US20150329491A1 - Fluorene compound and pharmaceutical use thereof - Google Patents

Fluorene compound and pharmaceutical use thereof Download PDF

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Publication number
US20150329491A1
US20150329491A1 US14/484,666 US201414484666A US2015329491A1 US 20150329491 A1 US20150329491 A1 US 20150329491A1 US 201414484666 A US201414484666 A US 201414484666A US 2015329491 A1 US2015329491 A1 US 2015329491A1
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United States
Prior art keywords
group
compound
different
same
optionally substituted
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US14/484,666
Inventor
Takahisa Motomura
Hironobu Nagamori
Koichi Suzawa
Hirotsugu Ito
Toru Morita
Satoru Kobayashi
Hisashi Shinkai
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Japan Tobacco Inc
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Japan Tobacco Inc
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Priority to US14/484,666 priority Critical patent/US20150329491A1/en
Publication of US20150329491A1 publication Critical patent/US20150329491A1/en
Priority to US16/042,271 priority patent/US20190177271A1/en
Priority to US16/670,264 priority patent/US20200308109A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to a fluorene compound and a pharmaceutical use thereof. More particularly, the present invention relates to a compound for the prophylaxis or treatment of diabetes, cardiovascular diseases, hyperlactacidemia and cancer based on activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK), and use thereof. Furthermore, the present invention relates to a compound for the prophylaxis or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, and use thereof.
  • diabetic complications e.g., neuropathy, retinopathy, nephropathy, cataract etc.
  • ATP adenosine triphosphate
  • metabolic fuel which yields much energy, such as glucose and free fatty acids.
  • ATP is mostly produced from acetyl-CoA that enters citric acid cycle.
  • Acetyl-CoA is produced by oxidation of glucose via glycolytic pathway or ⁇ oxidation of free fatty acid.
  • An enzyme that plays a pivotal role in controlling acetyl-CoA production from glucose is PDH.
  • PDH catalyses the oxidation of pyruvate to acetyl-CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH.
  • NAD nicotinamide adenine dinucleotide
  • PDH is a multienzyme complex consisting of three enzyme components (E1, E2 and E3) and some subunits localized in mitochondria matrix.
  • E1, E2 and E3 are responsible for decarboxylation from pyruvate, production of acetyl-CoA and reduction of NAD to NADH, respectively.
  • Two classes of enzyme having regulatory function are associated with the complex.
  • One is PDHK, which are protein kinases having specificity to PDH. The role thereof is to inactivate E1 ⁇ subunit of the complex by phosphorylation.
  • the other is PDH phosphatases, which are specific protein phosphatases which activate PDH via dephosphorylation of E1 ⁇ subunit.
  • the proportion of PDH in its active (dephosphorylated) state is determined by the balance of kinase activity and phosphatase activity.
  • the kinase activity is regulated by relative concentrations of metabolic substrates.
  • the kinase activity is activated by an increase in the NADH/NAD, acetyl-CoA/CoA or ATP/adenosine diphosphate (ADP) ratios, and inhibited by pyruvate.
  • PDHK isoenzymes have been identified in mammalian tissues. Particularly, PDHK2 is expressed in a wide range of tissues including the liver, skeletal muscles and adipose tissues involved in glucose metabolism. Since it shows comparatively high sensitivity to activation by increased NADH/NAD or acetyl-CoA/CoA and inhibition by pyruvate, involvement in a short-term regulation of glucose metabolism is suggested.
  • oxidation of lipids is increased with a concomitant reduction in utilization of glucose. This is one of the factors causing hyperglycemia.
  • PDH activity is also reduced. It suggests involvement of reduced PDH activity in the reduced utilization of glucose in type 1 and type 2 diabetes.
  • hepatic gluconeogenesis is enhanced in type 1 and type 2 diabetes, which also forms one factor causing hyperglycemia.
  • the reduced PDH activity increases pyruvate concentration, which in turn increases availability of lactate as a substrate for hepatic gluconeogenesis.
  • a drug that activates PDH by inhibition of PDHK is considered to decrease lactate production since it promotes pyruvate metabolism.
  • such drug is expected to be useful for the treatment of hyperlactacidemia such as mitochondrial disease, mitochondrial encephalomyopathy and sepsis.
  • Pulmonary hypertension is characterized by high blood pressure caused by partial narrowing of the pulmonary artery due to promoted cell proliferation therein. In pulmonary hypertension, therefore, activation of PDH in the pulmonary artery cell is expected to promote oxidative phosphorylation in mitochondria, and induce apoptosis of the pulmonary artery cells. Therefore, the mechanism is useful for the treatment of pulmonary hypertension.
  • dichloroacetic acid which is a drug having a PDH activating action, provides promising effects for amelioration of hyperglycemia, treatment of myocardial ischemia, treatment of hyperlactacidemia and treatment of cancer diseases. Moreover, usefulness of dichloroacetic acid for the treatment of cerebral ischemia, cerebral apoplexy or pulmonary hypertension has been shown.
  • a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases relating to glucose utilization disorder, for example, diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia and hyperlactacidemia.
  • a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.).
  • a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases caused by limited energy substrate supply to the tissues, for example, cardiac failure, cardiomyopathy, myocardial ischemia, dyslipidemia and atherosclerosis.
  • a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of mitochondrial disease, mitochondrial encephalomyopathy, cancer and the like. Also, it is considered to be useful for the treatment or prophylaxis of pulmonary hypertension.
  • the present invention aims to provide an agent for the prophylactic or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like.
  • a PDHK inhibitor also useful as an agent for the prophylactic or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, and the like.
  • the present inventors have conducted intensive studies in an attempt to develop an agent for the prophylactic or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy, cancer, diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, which is based on a PDHK inhibitory action and found a fluorene compound having a PDHK inhibitory action, and completed the present invention.
  • diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • insulin resistance syndrome e.g., type 1 diabetes, type 2 diabetes etc.
  • metabolic syndrome e.g., insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardio
  • the present invention provides the following.
  • R b is
  • R b16 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B;
  • ring T is (i) a C 6-10 aryl group, (ii) a C 3-10 cycloalkyl group, (iii) a C 5-10 bridged cycloalkyl group, (iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or (v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, R j are the same or different and each
  • R d is (i) a hydrogen atom, (ii) a halogen atom, (iii) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A, (iv) a C 2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (v) a C 2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (vi) a cyano group, (vii) —C( ⁇ O)—R d1 wherein R d1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (viii) —C( ⁇ O)—OR d2 wherein R d2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituent
  • ring U is (I) a C 6-10 aryl group, (II) a C 3-10 cycloalkyl group, (III) a C 5-10 bridged cycloalkyl group, (IV) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or (V) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, R k are the same or different and each is a substituent selected from the following group D, and m is an integer of 0, or 1 to 4; R e are the same or different and each is, (1) a halogen atom, or (2) a C 1-6 alkyl group
  • Group A is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C( ⁇ O)—R A1 wherein R A1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (d) —C( ⁇ O)—OR A2 wherein R A2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (e) —C( ⁇ O)—NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (f) —C( ⁇ O)—NR A5 —OR A6 wherein R A5 and R A6 are the same or different and each is a
  • Group B is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C( ⁇ O)—R B1 wherein R B1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (d) —C( ⁇ O)—OR B2 wherein R B2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (e) —C( ⁇ O)—NR B3 R B4 wherein R B3 and R B4 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (f) —C( ⁇ O)—NR B5 —OR B6 wherein R B5 and R B6 are the same or different and each is a
  • Group C is selected from the group consisting of (a) a halogen atom, (b) —C( ⁇ O)—R C1 wherein R C1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 halogen atoms, (c) —C( ⁇ O)—OR C2 wherein R C2 is a hydrogen atom or a C 1-6 alkyl group, and (d) —OR C3 wherein R C3 is a hydrogen atom or a C 1-6 alkyl group.
  • Group D is selected from the group consisting of (a) a halogen atom, (b) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (c) a C 1-6 alkyl group substituted by a C 6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (d) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (e) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (f) a C 1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C 1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains
  • Group E is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C( ⁇ O)—R E1 wherein R E1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (d) —C( ⁇ O)—OR E2 wherein R E2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (e) —C( ⁇ O)—NR E3 R E4 wherein R E3 and R E4 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (f) —C( ⁇ O)—NR E5 —OR E6 wherein R E5 and R E6 are the same or different and each is a
  • Group F is selected from the group consisting of (a) —(CH 2 ) nF1 —C( ⁇ O)—OR F1 wherein R F1 is a hydrogen atom or a C 1-6 alkyl group, and nF1 is an integer of 0, or 1 to 4, and (b) —(CH 2 ) nF2 —OR F2 wherein R F2 is a hydrogen atom or a C 1-6 alkyl group, and nF2 is an integer of 0, or 1 to 4.
  • a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E (2) a C 1-6 alkyl group substituted by a C 6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C 1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C 1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7
  • R m is (1) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′, (2) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and group E′ is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C( ⁇ O)
  • R m is (1) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from (i) —C( ⁇ O)—OR E2 wherein R E2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (ii) —C( ⁇ O)—NR E3 R E4 wherein R E3 and R E4 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (iii) —OR E7 wherein R E7 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, and (iv) —NR E12 —C( ⁇ O)—R E13 wherein R E12 and R E13
  • R m is (1) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from (i) —C( ⁇ O)—OR E2 wherein R E2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, and (ii) —OR E7 wherein R E7 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C 3-10 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or (3) a C 5-10 bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R m is (1) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents
  • a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
  • a PDHK inhibitor comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a PDH activator comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a PDHK2 inhibitor comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a blood glucose level-lowering agent comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a lactate level-lowering agent comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • An agent for the treatment or prophylaxis of diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • insulin resistance syndrome e.g., type 1 diabetes, type 2 diabetes etc.
  • metabolic syndrome e.g., hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • An agent for the treatment or prophylaxis of diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • diabetic complications e.g., neuropathy, retinopathy, nephropathy, cataract etc.
  • insulin resistance syndrome e.g., metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a method of inhibiting PDHK in a mammal comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a method of activating PDH in a mammal comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a method of inhibiting PDHK2 in a mammal comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a method of decreasing the blood glucose level in a mammal comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a method of decreasing lactate level in a mammal comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a method for the treatment or prophylaxis of diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • insulin resistance syndrome e.g., type 1 diabetes, type 2 diabetes etc.
  • metabolic syndrome e.g., hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal
  • administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a method for the treatment or prophylaxis of diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • diabetic complications e.g., neuropathy, retinopathy, nephropathy, cataract etc.
  • insulin resistance syndrome e.g., metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
  • a commercial kit comprising (a) a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof as active ingredient, and (b) a written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
  • diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • diabetic complications e.g., neuropathy, retinopathy, nephropathy, cataract etc.
  • insulin resistance syndrome
  • a commercial package comprising (a) a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof as active ingredient, and (b) a written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
  • diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • diabetic complications e.g., neuropathy, retinopathy, nephropathy, cataract etc.
  • insulin resistance syndrome
  • the fluorene compound of the present invention effectively inhibits the PDHK activity, and further, has preferable properties as a drug such as chemical stability and the like, it is effective as an agent for the prophylaxis or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, and the like.
  • diabetes e.g., type 1 diabetes, type 2 diabetes etc.
  • insulin resistance syndrome e.g., type 1 diabetes, type 2 diabetes etc.
  • metabolic syndrome e.g., hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, and the like.
  • diabetes e.g., type 1 diabetes, type 2 diabetes
  • the fluorene compound of the present invention is also effective as an agent for the prophylaxis or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.
  • diabetic complications e.g., neuropathy, retinopathy, nephropathy, cataract etc.
  • brain ischemia e.g., cerebral apoplexy or pulmonary hypertension.
  • the “optionally substituted” includes both being substituted at substitutable position(s) of an object group and being unsubstituted.
  • the “unsubstituted” means that all substitutable positions of an object group are occupied by hydrogen atoms.
  • a “C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A” means both when the substitutable position(s) of a C 1-6 alkyl group is(are) substituted by the same or different 1 to 5 substituents selected from group A, and is(are) not substituted (unsubstituted).
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • the “C 1-6 alkyl group” means a straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group and the like.
  • the “C 2-6 alkenyl group” means a linear or branched chain unsaturated hydrocarbon group having 2 to 6 a carbon atoms and containing one or more double bonds.
  • Examples thereof include a vinyl group, a 1-methylvinyl group, a 1-propenyl group, an allyl group, a methylpropenyl group (1-methyl-1-propenyl group, 2-methyl-1-propenyl group etc.), a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a methylbutenyl group (1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group etc.), a pentenyl group, a methylpentenyl group, a hexenyl group and the like.
  • Preferred are a vinyl group, a 1-methylvinyl group, a 1-propenyl group, a methylpropenyl group and the
  • the “C 2-6 alkynyl group” means a linear or branched chain unsaturated hydrocarbon group having 2 to 6 a carbon atoms and containing one or more triple bonds. Examples thereof include an ethynyl group, a propynyl group (1-propynyl group, 2-propynyl group), a butynyl group, a pentynyl group, a hexynyl group and the like. Preferred are an ethynyl group, a 1-propynyl group and the like.
  • C 1-6 alkylene means a divalent group derived from the above-mentioned “C 1-6 alkyl group”. Examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. Preferred are methylene, ethylene, trimethylene and the like.
  • C 2-6 alkenylene means a divalent group derived from the above-mentioned “C 2-6 alkenyl group”. Examples thereof include vinylene, propenylene, butenylene, pentenylene, hexenylene and the like. Preferred are vinylene and the like.
  • the “C 6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like. Preferred is a phenyl group.
  • the “C 3-10 cycloalkyl group” means a monocycle saturated hydrocarbon group having 3 to 10 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like. Particularly, a C 3-6 cycloalkyl group (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group etc.) is preferable.
  • a C 3-6 cycloalkyl group e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group etc.
  • the “C 5-10 bridged cycloalkyl group” means a bridged cyclic saturated hydrocarbon group having 5 to 10 carbon atoms. Examples thereof include a bicyclopentanyl group, a bicyclohexyl group, a bicycloheptyl group, a tricycloheptyl group, a bicyclooctyl group, an adamantyl group and the like. Particularly, an adamantyl group is preferable.
  • the “monocyclic aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group, containing, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 7 ring-constituting atoms.
  • Examples thereof include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group (1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group), a thiadiazolyl group (1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group), a triazolyl group (1,2,3-triazolyl group, 1,2,4-triazolyl group), a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a tria
  • the “monocyclic non-aromatic heterocyclic group” means a monocyclic saturated or partially unsaturated heterocyclic group, which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms.
  • Examples thereof include an oxiranyl group, a thioranyl group, an aziridinyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a pyrrolidino group (1-pyrrolidinyl group), a tetrahydrofuranyl group, a tetrahydrothienyl group, an oxazolinyl group, an oxazolidinyl group, an isoxazolinyl group, an isoxazolidinyl group, a thiazolinyl group, a thiazolidinyl group, an isothiazolinyl group, an isothiazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolinyl group, a pyrazolidinyl group, a piperidinyl group, a piperidino group (1-
  • an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a 2-oxopyrrolidinyl group, a 2-oxopyrrolidino group, an oxazolidinyl group, a 2-oxooxazolidinyl group, an isothiazolidinyl group, a 1,1-dioxoisothiazolidinyl group, an imidazolidinyl group, a 2-oxoimidazolidinyl group, a 2-oxopiperidinyl group, a 2-oxopiperidino group, a morpholinyl group, a morpholino group, a 2-oxomorpholino group, a piperazinyl group, a piperazino group, a 2-oxopiperazino group, a hexahydro-2-oxo-1,3-oxazinyl group and the like are preferable.
  • R b3 and R b4 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.
  • R b5 and R b6 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.
  • R a is (1) a hydrogen atom, or (2) a halogen atom, preferably, a hydrogen atom, a fluorine atom or a chlorine atom, more preferably, a hydrogen atom.
  • R b Preferable embodiments of R b are classified into the following type A and type B.
  • R b is a group represented by the following formula:
  • R b16 is a hydrogen atom or a C 1-6 alkyl group (particularly, a methyl group); more preferably, a single bond, —O—CH 2 —, —O—(CH 2 ) 2 —, —O—CH 2 —C( ⁇ O)—, or —C( ⁇ O)—.
  • a C 6-10 aryl group (i) a C 3-6 cycloalkyl group, (iii) a C 5-10 bridged cycloalkyl group, (iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 5 or 6 ring-constituting atoms, or (v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 3 or 6 ring-constituting atoms; more preferred is (i) a phenyl group, (ii) a C 3-6 cycloalkyl group (particularly, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexy
  • R j is preferably,
  • a halogen atom (2) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (3) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a cyano group, (5) —C( ⁇ O)—R D1 wherein R D1 is a hydrogen atom, a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by the same or different 1 to 5 substituents selected from group F (the monocyclic non-aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (6) —C( ⁇ O)—
  • R j include a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a hydroxy group, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxy-2-methylpropyl group, a carboxymethyl group, a carbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a cyclohexylmethyl group, a cyano group, an acetyl group, a propionyl group, an isobutyryl group, a 2,2-dimethylpropionyl group, a pyrrolidinocarbonyl group, a piperidinocarbonyl group, a 4-hydroxypiperidinocarbonyl group
  • p is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.
  • R b specifically preferable examples include a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 3,5-dichlorophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-(hydroxymethyl)phenyl group, a 4-(hydroxymethyl)phenyl group, a 4-hydroxyphenyl group, a 4-hydroxyphenyl group, a 2-methoxyphenyl group, a 3-methoxycarbonylphenyl group, a 4-methoxyphenyl group, a 3-chloro-4-methoxyphenyl group, a 3-chloro-4-methoxycarbonylphenyl group, a 2-carboxyphenyl group, a 3-carboxypheny
  • R b preferable examples of R b include
  • a hydrogen atom (2) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom), (3) a C 1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, an isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group) optionally substituted by the same or different 1 to 5 substituents selected from group A [particularly, (i) —C( ⁇ O)—OR A2 wherein R A2 is a hydrogen atom or a C 1-6 alkyl group (particularly, a methyl group), (ii) —C( ⁇ O)—NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group, (iii) —OR A7 wherein R A7 is
  • R b specifically preferable examples include, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a neopentyl group, a 3,3-dimethylbutyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, a 3-hydroxy-3-methylbutyl group, a 4-hydroxy-3,3-dimethylbutyl group, a methoxycarbonylmethyl group, a carboxymethyl group, a carbamoylmethyl group, an acetylaminomethyl group, a methylaminomethyl group, an N-acetyl-N-methylaminomethyl group, a (triethylsilyl)ethy
  • R c5 and R c6 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), particularly preferably, a hydrogen atom.
  • R c include a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxy group, a methoxy group, an ethoxy group, an amino group, an acetylamino group, a propionylamino group, an isobutyrylamino group, a carboxyl group, a methoxycarbonyl group and the like.
  • Preferable embodiments of X d are classified into the following type C to type E.
  • X d is a nitrogen atom.
  • R k is preferably
  • a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E (2) a C 1-6 alkyl group substituted by a C 6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C 1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C 1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7
  • R k Specifically preferable examples of R k include
  • n is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.
  • R d include a phenyl group, a cyclopropyl group, a cyclopropanecarbonyl group, an oxazol-5-yl group, a 2-methyl-oxazol-5-yl group, an oxazol-2-yl group, a 2-(2-hydroxy-1-(hydroxymethyl)ethyl)-oxazol-5-yl group, a 2-pyridyl group, a 3-pyridyl group, a 4-methyl-3-pyridyl group, a 6-methyl-3-pyridyl group, a 4-pyridyl group, a 1,3,4-oxadiazol-2-yl group, a 5-methyl-1,3,4-oxadiazol-2-yl group, a 3-methyl-1,2,4-oxadiazol-5-yl group, a 5-methyl-1,2,4-oxadiazol-3-yl group, a 3-(2-hydroxy-1-(hydroxymethyl)ethyl)-1
  • Ring U is preferably a monocyclic aromatic heterocyclic group.
  • a pyrazolyl group particularly, a pyrazol-4-yl group
  • a pyrimidinyl group particularly, a pyrimidin-5-yl group
  • Still more preferred is a compound represented by the following formula, which is a compound wherein ring U is a pyrazol-4-yl group:
  • a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E (2) a C 1-6 alkyl group substituted by a C 6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 1-6 alkyl group substituted by a C 6-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C 1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C 1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7
  • R m preferred is
  • a C 1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 1-ethylpropyl group, a 1,1,2-trimethylpropyl group) optionally substituted by the same or different 1 to 5 substituents selected from (i) a halogen atom (particularly, a fluorine atom), (ii) —C( ⁇ O)—OR E2 wherein R E2 is a hydrogen atom or a C 1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (iii) —C( ⁇ O)—NR E3 R E4 wherein R E3 and R E4 are the same or different and each is
  • R m include a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1-benzyl group, an adamantan-1-yl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-(acetylamino)ethyl group, a 2-(N-acetyl-N-methylamino)ethyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, an ethylcarbamoylmethyl group, an isopropylcarbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a 2-(methylcarbamoyl)eth
  • R m preferred is
  • a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′ (2) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferred is, (1) a C 1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a ter
  • R c is preferably a hydrogen atom;
  • R b is preferably (1) a hydrogen atom, (2) a halogen atom, (3) a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, (4) a C 2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (5) a C 2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (6) a cyano group, (7) —C( ⁇ O)—R b1 wherein R b1 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (8) —C( ⁇ O)—OR b2 wherein R b2 is a hydrogen atom or a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (9)
  • n is preferably 0;
  • R a is preferably a hydrogen atom; and n is preferably 0.
  • R d is preferably
  • R d include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a methoxymethyl group, a trifluoromethyl group, an aminomethyl group, a cyanomethyl group, a carboxymethyl group, a carbamoylmethyl group, a 1-methylvinyl group, an ethynyl group, a 3-hydroxypropynyl group, a cyano group, an acetyl group, a propionyl group, an isobutyryl group, a carboxy group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a carbamoyl group
  • type C and type D are preferable, and type C is more preferable.
  • R e is preferably the same or different and each is
  • a halogen atom particularly, a chlorine atom, a fluorine atom
  • a C 1-6 alkyl group particularly, a methyl group
  • substituents particularly, a hydroxy group
  • group C more preferably, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group and the like.
  • n is an integer of 0, or 1 to 3, preferably an integer of 0, or 1 to 2, particularly preferably 0.
  • R a is a hydrogen atom
  • R c is a hydrogen atom
  • R d is —CH 3 , —CH 2 —OH or —C( ⁇ O)—NH 2
  • n 0.
  • R a is a hydrogen atom, a fluorine atom or a chlorine atom, particularly a hydrogen atom,
  • R b is
  • R c5 and R c6 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), particularly a hydrogen atom,
  • a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E (2) a C 1-6 alkyl group substituted by a C 6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C 1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C 1-6 alkyl group (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7
  • R e is the same or different and each is a fluorine atom, a chlorine atom, a methyl group, or a hydroxymethyl group, n is an integer of 0, or 1 to 2, particularly 0.
  • an optical active form of the compound represented by the following chemical formulas and a mixture thereof are encompassed in the present invention.
  • an optically active form of the compound represented by the following chemical formulas which is a preferable embodiment of the compound of the present invention, and a mixture thereof are encompassed in the present invention.
  • a C 1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′ (2) a C 1-6 alkyl group substituted by a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C 1-6 alkyl group substituted by a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C 3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C 5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F.
  • a specifically preferable compound of the compound represented by the formula [I] is the following compound.
  • a pharmaceutically acceptable salt of the compound represented by the formula [I] may be any salt as long as it forms a nontoxic salt with the compound of the present invention.
  • examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids and the like.
  • Examples of the salt with inorganic acid include a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • salt with organic acid examples include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Examples of the salt with inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
  • Examples of the salt with organic base include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine and the like.
  • salt with amino acid examples include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
  • each salt can be obtained by reacting a compound represented by the formula [I] with an inorganic base, organic base, inorganic acid, organic acid or amino acid according to a known method.
  • the “solvate” is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof wherein a molecule of the solvent is coordinated, and also includes hydrates.
  • a pharmaceutically acceptable solvate is preferable and includes, for example, hydrate, ethanolate, dimethylsulfoxidate and the like of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof. Specific examples thereof include hemihydrate, monohydrate, dihydrate and monoethanolate of the compound represented by the formula [I], monohydrate of sodium salt, 2/3 ethanolate of dihydrochloride, and the like of the compound represented by the formula [I].
  • the solvate can be obtained according to a method known per se.
  • the compound represented by the formula [I] may be labeled with an isotope (e.g., 3 H, 14 C, 35 S etc.).
  • a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each of which is substantially purified, is preferable. More preferred is, a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each of which is purified to a purity of not less than 80%.
  • a prodrug of the compound represented by the formula [I] can also be a useful medicament.
  • the “prodrug” is a derivative of the compound of the present invention having a chemically or metabolically degradable group which, after administration to the body, restores to the original compound by, for example, hydrolysis, solvolysis or decomposition under physiological conditions, and shows inherent efficacy. It is considered to include a noncovalent complex, and a salt. Prodrug is utilized for, for example, improvement of absorption on oral administration, or targeting to a target moiety.
  • modified moiety examples include, in the compound of the present invention, a highly reactive functional group such as a hydroxyl group, a carboxyl group, an amino group and the like.
  • hydroxyl-modifying group examples include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, a fumaryl group, a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group and the like.
  • sodium salt of 3-carboxybenzoyl group, 2-carboxyethylcarbonyl group and the like can be mentioned.
  • carboxyl-modifying group examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, a 1-(acetyloxy)ethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a 1-(isopropyloxycarbonyloxy)ethyl group, a 1-(cyclohexyloxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a phenyl group, an o-tolyl group, a morpholinoethyl group, an N,N-diethylcarbamoylmethyl group,
  • amino-modifying group examples include a tert-butyl group, a docosanoyl group, a pivaloyloxymethyl group, an alanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a 3-methylthio-1-(acetylamino)propylcarbonyl group, a 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, a tetrahydrofuranyl group, a pyrrolidylmethyl group and the like.
  • compositions examples include oral preparations such as tablet, capsule, granule, powder, troche, syrup, emulsion, suspension and the like, and parenteral agents such as external preparation, suppository, injection, eye drop, nasal preparation, pulmonary preparation and the like.
  • the pharmaceutical composition of the present invention is produced according to a method known in the art of pharmaceutical preparations, by mixing a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof with a suitable amount of at least one kind of pharmaceutically acceptable carrier and the like as appropriate. While the content of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dose and the like, it is, for example, 0.1 to 100 wt % of the whole composition.
  • “pharmaceutically acceptable carrier” examples include various organic or inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, fluidizer, lubricant and the like for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffering agent, soothing agent and the like for liquid preparations. Where necessary, moreover, additives such as preservative, antioxidant, colorant, sweetening agent and the like are used.
  • excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, gum arabic and the like.
  • disintegrant examples include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
  • fluidizer examples include light anhydrous silicic acid, magnesium stearate and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc and the like.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the “solubilizing agents” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate and the like.
  • isotonicity agent examples include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
  • buffering agent examples include sodium hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • Examples of the “soothing agent” include benzyl alcohol and the like.
  • preservative examples include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • antioxidant examples include sodium sulfite, ascorbic acid and the like.
  • colorant examples include food colors (e.g., Food Color Red No. 2 or 3, Food Color yellow No. 4 or 5 etc.), ⁇ -carotene and the like.
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., topical, rectal, intravenous administration etc.) to human as well as mammals other than human (e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog, swine, bovine, horse, sheep, monkey etc.).
  • the dose varies depending on the subject of administration, disease, symptom, dosage form, administration route and the like.
  • the daily dose for oral administration to an adult patient is generally within the range of about 1 mg to 1 g, based on the compound of the present invention as the active ingredient. This amount can be administered in one to several portions.
  • the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof has inhibitory activity against pyruvate dehydrogenase kinase (PDHK, particularly PDHK2), and can activate pyruvate dehydrogenase (PDH) effectively.
  • PDHK pyruvate dehydrogenase kinase
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used as an active ingredient of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
  • the compound can be used as an active ingredient of an agent for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), cerebral ischemia, cerebral apoplexy or pulmonary hypertension.
  • To “inhibit PDHK” means to specifically inhibit the function of PDHK and eliminate or attenuate the activity.
  • human PDHK is preferably inhibited.
  • a “PDHK inhibitor” preferred is a “human PDHK inhibitor”.
  • inhibit PDHK2 means to specifically inhibit the function of PDHK2 and eliminate or attenuate the activity. For example, it means to specifically inhibit the function as PDHK2 based on the conditions in the below-mentioned Experimental Example 1.
  • human PDHK2 is preferably inhibited.
  • PDHK2 inhibitor preferred is a “human PDHK2 inhibitor”.
  • To “activate PDH” means to activate PDH in a target organ (e.g., liver, skeletal muscle, adipose tissue, heart, brain) and the like, cancer or the like.
  • a target organ e.g., liver, skeletal muscle, adipose tissue, heart, brain
  • To “decrease blood glucose level” means to decrease the glucose concentration in blood (including in serum and plasma), preferably to decrease high blood glucose level, more preferably, to decrease the blood glucose level to normal level for human.
  • the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination with one or a plurality of other medicaments (hereinafter to be also referred to as a concomitant drug) according to a method generally employed in the medical field (hereinafter to be referred to as combined use).
  • the administration period of the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a concomitant drug is not limited, and they may be administered to an administration subject as combination preparation, or the both preparations may be administered simultaneously or at given intervals.
  • the pharmaceutical composition of the present invention and a concomitant drug may be used as a medicament in the form of a kit.
  • the dose of the concomitant drug is similar to the clinically-employed dose and can be appropriately selected according to the subject of administration, disease, symptom, dosage form, administration route, administration time, combination and the like.
  • the administration form of the concomitant drug is not particularly limited, and it only needs to be combined with the compound of the present invention or a salt thereof, or a solvate thereof.
  • Examples of the concomitant drug include an agent for the treatment and/or prophylaxis of diabetes and the like, and 1 to 3 agents therefrom and the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination.
  • agents for the treatment and/or prophylaxis of diabetes include insulin preparation, sulfonylurea hypoglycemic agent and the like.
  • the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional group with deprotection in a subsequent step, subjecting a functional group as a precursor to each step, followed by conversion to a desired functional group at a suitable stage, changing the order of Production Methods and steps, and the like.
  • the treatment after reaction in each step may be conventional ones, where isolation and purification can be performed as necessary according to a method appropriately selected from conventional methods such as crystallization, recrystallization, distillation, partitioning, silica gel chromatography, preparative HPLC and the like, or a combination of those methods.
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide, N,N-dimethylacetamide etc. and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride etc., and the like. Preferred is potassium carbonate or lithium acetate.
  • the reaction temperature of the trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time of the trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • the amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [Ia].
  • the amount of the catalyst of the trifluoromethylation reaction to be used is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [Ia].
  • Examples of the reagent to be used for the hydrolysis of trimethylsilyl ether include alkali metal fluorides such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride etc., and the like.
  • the reaction temperature is generally about ⁇ 10 to 50° C., preferably about 0° C. to room temperature.
  • reaction time is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • the amount of the reagent to be used for the hydrolysis of trimethylsilyl ether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Ia].
  • the desired optically active compound [I] can be obtained by separating racemate according to preferential crystallization method, diastereomer method, optical resolution method using chiral stationary phase column and the like.
  • Hal 1 is a halogen atom, preferably a bromine atom, a chlorine atom or an iodine atom
  • Hal 2 is a halogen atom, preferably a chlorine atom or a bromine atom
  • R Y1 ” and “R Y2 ” are the same or different and each is a carboxyl-protecting group such as a C 1-4 alkyl group (e.g., a methyl group, an ethyl group, t-butyl etc.), a benzyl group and the like; at least one of the substituents “R Z1 ” to “R Z3 ” of amine has an asymmetric center and a single steric configuration (e.g., (R)-1-phenylethyl-1-yl, (S)-1-phenylethyl-1-yl, (R)-1-(1-naphthyl)ethyl-1-yl,
  • M of compound [IIb] is a group containing boron, zinc, tin or the like.
  • examples thereof include boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like.
  • dialkoxyboron and boronic acid Preferred are dialkoxyboron and boronic acid, and particularly preferred is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • the metal catalyst to be used for the reaction examples include those having palladium or nickel, and preferred are palladium, particularly preferably palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0).
  • the amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIa].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetate such as sodium acetate and the like; organic bases such as triethylamine and the like, preferably tripotassium phosphate.
  • alkali metal phosphates such as tripotassium phosphate and the like
  • alkali metal carbonates such as sodium carbonate and the like
  • alkali metal acetate such as sodium acetate and the like
  • organic bases such as triethylamine and the like, preferably tripotassium phosphate.
  • the reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.
  • the amount of compound [IIb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIa].
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IIa].
  • Compound [IId] can be obtained by subjecting compound [IIc] to ester hydrolysis in a solvent.
  • the ester hydrolysis may be performed under general conditions, for example, under alkaline conditions or acidic conditions.
  • compound [IIc] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like) per 1 mol of compound [IIc] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.
  • a base alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like
  • compound [IIc] is reacted in the presence of, for example, about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IIc] in, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
  • an acid hydrochloric acid, sulfuric acid etc.
  • carboxylic acid solvents such as acetic acid and the like
  • ether solvents such as tetrahydrofuran, dioxane, etc., and the like
  • a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
  • Compound [IIe] can be obtained by cyclization reaction of compound [IId] in the presence of an acid without solvent or in a solvent.
  • Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like.
  • the amount thereof to be used is generally about 1 mol to a large excess per 1 mol of compound [IId].
  • a solvent for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without a solvent or in methanesulfonic acid as a solvent.
  • the reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride etc., and the like. Preferred is potassium carbonate or lithium acetate.
  • the reaction temperature of the trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time of the trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • the amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IIe].
  • the amount of the catalyst for the trifluoromethylation reaction to be used is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IIe].
  • Examples of the reagent to be used for hydrolysis of trimethylsilyl ether include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salt such as tetrabutylammonium fluoride etc., and the like.
  • the reaction temperature is generally about ⁇ 10 to 50° C., preferably about 0° C. to room temperature.
  • reaction time is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • the amount of the reagent to be used for hydrolysis of trimethylsilyl ether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIe].
  • optically active compound [IIf] As a method for obtaining optically active compound [IIf], a method comprising steps 14a-14e from compound [IIe] or compound [IIf] can be mentioned. By selecting an appropriate optically active amine for this method, (+) or ( ⁇ ) form of compound [IIf] can be produced.
  • Compound [IIg] wherein an acetic acid ester moiety is introduced can be obtained by trifluoromethylation reaction and hydrolysis of trimethylsilyl ether in the same manner as in Step 13, followed by reaction with halogenated acetic acid ester.
  • halogen atom of halogenated acetic acid ester examples include a chlorine atom, a bromine atom and an iodine atom.
  • carboxyl-protecting group (R Y2 ) examples include methyl, ethyl, t-butyl and the like.
  • the halogenated acetic acid ester is preferably ethyl bromoacetate.
  • This acetic acid ester introduction reaction is performed by directly adding halogenated acetic acid ester to a mixture of the trifluoromethylation reaction product and the trimethylsilyl ether hydrolysis product.
  • the reaction temperature is generally about 0 to 50° C., preferably about 15 to 30° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1 hr to 5 hr.
  • the amount of the halogenated acetic acid ester to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIe].
  • Compound [IIg] wherein an acetic acid ester moiety is introduced can also be obtained by reacting isolated compound [IIf] with halogenated acetic acid ester.
  • the reaction for introducing acetic acid ester is performed by reacting compound [IIf] with halogenated acetic acid ester in the presence of 1-5 equivalents (preferably, 2 equivalents) of a base (e.g., potassium carbonate etc.) at 0° C.-80° C. (preferably, room temperature) for 1-24 hr (preferably, overnight).
  • a base e.g., potassium carbonate etc.
  • Compound [IIh] can be obtained by general ester hydrolysis of compound [IIg] in the same manner as in Step 11 in a solvent.
  • Compound [IIi] which is a salt of a single diastereomer, can be obtained as a solid by mixing compound [IIh] with an optically active amine in a solvent.
  • optically active amine examples include (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-( ⁇ )-1-(1-naphthyl)-ethylamine and the like.
  • the amount of the optically active amine to be used is generally about 0.1 to 1 mol, preferably about 0.4 to 0.6 mol, per 1 mol of compound [IIh].
  • solvent to be used examples include ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone and the like; ester solvents such as ethyl acetate and the like; ether solvents such as isopropyl ether etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is methyl ethyl ketone, methyl isobutyl ketone.
  • the temperature for mixing is generally about 0 to 100° C., preferably about 20 to 70° C.
  • the time for the mixing is generally about 1 hr to 10 days, preferably about 1 to 5 days.
  • Compound [IIj] can be obtained by treating compound [IIi] with an acidic aqueous solution in a solvent to liberate carboxylic acid.
  • solvent to be used examples include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.
  • Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.
  • the treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the treatment time is generally about 1 min to 2 hr.
  • the amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IIi].
  • Optically active compound [IIf] can be obtained by reacting compound [IIj] in a solvent.
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide and the like; alcohol solvents such as t-butyl alcohol and the like; ether solvents such as dioxane and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture.
  • Preferable solvent for this reaction is a mixed solvent of dimethylformamide and t-butyl alcohol.
  • the reagent to be used for the reaction is preferably diphenylphosphoryl azide, and the base to be used for the reaction is a tertiary amine such as triethylamine, N-ethyldiisopropylamine and the like.
  • the reaction temperature is generally about 0 to 150° C., preferably about 0 to 100° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 30 min to 5 hr.
  • the amount of diphenylphosphoryl azide to be used is generally about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].
  • the amount of the base to be used is generally about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].
  • racemic compound [IIf] By treating racemic compound [IIf] using a chiral stationary phase column and the like, a desired optically active compound [IIf] can be separated from the other isomer.
  • Compound [IIm] can be obtained by introducing R k0 into compound [IIk] in a solvent in the presence of a base such as potassium carbonate, cesium fluoride and the like.
  • compound [IIm] when R k0 is a (cyclo)alkyl group, compound [IIm] can be obtained by reacting compound [IIk] with (cyclo)alkyl halide such as (cyclo)alkyl iodide and (cyclo)alkyl bromide, (cyclo)alkyl sulfonic acid ester such as (cyclo)alkyl tosylate, or an ⁇ , ⁇ -unsaturated carbonyl compound such as acrylic acid ester and the like in amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.
  • amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.
  • Compound [IIn] can be obtained by reacting compound [IIf] in the form of a racemate or an optically active form with compound [IIm] in a solvent in the presence of a metal catalyst, a ligand and a base.
  • Boronic acid moiety of compound [IIm] is boronic acid per se, or boronic acid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • the metal catalyst to be used for the reaction is palladium such as palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), dichlorobis(triphenylphosphine)palladium(II) and tetrakis(triphenylphosphine)palladium(0), with preference given to palladium(II) acetate.
  • the amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIf].
  • the ligand to be used for the reaction is phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, with preference given to 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
  • phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, with preference given to 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
  • Examples of the base to be used for the reaction include alkali metal phosphate such as tripotassium phosphate and the like; alkali metal carbonate such as sodium carbonate and the like; alkali metal hydrogencarbonate such as sodium hydrogencarbonate and the like; alkali metal acetate such as sodium acetate and the like; organic base such as triethylamine and the like, with preference given to tripotassium phosphate.
  • alkali metal phosphate such as tripotassium phosphate and the like
  • alkali metal carbonate such as sodium carbonate and the like
  • alkali metal hydrogencarbonate such as sodium hydrogencarbonate and the like
  • alkali metal acetate such as sodium acetate and the like
  • organic base such as triethylamine and the like, with preference given to tripotassium phosphate.
  • the reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • the amount of compound [IIm] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIf].
  • the amount of the ligand to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the metal catalyst.
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IIf].
  • the object compound [IIo] is obtained from compound [IIn] by general functional group conversion or deprotection.
  • compound [IIo] contains a hydroxyl group
  • the compound can be converted by removal of the hydroxyl-protecting group or reduction of an ester thereof, which is a precursor.
  • the compound when a hydroxyl group is protected by a benzyl group, the compound can be converted by catalytic hydrogenation reaction.
  • the hydroxyl group is protected by a silyl group such as t-butyldimethylsilyl group and the like, the compound can be converted by deprotection with tetrabutylammonium fluoride or the like.
  • diol is protected by a ketal such as acetonide and the like, the compound can be converted by deprotection with acid such as pyridinium p-toluenesulfonate and the like.
  • the compound can be converted by a hydride reduction reaction using sodium borohydride, lithium aluminum hydride or the like in a single solvent such as tetrahydrofuran, tetrahydropyran, water and the like or a mixture thereof.
  • conversion is possible by converting ester to carboxylic acid under general hydrolysis conditions, and reducing the acid with a reducing agent such as borane and the like.
  • compound [IIo] having a hydroxyl group can also be obtained by newly introducing a hydroxyl group.
  • a hydroxymethyl group can be introduced by reacting compound [IIn] having an ester with paraformaldehyde in the presence of a base such as tetrabutylammonium fluoride and the like.
  • compound [IIo] having a hydroxyl group can also be obtained by introducing formyl group by reacting compound [IIn] having an ester with formic acid ester such as ethyl formate, t-butyl formate and the like in the presence of a base such as sodium hydride, potassium t-butoxide and the like, followed by hydride reduction.
  • compound [IIo] When compound [IIo] has a carboxylic acid, compound [IIo] can be obtained by reacting an ester of compound [IIn] in the same manner as in Step 11 under general hydrolysis conditions. For example, when compound [IIn] is t-butyl ester, it can be converted to compound [IIo] under acidic conditions such as trifluoroacetic acid and the like.
  • the tetrazole ring can be introduced by reacting a cyano group with trimethylsilylazide or the like.
  • a cyano group can be introduced by converting carboxylic acid and the like to an amide and dehydrating the amide with trifluoroacetic anhydride and the like, or by the use of an alkylating agent having a cyano group and the like.
  • a sulfonamide group can be introduced by amidating an amino group with sulfonyl chloride or the like.
  • the amino group can be introduced by subjecting carboxylic acid to a rearrangement reaction, reacting alkyl halide with an amino source such as phthalimide potassium salt or the like.
  • the compound can be synthesized by an amidation reaction of the corresponding carboxylic acid or an activated derivative thereof with cyclic amine and the like, a reaction with a cyclic organometallic reagent or the like.
  • Compound [IVc] can be obtained by reacting compound [IVa] with compound [IVb] in a solvent in the presence of a metal catalyst and a base.
  • M in compound [IVb] is a group containing boron, zinc, tin or the like and, for example, boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like can be mentioned. It is preferably dialkoxyboron or boronic acid, particularly preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • a metal catalyst to be used for the reaction is one containing palladium or nickel.
  • Preferred is palladium, particularly preferably palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0).
  • the amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVa].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like; organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.
  • alkali metal phosphates such as tripotassium phosphate and the like
  • alkali metal carbonates such as sodium carbonate and the like
  • alkali metal acetates such as sodium acetate and the like
  • organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.
  • the reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.
  • the amount of compound [IVb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVa].
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IVa].
  • Compound [IVd] can be obtained by subjecting compound [IVc] to ester hydrolysis in a solvent.
  • Ester hydrolysis can be performed under general conditions and, for example, under alkaline conditions or acidic conditions.
  • compound [IVc] When it is performed under alkaline conditions, compound [IVc] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like etc.) per 1 mol of compound [IVc] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.
  • a base alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like etc.
  • compound [IVc] When it is performed under acidic conditions, compound [IVc] is reacted, for example, in the presence of about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVc] in the presence of, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
  • an acid hydrochloric acid, sulfuric acid etc.
  • carboxylic acid solvents such as acetic acid and the like
  • ether solvents such as tetrahydrofuran, dioxane, etc., and the like
  • a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
  • Compound [IVe] can be obtained by reacting compound [IVd] to cyclization in the presence of an acid with or without a solvent.
  • Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like.
  • the amount thereof to be used is generally about 1 mol to a large excess, per 1 mol of compound [IVd].
  • a solvent for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without solvent or in methanesulfonic acid as a solvent.
  • the reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like and the like, with preference given to potassium carbonate or lithium acetate.
  • the reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • the amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IVe].
  • the amount of the catalyst to be used for the trifluoromethylation reaction is generally for about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IVe].
  • Examples of the reagent to be used for trimethylsilyl ether hydrolysis include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like and the like.
  • the reaction temperature when trimethylsilyl ether is hydrolyzed is generally about ⁇ 10 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • the amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Ive].
  • Compound [IVg] can be obtained by reacting compound [IVf] in a solvent in the presence of an oxidant.
  • solvent to be used for the reaction examples include water, pyridine, t-butyl alcohol, acetone, acetic acid, sulfuric acid and the like. They can be used alone or in a mixture with water. Preferable solvent for this reaction is a mixed solvent of water and pyridine.
  • Examples of the oxidant to be used for the reaction include permanganates such as potassium permanganate and the like, chromates such as sodium chromate and the like and the like, with preference given to potassium permanganate.
  • the reaction temperature is generally about 0 to 120° C., preferably 50 to 110° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1 to 8 hr.
  • the amount of potassium permanganate to be used is generally about 2 to 20 mol, preferably about 2 to 10 mol, per 1 mol of compound [IVf].
  • a method for obtaining optically active compound [IVg] includes Steps 25a-25b from a racemic compound [IVg].
  • (+) or ( ⁇ ) form of compound [IVg] can be produced by appropriately selecting an optically active amine.
  • Compound [IVh] which is a salt of single diastereomer, can be obtained as a solid by mixing compound [IVg] with optically active amine in a solvent.
  • optically active amine examples include (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-( ⁇ )-1-(1-naphthyl)-ethylamine and the like.
  • the amount of the optically active amine to be used is generally about 0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound [IVg].
  • the solvent to be used examples include ester solvents such as ethyl acetate and the like; ether solvents such as isopropyl ether and the like; ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is ethyl acetate.
  • the temperature for mixing is generally about 0 to 100° C., preferably about 15 to 30° C.
  • the time for mixing is generally about 1 hr to 10 days, preferably about 1 day to 3 days.
  • Optically active compound [IVg] can be obtained by treating compound [IVh] with acidic aqueous solution in a solvent, and liberating carboxylic acid.
  • solvent to be used examples include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.
  • Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.
  • the treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the treatment time is generally about 1 min to 2 hr.
  • the amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IVh].
  • racemic compound [IVg] By treating racemic compound [IVg] using a chiral stationary phase column and the like, a desired optically active compound [IVg] can be separated from the other isomer.
  • the chiral stationary phase column to be used is, for example, Daicel, CHIRALCEL OD-RH.
  • Examples of the solvent for separation include a mixed solution of acetonitrile and phosphate buffer wherein the composition ratio thereof is constant or varied.
  • a conventional high performance liquid chromatography apparatus is used, which is performed while monitoring with a detector such as ultraviolet absorption and the like.
  • Compound [IVk] can be obtained by introducing R j into compound [IVj] in a solvent in the presence of a base such as potassium carbonate and the like.
  • compound [IVk] when R j is a (cyclo)alkyl group, compound [IVk] can be obtained by reacting compound [IVj] with (cyclo)alkyl halide such as (cyclo)alkyl iodide, (cyclo)alkyl sulfonic acid ester such as (cyclo)alkyl tosylate or the like in amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.
  • amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.
  • Compound [IVm] can be obtained by reacting compound [IVg] in the form of a racemate or an optically active form with compound [IVk] in a solvent in the presence of a metal catalyst, a ligand and a base.
  • Boronic acid moiety of compound [IVk] is boronic acid per se, or boronic acid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of dioxane and water.
  • the metal catalyst to be used for the reaction is palladium, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), with preference given to palladium(II) acetate.
  • the amount of the metal catalyst to be used is generally for about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVg].
  • the ligand to be used for the reaction is phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like. Preferred is 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetate such as sodium acetate and the like, with preference given to tripotassium phosphate.
  • alkali metal phosphates such as tripotassium phosphate and the like
  • alkali metal carbonates such as sodium carbonate and the like
  • alkali metal acetate such as sodium acetate and the like, with preference given to tripotassium phosphate.
  • the reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110°.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • the amount of compound [IVk] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVg].
  • the amount of the ligand to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the metal catalyst.
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVg].
  • the object compound [IVn] is obtained from compound [IVm] by general functional group conversion or deprotection.
  • the compound when compound [IVn] contains carboxamide, the compound can be obtained by reacting carboxylic acid with amine to allow amidation with, for example, a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like in the presence of 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like.
  • carboxylic acid may be converted in advance to acid chloride, mixed acid anhydride or the like, and reacted with amine to allow amidation, whereby compound [IVn] containing carboxamide can be obtained.
  • compound [IVn] has an ester
  • a general esterification reaction with alcohol needs to be performed.
  • carboxylic acid may be converted in advance to an acid chloride, and reacted with alcohol in the presence of a base such as pyridine and the like without solvent or in chloroform, whereby compound [IVn] having an ester can be obtained.
  • Compound [IVn] having an ester can also be obtained by reacting carboxylic acid with alkyl halide in the presence of a base such as potassium carbonate in, for example, dimethylformamide.
  • compound [IVn] contains a hydroxyl group, it can be obtained by reduction of carboxylic acid or a reaction with an organiometalic reagent.
  • compound [IVn] containing a hydroxyl group can be obtained by performing a hydride reduction reaction using borane, lithium aluminum hydride and the like in a single or mixed solvent of ethyl ether, tetrahydrofuran, tetrahydropyran and the like.
  • Y b is an amine bond compound [IVn] wherein Y b is an amine bond
  • compound [IVg] When Y b is an amine bond compound [IVn] wherein Y b is an amine bond can be synthesized by subjecting compound [IVg] to a condensation reaction with amine compound or the like in the presence of a catalyst such as palladium and the like.
  • compound [IVn] wherein Y b is alkanediyl can be synthesized by subjecting compound [IVg] to a condensation reaction with an organic zinc compound and the like in the presence of a catalyst such as palladium and the like.
  • compound [IVn] wherein Y b is alkenediyl can be synthesized by subjecting compound [IVg] to a condensation reaction with an alkenylboron compound and the like in the presence of a catalyst such as palladium and the like.
  • R Y3 and “R Y4 ” are the same or different and each is a carboxyl-protecting group such as a C 1-4 alkyl group (e.g., a methyl group, an ethyl group, a t-butyl group etc.), a benzyl group and the like;
  • R j0 is a substituent (e.g., a carboxyl group etc.) that can be converted to “R j ” (e.g., a carbamoyl group etc.) by various functional group conversion reactions, and other symbols are as defined above.
  • Compound [IVp] can be obtained by reacting compound [IVo] with compound [IVb] in a solvent, in the presence of a metal catalyst and a base.
  • M of compound [IVb] is a group containing boron, zinc, tin or the like.
  • examples thereof include boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like.
  • dialkoxyboron and boronic acid Preferred are dialkoxyboron and boronic acid, and particularly preferred is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • metal catalyst to be used for the reaction examples include those having palladium or nickel, and preferred are palladium, and particularly preferred are palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0).
  • the amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVo].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like; organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.
  • alkali metal phosphates such as tripotassium phosphate and the like
  • alkali metal carbonates such as sodium carbonate and the like
  • alkali metal acetates such as sodium acetate and the like
  • organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.
  • the reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110°.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.
  • the amount of compound [IVb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVo].
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IVo].
  • Compound [IVq] can be obtained by subjecting compound [IVp] to ester hydrolysis in a solvent.
  • the ester hydrolysis may be performed under general conditions, for example, under alkaline conditions or acidic conditions.
  • compound [IVp] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like) per 1 mol of compound [IVp] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.
  • a base alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like
  • compound [IVp] is reacted in the presence of, for example, about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVp] in, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
  • an acid hydrochloric acid, sulfuric acid etc.
  • carboxylic acid solvents such as acetic acid and the like
  • ether solvents such as tetrahydrofuran, dioxane, etc., and the like
  • a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
  • Compound [IVr] can be obtained by cyclization reaction of compound [IVq] in the presence of an acid without solvent or in a solvent.
  • Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like.
  • the amount thereof to be used is generally about 1 mol to a large excess per 1 mol of compound [IVq].
  • a solvent for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without a solvent or in methanesulfonic acid as a solvent.
  • the reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • Compound [IVs] can be obtained by esterification reaction of compound [IVr] with alkyl halide in a solvent in the presence of a base.
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like; dimethyl sulfoxide; water and the like.
  • amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like
  • dimethyl sulfoxide dimethyl sulfoxide
  • water and the like Preferable solvent for this reaction is dimethylformamide.
  • Examples of the base to be used for the reaction include alkali metal carbonates such as potassium carbonate and the like, alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides such as sodium hydroxide and the like, and the like; with preference given to potassium carbonate.
  • Examples of the halogen of the alkyl halide to be used for the reaction include iodine, bromine and the like, and examples of the alkyl include methyl, ethyl and the like. Preferred for this step is methyl iodide.
  • the reaction temperature is generally about 0 to 100° C., preferably about 0 to 80° C.
  • the reaction time is generally about 10 min to 1 day, preferably about 30 min to 12 hr.
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVr].
  • the amount of the alkyl halide to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVr].
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like, and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like; and the like, with preference given to potassium carbonate and lithium acetate.
  • the reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • the amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IVs].
  • the amount of the catalyst to be used for the trifluoromethylation reaction is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IVs].
  • Examples of the reagent to be used for the trimethylsilyl ether hydrolysis include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like; and the like.
  • the reaction temperature when trimethylsilyl ether is hydrolyzed is generally about ⁇ 10 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • the amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVs].
  • Compound [IVu] can be obtained by subjecting compound [IVt] to ester hydrolysis in a solvent under alkaline conditions.
  • solvent to be used for the reaction examples include water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture.
  • Preferable solvents for this reaction is a mixed solvent of water, methanol and tetrahydrofuran.
  • alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, and the like, with preference given to sodium hydroxide.
  • the reaction temperature is generally about 0 to 120° C., preferably about 0 to 90° C.
  • the reaction time is generally about 10 min to 1 day, preferably about 30 min to 12 hr.
  • the amount of the alkali to be used is generally about 1 mol to large excess, preferably about 1 to 10 mol, per 1 mol of compound [IVt].
  • a method for obtaining optically active compound [IVu] includes Steps 36a-36b from a racemic compound [IVu].
  • (+) or ( ⁇ ) form of compound [IVu] can be produced by appropriately selecting an optically active amine.
  • Compound [IVv] which is a salt of single diastereomer, can be obtained as a solid by mixing compound [IVu] with an optically active amine in a solvent.
  • optically active amine examples include (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-( ⁇ )-1-(1-naphthyl)-ethylamine and the like.
  • the amount of the optically active amine to be used is generally about 0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound [IVu].
  • the solvent to be used examples include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is ethyl acetate.
  • the temperature for mixing is generally about 0 to 100° C., preferably about 15 to 80° C.
  • the time for mixing is generally about 1 hr to 10 days, preferably about 1 to 12 hr.
  • Optically active compound [IVu] can be obtained by treating compound [IVv] with acidic aqueous solution in a solvent, and liberating carboxylic acid.
  • solvent to be used examples include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.
  • Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.
  • the treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the treatment time is generally about 1 min to 2 hr.
  • the amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IVv].
  • racemic compound [IVu] By treating racemic compound [IVu] using a chiral stationary phase column and the like, a desired optically active compound [IVu] can be separated from the other isomer.
  • the chiral stationary phase column to be used is, for example, Daicel, CHIRALCEL OD-RH.
  • Examples of the solvent for separation include a mixed solution of acetonitrile and phosphate buffer wherein the composition ratio thereof is constant or varied.
  • a conventional high performance liquid chromatography apparatus is used, which is performed while monitoring with a detector such as ultraviolet absorption and the like.
  • Compound [IVy] can be obtained by converting a precursor in R j0 of compound [IVx] to a functional group in R j of compound [Ivy].
  • compound [IVy] having amide in R j can be obtained by amidation reaction of compound [IVx] having carboxylic acid for R j0 with amine in the presence of a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like and 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like.
  • a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like
  • 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like.
  • a protecting group may be introduced as appropriate.
  • a protecting group such as t-butyloxycarbonyl group, benzyloxycarbonyl group and the like is introduced into the amino group by a conventional method, a desired amidation reaction is performed, and then deprotection is performed by a general method.
  • Compound [IVz] can be obtained by reacting compound [IVu], which is a racemate or an optically active form, with compound [IVy].
  • compound [IVz] can be obtained by general amidation reaction.
  • compound [IVu] and compound [IVy] are reacted in a solvent in the presence of a condensation agent.
  • the condensation agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the copresence of 1-hydroxybenzotriazole hydrate and the like
  • the solvent include dimethylformamide, chloroform and the like.
  • compound [IVu] which is a racemate or an optically active form, may be converted in advance to acid chloride, mixed acid anhydride or the like and reacted with compound [IVy], whereby compound [IVz] can be obtained.
  • compound [IVz] is obtained by reacting compound [IVy] with an organic base such as LDA and the like, and reacting the resultant with compound [IVu] or, for example, an amide compound thereof with N,O-dimethylhydroxyamine or the like.
  • compound [IVz] wherein Y b is an ether bond etc. can be synthesized by subjecting the corresponding phenol compound to reactions such as Mitsunobu reaction, alkylation reaction with alkyl halide or alkyl sulfonate, and the like.
  • R b00 is a substituent (e.g., a hydroxy group etc.) that can be converted to “R b0 ” (e.g., a methoxy group etc.) by various functional group conversion reactions
  • R b0 is a substituent (e.g., a methoxy group etc.) that can be converted to “R b ” (e.g., carboxamide, an alkoxy group substituted by lactam and the like, an alkyl group etc.) by various functional group conversion reactions
  • R b e.g., carboxamide, an alkoxy group substituted by lactam and the like, an alkyl group etc.
  • compound [Va] when the functional group influenced by the reaction is a hydroxyl group, compound [Va] is subjected to alkylation reaction with an alkylating agent in a solvent in the presence of a base to give compound [Vb].
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide and the like; ether solvents such as tetrahydrofuran and the like; dimethylsulfoxide and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • alkylating agent to be used for the reaction examples include alkyl halide such as methyl iodide and the like; alkyl sulfonates such as ethyl tosylate and the like; sulfuric acid esters such as methyl sulfate and the like; and the like, with preference given to methyl iodide.
  • Examples of the base to be used for the reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides such as sodium hydroxide and the like; and the like, with preference given to potassium carbonate.
  • the reaction temperature is generally about 0 to 120° C., preferably about 0 to 80° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1 hr to 1 day.
  • the amount of the alkylating agent to be used is generally about 1 to 3 mol, preferably about 1 to 2 mol, per 1 mol of compound [Va].
  • the amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound [Va].
  • Compound [Vd] can be obtained by reacting compound [Vb] with compound [Vc] in a solvent in the presence of a metal catalyst and a base.
  • the boronic acid moiety of compound [Vc] is boronic acid per se, or boronic acid ester, preferably boronic acid per se.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of so toluene and water.
  • metal catalyst to be used for the reaction examples include one containing palladium. Particularly preferred is 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride.
  • the amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [Vb].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like, with preference given to tripotassium phosphate.
  • alkali metal phosphates such as tripotassium phosphate and the like
  • alkali metal carbonates such as sodium carbonate and the like
  • alkali metal acetates such as sodium acetate and the like, with preference given to tripotassium phosphate.
  • the reaction temperature is generally about room temperature to 120° C., preferably about 70 to 110° C.
  • the reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • the amount of compound [Vc] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Vb].
  • the amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [Vb].
  • Compound [Ve] can be obtained by cyclization reaction of compound [Vd] in a solvent in the presence of a base.
  • solvent to be used for the reaction examples include hydrocarbon solvents such as n-hexane and the like; ether solvents such as tetrahydrofuran and the like; amide solvents such as N-methylpyrrolidone and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is tetrahydrofuran.
  • Examples of the base to be used for the reaction include amide bases such as lithium N,N-diisopropylamide, lithium hexamethyldisilazide and the like; organometallics such as butyllithium and the like; and the like, with preference given to lithium N,N-diisopropylamide.
  • the reaction temperature is generally about ⁇ 78 to 100° C., preferably about ⁇ 10 to 50° C.
  • the reaction time is generally about 10 min to 1 day, preferably about 10 min to 3 hr.
  • the amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound [Vd].
  • Compound [Vf] is obtained from compound [Ve] by general functional group conversion or deprotection.
  • compound [Vf] wherein R b is a (substituted) alkoxy group can be obtained by deprotection to regenerate the hydroxyl group according to a conventional method, for example, by fusing compound [Ve] and pyridinium chloride and the like and, alkylation by, for example, Mitsunobu reaction and the like.
  • compound [Vf] wherein R b is a (substituted) alkyl group can be obtained by deprotection according to a conventional method to regenerate the hydroxyl group, conversion to trifluoromethanesulfonate, a reaction of the trifluoromethanesulfonate compound with a terminal acetylene compound or an alkenyl metal compound such as an alkenylboron compound and the like in the presence of a metal catalyst such as palladium and the like, and a hydrogenation reaction.
  • Compound [V] can be obtained as a racemate by reacting compound [Vf] with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to cause trifluoromethylation reaction, whereby a trimethylsilyl ether of compound [V] is obtained, then hydrolyzing the resulting trimethylsilyl ether.
  • solvent to be used for the reaction examples include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like, and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like; and the like, with preference given to potassium carbonate and lithium acetate.
  • the reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • the amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [Vf].
  • the amount of the catalyst to be used for the trifluoromethylation reaction is generally for about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [Vf].
  • Examples of the reagent to be used for the trimethylsilyl ether hydrolysis include alkali metal fluorides such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like; and the like.
  • the reaction temperature when trimethylsilyl ether is hydrolyzed is generally about ⁇ 10 to 50° C., preferably about 0° C. to room temperature.
  • the reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • the amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Vf].
  • a desired optically active compound [V] can be separated from the other isomer by a preferential crystallization method, a diastereomer method, an optical resolution method using a chiral stationary phase column, or the like.
  • the room temperature in the Examples means 1-40° C.
  • a solid (0.002-0.003 g) to be analyzed is shaken with ethyl acetate (0.1 ml) and 1N hydrochloric acid (0.1 ml), the mixture was stood still to separate layers.
  • the upper layer (0.010 ml) was added to the following preparation solution (0.1 ml), and the mixture was shaken at 50° C. for 30 min.
  • the obtained mixture was analyzed by HPLC.
  • Dimethylformamide was added to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.191 g) and 1-hydroxybenzotriazole hydrate (0.153 g) to a total amount of 10 ml.
  • (S)-( ⁇ )-1-(1-Naphthyl)-ethylamine (0.258 ml) was added to the mixture to give the title preparation solution.
  • Potassium dihydrogen phosphate (4.08 g) was dissolved in water (3000 mL) and adjusted to pH 2.0 with phosphoric acid to give the title buffer.
  • the mixture was stirred at room temperature for 1 hr, and filtered through celite.
  • the filtrate was partitioned in a separatory funnel.
  • the aqueous layer was extracted with toluene, and the organic layers were combined.
  • the organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure to give the title compound (41.8 g).
  • the obtained solid was directly used for the next reaction without further purification.
  • the filtrate was concentrated under reduced pressure, and the obtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2N aqueous sodium hydroxide solution (37 ml) were mixed, and the mixture was stirred at 60° C. for 3 hr.
  • the reaction mixture was cooled to room temperature, water (180 ml) was added, and the mixture was placed in a separatory funnel, and extracted twice with toluene (180 ml). The organic layer was washed twice with water (180 ml) and once with saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was filtered through celite. The filtered substance was further washed with toluene and water. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene. The combined organic layer was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from n-hexane/2-propanol (10:1, 165 ml) to give the title compound (11.1 g, 60%).
  • the obtained title compound can be crystallized from a solvent (toluene/ethyl acetate (7:1)) containing 1 mol of water per 1 mol of the compound.
  • the solid was suspended in 50 v/v % ethanol-water (1500 ml), and the slurry was stirred at room temperature for 2 hr, and filtered. The obtained solid was air-dried for 1 hr and dried under reduced pressure at 80° C. to give the title compound (140.12 g, 99%).
  • potassium carbonate (18 g) was added to a mixture of dimethylformamide (500 ml) and 4-chloro-2-methyl-fluoren-9-one (100 g).
  • trimethyl(trifluoromethyl)silane (78 ml) was added dropwise over 80 min, and the mixture was further stirred at room temperature for 1 hr.
  • cesium fluoride (87 g) at room temperature, then ethyl bromoacetate (63 ml) was added dropwise over 15 min, and the mixture was further stirred at room temperature for 4 hr.
  • the activated carbon was filtered off, and washed with 33 v/v % ethanol-water (120 ml).
  • the filtrate was acidified by dropwise addition of acetic acid (151 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered, the obtained solid was washed with 33 v/v % ethanol-water (150 ml), and dried under reduced pressure at 80° C. to give the title compound (136.40 g, 87%).
  • the solid (0.170 g) was resuspended in ethyl acetate (3.4 ml), and the mixture was stirred at 50° C. for 1 hr. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.137 g). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.
  • Tripotassium phosphate (35.7 g), water (60 ml), toluene (240 ml), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (28.58 g), t-butyl 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-propionate (41.9 g), palladium(II) acetate (1.89 g) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.905 g) were mixed in a reaction vessel, and purged with argon.
  • the mixture was stirred at 100° C. for 3 hr.
  • the reaction mixture was cooled to room temperature, water (180 ml) was added and the mixture was stirred overnight.
  • Insoluble material was filtered off through celite, and washed with ethyl acetate (500 ml).
  • the filtrate was partitioned in a separatory funnel.
  • the aqueous layer was extracted with ethyl acetate, and the organic layers were combined.
  • the organic layer was successively washed with water (250 ml), saturated aqueous sodium hydrogen carbonate (250 ml) and saturated brine (200 ml), dried over anhydrous sodium sulfate and filtered.
  • Tripotassium phosphate 14.86 g
  • water 30 ml
  • toluene 60 ml
  • (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol 9.583 g
  • 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-butyric acid ethyl ester (12.08 g) were added to a reaction vessel, and purged with argon.
  • the obtained compound was crystallized from toluene/ethyl acetate (20:1).
  • the reaction mixture was cooled to room temperature, and the insoluble material was filtered off and washed with water (50 ml).
  • the filtrate was adjusted to pH 1 with 6N hydrochloric acid, and extracted with ethyl acetate (200 ml).
  • the organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • an optically active form (0.100 g) of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid, 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.133 g), tripotassium phosphate (0.191 g), palladium(II) acetate (0.0034 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0123 g), dioxane (3 ml) and water (0.6 ml) were mixed, and the mixture was stirred at 100° C.
  • methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate (1.009 g), trimethyl(trifluoromethyl)silane (0.89 ml) and dimethylformamide (50 ml) were mixed, lithium acetate (0.027 g) was added with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min.
  • Acetic acid (0.7 ml) and a 1M solution (6 ml) of tetrabutylammonium fluoride in tetrahydrofuran were added, and the mixture was further stirred at room temperature for 15 min.

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Abstract

The present invention provides an agent for the prophylactic or treatment of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof:
Figure US20150329491A1-20151119-C00001
wherein each symbol is as defined in the specification.

Description

    TECHNICAL FIELD OF THE INVENTION
  • The present invention relates to a fluorene compound and a pharmaceutical use thereof. More particularly, the present invention relates to a compound for the prophylaxis or treatment of diabetes, cardiovascular diseases, hyperlactacidemia and cancer based on activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK), and use thereof. Furthermore, the present invention relates to a compound for the prophylaxis or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, and use thereof.
    • BACKGROUND OF THE INVENTION
  • In tissue, for reaction using energy, for example, biosynthesis, active biological transport, muscle contraction etc., the energy is supplied by hydrolysis of adenosine triphosphate (ATP). ATP is produced by oxidation of metabolic fuel which yields much energy, such as glucose and free fatty acids. In oxidative tissues such as muscle, ATP is mostly produced from acetyl-CoA that enters citric acid cycle. Acetyl-CoA is produced by oxidation of glucose via glycolytic pathway or β oxidation of free fatty acid. An enzyme that plays a pivotal role in controlling acetyl-CoA production from glucose is PDH. PDH catalyses the oxidation of pyruvate to acetyl-CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH.
  • PDH is a multienzyme complex consisting of three enzyme components (E1, E2 and E3) and some subunits localized in mitochondria matrix. E1, E2 and E3 are responsible for decarboxylation from pyruvate, production of acetyl-CoA and reduction of NAD to NADH, respectively. Two classes of enzyme having regulatory function are associated with the complex. One is PDHK, which are protein kinases having specificity to PDH. The role thereof is to inactivate E1α subunit of the complex by phosphorylation. The other is PDH phosphatases, which are specific protein phosphatases which activate PDH via dephosphorylation of E1α subunit. The proportion of PDH in its active (dephosphorylated) state is determined by the balance of kinase activity and phosphatase activity. The kinase activity is regulated by relative concentrations of metabolic substrates. For example, the kinase activity is activated by an increase in the NADH/NAD, acetyl-CoA/CoA or ATP/adenosine diphosphate (ADP) ratios, and inhibited by pyruvate.
  • Four PDHK isoenzymes have been identified in mammalian tissues. Particularly, PDHK2 is expressed in a wide range of tissues including the liver, skeletal muscles and adipose tissues involved in glucose metabolism. Since it shows comparatively high sensitivity to activation by increased NADH/NAD or acetyl-CoA/CoA and inhibition by pyruvate, involvement in a short-term regulation of glucose metabolism is suggested.
  • In diseases such as insulin-dependent (type 1) diabetes and non-insulin-dependent (type 2) diabetes and the like, oxidation of lipids is increased with a concomitant reduction in utilization of glucose. This is one of the factors causing hyperglycemia. When the oxidative glucose metabolism is reduced in type 1 and type 2 diabetes and obesity, PDH activity is also reduced. It suggests involvement of reduced PDH activity in the reduced utilization of glucose in type 1 and type 2 diabetes. On the contrary, hepatic gluconeogenesis is enhanced in type 1 and type 2 diabetes, which also forms one factor causing hyperglycemia. The reduced PDH activity increases pyruvate concentration, which in turn increases availability of lactate as a substrate for hepatic gluconeogenesis. It suggests possible involvement of reduced PDH activity in the enhanced gluconeogenesis in type 1 and type 2 diabetes. When PDH is activated by inhibition of PDHK, the rate of glucose oxidation is considered to rise. As a result, glucose utilization in the body is promoted and hepatic gluconeogenesis is suppressed, whereby hyperglycemia in type 1 and type 2 diabetes is expected to be improved. Another factor contributing to diabetes is impaired insulin secretion, which is known to be associated with reduced PDH activity in pancreatic β cells. It is also known that sustained hyperglycemia due to diabetes causes complications such as neuropathy, retinopathy, nephropathy, cataract and the like. Thiamine and α-lipoic acid contribute to activation of PDH as coenzymes, and also, they or derivatives thereof have been shown to have a promising effect in the treatment of diabetic complications. Thus, activation of PDH is expected to improve diabetic complications.
  • Under ischemic conditions, limited oxygen supply reduces oxidation of both glucose and fatty acid oxidation and reduces the amount of ATP produced by oxidative phosphorylation in the tissues. In the absence of sufficient oxygen, ATP level is maintained by promoted anaerobic glycolysis. As a result, lactic acid increases and intracellular pH decreases. Even though the body tries to maintain homeostasis of ion by energy consumption, abnormally low ATP level and disrupted cellular osmolarity lead to cell death. In addition, adenosine monophosphate-activating kinase, activated during ischemia, phosphorylates and thus inactivates acetyl-CoA carboxylase. The levels of total malonyl-CoA in the tissue drop, carnitine palmitoyltransferase-I activity is therefore increased and fatty acid oxidation is favored over glucose oxidation by allowing the transport of acyl-CoA into mitochondria. Oxidation of glucose is capable yielding more ATP per mole of oxygen than is oxidation of fatty acids. Under ischemic conditions, therefore, when energy metabolism becomes glucose oxidation dominant by activation of PDH, the ability to maintain ATP level is considered to be enhanced. In addition, since activation of PDH causes oxidation of pyruvate produced by glycolysis, and reducing production of loactate, the net proton burden is considered to be reduced in ischemic tissues. Accordingly, PDH activation by inhibition of PDHK is expected to protectively act in ischemic diseases such as cardiac muscle ischemia.
  • A drug that activates PDH by inhibition of PDHK is considered to decrease lactate production since it promotes pyruvate metabolism. Hence, such drug is expected to be useful for the treatment of hyperlactacidemia such as mitochondrial disease, mitochondrial encephalomyopathy and sepsis.
  • In cancer cells, ATP production by oxidative phosphorylation in mitochondria decreases, and ATP production via the anaerobic glycolysis in cytoplasm increases. PDH activation by inhibition of PDHK is expected to promote oxidative phosphorylation in mitochondria, which will induce apoptosis of cancer cells. Therefore, the mechanism is useful for the treatment of cancer diseases. Pulmonary hypertension is characterized by high blood pressure caused by partial narrowing of the pulmonary artery due to promoted cell proliferation therein. In pulmonary hypertension, therefore, activation of PDH in the pulmonary artery cell is expected to promote oxidative phosphorylation in mitochondria, and induce apoptosis of the pulmonary artery cells. Therefore, the mechanism is useful for the treatment of pulmonary hypertension.
  • It has been shown that dichloroacetic acid, which is a drug having a PDH activating action, provides promising effects for amelioration of hyperglycemia, treatment of myocardial ischemia, treatment of hyperlactacidemia and treatment of cancer diseases. Moreover, usefulness of dichloroacetic acid for the treatment of cerebral ischemia, cerebral apoplexy or pulmonary hypertension has been shown.
  • From the foregoing findings, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases relating to glucose utilization disorder, for example, diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia and hyperlactacidemia. In addition, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.). Furthermore, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases caused by limited energy substrate supply to the tissues, for example, cardiac failure, cardiomyopathy, myocardial ischemia, dyslipidemia and atherosclerosis. Additionally, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of mitochondrial disease, mitochondrial encephalomyopathy, cancer and the like. Also, it is considered to be useful for the treatment or prophylaxis of pulmonary hypertension.
    • SUMMARY OF THE INVENTION Problems to be Solved by the Invention
  • The present invention aims to provide an agent for the prophylactic or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. Moreover, the present invention aims to provide a PDHK inhibitor also useful as an agent for the prophylactic or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, and the like.
    • Means of Solving the Problems
  • The present inventors have conducted intensive studies in an attempt to develop an agent for the prophylactic or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy, cancer, diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, which is based on a PDHK inhibitory action and found a fluorene compound having a PDHK inhibitory action, and completed the present invention.
  • Accordingly, the present invention provides the following.
  • [1] A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00002
  • wherein,
    • Ra is
  • (1) a hydrogen atom, or
    (2) a halogen atom;
    • Rb is
  • (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A,
    (4) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (5) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (8) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (10) —C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (11) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (12) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (13) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (14) —NRb12—C(═O)—ORb13 wherein Rb12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and Rb13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (15) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or
    (16) a group represented by the following formula:
  • Figure US20150329491A1-20151119-C00003
  • wherein
    • Yb is
  • (i) a single bond,
    (ii) a C1-6 alkylene,
    (iii) a C2-6 alkenylene,
    (iv) —O—(CH2)n1— wherein n1 is an integer of 0, or 1 to 4,
    (v) —O—(CH2)n2—C(═O)— wherein n2 is an integer of 0, or 1 to 4,
    • (vi) —C(═O)—, or
  • (vii) —NRb16— wherein Rb16 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B;
    ring T is
    (i) a C6-10 aryl group,
    (ii) a C3-10 cycloalkyl group,
    (iii) a C5-10 bridged cycloalkyl group,
    (iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or
    (v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms,
    Rj are the same or different and each is a substituent selected from the following group D, and p is an integer of 0, or 1 to 4;
    • Rc is
  • (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group,
    (4) —C(═O)—ORc1 wherein Rc1 is a hydrogen atom or a C1-6 alkyl group,
    (5) —ORc2 wherein Rc2 is a hydrogen atom or a C1-6 alkyl group,
    (6) —NRc3Rc4 wherein Rc3 and Rc4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group, or
    (7) —NRc5—C(═O)—Rc6 wherein Rc5 and Rc6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group;
    • Xd is
  • (1) a nitrogen atom, or
    • (2) C—Rd
  • wherein Rd is
    (i) a hydrogen atom,
    (ii) a halogen atom,
    (iii) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A,
    (iv) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (v) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (vi) a cyano group,
    (vii) —C(═O)—Rd1 wherein Rd1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (viii) —C(═O)—ORd2 wherein Rd2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (ix) —C(═O)—NRd3Rd4 wherein Rd3 and Rd4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (x) —C(═O)—NRd5—ORd6 wherein Rd5 and Rd6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (xi) —ORd7 wherein Rd7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (xii) —NRd8Rd9 wherein Rd8 and Rd9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (xiii) —NRd10—C(═O)—Rd11 wherein Rd10 and Rd11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (xiv) —NRd12—C(═O)—ORd13 wherein Rd12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and Rd13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or
    (xv) a group represented by the following formula:
  • Figure US20150329491A1-20151119-C00004
  • wherein
    • Yd is
  • (I) a single bond, or
    • (II) —C(═O)—,
  • ring U is
    (I) a C6-10 aryl group,
    (II) a C3-10 cycloalkyl group,
    (III) a C5-10 bridged cycloalkyl group,
    (IV) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or
    (V) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms,
    Rk are the same or different and each is a substituent selected from the following group D, and
    m is an integer of 0, or 1 to 4;
    Re are the same or different and each is,
    (1) a halogen atom, or
    (2) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C; and
    n is an integer of 0, or 1 to 3,
    provided when Xd is C—Rd, and Rd is a hydrogen atom, at least one of Ra, Rb and Rc is not a hydrogen atom.
    Group A is selected from the group consisting of
    (a) a halogen atom,
    (b) a cyano group,
    (c) —C(═O)—RA1 wherein RA1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (d) —C(═O)—ORA2 wherein RA2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (e) —C(═O)—NRA3RA4 wherein RA3 and RA4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (f) —C(═O)—NRA5—ORA6 wherein RA5 and RA6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (g) —ORA7 wherein RA7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (h) —NRA8RA9 wherein RA8 and RA9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (i) —NRA10—C(═O)—RA11 wherein RA10 and RA11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (j) —NRA12—C(═O)—ORA13 wherein RA12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and RA13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (k) —S(═O)2—RA14 wherein RA14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
    (l) —S(═O)2—ORA15 wherein RA15 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and
    • (m) —Si—(CH2—CH3)3.
  • Group B is selected from the group consisting of
    (a) a halogen atom,
    (b) a cyano group,
    (c) —C(═O)—RB1 wherein RB1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (d) —C(═O)—ORB2 wherein RB2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (e) —C(═O)—NRB3RB4 wherein RB3 and RB4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (f) —C(═O)—NRB5—ORB6 wherein RB5 and RB6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (g) —ORB7 wherein RB7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (h) —NRB8RB9 wherein RB8 and RB9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (i) —NRB10—C(═O)—RB11 wherein RB10 and RB11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (j) —NRB12—S(═O)2—RB13 wherein RB12 and RB13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (k) —NRB14—C(═O)—ORB15 wherein RB14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and RB15 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
    (l) —S(═O)2—RB16 wherein RB16 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
    (m) —S(═O)2—ORB17 wherein RB17 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C.
    Group C is selected from the group consisting of
    (a) a halogen atom,
    (b) —C(═O)—RC1 wherein RC1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 halogen atoms,
    (c) —C(═O)—ORC2 wherein RC2 is a hydrogen atom or a C1-6 alkyl group, and
    (d) —ORC3 wherein RC3 is a hydrogen atom or a C1-6 alkyl group.
    Group D is selected from the group consisting of
    (a) a halogen atom,
    (b) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (c) a C1-6 alkyl group substituted by a C6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (d) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (e) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (f) a C1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (g) a C3-10 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (h) a C5-10 bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (i) a cyano group,
    (j) —C(═O)—RD1 wherein RD1 is a hydrogen atom, a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected frau the following group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by the same or different 1 to 5 substituents selected from the following group F (the monocyclic non-aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (k) —C(═O)—ORD2 wherein RD2 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (l) —C(═O)—NRD3RD4 wherein RD3 and RD4 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (m) —C(═O)—NRD5—ORD6 wherein RD5 and RD6 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (n) —ORD7 wherein RD7 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (o) —NRD8RD9 wherein RD8 and RD9 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (p) —NRD10—C(═O)—RD11 wherein RD10 and RD11 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (q) —NRD12—C(═O)—ORD13 wherein RD12 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, and RD13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
    (r) —S(═O)2—RD14 wherein RD14 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, and
    (s) —S(═O)2—ORD15 wherein RD15 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E.
    Group E is selected from the group consisting of
    (a) a halogen atom,
    (b) a cyano group,
    (c) —C(═O)—RE1 wherein RE1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (d) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (e) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (f) —C(═O)—NRE5—ORE6 wherein RE5 and RE6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (g) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (h) —NRE8RE9 wherein RE8 and RE9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (i) —NRE10—C(═O)—RE11 wherein RE10 and RE11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (j) —NRE12—C(═O)—ORE13 wherein RE12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and RE13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (k) —S(═O)2—RE14 wherein RE14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (l) —S(═O)2—ORE15 wherein RE15 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and
    (m) —NRE16—S(═O)2—RE17 wherein RE16 and RE17 are the same or different and each is a hydrogen atom or a C1-6 alkyl group. Group F is selected from the group consisting of
    (a) —(CH2)nF1—C(═O)—ORF1 wherein RF1 is a hydrogen atom or a C1-6 alkyl group, and nF1 is an integer of 0, or 1 to 4, and
    (b) —(CH2)nF2—ORF2 wherein RF2 is a hydrogen atom or a C1-6 alkyl group, and nF2 is an integer of 0, or 1 to 4.
    [2] The compound of the above-mentioned [1], wherein Xd is C—Rd wherein Rd is as defined in the above-mentioned [1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [3] The compound of the above-mentioned [1] or [2], which is represented by the following formula [II], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00005
  • wherein each symbol is as defined in the above-mentioned [1].
    [4] The compound of the above-mentioned [3], wherein ring U is a monocyclic aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [5] The compound of the above-mentioned [3], wherein Yd is a single bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [6] The compound of the above-mentioned [4], which is represented by the following formula [III], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00006
  • wherein
    • Rm is
  • (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (2) a C1-6 alkyl group substituted by a C6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (5) a C1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (6) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (7) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and other symbols are as defined in the above-mentioned [1].
    [7] The compound of the above-mentioned [6], wherein Rm is
    (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′,
    (2) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (5) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and group E′ is selected from the group consisting of
    (a) a halogen atom,
    (b) a cyano group,
    (c) —C(═O)—RE1 wherein RE1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (d) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (e) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (f) —C(═O)—NRE5—ORE6 wherein RE5 and RE6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (g) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (h) —NRE8RE9 wherein RE8 and RE9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (i) —NRE10—C(═O)—RE11 wherein RE10 and RE11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (j) —NRE12—C(═O)—ORE13 wherein RE12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and RE13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    (k) —S(═O)2—RE14 wherein RE14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and
    (l) —S(═O)2—ORE15 wherein RE15 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
    or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [8] The compound of the above-mentioned [7], which is represented by the following formula [III-A], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00007
  • wherein each symbol is as defined in the above-mentioned [7].
    [9] The compound of the above-mentioned [7], wherein Rc is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [10] The compound of the above-mentioned [7], wherein Rb is
    (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
    (4) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (5) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (8) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (10) —C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (11) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (12) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (13) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (14) —NRb12—C(═O)—ORb13 wherein Rb12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and Rb13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or
    (15) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [11] The compound of the above-mentioned [7], wherein Ra is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [12] The compound of the above-mentioned [7], wherein n is 0, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [13] The compound of the above-mentioned [7], wherein Rm is (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from
    (i) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (ii) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (iii) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (iv) —NRE12—C(═O)—RE13 wherein RE12 and RE13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (2) a C3-10 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (3) a C5-10 bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [14] The compound of the above-mentioned [7], wherein Rm is (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from
    (i) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (ii) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (2) a C3-10 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (3) a C5-10 bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [15] The compound of the above-mentioned [4], which is represented by the following formula [VI], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00008
  • wherein each symbol is as defined in the above-mentioned [4].
    [16] The compound of the above-mentioned [1], which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00009
    Figure US20150329491A1-20151119-C00010
    Figure US20150329491A1-20151119-C00011
    Figure US20150329491A1-20151119-C00012
    Figure US20150329491A1-20151119-C00013
  • [17] The compound of the above-mentioned [1], which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Figure US20150329491A1-20151119-C00014
    Figure US20150329491A1-20151119-C00015
    Figure US20150329491A1-20151119-C00016
  • [18] A pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
    [19] A PDHK inhibitor comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [20] A PDH activator comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [21] A PDHK2 inhibitor comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [22] A blood glucose level-lowering agent comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [23] A lactate level-lowering agent comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [24] An agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [25] An agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
    [26] A method of inhibiting PDHK in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [27] A method of activating PDH in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [28] A method of inhibiting PDHK2 in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [29] A method of decreasing the blood glucose level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [30] A method of decreasing lactate level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [31] A method for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [32] A method for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
    [33] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a PDHK inhibitor.
    [34] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a PDH activator.
    [35] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a PDHK2 inhibitor.
    [36] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a blood glucose level-lowering agent.
    [37] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a lactate level-lowering agent.
    [38] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
    [39] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
    [40] A commercial kit comprising (a) a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof as active ingredient, and (b) a written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
    [41] A commercial package comprising (a) a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof as active ingredient, and (b) a written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.
    • Effect of the Invention
  • Since the fluorene compound of the present invention effectively inhibits the PDHK activity, and further, has preferable properties as a drug such as chemical stability and the like, it is effective as an agent for the prophylaxis or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, and the like. Furthermore, the fluorene compound of the present invention is also effective as an agent for the prophylaxis or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.
    • Embodiment of the Invention
  • The present invention is explained in detail in the following.
  • The definitions of the terms used in the present specification are as follows.
  • The “optionally substituted” includes both being substituted at substitutable position(s) of an object group and being unsubstituted. Here, the “unsubstituted” means that all substitutable positions of an object group are occupied by hydrogen atoms.
  • For example, a “C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A” means both when the substitutable position(s) of a C1-6 alkyl group is(are) substituted by the same or different 1 to 5 substituents selected from group A, and is(are) not substituted (unsubstituted).
  • Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • The “C1-6 alkyl group” means a straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group and the like. Preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, an isohexyl group, a 3,3-dimethylbutyl group and the like.
  • The “C2-6 alkenyl group” means a linear or branched chain unsaturated hydrocarbon group having 2 to 6 a carbon atoms and containing one or more double bonds. Examples thereof include a vinyl group, a 1-methylvinyl group, a 1-propenyl group, an allyl group, a methylpropenyl group (1-methyl-1-propenyl group, 2-methyl-1-propenyl group etc.), a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a methylbutenyl group (1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group etc.), a pentenyl group, a methylpentenyl group, a hexenyl group and the like. Preferred are a vinyl group, a 1-methylvinyl group, a 1-propenyl group, a methylpropenyl group and the like.
  • The “C2-6 alkynyl group” means a linear or branched chain unsaturated hydrocarbon group having 2 to 6 a carbon atoms and containing one or more triple bonds. Examples thereof include an ethynyl group, a propynyl group (1-propynyl group, 2-propynyl group), a butynyl group, a pentynyl group, a hexynyl group and the like. Preferred are an ethynyl group, a 1-propynyl group and the like.
  • The “C1-6 alkylene” means a divalent group derived from the above-mentioned “C1-6 alkyl group”. Examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. Preferred are methylene, ethylene, trimethylene and the like.
  • The “C2-6 alkenylene” means a divalent group derived from the above-mentioned “C2-6 alkenyl group”. Examples thereof include vinylene, propenylene, butenylene, pentenylene, hexenylene and the like. Preferred are vinylene and the like.
  • The “C6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like. Preferred is a phenyl group.
  • The “C3-10 cycloalkyl group” means a monocycle saturated hydrocarbon group having 3 to 10 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like. Particularly, a C3-6 cycloalkyl group (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group etc.) is preferable.
  • The “C5-10 bridged cycloalkyl group” means a bridged cyclic saturated hydrocarbon group having 5 to 10 carbon atoms. Examples thereof include a bicyclopentanyl group, a bicyclohexyl group, a bicycloheptyl group, a tricycloheptyl group, a bicyclooctyl group, an adamantyl group and the like. Particularly, an adamantyl group is preferable.
  • The “monocyclic aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group, containing, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 7 ring-constituting atoms. Examples thereof include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group (1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group), a thiadiazolyl group (1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group), a triazolyl group (1,2,3-triazolyl group, 1,2,4-triazolyl group), a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group and the like. Preferred are a thienyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group (1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group), a triazolyl group (1,2,4-triazolyl group), a tetrazolyl group, a pyridyl group, a pyrimidinyl group and the like.
  • The “monocyclic non-aromatic heterocyclic group” means a monocyclic saturated or partially unsaturated heterocyclic group, which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms. Examples thereof include an oxiranyl group, a thioranyl group, an aziridinyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a pyrrolidino group (1-pyrrolidinyl group), a tetrahydrofuranyl group, a tetrahydrothienyl group, an oxazolinyl group, an oxazolidinyl group, an isoxazolinyl group, an isoxazolidinyl group, a thiazolinyl group, a thiazolidinyl group, an isothiazolinyl group, an isothiazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolinyl group, a pyrazolidinyl group, a piperidinyl group, a piperidino group (1-piperidinyl group), a morpholinyl group, a morpholino group (4-morpholinyl group), a thiomorpholinyl group, a thiomorpholino group (4-thiomorpholinyl group), a piperazinyl group, a piperazino group (1-piperazinyl group), a hexahydro-1,3-oxazinyl group and the like. The group may have 1 or 2 oxo groups. In addition, when the group contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxide.
  • Particularly, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a 2-oxopyrrolidinyl group, a 2-oxopyrrolidino group, an oxazolidinyl group, a 2-oxooxazolidinyl group, an isothiazolidinyl group, a 1,1-dioxoisothiazolidinyl group, an imidazolidinyl group, a 2-oxoimidazolidinyl group, a 2-oxopiperidinyl group, a 2-oxopiperidino group, a morpholinyl group, a morpholino group, a 2-oxomorpholino group, a piperazinyl group, a piperazino group, a 2-oxopiperazino group, a hexahydro-2-oxo-1,3-oxazinyl group and the like are preferable.
  • The “—C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B” in the specification is represented by the following formula
  • Figure US20150329491A1-20151119-C00017
  • wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.
  • Specific examples thereof include
  • Figure US20150329491A1-20151119-C00018
  • Furthermore, the “—C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B” is represented by the following formula
  • Figure US20150329491A1-20151119-C00019
  • wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.
  • Specific examples thereof include
  • Figure US20150329491A1-20151119-C00020
  • Preferable embodiment of each group of the compound represented by the formula [I] (hereinafter to be sometimes abbreviated as compound [I]) is explained in the following.
    • Ra
  • Ra is (1) a hydrogen atom, or (2) a halogen atom, preferably, a hydrogen atom, a fluorine atom or a chlorine atom, more preferably, a hydrogen atom.
    • Rb
  • Preferable embodiments of Rb are classified into the following type A and type B.
    • [Type A]
  • A type wherein Rb is a group represented by the following formula:
  • Figure US20150329491A1-20151119-C00021
  • wherein each symbol is as defined above. When Xd is C—Rd, compound [I] is represented by the formula [IV]
  • Figure US20150329491A1-20151119-C00022
    • [Type B]
  • A type wherein Rb is
  • (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
    (4) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (5) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (8) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (10) —C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (11) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (12) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (13) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (14) —NRb12—C(═O)—ORb13 wherein Rb12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and Rb13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or
    (15) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.
  • Preferable embodiments of type A and type B are explained in the following.
    • [Type A]
  • As Yb, preferred is
  • (i) a single bond,
    (ii) a C1-3 alkylene (particularly, methylene, trimethylene),
    (iii) a C2-3 alkenylene (particularly, vinylene),
    (iv) —O—(CH2)n1— wherein n1 is an integer of 0, or 1 to 4 (particularly, 0, or 1 to 3),
    (v) —O—(CH2)n2—C(═O)— wherein n2 is an integer of 0, or 1 to 4 (particularly, 1),
    • (vi) —C(═O)—, or
  • (vii) —NRb16— wherein Rb16 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group);
    more preferably, a single bond, —O—CH2—, —O—(CH2)2—, —O—CH2—C(═O)—, or —C(═O)—.
  • As ring T, preferred is
  • (i) a C6-10 aryl group,
    (ii) a C3-6 cycloalkyl group,
    (iii) a C5-10 bridged cycloalkyl group,
    (iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 5 or 6 ring-constituting atoms, or
    (v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 3 or 6 ring-constituting atoms;
    more preferred is
    (i) a phenyl group,
    (ii) a C3-6 cycloalkyl group (particularly, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group),
    (iii) an adamantyl group,
    (iv) a monocyclic aromatic heterocyclic group selected from a thiazolyl group, a pyridyl group, a thienyl group, an oxazolyl group, a 1,2,4-oxadiazolyl group, a pyrazolyl group, a tetrazolyl group, and a pyrimidinyl group, or
    (v) a monocyclic non-aromatic heterocyclic group selected from a piperidino group, a pyrrolidino group, an azetidinyl group, an aziridinyl group, a morpholino group, a piperazino group, a 2-oxopyrrolidino group, a 2-oxopiperidino group, a 2-oxopyrrolidin-5-yl group, a 2-oxo-1,3-oxazolidin-3-yl group, a 3-oxomorpholino group, a 1,1-dioxoisothiazolidinyl group, a 2-oxoimidazolidinyl group and a hexahydro-2-oxo-1,3-oxazinyl group.
  • Rj is preferably,
  • (1) a halogen atom,
    (2) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a cyano group,
    (5) —C(═O)—RD1 wherein RD1 is a hydrogen atom, a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by the same or different 1 to 5 substituents selected from group F (the monocyclic non-aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (6) —C(═O)—ORD2 wherein RD2 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (7) —C(═O)—NRD3RD4 wherein RD3 and RD4 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (8) —ORD7 wherein RD7 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (9) —NRD8RD9 wherein RD8 and RD9 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, or
    (10) —NRD10—C(═O)—RD11 wherein RD10 and RD11 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    more preferably,
    (1) a halogen atom (particularly, a fluorine atom, a chlorine atom),
    (2) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group E (particularly, a hydroxy group, a methoxymethoxy group, a carboxyl group, a carbamoyl group),
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl (particularly, a cyclohexylmethyl group),
    (4) a cyano group,
    (5) —C(═O)—RD1 wherein RD1 is a hydrogen atom, a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group), or a monocyclic non-aromatic heterocyclic group which contains besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms (particularly, a pyrrolidino group, a piperidino group, a 4-hydroxypiperidino group, a 3-hydroxypyrrolidino group),
    (6) —C(═O)—ORD2 wherein RD2 is a hydrogen atom, or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group),
    (7) —C(═O)—NRD3RD4 wherein RD3 and RD4 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group (particularly, a methyl group, an ethyl group),
    (8) —ORD7 wherein RD7 is a hydrogen atom, or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group) optionally substituted by the same or different 1 to 5 substituents selected from group E (particularly, a methoxy group, a carboxy group, a hydroxy group, a methoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group),
    (9) —NRD8RD9 wherein RD8 and RD9 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group (particularly, a methyl group), or
    (10) —NRD10—C(═O)—RD11 wherein RD10 and RD11 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group (particularly, a methyl group).
  • Specifically preferable examples of Rj include a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a hydroxy group, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxy-2-methylpropyl group, a carboxymethyl group, a carbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a cyclohexylmethyl group, a cyano group, an acetyl group, a propionyl group, an isobutyryl group, a 2,2-dimethylpropionyl group, a pyrrolidinocarbonyl group, a piperidinocarbonyl group, a 4-hydroxypiperidinocarbonyl group, a 3-hydroxypyrrolidinocarbonyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, a methoxy group, an ethoxy group, a propoxy group, a 2-methoxyethoxy group, a 2-hydroxyethoxy group, a carboxymethoxy group, a methoxycarbonylmethoxy group, a carbamoylmethoxy group, a methylcarbamoylmethoxy group, a dimethylcarbamoylmethoxy group, an amino group, a methylamino group, a dimethylamino group, an acetylamino group, an N-methyl-N-acetylamino group, a 2-(methoxymethoxy)ethyl group and the like.
  • p is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.
  • In type A, specifically preferable examples of Rb include a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 3,5-dichlorophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-(hydroxymethyl)phenyl group, a 4-(hydroxymethyl)phenyl group, a 4-hydroxyphenyl group, a 2-methoxyphenyl group, a 3-methoxycarbonylphenyl group, a 4-methoxyphenyl group, a 3-chloro-4-methoxyphenyl group, a 3-chloro-4-methoxycarbonylphenyl group, a 2-carboxyphenyl group, a 3-carboxyphenyl group, a 4-carboxyphenyl group, a 2-ethoxycarbonylphenyl group, a 4-ethoxycarbonylphenyl group, a 4-(tert-butoxycarbonyl)phenyl group, a 3-carbamoylphenyl group, a 3-(methylcarbamoyl)phenyl group, a 3-(dimethylcarbamoyl)phenyl group, a 2-carbamoylphenyl group, a 2-(methylcarbamoyl)phenyl group, a 2-(dimethylcarbamoyl)phenyl group, a 4-carbamoylphenyl group, a 4-(methylcarbamoyl)phenyl group, a 4-(dimethylcarbamoyl)phenyl group, a 3-chloro-4-carboxyphenyl group, a 3-chloro-4-carbamoylphenyl group, a 3-chloro-4-(methylcarbamoyl)phenyl group, a 3-chloro-4-(dimethylcarbamoyl)phenyl group, a 4-aminophenyl group, a 2-(acetylamino)phenyl group, a 4-(acetylamino)phenyl group, a 3-cyanophenyl group, a 4-cyanophenyl group, a benzyl group, a 2-phenylethenyl group, a benzoyl group, a phenoxy group, a phenylamino group, an N-phenyl-N-methylamino group, a benzyloxy group, a cyclopropyl group, a cyclohexyl group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cyclobutanecarbonyl group, a cyclopentanecarbonyl group, a cyclopropylmethyloxy group, a cyclobutylmethyloxy group, a cyclopentylmethyloxy group, a cyclohexylmethyloxy group, a 2-(adamantan-1-yl)ethoxy group, a 2-(3-hydroxyadamantan-1-yl)ethoxy group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-thienyl group, a 3-thienyl group, a 2-methyl-4-pyridyl group, a 5-pyrimidinyl group, a 5-oxazolyl group, a 3-methyl-1,2,4-oxadiazol-5-yl group, a 1-methyl-pyrazol-4-yl group, a 1,3,5-trimethyl-pyrazol-4-yl group, a 1-ethyl-pyrazol-4-yl group, a 1-isopropyl-pyrazol-4-yl group, a 1-isobutyl-pyrazol-4-yl group, a 1-tert-butyl-pyrazol-4-yl group, a 1-neopentyl-pyrazol-4-yl group, a 1-carboxymethyl-pyrazol-4-yl group, a 1-(2-hydroxyethyl)-pyrazol-4-yl group, a 1-carbamoylmethyl-pyrazol-4-yl group, a 1-(2-carboxyethyl)-pyrazol-4-yl group, a 1-(2-carbamoylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-2-methylpropyl)-pyrazol-4-yl group, a 1-cyclohexylmethyl-pyrazol-4-yl group, a pyrazol-1-yl group, a 2-thienylcarbonyl group, a 2-thienylmethyloxy group, a pyrazol-1-ylmethyl group, a 3-(2-oxopyrrolidino)propyl group, a 3-(tetrazol-5-yl)propoxy group, a 2-oxopyrrolidino group, a pyrrolidino group, a piperidino group, a morpholino group, a piperazino group, a 2-methylpyrrolidino group, a 3-methylpyrrolidino group, a 4-carboxypiperidino group, a 4-methylpiperazino group, a 4-acetylpiperazino group, a 4-propionylpiperazino group, a 4-isobutyrylpiperazino group, a 4-(2,2-dimethylpropionyl)piperazino group, a 4-(tert-butoxycarbonyl)piperazino group, a 4-(methoxycarbonyl)piperazino group, a 4-(ethoxycarbonyl)piperazino group, a 4-(isopropoxycarbonyl)piperazino group, an aziridinocarbonyl group, an azetidinocarbonyl group, a piperidinocarbonyl group, a pyrrolidinocarbonyl group, a morpholinocarbonyl group, a 2-methylazetidinocarbonyl group, a 3-methylazetidinocarbonyl group, a 3-hydroxyazetidinocarbonyl group, a 3-hydroxymethylazetidinocarbonyl group, a 3-methoxyazetidinocarbonyl group, a 3-ethoxyazetidinocarbonyl group, a 3-propoxyazetidinocarbonyl group, a 3-(2-methoxyethoxy)azetidinocarbonyl group, a 3-(2-hydroxyethoxy)azetidinocarbonyl group, a 3-(carboxymethoxy)azetidinocarbonyl group, a 3-(methoxycarbonylmethoxy)azetidinocarbonyl group, a 3-(carbamoylmethoxy)azetidinocarbonyl group, a 3-(methylcarbamoylmethoxy)azetidinocarbonyl group, a 3-(dimethylcarbamoylmethoxy)azetidinocarbonyl group, a 2-methoxycarbonylazetidinocarbonyl group, a 2-carboxyazetidinocarbonyl group, a 2-(ethylcarbamoyl)azetidinocarbonyl group, a 2-(propylcarbamoyl)azetidinocarbonyl group, a 3-methoxycarbonylazetidinocarbonyl group, a 3-carboxyazetidinocarbonyl group, a 3-carbamoylazetidinocarbonyl group, a 3-(methylcarbamoyl)azetidinocarbonyl group, a 3-(dimethylcarbamoyl)azetidinocarbonyl group, a 3-dimethylaminoazetidinocarbonyl group, a 3-(diethylcarbamoyl)azetidinocarbonyl group, a 3-(pyrrolidinocarbonyl)azetidinocarbonyl group, a 3-(3-hydroxypyrrolidinocarbonyl)azetidinocarbonyl group, a 3-(piperidinocarbonyl)azetidinocarbonyl group, a 3-(4-hydroxypiperidinocarbonyl)azetidinocarbonyl group, a 2-methylpyrrolidinocarbonyl group, a 3-hydroxypyrrolidinocarbonyl group, a 2-methoxycarbonylpyrrolidinocarbonyl group, a 3-methoxycarbonylpyrrolidinocarbonyl group, a 2-carboxypyrrolidinocarbonyl group, a 3-carboxypyrrolidinocarbonyl group, a 2-carbamoylpyrrolidinocarbonyl group, a 2-(methylcarbamoyl)pyrrolidinocarbonyl group, a 2-(dimethylcarbamoyl)pyrrolidinocarbonyl group, a 3-carbamoylpyrrolidinocarbonyl group, a 3-(methylcarbamoyl)pyrrolidinocarbonyl group, a 3-(dimethylcarbamoyl)pyrrolidinocarbonyl group, a 2-(hydroxymethyl)pyrrolidinocarbonyl group, a 3-(hydroxymethyl)pyrrolidinocarbonyl group, a 3-methylaminopyrrolidinocarbonyl group, a 3-dimethylaminopyrrolidinocarbonyl group, a 3-(N-acetyl-N-methylamino)pyrrolidinocarbonyl group, a 4-hydroxypiperidinocarbonyl group, a 4-methoxycarbonylpiperidinocarbonyl group, a 4-methoxycarbonylpiperidino group, a 4-ethoxycarbonylpiperidinocarbonyl group, a 4-ethoxycarbonylpiperidino group, a 4-carboxypiperidinocarbonyl group, a 4-carbamoylpiperidinocarbonyl group, a 4-carbamoylpiperidino group, a 4-(methylcarbamoyl)piperidinocarbonyl group, a 4-(methylcarbamoyl)piperidino group, a 4-(dimethylcarbamoyl)piperidinocarbonyl group, a 4-(dimethylcarbamoyl)piperidino group, a 4-(hydroxymethyl)piperidinocarbonyl group, a 2-(2-oxopyrrolidino)ethoxy group, a 2-(5-hydroxymethyl-2-oxopyrrolidino)ethoxy group, a 3-(2-oxopyrrolidino)propoxy group, a 2-(2-oxopiperidino)ethoxy group, a 3-(2-oxopiperidino)propoxy group, a 2-(2-oxo-1,3-oxazolidin-3-yl)ethoxy group, a 2-(1,1-dioxoisothiazolidin-2-yl)ethoxy group, a 2-(2-oxo-imidazolidin-1-yl)ethoxy group, a 2-(hexahydro-2-oxo-1,3-oxazin-3-yl)ethoxy group, a 2-(3-oxomorpholino)ethoxy group, a (2-oxopyrrolidin-5-yl)methoxy group, an (1-methyl-2-oxopyrrolidin-5-yl)methoxy group, an (1-(3-hydroxypropyl)-2-oxopyrrolidin-5-yl)methoxy group, an (1-(2-(methoxymethoxy)ethyl)-2-oxopyrrolidin-5-yl)methoxy group, an (1-(2-hydroxyethyl)-2-oxopyrrolidin-5-yl)methoxy group, an azetidinocarbonylmethoxy group, a pyrrolidinocarbonylmethoxy group, a piperidinocarbonylmethoxy group, a morpholinocarbonylmethoxy group, a (3-hydroxyazetidino)carbonylmethoxy group, a (3-hydroxymethylazetidino)carbonylmethoxy group, a (2-hydroxymethylpyrrolidino)carbonylmethoxy group, a (3-hydroxypyrrolidino)carbonylmethoxy group, a (4-hydroxypiperidino)carbonylmethoxy group, a (4-hydroxymethylpiperidino)carbonylmethoxy group and the like.
  • Specific structural formulas of Rb in type A are as follows.
  • Figure US20150329491A1-20151119-C00023
    • [Type B]
  • In type B, preferable examples of Rb include
  • (1) a hydrogen atom,
    (2) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom),
    (3) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, an isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group) optionally substituted by the same or different 1 to 5 substituents selected from group A [particularly,
    (i) —C(═O)—ORA2 wherein RA2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (ii) —C(═O)—NRA3RA4 wherein RA3 and RA4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group,
    (iii) —ORA7 wherein RA7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (iv) —NRA8RA9 wherein RA8 and RA9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (v) —NRA10—C(═O)—RA11 wherein RA10 and RA11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), and
    • (vi) —Si—(CH2—CH3)3]
  • (particularly, a hydroxy group, a methoxy group, a carboxy group, a methoxycarbonyl group, a carbamoyl group, an acetylamino group, a methylamino group, an N-acetyl-N-methylamino group, a triethylsilyl group),
    (4) a C2-6 alkenyl group (particularly, a 1-propenyl group, a 2-methyl-1-propenyl group),
    (5) a C2-6 alkynyl group (particularly, an ethynyl group),
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (B) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, a butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B (particularly, a hydroxy group),
    (10) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B [particularly,
    (i) —C(═O)—ORB2 wherein RB2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group),
    (ii) —C(═O)—NRB3RB4 wherein RB3 and RB4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group),
    (iii) —ORB7 wherein RB7 is a hydrogen atom or a C1-6 alkyl group,
    (iv) —NRB8RB9 wherein RB8 and RB9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a carboxyl group),
    (v) —NRB10—C(═O)—RB11 wherein RB10 and RB11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group, a trifluoroacetyl group),
    (vi) —NRB12—S(═O)2—RB13 wherein RB12 and RB13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), and
    (vii) —NRB14—C(═O)—ORB15 wherein RB14 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, a tert-butyl group), and RB15 is a C1-6 alkyl group (particularly, a methyl group, a tert-butyl group)]
    (particularly, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a hydroxy group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an amino group, a methylamino group, a dimethylamino group, a tert-butoxycarbonylamino group, an acetylamino group, an N-tert-butoxycarbonyl-N-methylamino group, an N-acetyl-N-methylamino group, an N-hydroxyacetyl-N-methylamino group, an N-acetyl-N-(2-hydroxyethyl)amino group, an N-(2-hydroxyethyl)carbamoyl group, an N-(2-hydroxyethyl)-N-methylcarbamoyl group, an N,N-bis(2-hydroxyethyl)carbamoyl group, an N-methyl-N-methanesulfonylamino group, an N-acetyl-N-(2-carboxyethyl)amino group, an N-carboxymethyl-N-methylamino group, an N-carboxymethyl-N-methylcarbamoyl group, an N-(2-carboxyethyl)-N-methylcarbamoyl group, a 3-(trifluoroacetyl)propionylamino group, an N-(2,2-dimethylpropionyl)-N-methylamino group, an N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino group, an N-(2-hydroxy-2-methylpropionyl)-N-methylamino group),
    (11) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (12) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), or
    (13) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group).
  • In type B, specifically preferable examples of Rb include, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a neopentyl group, a 3,3-dimethylbutyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, a 3-hydroxy-3-methylbutyl group, a 4-hydroxy-3,3-dimethylbutyl group, a methoxycarbonylmethyl group, a carboxymethyl group, a carbamoylmethyl group, an acetylaminomethyl group, a methylaminomethyl group, an N-acetyl-N-methylaminomethyl group, a (triethylsilyl)ethyl group, a 1-propenyl group, a 2-methyl-1-propenyl group, an ethynyl group, an acetyl group, a carboxyl group, a methoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, an N-methyl-N-ethylcarbamoyl group, an N-(2-hydroxyethyl)carbamoyl group, an N-(2-hydroxyethyl)-N-methylcarbamoyl group, an N-methyl-N-propylcarbamoyl group, an N-(3-hydroxypropyl)carbamoyl group, an N-(3-hydroxypropyl)-N-methylcarbamoyl group, an N-butyl-N-methylcarbamoyl group, an N-(4-hydroxybutyl) carbamoyl group, an N-(4-hydroxybutyl)-N-methylcarbamoyl group, a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentoxy group, an isopentoxy group, a neopentoxy group, a hexyloxy group, a carboxymethoxy group, a methoxycarbonylmethoxy group, a carbamoylmethoxy group, a methylcarbamoylmethoxy group, a dimethylcarbamoylmethoxy group, a (2-hydroxyethyl)carbamoylmethoxy group, a bis(2-hydroxyethyl)carbamoylmethoxy group, an N-(2-hydroxyethyl)-N-methylcarbamoylmethoxy group, an N-carboxymethyl-N-methylcarbamoylmethoxy group, a 2-hydroxyethoxy group, a 2-carboxyethoxy group, a 2-hydroxy-1,1-dimethylethoxy group, a 2-carbamoylethoxy group, a 1-carbamoylethoxy group, a 2-(methylcarbamoyl)ethoxy group, a 2-(dimethylcarbamoyl)ethoxy group, a 2-aminoethoxy group, a 2-(methylamino)ethoxy group, a 2-(dimethylamino)ethoxy group, a 2-(tert-butoxycarbonylamino)ethoxy group, a 2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy group, a 2-(acetylamino)ethoxy group, a 2-(N-acetyl-N-methylamino) ethoxy group, a 2-(N-hydroxyacetyl-N-methylamino)ethoxy group, a 2-(N-acetyl-N-(2-hydroxyethyl)amino)ethoxy group, a 2-(N-acetyl-N-methylamino)-1-methylethoxy group, a 2-(N-acetyl-N-methylamino)-2-methylethoxy group, a 2-(N-methanesulfonyl-N-methylamino)-2-methylethoxy group, a 2-(N-methanesulfonyl-N-methylamino)ethoxy group, a 2-(N-acetyl-N-(2-carboxyethyl)amino)ethoxy group, a 2-(N-carboxymethyl-N-methylamino)ethoxy group, a 2-(4-oxo-5,5,5-trifluoropentanoylamino)ethoxy group, a 2-(N-(2,2-dimethylpropionyl)-N-methylamino)ethoxy group, a 2-(N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino)ethoxy group, a 2-(N-(2-methyl-2-hydroxypropionyl)-N-methylamino)ethoxy group, a 2-hydroxy-1-(hydroxymethyl)ethoxy group, a 3-hydroxypropoxy group, a 3-ethoxycarbonylpropoxy group, a 3-carboxypropoxy group, a 3-carbamoylpropoxy group, a 3-(methylcarbamoyl)propoxy group, a 3-(dimethylcarbamoyl)propoxy group, a 3-aminopropoxy group, a 3-(methylamino)propoxy group, a 3-(dimethylamino)propoxy group, a 3-(acetylamino)propoxy group, a 3-(N-acetyl-N-methylamino)propoxy group, a 3-(N-acetyl-N-methylamino)-2-hydroxypropoxy group, a 2-(N-acetyl-N-methylamino)propoxy group, a 2,3-dihydroxypropoxy group, a 2-(hydroxymethyl)-3-hydroxypropoxy group, a 2-hydroxy-2-methylpropoxy group, a 3-hydroxy-2,2-dimethylpropoxy group, a 4-hydroxybutoxy group, a 4-ethoxycarbonylbutoxy group, a 3-carboxybutoxy group, a 4-carboxybutoxy group, a 4-carbamoylbutoxy group, a 4-(methylcarbamoyl)butoxy group, a 4-(dimethylcarbamoyl)butoxy group, a 5-hydroxypentoxy group, a 5-carboxypentoxy group, a 6-hydroxyhexyloxy group, an amino group, a dimethylamino group, a methylamino group, an acetylamino group, an N-acetyl-N-methylamino group, a dimethylaminocarbonyloxy group and the like.
    • Rc
  • Rc is
  • (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group,
    (4) —C(═O)—ORc1 wherein Rc1 is a hydrogen atom or a C1-6 alkyl group,
    (5) —ORc2 wherein Rc2 is a hydrogen atom or a C1-6 alkyl group,
    (6) —NRc3Rc4 wherein Rc3 and Rc4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group, or
    (7) —NRc5—C(═O)—Rc6 wherein Rc5 and Rc6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group.
  • As Rc, preferred is
  • (1) a hydrogen atom,
    (2) a halogen atom (particularly, a fluorine atom, a chlorine atom),
    (3) a methyl group,
    (4) —C(═O)—ORc1 wherein Rc1 is a hydrogen atom or a methyl group,
    (5) —ORc2 wherein Rc2 is a hydrogen atom, a methyl group or an ethyl group,
    • (6) —NH2, or
  • (7) —NRc5—C(═O)—Rc6 wherein Rc5 and Rc6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), particularly preferably, a hydrogen atom.
  • Specifically preferable examples of Rc include a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxy group, a methoxy group, an ethoxy group, an amino group, an acetylamino group, a propionylamino group, an isobutyrylamino group, a carboxyl group, a methoxycarbonyl group and the like.
    • Xd
  • Preferable embodiments of Xd are classified into the following type C to type E.
    • [Type C]
  • A type wherein Xd is C—Rd, and Rd is a group represented by the following formula:
  • Figure US20150329491A1-20151119-C00024
  • wherein each symbol is as defined above. In this case, compound [I] is represented by the formula [II]
  • Figure US20150329491A1-20151119-C00025
    • [Type D]
  • A type wherein Xd is C—Rd, and Rd is
  • (i) a hydrogen atom,
    (ii) a halogen atom,
    (iii) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
    (iv) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (v) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (vi) a cyano group,
    (vii) —C(═O)—Rd1 wherein Rd1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (viii) —C(═O)—ORd2 wherein Rd2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (ix) —C(═O)—NRd3Rd4 wherein Rd3 and Rd4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (x) —C(═O)—NRd5—ORd6 wherein Rd5 and Rd6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (xi) —ORd7 wherein Rd7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (xii) —NRd8Rd9 wherein Rd8 and Rd9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (xiii) —NRd10—C(═O)—Rd11 wherein Rd10 and Rd11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or
    (xiv) —NRd12—C(═O)—ORd13 wherein Rd12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and Rd13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.
    • [Type E]
  • In this type, Xd is a nitrogen atom.
  • In this case, compound [I] is represented by the formula [V]
  • Figure US20150329491A1-20151119-C00026
  • Preferable embodiment of type C is explained in the following.
    • [Type C]
  • As Yd, preferred is
  • (I) a single bond, or.
    (II) —C(═O)—, more preferred is a single bond.
  • As ring U, preferred is
  • (I) a C6-10 aryl group,
    (II) a C3-10 cycloalkyl group,
    (III) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or
    (IV) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms,
    more preferred is
    (I) a phenyl group,
    (II) a cyclopropyl group,
    (III) a monocyclic aromatic heterocyclic group selected from an oxazolyl group, a pyridyl group, a 1,3,4-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a tetrazolyl group, a pyrazolyl group, a pyrimidinyl group, a thienyl group, a 1,2,4-triazolyl group, or
    (IV) an aziridinyl group.
  • Rk is preferably
  • (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (2) a C1-6 alkyl group substituted by a C6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (5) a C1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (6) a C3-10 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (7) a C5-10 bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferably,
    (1) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 1-ethylpropyl group, a 1,1,2-trimethylpropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group E (particularly, a halogen atom (particularly, a fluorine atom), a hydroxy group, a carboxyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, an isopropylcarbamoyl group, a dimethylcarbamoyl group, an acetylamino group, an N-acetyl-N-methylamino group, a methanesulfonylamino group, a cyano group),
    (2) a C1-6 alkyl group substituted by a C6-10 aryl group (particularly, a benzyl group),
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl (particularly, a cyclohexylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group),
    (4) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl (particularly, an adamantan-1-ylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group),
    (5) a C1-6 alkyl group (particularly, a propyl group) substituted by a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms (particularly, tetrazolyl) (particularly, a 3-(5-tetrazolyl)propyl group) optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (particularly, a methyl group),
    (6) a C3-10 cycloalkyl group, (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxymethyl group, a carboxyl group),
    (7) a C5-10 bridged cycloalkyl group (particularly, a 1-adamantyl group).
  • Specifically preferable examples of Rk include
  • a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a 2-hydroxy-1-(hydroxymethyl)ethyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, an ethylcarbamoylmethyl group, an isopropylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a 2-(methylcarbamoyl)ethyl group, a 2-(dimethylcarbamoyl)ethyl group, a 2-(acetylamino)ethyl group, a 2-(N-acetyl-N-methylamino)ethyl group, a 2-hydroxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)-1-methylethyl group, a 1-carbamoyl-1-methylethyl group, a 1-methylcarbamoyl-1-methylethyl group, a 1-dimethylcarbamoyl-1-methylethyl group, a 2-hydroxy-1,1-bis(hydroxymethyl)ethyl group, a 3-hydroxy-2-(hydroxymethyl)propyl group, a 2-hydroxy-2-methylpropyl group, a 2-hydroxy-1,1,2-trimethylpropyl group, a 2-hydroxy-3,3,3-trifluoropropyl group, a 3-methanesulfonylaminopropyl group, a 3-(5-tetrazolyl)propyl group, a 3-(1-methyl-5-tetrazolyl)propyl group, a 3-(2-methyl-5-tetrazolyl)propyl group, a 1,1-bis(hydroxymethyl)propyl group, a 3-hydroxy-1-(2-hydroxyethyl)propyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 1-carboxy-1-methylethyl group, a 2-carboxy-2-methylpropyl group, a 2-carboxy-1,1-dimethylethyl group, a cyanomethyl group, a benzyl group, an (1-hydroxycyclohexyl)methyl group, a 3-hydroxyadamantan-1-ylmethyl group, a 1-hydroxymethylcyclohexyl group, a 1-hydroxymethylcyclopentyl group, a 1-carboxycyclopentyl group, a 1-adamantyl group and the like.
  • m is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.
  • Specifically preferable examples of Rd include a phenyl group, a cyclopropyl group, a cyclopropanecarbonyl group, an oxazol-5-yl group, a 2-methyl-oxazol-5-yl group, an oxazol-2-yl group, a 2-(2-hydroxy-1-(hydroxymethyl)ethyl)-oxazol-5-yl group, a 2-pyridyl group, a 3-pyridyl group, a 4-methyl-3-pyridyl group, a 6-methyl-3-pyridyl group, a 4-pyridyl group, a 1,3,4-oxadiazol-2-yl group, a 5-methyl-1,3,4-oxadiazol-2-yl group, a 3-methyl-1,2,4-oxadiazol-5-yl group, a 5-methyl-1,2,4-oxadiazol-3-yl group, a 3-(2-hydroxy-1-(hydroxymethyl)ethyl)-1,2,4-oxadiazol-5-yl group, a 2-methyl-5-tetrazolyl group, a 1-methyl-5-tetrazolyl group, a pyrazol-4-yl group, a 1-methyl-pyrazol-4-yl group, a 1,3,5-trimethyl-pyrazol-4-yl group, a 1-ethyl-pyrazol-4-yl group, a 1-isopropyl-pyrazol-4-yl group, a 1-isobutyl-pyrazol-4-yl group, a 1-tert-butyl-pyrazol-4-yl group, a 1-neopentyl-pyrazol-4-yl group, a 1-benzyl-pyrazol-4-yl group, a 1-(adamantan-1-yl)-pyrazol-4-yl group, a 1-(2-hydroxyethyl)-pyrazol-4-yl group, a 1-(3-hydroxypropyl)-pyrazol-4-yl group, a 1-(2-(acetylamino)ethyl)-pyrazol-4-yl group, a 1-(2-(N-acetyl-N-methylamino)ethyl)-pyrazol-4-yl group, a 1-carboxymethyl-pyrazol-4-yl group, a 1-carbamoylmethyl-pyrazol-4-yl group, a 1-methylcarbamoylmethyl-pyrazol-4-yl group, a 1-dimethylcarbamoylmethyl-pyrazol-4-yl group, a 1-ethylcarbamoylmethyl-pyrazol-4-yl group, a 1-isopropylcarbamoylmethyl-pyrazol-4-yl group, a 1-(2-carboxyethyl)-pyrazol-4-yl group, a 1-(2-carbamoylethyl)-pyrazol-4-yl group, a 1-(2-(methylcarbamoyl)ethyl)-pyrazol-4-yl group, a 1-(2-(dimethylcarbamoyl)ethyl)-pyrazol-4-yl group, a 1-(3-carboxypropyl)-pyrazol-4-yl group, a 1-(4-carboxybutyl)-pyrazol-4-yl group, a 5-pyrimidinyl group, a 3-thienyl group, a 3-methyl-1,2,4-triazol-5-yltriazolyl group, a 3-methyl-1,2,4-triazol-5-yl group, a 1-(1-hydroxycyclohexylmethyl)-pyrazol-4-yl group, a 1-(1-(hydroxymethyl)cyclohexyl)-pyrazol-4-yl group, a 1-(1-(hydroxymethyl)cyclopentyl)-pyrazol-4-yl group, a 1-(1-(3-hydroxyadamantan-1-ylmethyl)-pyrazol-4-yl group, a 1-(1-carboxycyclohexyl)-pyrazol-4-yl group, a 1-(1-carboxycyclopentyl)-pyrazol-4-yl group, a 1-(2,3-dihydroxypropyl)-pyrazol-4-yl group, a 1-(1-carboxy-1-methylethyl)-pyrazol-4-yl group, a 1-(2-carboxy-2-methylpropyl)-pyrazol-4-yl group, a 1-(2-carboxy-1,1-dimethylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1,1-dimethylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1-(hydroxymethyl)ethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1-(hydroxymethyl)-1-methylethyl)-pyrazol-4-yl group, a 1-(1-carbamoyl-1-methylethyl)-pyrazol-4-yl group, a 1-(1-methylcarbamoyl-1-methylethyl)-pyrazol-4-yl group, a 1-(1-dimethylcarbamoyl-1-methylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)-pyrazol-4-yl group, a 1-(3-hydroxy-2-(hydroxymethyl)propyl)-pyrazol-4-yl group, a 1-(2-hydroxy-2-methylpropyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1,1,2-trimethylpropyl)-pyrazol-4-yl group, a 1-(2-hydroxy-3,3,3-trifluoropropyl)-pyrazol-4-yl group, a 1-(3-methanesulfonylaminopropyl)-pyrazol-4-yl group, a 1-(3-(5-tetrazolyl)propyl)-pyrazol-4-yl group, a 1-(3-(1-methyl-5-tetrazolyl)propyl)-pyrazol-4-yl group, a 1-(3-(2-methyl-5-tetrazolyl)propyl)-pyrazol-4-yl group, a 1-(1,1-bis(hydroxymethyl)propyl)-pyrazol-4-yl group, a 1-(3-hydroxy-1-(2-hydroxyethyl)propyl)-pyrazol-4-yl group, an aziridinocarbonyl group and the like.
  • Ring U is preferably a monocyclic aromatic heterocyclic group.
  • Furthermore, a compound wherein Yd is a single bond is preferable, and
  • more preferred is a pyrazolyl group (particularly, a pyrazol-4-yl group) or a pyrimidinyl group (particularly, a pyrimidin-5-yl group) for ring U.
    Still more preferred is a compound represented by the following formula, which is a compound wherein ring U is a pyrazol-4-yl group:
  • Figure US20150329491A1-20151119-C00027
  • wherein
    • Rm is
  • (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (2) a C1-6 alkyl group substituted by a C6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C1-6 alkyl group substituted by a C6-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (5) a C1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (6) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (7) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and other symbols are as defined above.
  • Here, as Rm, preferred is
  • (1) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 1-ethylpropyl group, a 1,1,2-trimethylpropyl group) optionally substituted by the same or different 1 to 5 substituents selected from
    (i) a halogen atom (particularly, a fluorine atom),
    (ii) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (iii) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (iv) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (v) —NRE12—C(═O)—RE13 wherein RE12 and RE13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (vi) —NRE16—S(═O)2—RE17 wherein RE16 and RE17 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (2) a C1-6 alkyl group substituted by a C6-10 aryl group (particularly, a benzyl group),
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl (particularly, a cyclohexylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group),
    (4) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl (particularly, an adamantan-1-ylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group),
    (5) a C1-6 alkyl group (particularly, a propyl group) substituted by a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms (particularly, tetrazolyl) (particularly, a 3-(5-tetrazolyl)propyl group) optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (particularly, a methyl group),
    (6) a C3-10 cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), and
    (7) a C5-10 bridged cycloalkyl group (particularly, an adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F.
  • Specifically preferable examples of Rm include a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1-benzyl group, an adamantan-1-yl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-(acetylamino)ethyl group, a 2-(N-acetyl-N-methylamino)ethyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, an ethylcarbamoylmethyl group, an isopropylcarbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a 2-(methylcarbamoyl)ethyl group, a 2-(dimethylcarbamoyl)ethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 1-hydroxycyclohexylmethyl group, a 1-(hydroxymethyl)cyclohexyl group, a 1-(hydroxymethyl)cyclopentyl group, a (3-hydroxyadamantan-1-yl)methyl group, a 1-carboxycyclohexyl group, a 1-carboxycyclopentyl group, a 2,3-dihydroxypropyl group, a 1-carboxy-1-methylethyl group, a 2-carboxy-2-methylpropyl group, a 2-carboxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)ethyl group, a 3-hydroxy-2-(hydroxymethyl)propyl group, a 2-hydroxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)-1-methylethyl group, a 1-carbamoyl-1-methylethyl group, a 1-methylcarbamoyl-1-methylethyl group, a 1-dimethylcarbamoyl-1-methylethyl group, a 2-hydroxy-1,1-bis(hydroxymethyl)ethyl group, a 2-hydroxy-2-methylpropyl group, a 2-hydroxy-1,1,2-trimethylpropyl group, a 2-hydroxy-3,3,3-trifluoropropyl group, a 3-methanesulfonylaminopropyl group, a 3-(5-tetrazolyl)propyl group, a 3-(1-methyl-5-tetrazolyl)propyl group, a 3-(2-methyl-5-tetrazolyl)propyl group, a 1,1-bis(hydroxymethyl)propyl group, a 3-hydroxy-1-(2-hydroxyethyl)propyl group and the like.
  • In other embodiments, as Rm, preferred is
  • (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′,
    (2) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (5) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferred is,
    (1) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from
    (i) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (ii) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (iii) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (iv) —NRE12—C(═O)—RE13 wherein RE12 and RE13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (2) a C3-10 cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or
    (3) a C5-10 bridged cycloalkyl group (particularly, an adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    and further preferably,
    (1) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from
    (i) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (ii) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (2) a C3-10 cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or
    (3) a C5-10 bridged cycloalkyl group (particularly, a 1-adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F.
  • In the above-mentioned formula [III],
  • Rc is preferably a hydrogen atom;
    Rb is preferably
    (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
    (4) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (5) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (8) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (10) —C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (11) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (12) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (13) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (14) —NRb12—C(═O)—ORb13 wherein Rb12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and Rb13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or
    (15) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B;
    Ra is preferably a hydrogen atom; and
    n is preferably 0.
  • In addition, a compound wherein Yd is a single bond and ring U is a pyrimidin-5-yl group, which is represented by the following formula:
  • Figure US20150329491A1-20151119-C00028
  • wherein each symbol is as defined above,
    is preferable.
  • Here, m is preferably 0;
  • Ra is preferably a hydrogen atom; and
    n is preferably 0.
  • In the following, a preferable embodiment of type D is explained.
    • [Type D]
  • Rd is preferably
  • (i) a hydrogen atom,
    (ii) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom),
    (iii) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A [particularly,
    (1) a halogen atom (particularly, a fluorine atom),
    (2) a cyano group,
    (3) —C(═O)—NRA3RA4 wherein RA3 and RA4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group,
    (4) —ORA7 wherein RA7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), and
    (5) —NRA8RA9 wherein RA8 and RA9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group)] (particularly, a fluorine atom, a hydroxy group, a methoxy group, an amino group, a cyano group, a carbamoyl group) (particularly, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, an aminomethyl group),
    (iv) a C2-6 alkenyl group (particularly, a 1-methylvinyl group),
    (v) a C2-6 alkynyl group (particularly, an ethynyl group, a 3-hydroxy-1-propynyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group),
    (vi) a cyano group,
    (vii) —C(═O)—Rd1 wherein Rd1 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group),
    (viii) —C(═O)—ORd2 wherein Rd2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group),
    (ix) —C(═O)—NRd3Rd4 wherein Rd3 and Rd4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (x) —C(═O)—NRd5—ORd6 wherein Rd5 and Rd6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (xi) —ORd7 wherein Rd7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group),
    (xii) —NRd8Rd9 wherein Rd8 and Rd9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (xiii) —NRd10—C(═O)—Rd11 wherein Rd10 and Rd11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), or
    (xiv) —NRd12—C(═O)—ORd13 wherein Rd12 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), and Rd13 is a C1-6 alkyl group (particularly, a methyl group).
  • In type D, specifically preferable examples of Rd include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a methoxymethyl group, a trifluoromethyl group, an aminomethyl group, a cyanomethyl group, a carboxymethyl group, a carbamoylmethyl group, a 1-methylvinyl group, an ethynyl group, a 3-hydroxypropynyl group, a cyano group, an acetyl group, a propionyl group, an isobutyryl group, a carboxy group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an N-methyl-N-methoxycarbamoyl group, a hydroxy group, a methoxy group, an ethoxy group, an amino group, a methylamino group, a dimethylamino group, an acetylamino group, a methoxycarbonylamino group and the like.
  • As Xd, type C and type D are preferable, and type C is more preferable.
    • Re
  • Re is preferably the same or different and each is
  • (1) a halogen atom (particularly, a chlorine atom, a fluorine atom), or
    (2) a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents (particularly, a hydroxy group) selected from group C; more preferably, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group and the like.
    n
  • n is an integer of 0, or 1 to 3, preferably an integer of 0, or 1 to 2, particularly preferably 0.
  • As preferable embodiment of the compound represented by the formula [I], a compound represented by the following formula can be mentioned.
  • Figure US20150329491A1-20151119-C00029
    Figure US20150329491A1-20151119-C00030
    Figure US20150329491A1-20151119-C00031
  • Here, as the compound represented by the formula [I], preferred is a compound represented by the formula [II], more preferred is a compound represented by the formula [III] or a compound represented by the formula [VI].
  • As a compound represented by the formula [III], preferred is the formula [III-E], and as a compound represented by the formula [VI], preferred is a compound represented by the formula [VI-A].
  • As a compound represented by the formula [IV], preferred is a compound represented by the formula [IV-D] or [IV-F].
  • As a compound represented by the formula [IV-D], preferred is a compound wherein Ra is a hydrogen atom, Rc is a hydrogen atom, Rd is —CH3, —CH2—OH or —C(═O)—NH2, and n=0.
  • As a compound represented by the formula [IV-F], preferred is a compound wherein Ra is a hydrogen atom, Rc is a hydrogen atom, Rd is —CH3, and n=0.
  • One example of preferable combination of each symbol in a compound represented by the formula [III] is explained in the following.
  • In a preferable combination,
  • Ra is a hydrogen atom, a fluorine atom or a chlorine atom, particularly a hydrogen atom,
    • Rb is
  • (1) a hydrogen atom,
    (2) a halogen atom,
    (3) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A,
    (4) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (5) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C,
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (8) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents so selected from group B,
    (10) —C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (11) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (12) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (13) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    (14) —NRb12—C(═O)—ORb13 wherein Rb12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and Rb13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or
    (15) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B,
    particularly,
    (1) a hydrogen atom,
    (2) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom),
    (3) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, an isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group) optionally substituted by the same or different 1 to 5 substituents selected from group A
    [particularly,
    (i) —C(═O)—ORA2 wherein RA2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (ii) —C(═O)—NRA3RA4 wherein RA3 and RA4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group,
    (iii) —ORA7 wherein RA7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (iv) —NRA8RA9 wherein RA8 and RA9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (v) —NRA10—C(═O)—RA11 wherein RA10 and RA11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), and
    • (vi) —Si—(CH2—CH3)3]
  • (particularly, a hydroxy group, a methoxy group, a carboxy group, a methoxycarbonyl group, a carbamoyl group, an acetylamino group, a methylamino group, an N-acetyl-N-methylamino group, a triethylsilyl group),
    (4) a C2-6 alkenyl group (particularly, a 1-propenyl group, a 2-methyl-1-propenyl group),
    (5) a C2-6 alkynyl group (particularly, an ethynyl group),
    (6) a cyano group,
    (7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (8) —C(═O)—ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, a butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B (particularly, a hydroxy group),
    (10) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B [particularly,
    (i) —C(═O)—ORB2 wherein RB2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group),
    (ii) —C(═O)—NRB3RB4 wherein RB3 and RB4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group),
    (iii) —ORB7 wherein RB7 is a hydrogen atom or a C1-6 alkyl group,
    (iv) —NRB8RB9 wherein RB8 and RB9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a carboxyl group),
    (v) —NRB10—C(═O)—RB11 wherein RB10 and RB11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group, a trifluoroacetyl group),
    (vi) —NRB12—S(═O)2—RB13 wherein RB12 and RB13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), and
    (vii) —NRB14—C(═O)—ORB15 wherein RB14 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, a tert-butyl group), and RB15 is a C1-6 alkyl group (particularly, a methyl group, a tert-butyl group)]
    (particularly, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a hydroxy group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an amino group, a methylamino group, a dimethylamino group, a tert-butoxycarbonylamino group, an acetylamino group, an N-tert-butoxycarbonyl-N-methylamino group, an N-acetyl-N-methylamino group, an N-hydroxyacetyl-N-methylamino group, an N-acetyl-N-(2-hydroxyethyl)amino group, an N-(2-hydroxyethyl)carbamoyl group, an N-(2-hydroxyethyl)-N-methylcarbamoyl group, an N,N-bis(2-hydroxyethyl) carbamoyl group, an N-methyl-N-methanesulfonylamino group, an N-acetyl-N-(2-carboxyethyl)amino group, an N-carboxymethyl-N-methylamino group, an N-carboxymethyl-N-methylcarbamoyl group, an N-(2-carboxyethyl)-N-methylcarbamoyl group, a 3-(trifluoroacetyl)propionylamino group, an N-(2,2-dimethylpropionyl)-N-methylamino group, an N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino group, an N-(2-hydroxy-2-methylpropionyl)-N-methylamino group),
    (11) —NRb8Rb9 wherein Rb8 and Rb9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    (12) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group), or
    (13) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group),
    • Rc is
  • (1) a hydrogen atom,
    (2) a halogen atom (particularly, a fluorine atom, a chlorine atom),
    (3) a methyl group,
    (4) —C(═O)—ORc1 wherein Rc1 is a hydrogen atom or a methyl group,
    (5) —ORc2 wherein Rc2 is a hydrogen atom, a methyl group or an ethyl group,
    • (6) —NH2, or
  • (7) —NRc5—C(═O)—Rc6 wherein Rc5 and Rc6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), particularly a hydrogen atom,
    • Rm is
  • (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E,
    (2) a C1-6 alkyl group substituted by a C6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (5) a C1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C1-6 alkyl group (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
    (6) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (7) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferably,
    (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′,
    (2) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (5) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, particularly,
    (1) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from
    (i) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (ii) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (iii) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (iv) —NRE12—C(═O)—RE13 wherein RE12 and RE13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (2) a C3-10 cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or
    (3) a C5-10 bridged cycloalkyl group (particularly, an adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    further particularly,
    (1) a C1-6 alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from
    (i) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and
    (ii) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (2) a C3-10 cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or
    (3) a C5-10 bridged cycloalkyl group (particularly, a 1-adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F,
    particularly,
  • Figure US20150329491A1-20151119-C00032
  • is a group represented by the following,
  • Figure US20150329491A1-20151119-C00033
  • Re is the same or different and each is a fluorine atom, a chlorine atom, a methyl group, or a hydroxymethyl group,
    n is an integer of 0, or 1 to 2, particularly 0.
  • As specifically preferable compounds of the compound represented by the formula [I], the following compounds can be mentioned.
    • 1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic acid dimethylamide (compound No. 153)
    • 1-[2-(5-hydroxy-5-trifluoromethyl-5H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one (compound No. 430)
    • 4-hydroxymethyl-2-(1-ethyl-1H-pyrazol-4-yl)-9-trifluoromethyl-9H-fluoren-9-ol (compound No. 629)
    • 2-[1-(2,2-dimethyl-propyl)-1H-pyrazol-4-yl]-4-hydroxymethyl-9-trifluoromethyl-9H-fluoren-9-ol (compound No. 660)
    • (−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid amide (compound No. 630)
    • 2-[1-(2,2-dimethyl-propyl)-1H-pyrazol-4-yl]-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid amide (compound No. 659)
    • 2-(1-cyclohexylmethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid amide (compound No. 667)
    • (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol (compound No. 595)
    • (+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid (compound No. 538)
    • (+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid (compound No. 539)
  • In addition, in the compound represented by the formula [I], various “isomers” are present. When an asymmetric carbon atom is present at the 9-position of the fluorene ring of the compound represented by the formula [I], enantiomers exist as a stereoisomer based thereon, and when an asymmetric carbon atom is further present in a substituent, diastereomers exist.
  • Specifically, an optical active form of the compound represented by the following chemical formulas and a mixture thereof are encompassed in the present invention.
  • Figure US20150329491A1-20151119-C00034
  • In addition, an optically active form of the compound represented by the following chemical formulas, which is a preferable embodiment of the compound of the present invention, and a mixture thereof are encompassed in the present invention.
  • Figure US20150329491A1-20151119-C00035
    Figure US20150329491A1-20151119-C00036
  • In addition, when E form and Z form exist as geometric isomers, and an axial chirality is present, stereoisomers based on these exist. In some cases, tautomers may exist. Therefore, all of these isomers and mixtures thereof are encompassed in the present invention.
  • As a compound represented by the formula [III], preferred is a compound represented by the formula [III-A].
  • As a compound represented by the formula [III-A], preferred is a compound wherein Rm is
  • (1) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′,
    (2) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (3) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F,
    (4) a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or
    (5) a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F.
  • In another embodiment, a specifically preferable compound of the compound represented by the formula [I] is the following compound.
  • Figure US20150329491A1-20151119-C00037
    Figure US20150329491A1-20151119-C00038
    Figure US20150329491A1-20151119-C00039
    Figure US20150329491A1-20151119-C00040
  • Particularly preferred is the following compound.
  • Figure US20150329491A1-20151119-C00041
    Figure US20150329491A1-20151119-C00042
    Figure US20150329491A1-20151119-C00043
  • A pharmaceutically acceptable salt of the compound represented by the formula [I] (hereinafter to be also referred to as the compound of the present invention) may be any salt as long as it forms a nontoxic salt with the compound of the present invention. Examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids and the like.
  • Examples of the salt with inorganic acid include a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • Examples of the salt with organic acid include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Examples of the salt with inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
  • Examples of the salt with organic base include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine and the like.
  • Examples of the salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
  • When a salt of the formula [I] is desired, each salt can be obtained by reacting a compound represented by the formula [I] with an inorganic base, organic base, inorganic acid, organic acid or amino acid according to a known method.
  • The “solvate” is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof wherein a molecule of the solvent is coordinated, and also includes hydrates. As the solvate, a pharmaceutically acceptable solvate is preferable and includes, for example, hydrate, ethanolate, dimethylsulfoxidate and the like of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof. Specific examples thereof include hemihydrate, monohydrate, dihydrate and monoethanolate of the compound represented by the formula [I], monohydrate of sodium salt, 2/3 ethanolate of dihydrochloride, and the like of the compound represented by the formula [I].
  • The solvate can be obtained according to a method known per se.
  • In addition, the compound represented by the formula [I] may be labeled with an isotope (e.g., 3H, 14C, 35S etc.).
  • The deuterium derivative wherein 1H of the compound represented by the formula [I] is substituted with 2H(D) is also encompassed in the compound represented by the formula [I].
  • As the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each of which is substantially purified, is preferable. More preferred is, a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each of which is purified to a purity of not less than 80%.
  • In the present invention, a prodrug of the compound represented by the formula [I] can also be a useful medicament. The “prodrug” is a derivative of the compound of the present invention having a chemically or metabolically degradable group which, after administration to the body, restores to the original compound by, for example, hydrolysis, solvolysis or decomposition under physiological conditions, and shows inherent efficacy. It is considered to include a noncovalent complex, and a salt. Prodrug is utilized for, for example, improvement of absorption on oral administration, or targeting to a target moiety.
  • Examples of the modified moiety include, in the compound of the present invention, a highly reactive functional group such as a hydroxyl group, a carboxyl group, an amino group and the like.
  • Specific examples of the hydroxyl-modifying group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, a fumaryl group, a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group and the like. In addition, sodium salt of 3-carboxybenzoyl group, 2-carboxyethylcarbonyl group and the like can be mentioned.
  • Specific examples of the carboxyl-modifying group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, a 1-(acetyloxy)ethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a 1-(isopropyloxycarbonyloxy)ethyl group, a 1-(cyclohexyloxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a phenyl group, an o-tolyl group, a morpholinoethyl group, an N,N-diethylcarbamoylmethyl group, a phthalidyl group and the like.
  • Specific examples of the amino-modifying group include a tert-butyl group, a docosanoyl group, a pivaloyloxymethyl group, an alanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a 3-methylthio-1-(acetylamino)propylcarbonyl group, a 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, a tetrahydrofuranyl group, a pyrrolidylmethyl group and the like.
  • Examples of the “pharmaceutical composition” include oral preparations such as tablet, capsule, granule, powder, troche, syrup, emulsion, suspension and the like, and parenteral agents such as external preparation, suppository, injection, eye drop, nasal preparation, pulmonary preparation and the like.
  • The pharmaceutical composition of the present invention is produced according to a method known in the art of pharmaceutical preparations, by mixing a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof with a suitable amount of at least one kind of pharmaceutically acceptable carrier and the like as appropriate. While the content of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dose and the like, it is, for example, 0.1 to 100 wt % of the whole composition.
  • Examples of the “pharmaceutically acceptable carrier” include various organic or inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, fluidizer, lubricant and the like for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffering agent, soothing agent and the like for liquid preparations. Where necessary, moreover, additives such as preservative, antioxidant, colorant, sweetening agent and the like are used.
  • Examples of the “excipient” include lactose, sucrose, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, gum arabic and the like.
  • Examples of the “disintegrant” include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
  • Examples of the “binder” include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
  • Examples of the “fluidizer” include light anhydrous silicic acid, magnesium stearate and the like.
  • Examples of the “lubricant” include magnesium stearate, calcium stearate, talc and the like.
  • Examples of the “solvent” include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the “solubilizing agents” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • Examples of the “suspending agent” include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate and the like.
  • Examples of the “isotonicity agent” include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
  • Examples of the “buffering agent” include sodium hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • Examples of the “soothing agent” include benzyl alcohol and the like.
  • Examples of the “preservative” include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • Examples of the “antioxidant” include sodium sulfite, ascorbic acid and the like.
  • Examples of the “colorant” include food colors (e.g., Food Color Red No. 2 or 3, Food Color yellow No. 4 or 5 etc.), β-carotene and the like.
  • Examples of the “sweetening agent” include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
  • The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., topical, rectal, intravenous administration etc.) to human as well as mammals other than human (e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog, swine, bovine, horse, sheep, monkey etc.). The dose varies depending on the subject of administration, disease, symptom, dosage form, administration route and the like. For example, the daily dose for oral administration to an adult patient (body weight: about 60 kg) is generally within the range of about 1 mg to 1 g, based on the compound of the present invention as the active ingredient. This amount can be administered in one to several portions.
  • The compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof has inhibitory activity against pyruvate dehydrogenase kinase (PDHK, particularly PDHK2), and can activate pyruvate dehydrogenase (PDH) effectively. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used as an active ingredient of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer. Furthermore, the compound can be used as an active ingredient of an agent for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), cerebral ischemia, cerebral apoplexy or pulmonary hypertension.
  • To “inhibit PDHK” means to specifically inhibit the function of PDHK and eliminate or attenuate the activity. To “inhibit PDHK”, human PDHK is preferably inhibited. As a “PDHK inhibitor”, preferred is a “human PDHK inhibitor”.
  • To “inhibit PDHK2” means to specifically inhibit the function of PDHK2 and eliminate or attenuate the activity. For example, it means to specifically inhibit the function as PDHK2 based on the conditions in the below-mentioned Experimental Example 1. To “inhibit PDHK2”, human PDHK2 is preferably inhibited. As a “PDHK2 inhibitor”, preferred is a “human PDHK2 inhibitor”.
  • To “activate PDH” means to activate PDH in a target organ (e.g., liver, skeletal muscle, adipose tissue, heart, brain) and the like, cancer or the like.
  • To “decrease blood glucose level” means to decrease the glucose concentration in blood (including in serum and plasma), preferably to decrease high blood glucose level, more preferably, to decrease the blood glucose level to normal level for human.
  • The above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination with one or a plurality of other medicaments (hereinafter to be also referred to as a concomitant drug) according to a method generally employed in the medical field (hereinafter to be referred to as combined use).
  • The administration period of the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a concomitant drug is not limited, and they may be administered to an administration subject as combination preparation, or the both preparations may be administered simultaneously or at given intervals. In addition, the pharmaceutical composition of the present invention and a concomitant drug may be used as a medicament in the form of a kit. The dose of the concomitant drug is similar to the clinically-employed dose and can be appropriately selected according to the subject of administration, disease, symptom, dosage form, administration route, administration time, combination and the like. The administration form of the concomitant drug is not particularly limited, and it only needs to be combined with the compound of the present invention or a salt thereof, or a solvate thereof.
  • Examples of the concomitant drug include an agent for the treatment and/or prophylaxis of diabetes and the like, and 1 to 3 agents therefrom and the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination.
  • Examples of the “agent for the treatment and/or prophylaxis of diabetes” include insulin preparation, sulfonylurea hypoglycemic agent and the like.
  • In the following, one example of the production method of the compound to be used for the embodiment of the present invention is explained. However, the production method of the compound of the present invention is not limited thereto.
  • Even if no directly corresponding disclosure is found in the following Production Methods, the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional group with deprotection in a subsequent step, subjecting a functional group as a precursor to each step, followed by conversion to a desired functional group at a suitable stage, changing the order of Production Methods and steps, and the like.
  • The treatment after reaction in each step may be conventional ones, where isolation and purification can be performed as necessary according to a method appropriately selected from conventional methods such as crystallization, recrystallization, distillation, partitioning, silica gel chromatography, preparative HPLC and the like, or a combination of those methods.
    • Production Method 1 (Production Method of a Compound Represented by the Formula [I])
  • Figure US20150329491A1-20151119-C00044
  • wherein each symbol is as defined above.
    • (Step 1)
  • Compound [Ia] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to allow trifluoromethylation to give trimethylsilyl ether of compound [1]. Then, the obtained trimethylsilyl ether is hydrolyzed to give compound [1] as a racemate.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide etc. and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride etc., and the like. Preferred is potassium carbonate or lithium acetate.
  • The reaction temperature of the trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time of the trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [Ia].
  • The amount of the catalyst of the trifluoromethylation reaction to be used is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [Ia].
  • Examples of the reagent to be used for the hydrolysis of trimethylsilyl ether include alkali metal fluorides such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride etc., and the like.
  • When trimethylsilyl ether is hydrolyzed, the reaction temperature is generally about −10 to 50° C., preferably about 0° C. to room temperature.
  • When trimethylsilyl ether is hydrolyzed, the reaction time is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • The amount of the reagent to be used for the hydrolysis of trimethylsilyl ether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Ia].
  • When optically active compound [I] is desired, the desired optically active compound [I] can be obtained by separating racemate according to preferential crystallization method, diastereomer method, optical resolution method using chiral stationary phase column and the like.
    • Production Method 2 (Production Method of a Compound Represented by the Formula [II] Wherein Yd is a Single Bond (Compound [IIo]))
  • Figure US20150329491A1-20151119-C00045
    Figure US20150329491A1-20151119-C00046
  • wherein
    “Hal1” is a halogen atom, preferably a bromine atom, a chlorine atom or an iodine atom;
    “Hal2” is a halogen atom, preferably a chlorine atom or a bromine atom;
    “RY1” and “RY2” are the same or different and each is a carboxyl-protecting group such as a C1-4 alkyl group (e.g., a methyl group, an ethyl group, t-butyl etc.), a benzyl group and the like;
    at least one of the substituents “RZ1” to “RZ3” of amine has an asymmetric center and a single steric configuration (e.g., (R)-1-phenylethyl-1-yl, (S)-1-phenylethyl-1-yl, (R)-1-(1-naphthyl)ethyl-1-yl, (S)-1-(1-naphthyl)ethyl-1-yl etc.), and the rest is, for example, a hydrogen atom, alkyl groups such as a methyl group, an ethyl group and the like, an optionally substituted aralkyl group such as a benzyl group and the like, and the like;
    “M” is a group including boron, zinc, tin or the like, for example, boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like;
    the substituent “RX” of the boron compound is, for example, a hydrogen atom, an alkyl group such as a methyl group and the like, or when it is “—B(ORX)2”, two RX, oxygen atoms and a boron atom bonded thereto in combination optionally form 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl or the like;
    “Rk0” is a substituent capable of conversion to “Rk” (e.g., (cyclo)alkyl group etc. substituted by carboxylic acid, carboxamide, alcohol etc.) by various functional group conversion reactions (e.g., (cyclo)alkyl group etc. substituted by ester, ether etc.);
    “*” is an asymmetric center;
    a compound having “*” is an optically active form;
    a compound having “(*)” is a racemate or an optically active form; and
    other symbols are as defined above.
    • (Step 10)
  • Compound [IIa] is reacted with compound [IIb] in a solvent in the presence of a metal catalyst and a base to give compound [IIc].
  • Here, M of compound [IIb] is a group containing boron, zinc, tin or the like. Examples thereof include boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like. Preferred are dialkoxyboron and boronic acid, and particularly preferred is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • Examples of the metal catalyst to be used for the reaction include those having palladium or nickel, and preferred are palladium, particularly preferably palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0).
  • The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIa].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetate such as sodium acetate and the like; organic bases such as triethylamine and the like, preferably tripotassium phosphate.
  • The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.
  • The amount of compound [IIb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIa].
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IIa].
    • (Step 11)
  • Compound [IId] can be obtained by subjecting compound [IIc] to ester hydrolysis in a solvent.
  • The ester hydrolysis may be performed under general conditions, for example, under alkaline conditions or acidic conditions.
  • When the hydrolysis is performed under alkaline conditions, compound [IIc] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like) per 1 mol of compound [IIc] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.
  • For reaction under acidic conditions, compound [IIc] is reacted in the presence of, for example, about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IIc] in, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
    • (Step 12)
  • Compound [IIe] can be obtained by cyclization reaction of compound [IId] in the presence of an acid without solvent or in a solvent.
  • Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like. The amount thereof to be used is generally about 1 mol to a large excess per 1 mol of compound [IId]. In addition, when a solvent is used, for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without a solvent or in methanesulfonic acid as a solvent.
  • The reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
    • (Step 13)
  • Compound [IIe] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to allow a trifluoromethylation reaction to give trimethylsilyl ether of compound [IIf], and the produced trimethylsilyl ether is hydrolyzed to give compound [IIf] as a racemate.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride etc., and the like. Preferred is potassium carbonate or lithium acetate.
  • The reaction temperature of the trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time of the trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IIe].
  • The amount of the catalyst for the trifluoromethylation reaction to be used is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IIe].
  • Examples of the reagent to be used for hydrolysis of trimethylsilyl ether include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salt such as tetrabutylammonium fluoride etc., and the like.
  • When trimethylsilyl ether is hydrolyzed, the reaction temperature is generally about −10 to 50° C., preferably about 0° C. to room temperature.
  • When trimethylsilyl ether is hydrolyzed, the reaction time is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • The amount of the reagent to be used for hydrolysis of trimethylsilyl ether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIe].
    • (Step 14)
  • As a method for obtaining optically active compound [IIf], a method comprising steps 14a-14e from compound [IIe] or compound [IIf] can be mentioned. By selecting an appropriate optically active amine for this method, (+) or (−) form of compound [IIf] can be produced.
    • (Step 14a)
  • Compound [IIg] wherein an acetic acid ester moiety is introduced can be obtained by trifluoromethylation reaction and hydrolysis of trimethylsilyl ether in the same manner as in Step 13, followed by reaction with halogenated acetic acid ester.
  • Examples of the halogen atom of halogenated acetic acid ester to be used include a chlorine atom, a bromine atom and an iodine atom. In addition, examples of the carboxyl-protecting group (RY2) include methyl, ethyl, t-butyl and the like. In this reaction, the halogenated acetic acid ester is preferably ethyl bromoacetate.
  • This acetic acid ester introduction reaction is performed by directly adding halogenated acetic acid ester to a mixture of the trifluoromethylation reaction product and the trimethylsilyl ether hydrolysis product.
  • The reaction temperature is generally about 0 to 50° C., preferably about 15 to 30° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1 hr to 5 hr.
  • The amount of the halogenated acetic acid ester to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIe].
  • (Step 14a-2)
  • Compound [IIg] wherein an acetic acid ester moiety is introduced can also be obtained by reacting isolated compound [IIf] with halogenated acetic acid ester. The reaction for introducing acetic acid ester is performed by reacting compound [IIf] with halogenated acetic acid ester in the presence of 1-5 equivalents (preferably, 2 equivalents) of a base (e.g., potassium carbonate etc.) at 0° C.-80° C. (preferably, room temperature) for 1-24 hr (preferably, overnight).
    • (Step 14b)
  • Compound [IIh] can be obtained by general ester hydrolysis of compound [IIg] in the same manner as in Step 11 in a solvent.
    • (Step 14c)
  • Compound [IIi], which is a salt of a single diastereomer, can be obtained as a solid by mixing compound [IIh] with an optically active amine in a solvent.
  • Examples of the optically active amine to be used include (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine and the like.
  • The amount of the optically active amine to be used is generally about 0.1 to 1 mol, preferably about 0.4 to 0.6 mol, per 1 mol of compound [IIh].
  • Examples of the solvent to be used include ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone and the like; ester solvents such as ethyl acetate and the like; ether solvents such as isopropyl ether etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is methyl ethyl ketone, methyl isobutyl ketone.
  • The temperature for mixing is generally about 0 to 100° C., preferably about 20 to 70° C.
  • The time for the mixing is generally about 1 hr to 10 days, preferably about 1 to 5 days.
    • (Step 14d)
  • Compound [IIj] can be obtained by treating compound [IIi] with an acidic aqueous solution in a solvent to liberate carboxylic acid.
  • Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.
  • Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.
  • The treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The treatment time is generally about 1 min to 2 hr.
  • The amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IIi].
    • (Step 14e)
  • Optically active compound [IIf] can be obtained by reacting compound [IIj] in a solvent.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide and the like; alcohol solvents such as t-butyl alcohol and the like; ether solvents such as dioxane and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of dimethylformamide and t-butyl alcohol.
  • The reagent to be used for the reaction is preferably diphenylphosphoryl azide, and the base to be used for the reaction is a tertiary amine such as triethylamine, N-ethyldiisopropylamine and the like.
  • The reaction temperature is generally about 0 to 150° C., preferably about 0 to 100° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 30 min to 5 hr.
  • The amount of diphenylphosphoryl azide to be used is generally about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].
  • The amount of the base to be used is generally about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].
    • (Step 15)
  • By treating racemic compound [IIf] using a chiral stationary phase column and the like, a desired optically active compound [IIf] can be separated from the other isomer.
    • (Step 16)
  • Compound [IIm] can be obtained by introducing Rk0 into compound [IIk] in a solvent in the presence of a base such as potassium carbonate, cesium fluoride and the like.
  • For example, when Rk0 is a (cyclo)alkyl group, compound [IIm] can be obtained by reacting compound [IIk] with (cyclo)alkyl halide such as (cyclo)alkyl iodide and (cyclo)alkyl bromide, (cyclo)alkyl sulfonic acid ester such as (cyclo)alkyl tosylate, or an α,β-unsaturated carbonyl compound such as acrylic acid ester and the like in amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.
    • (Step 17)
  • Compound [IIn] can be obtained by reacting compound [IIf] in the form of a racemate or an optically active form with compound [IIm] in a solvent in the presence of a metal catalyst, a ligand and a base.
  • Boronic acid moiety of compound [IIm] is boronic acid per se, or boronic acid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • The metal catalyst to be used for the reaction is palladium such as palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), dichlorobis(triphenylphosphine)palladium(II) and tetrakis(triphenylphosphine)palladium(0), with preference given to palladium(II) acetate.
  • The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIf].
  • The ligand to be used for the reaction is phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, with preference given to 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
  • Examples of the base to be used for the reaction include alkali metal phosphate such as tripotassium phosphate and the like; alkali metal carbonate such as sodium carbonate and the like; alkali metal hydrogencarbonate such as sodium hydrogencarbonate and the like; alkali metal acetate such as sodium acetate and the like; organic base such as triethylamine and the like, with preference given to tripotassium phosphate.
  • The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • The amount of compound [IIm] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIf].
  • The amount of the ligand to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the metal catalyst.
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IIf].
    • (Step 18)
  • The object compound [IIo] is obtained from compound [IIn] by general functional group conversion or deprotection.
  • For example, when compound [IIo] contains a hydroxyl group, the compound can be converted by removal of the hydroxyl-protecting group or reduction of an ester thereof, which is a precursor.
  • For example, in the case of the former, when a hydroxyl group is protected by a benzyl group, the compound can be converted by catalytic hydrogenation reaction. When the hydroxyl group is protected by a silyl group such as t-butyldimethylsilyl group and the like, the compound can be converted by deprotection with tetrabutylammonium fluoride or the like. When diol is protected by a ketal such as acetonide and the like, the compound can be converted by deprotection with acid such as pyridinium p-toluenesulfonate and the like. In the case of the latter, for example, the compound can be converted by a hydride reduction reaction using sodium borohydride, lithium aluminum hydride or the like in a single solvent such as tetrahydrofuran, tetrahydropyran, water and the like or a mixture thereof. Alternatively, conversion is possible by converting ester to carboxylic acid under general hydrolysis conditions, and reducing the acid with a reducing agent such as borane and the like.
  • Alternatively, compound [IIo] having a hydroxyl group can also be obtained by newly introducing a hydroxyl group. For example, a hydroxymethyl group can be introduced by reacting compound [IIn] having an ester with paraformaldehyde in the presence of a base such as tetrabutylammonium fluoride and the like. Alternatively, compound [IIo] having a hydroxyl group can also be obtained by introducing formyl group by reacting compound [IIn] having an ester with formic acid ester such as ethyl formate, t-butyl formate and the like in the presence of a base such as sodium hydride, potassium t-butoxide and the like, followed by hydride reduction.
  • When compound [IIo] has a carboxylic acid, compound [IIo] can be obtained by reacting an ester of compound [IIn] in the same manner as in Step 11 under general hydrolysis conditions. For example, when compound [IIn] is t-butyl ester, it can be converted to compound [IIo] under acidic conditions such as trifluoroacetic acid and the like.
  • When compound [IIo] has a tetrazole ring, the tetrazole ring can be introduced by reacting a cyano group with trimethylsilylazide or the like. A cyano group can be introduced by converting carboxylic acid and the like to an amide and dehydrating the amide with trifluoroacetic anhydride and the like, or by the use of an alkylating agent having a cyano group and the like.
  • When compound [IIo] has a sulfonamide group, a sulfonamide group can be introduced by amidating an amino group with sulfonyl chloride or the like. The amino group can be introduced by subjecting carboxylic acid to a rearrangement reaction, reacting alkyl halide with an amino source such as phthalimide potassium salt or the like.
  • The case wherein ring U is pyrazole in the step of obtaining compound [IIo] from compound [IIn] by a functional group conversion is exemplified below.
  • Figure US20150329491A1-20151119-C00047
    Figure US20150329491A1-20151119-C00048
  • When Yd is —C(═O)— bond, the compound can be synthesized by an amidation reaction of the corresponding carboxylic acid or an activated derivative thereof with cyclic amine and the like, a reaction with a cyclic organometallic reagent or the like.
  • For example, various derivatives can be synthesized by the following step.
  • Figure US20150329491A1-20151119-C00049
  • wherein each symbol is as defined above.
    • Production Method 3 (Production Method of a Compound Represented by the Formula [IV] Wherein Yb is a Single Bond (Compound [IVn]))
  • Figure US20150329491A1-20151119-C00050
    Figure US20150329491A1-20151119-C00051
  • wherein each symbol is as defined above.
    • (Step 20)
  • Compound [IVc] can be obtained by reacting compound [IVa] with compound [IVb] in a solvent in the presence of a metal catalyst and a base.
  • Here, M in compound [IVb] is a group containing boron, zinc, tin or the like and, for example, boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like can be mentioned. It is preferably dialkoxyboron or boronic acid, particularly preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • A metal catalyst to be used for the reaction is one containing palladium or nickel. Preferred is palladium, particularly preferably palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0).
  • The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVa].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like; organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.
  • The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.
  • The amount of compound [IVb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVa].
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IVa].
    • (Step 21)
  • Compound [IVd] can be obtained by subjecting compound [IVc] to ester hydrolysis in a solvent.
  • Ester hydrolysis can be performed under general conditions and, for example, under alkaline conditions or acidic conditions.
  • When it is performed under alkaline conditions, compound [IVc] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like etc.) per 1 mol of compound [IVc] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.
  • When it is performed under acidic conditions, compound [IVc] is reacted, for example, in the presence of about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVc] in the presence of, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
    • (Step 22)
  • Compound [IVe] can be obtained by reacting compound [IVd] to cyclization in the presence of an acid with or without a solvent.
  • Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like. The amount thereof to be used is generally about 1 mol to a large excess, per 1 mol of compound [IVd]. When a solvent is used, for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without solvent or in methanesulfonic acid as a solvent.
  • The reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
    • (Step 23)
  • Compound [IVe] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to perform a trifluoromethylation reaction to give a trimethylsilyl ether of compound [IVf], then the resulting trimethylsilyl ether is hydrolyzed to give compound [IVf] as a racemate.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like and the like, with preference given to potassium carbonate or lithium acetate.
  • The reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IVe].
  • The amount of the catalyst to be used for the trifluoromethylation reaction is generally for about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IVe].
  • Examples of the reagent to be used for trimethylsilyl ether hydrolysis include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like and the like.
  • The reaction temperature when trimethylsilyl ether is hydrolyzed is generally about −10 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • The amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Ive].
    • (Step 24)
  • Compound [IVg] can be obtained by reacting compound [IVf] in a solvent in the presence of an oxidant.
  • Examples of the solvent to be used for the reaction include water, pyridine, t-butyl alcohol, acetone, acetic acid, sulfuric acid and the like. They can be used alone or in a mixture with water. Preferable solvent for this reaction is a mixed solvent of water and pyridine.
  • Examples of the oxidant to be used for the reaction include permanganates such as potassium permanganate and the like, chromates such as sodium chromate and the like and the like, with preference given to potassium permanganate.
  • The reaction temperature is generally about 0 to 120° C., preferably 50 to 110° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1 to 8 hr.
  • The amount of potassium permanganate to be used is generally about 2 to 20 mol, preferably about 2 to 10 mol, per 1 mol of compound [IVf].
    • (Step 25)
  • As a method for obtaining optically active compound [IVg], a method includes Steps 25a-25b from a racemic compound [IVg]. In this method, (+) or (−) form of compound [IVg] can be produced by appropriately selecting an optically active amine.
    • (Step 25a)
  • Compound [IVh], which is a salt of single diastereomer, can be obtained as a solid by mixing compound [IVg] with optically active amine in a solvent.
  • Examples of the optically active amine to be used include (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine and the like.
  • The amount of the optically active amine to be used is generally about 0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound [IVg].
  • Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as isopropyl ether and the like; ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is ethyl acetate.
  • The temperature for mixing is generally about 0 to 100° C., preferably about 15 to 30° C.
  • The time for mixing is generally about 1 hr to 10 days, preferably about 1 day to 3 days.
    • (Step 25b)
  • Optically active compound [IVg] can be obtained by treating compound [IVh] with acidic aqueous solution in a solvent, and liberating carboxylic acid.
  • Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.
  • Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.
  • The treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The treatment time is generally about 1 min to 2 hr.
  • The amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IVh].
    • (Step 26)
  • By treating racemic compound [IVg] using a chiral stationary phase column and the like, a desired optically active compound [IVg] can be separated from the other isomer.
  • The chiral stationary phase column to be used is, for example, Daicel, CHIRALCEL OD-RH.
  • Examples of the solvent for separation include a mixed solution of acetonitrile and phosphate buffer wherein the composition ratio thereof is constant or varied.
  • For separation, a conventional high performance liquid chromatography apparatus is used, which is performed while monitoring with a detector such as ultraviolet absorption and the like.
    • (Step 27)
  • Compound [IVk] can be obtained by introducing Rj into compound [IVj] in a solvent in the presence of a base such as potassium carbonate and the like.
  • For example, when Rj is a (cyclo)alkyl group, compound [IVk] can be obtained by reacting compound [IVj] with (cyclo)alkyl halide such as (cyclo)alkyl iodide, (cyclo)alkyl sulfonic acid ester such as (cyclo)alkyl tosylate or the like in amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.
    • (Step 28)
  • Compound [IVm] can be obtained by reacting compound [IVg] in the form of a racemate or an optically active form with compound [IVk] in a solvent in the presence of a metal catalyst, a ligand and a base.
  • Boronic acid moiety of compound [IVk] is boronic acid per se, or boronic acid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of dioxane and water.
  • The metal catalyst to be used for the reaction is palladium, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), with preference given to palladium(II) acetate.
  • The amount of the metal catalyst to be used is generally for about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVg].
  • The ligand to be used for the reaction is phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like. Preferred is 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetate such as sodium acetate and the like, with preference given to tripotassium phosphate.
  • The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110°.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • The amount of compound [IVk] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVg].
  • The amount of the ligand to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the metal catalyst.
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVg].
    • (Step 29)
  • The object compound [IVn] is obtained from compound [IVm] by general functional group conversion or deprotection.
  • For example, when compound [IVn] contains carboxamide, the compound can be obtained by reacting carboxylic acid with amine to allow amidation with, for example, a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like in the presence of 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like. In this case, carboxylic acid may be converted in advance to acid chloride, mixed acid anhydride or the like, and reacted with amine to allow amidation, whereby compound [IVn] containing carboxamide can be obtained.
  • When compound [IVn] has an ester, a general esterification reaction with alcohol needs to be performed. For example, carboxylic acid may be converted in advance to an acid chloride, and reacted with alcohol in the presence of a base such as pyridine and the like without solvent or in chloroform, whereby compound [IVn] having an ester can be obtained. Compound [IVn] having an ester can also be obtained by reacting carboxylic acid with alkyl halide in the presence of a base such as potassium carbonate in, for example, dimethylformamide.
  • When compound [IVn] contains a hydroxyl group, it can be obtained by reduction of carboxylic acid or a reaction with an organiometalic reagent. In the case of the former, for example, compound [IVn] containing a hydroxyl group can be obtained by performing a hydride reduction reaction using borane, lithium aluminum hydride and the like in a single or mixed solvent of ethyl ether, tetrahydrofuran, tetrahydropyran and the like.
  • When Yb is an amine bond compound [IVn] wherein Yb is an amine bond can be synthesized by subjecting compound [IVg] to a condensation reaction with amine compound or the like in the presence of a catalyst such as palladium and the like.
  • When Yb is alkanediyl, compound [IVn] wherein Yb is alkanediyl can be synthesized by subjecting compound [IVg] to a condensation reaction with an organic zinc compound and the like in the presence of a catalyst such as palladium and the like.
  • When Yb is alkenediyl, compound [IVn] wherein Yb is alkenediyl can be synthesized by subjecting compound [IVg] to a condensation reaction with an alkenylboron compound and the like in the presence of a catalyst such as palladium and the like.
    • Production Method 4 (Production Method of a Compound Represented by the Formula [IV] Wherein Yb is —C(═O)— Bond (Compound [IVz]))
  • Figure US20150329491A1-20151119-C00052
    Figure US20150329491A1-20151119-C00053
  • wherein
    “RY3” and “RY4” are the same or different and each is a carboxyl-protecting group such as a C1-4 alkyl group (e.g., a methyl group, an ethyl group, a t-butyl group etc.), a benzyl group and the like;
    “Rj0” is a substituent (e.g., a carboxyl group etc.) that can be converted to “Rj” (e.g., a carbamoyl group etc.) by various functional group conversion reactions, and
    other symbols are as defined above.
    • (Step 30)
  • Compound [IVp] can be obtained by reacting compound [IVo] with compound [IVb] in a solvent, in the presence of a metal catalyst and a base.
  • Here, M of compound [IVb] is a group containing boron, zinc, tin or the like. Examples thereof include boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like. Preferred are dialkoxyboron and boronic acid, and particularly preferred is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.
  • Examples of the metal catalyst to be used for the reaction include those having palladium or nickel, and preferred are palladium, and particularly preferred are palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0).
  • The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVo].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like; organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.
  • The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110°.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.
  • The amount of compound [IVb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVo].
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IVo].
    • (Step 31)
  • Compound [IVq] can be obtained by subjecting compound [IVp] to ester hydrolysis in a solvent.
  • The ester hydrolysis may be performed under general conditions, for example, under alkaline conditions or acidic conditions.
  • When the hydrolysis is performed under alkaline conditions, compound [IVp] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like) per 1 mol of compound [IVp] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.
  • For reaction under acidic conditions, compound [IVp] is reacted in the presence of, for example, about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVp] in, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.
    • (Step 32)
  • Compound [IVr] can be obtained by cyclization reaction of compound [IVq] in the presence of an acid without solvent or in a solvent.
  • Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like. The amount thereof to be used is generally about 1 mol to a large excess per 1 mol of compound [IVq]. In addition, when a solvent is used, for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without a solvent or in methanesulfonic acid as a solvent.
  • The reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
    • (Step 33)
  • Compound [IVs] can be obtained by esterification reaction of compound [IVr] with alkyl halide in a solvent in the presence of a base.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like; dimethyl sulfoxide; water and the like. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the base to be used for the reaction include alkali metal carbonates such as potassium carbonate and the like, alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides such as sodium hydroxide and the like, and the like; with preference given to potassium carbonate.
  • Examples of the halogen of the alkyl halide to be used for the reaction include iodine, bromine and the like, and examples of the alkyl include methyl, ethyl and the like. Preferred for this step is methyl iodide.
  • The reaction temperature is generally about 0 to 100° C., preferably about 0 to 80° C.
  • The reaction time is generally about 10 min to 1 day, preferably about 30 min to 12 hr.
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVr].
  • The amount of the alkyl halide to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVr].
    • (Step 34)
  • Compound [IVs] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to perform a trifluoromethylation reaction to give a trimethylsilyl ether of compound [IVt], then the resulting trimethylsilyl ether is hydrolyzed to give compound [IVt] as a racemate.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like, and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like; and the like, with preference given to potassium carbonate and lithium acetate.
  • The reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IVs].
  • The amount of the catalyst to be used for the trifluoromethylation reaction is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IVs].
  • Examples of the reagent to be used for the trimethylsilyl ether hydrolysis include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like; and the like.
  • The reaction temperature when trimethylsilyl ether is hydrolyzed is generally about −10 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • The amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVs].
    • (Step 35)
  • Compound [IVu] can be obtained by subjecting compound [IVt] to ester hydrolysis in a solvent under alkaline conditions.
  • Examples of the solvent to be used for the reaction include water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvents for this reaction is a mixed solvent of water, methanol and tetrahydrofuran.
  • Examples of the alkali to be used for the reaction include alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, and the like, with preference given to sodium hydroxide.
  • The reaction temperature is generally about 0 to 120° C., preferably about 0 to 90° C.
  • The reaction time is generally about 10 min to 1 day, preferably about 30 min to 12 hr.
  • The amount of the alkali to be used is generally about 1 mol to large excess, preferably about 1 to 10 mol, per 1 mol of compound [IVt].
    • (Step 36)
  • As a method for obtaining optically active compound [IVu], a method includes Steps 36a-36b from a racemic compound [IVu]. In this method, (+) or (−) form of compound [IVu] can be produced by appropriately selecting an optically active amine.
    • (Step 36a)
  • Compound [IVv], which is a salt of single diastereomer, can be obtained as a solid by mixing compound [IVu] with an optically active amine in a solvent.
  • Examples of the optically active amine to be used include (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine and the like.
  • The amount of the optically active amine to be used is generally about 0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound [IVu].
  • Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is ethyl acetate.
  • The temperature for mixing is generally about 0 to 100° C., preferably about 15 to 80° C.
  • The time for mixing is generally about 1 hr to 10 days, preferably about 1 to 12 hr.
    • (Step 36b)
  • Optically active compound [IVu] can be obtained by treating compound [IVv] with acidic aqueous solution in a solvent, and liberating carboxylic acid.
  • Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.
  • Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.
  • The treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The treatment time is generally about 1 min to 2 hr.
  • The amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IVv].
    • (Step 37)
  • By treating racemic compound [IVu] using a chiral stationary phase column and the like, a desired optically active compound [IVu] can be separated from the other isomer.
  • The chiral stationary phase column to be used is, for example, Daicel, CHIRALCEL OD-RH.
  • Examples of the solvent for separation include a mixed solution of acetonitrile and phosphate buffer wherein the composition ratio thereof is constant or varied.
  • For separation, a conventional high performance liquid chromatography apparatus is used, which is performed while monitoring with a detector such as ultraviolet absorption and the like.
    • (Step 38)
  • Compound [IVy] can be obtained by converting a precursor in Rj0 of compound [IVx] to a functional group in Rj of compound [Ivy].
  • For example, when Rj contains amide, compound [IVy] having amide in Rj can be obtained by amidation reaction of compound [IVx] having carboxylic acid for Rj0 with amine in the presence of a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like and 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like.
  • When a functional group influenced by conversion of a precursor in Rj0 of compound [IVx] to a functional group in Rj of compound [Ivy] is present in other part of compound [IVx], a protecting group may be introduced as appropriate. For example, when an amino group is present in other part during production of compound [IVy] having amide in Rj by amidation of compound [IVx] having carboxylic acid for Rj0, a protecting group such as t-butyloxycarbonyl group, benzyloxycarbonyl group and the like is introduced into the amino group by a conventional method, a desired amidation reaction is performed, and then deprotection is performed by a general method.
    • (Step 39)
  • Compound [IVz] can be obtained by reacting compound [IVu], which is a racemate or an optically active form, with compound [IVy].
  • When compound [IVy] is cyclic amine, compound [IVz] can be obtained by general amidation reaction. For example, compound [IVu] and compound [IVy] are reacted in a solvent in the presence of a condensation agent. Examples of the condensation agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the copresence of 1-hydroxybenzotriazole hydrate and the like, and examples of the solvent include dimethylformamide, chloroform and the like.
  • Alternatively, compound [IVu], which is a racemate or an optically active form, may be converted in advance to acid chloride, mixed acid anhydride or the like and reacted with compound [IVy], whereby compound [IVz] can be obtained.
  • In addition, compound [IVz] is obtained by reacting compound [IVy] with an organic base such as LDA and the like, and reacting the resultant with compound [IVu] or, for example, an amide compound thereof with N,O-dimethylhydroxyamine or the like.
  • When Yb is an ether bond etc., compound [IVz] wherein Yb is an ether bond etc. can be synthesized by subjecting the corresponding phenol compound to reactions such as Mitsunobu reaction, alkylation reaction with alkyl halide or alkyl sulfonate, and the like.
  • For example, various derivatives can be synthesized by the following steps.
  • Figure US20150329491A1-20151119-C00054
    Figure US20150329491A1-20151119-C00055
  • wherein
    “Po” is a hydroxyl-protecting group (e.g., a methyl group etc.); and
    other symbols are as defined above.
    • Production Method 5 (Production Method of a Compound Represented by the Formula [I] Wherein Xd is a Nitrogen Atom (Compound [V]))
  • Figure US20150329491A1-20151119-C00056
    Figure US20150329491A1-20151119-C00057
  • wherein
    “Rb00” is a substituent (e.g., a hydroxy group etc.) that can be converted to “Rb0” (e.g., a methoxy group etc.) by various functional group conversion reactions;
    “Rb0” is a substituent (e.g., a methoxy group etc.) that can be converted to “Rb” (e.g., carboxamide, an alkoxy group substituted by lactam and the like, an alkyl group etc.) by various functional group conversion reactions; and
    other symbols are as defined above.
    • (Step 41)
  • When a functional group influenced by the reaction in the next Step 42 is present in compound [Va], a protecting group may be introduced into the functional group as appropriate to give compound [Vb].
  • For example, when the functional group influenced by the reaction is a hydroxyl group, compound [Va] is subjected to alkylation reaction with an alkylating agent in a solvent in the presence of a base to give compound [Vb].
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide and the like; ether solvents such as tetrahydrofuran and the like; dimethylsulfoxide and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the alkylating agent to be used for the reaction include alkyl halide such as methyl iodide and the like; alkyl sulfonates such as ethyl tosylate and the like; sulfuric acid esters such as methyl sulfate and the like; and the like, with preference given to methyl iodide.
  • Examples of the base to be used for the reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides such as sodium hydroxide and the like; and the like, with preference given to potassium carbonate.
  • The reaction temperature is generally about 0 to 120° C., preferably about 0 to 80° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1 hr to 1 day.
  • The amount of the alkylating agent to be used is generally about 1 to 3 mol, preferably about 1 to 2 mol, per 1 mol of compound [Va].
  • The amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound [Va].
    • (Step 42)
  • Compound [Vd] can be obtained by reacting compound [Vb] with compound [Vc] in a solvent in the presence of a metal catalyst and a base.
  • The boronic acid moiety of compound [Vc] is boronic acid per se, or boronic acid ester, preferably boronic acid per se.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of so toluene and water.
  • Examples of the metal catalyst to be used for the reaction include one containing palladium. Particularly preferred is 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride.
  • The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [Vb].
  • Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like, with preference given to tripotassium phosphate.
  • The reaction temperature is generally about room temperature to 120° C., preferably about 70 to 110° C.
  • The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.
  • The amount of compound [Vc] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Vb].
  • The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [Vb].
    • (Step 43)
  • Compound [Ve] can be obtained by cyclization reaction of compound [Vd] in a solvent in the presence of a base.
  • Examples of the solvent to be used for the reaction include hydrocarbon solvents such as n-hexane and the like; ether solvents such as tetrahydrofuran and the like; amide solvents such as N-methylpyrrolidone and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is tetrahydrofuran.
  • Examples of the base to be used for the reaction include amide bases such as lithium N,N-diisopropylamide, lithium hexamethyldisilazide and the like; organometallics such as butyllithium and the like; and the like, with preference given to lithium N,N-diisopropylamide.
  • The reaction temperature is generally about −78 to 100° C., preferably about −10 to 50° C.
  • The reaction time is generally about 10 min to 1 day, preferably about 10 min to 3 hr.
  • The amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound [Vd].
    • (Step 44)
  • Compound [Vf] is obtained from compound [Ve] by general functional group conversion or deprotection.
  • For example, when Rb is a (substituted) alkoxy group and Rb00 of compound [Va] is a hydroxyl group which is subjected to alkyl group protection in the earlier Step 41, compound [Vf] wherein Rb is a (substituted) alkoxy group can be obtained by deprotection to regenerate the hydroxyl group according to a conventional method, for example, by fusing compound [Ve] and pyridinium chloride and the like and, alkylation by, for example, Mitsunobu reaction and the like.
  • When Rb is a (substituted) alkyl group and Rb00 of compound [Va] is a hydroxyl group which is subjected to alkyl group protection in the earlier Step 41, compound [Vf] wherein Rb is a (substituted) alkyl group can be obtained by deprotection according to a conventional method to regenerate the hydroxyl group, conversion to trifluoromethanesulfonate, a reaction of the trifluoromethanesulfonate compound with a terminal acetylene compound or an alkenyl metal compound such as an alkenylboron compound and the like in the presence of a metal catalyst such as palladium and the like, and a hydrogenation reaction.
    • (Step 45)
  • Compound [V] can be obtained as a racemate by reacting compound [Vf] with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to cause trifluoromethylation reaction, whereby a trimethylsilyl ether of compound [V] is obtained, then hydrolyzing the resulting trimethylsilyl ether.
  • Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like, and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.
  • Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like; and the like, with preference given to potassium carbonate and lithium acetate.
  • The reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.
  • The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [Vf].
  • The amount of the catalyst to be used for the trifluoromethylation reaction is generally for about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [Vf].
  • Examples of the reagent to be used for the trimethylsilyl ether hydrolysis include alkali metal fluorides such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like; and the like.
  • The reaction temperature when trimethylsilyl ether is hydrolyzed is generally about −10 to 50° C., preferably about 0° C. to room temperature.
  • The reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.
  • The amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Vf].
  • As for compound [V], a desired optically active compound [V] can be separated from the other isomer by a preferential crystallization method, a diastereomer method, an optical resolution method using a chiral stationary phase column, or the like.
    • EXAMPLES
  • The production of the compound of the present invention is specifically explained by Examples. However, the present invention is not limited by these Examples.
  • The room temperature in the Examples means 1-40° C.
    • (Derivatization Method a for Determination of Optical Purity)
  • A solid (0.002-0.003 g) to be analyzed is shaken with ethyl acetate (0.1 ml) and 1N hydrochloric acid (0.1 ml), the mixture was stood still to separate layers. The upper layer (0.010 ml) was added to the following preparation solution (0.1 ml), and the mixture was shaken at 50° C. for 30 min. The obtained mixture was analyzed by HPLC.
    • (Preparation Solution)
  • Dimethylformamide was added to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.191 g) and 1-hydroxybenzotriazole hydrate (0.153 g) to a total amount of 10 ml. (S)-(−)-1-(1-Naphthyl)-ethylamine (0.258 ml) was added to the mixture to give the title preparation solution.
    • (10 mM Phosphate Buffer (pH 2.0))
  • Potassium dihydrogen phosphate (4.08 g) was dissolved in water (3000 mL) and adjusted to pH 2.0 with phosphoric acid to give the title buffer.
    • HPLC Analysis Conditions Analysis Condition 1
  • instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence
    column: Daicel CHIRALCEL OD-RH 4.6 mmφ×150 mm
    column temperature: 40° C.
    mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile
    the composition (SOLUTION A:SOLUTION B) of the mobile phase was changed linearly from 50:50 to 20:80 over 20 min, thereafter, kept constant at 20:80 for 5 min.
    flow rate: 0.5 ml/min
    detection: UV (220 nm)
    • Analysis Condition 2
  • instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence
    column: Daicel CHIRALCEL OD-RH 4.6 mmφ×150 mm
    column temperature: 40° C.
    mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile
    the composition (SOLUTION A:SOLUTION B) of the mobile phase was changed linearly from 70:30 to 40:60 over 20 min, thereafter, kept constant at 40:60 for 5 min.
    flow rate: 0.5 ml/min
    detection: UV (220 nm)
    • Analysis Condition 3
  • instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence
    column: Daicel CHIRALCEL OJ-RH 4.6 mmφ×150 mm
    column temperature: 40° C.
    mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile
    the composition (SOLUTION A:SOLUTION B) of the mobile phase was kept constant at 70:30 for 25 min, thereafter, at 40:60 for 10 min.
    flow rate: 0.5 ml/min
    detection: UV (294 nm)
    • Analysis Condition 4
  • instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence
    column: Daicel CHIRALPAK AD-RH 4.6 mmφ×150 mm
    column temperature: 40° C.
    mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile
    the composition (SOLUTION A:SOLUTION B) of the mobile phase was changed linearly from 70:30 to 50:50 over 20 min, thereafter, kept constant at 50:50 for 5 min.
    flow rate: 0.5 ml/min
    detection: UV (220 nm)
    • Example 1 Synthesis of (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (compound No. 526) Step 1
  • 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester
  • Figure US20150329491A1-20151119-C00058
  • To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification.
  • 1H-NMR (CDCl3) δ: 8.06-8.02 (1H, m), 7.60-7.54 (1H, m), 7.52-7.45 (1H, m), 7.27-7.16 (3H, m), 7.06-7.00 (1H, m), 4.18-4.09 (2H, m), 1.11-1.06 (3H, m).
    • Step 2
  • 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid
  • Figure US20150329491A1-20151119-C00059
  • To a mixture of ethanol (179 ml) and 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester (41.8 g) was added 2N aqueous sodium hydroxide solution (179 ml), and the mixture was stirred in an oil bath at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (2.5 g) was added and the mixture was stirred for 2.5 hr. The activated carbon was filtered off through celite and washed with 50 v/v % ethanol-water (100 ml). The filtrate was acidified with 2N hydrochloric acid (196 ml). Then, to this mixture was added water (33 ml) and the mixture was stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was air-dried for 2 hr, and dried under reduced pressure at 60° C. to give the title compound (28.6 g, 2 steps 93%).
  • 1H-NMR (CDCl3) δ: 8.12-8.08 (1H, m), 7.64-7.59 (1H, m), 7.52-7.47 (1H, m), 7.27-7.24 (1H, m), 7.22-7.16 (2H, m), 7.05-7.00 (1H, m).
    • Step 3
  • 4-chloro-2-fluoro-fluoren-9-one
  • Figure US20150329491A1-20151119-C00060
  • To a mixture of phosphorus pentoxide (133 g) and methanesulfonic acid (1300 ml) was added 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid (132.9 g), and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was ice-cooled, water (1300 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was washed with water (300 ml). The solid was mixed with 50 v/v % ethanol-water (1300 ml), and the slurry was stirred at room temperature for 1.5 hr, and filtered. The obtained solid was washed with 50 v/v % ethanol-water (200 ml), air-dried for 3 hr, and dried under reduced pressure at 60° C. to give the title compound (121.6 g, 99%).
  • 1H-NMR (CDCl3) δ: 8.13-8.10 (1H, m), 7.72-7.69 (1H, m), 7.57-7.53 (1H, m), 7.36-7.30 (2H, m), 7.20-7.17 (1H, m).
    • Step 4
  • (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid ethyl ester
  • Figure US20150329491A1-20151119-C00061
  • To a mixture of dimethylformamide (1000 ml) and 4-chloro-2-fluoro-fluoren-9-one (204 g) was added potassium carbonate (36.4 g), and the mixture was stirred in a water bath. To this mixture was added dropwise trimethyl(trifluoromethyl)silane (156 ml) over 30 min, and the mixture was further stirred at room temperature for 30 min. To the reaction mixture was added cesium fluoride (173 g), ethyl bromoacetate (75 ml) was added dropwise over 20 min, and the mixture was stirred at room temperature. Water (1000 ml) was added to the reaction mixture, and the mixture was placed in a separatory funnel, and extracted with ethyl acetate (1000 ml). The organic layer was washed twice with brine (water:saturated brine=4:1, 1000 ml) and once with saturated brine (500 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (360 g). The obtained residue was directly used for the next reaction without further purification.
  • 1H-NMR (CDCl3) δ: 8.30-8.27 (1H, m), 7.73-7.69 (1H, m), 7.57-7.52 (1H, m), 7.43-7.37 (2H, m), 7.25-7.21 (1H, m), 4.11 (2H, q, J=7.1 Hz), 3.60 (1H, d, J=15.5 Hz), 3.53 (1H, d, J=15.3 Hz), 1.19 (3H, t, J=7.2 Hz).
    • Step 5
  • (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid
  • Figure US20150329491A1-20151119-C00062
  • To a mixture of ethanol (440 ml) and (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid ethyl ester (360 g) was added 2N aqueous sodium hydroxide solution (877 ml), and the mixture was stirred at 80° C. for 3.5 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off through celite, and washed with water (500 ml) and ethanol (60 ml). Water (120 ml) was added to the filtrate and the mixture was ice-cooled, and formic acid (199 ml) was added dropwise. This suspension was stirred at room temperature overnight, and filtered. The obtained solid was washed with 25 v/v % ethanol-water (400 ml), air-dried overnight, and dried under reduced pressure at 60° C. to give the title compound (285 g, 2 steps 90%).
  • 1H-NMR (CDCl3) δ: 8.32-8.29 (1H, m), 7.71-7.67 (1H, m), 7.59-7.54 (1H, m), 7.45-7.40 (1H, m), 7.38-7.34 (1H, m), 7.27-7.23 (1H, m), 3.65 (1H, d, J=16.0 Hz), 3.60 (1H, d, J=16.0 Hz).
    • Step 6
  • salt of optically active form of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-(1-naphthyl)-ethylamine
  • Figure US20150329491A1-20151119-C00063
  • To a mixture of methyl ethyl ketone (250 ml) and (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (50 g) was added (R)-(+)-1-(1-naphthyl)-ethylamine (11.1 ml), and the mixture was stirred at 50° C. for 3 days. This suspension was cooled to room temperature, further stirred for 4 days, and filtered. The obtained solid was dried under reduced pressure to give the title compound (25.5 g, 35%). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 22.58 min)
    isomer with long retention time (retention time 22.73 min)
    • Step 7
  • optically active form of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid
  • Figure US20150329491A1-20151119-C00064
  • To a mixture of ethyl acetate (178 ml), and a salt (25.45 g) of an optically active form of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-(1-naphthyl)-ethylamine were added 2N hydrochloric acid (51 ml) and water (127 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was partitioned in a separatory funnel. The organic layer was washed twice with water (100 ml) and then with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, n-hexane (127 ml) was added to the obtained residue and the mixture was stirred at room temperature for 1 hr. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (16.33 g, 95%).
  • 1H-NMR (DMSO-D6) δ: 12.78 (1H, br s), 8.31-8.28 (1H, m), 7.73-7.65 (3H, m), 7.56-7.49 (2H, m), 3.57 (1H, d, J=15.8 Hz), 3.51 (1H, d, J=15.5 Hz).
    • Step 8
  • (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol
  • Figure US20150329491A1-20151119-C00065
  • To a mixture of dimethylformamide (184 ml) and an optically active form (36.74 g) of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added N-ethyldiisopropylamine (20.9 ml), and the mixture was stirred at 0° C. Thereto, diphenylphosphoryl azide (23.7 ml) was added dropwise over 30 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added acetic acid (2.86 ml) and the mixture was warmed to room temperature. t-Butyl alcohol (96 ml) was added, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (367 ml) was added, placed in a separatory funnel and the mixture was extracted 3 times with toluene (180 ml). The combined organic layer was successively washed with water (180 ml), 1N aqueous sodium hydroxide solution (180 ml), water (180 ml) and saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2N aqueous sodium hydroxide solution (37 ml) were mixed, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, water (180 ml) was added, and the mixture was placed in a separatory funnel, and extracted twice with toluene (180 ml). The organic layer was washed twice with water (180 ml) and once with saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to give the title compound (21.69 g, 70%).
  • [α]D=+30.60° (20° C., c=1.00, methanol)
  • 1H-NMR (CDCl3) δ: 8.29-8.26 (1H, m), 7.73-7.69 (1H, m), 7.55-7.50 (1H, m), 7.43-7.35 (2H, m), 7.21-7.18 (1H, m), 2.82 (1H, s).
    • Example 2 Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol (compound No. 595) Step 1
  • [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid t-butyl ester
  • Figure US20150329491A1-20151119-C00066
  • 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (10 g), N,N-dimethylacetamide (100 ml), potassium carbonate (17.8 g) and t-butyl bromoacetate (9.9 ml) were mixed, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through celite. Water and ethyl ether were added to the filtrate, and the mixture was partitioned in a separatory funnel. The aqueous layer was extracted with ethyl ether, and the organic layers were combined. The organic layer was washed 3 times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was stirred. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (12.23 g, 77%).
  • 1H-NMR (DMSO-D6) δ: 7.92 (1H, d, J=0.7 Hz), 7.59 (1H, d, J=0.5 Hz), 4.95 (2H, s), 1.42 (9H, s), 1.25 (12H, s).
    • Step 2
  • optically active form of t-butyl [4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate
  • Figure US20150329491A1-20151119-C00067
  • Sodium hydrogen carbonate (5.54 g), water (33 ml), toluene (100 ml), (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (10.0 g), t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-acetate (15.3 g), palladium(II) acetate (370 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.35 g) were mixed, and purged with argon. The mixture was stirred at 100° C. for 180 min. The reaction mixture was cooled to room temperature, water was added, and the mixture was filtered through celite. The filtered substance was further washed with toluene and water. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene. The combined organic layer was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from n-hexane/2-propanol (10:1, 165 ml) to give the title compound (11.1 g, 60%).
  • 1H-NMR (CDCl3) δ: 7.69-7.66 (1H, m), 7.66 (1H, d, J=0.7 Hz), 7.63 (1H, d, J=0.7 Hz), 7.42-7.37 (2H, m), 7.31-7.25 (2H, m), 7.03 (1H, dd, J=9.5, 2.6 Hz), 4.94 (1H, d, J=17.2 Hz), 4.89 (1H, d, J=17.4 Hz), 2.85 (1H, br s), 1.52 (9H, s).
    • Step 3
  • optically active form of ethyl 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate
  • Figure US20150329491A1-20151119-C00068
  • To a mixture of tetrahydrofuran (80 ml) and an optically active form (10.1 g) of t-butyl [4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate was added ethyl formate (4.13 ml), and the mixture was stirred at 0° C. To this mixture was added sodium hydride (60 w/w % mineral oil dispersion, 2.57 g). The reaction mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was ice-cooled, 1N hydrochloric acid was added and the mixture was stirred. Ethyl acetate and water were added thereto, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (13.2 g). The obtained residue was directly used for the next reaction without further purification.
  • 1H-NMR (DMSO-D6) δ: 11.98 (1H, br s), 7.98 (1H, br s), 7.97 (1H, d, J=0.5 Hz), 7.77 (1H, d, J=0.7 Hz), 7.66-7.62 (1H, m), 7.44-7.39 (3H, m), 7.36-7.32 (1H, m), 7.30-7.24 (1H, m), 7.21 (1H, dd, J=9.9, 2.4 Hz), 4.18 (2H, q, J=7.1 Hz), 1.22 (3H, t, J=7.1 Hz).
    • Step 4
  • (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol
  • Figure US20150329491A1-20151119-C00069
  • To a mixture of ethanol (80 ml) and sodium borohydride (16.2 g), a solution of an optically active form (13.2 g) of ethyl 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate in tetrahydrofuran (80 ml) was added dropwise over 25 min. At this time, the temperature of the reaction mixture was controlled with an ice-bath not to exceed 30° C. The ice-bath was changed to a water-bath, and the mixture was stirred for 17 hr. Then, the water-bath was removed and the mixture was further stirred for 4 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid was added and the mixture was stirred. To this mixture were added ethyl acetate and water, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1 to 15/1) to give the title compound (7.38 g, 84%).
  • [α]D=+67.50° (20° C., c=1.00, methanol)
  • 1H-NMR (DMSO-D6) δ: 8.02 (1H, s), 7.68 (1H, s), 7.66-7.61 (1H, m), 7.44-7.37 (3H, m), 7.36-7.31 (1H, m), 7.30-7.26 (1H, m), 7.18 (1H, dd, J=10.0, 2.6 Hz), 4.99-4.94 (2H, m), 4.39-4.32 (1H, m), 3.86-3.76 (4H, m).
  • The obtained title compound can be crystallized from a solvent (toluene/ethyl acetate (7:1)) containing 1 mol of water per 1 mol of the compound.
  • Using the above-mentioned (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol as an intermediate and by a similar method, compound Nos. 531, 534, 537, 543, 544, 545, 548, 549, 551, 565, 566, 607, 610, 672, 674, 675, 682, 685, 687, 692, 693, 694, 695, 704 and 705 were synthesized.
    • Example 3 Synthesis of (+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid (compound No. 538) Step 1
  • 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester
  • Figure US20150329491A1-20151119-C00070
  • Under an argon atmosphere, 4-bromo-3-chlorotoluene (200 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (376 g), toluene (1000 ml), water (1000 ml), tripotassium phosphate (412 g) and dichlorobis(triphenylphosphine)palladium(II) (14 g) were added to a reaction vessel and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with water (500 ml) and toluene (500 ml). The filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water (1000 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (337 g). The obtained residue was directly used for the next reaction without further purification.
  • 1H-NMR (CDCl3) δ: 8.02-7.99 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.28-7.23 (2H, m), 7.13-7.11 (2H, m), 4.17-4.08 (2H, m), 2.38 (3H, s), 1.06 (3H, t, J=7.1 Hz).
    • Step 2
  • 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid
  • Figure US20150329491A1-20151119-C00071
  • To a mixture of ethanol (728 ml) and 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester (337 g) was added 4N aqueous sodium hydroxide solution (728 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (17 g) was added and the mixture was stirred overnight. The activated carbon was filtered off, and washed with 50 v/v % ethanol-water (200 ml). The filtrate was acidified by dropwise addition of acetic acid (500 ml) at room temperature. To this mixture, water (414 ml) was added dropwise at room temperature, and the mixture was stirred for 2 hr. This suspension was filtered, and the obtained solid was washed with 40 v/v % ethanol-water (250 ml), and dried under reduced pressure at 80° C. to give the title compound (203 g, 2 steps 85%).
  • 1H-NMR (DMSO-D6) δ: 12.60 (1H, br s), 7.93-7.89 (1H, m), 7.64-7.58 (1H, m), 7.53-7.47 (1H, m), 7.32-7.29 (1H, m), 7.25-7.21 (1H, m), 7.20-7.13 (2H, m), 2.34 (3H, s).
    • Step 3
  • 4-chloro-2-methyl-fluoren-9-one
  • Figure US20150329491A1-20151119-C00072
  • To a mixture of phosphorus pentoxide (150 g) and methanesulfonic acid (1500 ml) was added 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid (153 g), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to 0° C. While keeping the temperature of the reaction mixture at 90° C. or below, water (1500 ml) was added dropwise, and the mixture was further stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with water (1000 ml). The solid was suspended in 50 v/v % ethanol-water (1500 ml), and the slurry was stirred at room temperature for 2 hr, and filtered. The obtained solid was air-dried for 1 hr and dried under reduced pressure at 80° C. to give the title compound (140.12 g, 99%).
  • 1H-NMR (DMSO-D6) δ: 8.10-8.07 (1H, m), 7.69-7.64 (2H, m), 7.49-7.41 (3H, m), 2.36 (3H, s).
    • Step 4
  • (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid
  • Figure US20150329491A1-20151119-C00073
  • Under an argon stream, potassium carbonate (18 g) was added to a mixture of dimethylformamide (500 ml) and 4-chloro-2-methyl-fluoren-9-one (100 g). To this mixture, trimethyl(trifluoromethyl)silane (78 ml) was added dropwise over 80 min, and the mixture was further stirred at room temperature for 1 hr. To the reaction mixture was added cesium fluoride (87 g) at room temperature, then ethyl bromoacetate (63 ml) was added dropwise over 15 min, and the mixture was further stirred at room temperature for 4 hr. To the reaction mixture was added water (500 ml), and the aqueous layer was extracted twice with toluene (500 ml). The combined organic layer was washed with water (500 ml) and saturated brine (500 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. To the obtained residue were added ethanol (220 ml) and 2N aqueous sodium hydroxide solution (440 ml), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (15 g) was added, and the mixture was stirred at room temperature overnight. The activated carbon was filtered off, and washed with 33 v/v % ethanol-water (120 ml). The filtrate was acidified by dropwise addition of acetic acid (151 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered, the obtained solid was washed with 33 v/v % ethanol-water (150 ml), and dried under reduced pressure at 80° C. to give the title compound (136.40 g, 87%).
  • 1H-NMR (DMSO-D6) δ: 12.76 (1H, br s), 8.26 (1H, d, J=7.7 Hz), 7.69-7.62 (2H, m), 7.53-7.45 (3H, m), 3.50 (1H, d, J=15.5 Hz), 3.43 (1H, d, J=15.5 Hz), 2.41 (3H, s).
    • Step 5
  • salt of optically active form of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00074
    • Step 5-1 Synthesis of Seed Crystal
  • To a mixture of isopropyl ether (16 ml) and (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (0.400 g) was added (R)-(+)-1-phenylethylamine (0.058 ml). The mixture was stirred at room temperature for 1 hr 40 min. This suspension was filtered, and the obtained filtrate was dried under reduced pressure to give a solid (0.240 g). The solid (0.210 g) was suspended in ethyl acetate (4.2 ml), and the suspension was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained filtered substance was dried under reduced pressure to give a solid (0.178 g). The solid (0.170 g) was resuspended in ethyl acetate (3.4 ml), and the mixture was stirred at 50° C. for 1 hr. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.137 g). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 20.19 min)
    isomer with long retention time (retention time 21.41 min)
    • Step 5-2
  • To a mixture of methyl isobutyl ketone (575 ml) and (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (191.60 g) was added (R)-(+)-1-phenylethylamine (34.81 ml). To this mixture was added a seed crystal, and the mixture was stirred at 50° C. for 3 days. This suspension was filtered, and the obtained solid was washed with methyl isobutyl ketone (192 ml), and dried under reduced pressure to give the title compound (71.10 g, 28%). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 24.11 min)
    isomer with long retention time (retention time 25.43 min)
    • Step 6
  • optically active form of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid
  • Figure US20150329491A1-20151119-C00075
  • To a mixture of ethyl acetate (796 ml) and a salt (159.16 g) of an optically active form of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-phenylethylamine was added 2N hydrochloric acid (318 ml), and the mixture was stirred at room temperature for 2 hr. The mixture was partitioned in a separatory funnel. The organic layer was washed twice with water (600 ml) and once with saturated brine (300 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the mixture was stirred at room temperature for 1 hr. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (112.33 g, 95%).
  • 1H-NMR (DMSO-D6) δ: 12.75 (1H, br s), 8.26 (1H, d, J=7.7 Hz), 7.71-7.62 (2H, m), 7.54-7.45 (3H, m), 3.50 (1H, d, J=15.5 Hz), 3.43 (1H, d, J=15.5 Hz), 2.41 (3H, s).
    • Step 7
  • (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol
  • Figure US20150329491A1-20151119-C00076
  • To a mixture of dimethylformamide (90 ml) and an optically active form (30 g) of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added triethylamine (14.1 ml), and the mixture was stirred at 0° C. A solution of diphenylphosphoryl azide (20.0 ml) in dimethylformamide (60 ml) was added dropwise over 20 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added t-butyl alcohol (75 ml), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (300 ml) was added and the mixture was stirred at room temperature overnight. To this mixture was added water (100 ml) and the mixture was placed in a separatory funnel. The aqueous layer was extracted twice with toluene (300 ml, 200 ml). The combined organic layer was successively washed twice with water (200 ml), twice with 1N aqueous sodium hydroxide solution (150 ml) and once with saturated brine (150 ml), and dried over anhydrous sodium sulfate. Thereto was added silica gel (6 g) and the mixture was stirred at room temperature. The insoluble material was filtered off, and washed with toluene (500 ml). The filtrate was concentrated under reduced pressure to give the title compound (28.58 g).
  • [α]D=+22.50° (20° C., c=1.00, methanol)
  • 1H-NMR (CDCl3) δ: 8.27 (1H, d, J=7.7 Hz), 7.70-7.69 (1H, m), 7.52-7.47 (1H, m), 7.44-7.42 (1H, m), 7.40-7.35 (1H, m), 7.25 (1H, s), 2.82 (1H, br s), 2.41 (3H, s).
    • Step 8
  • t-butyl 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionate
  • Figure US20150329491A1-20151119-C00077
  • 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.82 g), acetonitrile (50 ml), cesium fluoride (455.7 mg) and t-butyl acrylate (5.7 ml) were mixed at room temperature, and the mixture was stirred at 80° C. for 17.5 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the obtained residue were added water and ethyl ether, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether, and the organic layers were combined. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 4/6) to give the title compound (8.38 g, 87%).
  • 1H-NMR (CDCl3) δ: 7.77 (1H, s), 7.71 (1H, s), 4.38 (2H, t, J=6.9 Hz), 2.80 (2H, t, J=6.8 Hz), 1.41 (9H, s), 1.31 (12H, s).
    • Step 9
  • optically active form of t-butyl 3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionate
  • Figure US20150329491A1-20151119-C00078
  • Tripotassium phosphate (35.7 g), water (60 ml), toluene (240 ml), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (28.58 g), t-butyl 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-propionate (41.9 g), palladium(II) acetate (1.89 g) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.905 g) were mixed in a reaction vessel, and purged with argon. The mixture was stirred at 100° C. for 3 hr. The reaction mixture was cooled to room temperature, water (180 ml) was added and the mixture was stirred overnight. Insoluble material was filtered off through celite, and washed with ethyl acetate (500 ml). The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. The organic layer was successively washed with water (250 ml), saturated aqueous sodium hydrogen carbonate (250 ml) and saturated brine (200 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in toluene/ethyl acetate (3:1, 270 ml). Silica gel (30 g) was added and the mixture was stirred at room temperature for 3 hr. The mixture was filtered, and washed with toluene/ethyl acetate (3:1, 500 ml). The filtrate was concentrated under reduced pressure, isopropyl ether (100 ml) was added to the obtained residue and the mixture was stirred at room temperature for 4 hr. This slurry was filtered, and the obtained solid was washed with isopropyl ether (40 ml), and dried under reduced pressure at 50° C. The solid was mixed with chloroform (27 ml) and the mixture was stirred at room temperature for 5 min. Hexane (107 ml) was added, and the mixture was further stirred for 2 hr 50 min. This suspension was filtered, and the filtered substance was washed with hexane/chloroform (4:1, 40 ml), and dried under reduced pressure at 50° C. to give the title compound (24.75 g, 64%).
  • 1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.54 (1H, s), 7.51-7.47 (1H, m), 7.50 (1H, s), 7.28-7.19 (3H, m), 7.06-7.03 (1H, m), 4.44 (2H, t, J=6.6 Hz), 3.16 (1H, br s), 2.88 (2H, t, J=6.5 Hz), 2.41 (3H, s), 1.43 (9H, s).
    • Step 10
  • (+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid
  • Figure US20150329491A1-20151119-C00079
  • To a mixture of 1,4-dioxane (6.7 ml) and an optically active form (1.34 g) of t-butyl 3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionate was added trifluoroacetic acid (6.7 ml), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. Toluene was added to the obtained residue and the mixture was concentrated under reduced pressure. To the residue was added water (10 ml) and the mixture was extracted twice with ethyl acetate (10 ml). The combined organic layer was washed twice with water (10 ml) and once with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the obtained filtrate was concentrated under reduced pressure. Toluene was added to the obtained residue and the mixture was concentrated under reduced pressure. n-Hexane (10 ml) was added to the concentrated residue, and the slurry was stirred and filtered. The obtained solid was washed with n-hexane, and dried under reduced pressure to give the title compound (1.12 g, 96%).
  • [α]D=+65.10° (25° C., c=1.00, methanol)
  • 1H-NMR (DMSO-D6) δ: 12.40 (1H, br s), 7.93 (1H, s), 7.61-7.56 (1H, m), 7.57 (1H, s), 7.41-7.39 (1H, m), 7.30-7.21 (3H, m), 7.13 (1H, br s), 7.09-7.08 (1H, m), 4.40 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 2.36 (3H, s).
    • Example 4 Synthesis of (+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid (compound No. 539) Step 1
  • 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-butyric acid ethyl ester
  • Figure US20150329491A1-20151119-C00080
  • 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (25.0 g), dimethylformamide (200 ml), potassium carbonate (44.5 g) and ethyl 4-bromobutyrate (36.9 ml) were mixed at room temperature and stirred at 75° C. for 6 hr. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off through celite. To the filtrate was added water (150 ml) and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). To the aqueous layer was added water (100 ml) again and the mixture was extracted twice with ethyl acetate (50 ml). To the combined organic layer was added n-hexane (100 ml), and the mixture was washed 3 times with water (100 ml) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate-5/1 to 1/1) to give the title compound (33.4 g, 84%).
  • 1H-NMR (DMSO-D6) δ: 7.92 (1H, d, J=0.4 Hz), 7.58 (1H, d, J=0.7 Hz), 4.14 (2H, t, J=6.7 Hz), 4.03 (2H, q, J=7.1 Hz), 2.22 (2H, t, J=7.4 Hz), 2.04-1.96 (2H, m), 1.25 (12H, s), 1.17 (3H, t, J=7.2 Hz).
    • Step 2
  • optically active form of 4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid ethyl ester
  • Figure US20150329491A1-20151119-C00081
  • Tripotassium phosphate (14.86 g), water (30 ml), toluene (60 ml), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (9.583 g) and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-butyric acid ethyl ester (12.08 g) were added to a reaction vessel, and purged with argon. To this mixture were added palladium(II) acetate (314 mg) and a solution (30 ml) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.149 g) in toluene and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (2 g) was added and the mixture was stirred for 30 min. The insoluble material was filtered off. The filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water (50 ml) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from isopropyl ether (50 ml) to give the title compound (7.926 g, 64%).
  • 1H-NMR (CDCl3) δ: 7.70-7.66 (1H, m), 7.53-7.51 (1H, m), 7.42 (1H, s), 7.27-7.21 (2H, m), 7.20-7.15 (1H, m), 7.12-7.08 (1H, m), 7.04-7.02 (1H, m), 4.18 (2H, t, J=6.7 Hz), 4.14 (2H, q, J=7.1 Hz), 4.03 (1H, brs), 2.41 (3H, s), 2.34-2.28 (2H, m), 2.23-2.15 (2H, m), 1.25 (3H, t, J=7.2 Hz).
    • Step 3
  • (+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid
  • Figure US20150329491A1-20151119-C00082
  • To a mixture of ethanol (5.4 ml) and an optically active form (3.55 g) of 4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid ethyl ester was added 2N aqueous sodium hydroxide solution (18 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was acidified with 2N hydrochloric acid (36 ml). To this mixture was added water (36 ml), and the mixture was extracted 3 times with ethyl acetate (30 ml). The combined organic layer was washed 3 times with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.40 g, 100%).
  • [α]D=+63.00° (20° C., c=1.00, methanol)
  • 1H-NMR (DMSO-D6) δ: 12.21 (1H, br s), 7.98 (1H, s), 7.64-7.59 (1H, m), 7.60 (1H, s), 7.44-7.42 (1H, m), 7.33-7.22 (3H, m), 7.17 (1H, br s), 7.14-7.12 (1H, m), 4.24 (2H, t, J=6.7 Hz), 2.39 (3H, s), 2.27 (2H, t, J=7.3 Hz), 2.12-2.05 (2H, m).
  • The obtained compound was crystallized from toluene/ethyl acetate (20:1).
  • Using the above-mentioned (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol as an intermediate and by a similar method, compound Nos. 529, 532, 533, 546, 550, 574, 575, 576, 605, 606, 663, 686, 690, 691, 696, 697, 699, 700, 701, 702, 706 and 707 were synthesized.
    • Example 5 Synthesis of (−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxamide (compound No. 630) Step 1
  • ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate
  • Figure US20150329491A1-20151119-C00083
  • Under an argon atmosphere, a mixture of 2-bromo-5-chlorotoluene (20.55 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55.23 g), toluene (200 ml), water (125 ml), tripotassium phosphate (53.07 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (1.633 g) was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (1 g) was added and the mixture was stirred for 10 min at room temperature. The insoluble material was filtered off, and the filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (27.20 g, 99%).
  • 1H-NMR (CDCl3) δ: 7.98 (1H, dd, J=7.7, 1.1 Hz), 7.56-7.51 (1H, m), 7.46-7.42 (1H, m), 7.23-7.22 (1H, m), 7.20-7.16 (2H, m), 7.00 (1H, d, J=7.9 Hz), 4.07 (2H, q, J=7.1 Hz), 2.04 (3H, s), 1.02 (3H, t, J=7.2 Hz).
    • Step 2
  • 4′-chloro-2′-methyl-biphenyl-2-carboxylic acid
  • Figure US20150329491A1-20151119-C00084
  • A mixture of ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate (27.10 g), ethanol (60 ml) and 1N aqueous sodium hydroxide solution (120 ml) was stirred at 100° C. for 2 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution (10 ml), and the mixture was further stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with 33 v/v % ethanol-water (100 ml). The filtrate was adjusted to pH 2 with formic acid (23 ml) and the mixture was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was air-dried for 1 hr and dried under reduced pressure at 60° C. to give the title compound (22.082 g, 91%).
  • 1H-NMR (DMSO-D6) δ: 12.64 (1H, s), 7.89 (1H, dd, J=7.8, 1.0 Hz), 7.63-7.58 (1H, m), 7.52-7.48 (1H, m), 7.33-7.32 (1H, m), 7.26-7.19 (2H, m), 7.05 (1H, d, J=8.2 Hz), 2.00 (3H, s).
    • Step 3
  • 2-chloro-4-methyl-fluoren-9-one
  • Figure US20150329491A1-20151119-C00085
  • Under anhydrous calcium chloride drying conditions, a mixture of 4′-chloro-2′-methyl-biphenyl-2-carboxylic acid (21.60 g) and Eaton's reagent (7.7 w/w % solution of phosphorus pentoxide in methanesulfonic acid) (170 ml) was stirred at 100° C. for 2.5 hr. The reaction mixture was ice-cooled, water (500 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was mixed with 30 v/v % aqueous ethanol solution (200 ml), and the slurry was stirred at room temperature for 10 min, and filtered. The obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (19.744 g, 99%).
  • 1H-NMR (CDCl3) δ: 7.69-7.66 (1H, m), 7.60-7.57 (1H, m), 7.52-7.46 (2H, m), 7.32-7.27 (1H, m), 7.25-7.23 (1H, m), 2.56 (3H, s).
    • Step 4
  • 2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol
  • Figure US20150329491A1-20151119-C00086
  • Under anhydrous calcium chloride drying conditions, 2-chloro-4-methyl-fluoren-9-one (18.627 g), potassium carbonate (3.372 g) and dimethylformamide (100 ml) were mixed, trimethyl(trifluoromethyl)silane (16 ml) was added dropwise over 25 min at room temperature with stirring, and the mixture was further stirred at room temperature for 14 min. To this mixture, a 1M solution (122 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise over 6 min. To the reaction mixture was added aqueous ammonium chloride (400 ml), and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed once with water (100 ml), once with saturated aqueous sodium hydrogen carbonate and 3 times with water, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (200 ml), activated carbon (1.5 g) was added, and the mixture was stirred at room temperature for 10 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (24.689 g). The obtained residue was directly used for the next reaction without further purification.
  • 1H-NMR (CDCl3) δ: 7.78-7.75 (1H, m), 7.74-7.70 (1H, m), 7.55-7.53 (1H, m), 7.52-7.47 (1H, m), 7.40-7.35 (1H, m), 7.27-7.25 (1H, m), 2.80 (1H, brs), 2.64 (3H, s).
    • Step 5
  • 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid
  • Figure US20150329491A1-20151119-C00087
  • To a mixture of 2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol (2.987 g), pyridine (6 ml) and water (24 ml) was added potassium permanganate (7.902 g) at 100° C., and the mixture was stirred for 2 hr. To this mixture were added further potassium permanganate (4.70 g) and pyridine (6 ml) and the mixture was stirred at 100° C. for 2 hr. Potassium permanganate (4.70 g) was further added and the mixture was stirred at 100° C. for 2 hr. This operation was repeated twice. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off and washed with water (50 ml). The filtrate was adjusted to pH 1 with 6N hydrochloric acid, and extracted with ethyl acetate (200 ml). The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was treated with hexane/ethyl acetate mixed solution (hexane:ethyl acetate=9:1) (30 ml). This slurry was filtered, and the obtained solid was dried to give the title compound (2.509 g, 76%).
  • 1H-NMR (DMSO-D6) δ: 13.91 (1H, br s), 8.22-8.19 (1H, m), 7.87 (1H, d, J=2.0 Hz), 7.81-7.79 (1H, m), 7.72-7.68 (1H, m), 7.57-7.51 (2H, m), 7.51-7.46 (1H, m).
    • Step 6
  • salt of optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and (S)-(−)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00088
    • Step 6-1 Synthesis of Seed Crystal
  • To a solution of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid (0.100 g) in ethyl acetate (0.50 ml) was added (S)-(−)-1-phenylethylamine (0.040 ml), and the mixture was stirred at room temperature for 2 days. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.062 g, containing 8 w/w % ethyl acetate, 41%). The solid was analyzed under HPLC analysis condition 2 to find that the isomer with a short retention time was the main component.
  • isomer with short retention time (retention time 20.35 min)
    isomer with long retention time (retention time 21.10 min)
  • 1H-NMR (DMSO-D6) δ: 8.38 (1H, d, J=7.2 Hz), 8.29 (3H, br s), 7.61-7.57 (1H, m), 7.51-7.48 (2H, m), 7.45-7.32 (7H, m), 7.30 (1H, br s), 4.38 (1H, q, J=6.8 Hz), 1.49 (3H, d, J=6.7 Hz).
    • Step 6-2
  • To a solution of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid (0.972 g) in ethyl acetate (5.0 ml) were added (S)-(−)-1-phenylethylamine (0.38 ml) and a seed crystal of a salt of an optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and (S)-(−)-1-phenylethylamine, and the mixture was stirred at room temperature for 2 days. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.608 g, containing 16 w/w % ethyl acetate, 38%). The solid was analyzed under HPLC analysis condition 2 to find that the isomer with a short retention time was the main component.
  • isomer with short retention time (retention time 20.31 min)
    isomer with long retention time (retention time 21.06 min)
  • 1H-NMR (DMSO-D6) δ: 8.38 (1H, d, J=7.1 Hz), 8.34 (3H, br s), 7.61-7.57 (1H, m), 7.51-7.48 (2H, m), 7.46-7.32 (7H, m), 7.30 (1H, br s), 4.38 (1H, q, J=6.8 Hz), 1.50 (3H, d, J=6.8 Hz).
    • Step 7
  • optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid
  • Figure US20150329491A1-20151119-C00089
  • A salt of an optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and (S)-(−)-1-phenylethylamine (0.575 g) was dissolved in ethyl acetate, and the mixture was placed in a separatory funnel, hydrochloric acid was added, and the mixture was partitioned. The organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.357 g).
  • 1H-NMR (DMSO-D6) δ: 13.90 (1H, br s), 8.22-8.19 (1H, m), 7.87 (1H, d, J=2.0 Hz), 7.81-7.79 (1H, m), 7.72-7.68 (1H, m), 7.57-7.46 (3H, m).
    • Step 8
  • 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
  • Figure US20150329491A1-20151119-C00090
  • 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.0 g), N,N-dimethylacetamide (50 ml), potassium carbonate (5.3 g) and ethyl iodide (2.1 ml) were mixed, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, water (100 ml) and ethyl ether (100 ml) were added, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether (100 ml), and the organic layers were combined. The organic layer was washed 3 times with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was partitioned in a separatory funnel. The organic layer was washed 3 times with water (40 ml) and once with saturated brine (40 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.1691 g, 38%).
  • 1H-NMR (CDCl3) δ: 7.79 (1H, s), 7.70 (1H, s), 4.19 (2H, q, J=7.3 Hz), 1.49 (3H, t, J=7.3 Hz), 1.32 (12H, s).
    • Step 9
  • optically active form of 2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid
  • Figure US20150329491A1-20151119-C00091
  • Under an argon atmosphere, an optically active form (0.100 g) of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid, 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.133 g), tripotassium phosphate (0.191 g), palladium(II) acetate (0.0034 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0123 g), dioxane (3 ml) and water (0.6 ml) were mixed, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, hydrochloric acid and ethyl acetate were added, and the mixture was partitioned in a separatory funnel. The organic layer was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was treated with hexane/ethyl acetate mixed solution (hexane:ethyl acetate-1:2.2 ml). This slurry was filtered, and the obtained solid was dried to give the title compound (0.075 g, 63%).
  • 1H-NMR (DMSO-D6) δ: 13.60 (1H, s), 8.43 (1H, s), 8.18-8.15 (1H, m), 8.01 (1H, d, J=0.7 Hz), 8.00 (1H, d, J=1.6 Hz), 7.97-7.95 (1H, m), 7.70-7.66 (1H, m), 7.53-7.48 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17 (2H, q, J=7.3 Hz), 1.43 (3H, t, J=7.3 Hz).
    • Step 10
  • (−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxamide
  • Figure US20150329491A1-20151119-C00092
  • To a mixture of an optically active form (0.051 g) of 2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g), 1-hydroxybenzotriazole hydrate (0.030 g), ammonium chloride (0.022 g) and dimethylformamide (1 ml) was added triethylamine (0.055 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (10 ml), and the organic layer was successively washed once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate, 3 times with water and once with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.043 g, 85%).
  • [α]D=−3.00° (20° C., c=0.20, methanol)
  • 1H-NMR (DMSO-D6) δ: 8.37 (1H, s), 8.14 (1H, br s), 7.98 (1H, J=0.7 Hz), 7.93-7.90 (1H, m), 7.85-7.83 (1H, m), 7.74 (1H, br s), 7.70 (1H, d, J=1.5 Hz), 7.67-7.64 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 4.17 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3 Hz).
  • Using the above-mentioned optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid as an intermediate and by a similar method, compound Nos. 629, 659, 660, 667 and 668 were synthesized.
    • Example 6 Synthesis of (−)-1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic acid dimethylamide (compound No. 153) Step 1
  • 2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate
  • Figure US20150329491A1-20151119-C00093
  • Under a nitrogen atmosphere, to a mixture of methyl 4-bromo-3-methylbenzoate (2.291 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.313 g), toluene (20 ml), water (10 ml) and tripotassium phosphate (4.246 g) was added tetrakis(triphenylphosphine)palladium(0) (0.578 g) at room temperature, and the mixture was stirred with heating under reflux overnight. The reaction mixture was cooled to room temperature, and partitioned in a separatory funnel. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (2.404 g, 81%)
  • 1H-NMR (CDCl3) δ: 8.03-7.99 (1H, m), 7.94-7.91 (1H, m), 7.89-7.85 (1H, m), 7.59-7.53 (1H, m), 7.49-7.43 (1H, m), 7.21-7.18 (1H, m), 7.17-7.14 (1H, m), 4.07-4.01 (2H, m), 3.93 (3H, s), 2.11 (3H, s), 0.98-0.93 (3H, m).
    • Step 2
  • 2′-methyl-biphenyl-2,4′-dicarboxylic acid
  • Figure US20150329491A1-20151119-C00094
  • A mixture of 2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate (2.404 g), ethanol (12 ml) and 4N aqueous sodium hydroxide solution (6 ml) was stirred at 100° C. overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (50 ml) was added to the obtained residue. This mixture was adjusted to pH 1 with 6N hydrochloric acid (5 ml), ethanol (10 ml) was added, and the mixture was stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was washed with 20 v/v % ethanol-water (10 ml), air-dried, and dried under reduced pressure at 80° C. to give the title compound (1.957 g, 95%).
  • 1H-NMR (DMSO-D6) δ: 12.74 (2H, br s), 7.92 (1H, dd, J=7.8, 1.3 Hz), 7.82-7.80 (1H, m), 7.76 (1H, dd, J=7.9, 1.6 Hz), 7.65-7.60 (1H, m), 7.54-7.49 (1H, m), 7.22 (1H, dd, J=7.7, 1.2 Hz), 7.15 (1H, d, J=7.9 Hz), 2.06 (3H, s).
    • Step 3
  • 4-methyl-9-oxo-9H-fluorene-2-carboxylic acid
  • Figure US20150329491A1-20151119-C00095
  • A mixture of 2′-methyl-biphenyl-2,4′-dicarboxylic acid (1.94 g) and polyphosphoric acid (50 g) was stirred at 180° C. for 3 hr. The reaction mixture was cooled to room temperature, water (100 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 10 min. This suspension was filtered, and the obtained solid was successively washed with water (50 ml) and 50 v/v % aqueous methanol solution (50 ml). The obtained solid was air-dried, and dried under reduced pressure at 80° C. to give the title compound (1.745 g, 97%).
  • 1H-NMR (DMSO-D6) δ: 12.98 (1H, br s), 8.00-7.99 (1H, m), 7.88 (1H, d, J=1.6 Hz), 7.86 (1H, d, J=7.4 Hz), 7.71-7.66 (2H, m), 7.49-7.45 (1H, m), 2.65 (3H, s).
    • Step 4
  • methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate
  • Figure US20150329491A1-20151119-C00096
  • Under anhydrous calcium chloride drying conditions, 4-methyl-9-oxo-9H-fluorene-2-carboxylic acid (1.745 g), potassium carbonate (3.03 g) and dimethylformamide (20 ml) were mixed. To this mixture was added methyl iodide (0.92 ml) at room temperature, and the mixture was stirred for 3 hr 15 min. To the reaction mixture was added water (60 ml), and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (1.778 g, 96%).
  • 1H-NMR (CDCl3) δ: 8.17 (1H, s), 8.01 (1H, s), 7.76-7.70 (2H, m), 7.58-7.52 (1H, m), 7.40-7.35 (1H, m), 3.94 (3H, s), 2.67 (3H, s).
    • Step 5
  • methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate
  • Figure US20150329491A1-20151119-C00097
  • Under an argon atmosphere, methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate (1.009 g), trimethyl(trifluoromethyl)silane (0.89 ml) and dimethylformamide (50 ml) were mixed, lithium acetate (0.027 g) was added with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min. Acetic acid (0.7 ml) and a 1M solution (6 ml) of tetrabutylammonium fluoride in tetrahydrofuran were added, and the mixture was further stirred at room temperature for 15 min. To the reaction mixture was added aqueous sodium hydrogen carbonate (300 ml), and the mixture was extracted twice with ethyl acetate (50 ml). The combined organic layer was washed once with saturated aqueous sodium hydrogen carbonate, 4 times with water and once with saturated brine, and concentrated under reduced pressure. To the obtained residue was added hexane/ethyl acetate (8:2, 10 ml) and the mixture was stirred for 10 min. This slurry was filtered, and the obtained solid was dried to give the title compound (1.000 g, 78%).
  • 1H-NMR (CDCl3) δ: 8.20-8.19 (1H, m), 7.98-7.96 (1H, m), 7.86 (1H, d, J=7.7 Hz), 7.79-7.75 (1H, m), 7.56-7.51 (1H, m), 7.46-7.40 (1H, m), 3.93 (3H, s), 2.84 (1H, s), 2.71 (3H, s).
    • Step 6
  • 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid
  • Figure US20150329491A1-20151119-C00098
  • A mixture of methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate (1.000 g), tetrahydrofuran (4 ml), methanol (6 ml) and 4N aqueous sodium hydroxide solution (1.6 ml) was stirred with heating under reflux for 3 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water (30 ml) was added to the obtained residue, and the mixture was adjusted to pH 1 with 6N hydrochloric acid (2 ml), and extracted with ethyl acetate (30 ml). The organic layer was successively washed with water and saturated brine. After addition of anhydrous magnesium sulfate and activated carbon (0.2 g), the mixture was stirred at room temperature for 10 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.053 g). The residue was directly used for the next reaction without further purification.
  • 1H-NMR (DMSO-D6) δ: 13.07 (1H, br s), 8.06-8.03 (1H, m), 7.97-7.91 (2H, m), 7.74-7.71 (1H, m), 7.61-7.56 (1H, m), 7.51-7.46 (1H, m), 7.33 (1H, s), 2.70 (3H, s).
    • Step 7
  • salt of racemic 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00099
  • A mixture of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.159 g), (R)-(+)-1-phenylethylamine (0.066 ml), and ethyl acetate (2 ml) was concentrated under reduced pressure, ethyl acetate was added to the residue and the mixture was concentrated under reduced pressure again to give the title compound (0.229 g).
    • Step 8
  • salt of optically active form (enantiomer with long retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00100
  • Salt (0.010 g) of the racemic 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine obtained in Step 7 was dissolved in ethyl acetate (0.2 ml) and the mixture was stood at room temperature overnight. The obtained solid was collected by filtration, and dried under reduced pressure to give the title compound (0.0017 g). The solid was analyzed under HPLC analysis condition 3 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 23.27 min)
    isomer with long retention time (retention time 25.39 min)
    • Step 9
  • salt of optically active form (enantiomer with short retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine
    • Step 9-1 Synthesis of Seed Crystal
  • Figure US20150329491A1-20151119-C00101
  • To a mixture of a salt (0.141 g) of the racemic 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine obtained in Step 7 and ethyl acetate (0.70 ml) was added a salt of an optically active form (enantiomer with long retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine obtained in Step 8 as a seed crystal, and the mixture was stirred at room temperature for 30 min. Ethyl acetate (0.7 ml) was added to the mixture, and the mixture was further stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with ethyl acetate (4 ml). The filtrate was successively washed with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue (0.046 g). The residue was dissolved in ethyl acetate (0.50 ml), (S)-(−)-1-phenylethylamine (0.019 ml) was added, and the mixture was stirred at room temperature overnight. This suspension was filtered, and the obtained solid was washed with ethyl acetate (2 ml), and dried. The solid was further mixed with ethyl acetate (0.5 ml), and the mixture was stirred at 70° C. for 30 min, and further at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with ethyl acetate (2 ml), and dried to give the title compound (0.0357 g). The solid was analyzed under HPLC analysis condition 3 to find that an isomer with a short retention time was the main component.
  • isomer with short retention time (retention time 23.57 min)
    isomer with long retention time (retention time 25.65 min)
    • Step 9-2
  • Figure US20150329491A1-20151119-C00102
  • To a solution of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (1.053 g) in ethyl acetate (15 ml) were added at 50° C. (S)-(−)-1-phenylethylamine (0.200 ml) and a seed crystal of a salt of an optically active form (enantiomer with short retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine obtained in Step 9-1, and the mixture was stirred at 50° C. for 5 min and at room temperature for 4 hr. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.400 g). The solid was analyzed under HPLC analysis condition 3 to find that an isomer with a short retention time was the main component.
  • isomer with short retention time (retention time 23.49 min)
    isomer with long retention time (retention time 25.52 min)
    • Step 10
  • optically active form of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid
  • Figure US20150329491A1-20151119-C00103
  • Salt (0.390 g) of an optically active form (enantiomer with short retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine was mixed with ethyl acetate (10 ml), hydrochloric acid was added, and the mixture was partitioned. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.310 g).
  • 1H-NMR (DMSO-D6) δ: 13.10 (1H, br s), 8.06-8.03 (1H, m), 7.97-7.91 (2H, m), 7.75-7.71 (1H, m), 7.61-7.56 (1H, m), 7.51-7.46 (1H, m), 7.35 (1H, s), 2.70 (3H, s).
    • Step 11
  • t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate
  • Figure US20150329491A1-20151119-C00104
  • Under a nitrogen atmosphere, triethylamine (1.2 ml) was added to a mixture of 1-(t-butyloxycarbonyl)-azetidine-3-carboxylic acid (0.804 g), dimethylamine hydrochloride (0.489 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.997 g), 1-hydroxybenzotriazole hydrate (0.796 g), and dimethylformamide (8 ml), and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added ethyl acetate (30 ml), and the mixture was successively washed once with water, once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate and twice with water. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.364 g, 40%).
  • 1H-NMR (CDCl3) δ: 4.17 (2H, br s), 4.05 (2H, t, J=8.5 Hz), 3.52-3.43 (1H, m), 2.97 (3H, s), 2.88 (3H, s), 1.43 (9H, s).
    • Step 12
  • azetidine-3-carboxylic acid dimethylamide hydrochloride
  • Figure US20150329491A1-20151119-C00105
  • A mixture of t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate (0.365 g) and 4N hydrogen chloride/dioxane solution (5 ml) was stirred at room temperature for 5 hr 15 min. The reaction mixture was concentrated under reduced pressure, dioxane was added to the obtained residue and the mixture was concentrated again under reduced pressure. The obtained residue was dried under reduced pressure at 60° C. to give the title compound (0.290 g). The obtained residue was directly used for the next reaction without further purification.
  • 1H-NMR (DMSO-D6) δ: 9.38 (1H, br s), 8.95 (1H, br s), 4.10-3.99 (4H, m), 3.94-3.85 (1H, m), 2.85 (3H, s), 2.82 (3H, s).
    • Step 13
  • (−)-1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic acid dimethylamide
  • Figure US20150329491A1-20151119-C00106
  • To a mixture of an optically active form (0.080 g) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid, azetidine-3-carboxylic acid dimethylamide hydrochloride (0.060 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.065 g), 1-hydroxybenzotriazole hydrate (0.052 g) and dimethylformamide (2 ml) was added triethylamine (0.073 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ethyl acetate (15 ml), and the mixture was successively washed once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate and 3 times with water. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was treated with ethyl ether. This slurry was filtered and the obtained solid was dried to give the title compound (0.054 g, 50%).
  • [α]D=−12.53° (25° C., c=0.744, methanol)
  • 1H-NMR (CDCl3) δ: 7.85-7.74 (3H, m), 7.54-7.48 (1H, m), 7.45-7.38 (2H, m), 4.74-4.64 (1H, m), 4.43-4.32 (2H, m), 4.25-4.11 (1H, m), 3.94-3.86 (1H, m), 3.65-3.54 (1H, m), 2.98 (3H, s), 2.91 (3H, s), 2.64 (3H, s).
  • Using the above-mentioned optically active form of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid as an intermediate and by a similar method, compound Nos. 136 and 152 were synthesized.
    • Example 7 Synthesis of 1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one (compound No. 430) Step 1
  • 2-chloro-5-methoxy-pyridine
  • Figure US20150329491A1-20151119-C00107
  • Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to a mixture of 2-chloro-5-hydroxy-pyridine (2.591 g), methyl iodide (1.50 ml) and dimethylformamide (26 ml), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate and the mixture was placed in a separatory funnel. The organic layer was washed 4 times with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.403 g, 84%).
  • 1H-NMR (CDCl3) δ: 8.07 (1H, d, J=3.0 Hz), 7.24 (1H, dd, J=8.8, 0.7 Hz), 7.20 (1H, dd, J=8.6, 3.0 Hz), 3.87 (3H, s).
    • Step 2
  • 2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide
  • Figure US20150329491A1-20151119-C00108
  • Under an argon atmosphere, a mixture of tripotassium phosphate (6.24 g) and water (15 ml) was added to a mixture of 2-chloro-5-methoxy-pyridine (2.05 g), 2-(diethylcarbamoyl)benzeneboronic acid (4.65 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.584 g) and toluene (30 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, water (20 ml), citric acid (2.2 g) and ethyl acetate were added and the mixture was stirred and filtered through celite. The filtrate was partitioned in a separatory funnel. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/2) to give a roughly purified product (1.144 g) of the title compound. This product was directly used for the next reaction without further purification.
  • 1H-NMR (CDCl3) δ: 8.33 (1H, d, J=2.9 Hz), 7.68 (1H, dd, J=7.7, 1.3 Hz), 7.60 (1H, d, J=8.6 Hz), 7.48-7.32 (3H, m), 7.25-7.15 (1H, m), 3.88 (3H, s), 3.32-2.78 (4H, m), 1.07 (3H, t, J=7.1 Hz), 0.81 (3H, t, J=7.2 Hz).
    • Step 3
  • 3-methoxy-indeno[1,2-b]pyridin-5-one
  • Figure US20150329491A1-20151119-C00109
  • Under an argon atmosphere, a 2.66M solution (1.96 ml) of n-butyllithium in n-hexane was added to a solution of N,N-diisopropylamine (0.734 ml) in tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at 0° C. for 30 min. To this mixture was added a solution (10 ml) of 2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide (1.14 g) in tetrahydrofuran at 0° C. and the mixture was stirred at 0° C. for 30 min, and further at room temperature for 1 hr. To the reaction mixture was added aqueous ammonium chloride solution and the mixture was placed in a separatory funnel, and separated into layers by adding ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was treated with ethyl ether at room temperature for 1 hr. This slurry was filtered, and the obtained solid was dried to give the title compound (0.183 g, 22%). The filtrate was concentrated under reduced pressure and the obtained residue was treated with ethyl ether at room temperature for 20 min. This slurry was filtered, and the obtained solid was dried to further give the title compound (0.128 g, 15%). The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to further give the title compound (0.134 g, 16%).
  • 1H-NMR (DMSO-D6) δ: 8.37 (1H, d, J=2.8 Hz), 7.73-7.64 (3H, m), 7.60 (1H, d, J=3.0 Hz), 7.46-7.42 (1H, m), 3.91 (3H, s).
    • Step 4
  • 3-hydroxy-indeno[1,2-b]pyridin-5-one
    [
    Figure US20150329491A1-20151119-P00001
    118]
  • Figure US20150329491A1-20151119-C00110
  • Under an argon atmosphere, 3-methoxy-indeno[1,2-b]pyridin-5-one (0.545 g) and pyridinium chloride (5.89 g) were mixed with pyridine (1.0 ml). The reaction mixture was stirred with heating at 180° C. for 30 min while evaporating pyridine, and further stirred with heating at 200° C. for 4 hr. The mixture was cooled to room temperature, water was added and the mixture was stirred for 30 min. This slurry was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.054 g). The obtained solid was used for the next reaction without further purification.
  • 1H-NMR (DMSO-D6) δ: 10.53 (1H, br s), 8.19 (1H, d, J=2.8 Hz), 7.68-7.61 (3H, m), 7.43-7.38 (1H, m), 7.29 (1H, d, J=2.6 Hz).
    • Step 5
  • 3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one
  • Figure US20150329491A1-20151119-C00111
  • 3-Hydroxy-indeno[1,2-b]pyridin-5-one (0.0500 g), di-t-butyl azodicarboxylate (0.087 g) and triphenylphosphine (0.10 g) were mixed with tetrahydrofuran (1.0 ml), 1-(2-hydroxy-ethyl)-2-pyrrolidone (0.043 ml) was added thereto, and the mixture was stirred at room temperature for 1 day. The mixture was purified by preparative thin layer chromatography (silica gel, eluent: ethyl acetate/methanol=10/1) to give the title compound (0.0386 g, 49%).
  • 1H-NMR (DMSO-D6) δ: 8.36 (1H, d, J=2.8 Hz), 7.73-7.64 (3H, m), 7.63 (1H, d, J=2.8 Hz), 7.47-7.42 (1H, m), 4.27 (2H, t, J=5.4 Hz), 3.57 (2H, t, J=5.4 Hz), 3.49-3.44 (2H, m), 2.25-2.19 (2H, m), 1.97-1.87 (2H, m).
    • Step 6
  • 1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one
  • Figure US20150329491A1-20151119-C00112
  • 3-[2-(2-Oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one (0.0376 g) and potassium carbonate (0.001 g) were mixed with dimethylformamide (1.0 ml), and the mixture was stirred at 0° C. To this mixture was added trimethyl(trifluoromethyl)silane (0.035 ml), and the mixture was stirred at 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.018 ml) was further added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added acetic acid (0.010 ml), then a 1M solution (0.12 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added ethyl acetate (20 ml), and the mixture was placed in a separatory funnel. The organic layer was washed 3 times with water (10 ml) and once with saturated brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica gel, eluent: n-hexane/ethyl acetate=7/3) to give the title compound (0.0389 g, 68%).
  • 1H-NMR (DMSO-D6) δ: 8.36 (1H, d, J=2.8 Hz), 7.82-7.78 (1H, m), 7.71-7.66 (1H, m), 7.60-7.54 (2H, m), 7.50 (1H, s), 7.48-7.43 (1H, m), 4.25 (2H, t, J=5.4 Hz), 3.59 (2H, t, J=5.4 Hz), 3.51-3.45 (2H, m), 2.26-2.19 (2H, m), 1.97-1.88 (2H, m).
    • Example 8 Synthesis of optically active form of (4-bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid methyl ester (compound No. 451) and the like Step 1
  • salt of optically active form of (4-bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid and (S)-(−)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00113
  • (4-Bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid (0.176 g) and (S)-(−)-1-phenylethylamine (0.057 ml) were mixed with ethyl acetate (1 ml). The mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and the mixture was concentrated under reduced pressure to give a residue (0.233 g). Under a nitrogen atmosphere, the residue (0.160 g) and ethyl acetate (2.0 ml) were mixed. The mixture was stirred with heating at 80° C. until insoluble material was solved, and stirred at room temperature overnight. This suspension was filtered to give a solid (0.044 g). The solid was mixed with ethyl ether/ethyl acetate (1:1, 1 ml), and the mixture was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was washed with ethyl ether/ethyl acetate (1:1, 2 ml). The obtained solid was dried under reduced pressure to give the title compound (0.023 g). The solid was analyzed under HPLC analysis condition 2 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 16.50 min)
    isomer with long retention time (retention time 17.58 min)
  • Using the salt as an intermediate, compound Nos. 451, 467, 474, 475 and 477 were synthesized.
    • Example 9 Synthesis of optically active form of 4-[9-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-9-trifluoromethyl-9H-fluoren-2-yloxy]-butyric acid (compound No. 504) and the like Step 1
  • salt of optically active form of 4-(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid and (S)-(−)-1-(4-methylphenyl)ethylamine
  • Figure US20150329491A1-20151119-C00114
  • 4-(4-Chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid (0.100 g) and isopropyl ether (2.0 ml) were mixed, (S)-(−)-1-(4-methylphenyl)ethylamine (0.0189 ml) was added, and the mixture was stirred at room temperature for 17 hr. This suspension was filtered to give a salt (0.0403 g) of an optically active form of 4-(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid and (S)-(−)-1-(4-methylphenyl)ethylamine. The solid was analyzed under HPLC analysis condition 2 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 19.97 min)
    isomer with long retention time (retention time 22.06 min)
  • Using this salt as an intermediate, compound Nos. 504, 553, 554, 561, 573, 577, 604, 624, 669, 676, 678, 679, 680, 681, 683, 684, 688, 689 and 698 were synthesized.
    • Example 10 Synthesis of optically active form of (4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid methyl ester (compound No. 481) and the like Step 1
  • salt of optically active form of (4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid and (S)-(−)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00115
  • Under a nitrogen atmosphere, (S)-(−)-1-phenylethylamine (0.011 ml) was added to a mixture of (4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid (0.100 g) and isopropyl ether (5.0 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.0414 g). The solid was analyzed under HPLC analysis condition 2 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 15.67 min)
    isomer with long retention time (retention time 16.39 min)
  • Using this salt as an intermediate, compound Nos. 481, 540, 541, 542, 552, 581, 582, 588, 589, 614 and 619 were synthesized.
    • Example 11 Synthesis of optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid methyl ester (compound No. 647) and the like
  • Salt of optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine
  • Figure US20150329491A1-20151119-C00116
    • Step 1-1 Synthesis of Seed Crystal
  • To a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.050 g) and isopropyl ether (0.250 ml) was added (S)-(−)-1-phenylethylamine (0.020 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered to give a solid (0.060 g). The solid was added as a seed crystal to a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.050 g), (S)-(−)-1-phenylethylamine (0.020 ml) and ethyl acetate (0.250 ml), which had been stirred overnight at room temperature in advance, and the mixture was further stirred at room temperature overnight. The resulting suspension was filtered, and the obtained solid was washed with ethyl acetate. The solid was dried under reduced pressure to give the title compound (0.019 g). The solid was analyzed under HPLC analysis condition 4 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 20.09 min)
    isomer with long retention time (retention time 21.19 min)
    • Step 1-2
  • Under an argon atmosphere, (S)-(−)-1-phenylethylamine (0.392 ml) and a seed crystal of a salt of an optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine were added to a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (1.000 g) and ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 days. This suspension was filtered, and the obtained solid was washed with ethyl acetate (3 ml). The solid was dried under reduced pressure to give the title compound (0.466 g). The solid was analyzed under HPLC analysis condition 4 to find that an isomer with a long retention time was the main component.
  • isomer with short retention time (retention time 19.91 min)
    isomer with long retention time (retention time 21.00 min)
  • Using this salt as an intermediate, compound Nos. 647, 657, 664 and 665 were synthesized.
    • Example 12 Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-hydroxymethyl-propane-1,3-diol (compound No. 703) Step 1
  • optically active form of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionic acid
  • Figure US20150329491A1-20151119-C00117
  • To a solution of an optically active form (33.3 g) of t-butyl [4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate and paraformaldehyde (18.3 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (244 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 90° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid (400 ml), m and the mixture was extracted with ethyl acetate (200 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (28.3 g).
  • 1H-NMR (DMSO-D6) δ: 13.13 (1H, br s), 8.12 (1H, d, J=0.7 Hz), 7.73 (1H, d, J=0.5 Hz), 7.66-7.61 (1H, m), 7.48-7.45 (1H, m), 7.42-7.38 (2H, m), 7.36-7.31 (1H, m), 7.28-7.19 (2H, m), 5.15 (2H, br s), 4.24-4.07 (4H, m).
    • Step 2
  • (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-hydroxymethyl-propane-1,3-diol
  • Figure US20150329491A1-20151119-C00118
  • To a solution of an optically active form (28.3 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionic acid in tetrahydrofuran (40 ml) were successively added dropwise at room temperature a 0.93M solution (225 ml) of borane-tetrahydrofuran complex in tetrahydrofuran and a 1.09M solution (32 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture, ethanol (57 ml) was added dropwise at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (150 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. A solution of the obtained residue in ethanol (50 ml) was cooled to 0° C., sodium borohydride (2.3 g) was added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted again with ethyl acetate (50 ml). The combined organic layer was successively washed with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 9/1) to give the title compound (21.6 g).
  • [α]D=+71.5° (25° C., c=1.000, methanol)
  • 1H-NMR (DMSO-D6) δ: 8.05 (1H, d, J=0.7 Hz), 7.70 (1H, d, J=0.7 Hz), 7.65-7.61 (1H, m), 7.51-7.47 (1H, m), 7.40-7.36 (2H, m), 7.35-7.30 (1H, m), 7.29-7.24 (1H, m), 7.21-7.17 (1H, m), 4.83 (3H, t, J=5.4 Hz), 3.90 (6H, d, J=5.6 Hz).
    • Example 13 Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-methyl-propane-1,3-diol (compound No. 673) Step 1
  • 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester
  • Figure US20150329491A1-20151119-C00119
  • To a suspension of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added 2-bromo-propionic acid ethyl ester (13 ml) and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled to 0° C., and toluene (100 ml) and water (150 ml) were successively added dropwise. The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml). The combined organic layer was successively washed once with 10% aqueous potassium carbonate (50 ml), twice with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21.6 g).
  • 1H-NMR (CDCl3) δ: 7.85 (1H, s), 7.81 (1H, s), 5.10 (1H, q, J=7.3 Hz), 4.19 (2H, q, J=7.1 Hz), 1.78 (3H, d, J=7.4 Hz), 1.32 (12H, s), 1.25 (3H, t, J=7.2 Hz).
    • Step 2
  • optically active form of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester
  • Figure US20150329491A1-20151119-C00120
  • To a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester (29.2 g), (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (20.4 g), and sodium hydrogen carbonate (11.1 g) in toluene/water (200 ml/66 ml) were added palladium acetate (743 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.72 g) at room temperature, and the mixture was stirred at 115° C. for 8 hr. To the reaction mixture were added activated carbon (10 g) and Celite (10 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with toluene (100 ml). The filtrate was partitioned, and the aqueous layer was extracted with toluene (60 ml). The combined organic layer was washed 3 times with water (100 ml), and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in toluene/ethyl acetate (3/1, 130 ml) was added silica gel (40 g), and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1 to 2/1) to give the title compound (27.9 g).
  • 1H-NMR (DMSO-D6) δ: 8.20-8.18 (1H, m), 7.72-7.71 (1H, m), 7.67-7.63 (1H, m), 7.44-7.40 (2H, m), 7.37-7.23 (4H, m), 5.40-5.34 (1H, m), 4.22-4.15 (2H, m), 1.78-1.75 (3H, m), 1.23-1.18 (3H, m).
    • Step 3
  • optically active form of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid
  • Figure US20150329491A1-20151119-C00121
  • To a solution of an optically active form (27.9 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester and paraformaldehyde (17.0 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (170 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was filtered through celite, and the solid was washed with ethyl acetate (100 ml). To the filtrate was added 1N hydrochloric acid (400 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (26.6 g).
  • 1H-NMR (DMSO-D6) δ: 8.19-8.17 (1H, m), 7.71-7.70 (1H, m), 7.66-7.61 (1H, m), 7.46-7.19 (7H, m), 5.35-5.22 (1H, m), 4.21-4.12 (1H, m), 3.96-3.88 (1H, m), 1.80 (3H, s).
    • Step 4
  • (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-methyl-propane-1,3-diol
  • Figure US20150329491A1-20151119-C00122
  • To a solution of an optically active form (26.6 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid in tetrahydrofuran (40 ml) was added dropwise at room temperature a 1.09M solution (200 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture was added dropwise ethanol (25 ml) at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) and the mixture was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (17.4 g).
  • [α]D=+72.4° (25° C., c=1.004, methanol)
  • 1H-NMR (DMSO-D6) δ: 8.05 (1H, d, J=0.7 Hz), 7.68 (1H, d, J=0.7 Hz), 7.65-7.62 (1H, m), 7.44-7.42 (1H, m), 7.40-7.36 (2H, m), 7.35-7.26 (2H, m), 7.21-7.17 (1H, m), 4.98-4.93 (2H, m), 3.84-3.79 (2H, m), 3.76-3.70 (2H, m), 1.52 (3H, s).
    • Example 14 Synthesis of (+)-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol (compound No. 707) Step 1
  • optically active form of [4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetic acid t-butyl ester
  • Figure US20150329491A1-20151119-C00123
  • To a suspension of t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetate (24.8 g), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (20.0 g), and sodium hydrogen carbonate (11.3 g) in toluene/water (200 ml/60 ml) were added palladium acetate (750 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.75 g) at room temperature and the mixture was stirred at 110° C. for 2 hr. To the reaction mixture were added water (80 ml) and activated carbon (2.0 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with tetrahydrofuran (100 ml). The filtrate was partitioned and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), anhydrous sodium sulfate and silica gel (40 g) were added, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was treated with n-hexane/ethyl acetate (2/1, 120 ml) solution, and the resulting slurry was filtered to give the title compound (17.8 g).
  • 1H-NMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.65 (1H, d, J=0.7 Hz), 7.60 (1H, d, J=0.7 Hz), 7.51-7.49 (1H, m), 7.40-7.37 (1H, m), 7.28-7.23 (2H, m), 7.14-7.13 (1H, m), 4.93 (1H, d, J=17.4 Hz), 4.88 (1H, d, J=17.4 Hz), 4.80 (1H, s), 2.42 (3H, s), 1.52 (9H, s).
    • Step 2
  • optically active form of 3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid
  • Figure US20150329491A1-20151119-C00124
  • To a solution of an optically active form (17.8 g) of t-butyl [4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate and paraformaldehyde (12.0 g) in dimethylformamide (60 ml) was added at room temperature a 1M solution (120 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 95° C. for 3 hr. To the reaction mixture were added 1N hydrochloric acid (180 ml) and water (90 ml), and the mixture was extracted with ethyl acetate (180 ml). The separated aqueous layer was extracted twice with ethyl acetate (90 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (90 ml), twice with water (90 ml) and once with saturated brine (90 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (15.5 g).
  • 1H-NMR (DMSO-D6) δ: 13.10 (1H, br s), 8.03 (1H, s), 7.65 (1H, s), 7.63-7.59 (1H, m), 7.44-7.40 (2H, m), 7.31-7.27 (1H, m), 7.25-7.20 (1H, m), 7.15 (2H, s), 5.14 (2H, br s), 4.21-4.09 (4H, m), 2.39 (3H, s).
    • Step 3
  • (+)-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol
  • Figure US20150329491A1-20151119-C00125
  • To a solution of an optically active form (15.5 g) of 3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid in tetrahydrofuran (31 ml) was added dropwise at room temperature a 1.09M solution (127 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 5 hr. To the reaction mixture was added dropwise ethanol (15 ml) at room temperature and the mixture was stirred at 75° C. for 1 hr. To this mixture were added water (90 ml) and saturated aqueous sodium hydrogen carbonate (150 ml), and the mixture was extracted twice with ethyl acetate (150 ml, 75 ml). The combined organic layer was successively washed once with saturated aqueous sodium hydrogen carbonate (75 ml), twice with water (75 ml) and once with saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in ethanol (45 ml) was added sodium borohydride (1.3 g) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid (150 ml), and the mixture was extracted with ethyl acetate (150 ml). The separated aqueous layer was extracted again with ethyl acetate (75 ml). The combined organic layer was successively washed with water (75 ml), saturated aqueous sodium hydrogen carbonate (75 ml), water (75 ml) and saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (12.6 g).
  • [α]D=+65.6° (25° C., c=1.008, methanol)
  • 1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J=0.7 Hz), 7.63-7.59 (1H, m), 7.62 (1H, d, J=0.7 Hz), 7.46-7.40 (2H, m), 7.31-7.21 (2H, m), 7.14 (2H, s), 4.82 (3H, t, J=5.6 Hz), 3.91 (6H, d, J=5.6 Hz), 2.39 (3H, s).
  • In the same manner as in the above-mentioned Examples, the compound Nos. 1 to 707 including the compounds shown in the above-mentioned Examples were obtained. The structural formulas and 1H-NMR spectrum data of the obtained compounds are shown in Table 1-1 to Table 1-106.
  • In the Tables, optically active compounds are indicated with (optically active form) under compound No. Among them, those measured for optical rotation are marked with (+) or (−) in the structural formulas.
  • 1H-NMR spectrum was measured in CDCl3 or DMSO-D6 using tetramethylsilane as an internal standard, and all δ values are shown in ppm.
  • The symbols in the Tables mean the following.
  • s: singlet
    d: doublet
    t: triplet
    q: quartet
    dd: double doublet
    ddd: double double doublet
    brs: broad singlet
    m: multiplet
    J: coupling constant
  • TABLE 1-1
    com-
    pound
    No. structural formula NMR
    1
    Figure US20150329491A1-20151119-C00126
         		1H-NMR (DMSO-D6) δ: 8.65 (1H, dd, J = 5.1, 1.6 Hz), 8.04-8.01 (1H, m), 7.92-7.90 (1H, m), 7.75-7.72 (1H, m), 7.63- 7.59 (1H, m), 7.57-7.52 (1H, m), 7.50 (1H, s), 7.39 (1H, dd, J = 7.7, 4.9 Hz).
    2
    Figure US20150329491A1-20151119-C00127
         		1H-NMR (DMSO-D6) δ: 7.85 (1H, d, J = 7.7 Hz), 7.70-7.66 (1H, m), 7.55- 7.49 (2H, m), 7.42-7.38 (1H, m), 7.32-7.27 (2H, m), 7.17 (1H, s), 2.64 (3H, s).
    3
    Figure US20150329491A1-20151119-C00128
         		1H-NMR (DMSO-D6) δ: 7.79 (1H, d, J = 7.5 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.63-7.59 (1H, m), 7.50- 7.44 (2H, m), 7.37-7.30 (2H, m), 7.17 (1H, s), 2.39 (3H, s).
    4
    Figure US20150329491A1-20151119-C00129
         		1H-NMR (DMSO-D6) δ: 7.92 (1H, dd, J = 8.4, 5.1 Hz), 7.86 (1H, d, J = 7.5 Hz), 7.66-7.62 (1H, m), 7.54-7.49 (1H, m), 7.44-7.34 (4H, m).
    5
    Figure US20150329491A1-20151119-C00130
         		1H-NMR (CDCl3) δ: 7.71-7.67 (2H, m), 7.65-7.63 (1H, m), 7.59 (1H, d, J = 7.9 Hz), 7.51-7.44 (2H, m), 7.40-7.36 (1H, m), 2.71 (1H, s).
    6
    Figure US20150329491A1-20151119-C00131
         		1H-NMR (CDCl3) δ: 8.34 (1H, d, J = 7.7 Hz), 7.75-7.71 (1H, m), 7.65-7.61 (1H, m), 7.55- 7.51 (1H, m), 7.46-7.40 (2H, m), 7.32-7.27 (1H, m), 2.71 (1H, br s).
    7
    Figure US20150329491A1-20151119-C00132
         		1H-NMR (CDCl3) δ: 7.86- 7.83 (1H, m), 7.72-7.61 (3H, m),m7.56-7.48 (2H, m), 7.43-7.38 (1H, m), 2.73 (1H, s).
  • TABLE 1-2
    compound
    No. structural formula NMR
     8
    Figure US20150329491A1-20151119-C00133
         		1H-NMR (CDCl3) δ: 7.74-7.71 (1H, m), 7.66-7.63 (1H, m), 7.60-7.57 (1H, m), 7.51-7.46 (1H, m), 7.43-7.37 (2H, m), 7.29-7.26 (1H, m), 3.73 (1H, s).
     9
    Figure US20150329491A1-20151119-C00134
         		1H-NMR (CDCl3) δ: 7.72-7.68 (1H, m), 7.65-7.60 (3H, m), 7.52-7.47 (1H, m), 7.42-7.37 (1H, m), 7.33 (1H, dd, J = 8.1, 1.9 Hz), 2.69 (1H, s).
    10
    Figure US20150329491A1-20151119-C00135
         		1H-NMR (DMSO-D6) δ: 7.81 (1H, d, J = 7.5 Hz), 7.68-7.66 (1H, m), 7.64-7.60 (1H, m), 7.53- 7.47 (2H, m), 7.39-7.35 (1H, m), 7.21-7.17 (1H, m), 7.15 (1H, s), 2.40 (3H, s).
    11
    Figure US20150329491A1-20151119-C00136
         		1H-NMR (DMSO-D6) δ: 7.81-7.78 (1H, m), 7.71-7.68 (1H, m), 7.59-7.54 (1H, m), 7.53-7.50 (1H, m), 7.49-7.43 (2H, m), 7.44 (1H, s), 7.41-7.36 (1H, m).
    12
    Figure US20150329491A1-20151119-C00137
         		1H-NMR (DMSO-D6) δ: 7.93-7.90 (1H, m), 7.79 (1H, dd, J = 9.0, 2.3 Hz), 7.67-7.63 (2H, m), 7.56-7.52 (1H, m), 7.45- 7.41 (1H, m), 7.31 (1H, s), 7.23-7.17 (1H, m).
    13
    Figure US20150329491A1-20151119-C00138
         		1H-NMR (DMSO-D6) δ: 7.90 (1H, d, J = 7.4 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.68-7.65 (1H, m), 7.60-7.52 (2H, m), 7.46- 7.41 (1H, m), 7.40 (1H, s), 7.21-7.15 (1H, m).
    14
    Figure US20150329491A1-20151119-C00139
         		1H-NMR (CDCl3) δ: 7.67-7.65 (2H, m), 7.55 (2H, d, J = 8.1 Hz), 7.46 (2H, dd, J = 8.1, 2.1 Hz), 2.77 (1H, s).
  • TABLE 1-3
    compound
    No. structural formula NMR
    15
    Figure US20150329491A1-20151119-C00140
         		1H-NMR (DMSO-D6) δ: 8.67 (1H, dd, J = 5.1, 1.5 Hz), 8.03- 7.99 (1H, m), 7.57-7.53 (1H, m), 7.43-7.34 (4H, m), 2.80 (3H, s).
    16
    Figure US20150329491A1-20151119-C00141
         		1H-NMR (DMSO-D6) δ: 8.61 (1H, dd, J = 5.1, 1.3 Hz), 7.98 (1H, d, J = 7.5 Hz), 7.78 (1H, d, J = 7.7 Hz), 7.56-7.53 (1H, m), 7.44-7.40 (2H, m), 7.35 (1H, dd, J = 7.6, 5.0 Hz), 2.43 (3H, s).
    17
    Figure US20150329491A1-20151119-C00142
         		1H-NMR (CDCl3) δ: 7.67 (1H, d, J = 7.9 Hz), 7.56-7.53 (2H, m), 7.30-7.27 (1H, m), 7.24- 7.22 (2H, m), 2.66 (1H, br s), 2.64 (3H, s), 2.44 (3H, s).
    18
    Figure US20150329491A1-20151119-C00143
         		1H-NMR (CDCl3) δ: 7.74 (1H, d, J = 7.7 Hz), 7.72-7.69 (1H, m), 7.49-7.44 (1H, m), 7.38- 7.36 (1H, m), 7.34-7.30 (1H, m), 7.08-7.06 (1H, m), 2.66 (1H, br s), 2.62 (3H, s), 2.39 (3H, s).
    19
    Figure US20150329491A1-20151119-C00144
         		1H-NMR (DMSO-D6) δ: 9.95 (1H, br s), 7.77 (1H, d, J = 7.5 Hz), 7.67-7.62 (1H, m), 7.54- 7.48 (2H, m), 7.42-7.35 (3H, m), 7.26 (1H, s), 2.17 (3H, br s).
    20
    Figure US20150329491A1-20151119-C00145
         		1H-NMR (DMSO-D6) δ: 7.89 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m), 7.50-7.45 (1H, m), 7.35- 7.31 (1H, m), 7.21-7.17 (1H, m), 7.15-7.07 (1H, m), 7.05- 6.98 (1H, m), 6.13 (3H, br s).
    21
    Figure US20150329491A1-20151119-C00146
         		1H-NMR (DMSO-D6) δ: 8.28-8.25 (1H, m), 7.80 (1H, d, J = 1.8 Hz), 7.74-7.71 (1H, m), 7.66- 7.64 (1H, m), 7.64-7.59 (1H, m), 7.61 (1H, s), 7.55-7.51 (1H, m).
  • TABLE 1-4
    compound
    No. structural formula NMR
    22
    Figure US20150329491A1-20151119-C00147
         		1H-NMR (DMSO-D6) δ: 10.14 (1H, br s), 7.97-7.96 (1H, m), 7.77-7.74 (2H, m), 7.71-7.68 (1H, m), 7.62-7.59 (1H, m), 7.49-7.45 (1H, m), 7.34-7.30 (1H, m), 7.22 (1H, s), 2.07 (3H, s).
    23
    Figure US20150329491A1-20151119-C00148
         		1H-NMR (DMSO-D6) δ: 8.20-8.18 (1H, m), 8.14 (1H, dd, J = 8.0, 1.5 Hz), 8.03 (1H, d, J = 7.7 Hz), 8.00-7.97 (1H, m), 7.72-7.68 (1H, m), 7.60-7.56 (1H, m), 7.51-7.47 (1H, m), 7.48 (1H, s), 3.90 (3H, s).
    24
    Figure US20150329491A1-20151119-C00149
         		1H-NMR (DMSO-D6) δ: 13.18 (1H, br s), 8.19-8.17 (1H, m), 8.11 (1H, dd, J = 8.0, 1.5 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.98-7.95 (1H, m), 7.71-7.68 (1H, m), 7.59-7.55 (1H, m), 7.50-7.45 (1H, m), 7.43 (1H, s).
    25
    Figure US20150329491A1-20151119-C00150
         		1H-NMR (DMSO-D6) δ: 7.83 (1H, d, J = 7.7 Hz), 7.70-7.66 (1H, m), 7.56-7.49 (2H, m), 7.42- 7.37 (1H, m), 7.33 (2H, d, J = 4.9 Hz), 7.16 (1H, s), 3.09- 2.95 (2H, m), 1.28 (3H, t, J = 7.5 Hz).
    26
    Figure US20150329491A1-20151119-C00151
         		1H-NMR (DMSO-D6) δ: 7.62 (1H, d, J = 7.5 Hz), 7.57-7.54 (1H, m), 7.47-7.41 (1H, m), 7.34- 7.29 (1H, m), 7.28-7.24 (1H, m), 6.92 (1H, d, J = 2.0 Hz), 6.83 (1H, s), 6.53 (1H, dd, J = 8.3, 2.1 Hz), 5.44 (2H, br s).
    27
    Figure US20150329491A1-20151119-C00152
         		1H-NMR (DMSO-D6) δ: 8.07-8.04 (1H, m), 7.88-7.82 (2H, m), 7.72-7.68 (1H, m), 7.55-7.44 (3H, m), 7.36 (1H, s), 3.97 (3H, s).
    28
    Figure US20150329491A1-20151119-C00153
         		1H-NMR (DMSO-D6) δ: 10.17 (1H, br s), 8.06 (1H, d, J = 1.6 Hz), 7.73-7.70 (1H, m), 7.64- 7.61 (1H, m), 7.57-7.53 (1H, m), 7.53-7.47 (2H, m), 7.41- 7.37 (1H, m), 7.16 (1H, s), 2.09 (3H, 3).
  • TABLE 1-5
    compound
    No. structural formula NMR
    29
    Figure US20150329491A1-20151119-C00154
         		1H-NMR (DMSO-D6) δ: 8.18-8.16 (1H, m), 8.12 (1H, br s), 8.05 (1H, dd, J = 8.0, 1.5 Hz), 7.96-7.92 (2H, m), 7.69-7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (2H, m), 7.35 (1H, s).
    30
    Figure US20150329491A1-20151119-C00155
         		1H-NMR (DMSO-D6) δ: 8.63-8.55 (1H, m), 8.15-8.11 (1H, m), 8.00 (1H, dd, J = 7.9, 1.6 Hz), 7.96-7.91 (2H, m), 7.69- 7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.42 (1H, m), 7.36 (1H, s), 2.81 (3H, d, J = 4.6 Hz).
    31
    Figure US20150329491A1-20151119-C00156
         		1H-NMR (DMSO-D6) δ: 7.94-7.91 (2H, m), 7.68-7.65 (1H, m), 7.63-7.62 (1H, m), 7.58-7.52 (2H, m), 7.46-7.41 (1H, m), 7.37 (1H, s), 3.00 (3H, br s), 2.96 (3H, br s).
    32
    Figure US20150329491A1-20151119-C00157
         		1H-NMR (DMSO-D6) δ: 13.52 (1H, br s), 8.23 (1H, d, J = 7.5 Hz), 7.84-7.80 (2H, m), 7.71- 7.67 (1H, m), 7.54-7.42 (3H, m), 7.31 (1H, br s).
    33
    Figure US20150329491A1-20151119-C00158
         		1H-NMR (DMSO-D6) δ: 8.11 (1H, br s), 7.94 (1H, d, J = 7.7 Hz), 7.72-7.64 (3H, m), 7.50- 7.38 (4H, m), 7.28 (1H, s).
    34
    Figure US20150329491A1-20151119-C00159
         		1H-NMR (DMSO-D6) δ: 8.62-8.54 (1H, m), 7.77-7.74 (1H, m), 7.72-7.69 (1H, m), 7.68-7.64 (1H, m), 7.50-7.38 (4H, m), 7.29 (1H, s), 2.86 (3H, d, J = 4.4 Hz).
    35
    Figure US20150329491A1-20151119-C00160
         		1H-NMR (DMSO-D6) δ: 7.71-7.66 (2H, m), 7.53-7.34 (5H, m), 7.33 (1H, br s), 3.14 (3H, s), 2.76 (3H, s).
  • TABLE 1-6
    compound
    No. structural formula NMR
    36
    Figure US20150329491A1-20151119-C00161
         		1H-NMR (DMSO-D6) δ: 8.73 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 1.5 Hz), 7.93-7.89 (1H, m), 7.76-7.73 (1H, m), 7.67-7.56 (2H, m), 7.66 (1H, s).
    37
    Figure US20150329491A1-20151119-C00162
         		1H-NMR (DMSO-D6) δ: 7.78-7.73 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.17- 7.15 (1H, m), 7.07 (1H, dd, J = 8.3, 2.6 Hz), 3.83 (3H, s).
    38
    Figure US20150329491A1-20151119-C00163
         		1H-NMR (DMSO-D6) δ: 9.82 (1H, s), 7.67 (1H, d, J = 7.4 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.15 (1H, s), 7.07-7.04 (1H, m), 6.87 (1H, dd, J = 8.1, 2.3 Hz).
    39
    Figure US20150329491A1-20151119-C00164
         		1H-NMR (DMSO-D6) δ: 7.80 (1H, d, J = 7.4 Hz), 7.75 (1H, d, J = 7.7 Hz), 7.63-7.59 (1H, m), 7.50-7.46 (2H, m), 7.37-7.32 (2H, m), 7.19 (1H, s), 2.69 (2H, q, J = 7.6 Hz), 1.22 (3H, t, J = 7.5 Hz).
    40
    Figure US20150329491A1-20151119-C00165
         		1H-NMR (DMSO-D6) δ: 8.41 (1H, d, J = 0.9 Hz), 8.05-7.99 (2H, m), 7.81-7.77 (1H, m), 7.70- 7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.44 (1H, s), 3.92 (3H, s).
    41
    Figure US20150329491A1-20151119-C00166
         		1H-NMR (DMSO-D6) δ: 13.23 (1H, br s), 8.38 (1H, d, J = 0.9 Hz), 8.02-7.97 (2H, m), 7.78- 7.74 (1H, m), 7.69-7.65 (1H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.41 (1H, s).
    42
    Figure US20150329491A1-20151119-C00167
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 1.1 Hz), 8.08 (1H, br s), 7.90-7.86 (2H, m), 7.71- 7.65 (2H, m), 7.57-7.53 (1H, m), 7.51 (1H, br s), 7.45-7.41 (1H, m), 7.35 (1H, s).
  • TABLE 1-7
    compound
    No. structural formula NMR
    43
    Figure US20150329491A1-20151119-C00168
         		1H-NMR (DMSO-D6) δ: 8.59-8.53 (1H, m), 8.26 (1H, d, J = 1.1 Hz), 7.89 (1H, d, J = 7.5 Hz) 7.82 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.69 (1H, m), 7.68- 7.65 (1H, m), 7.58-7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 2.83 (3H, d, J = 4.6 Hz).
    44
    Figure US20150329491A1-20151119-C00169
         		1H-NMR (DMSO-D6) δ: 7.96-7.91 (2H, m), 7.69-7.64 (2H, m), 7.55-7.50 (1H, m), 7.44-7.37 (2H, m), 7.33 (1H, s), 3.03 (3H, br s), 2.94 (3H, br s).
    45
    Figure US20150329491A1-20151119-C00170
         		1H-NMR (DMSO-D6) δ: 8.07-8.04 (1H, m), 7.98-7.94 (2H, m), 7.76-7.71 (1H, m), 7.62-7.57 (1H, m), 7.52-7.47 (1H, m), 7.41 (1H, s), 3.89 (3H, s), 2.71 (3H, s).
    46
    Figure US20150329491A1-20151119-C00171
         		1H-NMR (DMSO-D6) δ: 7.93 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m), 7.50-7.45 (1H, m), 7.40- 7.32 (2H, m), 7.27-7.23 (1H, m), 7.20 (1H, s), 7.17 (1H, d, J = 8.4 Hz), 3.98 (3H, s).
    47
    Figure US20150329491A1-20151119-C00172
         		1H-NMR (DMSO-D6) δ: 7.87 (1H, d, J = 7.5 Hz), 7.63-7.59 (1H, m), 7.54-7.47 (2H, m), 7.46 (1H, d, J = 2.4 Hz), 7.40-7.35 (1H, m), 7.10 (1H, s), 6.92 (1H, dd, J = 8.4, 2.4 Hz), 3.85 (3H, s).
    48
    Figure US20150329491A1-20151119-C00173
         		1H-NMR (CDCl3) δ: 8.29 (1H, d, J = 7.9 Hz), 7.91-7.84 (2H, m), 7.75-7.70 (1H, m), 7.50- 7.45 (1H, m), 7.42-7.38 (2H, m), 4.48 (2H, q, J = 7.1 Hz), 2.72 (1H, s), 1.45 (3H, t, J = 7.2 Hz).
    49
    Figure US20150329491A1-20151119-C00174
         		1H-NMR (DMSO-D6) δ: 8.23-8.19 (1H, m), 7.98 (2H, d, J = 7.9 Hz), 7.79-7.75 (1H, m), 7.71- 7.66 (1H, m), 7.63-7.54 (2H, m), 7.55 (1H, s).
  • TABLE 1-8
    compound
    No. structural formula NMR
    50
    Figure US20150329491A1-20151119-C00175
         		1H-NMR (CDCl3) δ: 8.54 (1H, d, J = 1.5 Hz), 8.45 (1H, br s), 8.37-8.33 (1H, m), 7.79-7.74 (1H, m), 7.54-7.44 (2H, m), 4.03 (3H, s), 3.96 (3H, s), 3.03 (0H, s).
    51
    Figure US20150329491A1-20151119-C00176
         		1H-NMR (CDCl3) δ: 7.76-7.72 (1H, m), 7.68-7.65 (1H, m), 7.64-7.61 (1H, m), 7.59 (1H, d, J = 7.7 Hz), 7.52-7.47 (1H, m), 7.42-7.34 (2H, m), 3.97 (1H, br s), 3.53 (1H, br s), 3.26 (1H, br s), 3.03-2.91 (3H, m), 1.26-1.10 (3H, m).
    52
    Figure US20150329491A1-20151119-C00177
         		1H-NMR (CDCl3) δ: 7.75-7.72 (1H, m), 7.68-7.65 (1H, m), 7.63-7.61 (1H, m), 7.60 (1H, d, J = 7.7 Hz), 7.52-7.47 (1H, m), 7.42-7.36 (2H, m), 3.87 (1H, s), 3.75-3.22 (4H, m), 1.73-1.43 (6H, m).
    53
    Figure US20150329491A1-20151119-C00178
         		1H-NMR (CDCl3) δ: 7.77-7.72 (2H, m), 7.69-7.65 (1H, m), 7.60-7.57 (1H, m), 7.52-7.47 (2H, m), 7.43-7.38 (1H, m), 4.36 (1H, br s), 3.62-3.35 (4H, m), 1.98-1.80 (4H, m).
    54
    Figure US20150329491A1-20151119-C00179
         		1H-NMR (CDCl3) δ: 7.76-7-72 (1H, m), 7.68-7.65 (1H, m), 7.63-7.57 (2H, m), 7.52-7.47 (1H, m), 7.42-7.37 (1H, m), 7.36-7.32 (1H, m), 3.93 (1H, br s), 3.50 (2H, br s), 3.25 (2H, br s), 1.22 (3H, br s), 1.12 (3H, br 3).
    55
    Figure US20150329491A1-20151119-C00180
         		1H-NMR (DMSO-D6) δ: 7.84 (1H, d, J = 8.1 Hz), 7.81 (1H, d, J = 7.4 Hz), 7.65-7.61 (1H, m), 7.53-7.48 (1H, m), 7.46-7.43 (1H, m), 7.39-7.34 (1H, m), 7.31-7.27 (1H, m).
    56
    Figure US20150329491A1-20151119-C00181
         		1H-NMR (CDCl3) δ: 7.67-7.64 (1H, m), 7.61-7.58 (1H, m), 7.53-7.42 (4H, m), 7.37-7.33 (1H, m), 7.25-7.20 (2H, m), 7.17-7.12 (1H, m), 7.07-7.02 (2H, m), 3.50 (3H, s), 2.84 (1H, br s).
  • TABLE 1-9
    compound
    No. structural formula NMR
    57
    Figure US20150329491A1-20151119-C00182
         		1H-NMR (CDCl3) δ: 7.76-7.72 (1H, m), 7.69-7.66 (1H, m), 7.65-7.60 (2H, m), 7.53-7.48 (1H, m), 7.43-7.37 (2H, m), 4.33-3.47 (1H, m), 3.13-2.80 (3H, m), 2.33-1.93 (4H, m), 1.79-1.37 (2H, m).
    58
    Figure US20150329491A1-20151119-C00183
         		1H-NMR (CDCl3) δ: 7.83-7.80 (1H, m), 7.78-7.73 (1H, m), 7.71-7.67 (2H, m), 7.66-7.62 (1H, m), 7.52-7.47 (1H, m), 7.43-7.39 (1H, m), 4.39-3.99 (5H, m), 2.37-2.26 (2H, m).
    59
    Figure US20150329491A1-20151119-C00184
         		1H-NMR (DMSO-D6) δ: 8.07 (1H, d, J = 7.7 Hz), 7.87-7.84 (1H, m), 7.83 (1H, dd, J = 7.8, 1.0 Hz), 7.72-7.68 (1H, m), 7.54- 7.44 (3H, m), 7.36 (1H, s), 4.36 (2H, t, J = 6.6 Hz), 1.83-1.73 (2H, m), 0.99 (3H, t, J = 7.4 Hz).
    60
    Figure US20150329491A1-20151119-C00185
         		1H-NMR (DMSO-D6) δ: 8.09 (1H, d, J = 7.4 Hz), 7.86-7.83 (1H, m), 7.79 (1H, dd, J = 7.9, 1.2 Hz), 7.71-7.68 (1H, m), 7.55- 7.44 (3H, m), 7.35 (1H, s), 5.33-5.23 (1H, m), 1.40 (3H, d, J = 3.7 Hz), 1.38 (3H, d, J = 3.7 Hz).
    61
    Figure US20150329491A1-20151119-C00186
         		1H-NMR (DMSO-D6) δ: 8.36 (1H, d, J = 7.4 Hz), 8.14-8.13 (1H, m), 8.09 (1H, d, J = 1.4 Hz), 7.79-7.76 (1H, m), 7.68-7.64 (1H, m), 7.66 (1H, s), 7.61- 7.57 (1H, m), 3.92 (3H, s).
    62
    Figure US20150329491A1-20151119-C00187
         		1H-NMR (DMSO-D6) δ: 9.81 (1H, s), 7.74 (1H, d, J = 7.5 Hz), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.43-7.39 (1H, m), 7.38-7.33 (1H, m), 7.18 (1H, d, J = 2.2 Hz), 6.99 (1H, s), 6.75 (1H, dd, J = 8.3, 2.3 Hz).
    63
    Figure US20150329491A1-20151119-C00188
         		1H-NMR (DMSO-D6) δ: 10.27 (1H, s), 7.94 (1H, d, J = 7.4 Hz), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.33-7.28 (1H, m), 7.21-7.17 (1H, m), 7.12-7.08 (2H, m), 6.94 (1H, dd, J = 8.1, 0.9 Hz).
  • TABLE 1-10
    compound
    No. structural formula NMR
    64
    Figure US20150329491A1-20151119-C00189
         		1H-NMR (DMSO-D6) δ: 8.00-7.97 (1H, m), 7.92-7-89 (2H, m), 7.78-7.75 (1H, m), 7.66-7.60 (2H, m), 7.56-7.52 (1H, m), 7.48 (1H, s).
    65
    Figure US20150329491A1-20151119-C00190
         		1H-NMR (DMSO-D6) δ: 7.74-7.65 (2H, m), 7.53-7.39 (5H, m), 7.35 (1H, s), 3.42 (3H, br s), 3.36 (3H, br s).
    66
    Figure US20150329491A1-20151119-C00191
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m), 7.51-7.46 (1H, m), 7.37- 7.32 (2H, m), 7.25-7.22 (1H, m), 7.18 (1H, s), 7.14 (1H, d, J = 8.2 Hz), 4.23 (2H, q, J = 7.0 Hz), 1.48 (3H, t, J = 6.9 Hz).
    67
    Figure US20150329491A1-20151119-C00192
         		1H-NMR (DMSO-D6) δ: 7.85 (1H, d, J = 7.5 Hz), 7.62-7.59 (1H, m), 7.53-7.47 (2H, m), 7.45 (1H, d, J = 2.4 Hz), 7.39-7.35 (1H, m), 7.08 (1H, s), 6.90 (1H, dd, J = 8.4, 2.4 Hz), 4.13 (2H, q, J = 6.9 Hz), 1.37 (3H, t, J = 6.9 Hz).
    68
    Figure US20150329491A1-20151119-C00193
         		1H-NMR (DMSO-D6) δ: 7.89-7.79 (3H, m), 7.70-7.66 (1H, m), 7.54-7.40 (3H, m), 7.31 (1H, s), 2.71 (3H, s).
    69
    Figure US20150329491A1-20151119-C00194
         		1H-NMR (DMSO-D6) δ: 7.82 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 7.9 Hz), 7.65-7.61 (2H, m), 7.52-7.47 (1H, m), 7.45-7.41 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s), 5.33 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.6 Hz).
    70
    Figure US20150329491A1-20151119-C00195
         		1H-NMR (CDCl3) δ: 7.70-7.66 (1H, m), 7.64-7.60 (1H, m), 7.56 (1H, d, J = 7.9 Hz), 7.52-7.50 (1H, m), 7.47-7.43 (1H, m), 7.34-7.27 (2H, m), 2.70 (1H, br s), 2.69-2.63 (2H, m), 1.74-1.64 (2H, m), 0.97 (3H, t, J = 7.3 Hz).
  • TABLE 1-11
    compound
    No. structural formula NMR
    71
    Figure US20150329491A1-20151119-C00196
         		1H-NMR (CDCl3) δ: 7.70-7.66 (1H, m), 7.64-7.61 (1H, m), 7.59-7.55 (2H, m), 7.48-7.43 (1H, m), 7.35-7.30 (2H, m), 3.05-2.93 (1H, m), 2.70 (1H, s), 1.31 (3H, d, J = 1.4 Hz), 1.29 (3H, d, J = 1.4 Hz).
    72
    Figure US20150329491A1-20151119-C00197
         		1H-NMR (DMSO-D6) δ: 8.59-8.55 (1H, m), 8.26 (1H, d, J = 1.3 Hz), 7.90 (1H, d, J = 7.5 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.65 (2H, m), 7.57- 7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 3.37-3.29 (2H, m), 1.16 (3H, t, J = 7.2 Hz).
    73
    Figure US20150329491A1-20151119-C00198
         		1H-NMR (DMSO-D6) δ: 8.35-8.31 (1H, m), 8.27-8.25 (1H, m), 7.91 (1H, d, J = 7.5 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.65 (2H, m), 7.57-7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17-4.08 (1H, m), 1.21 (3H, s), 1.19 (3H, s).
    74
    Figure US20150329491A1-20151119-C00199
         		1H-NMR (DMSO-D6) δ: 7.83 (1H, d, J = 7.7 Hz), 7.69-7.65 (1H, m), 7.58-7.50 (3H, m), 7.41- 7.35 (2H, m), 7.17 (1H, s), 5.43 (1H, t, J = 5.4 Hz), 4.91-4.81 (2H, m).
    75
    Figure US20150329491A1-20151119-C00200
         		1H-NMR (DMSO-D6) δ: 7.86-7.81 (2H, m), 7.66-7.62 (1H, m), 7.61-7.58 (1H, m), 7.53-7.48 (1H, m), 7.46-7.43 (1H, m), 7.40-7.36 (1H, m), 7.24 (1H, s), 4.49 (2H, s), 3.34 (3H, s).
    76
    Figure US20150329491A1-20151119-C00201
         		1H-NMR (DMSO-D6) δ: 8.18-8.15 (2H, m), 8.05-7.98 (2H, m), 7.72-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.44 (1H, s), 2.64 (3H, s).
    77
    Figure US20150329491A1-20151119-C00202
         		1H-NMR (DMSO-D6) δ: 7.92 (2H, d, J = 7.4 Hz), 7.73-7.61 (3H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.39 (0.5H, s), 7.35 (0.5H, s), 4.23-3.94 (1H, m), 3.60-3.47 (1H, m), 3.38- 3.29 (1H, m), 2.14-2.03 (1H, m), 1.97-1.82 (1H, m), 1.78- 1.66 (1H, m), 1.62-1.50 (1H, m), 1.33-1.20 (2H, m), 0.95- 0.77 (1H, m).
  • TABLE 1-12
    compound
    No. structural formula NMR
    78
    Figure US20150329491A1-20151119-C00203
         		1H-NMR (DMSO-D6) δ: 8.13-8.11 (1H, m), 8.03-7.92 (3H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.41 (1H, s), 4.48-4.42 (2H, m), 4.02-3.97 (2H, m).
    79
    Figure US20150329491A1-20151119-C00204
         		1H-MMR (DMSO-D6) δ: 7.96-7.91 (2H, m), 7.87-7.85 (1H, m), 7.78-7.74 (1H, m), 7.69-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.43 (1H, m), 7.39 (1H, s), 5.76 (1H, d, J = 6.0 Hz), 4.56-4.43 (2H, m), 4.34-4.22 (1H, m), 4.13-4.00 (1H, m), 3.89-3.71 (1H, m).
    80
    Figure US20150329491A1-20151119-C00205
         		1H-NMR (CDCl3) δ: 7.64-7.60 (1H, m), 7.51-7.47 (2H, m), 7.42- 7.37 (1H, m), 7.23-7.18 (1H, m), 7.06-7.03 (1H, m), 6.76 (1H, dd, J = 8.5, 2.4 Hz), 3.03 (6H, s), 2.69 (1H, br s).
    81
    Figure US20150329491A1-20151119-C00206
         		1H-NMR (DMSO-D6) δ: 7.80-7.76 (2H, m), 7.69-7.66 (1H, m), 7.64-7.61 (1H, m), 7.52-7.40 (3H, m), 7.32 (1H, s), 3.16- 2.97 (2H, m), 1.17 (3H, t, J = 7.2 Hz).
    82
    Figure US20150329491A1-20151119-C00207
         		1H-NMR (DMSO-D6) δ: 7.75 (1H, d, J = 7.7 Hz), 7.69-7.65 (1H, m), 7.64-7.60 (1H, m), 7.56-7.48 (2H, m), 7.43-7.36 (2H, m), 7.22 (1H, s), 4.79 (1H, d, J = 12.3 Hz), 4.74 (1H, d, J = 12.3 Hz), 3.40 (3H, s).
    83
    Figure US20150329491A1-20151119-C00208
         		1H-NMR (DMSO-D6) δ: 7.83-7.78 (2H, m), 7.72-7.66 (2H, m), 7.55-7.51 (1H, m), 7.49-7.40 (2H, m), 7.33 (1H, s), 2.62- 2.55 (1H, m), 1.26-1.14 (4H, m).
    84
    Figure US20150329491A1-20151119-C00209
         		1H-NMR (DMSO-D6) δ: 7.96-7.92 (1H, m), 7.65-7.62 (1H, m), 7.54-7.49 (1H, m), 7.38-7.30 (3H, m), 7.23 (1H, dd, J = 7.1, 2.0 Hz), 7.13 (1H, s), 2.76 (6H, s).
  • TABLE 1-13
    compound
    No. structural formula NMR
    85
    Figure US20150329491A1-20151119-C00210
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J = 7.7 Hz), 7.63-7.61 (1H, m), 7.49-7.44 (1H, m), 7.33-7.24 (2H, m), 7.05-7.00 (1H, m), 6.82 (2H, br s), 6.67 (2H, s), 2.88 (3H, s).
    86
    Figure US20150329491A1-20151119-C00211
         		1H-NMR (DMSO-D6) δ: 7.96-7.92 (2H, m), 7.90-7.87 (1H, m), 7.80- 7.76 (1H, m), 7.70-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H, br s), 4.55-4.40 (1H, m), 4.32-4.23 (2H, m), 4.22- 4.11 (1H, m), 3.97-3.78 (1H, m), 3.24 (3H, s).
    87
    Figure US20150329491A1-20151119-C00212
         		1H-NMR (DMSO-D6) δ: 7.94 (2H, d, J = 7.9 Hz), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.40 (1H, s), 4.83 (1H, t, J = 5.3 Hz), 4.40-4.31 (1H, m), 4.10-4.03 (2H, m), 3.84-3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.80-2.69 (1H, m).
    88
    Figure US20150329491A1-20151119-C00213
         		1H-NMR (DMSO-D6) δ: 8.14-8.11 (1H, m), 8.01-7.96 (1H, m), 7.92- 7.86 (2H, m), 7.69-7.63 (1H, m), 7.57-7.50 (1H, m), 7.45-7.39 (1H, m), 7.32 (1H, s), 4.41-4.33 (1H, m), 3.95-3.85 (1H, m), 3.65-3.54 (1H, m), 3.19-3.07 (1H, m), 2.11- 1.94 (1H, m), 0.95 (3H, d, J = 6.4 Hz).
    89
    Figure US20150329491A1-20151119-C00214
         		1H-NMR (CDCl3) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.45- 7.41 (1H, m), 7.30-7.23 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 4.10 (2H, q, J = 7.0 Hz), 2.67 (1H, s), 1.44 (3H, t, J = 6.9 Hz).
    90
    Figure US20150329491A1-20151119-C00215
         		1H-NMR (DMSO-D6) δ: 7.95-7.91 (2H, m), 7.87-7.71 (2H, m), 7.69- 7.65 (1H, m), 7.57-7.52 (1H, m), 7.47-7.42 (1H, m), 7.40 (0.5H, s), 7.36 (0.5H, s), 4.84-3.87 (3H, m), 2.46-2.31 (1H, m), 1.94-1.74 (1H, m), 1.55-1.35 (2H, m), 1.21-1.00 (1H, m).
    91
    Figure US20150329491A1-20151119-C00216
         		1H-NMR (DMSO-D6) δ: 7.93- 7.88 (1H, m), 7.74-7.68 (2H, m), 7.60-7.54 (2H, m), 7.48-7.43 (1H, m), 7.32 (1H, s), 4.39-4.29 (2H, m), 4.12-4.02 (2H, m), 2.68 (3H, s), 2.34-2.23 (2H, m).
  • TABLE 1-14
    compound
    No. structural formula NMR
    92
    Figure US20150329491A1-20151119-C00217
         		1H-NMR (DMSO-D6) δ: 8.64 (1H, s), 7.79 (1H, d, J = 7.3 Hz), 7.72-7.68 (1H, m), 7.59-7.56 (2H, m), 7.53-7.49 (1H, m), 7.44-7.40 (2H, m), 7.35 (1H, s), 7.11-7.06 (1H, m).
    93
    Figure US20150329491A1-20151119-C00218
         		1H-NMR (DMSO-D6) δ: 7.80- 7.76 (1H, m), 7.75-7.11 (1H, m), 7.69-7.66 (1H, m), 7.52-7.39 (4H, m), 7.32 (1H, s), 3.50-3.42 (1H, m), 1.18 (3H, d, J = 7.0 Hz), 1.13 (3H, d, J = 7.0 Hz).
    94
    Figure US20150329491A1-20151119-C00219
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 7.7 Hz), 7.83-7.81 (1H, m), 7.78-7.73 (2H, m), 7.65-7.61 (1H, m), 7.58-7.52 (1H, m), 7.57 (1H, s), 4.39-4.33 (2H, m), 4.11-4.04 (2H, m), 2.34-2.24 (2H, m).
    95
    Figure US20150329491A1-20151119-C00220
         		1H-NMR (DMSO-D6) δ: 7.73- 7.66 (2H, m), 7.59-7.54 (1H, m), 7.46-7.41 (1H, m), 7.29-7.23 (1H, m), 7.17 (1H, br s), 6.99 (1H, br s), 4.64 (2H, br s), 2.81 (3H, br s).
    96
    Figure US20150329491A1-20151119-C00221
         		1H-NMR (CDCl3) δ: 7.74-7.65 (3H, m), 7.54-7.48 (2H, m), 7.43-7.37 (1H, m), 7.32-7.27 (1H, m), 3.29 (3H, br s), 3.10 (1H, br s), 1.91 (3H, br s).
    97
    Figure US20150329491A1-20151119-C00222
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J = 7.9 Hz), 7.91 (1H, d, J = 7.4 Hz), 7.89-7.87 (1H, m), 7.83 (1H, dd, J = 7.9, 1.6 Hz), 7.73-7.69 (2H, m), 7.68- 7.64 (1H, m), 7.56-7.49 (3H, m), 7.44-7.38 (2H, m), 7.35 (1H, s).
    98
    Figure US20150329491A1-20151119-C00223
         		1H-NMR (DMSO-D6) δ: 8.06 (1H, d, J = 7.9 Hz), 8.02-7.99 (2H, m), 7.92 (1H, dd, J = 7.9, 1.6 Hz), 7.79-7.75 (2H, m), 7.74-7.69 (2H, m), 7.63-7.57 (3H, m), 7.52-7.47 (2H, m).
  • TABLE 1-15
    compound
    No. structural formula NMR
    99
    Figure US20150329491A1-20151119-C00224
         		1H-NMR (DMSO-D6) δ: 8.18- 8.16 (1H, m), 8.09-8.00 (4H, m), 7.79-7.77 (1H, m), 7.73-7.70 (1H, m), 7.62-7.57 (1H, m), 7.52-7.47 (2H, m), 7.36-7.33 (1H, m).
    100
    Figure US20150329491A1-20151119-C00225
         		1H-NMR (DMSO-D6) δ: 10.09 (1H, s), 8.10-8.08 (1H, m), 7.71 (1H, d, J = 7.4 Hz), 7.64-7.61 (1H, m), 7.57-7.47 (3H, m), 7.41-7.36 (1H, m), 7.14 (1H, s), 2.37 (2H, q, J = 7.6 Hz), 1.11 (3H, t, J = 7.5 Hz).
    101
    Figure US20150329491A1-20151119-C00226
         		1H-NMR (DMSO-D6) δ: 10.05 (1H, s), 8.12 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 7.7 Hz), 7.63 (1H, d, J = 7.4 Hz), 7.57-7.48 (3H, m), 7.41-7.37 (1H, m), 7.15 (1H, s), 2.69-2.58 (1H, m), 1.13 (6H, d, J = 6.7 Hz).
    102
    Figure US20150329491A1-20151119-C00227
         		1H-NMR (CDCl3) δ: 8.61 (1H, d, J = 2.3 Hz), 8.44-8.42 (1H, m), 7.89-7.85 (2H, m), 7.77 (1H, d, J = 13.9 Hz), 7.72 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.7 Hz), 7.60-7.57 (1H, m), 7.53-7.49 (1H, m), 7.43- 7.38 (1H, m), 7.33 (1H, dd, J = 8.0, 4.8 Hz), 4.49 (1H, br s).
    103
    Figure US20150329491A1-20151119-C00228
         		1H-NMR (CDCl3) δ: 8.58-8.55 (2H, m), 7.87-7.85 (1H, m), 7.78-7.69 (4H, m), 7.54-7.47 (3H, m), 7.43-7.38 (1H, m), 4.19 (1H, br s).
    104
    Figure US20150329491A1-20151119-C00229
         		1H-NMR (DMSO-D6) δ: 7.96- 7.90 (2H, m), 7.87 (1H, s), 7.79- 7.74 (1H, m), 7.69-7.64 (1H, m), 7.57-7.52 (1H, m), 7.47- 7.41 (1H, m), 7.38 (1H, s), 4.52-4.43 (1H, m), 4.37-4.23 (2H, m), 4.21-4.11 (1H, m), 3.89-3.82 (1H, m), 3.42 (2H, q, J = 6.9 Hz), 1.13 (3H, t, J = 7.0 Hz).
    105
    Figure US20150329491A1-20151119-C00230
         		1H-NMR (DMSO-D6) δ: 7.97- 7.91 (2H, m), 7.88 (1H, s), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.42 (1H, m), 7.39 (1H, br s), 4.54-4.43 (1H, m), 4.37- 4.24 (2H, m), 4.22-4.12 (1H, m), 3.90-3.83 (1H, m), 3.36- 3.27 (2H, m), 1.58-1.48 (2H, m), 0.88 (3H, t, J = 7.4 Hz).
  • TABLE 1-16
    compound
    No. structural formula NMR
    106
    Figure US20150329491A1-20151119-C00231
         		1H-NMR (DMSO-D6) δ: 7.97- 7.91 (2H, m), 7.90-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.52 (1H, m), 7.48- 7.42 (1H, m), 7.39 (1H, br s), 4.53-4.42 (1H, m), 4.41-4.34 (1H, m), 4.32-4.24 (1H, m), 4.21-4.12 (1H, m), 3.92-3.82 (1H, m), 3.55- 3.49 (2H, m), 3.48-3.43 (2H, m), 3.25 (3H, s).
    107
    Figure US20150329491A1-20151119-C00232
         		1H-NMR (DMSO-D6) δ: 12.73 (1H, br s), 7.97-7.92 (2H, m), 7.89-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.42 (1H, m), 7.40 (1H, br s), 4.53- 4.42 (2H, m), 4.33-4.19 (2H, m), 4.07 (2H, s), 3.98-3.90 (1H, m).
    108
    Figure US20150329491A1-20151119-C00233
         		1H-NMR (DMSO-D6) δ: 7.96- 7.92 (2H, m), 7.89-7.86 (1H, m), 7.79-7.76 (1H, m), 7.70-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H, s), 4.67 (1H, t, J = 5.3 Hz), 4.54-4.45 (1H, m), 4.41-4.35 (1H, m), 4.32-4.24 (1H, m), 4.21-4.13 (1H, m), 3.94-3.84 (1H, m), 3.53-3.48 (2H, m), 3.45-3.40 (2H, m).
    109
    Figure US20150329491A1-20151119-C00234
         		1H-NMR (DMSO-D6) δ: 8.21- 8.17 (2H, m), 8.02 (1H, d, J = 8.3 Hz), 8.00-7.97 (1H, m), 7.71-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.43 (1H, s), 3.92-3.83 (1H, m), 1.99-1.88 (2H, m), 1.84-1.70 (2H, m), 1.66-1.61 (4H, m).
    110
    Figure US20150329491A1-20151119-C00235
         		1H-NMR (DMSO-D6) δ: 7.73 (2H, d, J = 8.1 Hz), 7.60-7.56 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 7.04 (1H, dd, J = 8.3, 2.3 Hz), 4.71-4.61 (1H, m), 1.31 (3H, d, J = 4.6 Hz), 1.29 (3H, d, J = 4.4 Hz).
    111
    Figure US20150329491A1-20151119-C00236
         		1H-NMR (DMSO-D6) δ: 8.20 (1H, d, J = 7.9 Hz), 7.81-7.78 (1H, m), 7.74-7.71 (1H, m), 7.70-7.66 (1H, m), 7.52-7.41 (3H, m), 7.32 (1H, s), 4.55- 4.49 (2H, m), 4.16-4.10 (2H, m).
    112
    Figure US20150329491A1-20151119-C00237
         		1H-NMR (CDCl3) δ: 8.54-8.52 (1H, m), 8.18-8.16 (1H, m), 8.04 (1H, dd, J = 7.9, 1.8 Hz), 7.77-7.64 (4H, m), 7.61- 7.58 (1H, m), 7.47-7.43 (1H, m), 7.39-7.35 (1H, m), 7.17- 7.13 (1H, m), 4.05 (1H, br s).
  • TABLE 1-17
    compound
    No. structural formula NMR
    113
    Figure US20150329491A1-20151119-C00238
         		1H-NMR (DMSO-D6) δ: 8.45 (1H, d, J = 7.7 Hz), 7.76-7.67 (3H, m), 7.63-7.58 (1H, m), 7.53-7.48 (1H, m), 7.40 (1H, br s), 7.37-7.33 (1H, m).
    114
    Figure US20150329491A1-20151119-C00239
         		1H-NMR (DMSO-D6) δ: 8.50- 8.47 (1H, m), 7.91 (1H, d, J = 1.3 Hz), 7.87-7.84 (1H, m), 7.76-7.73 (1H, m), 7.67-7.62 (1H, m), 7.58-7.53 (1H, m), 7.55 (1H, s), 4.41-4.30 (2H, m), 4.14-4.02 (2H, m), 2.34- 2.23 (2H, m).
    115
    Figure US20150329491A1-20151119-C00240
         		1H-NMR (CDCl3) δ: 7.78-7.64 (3H, m), 7.61-7.57 (2H, m), 7.51-7.46 (1H, m), 7.44-7.38 (1H, m), 5.34 (0.5H, br s), 5.16 (0.5H, br s), 4.48-3.93 (7H, m), 3.76 (3H, s).
    116
    Figure US20150329491A1-20151119-C00241
         		1H-NMR (DMSO-D6) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.87 (1H, m), 7.79-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.40 (1H, s), 7.36 (1H, br s), 7.27 (1H, br s), 4.55-4.45 (1H, m), 4.45-4.39 (1H, m), 4.31- 4.21 (2H, m), 4.01-3.92 (1H, m), 3.83 (2H, s).
    117
    Figure US20150329491A1-20151119-C00242
         		1H-NMR (DMSO-D6) δ: 7.96- 7.93 (2H, m), 7.89-7.87 (1H, m), 7.84 (1H, br s), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58- 7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H, br s), 4.58-4.46 (1H, m), 4.45-4.38 (1H, m), 4.34-4.17 (2H, m), 4.01-3.91 (1H, m), 3.87 (2H, s), 2.62 (3H, d, J = 4.6 Hz).
    118
    Figure US20150329491A1-20151119-C00243
         		1H-NMR (DMSO-D6) δ: 7.96- 7.92 (2H, m), 7.88-7.87 (1H, m), 7.79-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.40 (1H, br s), 4.54-4.39 (2H, m), 4.32-4.17 (2H, m), 4.20 (2H, s), 3.99-3.87 (1H, m), 2.89 (3H, s), 2.81 (3H, s).
    119
    Figure US20150329491A1-20151119-C00244
         		1H-NMR (DMSO-D6) δ: 8.15- 8.11 (1H, m), 8.08-8.05 (1H, m), 8.03-7.96 (2H, m), 7.72-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.44 (1H, s), 4.23-4.14 (1H, m), 2.33- 2.23 (4H, m), 2.13-2.00 (1H, m), 1.87-1.75 (1H, m).
  • TABLE 1-18
    compound
    No. structural formula NMR
    120
    Figure US20150329491A1-20151119-C00245
         		1H-NMR (CDCl3) δ: 7.83-7.63 (5H, m), 7.53-7.48 (1H, m), 7.44-7.39 (1H, m), 4.58-4.06 (5H, m), 3.82-3.72 (3H, m), 3.52-3.40 (1H, m).
    121
    Figure US20150329491A1-20151119-C00246
         		1H-NMR (DMSO-D6) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.41 (1H, br s), 4.58-3.99 (4H, m), 3.55-3.43 (1H, m).
    122
    Figure US20150329491A1-20151119-C00247
         		1H-NMR (DMSO-D6) δ: 8.03 (1H, d, J = 1.5 Hz), 7.98 (1H, br s), 7.86-7.83 (1H, m), 7.73- 7.68 (1H, m), 7.53-7.46 (3H, m), 4.43-4.34 (2H, m), 4.13- 4.06 (2H, m), 2.75 (3H, s), 2.34-2.26 (2H, m).
    123
    Figure US20150329491A1-20151119-C00248
         		1H-NMR (DMSO-D6) δ: 7.94 (2H, d, J = 7.9 Hz), 7.89-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.52 (1H, s), 7.48- 7.43 (1H, m), 7.42-7.40 (1H, m), 7.09 (1H, br s), 4.48- 4.40 (1H, m), 4.37-4.30 (1H, m), 4.22-4.14 (1H, m), 4.08- 4.00 (1H, m), 3.42-3.35 (1H, m).
    124
    Figure US20150329491A1-20151119-C00249
         		1H-NMR (DMSO-D6) δ: 8.02- 7.97 (1H, m), 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.42-7.39 (1H, m), 4.49-4.40 (1H, m), 4.37-4.29 (1H, m), 4.22-4.14 (1H, m), 4.08-4.01 (1H, m), 3.41-3.34 (1H, m), 2.62 (3H, d, J = 4.6 Hz).
    125
    Figure US20150329491A1-20151119-C00250
         		1H-NMR (CDCl3) δ: 7.89 (0.5H, br s), 7.81 (0.5H, br s), 7.78-7.63 (4H, m), 7.51-7.46 (1H, m), 7.43-7.37 (1H, m), 4.71-4.62 (1H, m), 4.49 (0.5H, br s), 4.38-3.98 (3.5H, m), 3.63-3.48 (1H, m), 2.97 (3H, s), 2.92-2.85 (3H, m).
    126
    Figure US20150329491A1-20151119-C00251
         		1H-NMR (CDCl3) δ: 7.72 (1H, d, J = 7.4 Hz), 7.68 (1H, d, J = 7.7 Hz), 7.54-7.36 (6H, m), 7.32 (1H, dd, J = 7.7, 0.7 Hz), 7.29-7.24 (1H, m), 7.17-7.12 (1H, m), 6.82 (1H, d, J = 7.9 Hz), 2.04 (1H, br s).
  • TABLE 1-19
    compound
    No. structural formula NMR
    127
    Figure US20150329491A1-20151119-C00252
         		1H-NMR (DMSO-D6) δ: 7.96- 7.91 (2H, m), 7.68-7.63 (2H, m), 7.59-7.52 (2H, m), 7.46-7.41 (1H, m), 7.39 (1H, br s), 3.82-3.35 (8H, m).
    128
    Figure US20150329491A1-20151119-C00253
         		1H-NMR (DMSO-D6) δ: 7.73 (2H, d, J = 8.1 Hz), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.22 (1H, s), 7.08-7.05 (1H, m), 6.96 (1H, dd, J = 8.3, 2.3 Hz), 4.79-4.71 (1H, m), 2.48-2.41 (2H, m), 2.13-2.01 (2H, m), 1.85-1.75 (1H, m), 1.74-1.64 (1H, m).
    129
    Figure US20150329491A1-20151119-C00254
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 7.9 Hz), 7.94-7.90 (2H, m), 7.87 (1H, dd, J = 8.0, 1.7 Hz), 7.69-7.65 (1H, m), 7.59-7.51 (4H, m), 7.44- 7.40 (1H, m), 7.36 (1H, s), 7.28-7.21 (1H, m).
    130
    Figure US20150329491A1-20151119-C00255
         		1H-NMR (DMSO-D6) δ: 9.46 (1H, br s), 7.76-7.72 (1H, m), 7.67-7.63 (1H, m), 7.54-7.48 (2H, m), 7.41-7.35 (3H, m), 7.26 (1H, s), 3.32 (1.5H, s), 3.29 (1.5H, s).
    131
    Figure US20150329491A1-20151119-C00256
         		1H-NMR (DMSO-D6) δ: 8.39 (1H, d, J = 0.9 Hz), 8.10-8.07 (1H, m), 7.88 (1H, dd, J = 7.8, 1.2 Hz), 7.86-7.82 (1H, m), 7.73-7.69 (1H, m), 7.59- 7.54 (2H, m), 7.49-7.42 (2H, m), 7.36 (1H, s).
    132
    Figure US20150329491A1-20151119-C00257
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 7.9 Hz), 7.94-7.86 (3H, m), 7.78-7.76 (1H, m), 7.71-7.65 (2H, m), 7.57-7.52 (2H, m), 7.49-7.46 (1H, m), 7.44-7.40 (1H, m), 7.36 (1H, s).
    133
    Figure US20150329491A1-20151119-C00258
         		1H-NMR (CDCl3) δ: 7.92-7.58 (5H, m), 7.52-7.47 (1H, m), 7.43-7.38 (1H, m), 5.81 (0.5H, br s), 5.54 (0.5H, br s), 4.22-4.09 (1H, m), 4.06- 3.93 (2H, m), 3.82-3.77 (0.5H, m), 3.68-3.62 (0.5H, m), 3.05-2.89 (1H, m), 2.05 (3H, s), 1.97 (3H, s).
  • TABLE 1-20
    compound
    No. structural formula NMR
    134
    Figure US20150329491A1-20151119-C00259
         		1H-NMR (CDCl3) δ: 8.79-8.75 (1H, m), 7.83-7.77 (1H, m), 7.73-7.66 (2H, m), 7.51-7.47 (1H, m), 7.41-7.37 (1H, m), 7.31-7.20 (3H, m), 7.14-7.07 (1H, m), 6.66 (1H, d, J = 7.9 Hz).
    135 (optically active form)
    Figure US20150329491A1-20151119-C00260
         		1H-NMR (DMSO-D6) δ: 7.92- 7.89 (1H, m), 7.72-7.69 (2H, m), 7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.31 (1H, s), 4.38- 4.29 (2H, m), 4.12-4.03 (2H, m), 2.68 (3H, s), 2.32-2.24 (2H, m).
    136 (optically active form)
    Figure US20150329491A1-20151119-C00261
         		1H-NMR (DMSO-D6) δ: 7.92- 7.89 (1H, m), 7.73-7.68 (2H, m), 7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.31 (1H, s), 4.39- 4.28 (2H, m), 4.11-4.02 (2H, m), 2.58 (3H, s), 2.32-2.23 (2H, m).
    137
    Figure US20150329491A1-20151119-C00262
         		1H-NMR (DMSO-D6) δ: 7.96- 7.92 (1H, m), 7.92-7.85 (2H, m), 7.83-7.79 (1H, m), 7.69-7.64 (1H, m), 7.56-7.47 (3H, m), 7.43-7.37 (2H, m), 7.33 (1H, s), 7.24-7.20 (1H, m), 2.41 (3H, s).
    138
    Figure US20150329491A1-20151119-C00263
         		1H-NMR (CDCl3) δ: 7.88-7.84 (1H, m), 7.73-7.68 (1H, m), 7.64-7.59 (1H, m), 7.44-7.38 (1H, m), 7.35-7.28 (2H, m), 7.22-7.19 (1H, m), 5.36-5.33 (1H, m), 5.09-5.07 (1H, m), 2.66 (1H, br s), 2.16 (3H, s).
    139
    Figure US20150329491A1-20151119-C00264
         		1H-NMR (DMSO-D6) δ: 8.76 (2H, d, J = 5.5 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.54-7.47 (3H, m), 7.37-7.32 (2H, m), 7.32 (1H, s), 7.28-7.23 (1H, m), 6.79 (1H, d, J = 7.7 Hz).
    140
    Figure US20150329491A1-20151119-C00265
         		1H-NMR (DMSO-D6) δ: 9.52 (1H, s), 8.05-8.02 (1H, m), 7.94-7.90 (2H, m), 7.75-7.70 (1H, m), 7.64-7.59 (1H, m), 7.52-7.45 (2H, m), 7.44 (1H, s).
  • TABLE 1-21
    compound
    No. structural formula NMR
    141
    Figure US20150329491A1-20151119-C00266
         		1H-NMR (DMSO-D6) δ: 8.26- 8.23 (1H, m), 8.17 (1H, d, J = 1.4 Hz), 8.14-8.11 (1H, m), 7.82-7.78 (1H, m), 7.74-7.69 (2H, m), 7.65-7.61 (1H, m), 4.45-4.34 (2H, m), 4.14-4.05 (2H, m), 2.34-2.24 (2H, m).
    142
    Figure US20150329491A1-20151119-C00267
         		1H-NMR (DMSO-D6) δ: 7.98- 7.94 (3H, m), 7.75-7.71 (1H, m), 7.65-7.60 (1H, m), 7.53-7.48 (2H, m), 7.46 (1H, s), 2.54 (3H, s).
    143
    Figure US20150329491A1-20151119-C00268
         		1H-NMR (CDCl3) δ: 8.60-8.57 (1H, m), 8.21-8.18 (1H, m), 8.03-8.00 (1H, m), 7.81-7.77 (1H, m), 7.60-7.54 (2H, m), 7.51-7.47 (1H, m), 3.21 (3H, s), 2.96 (1H, br s).
    144
    Figure US20150329491A1-20151119-C00269
         		1H-NMR (CDCl3) δ: 7.95-7.92 (1H, m), 7.74-7.70 (2H, m), 7.68-7.64 (2H, m), 7.51-7.47 (1H, m), 7.40-7.31 (3H, m), 7.11 (1H, dd, J = 5.1, 3.7 Hz), 2.79 (1H, br s).
    145
    Figure US20150329491A1-20151119-C00270
         		1H-NMR (CDCl3) δ: 7.91-7.89 (1H, m), 7.70-7.66 (2H, m), 7.65-7.61 (2H, m), 7.52-7.49 (1H, m), 7.48-7.43 (1H, m), 7.43-7.38 (2H, m), 7.36-7.31 (1H, m), 2.91 (1H, br s).
    146
    Figure US20150329491A1-20151119-C00271
         		1H-NMR (DMSO-D6) δ: 8.74 (1H, dd, J = 4.9, 1.5 Hz), 8.65 (1H, br s), 7.94-7.86 (1H, m), 7.74 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.60 (1H, dd, J = 7.9, 5.1 Hz), 7.52-7.48 (1H, m), 7.39- 7.32 (2H, m), 7.31 (1H, s), 7.26-7.22 (1H, m), 6.66 (1H, d, J = 7.7 Hz).
    147
    Figure US20150329491A1-20151119-C00272
         		1H-NMR (DMSO-D6) δ: 8.13- 8.11 (1H, m), 7.84 (1H, d, J = 8.3 Hz), 7.82-7.79 (1H, m), 7.65 (1H, dd, J = 8.5, 2.0 Hz), 7.64-7.61 (1H, m), 7.51-7.47 (1H, m), 7.37-7.32 (1H, m), 7.27 (1H, s), 3.95-3.83 (2H, m), 2.56-2.51 (2H, m), 2.13- 2.05 (2H, m).
  • TABLE 1-22
    compound
    No. structural formula NMR
    148
    Figure US20150329491A1-20151119-C00273
         		1H-NMR (CDCl3) δ: 7.65-7.62 (1H, m), 7.53-7.50 (1H, m), 7.48 (1H, d, J = 8.4 Hz), 7.43-7.38 (1H, m), 7.26-7.20 (2H, m), 6.96 (1H, dd, J = 8.4, 2.4 Hz), 3.24-3.20 (4H, m), 2.78 (1H, br s), 1.76- 1.68 (4H, m), 1.63-1.57 (2H, m).
    149
    Figure US20150329491A1-20151119-C00274
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 7.9 Hz), 7.93-7.90 (1H, m), 7.80-7.78 (1H, m), 7.73-7.65 (2H, m), 7.62-7.52 (2H, m), 7.50-7.33 (5H, m).
    150
    Figure US20150329491A1-20151119-C00275
         		1H-NMR (CDCl3) δ: 7.98-7.90 (2H, m), 7.70-7.65 (2H, m), 7.64-7.52 (3H, m), 7.84-7.40 (4H, m), 7.34 (1H, s).
    151
    Figure US20150329491A1-20151119-C00276
         		1H-NMR (CDCl3) δ: 7.74-7.67 (4H, m), 7.52-7.43 (2H, m), 7.39-7.35 (1H, m), 7.32-7.27 (4H, m), 2.76 (1H, br s), 2.31 (3H, s).
    152 (optically active form)
    Figure US20150329491A1-20151119-C00277
         		1H-NMR (CDCl3) δ: 7.82-7.76 (2H, m), 7.75-7.64 (1H, m), 7.53-7.48 (1H, m), 7.44-7.38 (2H, m), 4.48-3.99 (6H, m), 3.80-3.71 (2H, m), 3.53 (2H, br s), 2.66-2.50 (3H, m), 2.31 (0.5H, br s), 2.03 (0.5H, br s).
    153 (optically active form)
    Figure US20150329491A1-20151119-C00278
         		1H-NMR (CDCl3) δ: 7.83-7.73 (3H, m), 7.53-7.38 (3H, m), 4.73-4.65 (1H, m), 4.43-4.32 (2H, m), 4.24-4.11 (1H, m), 3.93-3.86 (1H, m), 3.64-3.56 (1H, m), 2.98 (3H, s), 2.91 (3H, s), 2.64 (3H, s).
    154
    Figure US20150329491A1-20151119-C00279
         		1H-NMR (CDCl3) δ: 8.31-8.30 (1H, m), 8.06-8.03 (1H, m), 7.96-7.94 (1H, m), 7.85-7.81 (1H, m), 7.75-7.69 (4H, m), 7.57-7.48 (2H, m), 7.41-7.36 (1H, m), 3.96 (3H, s), 2.94 (1H, br s).
  • TABLE 1-23
    compound
    No. structural formula NMR
    155
    Figure US20150329491A1-20151119-C00280
         		1H-NMR (CDCl3) δ: 8.40-8.38 (1H, m), 8.14-8.11 (1H, m), 7.98-7.95 (1H, m), 7.91-7.88 (1H, m), 7.77-7.69 (4H, m), 7.62-7.57 (1H, m), 7.54-7.49 (1H, m), 7.42-7.36 (1H, m), 2.04 (1H, br s).
    156
    Figure US20150329491A1-20151119-C00281
         		1H-NMR (DMSO-D6) δ: 8.22- 8.20 (1H, m), 8.18 (1H, br s), 8.00-7.97 (2H, m), 7.94-7.85 (4H, m), 7.70-7.66 (1H, m), 7.61-7.52 (2H, m), 7.47 (1H, br s), 7.44-7.39 (1H, m), 7.38 (1H, s).
    157
    Figure US20150329491A1-20151119-C00282
         		1H-NMR (DMSO-D6) δ: 8.65- 8.60 (1H, m), 8.17-8.14 (1H, m), 8.01-7.96 (2H, m), 7.94-7.84 (4H, m), 7.70-7.66 (1H, m), 7.61-7.57 (1H, m), 7.56-7.52 (1H, m), 7.44-7.40 (1H, m), 7.39 (1H, s), 2.83 (3H, d, J = 4.4 Hz).
    158
    Figure US20150329491A1-20151119-C00283
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 7.9 Hz), 7.93-7.90 (2H, m), 7.87 (1H, dd, J = 7.9, 1.9 Hz), 7.81-7.77 (1H, m), 7.71-7.69 (1H, m), 7.69- 7.65 (1H, m), 7.59-7.51 (2H, m), 7.44-7.39 (2H, m), 7.36 (1H, br s), 3.05-2.94 (6H, m).
    159
    Figure US20150329491A1-20151119-C00284
         		1H-NMR (DMSO-D6) δ: 8.29 (1H, d, J = 7.7 Hz), 7.89 (2H, s), 7.78-7.72 (3H, m), 7.63-7.59 (1H, m), 7.55-7.42 (5H, m).
    160
    Figure US20150329491A1-20151119-C00285
         		1H-NMR (CDCl3) δ: 7.63-7.59 (1H, m), 7.49-7.45 (2H, m), 7.40-7.36 (1H, m), 7.20-7.15 (1H, m), 6.89-6.87 (1H, m), 6.60 (1H, dd, J = 8.4, 2.2 Hz), 3.38-3.33 (4H, m), 2.67 (1H, s), 2.07-1.99 (4H, m).
    161
    Figure US20150329491A1-20151119-C00286
         		1H-NMR (DMSO-D6) δ: 7.70- 7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.27-7.23 (1H, m), 7.19-7.18 (1H, m), 7.12 (1H, s), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 3.78-3.74 (4H, m), 3.20-3.16 (4H, m).
  • TABLE 1-24
    compound
    No. structural formula NMR
    162
    Figure US20150329491A1-20151119-C00287
         		1H-NMR (DMSO-D6) δ: 7.69-7.63 (2H, m), 7.57-7.54 (1H, m), 7.44-7.40 (1H, m), 7.27-7.22 (1H, m), 7.19-7.16 (1H, m), 7.10 (1H, s), 7.05 (1H, dd, J = 8.5, 2.3 Hz), 3.23-3.18 (4H, m), 2.49-2.45 (4H, m), 2.23 (3H, s).
    163
    Figure US20150329491A1-20151119-C00288
         		1H-NMR (CDCl3) δ: 7.67-7.63 (1H, m), 7.56-7.51 (2H, m), 7.45-7.40 (1H, m), 7.28-7.24 (2H, m), 6.97 (1H, dd, J = 8.3, 2.3 Hz), 3.62-3.57 (4H, m), 3.23-3.18 (4H, m), 2.77 (1H, br s), 1.49 (9H, s).
    164
    Figure US20150329491A1-20151119-C00289
         		1H-NMR (DMSO-D6) δ: 9.11 (2H, br s), 7.72 (2H, d, J = 8.2 Hz), 7.60-7.56 (1H, m), 7.47-7.42 (1H, m), 7.30-7.26 (1H, m), 7.25-7.22 (1H, m), 7.11 (1H, dd, J = 8.5, 2.3 Hz), 4.96 (2H, br s), 3.46-3.41 (4H, m), 3.28-3.21 (4H, m).
    165
    Figure US20150329491A1-20151119-C00290
         		1H-NMR (DMSO-D6) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.22-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.3, 2.1 Hz), 3.63-3.58 (4H, m), 3.30-3.11 (4H, m), 2.05 (3H, s).
    166
    Figure US20150329491A1-20151119-C00291
         		1H-NMR (DMSO-D6) δ: 8.49 (1H, s), 7.69-7.65 (2H, m), 7.58-7.55 (1H, m), 7.46-7.41 (1H, m), 7.37-7.35 (1H, m), 7.31-7.23 (3H, m), 7.18-7.11 (4H, m), 6.91-6.87 (1H, m).
    167
    Figure US20150329491A1-20151119-C00292
         		1H-NMR (CDCl3) δ: 7.86-7.32 (7H, m), 4.63-4.49 (1H, m), 3.76 (3H, s), 3.73-3.47 (2H, m), 2.38-2.16 (1H, m), 2.09-1.82 (3H, m).
    168
    Figure US20150329491A1-20151119-C00293
         		1H-NMR (DMSO-D6) δ: 12.57 (1H, br s), 7.97-7.87 (2H, m), 7.77-7.73 (1H, m), 7.72-7.61 (2H, m), 7.58-7.50 (1H, m), 7.48-7.38 (2H, m), 4.47-4.37 (1H, m), 3.65-3.46 (2H, m), 2.35-2.22 (1H, m), 2.04-1.77 (3H, m).
  • TABLE 1-25
    compound
    No. structural formula NMR
    169
    Figure US20150329491A1-20151119-C00294
         		1H-NMR (CDCl3) δ: 7.69-7.66 (1H, m), 7.63-7.60 (1H, m), 7.57 (1H, d, J = 7.9 Hz), 7.55-7.54 (1H, m), 7.47-7.43 (1H, m), 7.34-7.29 (2H, m), 2.65 (1H, br s), 2.62-2.54 (1H, m), 1.95-1.83 (4H, m), 1.80-1.74 (1H, m), 1.49-1.38 (4H, m), 1.34-1.23 (1H, m).
    170
    Figure US20150329491A1-20151119-C00295
         		1H-NMR (DMSO-D6) δ: 7.90-7.86 (2H, m), 7.75-7.74 (1H, m), 7.67-7.61 (2H, m), 7.54-7.50 (1H, m), 7.42-7.33 (3H, m), 7.28 (1H, br s), 7.15 (1H, d, J = 8.1 Hz), 7.09-7.05 (1H, m), 3.80 (3H, s).
    171
    Figure US20150329491A1-20151119-C00296
         		1H-NMR (CDCl3) δ: 7.88-7.87 (1H, m), 7.74-7.64 (4H, m), 7.63-7.57 (2H, m), 7.52-7.48 (1H, m), 7.40-7.36 (1H, m), 7.19-7.13 (2H, m), 2.75 (1H, br s).
    172
    Figure US20150329491A1-20151119-C00297
         		1H-NMR (CDCl3) δ: 7.89-7.87 (1H, m), 7.73-7.64 (4H, m), 7.60-7.56 (2H, m), 7.51-7.46 (1H, m), 7.38-7.33 (1H, m), 7.02-6.98 (2H, m), 3.87 (3H, s), 2.75 (1H, br s).
    173
    Figure US20150329491A1-20151119-C00298
         		1H-NMR (CDCl3) δ: 7.88 (1H, d, J = 7.7 Hz), 7.73-7.67 (3H, m), 7.65-7.63 (1H, m), 7.58-7.53 (1H, m), 7.52-7.35 (5H, m), 4.15-4.05 (2H, m), 2.92 (1H, s), 1.04-0.99 (3H, m).
    174
    Figure US20150329491A1-20151119-C00299
         		1H-NMR (DMSO-D6) δ: 8.22 (1H, br s), 7.97 (1H, d, J = 7.7 Hz), 7.90 (1H, br s), 7.80 (1H, br s), 7.71-7.67 (2H, m), 7.54-7.49 (1H, m), 7.48-7.43 (1H, m), 7.45 (1H, s), 4.40-4.32 (2H, m), 4.13-4.04 (2H, m), 2.34-2.25 (2H, m).
    175
    Figure US20150329491A1-20151119-C00300
         		1H-NMR (CDCl3) δ: 8.15-8.11 (2H, m), 7.96-7.95 (1H, m), 7.75-7.74 (2H, m), 7.73-7.69 (4H, m), 7.53-7.49 (1H, m), 7.42-7.37 (1H, m), 4.41 (2H, q, J = 7.1 Hz), 2.85 (1H, s), 1.42 (3H, t, J = 7.2 Hz).
  • TABLE 1-26
    compound
    No. structural formula NMR
    176
    Figure US20150329491A1-20151119-C00301
         		1H-NMR (DMSO-D6) δ: 7.95-7.23 (9H, m), 7.01-6.92 (1H, m), 4.41-4.36 (0.8H, m), 4.25-4.17 (0.2H, m), 3.66-3.56 (1.2H, m), 3.49-3.38 (0.8H, m), 2.26-2.11 (1H, m), 1.95-1.75 (3H, m).
    177
    Figure US20150329491A1-20151119-C00302
         		1H-NMR (DMSO-D6) δ: 7.95-7.30 (8H, m), 4.45-4.39 (0.7H, m), 4.21-4.13 (0.3H, m), 3.68-3.55 (1.4H, m), 3.49-3.38 (0.6H, m), 2.63-2.62 (2.1H, m), 2.52-2.49 (0.4H, m), 2.40-2.39 (0.5H, m), 2.23-2.11 (1H, m), 1.97-1.74 (3H, m).
    178
    Figure US20150329491A1-20151119-C00303
         		1H-NMR (DMSO-D6) δ: 7.95-7.86 (2H, m), 7.75-7.71 (0.7H, m), 7.69-7.64 (2H, m), 7.57-7.38 (3H, m), 7.31 (0.3H, d, J = 7.4 Hz), 4.98-4.93 (0.7H, m), 4.78-4.69 (0.3H, m), 3.70-3.45 (2H, m), 3.11 (2.1H, s), 2.86 (2.1H, s), 2.67 (0.4H, s), 2.64 (0.4H, s), 2.62 (0.5H, s), 2.58 (0.5H, s), 2.34-2.23 (1H, m), 1.97-1.71 (3H, m).
    179
    Figure US20150329491A1-20151119-C00304
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J = 7.9 Hz), 7.92-7.89 (1H, m), 7.88 (1H, br s), 7.83 (1H, dd, J = 7.9, 1.8 Hz), 7.76-7.73 (2H, m), 7.69-7.65 (1H, m), 7.58-7.51 (3H, m), 7.44-7.39 (1H, m), 7.35 (1H, br s).
    180
    Figure US20150329491A1-20151119-C00305
         		1H-NMR (DMSO-D6) δ: 12.88 (1H, br s), 7.89 (2H, d, J = 7.9 Hz), 7.79-7.75 (1H, m), 7.67-7.64 (1H, m), 7.63-7.58 (2H, m), 7.55-7.46 (3H, m), 7.44-7.38 (2H, m), 7.31 (1H, br s).
    181
    Figure US20150329491A1-20151119-C00306
         		1H-NMR (CDCl3) δ: 7.91-7.90 (1H, m), 7.73-7.66 (4H, m), 7.54 (2H, d, J = 8.1 Hz), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 7.28 (2H, d, J = 8.6 Hz), 2.76 (1H, s), 2.41 (3H, s).
    182
    Figure US20150329491A1-20151119-C00307
         		1H-NMR (DMSO-D6) δ: 7.88 (2H, d, J = 7.7 Hz), 7.76 (1H, br s), 7.70 (1H, br s), 7.67-7.64 (1H, m), 7.57 (1H, dd, J = 7.9, 1.6 Hz), 7.55-7.37 (6H, m), 7.34 (1H, br s), 7.29 (1H, s).
  • TABLE 1-27
    compound
    No. structural formula NMR
    183
    Figure US20150329491A1-20151119-C00308
         		1H-NMR (DMSO-D6) δ: 8.19-8.14 (1H, m), 7.91-7.86 (2H, m), 7.67-7.63 (2H, m), 7.56-7.50 (3H, m), 7.47-7.42 (3H, m), 7.42-7.37 (1H, m), 7.26 (1H, s), 2.59 (3H, d, J = 4.6 Hz).
    184
    Figure US20150329491A1-20151119-C00309
         		1H-NMR (DMSO-D6) δ: 7.92 (1H, d, J = 7.7 Hz), 7.90 (1H, d, J = 7.5 Hz), 7.68-7.64 (1H, m), 7.63 (1H, br s), 7.57-7.45 (5H, m), 7.43-7.39 (1H, m), 7.38-7.36 (1H, m), 7.26 (1H, s), 2.77 (3H, br s), 2.52-2.43 (3H, m).
    185
    Figure US20150329491A1-20151119-C00310
         		1H-NMR (DMSO-D6) δ: 8.71-8.68 (2H, m), 8.34-8.31 (1H, m), 8.06 (1H, d, J = 1.5 Hz), 8.01-8.00 (1H, m), 7.83-7.80 (2H, m), 7.78-7.74 (1H, m), 7.66-7.61 (1H, m), 7.58 (1H, s), 7.57-7.52 (1H, m).
    186
    Figure US20150329491A1-20151119-C00311
         		1H-NMR (DMSO-D6) δ: 7.72-7.68 (2H, m), 7.58-7.55 (1H, m), 7.46-7.42 (1H, m), 7.38-7.33 (2H, m), 7.29-7.25 (1H, m), 7.19-7.17 (1H, m), 7.16 (1H, s), 7.15-7.11 (2H, m), 7.08-7.03 (2H, m), 3.32 (3H, s).
    187
    Figure US20150329491A1-20151119-C00312
         		1H-NMR (CDCl3) δ: 7.69-7.66 (1H, m), 7.62-7.58 (2H, m), 7.49-7.44 (1H, m), 7.40-7.35 (3H, m), 7.34-7.30 (1H, m), 7.18-7.13 (1H, m), 7.09 (1H, dd, J = 8.3, 2.3 Hz), 7.07-7.04 (2H, m), 2.69 (1H, s).
    188
    Figure US20150329491A1-20151119-C00313
         		1H-NMR (DMSO-D6) δ: 8.08-8.05 (2H, m), 8.01-7.99 (1H, m), 7.96-7.89 (3H, m), 7.87-7.83 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.45-7.40 (1H, m), 7.39 (1H, br s).
    189
    Figure US20150329491A1-20151119-C00314
         		1H-NMR (CDCl3) δ: 7.74-7.68 (4H, m), 7.58-7.54 (1H, m), 7.52-7.47 (2H, m), 7.45-7.33 (4H, m), 4.64 (1H, d, J = 13.2 Hz), 4.60 (1H, d, J = 12.8 Hz), 1.78 (1H, br s).
  • TABLE 1-28
    compound
    No. structural formula NMR
    190
    Figure US20150329491A1-20151119-C00315
         		1H-NMR (DMSO-D6) δ: 9.39 (1H, br s), 7.92 (1H, d, J = 7.7 Hz), 7.89 (1H, d, J = 7.3 Hz), 7.67-7.64 (2H, m), 7.55-7.50 (2H, m), 7.43-7.30 (5H, m), 7.27 (1H, s), 1.88 (3H, br s).
    191
    Figure US20150329491A1-20151119-C00316
         		1H-NMR (DMSO-D6) δ: 8.54-8.49 (1H, m), 8.00-7.88 (6H, m), 7.83-7.79 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.45-7.40 (1H, m), 7.37 (1H, s), 2.82 (3H, d, J = 4.6 Hz).
    192
    Figure US20150329491A1-20151119-C00317
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 7.9 Hz), 7.93-7.90 (2H, m), 7.87 (1H, dd, J = 7.9, 1.6 Hz), 7.79-7.76 (2H, m), 7.69-7.66 (1H, m), 7.56-7.52 (3H, m), 7.44-7.40 (1H, m), 7.37 (1H, s), 3.06-2.92 (6H, m).
    193
    Figure US20150329491A1-20151119-C00318
         		1H-NMR (DMSO-D6) δ: 7.85-7.82 (2H, m), 7.77-7.75 (1H, m), 7.68 (1H, dd, J = 7.9, 1.6 Hz), 7.65-7.61 (1H, m), 7.52-7.47 (1H, m), 7.43-7.39 (2H, m), 7.38-7.33 (1H, m), 7.25 (1H, s), 6.69-6.65 (2H, m), 5.31 (2H, s).
    194
    Figure US20150329491A1-20151119-C00319
         		1H-NMR (CDCl3) δ: 7.93-7.91 (1H, m), 7.75-7.63 (6H, m), 7.52-7.45 (3H, m), 7.40-7.35 (1H, m), 4.77 (2H, d, J = 5.5 Hz), 2.82 (1H, s), 1.69 (1H, t, J = 6.0 Hz).
    195
    Figure US20150329491A1-20151119-C00320
         		1H-NMR (DMSO-D6) δ: 7.94-7.90 (2H, m), 7.77-7.72 (1H, m), 7.69-7.61 (2H, m), 7.56-7.52 (1H, m), 7.46-7.41 (1H, m), 7.37 (0.5H, s), 7.33 (0.5H, s), 4.83-4.78 (0.5H, m), 4.21-4.12 (0.5H, m), 3.65-3.00 (5H, m), 2.01-1.64 (4H, m).
    196
    Figure US20150329491A1-20151119-C00321
         		1H-NMR (DMSO-D6) δ: 8.50-8.47 (1H, m), 7.88-7.83 (2H, m), 7.73-7.69 (1H, m), 7.60-7.56 (1H, m), 7.52-7.48 (1H, m), 7.42 (1H, s), 2.39 (3H, s).
  • TABLE 1-29
    compound
    No. structural formula NMR
    197
    Figure US20150329491A1-20151119-C00322
         		1H-NMR (DMSO-D6) δ: 10.07 (1H, br s), 7.92 (1H, d, J = 7.9 Hz), 7.88 (1H, d, J = 7.4 Hz), 7.87-7.85 (1H, m), 7.79 (1H, dd, J = 7.9, 1.6 Hz), 7.74-7.70 (2H, m), 7.68-7.64 (3H, m), 7.54-7.50 (1H, m), 7.42-7.37 (1H, m), 7.32 (1H, s), 2.08 (3H, s).
    198
    Figure US20150329491A1-20151119-C00323
         		1H-NMR (DMSO-D6) δ: 8.53 (1H, d, J = 5.1 Hz), 8.03-7.93 (4H, m), 7.70-7.67 (1H, m), 7.64-7.62 (1H, m), 7.58-7.53 (2H, m), 7.46-7.42 (1H, m), 7.40 (1H, s), 2.56 (3H, s).
    199
    Figure US20150329491A1-20151119-C00324
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, br s), 8.03-7.97 (3H, m), 7.95-7.88 (3H, m), 7.82-7.78 (2H, m), 7.69-7.66 (1H, m), 7.56-7.52 (1H, m), 7.44-7.40 (1H, m), 7.39 (1H, br s), 7.36 (1H, s).
    200
    Figure US20150329491A1-20151119-C00325
         		1H-NMR (DMSO-D6) δ: 7.96-7.92 (2H, m), 7.89-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.41 (1H, br s), 4.54-4.38 (2H, m), 4.31-4.22 (1H, m), 4.13-4.05 (1H, m), 3.81-3.73 (1H, m), 3.33-3.27 (2H, m), 3.21-3.16 (2H, m), 1.10-1.01 (6H, m).
    201
    Figure US20150329491A1-20151119-C00326
         		1H-NMR (DMSO-D6) δ: 7.96-7.93 (2H, m), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.41 (1H, br s), 4.55-4.38 (2H, m), 4.30-4.21 (1H, m), 4.17-4.09 (1H, m), 3.72-3.64 (1H, m), 3.34-3.27 (4H, m), 1.90-1.82 (2H, m), 1.81-1.73 (2H, m).
    202
    Figure US20150329491A1-20151119-C00327
         		1H-NMR (DMSO-D6) δ: 7.97-7.93 (2H, m), 7.89-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.42 (1H, br s), 4.55-4.41 (2H, m), 4.31-4.23 (1H, m), 4.17-4.07 (1H, m), 3.81-3.72 (1H, m), 3.48-3.43 (2H, m), 3.25-3.20 (2H, m), 1.61-1.54 (2H, m), 1.50-1.41 (4H, m).
  • TABLE 1-30
    compound
    No. structural formula NMR
    203
    Figure US20150329491A1-20151119-C00328
         		1H-NMR (DMSO-D6) δ: 7.96-7.93 (2H, m), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.42 (1H, br s), 4.74 (1H, d, J = 3.9 Hz), 4.55-4.39 (2H, m), 4.32-4.23 (1H, m), 4.16-4.07 (1H, m), 3.94-3.86 (1H, m), 3.82-3.74 (1H, m), 3.73-3.65 (1H, m), 3.49-3.41 (1H, m), 3.12-3.01 (2H, m), 1.76-1.66 (2H, m), 1.36-1.22 (2H, m).
    204
    Figure US20150329491A1-20151119-C00329
         		1H-NMR (DMSO-D6) δ: 8.61 (1H, d, J = 4.6 Hz), 8.39 (1H, d, J = 5.1 Hz), 7.75 (1H, d, J = 6.8 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.56-7.44 (2H, m), 7.38-7.28 (3H, m), 7.26-7.19 (1H, m), 6.38-6.29 (1H, m), 2.07-1.99 (3H, m).
    205
    Figure US20150329491A1-20151119-C00330
         		1H-NMR (CDCl3) δ: 7.88-7.85 (1H, m), 7.73-7.63 (4H, m), 7.55-7.51 (2H, m), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 6.95-6.91 (2H, m), 4.82 (1H, s), 2.74 (1H, s).
    206
    Figure US20150329491A1-20151119-C00331
         		1H-NMR (DMSO-D6) δ: 7.95-7.91 (2H, m), 7.75-7.73 (1H, m), 7.70-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.41-7.37 (1H, m), 3.79-3.47 (7H, m), 3.30-3.18 (1H, m), 2.26-2.00 (2H, m).
    207
    Figure US20150329491A1-20151119-C00332
         		1H-NMR (DMSO-D6) δ: 7.70-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.6, 2.3 Hz), 3.67-3.56 (4H, m), 3.27-3.13 (4H, m), 2.37 (2H, q, J = 7.4 Hz), 1.02 (3H, t, J = 7.4 Hz).
    208
    Figure US20150329491A1-20151119-C00333
         		1H-NMR (DMSO-D6) δ: 7.71-7.67 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.22-7.20 (1H, m), 7.15 (1H, s), 7.08 (1H, dd, J = 8.5, 2.2 Hz), 3.74-3.58 (4H, m), 3.27-3.13 (4H, m), 2.96-2.88 (1H, m), 1.04 (3H, s), 1.02 (3H, s).
    209
    Figure US20150329491A1-20151119-C00334
         		1H-NMR (DMSO-D6) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.41 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.14 (1H, s), 7.07 (1H, dd, J = 8.3, 2.3 Hz), 3.75-3.69 (4H, m), 3.23-3.16 (4H, m), 1.23 (9H, s).
  • TABLE 1-31
    compound
    No. structural formula NMR
    210
    Figure US20150329491A1-20151119-C00335
         		1H-NMR (DMSO-D6) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.5, 2.2 Hz), 3.64 (3H, s), 3.56-3.51 (4H, m), 3.23-3.18 (4H, m).
    211
    Figure US20150329491A1-20151119-C00336
         		1H-NMR (DMSO-D6) δ: 7.70-7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.3, 2.3 Hz), 4.08 (2H, q, J = 7.1 Hz), 3.57-3.50 (4H, m), 3.24-3.17 (4H, m), 1.21 (3H, t, J = 7.1 Hz).
    212
    Figure US20150329491A1-20151119-C00337
         		1H-NMR (DMSO-D6) δ: 7.71-7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.06 (1H, dd, J = 8.3, 2.1 Hz), 4.86-4.74 (1H, m), 3.55-3.49 (4H, m), 3.24-3.15 (4H, m), 1.21 (6H, d, J = 6.3 Hz).
    213
    Figure US20150329491A1-20151119-C00338
         		1H-NMR (DMSO-D6) δ: 8.88 (1H, d, J = 2.0 Hz), 8.17-8.16 (1H, m), 7.97-7.94 (1H, m), 7.78-7.75 (1H, m), 7.68-7.58 (2H, m), 7.64 (1H, s), 4.45-4.35 (2H, m), 4.15-4.06 (2H, m), 2.34-2.26 (2H, m).
    214
    Figure US20150329491A1-20151119-C00339
         		1H-NMR (CDCl3) δ: 7.92-7.85 (3H, m), 7.78-7.65 (5H, m), 7.61-7.56 (1H, m), 7.54-7.49 (1H, m), 7.43-7.38 (1H, m), 2.87 (1H, br s).
    215
    Figure US20150329491A1-20151119-C00340
         		1H-NMR (DMSO-D6) δ: 7.94-7.91 (2H, m), 7.77-7.73 (1H, m), 7.70-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35 (1H, m), 5.03 (0.5H, d, J = 3.7 Hz), 4.97 (0.5H, d, J = 3.3 Hz), 4.37-4.32 (0.5H, m), 4.29-4.24 (0.5H, m), 3.69-3.50 (2H, m), 3.49-3.20 (2H, m), 2.03-1.76 (2H, m).
    216
    Figure US20150329491A1-20151119-C00341
         		1H-NMR (DMSO-D6) δ: 7.94-7.90 (2H, m), 7.76-7.72 (1H, m), 7.71-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.34 (1H, m), 3.77-3.60 (1H, m), 3.57-3.43 (2H, m), 3.30-3.20 (1H, m), 2.78-2.63 (1H, m), 2.19 (3H, s), 2.10-2.09 (3H, m), 2.07-1.98 (1H, m), 1.81-1.68 (1H, m).
  • TABLE 1-32
    compound
    No. structural formula NMR
    217
    Figure US20150329491A1-20151119-C00342
         		1H-NMR (DMSO-D6) δ: 12.52 (1H, br s), 7.95-7.91 (2H, m), 7.76-7.73 (1H, m), 7.71-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35 (1H, m), 3.77-3.47 (4H, m), 3.20-3.05 (1H, m), 2.24-1.96 (2H, m).
    218
    Figure US20150329491A1-20151119-C00343
         		1H-NMR (DMSO-D6) δ: 7.69-7.62 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.27-7.22 (1H, m), 7.20-7.16 (1H, m), 7.11 (1H, s), 7.06 (1H, dd, J = 8.6, 2.4 Hz), 3.74-3.66 (2H, m), 3.63 (3H, s), 2.90-2.82 (2H, m), 2.61-2.52 (1H, m), 2.00-1.90 (2H, m), 1.74-1.62 (2H, m).
    219
    Figure US20150329491A1-20151119-C00344
         		1H-NMR (CDCl3) δ: 8.37 (1H, dd, J = 8.8, 5.1 Hz), 7.93 (1H, dd, J = 7.8, 1.2 Hz), 7.87-7.84 (1H, m), 7.44-7.37 (2H, m), 7.19-7.13 (1H, m), 4.01 (3H, s), 2.77 (1H, s).
    220
    Figure US20150329491A1-20151119-C00345
         		1H-NMR (CDCl3) δ: 8.12 (1H, dd, J = 10.4, 2.4 Hz), 7.95 (1H, dd, J = 7.9, 1.1 Hz), 7.89-7.86 (1H, m), 7.70-7.65 (1H, m), 7.47-7.41 (1H, m), 7.12-7.07 (1H, m), 4.02 (3H, s), 2.72 (1H, s).
    221
    Figure US20150329491A1-20151119-C00346
         		1H-NMR (CDCl3) δ: 8.36-8.32 (1H, m), 7.94 (1H, dd, J = 8.7, 5.2 Hz), 7.75-7.72 (1H, m), 7.53-7.48 (1H, m), 7.47-7.42 (1H, m), 7.09-7.04 (1H, m), 4.01 (3H, s), 3.21-3.19 (1H, m).
    222
    Figure US20150329491A1-20151119-C00347
         		1H-NMR (DMSO-D6) δ: 7.78-7.71 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (2H, m), 7.34-7.25 (2H, m), 3.72-3.63 (2H, m), 3.08 (2H, br s), 2.57-2.46 (1H, m), 2.04-1.96 (2H, m), 1.89-1.72 (2H, m).
    223
    Figure US20150329491A1-20151119-C00348
         		1H-NMR (DMSO-D6) δ: 7.68-7.63 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.26-7.22 (1H, m), 7.19-7.17 (1H, m), 7.11 (1H, s), 7.06 (1H, dd, J = 8.5, 2.3 Hz), 4.09 (2H, q, J = 7.1 Hz), 3.74-3.66 (2H, m), 2.90-2.82 (2H, m), 2.58-2.48 (1H, m), 1.98-1.90 (2H, m), 1.73-1.62 (2H, m), 1.20 (3H, t, J = 7.1 Hz).
  • TABLE 1-33
    compound
    No. structural formula NMR
    224
    Figure US20150329491A1-20151119-C00349
         		1H-NMR (CDCl3) δ: 7.93-7.91 (1H, m), 7.79-7.70 (8H, m), 7.54-7.50 (1H, m), 7.43-7.39 (1H, m), 2.81 (1H, br s).
    225
    Figure US20150329491A1-20151119-C00350
         		1H-NMR (DMSO-D6) δ: 7.92 (2H, d, J = 7.7 Hz), 7.75-7.72 (1H, m), 7.69-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35 (1H, m), 4.75-4.63 (1H, m), 3.64-3.21 (6H, m), 2.42-2.24 (1H, m), 2.00-1.85 (1H, m), 1.72-1.59 (1H, m).
    226
    Figure US20150329491A1-20151119-C00351
         		1H-NMR (DMSO-D6) δ: 7.92 (2H, d, J = 7.4 Hz), 7.76-7.73 (1H, m), 7.70-7.64 (2H, m), 7.56-7.36 (4H, m), 7.00-6.91 (1H, m), 3.75-3.43 (4H, m), 3.04-2.90 (1H, m), 2.17-1.91 (2H, m).
    227
    Figure US20150329491A1-20151119-C00352
         		1H-NMR (DMSO-D6) δ: 8.01-7.96 (0.5H, m), 7.92 (2H, d, J = 7.7 Hz), 7.90-7.85 (0.5H, m), 7.75-7.72 (1H, m), 7.70-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.35 (2H, m), 3.73-3.43 (4H, m), 3.03-2.88 (1H, m), 2.62 (1.5H, d, J = 4.4 Hz), 2.55 (1.5H, d, J = 4.4 Hz), 2.16-1.91 (2H, m).
    228
    Figure US20150329491A1-20151119-C00353
         		1H-NMR (DMSO-D6) δ: 7.94-7.90 (2H, m), 7.75-7.72 (1H, m), 7.69-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.38-7.36 (1H, m), 3.62-3.37 (3H, m), 3.24-3.08 (2H, m), 2.30 (1.4H, s), 2.18 (1.6H, d, J = 4.9 Hz), 2.05-1.87 (1H, m), 1.79-1.68 (1H, m).
    229
    Figure US20150329491A1-20151119-C00354
         		1H-NMR (DMSO-D6) δ: 7.94-7.91 (2H, m), 7.76-7.72 (1H, m), 7.71-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.36 (2H, m), 3.77-3.40 (5H, m), 3.07 (1.5H, s), 2.98 (1.5H, s), 2.86 (1.5H, s), 2.80 (1.5H, s), 2.22-2.03 (1H, m), 2.01-1.89 (1H, m).
    230
    Figure US20150329491A1-20151119-C00355
         		1H-NMR (DMSO-D6) δ: 7.66 (1H, d, J = 7.3 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.29 (1H, s), 7.26-7.21 (1H, m), 7.19-7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.5, 2.3 Hz), 6.77 (1H, br s), 3.81-3.73 (2H, m), 2.81-2.73 (2H, m), 2.33-2.24 (1H, m), 1.84-1.77 (2H, m), 1.71-1.60 (2H, m).
  • TABLE 1-34
    compound
    No. structural formula NMR
    231
    Figure US20150329491A1-20151119-C00356
         		1H-NMR (DMSO-D6) δ: 7.77-7.72 (1H, m), 7.68-7.62 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.26-7.21 (1H, m), 7.19-7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.6, 2.4 Hz), 3.82-3.73 (2H, m), 2.81-2.72 (2H, m), 2.58 (3H, d, J = 4.6 Hz), 2.34-2.24 (1H, m), 1.81-1.74 (2H, m), 1.73-1.61 (2H, m).
    232
    Figure US20150329491A1-20151119-C00357
         		1H-NMR (DMSO-D6) δ: 7.68-7.62 (2H, m), 7.57-7.53 (1H, m), 7.45-7.39 (1H, m), 7.27-7.21 (1H, m), 7.19-7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.4, 2.2 Hz), 3.83-3.74 (2H, m), 3.06 (3H, s), 2.90-2.78 (3H, m), 2.82 (3H, s), 1.77-1.60 (4H, m).
    233
    Figure US20150329491A1-20151119-C00358
         		1H-NMR (DMSO-D6) δ: 8.33-8.30 (1H, m), 8.11-8.07 (2H, m), 7.99 (1H, d, J = 1.5 Hz), 7.97-7.92 (3H, m), 7.77-7.74 (1H, m), 7.65-7.60 (1H, m), 7.58 (1H, s), 7.56-7.51 (1H, m), 4.36 (2H, q, J = 7.1 Hz), 1.36 (3H, t, J = 7.2 Hz).
    234
    Figure US20150329491A1-20151119-C00359
         		1H-NMR (DMSO-D6) δ: 13.08 (1H, br s), 8.32-8.29 (1H, m), 8.09-8.05 (2H, m), 7.98 (1H, d, J = 1.5 Hz), 7.96-7.94 (1H, m), 7.92-7.88 (2H, m), 7.77-7.73 (1H, m), 7.65-7.60 (1H, m), 7.59-7.50 (2H, m).
    235
    Figure US20150329491A1-20151119-C00360
         		1H-NMR (DMSO-D6) δ: 7.92 (1H, s), 7.88-7.85 (1H, m), 7.73-7.70 (1H, m), 7.63-7.59 (1H, m), 7.58-7.53 (1H, m), 7.45 (1H, s), 4.08 (3H, s), 4.06-3.95 (4H, m), 2.30-2.20 (2H, m).
    236
    Figure US20150329491A1-20151119-C00361
         		1H-NMR (DMSO-D6) δ: 8.01 (1H, d, J = 7.9 Hz), 7.99-7.92 (5H, m), 7.83 (1H, dd, J = 8.1, 1.6 Hz), 7.70-7.67 (1H, m), 7.58-7.53 (1H, m), 7.46-7.42 (1H, m), 7.40 (1H, s), 3.90 (3H, s).
    237
    Figure US20150329491A1-20151119-C00362
         		1H-NMR (DMSO-D6) δ: 7.87-7.83 (2H, m), 7.65-7.61 (1H, m), 7.53-7.49 (1H, m), 7.40-7.33 (2H, m), 7.34 (1H, s), 7.26 (1H, dd, J = 8.2, 2.2 Hz), 3.07 (3H, s), 2.93 (3H, s).
  • TABLE 1-35
    compound
    No. structural formula NMR
    238
    Figure US20150329491A1-20151119-C00363
         		1H-NMR (DMSO-D6) δ: 13.44 (1H, br s), 8.02-7.99 (1H, m), 7.97-7.92 (4H, m), 7.89-7.86 (1H, m), 7.80- 7.77 (1H, m), 7.70-7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.39 (1H, br s).
    239
    Figure US20150329491A1-20151119-C00364
         		1H-NMR (DMSO-D6) δ: 7.99 (1H, d, J = 7.9 Hz), 7.95- 7.88 (4H, m), 7.81 (1H, d, J = 1.6 Hz), 7.73 (1H, dd, J = 8.0, 1.5 Hz), 7.69-7.62 (2H, m), 7.59-7.57 (1H, m), 7.55-7.52 (1H, m), 7.45- 7.40 (1H, m), 7.38 (1H, s).
    240
    Figure US20150329491A1-20151119-C00365
         		1H-NMR (DMSO-D6) δ: 8.43- 8.37 (1H, m), 8.01-7.97 (1H, m), 7.96-7.88 (3H, m), 7.83-7.81 (1H, m), 7.75- 7.71 (1H, m), 7.70-7.66 (1H, m), 7.58-7.52 (2H, m), 7.45-7.40 (1H, m), 7.37 (1H, s), 2.79 (3H, d, J = 4.4 Hz).
    241
    Figure US20150329491A1-20151119-C00366
         		1H-NMR (DMSO-D6) δ: 7.99 (1H, d, J = 7.9 Hz), 7.95- 7.90 (3H, m), 7.86 (1H, d, J = 1.6 Hz), 7.76 (1H, dd, J = 8.1, 1.6 Hz), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.48 (1H, d, J = 7.9 Hz), 7.45-7.40 (1H, m), 7.38 (1H, s), 3.04 (3H, s), 2.84 (3H, s).
    242
    Figure US20150329491A1-20151119-C00367
         		1H-NMR (DMSO-D6) δ: 8.77 (1H, dd, J = 4.9, 1.8 Hz), 8.68 (1H, br s), 7.94 (2H, br s), 7.72-7.68 (1H, m), 7.64-7.59 (1H, m), 7.58 (1H, d, J = 1.5 Hz), 7.48 (1H, s), 7.42-7.37 (1H, m), 7.31-7.26 (1H, m), 6.71 (1H, d, J = 7.5 Hz), 4.42- 4.33 (2H, m), 4.13-4.05 (2H, m), 2.34-2.24 (2H, m).
    243
    Figure US20150329491A1-20151119-C00368
         		1H-NMR (DMSO-D6) δ: 8.78- 8.76 (1H, m), 8.70-8.66 (1H, m), 7.98-7.91 (1H, m), 7.72 (1H, d, J = 1.1 Hz), 7.68 (1H, d, J = 7.5 Hz), 7.63-7.59 (1H, m), 7.54- 7.50 (2H, m), 7.40-7.35 (1H, m), 7.29-7.24 (1H, m), 6.63 (1H, d, J = 7.7 Hz).
    244
    Figure US20150329491A1-20151119-C00369
         		1H-NMR (DMSO-D6) δ: 7.79- 7.76 (1H, m), 7.71 (1H, d, J = 7.9 Hz), 7.62-7.58 (1H, m), 7.49-7.45 (1H, m), 7.36-7.30 (2H, m), 7.19 (1H, dd, J = 7.9, 1.5 Hz), 7.16 (1H, s), 2.06-1.98 (1H, m), 1.04-0.98 (2H, m), 0.75-0.68 (2H, m).
  • TABLE 1-36
    compound
    No. structural formula NMR
    245
    Figure US20150329491A1-20151119-C00370
         		1H-NMR (CDCl3) δ: 7.98-7.96 (1H, m), 7.93 (1H, s), 7.79-7.76 (1H, m), 7.75- 7.67 (3H, m), 7.53-7.49 (1H, m), 7.42-7.37 (2H, m), 2.96 (1H, br s).
    246
    Figure US20150329491A1-20151119-C00371
         		1H-NMR (DMSO-D6) δ: 7.95- 7.90 (2H, m), 7.80-7.64 (3H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.39- 7.34 (1H, m), 5.16-4.47 (1H, m), 3.77-3.34 (4H, m), 2.92-2.71 (3H, m), 2.14- 1.91 (5H, m).
    247
    Figure US20150329491A1-20151119-C00372
         		1H-NMR (CDCl3) δ: 8.42 (1H, s), 8.21-8.18 (1H, m), 7.80-7.76 (2H, m), 7.75- 7.72 (1H, m), 7.56-7.52 (1H, m), 7.49-7.44 (1H, m), 3.48 (1H, br s), 2.37 (3H, s).
    248
    Figure US20150329491A1-20151119-C00373
         		1H-NMR (CDCl3) δ: 7.70-7.67 (2H, m), 7.63 (1H, d, J = 7.7 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.48-7.44 (1H, m), 7.43-7.40 (1H, m), 7.36- 7.31 (1H, m), 6.49-6.43 (1H, m), 6.38-6.29 (1H, m), 2.70 (1H, s), 1.92 (3H, d, J = 6.3 Hz).
    249
    Figure US20150329491A1-20151119-C00374
         		1H-NMR (CDCl3) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.02 (2H, t, J = 6.4 Hz), 2.70 (1H, s), 1.84-1.76 (2H, m), 1.57- 1.47 (2H, m), 1.02-0.97 (3H, m).
    250
    Figure US20150329491A1-20151119-C00375
         		1H-NMR (DMSO-D6) δ: 7.85 (1H, d, J = 7.7 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.70 (1H, d, J = 7.2 Hz), 7.60- 7.54 (2H, m), 7.45-7.36 (2H, m), 7.37 (1H, s), 4.54 (3H, s).
    251
    Figure US20150329491A1-20151119-C00376
         		1H-NMR (DMSO-D6) δ: 7.93 (1H, d, J = 7.7 Hz), 7.73- 7.68 (2H, m), 7.66-7.61 (1H, m), 7.48 (1H, s), 7.45-7.41 (1H, m), 7.39- 7.34 (1H, m), 6.44 (1H, d, J = 7.4 Hz), 3.92 (3H, s).
  • TABLE 1-37
    compound
    No. structural formula NMR
    252
    Figure US20150329491A1-20151119-C00377
         		1H-NMR (CDCl3) δ: 7.88-7.86 (1H, m), 7.73-7.69 (1H, m), 7.67-7.58 (3H, m), 7.56- 7.53 (2H, m), 7.50-7.46 (1H, m), 7.41-7.33 (3H, m), 7.30-7.26 (1H, m), 7.20 (1H, d, J = 16.5 Hz), 7.15 (1H, d, J = 16.3 Hz), 2.75 (1H, br s).
    253
    Figure US20150329491A1-20151119-C00378
         		1H-NMR (DMSO-D6) δ: 7.75- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.20 (1H, s), 7.15-7.13 (1H, m), 7.05 (1H, dd, J = 8.4, 2.4 Hz), 3.84 (2H, d, J = 6.2 Hz), 1.86-1.64 (6H, m), 1.32-1.02 (5H, m).
    254
    Figure US20150329491A1-20151119-C00379
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.20 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 3.91 (2H, d, J = 7.1 Hz), 2.39-2.27 (1H, m), 1.84-1.74 (2H, m), 1.68- 1.50 (4H, m), 1.41-1.31 (2H, m).
    255
    Figure US20150329491A1-20151119-C00380
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.01 (2H, d, J = 6.6 Hz), 2.78-2.70 (1H, m), 2.14-2.04 (2H, m), 1.97- 1.80 (4H, m).
    256
    Figure US20150329491A1-20151119-C00381
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.31-7.26 (1H, m), 7.21 (1H, s), 7.15-7.13 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 3.88 (2H, d, J = 7.0 Hz), 1.29-1.19 (1H, m), 0.61-0.56 (2H, m), 0.38- 0.33 (2H, m).
    257
    Figure US20150329491A1-20151119-C00382
         		1H-NMR (CDCl3) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.25 (1H, m), 7.24-7.22 (1H, m), 6.99-6.95 (1H, m), 4.18-4.12 (2H, m), 4.07 (2H, t, J = 6.0 Hz), 2.77 (1H, s), 2.53 (2H, t, J = 7.3 Hz), 2.17-2.10 (2H, m), 1.29-1.24 (3H, m).
    258
    Figure US20150329491A1-20151119-C00383
         		1H-NMR (DMSO-D6) δ: 12.16 (1H, br s), 7.76-7.73 (2H, m), 7.61-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.21 (1H, m), 7.18-7.14 (1H, m), 7.06 (1H, dd, J = 8.2, 2.0 Hz), 4.05 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.93 (2H, m).
  • TABLE 1-38
    compound
    No. structural formula NMR
    259
    Figure US20150329491A1-20151119-C00384
         		1H-NMR (DMSO-D6) δ: 7.75- 7.71 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.15-7.12 (1H, m), 7.08-7.05 (1H, m), 4.43- 4.37 (1H, m), 2.00-1.91 (2H, m), 1.77-1.68 (2H, m), 1.59-1.22 (6H, m).
    260
    Figure US20150329491A1-20151119-C00385
         		1H-NMR (DMSO-D6) δ: 7.75- 7.71 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.15-7.12 (1H, m), 7.08-7.05 (1H, m), 4.43- 4.37 (1H, m), 2.00-1.91 (2H, m), 1.77-1.68 (2H, m), 1.59-1.22 (6H, m).
    261
    Figure US20150329491A1-20151119-C00386
         		1H-NMR (DMSO-D6) δ: 7.78- 7.74 (2H, m), 7.61-7.56 (2H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.26- 7.23 (2H, m), 7.23 (1H, s), 7.17 (1H, dd, J = 8.4, 2.4 Hz), 7.05 (1H, dd, J = 5.1, 3.5 Hz), 5.38 (1H, d, J = 12.1 Hz), 5.35 (1H, d, J = 12.1 Hz).
    262
    Figure US20150329491A1-20151119-C00387
         		1H-NMR (DMSO-D6) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.51-7.23 (9H, m), 7.16 (1H, dd, J = 8.3, 2.3 Hz), 5.17 (2H, s).
    263
    Figure US20150329491A1-20151119-C00388
         		1H-NMR (CDCl3) δ: 7.72-7.67 (2H, m), 7.48 (1H, s), 7.47 (1H, s), 7.36-7.22 (5H, m), 4.00 (3H, s), 3.20 (1H, br s).
    264
    Figure US20150329491A1-20151119-C00389
         		1H-NMR (CDCl3) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.45-7.41 (1H, m), 7.29- 7.25 (1H, m), 7.24-7.23 (1H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 3.78 (2H, d, J = 6.6 Hz), 2.66 (1H, s), 2.17-2.05 (1H, m), 1.06 (3H, d, J = 0.9 Hz), 1.04 (3H, d, J = 0.9 Hz).
    265
    Figure US20150329491A1-20151119-C00390
         		1H-NMR (CDCl3) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 6.99 (1H, dd, J = 8.2, 2.4 Hz), 3.98 (2H, t, J = 6.5 Hz), 2.66 (1H, s), 1.89-1.79 (2H, m), 1.06 (3H, t, J = 7.4 Hz).
  • TABLE 1-39
    compound
    No. structural formula NMR
    266
    Figure US20150329491A1-20151119-C00391
         		1H-NMR (CDCl3) δ: 7.87-7.85 (1H, m), 7.76-7.64 (4H, m), 7.54-7.49 (3H, m), 7.43- 7.36 (2H, m), 2.77 (1H, s).
    267
    Figure US20150329491A1-20151119-C00392
         		1H-NMR (DMSO-D6) δ: 8.17- 8.13 (1H, m), 7.92-7.89 (1H, m), 7.88 (1H, dd, J = 7.9, 1.1 Hz), 7.74-7.71 (1H, m), 7.63-7.58 (1H, m), 7.53-7.45 (2H, m), 7.42 (1H, s), 2.66 (3H, s).
    268
    Figure US20150329491A1-20151119-C00393
         		1H-NMR (DMSO-D6) δ: 8.18 (1H, d, J = 7.7 Hz), 7.70- 7.66 (1H, m), 7.56-7.48 (2H, m), 7.43-7.38 (1H, m), 7.33-7.25 (2H, m), 7.15 (1H, s), 2.37-2.29 (1H, m), 1.17-1.05 (2H, m), 0.85- 0.79 (1H, m), 0.72-0.65 (1H, m).
    269
    Figure US20150329491A1-20151119-C00394
         		1H-NMR (CDCl3) δ: 7.63-7.59 (1H, m), 7.47 (2H, d, J = 8.1 Hz), 7.41-7.36 (1H, m), 7.20-7.16 (1H, m), 6.87- 6.85 (1H, m), 6.58 (1H, dd, J = 8.5, 2.0 Hz), 3.55-3.34 (3H, m), 2.97-2.91 (1H, m), 2.63 (1H, s), 2.48-2.38 (1H, m), 2.20-2.12 (1H, m), 1.71-1.61 (1H, m), 1.15 (3H, d, J = 6.7 Hz).
    270
    Figure US20150329491A1-20151119-C00395
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m) 7.32-7.27 (1H, m), 7.23 (1H, s), 7.16-7.14 (1H, m) 7.06 (1H, dd, J = 8.3, 2.1 Hz), 4.46 (1H, t, J = 5.1 Hz), 4.04 (2H, t, J = 6.5 Hz), 3.50-3.44 (2H, m), 1.82-1.73 (2H, m), 1.63- 1.54 (2H, m).
    271
    Figure US20150329491A1-20151119-C00396
         		1H-NMR (DMSO-D6) δ: 8.07 (1H, d, J = 7.5 Hz), 7.65- 7.61 (1H, m), 7.53-7.47 (1H, m), 7.37-7.33 (1H, m), 7.31 (1H, s), 7.20-7.18 (1H, m), 7.03 (1H, d, J = 2.2 Hz), 3.74-3.68 (4H, m). 3.29-3.24 (4H, m), 1.23 (9H, s).
    272
    Figure US20150329491A1-20151119-C00397
         		1H-NMR (CDCl3) δ: 8.47 (1H, d, J = 7.7 Hz), 7.73-7.70 (1H, m), 7.65 (2H, s), 7.57-7.52 (1H, m), 7.46- 7.42 (1H, m), 2.70 (1H, s).
  • TABLE 1-40
    compound
    No. structural formula NMR
    273
    Figure US20150329491A1-20151119-C00398
         		1H-NMR (DMSO-D6) δ: 8.53- 8.47 (1H, m), 7.82-7.75 (1H, m), 7.72 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.50-7.46 (1H, m), 7.46-7.42 (1H, m), 7.36- 7.31 (2H, m), 7.29 (1H, s), 7.28-7.23 (1H, m), 6.76 (1H, d, J = 7.5 Hz), 2.60 (3H, s).
    274
    Figure US20150329491A1-20151119-C00399
         		1H-NMR (DMSO-D6) δ: 7.90- 7.86 (1H, m), 7.79-7.68 (3H, m), 7.59-7.54 (1H, m), 7.48-7.41 (2H, m), 7.39 (1H, s), 2.77 (3H, s).
    275
    Figure US20150329491A1-20151119-C00400
         		1H-NMR (DMSO-D6) δ: 7.77- 7.74 (1H, m), 7.71-7.67 (1H, m), 7.54 (1H, dd, J = 7.7, 1.3 Hz), 7.51-7.47 (1H, m), 7.47-7.39 (2H, m), 7.39 (1H, s), 7.33 (1H, s), 7.25 (1H, dd, J = 6.5, 2.1 Hz), 2.55 (3H, s).
    276
    Figure US20150329491A1-20151119-C00401
         		1H-NMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.97 (1H, m), 4.07-4.02 (2H, m), 2.69 (1H, s), 1.92-1.81 (1H, m), 1.74-1.68 (2H, m), 1.00-0.96 (6H, m).
    277
    Figure US20150329491A1-20151119-C00402
         		1H-NMR (DMSO-D6) δ: 13.15 (1H, br s), 7.99 (1H, br s), 7.70-7.58 (3H, m), 7.41-7.27 (4H, m), 7.25- 7.20 (2H, m).
    278
    Figure US20150329491A1-20151119-C00403
         		1H-NMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.40 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.97 (1H, m), 4.04-3.99 (2H, m), 2.69 (1H, br s), 1.86-1.78 (2H, m), 1.52-1.35 (4H, m), 0.98-0.92 (3H, m).
    279
    Figure US20150329491A1-20151119-C00404
         		1H-MMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.24 (2H, m), 7.01-6.98 (1H, m), 3.66 (2H, s), 2.70 (1H, s), 1.07 (9H, s).
  • TABLE 1-41
    compound
    No. structural formula NMR
    280
    Figure US20150329491A1-20151119-C00405
         		1H-NMR (DMSO-D6) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.33 (1H, br s), 7.32-7.27 (1H, m), 7.25-7.22 (1H, m), 7.16-7.14 (1H, m), 7.08- 7.04 (1H, m), 6.78 (1H, br s), 4.03 (2H, t, J = 6.3 Hz), 2.25 (2H, t, J = 7.2 Hz), 1.99-1.91 (2H, m).
    281
    Figure US20150329491A1-20151119-C00406
         		1H-NMR (DMSO-D6) δ: 7.79 (1H, br s), 7.77-7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.22 (1H, m), 7.16-7.13 (1H, m), 7.08-7.04 (1H, m), 4.05- 3.99 (2H, m), 2.60-2.56 (3H, m), 2.28-2.23 (2H, m), 2.01-1.92 (2H, m).
    282
    Figure US20150329491A1-20151119-C00407
         		1H-NMR (DMSO-D6) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m), 7.09-7.05 (1H, m), 4.06 (2H, t, J = 6.4 Hz), 2.97 (3H, s), 2.83 (3H, s), 2.50-2.45 (2H, m), 2.00- 1.92 (2H, m).
    283
    Figure US20150329491A1-20151119-C00408
         		1H-NMR (CDCl3) δ: 7.67-7.64 (1H, m), 7.58-7.52 (2H, m), 7.45-7.41 (1H, m), 7.45 (1H, s), 7.30-7.25 (1H, m), 7.25-7.23 (1H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.07-4.01 (2H, m), 2.43- 2.37 (2H, m), 1.92-1.78 (4H, m), 1.26 (3H, t, J = 7.2 Hz).
    284
    Figure US20150329491A1-20151119-C00409
         		1H-NMR (DMSO-D6) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.18-7.14 (1H, m), 7.08-7.05 (1H, m), 4.60-4.56 (1H, m), 4.13- 4.07 (2H, m), 3.61-3.55 (2H, m), 1.94-1.85 (2H, m).
    285
    Figure US20150329491A1-20151119-C00410
         		1H-NMR (DMSO-D6) δ: 8.72 (1H, dd, J = 4.9, 1.5 Hz), 8.64 (1H, d, J = 1.5 Hz), 7.92-7.86 (1H, m), 7.61- 7.55 (2H, m), 7.30-7.27 (1H, m), 7.22 (1H, s), 7.21-7.14 (2H, m), 6.86 (1H, d, J = 2.4 Hz), 6.55 (1H, d, J = 6.8 Hz), 3.75- 3.68 (4H, m), 3.29-3.24 (4H, m), 1.23 (9H, s).
    286
    Figure US20150329491A1-20151119-C00411
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.68-7.63 (1H, m) 7.66 (1H, d, J = 0.7 Hz), 7.60-7.57 (1H, m), 7.41 (1H, s), 7.40-7.34 (4H, m) 3.96 (3H, s).
  • TABLE 1-42
    compound
    No. structural formula NMR
    287
    Figure US20150329491A1-20151119-C00412
         		1H-NMR (DMSO-D6) δ: 13.07 (1H, br s), 7.78-7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43 (1H, m), 7.33- 7.28 (1H, m), 7.27-7.24 (1H, m), 7.15-7.13 (1H, m), 7.06-7.02 (1H, m), 4.75 (2H, s).
    288
    Figure US20150329491A1-20151119-C00413
         		1H-NMR (DMSO-D6) δ: 7.79- 7.74 (2H, m), 7.63 (1H, br s), 7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.43 (1H, br s), 7.34-7.29 (1H, m), 7.27-7.22 (2H, m), 7.10-7.06 (1H, m), 4.49 (2H, s).
    289
    Figure US20150329491A1-20151119-C00414
         		1H-NMR (DMSO-D6) δ: 8.17- 8.11 (1H, m), 7.80-7.74 (2H, m), 7.62-7.58 (1H, m), 7.49-7.45 (1H, m), 7.34- 7.28 (1H, m), 7.27-7.24 (2H, m), 7.11-7.07 (1H, m), 4.53 (2H, s), 2.70-2.65 (3H, m).
    290
    Figure US20150329491A1-20151119-C00415
         		1H-NMR (DMSO-D6) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.26- 7.23 (1H, m), 7.17-7.14 (1H, m), 7.06-7.01 (1H, m), 4.88 (2H, s), 3.02 (3H, s), 2.86 (3H, s).
    291
    Figure US20150329491A1-20151119-C00416
         		1H-NMR (DMSO-D6) δ: 12.40 (1H, br s), 7.80-7.71 (2H, m), 7.62-7.56 (1H, m), 7.49-7.42 (1H, m), 7.34- 7.21 (2H, m), 7.15 (1H, s), 7.11-7.04 (1H, m), 4.28- 4.18 (2H, m), 2.77-2.69 (2H, m).
    292
    Figure US20150329491A1-20151119-C00417
         		1H-NMR (DMSO-D6) δ: 7.78- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.23 (1H, s), 7.18-7.16 (1H, m), 7.07 (1H, dd, J = 8.4, 2.4 Hz), 4.89 (1H, t, J = 5.5 Hz), 4.07-4.03 (2H, m), 3.77-3.72 (2H, m).
    293
    Figure US20150329491A1-20151119-C00418
         		1H-HMR (DMSO-D6) δ: 7.60- 7.56 (2H, m), 7.54-7.50 (1H, m), 7.40-7.36 (1H, m), 7.20-7.15 (1H, m), 7.08- 7.05 (1H, m), 6.83-6.80 (1H, m), 6.65-6.61 (1H, m), 3.98-3.88 (1H, m), 3.46- 3.39 (1H, m), 3.22-3.13 (1H, m), 2.11-1.94 (3H, m), 1.70 (1H, d, J = 42.9 Hz), 1.15 (3H, t, J = 6.8 Hz).
  • TABLE 1-43
    compound
    No. structural formula NMR
    294
    Figure US20150329491A1-20151119-C00419
         		1H-NMR (CDCl3) δ: 7.67-7.63 (1H, m), 7.57-7.52 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.01 (2H, t, J = 6.5 Hz), 2.70-2.70 (1H, m), 1.84-1.76 (2H, m), 1.53- 1.44 (2H, m), 1.39-1.32, (4H, m), 0.95-0.89 (3H, m).
    295
    Figure US20150329491A1-20151119-C00420
         		1H-NMR (DMSO-D6) δ: 12.05 (1H, br s), 7.77-7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.22 (1H, s), 7.16-7.14 (1H, m), 7.08- 7.05 (1H, m), 4.04 (2H, t, J = 5.9 Hz), 2.31 (2H, t, J = 7.2 Hz), 1.80-1.63 (4H, m).
    296
    Figure US20150329491A1-20151119-C00421
         		1H-NMR (CDCl3) δ: 7.67-7.64 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.04 (2H, t, J = 6.4 Hz), 3.70 (2H, t, J = 5.8 Hz), 2.79 (1H, s), 1.89-1.81 (2H, m), 1.71- 1.63 (2H, m), 1.62-1.53 (2H, m), 1.32-1.20 (1H, m).
    297
    Figure US20150329491A1-20151119-C00422
         		1H-NMR (DMSO-D6) δ: 7.94- 7.88 (2H, m), 7.68-7.61 (2H, m), 7.58-7.51 (2H, m), 7.45-7.40 (1H, m), 7.35 (1H, br s), 4.81 (1H, t, J = 5.4 Hz), 3.68-3.45 (4H, m), 3.00 (3H, br s).
    298
    Figure US20150329491A1-20151119-C00423
         		1H-NMR (CDCl3) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 6.98 (1H, dd, J = 8.4, 2.4 Hz), 4.03 (2H, t, J = 6.4 Hz), 3.67 (2H, t, J = 6.4 Hz), 2.81 (1H, s), 1.87-1.79 (2H, m), 1.66-1.58 (2H, m), 1.52- 1.41 (4H, m), 1.29-1.20 (1H, m).
    299
    Figure US20150329491A1-20151119-C00424
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.04 (2H, t, J = 6.3 Hz), 2.96 (3H, s), 2.81 (3H, s), 2.37 (2H, t, J = 7.3 Hz), 1.80-1.72 (2H, m), 1.70-1.62 (2H, m).
    300
    Figure US20150329491A1-20151119-C00425
         		1H-NMR (DMSO-D6) δ: 9.38 (1H, s), 8.96 (2H, br s), 7.81-7.77 (1H, m), 7.71- 7.67 (1H, m), 7.56-7.52 (1H, m), 7.45 (1H, dd, J = 7.7, 1.1 Hz), 7.40-7.35 (1H, m), 7.37 (1H, s), 7.31-7.26 (1H, m), 6.71 (1H, d, J = 7.7 Hz).
  • TABLE 1-44
    compound
    No. structural formula NMR
    301
    Figure US20150329491A1-20151119-C00426
         		1H-NMR (DMSO-D6) δ: 7.78-7.72 (2H, m), 7.61-7.57 (1H, m), 7.50-7.43 (2H, m), 7.33-7.27 (1H, m), 7.25- 7.23 (1H, m), 7.16-7.13 (1H, m), 7.08-7.04 (1H, m), 6.95 (1H, br s), 4.25-4.20 (2H, m), 2.59-2.53 (2H, m).
    302
    Figure US20150329491A1-20151119-C00427
         		1H-NMR (DMSO-D6) δ: 7.98-7.91 (1H, m), 7.77-7.72 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.15-7.12 (1H, m), 7.08-7.04 (1H, m), 4.24 (2H, t, J = 5.3 Hz), 2.63- 2.60 (3H, m), 2.59-2.54 (2H, m).
    303
    Figure US20150329491A1-20151119-C00428
         		1H-NMR (DMSO-D6) δ: 7.77-7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.08-7.04 (1H, m), 4.25 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 2.85 (3H, s), 2.82 (2H, t, J = 6.3 Hz).
    304
    Figure US20150329491A1-20151119-C00429
         		1H-NMR (CDCl3) δ: 8.03- 7.87 (1H, m), 7.84-7.64 (4H, m), 7.54-7.48 (1H, m), 7.45- 7.39 (1H, m), 5.01-4.86 (1H, m), 4.59-4.09 (1H, m), 3.88- 3.47 (4H, m), 2.77-2.61 (1H, m), 2.44-2.21 (1H, m).
    305
    Figure US20150329491A1-20151119-C00430
         		1H-NMR (DMSO-D6) δ: 7.79-7.71 (3H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m), 7.09-7.04 (1H, m), 4.06-4.00 (2H, m), 2.59- 2.55 (3H, m), 2.16-2.11 (2H, m), 1.76-1.62 (4H, m).
    306
    Figure US20150329491A1-20151119-C00431
         		1H-NMR (DMSO-D6) δ: 7.77-7.72 (2H, m), 7.61- 7.57 (1H, m), 7.49-7.43 (1H, m), 7.33-7.26 (2H, m), 7.24-7.22 (1H, m), 7.17-7.14 (1H, m), 7.09-7.04 (1H, m), 6.73 (1H, br s), 4.06-4.01 (2H, m), 2.16-2.10 (2H, m), 1.78-1.63 (4H, m).
    307
    Figure US20150329491A1-20151119-C00432
         		1H-NMR (DMSO-D6) δ: 7.94-7.90 (2H, m), 7.68- 7.64 (1H, m), 7.60-7.47 (3H, m), 7.45-7.40 (1H, m), 7.36 (1H, s), 3.50-3.35 (1H, m), 3.26-3.09 (1H, m), 3.01-2.88 (3H, m), 1.71-1.47 (2H, m), 1.00-0.59 (3H, m).
  • TABLE 1-45
    compound
    No. structural formula NMR
    308
    Figure US20150329491A1-20151119-C00433
         		1H-NMR (DMSO-D6) δ: 7.94-7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.49 (3H, m), 7.45-7.40 (1H, m), 7.36 (1H, s), 3.53-3.11 (2H, m), 3.01- 2.89 (3H, m), 1.65-0.68 (7H, m).
    309
    Figure US20150329491A1-20151119-C00434
         		1H-NMR (DMSO-D6) δ: 7.78 (1H, dd, J = 4.9, 3.1 Hz), 7.70-7.64 (2H, m), 7.65 (1H, dd, J = 4.2, 2.1 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.37-7.21 (4H, m), 7.26 (1H, s), 6.89 (1H, d, J = 7.3 Hz).
    310
    Figure US20150329491A1-20151119-C00435
         		1H-NMR (DMSO-D6) δ: 8.62- 8.57 (1H, m), 8.17-8.14 (1H, m), 8.06-8.01 (1H, m), 7.97- 7.92 (2H, m), 7.70-7.66 (1H, m), 7.58-7.52 (1H, m), 7.48- 7.43 (1H, m), 7.37-7.34 (1H, m), 4.78-4.72 (1H, m), 3.58- 3.49 (2H, m), 3.43-3.27 (2H, m).
    311
    Figure US20150329491A1-20151119-C00436
         		1H-NMR (DMSO-D6) δ: 8.63- 8.57 (1H, m), 8.16-8.11 (1H, m), 8.04-7.99 (1H, m), 7.97- 7.91 (2H, m), 7.58-7.52 (1H, m), 7.48-7.42 (1H, m), 7.37- 7.33 (1H, m), 4.51-4.47 (1H, m), 3.52-3.45 (2H, m), 3.39- 3.27 (2H, m), 1.75-1.67 (2H, m).
    312
    Figure US20150329491A1-20151119-C00437
         		1H-NMR (DMSO-D6) δ: 8.62 (1H, t, J = 5.1 Hz), 8.16-8.13 (1H, m), 8.04-8.00 (1H, m), 7.96-7.91 (2H, m), 7.70-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.37-7.35 (1H, m), 4.44-4.40 (1H, m), 3.46-3.40 (2H, m), 3.35-3.24 (2H, m), 1.62-1.53 (2H, m), 1.52-1.44 (2H, m).
    313
    Figure US20150329491A1-20151119-C00438
         		1H-NMR (CD3OD) δ: 7.81 (1H, d, J = 7.1 Hz), 7.69 (1H, d, J = 7.3 Hz), 7.57 (1H, d, J = 7.5 Hz), 7.49-7.43 (1H, m), 7.37-7.27 (3H, m), 2.56 (3H, s).
    314
    Figure US20150329491A1-20151119-C00439
         		1H-NMR (DMSO-D6) δ: 12.86 (1H, br s), 7.99-7.76 (4H, m), 7.67 (1H, d, J = 7.1 Hz), 7.58-7.52 (1H, m), 7.48- 7.35 (2H, m), 5.20-5.04 (0.3H, m), 4.81-4.72 (0.7H, m), 4.47-3.91 (2H, m), 2.81-2.57 (1H, m), 2.29-2.05 (1H, m).
  • TABLE 1-46
    compound
    No. structural formula NMR
    315
    Figure US20150329491A1-20151119-C00440
         		1H-NMR (DMSO-D6) δ: 8.62 (1H, t, J = 5.6 Hz), 8.15-8.13 (1H, m), 8.01 (1H, dd, J = 7.9, 1.8 Hz), 7.96-7.91 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.42 (1H, m), 7.34 (1H, s), 3.36-3.27 (2H, m), 1.15 (3H, t, J = 7.2 Hz).
    316
    Figure US20150329491A1-20151119-C00441
         		1H-NMR (DMSO-D6) δ: 8.60 (1H, t, J = 5.5 Hz), 8.15-8.13 (1H, m), 8.02 (1H, dd, J = 7.9, 1.5 Hz), 7.96-7.91 (2H, m), 7.69- 7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.42 (1H, m), 7.34 (1H, s), 3.28-3.21 (2H, m), 1.61-1.51 (2H, m), 0.91 (3H, t, J = 7.5 Hz).
    317
    Figure US20150329491A1-20151119-C00442
         		1H-NMR (DMSO-D6) δ: 7.80- 7.78 (1H, m), 7.76 (1H, d, J = 7.7 Hz), 7.62-7.59 (1H, m), 7.52-7.45 (2H, m), 7.40- 7.26 (6H, m), 7.23-7.17 (1H, m), 7.18 (1H, s), 4.03 (2H, s).
    318
    Figure US20150329491A1-20151119-C00443
         		1H-NMR (DMSO-D6) δ: 11.99 (1H, br s), 7.76-7.72 (2H, m), 7.60-7.56 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.21 (1H, s), 7.15-7.13 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.02 (2H, t, J = 6.6 Hz), 2.24 (2H, t, J = 7.3 Hz), 1.78- 1.70 (2H, m), 1.62-1.53 (2H, m), 1.49-1.42 (2H, m).
    319
    Figure US20150329491A1-20151119-C00444
         		1H-NMR (DMSO-D6) δ: 7.94- 7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.48 (3H, m), 7.45- 7.41 (1H, m), 7.37 (1H, s), 4.46-4.34 (1H, m), 3.53-3.14 (4H, m), 3.01-2.86 (3H, m), 1.69-1.13 (4H, m).
    320
    Figure US20150329491A1-20151119-C00445
         		1H-NMR (DMSO-D6) δ: 8.13 (3H, br s), 7.80 (1H, d, J = 8.3 Hz), 7.77 (1H, d, J = 7.4 Hz), 7.62-7.59 (1H, m), 7.50- 7.45 (1H, m), 7.34-7.30 (1H, m), 7.24-7.22 (1H, m), 7.13 (1H, dd, J = 8.5, 2.4 Hz), 4.24 (2H, t, J = 5.1 Hz), 3.57 (1H, s), 3.25 (2H, br s).
    321
    Figure US20150329491A1-20151119-C00446
         		1H-NMR (DMSO-D6) δ: 8.91 (2H, br s), 7.81 (1H, d, J = 8.3 Hz), 7.79-7.76 (1H, m), 7.63- 7.59 (1H, m), 7.50-7.45 (1H, m), 7.34-7.30 (1H, m), 7.24-7.23 (1H, m), 7.24-7.23 (1H, m), 7.14 (1H, dd, J = 8.3, 2.3 Hz), 4.31 (2H, t, J = 5.1 Hz), 3.39-3.34 (2H, m), 2.65 (3H, br s).
  • TABLE 1-47
    compound
    No. structural formula NMR
    322
    Figure US20150329491A1-20151119-C00447
         		1H-NMR (DMSO-D6) δ: 7.76- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.21 (1H, s), 7.17-7.15 (1H, m), 7.08 (1H, dd, J = 8.4, 2.4 Hz), 4.11 (2H, t, J = 5.7 Hz), 2.64 (2H, t, J = 5.7 Hz), 2.23 (6H, s).
    323
    Figure US20150329491A1-20151119-C00448
         		1H-NMR (CDCl3) δ: 7.68- 7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H, m), 7.31-7.23 (2H, m), 6.98 (1H, dd, J = 8.3, 2.6 Hz), 5.00 (1H, br s), 4.08 (2H, t, J = 5.1 Hz), 3.59-3.52 (2H, m), 2.87 (1H, br s), 1.46 (9H, s).
    324
    Figure US20150329491A1-20151119-C00449
         		1H-NMR (CDCl3) δ: 7.68-7.65 (1H, m), 7.58-7.54 (2H, m), 7.46-7.42 (1H, m), 7.31-7.21 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 4.15 (2H, br s), 3.65- 3.59 (2H, m), 2.99 (3H, br s), 2.96-2.90 (1H, m), 1.46 (9H, s).
    325
    Figure US20150329491A1-20151119-C00450
         		1H-NMR (CDCl3) δ: 7.68-7.65 (1H, m), 7.58-7.55 (2H, m), 7.47-7.42 (1H, m), 7.32-7.27 (1H, m), 7.27-7.24 (1H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 5.94 (1H, br s), 4.09 (2H, t, J = 5.0 Hz), 3.70-3.65 (2H, m), 3.03 (1H, br s), 2.01 (3H, s).
    326
    Figure US20150329491A1-20151119-C00451
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.58-7.53 (2H, m), 7.47-7.41 (1H, m), 7.32-7.21 (2H, m), 6.97 (1H, dd, J = 8.3, 2.6 Hz), 4.19-4.15 (2H, m), 3.80-3.68 (2H, m), 3.26 (0.7H, s), 3.22 (0.3H, s), 3.17 (2.1H, s), 3.00 (0.9H, s), 2.18 (0.9H, s), 2.08 (2.1H, s).
    327
    Figure US20150329491A1-20151119-C00452
         		1H-NMR (DMSO-D6) δ: 7.92 (2H, d, J = 7.5 Hz), 7.68-7.65 (1H, m), 7.62-7.49 (3H, m), 7.45-7.41 (1H, m), 7.38 (1H, s), 4.55-4.38 (1H, m), 3.57-3.21 (4H, m), 3.01-2.91 (3H, m), 1.81-1.63 (2H, m).
    328
    Figure US20150329491A1-20151119-C00453
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 7.5 Hz), 7.83 (1H, s), 7.79 (1H, s), 7.77-7.73 (1H, m), 7.66-7.61 (1H, m), 7.59-7.52 (2H, m), 4.67 (1H, t, J = 5.4 Hz), 4.56-4.45 (1H, m), 4.42-4.36 (1H, m), 4.33-4.15 (2H, m), 3.94-3.86 (1H, m), 3.54-3.48 (2H, m), 3.46-3.40 (2H, m).
  • TABLE 1-48
    compound
    No. structural formula NMR
    329
    Figure US20150329491A1-20151119-C00454
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 7.5 Hz), 7.83 (1H, s), 7.79-7.73 (2H, m), 7.66- 7.53 (3H, m), 4.58-4.41 (2H, m), 4.32-4.23 (1H, m), 4.18- 4.10 (1H, m), 3.83-3.74 (1H, m), 2.86 (3H, s), 2.86 (3H, s).
    330
    Figure US20150329491A1-20151119-C00455
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 7.7 Hz), 7.83 (1H, s), 7.79-7.73 (2H, m), 7.66- 7.61 (1H, m), 7.59-7.52 (1H, m), 7.58 (1H, s), 4.83 (1H, t, J = 5.3 Hz), 4.41-4.32 (1H, m), 4.12-4.03 (2H, m), 3.85- 3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.80-2.69 (1H, m).
    331
    Figure US20150329491A1-20151119-C00456
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.42 (1H, m), 7.32- 7.26 (1H, m), 7.22 (1H, s), 7.17-7.14 (1H, m), 7.06 (1H, dd, J = 8.5, 2.4 Hz), 4.09 (2H, t, J = 6.4 Hz), 2.71 (2H, t, J = 6.8 Hz), 1.86-1.75 (2H, m).
    332
    Figure US20150329491A1-20151119-C00457
         		1H-NMR (DMSO-D6) δ: 8.74 (1H, br s), 7.79-7.74 (2H, m), 7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19-7.17 (1H, m), 7.08 (1H, dd, J = 8.3, 2.6 Hz), 4.13 (2H, t, J = 6.0 Hz), 3.08 (2H, br s), 2.58 (3H, br s), 2.14-2.06 (2H, m).
    333
    Figure US20150329491A1-20151119-C00458
         		1H-NMR (CDCl3) δ: 7.71-7.67 (1H, m), 7.55 (2H, d, J = 8.3 Hz), 7.44-7.38 (1H, m), 7.30- 7.23 (2H, m), 6.95 (1H, dd, J = 8.3, 2.3 Hz), 3.87-3.80 (2H, m), 2.18-2.11 (2H, m), 1.88 (6H, s), 1.81-1.70 (2H, m).
    334
    Figure US20150329491A1-20151119-C00459
         		1H-NMR (CDCl3) δ: 7.69-7.64 (1H, m), 7.58-7.52 (2H, m), 7.47-7.40 (1H, m), 7.34-7.23 (2H, m), 7.00-6.95 (1H, m), 4.07-4.05 (2H, m), 3.66-3.43 (2H, m), 3.03 (1.7H, s), 2.94 (1.3H, s), 2.10-2.00 (2H, m), 2.08 (1.3H, s), 2.05 (1.8H, s).
    335
    Figure US20150329491A1-20151119-C00460
         		1H-NMR (DMSO-D6) δ: 9.40 (1H, s), 8.99 (2H, br s), 7.78- 7.75 (1H, m), 7.72-7.68 (1H, m), 7.63 (1H, d, J = 2.0 Hz), 7.58 (1H, s), 7.43-7.38 (1H, m), 7.34-7.29 (1H, m), 6.68 (1H, d, J = 7.5 Hz).
  • TABLE 1-49
    compound
    No. structural formula NMR
    336
    Figure US20150329491A1-20151119-C00461
         		1H-NMR (DMSO-D6) δ: 8.59 (3H, br s), 7.81 (1H, d, J = 7.9 Hz), 7.75-7.67 (2H, m), 7.60- 7.54 (2H, m), 7.50-7.44 (2H, m), 7.34 (1H, s), 4.53 (1H, d, J = 15.0 Hz), 4.46 (1H, d, J = 15.0 Hz).
    337
    Figure US20150329491A1-20151119-C00462
         		1H-NMR (DMSO-D6) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.43 (1H, m), 7.41 (1H, s), 5.02-4.89 (1H, m), 4.55-4.06 (5H, m), 3.75- 3.61 (1H, m), 3.47-3.12 (4H, m), 2.00-1.70 (2H, m).
    338
    Figure US20150329491A1-20151119-C00463
         		1H-NMR (DMSO-D6) δ: 8.56 (1H, t, J = 5.6 Hz), 8.01-7.98 (1H, m), 7.91 (1H, d, J = 7.7 Hz), 7.84-7.82 (1H, m), 7.73- 7.69 (1H, m), 7.59-7.54 (1H, m), 7.48-7.43 (1H, m), 7.27 (1H, s), 4.40 (1H, t, J = 5.1 Hz), 3.46-3.40 (2H, m), 3.30- 3.25 (2H, m), 2.68 (3H, s), 1.61-1.53 (2H, m), 1.51-1.43 (2H, m).
    339
    Figure US20150329491A1-20151119-C00464
         		1H-NMR (DMSO-D6) δ: 8.34- 8.30 (1H, m), 7.83-7.80 (1H, m), 7.77-7.73 (2H, m), 7.65- 7.61 (1H, m), 7.59-7.53 (2H, m), 5.77 (1H, d, J = 6.2 Hz), 4.56-4.42 (2H, m), 4.34-4.24 (1H, m), 4.15-4.02 (1H, m), 3.87-3.77 (1H, m).
    340
    Figure US20150329491A1-20151119-C00465
         		1H-NMR (CDCl3) δ: 7.69-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.41 (1H, m), 7.32- 7.24 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 5.76 (1H, br s), 4.10 (2H, t, J = 5.8 Hz), 3.51-3.42 (2H, m), 3.11 (1H, br s), 2.07-1.96 (2H, m), 1.98 (3H, s).
    341
    Figure US20150329491A1-20151119-C00466
         		1H-NMR (DMSO-D6) δ: 8.78 (1H, dd, J = 4.7, 1.7 Hz), 8.76- 8.74 (1H, m), 8.06-7.99 (4H, m), 7.95-7.91 (2H, m), 7.75 (1H, d, J = 1.8 Hz), 7.37-7.69 (1H, m), 7.63 (1H, dd, J = 7.6, 5.2 Hz), 7.49 (1H, s), 7.41- 7.36 (1H, m), 7.31-7.26 (1H, m), 6.72 (1H, d, J = 7.7 Hz), 1.58 (9H, s).
    342
    Figure US20150329491A1-20151119-C00467
         		1H-NMR (DMSO-D6) δ: 9.00- 8.96 (1H, m), 8.91 (1H, dd, J = 5.2, 1.4 Hz), 8.37-8.32 (1H, m), 8.11-8.05 (3H, m), 7.97-7.92 (2H, m), 7.91-7.86 (1H, m), 7.84-7.81 (1H, m), 7.74-7.70 (1H, m), 7.52 (1H, br s), 7.43-7.38 (1H, m), 7.32- 7.27 (1H, m), 6.79 (1H, d, J = 7.5 Hz).
  • TABLE 1-50
    compound
    No. structural formula NMR
    343
    Figure US20150329491A1-20151119-C00468
         		1H-NMR (DMSO-D6) δ: 8.15- 8.13 (1H, m), 8.08-8.05 (1H, m), 7.85 (1H, d, J = 1.5 Hz), 7.73-7.68 (1H, m), 7.67 (1H, d, J = 0.9 Hz), 7.49-7.35 (4H, m), 3.97 (3H, s), 3.90 (3H, s).
    344
    Figure US20150329491A1-20151119-C00469
         		1H-NMR (DMSO-D6) δ: 13.24 (1H, br s), 8.14-8.12 (1H, m), 8.06-8.05 (1H, m), 7.83 (1H, d, J = 1.6 Hz), 7.72-7.68 (1H, m), 7.66 (1H, d, J = 0.7 Hz), 7.47-7.36 (4H, m), 3.97 (3H, s).
    345
    Figure US20150329491A1-20151119-C00470
         		1H-NMR (DMSO-D6) δ: 8.62 (1H, t, J = 5.7 Hz), 8.10 (1H, s), 8.02 (1H, s), 7.82 (1H, d, J = 1.5 Hz), 7.72-7.62 (1H, m), 7.65 (1H, s), 7.44-7.30 (3H, m), 7.34 (1H, s), 4.40 (1H, t, J = 5.1 Hz), 3.98 (3H, s), 3.44-3.39 (2H, m), 3.36- 3.19 (2H, m), 1.63-1.39 (4H, m).
    346
    Figure US20150329491A1-20151119-C00471
         		1H-NMR (DMSO-D6) δ: 8.04- 8.00 (1H, m), 7.69-7.63 (2H, m), 7.62-7.58 (1H, m), 7.43- 7.30 (5H, m), 4.82 (1H, t, J = 5.3 Hz), 3.96 (3H, s), 3.68- 3.59 (1H, m), 3.56-3.48 (2H, m), 3.40-3.33 (1H, m), 3.01 (3H, s).
    347
    Figure US20150329491A1-20151119-C00472
         		1H-NMR (CDCl3) δ: 7.72-7.67 (2H, m), 7.52 (1H, s), 7.49 (1H, s), 7.36-7.21 (5H, m), 4.26 (2H, q, J = 7.3 Hz), 3.15 (1H, br s), 1.57 (3H, t, J = 7.3 Hz).
    348
    Figure US20150329491A1-20151119-C00473
         		1H-NMR (DMSO-D6) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33- 7.23 (2H, m), 7.17-7.15 (1H, m), 7.11-7.06 (1H, m), 4.54- 4.45 (1H, m), 4.23-4.07 (4H, m), 3.73-3.62 (2H, m), 3.00 (1.6H, s), 2.94 (1.4H, s).
    349
    Figure US20150329491A1-20151119-C00474
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 7.5 Hz), 7.84-7.82 (1H, m), 7.78 (1H, d, J = 1.3 Hz), 7.77-7.73 (1H, m), 7.65- 7.61 (1H, m), 7.58-7.53 (1H, m), 7.57 (1H, s), 7.35 (1H, br s), 7.26 (1H, br s), 4.56-4.48 (1H, m), 4.45-4.39 (1H, m), 4.32-4.23 (2H, m), 4.01-3.93 (1H, m), 3.84 (2H, s).
  • TABLE 1-51
    compound
    No. structural formula NMR
    350
    Figure US20150329491A1-20151119-C00475
         		1H-NMR (DMSO-D6) δ: 7.91 (1H, d, J = 7.7 Hz), 7.73-7.69 (2H, m), 7.59-7.54 (2H, m), 7.48-7.44 (1H, m), 7.33 (1H, s), 5.76 (1H, d, J = 6.3 Hz), 4.55-4.53 (2H, m), 4.31-4.23 (1H, m), 4.13-4.00 (1H, m), 3.87-3.75 (1H, m), 2.68 (3H, s).
    351
    Figure US20150329491A1-20151119-C00476
         		1H-NMR (DMSO-D6) δ: 7.91 (1H, d, J = 7.7 Hz), 7.73-7.69 (2H, m), 7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.33 (1H, s), 4.83 (1H, t, J = 5.4 Hz), 4.38-4.31 (1H, m), 4.09-4.03 (2H, m), 3.82-3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.78- 2.70 (1H, m), 2.68 (3H, s).
    352
    Figure US20150329491A1-20151119-C00477
         		1H-NMR (DMSO-D6) δ: 7.93- 7.90 (1H, m), 7.74-7.69 (2H, m), 7.60-7.54 (2H, m), 7.48- 7.44 (1H, m), 7.35 (1H, br s), 7.33 (1H, s), 7.26 (1H, br s), 4.54-4.45 (1H, m), 4.44-4.38 (1H, m), 4.31-4.21 (2H, m), 3.99-3.92 (1H, m), 3.83 (2H, s), 2.69 (3H, s).
    353
    Figure US20150329491A1-20151119-C00478
         		1H-NMR (DMSO-D6) δ: 7.84- 7.79 (2H, m), 7.64-7.61 (1H, m), 7.56-7.54 (1H, m), 7.52- 7.48 (1H, m), 7.42-7.35 (2H, m), 7.23 (1H, s), 3.79 (2H, s), 3.64 (3H, s).
    354
    Figure US20150329491A1-20151119-C00479
         		1H-NMR (DMSO-D6) δ: 8.03 (1H, s), 7.69-7.65 (1H, m), 7.65 (1H, d, J = 0.7 Hz), 7.60- 7.59 (1H, m), 7.42-7.35 (4H, m), 7.30 (1H, d, J = 1.4 Hz), 3.96 (3H, s), 2.99 (6H, s).
    355
    Figure US20150329491A1-20151119-C00480
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.83-7.81 (1H, m), 7.70-7.67 (1H, m), 7.66 (1H, d, J = 0.7 Hz), 7.49 (1H, d, J = 1.6 Hz), 7.43-7.36 (4H, m), 4.38-4.32 (2H, m), 4.10- 4.04 (2H, m), 3.97 (3H, s), 2.32-2.23 (2H, m).
    356
    Figure US20150329491A1-20151119-C00481
         		1H-NMR (DMSO-D6) δ: 8.03 (1H, s), 7.72-7.70 (1H, m), 7.69-7.65 (1H, m), 7.66 (1H, d, J = 0.9 Hz), 7.43-7.34 (5H, m), 3.96 (3H, s), 3.51-3.42 (4H, m), 1.91-1.81 (4H, m).
  • TABLE 1-52
    compound
    No. structural formula NMR
    357
    Figure US20150329491A1-20151119-C00482
         		1H-NMR (DMSO-D6) δ: 7.78- 7.74 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33- 7.29 (1H, m), 7.27 (1H, s), 7.16-7.14 (1H, m), 7.07 (1H, dd, J = 8.3, 2.6 Hz), 4.88 (2H, s), 3.72 (3H, s).
    358
    Figure US20150329491A1-20151119-C00483
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.64-7.57 (2H, m), 7.60 (1H, s), 7.41 (1H, br s), 7.30-7.25 (3H, m), 7.24 (1H, s), 7.23-7.20 (1H, m), 6.84 (1H, d, J = 2.6 Hz), 4.50 (2H, s), 3.96 (3H, s).
    359
    Figure US20150329491A1-20151119-C00484
         		1H-NMR (CDCl3) δ: 7.69-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.41 (1H, m), 7.32-7.23 (2H, m), 6.97 (1H, dd, J = 8.5, 2.4 Hz), 4.17 (2H, t, J = 5.3 Hz), 3.71-3.67 (2H, m), 3.59 (2H, t, J = 7.2 Hz), 3.11 (1H, br s), 2.38 (2H, t, J = 8.3 Hz), 2.09-1.98 (2H, m).
    360
    Figure US20150329491A1-20151119-C00485
         		1H-NMR (DMSO-D6) δ: 7.74 (2H, d, J = 8.3 Hz), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H, dd, J = 8.3, 2.3 Hz), 4.79 (2H, s), 3.52-3.46 (2H, m), 3.36-3.31 (2H, m), 1.95-1.87 (2H, m), 1.82-1.74 (2H, m).
    361
    Figure US20150329491A1-20151119-C00486
         		1H-NMR (DMSO-D6) δ: 7.76- 7.73 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32- 7.28 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.03 (1H, dd, J = 8.3, 2.6 Hz), 4.87 (2H, s), 3.46-3.40 (4H, m), 1.63- 1.52 (4H, m), 1.47-1.42 (2H, m).
    362
    Figure US20150329491A1-20151119-C00487
         		1H-NMR (DMSO-D6) δ: 7.77- 7.73 (2H, m), 7.61-7.58 (1H, m), 7.48-7.44 (1H, m), 7.32- 7.28 (1H, m), 7.25 (1H, s), 7.18-7.16 (1H, m), 7.05 (1H, dd, J = 8.5, 2.4 Hz), 4.91 (2H, s), 3.64-3.55 (4H, m), 3.52- 3.44 (4H, m).
    363
    Figure US20150329491A1-20151119-C00488
         		1H-NMR (DMSO-D6) δ: 9.38 (1H, s), 8.96 (2H, br s), 7.67- 7.62 (2H, m), 7.43 (1H, br s), 7.40-7.37 (1H, m), 7.39 (1H, s), 7.31-7.22 (2H, m), 7.05 (1H, d, J = 2.4 Hz), 6.64 (1H, d, J = 7.1 Hz), 4.56 (2H, s).
  • TABLE 1-53
    compound
    No. structural formula NMR
    364
    Figure US20150329491A1-20151119-C00489
         		1H-NMR (DMSO-D6) δ: 9.41 (1H, s), 9.01 (2H, br s), 8.31- 8.28 (1H, m), 8.01 (1H, d, J = 1.4 Hz), 7.77-7.73 (1H, m), 7.63 (1H, s), 7.49-7.44 (1H, m), 7.38-7.33 (1H, m), 6.75 (1H, d, J = 7.9 Hz), 3.92 (3H, s).
    365
    Figure US20150329491A1-20151119-C00490
         		1H-NMR (DMSO-D6) δ: 8.13 (1H, t, J = 5.6 Hz), 7.79-7.74 (2H, m), 7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.29 (1H, m), 7.27-7.23 (1H, m), 7.26 (1H, s), 7.09 (1H, dd, J = 8.3, 2.6 Hz), 4.73 (1H, t, J = 5.6 Hz), 4.54 (2H, s), 3.47- 3.42 (2H, m), 3.25-3.20 (2H, m).
    366
    Figure US20150329491A1-20151119-C00491
         		1H-NMR (DMSO-D6) δ: 7.76- 7.71 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.04-7.00 (1H, m), 5.00 (0.6H, t, J = 5.1 Hz), 4.96 (1.2H, s), 4.88 (0.8H, s), 4.69 (0.4H, t, J = 5.6 Hz), 3.61-3.57 (1.2H, m), 3.51-3.47 (0.8H, m), 3.42- 3.33 (2H, m), 3.06 (1.2H, s), 2.86 (1.8H, s).
    367
    Figure US20150329491A1-20151119-C00492
         		1H-NMR (DMSO-D6) δ: 13.42 (1H, br s), 9.41 (1H, s), 9.01 (2H, br s), 8.30-8.28 (1H, m), 7.97 (1H, d, J = 1.4 Hz), 7.76- 7.72 (1H, m), 7.58 (1H, s), 7.48-7.43 (1H, m), 7.37-7.32 (1H, m), 6.74 (1H, d, J = 7.7 Hz).
    368
    Figure US20150329491A1-20151119-C00493
         		1H-NMR (DMSO-D6) δ: 9.39 (1H, s), 9.00 (2H, br s), 7.78- 7.76 (1H, m), 7.74-7.69 (1H, m), 7.52-7.51 (2H, m), 7.44- 7.39 (1H, m), 7.35-7.30 (1H, m), 6.74 (1H, d, J = 7.7 Hz), 3.02 (6H, s).
    369
    Figure US20150329491A1-20151119-C00494
         		1H-NMR (DMSO-D6) δ: 9.40 (1H, s), 8.99 (2H, br s), 7.99- 7.97 (1H, m), 7.74-7.70 (1H, m), 7.66 (1H, d, J = 1.6 Hz), 7.54 (1H, s), 7.45-7.40 (1H, m), 7.35-7.31 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 4.42- 4.34 (2H, m), 4.13-4.05 (2H, m), 2.33-2.24 (2H, m).
    370
    Figure US20150329491A1-20151119-C00495
         		1H-NMR (DMSO-D6) δ: 9.39 (1H, s), 9.00 (2H, br s), 7.89- 7.86 (1H, m), 7.74-7.70 (1H, m), 7.62 (1H, d, J = 1.6 Hz), 7.51 (1H, s), 7.44-7.39 (1H, m), 7.35-7.30 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 3.56-3.44 (4H, m), 1.93-1.81 (4H, m).
  • TABLE 1-54
    compound
    No. structural formula NMR
    371
    Figure US20150329491A1-20151119-C00496
         		1H-NMR (DMSO-D6) δ: 9.41 (1H, s), 9.02 (2H, br s), 8.67 (1H, t, J = 5.7 Hz), 8.29-8.25 (1H, m), 7.95 (1H, d, J = 1.6 Hz), 7.75- 7.71 (1H, m), 7.51 (1H, s), 7.45-7.40 (1H, m), 7.36- 7.31 (1H, m), 6.79 (1H, d, J = 7.7 Hz), 4.41 (1H, t, J = 5.1 Hz), 3.45-3.39 (2H, m), 3.37-3.25 (2H, m), 1.61-1.52 (2H, m), 1.51- 1.42 (2H, m).
    372
    Figure US20150329491A1-20151119-C00497
         		1H-NMR (DMSO-D6) δ: 9.39 (1H, s), 8.99 (2H, br s), 7.79-7.76 (1H, m), 7.73- 7.69 (1H, m), 7.54-7.48 (2H, m), 7.43-7.38 (1H, m), 7.34-7.29 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 4.88- 4.79 (1H, m), 3.67-3.60 (1H, m), 3.57-3.50 (2H, m), 3.41-3.36 (1H, m), 3.06- 2.99 (3H, m).
    373
    Figure US20150329491A1-20151119-C00498
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.82-7.79 (1H, m), 7.70-7.65 (1H, m), 7.66 (1H, s), 7.48 (1H, d, J = 1.5 Hz), 7.43-7.36 (4H, m), 5.76 (1H, d, J = 5.7 Hz), 4.54-4.47 (2H, m), 4.31- 4.24 (1H, m), 4.09-4.03 (1H, m), 3.97 (3H, s), 3.84-3.78 (1H, m).
    374
    Figure US20150329491A1-20151119-C00499
         		H-NMR (DMSO-D6) δ: 8.03 (1H, s), 7.84-7.81 (1H, m), 7.71-7.66 (1H, m), 7.65 (1H, d, J = 0.7 Hz), 7.52- 7.48 (1H, m), 7.42-7.36 (4H, m), 4.83 (1H, t, J = 5.4 Hz), 4.39-4.32 (1H, m), 4.12-4.02 (2H, m), 3.97 (3H, s), 3.84-3.77 (1H, m), 3.55 (2H, t, J = 5.5 Hz), 2.79-2.69 (1H, m).
    375
    Figure US20150329491A1-20151119-C00500
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.84-7.81 (1H, m), 7.70-7.66 (2H, m), 7.51- 7.48 (1H, m), 7.44-7.35 (4H, m), 4.66 (1H, t, J = 5.4 Hz), 4.55-4.46 (1H, m), 4.41-4.35 (1H, m), 4.32- 4.24 (1H, m), 4.19-4.13 (1H, m), 3.97 (3H, s), 3.92-3.86 (1H, m), 3.53- 3.48 (2H, m), 3.44-3.39 (2H, m).
    376
    Figure US20150329491A1-20151119-C00501
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, s), 7.72-7.65 (3H, m), 7.44-7.34 (5H, m), 5.04- 4.95 (1H, m), 4.37-4.23 (1H, m), 3.96 (3H, s), 3.68-3.24 (4H, m), 2.03- 1.88 (1H, m), 1.87-1.77 (1H, m).
  • TABLE 1-55
    compound
    No. structural formula NMR
    377
    Figure US20150329491A1-20151119-C00502
         		1H-NMR (DMSO-D6) δ: 8.25 (1H, s), 7.93 (1H, d, J = 0.7 Hz), 7.85-7.81 (2H, m), 7.79-7.77 (1H, m), 7.71 (1H, dd, J = 7.9, 1.5 Hz), 7.65-7.61 (1H, m), 7.52- 7.47 (1H, m), 7.39-7.34 (1H, m), 7.25 (1H, s), 3.88 (3H, s).
    378
    Figure US20150329491A1-20151119-C00503
         		1H-NMR (DMSO-D6) δ: 8.36 (1H, d, J = 2.6 Hz), 7.79 (1H, d, J = 7.5 Hz), 7.71- 7.66 (1H, m), 7.59-7.53 (2H, m), 7.49 (1H, s), 7.48-7.43 (1H, m), 3.91 (3H, s).
    379
    Figure US20150329491A1-20151119-C00504
         		1H-NMR (DMSO-D6) δ: 7.79- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.24 (0.4H, s), 7.23 (0.6H, s), 7.18-7.14 (1H, m), 7.11- 7.06 (1H, m), 4.85 (0.6H, t, J = 5.5 Hz), 4.68 (0.4H, t, J = 5.3 Hz), 4.20 (0.8H, t, J = 5.5 Hz), 4.12 (1.2H,
    t, J = 6.0 Hz), 3.79-3.73
    (0.8H, m), 3.69-3.63 (1.2H,
    m), 3.61-3.54 (1.2H, m),
    3.51-3.38 (2.8H, m), 2.10
    (1.2H, s), 2.05 (1.8H, s).
    380
    Figure US20150329491A1-20151119-C00505
         		1H-NMR (DMSO-D6) δ: 7.77- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.49-7.43 (1H, m), 7.32-7.21 (2H, m), 7.17- 7.13 (1H, m), 7.11-7.04 (1H, m), 4.82-4.65 (1H, m), 3.71-3.62 (0.4H, m), 3.52- 3.39 (1.6H, m), 3.03 (1.8H, s), 2.85 (0.6H, s), 2.84
    (0.6H, s), 2.10 (1.2H, s),
    1.96 (0.9H, s), 1.95 (0.9H,
    s), 1.29-1.21 (3H, m).
    381
    Figure US20150329491A1-20151119-C00506
         		1H-NMR (DMSO-D6) δ: 7.79- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.25- 7.22 (1H, m), 7.18-7.14 (1H, m), 7.11-7.05 (1H, m), 4.92-4.79 (0.5H, m), 4.37- 4.25 (0.5H, m), 4.15-3.96 (2H, m), 2.88 (1.5H, s),
    2.70 (1.5H, s), 2.05 (1.5H,
    s), 2.00 (1.5H, s), 1.25-
    1.13 (3H, m).
    382
    Figure US20150329491A1-20151119-C00507
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.12 (1H, m), 7.05-7.01 (1H, m), 5.14- 5.10 (0.3H, m), 4.93 (0.6H, s), 4.80-4.77 (1.4H, m), 4.73 (0.7H, t, J = 5.6 Hz), 4.12-4.04 (0.3H, m), 4.01- 3.94 (0.7H, m), 3.55-3.26
    (4H, m), 2.01-1.76 (4H, m).
  • TABLE 1-56
    compound
    No. structural formula NMR
    383
    Figure US20150329491A1-20151119-C00508
         		1H-NMR (DMSO-D6) δ: 7.76- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.13 (1H, m), 7.05-7.01 (1H, m), 5.14- 5.10 (0.3H, m), 4.95-4.91 (0.6H, m), 4.81-4.77 (1.4H, m), 4.75-4.71 (0.7H, m), 4.12-4.04 (0.3H, m), 4.00- 3.94 (0.7H, m), 3.55-3.26 (4H, m), 2.00-1.76 (4H, m).
    384
    Figure US20150329491A1-20151119-C00509
         		1H-NMR (DMSO-D6) δ: 12.03 (1H, br s), 8.14 (1H, d, J = 7.7 Hz), 7.68-7.64 (1H, m), 7.56-7.51 (1H, m), 7.42-7.38 (2H, m), 7.17- 7.14 (2H, m), 4.08 (2H, t, J = 6.3 Hz), 2.30 (2H, t, J = 7.2 Hz), 1.80-1.72 (2H, m), 1.71-1.64 (2H, m).
    385
    Figure US20150329491A1-20151119-C00510
         		1H-NMR (DMSO-D6) δ: 8.15 (1H, d, J = 7.5 Hz), 7.69- 7.64 (2H, m), 7.57-7.52 (1H, m), 7.48-7.39 (3H, m), 7.27-7.25 (1H, m), 7.15 (1H, d, J = 2.4 Hz), 4.55 (2H, s).
    386
    Figure US20150329491A1-20151119-C00511
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.67-7.59 (2H, m), 7.61 (1H, s), 7.41-7.26 (5H, m), 7.21 (1H, s), 4.03 (2H, d, J = 7.3 Hz), 2.27- 2.16 (1H, m), 0.93 (3H, d, J = 2.0 Hz), 0.92 (3H, d, J = 2.0 Hz).
    387
    Figure US20150329491A1-20151119-C00512
         		1H-NMR (CDCl3) δ: 8.20 (1H, d, J = 7.9 Hz), 7.70-7.65 (1H, m), 7.50-7.46 (1H, m), 7.36-7.31 (1H, m), 7.20- 7.17 (1H, m), 6.95 (1H, d, J = 2.2 Hz), 4.02 (2H, t, J = 6.4 Hz), 3.68 (2H, t, J = 6.3 Hz), 2.88 (1H, br s), 1.88-1.80 (2H, m), 1.69- 1.61 (4H, m).
    388
    Figure US20150329491A1-20151119-C00513
         		1H-NMR (CDCl3) δ: 8.22-8.17 (1H, m), 7.71-7.66 (1H, m), 7.51-7.45 (1H, m), 7.37- 7.30 (1H, m), 7.20-7.16 (1H, m), 6.95-6.92 (1H, m), 4.16-4.09 (2H, m), 3.90 (0.7H, br s), 3.77 (0.3H, br s), 3.73-3.61 (2H, m), 3.13 (2.2H, s), 2.96 (0.8H, s), 2.14 (0.8H, s), 2.03 (2.2H, s).
    389
    Figure US20150329491A1-20151119-C00514
         		1H-NMR (DMSO-D6) δ: 7.75 (2H, d, J = 8.3 Hz), 7.61- 7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.18-7.15 (1H, m), 7.04 (1H, dd, J = 8.5, 2.4 Hz), 5.07 (0.5H, d, J = 3.7 Hz), 4.96 (0.5H, d, J = 3.2 Hz), 4.81 (1.0H, s), 4.76 (1.0H, s), 4.36 (0.5H, d, J = 20.4 Hz), 4.27 (0.5H, d, J = 18.3 Hz), 3.65-3.53 (1.5H, m), 3.49-3.27 (2.5H, m), 2.01- 1.92 (0.5H, m), 1.91-1.81 (1.0H, m), 1.79-1.71 (0.5H, m).
  • TABLE 1-57
    compound
    No. structural formula NMR
    390
    Figure US20150329491A1-20151119-C00515
         		1H-NMR (DMSO-D6) δ: 7.74 (2H, d, J = 8.1 Hz), 7.60- 7.56 (1H, m), 7.47-7.43 (1H, m), 7.32-7.27 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H, dd, J = 8.5, 2.4 Hz), 5.06 (0.5H, d, J = 3.7 Hz), 4.96 (0.5H, d, J = 3.2 Hz), 4.80 (1.0H, s), 4.75 (1.0H, s), 4.38- 4.33 (0.5H, m), 4.28-4.24 (0.5H, m), 3.64-3.52 (1.5H, m), 3.48-3.23 (2.5H, m), 1.99-1.91 (0.5H, m), 1.90- 1.80 (1.0H, m), 1.78-1.69 (0.5H, m).
    391
    Figure US20150329491A1-20151119-C00516
         		1H-NMR (DMSO-D6) δ: 7.78- 7.74 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.26 (1H, s), 7.16-7.14 (1H, m), 7.04 (1H, dd, J = 8.3, 2.6 Hz), 4.64 (2H, s), 4.26 (2H, t, J = 8.5 Hz), 3.92 (2H, t, J = 7.8 Hz), 2.30- 2.20 (2H, m).
    392
    Figure US20150329491A1-20151119-C00517
         		1H-NMR (DMSO-D6) δ: 8.02 (1H, s), 7.73-7.63 (2H, m), 7.65 (1H, s), 7.43-7.32 (5H, m), 4.82-4.76 (1H, m), 4.21-4.12 (1H, m), 3.96 (3H, s), 3.61-3.55 (2H, m), 3.51-3.44 (1H, m), 3.41- 3.34 (1H, m), 2.02-1.83 (3H, m), 1.77-1.64 (1H, m).
    393
    Figure US20150329491A1-20151119-C00518
         		1H-NMR (DMSO-D6) δ: 8.03 (1H, s), 7.73-7.63 (2H, m), 7.65 (1H, s), 7.43-7.32 (5H, m), 4.82-4.75 (1H, m), 4.21-4.12 (1H, m), 3.96 (3H, s), 3.61-3.54 (2H, m), 3.51-3.44 (1H, m), 3.43- 3.34 (1H, m), 2.01-1.82 (3H, m), 1.78-1.66 (1H, m).
    394
    Figure US20150329491A1-20151119-C00519
         		1H-NMR (DMSO-D6) δ: 8.03 (1H, s), 7.72-7.64 (3H, m), 7.42-7.34 (5H, m), 4.73- 4.62 (1H, m), 3.96 (3H, s), 3.63-3.24 (6H, m), 2.39- 2.26 (1H, m), 2.00-1.86 (1H, m), 1.71-1.60 (1H, m).
    395
    Figure US20150329491A1-20151119-C00520
         		1H-NMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.57-7.51 (2H, m), 7.46-7.40 (1H, m), 7.30- 7.23 (2H, m), 6.97 (1H, dd, J = 8.3, 2.3 Hz), 4.04 (2H, t, J = 6.2 Hz), 3.52-3.38 (5H, m), 2.36-2.29 (2H, m), 2.06-1.95 (4H, m).
  • TABLE 1-58
    compound
    No. structural formula NMR
    396
    Figure US20150329491A1-20151119-C00521
         		1H-NMR (DMSO-D6) δ: 7.77- 7.73 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H, dd, J = 8.3, 2.6 Hz), 4.91 (1H, d, J = 13.9 Hz), 4.86 (1H, d, J = 15.5 Hz), 4.78 (1H, d, J = 3.7 Hz), 3.92-3.84 (1H, m), 3.76-3.65 (2H, m), 3.25- 3.15 (1H, m), 3.12-3.01 (1H, m), 1.83-1.66 (2H, m), 1.47-1.35 (1H, m), 1.32- 1.21 (1H, m).
    397
    Figure US20150329491A1-20151119-C00522
         		1H-NMR (DMSO-D6) δ: 7.77- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.16-7.13 (1H, m), 7.04 (1H, dd, J = 8.3, 2.3 Hz), 4.95-4.81 (2H, m), 4.52 (1H, t, J = 5.1 Hz), 4.38-4.29 (1H, m), 3.92- 3.83 (1H, m), 3.26 (2H, t, J = 5.6 Hz), 3.07-2.97 (1H, m), 2.63-2.54 (1H, m), 1.75-1.58 (3H, m), 1.21- 1.07 (1H, m), 1.03-0.90 (1H, m).
    398
    Figure US20150329491A1-20151119-C00523
         		1H-NMR (CDCl3) δ: 8.15 (1H, d, J = 2.2 Hz), 7.81 (1H, d, J = 7.5 Hz), 7.72 (1H, d, J = 7.5 Hz), 7.53-7.47 (2H, m), 7.43-7.38 (1H, m), 4.18-4.03 (2H, m), 3.76- 3.67 (3H, m), 3.15 (2.3H, s), 2.98 (0.7H, s), 2.16 (0.7H, s), 2.06 (2.3H, s).
    399
    Figure US20150329491A1-20151119-C00524
         		1H-NMR (CDCl3) δ: 8.16-8.12 (1H, m), 7.86-7.81 (1H, m), 7.74-7.69 (1H, m), 7.56- 7.48 (1H, m), 7.48-7.38 (2H, m), 4.27-4.12 (4H, m), 3.89-3.49 (4H, m), 3.09 (0.7H, s), 3.04 (2.3H, s).
    400
    Figure US20150329491A1-20151119-C00525
         		1H-NMR (DMSO-D6) δ: 7.76- 7.71 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44 (1H, m), 7.30 (1H, d, J = 18.6 Hz), 7.24 (1H, s), 7.16-7.13 (1H, m), 7.01 (1H, dd, J = 8.5, 2.4 Hz), 5.02 (1H, t, J = 5.1 Hz), 4.97 (2H, s), 4.71 (1H, t, J = 5.4 Hz), 3.63-3.57 (2H, m), 3.53- 3.32 (6H, m).
    401
    Figure US20150329491A1-20151119-C00526
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.58-7.52 (2H, m), 7.45-7.40 (1H, m), 7.30- 7.25 (2H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.05 (2H, t, J = 6.2 Hz), 3.74 (1H, s), 3.62-3.54 (1H, m), 3.47-3.39 (1H, m), 3.34- 3.27 (2H, m), 2.33-2.28 (2H, m), 2.06-1.99 (2H, m), 1.81-1.71 (4H, m).
    402
    Figure US20150329491A1-20151119-C00527
         		1H-NMR (DMSO-D6) δ: 12.39 (1H, br s), 7.83 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 7.9 Hz), 7.65-7.61 (1H, m), 7.56-7.53 (1H, m), 7.52- 7.47 (1H, m), 7.41-7.35 (2H, m), 7.24 (1H, s), 3.67 (2H, s).
  • TABLE 1-59
    compound
    No. structural formula NMR
    403
    Figure US20150329491A1-20151119-C00528
         		1H-NMR (DMSO-D6) δ: 7.81 (1H, d, J = 7.5 Hz), 7.77 (1H, d, J = 7.7 Hz), 7.64- 7.60 (1H, m), 7.58-7.52 (2H, m), 7.51-7.46 (1H, m), 7.41-7.34 (2H, m), 7.22 (1H, s), 6.92 (1H, br s), 3.47 (1H, d, J = 14.1 Hz), 3.43 (1H, d, J = 14.3 Hz).
    404
    Figure US20150329491A1-20151119-C00529
         		1H-NMR (CDCl3) δ: 8.39-8.36 (1H, m), 7.69-7.65 (1H, m), 7.52-7.47 (1H, m), 7.37- 7.32 (1H, m), 7.26 (2H, s), 7.23-7.21 (1H, m), 7.14 (1H, d, J = 2.4 Hz), 4.09 (2H, t, J = 6.1 Hz), 2.61 (2H, t, J = 7.2 Hz), 2.20- 2.12 (2H, m).
    405
    Figure US20150329491A1-20151119-C00530
         		1H-NMR (DMSO-D6) δ: 7.80 (1H, d, J = 7.5 Hz), 7.74 (1H, d, J = 7.7 Hz), 7.64- 7.59 (1H, m), 7.51-7.45 (2H, m), 7.38-7.32 (2H, m), 7.18 (1H, s), 4.68 (1H, t, J = 5.1 Hz), 3.64 (2H, dt, J = 6.8, 5.1 Hz), 2.80 (2H, t, J = 6.8 Hz).
    406
    Figure US20150329491A1-20151119-C00531
         		1H-NMR (CDCl3) δ: 9.20 (1H, s), 8.98-7.98 (2H, m), 7.72-7.69 (1H, m), 7.42- 7.39 (1H, m), 7.25-7.21 (1H, m), 7.11-7.07 (1H, m), 6.69 (1H, d, J = 2.3 Hz), 6.46 (1H, d, J = 7.9 Hz), 4.48 (1H, s), 4.10-4.04 (2H, m), 3.70 (2H, t, J = 6.1 Hz), 1.90-1.83 (2H, m), 1.71-1.54 (4H, m), 1.41 (1H, br s).
    407
    Figure US20150329491A1-20151119-C00532
         		1H-NMR (CDCl3) δ: 7.68-7.63 (1H, m), 7.54 (1H, d, J = 0.7 Hz), 7.49 (1H, s), 7.25-7.21 (4H, m), 6.78 (1H, d, J = 2.3 Hz), 4.04 (2H, t, J = 6.4 Hz), 4.00 (3H, s), 3.69 (2H, t, J = 6.3 Hz), 3.24 (1H, br s), 1.89-1.81 (2H, m), 1.70- 1.52 (4H, m), 1.34 (1H, br s).
    408
    Figure US20150329491A1-20151119-C00533
         		1H-NMR (DMSO-D6) δ: 8.15 (1H, d, J = 7.7 Hz), 7.69- 7.65 (1H, m), 7.57-7.52 (1H, m), 7.44 (1H, s), 7.43-7.39 (1H, m), 7.21 (1H, d, J = 2.2 Hz), 7.20- 7.18 (1H, m), 4.24 (2H, t, J = 5.4 Hz), 3.50 (2H, t, J = 5.4 Hz), 2.95 (3H, s), 2.89 (3H, s).
    409
    Figure US20150329491A1-20151119-C00534
         		1H-NMR (DMSO-D6) δ: 8.15- (1H, d, J = 7.7 Hz), 7.68- 7.64 (1H, m), 7.56-7.52 (1H, m), 7.46-7.38 (2H, m), 7.20-7.16 (2H, m), 4.53 (0.4H, t, J = 5.4 Hz), 4.48 (0.6H, t, J = 5.5 Hz), 4.26-4.17 (3H, m), 4.09 (1H, d, J = 5.5 Hz), 3.70 (1.1H, t, J = 5.7 Hz), 3.64 (0.9H, t, J = 5.1 Hz), 2.99 (1.6H, s), 2.93 (1.4H, s).
    410
    Figure US20150329491A1-20151119-C00535
         		1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 7.7 Hz), 7.68- 7.63 (1H, m), 7.56-7.51 (1H, m), 7.46-7.38 (2H, m), 7.33 (1H, br s), 7.16 (2H, s), 6.79 (1H, br s), 4.07 (2H, t, J = 6.4 Hz), 2.24 (2H, t, J = 7.4 Hz), 1.98- 1.90 (2H, m).
  • TABLE 1-60
    compound
    No. structural formula NMR
    411
    Figure US20150329491A1-20151119-C00536
         		1H-NMR (CDCl3) δ: 7.73-7.67 (2H, m), 7.59 (1H, s), 7.57 (1H, s), 7.37-7.23 (5H, m), 4.36-4.32 (2H, m), 4.13- 4.06 (2H, m), 3.07 (1H, br s), 2.96 (1H, br s).
    412
    Figure US20150329491A1-20151119-C00537
         		1H-NMR (CDCl3) δ: 7.68-7.63 (1H, m), 7.59 (1H, s), 7.50 (1H, s), 7.28-7.21 (4H, m), 6.77 (1H, d, J = 2.6 Hz), 4.16 (2H, t, J = 5.2 Hz), 4.02 (3H, s), 3.71-3.66 (2H, m), 3.62-3.56 (2H, m), 3.15 (1H, br s), 2.40-2.35 (2H, m), 2.08-1.99 (2H, m).
    413
    Figure US20150329491A1-20151119-C00538
         		1H-NMR (DMSO-D6) δ: 7.78- 7.72 (2H, m), 7.65-7.56 (2H, m), 7.48-7.43 (1H, m), 7.32-7.27 (2H, m), 7.24 (1H, d, J = 4.6 Hz), 7.20- 7.16 (1H, m), 7.05-7.01 (1H, m), 4.71-4.64 (1H, m), 1.49-1.44 (3H, m).
    414
    Figure US20150329491A1-20151119-C00539
         		1H-NMR (CDCl3) δ: 7.93-7.91 (1H, m), 7.83-7.79 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.53 (1H, d, J = 1.6 Hz), 7.47-7.45 (1H, m), 7.40- 7.33 (2H, m), 7.29-7.25 (1H, m), 6.20 (1H, br s), 4.10-3.97 (2H, m), 4.04 (3H, s), 3.25-3.18 (2H, m).
    415
    Figure US20150329491A1-20151119-C00540
         		1H-NMR (CDCl3) δ: 7.71-7.69 (1H, m), 7.65-7.57 (3H, m), 7.55-7.45 (1H, m), 7.39- 7.33 (2H, m), 5.84 (1H, br s), 4.50-4.39 (2H, m), 3.36 (1H, br s), 2.01 (3H, s).
    416
    Figure US20150329491A1-20151119-C00541
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H, m), 7.31- 7.24 (2H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.20 (2H, t, J = 5.4 Hz), 3.77-3.65 (2H, m), 3.55-3.44 (3H, m), 2.33 (2H, t, J = 6.3 Hz), 1.84-1.71 (4H, m).
    417
    Figure US20150329491A1-20151119-C00542
         		1H-NMR (CDCl3) δ: 7.76-7.72 (1H, m), 7.65-7.60 (2H, m), 7.53 (1H, d, J = 7.7 Hz), 7.48-7.43 (1H, m), 7.37- 7.33 (1H, m), 7.23-7.20 (1H, m), 3.57 (1H, d, J = 13.2 Hz), 3.45 (1H, d, J = 13.2 Hz), 2.09 (3H, s).
  • TABLE 1-61
    compound
    No. structural formula NMR
    418
    Figure US20150329491A1-20151119-C00543
         		1H-NMR (DMSO-D6) δ: 7.87- 7.79 (2H, m), 7.65-7.61 (1H, m), 7.53-7.46 (2H, m), 7.40-7.33 (2H, m), 7.30 (0.4H, s), 7.24 (0.6H, s), 4.65 (0.8H, s), 4.59 (0.6H, d, J = 15.2 Hz), 4.53 (0.6H, d, J = 15.0 Hz), 2.94 (1.8H, s), 2.82 (1.2H, s), 2.09 (1.8H, s), 2.06 (1.2H, s).
    419
    Figure US20150329491A1-20151119-C00544
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.22 (1H, m), 6.99-6.95 (1H, m), 5.99 (1H, br s), 4.11-4.04 (2H, m), 3.90-3.84 (1H, m), 3.69 (1H, s), 2.48-2.29 (3H, m), 1.98-1.87 (1H, m).
    420
    Figure US20150329491A1-20151119-C00545
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.17-4.13 (1H, m), 4.07- 4.02 (1H, m), 3.94-3.88 (1H, m), 3.17-3.07 (1H, m), 2.92 (2H, s), 2.90 (1H, s), 2.60-2.48 (1H, m), 2.43- 2.33 (1H, m), 2.31-2.20 (1H, m), 2.03-1.94 (1H, m).
    421
    Figure US20150329491A1-20151119-C00546
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.24-7.22 (1H, m), 6.99-6.95 (1H, m), 4.18-4.13 (1H, m), 4.07- 4.03 (1H, m), 4.01-3.95 (1H, m), 3.73 (1H, br s), 3.61-3.52 (2H, m), 3.51- 3.42 (2H, m), 3.31-3.25 (1H, m), 2.66-2.56 (1H, m), 2.48-2.39 (1H, m), 2.33- 2.23 (1H, m), 2.07-1.98 (1H, m), 1.75-1.52 (2H, m).
    422
    Figure US20150329491A1-20151119-C00547
         		1H-NMR (DMSO-D6) δ: 9.38 (0.5H, s), 9.37 (0.5H, s), 8.96 (2H, br s), 7.66-7.62 (1H, m), 7.39 (1H, d, J = 6.5 Hz), 7.32-7.22 (3H, m), 7.07 (1H, dd, J = 4.6, 2.3 Hz), 6.65-6.61 (1H, m), 4.26 (1.0H, t, J = 5.2 Hz), 4.18 (1.0H, t, J = 5.8 Hz), 3.73 (1.0H, t, J = 5.2 Hz), 3.66 (1.0H, t, J = 5.9 Hz), 3.08 (1.5H, s), 2.88 (1.5H, s), 2.09 (1.5H, s), 2.00 (1.5H, s).
    423
    Figure US20150329491A1-20151119-C00548
         		1H-NMR (CDCl3) δ: 7.69-7.64 (1H, m), 7.55-7.53 (1H, m), 7.50-7.48 (1H, m), 7.25- 7.20 (4H, m), 6.75 (1H, d, J = 2.6 Hz), 4.18-4.13 (2H, m), 4.00 (2.1H, s), 3.99 (0.9H, s), 3.79-3.62 (3H, m), 3.16 (2.1H, s), 2.98 (0.9H, s), 2.16 (0.9H, s), 2.07 (2.1H, s).
  • TABLE 1-62
    compound
    No. structural formula NMR
    424
    Figure US20150329491A1-20151119-C00549
         		1H-NMR (DMSO-D6) δ: 9.38 (0.4H, s), 9.37 (0.5H, s), 8.96 (2H, br s), 7.66-7.62 (1H, m), 7.39 (1H, d, J = 7.2 Hz), 7.32-7.22 (3H, m), 7.07 (1H, d, J = 2.3 Hz), 6.63 (1H, dd, J = 7.1, 3.4 Hz), 4.53 (0.4H, t, J = 5.6 Hz), 4.48 (0.5H, t, J = 5.4 Hz), 4.28-4.19 (3H, m), 4.08 (1H, d, J = 5.8 Hz), 3.72 (1.1H, t, J = 5.8 Hz), 3.66 (0.9H, t, J = 5.2 Hz), 2.99 (1.7H, s), 2.94 (1.4H, s).
    425
    Figure US20150329491A1-20151119-C00550
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.64-7.58 (1H, m), 7.62 (1H, s), 7.31-7.22 (4H, m), 7.16-7.13 (1H, m), 6.84 (1H, d, J = 2.3 Hz), 4.52 (0.4H, t, J = 5.6 Hz), 4.48 (0.6H, t, J = 5.4 Hz), 4.23-4.14 (3.0H, m), 4.09 (1.0H, d, J = 5.3 Hz), 3.95 (3H, s), 3.70 (1.1H, t, J = 5.7 Hz), 3.64 (0.9H, t, J = 5.2 Hz), 2.99 (1.6H, s), 2.93 (1.4H, s).
    426
    Figure US20150329491A1-20151119-C00551
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.66-7.53 (3H, m), 7.31-7.21 (2H, m), 7.22 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.95 (3H, s), 3.49-3.43 (2H, m), 1.81-1.74 (2H, m), 1.62-1.54 (2H, m).
    427
    Figure US20150329491A1-20151119-C00552
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, s), 7.29-7.23 (3H, m), 7.22 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.4 Hz), 4.07 (2H, t, J = 6.5 Hz), 3.95 (3H, s), 2.97 (3H, s), 2.83 (3H, s), 2.47 (2H, t, J = 7.3 Hz), 1.99-1.92 (2H, m).
    428
    Figure US20150329491A1-20151119-C00553
         		1H-NMR (DMSO-D6) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.65-7.61 (1H, m), 7.38- 7.35 (1H, m), 7.30-7.21 (3H, m), 7.03 (1H, d, J = 2.4 Hz), 6.61 (1H, d, J = 6.8 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.10 (2H, t, J = 6.5 Hz), 3.47 (2H, dt, J = 6.5, 5.2 Hz), 1.82-1.75 (2H, m), 1.63-1.54 (2H, m).
    429
    Figure US20150329491A1-20151119-C00554
         		1H-NMR (DMSO-D6) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.65-7.62 (1H, m), 7.38 (1H, s), 7.31-7.22 (3H, m), 7.04 (1H, d, J = 2.3 Hz), 6.61 (1H, dd, J = 6.7, 0.9 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.97 (3H, s), 2.82 (3H, s), 2.47 (2H, t, J = 7.0 Hz), 2.01-1.94 (2H, m).
  • TABLE 1-63
    compound
    No. structural formula NMR
    430
    Figure US20150329491A1-20151119-C00555
         		1H-NMR (DMSO-D6) δ: 8.36 (1H, d, J = 2.8 Hz), 7.81- 7.78 (1H, m), 7.70-7.67 (1H, m), 7.60-7.54 (2H, m), 7.50 (1H, s), 7.48-7.44 (1H, m), 4.25 (2H, t, J = 5.4 Hz), 3.59 (2H, t, J = 5.4 Hz), 3.48 (2H, t, J = 7.1 Hz), 2.22 (2H, t, J = 8.1 Hz), 1.97-1.88 (2H, m).
    431
    Figure US20150329491A1-20151119-C00556
         		1H-NMR (CDCl3) δ: 7.68-7.65 (1H, m), 7.59-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.57-4.52 (2H, m), 4.24- 4.05 (3H, m), 3.84-3.77 (1H, m), 3.70-3.65 (2H, m), 3.42-3.32 (1H, m), 3.31 (1.5H, s), 3.29 (1.5H, s), 3.04 (0.5H, s), 3.00 (0.5H, s), 2.64-2.53 (1H, m), 2.46-2.36 (1H, m), 2.32- 2.21 (1H, m), 2.08-1.98 (1H, m).
    432
    Figure US20150329491A1-20151119-C00557
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.25-7.22 (1H, m), 6.98 (1H, dd, J = 8.2, 2.4 Hz), 4.21-4.13 (1H, m), 4.10-4.03 (2H, m), 3.84-3.67 (2H, m), 3.66- 3.57 (1H, m), 3.49-3.42 (1H, m), 3.28 (1H, d, J = 23.9 Hz), 3.23-3.15 (1H, m), 2.65-2.54 (1H, m), 2.47-2.38 (1H, m), 2.37- 2.26 (1H, m), 2.08-1.98 (1H, m).
    433
    Figure US20150329491A1-20151119-C00558
         		1H-NMR (DMSO-D6) δ: 13.07 (1H, br s), 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, s), 7.30-7.23 (4H, m), 7.14-7.11 (1H, m), 6.80 (1H, d, J = 2.4 Hz), 4.77 (2H, s), 3.96 (3H, s).
    434
    Figure US20150329491A1-20151119-C00559
         		1H-NMR (DMSO-D6) δ: 8.37 (1H, d, J = 2.8 Hz), 7.80 (1H, d, J = 7.4 Hz), 7.72- 7.67 (2H, m), 7.61-7.59 (1H, m), 7.59-7.54 (1H, m), 7.52 (1H, s), 7.49-7.44 (2H, m), 4.62 (2H, s).
    435
    Figure US20150329491A1-20151119-C00560
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59 (0.2H, s), 7.56 (0.8H, s), 7.51 (0.2H, s), 7.50 (0.8H, s), 7.28- 7.22 (4H, m), 6.77 (0.8H, d, J = 2.6 Hz), 6.76 (0.2H, d, J = 2.6 Hz), 5.95 (1H, br s), 4.12-4.08 (2H, m), 4.02 (0.6H, s), 4.02 (2.4H, s), 3.70-3.65 (2H, m), 2.02 (0.6H, s), 2.02 (2.4H, s).
  • TABLE 1-64
    compound
    No. structural formula NMR
    436
    Figure US20150329491A1-20151119-C00561
         		1H-NMR (CDCl3) δ: 7.73-7.68 (2H, m), 7.52 (1H, s), 7.50 (1H, s), 7.36-7.22 (5H, m), 4.37 (2H, t, J = 6.4 Hz), 3.71 (2H, t, J = 5.7 Hz), 3.34 (1H, br s), 2.59 (1H, br s), 2.16-2.10 (2H, m).
    437
    Figure US20150329491A1-20151119-C00562
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 7.9 Hz), 7.68- 7.64 (1H, m), 7.58-7.53 (1H, m), 7.45-7.40 (1H, m), 7.44 (1H, s), 7.28 (1H, d, J = 2.4 Hz), 7.22-7.20 (1H, m), 4.71 (2H, s), 4.28-4.22 (2H, m), 3.95-3.89 (2H, m), 2.30-2.22 (2H, m).
    438
    Figure US20150329491A1-20151119-C00563
         		1H-NMR (DMSO-D6) δ: 8.33 (1H, d, J = 7.7 Hz), 8.19- 8.14 (1H, m), 7.69-7.65 (1H, m), 7.59-7.54 (1H, m), 7.45-7.40 (1H, m), 7.44 (1H, s), 7.33-7.30 (2H, m), 4.58 (2H, s), 2.67 (3H, d, J = 4.6 Hz).
    439
    Figure US20150329491A1-20151119-C00564
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, d, J = 0.4 Hz), 7.31-7.24 (4H, m), 7.15- 7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.83-4.78 (1H, m), 4.65 (2H, s), 4.29-4.20 (1H, m), 4.01-3.87 (2H, m), 3.96 (3H, s), 3.67-3.61 (1H, m), 3.55-3.50 (2H, m), 2.74-2.65 (1H, m).
    440
    Figure US20150329491A1-20151119-C00565
         		1H-NMR (DMSO-D6) δ: 7.95 (1H, s), 7.61-7.48 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.31-7.22 (3H, m), 7.23 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.96-4.81 (2H, m), 4.53- 4.49 (1H, m), 4.37-4.30 (1H, m), 3.96 (3H, s), 3.91-3.83 (1H, m), 3.27- 3.22 (2H, m), 3.06-2.96 (1H, m), 2.63-2.53 (1H, m), 1.76-1.57 (3H, m), 1.20- 1.06 (1H, m), 1.01-0.88 (1H, m).
    441
    Figure US20150329491A1-20151119-C00566
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.32-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.65 (2H, s), 4.25 (2H, t, J = 8.0 Hz), 3.96 (3H, s), 3.91 (2H, t, J = 7.8 Hz), 2.28-2.20 (2H, m).
    442
    Figure US20150329491A1-20151119-C00567
         		1H-NMR (DMSO-D6) δ: 8.16- 8.11 (1H, m), 7.97 (1H, s), 7.63-7.59 (1H, m), 7.61 (1H, d, J = 0.4 Hz), 7.31- 7.24 (3H, m), 7.25 (1H, s), 7.24-7.22 (1H, m), 6.85 (1H, d, J = 2.6 Hz), 4.54 (2H, s), 3.96 (3H, s), 2.67 (3H, d, J = 4.6 Hz).
  • TABLE 1-65
    compound
    No. structural formula NMR
    443
    Figure US20150329491A1-20151119-C00568
         		1H-NMR (DMSO-D6) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.26 (1H, br s), 7.18-7.15 (1H, m), 7.11-7.06 (1H, m), 4.19 (1H, t, J = 5.1 Hz), 4.11 (1H, t, J = 5.8 Hz), 3.74 (1H, t, J = 5.4 Hz), 3.66- 3.61 (2H, m), 3.54-3.49 (1H, m), 2.60 (1H, t, J = 7.2 Hz), 2.50-2.45 (1H, m), 2.08 (1.5H, s), 2.06 (1.5H, s).
    444
    Figure US20150329491A1-20151119-C00569
         		1H-NMR (DMSO-D6) δ: 7.78- 7.73 (2H, m), 7.61-7.47 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.18- 7.16 (1H, m), 7.08 (1H, dd, J = 8.3, 2.3 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.32 (2H, s), 3.01 (2H, t, J = 5.7 Hz), 2.46 (3H, s).
    445
    Figure US20150329491A1-20151119-C00570
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.24-7.22 (1H, m), 6.99-6.94 (1H, m), 6.00 (1H, br s), 4.11-4.03 (2H, m), 3.89-3.84 (1H, m), 3.39 (0.5H, br s), 3.35 (0.5H, br s), 2.46-2.28 (3H, m), 1.98-1.85 (1H, m).
    446
    Figure US20150329491A1-20151119-C00571
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.24-7.22 (1H, m), 6.99-6.94 (1H, m), 6.00 (1H, br s), 4.10-4.03 (2H, m), 3.89-3.83 (1H, m), 3.40-3.34 (1H, m), 2.47- 2.28 (3H, m), 1.97-1.85 (1H, m).
    447
    Figure US20150329491A1-20151119-C00572
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.17-4.12 (1H, m), 4.07- 4.01 (1H, m), 3.94-3.87 (1H, m), 3.16 (0.5H, s), 3.12 (0.5H, s), 2.91 (1.5H,
    s), 2.90 (1.5H, s), 2.59-
    2.48 (1H, m), 2.42-2.33
    (1H, m), 2.31-2.20 (1H, m),
    2.03-1.93 (1H, m).
    448
    Figure US20150329491A1-20151119-C00573
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.18-4.13 (1H, m), 4.07- 4.02 (1H, m), 3.94-3.88 (1H, m), 3.06 (0.5H, s), 3.04 (0.5H, s), 2.92 (1.5H,
    s), 2.91 (1.5H, s), 2.60-
    2.49 (1H, m), 2.43-2.33
    (1H, m), 2.31-2.21 (1H, m),
    2.03-1.94 (1H, m).
  • TABLE 1-66
    compound
    No. structural formula NMR
    449
    Figure US20150329491A1-20151119-C00574
         		1H-NMR (DMSO-D6) δ: 12.16 (1H, br s), 7.98 (1H, s), 7.61-7.58 (1H, m), 7.61 (1H, s), 7.31-7.22 (3H, m), 7.22 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 2.40 (2H, t, J = 7.2 Hz), 2.00- 1.92 (2H, m).
    450
    Figure US20150329491A1-20151119-C00575
         		1H-NMR (DMSO-D6) δ: 7.78- 7.74 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25- 7.24 (1H, m), 7.16-7.14 (1H, m), 7.10-7.06 (1H, m), 4.86 (1H, t, J = 5.3 Hz), 4.20-4.07 (2H, m), 3.87- 3.79 (1H, m), 3.76-3.68 (1H, m), 3.65-3.59 (1H, m),
    3.50-3.36 (2H, m), 2.34-
    2.23 (1H, m), 2.20-2.11
    (1H, m), 2.03-1.93 (1H, m),
    1.84-1.74 (1H, m).
    451 (optically active form)
    Figure US20150329491A1-20151119-C00576
         		1H-NMR (CDCl3) δ: 8.39 (1H, d, J = 7.9 Hz), 7.70-7.67 (1H, m), 7.53-7.48 (1H, m), 7.39-7.35 (1H, m), 7.26- 7.24 (1H, m), 7.16 (1H, d, J = 2.3 Hz), 4.68 (2H, s), 3.83 (3H, s), 2.77 (1H, s).
    452 (optically active form)
    Figure US20150329491A1-20151119-C00577
         		1H-NMR (CDCl3) δ: 8.41-8.38 (1H, m), 7.70-7.67 (1H, m), 7.53-7.49 (1H, m), 7.39- 7.35 (1H, m), 7.27-7.25 (1H, m), 7.17 (1H, d, J = 2.3 Hz), 4.69 (2H, s), 3.84 (3H, s), 2.73 (1H, s).
    453
    Figure US20150329491A1-20151119-C00578
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.64-7.58 (1H, m), 7.61 (1H, s), 7.29-7.21 (3H, m), 7.22 (1H, s), 7.16-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.57 (1H, t, J = 5.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 3.95 (3H, s), 3.57 (2H, dt, J = 6.6, 5.3 Hz), 1.93-1.84 (2H, m).
    454
    Figure US20150329491A1-20151119-C00579
         		1H-NMR (DMSO-D6) δ: 12.41 (1H, br s), 7.99 (1H, s), 7.63-7.57 (1H, m), 7.62 (1H, s), 7.31-7.23 (3H, m), 7.24 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.3 Hz), 4.25 (2H, t, J = 6.0 Hz), 3.96 (3H, s), 2.73 (2H, t, J = 6.0 Hz).
    455
    Figure US20150329491A1-20151119-C00580
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.63-7.56 (1H, m), 7.61 (1H, s), 7.29-7.22 (3H, m), 7.24 (1H, s), 7.14-7.11 (1H, m), 6.80 (1H, d, J = 2.6 Hz), 4.26 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 3.01 (3H, s), 2.86-2.79 (2H, m), 2.85 (3H, s).
  • TABLE 1-67
    compound
    No. structural formula NMR
    456
    Figure US20150329491A1-20151119-C00581
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.31-7.22 (4H, m), 7.16-7.14 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.90 (1H, t, J = 5.6 Hz), 4.06 (2H, t, J = 4.9 Hz), 3.95 (3H, s), 3.73 (2H, dt, J = 5.6, 4.9 Hz).
    457
    Figure US20150329491A1-20151119-C00582
         		1H-NMR (DMSO-D6) δ: 7.95-7.94 (1H, m), 7.61-7.57 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.30-7.21 (3H, m), 7.22 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.89 (2H, br s), 3.95 (3H, s), 3.00 (3H, s), 2.85 (3H, s).
    458
    Figure US20150329491A1-20151119-C00583
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.61-7.57 (1H, m), 7.33-7.22 (3H, m), 7.23 (1H, s), 7.15-7.13 (1H, m), 6.84 (1H, d, J = 2.3 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.85-3.80 (2H, m), 3.84 (3H, s).
    459
    Figure US20150329491A1-20151119-C00584
         		1H-NMR (DMSO-D6) δ: 7.79-7.74 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19- 7.16 (1H, m), 7.10 (1H, dd, J = 8.4, 2.4 Hz), 4.30-4.24 (2H, m), 4.19 (2H, t, J = 5.3 Hz), 3.70-3.65 (2H, m), 3.57 (2H, t, J = 5.3 Hz).
    460
    Figure US20150329491A1-20151119-C00585
         		1H-NMR (CDCl3) δ: 7.71-7.68 (1H, m), 7.67-7.65 (1H, m), 7.62 (1H, d ,J = 0.7 Hz), 7.60 (1H, s), 7.35-7.26 (4H, m), 4.37-4.34 (2H, m), 4.13-4.08 (2H, m), 3.03 (1H, s), 2.89 (1H, t, J = 5.9 Hz).
    461
    Figure US20150329491A1-20151119-C00586
         		1H-NMR (CDCl3) δ: 7.78-7.74 (2H, m), 7.47-7.44 (1H, m), 7.41-7.33 (4H, m), 7.29-7.24 (1H, m), 4.96 (1H, br s), 4.38-4.24 (4H, m), 4.18-4.10 (2H, m), 4.08-4.03 (2H, m), 3.47 (1H, br s), 2.37-2.28 (2H, m).
    462
    Figure US20150329491A1-20151119-C00587
         		1H-NMR (DMSO-D6) δ: 12.85 (1H, br s), 7.76-7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.23 (1H, br s), 7.18-7.15 (1H, m), 7.03-6.99 (1H, m), 4.96 (1.2H, s), 4.80 (0.8H, s), 4.19 (0.8H, s), 4.02 (1.2H, s), 3.07 (1.8H, s), 2.86 (1.2H, s).
  • TABLE 1-68
    compound
    No. structural formula NMR
    463
    Figure US20150329491A1-20151119-C00588
         		1H-NMR (CDCl3) δ: 7.68-7.63 (1H, m), 7.51-7.46 (1H, m), 7.47 (1H, s), 7.29-7.19 (4H, m), 6.77 (1H, d, J = 2.4 Hz), 3.99 (3H, s), 3.87 (3H, s), 3.24 (1H, br s).
    464
    Figure US20150329491A1-20151119-C00589
         		1H-NMR (DMSO-D6) δ: 7.99 (1H, s), 7.72 (1H, br s), 7.63-7.59 (1H, m), 7.62 (1H, s), 7.31-7.23 (3H, m), 7.28 (1H, s), 7.17-7.13 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.23-4.08 (2H, m), 3.96 (3H, s), 3.78-3.67 (1H, m), 3.55-3.45 (1H, m), 2.53-2.42 (3H, m), 2.20- 2.08 (1H, m).
    465
    Figure US20150329491A1-20151119-C00590
         		1H-NMR (CDCl3) δ: 7.73-7.68 (2H, m), 7.51-7.50 (1H, m), 7.36-7.14 (6H, m), 4.57- 4.50 (1H, m), 3.70 (1H, br s), 1.55 (3H, s), 1.54 (3H, s).
    466
    Figure US20150329491A1-20151119-C00591
         		1H-NMR (CDCl3) δ: 7.70-7.65 (2H, m), 7.57 (1H, s), 7.50 (1H, s), 7.42-7.25 (8H, m), 7.22-7.14 (2H, m), 5.39 (2H, s), 2.99 (1H, br s).
    467 (optically active form)
    Figure US20150329491A1-20151119-C00592
         		H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.64-7.59 (2H, m), 7.60 (1H, s), 7.41 (1H, br s), 7.30-7.25 (3H, m), 7.24 (1H, s), 7.23-7.20 (1H, m), 6.84 (1H, d, J = 2.4 Hz), 4.50 (2H, s), 3.96 (3H, s).
    468
    Figure US20150329491A1-20151119-C00593
         		1H-NMR (DMSO-D6) δ: 7.78- 7.75 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19-7.16 (1H, m), 7.09 (1H, dd, J = 8.4, 2.4 Hz), 4.19 (2H, t, J = 5.4 Hz), 3.39-3.30 (4H, m), 3.23-3.18 (2H, m), 2.29- 2.21 (2H, m).
    469
    Figure US20150329491A1-20151119-C00594
         		1H-NMR (DMSO-D6) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.18-7.15 (1H, m), 7.09 (1H, dd, J = 8.4, 2.4 Hz), 6.38 (1H, s), 4.15- 4.09 (2H, m), 3.50-3.41 (4H, m), 3.26-3.20 (2H, m).
  • TABLE 1-69
    compound
    No. structural formula NMR
    470
    Figure US20150329491A1-20151119-C00595
         		1H-NMR (DMSO-D6) δ: 7.78- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.25 (1H, s), 7.19-7.17 (1H, m), 7.10 (1H, dd, J = 8.3, 2.3 Hz), 4.21-4.14 (4H, m), 3.66-3.56 (2H, m), 3.45 (2H, t, J = 6.2 Hz), 1.97- 1.90 (2H, m).
    471
    Figure US20150329491A1-20151119-C00596
         		1H-NMR (CDCl3) δ : 7.67-7.63 (1H, m), 7.59 (1H, s), 7.50 (1H, s), 7.28-7.21 (4H, m), 6.77 (1H, d, J = 2.3 Hz), 4.19 (2H, t, J = 5.4 Hz), 4.01 (3H, s), 3.81-3.68 (2H, m), 3.26 (3H, br s), 3.14 (1H, s), 1.28 (9H, s).
    472
    Figure US20150329491A1-20151119-C00597
         		1H-NMR (DMSO-D6) δ: 8.54 (1H, d, J = 7.9 Hz), 8.24 (1H, d, J = 1.5 Hz), 8.18- 8.16 (1H, m), 7.79-7.76 (1H, m), 7.70-7.65 (1H, m), 7.64 (1H, s), 7.62-7.58 (1H, m), 3.92 (3H, s).
    473 (optically active form)
    Figure US20150329491A1-20151119-C00598
         		1H-NMR (CDCl3) δ: 8.58 (1H, d, J = 7.7 Hz), 8.34 (1H, d, J = 1.3 Hz), 8.30-8.29 (1H, m), 7.78-7.75 (1H, m), 7.60-7.56 (1H, m), 7.52- 7.48 (1H, m), 3.95 (3H, s), 2.84 (1H, s).
    474 (optically active form)
    Figure US20150329491A1-20151119-C00599
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, s), 7.32-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.82- 4.79 (1H, m), 4.65 (2H, s), 4.28-4.22 (1H, m), 4.01- 3.87 (2H, m), 3.96 (3H, s), 3.64 (1H, dd, J = 9.5, 5.3 Hz), 3.54-3.49 (2H, m), 2.74-2.66 (1H, m).
    475 (optically active form)
    Figure US20150329491A1-20151119-C00600
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, s), 7.30-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 5.76 (1H, d, J = 6.0 Hz), 4.69 (1H, d, J = 14.8 Hz), 4.65 (1H, d, J = 14.8 Hz), 4.54- 4.39 (2H, m), 4.15-4.08 (1H, m), 4.00-3.94 (1H, m), 3.96 (3H, s), 3.67-3.62 (1H, m).
    476
    Figure US20150329491A1-20151119-C00601
         		1H-NMR (CDCl3) δ: 7.80-7.76 (1H, m), 7.72-7.70 (1H, m), 7.38-7.32 (3H, m), 7.27- 7.22 (1H, m), 7.13 (1H, d, J = 1.6 Hz), 7.06 (1H, s), 5.42 (1H, br s), 4.22-4.18 (2H, m), 4.02-3.98 (2H, m), 3.96 (1H, br s), 3.64-3.58 (2H, m), 3.47-3.40 (2H, m), 2.02-1.85 (4H, m).
  • TABLE 1-70
    compound
    No. structural formula NMR
    477 (optically active form)
    Figure US20150329491A1-20151119-C00602
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.63 (1H, s), 7.62-7.59 (2H, m), 7.41 (1H, br s), 7.34-7.30 (1H, m), 7.29-7.23 (3H, m), 7.22-7.20 (1H, m), 6.86 (1H, d, J = 2.2 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.51 (2H, s), 4.26 (2H, t, J = 5.6 Hz), 3.83 (2H, dt, J = 5.6, 5.2 Hz).
    478
    Figure US20150329491A1-20151119-C00603
         		1H-NMR (DMSO-D6) δ: 12.17 (1H, s), 8.14 (1H, d, J = 7.7 Hz), 7.67-7.64 (1H, m), 7.56-7.51 (1H, m), 7.43- 7.38 (1H, m), 7.42 (1H, s), 7.17-7.15 (2H, m), 4.09 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01- 1.92 (2H, m).
    479 (optically active form)
    Figure US20150329491A1-20151119-C00604
         		1H-NMR (DMSO-D6) δ: 8.14 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = 7.7 Hz), 7.56- 7.52 (1H, m), 7.43-7.38 (1H, m), 7.42 (1H, br s), 7.16 (2H, s), 4.09 (2H, t, J = 6.5 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99-1.93 (2H, m).
    480
    Figure US20150329491A1-20151119-C00605
         		1H-NMR (CDCl3) δ: 8.23-8.20 (1H, m), 7.70-7.67 (1H, m), 7.51-7.47 (1H, m), 7.38- 7.33 (1H, m), 7.21-7.19 (1H, m), 6.97 (1H, d, J = 2.2 Hz), 4.68 (2H, s), 3.83 (3H, s), 2.78 (1H, s).
    481 (optically active form)
    Figure US20150329491A1-20151119-C00606
         		1H-NMR (CDCl3) δ: 8.23-8.20 (1H, m), 7.70-7.67 (1H, m), 7.52-7.47 (1H, m), 7.38- 7.33 (1H, m), 7.21-7.20 (1H, m), 6.97 (1H, d, J = 2.2 Hz), 4.69 (2H, s), 3.84 (3H, s), 2.75 (1H, s).
    482
    Figure US20150329491A1-20151119-C00607
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.56 (1H, m), 7.34- 7.29 (1H, m), 7.28-7.19 (3H, m), 7.15-7.12 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.25 (2H, t, J = 5.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 3.82 (2H, t, J = 5.6 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00-1.93 (2H, m).
    483
    Figure US20150329491A1-20151119-C00608
         		1H-NMR (DMSO-D6) δ: 13.20 (1H, br s), 8.00 (1H, d, J = 0.7 Hz), 7.66-7.61 (2H, m), 7.63 (1H, d, J = 0.7 Hz), 7.42-7.37 (2H, m), 7.36-7.21 (4H, m), 6.07 (2H, s).
  • TABLE 1-71
    compound
    No. structural formula NMR
    484
    Figure US20150329491A1-20151119-C00609
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.64 (1H, s), 7.61-7.58 (1H, m), 7.35- 7.32 (1H, m), 7.28-7.23 (2H, m), 7.24 (1H, s), 7.14-7.12 (1H, m), 6.85 (1H, d, J = 2.3 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.7 Hz), 4.16 (2H, t, J = 5.2 Hz), 3.85- 3.79 (2H, m), 3.57 (2H, t, J = 5.4 Hz), 3.47 (2H, t, J = 7.3 Hz), 2.22 (2H, t, J = 8.1 Hz), 1.96-1.88 (2H, m).
    485
    Figure US20150329491A1-20151119-C00610
         		1H-NMR (DMSO-D6) δ: 12.44 (1H, br s), 7.98 (1H, s), 7.66-7.60 (2H, m), 7.61 (1H, s), 7.41-7.26 (5H, m), 7.21 (1H, s), 4.43 (2H, t, J = 6.6 Hz), 2.90 (2H, t, J = 6.5 Hz).
    486
    Figure US20150329491A1-20151119-C00611
         		1H-NMR (CDCl3) δ: 7.72-7.67 (2H, m), 7.61 (1H, s), 7.59 (1H, s), 7.36-7.22 (5H, m), 5.76 (1H, br s), 5.33 (1H, br s), 4.55 (2H, t, J = 6.3 Hz), 2.95 (1H, br s), 2.91 (2H, t, J = 6.1 Hz).
    487
    Figure US20150329491A1-20151119-C00612
         		1H-NMR (CDCl3) δ: 7.72-7.67 (2H, m), 7.54 (1H, s), 7.52 (1H, s), 7.35-7.21 (5H, m), 5.69 (1H, br s), 4.51 (2H, t, J = 6.3 Hz), 3.26 (1H, br s), 2.82 (2H, t, J = 6.3 Hz), 2.77 (3H, d, J = 4.6 Hz).
    488
    Figure US20150329491A1-20151119-C00613
         		1H-NMR (CDCl3) δ: 7.72-7.66 (2H, m), 7.59 (1H, s), 7.55 (1H, s), 7.34-7.23 (5H, m), 4.53 (2H, t, J = 6.5 Hz), 3.22 (1H, br s), 3.01 (3H, s), 3.00-2.96 (2H, m), 2.95 (3H, s).
    489
    Figure US20150329491A1-20151119-C00614
         		1H-NMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.58 (1H, s), 7.50 (1H, s), 7.25-7.20 (4H, m), 6.77 (1H, d, J = 1.6 Hz), 4.29-4.17 (2H, m), 4.01 (3H, s), 3.80-3.72 (2H, m), 3.68 (1H, t, J = 7.2 Hz), 3.53-3.40 (2H, m), 3.42 (1H, br s), 3.24 (3H, br s), 1.27 (3H, s), 1.24 (3H, s).
    490
    Figure US20150329491A1-20151119-C00615
         		1H-NMR (DMSO-D6) δ: 7.79- 7.74 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.24 (1H, s), 7.19-7.16 (1H, m), 7.10 (1H, dd, J = 8.4, 2.4 Hz), 4.20 (2H, t, J = 5.6 Hz), 4.05 (2H, s), 3.82 (2H, t, J = 5.1 Hz), 3.74- 3.69 (2H, m), 3.54-3.50 (2H, m).
  • TABLE 1-72
    compound
    No. structural formula NMR
    491
    Figure US20150329491A1-20151119-C00616
         		1H-NMR (DMSO-D6) δ: 13.15 (1H, br s), 8.01 (1H, br s), 7.67 (1H, br s), 7.61- 7.58 (1H, m), 7.28-7.24 (2H, m), 7.22 (1H, s), 7.20-7.17 (1H, m), 7.15- 7.13 (1H, m), 6.86 (1H, d, J = 2.4 Hz), 4.16 (2H, t, J = 5.4 Hz), 3.57 (2H, t, J = 5.5 Hz), 3.47 (2H, t, J = 7.2 Hz), 2.22 (2H, t, J = 8.0 Hz), 1.96-1.88 (2H, m).
    492
    Figure US20150329491A1-20151119-C00617
         		1H-NMR (DMSO-D6) δ: 7.93 (1H, s), 7.64-7.58 (1H, m), 7.60 (1H, s), 7.44-7.41 (1H, m), 7.36-7.25 (3H, m), 7.14 (1H, s), 7.12 (1H, d, J = 7.0 Hz), 4.95 (1H, t, J = 5.1 Hz), 4.25 (2H, t, J = 5.7 Hz), 3.83 (2H, dt, J = 5.7, 5.1 Hz), 2.39 (3H, s).
    493
    Figure US20150329491A1-20151119-C00618
         		1H-NMR (CDCl3) δ: 7.77 (1H, s), 7.73-7.69 (2H, m), 7.64 (1H, s), 7.38-7.25 (5H, m), 6.42 (1H, br s), 5.52 (1H, br s), 4.92 (2H, s), 2.79 (1H, br s).
    494
    Figure US20150329491A1-20151119-C00619
         		1H-NMR (CDCl3) δ: 7.76 (1H, s), 7.73-7.70 (2H, m), 7.61 (1H, s), 7.39-7.25 (5H, m), 6.42 (1H, br s), 4.90 (2H, s), 2.89 (3H, d, J = 4.9 Hz), 2.84 (1H, br s).
    495
    Figure US20150329491A1-20151119-C00620
         		1H-NMR (CDCl3) δ: 7.70-7.66 (2H, m), 7.63 (1H, s), 7.61 (1H, s), 7.45-7.42 (1H, m), 7.35-7.27 (4H, m), 5.09 (1H, d, J = 16.0 Hz), 5.03 (1H, d, J = 16.0 Hz), 3.14 (3H, s), 3.03 (3H, s), 2.99 (1H, br s).
    496
    Figure US20150329491A1-20151119-C00621
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, s), 7.62 (1H, s), 7.61-7.57 (1H, m), 7.33- 7.29 (1H, m), 7.28-7.23 (3H, m), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.4 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.66 (2H, s), 4.25 (4H, t, J = 5.7 Hz), 3.91 (2H, t, J = 7.7 Hz), 3.82 (2H, dt, J = 5.7, 5.2 Hz), 2.28-2.21 (2H, m).
    497
    Figure US20150329491A1-20151119-C00622
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.58 (1H, m), 7.33- 7.29 (1H, m), 7.28-7.24 (3H, m), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 5.77 (1H, d, J = 5.5 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.72-4.64 (2H, m), 4.52- 4.40 (2H, m), 4.25 (2H, t, J = 5.5 Hz), 4.14-4.08 (1H, m), 4.00-3.94 (1H, m), 3.82 (2H, dt, J = 5.5, 5.2 Hz), 3.67-3.61 (1H, m).
  • TABLE 1-73
    compound
    No. structural formula NMR
    498
    Figure US20150329491A1-20151119-C00623
         		1H-NMR (DMSO-D6) δ: 7.83 (2H, br s), 7.61-7.57 (1H, m) , 7.29-7.12 (5H, m), 6.84 (1H, d, J = 2.4 Hz), 4.06 (2H, t, J = 6.4 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00- 1.92 (2H, m).
    499
    Figure US20150329491A1-20151119-C00624
         		1H-NMR (CDCl3) δ: 7.69-7.64 (1H, m), 7.52 (1H, s), 7.47 (1H, s), 7.25-7.20 (4H, m), 6.78-6.76 (1H, m), 4.25- 4.11 (2H, m), 4.06-3.89 (2H, m), 3.98 (3H, s), 3.68-3.52 (2H, m), 3.10 (3H, s), 2.11 (3H, s).
    500
    Figure US20150329491A1-20151119-C00625
         		1H-NMR (CDCl3) δ: 7.70-7.65 (1H, m), 7.52 (1H, s), 7.48 (1H, s), 7.25-7.21 (4H, m), 6.79-6.76 (1H, m), 4.27 (1H, dd, J = 20.9, 4.2 Hz), 4.21-4.12 (1H, m), 4.06- 3.89 (2H, m), 3.99 (3H, s), 3.69-3.53 (2H, m), 3.11 (3H, s), 2.12 (3H, s).
    501
    Figure US20150329491A1-20151119-C00626
         		1H-NMR (CDCl3) δ: 7.68-7.64 (1H, m), 7.56 (1H, s), 7.50 (1H, s), 7.25-7.22 (4H, m), 6.78-6.75 (1H, m), 4.43 (1H, br s), 4.26-4.21 (2H, m), 4.02-3.99 (3H, m), 3.87-3.77 (2H, m), 3.37- 3.21 (3H, m), 1.58-1.56 (6H, m).
    502
    Figure US20150329491A1-20151119-C00627
         		1H-NMR (DMSO-D6) δ: 8.09 (1H, br s), 7.87-7.84 (1H, m), 7.72 (1H, br s), 7.63- 7.59 (1H, m), 7.46-7.40 (1H, m), 7.35-7.29 (2H, m), 7.23-7.21 (1H, m), 7.06- 7.04 (1H, m), 4.22-4.16 (2H, m), 3.61-3.56 (2H, m), 3.51-3.45 (2H, m), 2.27- 2.20 (2H, m), 1.98-1.89
    (2H, m).
    503
    Figure US20150329491A1-20151119-C00628
         		1H-NMR (DMSO-D6) δ: 7.82 (2H, br s), 7.63 (1H, br s), 7.61-7.58 (1H, m), 7.41 (1H, br s), 7.28-7.16 (5H, m), 6.86 (1H, d, J = 2.4 Hz), 4.51 (2H, s).
    504 (optically active form)
    Figure US20150329491A1-20151119-C00629
         		1H-NMR (DMSO-D6) δ: 12.26 (1H, br s), 7.99-7.96 (1H, m), 7.62-7.57 (2H, m), 7.29-7.20 (4H, m), 7.15- 7.12 (1H, m), 6.83-6.80 (1H, m), 4.05 (2H, t, J = 6.1 Hz), 3.95 (3H, s), 2.39 (2H, t, J = 7.0 Hz), 2.00- 1.92 (2H, m).
  • TABLE 1-74
    compound
    No. structural formula NMR
    505
    Figure US20150329491A1-20151119-C00630
         		1H-NMR (DMSO-D6) δ: 8.02 (1H, d, J = 1.2 Hz), 7.67 (1H, d, J = 1.2 Hz), 7.65- 7.61 (1H, m), 7.41-7.36 (3H, m), 7.35-7.27 (2H, m), 7.18-7.14 (1H, m), 4.99- 4.95 (1H, m), 4.24 (2H, t, J = 4.9 Hz), 3.84-3.78 (2H, m).
    506
    Figure US20150329491A1-20151119-C00631
         		1H-NMR (CDCl3) δ: 7.76-7.73 (1H, m), 7.72-7.67 (2H, m), 7.66-7.63 (1H, m), 7.36- 7.22 (4H, m), 6.38 (1H, s), 5.57 (1H, s), 4.93-4.88 (2H, m), 2.98 (1H, br s).
    507
    Figure US20150329491A1-20151119-C00632
         		1H-NMR (CDCl3) δ: 7.74-7.73 (1H, m), 7.71-7.67 (1H, m), 7.61-7.61 (1H, m), 7.54- 7.51 (1H, m), 7.32-7.19 (3H, m), 7.11-7.09 (1H, m), 6.41 (1H, br s), 5.58 (1H, br s), 4.90-4.88 (2H, m), 2.97 (1H, br s), 2.45-2.42 (3H, m).
    508
    Figure US20150329491A1-20151119-C00633
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.9 Hz), 7.60- 7.55 (1H, m), 7.57 (1H, br s), 7.42-7.37 (1H, m), 7.32 (1H, br s), 7.27-7.22 (2H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.84 (1H, d, J = 2.4 Hz), 4.87 (2H, s), 4.10 (2H, t, J = 6.8 Hz), 1.97- 1.91 (3H, m), 1.72-1.53 (14H, m).
    509
    Figure US20150329491A1-20151119-C00634
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 0.4 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.60- 7.57 (1H, m), 7.32-7.22 (3H, m), 7.20 (1H, s), 7.13-7.11 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.6 Hz), 4.10 (2H, t, J = 6.8 Hz), 3.84- 3.80 (2H, m), 1.97-1.91 (3H, m), 1.71-1.52 (14H, m).
    510
    Figure US20150329491A1-20151119-C00635
         		1H-NMR (DMSO-D6) δ: 9.37 (1H, s), 8.95 (2H, br s), 7.65-7.62 (1H, m), 7.37 (1H, br s), 7.31-7.21 (3H, m), 7.04-7.04 (1H, m), 6.61 (1H, dd, J = 6.7, 1.0 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.01-1.95 (2H, m).
    511
    Figure US20150329491A1-20151119-C00636
         		1H-NMR (DMSO-D6) δ: 8.20- 8.16 (1H, m), 7.96 (1H, d, J = 0.7 Hz), 7.66-7.60 (2H, m), 7.62 (1H, d, J = 0.9 Hz), 7.46-7.43 (1H, m), 7.42-7.27 (4H, m), 7.22 (1H, s), 4.87 (2H, s), 3.20-3.13 (2H, m), 1.08 (3H, t, J = 7.2 Hz).
  • TABLE 1-75
    compound
    No. structural formula NMR
    512
    Figure US20150329491A1-20151119-C00637
         		1H-NMR (DMSO-D6) δ: 8.13- 8.08 (1H, m), 7.95 (1H, d, J = 2.6 Hz), 7.64-7.59 (1H, m), 7.61 (1H, d, J = 2.6 Hz), 7.45-7.40 (2H, m), 7.34-7.25 (2H, m), 7.19- 7.12 (2H, m), 4.90-4.86 (2H, m), 2.70-2.67 (3H, m), 2.41-2.37 (3H, m).
    513
    Figure US20150329491A1-20151119-C00638
         		1H-NMR (DMSO-D6) δ: 8.13- 8.07 (1H, m), 8.06 (1H, d, J = 2.6 Hz), 7.70 (1H, d, J = 2.6 Hz), 7.68-7.64 (1H, m), 7.61-7.58 (1H, m), 7.51-7.47 (1H, m), 7.45- 7.43 (1H, m), 7.42-7.31 (3H, m), 4.91-4.87 (2H, m), 2.70-2.66 (3H, m).
    514
    Figure US20150329491A1-20151119-C00639
         		1H-NMR (DMSO-D6) δ: 8.12- 8.08 (1H, m), 7.95 (1H, d, J = 0.7 Hz), 7.66-7.60 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.46-7.26 (5H, m), 7.22 (1H, s), 4.85 (2H, s), 3.93-3.85 (1H, m), 1.11 (6H, d, J = 6.6 Hz).
    515
    Figure US20150329491A1-20151119-C00640
         		1H-NMR (DMSO-D6) δ: 8.13- 8.08 (1H, m), 8.04 (1H, d, J = 0.9 Hz), 7.68 (1H, d, J = 0.9 Hz), 7.67-7.63 (1H, m), 7.49-7.45 (1H, m), 7.43-7.39 (2H, m), 7.37- 7.29 (2H, m), 7.18 (1H, dd, J = 9.9, 2.4 Hz), 4.89 (2H, s), 2.68 (3H, d, J = 4.4 Hz).
    516
    Figure US20150329491A1-20151119-C00641
         		1H-NMR (DMSO-D6) δ: 13.18 (1H, br s), 8.40 (1H, s), 8.23 (1H, d, J = 7.9 Hz), 8.10 (1H, s), 7.84 (1H, d, J = 1.4 Hz), 7.80-7.78 (1H, m) , 7.72-7.69 (1H, m), 7.61-7.56 (1H, m), 7.49- 7.45 (2H, m), 5.00 (2H, s).
    517
    Figure US20150329491A1-20151119-C00642
         		1H-NMR (DMSO-D6) δ: 12.42 (1H, s), 8.41 (1H, s), 8.22 (1H, d, J = 7.9 Hz), 8.06 (1H, d, J = 0.7 Hz), 7.82 (1H, d, J = 1.6 Hz), 7.80- 7.78 (1H, m), 7.72-7.69 (1H, m), 7.60-7.55 (1H, m), 7.49-7.44 (1H, m), 7.45 (1H, s), 4.35 (2H, t, J = 6.7 Hz), 2.86 (2H, t, J = 6.8 Hz).
    518
    Figure US20150329491A1-20151119-C00643
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.15 (1H, br s), 7.98 (1H, d, J = 0.8 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.84-7.81 (1H, m), 7.75 (1H, br s), 7.69 (1H, d, J = 1.9 Hz), 7.67-7.63 (1H, m), 7.49-7.43 (1H, m), 7.40-7.34 (1H, m), 7.31 (1H, s), 3.89 (3H, s).
  • TABLE 1-76
    compound
    No. structural formula NMR
    519
    Figure US20150329491A1-20151119-C00644
         		1H-NMR (CDCl3) δ: 8.27 (1H, d, J = 7.9 Hz), 7.72-7.68 (1H, m), 7.53-7.47 (1H, m), 7.44-7.42 (1H, m), 7.40- 7.35 (1H, m), 7.26-7.25 (1H, m), 2.76 (1H, s), 2.41 (3H, s).
    520 (optically active form)
    Figure US20150329491A1-20151119-C00645
         		1H-NMR (CDCl3) δ: 8.28 (1H, d, J = 7.7 Hz), 7.72-7.68 (1H, m), 7.53-7.48 (1H, m), 7.44-7.42 (1H, m), 7.41- 7.36 (1H, m), 7.27-7.25 (1H, m), 2.69 (1H, s), 2.41 (3H, s).
    521
    Figure US20150329491A1-20151119-C00646
         		1H-NMR (DMSO-D6) δ: 8-34 (1H, s), 8.22 (1H, d, J = 7.7 Hz), 8.05 (1H, d, J = 0.7 Hz), 7.81 (1H, d, J = 1.5 Hz), 7.79-7.76 (1H, m), 7.72-7.68 (1H, m), 7.60- 7.55 (1H, m), 7.49-7.43 (1H, m), 7.44 (1H, s), 7.42 (1H, br s), 6.91 (1H, br s), 4.33 (2H, t, J = 6.8 Hz),
    2.67 (2H, t, J = 6.9 Hz).
    522
    Figure US20150329491A1-20151119-C00647
         		1H-NMR (CDCl3) δ: 7.71-7.66 (2H, m), 7.64 (1H, d, J = 0.7 Hz), 7.51 (1H, d, J = 0.7 Hz), 7.36-7.22 (5H, m), 3.06 (1H, br s), 2.30-2.25 (3H, m), 2.24-2.22 (6H, m), 1.82-1.78 (6H, m).
    523
    Figure US20150329491A1-20151119-C00648
         		1H-NMR (CDCl3) δ: 7.72-7.66 (2H, m), 7.64 (1H, d, J = 0.7 Hz), 7.53-7.50 (1H, m), 7.36-7.22 (5H, m), 3.06- 3.00 (1H, br m), 1.67 (9H, s).
    524
    Figure US20150329491A1-20151119-C00649
         		1H-NMR (CDCl3) δ: 7.72-7.67 (2H, m), 7.51-7.49 (1H, m), 7.47 (1H, s), 7.36-7.19 (5H, m), 3.99 (2H, s), 3.10 (1H, s), 1.04 (9H, br s).
    525
    Figure US20150329491A1-20151119-C00650
         		1H-NMR (CDCl3) δ: 8.30-8.26 (1H, m), 7.74-7.70 (1H, m), 7.56-7.50 (1H, m), 7.44- 7.35 (2H, m), 7.23-7.18 (1H, m), 2.83-2.81 (1H, m).
  • TABLE 1-77
    compound
    No. structural formula NMR
    526 (optically active form)
    Figure US20150329491A1-20151119-C00651
         		1H-NMR (CDCl3) δ: 8.27 (1H, d, J = 7.7 Hz), 7.73-7.70 (1H, m), 7.55-7.50 (1H, m), 7.43-7-35 (2H, m), 7.20 (1H, dd, J = 8.6, 2.2 Hz), 2.76 (1H, s).
    527
    Figure US20150329491A1-20151119-C00652
         		1H-NMR (CDCl3) δ: 7.74-7.69 (2H, m), 7.51 (1H, s), 7.46 (1H, s), 7.36-7.28 (2H, m), 7.24-7.21 (3H, m), 6.11 (1H, br s), 4.30 (2H, dd, J = 6.2, 4.9 Hz), 3.77-3.72 (2H, m), 3.54 (1H, br s), 1.98 (3H, s).
    528
    Figure US20150329491A1-20151119-C00653
         		1H-NMR (DMSO-D6) δ: 8.42 (1H, d, J = 0.7 Hz), 8.14 (1H, br s), 7.98 (1H, d, J = 0.7 Hz), 7.93-7.90 (1H, m), 7.87-7.85 (1H, m), 7.75 (1H, br s), 7.72 (1H, d, J = 1.6 Hz), 7.67-7-63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 4.58-4.48 (1H, m), 1.47 (3H, s), 1.46 (3H, s).
    529 (optically active form)
    Figure US20150329491A1-20151119-C00654
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.9 Hz), 7.63- 7.58 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.36-7.33 (1H, m), 7.32-7.25 (2H, m), 7.16 (1H, s), 7.12 (1H, dd, J = 1.7, 0.8 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.3, 5.6 Hz), 2.38 (3H, s) .
    530
    Figure US20150329491A1-20151119-C00655
         		1H-NMR (DMSO-D6) δ: 8.38 (1H, s), 8.15 (1H, br s), 7.98 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 7.85-7.83 (1H, m), 7.75 (1H, br s), 7.70 (1H, d, J = 1.6 Hz), 7.66- 7.64 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.2 Hz).
    531 (optically active form)
    Figure US20150329491A1-20151119-C00656
         		1H-NMR (DMSO-D6) δ: 8.03 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.7 Hz), 7.66- 7.63 (1H, m), 7.42-7.38 (3H, m), 7.36-7.29 (2H, m), 7.18 (1H, dd, J = 10.0, 2.6 Hz), 4.99 (1H, t, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.6, 5.3 Hz).
    532 (optically active form)
    Figure US20150329491A1-20151119-C00657
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.59 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.57 (1H, br s), 7.46-7.43 (2H, m), 7.32-7.24 (2H, m), 7.32 (1H, br s), 7.17 (1H, s), 7.14 (1H, dd, J = 1.5, 0.9 Hz), 4.88 (2H, s), 2.40 (3H, s).
  • TABLE 1-78
    compound
    No. structural formula NMR
    533 (optically active form)
    Figure US20150329491A1-20151119-C00658
         		1H-NMR (DMSO-D6) δ: 8.12- 8.06 (1H, m), 7.95 (1H, d, J = 0.7 Hz), 7.64-7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.39 (2H, m), 7.33-7.25 (2H, m), 7.17 (1H, s), 7.13 (1H, d, J = 0.7 Hz), 4.88 (2H, s), 2.68 (3H, d, J = 4.6 Hz), 2.39 (3H, s).
    534 (optically active form)
    Figure US20150329491A1-20151119-C00659
         		1H-NMR (CDCl3) δ: 7.74 (1H, s), 7.72-7.68 (1H, m), 7.62 (1H, s), 7.46-7.40 (1H, m), 7.34-7.19 (3H, m), 7.01 (1H, dd, J = 9.4, 2.6 Hz), 6.40 (1H, s), 4.88 (2H, s), 3.06 (1H, s), 2.88 (3H, br s).
    535
    Figure US20150329491A1-20151119-C00660
         		1H-NMR (CDCl3) δ: 7.75-7.69 (2H, m), 7.62 (0.2H, s), 7.56 (0.8H, s), 7.45 (0.2H, s), 7.41 (0.8H, s), 7.36- 7.20 (5H, m), 4.39-4.32 (2H, m), 3.87-3.79 (2H, m), 2.96 (0.8H, s), 2.82 (2.2H, s), 2.04 (2.2H, s), 1.83 (0.8H, s).
    536
    Figure US20150329491A1-20151119-C00661
         		1H-NMR (DMSO-D6) δ: 8.33- 8.31 (1H, m), 8.16 (1H, br s), 8.01-7.99 (1H, m), 7.94-7.90 (1H, m), 7.86- 7.83 (1H, m), 7.76 (1H, br s), 1.12-1.69 (1H, m), 7.68-7.63 (1H, m), 7.50- 7.44 (1H, m), 7.41-7.35 (1H, m), 7.33 (1H, br s), 4.95 (1H, br s), 4.21-4.16 (2H, m), 3.82-3.76 (2H, m).
    537 (optically active form)
    Figure US20150329491A1-20151119-C00662
         		1H-NMR (CDCl3) δ: 7.70-7.67 (1H, m), 7.54 (1H, s), 7.53 (1H, s), 7.42-7.38 (1H, m), 7.30-7.19 (3H, m), 6.98 (1H, dd, J = 9.4, 2.5 Hz), 4.30 (2H, t, J = 6.7 Hz), 2.42 (2H, t, J = 7.1 Hz), 2.27-2.20 (2H, m).
    538 (optically active form)
    Figure US20150329491A1-20151119-C00663
         		1H-NMR (CDCl3) δ: 7.69-7.63 (1H, m), 7.58-7.54 (2H, m), 7.52-7.49 (1H, m), 7.25- 7.14 (3H, m), 7.07-7.05 (1H, m), 4.48 (2H, t, J = 6.2 Hz), 3.00 (2H, t, J = 6.2 Hz), 2.41 (3H, s).
    539 (optically active form)
    Figure US20150329491A1-20151119-C00664
         		1H-NMR (CDCl3) δ: 7.70-7.65 (1H, m), 7.55 (1H, s), 7.52-7.49 (2H, m), 7.29- 7.20 (3H, m), 7.09-7.07 (1H, m), 4.31 (2H, t, J = 6.6 Hz), 2.45-2.39 (2H, m), 2.42 (3H, s), 2.28-2.20 (2H, m).
  • TABLE 1-79
    compound
    No. structural formula NMR
    540 (optically active form)
    Figure US20150329491A1-20151119-C00665
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.62 (1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.29-7.23 (3H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.35 (1H, s), 4.09 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 2.13-2.07 (2H, m), 1.61 (2H, t, J = 6.8 Hz), 1.57- 1.43 (12H, m).
    541 (optically active form)
    Figure US20150329491A1-20151119-C00666
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 0.9 Hz), 7.64 (1H, d, J = 0.9 Hz), 7.60- 7.56 (2H, m), 7.41-7.38 (1H, m), 7.32 (1H, br s), 7.26-7.22 (2H, m), 7.21 (1H, s), 7.13-7.12 (1H, m), 6-84 (1H, d, J = 2.4 Hz), 4.87 (2H, s), 4.09 (2H, t, J = 6.9 Hz), 3.57 (1H, s), 2.12-2.07 (2H, m), 1.61 (2H, t, J = 7.2 Hz), 1.56- 1.42 (12H, m).
    542 (optically active form)
    Figure US20150329491A1-20151119-C00667
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.61- 7.56 (1H, m), 7.33-7.28 (1H, m), 7.28-7.22 (2H, m), 7.21 (1H, s), 7.13-7.11 (1H, m), 6.83 (1H, d, J = 2.6 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.36 (1H, s), 4.25 (2H, t, J = 5.7 Hz), 4.09 (2H, t, J = 7.1 Hz), 3.82 (2H, dt, J = 5.3, 5.7 Hz), 2.12-2.07 (2H, m), 1.60 (2H, t, J = 7.0 Hz), 1.56- 1.42 (13H, m) .
    543 (optically active form)
    Figure US20150329491A1-20151119-C00668
         		1H-NMR (DMSO-D6) δ: 8.06 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.9 Hz), 7.66- 7.62 (1H, m), 7.43-7.38 (1H, m), 7.36-7.28 (4H, m), 7.17 (1H, dd, J = 10.0, 2.6 Hz), 4.43 (2H, t, J = 6.6 Hz), 2.91 (2H, t, J = 6.6 Hz) .
    544 (optically active form)
    Figure US20150329491A1-20151119-C00669
         		1H-NMR (CDCl3) δ: 7.70-7.67 (1H, m), 7.62 (1H, d, J = 0.7 Hz), 7.57 (1H, d, J = 0.7 Hz), 7.42-7.38 (1H, m), 7.31-7.20 (3H, m), 7.00 (1H, dd, J = 9.5, 2.4 Hz), 4.17 (2H, s), 3.47 (1H, br s), 2.98 (1H, br s), 1.74- 1.25 (10H, m).
    545 (optically active form)
    Figure US20150329491A1-20151119-C00670
         		1H-NMR (DMSO-D6) δ: 8.05 (1H, d, J = 0.7 Hz), 7.67- 7.63 (2H, m), 7.42-7.38 (2H, m), 7.35-7.30 (3H, m), 7.21-7.16 (1H, m), 4.47- 4.43 (1H, m), 4.17-4.09 (1H, m), 3.20-3.13 (1H, m), 3.09-3.02 (1H, m), 2.04- 1.71 (6H, m), 1.45-1.22 (3H, m) .
  • TABLE 1-80
    compound
    No. structural formula NMR
    546 (optically active form)
    Figure US20150329491A1-20151119-C00671
         		1H-NMR (DMSO-D6) δ: 7.99 (1H, d, J = 0.7 Hz), 7.64- 7.58 (1H, m), 7.60 (1H, s), 7.43-7.40 (1H, m), 7.32- 7.23 (3H, m), 7.16 (1H, d, J = 2.2 Hz), 7.14-7.13 (1H, m), 4.70-4.65 (1H, m), 4.57-4.50 (1H, m), 3.51- 3.37 (2H, m), 2.48-2.39 (1H, m), 2.38 (3H, s), 2.21-2.03 (2H, m), 1.99- 1.89 (1H, m), 1.88-1.78 (1H, m), 1.74-1.63 (1H, m), 1.57-1.47 (1H, m).
    547
    Figure US20150329491A1-20151119-C00672
         		1H-NMR (DMSO-D6) δ: 7.87 (1H, d, J = 0.7 Hz), 7.67- 7.60 (2H, m), 7.59 (1H, d, J = 0.7 Hz), 7.41-7.22 (6H, m), 4.47 (1H, s), 3.96 (2H, s), 2.16-2.12 (2H, m), 1.60-1.41 (12H, m).
    548 (optically active form)
    Figure US20150329491A1-20151119-C00673
         		1H-NMR (DMSO-D6) δ: 8.09 (1H, s), 7.67 (1H, s), 7.66-7.62 (1H, m), 7.41- 7.37 (2H, m), 7.36-7.27 (3H, m), 7.20 (1H, dd, J = 10.0, 2.5 Hz), 4.71-4.66 (1H, m), 4.58-4.51 (1H, m), 3.51-3.38 (2H, m), 2.48- 2.37 (1H, m), 2.21-2.04 (2H, m), 1.99-1.89 (1H, m), 1.88-1.78 (1H, m), 1.74- 1.63 (1H, m), 1.57-1.47 (1H, m).
    549 (optically active form)
    Figure US20150329491A1-20151119-C00674
         		1H-NMR (DMSO-D6) δ: 12.43 (1H, br s), 8.12 (1H, s), 7.69 (1H, d, J = 0.9 Hz), 7.66-7.62 (1H, m), 7.42- 7.38 (2H, m), 7.36-7.31 (2H, m), 7.27-7.24 (1H, m), 7.19 (1H, dd, J = 9.9, 2.6 Hz), 5.00-4.94 (1H, m), 3.28-3.19 (1H, m), 2.27- 2.05 (3H, m), 1.94-1.74 (3H, m).
    550 (optically active form)
    Figure US20150329491A1-20151119-C00675
         		1H-NMR (DMSO-D6) δ: 13.17 (1H, br s), 7.97 (1H, d, J = 0.7 Hz), 7.63-7.60 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.43 (1H, m), 7.38-7.34 (1H, m), 7.32- 7.27 (1H, m), 7.26-7.22 (1H, m), 7.17 (1H, s), 7.14-7.12 (1H, m), 5.06 (2H, s), 2.39 (3H, s).
    551 (optically active form)
    Figure US20150329491A1-20151119-C00676
         		1H-NMR (DMSO-D6) δ: 13.22 (1 H, br s), 8.07 (1H, d, J = 0.7 Hz), 7.69 (1H, d, J = 0.7 Hz), 7.66-7.62 (1H, m), 7.43-7.38 (3H, m), 7.36- 7.31 (1H, m), 7.30-7.25 (1H, m), 7.18 (1H, dd, J = 9.9, 2.4 Hz), 5.07 (2H, s).
  • TABLE 1-81
    compound
    No. structural formula NMR
    552 (optically active form)
    Figure US20150329491A1-20151119-C00677
         		1H-NMR (CDCl3) δ: 7.70-7.66 (1H, m), 7.43 (1H, s), 7.30 (1H, d, J = 0.7 Hz), 7.25- 7.14 (3H, m), 7.12-7.09 (1H, m), 6.70 (1H, d, J = 2.6 Hz), 4.05-3.93 (2H, m), 3.90 (3H, s), 2.37 (2H, t, J = 6.6 Hz), 1.88-1.73 (4H, m) .
    553 (optically active form)
    Figure US20150329491A1-20151119-C00678
         		1H-NMR (DMSO-D6) δ: 12.17 (1H, br s), 8.05 (1H, d, J = 0.7 Hz), 7.62 (1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.31-7.19 (4H, m), 7.16- 7.13 (1H, m), 6.85 (1H, d, J = 2.3 Hz), 4.64-4.57 (1H, m), 4.07 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m), 1.52 (3H, d, J = 6.5 Hz), 1.51 (3H, d, J = 6.5 Hz).
    554 (optically active form)
    Figure US20150329491A1-20151119-C00679
         		1H-NMR (DMSO-D6) δ: 12.16 (1H, br s), 8.02 (1H, d, J = 0.7 Hz), 7.61 (1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.30-7.20 (4H, m), 7.13 (1H, d, J = 1.9 Hz), 6.83 (1H, d, J = 2.6 Hz), 4.24 (2H, q, J = 7.3 Hz), 4.06 (2H, t, J = 6.4 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00- 1.93 (2H, m), 1.46 (3H, t, J = 7.3 Hz).
    555
    Figure US20150329491A1-20151119-C00680
         		1H-NMR (DMSO-D6) δ: 7.88 (1H, d, J = 7.9 Hz), 7.86 (1H, d, J = 7.7 Hz), 7.66- 7.62 (1H, m), 7.53-7.47 (2H, m), 7.41-7.35 (2H, m), 7.28 (1H, s), 3.72 (3H, s), 2.26 (3H, s), 2.17 (3H, s).
    556
    Figure US20150329491A1-20151119-C00681
         		1H-NMR (DMSO-D6) δ: 7.87- 7.84 (1H, m), 7.83-7.82 (1H, m), 7.79-7.77 (1H, m), 7.72-7.67 (1H, m), 7.58- 7.53 (1H, m), 7.48-7.43 (1H, m), 7.35 (1H, s), 5.56 (1H, t, J = 5.5 Hz), 4.95- 4.85 (2H, m), 4.39-4.24 (2H, m), 4.16-3.99 (2H, m), 2.34-2.25 (2H, m).
    557
    Figure US20150329491A1-20151119-C00682
         		1H-NMR (DMSO-D6) δ: 7.95 (1H, s), 7.66-7.56 (3H, m), 7.35-7.28 (3H, m), 7.22- 7.18 (2H, m), 5.35 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.7 Hz), 3.96 (3H, s).
    558
    Figure US20150329491A1-20151119-C00683
         		1H-NMR (DMSO-D6) δ: 12.25 (1H, br s), 7.94 (1H, d, J = 0.5 Hz), 7.58 (1H, d, J = 0.7 Hz), 7.57-7.54 (1H, m), 7.27-7.15 (4H, m), 7.11 (1H, s), 6.77 (1H, d, J = 2.3 Hz), 3.94 (3H, s), 3.77-3.69 (2H, m), 2.90- 2.81 (2H, m), 2.48-2.40 (1H, m), 1.96-1.88 (2H, m), 1.70-1.59 (2H, m).
  • TABLE 1-82
    compound
    No. structural formula NMR
    559
    Figure US20150329491A1-20151119-C00684
         		1H-NMR (DMSO-D6) δ: 7.72- 7.67 (1H, m), 7.63 (1H, d, J = 7.2 Hz), 7.57 (1H, d, J = 7.9 Hz), 7.50-7.33 (5H, m), 7.23-7.19 (1H, m), 6.29-6.28 (1H, m), 5.30 (2H, s), 3.62 (1H, br s).
    560
    Figure US20150329491A1-20151119-C00685
         		1H-NMR (CDCl3) δ: 7.90-7.86 (2H, m), 7.77-7.72 (2H, m), 7.65 (1H, d, J = 8.3 Hz), 7.62-7.59 (1H, m), 7.54 (1H, d, J = 1.5 Hz), 7.51- 7.45 (1H, m), 7.41-7.35 (1H, m), 6.40 (1H, dd, J = 2.4, 1.7 Hz), 3.86 (1H, s).
    561 (optically active form)
    Figure US20150329491A1-20151119-C00686
         		1H-NMR (DMSO-D6) δ: 8.90- 8.82 (2H, m), 8.29-8.16 (1H, m), 7.90-7.75 (1H, m), 7.63 (1H, d, J = 6.4 Hz), 7.31-7.13 (5H, m), 7.01- 7.00 (1H, m), 6.62 (1H, d, J = 7.9 Hz), 4.10 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.2 Hz), 1.98 (2H, t, J = 7.0 Hz).
    562
    Figure US20150329491A1-20151119-C00687
         		1H-NMR (DMSO-D6) δ: 8.91 (1H, d, J = 2.1 Hz), 8.40 (1H, s), 8.14 (1H, d, J = 1.4 Hz), 8.07 (1H, s), 7.89-7.86 (1H, m), 7.74- 7.71 (1H, m), 7.62-7.58 (1H, m), 7.54-7.49 (1H, m), 7.50 (1H, s), 3.90 (3H, s).
    563
    Figure US20150329491A1-20151119-C00688
         		1H-NMR (DMSO-D6) δ: 8.92 (1H, d, J = 1.8 Hz), 8.41 (1H, s), 8.16-8.14 (1H, m), 8.09 (1H, s), 7.89-7.86 (1H, m), 7.74-7.71 (1H, m), 7.62-7.58 (1H, m), 7.54- 7.48 (1H, m), 7.50 (1H, s), 4.95 (1H, t, J = 5.3 Hz), 4.19 (2H, t, J = 5.5 Hz),
    3.79 (2H, dt, J = 5.5, 5.3
    Hz).
    564
    Figure US20150329491A1-20151119-C00689
         		1H-NMR (DMSO-D6) δ: 9.90 (1H, s), 7.92 (1H, s), 7.58-7.53 (1H, m), 7.56 (1H, d, J = 0.7 Hz), 7.27- 7.17 (3H, m), 7.13 (1H, s), 7.05-7.01 (1H, m), 6.64 (1H, d, J = 2.2 Hz), 3.94 (3H, s).
    565 (optically active form)
    Figure US20150329491A1-20151119-C00690
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz), 7.66- 7.62 (1H, m), 7.44-7.29 (5H, m), 7.17 (1H, dd, J = 9.9, 2.6 Hz), 5.06 (1H, d, J = 5.3 Hz), 4.79 (1H, t, J = 5.6 Hz), 4.33 (1H, dd, J = 13.8, 4.1 Hz), 4.11 (1H, dd, J = 13.7, 7.7 Hz), 3.95-3.87 (1H, m), 3.46- 3.35 (2H, m).
  • TABLE 1-83
    compound
    No. structural formula NMR
    566 (optically active form)
    Figure US20150329491A1-20151119-C00691
         		1H-NMR (DMSO-D6) δ: 7.99 (1H, s), 7.68 (1H, s), 7.66-7.62 (1H, m), 7.45- 7.29 (5H, m), 7.16 (1H, dd, J = 9.9, 2.4 Hz), 5.07 (1H, d, J = 5.5 Hz), 4.79 (1H, t, J = 5.5 Hz), 4.34 (1H, dd, J = 13.7, 4.0 Hz), 4.10 (1H, dt, J = 13.7, 7.9 Hz), 3.95-3.86 (1H, m), 3.47- 3.35 (2H, m).
    567
    Figure US20150329491A1-20151119-C00692
         		1H-NMR (DMSO-D6) δ: 7.63 (2H, d, J = 7.0 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.36- 7.28 (2H, m), 7.26-7.18 (2H, m), 6.90-6.85 (1H, m), 3.79 (1.3H, s), 3.78 (1.7H, s), 2.07 (1.3H, s), 1.97 (1.7H, s), 1.95 (1.7H, s), 1.86 (1.3H, s).
    568
    Figure US20150329491A1-20151119-C00693
         		1H-NMR (DMSO-D6) δ: 8.91 (1H, d, J = 2.0 Hz), 8.44 (1H, s), 8.16-8.13 (1H, m), 8.09 (1H, s), 7.89-7.86 (1H, m), 7.74-7.70 (1H, m), 7.62-7.57 (1H, m), 7.54- 7.49 (2H, m), 4.36 (2H, t, J = 6.7 Hz), 2.84 (2H, t, J = 6.6 Hz).
    569
    Figure US20150329491A1-20151119-C00694
         		1H-NMR (DMSO-D6) δ: 7.95 (1H, s), 7.59 (1H, d, J = 0.7 Hz), 7.58-7.55 (1H, m), 7.28-7.19 (3H, m), 7.19- 7.16 (1H, m), 7.13 (1H, s), 6.78 (1H, d, J = 2.3 Hz), 3.95 (3H, s), 3.78-3.73 (4H, m), 3.21-3.17 (4H, m).
    570
    Figure US20150329491A1-20151119-C00695
         		1H-NMR (DMSO-D6) δ: 8.26 (1H, s), 7.91 (1H, s), 7.82-7.78 (1H, m), 7.75- 7.73 (1H, m), 7.72-7.70 (1H, m), 7.68-7.63 (1H, m), 7.54-7.48 (1H, m), 7.40- 7.34 (1H, m), 7.22 (1H, s), 5.47 (1H, t, J = 5.3 Hz), 4.87 (2H, d, J = 5.3 Hz), 3.89 (3H, s).
    571
    Figure US20150329491A1-20151119-C00696
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 3.1 Hz), 7.62- 7.57 (2H, m), 7.33-7.18 (4H, m), 7.17-7.13 (1H, m), 6.84-6.80 (1H, m), 5.00- 4.97 (1H, m), 4.72-4.67 (1H, m), 4.11-4.05 (1H, m), 3.98-3.89 (4H, m), 3.86- 3.77 (1H, m), 3.49-3.42 (2H, m).
    572
    Figure US20150329491A1-20151119-C00697
         		1H-NMR (DMSO-D6) δ: 7.85 (1H, d, J = 7.7 Hz), 7.72 (1H, d, J = 1.5 Hz), 7.71- 7.66 (2H, m), 7.58-7.53 (1H, m), 7.47-7.42 (1H, m), 7.33 (1H, s), 5.54 (1H, t, J = 5.5 Hz), 4.95-4.85 (2H, m), 3.50 (2H, t, J = 6.6 Hz), 3.47-3.38 (2H, m), 1.94-1.80 (4H, m).
  • TABLE 1-84
    compound
    No. structural formula NMR
    573 (optically active form)
    Figure US20150329491A1-20151119-C00698
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.61 (1H, d, J = 0.7 Hz), 7.60-7.57 (1H, m), 7.29-7.22 (4H, m), 7.12 (1H, d, J = 1.9 Hz), 6.80 (1H, d, J = 2.3 Hz), 4.12 (2H, t, J = 6.1 Hz), 3.95 (3H, s), 3.07 (2H, t, J = 7.5 Hz), 2.22-2.15 (2H, m).
    574 (optically active form)
    Figure US20150329491A1-20151119-C00699
         		1H-NMR (CDCl3) δ: 7.77 (1H, d, J = 0.7 Hz), 7.76 (1H, d, J = 0.7 Hz), 7.70-7.66 (1H, m), 7.54-7.51 (1H, m), 7.29-7.18 (4H, m), 7.13 (1H, dd, J = 1.5, 0.8 Hz), 2.44 (3H, s), 1.97 (6H, s).
    575 (optically active form)
    Figure US20150329491A1-20151119-C00700
         		1H-NMR (DMSO-D6) δ: 12.53 (1H, br s), 7.85 (1H, d, J = 0.7 Hz), 7.64-7.60 (1H, m), 7.59 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.32-7.20 (3H, m), 7.17 (1H, s), 7.10 (1H, dd, J = 1.7, 0.8 Hz), 4.35 (2H, s), 2.38 (3H, s), 1.17 (6H, s).
    576 (optically active form)
    Figure US20150329491A1-20151119-C00701
         		1H-NMR (DMSO-D6) δ: 12.16 (1H, br s), 8.04 (1H, d, J = 0.7 Hz), 7.63-7.57 (1H, m), 7.58 (1H, d, J = 0.7 Hz), 7.43-7.40 (1H, m), 7.32-7.26 (3H, m), 7.15 (1H, s), 7.13 (1H, d, J = 0.9 Hz), 2.94 (2H, s), 2.38 (3H, s), 1.70 (3H, s), 1.69 (3H, s).
    577 (optically active form)
    Figure US20150329491A1-20151119-C00702
         		1H-NMR (DMSO-D6) δ: 12.21 (1H, br s), 7.98 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.29- 7.21 (4H, m), 7.14-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.07 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 2.60-2.54 (1H, m), 2.11- 2.01 (1H, m), 1.85-1.75 (1H, m), 1.15 (3H, d, J = 6.7 Hz).
    578
    Figure US20150329491A1-20151119-C00703
         		1H-NMR (CDCl3) δ: 8.42 (1H, d, J = 7.5 Hz), 7.78-7.77 (1H, m), 7.76-7.70 (2H, m), 7.69-7.68 (1H, m), 7.67 (1H, d, J = 1.5 Hz), 7.54- 7.48 (1H, m), 7.42-7.36 (1H, m), 3.94 (3H, s), 3.53 (1H, s), 3.09 (1H, br s).
    579
    Figure US20150329491A1-20151119-C00704
         		1H-NMR (DMSO-D6) δ: 8.29 (1H, s), 8.00 (1H, s), 7.94 (1H, d, J = 0.7 Hz), 7.77- 7.74 (1H, m), 7.67-7.61 (2H, m), 7.50 (1H, d, J = 1.8 Hz), 7.34-7.30 (3H, m), 7.25 (1H, s), 3.97 (3H, s), 3.87 (3H, s).
  • TABLE 1-85
    compound
    No. structural formula NMR
    580
    Figure US20150329491A1-20151119-C00705
         		1H-NMR (DMSO-D6) δ: 8.30 (1H, d, J = 0.7 Hz), 8.01 (1H, d, J = 0.7 Hz), 7.97 (1H, d, J = 0.7 Hz), 7.78- 7.75 (1H, m), 7.67 (1H, d, J = 0.7 Hz), 7.66-7.62 (1H, m), 7.53 (1H, d, J = 1.6 Hz), 7.39-7.27 (3H, m), 7.26 (1H, s), 5.00 (1H, t, J = 5.2 Hz), 4.95 (1H, t, J = 5.3 Hz), 4.28 (2H, t, J = 5.7 Hz), 4.18 (2H, t, J = 5.7 Hz), 3.85 (2H, dt, J = 5.2, 5.7 Hz), 3.79 (2H, dt, J = 5.2, 5.7 Hz).
    581 (optically active form)
    Figure US20150329491A1-20151119-C00706
         		1H-NMR (DMSO-D6) δ: 7.99 (1H, s), 7.63 (1H, d, J = 0.7 Hz), 7.61-7.57 (1H, m), 7.30-7.20 (4H, m), 7.13- 7.11 (1H, m), 6.80 (1H, d, J = 2.6 Hz), 4.42 (2H, t, J = 6.6 Hz), 4.10 (2H, q, J = 7.0 Hz), 2.90 (2H, t, J = 6.7 Hz).
    582 (optically active form)
    Figure US20150329491A1-20151119-C00707
         		1H-NMR (DMSO-D6) δ: 12.20 (1H, br s), 8.01 (1H, s), 7.63 (1H, d, J = 0.7 Hz), 7.62-7.56 (1H, m), 7.28- 7.19 (4H, m), 7.14-7.11 (1H, m), 6.83 (1H, d, J = 2.3 Hz), 4.23 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.0 Hz), 2.27 (2H, t, J = 7.3 Hz), 2.12-2.05 (2H, m), 1.35 (3H, t, J = 7.0 Hz).
    583
    Figure US20150329491A1-20151119-C00708
         		1H-NMR (DMSO-D6) δ: 7.69- 7.66 (1H, m), 7.63-7.60 (1H, m), 7.49-7.45 (1H, m), 7.33-7.29 (1H, m), 7.20 (1H, s), 7.14 (1H, d, J = 2.6 Hz), 7.09-7.07 (1H, m), 5.47 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 4.15 (2H, t, J = 5.6 Hz), 3.58 (2H, t, J = 5.4 Hz), 3.48 (2H, t, J = 7.2 Hz), 2.23
    (2H, t, J = 8.1 Hz), 1.98-
    1.88 (2H, m).
    854
    Figure US20150329491A1-20151119-C00709
         		1H-NMR (DMSO-D6) δ: 8.24 (1H, d, J = 0.9 Hz), 7.94 (1H, d, J = 0.7 Hz), 7.81 (1H, d, J = 7.7 Hz), 7.69- 7.64 (2H, m), 7.57-7.55 (1H, m), 7.54-7.49 (1H, m), 7.39-7.35 (1H, m), 7.19 (1H, s), 4.94 (1H, t, J = 5.3 Hz), 4.18 (2H, t, J = 5.6 Hz), 3.78 (2H, dt, J = 5.6, 5.3 Hz), 2.65 (3H, s).
    855
    Figure US20150329491A1-20151119-C00710
         		1H-NMR (DMSO-D6) δ: 8.39 (1H, d, J = 0.7 Hz), 8.08 (1H, d, J = 0.7 Hz), 8.05 (1H, d, J = 1.6 Hz), 7.95- 7.93 (1H, m), 7.78-7.75 (1H, m), 7.68-7.65 (1H, m), 7.47-7.43 (1H, m), 7.42- 7.38 (1H, m), 7.35 (1H, s), 4.96 (1H, t, J = 5.4 Hz), 4.19 (2H, t, J = 5.6 Hz), 3.79 (2H, dt, J = 5.6, 5.4 Hz), 2.77 (3H, s).
  • TABLE 1-86
    compound
    No. structural formula NMR
    586
    Figure US20150329491A1-20151119-C00711
         		1H-NMR (DMSO-D6) δ: 8.25- 8.23 (1H, m), 7.91-7.78 (3H, m), 7.71-7.65 (2H, m), 7.54-7.49 (1H, m), 7.39- 7.34 (1H, m), 7.21 (1H, s), 5.51-5.47 (1H, m), 5.46- 5.35 (1H, m), 4.94 (1H, t, J = 5.3 Hz), 4.19 (2H, t, J = 5.7 Hz), 3.81-3.75 (2H, m), 1.50-1.43 (3H, m).
    587
    Figure US20150329491A1-20151119-C00712
         		1H-NMR (DMSO-D) δ: 8.44 (1H, s), 8.07 (1H, d, J = 0.5 Hz), 8.05 (1H, d, J = 1.6 Hz), 7.95-7.93 (1H, m), 7.78-7.75 (1H, m), 7.68- 7.65 (1H, m), 7.47-7.43 (1H, m), 7.42-7.38 (1H, m), 7.34 (1H, s), 4.18 (2H, q, J = 7.3 Hz), 2.77 (3H, s), 1.43 (3H, t, J = 7.3 Hz).
    588 (optically active form)
    Figure US20150329491A1-20151119-C00713
         		1H-NMR (DMSO-D6) δ: 12.45 (1H, br s), 8.00 (1H, s), 7.64 (1H, d, J = 0.7 Hz), 7.62-7.58 (1H, m), 7.31- 7.20 (4H, m), 7.16-7.14 (1H, m), 6.84 (1H, d, J = 2.6 Hz), 4.43 (2H, t, J = 6.7 Hz), 3.84 (3H, s), 2.91 (2H, t, J = 6.7 Hz).
    589 (optically active form)
    Figure US20150329491A1-20151119-C00714
         		1H-NMR (DMSO-D6) δ: 12.22 (1H, br s), 8.02 (1H, s), 7.64 (1H, s), 7.62-7.57 (1H, m), 7.30-7.18 (4H, m), 7.16-7.13 (1H, m), 6.86 (1H, d, J = 2.1 Hz), 4.24 (2H, t, J = 6.8 Hz), 3.84 (3H, s), 2.28 (2H, t, J = 7.3 Hz), 2.13-2.06 (2H, m).
    590
    Figure US20150329491A1-20151119-C00715
         		1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 0.7 Hz), 7.95 (1H, d, J = 0.9 Hz), 7.82- 7.81 (1H, m), 7.79 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J = 8.0, 1.7 Hz), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.22 (1H, s), 5.44 (1H, t, J = 5.4 Hz), 4.94 (1H, t, J = 5.4 Hz), 4.91-4.81 (2H, m), 4.18 (2H, t, J = 5.6 Hz), 3.78 (2H, dt, J = 5.6,
    5.4 Hz).
    591
    Figure US20150329491A1-20151119-C00716
         		1H-NMR (DMSO-D6) δ: 8.75 (1H, d, J = 7.9 Hz), 8.28 (1H, s), 7.92 (1H, d, J = 0.9 Hz), 7.71-7.69 (1H, m), 7.65 (1H, d, J = 1.5 Hz), 7.64-7.61 (1H, m), 7.48- 7.43 (1H, m), 7.35-7.30 (1H, m), 7.14 (1H, s), 5.40 (1H, s), 3.89 (3H, s), 1.73 (3H, s), 1.63 (3H, s).
    592
    Figure US20150329491A1-20151119-C00717
         		1H-NMR (DMSO-D6) δ: 8.75 (1H, d, J = 7.9 Hz), 8.27 (1H, d, J = 0.7 Hz), 7.94 (1H, d, J = 0.7 Hz), 7.72- 7.70 (1H, m), 7.65 (1H, d, J = 1.6 Hz), 7.65-7.61 (1H, m), 7.48-7.43 (1H, m), 7.35-7.30 (1H, m), 7.14 (1H, s), 5.41 (1H, s), 4.94 (1H, t, J = 5.3 Hz), 4.18 (2H, t, J = 5.6 Hz), 3.79 (2H, q, J = 5.6 Hz), 1.73 (3H, s), 1.64 (3H, s).
  • TABLE 1-87
    compound
    No. structural formula NMR
    593
    Figure US20150329491A1-20151119-C00718
         		1H-NMR (DMSO-D6) δ: 8.35 (1H, s), 7.94 (1H, s), 7.85-7.82 (1H, m), 7.78 (1H, d, J = 8.1 Hz), 7.73 (1H, dd, J = 8.1, 1.6 Hz), 7.58-7.51 (2H, m), 7.37- 7.33 (1H, m), 7.21 (1H, s), 5.44 (1H, t, J = 5.3 Hz), 4.90-4.81 (2H, m), 4.57- 4.50 (1H, m), 1.47 (3H, s), 1.46 (3H, s).
    594
    Figure US20150329491A1-20151119-C00719
         		1H-NMR (DMSO-D6) δ: 12.42 (1H, br s), 8.42 (1H, d, J = 0.7 Hz), 8.08 (1H, d, J = 0.9 Hz), 8.04 (1H, d, J = 1.5 Hz), 7.94-7.92 (1H, m), 7.78-7.75 (1H, m), 7.68- 7.65 (1H, m), 7.47-7.43 (1H, m), 7.42-7.38 (1H, m), 7.35 (1H, s), 4.36 (2H, t, J = 6.7 Hz), 3.38 (3H, t, J = 6.9 Hz), 2.87 (2H, t, J =
    6.7 Hz), 2.77 (3H, s).
    595 (optically active form)
    Figure US20150329491A1-20151119-C00720
         		1H-NMR (DMSO-D6) δ: 8.02 (1H, d, J = 0.5 Hz), 7.68 (1H, d, J = 0.5 Hz), 7.65- 7.61 (1H, m), 7.44-7.37 (2H, m), 7.40 (1H, s), 7.36-7.25 (2H, m), 7.18 (1H, dd, J = 10.0, 2.6 Hz), 4.97 (2H, t, J = 5.3 Hz), 4.39-4.32 (1H, m), 3.86- 3.76 (4H, m).
    596
    Figure US20150329491A1-20151119-C00721
         		1H-NMR (DMSO-D6) δ: 8.38 (1H, s), 8.06 (1H, d, J = 0.5 Hz), 8.04 (1H, d, J = 1.6 Hz), 7.94-7.91 (1H, m), 7.76 (1H, d, J = 7.4 Hz), 7.68-7.64 (1H, m), 7.48- 7.43 (1H, m), 7.42-7.38 (1H, m), 7.35 (1H, s), 3.90 (3H, s), 2.77 (3H, s).
    597
    Figure US20150329491A1-20151119-C00722
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, d, J = 0.5 Hz), 7.94 (1H, d, J = 0.7 Hz), 7.82 (1H, br s), 7.79 (1H, d, J = 8.1 Hz), 7.72 (1H, dd, J = 8.1, .16 Hz), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.22 (1H, s), 5.44 (1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz).
    598
    Figure US20150329491A1-20151119-C00723
         		1H-NMR (DMSO-D6) δ: 8.26 (1H, d, J = 4.4 Hz), 7.90- 7.79 (3H, m), 7.69-7.65 (2H, m), 7.54-7.49 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s), 5.48 (1H, br s), 5.44 (0.5H, q, J = 6.3 Hz), 5.38 (0.5H, q, J = 6.4 Hz), 3.89 (3H, s), 1.48 (1.6H, d, J = 6.3 Hz), 1.45 (1.4H, d, J = 6.3 Hz).
    599
    Figure US20150329491A1-20151119-C00724
         		1H-NMR (CDCl3) δ: 7.82-7.80 (1H, m), 7.71-7.66 (1H, m), 7.43-7.35 (2H, m), 7.35- 7.29 (1H, m), 7.11 (1H, d, J = 2.3 Hz), 4.16 (2H, t, J = 5.3 Hz), 3.70 (1H, br s), 3.64 (2H, t, J = 5.2 Hz), 3.57 (2H, t, J = 7.0 Hz), 2.68 (3H, s), 2.34 (2H, t, J = 8.0 Hz), 2.08-1.98 (2H, m).
  • TABLE 1-88
    compound
    No. structural formula NMR
    600
    Figure US20150329491A1-20151119-C00725
         		1H-NMR (DMSO-D6) δ: 8.29 (1H, s), 7.96 (1H, s), 7.82-7.77 (2H, m), 7.72 (1H, dd, J = 8.0, 1.7 Hz), 7.58-7.52 (2H, m), 7.37- 7.33 (1H, m), 4.88 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.36 (2H, t, J = 6.7 Hz), 2.86 (2H, t, J = 6.7 Hz).
    601
    Figure US20150329491A1-20151119-C00726
         		1H-NMR (DMSO-D6) δ: 8.23 (1H, d, J = 0.5 Hz), 7.95 (1H, d, J = 0.7 Hz), 7.80- 7.77 (2H, m), 7.71 (1H, dd, J = 8.0, 1.7 Hz), 7.57-7.52 (2H, m), 7.42 (1H, br s), 7.37-7.33 (1H, m), 7.23 (1H, s), 6.92 (1H, br s), 5.44 (1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 4.34 (2H, t, J = 6.8 Hz), 2.67 (2H, t, J = 7.0 Hz).
    602
    Figure US20150329491A1-20151119-C00727
         		1H-NMR (DMSO-D6) δ: 8.39 (1H, s), 7.95 (1H, s), 7.88-7.86 (1H, m), 7.79- 7.74 (2H, m), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.20 (1H, s), 5.44 (1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 1.58 (9H, s).
    603
    Figure US20150329491A1-20151119-C00728
         		1H-NMR (DMSO-D6) δ: 8.39- 8.36 (1H, m), 8.34 (1H, d, J = 0.4 Hz), 7.99 (1H, d, J = 0.9 Hz), 7.81-7.79 (1H, m), 7.75 (1H, d, J = 1.5 Hz), 7.69-7.66 (1H, m), 7.56-7.52 (1H, m), 7.45- 7.41 (1H, m), 7.35 (1H, s), 5.56 (1H, t, J = 6.0 Hz), 4.50 (2H, d, J = 6.0 Hz), 3.87 (3H, s).
    604 (optically active form)
    Figure US20150329491A1-20151119-C00729
         		1H-NMR (DMSO-D6) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.63 (1H, d, J = 7.3 Hz), 7.38 (1H, br s), 7.31-7.21 (3H, m), 7.04 (1H, d, J = 2.4 Hz), 6.63-6.59 (1H, m), 4.11 (2H, t, J = 6.5 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m).
    605 (optically active form)
    Figure US20150329491A1-20151119-C00730
         		1H-NMR (DMSO-D6) δ: 7.93 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.42 (1H, s), 7.37 (1H, dd, J = 6.7, 0.9 Hz), 7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, dd, J = 1.6, 0.7 Hz), 4.96 (2H, td, J = 5.3, 1.2 Hz), 4.38- 4.32 (1H, m), 3.86-3.76 (4H, m), 2.39 (3H, s).
    606 (optically active form)
    Figure US20150329491A1-20151119-C00731
         		1H-NMR (DMSO-D6) δ: 12.07 (1H, br s), 7.99 (1H, d, J = 0.7 Hz), 7.64-7.60 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.42 (1H, s), 7.32- 7.21 (3H, m), 7.17 (1H, s), 7.12 (1H, dd, J = 1.5, 0.8 Hz), 4.21 (2H, t, J = 6.7 Hz), 2.38 (3H, s), 2.28 (2H, t, J = 7.4 Hz), 1.91- 1.84 (2H, m), 1.55-1.48 (2H, m).
  • TABLE 1-89
    compound
    No. structural formula NMR
    607 (optically active form)
    Figure US20150329491A1-20151119-C00732
         		1H-NMR (DMSO-D6) δ: 12.53 (1H, br s), 7.94 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz), 7.65 (1H, d, J = 7.0 Hz), 7.43-7.39 (2H, m), 7.37-7.24 (3H, m), 7.17 (1H, dd, J = 10.0, 2.6 Hz), 4.36 (2H, s), 1.18 (6H, s).
    608
    Figure US20150329491A1-20151119-C00733
         		1H-NMR (DMSO-D6) δ: 13.15 (1H, br s), 8.29 (1H, s), 7.99 (1H, d, J = 0.5 Hz), 7.83-7.79 (2H, m), 7.74 (1H, dd, J = 8.1, 1.6 Hz), 7.58-7.52 (2H, m), 7.38- 7.33 (1H, m), 7.24 (1H, s), 5.45 (1H, t, J = 5.3 Hz), 5.00 (2H, s), 4.91-4.82 (2H, m).
    609
    Figure US20150329491A1-20151119-C00734
         		1H-NMR (DMSO-D6) δ: 8.27- 8.25 (1H, m), 7.98-7.96 (1H, m), 7.84-7.79 (2H, m), 7.76-7.72 (1H, m), 7.58- 7.51 (3H, m), 7.38-7.33 (1H, m), 7.31 (1H, br s), 7.24 (1H, d, J = 1.9 Hz), 5.47-5.43 (1H, m), 4.87- 4.86 (2H, m), 4.80 (2H, d, J = 1.6 Hz).
    610 (optically active form)
    Figure US20150329491A1-20151119-C00735
         		1H-NMR (DMSO-D6) δ: 12.19 (1H, br s), 8.14 (1H, d, J = 0.7 Hz), 7.66 (1H, s), 7.65-7.61 (1H, m), 7.41- 7.37 (2H, m), 7.37-7.29 (3H, m), 7.18 (1H, dd, J = 10.0, 2.6 Hz), 2.94 (2H, s), 1.70 (3H, s), 1.69 (3H, s).
    611
    Figure US20150329491A1-20151119-C00736
         		1H-NMR (DMSO-D6) δ: 7.67 (1H, d, J = 7.7 Hz), 7.61 (1H, d, J = 7.4 Hz), 7.49- 7.44 (1H, m), 7.32-7.28 (1H, m), 7.19 (1H, s), 7.13 (1H, d, J = 2.3 Hz), 7.07- 7.05 (1H, m), 5.46 (1H, t, J = 5.4 Hz), 4.87-4.78 (2H, m), 4.47 (1H, t, J = 5.2 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.47 (2H, dd, J =
    11.6, 6.5 Hz), 1.82-1.75
    (2H, m), 1.63-1.55 (2H, m).
    612
    Figure US20150329491A1-20151119-C00737
         		1H-NMR (DMSO-D6) δ: 8.09 (1H, br s), 7.86 (1H, d, J = 7.6 Hz), 7.72 (1H, br s), 7.61 (1H, d, J = 7.4 Hz), 7.46-7.41 (1H, m), 7.35- 7.29 (1H, m), 7.30 (1H, s), 7.25-7.23 (1H, m), 7.07 (1H, d, J = 2.5 Hz), 4.23 (2H, t, J = 5.7 Hz), 4.20- 4.16 (2H, m), 3.67-3.59 (2H, m), 3.46 (2H, t, J =
    6.4 Hz), 1.98-1.92 (2H, m).
    613
    Figure US20150329491A1-20151119-C00738
         		1H-NMR (DMSO-D6) δ: 12.16 (1H, br s), 8.64 (1H, s), 7.64 (1H, d, J = 7.4 Hz), 7.59 (1H, s), 7.40-7.31 (3H, m), 7.30-7.28 (1H, m), 7.13 (1H, d, J = 2.6 Hz), 7.06 (1H, d, J = 7.0 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.42 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m).
  • TABLE 1-90
    compound
    No. structural formula NMR
    614 (optically active form)
    Figure US20150329491A1-20151119-C00739
         		1H-NMR (CDCl3) δ: 7.71 (2H, s), 7.68-7.64 (1H, m), 7.25-7.22 (3H, m), 7.11- 7.08 (1H, m), 6.80-6.79 (1H, m), 3.88 (3H, s), 3.15 (2H, s), 2.79 (1H, s), 1.78 (3H, s), 1.77 (3H, s).
    615
    Figure US20150329491A1-20151119-C00740
         		1H-NMR (DMSO-D6) δ: 8.25 (1H, s), 7.93 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.76- 7.74 (1H, m), 7.73-7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.49 (1H, m), 7.39- 7.34 (1H, m), 7.23 (1H, s), 5.47 (1H, t, J = 5.3 Hz), 4.95 (1H, t, J = 5.3 Hz), 4.91-4.83 (2H, m), 4.19 (2H, t, J = 5.6 Hz), 3.78
    (2H, q, J = 5.5 Hz).
    616
    Figure US20150329491A1-20151119-C00741
         		1H-NMR (CDCl3) δ: 8.28-8.25 (1H, m), 7.88 (1H, d, J = 2.0 Hz), 7.84-7.82 (1H, m), 7.73-7.69 (1H, m), 7.51- 7.46 (1H, m), 7.44-7.40 (1H, m), 4.01 (3H, s), 2.83 (1H, br s).
    617 (optically active form)
    Figure US20150329491A1-20151119-C00742
         		1H-NMR (CDCl3) δ: 8.30-8.27 (1H, m), 7.89 (1H, d, J = 2.0 Hz), 7.84-7.82 (1H, m), 7.73-7.70 (1H, m), 7.52- 7.47 (1H, m), 7.44-7.40 (1H, m), 4.02 (3H, s), 2.77 (1H, br s).
    618
    Figure US20150329491A1-20151119-C00743
         		1H-NMR (DMSO-D6) δ: 8.31 (1H, d, J = 0.7 Hz), 7.92 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.4 Hz), 7.73- 7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.22 (1H, s), 5.47 (1H, t, J = 5.4 Hz), 4.91-4.82 (2H, m), 4.18 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz).
    619 (optically active form)
    Figure US20150329491A1-20151119-C00744
         		1H-NMR (DMSO-D6) δ: 12.55 (1H, br s), 7.89 (1H, d, J = 0.7 Hz), 7.63 (1H, d, J = 0.7 Hz), 7.62-7.59 (1H, m), 7.28-7.24 (3H, m), 7.21- 7.15 (2H, m), 6.83 (1H, d, J = 2.3 Hz), 4.36 (2H, s), 3.84 (3H, s), 1.19 (6H, s).
    620
    Figure US20150329491A1-20151119-C00745
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.58 (2H, m), 7.60 (1H, d, J = 0.7 Hz), 7.38-7.26 (3H, m), 7.24-7.21 (1H, m), 7.19 (1H, br s), 5.35 (1H, t, J = 5.6 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.57 (2H, d, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.6, 5.6 Hz).
  • TABLE 1-91
    compound
    No. structural formula NMR
    621
    Figure US20150329491A1-20151119-C00746
         		1H-NMR (DMSO-D6) δ: 8.34 (1H, s), 7.91 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.76- 7.75 (1H, m), 7.75-7.73 (1H, m), 7.68-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39- 7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.4 Hz), 4.91-4.82 (2H, m), 4.59- 4.49 (1H, m), 1.48 (3H, s), 1.46 (3H, s).
    622
    Figure US20150329491A1-20151119-C00747
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.31-7.22 (4H, m), 7.17- 7.13 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.56 (2H, t, J = 5.2 Hz), 4.04 (2H, d, J = 6.0 Hz), 3.95 (3H, s), 3.58-3.48 (4H, m), 2.04- 1.95 (1H, m).
    623
    Figure US20150329491A1-20151119-C00748
         		1H-NMR (DMSO-D6) δ: 12.20 (1H, br s), 7.98 (1H, d, J = 0.5 Hz), 7.65-7.58 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.34-7.20 (5H, m), 5.35 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.3 Hz), 4.24 (2H, t, J = 6.8 Hz), 2.27 (2H, t, J = 7.4 Hz), 2.12-2.05 (2H, m).
    624 (optically active form)
    Figure US20150329491A1-20151119-C00749
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, d, J = 0.7 Hz), 7.63 (1H, d, J = 0.7 Hz), 7.61- 7.56 (1H, m), 7.34-7.29 (1H, m), 7.28-7.23 (2H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.82 (1H, d, J = 2.3 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.7 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.85-3.79 (2H, m), 3.49-3.43 (2H, m), 1.81- 1.74 (2H, m), 1.61-1.54
    (2H, m).
    625
    Figure US20150329491A1-20151119-C00750
         		1H-NMR (DMSO-D6) δ: 7.89 (1H, d, J = 7.7 Hz), 7.74- 7.70 (1H, m), 7.66-7.58 (3H, m), 7.52 (1H, s), 7.52-7.47 (1H, m), 4.54 (1H, d, J = 18.8 Hz), 4.49 (1H, d, J = 18.8 Hz).
    626
    Figure US20150329491A1-20151119-C00751
         		1H-NMR (DMSO-D6) δ: 8.10 (1H, br s), 7.85 (1H, d, J = 7.7 Hz), 7.72 (1H, br s), 7.63-7.59 (1H, m), 7.45- 7.40 (1H, m), 7.34-7.29 (1H, m), 7.30 (1H, s), 7.23-7.21 (1H, m), 7.04 (1H, d, J = 2.6 Hz), 3.86 (3H, s).
  • TABLE 1-92
    compound
    No. structural formula NMR
    627
    Figure US20150329491A1-20151119-C00752
         		1H-NMR (DMSO-D6) δ: 7.67 (1H, d, J = 7.9 Hz), 7.63- 7.60 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.20 (1H, s), 7.14 (1H, d, J = 2.3 Hz), 7.09-7.07 (1H, m), 5.48 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 3.83 (3H, s).
    628
    Figure US20150329491A1-20151119-C00753
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, s), 7.61-7.57 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.30-7.18 (5H, m), 6.87 (1H, d, J = 2.4 Hz), 4.87- 4.82 (2H, m), 4.35-4.29 (1H, m), 3.95 (3H, s), 3.66-3.54 (4H, m).
    629 (optically active form)
    Figure US20150329491A1-20151119-C00754
         		1H-NMR (DMSO-D6) δ: 8.31 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 0.9 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.73- 7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.4 Hz), 4.92-4.82 (2H, m), 4.18 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz).
    630 (optically active form)
    Figure US20150329491A1-20151119-C00755
         		1H-NMR (DMSO-D6) δ: 8.37 (1H, s), 8.14 (1H, br s), 7.98 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 7.7 Hz), 7.85-7.83 (1H, m), 7.74 (1H, br s), 7.70 (1H, d, J = 1.5 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz).
    631
    Figure US20150329491A1-20151119-C00756
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J = 0.9 Hz), 7.65- 7.60 (1H, m), 7.62 (1H, d, J = 0.9 Hz), 7.42-7.35 (2H, m), 7.33-7.27 (2H, m), 7.17 (1H, s), 7.09 (1H, d, J = 1.6 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.26 (2H, t, J = 5.7 Hz), 3.83 (2H, q, J = 5.5 Hz), 2.60-2.47 (2H, m), 1.92-1.82 (1H, m), 0.93 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J = 6.5 Hz).
    632
    Figure US20150329491A1-20151119-C00757
         		1H-NMR (DMSO-D6) δ: 8.22 (1H, br s), 7.95-7.92 (1H, m), 7.81 (1H, br s), 7.73- 7.66 (2H, m), 7.58 (1H, d, J = 1.4 Hz), 7.53-7.48 (1H, m), 7.47-7.42 (1H, m), 7.44 (1H, s), 4.41 (1H, s).
    633
    Figure US20150329491A1-20151119-C00758
         		1H-NMR (DMSO-D6) δ: 8.09 (1H, br s), 7.90 (1H, d, J = 7.7 Hz), 7.68 (1H, br s), 7.65-7.62 (1H, m), 7.55- 7.53 (1H, m), 7.47-7.43 (1H, m), 7.39-7.34 (1H, m), 7.33 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 2.71 (2H, q, J = 7.6 Hz), 1.23 (3H, t, J = 7.5 Hz).
  • TABLE 1-93
    compound
    No. structural formula NMR
    634
    Figure US20150329491A1-20151119-C00759
         		1H-NMR (DMSO-D6) δ: 8.06 (1H, br s), 7.91 (1H, d, J = 7.7 Hz), 7.67 (1H, br s), 7.65-7.61 (1H, m), 7.55- 7.52 (1H, m), 7.47-7.42 (1H, m), 7.38-7.32 (2H, m), 7.23 (1H, s), 2.71-2.63 (2H, m), 0.95 (9H, t, J = 7.9 Hz), 0.92-0.86 (2H, m), 0.56 (6H, q, J = 7.9 Hz).
    635
    Figure US20150329491A1-20151119-C00760
         		1H-NMR (DMSO-D6) δ: 7.78 (1H, d, J = 7.7 Hz), 7.70- 7.66 (1H, m), 7.64-7.61 (1H, m), 7.57-7.52 (2H, m), 7.46-7.40 (1H, m), 7.41 (1H, s), 5.62 (1H, t, J = 5.6 Hz), 4.93-4.82 (2H, m).
    636
    Figure US20150329491A1-20151119-C00761
         		1H-NMR (DMSO-D6) δ: 8.24 (1H, br s), 7.92-7.89 (1H, m), 7.86 (1H, br s), 7.69- 7.64 (2H, m), 7.56 (1H, d, J = 2.1 Hz), 7.53-7.47 (1H, m), 7.49 (1H, s), 7.46-7.41 (1H, m).
    637
    Figure US20150329491A1-20151119-C00762
         		1H-NMR (DMSO-D6) δ: 8.22 (1H, s), 7.89 (1H, d, J = 0.8 Hz), 7.84 (1H, d, J = 7.7 Hz), 7.69-7.68 (1H, m), 7.67-7.63 (1H, m), 7.58 (1H, d, J = 1.6 Hz), 7.55 (1H, br s), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 7.22 (1H, s), 7.09 (1H, br s), 3.89 (3H, s), 3.89 (1H, d, J = 15.7 Hz), 3.81 (1H, d, J = 15.7 Hz).
    638
    Figure US20150329491A1-20151119-C00763
         		1H-NMR (DMSO-D6) δ: 8.38 (1H, s), 7.93 (1H, s), 7.81 (1H, d, J = 7.7 Hz), 7.78 (2H, s), 7.66 (1H, d, J = 7.4 Hz), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.20 (1H, s), 5.45 (1H, t, J = 5.4 Hz), 4.92-4.82 (2H, m), 1.58 (9H, s).
    639
    Figure US20150329491A1-20151119-C00764
         		1H-NMR (DMSO-D6) δ: 8.46 (1H, s), 8.13 (1H, br s), 7.99 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 7.89 (1H, br s), 7.78-7.73 (2H, m), 7.67-7.63 (1H, m), 7.49- 7.44 (1H, m), 7.40-7.34 (1H, m), 7.30 (1H, s), 1.57 (9H, s).
    640
    Figure US20150329491A1-20151119-C00765
         		1H-NMR (DMSO-D6) δ: 8.09 (1H, br s), 7.85 (1H, d, J = 7.7 Hz), 7.71 (1H, br s), 7.63-7.59 (1H, m), 7.45- 7.40 (1H, m), 7.34-7.28 (1H, m), 7.30 (1H, s), 7.24-7.21 (1H, m), 7.04 (1H, d, J = 2.3 Hz), 4.93 (1H, t, J = 5.6 Hz), 4.09 (2H, t, J = 4.9 Hz), 3.74 (2H, q, J = 5.0 Hz).
  • TABLE 1-94
    compound
    No. structural formula NMR
    641
    Figure US20150329491A1-20151119-C00766
         		1H-NMR (DMSO-D6) δ: 7.84- 7.81 (1H, m), 7.71-7.65 (2H, m), 7.60-7.58 (1H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.33 (1H, s), 5.53 (1H, t, J = 5.5 Hz), 4.91-4.81 (2H, m), 4.31 (1H, s).
    642
    Figure US20150329491A1-20151119-C00767
         		1H-NMR (DMSO-D6) δ: 7.79- 7.75 (1H, m), 7.66-7.62 (1H, m), 7.52-7.46 (1H, m), 7.42-7.38 (2H, m), 7.37- 7.33 (1H, m), 7.13 (1H, s), 5.40 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 2.69 (2H, q, J = 7.6 Hz), 1.23 (3H, t, J = 7.5 Hz).
    643
    Figure US20150329491A1-20151119-C00768
         		1H-NMR (DMSO-D6) δ: 8.24 (1H, s), 7.91 (1H, d, J = 0.7 Hz), 7.83 (1H, d, J = 7.7 Hz), 7.68-7.64 (2H, m), 7.56-7.50 (2H, m), 7.40- 7.35 (1H, m), 7.19 (1H, s), 4.91 (1H, t, J = 5.3 Hz), 3.88 (3H, s), 3.74-3.67 (2H, m), 3.24-3.09 (2H, m).
    644
    Figure US20150329491A1-20151119-C00769
         		1H-NMR (DMSO-D6) δ: 7.86 (1H, d, J = 7.7 Hz), 7.83- 7.81 (1H, m), 7.79-7.77 (1H, m), 7.70 (1H, d, J = 7.5 Hz), 7.58-7.54 (1H, m), 7.48-7.43 (1H, m), 7.35 (1H, s), 5.76 (1H, d, J = 6.2 Hz), 5.56 (1H, t, J = 5.5 Hz), 4.96-4.86 (2H, m), 4.56-4.43 (2H, m), 4.34- 4.24 (1H, m), 4.11-4.00 (1H, m), 3.88-3.76 (1H, m).
    645
    Figure US20150329491A1-20151119-C00770
         		1H-NMR (DMSO-D6) δ: 8.36 (1H, d, J = 0.7 Hz), 8.15 (1H, br s), 8.00 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 7.7 Hz), 7.86-7.83 (1H, m), 7.75 (1H, br s), 7.70 (1H, d, J = 1.6 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 3.95 (2H, d, J = 7.2 Hz), 2.20-2.13 (1H, m), 0.88 (3H, d, J = 1.2 Hz), 0.86 (3H, d, J = 1.4 Hz).
    646
    Figure US20150329491A1-20151119-C00771
         		1H-NMR (DMSO-D6) δ: 8.32 (1H, s), 8.15 (1H, br s), 8.00 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 7.86-7.84 (1H, m), 7.75 (1H, br s), 7.71 (1H, d, J = 1.6 Hz), 7.67- 7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 3.95 (2H, s), 0.94 (9H, s).
    647 (optically active form)
    Figure US20150329491A1-20151119-C00772
         		1H-NMR (CDCl3) δ: 8.41-8.37 (1H, m), 8.24-8.22 (1H, m), 8.11 (1H, d, J = 1.5 Hz), 7.79-7.75 (1H, m), 7.59- 7.54 (1H, m), 7.51-7.46 (1H, m), 3.92 (3H, s), 3.06 (1H, br s).
  • TABLE 1-95
    compound
    No. structural formula NMR
    648
    Figure US20150329491A1-20151119-C00773
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, s), 7.63-7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.40-7.37 (2H, m), 7.32- 7.22 (2H, m), 7.15 (1H, s), 7.10 (1H, d, J = 1.5 Hz), 4.96-4.92 (2H, m), 4.38- 4.32 (1H, m), 3.85-3.78 (4H, m), 2.58-2.48 (2H, m), 1.92-1.82 (1H, m), 0.92 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6.6 Hz).
    649
    Figure US20150329491A1-20151119-C00774
         		1H-NMR (DMSO-D6) δ: 8.28 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.9 Hz), 7.76- 7.74 (1H, m), 7.73-7.71 (1H, m), 7.66 (1H, d, J = 7.3 Hz), 7.53-7.48 (1H, m), 7.39-7.35 (1H, m), 4.89 (1H, d, J = 13.5 Hz), 4.85 (1H, d, J = 13.7 Hz), 3.96 (2H, d, J = 7.1 Hz), 2.21- 2.13 (1H, m), 0.88 (3H, d, J = 1.1 Hz), 0.86 (3H, d, J =
    1.1 Hz).
    650
    Figure US20150329491A1-20151119-C00775
         		1H-NMR (DMSO-D6) δ: 8.24 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 1.8 Hz), 7.73 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.53-7.49 (1H, m), 7.39-7.34 (1H, m), 4.89 (1H, d, J = 13.7 Hz), 4.85 (1H, d, J = 14.1 Hz), 3.95 (3H, s), 0.94 (8H, s).
    651
    Figure US20150329491A1-20151119-C00776
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, s), 7.64-7.59 (2H, m), 7.63 (1H, s), 7.39-7.35 (1H, m), 7.33-7.23 (3H, m), 7.21 (1H, s), 6.55-6.48 (1H, m), 6.40 (1H, dq, J = 17.2, 5.3 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86-3.77 (4H, m), 1.88 (3H, dd, J = 6.5, 1.2 Hz).
    652
    Figure US20150329491A1-20151119-C00777
         		1H-NMR (DMSO-D6) δ: 7.93 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.39-7.36 (1H, m), 7.32-7.22 (2H, m), 7.15 (1H, s), 7.13 (1H, d, J = 1.5 Hz), 4.96-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 3.69-2.60 (2H, m), 1.70-1.57 (2H, m), 0.93 (3H, t, J = 7.4 Hz).
    653
    Figure US20150329491A1-20151119-C00778
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, s), 7.64-7.59 (1H, m), 7.61 (1H, s), 7.47-7.44 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.17 (1H, s), 7.15 (1H, d, J = 1.2 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 2.69 (2H, q, J = 7.5 Hz), 1.23 (3H, t, J = 7.7 Hz).
  • TABLE 1-96
    compound
    No. structural formula NMR
    654
    Figure US20150329491A1-20151119-C00779
         		1H-NMR (DMSO-D6) δ: 7.93 (1H, d, J = 0,7 Hz), 7.61 (1H, d, J = 0.7 Hz), 7.60- 7.58 (1H, m), 7.49-7.46 (1H, m), 7.38-7.33 (1H, m), 7.31-7.21 (2H, m), 7.16 (2H, br s), 4.98-4.93 (2H, m), 4.37-4.31 (1H, m), 3.85-3.76 (4H, m), 3.02- 2.94 (1H, m), 1.26 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J = 7.2 Hz).
    655
    Figure US20150329491A1-20151119-C00780
         		1H-NMR (DMSO-D6) δ: 8.06 (1H, br s), 7.92 (1H, d, J = 7.7 Hz), 7.69 (1H, br s), 7.63 (1H, d, J = 7.2 Hz), 7.55 (1H, br s), 7.47-7.42 (1H, m), 7.38-7.34 (1H, m), 7.34 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 3.34 (2H, t, J = 6.8 Hz), 3.28-3.20 (2H, m), 2.68-2.60 (2H, m),
    2.23-2.17 (2H, m), 1.94-
    1.85 (2H, m), 1.85-1.75
    (2H, m).
    656
    Figure US20150329491A1-20151119-C00781
         		1H-NMR (DMSO-D6) δ: 7.77 (1H, d, J = 7.7 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.52- 7.47 (1H, m), 7.41 (1H, br s), 7.40 (1H, br s), 7.38- 7.33 (1H, m), 7.15 (1H, s), 5.41 (1H, t, J = 5.3 Hz), 4.87-4.78 (2H, m), 3.34 (2H, t, J = 6.7 Hz), 3.24 (2H, t, J = 7.2 Hz), 2.65- 2.61 (2H, m), 2.23-2.18 (2H, m), 1.94-1.86 (2H, m), 1.83-1.74 (2H, m).
    657 (optically active form)
    Figure US20150329491A1-20151119-C00782
         		1H-NMR (DMSO-D6) δ: 8.02 (1H, d, J = 0.7 Hz), 7.71- 7.65 (2H, m), 7.67 (1H, d, J = 0.7 Hz), 7.48-7.31 (4H, m), 7.34 (1H, s), 4.97 (1H, t, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.83 (2H, dt, J = 5.3, 5.6 Hz), 3.52- 3.42 (4H, m), 1.93-1.80 (4H, m).
    658
    Figure US20150329491A1-20151119-C00783
         		1H-NMR (DMSO-D6) δ: 9.24 (1H, s), 9.23 (2H, br s), 8.23 (1H, br s), 8.09 (1H, br s), 8.03 (1H, d, J = 7.7 Hz), 7.97 (1H, d, J = 1.9 Hz), 7.86 (1H, br s), 7.71 (1H, d, J = 7.4 Hz), 7.55- 7.50 (1H, m), 7.48-7.43 (1H, m), 7.45 (1H, s).
    659 (optically active form)
    Figure US20150329491A1-20151119-C00784
         		1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 8.14 (1H, br s), 7.99 (1H, d, J = 0.5 Hz), 7.91 (1H, d, J = 7.4 Hz), 7.84 (1H, br s), 7.74 (1H, br s), 7.71 (1H, d, J = 1.6 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.48-7.43 (1H, m), 7.40-7.34 (1H, m), 7.31 (1H, s), 3.94 (2H, s), 0.93 (9H, s).
  • TABLE 1-97
    compound
    No. structural formula NMR
    660 (optically active form)
    Figure US20150329491A1-20151119-C00785
         		1H-NMR (DMSO-D6) δ: 8.25 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.9 Hz), 7.76 (1H, d, J = 1.6 Hz), 7.74- 7.72 (1H, m), 7.66 (1H, d, J = 7.4 Hz), 7.54-7.48 (1H, m), 7.40-7.34 (1H, m), 7.22 (1H, s), 5.46 (1H, br s), 4.92-4.83 (2H, m), 3.95 (2H, s), 0.94 (9H, s).
    661
    Figure US20150329491A1-20151119-C00786
         		1H-NMR (DMSO-D6) δ: 8.18 (1H, s), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.4 Hz), 7.73-7.71 (1H, m), 7.66 (1H, d, J = 7.7 Hz), 7.54-7.48 (1H, m), 7.39- 7.34 (1H, m), 7.23 (1H, s), 5.47 (1H, t, J = 5.4 Hz), 4.92-4.83 (2H, m), 4.76 (1H, s), 4.06 (2H, s), 1.10 (3H, s), 1.10 (3H, s).
    662
    Figure US20150329491A1-20151119-C00787
         		1H-NMR (DMSO-D6) δ: 8.33 (1H, s), 8.13 (1H, br s), 7.98 (1H, s), 7.92 (1H, d, J = 7.7 Hz), 7.84 (1H, br s), 7.73 (1H, br s), 7.70 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.5 Hz), 7.49- 7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 3.98 (2H, d, J = 7.1 Hz), 1.92- 1.80 (1H, m), 1.72-1.50 (5H, m), 1.26-1.10 (3H, m),
    1.03-0.92 (2H, m).
    663 (optically active form)
    Figure US20150329491A1-20151119-C00788
         		1H-NMR (DMSO-D6) δ: 7.92 (1H, s), 7.63-7.59 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.33- 7.25 (3H, m), 7.16 (1H, s), 7.13-7.11 (1H, m), 4.59 (2H, t, J = 4.9 Hz), 4.22 (2H, d, J = 7.1 Hz), 3.48- 3.40 (4H, m), 2.39 (3H, s), 2.19-2.13 (1H, m).
    664 (optically active form)
    Figure US20150329491A1-20151119-C00789
         		1H-NMR (CDCl3) δ: 7.72-7.68 (1H, m), 7.66-7.64 (1H, m), 7.59-7.55 (2H, m), 7.31- 7.21 (3H, m), 7.15-7.13 (1H, m), 6.32-6.29 (1H, m), 4.37-4.31 (1H, m), 4.21- 4.10 (4H, m), 3.23-3.07 (1H, m), 2.90-2.71 (2H, m), 1.95 (3H, d, J = 1.3 Hz), 1.93 (3H, d, J = 1.3 Hz).
    665 (optically active form)
    Figure US20150329491A1-20151119-C00790
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.41-7.37 (2H, m), 7.32-7.22 (2H, m), 7.15 (1H, s), 7.10 (1H, d, J = 1.5 Hz), 4.97-4.92 (2H, m), 4.39-4.32 (1H, m), 3.86-3.79 (4H, m), 2.58- 2.48 (2H, m), 1.92-1.82 (1H, m), 0.93 (3H, d, J = 6.6 Hz), 0.91 (6H, d, J = 6.6 Hz).
  • TABLE 1-98
    compound
    No. structural formula NMR
    666
    Figure US20150329491A1-20151119-C00791
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, d, J = 1.62 Hz), 4.98-4.94 (2H, m), 4.38-4.32 (1H, m), 3.86-3.77 (4H, m), 2.65- 2.59 (2H, m), 1.53-1.47 (2H, m), 0.96 (9H, s).
    667 (optically active form)
    Figure US20150329491A1-20151119-C00792
         		1H-NMR (DMSO-D6) δ: 8.33 (1H, d, J = 0.7 Hz), 8.13 (1H, br s), 7.98 (1H, d, J = 0.9 Hz), 7.92 (1H, d, J = 7.5 Hz), 7.84 (1H, br s), 7.73 (1H, br s), 7.70 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.3 Hz), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 3.98 (2H, d, J = 7.3 Hz), 1.92-1.80 (1H, m), 1.73-1.50 (5H, m),
    1.26-1.10 (3H, m), 1.03-
    0.91 (2H, m).
    668 (optically active form)
    Figure US20150329491A1-20151119-C00793
         		1H-NMR (DMSO-D6) δ: 8.27 (1H, s), 7.92 (1H, s), 7.80 (1H, d, J = 7.9 Hz), 7.74 (1H, s), 7.72 (1H, s), 7.66 (1H, d, J = 7.4 Hz), 7.53- 7.48 (1H, m), 7.40-7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.3 Hz), 4.91- 4.82 (2H, m), 3.98 (2H, d, J = 7.2 Hz), 1.91-1.79 (1H, m), 1.72-1.50 (5H, m), 1.26-1.11 (3H, m), 1.03-
    0.92 (2H, m).
    669 (optically active form)
    Figure US20150329491A1-20151119-C00794
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.41 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, d, J = 1.6 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 2.65-2.59 (2H, m), 1.54-1.47 (2H, m), 0.96 (9H, s).
  • TABLE 1-99
    compound
    No. structural formula NMR
    670
    Figure US20150329491A1-20151119-C00795
         		1H-NMR (DMSO-D6) δ: 12.17 (1H, br s), 7.97 (1H, s), 7.65-7.58 (2H, m), 7.43 (1H, s), 7.32-7.22 (3H, m), 7.17 (1H, s), 7.13-7.12 (1H, m), 4.24 (2H, t, J = 6.7 Hz), 2.38 (3H, s), 2.27 (2H, t, J = 7.4 Hz), 2.13- 2.04 (2H, m).
    671
    Figure US20150329491A1-20151119-C00796
         		1H-NMR (DMSO-D6) δ: 8.14- 8.10 (1H, m), 8.07-8.01 (3H, m), 7.73-7.69 (1H, m), 7.63-7.57 (1H, m), 7.56- 7.49 (2H, m).
    672 (optically active form)
    Figure US20150329491A1-20151119-C00797
         		1H-NMR (DMSO-D6) δ: 8,03 (1H, d, J = 0.4 Hz), 7.67- 7.63 (1H, m), 7.66 (1H, d, J = 0.9 Hz), 7.42-7.38 (1H, m), 7.40 (1H, s), 7.36-7.32 (3H, m), 7.18-7.14 (1H, m), 3.96 (3H, s).
    673 (optically active form)
    Figure US20150329491A1-20151119-C00798
         		1H-NMR (DMSO-D6) δ: 8.05 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.7 Hz), 7.65- 7.62 (1H, m), 7.44-7.42 (1H, m), 7.40-7.36 (2H, m), 7.35-7.26 (2H, m), 7.21- 7.17 (1H, m), 4.98-4.93 (2H, m), 3.84-3.79 (2H, m), 3.76-3.70 (2H, m), 1.52 (3H, s).
    674 (optically active form)
    Figure US20150329491A1-20151119-C00799
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.67 (1H, s), 7.66-7.63 (1H, m), 7.44- 7.38 (3H, m), 7.36-7.27 (2H, m), 7.21-7.17 (1H, m), 4.79 (1H, s), 4.13 (2H, s), 1.15 (6H, s).
    675 (optically active form)
    Figure US20150329491A1-20151119-C00800
         		1H-NMR (DMSO-D6) δ: 8.08 (1H, d, J = 0.5 Hz), 7.68 (1H, s), 7.66-7.62 (1H, m), 7.41-7.36 (3H, m), 7.36- 7.28 (2H, m), 7.23-7.18 (1H, m), 5.08 (1H, t, J = 5.6 Hz), 3.66 (2H, d, J = 5.6 Hz), 1.55 (6H, s).
  • TABLE 1-100
    compound
    No. structural formula NMR
    676 (optically active form)
    Figure US20150329491A1-20151119-C00801
         		1H-NMR (CDCl3) δ: 7.70-7.66 (1H, m), 7.54-7.48 (2H, m), 7.32-7.21 (4H, m), 7.11- 7.09 (1H, m), 4.00 (3H, s), 2.80-2.74 (2H, m), 1.86- 1.80 (2H, m), 1.31 (6H, s).
    677 (optically active form)
    Figure US20150329491A1-20151119-C00802
         		1H-NMR (CDCl3) δ: 7.71-7.67 (1H, m), 7.59-7.57 (2H, m), 7.54-7.52 (1H, m), 7.30- 7.23 (3H, m), 7.13-7.11 (1H, m), 4.37-4.32 (2H, m), 4.13-4.07 (2H, m), 3.05 (1H, s), 3.00-2.95 (1H, m), 2.82-2.74 (2H, m), 1.87- 1.80 (2H, m), 1.31 (7H, s).
    678 (optically active form)
    Figure US20150329491A1-20151119-C00803
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.63-7.57 (1H, m), 7.61 (1H, s), 7.31-7.20 (3H, m), 7.22 (1H, s), 7.16-7.11 (1H, m), 6.82- 6.80 (1H, m), 4.64 (1H, t, J = 5.4 Hz), 3.95 (3H, s), 3.77 (2H, s), 3.29 (2H, d, J = 5.3 Hz), 0.94 (6H, s).
    679 (optically active form)
    Figure US20150329491A1-20151119-C00804
         		1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.57 (1H, m), 7.33- 7.30 (1H, m), 7.27-7.24 (2H, m), 7.22 (1H, s), 7.15-7.13 (1H, m), 6.83- 6.81 (1H, m), 4.97 (1H, t, J = 5.3 Hz), 4.65 (1H, t, J = 5.4 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.85-3.80 (2H, m), 3.77 (2H, s), 3.29 (2H, d, J = 5.3 Hz), 0.95 (6H, s).
    680 (optically active form)
    Figure US20150329491A1-20151119-C00805
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.63-7.59 (2H, m), 7.32-7.26 (3H, m), 7.26- 7.24 (1H, m), 7.23 (1H, s), 6.91-6.89 (1H, m), 4.96 (1H, t, J = 5.7 Hz), 3.95 (3H, s), 3.41 (2H, d, J = 5.6 Hz), 1.25 (3H, s), 1.24 (3H, s).
    681 (optically active form)
    Figure US20150329491A1-20151119-C00806
         		1H-NMR (CDCl3) δ: 7 .71-7.67 (1H, m), 7.58 (2H, s), 7.34-7.32 (1H, m), 7.30- 7.22 (3H, m), 6.90-6.89 (1H, m), 4.36-4.33 (2H, m), 4.13-4.09 (2H, m), 3.65- 3.61 (2H, m), 3.14 (1H, s), 3.03-2.98 (1H, m), 2.18- 2.13 (1H, m), 1.36 (3H, s), 1.33 (3H, s).
  • TABLE 1-101
    compound
    No. structural formula NMR
    682 (optically active form)
    Figure US20150329491A1-20151119-C00807
         		1H-NMR (DMSO-D6) δ: 7.70- 7.65 (1H, m), 7.57-7.53 (1H, m), 7.53-7.48 (3H, m), 7.46-7.38 (3H, m), 4.94- 4.89 (2H, m), 3.83-3.74 (4H, m), 3.23-3.19 (1H, m).
    683 (optically active form)
    Figure US20150329491A1-20151119-C00808
         		1H-NMR (DMSO-D6) δ: 7.96- 7.94 (1H, m), 7.64-7.59 (1H, m), 7.58 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.32-7.27 (3H, m), 7.16 (1H, s), 7.12-7.09 (1H, m), 4.53 (1H, t, J = 5.4 Hz), 3.95 (3H, s), 3.17 (2H, d, J = 5.5 Hz), 2.63-2.55 (2H, m), 1.53-1.44 (2H, m), 0.88 (6H, s).
    684 (optically active form)
    Figure US20150329491A1-20151119-C00809
         		1H-NMR (DMSO-D6) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.59 (1H, m), 7.61 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.37-7.24 (3H, m), 7.16 (1H, s), 7.13-7.10 (1H, m), 4.96 (1H, t, J = 5.2 Hz), 4.53 (1H, t, J = 5.4 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.85-3.79 (2H, m), 3.17 (2H, d, J = 5.3 Hz), 2.63- 2.56 (2H, m), 1.54-1.45 (2H, m), 0.88 (6H, s).
    685 (optically active form)
    Figure US20150329491A1-20151119-C00810
         		1H-NMR (DMSO-D6) δ: 8.11- 8.05 (1H, m), 7.91-7.86 (1H, m), 7.83-7.78 (1H, m), 7.75-7.70 (1H, m), 7.63 (1H, s), 7.51-7.45 (2H, m), 4.91-4.86 (2H, m), 3.89- 3.75 (4H, m), 3.31-3.23 (1H, m).
    686 (optically active form)
    Figure US20150329491A1-20151119-C00811
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, s), 7.64-7.58 (1H, m), 7.61 (1H, s), 7.44-7.35 (2H, m), 7.33-7.22 (2H, m), 7.18-7.13 (2H, m), 4.96 (2H, t, J = 5.4 Hz), 3.85- 3.78 (2H, m), 3.77-3.70 (2H, m), 2.39 (3H, s), 1.52 (3H, s).
  • TABLE 1-102
    compound
    No. structural formula NMR
    687 (optically active form)
    Figure US20150329491A1-20151119-C00812
         		1H-NMR (DMSO-D6) δ: 8.10 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz), 7.66- 7.62 (1H, m), 7.47-7.44 (1H, m), 7.40-7.37 (2H, m), 7.36-7.28 (2H, m), 7.22- 7.18 (1H, m), 4.78 (1H, s), 1.63 (3H, s), 1.63 (3H, s), 1.08 (3H, s), 1.07 (3H, s).
    688 (optically active form)
    Figure US20150329491A1-20151119-C00813
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.63-7.57 (1H, m), 7.61 (1H, s), 7.30-7.24 (3H, m), 7.22 (1H, s), 7.17-7.14 (1H, m), 6.84- 6.80 (1H, m), 4.66 (1H, br s), 3.95 (3H, s), 3.78 (2H, s), 1.22 (3H, s), 1.22 (3H, s).
    689 (optically active form)
    Figure US20150329491A1-20151119-C00814
         		1H-NMR (DMSO-D6) δ: 7-97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.61- 7.56 (1H, m), 7.34-7.30 (1H, m), 7.29-7.23 (2H, m), 7.21 (1H, s), 7.17-7.13 (1H, m), 6.85-6.82 (1H, m), 4.96 (1H, t, J = 5.3 Hz), 4.65 (1H, s), 4.25 (2H, t, J = 5.6 Hz), 3.84-3.80 (2H, m), 3.79 (2H, s), 1.22 (3H, s), 1.22 (3H, s).
    690 (optically active form)
    Figure US20150329491A1-20151119-C00815
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, s), 7.64-7.59 (2H, m), 7.44-7.40 (1H, m), 7.33- 7.21 (3H, m), 7.17 (1H, s), 7.15-7.10 (2H, m), 4.27 (2H, t, J = 6.5 Hz), 3.02- 2.95 (2H, m), 2.92-2.89 (3H, m), 2.37 (3H, s), 2.10-2.01 (2H, m).
    691 (optically active form)
    Figure US20150329491A1-20151119-C00816
         		1H-NMR (DMSO-D6) δ: 16.09 (1H, br s), 8.01 (1H, d, J = 0.7 Hz), 7.65-7.60 (1H, m), 7.63 (1H, d, J = 0.7 Hz), 7.45-7.42 (1H, m), 7.33-7.23 (3H, m), 7.20- 7.16 (1H, m), 7.15-7.11 (1H, m), 4.32 (2H, t, J = 6.6 Hz), 2.93 (2H, t, J = 7.7 Hz), 2.39 (3H, s), 2.36-2.27 (2H, m).
  • TABLE 1-103
    compound
    No. structural formula NMR
    692 (optically active form)
    Figure US20150329491A1-20151119-C00817
         		1H-NMR (DMSO-D6) δ: 8.13- 8.10 (1H, m), 7.77-7.73 (1H, m), 7.67-7.63 (1H, m), 7.44-7.40 (2H, m), 7.38- 7.28 (3H, m), 7.18-7.14 (1H, m), 6.83-6.78 (1H, m), 4.61-4.48 (2H, m), 4.42- 4.31 (1H, m).
    693 (optically active form)
    Figure US20150329491A1-20151119-C00818
         		1H-NMR (DMSO-D6) δ: 8.17 (1H, s), 7.72 (1H, s), 7.66-7.62 (1H, m), 7.46- 7.38 (3H, m), 7.36-7.27 (3H, m), 7.25-7.20 (1H, m), 7.02 (1H, br s), 1.80 (3H, s), 1.79 (3H, s).
    694 (optically active form)
    Figure US20150329491A1-20151119-C00819
         		1H-NMR (DMSO-D6) δ: 8.16 (1H, d, J = 0.7 Hz), 7.73 (1H, d, J = 0.4 Hz), 7.66- 7.63 (1H, m), 7.52-7.47 (1H, m), 7.43-7.38 (3H, m), 7.36-7.29 (2H, m), 7.24- 7.20 (1H, m), 2.63 (3H, d, J = 4.6 Hz), 1.79 (3H, s), 1.79 (3H, s).
    695 (optically active form)
    Figure US20150329491A1-20151119-C00820
         		1H-NMR (DMSO-D6) δ: 8.23 (1H, s), 7.80 (1H, s), 7.68-7.63 (1H, m), 7.44- 7.40 (2H, m), 7.37-7.31 (3H, m), 7.25-7.21 (1H, m), 3.00-2.20 (6H, m), 1.77 (3H, s), 1.77 (3H, s).
    696 (optically active form)
    Figure US20150329491A1-20151119-C00821
         		1H-NMR (CDCl3) δ: 7.69-7.65 (1H, m), 7.54 (1H, s), 7.51-7.49 (2H, m), 7.28- 7.19 (3H, m), 7.10-7.07 (1H, m), 4.34-4.29 (2H, m), 4.31 (3H, s), 3.20 (1H, s), 2.94 (2H, t, J = 7.2 Hz), 2.46-2.38 (2H, m), 2.42 (3H, s).
  • TABLE 1-104
    compound
    No. structural formula NMR
    697 (optically active form)
    Figure US20150329491A1-20151119-C00822
         		1H-NMR (CDCl3) δ: 7.69-7.66 (1H, m), 7.63 (1H, s), 7.55 (1H, s), 7.51-7.49 (1H, m), 7.31-7.20 (3H, m), 7.09- 7.08 (1H, m), 4.40 (2H, t, J = 6.4 Hz), 4.01 (3H, s), 2.93 (2H, t, J = 7.1 Hz), 2.78 (1H, s), 2.58-2.51 (2H, m), 2.43 (3H, s).
    698 (optically active form)
    Figure US20150329491A1-20151119-C00823
         		1H-NMR (CDCl3) δ: 7.72-7.67 (1H, m), 7.56-7.52 (1H, m), 7.48 (1H, s), 7.45 (1H, s), 7.33-7.21 (3H, m), 7.11 (1H, s), 3.99 (3H, s), 3.38 (1H, s), 2.84 (1H, d, J = 13.0 Hz), 2.80 (1H, d, J = 13.2 Hz), 1.43 (1H, br s), 1.28 (3H, s), 1.25 (3H, s).
    699 (optically active form)
    Figure US20150329491A1-20151119-C00824
         		1H-NMR (CDCl3) δ: 7.71-7.67 (1H, m), 7.56 (1H, s), 7.53 (1H, s), 7.47-7.44 (1H, m), 7.31-7.20 (3H, m), 7.04- 7.02 (1H, m), 4.35-4.31 (2H, m), 4.11-4.07 (2H, m), 3.10 (1H, br s), 2.96-2.91 (1H, m), 2.56 (2H, s), 0.95 (9H, s).
    700 (optically active form)
    Figure US20150329491A1-20151119-C00825
         		1H-NMR (CDCl3) δ: 7.94-7.92 (1H, m), 7.77-7.72 (1H, m), 7.64 (1H, s), 7.63 (1H, s), 7.59-7.57 (1H, m), 7.44- 7.30 (3H, m), 4.40-4.34 (2H, m), 4.15-4.06 (2H, m), 3.19 (1H, br s), 2.83 (1H, t, J = 5.8 Hz).
    701 (optically active form)
    Figure US20150329491A1-20151119-C00826
         		1H-NMR (CDCl3) δ: 8.24-8.22 (1H, m), 7.89-7.86 (1H, m), 7.77-7.73 (1H, m), 7.63 (2H, s), 7.41-7.36 (2H, m), 7.32-7.27 (1H, m), 4.38- 4.35 (2H, m), 4.14-4.09 (2H, m), 3.23 (1H, br s), 2.94 (1H, t, J = 5.9 Hz), 2.65 (3H, s).
  • TABLE 1-105
    compound
    No. structural formula NMR
    702 (optically active form)
    Figure US20150329491A1-20151119-C00827
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 0.7 Hz), 7.65- 7.58 (2H, m), 7.62 (1H, d, J = 0.7 Hz), 7.42-7.24 (5H, m), 7.19 (1H, s), 4.98-4.92 (2H, m), 3.84-3.79 (2H, m), 3.77-3.70 (2H, m), 1.52 (3H, s).
    703 (optically active form)
    Figure US20150329491A1-20151119-C00828
         		1H-NMR (DMSO-D6) δ: 8.05 (1H, d, J = 0.7 Hz), 7.70 (1H, d, J = 0.7 Hz), 7.65- 7.61 (1H, m), 7.51-7.47 (1H, m), 7.40-7.36 (2H, m), 7.35-7.30 (1H, m), 7.29- 7.24 (1H, m), 7.21-7.17 (1H, m), 4.83 (3H, t, J = 5.4 Hz), 3.90 (6H, d, J = 5.6 Hz).
    704 (optically active form)
    Figure US20150329491A1-20151119-C00829
         		1H-NMR (DMSO-D6) δ: 8.04 (1H, d, J = 0.7 Hz), 7.69 (1H, d, J = 0.7 Hz), 7.66- 7.62 (1H, m), 7.42-7.37 (2H, m), 7.38 (1H, s), 7.36-7.31 (1H, m), 7.29- 7.25 (1H, m), 7.21-7.16 (1H, m), 4.90-4.86 (2H, m), 3.91-3.81 (4H, m), 1.92 (2H, q, J = 7.4 Hz), 0.75 (3H, t, J = 7.5 Hz).
    705 (optically active form)
    Figure US20150329491A1-20151119-C00830
         		1H-NMR (DMSO-D6) δ: 8.01 (1H, s), 7.68 (1H, s), 7.66-7.61 (1H, m), 7.45- 7.37 (2H, m), 7.36-7.27 (3H, m), 7.20-7.15 (1H, m), 4.66-4.52 (3H, m), 3.42- 3.29 (2H, m), 3.27-3.15 (2H, m), 2.13-2.01 (2H, m), 1.99-1.86 (2H, m).
    706 (optically active form)
    Figure US20150329491A1-20151119-C00831
         		1H-NMR (DMSO-D6) δ: 7.98 (1H, d, J = 0.7 Hz), 7.65- 7.59 (2H, m), 7.64 (1H, s), 7.49-7.46 (1H, m), 7.41- 7.36 (1H, m), 7.35-7.30 (2H, m), 7.28-7.23 (1H, m), 7.19 (1H, s), 4.82 (3H, t, J = 5.4 Hz), 3.92 (6H, d, J = 5.5 Hz).
  • TABLE 1-106
    com-
    pound
    No. structural formula NMR
    707 (op- tically active form)
    Figure US20150329491A1-20151119-C00832
         		1H-NMR (DMSO-D6) δ: 7.96 (1H, d, J = 0.7 Hz), 7.63-7.59 (1H, m), 7.62 (1H, d, J = 0.7 Hz), 7.46-7.40 (2H, m), 7.31-7.21 (2H, m), 7.14 (2H, s), 4.82 (3H, t, J = 5.6 Hz), 3.91 (6H, d, J = 5.6 Hz), 2.39 (3H, s).
  • Among these compounds, compound Nos. 42-44, 56, 57, 72, 73 and 143 are Reference Examples.
  • Among the above-mentioned optically active compounds, the structural formulas of the compounds having a specified absolute configuration are shown in the following Table 2-1 to 2-11.
  • TABLE 2-1
    compound structural formula
    No. (absolute configuration)
    520
    Figure US20150329491A1-20151119-C00833
    526
    Figure US20150329491A1-20151119-C00834
    529
    Figure US20150329491A1-20151119-C00835
    531
    Figure US20150329491A1-20151119-C00836
    532
    Figure US20150329491A1-20151119-C00837
  • TABLE 2-2
    compound structural formula
    No. (absolute configuration)
    533
    Figure US20150329491A1-20151119-C00838
    534
    Figure US20150329491A1-20151119-C00839
    537
    Figure US20150329491A1-20151119-C00840
    538
    Figure US20150329491A1-20151119-C00841
    539
    Figure US20150329491A1-20151119-C00842
  • TABLE 2-3
    compound structural formula
    No. (absolute configuration)
    543
    Figure US20150329491A1-20151119-C00843
    544
    Figure US20150329491A1-20151119-C00844
    545
    Figure US20150329491A1-20151119-C00845
    546
    Figure US20150329491A1-20151119-C00846
    548
    Figure US20150329491A1-20151119-C00847
  • TABLE 2-4
    compound structural formula
    No. (absolute configuration)
    549
    Figure US20150329491A1-20151119-C00848
    550
    Figure US20150329491A1-20151119-C00849
    551
    Figure US20150329491A1-20151119-C00850
    565
    Figure US20150329491A1-20151119-C00851
    566
    Figure US20150329491A1-20151119-C00852
  • TABLE 2-5
    compound structural formula
    No. (absolute configuration)
    574
    Figure US20150329491A1-20151119-C00853
    575
    Figure US20150329491A1-20151119-C00854
    576
    Figure US20150329491A1-20151119-C00855
    595
    Figure US20150329491A1-20151119-C00856
    605
    Figure US20150329491A1-20151119-C00857
  • TABLE 2-6
    compound structural formula
    No. (absolute configuration)
    606
    Figure US20150329491A1-20151119-C00858
    607
    Figure US20150329491A1-20151119-C00859
    610
    Figure US20150329491A1-20151119-C00860
    663
    Figure US20150329491A1-20151119-C00861
  • TABLE 2-7
    compound structural formula
    No. (absolute configuration)
    670
    Figure US20150329491A1-20151119-C00862
    672
    Figure US20150329491A1-20151119-C00863
    673
    Figure US20150329491A1-20151119-C00864
    674
    Figure US20150329491A1-20151119-C00865
    675
    Figure US20150329491A1-20151119-C00866
  • TABLE 2-8
    compound structural formula
    No. (absolute configuration)
    682
    Figure US20150329491A1-20151119-C00867
    685
    Figure US20150329491A1-20151119-C00868
    686
    Figure US20150329491A1-20151119-C00869
    687
    Figure US20150329491A1-20151119-C00870
    690
    Figure US20150329491A1-20151119-C00871
  • TABLE 2-9
    compound structural formula
    No. (absolute configuration)
    691
    Figure US20150329491A1-20151119-C00872
    692
    Figure US20150329491A1-20151119-C00873
    693
    Figure US20150329491A1-20151119-C00874
    694
    Figure US20150329491A1-20151119-C00875
  • TABLE 2-10
    compound structural formula
    No. (absolute configuration)
    695
    Figure US20150329491A1-20151119-C00876
    696
    Figure US20150329491A1-20151119-C00877
    697
    Figure US20150329491A1-20151119-C00878
    702
    Figure US20150329491A1-20151119-C00879
  • TABLE 2-11
    compound structural formula
    No. (absolute configuration)
    703
    Figure US20150329491A1-20151119-C00880
    704
    Figure US20150329491A1-20151119-C00881
    705
    Figure US20150329491A1-20151119-C00882
    706
    Figure US20150329491A1-20151119-C00883
    707
    Figure US20150329491A1-20151119-C00884
  • The Formulation Examples of the present invention include the following preparations, which are not to be construed as limitative.
    • Formulation Example 1 Production of Capsule
  • 1) compound of Example 1 30 mg
    2) microcrystalline cellulose 10 mg
    3) lactose 19 mg
    4) magnesium stearate  1 mg
  • 1), 2), 3) and 4) are mixed and filled in a gelatin capsule.
    • Formulation Example 2 Production of Tablet
  • 1) compound of Example 1 10 g
    2) lactose 50 g
    3) cornstarch 15 g
    4) carmellose calcium 44 g
    5) magnesium stearate  1 g
  • The total amount of 1), 2) and 3), and 30 g of 4) are kneaded with water, dried in vacuo and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and the mixture is tableted by a tableting machine, whereby 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained.
    • Experimental Example 1 Inhibitory Action of PDHK Activity In Vitro
  • The inhibitory action of PDHK activity was indirectly evaluated by performing a kinase reaction in the presence of a test compound and measuring the residual PDH activity.
  • In the case of human PDHK2 (hPDHK2, Genbank Accession No. NM—002611), modified hPDHK2 cDNA wherein FLAG-Tag sequence is added to the N terminal by a polymerase linkage reaction was prepared based on hPDHK2 cDNA clone (pReceiver-M01/PDK2-GeneCopoeia), and cloned into a vector (pET17b-Novagen). The recombinant construct was transformed into Escherichia coli (DH5α-TOYOBO). The recombinant clones were identified, plasmid DNA was isolated and subjected to the DNA sequence analysis. One clone which had the expected nucleic acid sequence was selected for expression work.
  • For expression of hPDHK2 activity, Escherichia coli strain BL21(DE3) cells (Novagen) were transformed with the pET17b vector containing modified hPDHK2 cDNA. Escherichia coli were grown to an optical density 0.6 (600 nmol/L) at 30° C. Protein expression was induced by the addition of 500 μmol/L isopropyl-β-thiogalactopyranoside. Escherichia coli were cultured at 30° C. for 5 hr and harvested by centrifugation. Resuspension of the Escherichia coli paste was disrupted by a microfluidizer. FLAG-Tagged protein was separated using FLAG affinity gel (Sigma). The gel was washed with 20 mmol/L N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid-sodium hydroxide (HEPES-NaOH), 500 mmol/L sodium chloride, 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0), and the binding protein was eluted with 20 mmol/L HEPES-NaOH, 100 μg/mL FLAG peptide, 500 mmol/L sodium chloride, 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0). The eluted fractions containing FLAG-Tagged protein were pooled, dialyzed against 20 mmol/L HEPES-NaOH, 150 mmol/L sodium chloride, 0.5 mmol/L ethylenediaminetetraacetic acid (EDTA), 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0), and preserved at −80° C. During the assay, the hPDHK2 enzyme concentration was set to the minimal concentration at which PDH is inhibited the most.
  • 0.05 U/mL PDH (porcine heart PDH complex, Sigma P7032) and 1.6 μg/mL hPDHK2 were mixed in a buffer (50 mmol/L 3-morpholinopropanesulfonic acid (pH 7.0), 20 mmol/L dipotassium hydrogen phosphate, 60 mmol/L potassium chloride, 2 mmol/L magnesium chloride, 0.4 mmol/L EDTA, and 0.2% Pluronic F-68, 2 mmol/L dithiothreitol), the mixture was incubated at 4° C. overnight to give PDH/hPDHK2 complex. The test compound was diluted with dimethyl sulfoxide (DMSO). PDH/hPDHK2 complex (20 μL), test compound (1.5 μL) and 3.53 μmol/L ATP (diluted with buffer, 8.5 μL) were added to a half area 96 well UV-transparent microplate (Corning 3679), and PDHK reaction was performed at room temperature for 45 min. Instead of the test compound, DMSO (1.5 μL) was added to a control well. DMSO (1.5 μL) was added instead of the test compound to a blank well for the measurement of the maximum rate of PDH reaction, and hPDHK2 was not added. Than, 10 μL of substrates (5 mmol/L sodium pyruvate, 5 mmol/L Coenzyme A, 12 mmol/L NAD, and 5 mmol/L thiamine pyrophosphate, diluted with buffer) was added. The mixture was incubated at room temperature for 90 min, and the residual PDH activity was measured. The absorbance at 340 nm before and after PDH reaction was measured on a microplate reader to detect NADH produced by the PDH reaction. The PDHK inhibitory rate (%) of the test compound was calculated from the formula [{(PDH activity of test compound−PDH activity of control)/PDH activity of blank−PDH activity of control)}×100]. The IC50 value was calculated from the concentrations of the test compound at two points enclosing 50% inhibition of the PDHK activity.
  • The obtained results are shown in the following Table 3-1-Table 3-29. In the Tables, the inhibitory activity of the compound is shown as follows. +++: IC50 (μmol/L) of less than 0.1 μmol/L, ++: not less than 0.1 μmol/L and less than 1 μmol/L, +: not less than 1 μmol/L. The compounds for which the measurement was not conducted is shown as ND.
  • TABLE 3-1
    PDHK inhibitory activity
    compound No. IC50 (μmol/L)
    1 + 2.208
    2 + 2.286
    3 + 1.567
    4 + 2.292
    5 + 1.169
    6 + 2.294
    7 + 1.435
    8 + 45.643
    9 + 20.040
    10 + 30.793
    11 + 6.792
    12 + 5.495
    13 + 15.876
    14 + 56.574
    15 + 16.312
    16 + 19.303
    17 + 13.871
    18 ++ 0.457
    19 + >100
    20 + 3.497
    21 ++ 0.302
    22 + 16.691
    23 ++ 0.571
    24 + >100
    25 + 30.863
  • TABLE 3-2
    PDHK inhibitory activity
    compound No. IC50 (μmol/L)
    26 + 17.596
    27 ++ 0.848
    28 + 2.815
    29 + 5.739
    30 + 8.609
    31 + 1.353
    32 + >100
    33 + 1.814
    34 + 33.181
    35 + >100
    36 ++ 0.626
    37 + 3.959
    38 + 12.022
    39 + 4.522
    40 + 2.469
    41 + 68.593
    42 + 5.564
    43 + 3.920
    44 + >100
    45 ++ 0.247
    46 + 6.486
    47 + 4.909
    48 ++ 0.639
    49 + 1.787
    50 ++ 0.100
  • TABLE 3-3
    PDHK inhibitory activity
    compound No. IC50 (μmol/L)
    51 + 2.590
    52 + 4.010
    53 ++ 0.567
    54 + 21.913
    55 + 19.786
    56 + >100
    57 + 5.621
    58 ++ 0.195
    59 ++ 0.772
    60 + 2.037
    61 ++ 0.294
    62 + 15.728
    63 + 8.484
    64 + 17.963
    65 + >100
    66 + 66.305
    67 + 4.199
    68 ++ 0.624
    69 + 16.015
    70 + 2.213
    71 + 10.220
    72 + 4.424
    73 + 4.814
    74 + 3.317
    75 + 6.783
  • TABLE 3-4
    PDHK inhibitory activity
    compound No. IC50 (μmol/L)
    76 + 1.754
    77 + 2.497
    78 + 1.358
    79 ++ 0.696
    80 + 8.245
    81 + 2.762
    82 + 67.348
    83 + 1.141
    84 + 42.066
    85 + 23.099
    86 ++ 0.378
    87 ++ 0.669
    88 + 2.526
    89 + 2.147
    90 ++ 0.474
    91 +++ 0.072
    92 ++ 0.405
    93 + 29.507
    94 +++ 0.049
    95 + 7.831
    96 + 6.568
    97 ++ 0.849
    98 + 2.423
    99 ++ 0.718
    100 + 6.148
  • TABLE 3-5
    PDHK inhibitory activity
    compound No. IC50 (μmol/L)
    101 + 10.296
    102 ++ 0.323
    103 ++ 0.151
    104 ++ 0.279
    105 ++ 0.259
    106 ++ 0.461
    107 + 2.613
    108 ++ 0.462
    109 + 1.317
    110 + 2.488
    111 + >10
    112 + 1.230
    113 + 1.113
    114 +++ 0.051
    115 ++ 0.417
    116 ++ 0.601
    117 ++ 0.909
    118 ++ 0.839
    119 + 1.005
    120 ++ 0.174
    121 + 3.676
    122 +++ 0.049
    123 ++ 0.877
    124 ++ 0.736
    125 ++ 0.227
  • TABLE 3-6
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    126 + >10
    127 + >10
    128 + 2.395
    129 ++ 0.864
    130 + >10
    131 + >10
    132 ++ 0.694
    133 + 2.498
    134 + >10
    135 + >1
    136 +++ 0.025
    137 + 1.007
    138 + >10
    139 + >10
    140 + 2.402
    141 +++ 0.077
    142 ++ 0.543
    143 + >10
    144 + 1.122
    145 + 1.382
    146 ++ 0.213
    147 + 1.729
    148 + 8.450
    149 + 1.220
    150 + 6.838
  • TABLE 3-7
    PDHK inhibitory activity
    compound No. IC50 (μmol/L)
    151 + 5.213
    152 +++ 0.054
    153 +++ 0.036
    154 ++ 0.309
    155 ++ 0.805
    156 ++ 0.464
    157 ++ 0.358
    158 ++ 0.221
    159 ++ 0.318
    160 + 2.538
    161 + 2.113
    162 + 2.886
    163 ++ 0.232
    164 + 2.747
    165 ++ 0.957
    166 + 5.899
    167 + 1.947
    168 + >10
    169 + 7.362
    170 + 6.735
    171 ++ 0.951
    172 ++ 0.779
    173 + >10
    174 +++ 0.066
    175 ++ 0.517
  • TABLE 3-8
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    176 + 8.013
    177 + 9.189
    178 + >10
    179 + 1.340
    180 + >10
    181 + 1.514
    182 + >10
    183 + >10
    184 + >10
    185 +++ 0.053
    186 + 5.906
    187 + 2.478
    188 ++ 0.383
    189 + 6.000
    190 + >10
    191 ++ 0.216
    192 ++ 0.182
    193 ++ 0.560
    194 ++ 0.368
    195 + 5.485
    196 ++ 0.475
    197 ++ 0.298
    198 ++ 0.126
    199 ++ 0.182
    200 ++ 0.236
  • TABLE 3-9
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    201 ++ 0.162
    202 ++ 0.247
    203 ++ 0.423
    204 + >10
    205 ++ 0.707
    206 + 2.240
    207 ++ 0.998
    208 ++ 0.677
    209 ++ 0.281
    210 + 1.327
    211 + 1.012
    212 ++ 0.685
    213 ++ 0.173
    214 ++ 0.345
    215 + 4.599
    216 + 2.565
    217 + 5.329
    218 + 1.837
    219 + >10
    220 ++ 0.488
    221 + >10
    222 + 5.391
    223 + 2.327
    224 ++ 0.214
    225 ++ 0.619
  • TABLE 3-10
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    226 + 1.142
    227 + 1.048
    228 + 2.192
    229 ++ 0.552
    230 + 3.712
    231 + 3.607
    232 + 1.988
    233 ++ 0.142
    234 +++ 0.058
    235 ++ 0.803
    236 ++ 0.355
    237 + 1.999
    238 ++ 0.252
    239 ++ 0.178
    240 ++ 0.149
    241 +++ 0.098
    242 +++ 0.086
    243 +++ 0.075
    244 + 2.929
    245 ++ 0.190
    246 ++ 0.809
    247 ++ 0.547
    248 + 1.019
    249 ++ 0.719
    250 + 1.609
  • TABLE 3-11
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    251 + >10
    252 + 1.273
    253 + 1.947
    254 + 1.131
    255 + 1.078
    256 + 1.003
    257 ++ 0.567
    258 + 2.625
    259 + 1.386
    260 + 2.813
    261 + 1.404
    262 + 1.365
    263 ++ 0.133
    264 + 1.169
    265 + 1.258
    266 + 1.556
    267 + 1.197
    268 + >10
    269 + 1.338
    270 ++ 0.533
    271 +++ 0.056
    272 ++ 0.342
    273 ++ 0.396
    274 + 7.487
    275 ++ 0.278
  • TABLE 3-12
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    276 + 1.013
    277 ++ 0.125
    278 ++ 0.862
    279 + 1.849
    280 + 1.514
    281 + 1.000
    282 ++ 0.226
    283 ++ 0.571
    284 + 1.168
    285 +++ 0.020
    286 +++ 0.017
    287 + >10
    288 ++ 0.635
    289 ++ 0.641
    290 ++ 0.793
    291 + 5.826
    292 + 2.571
    293 + 4.947
    294 ++ 0.710
    295 ++ 0.861
    296 ++ 0.180
    297 + 3.034
    298 ++ 0.177
    299 ++ 0.235
    300 ++ 0.114
  • TABLE 3-13
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    301 + 1.586
    302 + 1.167
    303 ++ 0.755
    304 ++ 0.723
    305 ++ 0.562
    306 ++ 0.453
    307 + 3.198
    308 + 2.666
    309 + >10
    310 + >10
    311 + 7.151
    312 + 1.824
    313 + >10
    314 + >10
    315 + 6.371
    316 + 4.480
    317 + 2.313
    318 ++ 0.553
    319 + 3.086
    320 + 8.765
    321 + 5.385
    322 + 2.503
    323 ++ 0.362
    324 ++ 0.203
    325 + 1.080
  • TABLE 3-14
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    326 ++ 0.303
    327 + 2.941
    328 +++ 0.078
    329 +++ 0.066
    330 ++ 0.125
    331 + 1.415
    332 ++ 0.912
    333 ++ 0.924
    334 ++ 0.674
    335 +++ 0.080
    336 + >10
    337 ++ 0.499
    338 + >1
    339 ++ 0.177
    340 + 1.594
    341 +++ 0.079
    342 +++ 0.047
    343 +++ 0.053
    344 + >1
    345 ++ 0.121
    346 ++ 0.200
    347 +++ 0.088
    348 ++ 0.634
    349 ++ 0.126
    350 ++ 0.152
  • TABLE 3-15
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    351 ++ 0.168
    352 ++ 0.109
    353 + 7.398
    354 +++ 0.071
    355 +++ 0.040
    356 +++ 0.053
    357 + 1.939
    358 +++ 0.034
    359 ++ 0.187
    360 ++ 0.548
    361 ++ 0.436
    362 + 1.077
    363 +++ 0.047
    364 ++ 0.178
    365 + 1.327
    366 + 2.170
    367 + >1
    368 ++ 0.180
    369 +++ 0.081
    370 ++ 0.114
    371 ++ 0.617
    372 ++ 0.564
    373 +++ 0.049
    374 +++ 0.049
    375 +++ 0.050
  • TABLE 3-16
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    376 +++ 0.085
    377 ++ 0.189
    378 ++ 0.703
    379 ++ 0.351
    380 + 1.490
    381 ++ 0.495
    382 ++ 0.863
    383 + 1.225
    384 ++ 0.219
    385 ++ 0.234
    386 +++ 0.089
    387 +++ 0.063
    388 +++ 0.063
    389 ++ 0.822
    390 ++ 0.954
    391 ++ 0.485
    392 ++ 0.200
    393 ++ 0.176
    394 +++ 0.058
    395 ++ 0.699
    396 ++ 0.627
    397 ++ 0.424
    398 ++ 0.119
    399 ++ 0.149
    400 + 7.077
  • TABLE 3-17
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    401 ++ 0.554
    402 + >10
    403 + >10
    404 ++ 0.195
    405 + 6.377
    406 +++ 0.025
    407 +++ 0.031
    408 +++ 0.065
    409 +++ 0.067
    410 ++ 0.154
    411 +++ 0.066
    412 +++ 0.022
    413 + 1.230
    414 +++ 0.032
    415 + 9.190
    416 ++ 0.104
    417 + >1
    418 + 6.065
    419 ++ 0.504
    420 ++ 0.225
    421 ++ 0.233
    422 +++ 0.023
    423 +++ 0.021
    424 +++ 0.023
    425 +++ 0.021
  • TABLE 3-18
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    426 +++ 0.024
    427 +++ 0.020
    428 +++ 0.025
    429 +++ 0.019
    430 +++ 0.064
    431 ++ 0.250
    432 ++ 0.247
    433 ++ 0.388
    434 ++ 0.561
    435 +++ 0.039
    436 +++ 0.065
    437 +++ 0.060
    438 ++ 0.112
    439 +++ 0.034
    440 +++ 0.032
    441 +++ 0.036
    442 +++ 0.040
    443 + 1.152
    444 + 3.934
    445 ++ 0.605
    446 ++ 0.565
    447 ++ 0.202
    448 ++ 0.381
    449 +++ 0.047
    450 ++ 0.442
  • TABLE 3-19
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    451 ++ 0.102
    452 + 2.719
    453 +++ 0.028
    454 +++ 0.064
    455 +++ 0.026
    456 +++ 0.045
    457 +++ 0.030
    458 +++ 0.039
    459 ++ 0.185
    460 +++ 0.030
    461 +++ 0.030
    462 + 5.979
    463 +++ 0.047
    464 +++ 0.042
    465 +++ 0.061
    466 +++ 0.055
    467 +++ 0.018
    468 ++ 0.327
    469 ++ 0.193
    470 ++ 0.168
    471 +++ 0.026
    472 ++ 0.184
    473 +++ 0.090
    474 +++ 0.019
    475 +++ 0.020
  • TABLE 3-20
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    476 +++ 0.053
    477 +++ 0.018
    478 ++ 0.433
    479 + >10
    480 ++ 0.553
    481 ++ 0.251
    482 +++ 0.040
    483 ++ 0.542
    484 +++ 0.024
    485 ++ 0.117
    486 +++ 0.055
    487 +++ 0.064
    488 +++ 0.052
    489 +++ 0.022
    490 ++ 0.223
    491 +++ 0.020
    492 +++ 0.040
    493 +++ 0.039
    494 +++ 0.044
    495 ++ 0.119
    496 +++ 0.023
    497 +++ 0.031
    498 +++ 0.047
    499 +++ 0.039
    500 +++ 0.031
  • TABLE 3-21
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    501 +++ 0.032
    502 +++ 0.048
    503 +++ 0.045
    504 +++ 0.019
    505 +++ 0.046
    506 +++ 0.030
    507 +++ 0.026
    508 +++ 0.048
    509 +++ 0.051
    510 +++ 0.062
    511 +++ 0.056
    512 +++ 0.038
    513 +++ 0.032
    514 +++ 0.058
    515 +++ 0.038
    516 ++ 0.110
    517 +++ 0.057
    518 +++ 0.054
    519 ++ 0.418
    520 + 3.330
    521 +++ 0.036
    522 +++ 0.061
    523 +++ 0.048
    524 +++ 0.087
    525 ++ 0.677
  • TABLE 3-22
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    526 ++ 0.397
    527 +++ 0.079
    528 +++ 0.049
    529 +++ 0.017
    530 +++ 0.043
    531 +++ 0.020
    532 +++ 0.016
    533 +++ 0.015
    534 +++ 0.016
    535 ++ 0.197
    536 +++ 0.054
    537 +++ 0.035
    538 +++ 0.026
    539 +++ 0.027
    540 +++ 0.016
    541 +++ 0.015
    542 +++ 0.015
    543 +++ 0.036
    544 +++ 0.022
    545 +++ 0.017
    546 +++ 0.015
    547 +++ 0.062
    548 +++ 0.016
    549 +++ 0.027
    550 +++ 0.069
  • TABLE 3-23
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    551 ++ 0.109
    552 +++ 0.017
    553 +++ 0.018
    554 +++ 0.020
    555 + >1
    556 +++ 0.053
    557 +++ 0.077
    558 +++ 0.081
    559 + >1
    560 ++ 0.970
    561 +++ 0.050
    562 +++ 0.059
    563 +++ 0.063
    564 ++ 0.105
    565 +++ 0.018
    566 +++ 0.021
    567 + >1
    568 +++ 0.083
    569 +++ 0.044
    570 ++ 0.110
    571 +++ 0.050
    572 ++ 0.109
    573 +++ 0.018
    574 +++ 0.052
    575 +++ 0.036
  • TABLE 3-24
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    576 +++ 0.030
    577 +++ 0.023
    578 +++ 0.078
    579 +++ 0.019
    580 +++ 0.021
    581 +++ 0.019
    582 +++ 0.021
    583 +++ 0.064
    584 +++ 0.077
    585 +++ 0.026
    586 ++ 0.513
    587 +++ 0.021
    588 +++ 0.029
    589 +++ 0.025
    590 + 5.922
    591 + >1
    592 + >1
    593 + >1
    594 +++ 0.048
    595 +++ 0.022
    596 +++ 0.041
    597 + >1
    598 ++ 0.653
    599 +++ 0.033
    600 + >1
  • TABLE 3-25
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    601 + >1
    602 + >1
    603 ++ 0.228
    604 +++ 0.035
    605 +++ 0.019
    606 +++ 0.028
    607 +++ 0.045
    608 + >1
    609 + >1
    610 +++ 0.041
    611 ++ 0.329
    612 +++ 0.047
    613 +++ 0.076
    614 +++ 0.037
    615 ++ 0.105
    616 ++ 0.192
    617 +++ 0.084
    618 +++ 0.056
    619 +++ 0.033
    620 +++ 0.065
    621 +++ 0.065
    622 +++ 0.033
    623 ++ 0.133
    624 +++ 0.014
    625 + >1
  • TABLE 3-26
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    626 ++ 0.674
    627 + >1
    628 +++ 0.058
    629 +++ 0.045
    630 +++ 0.020
    631 +++ 0.062
    632 ++ 0.195
    633 ++ 0.560
    634 ++ 0.100
    635 ++ 0.515
    636 ++ 0.239
    637 + >1
    638 ++ 0.127
    639 +++ 0.063
    640 ++ 0.732
    641 ++ 0.510
    642 + >1
    643 ++ 0.184
    644 ++ 0.130
    645 +++ 0.037
    646 +++ 0.040
    647 ++ 0.169
    648 +++ 0.044
    649 +++ 0.037
    650 +++ 0.036
  • TABLE 3-27
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    651 +++ 0.025
    652 +++ 0.036
    653 +++ 0.037
    654 +++ 0.055
    655 +++ 0.073
    656 ++ 0.172
    657 +++ 0.020
    658 +++ 0.071
    659 +++ 0.016
    660 +++ 0.017
    661 +++ 0.059
    662 +++ 0.034
    663 +++ 0.018
    664 +++ 0.015
    665 +++ 0.023
    666 +++ 0.027
    667 +++ 0.015
    668 +++ 0.017
    669 +++ 0.017
    670 ND ND
    671 + 1.443
    672 ND ND
    673 +++ 0.022
    674 +++ 0.030
    675 ND ND
  • TABLE 3-28
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    676 ND ND
    677 ND ND
    678 ND ND
    679 ND ND
    680 ND ND
    681 ND ND
    682 +++ 0.079
    683 ND ND
    684 ND ND
    685 ++ 0.338
    686 ND ND
    687 +++ 0.051
    688 ND ND
    689 ND ND
    690 ND ND
    691 +++ 0.030
    692 ND ND
    693 ND ND
    694 ND ND
    695 ND ND
    696 ND ND
    697 ND ND
    698 ND ND
    699 ND ND
    700 ND ND
  • TABLE 3-29
    compound PDHK inhibitory activity
    No. IC50 (μmol/L)
    701 ND ND
    702 +++ 0.030
    703 +++ 0.020
    704 ND ND
    705 ND ND
    706 +++ 0.031
    707 +++ 0.019
  • As is clear from the above-mentioned Experimental Example 1, the compound of the present invention has a PDHK activity inhibitory action.
  • Therefrom it is suggested that the compound of the present invention provides an effect of strong inhibition of PDHK.
  • Therefore, by inhibition of PDHK, the compound of the present invention effectively activates pyruvate dehydrogenase (PDH), and can provide an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer and the like. Moreover, the compound of the present invention can provide an agent for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.
    • INDUSTRIAL APPLICABILITY
  • The present invention is useful for the treatment or prophylaxis and the like of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer and the like. In addition, the present invention is useful for the treatment or prophylaxis and the like of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.

Claims (9)

1-35. (canceled)
36. The compound which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
Figure US20150329491A1-20151119-C00885
37. The compound which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof:
Figure US20150329491A1-20151119-C00886
38. A pharmaceutical composition comprising the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
39. A method of inhibiting PDHK in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
40. A method of inhibiting PDHK2 in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
41. A method of decreasing the blood glucose level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
42. A method of decreasing lactate level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
43. A method for the treatment or prophylaxis of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
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