sodium hydroxide.
• Solvents include methanol, ethanol and water.
• Step 7-4 Compound [G5] can be obtained by amidation reaction of compound [G4] and N,O-dimethylhydroxylamine.
• compound [G5] can be obtained by reacting compound [G4] with N,O-dimethylhydroxylamine in a solvent in the presence of a base and a condensing agent under ice-cooling to room temperature.
• Bases include diisopropylethylamine and triethylamine.
• Condensing agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HCl).
• Solvents include pyridine and N,N-dimethylformamide.
• Step 7-5 Compound [G6] can be obtained by reacting compound [G5] with methylmagnesium halide.
• compound [G6] can be obtained by an operation similar to step 2-9.
• Step 7-6 Compound [G8] can be obtained by pyrazole cyclization reaction using compound [G6] and compound [G7].
• compound [G6] is reacted with compound [G7] in a solvent in the presence of a base under ice-cooling to room temperature, and then reacted with hydrazine under ice-cooling to room temperature to obtain compound [G8]. be able to.
• the intermediate After isolating the intermediate produced by the reaction with compound [G7], the intermediate may be reacted with hydrazine.
• Bases include potassium tert-butoxide.
• Solvents include tetrahydrofuran.
• Compound [G7] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 7-7 Compound [G9] can be obtained by performing the same reactions as in steps 6-1 to 6-6 using compound [G8].
• Step 7-8 Compound [II-3] can be obtained by deprotection of compound [G9].
• compound [II-3] can be obtained by treating compound [G9] with an acid in a solvent at room temperature to 70°C.
• Acids include 10-camphorsulfonic acid.
• Solvents include methanol.
• Step 7-9 Compound [G10] can be obtained by oxidation of the hydroxy group of compound [II-3].
• compound [G10] can be obtained by an operation similar to step 6-2.
• Compound [G11] can be obtained by reacting compound [G10] with an oxidizing agent in a solvent in the presence of an additive and a scavenger under ice-cooling to room temperature.
• Oxidizing agents include sodium chlorite.
• Additives include sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate.
• Scavengers include 2-methyl-2-butene.
• Solvents include tert-butanol and water.
• Step 7-11 Compound [G12] can be obtained by amidation reaction of compound [G11] and ammonia.
• compound [G12] can be obtained by an operation similar to step 7-4.
• Step 7-12 Compound [II-4] can be obtained by cyanation reaction of compound [G12].
• compound [II-4] can be obtained by reacting compound [G12] with an acid anhydride in a solvent in the presence of a base under ice-cooling to room temperature.
• Bases include triethylamine.
• Acid anhydrides include trifluoroacetic anhydride.
• Solvents include 1,4-dioxane and tetrahydrofuran.
• Step 7-13 Compound [G13] can be obtained by esterification reaction of compound [G11].
• compound [G13] can be obtained by reacting compound [G11] with trimethylsilyldiazomethane in a solvent under ice-cooling to room temperature.
• Solvents include toluene and methanol.
• Step 7-14 Compound [II-5] can be obtained by reacting compound [G13] with two equivalents of methylmagnesium halide.
• compound [II-5] can be obtained by an operation similar to step 2-9.
• R 19 and R 20 are each independently C 1-4 alkyl; Pr 4 is a protecting group for pyrazole such as 2-tetrahydropyranyl; Pr 5 is a hydroxy-protecting group such as benzyl; Cy 16 is a bridged C 5-10 cycloalkylene.
• Step 8-1 Compound [H2] can be obtained by reacting compound [H1] with hydrazine.
• compound [H2] can be obtained by reacting compound [H1] with hydrazine in a solvent at room temperature. If necessary, the reaction may be carried out in the presence of an acid.
• Solvents include acetonitrile, toluene and ethanol.
• Acids include acetic acid.
• Compound [H1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 8-2 Compound [H3] can be obtained by introducing a protecting group to pyrazole of compound [H2].
• compound [H3] when Pr4 is 2-tetrahydropyranyl, compound [H3] can be obtained by reacting compound [H2] with 3,4-dihydro-2H-pyran in a solvent at room temperature in the presence of an acid. can be done.
• Solvents include acetonitrile and N,N-dimethylformamide.
• Acids include pyridinium p-toluenesulfonate and p-toluenesulfonic acid.
• Step 8-3 Compound [H4] can be obtained by protecting the hydroxy group of compound [H3].
• compound [H4] can be obtained by reacting compound [H3] with benzyl halide in a solvent in the presence of a base at room temperature.
• Benzyl halides include benzyl chloride and benzyl bromide.
• Solvents include N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, toluene, isopropyl acetate, tetrahydrofuran and dimethylsulfoxide.
• Bases include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium tert-butoxide, potassium acetate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N - diisopropylethylamine.
• Step 8-4 Compound [H5] can be obtained by performing the same reactions as in steps 6-1 and 6-2 using compound [H4].
• Step 8-5 Compound [H6] can be obtained by deprotection of the pyrazole-protecting group of compound [H5].
• Pr 4 is 2-tetrahydropyranyl
• compound [H6] can be obtained by treating compound [H5] with an acid in a solvent at room temperature.
• Acids include hydrochloric acid, methanesulfonic acid, sulfuric acid and phosphoric acid.
• Solvents include 1,2-dimethoxyethane.
• Step 8-6 Compound [H7] can be obtained by performing the same reactions as in steps 6-3 to 6-6 using compound [H6].
• Step 8-7 Compound H8 can be obtained by deprotection of compound [H7].
• compound H8 can be obtained by treating compound [H7] with an acid at room temperature to 50°C.
• Compound H8 may be obtained as a salt with the acid used. Acids include concentrated hydrochloric acid.
• Step 8-8 Compound [II-6] can be obtained by Mitsunobu reaction of compound H8 and compound [H9].
• compound [II-6] can be obtained by an operation similar to step 4-3.
• Compound [H9] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 8-9 Compound [H10] can be obtained by hydrolysis of the ester of compound [II-6].
• compound [H10] can be obtained by an operation similar to step 7-3.
• Process 8-10 Compound [II-7] can be obtained by performing the same reactions as in steps 7-11 and 7-12 using compound [H10].
• Pr 6 is a protective group for an amino group such as tert-butoxycarbonyl; Each other symbol is synonymous with formula [II]. )
• Process 9-1 and 9-2 Compound [J4] can be obtained by a pyrazole cyclization reaction using compound [J1] and compound [J3].
• compound [J1] is reacted with N,N-dimethylformamide dimethylacetal in a solvent at room temperature to obtain compound [J2].
• compound [J4] can be obtained by reacting compound [J2] with compound [J3] in a solvent in the presence of an acid at 100°C to 200°C. Deprotection also proceeds when Pr6 is tert-butoxycarbonyl.
• Solvents for the reaction with N,N-dimethylformamide dimethylacetal include toluene.
• Solvents for the cyclization reaction include ethanol, isopropanol and water. Acids include acetic acid.
• Compound [J1] and compound [J3] may be commercially available products, or may be obtained by appropriately converting commercially available products by methods well known to those skilled in the art.
• Step 9-3 Compound [J5] can be obtained by reduction of compound [J4].
• compound [J5] can be obtained by reacting compound [J4] with a reducing agent in a solvent at room temperature to 90°C.
• Reducing agents include boranes and lithium aluminum hydride.
• Solvents include tetrahydrofuran.
• Step 9-4 Compound [J6] can be obtained by chlorination of compound [J5].
• compound [J6] can be obtained by reacting compound [J5] with a chlorinating agent in a solvent in the presence of a base under ice-cooling to room temperature.
• Bases include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
• Chlorinating agents include N-chlorosuccinimide.
• Solvents include dichloromethane.
• a compound [J7] can be obtained by an imination reaction of the compound [J6] and a cyclization reaction using p-toluenesulfonylmethylisocyanide.
• compound [J6] is reacted with a base in a solvent at room temperature to perform an imination reaction.
• the compound [J7] can be obtained by reacting the product with p-toluenesulfonylmethyl isocyanide in a solvent in the presence of a base under ice-cooling to room temperature.
• Solvents for the imination reaction include methanol and 1,2-dimethoxyethane.
• the base for the imination reaction include sodium hydroxide.
• a base for the cyclization reaction includes potassium carbonate.
• Solvents for the cyclization reaction include tetrahydrofuran and 1,2-dimethoxyethane.
• Step 9-6 Compound [J8] can be obtained by acylation reaction of compound [J7].
• compound [J8] can be obtained by reacting compound [J7] with N-methoxy-N-methylacetamide in a solvent in the presence of a base.
• Bases include lithium diisopropylamide.
• Solvents include tetrahydrofuran.
• Step 9-7 Compound [II-8] can be obtained by reacting compound [J8] with (trifluoromethyl)trimethylsilane.
• compound [II-8] can be obtained by an operation similar to step 2-10.
• the methyl group of compound [J8] becomes a steric hindrance, the reaction proceeds diastereoselectively, and compound [II-8] is obtained as an optically active form.
• Pr 7 is a protecting group such as p-methoxybenzyl
• Pr 8 is a hydroxy-protecting group such as tert-butyldimethylsilyl
• R 21 is C 1-4 alkyl
• each R 22 is independently hydrogen or C 1-4 alkyl, and one R 22 may combine with the other R 22 to form a ring;
• Each other symbol has the same meaning as in formula [III].
• Step 10-1 Protection of compound K1 can give compound [K2].
• compound [K2] when Pr 7 is p-methoxybenzyl, compound [K2] can be obtained by reacting compound K1 with p-methoxybenzyl halide in a solvent in the presence of a base. Additives may be used as necessary.
• p-Methoxybenzyl halides include p-methoxybenzyl chloride.
• Bases include potassium hydroxide and cesium carbonate.
• Additives include tetrabutylammonium bromide.
• Solvents include toluene and N,N-dimethylformamide.
• Compound [K1] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 10-2 Compound [K3] can be obtained by reacting compound [K2] with malonic acid diester.
• compound [K3] can be obtained by reacting compound [K2] with malonic acid diester in the presence of a base in a solvent.
• Malonic acid diesters include diethyl malonate.
• Bases include sodium tert-pentoxide.
• Solvents include tetrahydrofuran.
• Step 10-3 Compound [K4] can be obtained by heating compound [K3] in a solvent at 100°C to 140°C.
• Solvents include water and dimethylsulfoxide.
• Step 10-4 Compound [K5] can be obtained by methylation of compound [K4].
• compound [K5] can be obtained by reacting compound [K4] with a methylating agent at -78°C to room temperature in the presence of a base in a solvent.
• Bases include lithium bis(trimethylsilyl)amide.
• Methylating agents include methyl iodide.
• Solvents include tetrahydrofuran.
• Step 10-5 Compound [K6] can be obtained by reduction of the ester group of compound [K5].
• compound [K6] can be obtained by reacting compound [K5] with a reducing agent in a solvent under ice cooling.
• Reducing agents include lithium borohydride.
• Solvents include tetrahydrofuran, diethyl ether and cyclopentyl methyl ether.
• Step 10-6 Compound K7 can be obtained by deprotection of compound [K6].
• compound K7 when Pr 7 is p-methoxybenzyl, compound K7 can be obtained by reacting compound [K6] with ammonium cerium(IV) nitrate in a solvent under ice cooling to room temperature.
• Solvents include acetonitrile and water.
• Step 10-7 Protection of the hydroxy group of compound K7 can give compound [K8].
• compound [K8] can be obtained by reacting compound K7 with tert-butyldimethylsilyl chloride in a solvent in the presence of a base under ice cooling to room temperature.
• Bases include imidazole and 4-dimethylaminopyridine.
• Solvents include N,N-dimethylformamide.
• Step 10-8 Compounds [K9a] and [K9b] can be obtained by reacting compound [K8] with trifluoromethanesulfonic anhydride in a solvent in the presence of a base under ice-cooling.
• Bases include pyridine.
• Solvents include dichloromethane.
• a compound [K10] can be obtained by a coupling reaction using the compounds [K9a] and [K9b] and an organotin reagent.
• compound [K10] can be obtained by reacting compounds [K9a] and [K9b] with an organotin reagent in a solvent in the presence of a palladium catalyst and an additive at 100°C to 130°C.
• Palladium catalysts include tetrakis(triphenylphosphine)palladium.
• Additives include lithium chloride and copper iodide.
• Organotin reagents include tributyl(1-ethoxyvinyl)tin.
• Solvents include 1,4-dioxane.
• Compound [K12] can be obtained by Suzuki coupling of compound [K10] and compound [K11].
• compound [K12] can be obtained by an operation similar to step 4-5.
• Compound [K11] may be a commercially available product, or may be obtained by appropriately converting a commercially available product by a method well known to those skilled in the art.
• Step 10-11 Compound [K13] can be obtained by deprotection of compound [K12].
• compound [K13] can be obtained by reacting compound [K12] with a fluorine reagent in a solvent under ice-cooling to room temperature.
• Fluorine reagents include tetrabutylammonium fluoride.
• Solvents include tetrahydrofuran.
• Compound [K14] can be obtained by intramolecular Mitsunobu reaction of compound [K13].
• compound [K14] can be obtained by an operation similar to step 6-4.
• Process 10-13 Compound [K15] can be obtained by treating compound [K14] with an acid in a solvent at room temperature to 60°C.
• Acids include hydrochloric acid.
• Solvents include methanol and tetrahydrofuran.
• Process 10-14 Compound [K16] can be obtained by reacting compound [K15] with (trifluoromethyl)trimethylsilane.
• compound [K16] can be obtained by an operation similar to step 2-10.
• Compound [III] can be obtained by purifying compound [K16] by chiral column chromatography.
• the configuration of compound [III] can be determined, for example, by X-ray crystallography.
• Tetrabutylammonium iodide (0.221 g) and iodosobenzene (1.978 g) were added under ice-cooling, and the mixture was stirred at room temperature for 100 minutes.
• a saturated sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was stirred for 1 hour.
• the mixture was extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• Step 7 Ethyl 8-(benzyloxy)-9b-hydroxy-4-methyl-3a,4,5,9b-tetrahydroisoxazolo[5,4-c]pyrazolo[1,5-a]pyridine-3- carboxylate
• Step 8 Ethyl 8-(benzyloxy)-4-methyl-4,5-dihydroisoxazolo[5,4-c]pyrazolo[1,5-a]pyridine-3-carboxylate
• Step 12 (R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazolo[5,4- c]pyrazolo[1,5-a]pyridin-8-ol
• Step 13 Isopropyl 2-(((R)-4-methyl-3-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazolo) [5,4-c]pyrazolo[1,5-a]pyridin-8-yl)oxy)acetate
• Tetrahydrofuran 100 ml was mixed with ethyl 3-hydroxy-1H-pyrazole-5-carboxylate (10 g). Benzyl alcohol (8.0 ml) and triphenylphosphine (18.5 g) were added to the mixture. Diisopropyl azodicarboxylate (13.7 ml) was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (70 ml) and hexane (140 ml) were added, and the mixture was stirred at room temperature. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure.
• the configuration of the title compound was determined by X-ray crystallography.
• Triphenylphosphine (0.065 g), 3-hydroxy-1-methylcyclobutane-1-carbonitrile (0.022 g) and di-tert-butyl azodicarboxylate (0.057 g) were added to the reaction mixture and stirred for 75 minutes. bottom.
• Step 4 Ethyl 6-(4-methoxybenzyl)-4-methyl-5,6-dihydro-4H-isoxazolo[5,4-e]indazole-3-carboxylate and ethyl 7-(4-methoxybenzyl)- A mixture of 4-methyl-5,7-dihydro-4H-isoxazolo[5,4-e]indazole-3-carboxylates
• Cis-4-hydroxy-4-methylcyclohexyl methanesulfonate (1.1 g) obtained in the previous step was mixed with dichloromethane (20 ml). Chloromethyl methyl ether (0.74 ml) and N,N-diisopropylethylamine (2.1 ml) were added under ice-cooling, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and filtered through a phase separator. The filtrate was concentrated under reduced pressure.
• reaction mixture was stirred for 1 hour while warming to room temperature.
• Methanol (3.3 ml) and potassium carbonate (0.44 g) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with water and saturated aqueous sodium chloride solution, filtered through a phase separator, and the filtrate was concentrated under reduced pressure.
• the tert-butyl (S,E)-3-((dimethylamino)methylene)-6-methyl-2,4-dioxopiperidine-1-carboxylate (1.0 g) obtained in the previous step was treated with isopropanol ( 5.0 ml), acetic acid (0.53 ml) and water (7.0 ml). Phenylhydrazine (0.38 g) was added to the reaction solution, and the mixture was heated under reflux for 2 hours. Toluene (5.0 ml) was added to the reaction solution, and the mixture was further heated under reflux for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate.
• Lithium aluminum hydride (0.27 g) was dissolved in tetrahydrofuran (10 ml). To the reaction solution was added (S)-6-methyl-1-phenyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in the previous step (0. 53 g) was added, and the mixture was heated to reflux at 90° C. for 1 hour. Lithium aluminum hydride (0.27 g) was added to the reaction solution, and the mixture was further heated under reflux at 90°C for 1 hour. Water (0.53 ml), 4M aqueous sodium hydroxide solution (0.53 ml) and water (1.5 ml) were sequentially added to the reaction mixture at room temperature.
• the phosphate salt of the title compound (1.6387g) was mixed with ethyl acetate (16.22ml).
• a saturated aqueous sodium hydrogencarbonate solution (16.22 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. After layer separation, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.264 g).
• N,O-dimethylhydroxylamine hydrochloride (2.62 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.15 g) were added to the reaction mixture and stirred at room temperature for 2 hours.
• a 1N hydrochloric acid aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• the organic layer was washed successively with 1N hydrochloric acid aqueous solution, water and saturated sodium chloride aqueous solution, and dried over sodium sulfate. After removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure.
• Carboxamide (6.18 g) was mixed with toluene (57.8 ml).
• a 1.04 M methylmagnesium bromide/tetrahydrofuran solution (22.42 ml) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes.
• a saturated aqueous ammonium chloride solution and water were added at room temperature, and the mixture was extracted twice with ethyl acetate.
• N-Methoxy-N-methylacetamide (1.115 ml) was added to the mixture and stirred at -78°C for 30 minutes.
• a 2M lithium diisopropylamide/tetrahydrofuran-heptane-ethylbenzene solution (2.274 ml) was added dropwise to the mixture, and the mixture was stirred at -78°C for 1 hour.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• a 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and then extracted twice with ethyl acetate.
• the organic layer was washed successively with a 10% aqueous potassium carbonate solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over sodium sulfate.
• Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product (239 mg) of the title compound.
• a 5% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
• Tetrahydrofuran (12.45 ml) was mixed with lithium aluminum hydride (0.129 g) under an argon atmosphere. The mixture was ice-cooled and the 5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)bicyclo[2.2.2]octan-1-yl) obtained in the previous step was A solution of ethyl-1H-pyrazole-3-carboxylate (0.615 g) in tetrahydrofuran (6 ml) was added dropwise. After stirring for 150 minutes, saturated aqueous sodium potassium tartrate was added dropwise to the reaction mixture. After stirring at room temperature for 1 hour, the reaction solution was extracted with ethyl acetate.
• N-Methoxy-N-methylacetamide (0.286 ml) was added to the mixture and stirred for 1 hour.
• a 2M lithium diisopropylamide/tetrahydrofuran solution (0.596 ml) was added dropwise to the mixture, and the mixture was stirred for 1 hour.
• Water was added to the reaction mixture and extracted with ethyl acetate. After washing the organic layer with a saturated aqueous sodium chloride solution, sodium sulfate was added. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• a saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate.
• Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product (0.20 g) of the title compound.
• N,O-dimethylhydroxylamine hydrochloride (0.676 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.329 g) were added to the reaction mixture and stirred at room temperature for 3 hours.
• the organic layer was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and dried over sodium sulfate. After removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure.
• N-Methoxy-N-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)bicyclo[2.1.1]hexane-1-carboxamide (1. 17 g) was mixed with toluene (57.8 ml). A 1.04 M methylmagnesium bromide/tetrahydrofuran solution (4.57 ml) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution and water were added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate.
• N-Methoxy-N-methylacetamide (0.412 ml) was added to the mixture and stirred at -78°C for 30 minutes.
• a 2M lithium diisopropylamide/tetrahydrofuran-heptane-ethylbenzene solution (0.841 ml) was added dropwise to the mixture, and the mixture was stirred at -78°C for 1 hour.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• a 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added, and the mixture was stirred at room temperature for 1 hour and then extracted twice with ethyl acetate.
• the organic layer was washed successively with a 10% aqueous potassium carbonate solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over sodium sulfate.
• Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product (161 mg) of the title compound.
• a 5% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and then extracted three times with ethyl acetate.
• Ethyl 4-methylenecyclohexane-1-carboxylate (23.98g) was mixed with tetrahydrofuran (480ml). The mixture was cooled to ⁇ 78° C. and 2M lithium diisopropylamide/tetrahydrofuran-heptane-ethylbenzene solution (82 ml) was added dropwise. Stirred at -78°C for 30 minutes. Formaldehyde (6.42 g) was added to the mixture, and the mixture was stirred at ⁇ 78° C. for 30 minutes and then at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
• Ethyl 1-(hydroxymethyl)-4-methylenecyclohexane-1-carboxylate (13.65 g) obtained in the previous step was mixed with dichloromethane (341 ml).
• a solution of bis(2,4,6-trimethylpyridine)iodonium hexafluorophosphate (37.2 g)/dichloromethane (137 ml) was added dropwise to the mixture under ice cooling, and the mixture was stirred for 1 hour. After the reaction mixture was concentrated under reduced pressure, a 5% aqueous sodium thiosulfate solution was added, and the mixture was extracted twice with ethyl acetate.
• Ethyl 1-(iodomethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylate (10.176 g), potassium acetate (9.24 g) and 18-crown-6 obtained in the previous step (1.659 g) was mixed with dimethylsulfoxide (50.9 ml) and stirred at 110° C. for 2 days and 120° C. for 1 day.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, and the mixture was extracted twice with ethyl acetate.
• the organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• Step 13 Ethyl 3-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-oxabicyclo[2.2.2]octan-1-yl)-1H-pyrazole-5 - carboxylate
• N-Methoxy-N-methylacetamide (1.452 ml) was added to the mixture and stirred at -78°C for 30 minutes.
• a 2M lithium diisopropylamide/tetrahydrofuran-heptane-ethylbenzene solution (0.587 ml) was added dropwise to the mixture, and the mixture was stirred at -78°C for 1 hour.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• a saturated aqueous ammonium chloride solution was added at room temperature, and the mixture was extracted twice with ethyl acetate.
• the organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure.
• the resulting residue was mixed with tetrahydrofuran (1.8 ml). After dropwise addition of 1.04M methylmagnesium bromide/tetrahydrofuran solution (0.66 ml) at room temperature, the mixture was stirred for 2 hours.
• a saturated aqueous ammonium chloride solution was added at room temperature, and the mixture was extracted twice with ethyl acetate.
• Ethyl 1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylate (4.19 g) obtained in the previous step was mixed with tetrahydrofuran (30.8 ml). Potassium tert-butoxide (2.624 g) and benzyl bromide (4.308 g) were added to this mixture under ice-cooling, and the mixture was stirred for 1 hour. Ethanol (30.8 ml) and 2N aqueous sodium hydroxide solution (27 ml) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, diisopropyl ether was added and the layers were separated.
• the organic layer was washed with 1N aqueous sodium hydroxide solution.
• the aqueous layers were combined, adjusted to pH 2 using 6N hydrochloric acid, and extracted three times with ethyl acetate.
• the organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.9 g).
• Tetrahydrofuran 70 ml was mixed with lithium aluminum hydride (0.549 g) under an argon atmosphere. This mixture was ice-cooled. Ethyl 5-(1-((benzyloxy)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)-1H-pyrazole-3-carboxylate (2. 68g) in tetrahydrofuran (10ml) was added dropwise. The reaction was stirred at room temperature for 30 minutes. A saturated aqueous sodium potassium tartrate solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. After washing the organic layer with a saturated aqueous sodium chloride solution, sodium sulfate was added. Sodium sulfate was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2.14 g).
• a saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product (0.294 g) of the title compound.
• the reaction solution was added to silica gel (10 g) and eluted with ethyl acetate.
• 4,5-dichloropyridazin-3(2H)-one (18.5 g) was dissolved in toluene (185 ml).
• 4-Methoxybenzyl chloride (16.0 ml), tetrabutylammonium bromide (6.35 g) and 2N aqueous potassium hydroxide solution (59.1 ml) were added to the reaction solution at room temperature, and the mixture was heated under reflux at 120° C. for 7 hours. Water was added to this reaction mixture to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure.
• Step 4 Ethyl 2-(5-chloro-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazin-4-yl)propanoate

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