WO2013157511A1 - Arylaminopyrazole derivative - Google Patents

Arylaminopyrazole derivative Download PDF

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Publication number
WO2013157511A1
WO2013157511A1 PCT/JP2013/061153 JP2013061153W WO2013157511A1 WO 2013157511 A1 WO2013157511 A1 WO 2013157511A1 JP 2013061153 W JP2013061153 W JP 2013061153W WO 2013157511 A1 WO2013157511 A1 WO 2013157511A1
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group
methyl
amino
compound
pyrazole
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PCT/JP2013/061153
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French (fr)
Japanese (ja)
Inventor
良浩 堀内
仁志 須田
潔人 澤村
広陽 藤原
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大日本住友製薬株式会社
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Publication of WO2013157511A1 publication Critical patent/WO2013157511A1/en

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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an arylaminopyrazole derivative useful as a medicine, or a pharmacologically acceptable salt thereof. More specifically, the present invention relates to a pharmaceutical composition containing an arylaminopyrazole derivative or a pharmacologically acceptable salt thereof.
  • the present invention relates to a therapeutic or prophylactic agent for a disease state involving a glucocorticoid containing the compound, or an inhibitor of 11 ⁇ hydroxysteroid dehydrogenase type 1 enzyme (hereinafter referred to as “11 ⁇ HSD1”).
  • Glucocorticoid regulates peripheral glucose metabolism and amino acid metabolism.
  • glucocorticoids are metabolized in peripheral tissues such as fat and liver in addition to being produced in the adrenal glands.
  • 11 ⁇ HSD1 is an enzyme that converts inactive cortisone into active cortisol, and is expressed mainly in fat and liver. Therefore, 11 ⁇ HSD1 is considered to be involved in glucocorticoid activation in fat and liver. Since cortisol has an action of promoting fat accumulation in adipocytes and an action of promoting gluconeogenesis in the liver, 11 ⁇ HSD1 contributes to maintaining homeostasis throughout the body by regulating glucose and lipid metabolism in the periphery. Conceivable.
  • 11 ⁇ HSD1 activity of pancreatic ⁇ cells may contribute to a decrease in insulin secretion, and that 11 ⁇ HSD1 activity may be involved in a decrease in glucose uptake of muscle cells in human muscle cells. Therefore, it is considered that the 11 ⁇ HSD1 inhibitor can directly correct hyperglycemia.
  • 11 ⁇ HSD1 is expressed in the central nervous system including the hippocampus. It is known that patients with Cushing's disease, in which glucocorticoids are excessive, and patients who have been administered dexamethasone, a type of synthetic glucocorticoid, exhibit depressive symptoms. In addition, glucocorticoid receptor antagonists are also known to be effective against depression and manic depression, and glucocorticoids in the central nervous system are deeply involved in the pathogenesis of depression and manic depression (Non-Patent Documents 3 and 4). Since 11 ⁇ HSD1 is responsible for the production of active glucocorticoids in the central nervous system, 11 ⁇ HSD1 inhibitors are expected to show efficacy in the treatment of depression and manic depression.
  • mice treated with glucocorticoid for a long time cause amyloid ⁇ protein deposition that is strongly suggested to be associated with Alzheimer-type dementia, and 11 ⁇ HSD1 gene-deficient mice have a decline in cognitive function associated with aging. It is suggested that 11 ⁇ HSD1 is also deeply involved in the regulation of cognitive function because it is suppressed and cognitive retention is enhanced (Non-Patent Documents 5 to 7). These findings suggest that 11 ⁇ HSD1 inhibitors are useful as therapeutic agents for various dementias including Alzheimer type dementia. 11 ⁇ HSD1 has also been shown to function in immune cells, and 11 ⁇ HSD1 inhibitors are also expected to have therapeutic effects on diseases caused by abnormal immune functions.
  • Patent Document 1 discloses the following formula: [Wherein, R A and R B each independently represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, or a group represented by the formula: —Rw—Rx— This represents a group represented by Ry-Rz.
  • Rw represents an alkylene group which may be substituted.
  • Rx represents a single bond, an oxygen atom, or the like.
  • Ry represents a single bond or an optionally substituted alkylene group.
  • Rz represents an optionally substituted alkyl group or the like.
  • R C represents an optionally substituted alkyl group or the like.
  • RD represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, or the like.
  • R E represents a hydrogen atom or an optionally substituted alkyl group.
  • R F represents the following formula (G1): Represents a group in which one hydrogen atom is a bond, and these groups may be further substituted. The compound represented by this is disclosed. However, since it is not disclosed at all that R A or R B has an aryl group or a heteroaryl group, the structure is different from the present invention.
  • Patent Document 2 discloses the following formula:
  • R 1 is a hydrogen atom, or a C 1-4 alkyl group (the alkyl group is unsubstituted or substituted with hydroxy or 1 to 3 fluorine atoms), and R 2 is C 1 -4 alkyl, aryl, arylmethyl, heteroaryl, heteroarylmethyl and the like, R 3 is a hydrogen atom, a halogen atom, etc., R 4 is a hydrogen atom or a C 1-4 alkyl group, and R 4 is hydrogen represents an atom or alkyl, R 5 is (CH 2) n aryl, (CH 2) n C 4-9 cycloalkyl, (CH 2) n C 5-11 bicycloalkyl or (CH 2) n C 10-14 birds Cycloalkyl and the like, and n is independently 0, 1 or 2.
  • the compound represented by this is disclosed.
  • type II diabetes impaired glucose tolerance, hyperglycemia, insulin resistance, low HDL disease, hyper LDL disease, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, Vascular stenosis, atherosclerosis, obesity, dementia, cognitive impairment, glaucoma, retinopathy, Alzheimer's disease, osteoporosis, immune disorder, metabolic syndrome, depression, anxiety, manic depression, cardiovascular disease, neurodegenerative disease, As a prophylactic or therapeutic agent capable of preventing and / or treating diseases such as Cushing's syndrome and subclinical Cushing's syndrome, development of a compound having an 11 ⁇ HSD1 inhibitory action and satisfactory as a pharmaceutical is desired.
  • an arylaminopyrazole derivative represented by the following formula (1) (hereinafter sometimes referred to as “the compound of the present invention”) has not been produced at all. It was not known at all. Therefore, the present inventors have intensively studied these derivatives in order to achieve the above-mentioned problems, and as a result, have found that the arylaminopyrazole derivative represented by the formula (1) exhibits a strong 11 ⁇ HSD1 inhibitory activity. Furthermore, as a derivative, in addition to the 11 ⁇ HSD1 inhibitory activity, the balance of properties necessary as a drug such as metabolic stability, solubility, pharmacokinetics and tissue migration (for example, migration to adipose tissue and central nervous system tissue) is achieved. An excellent group of derivatives was found and the present invention was completed.
  • the present invention is as follows.
  • Item 1 A compound represented by formula (1) or a pharmacologically acceptable salt thereof.
  • R 1 is an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group
  • R 2 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, or an optionally substituted heterocyclic group
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group
  • R 4 is an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-7 cycloalkyl group
  • R 5 is a hydroxyl group, an aminocarbonyl group, a fluorine atom or methylsulfonyl It is a group.
  • Item 2 The optionally substituted C 6-10 aryl group in R 1 and the optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group substituents are: (1) deuterium atom, (2) a halogen atom, (3) hydroxyl group, (4) a cyano group, (5) a heterocyclic group, (6) a C 3-7 cycloalkyl group, (7) C 3-7 cycloalkyloxy group, (8) C 1-4 alkyl group (the alkyl group is (A) 1 to 3 halogen atoms, (B) hydroxy, (C) C 3-6 cycloalkyloxy, (D) C 1-4 alkoxy (the alkoxy is 1 to 3 halogen atoms, It may be substituted with C 1-4 alkoxy or hydroxy.
  • C 1-6 alkylcarbonyl group (the alkyl is (A) hydroxy, (B) 1 to 3 halogen atoms, (C) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (D) C 3-6 cycloalkoxy, or (e) C 3-6 optionally substituted by cycloalkyl.
  • C 3-6 cycloalkylcarbonyl group (the cycloalkyl is (A) hydroxy, (B) 1 to 3 halogen atoms, (C) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (D) C 3-6 cycloalkoxy, (E) optionally substituted with C 1-4 alkyl, or (f) C 3-6 cycloalkyl. ), (12) C 6-10 aryl group (the aryl group is (A) a halogen atom, (B) C 1-4 alkoxy, (C) C 3-7 cycloalkyl, or (d) C 1-4 alkyl may be substituted.
  • a 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl group is (A) a halogen atom, (B) C 1-4 alkyl (which may be substituted with 1 to 3 halogen atoms), or (c) optionally substituted with C 3-6 cycloalkyl. ),
  • the compound according to item 1 or a pharmacologically acceptable salt thereof which is a group selected from the group consisting of C 1-4 alkylsulfonyl groups.
  • R 1 is a C 6-10 aryl group (the aryl group is (1) a halogen atom, (2) a C 3-7 cycloalkyl group, (3) C 1-4 alkyl group (the alkyl group is (A) 1 to 3 fluorine atoms, (B) C 1-4 alkoxy, (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ), (4) C 1-4 alkoxy group (the alkoxy group is (A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. And (5) 1 to 5 groups of the same or different types selected from the group consisting of C 1-4 alkylcarbonyl groups.
  • R 1 is a C 6-10 aryl group (the aryl group is (1) a halogen atom, (2) C 1-4 alkyl (the alkyl group may be substituted with 1 to 3 fluorine atoms), and (3) the same or different selected from the group consisting of C 1-4 alkoxy May be substituted with 1 to 5 groups. Or a pharmacologically acceptable salt thereof.
  • R 1 is a 5-membered or 6-membered monocyclic heteroaryl group (the heteroaryl group is (1) a halogen atom, (2) a C 3-7 cycloalkyl group, (3) C 1-4 alkyl group (the alkyl group is (A) 1 to 3 fluorine atoms, (B) C 1-4 alkoxy, (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ), (4) C 1-4 alkoxy group (the alkoxy group is (A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. ), And (5) may be substituted with at least one or more substituents selected from the group consisting of C 1-4 alkylcarbonyl groups. Or a pharmacologically acceptable salt thereof.
  • the heteroaryl group is (1) a halogen atom, (2) a C 3-7 cycloal
  • R 1 is a 5-membered or 6-membered monocyclic heteroaryl group (the heteroaryl group is It may be substituted with at least one or more substituents selected from the group consisting of (1) a halogen atom, and (2) a C 1-4 alkyl group.
  • Item 6 The compound according to Item 5, or a pharmacologically acceptable salt thereof.
  • Item 7 The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a) to (d): [Wherein (a) to (d) may be substituted with a substituent defined in any one of Items 5 or 6. ] Item 7.
  • Item 8 The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a): [Here, (a) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
  • Item 8 The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
  • Item 9 The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a1): [Here, (a1) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
  • Item 9 The compound according to Item 8, which is a group represented by: or a pharmacologically acceptable salt thereof.
  • Item 10 The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (b): [Here, (b) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
  • Item 8 The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
  • Item 11 The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (c): [Here, (c) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
  • Item 8 The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
  • Item 12 The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (d): [Wherein (d) may be substituted with a substituent defined in any one of Items 5 or 6. ]
  • Item 8 The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
  • R 2 is a C 1-6 alkyl group (the group is (1) 1 to 5 halogen atoms, It may be substituted with (2) C 3-6 cycloalkyl or (3) C 1-4 alkoxy. 13.
  • Item 14 The compound according to Item 13, or a pharmacologically acceptable salt thereof, wherein R 2 is a methyl group or an ethyl group.
  • R 3 is (1) a hydrogen atom, (2) a halogen atom, or (3) a C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. 15. The compound according to any one of Items 1 to 14, or a pharmacologically acceptable salt thereof.
  • Item 16 The compound according to any one of Items 1 to 15, or a pharmacologically acceptable salt thereof, wherein R 3 is a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group.
  • Item 17 The compound according to Item 16, or a pharmacologically acceptable salt thereof, wherein R 3 is a hydrogen atom.
  • R 4 is (1) C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. ), Or (2) The compound according to any one of Items 1 to 17, which is a C 3-6 cycloalkyl group, or a pharmacologically acceptable salt thereof.
  • Item 19 The compound according to Item 18 or a pharmacologically acceptable salt thereof, wherein R 4 is a methyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, or an ethyl group. salt.
  • Item 20 The compound according to Item 19, or a pharmacologically acceptable salt thereof, wherein R 4 is an ethyl group.
  • Item 21 The compound according to any one of Items 1 to 20, or a pharmacologically acceptable salt thereof, wherein R 5 is a hydroxyl group.
  • Item 22 The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 is an aminocarbonyl group.
  • Item 23 The compound according to any one of Items 1 to 20, or a pharmacologically acceptable salt thereof, wherein R 5 is a methylsulfonyl group.
  • Item 24 The following compound group: 4-chloro-5-[(5-chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide , 5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide; 5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide; 1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- ⁇ methyl [4- (trifluoromethyl) -2-pyridinyl] amino ⁇ -1H-pyrazole-3
  • Item 25 The following compound group: 5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide; 5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide; 1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- ⁇ methyl [4- (trifluoromethyl) -2-pyridinyl] amino ⁇ -1H-pyrazole-3-carboxamide; 1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3
  • Item 26 A pharmaceutical composition comprising the compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient.
  • Item 27 Type II diabetes, glucose intolerance, hyperglycemia, insulin resistance, lipid metabolism abnormality containing the compound according to any one of items 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient
  • Disease hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atherosclerosis, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or epilepsy A treatment for depression.
  • Item 28 Glaucoma, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or manic depression containing the compound according to any one of items 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic agent.
  • Item 29 Type II diabetes, impaired glucose tolerance, hyperglycemia, insulin resistance, dyslipidemia, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular Item 26.
  • Item 30 The compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof for producing a therapeutic agent for glaucoma, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or manic depression Salt used.
  • Item 31 Type II diabetes, impaired glucose tolerance, comprising administering an effective amount of the compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof to a subject in need thereof Hyperglycemia, insulin resistance, dyslipidemia, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atherosclerosis, cognitive impairment, Treatment of dementia, Alzheimer's disease, depression, anxiety or manic depression.
  • Item 32 Glaucoma, cognitive impairment, dementia, comprising administering to a subject in need thereof an effective amount of the compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof. How to treat, Alzheimer's disease, depression, anxiety or manic depression.
  • the compound represented by the formula (1) or a pharmacologically acceptable salt thereof is useful as an 11 ⁇ HSD1 inhibitor.
  • the number of carbons in the definition of “substituent” may be expressed as “C 1-6 ”, for example.
  • C 1-6 alkyl is synonymous with an alkyl group having 1 to 6 carbon atoms.
  • a group that does not specifically indicate the term “optionally substituted” or “substituted” means an “unsubstituted” group.
  • C 1-6 alkyl means “unsubstituted C 1-6 alkyl”.
  • group means a monovalent group.
  • alkyl group means a monovalent saturated hydrocarbon group.
  • group may be omitted.
  • the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. Unless otherwise specified, the definition of each group also applies when the group is a part of another group or a substituent of another group.
  • Halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
  • C 1-6 alkyl group means a straight chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is a “C 1-4 alkyl group”. Specific examples of “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 3-7 cycloalkyl group means a cyclic saturated or unsaturated hydrocarbon group having 3 to 7 carbon atoms. Preferred is “C 3-6 cycloalkyl group”. Specific examples of “C 3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.
  • C 6-10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms.
  • a “C 6 aryl group” (that is, phenyl) is preferred.
  • Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • C 6 aryl contains one or more (for example, 1 to 4) of the same or different hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom. Also included are groups fused to membered to seven membered rings, or five to seven membered cycloalkyl rings (eg, cyclopentane, cyclohexane or cycloheptane). Specific examples of the group include groups represented by the following formulas.
  • the condensed C 6-10 aryl group is bonded to other “groups” only on the aromatic ring.
  • the following formula The “C 6-10 aryl group” represented by the formula means that it is bonded to another “group” at the 4-, 5-, 6-, or 7-position.
  • the “C 7-14 aralkyl group” means a “C 6-10 aryl C 1-4 alkyl group”, and the “C 1-4 alkyl group” is substituted with the “C 6-10 aryl group”. Means group. Of these, a “C 7-10 aralkyl group” (that is, a C 6 aryl C 1-4 alkyl group) is preferable. Specific examples of “C 7-14 aralkyl group” include, for example, benzyl, 2-phenylethyl, 1-phenylpropyl, 1-naphthylmethyl and the like.
  • the C 1-4 alkyl moiety in the aralkyl group may form a ring with 2-3 carbons on any one carbon of the alkyl moiety.
  • Specific examples of such aralkyl groups include, for example, the following groups The group etc. which are represented by these are mentioned.
  • heteroaryl group examples include a 5- to 12-membered monocyclic or polycyclic aromatic group, and the group is the same or different selected from a nitrogen atom, a sulfur atom or an oxygen atom. 1 or more (for example, 1 to 4) heteroatoms.
  • the “monocyclic heteroaryl group” is preferably a 5-membered or 6-membered group.
  • polycyclic heteroaryl group a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable.
  • the polycyclic heteroaryl group includes a condensed ring of the monocyclic heteroaryl group and an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, etc.).
  • aromatic ring benzene, pyridine, etc.
  • non-aromatic ring cyclohexyl, etc.
  • heteroaryl group include a group represented by the following formula.
  • the straight line across the ring in the above formula means that the “group” is bonded to another group at a substitutable position.
  • the heteroaryl group represented by the formula means 2-furyl group or 3-furyl group.
  • heteroaryl group is a polycyclic heteroaryl group, for example, the following formula
  • the heteroaryl group represented by may be 4-, 5-, 6- or 7-benzofuryl.
  • a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (such as piperidine) are condensed has a bond of the “group” only in the aromatic ring.
  • the “polycyclic heteroaryl group” represented by the above means that the “group” is bonded to another group at the 2-, 3-, or 4-position.
  • the “heteroaryl group” is preferably a 5- to 10-membered monocyclic or polycyclic heteroaryl group, more preferably a 5- or 6-membered monocyclic heteroaryl group.
  • heterocyclic group examples include a 3- to 7-membered heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • the nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring.
  • the heterocyclic group may be either saturated or partially unsaturated.
  • the nitrogen atom constituting the ring in the group does not have a bond with another “group”. That is, the group does not include concepts such as a 1-pyrrolidino group.
  • the “heterocyclic group” may be a condensed ring with a 6-membered aromatic hydrocarbon or 6-membered heteroaryl.
  • the heterocyclic group include a bicyclic 9-membered or 10-membered “condensed heterocyclic group” and a 6-membered aromatic hydrocarbon or 6-membered heteroaryl.
  • the 6-membered aromatic hydrocarbon include benzene.
  • 6-membered heteroaryl include pyridine, pyrimidine or pyridazine.
  • heterocyclic group examples include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, tetrahydroquinolinyl, decainyl. Examples thereof include hydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.
  • the “heterocyclic group” is preferably a saturated heterocyclic group, and more preferably a 5-membered or 6-membered saturated heterocyclic group.
  • C 1-6 alkyl part of the “C 1-6 alkoxy group” has the same meaning as the above “C 1-6 alkyl”. Preferred is a “C 1-4 alkoxy group”. Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 6-10 aryl part of the “C 6-10 arylthio group” has the same meaning as the above “C 6-10 aryl”.
  • Specific examples of “C 6-10 arylthio group” include, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
  • C 1-6 alkyl part of the “C 1-6 alkylsulfonyl group” has the same meaning as the above “C 1-6 alkyl”. Preferably, it is “C 1-4 alkylsulfonyl group”. Specific examples of “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
  • C 3-6 cycloalkyl part of the “C 3-6 cycloalkylsulfonyl group” has the same meaning as the above “C 3-6 cycloalkyl”. Specific examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.
  • C 6-10 aryl part of the “C 6-10 arylsulfonyl group” has the same meaning as the above “C 6-10 aryl”. Specific examples include phenylsulfonyl, 1-naphthylsulfonyl and the like.
  • C 3-7 cycloalkyl part of the “C 3-7 cycloalkoxy group” has the same meaning as the above “C 3-7 cycloalkyl”. Preferably, it is “C 3-6 cycloalkoxy group”. Specific examples of “C 3-7 cycloalkoxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 6-10 aryl part of the “C 6-10 aryloxy group” has the same meaning as the above “C 6-10 aryl”. “C 6 aryloxy” (ie, phenyloxy) is preferred. Specific examples of “C 6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • C 7-14 aralkyl moiety of the "C 7-14 aralkyloxy group” (i.e., C 6-10 aryl C 1-4 alkyloxy group) is the same as defined in the "C 7-14 aralkyl".
  • Preferable examples include “C 7-10 aralkyloxy group” (that is, “phenyl C 1-4 alkyloxy group”) and the like.
  • Specific examples of “C 7-14 aralkyloxy group” include, for example, benzyloxy, phenethyloxy, naphthylmethyloxy and the like.
  • the “5- to 12-membered monocyclic or polycyclic heteroaryl” part of the “5- to 12-membered monocyclic or polycyclic heteroaryloxy group” has the same meaning as described above. “C 6 aryloxy” (ie, phenyloxy) is preferred. Specific examples of “5- to 12-membered monocyclic or polycyclic heteroaryloxy group” include pyridyloxy and the like.
  • the “C 1-4 alkoxycarbonyl group” means a group in which the “C 1-4 alkoxy group” is bonded to a carbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, and the like.
  • C 3-6 cycloalkoxycarbonyl group means a group in which the “C 3-6 cycloalkoxy group” is bonded to a carbonyl group. Specific examples include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl and the like.
  • C 7-14 aralkyl part of the “C 7-14 aralkyloxycarbonyl group” has the same meaning as the above “C 7-14 aralkyl”.
  • Preferable examples include “C 7-10 aralkyloxycarbonyl group”.
  • Specific examples of “C 7-14 aralkyloxycarbonyl group” include, for example, benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl and the like.
  • C 1-4 alkylcarbonyl group means a group in which the “C 1-4 alkyl group” is bonded to a carbonyl group. Specific examples include acetyl, propionyl, butyryl and the like.
  • C 3-6 cycloalkylcarbonyl group means a group in which the “C 3-6 cycloalkyl group” is bonded to a carbonyl group. Specific examples include cyclopropylcarbonyl, cyclobutylcarbonyl and the like.
  • C 1-4 alkyl moiety of the "C 1-4 alkylcarbonyloxy group” is the same as defined in the "C 1-4 alkyl group”. Specific examples include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy and the like.
  • C 3-6 cycloalkyl moiety of the "C 3-6 cycloalkyl carbonyl group” is the same as defined in the "C 3-6 cycloalkyl group”. Specific examples include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy and the like.
  • “4- to 7-membered cyclic amino” means a 4- to 7-membered cyclic amino group in which the nitrogen atom of the ring has a bond with another “group”. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholinooxide, thiomorpholinooxide, piperazino, 2-pyrrolidone-1-yl and the like.
  • the ring may be substituted with, for example, a halogen atom, C 1-4 alkyl, or C 6 aryl optionally substituted with C 1-4 alkoxy.
  • the group also includes a cyclic amino group in which the ring contains a partially unsaturated bond.
  • the “4- to 7-membered cyclic amino” may be a condensed ring of a 5-membered or 6-membered aromatic ring and a 5-membered or 6-membered heterocyclic ring. Specific examples include “groups” shown below.
  • Examples of the substituent in the “optionally substituted C 1-6 alkyl group” include (a) a halogen atom, (B) a hydroxyl group, (C) a C 1-4 alkoxy group (the alkoxy is (C11) 1 to 3 halogen atoms, (C12) hydroxy, (C13) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (C14) C 3-6 cycloalkoxy, (C15) C 3-6 cycloalkyl, (C16) mono- or di-C 1-6 alkylamino, or (c17) optionally substituted with a 4- to 7-membered cyclic amino.
  • (D) a C 3-7 cycloalkoxy group (the cycloalkoxy represents (D11) 1 to 3 halogen atoms, (D12) hydroxy, (D13) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (D14) C 1-4 alkyl (the alkyl may be substituted with 1 to 3 halogen atoms), (D15) C 3-6 cycloalkoxy, (D16) C 3-6 cycloalkyl, (D17) amino, or (d18) optionally substituted with mono- or di-C 1-6 alkylamino.
  • the cycloalkoxy represents (D11) 1 to 3 halogen atoms, (D12) hydroxy, (D13) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (D14) C 1-4 alkyl (the alkyl may be substituted with 1 to 3 halogen atoms),
  • Suitable substituents for the “optionally substituted C 1-6 alkyl group” include, for example, (A2) 1 to 5 halogen atoms (more preferably 1 to 3 halogen atoms), (B2) a C 3-7 cycloalkyl group (wherein the cycloalkyl may be substituted with C 1-6 alkyl or 1 to 3 halogen atoms), or (c2) a C 1-4 alkoxy group ( The alkoxy is optionally substituted with 1 to 3 halogen atoms).
  • Examples of the substituent in the “optionally substituted C 3-7 cycloalkyl group” include the above (a) to (u), and a C 1-4 alkyl group (the alkyl is C 1-4 alkoxy, hydroxyl, Or may be substituted with a halogen atom).
  • Examples of the substituent in the “optionally substituted C 6-10 aryl group” and the “optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group” include (a3) Deuterium atom, (B3) a halogen atom, (C3) a hydroxyl group, (D3) a nitro group, (E3) a cyano group, (F3) a heterocyclic group, (G3) a C 3-7 cycloalkyl group, (H3) a C 3-7 cycloalkyloxy group, (I3) C 1-4 alkyl group (the alkyl group is (I301) 1 to 3 halogen atoms, (I302) hydroxy, (I303) C 3-6 cycloalkyloxy, (I304) C 1-4 alkoxy (the alkoxy is 1 to 3 halogen atoms, It may be substituted with C 1-4 alkoxy or hydroxy.
  • (J3) C 1-4 alkoxy group (the alkoxy group is (J31) 1 to 3 halogen atoms, (J32) hydroxy, (J33) C 1-4 alkoxy, (J34) C 3-6 cycloalkyloxy, (J35) carboxyl, (J36) C 1-4 alkoxycarbonyl, (J37) mono- or di-C 1-6 alkylaminocarbonyl, (J38) 4- to 7-membered cyclic aminocarbonyl, or (j39) C 3-6 cycloalkyl may be substituted.
  • the alkoxy group is (J31) 1 to 3 halogen atoms, (J32) hydroxy, (J33) C 1-4 alkoxy, (J34) C 3-6 cycloalkyloxy, (J35) carboxyl, (J36) C 1-4 alkoxycarbonyl, (J37) mono- or di-C 1-6 alkylaminocarbonyl, (J38) 4- to 7-membered
  • (K3) C 3-6 cycloalkylsulfonyl group (L3) C 1-6 alkylcarbonyl group (the alkyl is (L31) hydroxy, (L32) 1 to 3 halogen atoms, (L33) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), It may be substituted with (l34) C 3-6 cycloalkoxy, or (l35) C 3-6 cycloalkyl.
  • (M3) C 3-6 cycloalkylcarbonyl group (the cycloalkyl is (M31) hydroxy, (M32) 1 to 3 halogen atoms, (M33) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (M34) C 3-6 cycloalkoxy, (M35) C 1-4 alkyl, or (m36) C 3-6 cycloalkyl may be substituted.
  • (Q31) and (q33) may be further substituted with a group selected from the group consisting of the above (l31) to (l35), and (q32) and (q34) are the above (m31) to (m36 And may be further substituted with a group selected from the group consisting of: ), (R3) a 4- to 7-membered cyclic amino group, (S3) an aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (q31) to (q35)); (T3) a 4- to 7-membered cyclic aminocarbonyl group, (U3) an aminosulfonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (q31) and (q32)); (V3) a 4- to 7-membered cyclic aminosulfonyl group, (W3) C 6-10 aryl group (the aryl is (W31
  • (X3) 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl is (X31) a halogen atom, (X32) C 1-4 alkyl (the alkyl may be substituted with 1 to 3 halogen atoms), or (x33) C 3-6 cycloalkyl. ), (Y3) C 1-4 alkylsulfonyl group, (z3) C 3-6 cycloalkylsulfonyl group and the like can be mentioned.
  • Suitable substituents in the “optionally substituted C 6-10 aryl group” and the “optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group” include, for example, ( a4) deuterium atom, (B4) a halogen atom, (C4) hydroxyl group, (D4) a cyano group, (E4) a heterocyclic group, (F4) C 3-7 cycloalkyl group, (G4) a C 3-7 cycloalkyloxy group, (H4) C 1-4 alkyl group (the alkyl group is (H41) 1 to 3 halogen atoms, (H42) hydroxy, (H43) C 3-6 cycloalkyloxy, (H44) C 1-4 alkoxy (the alkoxy is 1 to 3 halogen atoms, It may be substituted with C 1-4 alkoxy or hydroxy.
  • (H45) C 3-6 cycloalkyl, (H46) amino (the amino may be substituted with 1 to 2 groups of the same or different types selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl), or (H47) It may be substituted with a 4- to 7-membered cyclic amino. ), (I4) C 1-4 alkoxy group (the alkoxy group is (I41) 1 to 3 halogen atoms, (I42) hydroxy, (I43) C 1-4 alkoxy, (I44) C 3-6 cycloalkyloxy, or (i45) C 3-6 cycloalkyl may be substituted.
  • (J4) C 1-6 alkylcarbonyl group (the alkyl is (J41) hydroxy, (J42) 1 to 3 halogen atoms, (J43) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (J44) C 3-6 cycloalkoxy or (j45) C 3-6 cycloalkyl may be substituted.
  • (K4) C 3-6 cycloalkylcarbonyl group (the cycloalkyl is (K41) hydroxy, (K42) 1 to 3 halogen atoms, (K43) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (K44) C 3-6 cycloalkoxy, (K45) C 1-4 alkyl, or (k46) C 3-6 cycloalkyl may be substituted.
  • (14) C 6-10 aryl group (the aryl group is (L41) a halogen atom, (L42) C 1-4 alkoxy, (144) C 3-7 cycloalkyl, or (144) C 1-4 alkyl may be substituted.
  • (M4) 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl group is (M41) a halogen atom, (M42) C 1-4 alkyl (wherein the alkyl may be substituted with 1 to 3 halogen atoms), or (m43) optionally substituted with C 3-6 cycloalkyl. ), Or (n4) C 1-4 alkylsulfonyl group and the like.
  • substituent of the “optionally substituted heterocyclic group” include a group selected from the group consisting of the above (c) to (u), and a C 1-4 alkyl group (wherein the alkyl is 1 to And may be substituted with three halogen atoms or C 1-4 alkoxy).
  • the “optionally substituted amino group” means an amino group, a mono- or di-substituted amino group, and an optionally substituted 4- to 7-membered cyclic amino group.
  • (A6) C 1-6 alkyl (the alkyl is (A61) hydroxy, (A62) 1 to 3 halogen atoms, (A63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (A64) C 3-6 cycloalkoxy or (a65) C 3-6 cycloalkyl may be substituted.
  • (B6) C 3-6 cycloalkyl (the cycloalkyl is (B61) hydroxy, (B62) 1 to 3 halogen atoms, (B63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (B64) C 3-6 cycloalkoxy, (B65) C 1-4 alkyl, or (b66) C 3-6 cycloalkyl may be substituted.
  • C6 C 1-4 alkylcarbonyl (wherein the alkyl is (C61) hydroxy, (C62) 1 to 3 halogen atoms, (C63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (C64) C 3-6 cycloalkoxy, or (c65) C 3-6 optionally substituted by cycloalkyl.
  • (D6) C 3-6 cycloalkylcarbonyl (the cycloalkyl is (B61) hydroxy, (B62) 1 to 3 halogen atoms, (B63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms), (B64) C 3-6 cycloalkoxy, (B65) C 1-4 alkyl, or (b66) C 3-6 cycloalkyl may be substituted. ), And (e6) the same or different 1-2 groups selected from the group consisting of C 1-6 alkylsulfonyl.
  • the “optionally substituted amino” in the “optionally substituted aminocarbonyl group” has the same meaning as the above “optionally substituted amino”. That is, it means an aminocarbonyl group, a mono- or di-substituted aminocarbonyl group, and an optionally substituted 4- to 7-membered cyclic aminocarbonyl group, and is “mono- or di-substituted.
  • the “amino” and “4- to 7-membered cyclic aminocarbonyl” moieties are the same as described above.
  • amino in the “aminosulfonyl group” may be substituted with one or two groups selected from the group consisting of the above (q31) and (q32), and the amino moiety is the same as above. .
  • the 4- to 7-membered cyclic amino moiety in the “4- to 7-membered cyclic aminosulfonyl group” is the same as described above.
  • R 1 includes a C 6-10 aryl group or a 5- or 6-membered monocyclic heteroaryl group (the aryl and heteroaryl groups are (1) a halogen atom, (2) a C 3-7 cycloalkyl group, (3) C 1-4 alkyl group (the alkyl group is (A) 1 to 3 fluorine atoms, (B) C 1-4 alkoxy, (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) 4 to 7 membered cyclic amino and the like. ), (4) C 1-4 alkoxy group (the alkoxy group is (A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. And (5) 1 to 5 groups of the same or different types selected from the group consisting of C 1-4 alkylcarbonyl groups. Is preferred.
  • R 1 is preferably an optionally substituted 5-membered or 6-membered monocyclic heteroaryl group (the substituents of the heteroaryl group are the same as those described above), and are preferably 5-membered or 6-membered. And a monocyclic heteroaryl group (which is optionally substituted with a group selected from the group consisting of a halogen atom and a C 1-4 alkyl group).
  • Examples of the 5-membered or 6-membered monocyclic heteroaryl group in “R 1 ” include the following (a) to (d): [Wherein (a) to (d) are substituted with a substituent selected from the group consisting of (a3) to (z3), (a4) to (n4) and (a5) to (e5). Also good. ] Any one group represented by is preferable.
  • R 2 is a C 1-6 alkyl group (the group is (1) 1 to 5 halogen atoms, It may be substituted with (2) C 3-6 cycloalkyl or (3) C 1-4 alkoxy. ) Is preferable, and a methyl group or an ethyl group is more preferable.
  • R 3 (1) a hydrogen atom, (2) a halogen atom, or (2) a C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. ) Is preferred, a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group is more preferred, a hydrogen atom, a chlorine atom or a methyl group is still more preferred, and a hydrogen atom is particularly preferred.
  • R 4 (1) C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. ), Or (2) a C 3-6 cycloalkyl group is preferred, a methyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, or an ethyl group is more preferred, and an ethyl group is more preferred. Even more preferred.
  • R 5 is preferably a hydroxyl group, an aminocarbonyl group or a methylsulfonyl group, more preferably a hydroxyl group or an aminocarbonyl group.
  • R 6a to R 6d are each independently (1) a hydrogen atom, (2) a halogen atom, (3) a C 3-7 cycloalkyl group, (4) C 1-4 alkyl group (the alkyl group is (A) 1 to 3 fluorine atoms, (B) C 1-4 alkoxy, (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino.
  • C 1-4 alkoxy group (the alkoxy group is (A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. ), Or (6) a C 1-4 alkylcarbonyl group. ]
  • R 6a to R 6d are each independently (1) a hydrogen atom, (2) a halogen atom, or (3) a C 1-4 alkyl group (the alkyl group is (A) 1 to 3 fluorine atoms, (B) C 1-4 alkoxy, (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ) Or a pharmacologically acceptable salt thereof is more preferred.
  • preferred embodiments of the respective definitions of the compound represented by the formula (2) are the same as preferred embodiments of the respective definitions of the compound represented by the formula (1).
  • the compound represented by Formula (1) and Formula (2) is preferably any one compound selected from the following group. 4-chloro-5-[(5-chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide , 5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide; 5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide; 1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- ⁇ methyl [4- (trifluoromethyl) -2
  • the compound represented by Formula (1) and Formula (2) is more preferably any one compound selected from the following group.
  • Production method 1 The compound represented by the formula (1) can be synthesized, for example, by the following method.
  • the compound represented by the formula (s-7) or a salt thereof is produced, for example, by the method shown below.
  • R a is a C 1-8 alkyl group (methyl group, ethyl group, octyl group etc.) or benzyl group Etc.)
  • Step (A-1) This step is a step for producing an amide compound (s-2) using an acid halide such as acetyl chloride for the amine compound (s-1) or a salt thereof.
  • the amide compound (s-2) can be produced using the amine compound (s-1) or a salt thereof and acetic acid.
  • the amide compound (s-2) can also be produced using the amine compound (s-1) or a salt thereof and acetic anhydride.
  • Examples of the method for activating the carboxyl group include a method of converting the carboxyl group into an acid anhydride, mixed acid anhydride, acid halide, active ester, or acid azide, or a method using a condensing agent.
  • an acid such as acetyl chloride prepared by reacting a carboxylic acid such as acetic acid with a halogenating reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride.
  • the halide can be reacted with the amine compound (s-1) or a salt thereof in the presence of a base to obtain the compound (s-2).
  • the base is not particularly limited.
  • Organics such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, or N-methylmorpholine (NMM)
  • bases or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide. Any solvent that does not react under the reaction conditions in this step can be used.
  • halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride
  • ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane, benzene, toluene, or xylene
  • aromatic hydrocarbon solvent such as ethyl ester solvent such as ethyl acetate or methyl acetate, water, or a mixture thereof.
  • the reaction temperature is from ⁇ 80 ° C. to the reflux temperature, and is usually from ⁇ 20 ° C. to room temperature.
  • the reaction time is usually 10 minutes to 48 hours.
  • a carboxylic acid such as acetic acid is reacted with an acid halide in the presence of a base to form a mixed acid anhydride, and then the amine compound (s-1) or its compound is used. It can be reacted with a salt to lead to compound (s-2).
  • the acid halide include methoxycarbonyl chloride, ethoxycarbonyl chloride, isopropyloxycarbonyl chloride, isobutyloxycarbonyl chloride, paranitrophenoxycarbonyl chloride, and t-butylcarbonyl chloride.
  • the base is not particularly limited.
  • Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, or N-methylmorpholine (NMM),
  • inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, or potassium carbonate, etc. are mentioned. Any solvent that does not react under the reaction conditions in this step can be used.
  • ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane
  • benzene, toluene or xylene
  • An aromatic hydrocarbon solvent such as ethyl ester, an ester solvent such as ethyl acetate or methyl acetate, water, or a mixture thereof.
  • the reaction temperature is from ⁇ 80 ° C. to heating under reflux temperature, and is usually from ⁇ 20 ° C. to ice-cooling temperature.
  • the reaction time is usually 30 minutes to 48 hours.
  • a compound (s-2) can also be produced by reacting a carboxylic acid such as acetic acid or a salt thereof with an amine compound (s-1) or a salt thereof in the presence or absence of a base with a condensing agent.
  • a condensing agent include those described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen) Vol.
  • phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide
  • carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, dicyclohexylcarbodiimide, 2,2′-dipyridyl disulfide, etc.
  • Combinations of disulfides and phosphines such as triphenylphosphine, phosphorus halides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, azodicarboxylic acid diesters such as diethyl azodicarboxylate and tri Combinations of phosphines such as phenylphosphine, 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 1,1′-carbonyldiimidazole, diphenylphosphoryl azide (D PA), diethyl phosphorylcyanide (DEPC), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), O- (1H) -
  • the solvent is not particularly limited, and any solvent that does not react under the reaction conditions in this step can be used. Specifically, the same solvent as that used in the acid halide method can be used, or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl- An aprotic polar solvent such as 2-imidazolidinone or dimethyl sulfoxide, water, or a mixed solvent thereof may be used.
  • the base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.
  • Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, or N-methylmorpholine (NMM) Can be mentioned.
  • the reaction temperature is usually from ⁇ 10 ° C. to the heating reflux temperature.
  • the reaction time varies depending mainly on the reaction temperature, the raw materials used, the solvent and other conditions, but is usually 0.5 to 48 hours.
  • Step (A-2) This step is a step for producing a ketoester compound (s-3) by adding a base to the compound (s-2) and then reacting with dialkyl oxalate (CO 2 R a ) 2 .
  • a metal hydride such as sodium hydride, lithium hydride, or potassium hydride, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium tert Metal alkoxides such as butoxide, lithium methoxide, lithium ethoxide, lithium methoxide, lithium tert-butoxide, metal amines such as potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, or lithium diisopropylamide Is mentioned.
  • the solvent examples include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, N -Methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone and the like.
  • the reaction temperature can be carried out at ⁇ 78 ° C. to a reflux temperature, and is usually from ⁇ 78 ° C. to room temperature.
  • the reaction time varies depending mainly on the reaction temperature, the raw materials used, the solvent and other conditions, but is usually 0.5 to 48 hours.
  • the ketoester compound (s-3) can also be produced by adding a base to (CO 2 R a ) 2 and then allowing the compound (s-2) to act. Further, the compound (s-2) and (CO 2 R a ) 2 may be added simultaneously to the base, or the base may be added to the mixture of the compound (s-2) and (CO 2 R 1 ) 2. In addition, a ketoester compound (s-3) can be produced.
  • Step (A-3) In this step, the keto ester compound (s-3) is treated with hydrazine R 4 NHNH 2 or a salt thereof in the presence of a thioating agent such as Lawesson's reagent or phosphorous pentasulfide to give a pyrazole ester compound (s-4).
  • a thioating agent such as Lawesson's reagent or phosphorous pentasulfide
  • Lawesson's reagent or phosphorous pentasulfide is usually used in an amount of 1 to 3 equivalents with respect to the ketoester compound (s-3).
  • Hydrazine R 4 NHNH 2 or a salt thereof is usually used in an amount of 1 to 2 equivalents.
  • the reaction temperature is usually from room temperature to heating reflux temperature, and the reaction time is usually from 2 hours to 48 hours, although it varies depending mainly on the reaction temperature, the raw materials used, the solvent and the like.
  • the reaction solvent pyridine, picoline, triethylamine, diisopropylethylamine, tributylamine or the like is used alone or in combination, or in addition to these, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or
  • An ether solvent such as 1,4-dioxane, an aromatic hydrocarbon solvent such as benzene, toluene or xylene, an ester solvent such as ethyl acetate, isopropyl acetate or methyl acetate can be added and used.
  • Step (A-4) This step is a step of producing a pyrazole carboxylic acid compound (s-5) by deprotecting the ester group of the pyrazole ester compound (s-4). To implement this process, Protective Groups in Organic Synthesis, Green, John Wiley & Sons Inc. (1981) ). Specifically, for example, the following method is used.
  • the pyrazole carboxylic acid compound (s-5) can be led by alkaline hydrolysis or acid hydrolysis.
  • alkaline hydrolysis in the presence of an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, etc., together with water, for example, methanol, ethanol, In the presence or absence of alcohol solvents such as 2-propanol and butanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, and aromatic hydrocarbon solvents such as benzene, toluene and xylene.
  • the compound of pyrazole carboxylic acid compound (s-5) can be obtained by reacting in the range of room temperature to heating reflux temperature for 0.5 to 48 hours.
  • Step (A-5) This step is a step of producing the target amide compound (s-7) by amidation of the pyrazole carboxylic acid compound (s-5) and the adamantylamine compound (s-6). This step can be performed by a method similar to the method in step (A-1).
  • Production method 2 The amide compound (s-7) can also be produced via the step (A-6) shown below.
  • R 1 , R 2 , R 4 , and R a are as defined above.
  • R b represents a halogen atom.
  • Step (A-6) This step introduces the group: R b into the 4-position of the pyrazole ring of the compound (s-8) produced according to the production method 1 steps (A-1) to (A-3) to give the compound (s-9). It is a manufacturing process.
  • Examples of the compound (s-8) include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, bromine, iodine, iodine chloride, sulfuryl chloride, SELECTFLUOR (registered trademark), 1-fluoro-4-hydroxy -1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate), N-fluorobenzenesulfonimide, N-fluoro-O-benzenedisulfonimide, 1-fluoropyridinium triflate, or 1-fluoro
  • a halogenating agent such as -2,6-dichloropyridinium tetrafluoroborate in the presence or absence of an acid, a halogen atom can be introduced at the 4-position.
  • the acid examples include a hydrogen halide such as hydrogen chloride or hydrogen bromide, or an organic acid such as acetic acid or propionic acid.
  • the solvent can be used as long as it is inert to the reaction.
  • ester solvents such as ethyl acetate or methyl acetate, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride.
  • ether solvent such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2
  • aprotic polar solvents such as pyrrolidinone and 1,3-dimethyl-2-imidazolidinone.
  • the reaction temperature is usually from ⁇ 10 ° C. to the heating reflux temperature.
  • the reaction time is usually 0.5 to 48 hours.
  • the compound (s-9) thus obtained is treated in the same manner as in production method 1 steps (A-4) and (A-5) to produce the corresponding amide compound (s-7). be able to.
  • Production method 4 The amide compound (s-7) can also be produced via the step (A-8) shown below.
  • R 1 , R 2 , R 4 , R a and R b are as defined above.
  • R c represents optionally substituted C 1-6 alkyl, cyano, etc.
  • Mtl is zinc
  • Step (A-8) In this step, compound (s-13) is obtained by reacting compound (s-9) obtained in step (A-6) of production method 2 with organometallic compound (s-12) in the presence of a metal catalyst. ). This process is described in Palladium Reagents and Catalysts, by Jiro Tsuji, John Wiley & Sons Inc. (2004). Methods and the like.
  • R b is a halogen atom, preferably bromine, iodine, or chlorine.
  • organometallic compound (s-12) include alkyl zinc halides such as methyl zinc chloride, dialkyl zinc such as dimethyl zinc, and metal cyanides such as zinc cyanide. These are usually compound (s-9) 1 equivalent to 10 equivalents are used.
  • the metal catalyst examples include tetrakis (triphenylphosphine) palladium [Pd (PPh 3 ) 4 ], bis (tritert-butylphosphine) palladium [Pd (PtBu 3 ) 2 ], 1,1′-bis (diphenylphosphino) Ferrocene] dichloropalladium (II) [PdCl 2 (dppf)], bis (dibenzylideneacetone) palladium [Pd (dba) 2 ], bis (tri-o-tolylphosphine) dichloropalladium PdCl 2 [P (o-tol) 3 ] 2 ] and the like, and these are usually used in an amount of 0.001 equivalent to 1 equivalent based on compound (s-9).
  • the solvent examples include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, N , N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or a protic polar solvent, or a mixed solvent thereof is used.
  • the reaction temperature is usually from room temperature to the reflux temperature.
  • the reaction time is usually 0.5 to 48 hours.
  • the compound (s-13) thus obtained is treated in the same manner as in production method 1 steps (A-4) and (A-5) to produce the corresponding amide compound (s-7). be able to.
  • Production method 5 Among the compounds represented by formula (1), the compound represented by formula (s-14) or a salt thereof can be produced by the method shown below. (Wherein R 1 , R 2 , R 4 , R 5 , R b , R c and Mtl are as defined above.)
  • Step (A-9) In this step, compound (s-14) is produced by reacting compound (s-11) obtained in step (A-7) of production method 3 with organometallic compound (s-12) in the presence of a metal catalyst. ). The introduction of the R c group into compound (s-11) can be carried out in the same manner as in production method 4, step (A-8).
  • Production method 6 The amide compound (s-7) can also be produced via steps (A-10) and (A-11) shown below.
  • R 1 is an optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group.
  • R d is a leaving group such as a benzyl group (the group may be substituted with a group selected from the above (a3) to (z3)),
  • X is a halogen atom, a boron atom
  • HetAr is a 5- to 12-membered monocyclic or polycyclic heteroaryl group which may be substituted.
  • Step (A-10) This step is a step for producing the compound (s-16) by removing the group R d from the compound (s-15) produced according to the production method 1 steps (A-1) to (A-3). is there.
  • R d is an optionally substituted benzyl group
  • hydrogen chloride, ammonium formate or the like is added if necessary in the presence of a metal catalyst such as palladium-carbon, palladium hydroxide, or nickel.
  • the compound (s-16) can be produced by reacting the compound (s-15) in a hydrogen gas atmosphere.
  • the solvent examples include alcohol solvents such as methanol, ethanol, 2-propanol, and butanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane, benzene, toluene, xylene, and the like.
  • Alcohol solvents such as methanol, ethanol, 2-propanol, and butanol
  • ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane
  • benzene toluene
  • xylene 1,4-dioxane
  • Aromatic hydrocarbon solvents, ester solvents such as ethyl acetate or methyl acetate
  • organic acids such as acetic acid, water, or a mixed solvent thereof can be used.
  • Step (A-11) This step is performed by reacting the compound (s-16) obtained in step (A-10) with the heteroaryl compound (s-17) which is heteroaryl borate or heteroaryl halide.
  • compound (s-18) can be produced by reacting compound (s-16) with a base and then adding 2-chloropyridine as compound (s-17).
  • a metal hydride such as sodium hydride, lithium hydride, or potassium hydride, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, or lithium Examples thereof include metal amines such as diisopropylamide.
  • the solvent examples include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, N , N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or a protic polar solvent, or a mixed solvent thereof is used.
  • the reaction temperature is usually from an ice cooling temperature to a heating reflux temperature.
  • the reaction time is usually 0.5 to 24 hours.
  • compound (s-16) can also be reacted with heteroaryl compound (s-17) which is a heteroaryl borate or a heteroaryl halide in the presence of a base and a metal catalyst.
  • a base examples include sodium t-butoxide, potassium t-butoxide, cesium carbonate, lithium hexamethyldisilazide and the like.
  • the metal catalyst examples include bis (tris-tert-butylphosphine) palladium, bis (triso-tolylphosphine) dichloropalladium, bis (triso-tolylphosphine) palladium, tetrakistriphenylphosphinepalladium, dichloropalladium (acetonitrile), Bis (tris-o-tolylphosphine) dichloropalladium, (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium, (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) ) Catalysts such as palladium (II) dichloride can be used.
  • ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene or xylene Ester solvents such as ethyl acetate or methyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc.
  • reaction temperature is usually from room temperature to a heating reflux temperature, and the reaction time is usually from 30 minutes to 48 hours.
  • a metal catalyst in place of the compound (s-17) such as a heteroaryl halide or a heteroaryl boronic acid described herein, an aryl halide or
  • R 1 is an optionally substituted C 6-10 aryl group.
  • the compound (s-18) thus obtained is treated in the same manner as in production method 1 steps (A-4) and (A-5) to produce the corresponding amide compound (s-7). be able to.
  • Production method 7 The amide compound (s-7) can also be produced via the step (A-12) shown below.
  • R 2 , R 3 , R 4 , R 5 , X and HetAr are as defined above.
  • R 1 is an optionally substituted 5- to 12-membered monocyclic or polycyclic A heteroaryl group.
  • Step (A-12) This step is a step for producing an amide compound (s-7) by reacting the compound (s-19) with a heteroaryl compound (s-17).
  • the introduction of the heteroaryl group can be carried out in the same manner as in production method 6, step (A-11).
  • step (A-11) when step (A-12) is performed in the presence of a metal catalyst, an aryl halide or aryl borate is used instead of the heteroaryl compound (s-17).
  • a compound (s-7) in which R 1 is an optionally substituted C 6-10 aryl group can also be obtained.
  • the desired compound can be obtained by deprotection.
  • the protecting group for example, a usual protecting group as described in the above-mentioned Protective Groups in Organic Synthesis etc. can be used. More specifically, as the protecting group for amine, for example, , Ethoxycarbonyl, t-butoxycarbonyl, acetyl, benzyl and the like, and examples of the hydroxyl-protecting group include tri-lower alkylsilyl, acetyl, benzyl and the like. Introduction and removal of protecting groups can be carried out by methods commonly used in organic synthetic chemistry (see, for example, the above-mentioned Protective Groups in Organic Synthesis) or methods based thereon.
  • the intermediate or final product in the above production method can be led to another compound included in the present invention by appropriately converting the functional group.
  • the functional group can be converted by a commonly used general method (for example, see Comprehensive Organic Transformations, RC Larock, 1989). it can.
  • the intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. it can.
  • the intermediate can also be used in the next reaction without any particular purification.
  • optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method.
  • An optically active substance can also be used as a starting material.
  • the present invention includes all possible isomers including these and their Includes mixtures.
  • the starting materials and intermediates in the above production method are known compounds or can be synthesized from known compounds by known methods.
  • the present invention includes a compound represented by the formula (1) or a prodrug thereof, or a pharmacologically acceptable salt thereof. Moreover, solvates, such as these hydrates or ethanol solvates, are also included. Furthermore, all forms of crystalline forms are also included. This also applies to the compound represented by the formula (2).
  • the term “prodrug of the compound represented by the formula (1) is a compound represented by the formula (1) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
  • a compound that can be converted into a compound of formula (1) that is, a compound that is enzymatically oxidized, reduced, hydrolyzed to change to a compound of formula (1), a gastric acid or the like that is hydrolyzed to a compound of formula (1) Means a compound.
  • Examples of the “pharmacologically acceptable salt” include alkali metal salts such as potassium salt and sodium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, N-methylglucamine (meglumine) and the like.
  • the compound of the present invention when it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is.
  • the salt may be formed by suspending and adding an acid or a base by a usual method.
  • this invention compound and its pharmacologically acceptable salt may exist in the form of an adduct with water or various solvents, these adducts are also included in the present invention.
  • the present invention also includes all tautomeric forms of the compounds of the present invention, all stereoisomers present, and all forms of crystalline forms.
  • the compound of the present invention or a pharmacologically acceptable salt thereof is type II diabetes, impaired glucose tolerance, hyperglycemia, insulin resistance, low HDL disease, hyper LDL disease, dyslipidemia, hyperlipidemia, hypertriglyceride blood Disease, hypercholesterolemia, hypertension, arteriosclerosis, cerebral arteriosclerosis, vascular stenosis, atherosclerosis, obesity, osteoporosis, immune disorder, metabolic syndrome, cardiovascular disease, Cushing syndrome, subclinical Cushing syndrome, NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic steatohepatitis), glaucoma, retinopathy, dementia, cognitive impairment, depression, anxiety, manic depression, neurodegenerative diseases, Alzheimer's dementia, cerebrovascular dementia , Lewy body dementia, Pick disease, Creutzfeldt-Jakob disease, Kraepelin disease, Parkins n disease, Huntington chorea, Hallervorden-Spats disease, spinocerebellar degeneration, progressive
  • the compound of the present invention or a pharmacologically acceptable salt thereof is orally or parenterally (for example, intravenous, subcutaneous, or intramuscular injection, topical, rectal use) as a pharmaceutical composition when used for treatment. , Transdermally, or nasally).
  • compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc.
  • compositions for parenteral administration include, for example, injections.
  • Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.
  • the amount used varies depending on symptoms, age, administration method, etc.
  • 0.01 mg (preferably 0.1 mg) to 1000 mg (preferably 30 mg) per day for an adult is divided into one or several times, The effect is expected by administering according to the symptoms.
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be used in combination with a drug that can be used in combination for the purpose of enhancing its action and effect (hereinafter abbreviated as “concomitant drug”).
  • a drug that can be used in combination for the purpose of enhancing its action and effect hereinafter abbreviated as “concomitant drug”.
  • the concomitant drug include drugs such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, and a diuretic.
  • the administration timing of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug is not limited, and these may be administered simultaneously to the administration subject as a single agent or administered at a time difference. Good.
  • the compound of the present invention or a pharmacologically acceptable salt thereof and a combination drug may be used.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention or a pharmacologically acceptable salt thereof.
  • diabetes therapeutic agents include insulin preparations (for example, animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast), insulin resistance improving agents (for example, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), ⁇ -glucosidase inhibitor ( For example, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, g Sulfonylureas such as clopyramide, glimepiride; repaglinide,
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (for example, tolrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, ranirestat, SK-860, CT-112, etc.), neurotrophic factors (for example, NGF) , NT-3, BDNF etc.), PKC inhibitors (eg LY-333531 etc.), AGE inhibitors (eg ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766) etc.), active oxygen elimination Examples thereof include drugs (for example, thioctic acid) and cerebral vasodilators (for example, thioprid, mexiletine, etc.).
  • aldose reductase inhibitors for example, tolrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, ranirestat, SK-860, CT-112, etc.
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Is mentioned.
  • HMG-CoA reductase inhibitors for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts
  • squalene synthase inhibitors for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts
  • squalene synthase inhibitors for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts
  • antihypertensive agent examples include angiotensin converting enzyme inhibitors (for example, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (for example, olmesartan medoxomilexilmil, candesartyl, Losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (for example, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.).
  • angiotensin converting enzyme inhibitors for example, captopril, enalapril,
  • anti-obesity agents examples include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (For example, leptin, CNTF (ciliary neurotrophic factor) and the like), cholecystokinin agonists (for example, lynchtrypto, FPL-15849, etc.) and the like.
  • central anti-obesity agents eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.
  • pancreatic lipase inhibitors eg, orlistat, etc.
  • peptide anorectic agents For example, leptin, CNTF (ciliary neurotrophic factor) and the like
  • diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide , Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and
  • the concomitant drugs are preferably GLP-1, GLP-1 analog, ⁇ -glucosidase inhibitor, biguanide agent, insulin secretagogue, insulin resistance improving agent, DPP-IV inhibitor and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of these drugs used can be reduced within a safe range in consideration of side effects of the drug.
  • biguanides can be reduced from normal dosages. Therefore, side effects that may be caused by these drugs can be safely prevented.
  • the dosage of diabetic complication therapeutic agents, antihyperlipidemic agents, antihypertensive agents and the like can be reduced, and as a result, side effects that may be caused by these agents can be effectively prevented.
  • the compound of the present invention or a pharmacologically acceptable salt thereof is an antidepressant, anxiolytic, schizophrenia drug, sleep inducer, dopamine receptor agonist, parkinson for the purpose of enhancing its action effect.
  • the administration timing of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug is not limited, and these may be administered simultaneously to the administration subject as a single agent or administered at a time difference. Good.
  • the compound of the present invention or a pharmacologically acceptable salt thereof and a combination drug may be used.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the administration subject is a human
  • 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention or a pharmacologically acceptable salt thereof.
  • it can be used in combination with concomitant drugs such as antiemetics, sleep inducers, anticonvulsants, etc. for the purpose of suppressing the side effects.
  • THF tetrahydrofuran
  • DMF N, N-dimethylformamide
  • Me methyl group Et: ethyl group
  • Bu butyl group
  • Bn benzyl group
  • NaBH (OAc) 3 sodium triacetoxyborohydride
  • WSC ⁇ HCl 1- (3-dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride
  • HOBt ⁇ H 2 O 1-hydroxybenzotriazole monohydrate
  • TFA trifluoroacetic acid
  • MeOH methanol
  • DIAD diisopropyl azocarboxylate
  • BINAP 2,2′-bis (diphenylphosphino) ) -1,1′-binaphthyl Boc: tert-butoxycarboxyl group
  • Cbz benzyloxycarbonyl group
  • Ns nosyl group
  • Ms methanesulfonyl group
  • Ac acetyl
  • Step (ii): (S) -Phenylethylamine (39.4 g) was added to a mixture of ice-cooled compound II (60 g) and dichloromethane (1500 mL). After stirring for 10 minutes, NaBH (OAc) 3 (101 g) was added and stirred overnight while warming to room temperature. Water (150 mL) and 2M NaOH (300 mL) were added to the ice-cooled reaction mixture to adjust the pH to about 9-10. The mixture was filtered through celite, and the cake was washed with chloroform (200 mL). The filtrate was separated and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated to give compound III (133 g, E / Z about 2.6 / 1).
  • Step (iii): Compound III (1311 g) obtained as in step (ii) was purified by silica gel column chromatography (elution solvent: chloroform / methanol 100/1 to 10/1) to give compound IV (618 g).
  • Step (i): After adding nosyl chloride (6.02 g) to a mixture of ice-cooled compound I (3.00 g), dichloromethane (30 mL) and triethylamine (8 mL), the mixture was stirred at room temperature overnight. To the reaction solution was added 1.2M hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 3/1) to give Compound II (4.56 g).
  • Step (ii): To a mixture of ice-cooled compound II (0.69 g), THF (20 mL), 2-methoxyethanol (0.71 g) and triphenylphosphine (1.47 g), DIAD (700 ⁇ L) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 6 days. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to obtain Compound III (1.60 g).
  • Step (iii): A mixture of Compound III (1.60 g), DMF (16 mL), mercaptoacetic acid (200 ⁇ L) and lithium hydroxide monohydrate (0.67 g) was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 4/1) to give Compound IV (243.4 mg).
  • Step (ii): A mixture of compound II (3.48 g) and DMF (35 mL) obtained as in step (i) was ice-cooled, and sodium hydride (0.90 g) was added. After stirring for 30 minutes, iodomethane (1.2 mL) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 4 days. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 1/2) to give the title compound III (2.69 g).
  • Step (i): A mixture of Compound I (4.53 g), THF (80 mL), (Boc) 2 O (13.21 g) and 10% Pd-carbon (2.04 g, 53% moisture) at room temperature under a hydrogen atmosphere of 0.2 MPa. Stir overnight. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound II (6.07 g).
  • Step (ii): Sodium hydride (3.5 g) was added to a solution of compound II (6.07 g) in ice-cooled DMF (60 mL). After stirring for 30 minutes, iodomethane (4.5 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 1/2) to give Compound III (2.14 g).
  • Step (i): Acetyl chloride (1.9 mL) was added dropwise to a mixture of ice-cooled compound I (2.17 g), THF (40 mL) and triethylamine (6.2 mL). After completion of dropping, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by amino silica gel chromatography (elution solvent: hexane / ethyl acetate 1/4) to obtain Compound II (2.82 g).
  • Step (i): Acetyl chloride (4.3 mL) was added dropwise to a mixture of ice-cooled compound I (4.93 g), THF (80 mL) and triethylamine (21 mL). After completion of the dropwise addition, the mixture was stirred overnight at room temperature. Methanol and amine silica gel were added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluent: hexane / ethyl acetate 1/4) to give Compound II (6.08 g).
  • Step (ii): Sodium hydride (1.35 g) was added to a solution of ice-cooled compound II (3.05 g) in DMF (30 mL). After stirring for 30 minutes, iodomethane (2 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution and saturated brine were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate 1/2) to give Compound III (3.08 g).
  • Step (ii): To a mixture of ice-cooled potassium tert-butoxide (92 g) and THF (800 mL), a solution of compound II (71.96 g) and diethyl oxalate (126 g) in THF (300 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. 1.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound III (82.56 g).
  • Step (iii): A mixture of Compound III (1.01 g), pyridine (10 mL), N-isopropylhydrazine monohydrochloride (0.46 g) and Lawesson's reagent (3.1 g) was stirred at 60 ° C. overnight. To the reaction solution was added 1.2 M hydrochloric acid, extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound IV (289.1 mg).
  • Step (iv): A mixture of compound IV (289.1 mg), methanol (20 mL), acetic acid (10 mL) and 20% Pd (OH) 2 -carbon (0.75 g, 60% moisture) was placed under a hydrogen atmosphere (4 atm) at room temperature for 3 days. Stir. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/2) to give the title compound V (195 mg).
  • Step (ii): To a mixture of ice-cooled potassium tert-butoxide (84 g) and THF (600 mL), a solution of compound II (66.48 g) and diethyl oxalate (110 g) in THF (200 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. 1.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 1/1) to give Compound III (81.62 g).
  • Step (iii): To a mixture of ice-cooled compound III (40.00 g) and pyridine (400 mL), N-methylhydrazine (9.1 ml) and Lawesson's reagent (100.48 g) were added. The mixture was stirred at 60 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature, extracted with ethyl acetate, and washed with 1.2 M hydrochloric acid. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/1) to give Compound IV (19.17 g).
  • Step (iv): A mixture of Compound IV (19.17 g), methanol (190 mL) and 20% Pd (OH) 2 -carbon (10.56 g, 60% moisture) was stirred overnight at room temperature under a hydrogen atmosphere (4 atm). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/3) to give the title compound V (8.38 g).
  • Step (ii): 1-Bromo-2-difluoroethane (6.7 mL) was added to a mixture of ice-cooled compound II (12 g), sodium hydride (3.34 g) and DMF (400 mL), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 8/2) to give Compound III (16.1 g).
  • Step (iv): A mixture of compound IV (9.57 g), compound V (13.5 g; compound III of Reference Example 8), Lawsson reagent (41.7 g), THF (247 mL) and pyridine (13 mL) was stirred at 60 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed successively with 1M hydrochloric acid and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give the title compound VI (3.76 g).
  • Reference Example 12 was produced by the same production method as in Reference Example 11.
  • Reference Example 13 was produced by the same production method as Reference Example 10. 1 H-NMR (CDCl 3 ) ⁇ 1.38-1.44 (m, 6H), 2.21 (s, 3H), 2.78 (brs, 4H), 4.14 (m, 2H), 4.39 (m, 2H)
  • Step (i): A mixture of Compound I (20.06 g), sodium bicarbonate (23.31 g), THF (200 mL) and water (100 mL) was ice-cooled, and CbzCl (19 mL) was added dropwise. After completion of dropping, the mixture was stirred overnight at room temperature. Saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/1) to give Compound II (25.80 g).
  • Step (ii): A mixture of Compound II (25.80 g), TEA (30 mL), and chloroform (300 mL) was ice-cooled, and methanesulfonyl chloride (12 mL) was added dropwise. After completion of dropping, the mixture was stirred overnight at room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound III (20.76 g).
  • Step (iii): A mixture of Compound III (10.00 g) and thioacetic acid (60 mL) was stirred at 70 ° C. overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 3/1) to give Compound IV (6.55 g).
  • Step (v): A mixture of the 3-chloroperbenzoic acid step (13.72 g) and chloroform (50 mL) was ice-cooled, and a solution of compound V (6.07 g) and chloroform (80 mL) was added dropwise. After completion of dropping, the mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled again, saturated sodium bisulfite was added, and the mixture was extracted with chloroform. The organic layer was washed with sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 1/3) to give compound VI (4.65 g). Obtained.
  • Step (i): A solution of Compound I (2.0 g) and diethyl oxalate (4.1 g) in THF (16 mL) was added dropwise to a mixture of ice-cooled potassium tert-butoxide (3.38 g) and THF (36 mL). After completion of dropping, the mixture was stirred overnight at room temperature. To the reaction solution was added 1.2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 3/1) to give Compound II (3.10 g).
  • Step (ii): A mixture of Compound II (3.10 g), pyridine (40 mL), N-methylhydrazine (0.72 ml) and Lawesson's reagent (10.0 g) was stirred at 60 ° C. overnight. 1.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound III (2.57 g).
  • Examples 2 to 22 Examples 2 to 22 were produced by the same production method as in Example 1.
  • Step (i): N-chlorosuccinimide (0.27 g) was added to a THF (10 mL) solution of Compound I (0.50 g; synthesis intermediate of Example 3) at room temperature, and the mixture was stirred overnight. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate 3/1) to obtain Compound II (0.51 g).
  • the mixture was stirred at room temperature overnight.
  • To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate.
  • Example 24 to Example 34 were manufactured by the same manufacturing method as Example 23.
  • N-chlorosuccinimide (17.1 mg) was added to a THF (3 mL) solution of Compound I (40.2 mg; Example 47), and the mixture was stirred overnight at room temperature.
  • Example 36 to Example 44 Example 36 to Example 44 were manufactured by the same manufacturing method as Example 35.
  • Step (i): A mixture of Compound I (20.07 g; Compound III of Reference Example 8), THF (180 mL), pyridine (20 mL), N-methylhydrazine (4.4 ml) and Lawesson's reagent (33.37 g) was stirred at 60 ° C. overnight. did. To the reaction solution was added 1.2 M hydrochloric acid, extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound II (8.09 g).
  • Step (ii): A mixture of Compound II (8.09 g), methanol (140 mL), acetic acid (10 mL) and 20% Pd (OH) 2 -carbon (9.39 g, 60% moisture) was added at room temperature under a hydrogen atmosphere (4 atm) at room temperature. Stir for days. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/3) to give Compound III (3.33 g).
  • Step (iii): Sodium hydride (0.14 g) was added to a mixture of ice-cooled compound III (529.9 mg), 2-chloropyridine (1 mL) and DMF (5 mL). Then, it stirred at 90 degreeC overnight. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 1/5) to give Compound IV (221 mg).
  • Example 46 to Example 77 were manufactured by the same manufacturing method as Example 45.
  • Example 78 to Example 89 were produced by the same production method as in Example 45 using Reference Example 9.
  • Example 90 to Example 91 were produced by the same production method as in Example 45 using Reference Example 10.
  • Step (ii): Compound II, DMF (20 mL), compound III (0.5 g), WSC.HCl (0.95 g), HOBt.H 2 O (1.02 g) and triethylamine (10 mL) obtained in step (i) was stirred at room temperature for 3 days. 2M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol 10/1). The obtained solid was repulp washed with diethyl ether to obtain Compound IV (332.7 mg).
  • Step (iii): A mixture of Compound IV (0.10 g), DMF (3 mL), 2-chloro-4-trifluoropyridine (0.08 g) and sodium hydride (51 mg) was stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol 10/1) to give the title compound V (69.4 mg). Got.
  • Step (i): Compound I (200 mg; Compound V of Example 45), N, N-dimethylformamide (4 mL), trisdibenzylideneacetone dipalladium (278 mg), Xhantphos (170 mg; 4,5-bis (diphenylphosphino) -9, A mixture of 9-dimethylxanthene), cesium carbonate (657 mg) and 2,4-dichloropyridine (221 mg) was stirred at 100 ° C. overnight. The reaction mixture was filtered through celite, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound II (56 mg).
  • Step (iii): A mixture of Compound III (61 mg), THF (5 mL), 1-chloro-2-methylpyridinium iodide (55 mg), Compound IV (36 mg) and triethylamine (75 ⁇ L) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform / ethyl acetate 1/1) to give the title compound V (33 mg).
  • Example 94 to Example 121 were manufactured by the same manufacturing method as Example 93.
  • Example 122 4-chloro-5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole -3-Carboxamide
  • Step (i): A mixture of Compound I (200 mg), toluene (5 mL), palladium acetate (46 mg), rac-BINAP (126 mg), cesium carbonate (493 mg) and 2,4-dichloropyridine (224 mg) was stirred at 100 ° C. overnight. The reaction mixture was filtered through celite, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound II (70 mg).
  • Step (ii): A mixture of Compound II (70 mg), N-chlorosuccinimide (33 mg) and THF (3 mL) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound III (42 mg).
  • Step (iv): A mixture of Compound IV (45 mg), THF (5 mL), 1-chloro-2-methylpyridinium iodide (37 mg), Compound V (24 mg) and triethylamine (0.051 mL) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform / ethyl acetate 1/1) to give the title compound VI (39 mg).
  • Example 123 to Example 126 were manufactured by the same manufacturing method as Example 122.
  • Example 127 to Example 132 were produced by the same production method as in Example 93 using Reference Example 10 or 13.
  • Step (i): A mixture of Compound I (738.2 mg; synthesis intermediate of Example 10), THF (25 mL) and N-bromosuccinimide (0.50 g) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 3/1) to give Compound II (0.86 g).
  • Step (ii): To a mixture of Compound II (0.86 g), THF (18 mL) and Pd (t-Bu 3 P) 2 (0.15 g) under a nitrogen atmosphere, a methylzinc chloride-hexane solution (7 mL, 2.0 M) was added dropwise. did. After stirring at room temperature overnight, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound III (0.20 g).
  • Example 134 was produced by the same production method as in Example 133.
  • Example 135 N-[(E) -5-hydroxyadamantan-2-yl] -1,4-dimethyl-5- [methyl (4-methylphenyl) amino] -1H-pyrazole-3-carboxamide
  • Step (i): A solution of compound I (3.50 g) in propionic anhydride (10.0 g) was stirred at 90 ° C. overnight. Methanol (30 mL) and 2M aqueous sodium hydroxide solution (50 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 3/1) to give Compound II (4.98 g).
  • Step (iii): A mixture of Compound III (7.62 g), THF (133 mL), pyridine (7 mL), N-methylhydrazine (1.6 mL) and Lawesson's reagent (12 g) was stirred at 60 ° C. overnight. To the reaction solution was added 1.2 M hydrochloric acid, extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound IV (3.58 g).
  • Example 136 was manufactured by the same manufacturing method as Example 135.
  • N-bromosuccinimide (32.2 mg) was added to a solution of compound I (60.2 mg; Example 47) in THF (4 mL), and the mixture was stirred at room temperature for 4 hours. It was added dropwise 2M methyl zinc chloride -THF solution (0.5 mL) to the reaction solution, followed by Pd a (t Bu 3 P) 2 ( 26.7mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 138 5-[(4,5-difluoro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3 -Carboxamide
  • Step (i): A mixture of Compound I (464.8 mg; synthesis intermediate of Example 112), sulfolane (5 mL), potassium fluoride (1.71 g) and 18-crown-6 (0.81 g) was stirred at 180 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate 2/1) to obtain a mixture (88.4 mg) of Compound I and Compound II.
  • Example 139 was produced by the same production method as in Example 138.
  • Example 140 5-[(5-chloro-1,3-thiazol-2-yl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H -Pyrazole-3-carboxamide
  • Step (i): Selectfluor (registered trademark, Aldrich product, 4.05 g) was added to a solution of ice-cooled compound I (2.53 g; compound II of Example 143) in acetonitrile (25 mL), and the mixture was stirred at room temperature for 2 hours. Selectfluor (650 mg) was added at room temperature and stirred for 3 hours. The reaction mixture was filtered, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. Sodium bicarbonate water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 4/1) to give Compound II (1.26 g).
  • Step (ii): A mixture of Compound II (1.26 g), methanol (20 mL) and 20% palladium-carbon (600 mg, 40% moisture) was stirred overnight at room temperature under a hydrogen atmosphere (4 atm). The reaction mixture was filtered through celite, and the cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 1/1) to give Compound III (698 mg).
  • Step (iii): A mixture of Compound III (402 mg), toluene (6 mL), palladium acetate (125 mg), rac-BINAP (349 mg), cesium carbonate (1.21 g) and 2,4-dichloropyridine (304 mg) was stirred at 100 ° C. overnight. . The reaction mixture was filtered through Celite, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound IV (173 mg).
  • Step (v): A mixture of Compound V (171 mg), THF (10 mL), 1-chloro-2-methylpyridinium iodide (202 mg), Compound VI (36 mg) and triethylamine (75 ⁇ L) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform / ethyl acetate 1/1) to give the title compound VII (212 mg).
  • Example 142 was produced in the same manner as in Example 141.
  • Example 143 1-ethyl-5-[(4-fluorophenyl) (methyl) amino] -N-[(2s, 5r) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3 -Carboxamide
  • Step (i): Triethylamine (87.0 g) was added dropwise to a mixture of Compound I (70.2 g; Compound III of Reference Example 8), ethylhydrazine hydrochloride (50.5 g), and THF (400 mL) at room temperature. And stirred overnight. The precipitate was filtered off, Lawesson's reagent (123.35 g) and pyridine (100 mL) were added to the filtrate, and the mixture was stirred at 60 ° C. for 9 hours. After concentration, ethyl acetate was added and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and 1.2M aqueous hydrochloric acid. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate 2/1) to give Compound II (35.47 g).
  • Step (iii): Compound III (5.01 g), DMF (64 mL), Compound IV (2.88 g; Compound VII of Reference Example 14), WSC ⁇ HCl (5.60 g), HOBt ⁇ H 2 O (5.25 g) and triethylamine ( 30 mL) was stirred at room temperature overnight. To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / chloroform 1/4) to obtain Compound V (3.91 g).
  • Step (v): A mixture of Compound VI (100 mg), toluene (1.3 mL), 4-fluorobromobenzene (43 ⁇ L), palladium acetate (12 mg), BINAP (35 mg) and cesium carbonate (257 mg) was stirred at 80 ° C. overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate 1/4) to give the title compound VII (28 mg).
  • Examples 144-155 In the same manner as in Example 143, Examples 144 to 155 were manufactured.
  • Test example 1 Inhibitory activity test on cortisone reducing activity of cultured human adipocytes Normal human preadipocytes (HPrAD-vis, manufactured by Cambrex) were seeded on a 48-well cell culture plate, and differentiation was induced according to the protocol attached to the kit. .
  • Cell culture medium on differentiation induction day 9-11 is 100 nM [1,2-3H] cortisone (1 ⁇ Ci / well, manufactured by Muromachi Yakuhin), 0.5% DMSO, test compound (test substance addition group, test substance) In the non-added section, the medium was replaced with 0.2 ml of D-MEM medium (Gibco) containing only DMSO. After culturing at 37 ° C.
  • a TLC plate was developed by putting a developing solvent of chloroform / methanol (90:10, v / v) in a sealed container, and then the TLC plate was dried at room temperature. The dried TLC plate was exposed to an imaging plate (TR-2040, Fuji Film) for at least 16 hours. After completion of the exposure, the imaging plate was analyzed with a bioimage analyzer (BAS 2500, Fuji Film Co., Ltd.), and [3H] radioactivity in a portion corresponding to the development position of cortisol on the TLC plate was measured.
  • the IC 50 value was calculated by linearly regressing the logarithmic value of the analyte concentration and the inhibitory activity value using two points of data showing the inhibitory activity around 50%.
  • the IC 50 value for human adipocyte cortisone reducing activity of the compound of the present invention is usually in the range of 0.01 to 1000 nM.
  • the IC 50 value for human adipocyte cortisone reduction activity of the following compounds of the present invention was measured. The results are shown in Table 19.
  • Test Example 2 Inhibitory activity test for cortisone reducing activity of primary cultured mouse fat cells Adipose tissue adhering to the mesentery and testicles of 10 ICR male mice (Japan SLC) 9-11 weeks old , Referred to as “visceral adipose tissue”) is phosphate buffer (0.20 g / L KCl, 0.20 g / L KH 2 PO 4 , 8.00 g / L NaCl, 2.16 g / L Na 2 HPO 4).
  • Visceral fat tissues extracted above were collagenase (type II, Sigma), penicillin (Gibco), streptomycin (Gibco) and amphotericin (Gibco), respectively, at final concentrations of 1 mg / ml, 100 units / ml, Dulbecco's modified Eagle's medium (containing 4.5 g / L D-glucose and 584 mg / L L-glutamine, Gibco) added to 100 ⁇ g / ml and 250 ng / ml to about 5 mm square using scissors Shredded. Next, this was shaken at 37 ° C.
  • FBS fetal bovine serum
  • Dulbecco's modified Eagle's medium (containing 4.5 g / L D-glucose and 584 mg / L L-glutamine, Gibco) added to final concentrations of 10%, 200 ⁇ M, 100 units / ml, 100 ⁇ g / ml and 250 ng / ml, respectively.
  • FBS-containing medium The suspension was suspended in 30 ml, and the suspension was filtered through a nylon mesh (420S [eye size is 25 ⁇ m], Sangen Industrial Co., Ltd.).
  • the filtrate was collected, centrifuged at 1800 rpm for 5 minutes at room temperature, the liquid layer was gently removed by decantation, and the sediment was suspended again in 30 ml of FBS-containing medium.
  • the suspension was centrifuged, liquid layer removed, and suspended in an FBS-containing medium two more times in the same manner as described above to prepare 90 ml of the suspension.
  • 30 ml of the suspension was dispensed into a cell culture flask (T150 for adherent cells, Iwaki Glass Co., Ltd.) and cultured in the presence of 37 ° C. and 5% CO 2 . After 5 to 6 hours from the start of the culture, the medium was removed, and the wall of the flask was washed with 15 ml of the phosphate buffer.
  • trypsin-EDTA trypsin-ethylenediaminetetraacetic acid
  • the number of cells in the cell suspension was measured using a hemocytometer, and the cell suspension was diluted by adding an FBS-containing medium to 1.4 ⁇ 10 5 cells / ml.
  • the diluted solution thus obtained was dispensed into a 48-well plate (for adherent cell culture, Iwaki Glass Co., Ltd.) at 300 ⁇ l per well and cultured at 37 ° C. for 1 to 2 days in the presence of 5% CO 2 . .
  • the medium was removed from each well of the 48-well plate, 10 ⁇ g / ml insulin (Sigma), 0.25 ⁇ M dexamethasone (Wako Pure Chemical Industries), 0.5 mM 3-isobutyl-1-methyl-xanthine (Sigma) and 5 ⁇ M 300 ⁇ l of FBS-containing medium containing 15-deoxy- ⁇ 12,14-prostaglandin J2 (Cayman) was added to each well and cultured at 37 ° C. for 3 days in the presence of 5% CO 2 .
  • the medium in each well was removed, and 300 ⁇ l of FBS-containing medium containing 10 ⁇ g / ml insulin and 5 ⁇ M 15-deoxy- ⁇ 12,14-prostaglandin J2 was added to each well and cultured for 2 days. Further, the medium in each well was removed, and 300 ⁇ l of FBS-containing medium containing 10 ⁇ g / ml insulin and 5 ⁇ M 15-deoxy- ⁇ 12,14-prostaglandin J2 was added to each well and cultured for 2 days.
  • the adipocyte culture medium in which differentiation was induced as described above was prepared using 100 nM [1,2-3H] cortisone (1 ⁇ Ci / well, Muromachi Pharmaceutical), 0.5% DMSO, test compound (test substance addition group, test substance) The medium was replaced with 0.2 ml of D-MEM medium (Gibco) containing DMSO for the additive-free group. After culturing at 37 ° C. for 3 hours, the whole medium was recovered. As a background section, a medium not added to the cells was used. The medium was mixed with 0.1 ml of ethyl acetate in an Eppendorf tube.
  • TLC plate thin layer chromatography
  • the IC 50 value was calculated by linearly regressing the logarithmic value of the analyte concentration and the inhibitory activity value using two points of data showing the inhibitory activity around 50%.
  • the IC 50 value for mouse adipocyte cortisone reducing activity of the compound of the present invention is usually in the range of 0.01 to 1000 nM.
  • IC 50 values for mouse adipocyte cortisone reduction activity of the following compounds of the present invention were measured. The results are shown in Table 20.
  • mice fasted for 18 hours or more are orally administered with a 20-30% glucose solution at a dose of 10 mL per kg body weight, and blood is collected from the tail vein over time from 15 minutes to 3 hours after administration. .
  • the area under the curve (AUC) is calculated from changes over time in the sugar and insulin concentrations contained in the blood.
  • AUC area under the curve
  • the same test is performed for a group administered with only the methylcellulose solution instead of the methylcellulose solution containing the 11 ⁇ HSD1 inhibitor.
  • the test compound is anti-obesity It can be determined that it has an action. Furthermore, the weights of the visceral fat, specifically mesenteric fat, epididymal fat and retroperitoneal fat of the test mice after the administration are measured. By confirming that each fat weight in the test compound administration group is statistically significantly lower than that in the control group, the test compound has a visceral fat accumulation-inhibiting action or a visceral fat reducing action. Can be determined.
  • Test Example 4 Mouse tail suspension test
  • the pharmacological evaluation of the 11 ⁇ HSD1 inhibitor against the antidepressant action can be performed by the following method.
  • a tail suspension test using 25-35 g male Crlj: CD1 (ICR) mice (Charles River Japan) mice (Charles River Japan) mice (Charles River Japan) mice (Charles River Japan) mice (Charles River Japan) mice (Charles River Japan) mice (Charles River Japan) mice (Charles River Japan), the mouse's tail is suspended and the escape behavior (postcard reaction) time for 6 minutes in the inverted fishing state is measured.
  • a decrease in escape behavior implies behavioral despair and is similar to depressive symptoms. Therefore, the compound of the present invention is administered once or multiple times before the test, and the antidepressant action (depression, manic depression) is evaluated by measuring the escape behavior time during the test.
  • Test Example 5 Cognitive function enhancing action in mouse object recognition test First trial (training) and second trial (test) in a novel object recognition test using 13-15 g of Slc: ddY mice (male, SLC Japan) Depending on the interval time, a decrease in memory for a known object is observed, and when the second trial is performed 24 hours later, significant forgetting is observed. Therefore, the compound of the present invention is administered before the first trial, and the memory enhancing action in the second trial is evaluated.
  • the compound of the present invention is useful as an 11 ⁇ HSD1 inhibitor.

Abstract

The invention provides a compound represented by formula (1) or a pharmacologically acceptable salt thereof. (In the formula, R1 is an optionally substituted C6-10 aryl group or an optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group; R2 is an optionally substituted C1-6 alkyl group or the like; R3 is a hydrogen atom, halogen atom, cyano group, or optionally substituted C1-6 alkyl group; R4 is an optionally substituted C1-6 alkyl group or optionally substituted C3-7 cycloalkyl group; and R5 is a hydroxyl group, aminocarbonyl group, fluorine atom, or methylsulfonyl group.)

Description

アリールアミノピラゾール誘導体Arylaminopyrazole derivatives
　本発明は、医薬として有用なアリールアミノピラゾール誘導体、またはその薬理学上許容される塩に関する。より詳しくは、アリールアミノピラゾール誘導体、またはその薬理学上許容される塩を含有する医薬組成物に関する。該化合物を含有するグルココルチコイドが関与する病態の治療剤または予防剤、または１１βヒドロキシステロイドデヒドロゲナーゼタイプ１酵素（以下、「１１βＨＳＤ１」と記す）阻害剤に関する。 The present invention relates to an arylaminopyrazole derivative useful as a medicine, or a pharmacologically acceptable salt thereof. More specifically, the present invention relates to a pharmaceutical composition containing an arylaminopyrazole derivative or a pharmacologically acceptable salt thereof. The present invention relates to a therapeutic or prophylactic agent for a disease state involving a glucocorticoid containing the compound, or an inhibitor of 11β hydroxysteroid dehydrogenase type 1 enzyme (hereinafter referred to as “11βHSD1”).
　グルココルチコイドは末梢での糖代謝やアミノ酸代謝を調節する。ヒトにおいて、グルココルチコイドは副腎で産生されるほかに、脂肪や肝臓などの末梢組織でも代謝が行われる。１１βＨＳＤ１は不活性型コルチゾンを活性型コルチゾールに変換する酵素であり、主に脂肪や肝臓にて発現することから、１１βＨＳＤ１は脂肪や肝臓でのグルココルチコイド活性化に関与すると考えられている。コルチゾールは脂肪細胞への脂肪蓄積促進作用や肝臓での糖新生促進作用を有することから、１１βＨＳＤ１は末梢での糖・脂質代謝を調節することによって、全身の恒常性維持に寄与しているものと考えられる。その一方で、ヒトにおいてはインスリン抵抗性患者で脂肪組織１１βＨＳＤ１が有意に活性上昇しており、１１βＨＳＤ１活性は皮下脂肪より内臓脂肪で顕著に高い。また、１１βＨＳＤ１遺伝子欠損マウスは高脂肪食負荷時に内臓脂肪蓄積、糖・脂質代謝異常の発症が抑制され、さらに脂肪細胞特異的１１βＨＳＤ１過剰発現マウスは顕著な内臓脂肪型肥満、糖・脂質代謝異常を呈する。これらの知見から、ヒトおよびマウスにおいて、１１βＨＳＤ１の過剰な活性化が内臓脂肪蓄積およびメタボリックシンドロームの発症と深く関連していることが示唆されている（非特許文献１及び２）。すなわち、本酵素の活性を阻害することにより、肝臓における糖新生の抑制、脂肪細胞での脂肪蓄積の抑制、さらには全身の糖・脂質代謝の改善という効果が期待されている。 Glucocorticoid regulates peripheral glucose metabolism and amino acid metabolism. In humans, glucocorticoids are metabolized in peripheral tissues such as fat and liver in addition to being produced in the adrenal glands. 11βHSD1 is an enzyme that converts inactive cortisone into active cortisol, and is expressed mainly in fat and liver. Therefore, 11βHSD1 is considered to be involved in glucocorticoid activation in fat and liver. Since cortisol has an action of promoting fat accumulation in adipocytes and an action of promoting gluconeogenesis in the liver, 11βHSD1 contributes to maintaining homeostasis throughout the body by regulating glucose and lipid metabolism in the periphery. Conceivable. On the other hand, in humans, adipose tissue 11βHSD1 is significantly increased in insulin resistant patients, and 11βHSD1 activity is significantly higher in visceral fat than subcutaneous fat. In addition, 11βHSD1 gene-deficient mice suppressed visceral fat accumulation and abnormal sugar / lipid metabolism when loaded with a high-fat diet. Present. These findings suggest that in humans and mice, excessive activation of 11βHSD1 is closely related to visceral fat accumulation and the development of metabolic syndrome (Non-patent Documents 1 and 2). That is, by inhibiting the activity of this enzyme, effects such as suppression of gluconeogenesis in the liver, suppression of fat accumulation in adipocytes, and improvement of systemic sugar / lipid metabolism are expected.
　糖代謝の改善については、膵臓β細胞の１１βＨＳＤ１活性がインスリン分泌の低下に寄与する可能性や、ヒト筋肉細胞において１１βＨＳＤ１活性が筋肉細胞の糖取込み低下に関与している可能性が報告されていることから、１１βＨＳＤ１阻害剤は直接的に高血糖を是正できると考えられる。 Regarding the improvement of glucose metabolism, it has been reported that 11βHSD1 activity of pancreatic β cells may contribute to a decrease in insulin secretion, and that 11βHSD1 activity may be involved in a decrease in glucose uptake of muscle cells in human muscle cells. Therefore, it is considered that the 11βHSD1 inhibitor can directly correct hyperglycemia.
　また、１１βＨＳＤ１は海馬を含む中枢神経系においても発現している。グルココルチコイドが過剰な疾患であるクッシング病の患者や合成グルココルチコイドの一種であるデキサメタゾンを投与された患者はうつ症状を呈することが知られている。また、グルココルチコイド受容体の拮抗薬がうつ病や躁うつ病に対して奏功することも知られており、うつ病ならびに躁うつ病の病態発現に中枢神経系におけるグルココルチコイドが深く関与していることが示唆されている（非特許文献３及び４）。中枢神経系における活性型グルココルチコイドの産生は、１１βＨＳＤ１が担っていることから、１１βＨＳＤ１阻害薬がうつ病および躁うつ病の治療に有効性を示すことが期待されている。 Also, 11βHSD1 is expressed in the central nervous system including the hippocampus. It is known that patients with Cushing's disease, in which glucocorticoids are excessive, and patients who have been administered dexamethasone, a type of synthetic glucocorticoid, exhibit depressive symptoms. In addition, glucocorticoid receptor antagonists are also known to be effective against depression and manic depression, and glucocorticoids in the central nervous system are deeply involved in the pathogenesis of depression and manic depression (Non-Patent Documents 3 and 4). Since 11βHSD1 is responsible for the production of active glucocorticoids in the central nervous system, 11βHSD1 inhibitors are expected to show efficacy in the treatment of depression and manic depression.
　さらには、グルココルチコイドを長期にわたって投与されたマウスは、アルツハイマー型認知症との関連が強く示唆されているアミロイドβたんぱく質の沈着を起こすこと、１１βＨＳＤ１遺伝子欠損マウスは、加齢に伴う認知機能低下が抑制され認知保持能の亢進が認められることなどから、認知機能の調節にも１１βＨＳＤ１が深く関与していることが示唆されている（非特許文献５～７）。これらの知見は１１βＨＳＤ１阻害薬がアルツハイマー型認知症をはじめとする種々の認知症の治療薬として有用であることを示唆している。１１βＨＳＤ１は、免疫細胞で機能することなども示されており、１１βＨＳＤ１阻害剤は免疫機能の異常に起因する疾患の治療効果も期待されている。 Furthermore, mice treated with glucocorticoid for a long time cause amyloid β protein deposition that is strongly suggested to be associated with Alzheimer-type dementia, and 11βHSD1 gene-deficient mice have a decline in cognitive function associated with aging. It is suggested that 11βHSD1 is also deeply involved in the regulation of cognitive function because it is suppressed and cognitive retention is enhanced (Non-Patent Documents 5 to 7). These findings suggest that 11βHSD1 inhibitors are useful as therapeutic agents for various dementias including Alzheimer type dementia. 11βHSD1 has also been shown to function in immune cells, and 11βHSD1 inhibitors are also expected to have therapeutic effects on diseases caused by abnormal immune functions.
　これまでに種々の１１βＨＳＤ１阻害剤が報告されている。例えば特許文献１には下記式
Figure JPOXMLDOC01-appb-C000008
 ［式中、ＲＡおよびＲＢは、それぞれ独立して置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいヘテロシクロアルキル基、または式：－Ｒｗ－Ｒｘ－Ｒｙ－Ｒｚで表される基を表す。Ｒｗは、置換されてもよいアルキレン基等を表す。Ｒｘは、単結合、酸素原子等を表す。Ｒｙは、単結合、または置換されてもよいアルキレン基を表す。Ｒｚは、置換されてもよいアルキル基等を表す。ＲＣは置換されてもよいアルキル基等を表す。ＲＤは水素原子、ハロゲン原子、置換されてもよいアルキル基等を表す。ＲＥは水素原子または置換されてもよいアルキル基を表す。ＲＦは下記式（Ｇ１）：
Figure JPOXMLDOC01-appb-C000009
 から選ばれ、１つの水素原子が結合手となった基を表し、これらの基はさらに置換されていてもよい。］で表される化合物が開示されている。しかしながら、ＲＡまたはＲＢとして、アリール基またはヘテロアリール基を持つことは全く開示されていないことから、本発明とは構造が異なる。 Various 11βHSD1 inhibitors have been reported so far. For example, Patent Document 1 discloses the following formula:
Figure JPOXMLDOC01-appb-C000008
 [Wherein, R A and R B each independently represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, or a group represented by the formula: —Rw—Rx— This represents a group represented by Ry-Rz. Rw represents an alkylene group which may be substituted. Rx represents a single bond, an oxygen atom, or the like. Ry represents a single bond or an optionally substituted alkylene group. Rz represents an optionally substituted alkyl group or the like. R C represents an optionally substituted alkyl group or the like. RD represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, or the like. R E represents a hydrogen atom or an optionally substituted alkyl group. R F represents the following formula (G1):
Figure JPOXMLDOC01-appb-C000009
 Represents a group in which one hydrogen atom is a bond, and these groups may be further substituted. The compound represented by this is disclosed. However, since it is not disclosed at all that R A or R B has an aryl group or a heteroaryl group, the structure is different from the present invention.
　また、特許文献２には下記式
Figure JPOXMLDOC01-appb-C000010
 Patent Document 2 discloses the following formula:
Figure JPOXMLDOC01-appb-C000010
［式中、Ｒ１は水素原子、またはＣ１－４アルキル基（該アルキル基は、非置換またはヒドロキシもしくは１～３個のフッ素原子で置換されている。）であり、Ｒ２はＣ１－４アルキル、アリール、アリールメチル、ヘテロアリールまたはヘテロアリールメチル等であり、Ｒ３は水素原子、ハロゲン原子等であり、Ｒ４は水素原子またはＣ１－４アルキル基であり、Ｒ４は水素原子またはアルキルを表し、Ｒ５は（ＣＨ２）ｎアリール、（ＣＨ２）ｎＣ４－９シクロアルキル、（ＣＨ２）ｎＣ５－１１ビシクロアルキルまたは（ＣＨ２）ｎＣ１０－１４トリシクロアルキル等であり、ｎは独立して、０、１または２である。］で表される化合物が開示されている。 [Wherein R 1 is a hydrogen atom, or a C 1-4 alkyl group (the alkyl group is unsubstituted or substituted with hydroxy or 1 to 3 fluorine atoms), and R 2 is C 1 -4 alkyl, aryl, arylmethyl, heteroaryl, heteroarylmethyl and the like, R 3 is a hydrogen atom, a halogen atom, etc., R 4 is a hydrogen atom or a C 1-4 alkyl group, and R 4 is hydrogen represents an atom or alkyl, R 5 is (CH 2) n aryl, (CH 2) n C 4-9 cycloalkyl, (CH 2) n C 5-11 bicycloalkyl or (CH 2) n C 10-14 birds Cycloalkyl and the like, and n is independently 0, 1 or 2. The compound represented by this is disclosed.
国際公開第２００９／０２０１３７号パンフレットInternational Publication No. 2009/020137 Pamphlet 国際公開第２００５／０１６８７７号パンフレットInternational Publication No. 2005/016877 Pamphlet
　現在、ＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、低ＨＤＬ症、高ＬＤＬ症、脂質代謝異常症、高脂血症、高トリグリセライド血症、高コレステロール血症、高血圧、動脈硬化、血管狭窄、アテローム性動脈硬化、肥満、認知症、認知障害、緑内障、網膜症、アルツハイマー症、骨粗しょう症、免疫障害、メタボリックシンドローム、うつ、不安、躁うつ病、心血管疾患、神経変性疾患、クッシング症候群、サブクリニカルクッシング症候群などの疾患を予防および／または治療することができる予防薬ないし治療薬として、１１βＨＳＤ１阻害作用を有し医薬品として満足できる化合物の開発が望まれている。 Currently, type II diabetes, impaired glucose tolerance, hyperglycemia, insulin resistance, low HDL disease, hyper LDL disease, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, arteriosclerosis, Vascular stenosis, atherosclerosis, obesity, dementia, cognitive impairment, glaucoma, retinopathy, Alzheimer's disease, osteoporosis, immune disorder, metabolic syndrome, depression, anxiety, manic depression, cardiovascular disease, neurodegenerative disease, As a prophylactic or therapeutic agent capable of preventing and / or treating diseases such as Cushing's syndrome and subclinical Cushing's syndrome, development of a compound having an 11βHSD1 inhibitory action and satisfactory as a pharmaceutical is desired.
　これまでに１１βＨＳＤ１阻害剤として、後述の式（１）で表されるアリールアミノピラゾール誘導体（以下、「本発明化合物」と称する場合もある。）は全く製造されておらず、その阻害活性については全く知られていなかった。そこで、本発明者らは上記課題を達成するために、これら誘導体について鋭意検討した結果、式（１）で表されるアリールアミノピラゾール誘導体が強い１１βＨＳＤ１阻害活性を示すことを見出した。更には、該誘導体として、１１βＨＳＤ１阻害活性に加えて、代謝安定性、溶解度、薬物動態および組織移行性（例えば、脂肪組織や中枢神経系組織への移行）などの薬物として必要な性質のバランスに優れた誘導体群を見出し、本発明を完成するに至った。 So far, as an 11βHSD1 inhibitor, an arylaminopyrazole derivative represented by the following formula (1) (hereinafter sometimes referred to as “the compound of the present invention”) has not been produced at all. It was not known at all. Therefore, the present inventors have intensively studied these derivatives in order to achieve the above-mentioned problems, and as a result, have found that the arylaminopyrazole derivative represented by the formula (1) exhibits a strong 11βHSD1 inhibitory activity. Furthermore, as a derivative, in addition to the 11βHSD1 inhibitory activity, the balance of properties necessary as a drug such as metabolic stability, solubility, pharmacokinetics and tissue migration (for example, migration to adipose tissue and central nervous system tissue) is achieved. An excellent group of derivatives was found and the present invention was completed.
　すなわち本発明は、以下の通りである。 That is, the present invention is as follows.
項１：式（１）で表される化合物、またはその薬理学上許容される塩。
Figure JPOXMLDOC01-appb-C000011
 ［式中、
　Ｒ１は、置換されていてもよいＣ６－１０アリール基、または置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基であり；
　Ｒ２は、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ３－７シクロアルキル基、または置換されていてもよい複素環基であり；
　Ｒ３は水素原子、ハロゲン原子、シアノ基、または置換されていてもよいＣ１－６アルキル基であり；
　Ｒ４は、置換されていてもよいＣ１－６アルキル基、または置換されていてもよいＣ３－７シクロアルキル基であり；および
　Ｒ５は、水酸基、アミノカルボニル基、フッ素原子またはメチルスルホニル基である。］ Item 1: A compound represented by formula (1) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000011
 [Where:
R 1 is an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group;
R 2 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, or an optionally substituted heterocyclic group;
R 3 is a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group;
R 4 is an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-7 cycloalkyl group; and R 5 is a hydroxyl group, an aminocarbonyl group, a fluorine atom or methylsulfonyl It is a group. ]
項２：Ｒ１における置換されていてもよいＣ６－１０アリール基、および置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基の置換基が、
（１）重水素原子、
（２）ハロゲン原子、
（３）水酸基、
（４）シアノ基、
（５）複素環基、
（６）Ｃ３－７シクロアルキル基、
（７）Ｃ３－７シクロアルキルオキシ基、
（８）Ｃ１－４アルキル基（該アルキル基は、
　（ａ）１～３個のハロゲン原子、
　（ｂ）ヒドロキシ、
　（ｃ）Ｃ３－６シクロアルキルオキシ、
　（ｄ）Ｃ１－４アルコキシ（該アルコキシは、
　　　　１～３個のハロゲン原子、
　　　　Ｃ１－４アルコキシ、または
　　　　ヒドロキシで置換されていてもよい。）、
　（ｅ）Ｃ３－６シクロアルキル、
　（ｆ）アミノ（該アミノは、Ｃ１－６アルキル、およびＣ３－６シクロアルキルからなる群から選択される同種または異種の１～２個の基で置換されていてもよい。）、または
　（ｇ）４員～７員の環状アミノで置換されていてもよい。）、
（９）Ｃ１－４アルコキシ基（該アルコキシ基は、
　（ａ）１～３個のハロゲン原子、
　（ｂ）ヒドロキシ、
　（ｃ）Ｃ１－４アルコキシ、
　（ｄ）Ｃ３－６シクロアルキルオキシ、または
　（ｅ）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（１０）Ｃ１－６アルキルカルボニル基（該アルキルは、
　（ａ）ヒドロキシ、
　（ｂ）１～３個のハロゲン原子、
　（ｃ）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　（ｄ）Ｃ３－６シクロアルコキシ、または
　（ｅ）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（１１）Ｃ３－６シクロアルキルカルボニル基（該シクロアルキルは、
　（ａ）ヒドロキシ、
　（ｂ）１～３個のハロゲン原子、
　（ｃ）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　（ｄ）Ｃ３－６シクロアルコキシ、
　（ｅ）Ｃ１－４アルキル、または
　（ｆ）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（１２）Ｃ６－１０アリール基（該アリール基は、
　（ａ）ハロゲン原子、
　（ｂ）Ｃ１－４アルコキシ、
　（ｃ）Ｃ３－７シクロアルキル、または
　（ｄ）Ｃ１－４アルキルで置換されていてもよい。）、
（１３）５員～１２員の単環式もしくは多環式のヘテロアリール基（該へテロアリール基は、
　（ａ）ハロゲン原子、
　（ｂ）Ｃ１－４アルキル（該アルキルは、１～３個のハロゲン原子で置換されていてもよい。）、または
　（ｃ）Ｃ３－６シクロアルキルで置換されていてもよい。）、および
（１４）Ｃ１－４アルキルスルホニル基
からなる群から選択される基である、項１に記載の化合物、またはその薬理学上許容される塩。 Item 2: The optionally substituted C 6-10 aryl group in R 1 and the optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group substituents are:
(1) deuterium atom,
(2) a halogen atom,
(3) hydroxyl group,
(4) a cyano group,
(5) a heterocyclic group,
(6) a C 3-7 cycloalkyl group,
(7) C 3-7 cycloalkyloxy group,
(8) C 1-4 alkyl group (the alkyl group is
(A) 1 to 3 halogen atoms,
(B) hydroxy,
(C) C 3-6 cycloalkyloxy,
(D) C 1-4 alkoxy (the alkoxy is
1 to 3 halogen atoms,
It may be substituted with C 1-4 alkoxy or hydroxy. ),
(E) C 3-6 cycloalkyl,
(F) amino (the amino may be substituted with 1 to 2 groups of the same or different types selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl), or (G) It may be substituted with a 4- to 7-membered cyclic amino. ),
(9) C 1-4 alkoxy group (the alkoxy group is
(A) 1 to 3 halogen atoms,
(B) hydroxy,
(C) C 1-4 alkoxy,
(D) C 3-6 cycloalkyloxy, or (e) C 3-6 optionally substituted by cycloalkyl. ),
(10) C 1-6 alkylcarbonyl group (the alkyl is
(A) hydroxy,
(B) 1 to 3 halogen atoms,
(C) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(D) C 3-6 cycloalkoxy, or (e) C 3-6 optionally substituted by cycloalkyl. ),
(11) C 3-6 cycloalkylcarbonyl group (the cycloalkyl is
(A) hydroxy,
(B) 1 to 3 halogen atoms,
(C) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(D) C 3-6 cycloalkoxy,
(E) optionally substituted with C 1-4 alkyl, or (f) C 3-6 cycloalkyl. ),
(12) C 6-10 aryl group (the aryl group is
(A) a halogen atom,
(B) C 1-4 alkoxy,
(C) C 3-7 cycloalkyl, or (d) C 1-4 alkyl may be substituted. ),
(13) a 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl group is
(A) a halogen atom,
(B) C 1-4 alkyl (which may be substituted with 1 to 3 halogen atoms), or (c) optionally substituted with C 3-6 cycloalkyl. ), And (14) The compound according to item 1 or a pharmacologically acceptable salt thereof, which is a group selected from the group consisting of C 1-4 alkylsulfonyl groups.
項３：Ｒ１が、Ｃ６－１０アリール基（該アリール基は、
（１）ハロゲン原子、
（２）Ｃ３－７シクロアルキル基、
（３）Ｃ１－４アルキル基（該アルキル基は、
　（ａ）１～３個のフッ素原子、
　（ｂ）Ｃ１－４アルコキシ、
　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
　（ｄ）４員～７員の環状アミノで置換されていてもよい。）、
（４）Ｃ１－４アルコキシ基（該アルコキシ基は、
　（ａ）１～３個のフッ素原子、または
　（ｂ）Ｃ１－４アルコキシで置換されていてもよい。）、および
（５）Ｃ１－４アルキルカルボニル基からなる群から選択される同種または異種の１～５個の基で置換されていてもよい。）である、項１または項２のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 3: R 1 is a C 6-10 aryl group (the aryl group is
(1) a halogen atom,
(2) a C 3-7 cycloalkyl group,
(3) C 1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C 1-4 alkoxy,
(C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ),
(4) C 1-4 alkoxy group (the alkoxy group is
(A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. And (5) 1 to 5 groups of the same or different types selected from the group consisting of C 1-4 alkylcarbonyl groups. The compound according to any one of Items 1 or 2, or a pharmaceutically acceptable salt thereof.
項４：Ｒ１が、Ｃ６－１０アリール基（該アリール基は、
（１）ハロゲン原子、
（２）Ｃ１－４アルキル（該アルキル基は、１～３個のフッ素原子で置換されていてもよい。）、および
（３）Ｃ１－４アルコキシからなる群から選択される同種または異種の１～５個の基で置換されていてもよい。）である、項３に記載の化合物、またはその薬理学上許容される塩。 Item 4: R 1 is a C 6-10 aryl group (the aryl group is
(1) a halogen atom,
(2) C 1-4 alkyl (the alkyl group may be substituted with 1 to 3 fluorine atoms), and (3) the same or different selected from the group consisting of C 1-4 alkoxy May be substituted with 1 to 5 groups. Or a pharmacologically acceptable salt thereof.
項５：Ｒ１が、５員もしくは６員の単環式ヘテロアリール基（該ヘテロアリール基は、
（１）ハロゲン原子、
（２）Ｃ３－７シクロアルキル基、
（３）Ｃ１－４アルキル基（該アルキル基は、
　（ａ）１～３個のフッ素原子、
　（ｂ）Ｃ１－４アルコキシ、
　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
　（ｄ）４員～７員の環状アミノで置換されていてもよい。）、
（４）Ｃ１－４アルコキシ基（該アルコキシ基は、
　（ａ）１～３個のフッ素原子、または
　（ｂ）Ｃ１－４アルコキシで置換されていてもよい。）、および
（５）Ｃ１－４アルキルカルボニル基からなる群から選択される同種または異種の少なくとも１以上の置換基で置換されていてもよい。）である、項２に記載の化合物、またはその薬理学上許容される塩。 Item 5: R 1 is a 5-membered or 6-membered monocyclic heteroaryl group (the heteroaryl group is
(1) a halogen atom,
(2) a C 3-7 cycloalkyl group,
(3) C 1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C 1-4 alkoxy,
(C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ),
(4) C 1-4 alkoxy group (the alkoxy group is
(A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. ), And (5) may be substituted with at least one or more substituents selected from the group consisting of C 1-4 alkylcarbonyl groups. Or a pharmacologically acceptable salt thereof.
項６：Ｒ１が、５員もしくは６員の単環式ヘテロアリール基（該ヘテロアリール基は、
（１）ハロゲン原子、および
（２）Ｃ１－４アルキル基からなる群から選択される同種または異種の少なくとも１以上の置換基で置換されていてもよい。）である、項５に記載の化合物、またはその薬理学上許容される塩。 Item 6: R 1 is a 5-membered or 6-membered monocyclic heteroaryl group (the heteroaryl group is
It may be substituted with at least one or more substituents selected from the group consisting of (1) a halogen atom, and (2) a C 1-4 alkyl group. Item 6. The compound according to Item 5, or a pharmacologically acceptable salt thereof.
項７：Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ａ）～（ｄ）
Figure JPOXMLDOC01-appb-C000012
 ［ここに、（ａ）～（ｄ）は項５または項６のいずれか一項にて定義される置換基で置換されていてもよい。］
で表されるいずれか一つの基である、項５または項６のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 7: The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a) to (d):
Figure JPOXMLDOC01-appb-C000012
 [Wherein (a) to (d) may be substituted with a substituent defined in any one of Items 5 or 6. ]
Item 7. The compound according to any one of Items 5 or 6, or a pharmacologically acceptable salt thereof, which is any one group represented by:
項８：Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ａ）
Figure JPOXMLDOC01-appb-C000013
 ［ここに、（ａ）は項５または項６のいずれか一項にて定義される置換基で置換されていてもよい。］
で表される基である、項７に記載の化合物、またはその薬理学上許容される塩。 Item 8: The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a):
Figure JPOXMLDOC01-appb-C000013
 [Here, (a) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
Item 8. The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
項９：Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ａ１）
Figure JPOXMLDOC01-appb-C000014
 ［ここに、（ａ１）は項５または項６のいずれか一項にて定義される置換基で置換されていてもよい。］
で表される基である、項８に記載の化合物、またはその薬理学上許容される塩。 Item 9: The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a1):
Figure JPOXMLDOC01-appb-C000014
 [Here, (a1) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
Item 9. The compound according to Item 8, which is a group represented by: or a pharmacologically acceptable salt thereof.
項１０：Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ｂ）
Figure JPOXMLDOC01-appb-C000015
 ［ここに、（ｂ）は項５または項６のいずれか一項にて定義される置換基で置換されていてもよい。］
で表される基である、項７に記載の化合物、またはその薬理学上許容される塩。 Item 10: The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (b):
Figure JPOXMLDOC01-appb-C000015
 [Here, (b) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
Item 8. The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
項１１：Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ｃ）
Figure JPOXMLDOC01-appb-C000016
 ［ここに、（ｃ）は項５または項６のいずれか一項にて定義される置換基で置換されていてもよい。］
で表される基である、項７に記載の化合物、またはその薬理学上許容される塩。 Item 11: The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (c):
Figure JPOXMLDOC01-appb-C000016
 [Here, (c) may be substituted with the substituent defined in any one of Item 5 or Item 6. ]
Item 8. The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
項１２：Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ｄ）
Figure JPOXMLDOC01-appb-C000017
 ［ここに、（ｄ）は項５または項６のいずれか一項にて定義される置換基で置換されていてもよい。］
で表される基である、項７に記載の化合物、またはその薬理学上許容される塩。 Item 12: The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (d):
Figure JPOXMLDOC01-appb-C000017
 [Wherein (d) may be substituted with a substituent defined in any one of Items 5 or 6. ]
Item 8. The compound according to Item 7, which is a group represented by: or a pharmacologically acceptable salt thereof.
項１３：Ｒ２が、Ｃ１－６アルキル基（該基は、
（１）１～５個のハロゲン原子、
（２）Ｃ３－６シクロアルキル、または
（３）Ｃ１－４アルコキシで置換されていてもよい。）である、項１～項１２のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 13: R 2 is a C 1-6 alkyl group (the group is
(1) 1 to 5 halogen atoms,
It may be substituted with (2) C 3-6 cycloalkyl or (3) C 1-4 alkoxy. 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
項１４：Ｒ２が、メチル基またはエチル基である、項１３に記載の化合物、またはその薬理学上許容される塩。 Item 14: The compound according to Item 13, or a pharmacologically acceptable salt thereof, wherein R 2 is a methyl group or an ethyl group.
項１５：Ｒ３が、
（１）水素原子、
（２）ハロゲン原子、または
（３）Ｃ１－６アルキル基（該基は、
　（ａ）１～３個のハロゲン原子、
　（ｂ）Ｃ３－６シクロアルキル、または
　（ｃ）Ｃ１－４アルコキシで置換されていてもよい。）である、項１～項１４のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 15: R 3 is
(1) a hydrogen atom,
(2) a halogen atom, or (3) a C 1-6 alkyl group (the group is
(A) 1 to 3 halogen atoms,
(B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. 15. The compound according to any one of Items 1 to 14, or a pharmacologically acceptable salt thereof.
項１６：Ｒ３が、水素原子、塩素原子、フッ素原子またはメチル基である、項１～項１５のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 16: The compound according to any one of Items 1 to 15, or a pharmacologically acceptable salt thereof, wherein R 3 is a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group.
項１７：Ｒ３が、水素原子である、項１６に記載の化合物、またはその薬理学上許容される塩。 Item 17: The compound according to Item 16, or a pharmacologically acceptable salt thereof, wherein R 3 is a hydrogen atom.
項１８：Ｒ４が、
（１）Ｃ１－６アルキル基（該基は、
　（ａ）１～３個のハロゲン原子、
　（ｂ）Ｃ３－６シクロアルキル、または
　（ｃ）Ｃ１－４アルコキシで置換されていてもよい。）、または
（２）Ｃ３－６シクロアルキル基である、項１～項１７のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 18: R 4 is
(1) C 1-6 alkyl group (the group is
(A) 1 to 3 halogen atoms,
(B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. ), Or (2) The compound according to any one of Items 1 to 17, which is a C 3-6 cycloalkyl group, or a pharmacologically acceptable salt thereof.
項１９：Ｒ４が、メチル基、２，２－ジフルオロエチル基、２，２，２－トリフルオロエチル基、またはエチル基である、項１８に記載の化合物、またはその薬理学上許容される塩。 Item 19: The compound according to Item 18 or a pharmacologically acceptable salt thereof, wherein R 4 is a methyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, or an ethyl group. salt.
項２０：Ｒ４が、エチル基である、項１９に記載の化合物、またはその薬理学上許容される塩。 Item 20: The compound according to Item 19, or a pharmacologically acceptable salt thereof, wherein R 4 is an ethyl group.
項２１：Ｒ５が、水酸基である、項１～項２０のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 Item 21: The compound according to any one of Items 1 to 20, or a pharmacologically acceptable salt thereof, wherein R 5 is a hydroxyl group.
項２２：Ｒ５が、アミノカルボニル基である、項１～項２０のいずれか一項に記載の化合物、またはその薬理学的に許容される塩。 Item 22: The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 is an aminocarbonyl group.
項２３：Ｒ５が、メチルスルホニル基である、項１～項２０のいずれか一項に記載の化合物、またはその薬理学的に許容される塩。 Item 23: The compound according to any one of Items 1 to 20, or a pharmacologically acceptable salt thereof, wherein R 5 is a methylsulfonyl group.
項２４：以下の化合物群：
４－クロロ－５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－５－［（３－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－｛［３－フルオロ－５－（トリフルオロメチル）－２－ピリジニル］（メチル）アミノ｝－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（３－フルオロ－５－メチル－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（４－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－４－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－１－エチル－５－［（４－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（４－フルオロフェニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、および
５－［（４－クロロ－２－フルオロフェニル）（メチル）アミノ］－１－エチル－Ｎ－［（２ｓ，５ｒ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド
から選択される化合物である、項１に記載の化合物、またはその薬理学上許容される塩。 Item 24: The following compound group:
4-chloro-5-[(5-chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide ,
5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3-carboxamide;
4-chloro-5-[(3-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide ,
4-Chloro-N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3 -Carboxamide,
1-ethyl-5-{[3-fluoro-5- (trifluoromethyl) -2-pyridinyl] (methyl) amino} -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole -3-carboxamide,
4-chloro-5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
1-ethyl-5-[(4-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -4-methyl-1H-pyrazole-3-carboxamide ,
4-Chloro-1-ethyl-5-[(4-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
1-ethyl-5-[(4-fluorophenyl) (methyl) amino] -N-[(E) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3-carboxamide, and 5- [(4-Chloro-2-fluorophenyl) (methyl) amino] -1-ethyl-N-[(2s, 5r) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3-carboxamide Item 2. The compound according to Item 1, which is a compound selected from: or a pharmacologically acceptable salt thereof.
項２５：以下の化合物群：
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（３－フルオロ－５－メチル－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、および
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド
から選択される化合物である、項１に記載の化合物、またはその薬理学上許容される塩。 Item 25: The following compound group:
5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3-carboxamide;
1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazol-3-carboxamide, and 5-[(5-chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl The compound according to Item 1, or a pharmacologically acceptable salt thereof, which is a compound selected from 1H-pyrazole-3-carboxamide.
項２６：項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩を有効成分として含有する医薬組成物。 Item 26: A pharmaceutical composition comprising the compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient.
項２７：項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩を有効成分として含有するＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、脂質代謝異常症、高血圧、動脈硬化、血管狭窄、肥満、クッシング症候群、サブクリニカルクッシング症候群、緑内障、骨粗鬆症、メタボリックシンドローム、心血管疾患、アテローム性動脈硬化、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療剤。 Item 27: Type II diabetes, glucose intolerance, hyperglycemia, insulin resistance, lipid metabolism abnormality containing the compound according to any one of items 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient Disease, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atherosclerosis, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or epilepsy A treatment for depression.
項２８：項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩を有効成分として含有する緑内障、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療剤。 Item 28: Glaucoma, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or manic depression containing the compound according to any one of items 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic agent.
項２９：ＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、脂質代謝異常症、高血圧、動脈硬化、血管狭窄、肥満、クッシング症候群、サブクリニカルクッシング症候群、緑内障、骨粗鬆症、メタボリックシンドローム、心血管疾患、アテローム性動脈硬化、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療剤を製造するための、項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩の使用。 Item 29: Type II diabetes, impaired glucose tolerance, hyperglycemia, insulin resistance, dyslipidemia, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular Item 26. The compound according to any one of Items 1 to 25 or a pharmacology thereof for producing a therapeutic agent for a disease, atherosclerosis, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or manic depression Use of top acceptable salts.
項３０：緑内障、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療剤を製造するための、項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩の使用。 Item 30: The compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof for producing a therapeutic agent for glaucoma, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or manic depression Salt used.
項３１：項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩の有効量をそれを必要とする対象に投与することを含む、ＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、脂質代謝異常症、高血圧、動脈硬化、血管狭窄、肥満、クッシング症候群、サブクリニカルクッシング症候群、緑内障、骨粗鬆症、メタボリックシンドローム、心血管疾患、アテローム性動脈硬化、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療方法。 Item 31: Type II diabetes, impaired glucose tolerance, comprising administering an effective amount of the compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof to a subject in need thereof Hyperglycemia, insulin resistance, dyslipidemia, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atherosclerosis, cognitive impairment, Treatment of dementia, Alzheimer's disease, depression, anxiety or manic depression.
項３２：項１～項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩の有効量をそれを必要とする対象に投与することを含む、緑内障、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療方法。 Item 32: Glaucoma, cognitive impairment, dementia, comprising administering to a subject in need thereof an effective amount of the compound according to any one of Items 1 to 25 or a pharmacologically acceptable salt thereof. How to treat, Alzheimer's disease, depression, anxiety or manic depression.
　式（１）で表される化合物、またはその薬理学上許容される塩は、１１βＨＳＤ１阻害剤として有用である。 The compound represented by the formula (1) or a pharmacologically acceptable salt thereof is useful as an 11βHSD1 inhibitor.
　以下に、本発明をさらに詳細に説明する。本明細書において「置換基」の定義における炭素の数を、例えば、「Ｃ１－６」などと表記する場合もある。具体的には、「Ｃ１－６アルキル」なる表記は、炭素数１から６を有するアルキル基と同義である。また、本明細書において、「置換されていてもよい」または「置換されている」なる用語を特に明示していない基は、「非置換」の基を意味する。例えば、「Ｃ１－６アルキル」とは、「非置換Ｃ１－６アルキル」であることを意味する。 The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C 1-6 ”, for example. Specifically, the expression “C 1-6 alkyl” is synonymous with an alkyl group having 1 to 6 carbon atoms. In the present specification, a group that does not specifically indicate the term “optionally substituted” or “substituted” means an “unsubstituted” group. For example, “C 1-6 alkyl” means “unsubstituted C 1-6 alkyl”.
　本明細書において「基」なる用語は、１価基を意味する。例えば、「アルキル基」は、１価の飽和炭化水素基を意味する。また、本明細書における置換基の説明において、「基」なる用語を省略する場合もある。尚、「置換されていてもよい」または「置換されている」で定義される基における置換基の数は、置換可能であれば特に制限はなく、１または複数である。また、特に指示した場合を除き、各々の基の定義は、その基が他の基の一部分である場合または他の基の置換基である場合にも該当する。 In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted. The number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. Unless otherwise specified, the definition of each group also applies when the group is a part of another group or a substituent of another group.
　「ハロゲン原子」は、例えばフッ素原子、塩素原子、臭素原子またはヨウ素原子等が挙げられる。好ましくは、フッ素原子、または塩素原子である。 “Halogen atom” includes, for example, fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
　「Ｃ１－６アルキル基」は、炭素数１～６個を有する直鎖または分枝状の飽和炭化水素基を意味する。好ましくは、「Ｃ１－４アルキル基」である。「Ｃ１－６アルキル基」の具体例としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、２－エチルブチル等が挙げられる。 “C 1-6 alkyl group” means a straight chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is a “C 1-4 alkyl group”. Specific examples of “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
　「Ｃ３－７シクロアルキル基」は、炭素数３～７個を有し、環状の飽和または不飽和炭化水素基を意味する。好ましくは、「Ｃ３－６シクロアルキル基」である。「Ｃ３－７シクロアルキル基」の具体例としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロペンテニル、シクロヘキセニル等が挙げられる。 “C 3-7 cycloalkyl group” means a cyclic saturated or unsaturated hydrocarbon group having 3 to 7 carbon atoms. Preferred is “C 3-6 cycloalkyl group”. Specific examples of “C 3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.
　「Ｃ６－１０アリール基」は、炭素数６～１０個を有する芳香族炭化水素基を意味する。好ましくは「Ｃ６アリール基」（すなわち、フェニル）である。「Ｃ６－１０アリール基」の具体例としては、例えば、フェニル、１－ナフチルまたは２－ナフチル等が挙げられる。 “C 6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. A “C 6 aryl group” (that is, phenyl) is preferred. Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
　前記「Ｃ６－１０アリール基」には、「Ｃ６アリール」が、窒素原子、硫黄原子または酸素原子から選ばれる同種または異種のヘテロ原子を１個以上（例えば１～４個）含有する５員～７員の環、または５員～７員のシクロアルキル環（例えば、シクロペンタン、シクロヘキサンまたはシクロヘプタン）と縮環した基も包含される。該基の具体例としては、例えば、下記式で表される基等が挙げられる。
Figure JPOXMLDOC01-appb-C000018
 In the “C 6-10 aryl group”, “C 6 aryl” contains one or more (for example, 1 to 4) of the same or different hetero atoms selected from a nitrogen atom, a sulfur atom or an oxygen atom. Also included are groups fused to membered to seven membered rings, or five to seven membered cycloalkyl rings (eg, cyclopentane, cyclohexane or cycloheptane). Specific examples of the group include groups represented by the following formulas.
Figure JPOXMLDOC01-appb-C000018
　但し、縮環したＣ６－１０アリール基は、芳香環上でのみ他の「基」と結合する。例えば、下記式
Figure JPOXMLDOC01-appb-C000019
 で表される「Ｃ６－１０アリール基」は、４－、５－、６－、または７－位で他の「基」と結合することを意味する。 However, the condensed C 6-10 aryl group is bonded to other “groups” only on the aromatic ring. For example, the following formula
Figure JPOXMLDOC01-appb-C000019
 The “C 6-10 aryl group” represented by the formula means that it is bonded to another “group” at the 4-, 5-, 6-, or 7-position.
　「Ｃ７－１４アラルキル基」とは、「Ｃ６－１０アリールＣ１－４アルキル基」を意味し、前記「Ｃ１－４アルキル基」に前記「Ｃ６－１０アリール基」が置換した基を意味する。このうち好ましくは、「Ｃ７－１０アラルキル基」（すなわち、Ｃ６アリールＣ１－４アルキル基）である。「Ｃ７－１４アラルキル基」の具体例としては、例えば、ベンジル、２－フェニルエチル、１－フェニルプロピルまたは１－ナフチルメチル等が挙げられる。 The “C 7-14 aralkyl group” means a “C 6-10 aryl C 1-4 alkyl group”, and the “C 1-4 alkyl group” is substituted with the “C 6-10 aryl group”. Means group. Of these, a “C 7-10 aralkyl group” (that is, a C 6 aryl C 1-4 alkyl group) is preferable. Specific examples of “C 7-14 aralkyl group” include, for example, benzyl, 2-phenylethyl, 1-phenylpropyl, 1-naphthylmethyl and the like.
　該アラルキル基におけるＣ１－４アルキル部分は、アルキル部分の任意の１の炭素上で２～３個の炭素と環を形成してもよい。このようなアラルキル基の具体例としては、例えば、下記群
Figure JPOXMLDOC01-appb-C000020
 で表される基等が挙げられる。 The C 1-4 alkyl moiety in the aralkyl group may form a ring with 2-3 carbons on any one carbon of the alkyl moiety. Specific examples of such aralkyl groups include, for example, the following groups
Figure JPOXMLDOC01-appb-C000020
 The group etc. which are represented by these are mentioned.
　「ヘテロアリール基」としては、例えば、５員～１２員の単環式または多環式の芳香族基等が挙げられ、該基は、窒素原子、硫黄原子または酸素原子から選ばれる同種または異種のヘテロ原子を１個以上（例えば１～４個）含有する。「単環式ヘテロアリール基」としては、５員または６員の基が好ましい。「多環式ヘテロアリール基」としては、二または三環式の基が好ましく、二環式の基がより好ましい。多環式ヘテロアリール基は、前記単環式へテロアリール基と芳香環（ベンゼン、ピリジンなど）または非芳香環（シクロヘキシルなど）とが縮環したものを含む。「ヘテロアリール基」の具体例としては、例えば、下記式で表される基が挙げられる。 Examples of the “heteroaryl group” include a 5- to 12-membered monocyclic or polycyclic aromatic group, and the group is the same or different selected from a nitrogen atom, a sulfur atom or an oxygen atom. 1 or more (for example, 1 to 4) heteroatoms. The “monocyclic heteroaryl group” is preferably a 5-membered or 6-membered group. As the “polycyclic heteroaryl group”, a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable. The polycyclic heteroaryl group includes a condensed ring of the monocyclic heteroaryl group and an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, etc.). Specific examples of the “heteroaryl group” include a group represented by the following formula.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　前記式において環を横切る直線は、当該「基」が置換可能な位置で他の基と結合することを意味する。例えば、下記式
Figure JPOXMLDOC01-appb-C000022
 で表されるヘテロアリール基は、２－フリル基、または３－フリル基であることを意味する。 The straight line across the ring in the above formula means that the “group” is bonded to another group at a substitutable position. For example, the following formula
Figure JPOXMLDOC01-appb-C000022
 The heteroaryl group represented by the formula means 2-furyl group or 3-furyl group.
　更に、「ヘテロアリール基」が多環式ヘテロアリール基である場合において、例えば、下記式
Figure JPOXMLDOC01-appb-C000023
 で表されるヘテロアリール基は、２－ベンゾフリル、または３－ベンゾフリルの他に、４－、５－、６－または７－ベンゾフリルであってもよい。 Further, when the “heteroaryl group” is a polycyclic heteroaryl group, for example, the following formula
Figure JPOXMLDOC01-appb-C000023
 In addition to 2-benzofuryl or 3-benzofuryl, the heteroaryl group represented by may be 4-, 5-, 6- or 7-benzofuryl.
　但し、芳香環と非芳香環（ピペリジンなど）とが縮環する多環式へテロアリール基は、芳香環のみにおいて当該「基」の結合手を有する。例えば、下記式
Figure JPOXMLDOC01-appb-C000024
 で表される「多環式ヘテロアリール基」は、当該「基」が２－、３－、または４－位で他の基と結合することを意味する。「ヘテロアリール基」は、５員～１０員の単環式または多環式のヘテロアリール基が好ましく、５員または６員の単環式のヘテロアリール基が更に好ましい。 However, a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (such as piperidine) are condensed has a bond of the “group” only in the aromatic ring. For example, the following formula
Figure JPOXMLDOC01-appb-C000024
 The “polycyclic heteroaryl group” represented by the above means that the “group” is bonded to another group at the 2-, 3-, or 4-position. The “heteroaryl group” is preferably a 5- to 10-membered monocyclic or polycyclic heteroaryl group, more preferably a 5- or 6-membered monocyclic heteroaryl group.
　「複素環基」としては、例えば、窒素原子、酸素原子および硫黄原子から選択される同種または異種の原子を１～３個有する３員～７員の複素環基等が挙げられる。前記窒素原子、酸素原子および硫黄原子はいずれも環を構成する原子である。該複素環基は、飽和または部分不飽和のいずれであってもよい。具体的には、ピラニル、テトラヒドロフリル、ピロリジニル、イミダゾリジニル、ピペリジニル、モルホリニル、チオモルホリニル、ジオキソチオモルホリニル、ヘキサメチレンイミニル、オキサゾリジニル、チアゾリジニル、イミダゾリジニル、オキソイミダゾリジニル、ジオキソイミダゾリジニル、オキソオキサゾリジニル、ジオキソオキサゾリジニル、ジオキソチアゾリジニル、テトラヒドロフラニルまたはテトラヒドロピリジニル等が挙げられる。該基において環を構成する窒素原子が、他の「基」との結合手を有することはない。すなわち、該基には、例えば、１－ピロリジノ基などの概念は包含されない。 Examples of the “heterocyclic group” include a 3- to 7-membered heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring. The heterocyclic group may be either saturated or partially unsaturated. Specifically, pyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxo Examples include oxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl and the like. The nitrogen atom constituting the ring in the group does not have a bond with another “group”. That is, the group does not include concepts such as a 1-pyrrolidino group.
　前記「複素環基」は、６員の芳香族炭化水素または６員のヘテロアリールとの縮合環であってもよい。当該複素環基としては、例えば、前記５員または６員の「複素環基」と６員の芳香族炭化水素または６員のヘテロアリールとが縮合した二環式の９員または１０員の「複素環」が挙げられる。６員の芳香族炭化水素としては、ベンゼンなどが挙げられる。６員のヘテロアリールとしては、ピリジン、ピリミジンまたはピリダジン等が挙げられる。このような「複素環基」としては、具体的には、ジヒドロインドリル、ジヒドロイソインドリル、ジヒドロプリニル、ジヒドロチアゾロピリミジニル、ジヒドロベンゾジオキサニル、イソインドリニル、インダゾリル、テトラヒドロキノリニル、デカヒドロキノリニル、テトラヒドロイソキノリニル、デカヒドロイソキノリニル、テトラヒドロナフチリジニルまたはテトラヒドロピリドアゼピニル等が挙げられる。当該「複素環基」は、飽和複素環基が好ましく、５員または６員の飽和複素環基が好ましい。 The “heterocyclic group” may be a condensed ring with a 6-membered aromatic hydrocarbon or 6-membered heteroaryl. Examples of the heterocyclic group include a bicyclic 9-membered or 10-membered “condensed heterocyclic group” and a 6-membered aromatic hydrocarbon or 6-membered heteroaryl. A "heterocycle". Examples of the 6-membered aromatic hydrocarbon include benzene. Examples of 6-membered heteroaryl include pyridine, pyrimidine or pyridazine. Specific examples of such “heterocyclic group” include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, tetrahydroquinolinyl, decainyl. Examples thereof include hydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like. The “heterocyclic group” is preferably a saturated heterocyclic group, and more preferably a 5-membered or 6-membered saturated heterocyclic group.
　「Ｃ１－６アルコキシ基」の「Ｃ１－６アルキル」部分は、前記「Ｃ１－６アルキル」と同義である。好ましくは、「Ｃ１－４アルコキシ基」である。「Ｃ１－６アルコキシ基」の具体例としては、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等が挙げられる。 The “C 1-6 alkyl” part of the “C 1-6 alkoxy group” has the same meaning as the above “C 1-6 alkyl”. Preferred is a “C 1-4 alkoxy group”. Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
　「Ｃ６－１０アリールチオ基」の「Ｃ６－１０アリール」部分は、前記「Ｃ６－１０アリール」と同義である。「Ｃ６－１０アリールチオ基」の具体例としては、例えば、フェニルチオ、１－ナフチルチオまたは２－ナフチルチオ等が挙げられる。 The “C 6-10 aryl” part of the “C 6-10 arylthio group” has the same meaning as the above “C 6-10 aryl”. Specific examples of “C 6-10 arylthio group” include, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
　「Ｃ１－６アルキルスルホニル基」の「Ｃ１－６アルキル」部分は、前記「Ｃ１－６アルキル」と同義である。好ましくは、「Ｃ１－４アルキルスルホニル基」である。「Ｃ１－６アルキルスルホニル基」の具体例としては、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、ペンチルスルホニルまたはヘキシルスルホニル等が挙げられる。 The “C 1-6 alkyl” part of the “C 1-6 alkylsulfonyl group” has the same meaning as the above “C 1-6 alkyl”. Preferably, it is “C 1-4 alkylsulfonyl group”. Specific examples of “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
　「Ｃ３－６シクロアルキルスルホニル基」の「Ｃ３－６シクロアルキル」部分は、前記「Ｃ３－６シクロアルキル」と同義である。具体例としては、例えば、シクロプロピルスルホニル、シクロブチルスルホニル、シクロペンチルスルホニル、シクロヘキシルスルホニル等が挙げられる。 The “C 3-6 cycloalkyl” part of the “C 3-6 cycloalkylsulfonyl group” has the same meaning as the above “C 3-6 cycloalkyl”. Specific examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.
　「Ｃ６－１０アリールスルホニル基」の「Ｃ６－１０アリール」部分は、前記「Ｃ６－１０アリール」と同義である。具体例としては、例えば、フェニルスルホニル、１－ナフチルスルホニル等が挙げられる。 The “C 6-10 aryl” part of the “C 6-10 arylsulfonyl group” has the same meaning as the above “C 6-10 aryl”. Specific examples include phenylsulfonyl, 1-naphthylsulfonyl and the like.
　「Ｃ３－７シクロアルコキシ基」の「Ｃ３－７シクロアルキル」部分は、前記「Ｃ３－７シクロアルキル」と同義である。好ましくは、「Ｃ３－６シクロアルコキシ基」である。「Ｃ３－７シクロアルコキシ基」の具体例としては、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ等が挙げられる。 The “C 3-7 cycloalkyl” part of the “C 3-7 cycloalkoxy group” has the same meaning as the above “C 3-7 cycloalkyl”. Preferably, it is “C 3-6 cycloalkoxy group”. Specific examples of “C 3-7 cycloalkoxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
　「Ｃ６－１０アリールオキシ基」の「Ｃ６－１０アリール」部分は、前記「Ｃ６－１０アリール」と同義である。「Ｃ６アリールオキシ」（すなわち、フェニルオキシ）が好ましい。「Ｃ６－１０アリールオキシ基」の具体例としては、フェノキシ、１－ナフチルオキシまたは２－ナフチルオキシ等が挙げられる。 The “C 6-10 aryl” part of the “C 6-10 aryloxy group” has the same meaning as the above “C 6-10 aryl”. “C 6 aryloxy” (ie, phenyloxy) is preferred. Specific examples of “C 6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
　「Ｃ７－１４アラルキルオキシ基」（すなわち、Ｃ６－１０アリールＣ１－４アルキルオキシ基）の「Ｃ７－１４アラルキル」部分は、前記「Ｃ７－１４アラルキル」と同義である。好ましくは、「Ｃ７－１０アラルキルオキシ基」（すなわち、「フェニルＣ１－４アルキルオキシ基」）などが挙げられる。「Ｃ７－１４アラルキルオキシ基」の具体例としては、例えば、ベンジルオキシ、フェネチルオキシ、ナフチルメチルオキシ等が挙げられる。 "C 7-14 aralkyl" moiety of the "C 7-14 aralkyloxy group" (i.e., C 6-10 aryl C 1-4 alkyloxy group) is the same as defined in the "C 7-14 aralkyl". Preferable examples include “C 7-10 aralkyloxy group” (that is, “phenyl C 1-4 alkyloxy group”) and the like. Specific examples of “C 7-14 aralkyloxy group” include, for example, benzyloxy, phenethyloxy, naphthylmethyloxy and the like.
　「５員～１２員の単環式もしくは多環式ヘテロアリールオキシ基」の「５員～１２員の単環式もしくは多環式ヘテロアリール」部分は、前記と同義である。「Ｃ６アリールオキシ」（すなわち、フェニルオキシ）が好ましい。「５員～１２員の単環式もしくは多環式ヘテロアリールオキシ基」の具体例としては、ピリジルオキシ等が挙げられる。 The “5- to 12-membered monocyclic or polycyclic heteroaryl” part of the “5- to 12-membered monocyclic or polycyclic heteroaryloxy group” has the same meaning as described above. “C 6 aryloxy” (ie, phenyloxy) is preferred. Specific examples of “5- to 12-membered monocyclic or polycyclic heteroaryloxy group” include pyridyloxy and the like.
　「Ｃ１－４アルコキシカルボニル基」は、前記「Ｃ１－４アルコキシ基」がカルボニル基に結合した基を意味する。具体的には、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、２－プロポキシカルボニルまたはｔｅｒｔ－ブトキシカルボニル等が挙げられる。 The “C 1-4 alkoxycarbonyl group” means a group in which the “C 1-4 alkoxy group” is bonded to a carbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, and the like.
　「Ｃ３－６シクロアルコキシカルボニル基」は、前記「Ｃ３－６シクロアルコキシ基」がカルボニル基に結合した基を意味する。具体例としては、シクロプロピルオキシカルボニル、シクロブチルオキシカルボニル等が挙げられる。 The “C 3-6 cycloalkoxycarbonyl group” means a group in which the “C 3-6 cycloalkoxy group” is bonded to a carbonyl group. Specific examples include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl and the like.
　「Ｃ７－１４アラルキルオキシカルボニル基」の「Ｃ７－１４アラルキル」部分は、前記「Ｃ７－１４アラルキル」と同義である。好ましくは、「Ｃ７－１０アラルキルオキシカルボニル基」などが挙げられる。「Ｃ７－１４アラルキルオキシカルボニル基」の具体例としては、例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル、ナフチルメチルオキシカルボニル等が挙げられる。 The “C 7-14 aralkyl” part of the “C 7-14 aralkyloxycarbonyl group” has the same meaning as the above “C 7-14 aralkyl”. Preferable examples include “C 7-10 aralkyloxycarbonyl group”. Specific examples of “C 7-14 aralkyloxycarbonyl group” include, for example, benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl and the like.
　「Ｃ１－４アルキルカルボニル基」は、前記「Ｃ１－４アルキル基」がカルボニル基に結合した基を意味する。具体的には、例えばアセチル、プロピオニルまたはブチリル等が挙げられる。 The “C 1-4 alkylcarbonyl group” means a group in which the “C 1-4 alkyl group” is bonded to a carbonyl group. Specific examples include acetyl, propionyl, butyryl and the like.
　「Ｃ３－６シクロアルキルカルボニル基」は、前記「Ｃ３－６シクロアルキル基」がカルボニル基に結合した基を意味する。具体例としては、シクロプロピルカルボニル、シクロブチルカルボニル等が挙げられる。 The “C 3-6 cycloalkylcarbonyl group” means a group in which the “C 3-6 cycloalkyl group” is bonded to a carbonyl group. Specific examples include cyclopropylcarbonyl, cyclobutylcarbonyl and the like.
　「Ｃ１－４アルキルカルボニルオキシ基」の「Ｃ１－４アルキル」部分は、前記「Ｃ１－４アルキル基」と同義である。具体例としては、例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、イソプロピルカルボニルオキシなどが挙げられる。 "C 1-4 alkyl" moiety of the "C 1-4 alkylcarbonyloxy group" is the same as defined in the "C 1-4 alkyl group". Specific examples include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy and the like.
　「Ｃ３－６シクロアルキルカルボニルオキシ基」の「Ｃ３－６シクロアルキル」部分は、前記「Ｃ３－６シクロアルキル基」と同義である。具体例としては、例えば、シクロプロピルカルボニルオキシ、シクロブチルカルボニルオキシ等が挙げられる。 "C 3-6 cycloalkyl" moiety of the "C 3-6 cycloalkyl carbonyl group" is the same as defined in the "C 3-6 cycloalkyl group". Specific examples include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy and the like.
　「４員～７員の環状アミノ」は、４員～７員からなる環状のアミノ基であって、該環の窒素原子が他の「基」との結合手を有する基を意味する。好ましくは、５員～７員であり、更に好ましくは５員または６員である。具体例としては、例えば、ピロリジノ、ピペリジノ、モルホリノ、チオモルホリノ、チオモルホリノオキシド、チオモルホリノジオキシド、ピペラジノ、２－ピロリドン－１－イル等が挙げられる。該環は、例えば、ハロゲン原子、Ｃ１－４アルキル、またはＣ１－４アルコキシで置換されてもよいＣ６アリールなどで置換されてもよい。尚、該基には、環が部分不飽和結合を含む環状アミノ基も含まれる。 “4- to 7-membered cyclic amino” means a 4- to 7-membered cyclic amino group in which the nitrogen atom of the ring has a bond with another “group”. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholinooxide, thiomorpholinooxide, piperazino, 2-pyrrolidone-1-yl and the like. The ring may be substituted with, for example, a halogen atom, C 1-4 alkyl, or C 6 aryl optionally substituted with C 1-4 alkoxy. The group also includes a cyclic amino group in which the ring contains a partially unsaturated bond.
　「４員～７員の環状アミノ」は、５員または６員の芳香環と５員または６員の複素環との縮合環であってもよい。具体例としては、下記で表される「基」等が挙げられる。
Figure JPOXMLDOC01-appb-C000025
 The “4- to 7-membered cyclic amino” may be a condensed ring of a 5-membered or 6-membered aromatic ring and a 5-membered or 6-membered heterocyclic ring. Specific examples include “groups” shown below.
Figure JPOXMLDOC01-appb-C000025
　「置換されていてもよいＣ１－６アルキル基」における置換基としては、例えば
（ａ）ハロゲン原子、
（ｂ）水酸基、
（ｃ）Ｃ１－４アルコキシ基（該アルコキシは、
　　（ｃ１１）１～３個のハロゲン原子、
　　（ｃ１２）ヒドロキシ、
　　（ｃ１３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｃ１４）Ｃ３－６シクロアルコキシ、
　　（ｃ１５）Ｃ３－６シクロアルキル、
　　（ｃ１６）モノ－もしくはジ－Ｃ１－６アルキルアミノ、または
　　（ｃ１７）４員～７員の環状アミノで置換されていてもよい。）、
（ｄ）Ｃ３－７シクロアルコキシ基（該シクロアルコキシは、
　　（ｄ１１）１～３個のハロゲン原子、
　　（ｄ１２）ヒドロキシ、
　　（ｄ１３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｄ１４）Ｃ１－４アルキル（該アルキルは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｄ１５）Ｃ３－６シクロアルコキシ、
　　（ｄ１６）Ｃ３－６シクロアルキル、
　　（ｄ１７）アミノ、または
　　（ｄ１８）モノ－もしくはジ－Ｃ１－６アルキルアミノで置換されていてもよい。）、
（ｅ）Ｃ１－４アルキルカルボニルオキシ基、
（ｆ）Ｃ３－６シクロアルキルカルボニルオキシ基、
（ｇ）Ｃ１－４アルキルカルボニル基（該アルキルは、前記（ｃ１１）～（ｃ１７）からなる群から選択される基で置換されていてもよい。）、
（ｈ）Ｃ３－６シクロアルキルカルボニル基（該シクロアルキルは、前記（ｄ１１）～（ｄ１８）からなる群から選択される基で置換されていてもよい。）、
（ｉ）Ｃ１－４アルコキシカルボニル基、
（ｊ）Ｃ３－６シクロアルコキシカルボニル基（該シクロアルコキシは、前記（ｄ１１）～（ｄ１８）からなる群から選択される基で置換されていてもよい。）、
（ｋ）置換されていてもよいＣ３－７シクロアルキル基、
（ｌ）置換されていてもよいアミノ基、
（ｍ）カルボキシ基、
（ｎ）置換されていてもよいアミノカルボニル基、
（ｏ）Ｃ１－４アルキルスルホニル基（該アルキルは、前記（ｄ１１）～（ｄ１７）からなる群から選択される基で置換されていてもよい。）、
（ｐ）Ｃ３－６シクロアルキルスルホニル基（該シクロアルキルは、前記（ｄ１１）～（ｄ１８）からなる群から選択される基で置換されていてもよい。）、
（ｑ）Ｃ６－１０アリールオキシ（該アリールは、
　　（ｑ１１）ハロゲン原子、
　　（ｑ１２）Ｃ１－４アルキル、または
　　（ｑ１３）Ｃ１－４アルコキシで置換されていてもよい。）、
（ｒ）Ｃ７－１４アラルキルオキシ、
（ｓ）５員～１２員の単環式もしくは多環式のヘテロアリールオキシ、
（ｔ）Ｃ６－１０アリールチオ（該アリールは、ハロゲン原子、またはＣ１－４アルキルで置換されていてもよい。）、
（ｕ）Ｃ６－１０アリールスルホニル（該アリールは、
　　（ｕ１１）ハロゲン原子、
　　（ｕ１２）Ｃ１－４アルキル、または
　　（ｕ１３）Ｃ１－４アルコキシで置換されていてもよい。）、または
（ｖ）重水素原子などが挙げられる。 Examples of the substituent in the “optionally substituted C 1-6 alkyl group” include (a) a halogen atom,
(B) a hydroxyl group,
(C) a C 1-4 alkoxy group (the alkoxy is
(C11) 1 to 3 halogen atoms,
(C12) hydroxy,
(C13) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(C14) C 3-6 cycloalkoxy,
(C15) C 3-6 cycloalkyl,
(C16) mono- or di-C 1-6 alkylamino, or (c17) optionally substituted with a 4- to 7-membered cyclic amino. ),
(D) a C 3-7 cycloalkoxy group (the cycloalkoxy represents
(D11) 1 to 3 halogen atoms,
(D12) hydroxy,
(D13) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(D14) C 1-4 alkyl (the alkyl may be substituted with 1 to 3 halogen atoms),
(D15) C 3-6 cycloalkoxy,
(D16) C 3-6 cycloalkyl,
(D17) amino, or (d18) optionally substituted with mono- or di-C 1-6 alkylamino. ),
(E) a C 1-4 alkylcarbonyloxy group,
(F) a C 3-6 cycloalkylcarbonyloxy group,
(G) a C 1-4 alkylcarbonyl group (the alkyl may be substituted with a group selected from the group consisting of the above (c11) to (c17));
(H) a C 3-6 cycloalkylcarbonyl group (the cycloalkyl may be substituted with a group selected from the group consisting of the above (d11) to (d18));
(I) a C 1-4 alkoxycarbonyl group,
(J) a C 3-6 cycloalkoxycarbonyl group (the cycloalkoxy may be substituted with a group selected from the group consisting of the above (d11) to (d18)),
(K) an optionally substituted C 3-7 cycloalkyl group,
(L) an optionally substituted amino group,
(M) a carboxy group,
(N) an optionally substituted aminocarbonyl group,
(O) a C 1-4 alkylsulfonyl group (the alkyl may be substituted with a group selected from the group consisting of the above (d11) to (d17)),
(P) a C 3-6 cycloalkylsulfonyl group (which may be substituted with a group selected from the group consisting of the above (d11) to (d18)),
(Q) C 6-10 aryloxy (the aryl is
(Q11) a halogen atom,
(Q12) C 1-4 alkyl, or (q13) C 1-4 alkoxy may be substituted. ),
(R) C 7-14 aralkyloxy,
(S) 5- to 12-membered monocyclic or polycyclic heteroaryloxy,
(T) C 6-10 arylthio (the aryl may be substituted with a halogen atom or C 1-4 alkyl),
(U) C 6-10 arylsulfonyl (wherein the aryl is
(U11) a halogen atom,
(U12) C 1-4 alkyl, or (u13) C 1-4 alkoxy may be substituted. ), Or (v) a deuterium atom.
　「置換されていてもよいＣ１－６アルキル基」の好適な置換基としては、例えば、
（ａ２）１～５個のハロゲン原子（より好ましくは１～３個のハロゲン原子）、
（ｂ２）Ｃ３－７シクロアルキル基（該シクロアルキルは、Ｃ１－６アルキルまたは１～３個のハロゲン原子で置換されていてもよい。）、または
（ｃ２）Ｃ１－４アルコキシ基（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）である。 Suitable substituents for the “optionally substituted C 1-6 alkyl group” include, for example,
(A2) 1 to 5 halogen atoms (more preferably 1 to 3 halogen atoms),
(B2) a C 3-7 cycloalkyl group (wherein the cycloalkyl may be substituted with C 1-6 alkyl or 1 to 3 halogen atoms), or (c2) a C 1-4 alkoxy group ( The alkoxy is optionally substituted with 1 to 3 halogen atoms).
　「置換されていてもよいＣ３－７シクロアルキル基」における置換基としては、前記（ａ）～（ｕ）、およびＣ１－４アルキル基（該アルキルは、Ｃ１－４アルコキシ、ヒドロキシル、またはハロゲン原子で置換されていてもよい。）などが挙げられる。 Examples of the substituent in the “optionally substituted C 3-7 cycloalkyl group” include the above (a) to (u), and a C 1-4 alkyl group (the alkyl is C 1-4 alkoxy, hydroxyl, Or may be substituted with a halogen atom).
　「置換されていてもよいＣ６－１０アリール基」、および「置換されていてもよい５員～１２員の単環式もしくは多環式へテロアリール基」における置換基としては、例えば
（ａ３）重水素原子、
（ｂ３）ハロゲン原子、
（ｃ３）水酸基、
（ｄ３）ニトロ基、
（ｅ３）シアノ基、
（ｆ３）複素環基、
（ｇ３）Ｃ３－７シクロアルキル基、
（ｈ３）Ｃ３－７シクロアルキルオキシ基、
（ｉ３）Ｃ１－４アルキル基（該アルキル基は、
　　（ｉ３０１）１～３個のハロゲン原子、
　　（ｉ３０２）ヒドロキシ、
　　（ｉ３０３）Ｃ３－６シクロアルキルオキシ、
　　（ｉ３０４）Ｃ１－４アルコキシ（該アルコキシは、
　　　　　　　　１～３個のハロゲン原子、
　　　　　　　　Ｃ１－４アルコキシ、または
　　　　　　　　ヒドロキシで置換されていてもよい。）、
　　（ｉ３０５）Ｃ３－６シクロアルキル、
　　（ｉ３０６）Ｃ１－４アルキルスルホニル、
　　（ｉ３０７）Ｃ３－６シクロアルキルスルホニル、
　　（ｉ３０８）Ｃ１－４アルコキシカルボニル、
　　（ｉ３０９）Ｃ７－１４アラルキルオキシカルボニル、
　　（ｉ３１０）カルボキシル、
　　（ｉ３１１）アミノ（該アミノは、Ｃ１－６アルキル、およびＣ３－６シクロアルキルからなる群から選択される同種または異種の１～２個の基で置換されていてもよい。）、
　　（ｉ３１２）４員～７員の環状アミノ、
　　（ｉ３１３）モノ－もしくはジ－Ｃ１－６アルキルアミノカルボニル、または
　　（ｉ３１４）４員～７員の環状アミノカルボニルなどで置換されていてもよい。）、
（ｊ３）Ｃ１－４アルコキシ基（該アルコキシ基は、
　　（ｊ３１）１～３個のハロゲン原子、
　　（ｊ３２）ヒドロキシ、
　　（ｊ３３）Ｃ１－４アルコキシ、
　　（ｊ３４）Ｃ３－６シクロアルキルオキシ、
　　（ｊ３５）カルボキシル、
　　（ｊ３６）Ｃ１－４アルコキシカルボニル、
　　（ｊ３７）モノ－もしくはジ－Ｃ１－６アルキルアミノカルボニル、
　　（ｊ３８）４員～７員の環状アミノカルボニル、または
　　（ｊ３９）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｋ３）Ｃ３－６シクロアルキルスルホニル基、
（ｌ３）Ｃ１－６アルキルカルボニル基（該アルキルは、
　　（ｌ３１）ヒドロキシ、
　　（ｌ３２）１～３個のハロゲン原子、
　　（ｌ３３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｌ３４）Ｃ３－６シクロアルコキシ、または
　　（ｌ３５）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｍ３）Ｃ３－６シクロアルキルカルボニル基（該シクロアルキルは、
　　（ｍ３１）ヒドロキシ、
　　（ｍ３２）１～３個のハロゲン原子、
　　（ｍ３３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｍ３４）Ｃ３－６シクロアルコキシ、
　　（ｍ３５）Ｃ１－４アルキル、または
　　（ｍ３６）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｎ３）Ｃ１－４アルコキシカルボニル基、
（ｏ３）Ｃ３－６シクロアルコキシカルボニル基、
（ｐ３）カルボキシ基、
（ｑ３）アミノ基（該アミノは、
　　（ｑ３１）Ｃ１－６アルキル、
　　（ｑ３２）Ｃ３－６シクロアルキル、
　　（ｑ３３）Ｃ１－４アルキルカルボニル、
　　（ｑ３４）Ｃ３－６シクロアルキルカルボニル、および
　　（ｑ３５）Ｃ１－６アルキルスルホニルからなる群から選択される同種または異種の１～２個の基で置換されていてもよい。（ｑ３１）および（ｑ３３）は、前記（ｌ３１）～（ｌ３５）からなる群から選択される基で更に置換されていてもよく、（ｑ３２）および（ｑ３４）は、前記（ｍ３１）～（ｍ３６）からなる群から選択される基で更に置換されていてもよい。）、
（ｒ３）４員～７員の環状アミノ基、
（ｓ３）アミノカルボニル基（該アミノは、前記（ｑ３１）～（ｑ３５）からなる群から選択される同種または異種の１～２個の基で置換されていてもよい。）、
（ｔ３）４員～７員の環状アミノカルボニル基、
（ｕ３）アミノスルホニル基（該アミノは、前記（ｑ３１）および（ｑ３２）からなる群から選択される同種または異種の１～２個の基で置換されていてもよい。）、
（ｖ３）４員～７員の環状アミノスルホニル基、
（ｗ３）Ｃ６－１０アリール基（該アリールは、
　　（ｗ３１）ハロゲン原子、
　　（ｗ３２）Ｃ１－４アルコキシ、
　　（ｗ３３）Ｃ１－４アルキル、または
　　（ｗ３４）Ｃ３－７シクロアルキルで置換されていてもよい。）、
（ｘ３）５員～１２員の単環式もしくは多環式のヘテロアリール基（該へテロアリールは、
　　（ｘ３１）ハロゲン原子、
　　（ｘ３２）Ｃ１－４アルキル（該アルキルは、１～３個のハロゲン原子で置換されていてもよい。）、または
　　（ｘ３３）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｙ３）Ｃ１－４アルキルスルホニル基、または
（ｚ３）Ｃ３－６シクロアルキルスルホニル基等が挙げられる。 Examples of the substituent in the “optionally substituted C 6-10 aryl group” and the “optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group” include (a3) Deuterium atom,
(B3) a halogen atom,
(C3) a hydroxyl group,
(D3) a nitro group,
(E3) a cyano group,
(F3) a heterocyclic group,
(G3) a C 3-7 cycloalkyl group,
(H3) a C 3-7 cycloalkyloxy group,
(I3) C 1-4 alkyl group (the alkyl group is
(I301) 1 to 3 halogen atoms,
(I302) hydroxy,
(I303) C 3-6 cycloalkyloxy,
(I304) C 1-4 alkoxy (the alkoxy is
1 to 3 halogen atoms,
It may be substituted with C 1-4 alkoxy or hydroxy. ),
(I305) C 3-6 cycloalkyl,
(I306) C 1-4 alkylsulfonyl,
(I307) C 3-6 cycloalkylsulfonyl,
(I308) C 1-4 alkoxycarbonyl,
(I309) C 7-14 aralkyloxycarbonyl,
(I310) carboxyl,
(I311) amino (the amino may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl);
(I312) 4- to 7-membered cyclic amino,
(I313) mono- or di-C 1-6 alkylaminocarbonyl, or (i314) 4- to 7-membered cyclic aminocarbonyl may be substituted. ),
(J3) C 1-4 alkoxy group (the alkoxy group is
(J31) 1 to 3 halogen atoms,
(J32) hydroxy,
(J33) C 1-4 alkoxy,
(J34) C 3-6 cycloalkyloxy,
(J35) carboxyl,
(J36) C 1-4 alkoxycarbonyl,
(J37) mono- or di-C 1-6 alkylaminocarbonyl,
(J38) 4- to 7-membered cyclic aminocarbonyl, or (j39) C 3-6 cycloalkyl may be substituted. ),
(K3) C 3-6 cycloalkylsulfonyl group,
(L3) C 1-6 alkylcarbonyl group (the alkyl is
(L31) hydroxy,
(L32) 1 to 3 halogen atoms,
(L33) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
It may be substituted with (l34) C 3-6 cycloalkoxy, or (l35) C 3-6 cycloalkyl. ),
(M3) C 3-6 cycloalkylcarbonyl group (the cycloalkyl is
(M31) hydroxy,
(M32) 1 to 3 halogen atoms,
(M33) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(M34) C 3-6 cycloalkoxy,
(M35) C 1-4 alkyl, or (m36) C 3-6 cycloalkyl may be substituted. ),
(N3) C 1-4 alkoxycarbonyl group,
(O3) C 3-6 cycloalkoxycarbonyl group,
(P3) a carboxy group,
(Q3) amino group (the amino is
(Q31) C 1-6 alkyl,
(Q32) C 3-6 cycloalkyl,
(Q33) C 1-4 alkylcarbonyl,
(Q34) C 3-6 cycloalkylcarbonyl, and (q35) C 1-6 alkylsulfonyl may be substituted with the same or different 1-2 groups selected from the group consisting of. (Q31) and (q33) may be further substituted with a group selected from the group consisting of the above (l31) to (l35), and (q32) and (q34) are the above (m31) to (m36 And may be further substituted with a group selected from the group consisting of: ),
(R3) a 4- to 7-membered cyclic amino group,
(S3) an aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (q31) to (q35));
(T3) a 4- to 7-membered cyclic aminocarbonyl group,
(U3) an aminosulfonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of the above (q31) and (q32));
(V3) a 4- to 7-membered cyclic aminosulfonyl group,
(W3) C 6-10 aryl group (the aryl is
(W31) a halogen atom,
(W32) C 1-4 alkoxy,
(W33) C 1-4 alkyl, or (w34) C 3-7 cycloalkyl may be substituted. ),
(X3) 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl is
(X31) a halogen atom,
(X32) C 1-4 alkyl (the alkyl may be substituted with 1 to 3 halogen atoms), or (x33) C 3-6 cycloalkyl. ),
(Y3) C 1-4 alkylsulfonyl group, (z3) C 3-6 cycloalkylsulfonyl group and the like can be mentioned.
　「置換されていてもよいＣ６－１０アリール基」、および「置換されていてもよい５員～１２員の単環式もしくは多環式へテロアリール基」における好適な置換基としては、例えば
（ａ４）重水素原子、
（ｂ４）ハロゲン原子、
（ｃ４）水酸基、
（ｄ４）シアノ基、
（ｅ４）複素環基、
（ｆ４）Ｃ３－７シクロアルキル基、
（ｇ４）Ｃ３－７シクロアルキルオキシ基、
（ｈ４）Ｃ１－４アルキル基（該アルキル基は、
　　（ｈ４１）１～３個のハロゲン原子、
　　（ｈ４２）ヒドロキシ、
　　（ｈ４３）Ｃ３－６シクロアルキルオキシ、
　　（ｈ４４）Ｃ１－４アルコキシ（該アルコキシは、
　　　　　　　１～３個のハロゲン原子、
　　　　　　　Ｃ１－４アルコキシ、または
　　　　　　　ヒドロキシで置換されていてもよい。）、
　　（ｈ４５）Ｃ３－６シクロアルキル、
　　（ｈ４６）アミノ（該アミノは、Ｃ１－６アルキル、およびＣ３－６シクロアルキルからなる群から選択される同種または異種の１～２個の基で置換されていてもよい。）、または
　　（ｈ４７）４員～７員の環状アミノで置換されていてもよい。）、
（ｉ４）Ｃ１－４アルコキシ基（該アルコキシ基は、
　　（ｉ４１）１～３個のハロゲン原子、
　　（ｉ４２）ヒドロキシ、
　　（ｉ４３）Ｃ１－４アルコキシ、
　　（ｉ４４）Ｃ３－６シクロアルキルオキシ、または
　　（ｉ４５）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｊ４）Ｃ１－６アルキルカルボニル基（該アルキルは、
　　（ｊ４１）ヒドロキシ、
　　（ｊ４２）１～３個のハロゲン原子、
　　（ｊ４３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｊ４４）Ｃ３－６シクロアルコキシ、または
　　（ｊ４５）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｋ４）Ｃ３－６シクロアルキルカルボニル基（該シクロアルキルは、
　　（ｋ４１）ヒドロキシ、
　　（ｋ４２）１～３個のハロゲン原子、
　　（ｋ４３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｋ４４）Ｃ３－６シクロアルコキシ、
　　（ｋ４５）Ｃ１－４アルキル、または
　　（ｋ４６）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｌ４）Ｃ６－１０アリール基（該アリール基は、
　　（ｌ４１）ハロゲン原子、
　　（ｌ４２）Ｃ１－４アルコキシ、
　　（ｌ４３）Ｃ３－７シクロアルキル、または
　　（ｌ４４）Ｃ１－４アルキルで置換されていてもよい。）、
（ｍ４）５員～１２員の単環式もしくは多環式のヘテロアリール基（該へテロアリール基は、
　　（ｍ４１）ハロゲン原子、
　　（ｍ４２）Ｃ１－４アルキル（該アルキルは、１～３個のハロゲン原子で置換されていてもよい。）、または
　　（ｍ４３）Ｃ３－６シクロアルキルで置換されていてもよい。）、または
（ｎ４）Ｃ１－４アルキルスルホニル基等が挙げられる。 Suitable substituents in the “optionally substituted C 6-10 aryl group” and the “optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group” include, for example, ( a4) deuterium atom,
(B4) a halogen atom,
(C4) hydroxyl group,
(D4) a cyano group,
(E4) a heterocyclic group,
(F4) C 3-7 cycloalkyl group,
(G4) a C 3-7 cycloalkyloxy group,
(H4) C 1-4 alkyl group (the alkyl group is
(H41) 1 to 3 halogen atoms,
(H42) hydroxy,
(H43) C 3-6 cycloalkyloxy,
(H44) C 1-4 alkoxy (the alkoxy is
1 to 3 halogen atoms,
It may be substituted with C 1-4 alkoxy or hydroxy. ),
(H45) C 3-6 cycloalkyl,
(H46) amino (the amino may be substituted with 1 to 2 groups of the same or different types selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl), or (H47) It may be substituted with a 4- to 7-membered cyclic amino. ),
(I4) C 1-4 alkoxy group (the alkoxy group is
(I41) 1 to 3 halogen atoms,
(I42) hydroxy,
(I43) C 1-4 alkoxy,
(I44) C 3-6 cycloalkyloxy, or (i45) C 3-6 cycloalkyl may be substituted. ),
(J4) C 1-6 alkylcarbonyl group (the alkyl is
(J41) hydroxy,
(J42) 1 to 3 halogen atoms,
(J43) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(J44) C 3-6 cycloalkoxy or (j45) C 3-6 cycloalkyl may be substituted. ),
(K4) C 3-6 cycloalkylcarbonyl group (the cycloalkyl is
(K41) hydroxy,
(K42) 1 to 3 halogen atoms,
(K43) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(K44) C 3-6 cycloalkoxy,
(K45) C 1-4 alkyl, or (k46) C 3-6 cycloalkyl may be substituted. ),
(14) C 6-10 aryl group (the aryl group is
(L41) a halogen atom,
(L42) C 1-4 alkoxy,
(144) C 3-7 cycloalkyl, or (144) C 1-4 alkyl may be substituted. ),
(M4) 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl group is
(M41) a halogen atom,
(M42) C 1-4 alkyl (wherein the alkyl may be substituted with 1 to 3 halogen atoms), or (m43) optionally substituted with C 3-6 cycloalkyl. ), Or (n4) C 1-4 alkylsulfonyl group and the like.
　「置換されていてもよいＣ６－１０アリール基」、および「置換されていてもよい５員～１２員の単環式もしくは多環式へテロアリール基」のより好適な置換基としては、例えば、
（ａ５）ハロゲン原子、
（ｂ５）Ｃ１－４アルコキシ（該アルコキシは、
　　（ｂ５１）１～３個のハロゲン原子、または
　　（ｂ５２）Ｃ１－４アルコキシで置換されていてもよい。）、
（ｃ５）Ｃ３－６シクロアルキル、
（ｄ５）Ｃ１－４アルキル（該アルキルは、
　　（ｄ５１）１～３個のハロゲン原子、
　　（ｄ５２）Ｃ１－４アルコキシ、
　　（ｄ５３）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
　　（ｄ５４）４員～７員の環状アミノで置換されていてもよい。）、および
（ｅ５）Ｃ１－６アルキルカルボニルからなる群から選択される同種または異種の１～５個の基である。 As more preferred substituents of “optionally substituted C 6-10 aryl group” and “optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group”, for example, ,
(A5) a halogen atom,
(B5) C 1-4 alkoxy (the alkoxy is
(B51) optionally substituted by 1 to 3 halogen atoms, or (b52) C 1-4 alkoxy. ),
(C5) C 3-6 cycloalkyl,
(D5) C 1-4 alkyl (the alkyl is
(D51) 1 to 3 halogen atoms,
(D52) C 1-4 alkoxy,
(D53) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d54) optionally substituted with 4 to 7 membered cyclic amino. And (e5) 1-5 groups of the same or different types selected from the group consisting of C 1-6 alkylcarbonyl.
　「置換されていてもよい複素環基」の置換基としては、例えば、前記（ｃ）～（ｕ）からなる群から選択される基、およびＣ１－４アルキル基（該アルキルは、１～３個のハロゲン原子、またはＣ１－４アルコキシで置換されていてもよい。）などが挙げられる。 Examples of the substituent of the “optionally substituted heterocyclic group” include a group selected from the group consisting of the above (c) to (u), and a C 1-4 alkyl group (wherein the alkyl is 1 to And may be substituted with three halogen atoms or C 1-4 alkoxy).
　「置換されていてもよいアミノ基」とは、アミノ基、モノ－もしくはジ－置換されているアミノ基、および置換されていてもよい４員～７員の環状アミノ基を意味する。 The “optionally substituted amino group” means an amino group, a mono- or di-substituted amino group, and an optionally substituted 4- to 7-membered cyclic amino group.
　「モノ－もしくはジ－置換されているアミノ基」の置換基としては、
（ａ６）Ｃ１－６アルキル（該アルキルは、
　　（ａ６１）ヒドロキシ、
　　（ａ６２）１～３個のハロゲン原子、
　　（ａ６３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ａ６４）Ｃ３－６シクロアルコキシ、または
　　（ａ６５）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｂ６）Ｃ３－６シクロアルキル（該シクロアルキルは、
　　（ｂ６１）ヒドロキシ、
　　（ｂ６２）１～３個のハロゲン原子、
　　（ｂ６３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｂ６４）Ｃ３－６シクロアルコキシ、
　　（ｂ６５）Ｃ１－４アルキル、または
　　（ｂ６６）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｃ６）Ｃ１－４アルキルカルボニル（該アルキルは、
　　（ｃ６１）ヒドロキシ、
　　（ｃ６２）１～３個のハロゲン原子、
　　（ｃ６３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｃ６４）Ｃ３－６シクロアルコキシ、または
　　（ｃ６５）Ｃ３－６シクロアルキルで置換されていてもよい。）、
（ｄ６）Ｃ３－６シクロアルキルカルボニル（該シクロアルキルは、
　　（ｂ６１）ヒドロキシ、
　　（ｂ６２）１～３個のハロゲン原子、
　　（ｂ６３）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
　　（ｂ６４）Ｃ３－６シクロアルコキシ、
　　（ｂ６５）Ｃ１－４アルキル、または
　　（ｂ６６）Ｃ３－６シクロアルキルで置換されていてもよい。）、および
（ｅ６）Ｃ１－６アルキルスルホニルからなる群から選択される同種または異種の１～２個の基が挙げられる。 As a substituent of “mono- or di-substituted amino group”,
(A6) C 1-6 alkyl (the alkyl is
(A61) hydroxy,
(A62) 1 to 3 halogen atoms,
(A63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(A64) C 3-6 cycloalkoxy or (a65) C 3-6 cycloalkyl may be substituted. ),
(B6) C 3-6 cycloalkyl (the cycloalkyl is
(B61) hydroxy,
(B62) 1 to 3 halogen atoms,
(B63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(B64) C 3-6 cycloalkoxy,
(B65) C 1-4 alkyl, or (b66) C 3-6 cycloalkyl may be substituted. ),
(C6) C 1-4 alkylcarbonyl (wherein the alkyl is
(C61) hydroxy,
(C62) 1 to 3 halogen atoms,
(C63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(C64) C 3-6 cycloalkoxy, or (c65) C 3-6 optionally substituted by cycloalkyl. ),
(D6) C 3-6 cycloalkylcarbonyl (the cycloalkyl is
(B61) hydroxy,
(B62) 1 to 3 halogen atoms,
(B63) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
(B64) C 3-6 cycloalkoxy,
(B65) C 1-4 alkyl, or (b66) C 3-6 cycloalkyl may be substituted. ), And (e6) the same or different 1-2 groups selected from the group consisting of C 1-6 alkylsulfonyl.
　「置換されていてもよい４員～７員の環状アミノ基」における置換基としては、前記「置換されていてもよい複素環基」の置換基と同じである。 The substituent in the “optionally substituted 4- to 7-membered cyclic amino group” is the same as the substituent in the “optionally substituted heterocyclic group”.
　「置換されていてもよいアミノカルボニル基」における「置換されていてもよいアミノ」は、前記「置換されていてもよいアミノ」と同義である。すなわち、アミノカルボニル基、モノ－もしくはジ－置換されているアミノカルボニル基、および置換されていてもよい４員～７員の環状アミノカルボニル基を意味し、「モノ－もしくはジ－置換されているアミノ」及び「４員～７員の環状アミノカルボニル」部分は、前掲と同じである。 The “optionally substituted amino” in the “optionally substituted aminocarbonyl group” has the same meaning as the above “optionally substituted amino”. That is, it means an aminocarbonyl group, a mono- or di-substituted aminocarbonyl group, and an optionally substituted 4- to 7-membered cyclic aminocarbonyl group, and is “mono- or di-substituted. The “amino” and “4- to 7-membered cyclic aminocarbonyl” moieties are the same as described above.
　「アミノスルホニル基」におけるアミノは、前記（ｑ３１）および（ｑ３２）からなる群から選択される同種または異種の１～２個の基で置換されてもよく、該アミノ部分は前掲と同じである。 The amino in the “aminosulfonyl group” may be substituted with one or two groups selected from the group consisting of the above (q31) and (q32), and the amino moiety is the same as above. .
　「４員～７員の環状アミノスルホニル基」における４員～７員の環状アミノ部分は、前掲と同じである。 The 4- to 7-membered cyclic amino moiety in the “4- to 7-membered cyclic aminosulfonyl group” is the same as described above.
　式（１）で表される化合物の定義における、好ましい態様について更に説明する。 Preferred embodiments in the definition of the compound represented by the formula (1) will be further described.
　「Ｒ１」としては、Ｃ６－１０アリール基または５員もしくは６員の単環式ヘテロアリール基（該アリールおよびヘテロアリール基は、
（１）ハロゲン原子、
（２）Ｃ３－７シクロアルキル基、
（３）Ｃ１－４アルキル基（該アルキル基は、
　（ａ）１～３個のフッ素原子、
　（ｂ）Ｃ１－４アルコキシ、
　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
　（ｄ）４員～７員の環状アミノなどで置換されていてもよい。）、
（４）Ｃ１－４アルコキシ基（該アルコキシ基は、
　（ａ）１～３個のフッ素原子、または
　（ｂ）Ｃ１－４アルコキシで置換されていてもよい。）、および
（５）Ｃ１－４アルキルカルボニル基からなる群から選択される同種または異種の１～５個の基で置換されていてもよい。）が好ましい。 “R 1 ” includes a C 6-10 aryl group or a 5- or 6-membered monocyclic heteroaryl group (the aryl and heteroaryl groups are
(1) a halogen atom,
(2) a C 3-7 cycloalkyl group,
(3) C 1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C 1-4 alkoxy,
(C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) 4 to 7 membered cyclic amino and the like. ),
(4) C 1-4 alkoxy group (the alkoxy group is
(A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. And (5) 1 to 5 groups of the same or different types selected from the group consisting of C 1-4 alkylcarbonyl groups. Is preferred.
　「Ｒ１」としては、置換されていてもよい５員もしくは６員の単環式ヘテロアリール基（該ヘテロアリール基の置換基は、前記と同じである。）が好ましく、５員もしくは６員の単環式ヘテロアリール基（該ヘテロアリール基は、ハロゲン原子およびＣ１－４アルキル基からなる群から選択される基で置換されていてもよい。）がより一層好ましい。 “R 1 ” is preferably an optionally substituted 5-membered or 6-membered monocyclic heteroaryl group (the substituents of the heteroaryl group are the same as those described above), and are preferably 5-membered or 6-membered. And a monocyclic heteroaryl group (which is optionally substituted with a group selected from the group consisting of a halogen atom and a C 1-4 alkyl group).
　「Ｒ１」おける５員もしくは６員の単環式へテロアリール基としては、下記（ａ）～（ｄ）
Figure JPOXMLDOC01-appb-C000026
 ［ここに、（ａ）～（ｄ）は前記（ａ３）～（ｚ３）、（ａ４）～（ｎ４）および（ａ５）～（ｅ５）からなる群から選択される置換基で置換されていてもよい。］
で表されるいずれか一つの基が好ましい。 Examples of the 5-membered or 6-membered monocyclic heteroaryl group in “R 1 ” include the following (a) to (d):
Figure JPOXMLDOC01-appb-C000026
 [Wherein (a) to (d) are substituted with a substituent selected from the group consisting of (a3) to (z3), (a4) to (n4) and (a5) to (e5). Also good. ]
Any one group represented by is preferable.
「Ｒ１」おける５員もしくは６員の単環式へテロアリール基としては、下記（ａ）
Figure JPOXMLDOC01-appb-C000027
 ［ここに、（ａ）は前記（ａ３）～（ｚ３）、（ａ４）～（ｎ４）および（ａ５）～（ｅ５）からなる群から選択される置換基で置換されていてもよい。］
で表される基が好ましく、下記（ａ１）
Figure JPOXMLDOC01-appb-C000028
 ［ここに、（ａ１）は前記（ａ３）～（ｚ３）、（ａ４）～（ｎ４）および（ａ５）～（ｅ５）からなる群から選択される置換基で置換されていてもよい。］
で表される基が更に好ましい。 As the 5-membered or 6-membered monocyclic heteroaryl group in “R 1 ”, the following (a):
Figure JPOXMLDOC01-appb-C000027
 [Wherein (a) may be substituted with a substituent selected from the group consisting of (a3) to (z3), (a4) to (n4) and (a5) to (e5)). ]
Is preferably represented by the following (a1):
Figure JPOXMLDOC01-appb-C000028
 [Wherein (a1) may be substituted with a substituent selected from the group consisting of (a3) to (z3), (a4) to (n4) and (a5) to (e5)). ]
Is more preferable.
　「Ｒ２」としては、Ｃ１－６アルキル基（該基は、
（１）１～５個のハロゲン原子、
（２）Ｃ３－６シクロアルキル、または
（３）Ｃ１－４アルコキシで置換されていてもよい。）が好ましく、メチル基またはエチル基がより好ましい。 “R 2 ” is a C 1-6 alkyl group (the group is
(1) 1 to 5 halogen atoms,
It may be substituted with (2) C 3-6 cycloalkyl or (3) C 1-4 alkoxy. ) Is preferable, and a methyl group or an ethyl group is more preferable.
　「Ｒ３」としては、
（１）水素原子、
（２）ハロゲン原子、または
（２）Ｃ１－６アルキル基（該基は、
　（ａ）１～３個のハロゲン原子、
　（ｂ）Ｃ３－６シクロアルキル、または
　（ｃ）Ｃ１－４アルコキシで置換されていてもよい。）が好ましく、水素原子、塩素原子、フッ素原子またはメチル基がより好ましく、水素原子、塩素原子またはメチル基がより一層好ましく、更に水素原子が特に好ましい。 As “R 3 ”,
(1) a hydrogen atom,
(2) a halogen atom, or (2) a C 1-6 alkyl group (the group is
(A) 1 to 3 halogen atoms,
(B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. ) Is preferred, a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group is more preferred, a hydrogen atom, a chlorine atom or a methyl group is still more preferred, and a hydrogen atom is particularly preferred.
　「Ｒ４」としては、
（１）Ｃ１－６アルキル基（該基は、
　（ａ）１～３個のハロゲン原子、
　（ｂ）Ｃ３－６シクロアルキル、または
　（ｃ）Ｃ１－４アルコキシで置換されていてもよい。）、または
（２）Ｃ３－６シクロアルキル基が好ましく、メチル基、２，２－ジフルオロエチル基、２，２，２－トリフルオロエチル基、またはエチル基がより好ましく、更にエチル基がより一層好ましい。 As “R 4 ”,
(1) C 1-6 alkyl group (the group is
(A) 1 to 3 halogen atoms,
(B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. ), Or (2) a C 3-6 cycloalkyl group is preferred, a methyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, or an ethyl group is more preferred, and an ethyl group is more preferred. Even more preferred.
　「Ｒ５」としては、水酸基、アミノカルボニル基またはメチルスルホニル基が好ましく、水酸基またはアミノカルボニル基がより好ましい。 “R 5 ” is preferably a hydroxyl group, an aminocarbonyl group or a methylsulfonyl group, more preferably a hydroxyl group or an aminocarbonyl group.
　本発明において、下記式（２）で表される化合物、またはその薬理学的に許容される塩が好ましい。
Figure JPOXMLDOC01-appb-C000029
 ［式中、
　Ｒ２、Ｒ３、Ｒ４、およびＲ５は、前記項１と同義であり、
　Ｒ６ａ～Ｒ６ｄは、各々独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）Ｃ３－７シクロアルキル基、
（４）Ｃ１－４アルキル基（該アルキル基は、
　（ａ）１～３個のフッ素原子、
　（ｂ）Ｃ１－４アルコキシ、
　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
　（ｄ）４員～７員の環状アミノで置換されていてもよい。）、
（５）Ｃ１－４アルコキシ基（該アルコキシ基は、
　（ａ）１～３個のフッ素原子、または
　（ｂ）Ｃ１－４アルコキシで置換されていてもよい。）、または
（６）Ｃ１－４アルキルカルボニル基である。］ In the present invention, a compound represented by the following formula (2) or a pharmacologically acceptable salt thereof is preferable.
Figure JPOXMLDOC01-appb-C000029
 [Where:
R 2 , R 3 , R 4 , and R 5 are as defined in item 1 above,
R 6a to R 6d are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C 3-7 cycloalkyl group,
(4) C 1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C 1-4 alkoxy,
(C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ),
(5) C 1-4 alkoxy group (the alkoxy group is
(A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. ), Or (6) a C 1-4 alkylcarbonyl group. ]
　本発明の式（２）で表される化合物において、Ｒ６ａ～Ｒ６ｄが、各々独立して、
（１）水素原子、
（２）ハロゲン原子、または
（３）Ｃ１－４アルキル基（該アルキル基は、
　（ａ）１～３個のフッ素原子、
　（ｂ）Ｃ１－４アルコキシ、
　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
　（ｄ）４員～７員の環状アミノで置換されていてもよい。）である化合物、またはその薬理学的に許容される塩がより好ましい。 In the compound represented by the formula (2) of the present invention, R 6a to R 6d are each independently
(1) a hydrogen atom,
(2) a halogen atom, or (3) a C 1-4 alkyl group (the alkyl group is
(A) 1 to 3 fluorine atoms,
(B) C 1-4 alkoxy,
(C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ) Or a pharmacologically acceptable salt thereof is more preferred.
　本発明において、式（２）で表される化合物の各定義の好ましい態様は、式（１）で表される化合物における各定義の好ましい態様と同じである。 In the present invention, preferred embodiments of the respective definitions of the compound represented by the formula (2) are the same as preferred embodiments of the respective definitions of the compound represented by the formula (1).
　本発明において、式（１）及び式（２）で表される化合物は、下記群から選択されるいずれか一つの化合物が好ましい。
４－クロロ－５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－５－［（３－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－｛［３－フルオロ－５－（トリフルオロメチル）－２－ピリジニル］（メチル）アミノ｝－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（３－フルオロ－５－メチル－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（４－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－４－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
４－クロロ－１－エチル－５－［（４－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（４－フルオロフェニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、および
５－［（４－クロロ－２－フルオロフェニル）（メチル）アミノ］－１－エチル－Ｎ－［（２ｓ，５ｒ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド。 In the present invention, the compound represented by Formula (1) and Formula (2) is preferably any one compound selected from the following group.
4-chloro-5-[(5-chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide ,
5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3-carboxamide;
4-chloro-5-[(3-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide ,
4-Chloro-N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3 -Carboxamide,
1-ethyl-5-{[3-fluoro-5- (trifluoromethyl) -2-pyridinyl] (methyl) amino} -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole -3-carboxamide,
4-chloro-5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
1-ethyl-5-[(4-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -4-methyl-1H-pyrazole-3-carboxamide ,
4-Chloro-1-ethyl-5-[(4-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
1-ethyl-5-[(4-fluorophenyl) (methyl) amino] -N-[(E) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3-carboxamide, and 5- [(4-Chloro-2-fluorophenyl) (methyl) amino] -1-ethyl-N-[(2s, 5r) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3-carboxamide .
　本発明において、式（１）及び式（２）で表される化合物は、下記群から選択されるいずれか一つの化合物がより好ましい。
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
１－エチル－５－［（３－フルオロ－５－メチル－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、および
５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド。 In the present invention, the compound represented by Formula (1) and Formula (2) is more preferably any one compound selected from the following group.
5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3-carboxamide;
1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
5-[(4-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
5-[(5-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazol-3-carboxamide, and 5-[(5-chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl ] -1H-pyrazole-3-carboxamide.
　以下に、本発明における式（１）で表される化合物の製造法について、例を挙げて説明するが、本発明はもとよりこれに限定されるものではない。 Hereinafter, the method for producing the compound represented by the formula (1) in the present invention will be described with reference to examples, but the present invention is not limited thereto.
製造法１：
　式（１）で表される化合物は、例えば、次の方法により合成することができる。 Production method 1:
The compound represented by the formula (1) can be synthesized, for example, by the following method.
　式（１）で表される化合物のうち、式（ｓ－７）で表される化合物またはその塩は、例えば下記に示される方法によって製造される。
Figure JPOXMLDOC01-appb-C000030
 Of the compounds represented by the formula (1), the compound represented by the formula (s-7) or a salt thereof is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000030
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５は、前記記載と同義である。ＲａはＣ１－８アルキル基（メチル基、エチル基、オクチル基等）またはベンジル基等を表す。） (Wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, R a is a C 1-8 alkyl group (methyl group, ethyl group, octyl group etc.) or benzyl group Etc.)
工程（Ａ－１）：
　本工程は、アミン化合物（ｓ－１）またはその塩に対して、例えばアセチルクロリド等の酸ハロゲン化物を用いてアミド化合物（ｓ－２）を製造する工程である。また、アミン化合物（ｓ－１）またはその塩と酢酸を用いてアミド化合物（ｓ－２）を製造することもできる。さらにはアミン化合物（ｓ－１）またはその塩と無水酢酸を用いてアミド化合物（ｓ－２）を製造することもできる。
　カルボキシル基の活性化方法としては、例えばカルボキシル基を酸無水物、混合酸無水物、酸ハロゲン化物、活性エステル、または酸アジドに変換する方法、または縮合剤を用いる方法等が挙げられる。 Step (A-1):
This step is a step for producing an amide compound (s-2) using an acid halide such as acetyl chloride for the amine compound (s-1) or a salt thereof. Alternatively, the amide compound (s-2) can be produced using the amine compound (s-1) or a salt thereof and acetic acid. Furthermore, the amide compound (s-2) can also be produced using the amine compound (s-1) or a salt thereof and acetic anhydride.
Examples of the method for activating the carboxyl group include a method of converting the carboxyl group into an acid anhydride, mixed acid anhydride, acid halide, active ester, or acid azide, or a method using a condensing agent.
　酸ハロゲン化物法を用いる場合、酢酸のようなカルボン酸に対して、例えばオキサリルクロリド、塩化チオニル、オキシ塩化リン、五塩化リン等のハロゲン化試薬を反応させて調製されたアセチルクロリドのような酸ハロゲン化物に対して、塩基の存在下でアミン化合物（ｓ－１）またはその塩と反応させ、化合物（ｓ－２）を得ることができる。ここで、塩基としては特に限定はないが、例えば、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、ピリジン、ジメチルアミノピリジン、ピコリン、またはＮ－メチルモルホリン（ＮＭＭ）等の有機塩基類、または炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、または水酸化カリウム等の無機塩基類などが挙げられる。溶媒は、本工程の反応条件で反応しない溶媒であれば使用できる。例えばジクロロメタン、クロロホルム、１，２－ジクロロエタン、または四塩化炭素等のハロゲン化炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、または１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、またはキシレン等の芳香族炭化水素系溶媒、酢酸エチルまたは酢酸メチル等のエステル系溶媒、水、またはこれらの混合物が挙げられる。反応温度は、－８０℃から加熱還流温度で行われ、通常－２０℃から室温である。反応時間は、通常１０分間から４８時間である。 When the acid halide method is used, an acid such as acetyl chloride prepared by reacting a carboxylic acid such as acetic acid with a halogenating reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride. The halide can be reacted with the amine compound (s-1) or a salt thereof in the presence of a base to obtain the compound (s-2). Here, the base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2 2.2.2] Organics such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, or N-methylmorpholine (NMM) Examples include bases, or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide. Any solvent that does not react under the reaction conditions in this step can be used. For example, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane, benzene, toluene, or xylene An aromatic hydrocarbon solvent such as ethyl ester solvent such as ethyl acetate or methyl acetate, water, or a mixture thereof. The reaction temperature is from −80 ° C. to the reflux temperature, and is usually from −20 ° C. to room temperature. The reaction time is usually 10 minutes to 48 hours.
　混合酸無水物法を用いる場合、例えば酢酸のようなカルボン酸に対して、塩基の存在下、酸ハロゲン化物と反応させることによって混合酸無水物とした後、アミン化合物（ｓ－１）またはその塩と反応させ、化合物（ｓ－２）に導くことができる。酸ハロゲン化物としては、例えばメトキシカルボニルクロリド、エトキシカルボニルクロリド、イソプロピルオキシカルボニルクロリド、イソブチルオキシカルボニルクロリド、パラニトロフェノキシカルボニルクロリド、またはｔ－ブチルカルボニルクロリドなどが挙げられる。塩基としては、特に限定はないが、例えばトリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、ピリジン、ジメチルアミノピリジン、ピコリン、またはＮ－メチルモルホリン（ＮＭＭ）等の有機塩基類、または、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、または炭酸カリウム等の無機塩基類などが挙げられる。溶媒は、本工程の反応条件で反応しない溶媒であれば使用できる。例えばジクロロメタン、クロロホルム、１，２－ジクロロエタンまたは、四塩化炭素等のハロゲン化炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、または１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、またはキシレン等の芳香族炭化水素系溶媒、酢酸エチルまたは酢酸メチル等のエステル系溶媒、水、またはそれらの混合物が挙げられる。反応温度は、－８０℃から加熱還流温度で行われ、通常－２０℃から氷冷温度である。反応時間は、通常３０分間から４８時間である。 In the case of using the mixed acid anhydride method, for example, a carboxylic acid such as acetic acid is reacted with an acid halide in the presence of a base to form a mixed acid anhydride, and then the amine compound (s-1) or its compound is used. It can be reacted with a salt to lead to compound (s-2). Examples of the acid halide include methoxycarbonyl chloride, ethoxycarbonyl chloride, isopropyloxycarbonyl chloride, isobutyloxycarbonyl chloride, paranitrophenoxycarbonyl chloride, and t-butylcarbonyl chloride. The base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, or N-methylmorpholine (NMM), Or inorganic bases, such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, or potassium carbonate, etc. are mentioned. Any solvent that does not react under the reaction conditions in this step can be used. For example, dichloromethane, chloroform, 1,2-dichloroethane, halogenated hydrocarbon solvents such as carbon tetrachloride, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane, benzene, toluene, or xylene An aromatic hydrocarbon solvent such as ethyl ester, an ester solvent such as ethyl acetate or methyl acetate, water, or a mixture thereof. The reaction temperature is from −80 ° C. to heating under reflux temperature, and is usually from −20 ° C. to ice-cooling temperature. The reaction time is usually 30 minutes to 48 hours.
　縮合剤により酢酸のようなカルボン酸またはその塩とアミン化合物（ｓ－１）またはその塩を、塩基存在下または非存在下に反応させ、化合物（ｓ－２）を製造することもできる。ここで縮合剤としては、実験化学講座（日本化学会編、丸善）２２巻に表記されているものなどが挙げられる。例えば、シアノリン酸ジエチル、ジフェニルホスホリルアジド等のリン酸エステル類、１－エチル－３－（３－ジメチルアミノプロピル）－カルボジイミド塩酸塩、ジシクロヘキシルカルボジイミド等のカルボジイミド類、２，２’－ジピリジルジスルフィド等のジスルフィド類とトリフェニルホスフィンのようなホスフィンとの組合せ、Ｎ，Ｎ’－ビス（２－オキソ－３－オキサゾリジニル）ホスフィニッククロリド等のリンハライド類、アゾジカルボン酸ジエチル等のアゾジカルボン酸ジエステルとトリフェニルホスフィン等のホスフィンの組み合わせ、２－クロロ－１－メチルピリジニウムヨーダイド等の２－ハロ－１－低級アルキルピリジニウムハライド類、１，１’－カルボニルジイミダゾール、ジフェニルホスホリルアジド（ＤＰＰＡ）、ジエチルホスホリルシアニド（ＤＥＰＣ）、ジシクロヘキシルカルボジイミド（ＤＣＣ）、カルボニルジイミダゾール（ＣＤＩ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）、Ｏ－（１Ｈ－ベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチル－ウロニウム　テトラヒドロボレイト（ＴＢＴＵ）、Ｏ－（１Ｈ－ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチル－ウロニウム　ヘキサフルオロホスフェイト（ＨＢＴＵ）、または（ベンゾトリアゾール－１－イルオキシ）トリス（ジメチルアミノ）ホスホニウムヘキサフルオロホスフェート等が挙げられる。溶媒は、特に限定されず、本工程の反応条件で反応しない溶媒であれば使用できる。具体的には酸ハロゲン化物法を用いる場合と同じ溶媒を用いることができ、あるいは、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、１，３－ジメチル－２－イミダゾリジノン、またはジメチルスルホキシド等の非プロトン性極性溶媒、水、またはそれらの混合溶媒を用いてもよい。塩基としては、特に限定はないが、例えばトリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、ピリジン、ジメチルアミノピリジン、ピコリン、またはＮ－メチルモルホリン（ＮＭＭ）等の有機塩基類が挙げられる。反応温度は、通常－１０℃から加熱還流温度で行われる。反応時間は、主に反応温度、使用される原料、および溶媒等の条件によって異なるが、通常０．５時間から４８時間である。 A compound (s-2) can also be produced by reacting a carboxylic acid such as acetic acid or a salt thereof with an amine compound (s-1) or a salt thereof in the presence or absence of a base with a condensing agent. Here, examples of the condensing agent include those described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen) Vol. For example, phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, dicyclohexylcarbodiimide, 2,2′-dipyridyl disulfide, etc. Combinations of disulfides and phosphines such as triphenylphosphine, phosphorus halides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, azodicarboxylic acid diesters such as diethyl azodicarboxylate and tri Combinations of phosphines such as phenylphosphine, 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 1,1′-carbonyldiimidazole, diphenylphosphoryl azide (D PA), diethyl phosphorylcyanide (DEPC), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), O- (1H) -Benzotriazol-1-yl) -1,1,3,3-tetramethyl-uronium tetrahydroborate (TBTU), O- (1H-benzotriazol-1-yl) -N, N, N ′, N ′ -Tetramethyl-uronium hexafluorophosphate (HBTU), (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate, etc. The solvent is not particularly limited, and any solvent that does not react under the reaction conditions in this step can be used. Specifically, the same solvent as that used in the acid halide method can be used, or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl- An aprotic polar solvent such as 2-imidazolidinone or dimethyl sulfoxide, water, or a mixed solvent thereof may be used. The base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, or N-methylmorpholine (NMM) Can be mentioned. The reaction temperature is usually from −10 ° C. to the heating reflux temperature. The reaction time varies depending mainly on the reaction temperature, the raw materials used, the solvent and other conditions, but is usually 0.5 to 48 hours.
工程（Ａ－２）：
　本工程は、化合物（ｓ－２）に塩基を加えた後、シュウ酸ジアルキル（ＣＯ２Ｒａ）２を作用させることより、ケトエステル化合物（ｓ－３）を製造する工程である。
　ここで、塩基としては、例えば、水素化ナトリウム、水素化リチウム、または水素化カリウム等の水素化金属、ナトリウムエトキシド、カリウムエトキシド、ナトリウムメトキシド、カリウムメトキシド、カリウム　ｔｅｒｔ－ブトキシド、ナトリウム　ｔｅｒｔ－ブトキシド、リチウム　メトキシド、リチウム　エトキシド、リチウム　メトキシド、リチウム　ｔｅｒｔ－ブトキシド等の金属アルコキシド、カリウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、リチウムヘキサメチルジシラジド、またはリチウムジイソプロピルアミド等の金属アミンが挙げられる。溶媒としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテルまたは１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、Ｎ－メチル－２－ピロリジノン、１，３－ジメチル－２－イミダゾリジノン等が挙げられる。
　反応温度は、－７８℃から加熱還流温度で実施できるが、通常－７８℃から室温である。反応時間は、主に反応温度、使用される原料、および溶媒等の条件によって異なるが、通常０．５時間から４８時間である。
　当該工程は、（ＣＯ２Ｒａ）２に塩基を加えた後、化合物（ｓ－２）を作用させることによっても、ケトエステル化合物（ｓ－３）を製造することができる。また、塩基に対して化合物（ｓ－２）と（ＣＯ２Ｒａ）２を同時に加えても、または化合物（ｓ－２）と（ＣＯ２Ｒ１）２の混合物に対して塩基を加えても、ケトエステル化合物（ｓ－３）を製造することができる。 Step (A-2):
This step is a step for producing a ketoester compound (s-3) by adding a base to the compound (s-2) and then reacting with dialkyl oxalate (CO 2 R a ) 2 .
Here, as the base, for example, a metal hydride such as sodium hydride, lithium hydride, or potassium hydride, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium tert Metal alkoxides such as butoxide, lithium methoxide, lithium ethoxide, lithium methoxide, lithium tert-butoxide, metal amines such as potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, or lithium diisopropylamide Is mentioned. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, N -Methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone and the like.
The reaction temperature can be carried out at −78 ° C. to a reflux temperature, and is usually from −78 ° C. to room temperature. The reaction time varies depending mainly on the reaction temperature, the raw materials used, the solvent and other conditions, but is usually 0.5 to 48 hours.
In this step, the ketoester compound (s-3) can also be produced by adding a base to (CO 2 R a ) 2 and then allowing the compound (s-2) to act. Further, the compound (s-2) and (CO 2 R a ) 2 may be added simultaneously to the base, or the base may be added to the mixture of the compound (s-2) and (CO 2 R 1 ) 2. In addition, a ketoester compound (s-3) can be produced.
工程（Ａ－３）：
　本工程は、ローソン試薬または５硫化２燐のようなチオ化剤の存在下に、ケトエステル化合物（ｓ－３）をヒドラジンＲ４ＮＨＮＨ２またはその塩で処理してピラゾールエステル化合物（ｓ－４）を製造する工程である。ローソン試薬または５硫化２燐は、ケトエステル化合物（ｓ－３）に対して、通常１から３当量用いて行われる。ヒドラジンＲ４ＮＨＮＨ２またはその塩は、通常１から２当量用いて行われる。反応温度は、通常、室温から加熱還流温度であり、反応時間は、主に反応温度、使用される原料、および溶媒等の条件によって異なるが、通常２時間から４８時間である。反応溶媒としては、ピリジン、ピコリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン等を単独または混合系を用いるか、もしくはこれらに加えて、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテルまたは１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、酢酸エチル、酢酸イソプロピルまたは酢酸メチル等のエステル系溶媒などを加えて用いることができる。 Step (A-3):
In this step, the keto ester compound (s-3) is treated with hydrazine R 4 NHNH 2 or a salt thereof in the presence of a thioating agent such as Lawesson's reagent or phosphorous pentasulfide to give a pyrazole ester compound (s-4). Is a process of manufacturing. Lawesson's reagent or phosphorous pentasulfide is usually used in an amount of 1 to 3 equivalents with respect to the ketoester compound (s-3). Hydrazine R 4 NHNH 2 or a salt thereof is usually used in an amount of 1 to 2 equivalents. The reaction temperature is usually from room temperature to heating reflux temperature, and the reaction time is usually from 2 hours to 48 hours, although it varies depending mainly on the reaction temperature, the raw materials used, the solvent and the like. As the reaction solvent, pyridine, picoline, triethylamine, diisopropylethylamine, tributylamine or the like is used alone or in combination, or in addition to these, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or An ether solvent such as 1,4-dioxane, an aromatic hydrocarbon solvent such as benzene, toluene or xylene, an ester solvent such as ethyl acetate, isopropyl acetate or methyl acetate can be added and used.
工程（Ａ－４）：
　本工程は、ピラゾールエステル化合物（ｓ－４）のエステル基の脱保護により、ピラゾールカルボン酸化合物（ｓ－５）を製造する工程である。
　本工程を実施するには、プロテクティブ・グループス・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、グリーン著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．）（１９８１年）に記載されている方法が挙げられる。
　具体的には、例えば以下のような方法で実施される。アルカリ加水分解、または酸加水分解によってピラゾールカルボン酸化合物（ｓ－５）へと導くことができる。すなわち、例えば、アルカリ加水分解の場合、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化マグネシウム等のアルカリ金属またはアルカリ土類金属の水酸化物の存在下、水とともに、例えばメタノール、エタノール、２－プロパノール、ブタノール等のアルコール系溶媒、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒の共存または非共存下において、通常、室温から加熱還流温度の範囲で、０．５時間から４８時間反応させることにより、ピラゾールカルボン酸化合物（ｓ－５）の化合物を得ることができる。 Step (A-4):
This step is a step of producing a pyrazole carboxylic acid compound (s-5) by deprotecting the ester group of the pyrazole ester compound (s-4).
To implement this process, Protective Groups in Organic Synthesis, Green, John Wiley & Sons Inc. (1981) ).
Specifically, for example, the following method is used. The pyrazole carboxylic acid compound (s-5) can be led by alkaline hydrolysis or acid hydrolysis. That is, for example, in the case of alkaline hydrolysis, in the presence of an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, etc., together with water, for example, methanol, ethanol, In the presence or absence of alcohol solvents such as 2-propanol and butanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, and aromatic hydrocarbon solvents such as benzene, toluene and xylene. Usually, the compound of pyrazole carboxylic acid compound (s-5) can be obtained by reacting in the range of room temperature to heating reflux temperature for 0.5 to 48 hours.
工程（Ａ－５）：
　本工程は、ピラゾールカルボン酸化合物（ｓ－５）とアダマンチルアミン化合物（ｓ－６）とのアミド化により目的物のアミド化合物（ｓ－７）を製造する工程である。本工程は、工程（Ａ－１）の方法と同様の方法で実施することができる。 Step (A-5):
This step is a step of producing the target amide compound (s-7) by amidation of the pyrazole carboxylic acid compound (s-5) and the adamantylamine compound (s-6). This step can be performed by a method similar to the method in step (A-1).
製造法２：
　アミド化合物（ｓ－７）はまた、下記に示される工程（Ａ－６）を経由しても製造することができる。
Figure JPOXMLDOC01-appb-C000031
 Production method 2:
The amide compound (s-7) can also be produced via the step (A-6) shown below.
Figure JPOXMLDOC01-appb-C000031
（式中、Ｒ１、Ｒ２、Ｒ４、およびＲａは、前記記載と同義である。Ｒｂはハロゲン原子を表す。） (In the formula, R 1 , R 2 , R 4 , and R a are as defined above. R b represents a halogen atom.)
工程（Ａ－６）：
　本工程は、製造法１工程（Ａ－１）～（Ａ－３）に従って製造された化合物（ｓ－８）のピラゾール環４位に基：Ｒｂを導入し、化合物（ｓ－９）を製造する工程である。
　化合物（ｓ－８）に、例えば、Ｎ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、Ｎ－ヨードスクシンイミド、塩素、臭素、ヨウ素、塩化ヨウ素、塩化スルフリル、ＳＥＬＥＣＴＦＬＵＯＲ（登録商標）、１－フルオロ－４－ヒドロキシ－１，４－ジアゾニアビシクロ［２．２．２］オクタン　ビス（テトラフルオロボレート）、Ｎ－フルオロベンゼンスルホンイミド、Ｎ－フルオロ－Ｏ－ベンゼンジスルホンイミド、１－フルオロピリジニウムトリフラート、または１－フルオロ－２，６－ジクロロピリジニウム　テトラフルオロボレート等のハロゲン化剤を、酸の存在下または非存在下に加えることで、４位にハロゲン原子を導入することができる。酸としては、例えば、塩化水素または臭化水素などのハロゲン化水素、または酢酸またはプロピオン酸などの有機酸等が挙げられる。溶媒は、反応に不活性な溶媒であれば用いることができ、例えば酢酸エチルまたは酢酸メチル等のエステル系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、または四塩化炭素等のハロゲン化炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテルまたは１，４－ジオキサン等のエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、または１，３－ジメチル－２－イミダゾリジノン等の非プロトン性極性溶媒等が挙げられる。反応温度は、通常－１０℃から加熱還流温度で行われる。反応時間は、通常０．５時間から４８時間である。
　このようにして得られた化合物（ｓ－９）を、製造法１の工程（Ａ－４）および（Ａ－５）と同様に処理して、対応するアミド化合物（ｓ－７）を製造することができる。 Step (A-6):
This step introduces the group: R b into the 4-position of the pyrazole ring of the compound (s-8) produced according to the production method 1 steps (A-1) to (A-3) to give the compound (s-9). It is a manufacturing process.
Examples of the compound (s-8) include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, bromine, iodine, iodine chloride, sulfuryl chloride, SELECTFLUOR (registered trademark), 1-fluoro-4-hydroxy -1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate), N-fluorobenzenesulfonimide, N-fluoro-O-benzenedisulfonimide, 1-fluoropyridinium triflate, or 1-fluoro By adding a halogenating agent such as -2,6-dichloropyridinium tetrafluoroborate in the presence or absence of an acid, a halogen atom can be introduced at the 4-position. Examples of the acid include a hydrogen halide such as hydrogen chloride or hydrogen bromide, or an organic acid such as acetic acid or propionic acid. The solvent can be used as long as it is inert to the reaction. For example, ester solvents such as ethyl acetate or methyl acetate, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, or carbon tetrachloride. Solvent, ether solvent such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 And aprotic polar solvents such as pyrrolidinone and 1,3-dimethyl-2-imidazolidinone. The reaction temperature is usually from −10 ° C. to the heating reflux temperature. The reaction time is usually 0.5 to 48 hours.
The compound (s-9) thus obtained is treated in the same manner as in production method 1 steps (A-4) and (A-5) to produce the corresponding amide compound (s-7). be able to.
製造法３：
　式（１）で表される化合物のうち、式（ｓ－１１）で表される化合物またはその塩は、下記に示される方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000032
 （式中、Ｒ１、Ｒ２、Ｒ４、Ｒ５およびＲｂは、前記記載と同義である。）
工程（Ａ－７）：
　本工程は、製造法１工程（Ａ－１）～（Ａ－５）に従って製造されたアミド体（ｓ－１０）のピラゾール環４位にＲｂ基（すなわち、ハロゲン原子）を導入し、化合物（ｓ－１１）を製造する工程である。Ｒｂ基の導入は、製造法２の工程（Ａ－６）と同様にして実施することができる。 Production method 3:
Among the compounds represented by the formula (1), the compound represented by the formula (s-11) or a salt thereof can be produced by the method shown below.
Figure JPOXMLDOC01-appb-C000032
 (In the formula, R 1 , R 2 , R 4 , R 5 and R b are as defined above.)
Step (A-7):
In this step, an R b group (that is, a halogen atom) is introduced into the 4-position of the pyrazole ring of the amide compound (s-10) produced according to Production Method 1 Steps (A-1) to (A-5), and the compound This is a process for manufacturing (s-11). Introduction of the R b group can be carried out in the same manner as in production method 2, step (A-6).
製造法４：
　アミド化合物（ｓ－７）はまた、下記に示される工程（Ａ－８）を経由しても製造することができる。
Figure JPOXMLDOC01-appb-C000033
 Production method 4:
The amide compound (s-7) can also be produced via the step (A-8) shown below.
Figure JPOXMLDOC01-appb-C000033
（式中、Ｒ１、Ｒ２、Ｒ４、ＲａおよびＲｂは、前記記載と同義である。Ｒｃは置換されていてもよいＣ１－６アルキル、シアノ等を表す。Ｍｔｌは亜鉛、マグネシウム、マンガンを含む金属種等を表す。） (Wherein R 1 , R 2 , R 4 , R a and R b are as defined above. R c represents optionally substituted C 1-6 alkyl, cyano, etc. Mtl is zinc) , Represents metal species including magnesium and manganese.)
工程（Ａ－８）：
　本工程は、製造法２の工程（Ａ－６）で得られた化合物（ｓ－９）に対して有機金属化合物（ｓ－１２）を金属触媒存在下で反応させることにより化合物（ｓ－１３）を製造する工程である。
　本工程を実施するには、パラジウム　リエージェント　アンド　カタリスツ（ｐａｌｌａｄｉｕｍ　ｒｅａｇｅｎｔｓ　ａｎｄ　ｃａｔａｌｙｓｔｓ、ジロウ　ツジ著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．）（２００４年）に記載されている方法等が挙げられる。 Step (A-8):
In this step, compound (s-13) is obtained by reacting compound (s-9) obtained in step (A-6) of production method 2 with organometallic compound (s-12) in the presence of a metal catalyst. ).
This process is described in Palladium Reagents and Catalysts, by Jiro Tsuji, John Wiley & Sons Inc. (2004). Methods and the like.
　例えば、有機亜鉛試薬を用いる方法では、Ｒｂはハロゲン原子であり、好ましくは臭素、ヨウ素、塩素があげられる。有機金属化合物（ｓ－１２）としては、メチルジンククロリドのようなアルキル亜鉛ハライド、ジメチルジンクのようなジアルキル亜鉛、ジンクシアニドのような金属シアン等が挙げられ、これらは通常、化合物（ｓ－９）に対して１当量から１０当量が用いられる。金属触媒としては、テトラキス（トリフェニルホスフィン）パラジウム［Ｐｄ（ＰＰｈ３）４］、ビス（トリｔｅｒｔ－ブチルホスフィン）パラジウム［Ｐｄ（ＰｔＢｕ３）２］、１，１’－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）　［ＰｄＣｌ２（ｄｐｐｆ）］、ビス（ジベンジリデンアセトン）パラジウム　［Ｐｄ（ｄｂａ）２］、ビス（トリ－ｏ－トリルホスフィン）ジクロロパラジウムＰｄＣｌ２［Ｐ（ｏ－ｔｏｌ）３］２］等が挙げられ、これらは通常、化合物（ｓ－９）に対して０．００１当量から１当量が用いられる。溶媒としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテルまたは１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、または１，３－ジメチル－２－イミダゾリジノン等の非プロトン性極性溶媒、またはこれらの混合溶媒等が用いられる。反応温度は、通常、室温から加熱還流温度で行われる。反応時間は、通常０．５時間から４８時間である。
　このようにして得られた化合物（ｓ－１３）を、製造法１の工程（Ａ－４）および（Ａ－５）と同様に処理して、対応するアミド化合物（ｓ－７）を製造することができる。 For example, in the method using an organozinc reagent, R b is a halogen atom, preferably bromine, iodine, or chlorine. Examples of the organometallic compound (s-12) include alkyl zinc halides such as methyl zinc chloride, dialkyl zinc such as dimethyl zinc, and metal cyanides such as zinc cyanide. These are usually compound (s-9) 1 equivalent to 10 equivalents are used. Examples of the metal catalyst include tetrakis (triphenylphosphine) palladium [Pd (PPh 3 ) 4 ], bis (tritert-butylphosphine) palladium [Pd (PtBu 3 ) 2 ], 1,1′-bis (diphenylphosphino) Ferrocene] dichloropalladium (II) [PdCl 2 (dppf)], bis (dibenzylideneacetone) palladium [Pd (dba) 2 ], bis (tri-o-tolylphosphine) dichloropalladium PdCl 2 [P (o-tol) 3 ] 2 ] and the like, and these are usually used in an amount of 0.001 equivalent to 1 equivalent based on compound (s-9). Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, N , N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or a protic polar solvent, or a mixed solvent thereof is used. . The reaction temperature is usually from room temperature to the reflux temperature. The reaction time is usually 0.5 to 48 hours.
The compound (s-13) thus obtained is treated in the same manner as in production method 1 steps (A-4) and (A-5) to produce the corresponding amide compound (s-7). be able to.
製造法５：
　式（１）で表される化合物のうち、式（ｓ－１４）で表される化合物またはその塩は、下記に示される方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000034
 （式中、Ｒ１、Ｒ２、Ｒ４、Ｒ５、Ｒｂ、ＲｃおよびＭｔｌは、前記記載と同義である。） Production method 5:
Among the compounds represented by formula (1), the compound represented by formula (s-14) or a salt thereof can be produced by the method shown below.
Figure JPOXMLDOC01-appb-C000034
 (Wherein R 1 , R 2 , R 4 , R 5 , R b , R c and Mtl are as defined above.)
工程（Ａ－９）：
　本工程は、製造法３の工程（Ａ－７）で得られた化合物（ｓ－１１）に対して有機金属化合物（ｓ－１２）を金属触媒存在下で反応させることにより化合物（ｓ－１４）を製造する工程である。化合物（ｓ－１１）に対するＲｃ基の導入は、製造法４の工程（Ａ－８）と同様に実施することができる。 Step (A-9):
In this step, compound (s-14) is produced by reacting compound (s-11) obtained in step (A-7) of production method 3 with organometallic compound (s-12) in the presence of a metal catalyst. ). The introduction of the R c group into compound (s-11) can be carried out in the same manner as in production method 4, step (A-8).
製造法６：
　アミド化合物（ｓ－７）はまた、下記に示される工程（Ａ－１０）および（Ａ－１１）を経由しても製造することができる。
Figure JPOXMLDOC01-appb-C000035
 Production method 6:
The amide compound (s-7) can also be produced via steps (A-10) and (A-11) shown below.
Figure JPOXMLDOC01-appb-C000035
（式中、Ｒ２、Ｒ３、Ｒ４およびＲａは、前記記載と同義である。Ｒ１は置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基であり、Ｒｄはベンジル基等の脱離基（該基は、前掲の（ａ３）～（ｚ３）から選択される基で置換されていてもよい。）である。Ｘはハロゲン原子、ホウ素原子等を表す。ＨｅｔＡｒは置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基である。） Wherein R 2 , R 3 , R 4 and R a are as defined above. R 1 is an optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group. R d is a leaving group such as a benzyl group (the group may be substituted with a group selected from the above (a3) to (z3)), X is a halogen atom, a boron atom And HetAr is a 5- to 12-membered monocyclic or polycyclic heteroaryl group which may be substituted.
工程（Ａ－１０）：
　本工程は、製造法１工程（Ａ－１）～（Ａ－３）に従って製造された化合物（ｓ－１５）から基：Ｒｄを脱離して、化合物（ｓ－１６）を製造する工程である。例えば、Ｒｄが置換されていてもよいベンジル基である場合、例えば、パラジウム－カーボン、水酸化パラジウム、またはニッケル等の金属触媒の存在下、必要ならば例えば塩化水素、ギ酸アンモニウム等を添加して、水素ガス雰囲気下で化合物（ｓ－１５）を反応させることにより、化合物（ｓ－１６）を製造することができる。溶媒としては、例えば、メタノール、エタノール、２－プロパノール、またはブタノール等のアルコール系溶媒、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、または１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、またはキシレン等の芳香族炭化水素系溶媒、酢酸エチルまたは酢酸メチル等のエステル系溶媒、酢酸等の有機酸、水またはそれらの混合溶媒等が挙げられる。 Step (A-10):
This step is a step for producing the compound (s-16) by removing the group R d from the compound (s-15) produced according to the production method 1 steps (A-1) to (A-3). is there. For example, when R d is an optionally substituted benzyl group, for example, hydrogen chloride, ammonium formate or the like is added if necessary in the presence of a metal catalyst such as palladium-carbon, palladium hydroxide, or nickel. The compound (s-16) can be produced by reacting the compound (s-15) in a hydrogen gas atmosphere. Examples of the solvent include alcohol solvents such as methanol, ethanol, 2-propanol, and butanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane, benzene, toluene, xylene, and the like. Aromatic hydrocarbon solvents, ester solvents such as ethyl acetate or methyl acetate, organic acids such as acetic acid, water, or a mixed solvent thereof can be used.
工程（Ａ－１１）：
　本工程は、工程（Ａ－１０）で得られた化合物（ｓ－１６）とホウ素酸へテロアリールまたはハロゲン化へテロアリールであるヘテロアリール化合物（ｓ－１７）との反応により化合物（ｓ－１８）を製造する工程である。例えば、化合物（ｓ－１６）に対して、塩基を作用させた後、化合物（ｓ－１７）として２－クロロピリジンを加えることにより、化合物（ｓ－１８）を製造することができる。ここで、塩基としては、例えば、水素化ナトリウム、水素化リチウム、または水素化カリウム等の水素化金属、カリウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、リチウムヘキサメチルジシラジド、またはリチウムジイソプロピルアミド等の金属アミンが挙げられる。溶媒としては、例えば、ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテルまたは１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、または１，３－ジメチル－２－イミダゾリジノン等の非プロトン性極性溶媒、またはこれらの混合溶媒等が用いられる。反応温度は、通常、氷冷温度から加熱還流温度で行われる。反応時間は、通常０．５時間から２４時間である。 Step (A-11):
This step is performed by reacting the compound (s-16) obtained in step (A-10) with the heteroaryl compound (s-17) which is heteroaryl borate or heteroaryl halide. Is a process of manufacturing. For example, compound (s-18) can be produced by reacting compound (s-16) with a base and then adding 2-chloropyridine as compound (s-17). Here, as the base, for example, a metal hydride such as sodium hydride, lithium hydride, or potassium hydride, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, or lithium Examples thereof include metal amines such as diisopropylamide. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, methylcyclopentyl ether or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, N , N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or a protic polar solvent, or a mixed solvent thereof is used. . The reaction temperature is usually from an ice cooling temperature to a heating reflux temperature. The reaction time is usually 0.5 to 24 hours.
　あるいは、例えば、化合物（ｓ－１６）に対して、塩基と金属触媒存在下にホウ素酸へテロアリールまたはハロゲン化へテロアリールであるヘテロアリール化合物（ｓ－１７）を作用させることによっても、化合物（ｓ－１８）を製造することができる。ここで、塩基としては、例えば、ナトリウム　ｔ－ブトキシド、カリウム　ｔ－ブトキシド、炭酸セシウム、またはリチウム　ヘキサメチルジシラジドなどが挙げられる。金属触媒としては、例えば、ビス（トリスｔｅｒｔ－ブチルホスフィン）パラジウム、ビス（トリスｏ－トリルホスフィン）ジクロロパラジウム、ビス（トリスｏ－トリルホスフィン）パラジウム、テトラキストリフェニルホスフィンパラジウム、ジクロロパラジウム（アセトニトリル）、ビス（トリスｏ－トリルホスフィン）ジクロロパラジウム、（１，１’－ビス（ジフェニルホスフィノ）フェロセン）ジクロロパラジウム、（１，３－ビス（２，６－ジイソプロピルフェニル）イミダゾリデン）　（３－クロロピリジル）パラジウム（ＩＩ）ジクロリドなどの触媒が使用できる。酢酸パラジウムや塩化パラジウムに対して、パラジウム　リエージェント　アンド　カタリスツ（ｐａｌｌａｄｉｕｍ　ｒｅａｇｅｎｔｓ　ａｎｄ　ｃａｔａｌｙｓｔｓ、ジロウ　ツジ著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ　Ｉｎｃ．）（２００４年）のテーブル１．１からテーブル１．１７に記載されている配位子から適切なもの（例えばＢＩＮＡＰ）を選択して使用することもできる。溶媒は、本工程の反応条件で反応しない溶媒であれば使用できる。例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテル、アニソールまたは１，４－ジオキサン等のエーテル系溶媒、ベンゼン、トルエンまたはキシレン等の芳香族炭化水素系溶媒、酢酸エチルまたは酢酸メチル等のエステル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリジノン、１，３－ジメチル－２－イミダゾリジノン、またはジメチルスルホキシド等の非プロトン性極性溶媒またはそれらの混合物が挙げられる。反応温度は、通常、室温から加熱還流温度で行われる。反応時間は、通常、３０分間から４８時間である。
　なお、このように金属触媒存在下にて工程（Ａ－１１）を行う場合、ここに記載するハロゲン化へテロアリールまたはホウ素酸へテロアリールなどの化合物（ｓ－１７）に換えて、ハロゲン化アリールまたはホウ素酸アリールを用いて同様に実施することにより、Ｒ１が置換されていてもよいＣ６－１０アリール基である化合物（ｓ－１８）を得ることもできる。
　このようにして得られた化合物（ｓ－１８）を、製造法１の工程（Ａ－４）および（Ａ－５）と同様に処理して、対応するアミド化合物（ｓ－７）を製造することができる。 Alternatively, for example, compound (s-16) can also be reacted with heteroaryl compound (s-17) which is a heteroaryl borate or a heteroaryl halide in the presence of a base and a metal catalyst. -18) can be produced. Examples of the base include sodium t-butoxide, potassium t-butoxide, cesium carbonate, lithium hexamethyldisilazide and the like. Examples of the metal catalyst include bis (tris-tert-butylphosphine) palladium, bis (triso-tolylphosphine) dichloropalladium, bis (triso-tolylphosphine) palladium, tetrakistriphenylphosphinepalladium, dichloropalladium (acetonitrile), Bis (tris-o-tolylphosphine) dichloropalladium, (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium, (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) ) Catalysts such as palladium (II) dichloride can be used. For palladium acetate and palladium chloride, Table 1. of Palladium Reagents and Catalysts, by Jiro Tsuji, John Wiley & Sons Inc. (2004). A suitable one (for example, BINAP) can be selected from the ligands described in Table 1 to Table 1.17, and any solvent that does not react under the reaction conditions in this step can be used. For example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene or xylene Ester solvents such as ethyl acetate or methyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, etc. Examples thereof include aprotic polar solvents or a mixture thereof The reaction temperature is usually from room temperature to a heating reflux temperature, and the reaction time is usually from 30 minutes to 48 hours.
When the step (A-11) is carried out in the presence of a metal catalyst in this way, in place of the compound (s-17) such as a heteroaryl halide or a heteroaryl boronic acid described herein, an aryl halide or By carrying out in the same manner using aryl borate, a compound (s-18) in which R 1 is an optionally substituted C 6-10 aryl group can also be obtained.
The compound (s-18) thus obtained is treated in the same manner as in production method 1 steps (A-4) and (A-5) to produce the corresponding amide compound (s-7). be able to.
製造法７：
　アミド化合物（ｓ－７）はまた、下記に示される工程（Ａ－１２）を経由しても製造することができる。
Figure JPOXMLDOC01-appb-C000036
 （式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５、ＸおよびＨｅｔＡｒは、前記記載と同義である。Ｒ１は置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基である。） Production method 7:
The amide compound (s-7) can also be produced via the step (A-12) shown below.
Figure JPOXMLDOC01-appb-C000036
 Wherein R 2 , R 3 , R 4 , R 5 , X and HetAr are as defined above. R 1 is an optionally substituted 5- to 12-membered monocyclic or polycyclic A heteroaryl group.)
工程（Ａ－１２）：
　本工程は、化合物（ｓ－１９）とヘテロアリール化合物（ｓ－１７）とを反応させることにより、アミド化合物（ｓ－７）を製造する工程である。ヘテロアリール基の導入は、製造法６の工程（Ａ－１１）と同様にして実施することができる。
　なお、工程（Ａ－１１）と同様に、金属触媒存在下にて工程（Ａ－１２）を行う場合、へテロアリール化合物（ｓ－１７）に換えて、ハロゲン化アリールまたはホウ素酸アリールを用いて同様に実施することにより、Ｒ１が置換されていてもよいＣ６－１０アリール基である化合物（ｓ－７）を得ることもできる。 Step (A-12):
This step is a step for producing an amide compound (s-7) by reacting the compound (s-19) with a heteroaryl compound (s-17). The introduction of the heteroaryl group can be carried out in the same manner as in production method 6, step (A-11).
As in step (A-11), when step (A-12) is performed in the presence of a metal catalyst, an aryl halide or aryl borate is used instead of the heteroaryl compound (s-17). By carrying out in the same manner, a compound (s-7) in which R 1 is an optionally substituted C 6-10 aryl group can also be obtained.
　上記において説明した製造法１～７において、反応点以外の何れかの官能基が、説明した反応条件下で変化するか、または説明した方法を実施するのに不適切な場合は、反応点以外を保護し、反応させた後、脱保護することにより目的化合物を得ることができる。保護基としては、例えば前述のプロテクティブ・グループス・イン・オーガニック・シンセシス等に記載されているような通常の保護基を用いることができ、更に具体的には、アミンの保護基としては、例えば、エトキシカルボニル、ｔ－ブトキシカルボニル、アセチル、またはベンジル等を、また水酸基の保護基としては、例えば、トリ低級アルキルシリル、アセチル、またはベンジル等をあげることができる。
　保護基の導入および脱離は、有機合成化学で常用される方法（例えば、上記のプロテクティブ・グループス・イン・オーガニック・シンセシス参照）、あるいはそれらに準じた方法により行うことができる。 In production methods 1 to 7 described above, if any functional group other than the reactive site changes under the described reaction conditions or is inappropriate for carrying out the described method, other than the reactive site After protecting and reacting, the desired compound can be obtained by deprotection. As the protecting group, for example, a usual protecting group as described in the above-mentioned Protective Groups in Organic Synthesis etc. can be used. More specifically, as the protecting group for amine, for example, , Ethoxycarbonyl, t-butoxycarbonyl, acetyl, benzyl and the like, and examples of the hydroxyl-protecting group include tri-lower alkylsilyl, acetyl, benzyl and the like.
Introduction and removal of protecting groups can be carried out by methods commonly used in organic synthetic chemistry (see, for example, the above-mentioned Protective Groups in Organic Synthesis) or methods based thereon.
　また、上記製造法における、中間体、または最終生成物は、その官能基を適宜変換することによって、本発明に含まれる別の化合物へ導くこともできる。官能基の変換は、通常行われる一般的方法（例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｏｒｇａｎｉｃ　Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ）、Ｒ．Ｃ．ラロック（Ｌａｒｏｃｋ）著（１９８９年）等参照）によって行うことができる。 In addition, the intermediate or final product in the above production method can be led to another compound included in the present invention by appropriately converting the functional group. The functional group can be converted by a commonly used general method (for example, see Comprehensive Organic Transformations, RC Larock, 1989). it can.
　上記各製造法における中間体および目的化合物は、有機合成化学で常用される精製法、例えば中和、濾過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等によって単離精製することができる。また、中間体については、特に精製することなく次の反応に用いることも可能である。
　また、光学異性体は前記製造法の適切な工程で、光学活性カラムを用いた方法、分別結晶化法などの公知の分離工程を実施することにより分離することができる。また、出発原料として光学活性体を使用することもできる。
　本発明の化合物が、光学異性体、立体異性体、ケトエノール体のような互変異性体、および／または幾何異性体を有する場合、本発明は、これらを含め全ての可能な異性体およびそれらの混合物を包含する。
　上記製造法における出発原料および中間体は、公知化合物であるか、公知化合物から公知の方法により合成することができる。 The intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. it can. The intermediate can also be used in the next reaction without any particular purification.
In addition, optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. An optically active substance can also be used as a starting material.
When a compound of the present invention has optical isomers, stereoisomers, tautomers such as keto enols, and / or geometric isomers, the present invention includes all possible isomers including these and their Includes mixtures.
The starting materials and intermediates in the above production method are known compounds or can be synthesized from known compounds by known methods.
　本明細書において、アダマンタン上の２つの置換基の立体配置は、文献（Ｃ．　Ｄ．　Ｊｏｎｅｓ，　Ｍ．　Ｋａｓｅｌｊ，　ｅｔａｌ．　Ｊ．　Ｏｒｇ．　Ｃｈｅｍ．　６３：２７５８－２７６０，　１９９８）を参考に、下記配置をＥまたはＺ相対配置と定義する。 In this specification, the configuration of two substituents on adamantane is as follows with reference to the literature (C. D. Jones, M. Kaselj, et al. J. Org. Chem. 63: 2758-2760, 1998). The arrangement is defined as an E or Z relative arrangement.
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　本発明には、式（１）で表される化合物もしくはそのプロドラッグ、またはその薬理学的に許容される塩が含まれる。また、これらの水和物またはエタノール溶媒和物等の溶媒和物も含まれる。さらに、あらゆる態様の結晶形態も包含する。これは式（２）で表される化合物にも当てはまる。 The present invention includes a compound represented by the formula (1) or a prodrug thereof, or a pharmacologically acceptable salt thereof. Moreover, solvates, such as these hydrates or ethanol solvates, are also included. Furthermore, all forms of crystalline forms are also included. This also applies to the compound represented by the formula (2).
　本明細書における「式（１）で表される化合物（すなわち、式（１）の化合物）のプロドラッグ」なる用語は、生体内における生理条件下で酵素や胃酸等による反応により式（１）の化合物に変換される化合物、すなわち酵素的に酸化、還元、加水分解等を起こして式（１）の化合物に変化する化合物、胃酸等により加水分解を起こして式（１）の化合物に変化する化合物を意味する。 In the present specification, the term “prodrug of the compound represented by the formula (1) (ie, the compound of the formula (1))” is a compound represented by the formula (1) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo. A compound that can be converted into a compound of formula (1), that is, a compound that is enzymatically oxidized, reduced, hydrolyzed to change to a compound of formula (1), a gastric acid or the like that is hydrolyzed to a compound of formula (1) Means a compound.
　「薬理学上許容される塩」としては、例えば、カリウム塩またはナトリウム塩等のアルカリ金属塩、カルシウム塩またはマグネシウム塩等のアルカリ土類金属塩、アンモニウム塩、Ｎ－メチルグルカミン（メグルミン）等の水溶性アミン付加塩、または有機アミンの低級アルカノールアンモニウム塩、および例えば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩、硫酸水素塩、リン酸塩、酢酸塩、乳酸塩、クエン酸塩、酒石酸塩、酒石酸水素塩、コハク酸塩、マレイン酸塩、フマル酸塩、グルコン酸塩、サッカラート、安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩、またはパモエート［１，１’－メチレン－ビス－（２－ヒドロキシ－３－ナフトエート）］との塩等が挙げられる。 Examples of the “pharmacologically acceptable salt” include alkali metal salts such as potassium salt and sodium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, N-methylglucamine (meglumine) and the like. Water-soluble amine addition salts of, or lower alkanol ammonium salts of organic amines and, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogensulfate, phosphate, acetate, lactic acid Salt, citrate, tartrate, hydrogen tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, Paratoluenesulfonate or salt with pamoate [1,1′-methylene-bis- (2-hydroxy-3-naphthoate)] And the like.
　本発明化合物の塩を取得したい場合において、本発明化合物が塩の形で得られる場合には、そのまま精製すればよく、また、遊離の形で得られる場合には、適当な有機溶媒に溶解もしくは懸濁させ、酸または塩基を加えて通常の方法により塩を形成させればよい。
　また、本発明化合物およびその薬理学上許容される塩は、水あるいは各種溶媒との付加物の形で存在することもあるが、これら付加物も本発明に包含される。さらに、本発明は、本発明化合物のあらゆる互変異性体、存在するあらゆる立体異性体、およびあらゆる態様の結晶形のものも包含する。 When it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is. The salt may be formed by suspending and adding an acid or a base by a usual method.
Moreover, although this invention compound and its pharmacologically acceptable salt may exist in the form of an adduct with water or various solvents, these adducts are also included in the present invention. Furthermore, the present invention also includes all tautomeric forms of the compounds of the present invention, all stereoisomers present, and all forms of crystalline forms.
　本発明化合物またはその薬理学上許容される塩は、ＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、低ＨＤＬ症、高ＬＤＬ症、脂質代謝異常症、高脂血症、高トリグリセライド血症、高コレステロール血症、高血圧、動脈硬化症、脳動脈硬化症、血管狭窄、アテローム性動脈硬化、肥満、骨粗しょう症、免疫障害、メタボリックシンドローム、心血管疾患、クッシング症候群、サブクリニカルクッシング症候群、ＮＡＳＨ（非アルコール性脂肪肝炎）、ＮＡＦＬＤ（非アルコール性脂肪肝）、緑内障、網膜症、認知症、認知障害、うつ、不安、躁うつ、神経変性疾患、アルツハイマー型認知症、脳血管性認知症、レビー小体型認知症、Ｐｉｃｋ病、Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ病、Ｋｒａｅｐｅｌｉｎ病、Ｐａｒｋｉｎｓｏｎ病、Ｈｕｎｔｉｎｇｔｏｎ舞踏病、Ｈａｌｌｅｒｖｏｒｄｅｎ－Ｓｐａｔｓ病、脊髄小脳変性症、進行性ミオクロヌスてんかん、進行性核上麻痺、粘性水腫、副甲状腺疾患、Ｗｉｌｓｏｎ病、肝疾患、低血糖症、癌の遠隔症候、尿毒症、慢性脳循環不全症、脳出血、脳梗塞、脳塞栓、くも膜下出血、慢性硬膜下出血、仮性球麻痺、大動脈弓症候群、Ｂｉｎｓｗａｎｇｅｒ病、動静脈奇形－閉塞性血栓性動脈炎、低酸素症、無酸素症、正常圧水頭症、Ｗｅｒｎｉｃｋｅ－Ｋｏｒｓａｋｏｆｆ症候群、ペラグラ、Ｍａｒｃｈｉａｆａｖａ－Ｂｉｇｎａｍｉ病、ビタミンＢ１２欠乏症、脳腫瘍、開放性及び閉鎖性頭部外傷、バンチー症候群、熱発作、感染症、細菌性髄膜炎、真菌性髄膜炎、脳炎、進行性多巣性白質脳症、Ｂｅｈｃｅｔ症候群、Ｋｕｒｕ、梅毒、多発性硬化症、筋ジストロフィー症、Ｗｈｉｐｐｌｅ病、収容所症候群、播種性紅斑性狼瘡、心停止、エイズ脳症、甲状腺機能低下症、下垂体機能低下症、慢性アルコール中毒を伴う認知症；金属、有機化合物、一酸化炭素、毒物もしくは薬物による障害；行動心理学的症候が随伴する症状または周辺症状として伴う認知障害、うつ病性障害、双極性障害、大うつ病性障害、気分変調性障害、季節的情動障害、不安障害、恐怖症、パニック障害、強迫性障害、外傷後ストレス障害、急性ストレス障害、広場恐怖症、社会的恐怖症、回避的人格異常、心身症、他の疾患（統合失調症、認知症など）に伴ううつ症状もしくは不安症状、神経性食欲不良、摂食行動の障害、睡眠障害、統合失調症、薬物依存症、群発性頭痛、片頭痛、慢性発作片頭痛、血管障害に関係した頭痛、パーキンソン病の認知症、抑うつ、不安、神経弛緩薬誘導パーキンソン症候群および晩発性ジスキネジーを含むパーキンソン病などの疾患の予防および／または治療できる予防薬ないし治療薬として有用である。 The compound of the present invention or a pharmacologically acceptable salt thereof is type II diabetes, impaired glucose tolerance, hyperglycemia, insulin resistance, low HDL disease, hyper LDL disease, dyslipidemia, hyperlipidemia, hypertriglyceride blood Disease, hypercholesterolemia, hypertension, arteriosclerosis, cerebral arteriosclerosis, vascular stenosis, atherosclerosis, obesity, osteoporosis, immune disorder, metabolic syndrome, cardiovascular disease, Cushing syndrome, subclinical Cushing syndrome, NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic steatohepatitis), glaucoma, retinopathy, dementia, cognitive impairment, depression, anxiety, manic depression, neurodegenerative diseases, Alzheimer's dementia, cerebrovascular dementia , Lewy body dementia, Pick disease, Creutzfeldt-Jakob disease, Kraepelin disease, Parkins n disease, Huntington chorea, Hallervorden-Spats disease, spinocerebellar degeneration, progressive myoclonus epilepsy, progressive supranuclear paralysis, viscous edema, parathyroid disease, Wilson disease, liver disease, hypoglycemia, distant symptoms of cancer, Uremia, chronic cerebral circulatory insufficiency, cerebral hemorrhage, cerebral infarction, cerebral embolism, subarachnoid hemorrhage, chronic subdural hemorrhage, pseudobulbar paralysis, aortic arch syndrome, Binswanger disease, arteriovenous malformation-occlusive thrombotic arteritis, low Oxygenosis, anoxia, normobaric hydrocephalus, Wernicke-Korsakoff syndrome, pellagra, Marchiafava-Bignami disease, vitamin B12 deficiency, brain tumor, open and closed head trauma, bunchy syndrome, fever, infection, bacterial Meningitis, fungal meningitis, encephalitis, progressive multifocal leukoencephalopathy, Behcet syndrome, uru, syphilis, multiple sclerosis, muscular dystrophy, Whipple disease, camp syndrome, disseminated lupus erythematosus, cardiac arrest, AIDS encephalopathy, hypothyroidism, hypopituitarism, dementia with chronic alcoholism; Disorders caused by metals, organic compounds, carbon monoxide, poisons or drugs; cognitive impairment associated with behavioral psychological symptoms or peripheral symptoms, depressive disorder, bipolar disorder, major depressive disorder, mood modulation Disability, seasonal affective disorder, anxiety disorder, phobia, panic disorder, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, agoraphobia, social phobia, evasive personality disorder, psychosomatic disorder, other diseases ( Depressive or anxiety symptoms associated with schizophrenia, dementia, etc., anorexia nervosa, eating disorder, sleep disorder, schizophrenia, drug addiction, cluster headache, migraine, Prophylactic drugs that can prevent and / or treat diseases such as chronic seizure migraines, headaches related to vascular disorders, Parkinson's disease dementia, depression, anxiety, neuroleptic-induced Parkinson's syndrome and late-onset dyskinesia Useful as a therapeutic agent.
　本発明化合物またはその薬理学上許容される塩は、治療に使用する場合に、医薬組成物として、経口的または非経口的（例えば、静脈内、皮下、もしくは筋肉内注射、局所的、経直腸的、経皮的、または経鼻的）に投与することができる。経口投与のための組成物としては、例えば、錠剤、カプセル剤、丸剤、顆粒剤、散剤、液剤、懸濁剤などが挙げられ、非経口投与のための組成物としては、例えば、注射用水性剤、もしくは油性剤、軟膏剤、クリーム剤、ローション剤、エアロゾル剤、坐剤、貼付剤などが挙げられる。これらの製剤は、従来公知の技術を用いて調製され、製剤分野において通常使用される無毒性かつ不活性な担体もしくは賦形剤を含有することができる。 The compound of the present invention or a pharmacologically acceptable salt thereof is orally or parenterally (for example, intravenous, subcutaneous, or intramuscular injection, topical, rectal use) as a pharmaceutical composition when used for treatment. , Transdermally, or nasally). Examples of compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc. Examples of compositions for parenteral administration include, for example, injections. Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned. These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.
　本発明化合物またはその薬理学上許容される塩を投与する場合、その使用量は、症状、年齢、投与方法等によって異なるが、例えば、経口投与の場合には、成人に対して、１日当たり、０．０１ｍｇ（好ましくは１ｍｇ）～５０００ｍｇ（好ましくは５００ｍｇ）を、１回または数回に分けて、症状に応じて投与することが望ましい。非経口投与（例えば静脈内投与）の場合には、成人に対して、１日当たり、０．０１ｍｇ（好ましくは０．１ｍｇ）～１０００ｍｇ（好ましくは３０ｍｇ）を、１回または数回に分けて、症状に応じて投与することにより効果が期待される。 When the compound of the present invention or a pharmacologically acceptable salt thereof is administered, the amount used varies depending on symptoms, age, administration method, etc. For example, in the case of oral administration, It is desirable to administer 0.01 mg (preferably 1 mg) to 5000 mg (preferably 500 mg) in one or several divided doses depending on the symptoms. In the case of parenteral administration (for example, intravenous administration), 0.01 mg (preferably 0.1 mg) to 1000 mg (preferably 30 mg) per day for an adult is divided into one or several times, The effect is expected by administering according to the symptoms.
　本発明化合物またはその薬理学上許容される塩は、その作用効果の増強を目的として併用することができる薬剤（以下、「併用薬剤」と略記する）と組み合わせて用いることができる。併用薬剤としては、例えば、糖尿病治療剤、糖尿病性合併症治療剤、抗高脂血症剤、降圧剤、抗肥満剤、利尿剤などの薬剤が挙げられる。本発明化合物またはその薬理学上許容される塩および併用薬剤の投与時期は限定されず、これらを投与対象に対し、それぞれ単剤として同時に投与してもよいし、時間差をおいて投与してもよい。また、本発明化合物またはその薬理学上許容される塩と併用薬剤の合剤としてもよい。併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物またはその薬理学上許容される塩と併用薬剤との配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。例えば投与対象がヒトである場合、本発明化合物またはその薬理学上許容される塩１重量部に対し、併用薬剤を０．０１～１００重量部用いればよい。 The compound of the present invention or a pharmacologically acceptable salt thereof can be used in combination with a drug that can be used in combination for the purpose of enhancing its action and effect (hereinafter abbreviated as “concomitant drug”). Examples of the concomitant drug include drugs such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, a hypotensive agent, an antiobesity agent, and a diuretic. The administration timing of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug is not limited, and these may be administered simultaneously to the administration subject as a single agent or administered at a time difference. Good. The compound of the present invention or a pharmacologically acceptable salt thereof and a combination drug may be used. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention or a pharmacologically acceptable salt thereof.
　なお、糖尿病治療剤としては、インスリン製剤（例えば、ウシまたはブタの膵臓から抽出された動物インスリン製剤；大腸菌またはイーストを用い、遺伝子工学的に合成したヒトインスリン製剤など）、インスリン抵抗性改善剤（例えば、ピオグリタゾンまたはその塩酸塩、トログリタゾン、ロシグリタゾンまたはそのマレイン酸塩、ＧＩ－２６２５７０、ＪＴＴ－５０１、ＭＣＣ－５５５、ＹＭ－４４０、ＫＲＰ－２９７、ＣＳ－０１１等）、α－グルコシダーゼ阻害剤（例えば、ボグリボース、アカルボース、ミグリトール、エミグリテート等）、ビグアナイド剤（例えば、メトホルミン等）、インスリン分泌促進剤（例えば、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド等のスルホニルウレア剤；レパグリニド、セナグリニド、ナテグリニド、ミチグリニド等）、ジペプチジルペプチダーゼ－ＩＶ（ＤＰＰ－ＩＶ）阻害剤（例えば、シタグリプチンまたはそのリン酸塩、ビルダグリプチン、アログリプチンまたはその安息香酸塩、デナグリプチンまたはそのトシル酸塩等）、ＧＬＰ－１、ＧＬＰ－１アナログ（例えば、エキセナタイド、リラグルタイド、ＳＵＮ－Ｅ７００１、ＡＶＥ０１０、ＢＩＭ－５１０７７、ＣＪＣ１１３１等）、プロテインチロシンホスファターゼ阻害剤（例えば、バナジン酸等）、β３アゴニスト（例えば、ＧＷ－４２７３５３Ｂ、Ｎ－５９８４等）が挙げられる。 Examples of diabetes therapeutic agents include insulin preparations (for example, animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast), insulin resistance improving agents ( For example, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, etc.), α-glucosidase inhibitor ( For example, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, g Sulfonylureas such as clopyramide, glimepiride; repaglinide, senagrinide, nateglinide, mitiglinide, etc., dipeptidyl peptidase-IV (DPP-IV) inhibitors (eg, sitagliptin or its phosphate, vildagliptin, alogliptin or its benzoate, denagliptin Or tosylate thereof, etc.), GLP-1, GLP-1 analog (eg, exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc.), protein tyrosine phosphatase inhibitor (eg, vanadic acid, etc.), β3 agonists (for example, GW-427353B, N-5984 and the like) can be mentioned.
　糖尿病性合併症治療剤としては、アルドース還元酵素阻害剤（例えば、トルレスタット、エパルレスタット、ゼナレスタット、ゾポレスタット、ミナレスタット、フィダレスタット、ラニレスタット、ＳＫ－８６０、ＣＴ－１１２等）、神経栄養因子（例えば、ＮＧＦ、ＮＴ－３、ＢＤＮＦ等）、ＰＫＣ阻害剤（例えば、ＬＹ－３３３５３１等）、ＡＧＥ阻害剤（例えば、ＡＬＴ９４６、ピマゲジン、ピラトキサチン、Ｎ－フェナシルチアゾリウムブロミド（ＡＬＴ７６６）等）、活性酸素消去薬（例えば、チオクト酸等）、脳血管拡張剤（例えば、チアプリド、メキシレチン等）が挙げられる。
　抗高脂血症剤としては、ＨＭＧ－ＣｏＡ還元酵素阻害剤（例えば、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、イタバスタチンまたはそれらのナトリウム塩等）、スクアレン合成酵素阻害剤、ＡＣＡＴ阻害剤等が挙げられる。
　降圧剤としては、アンジオテンシン変換酵素阻害剤（例えば、カプトプリル、エナラプリル、アラセプリル、デラプリル、リジノプリル、イミダプリル、ベナゼプリル、シラザプリル、テモカプリル、トランドラプリル等）、アンジオテンシンＩＩ拮抗剤（例えば、オルメサルタン　メドキソミル、カンデサルタン　シレキセチル、ロサルタン、エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、タソサルタン等）、カルシウム拮抗剤（例えば、塩酸ニカルジピン、塩酸マニジピン、ニソルジピン、ニトレンジピン、ニルバジピン、アムロジピン等）等が挙げられる。 Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (for example, tolrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, ranirestat, SK-860, CT-112, etc.), neurotrophic factors (for example, NGF) , NT-3, BDNF etc.), PKC inhibitors (eg LY-333531 etc.), AGE inhibitors (eg ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766) etc.), active oxygen elimination Examples thereof include drugs (for example, thioctic acid) and cerebral vasodilators (for example, thioprid, mexiletine, etc.).
Antihyperlipidemic agents include HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts), squalene synthase inhibitors, ACAT inhibitors, etc. Is mentioned.
Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (for example, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (for example, olmesartan medoxomilexilmil, candesartyl, Losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (for example, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.).
　抗肥満剤としては、例えば中枢性抗肥満薬（例えば、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、ＳＲ－１４１７１６Ａ等）、膵リパーゼ阻害薬（例えば、オルリスタット等）、ペプチド性食欲抑制薬（例えば、レプチン、ＣＮＴＦ（毛様体神経栄養因子）等）、コレシストキニンアゴニスト（例えば、リンチトリプト、ＦＰＬ－１５８４９等）等が挙げられる。
　利尿剤としては、例えばキサンチン誘導体（例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン等）、チアジド系製剤（例えば、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ペンフルチジド、ポリチアジド、メチクロチアジド等）、抗アルドステロン製剤（例えば、スピロノラクトン、トリアムテレン等）、炭酸脱水酵素阻害剤（例えば、アセタゾラミド等）、クロルベンゼンスルホンアミド系製剤（例えば、クロルタリドン、メフルシド、インダパミド等）、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミド等が挙げられる。 Examples of anti-obesity agents include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (For example, leptin, CNTF (ciliary neurotrophic factor) and the like), cholecystokinin agonists (for example, lynchtrypto, FPL-15849, etc.) and the like.
Examples of the diuretic include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide , Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and the like.
　併用薬剤は、好ましくはＧＬＰ－１、ＧＬＰ－１アナログ、α－グルコシダーゼ阻害剤、ビグアナイド剤、インスリン分泌促進剤、インスリン抵抗性改善剤、ＤＰＰ－ＩＶ阻害剤などである。上記併用薬剤は、２種以上を適宜の割合で組み合せて用いてもよい。
　本発明化合物またはその薬理学上許容される塩が、併用薬剤と組み合せて使用される場合には、これらの薬剤の使用量は、薬剤の副作用を考えて安全な範囲内で低減できる。例えば、ビグアナイド剤は通常の投与量よりも低減できる。したがって、これらの薬剤により引き起こされるであろう副作用は安全に防止できる。それに加えて、糖尿病性合併症治療剤、抗高脂血症剤、降圧剤などの投与量は低減でき、その結果これらの薬剤により引き起こされるであろう副作用は効果的に防止できる。 The concomitant drugs are preferably GLP-1, GLP-1 analog, α-glucosidase inhibitor, biguanide agent, insulin secretagogue, insulin resistance improving agent, DPP-IV inhibitor and the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
When the compound of the present invention or a pharmacologically acceptable salt thereof is used in combination with a concomitant drug, the amount of these drugs used can be reduced within a safe range in consideration of side effects of the drug. For example, biguanides can be reduced from normal dosages. Therefore, side effects that may be caused by these drugs can be safely prevented. In addition, the dosage of diabetic complication therapeutic agents, antihyperlipidemic agents, antihypertensive agents and the like can be reduced, and as a result, side effects that may be caused by these agents can be effectively prevented.
　また、本発明化合物またはその薬理学上許容される塩は、その作用効果の増強を目的として、抗うつ薬、抗不安薬、統合失調症治療薬、睡眠導入剤、ドパミン受容体作動薬、パーキンソン病治療薬、抗癲癇薬、抗痙攣薬、鎮痛薬、ホルモン製剤、偏頭痛治療薬、アドレナリンβ受容体拮抗薬、気分障害治療薬、アセチルコリンエステラーゼ阻害薬、ＮＭＤＡ受容体拮抗薬、ＣＯＸ－２阻害薬、ＰＰＡＲγ作動薬、ＬＴＢ４拮抗薬、ムスカリンＭ１受容体作動薬、ＡＭＰＡ受容体拮抗薬、ニコチン受容体作動薬、５－ＨＴ４受容体作動薬、５－ＨＴ６受容体拮抗薬、ＰＤＥ４阻害薬、Ａβ凝集阻害薬、ＢＡＣＥ阻害薬、γセクレターゼ阻害薬またはモジュレーター、ＧＳＫ－３β阻害薬、ＮＧＦ受容体作動薬、Ａβ抗体、ヒト免疫グロブリン、Ａβワクチン、神経保護薬、Ｄｉｍｅｂｏｎなどの併用薬剤と組み合わせて用いることもできる。 The compound of the present invention or a pharmacologically acceptable salt thereof is an antidepressant, anxiolytic, schizophrenia drug, sleep inducer, dopamine receptor agonist, parkinson for the purpose of enhancing its action effect. Disease treatment, antidepressant, anticonvulsant, analgesic, hormone preparation, migraine treatment, adrenergic β receptor antagonist, mood disorder treatment, acetylcholinesterase inhibitor, NMDA receptor antagonist, COX-2 inhibition Drugs, PPARγ agonists, LTB4 antagonists, muscarinic M1 receptor agonists, AMPA receptor antagonists, nicotine receptor agonists, 5-HT4 receptor agonists, 5-HT6 receptor antagonists, PDE4 inhibitors, Aβ Aggregation inhibitor, BACE inhibitor, γ-secretase inhibitor or modulator, GSK-3β inhibitor, NGF receptor agonist, Aβ antibody, human immunoglobulin, A Vaccines, neuroprotective agents, can also be used in combination with a combination drug, such as Dimebon.
　本発明化合物またはその薬理学上許容される塩および併用薬剤の投与時期は限定されず、これらを投与対象に対し、それぞれ単剤として同時に投与してもよいし、時間差をおいて投与してもよい。また、本発明化合物またはその薬理学上許容される塩と併用薬剤の合剤としてもよい。併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物またはその薬理学上許容される塩と併用薬剤との配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。例えば投与対象がヒトである場合、本発明化合物またはその薬理学上許容される塩１重量部に対し、併用薬剤を０．０１～１００重量部用いればよい。また、その副作用抑制を目的として、制吐剤、睡眠導入剤、抗痙攣薬などの併用薬剤と組み合わせて用いることができる。 The administration timing of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug is not limited, and these may be administered simultaneously to the administration subject as a single agent or administered at a time difference. Good. The compound of the present invention or a pharmacologically acceptable salt thereof and a combination drug may be used. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention or a pharmacologically acceptable salt thereof and a concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention or a pharmacologically acceptable salt thereof. Moreover, it can be used in combination with concomitant drugs such as antiemetics, sleep inducers, anticonvulsants, etc. for the purpose of suppressing the side effects.
　以下に本発明を、参考例、実施例および試験例により、さらに具体的に説明するが、本発明はもとよりこれに限定されるものではない。尚、以下の参考例および実施例において示された化合物名は、必ずしもＩＵＰＡＣ命名法に従うものではない。 Hereinafter, the present invention will be described more specifically with reference examples, examples and test examples. However, the present invention is not limited to these examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.
　実施例および参考例において以下の略語を使用することがある。
ＴＨＦ：テトラヒドロフラン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
Ｍｅ：メチル基
Ｅｔ：エチル基
Ｂｕ：ブチル基
Ｂｎ：ベンジル基
ＮａＢＨ（ＯＡｃ）３：トリアセトキシ水素化ホウ素ナトリウム
ＷＳＣ・ＨＣｌ：１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド　塩酸塩
ＨＯＢｔ・Ｈ２Ｏ：１－ヒドロキシベンゾトリアゾール１水和物
ＴＦＡ：トリフルオロ酢酸
ＭｅＯＨ：メタノール
ＤＩＡＤ：ジイソプロピル　アゾカルボキシレート
ＢＩＮＡＰ：２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボキル基
Ｃｂｚ：ベンジルオキシカルボニル基
Ｎｓ：ノシル基
Ｍｓ：メタンスルホニル基
Ａｃ：アセチル基
Ｍ：モル濃度（ｍｏｌ／Ｌ）
ｔｅｒｔ－またはｔ－：ターシャリー
ｒａｃ－：ラセミ The following abbreviations may be used in Examples and Reference Examples.
THF: tetrahydrofuran DMF: N, N-dimethylformamide Me: methyl group Et: ethyl group Bu: butyl group Bn: benzyl group NaBH (OAc) 3 : sodium triacetoxyborohydride WSC · HCl: 1- (3-dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride HOBt · H 2 O: 1-hydroxybenzotriazole monohydrate TFA: trifluoroacetic acid MeOH: methanol DIAD: diisopropyl azocarboxylate BINAP: 2,2′-bis (diphenylphosphino) ) -1,1′-binaphthyl Boc: tert-butoxycarboxyl group Cbz: benzyloxycarbonyl group Ns: nosyl group Ms: methanesulfonyl group Ac: acetyl group M: molar concentration (mol / L)
tert- or t-: tertiary rac-: racemic
参考例１：（Ｅ）－４－アミノ－１－アダマンタンカルボキサミド Reference Example 1: (E) -4-amino-1-adamantancarboxamide
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
工程（ｉ）：
　室温の１，１’－カルボニルジイミダゾール（７０ｇ）とＴＨＦ（１７０ｍＬ）の混合物に対して、化合物Ｉ（７０ｇ）のＴＨＦ（２５０ｍＬ）の混合液を滴下した。滴下終了後、５０℃で３時間撹拌した。室温にまで放冷した反応液を氷冷したアンモニア水（２００ｍＬ）に滴下した。室温で３０分間撹拌後、反応混合物を減圧濃縮した。氷冷した残渣に濃塩酸（８０ｍＬ）を加え、ｐＨ１～２とした。氷冷温度で、１５－２０分間撹拌後、固体をろ取し、１Ｍ塩酸（５０ｍＬ）で洗浄し、減圧乾燥した。ろ液に塩化ナトリウムを加えて飽和溶液として、クロロホルム（２５０ｍＬで５回）で抽出した。有機層を硫酸マグネシウムで乾燥し、ろ過、濃縮、乾燥し、固体を得た。ろ取した固体とあわせて、化合物ＩＩ（１３３．４ｇ）を得た。 Step (i):
To a mixture of 1,1′-carbonyldiimidazole (70 g) and THF (170 mL) at room temperature, a mixed solution of Compound I (70 g) in THF (250 mL) was added dropwise. After completion of dropping, the mixture was stirred at 50 ° C. for 3 hours. The reaction liquid allowed to cool to room temperature was added dropwise to ice-cooled aqueous ammonia (200 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. Concentrated hydrochloric acid (80 mL) was added to the ice-cooled residue to adjust the pH to 1-2. After stirring at ice-cooled temperature for 15-20 minutes, the solid was collected by filtration, washed with 1M hydrochloric acid (50 mL), and dried under reduced pressure. Sodium chloride was added to the filtrate to extract a saturated solution with chloroform (250 mL, 5 times). The organic layer was dried over magnesium sulfate, filtered, concentrated and dried to obtain a solid. Combined with the solid collected by filtration, Compound II (133.4 g) was obtained.
工程（ｉｉ）：
　氷冷した化合物ＩＩ（６０ｇ）とジクロロメタン（１５００ｍＬ）の混合物に（Ｓ）－フェニルエチルアミン（３９．４ｇ）を加えた。１０分間撹拌後、ＮａＢＨ（ＯＡｃ）３（１０１ｇ）を加え、室温まで昇温しながら終夜攪拌した。氷冷した反応混合物に水（１５０ｍＬ）と２Ｍ　ＮａＯＨ（３００ｍＬ）を加え、ｐＨ　９－１０程度に調整した。この混合液をセライトろ過し、ケーキをクロロホルム（２００ｍＬ）で洗浄した。ろ液をクロロホルムで分液抽出した。有機層を硫酸ナトリウムで乾燥し、ろ過、濃縮し、化合物ＩＩＩ（１３３ｇ、Ｅ／Ｚ＝約２．６／１）を得た。 Step (ii):
(S) -Phenylethylamine (39.4 g) was added to a mixture of ice-cooled compound II (60 g) and dichloromethane (1500 mL). After stirring for 10 minutes, NaBH (OAc) 3 (101 g) was added and stirred overnight while warming to room temperature. Water (150 mL) and 2M NaOH (300 mL) were added to the ice-cooled reaction mixture to adjust the pH to about 9-10. The mixture was filtered through celite, and the cake was washed with chloroform (200 mL). The filtrate was separated and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated to give compound III (133 g, E / Z = about 2.6 / 1).
工程（ｉｉｉ）：
　工程（ｉｉ）のようにして得られた化合物ＩＩＩ（１３１１ｇ）をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１００／１から１０／１）で精製し、化合物ＩＶ（６１８ｇ）を得た。 Step (iii):
Compound III (1311 g) obtained as in step (ii) was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 100/1 to 10/1) to give compound IV (618 g).
工程（ｉｖ）：
　化合物ＩＶ（６１８ｇ）、１０％パラジウム－カーボン（１２２ｇ、５０％ウェット）およびメタノール（１５Ｌ）の混合物を水素雰囲気下（４－５ｋｇ／ｃｍ２）に室温で７４時間撹拌した。反応混合物をセライト濾過し、ケーキをメタノールで洗浄した（１０Ｌ、２回）。ろ液を濃縮し、固体として表題化合物Ｖ（３７１．８ｇ）を得た。 Step (iv):
A mixture of Compound IV (618 g), 10% palladium-carbon (122 g, 50% wet) and methanol (15 L) was stirred under a hydrogen atmosphere (4-5 kg / cm 2 ) at room temperature for 74 hours. The reaction mixture was filtered through Celite and the cake was washed with methanol (10 L, 2 times). The filtrate was concentrated to give the title compound V (371.8 g) as a solid.
1H-NMR (DMSO-d6)δ 1.27 (m, 2H), 1.65-1.85(m, 9H), 1.99(m, 2H), 2.70(br, 2H), 2.82(brs, 1H), 6.66(brs, 1H), 6.93(brs, 1H) 1 H-NMR (DMSO-d 6 ) δ 1.27 (m, 2H), 1.65-1.85 (m, 9H), 1.99 (m, 2H), 2.70 (br, 2H), 2.82 (brs, 1H), 6.66 ( brs, 1H), 6.93 (brs, 1H)
参考例２：Ｎ－（４－フルオロフェニル）－Ｎ－（２－メトキシエチル）アセトアミド Reference Example 2: N- (4-fluorophenyl) -N- (2-methoxyethyl) acetamide
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
工程（ｉ）：
　氷冷した化合物Ｉ（３．００ｇ）、ジクロロメタン（３０ｍＬ）およびトリエチルアミン（８ｍＬ）の混合物にノシルクロリド（６．０２ｇ）を加えた後、室温で終夜攪拌した。反応溶液に１．２Ｍ塩酸を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、化合物ＩＩ（４．５６ｇ）を得た。 Step (i):
After adding nosyl chloride (6.02 g) to a mixture of ice-cooled compound I (3.00 g), dichloromethane (30 mL) and triethylamine (8 mL), the mixture was stirred at room temperature overnight. To the reaction solution was added 1.2M hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give Compound II (4.56 g).
工程（ｉｉ）：
　氷冷した化合物ＩＩ（０．６９ｇ）、ＴＨＦ（２０ｍＬ）、２－メトキシエタノール（０．７１ｇ）およびトリフェニルホスフィン（１．４７ｇ）の混合物に、ＤＩＡＤ（７００μＬ）を滴下した。滴下終了後、室温で６日間攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩＩ（１．６０ｇ）を得た。 Step (ii):
To a mixture of ice-cooled compound II (0.69 g), THF (20 mL), 2-methoxyethanol (0.71 g) and triphenylphosphine (1.47 g), DIAD (700 μL) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 6 days. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain Compound III (1.60 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（１．６０ｇ）、ＤＭＦ（１６ｍＬ）、メルカプト酢酸（２００μＬ）および水酸化リチウム１水和物（０．６７ｇ）の混合物を室温で４時間攪拌した。反応溶液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製し、化合物ＩＶ（２４３．４ｍｇ）を得た。 Step (iii):
A mixture of Compound III (1.60 g), DMF (16 mL), mercaptoacetic acid (200 μL) and lithium hydroxide monohydrate (0.67 g) was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give Compound IV (243.4 mg).
工程（ｉｖ）：
　化合物ＩＶ（２４３．４ｍｇ）と無水酢酸（５ｍＬ）の混合物を４０℃で５時間加熱攪拌した。反応溶液に飽和重曹水を加え、酢酸エチルで抽出した。有機層にトルエンを加えて減圧濃縮した後、表題化合物Ｖ（０．２８ｇ）を得た。 Step (iv):
A mixture of Compound IV (243.4 mg) and acetic anhydride (5 mL) was stirred with heating at 40 ° C. for 5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After adding toluene to the organic layer and concentrating under reduced pressure, the title compound V (0.28 g) was obtained.
1H-NMR (CDCl3)δ 1.84 (s, 3H), 3.31 (s, 3H), 3.52 (m, 2H), 3.85 (m, 2H), 7.10 (m, 2H), 7.20-7.23 (m, 2H) 1 H-NMR (CDCl 3 ) δ 1.84 (s, 3H), 3.31 (s, 3H), 3.52 (m, 2H), 3.85 (m, 2H), 7.10 (m, 2H), 7.20-7.23 (m, 2H)
参考例３：Ｎ－メチル－Ｎ－［６－（トリフルオロメチル）－３－ピリジニル］アセトアミド Reference Example 3: N-methyl-N- [6- (trifluoromethyl) -3-pyridinyl] acetamide
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
工程（ｉ）：
　化合物Ｉ（２．１３ｇ）に無水酢酸（３０ｍＬ）を加え、５０℃で終夜攪拌した。減圧濃縮後、残渣に飽和炭酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、化合物ＩＩ（２．８０ｇ）を得た。 Step (i):
Acetic anhydride (30 mL) was added to Compound I (2.13 g), and the mixture was stirred at 50 ° C. overnight. After concentration under reduced pressure, a saturated aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain Compound II (2.80 g).
工程（ｉｉ）：
　工程（ｉ）のようにして得られた化合物ＩＩ（３．４８ｇ）およびＤＭＦ（３５ｍＬ）の混合物を氷冷後、水素化ナトリウム（０．９０ｇ）を加えた。３０分間攪拌後に、ヨードメタン（１．２ｍＬ）を滴下した。滴下終了後、室温で４日間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製し、表題化合物ＩＩＩ（２．６９ｇ）を得た。 Step (ii):
A mixture of compound II (3.48 g) and DMF (35 mL) obtained as in step (i) was ice-cooled, and sodium hydride (0.90 g) was added. After stirring for 30 minutes, iodomethane (1.2 mL) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 4 days. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/2) to give the title compound III (2.69 g).
1H-NMR (CDCl3)δ 2.00 (br, 3H), 3.37 (s, 3H), 7.77 (br, 2H), 8.64 (s, 1H) 1 H-NMR (CDCl 3 ) δ 2.00 (br, 3H), 3.37 (s, 3H), 7.77 (br, 2H), 8.64 (s, 1H)
参考例４：Ｎ－メチル－Ｎ－（１－メチル－１Ｈ－ピラゾール－４－イル）アセトアミド Reference Example 4: N-methyl-N- (1-methyl-1H-pyrazol-4-yl) acetamide
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
工程（ｉ）：
　室温の化合物Ｉ（４．５３ｇ）、ＴＨＦ（８０ｍＬ）、（Ｂｏｃ）２Ｏ（１３．２１ｇ）および１０％Ｐｄ－カーボン（２．０４ｇ、５３％水分）の混合物を０．２ＭＰａの水素雰囲気下に終夜攪拌した。反応混合物をセライトろ過後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩ（６．０７ｇ）を得た。 Step (i):
A mixture of Compound I (4.53 g), THF (80 mL), (Boc) 2 O (13.21 g) and 10% Pd-carbon (2.04 g, 53% moisture) at room temperature under a hydrogen atmosphere of 0.2 MPa. Stir overnight. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound II (6.07 g).
工程（ｉｉ）：
　氷冷した化合物ＩＩ（６．０７ｇ）のＤＭＦ（６０ｍＬ）溶液に水素化ナトリウム（３．５ｇ）を加えた。３０分間攪拌後、ヨードメタン（４．５ｍＬ）を滴下した。滴下終了後、室温で終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製し、化合物ＩＩＩ（２．１４ｇ）を得た。 Step (ii):
Sodium hydride (3.5 g) was added to a solution of compound II (6.07 g) in ice-cooled DMF (60 mL). After stirring for 30 minutes, iodomethane (4.5 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/2) to give Compound III (2.14 g).
工程（ｉｉｉ）：
　室温の化合物ＩＩＩ（２．１４ｇ）のクロロホルム（３０ｍＬ）溶液に、４Ｍ塩酸－１，４－ジオキサン溶液（３０ｍＬ）を加え、１時間攪拌した。反応溶液を減圧濃縮後、残渣にジクロロメタン（６０ｍＬ）、アセチルクロリド（０．９ｍＬ）を加え、氷冷した。これにトリエチルアミン（４．５ｍＬ）を滴下後、室温で終夜攪拌した。反応溶液を減圧濃縮し、残渣をアミンシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／３）で精製し、表題化合物ＩＶ（０．９７ｇ）を得た。
1H-NMR (CDCl3)δ 1.95, 1.26 (s, 3H), 3.19, 3.35 (s, 3H), 3.88, 3.92 (s, 3H), 7.33-7.96 (m, 2H) Step (iii):
To a solution of compound III (2.14 g) in chloroform (30 mL) at room temperature was added 4M hydrochloric acid-1,4-dioxane solution (30 mL), and the mixture was stirred for 1 hr. The reaction solution was concentrated under reduced pressure, dichloromethane (60 mL) and acetyl chloride (0.9 mL) were added to the residue, and the mixture was ice-cooled. Triethylamine (4.5 mL) was added dropwise thereto, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by amine silica gel chromatography (eluent: hexane / ethyl acetate = 1/3) to give the title compound IV (0.97 g).
1 H-NMR (CDCl 3 ) δ 1.95, 1.26 (s, 3H), 3.19, 3.35 (s, 3H), 3.88, 3.92 (s, 3H), 7.33-7.96 (m, 2H)
参考例５：エチル　４－［メチル（１－メチル－１Ｈ－ピラゾール－５－イル）アミノ］－２，４－ジオキソブタノエイト Reference Example 5: Ethyl 4- [methyl (1-methyl-1H-pyrazol-5-yl) amino] -2,4-dioxobutanoate
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
工程（ｉ）：
　氷冷した化合物Ｉ（２．１７ｇ）、ＴＨＦ（４０ｍＬ）およびトリエチルアミン（６．２ｍＬ）の混合物に、アセチルクロリド（１．９ｍＬ）を滴下した。滴下終了後、室温で終夜攪拌した。反応溶液を減圧濃縮し、残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／４）で精製し、化合物ＩＩ（２．８２ｇ）を得た。 Step (i):
Acetyl chloride (1.9 mL) was added dropwise to a mixture of ice-cooled compound I (2.17 g), THF (40 mL) and triethylamine (6.2 mL). After completion of dropping, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by amino silica gel chromatography (elution solvent: hexane / ethyl acetate = 1/4) to obtain Compound II (2.82 g).
工程（ｉｉ）：
　氷冷した化合物ＩＩ（２．８２ｇ）のＴＨＦ（６０ｍＬ）溶液に水素化ナトリウム（１．１７ｇ）を加えた。３０分間攪拌後、ヨードメタン（１．６ｍＬ）を滴下した。滴下終了後、室温で終夜攪拌した。反応溶液にｔＢｕＯＨを加えた後、減圧濃縮した。得られた残渣にシュウ酸ジエチル（６．８ｇ）とＴＨＦ（１００ｍＬ）を加えた。混合物を氷冷した後、カリウム　ｔｅｒｔ－ブトキシド（４．４ｇ）を加え、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／５→０／１）で精製し、表題化合物ＩＩＩ（２．７１ｇ）を得た。 Step (ii):
Sodium hydride (1.17 g) was added to a solution of ice-cooled compound II (2.82 g) in THF (60 mL). After stirring for 30 minutes, iodomethane (1.6 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. TBuOH was added to the reaction solution, followed by concentration under reduced pressure. Diethyl oxalate (6.8 g) and THF (100 mL) were added to the obtained residue. The mixture was ice-cooled, potassium tert-butoxide (4.4 g) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/5 → 0/1) to give the title compound III (2.71 g). .
1H-NMR (CDCl3)δ 1.31 (m, 3H), 3.27 (s, 3H), 3.71 (s, 3H), 4.28 (m, 2H), 5.65 (s, 1H), 6.18 (m, 1H), 7.53 (m, 1H), 13.54 (brs, 1H) 1 H-NMR (CDCl 3 ) δ 1.31 (m, 3H), 3.27 (s, 3H), 3.71 (s, 3H), 4.28 (m, 2H), 5.65 (s, 1H), 6.18 (m, 1H) , 7.53 (m, 1H), 13.54 (brs, 1H)
参考例６：Ｎ－メチル－Ｎ－（１－メチル－１Ｈ－ピラゾール－３－イル）アセトアミド Reference Example 6: N-methyl-N- (1-methyl-1H-pyrazol-3-yl) acetamide
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
工程（ｉ）：
　氷冷した化合物Ｉ（４．９３ｇ）、ＴＨＦ（８０ｍＬ）およびトリエチルアミン（２１ｍＬ）の混合物に、アセチルクロリド（４．３ｍＬ）を滴下した。滴下終了後、室温で終夜攪拌した。反応溶液にメタノールとアミンシリカゲルを加え、減圧濃縮した。残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／４）で精製し、化合物ＩＩ（６．０８ｇ）を得た。 Step (i):
Acetyl chloride (4.3 mL) was added dropwise to a mixture of ice-cooled compound I (4.93 g), THF (80 mL) and triethylamine (21 mL). After completion of the dropwise addition, the mixture was stirred overnight at room temperature. Methanol and amine silica gel were added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by amino silica gel chromatography (eluent: hexane / ethyl acetate = 1/4) to give Compound II (6.08 g).
工程（ｉｉ）：
　氷冷した化合物ＩＩ（３．０５ｇ）のＤＭＦ（３０ｍＬ）溶液に、水素化ナトリウム（１．３５ｇ）を加えた。３０分間攪拌後、ヨードメタン（２ｍＬ）を滴下した。滴下終了後、室温で終夜攪拌した。反応溶液に飽和塩化アンモニウム水溶液と飽和食塩水を加え、クロロホルムで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をアミノシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製し、化合物ＩＩＩ（３．０８ｇ）を得た。 Step (ii):
Sodium hydride (1.35 g) was added to a solution of ice-cooled compound II (3.05 g) in DMF (30 mL). After stirring for 30 minutes, iodomethane (2 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution and saturated brine were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give Compound III (3.08 g).
1H-NMR (CDCl3)δ 2.00 (s, 3H), 3.24 (s, 3H), 3.88 (s, 3H), 6.04 (m, 1H), 7.33 (m, 1H) 1 H-NMR (CDCl 3 ) δ 2.00 (s, 3H), 3.24 (s, 3H), 3.88 (s, 3H), 6.04 (m, 1H), 7.33 (m, 1H)
参考例７：４－ジフルオロメチルブロモベンゼン Reference Example 7: 4-Difluoromethylbromobenzene
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　化合物Ｉ（１９１ｍｇ）、ジクロロエタン（５ｍＬ）、ＤｅｏｘｏＦｌｕｏｒ（０．２２ｍＬ；登録商標、アルドリッチ製品）、三フッ化水素・トリエチルアミン（０．１７ｍＬ）の混合物を室温で終夜攪拌した。氷冷した反応混合物に飽和重曹水を加え、ジクロロメタンで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝９／１）で精製し、表題化合物ＩＩ（１８３ｍｇ）を得た。 A mixture of Compound I (191 mg), dichloroethane (5 mL), DeoxoFluor (0.22 mL; registered trademark, Aldrich product) and hydrogen trifluoride / triethylamine (0.17 mL) was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added to the ice-cooled reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 9/1) to give the title compound II (183 mg).
1H-NMR (CDCl3)δ 6.61 (t, 1H, J = 56.2 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.60 (d, 2H, J = 8.0 Hz) 1 H-NMR (CDCl 3 ) δ 6.61 (t, 1H, J = 56.2 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.60 (d, 2H, J = 8.0 Hz)
参考例８：エチル　１－イソプロピル－５－（メチルアミノ）－１Ｈ－ピラゾール－３－カルボキシレート Reference Example 8: Ethyl 1-isopropyl-5- (methylamino) -1H-pyrazole-3-carboxylate
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
工程（ｉ）：
　氷冷した化合物Ｉ（４８．２９ｇ）に、無水酢酸（１４０ｍＬ）を滴下した。滴下終了後、１１０℃で終夜攪拌した。反応混合物にトルエンを加えて減圧濃縮することを３回繰り返し、化合物ＩＩ（７１．９６ｇ）を得た。 Step (i):
Acetic anhydride (140 mL) was added dropwise to the ice-cooled compound I (48.29 g). After completion of dropping, the mixture was stirred at 110 ° C. overnight. Addition of toluene to the reaction mixture and concentration under reduced pressure were repeated three times to obtain Compound II (71.96 g).
工程（ｉｉ）：
　氷冷したカリウム　ｔｅｒｔ－ブトキシド（９２ｇ）とＴＨＦ（８００ｍＬ）との混合物に、化合物ＩＩ（７１．９６ｇ）とシュウ酸ジエチル（１２６ｇ）のＴＨＦ（３００ｍＬ）溶液を滴下した。滴下終了後、室温で終夜攪拌した。反応混合物に１．２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩＩ（８２．５６ｇ）を得た。 Step (ii):
To a mixture of ice-cooled potassium tert-butoxide (92 g) and THF (800 mL), a solution of compound II (71.96 g) and diethyl oxalate (126 g) in THF (300 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. 1.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound III (82.56 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（１．０１ｇ）、ピリジン（１０ｍＬ）、Ｎ－イソプロピルヒドラジン１塩酸塩（０．４６ｇ）とＬａｗｅｓｓｏｎ試薬（３．１ｇ）の混合物を６０℃で終夜攪拌した。反応溶液に１．２Ｍ塩酸を加え、酢酸エチルで抽出し、飽和重曹水で洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＶ（２８９．１ｍｇ）を得た。 Step (iii):
A mixture of Compound III (1.01 g), pyridine (10 mL), N-isopropylhydrazine monohydrochloride (0.46 g) and Lawesson's reagent (3.1 g) was stirred at 60 ° C. overnight. To the reaction solution was added 1.2 M hydrochloric acid, extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound IV (289.1 mg).
工程（ｉｖ）：
　化合物ＩＶ（２８９．１ｍｇ）、メタノール（２０ｍＬ）、酢酸（１０ｍＬ）および２０％Ｐｄ（ＯＨ）２－カーボン（０．７５ｇ、６０％水分）の混合物を水素雰囲気下（４ａｔｍ）に室温で３日間攪拌した。反応混合物をセライトろ過し、ろ液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／２）で精製し、表題化合物Ｖ（１９５ｍｇ）を得た。 Step (iv):
A mixture of compound IV (289.1 mg), methanol (20 mL), acetic acid (10 mL) and 20% Pd (OH) 2 -carbon (0.75 g, 60% moisture) was placed under a hydrogen atmosphere (4 atm) at room temperature for 3 days. Stir. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) to give the title compound V (195 mg).
1H-NMR (CDCl3) δ1.38 (m, 3H), 1.49 (m, 6H), 2.87 (m, 3H), 3.27 (brs, 1H), 4.24-4.41 (m, 3H), 6.01 (s, 1H) 1 H-NMR (CDCl 3 ) δ1.38 (m, 3H), 1.49 (m, 6H), 2.87 (m, 3H), 3.27 (brs, 1H), 4.24-4.41 (m, 3H), 6.01 (s , 1H)
参考例９：エチル　４－クロロ－１－メチル－５－（メチルアミノ）－１Ｈ－ピラゾール－３－カルボキシレート Reference Example 9: Ethyl 4-chloro-1-methyl-5- (methylamino) -1H-pyrazole-3-carboxylate
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　化合物Ｉ（６．１４ｇ；実施例４５の化合物Ｖ）のＴＨＦ（６０ｍＬ）溶液にＮ－クロロスクシンイミド（５．００ｇ）を加え、終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／３）で精製し、化合物ＩＩ（５．５０ｇ）を得た。 N-chlorosuccinimide (5.00 g) was added to a solution of compound I (6.14 g; compound V of Example 45) in THF (60 mL) and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3) to give Compound II (5.50 g).
1H-NMR (CDCl3) δ1.40 (m, 3H), 2.89 (m, 2H), 3.25 (brs, 1H), 3.81 (s, 3H), 4.21 (m, 2H) 1 H-NMR (CDCl 3 ) δ1.40 (m, 3H), 2.89 (m, 2H), 3.25 (brs, 1H), 3.81 (s, 3H), 4.21 (m, 2H)
参考例１０：エチル　１，４－ジメチル－５－（メチルアミノ）－１Ｈ－ピラゾール－３－カルボキシレート Reference Example 10: Ethyl 1,4-dimethyl-5- (methylamino) -1H-pyrazole-3-carboxylate
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
工程（ｉ）：
　氷冷した化合物Ｉ（４８．２２ｇ）のＴＨＦ（１０ｍＬ）溶液に、無水プロピオン酸（２００ｍＬ）を滴下した。滴下終了後、５０℃で４日間攪拌した。氷冷した反応溶液に６Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、化合物ＩＩ（６６．４８ｇ）を得た。 Step (i):
Propionic anhydride (200 mL) was added dropwise to a solution of Compound I (48.22 g) in ice-cooled THF (10 mL). After completion of dropping, the mixture was stirred at 50 ° C. for 4 days. A 6M aqueous sodium hydroxide solution was added to the ice-cooled reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain Compound II (66.48 g).
工程（ｉｉ）：
　氷冷したカリウム　ｔｅｒｔ－ブトキシド（８４ｇ）とＴＨＦ（６００ｍＬ）との混合物に、化合物ＩＩ（６６．４８ｇ）とシュウ酸ジエチル（１１０ｇ）のＴＨＦ（２００ｍＬ）溶液を滴下した。滴下終了後、室温で終夜攪拌した。反応混合物に１．２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製し、化合物ＩＩＩ（８１．６２ｇ）を得た。 Step (ii):
To a mixture of ice-cooled potassium tert-butoxide (84 g) and THF (600 mL), a solution of compound II (66.48 g) and diethyl oxalate (110 g) in THF (200 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred overnight at room temperature. 1.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1) to give Compound III (81.62 g).
工程（ｉｉｉ）：
　氷冷した化合物ＩＩＩ（４０．００ｇ）とピリジン（４００ｍＬ）の混合物に、Ｎ－メチルヒドラジン（９．１ｍｌ）とＬａｗｅｓｓｏｎ試薬（１００．４８ｇ）を加えた。混合物を６０℃で終夜攪拌した。室温の反応混合物に飽和重曹水を加え、酢酸エチルで抽出し、１．２Ｍ塩酸で洗浄した。有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製し、化合物ＩＶ（１９．１７ｇ）を得た。 Step (iii):
To a mixture of ice-cooled compound III (40.00 g) and pyridine (400 mL), N-methylhydrazine (9.1 ml) and Lawesson's reagent (100.48 g) were added. The mixture was stirred at 60 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature, extracted with ethyl acetate, and washed with 1.2 M hydrochloric acid. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give Compound IV (19.17 g).
工程（ｉｖ）：
　化合物ＩＶ（１９．１７ｇ）、メタノール（１９０ｍＬ）および２０％Ｐｄ（ＯＨ）２－カーボン（１０．５６ｇ、６０％水分）の混合物を水素雰囲気下（４ａｔｍ）に室温で終夜攪拌した。反応混合物をセライトろ過し、ろ液を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／３）で精製し、表題化合物Ｖ（８．３８ｇ）を得た。 Step (iv):
A mixture of Compound IV (19.17 g), methanol (190 mL) and 20% Pd (OH) 2 -carbon (10.56 g, 60% moisture) was stirred overnight at room temperature under a hydrogen atmosphere (4 atm). The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3) to give the title compound V (8.38 g).
1H-NMR (CDCl3) δ1.40 (m, 3H), 2.21 (s, 3H), 2.77 (m, 3H) 2.86 (brs, 1H), 3.79 (s, 3H), 4.38 (m, 2H) 1 H-NMR (CDCl 3 ) δ1.40 (m, 3H), 2.21 (s, 3H), 2.77 (m, 3H) 2.86 (brs, 1H), 3.79 (s, 3H), 4.38 (m, 2H)
参考例１１：エチル　５－［ベンジル（メチル）アミノ］－１－（２，２－ジフルオロエチル）－１Ｈ－ピラゾール－３－カルボキシレート Reference Example 11: Ethyl 5- [benzyl (methyl) amino] -1- (2,2-difluoroethyl) -1H-pyrazole-3-carboxylate
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
工程（ｉ）：
　化合物Ｉ（５０ｇ）、酢酸（０．４ｍＬ）、硫酸マグネシウム（１０ｇ）およびアセトン（３７５ｍＬ）の混合物を加熱還流下に２時間攪拌した。室温の反応混合物をろ過した。ろ液を減圧濃縮し、化合物ＩＩ（６５．１ｇ）を得た。 Step (i):
A mixture of Compound I (50 g), acetic acid (0.4 mL), magnesium sulfate (10 g) and acetone (375 mL) was stirred with heating under reflux for 2 hours. The room temperature reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain Compound II (65.1 g).
工程（ｉｉ）：
　氷冷した化合物ＩＩ（１２ｇ）、水素化ナトリウム（３．３４ｇ）およびＤＭＦ（４００ｍＬ）の混合物に１－ブロモ－２－ジフルオロエタン（６．７ｍＬ）を加えた後、室温で２日間攪拌した。反応混合物に水を加え、酢酸エチルで抽出後、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝８／２）で精製し、化合物ＩＩＩ（１６．１ｇ）を得た。 Step (ii):
1-Bromo-2-difluoroethane (6.7 mL) was added to a mixture of ice-cooled compound II (12 g), sodium hydride (3.34 g) and DMF (400 mL), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/2) to give Compound III (16.1 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（１６．１ｇ）および塩酸－メタノール溶液（５－１０％塩酸，１６０ｍＬ）の混合物を４５℃で３時間攪拌した。反応混合物を減圧濃縮し、化合物ＩＶ（１１．３ｇ）を得た。 Step (iii):
A mixture of Compound III (16.1 g) and hydrochloric acid-methanol solution (5-10% hydrochloric acid, 160 mL) was stirred at 45 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain Compound IV (11.3 g).
工程（ｉｖ）：
　化合物ＩＶ（９．５７ｇ）、化合物Ｖ（１３．５ｇ；参考例８の化合物ＩＩＩ）、Ｌａｗｓｓｏｎ試薬（４１．７ｇ）、ＴＨＦ（２４７ｍＬ）およびピリジン（１３ｍＬ）の混合物を６０℃で終夜攪拌した。反応混合物に飽和重曹水を加え、酢酸エチルで抽出後、１Ｍ塩酸、飽和食塩水で順に洗浄した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、表題化合物ＶＩ（３．７６ｇ）を得た。
1H-NMR (CDCl3)δ 1.38-1.41 (m, 3H), 2.64 (s, 3H), 4.00 (s, 2H), 4.37-4.45 (m, 4H), 6.24 (tt, J = 55.9, 4.6 Hz, 1H), 6.53 (s, 1H), 7.25-7.35 (m, 5H) Step (iv):
A mixture of compound IV (9.57 g), compound V (13.5 g; compound III of Reference Example 8), Lawsson reagent (41.7 g), THF (247 mL) and pyridine (13 mL) was stirred at 60 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed successively with 1M hydrochloric acid and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give the title compound VI (3.76 g).
1 H-NMR (CDCl 3 ) δ 1.38-1.41 (m, 3H), 2.64 (s, 3H), 4.00 (s, 2H), 4.37-4.45 (m, 4H), 6.24 (tt, J = 55.9, 4.6 Hz, 1H), 6.53 (s, 1H), 7.25-7.35 (m, 5H)
参考例１２：エチル　５－［ベンジル（メチル）アミノ］－１－（２－フルオロエチル）－１Ｈ－ピラゾール－３－カルボキシレート Reference Example 12: Ethyl 5- [benzyl (methyl) amino] -1- (2-fluoroethyl) -1H-pyrazole-3-carboxylate
Figure JPOXMLDOC01-appb-C000049
 　参考例１１と同様の製造法により、参考例１２を製造した。
Figure JPOXMLDOC01-appb-C000049
 Reference Example 12 was produced by the same production method as in Reference Example 11.
1H-NMR (CDCl3)δ 1.39 (m, 3H), 2.63 (s, 3H), 4.01 (s, 2H), 4.35-4.43 (m, 4H), 4.79 (m, 1H), 4.91 (m, 1H), 6.50 (s, 1H), 7.26-7.35 (m, 5H) 1 H-NMR (CDCl 3 ) δ 1.39 (m, 3H), 2.63 (s, 3H), 4.01 (s, 2H), 4.35-4.43 (m, 4H), 4.79 (m, 1H), 4.91 (m, 1H), 6.50 (s, 1H), 7.26-7.35 (m, 5H)
参考例１３：エチル　１－エチル－４－メチル－５－（メチルアミノ）－１Ｈ－ピラゾール－３－カルボキシレイト Reference Example 13: Ethyl 1-ethyl-4-methyl-5- (methylamino) -1H-pyrazole-3-carboxylate
Figure JPOXMLDOC01-appb-C000050
 　参考例１０と同様の製造法により、参考例１３を製造した。
1H-NMR (CDCl3)δ 1.38-1.44 (m, 6H), 2.21 (s, 3H), 2.78 (brs, 4H), 4.14 (m, 2H), 4.39 (m, 2H)
Figure JPOXMLDOC01-appb-C000050
 Reference Example 13 was produced by the same production method as Reference Example 10.
1 H-NMR (CDCl 3 ) δ 1.38-1.44 (m, 6H), 2.21 (s, 3H), 2.78 (brs, 4H), 4.14 (m, 2H), 4.39 (m, 2H)
参考例１４：（２ｓ，５ｒ）－５－（メチルスルホニル）－２－アダマンタンアミン Reference Example 14: (2s, 5r) -5- (methylsulfonyl) -2-adamantanamine
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
工程（ｉ）：
　化合物Ｉ（２０．０６ｇ）、炭酸水素ナトリウム（２３．３１ｇ）、ＴＨＦ（２００ｍＬ）、水（１００ｍＬ）の混合物を氷冷し、ＣｂｚＣｌ（１９ｍＬ）を滴下した。滴下終了後、室温にて終夜攪拌した。反応溶液に飽和炭酸水素ナトリウムを加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製し、化合物ＩＩ（２５．８０ｇ）を得た。 Step (i):
A mixture of Compound I (20.06 g), sodium bicarbonate (23.31 g), THF (200 mL) and water (100 mL) was ice-cooled, and CbzCl (19 mL) was added dropwise. After completion of dropping, the mixture was stirred overnight at room temperature. Saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give Compound II (25.80 g).
工程（ｉｉ）：
　化合物ＩＩ（２５．８０ｇ）、ＴＥＡ（３０ｍＬ）、クロロホルム（３００ｍＬ）の混合物を氷冷し、メタンスルホニルクロダイド（１２ｍＬ）を滴下した。滴下終了後、室温にて終夜攪拌した。反応溶液に水を加え、クロロホルムで抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩＩ（２０．７６ｇ）を得た。 Step (ii):
A mixture of Compound II (25.80 g), TEA (30 mL), and chloroform (300 mL) was ice-cooled, and methanesulfonyl chloride (12 mL) was added dropwise. After completion of dropping, the mixture was stirred overnight at room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound III (20.76 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（１０．００ｇ）、チオ酢酸（６０ｍＬ）の混合物を７０℃で終夜攪拌した。反応溶液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、化合物ＩＶ（６．５５ｇ）を得た。 Step (iii):
A mixture of Compound III (10.00 g) and thioacetic acid (60 mL) was stirred at 70 ° C. overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give Compound IV (6.55 g).
工程（ｉｖ）：
　化合物ＩＶ（６．５５ｇ）、メタノール（８０ｍＬ）、ヨウ化メチル（１．７ｍＬ）の混合物を氷冷し、ナトリウムメトキサイド（３．８１ｇ）を加えにて終夜攪拌した。反応溶液を濃縮後、残渣に水を加え、酢酸エチルで抽出し粗野な化合物Ｖ（６．０７ｇ）を得た。 Step (iv):
A mixture of Compound IV (6.55 g), methanol (80 mL), and methyl iodide (1.7 mL) was ice-cooled, sodium methoxide (3.81 g) was added, and the mixture was stirred overnight. The reaction solution was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate to obtain crude compound V (6.07 g).
工程（ｖ）：
　３－クロロ過安息香酸工程（１３．７２ｇ）、クロロホルム（５０ｍＬ）の混合物を氷冷後、化合物Ｖ（６．０７ｇ）、クロロホルム（８０ｍＬ）の溶液を滴下した。滴下終了後、室温にて終夜攪拌した。反応液を再び氷冷し、飽和亜硫酸水素ナトリウムを加え、クロロホルムで抽出した。有機層を炭酸水素ナトリウムで洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／３）で精製し、化合物ＶＩ（４．６５ｇ）を得た。 Step (v):
A mixture of the 3-chloroperbenzoic acid step (13.72 g) and chloroform (50 mL) was ice-cooled, and a solution of compound V (6.07 g) and chloroform (80 mL) was added dropwise. After completion of dropping, the mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled again, saturated sodium bisulfite was added, and the mixture was extracted with chloroform. The organic layer was washed with sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/3) to give compound VI (4.65 g). Obtained.
工程（ｖｉ）：
　化合物ＶＩ（４．６５ｇ）、１０％パラジウム－カーボン（１．５３ｇ、５０％ウェット）、メタノール（１００ｍＬ）の混合物を水素雰囲気下（２ａｔｍ）、室温で１．５時間撹拌した。反応混合物をセライト濾過し、表題化合物ＶＩＩ（３．２３ｇ）を得た。 Step (vi):
A mixture of Compound VI (4.65 g), 10% palladium-carbon (1.53 g, 50% wet) and methanol (100 mL) was stirred under a hydrogen atmosphere (2 atm) at room temperature for 1.5 hours. The reaction mixture was filtered through celite to give the title compound VII (3.23 g).
1H-NMR (CDCl3) δ1.49-1.53 (m, 2H), 2.03-2.14 (m, 13H), 2.76 (s, 3H), 3.10 (m, 1H) 1 H-NMR (CDCl 3 ) δ1.49-1.53 (m, 2H), 2.03-2.14 (m, 13H), 2.76 (s, 3H), 3.10 (m, 1H)
実施例１：Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－［メチル（フェニル）アミノ］－１Ｈ－ピラゾール－３－カルボキサミド Example 1: N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- [methyl (phenyl) amino] -1H-pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
工程（ｉ）：
　氷冷したカリウム　ｔｅｒｔ－ブトキシド（３．３８ｇ）とＴＨＦ（３６ｍＬ）の混合物に、化合物Ｉ（２．０ｇ）およびシュウ酸ジエチル（４．１ｇ）のＴＨＦ（１６ｍＬ）溶液を滴下した。滴下終了後、室温で終夜攪拌した。反応溶液に１．２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、化合物ＩＩ（３．１０ｇ）を得た。 Step (i):
A solution of Compound I (2.0 g) and diethyl oxalate (4.1 g) in THF (16 mL) was added dropwise to a mixture of ice-cooled potassium tert-butoxide (3.38 g) and THF (36 mL). After completion of dropping, the mixture was stirred overnight at room temperature. To the reaction solution was added 1.2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give Compound II (3.10 g).
工程（ｉｉ）：
　化合物ＩＩ（３．１０ｇ）、ピリジン（４０ｍＬ）、Ｎ－メチルヒドラジン（０．７２ｍｌ）およびＬａｗｅｓｓｏｎ試薬（１０．０ｇ）の混合物を６０℃で終夜攪拌した。反応混合物に１．２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で順に洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩＩ（２．５７ｇ）を得た。 Step (ii):
A mixture of Compound II (3.10 g), pyridine (40 mL), N-methylhydrazine (0.72 ml) and Lawesson's reagent (10.0 g) was stirred at 60 ° C. overnight. 1.2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound III (2.57 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（１．０５ｇ）、メタノール（２０ｍＬ）および２Ｍ水酸化リチウム（４ｍＬ）の混合物を室温で終夜攪拌した。濃縮後、１．２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮後、化合物ＩＶを得た。 Step (iii):
A mixture of Compound III (1.05 g), methanol (20 mL) and 2M lithium hydroxide (4 mL) was stirred at room temperature overnight. After concentration, 1.2 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give compound IV.
工程（ｉｖ）：
　工程（ｉｉｉ）で得られた化合物ＩＶ（１３９．４ｍｇ）、ＤＭＦ（５ｍＬ）、化合物Ｖ（０．１２ｇ、参考文献ＷＯ２００９０２０１３７）、ＷＳＣ・ＨＣｌ（０．３ｇ）、ＨＯＢｔ・Ｈ２Ｏ（０．３ｇ）およびトリエチルアミン（１ｍＬ）の混合物を室温で終夜攪拌した。反応溶液に２Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。成績体を逆相系クロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ－水／０．０３５％ＴＦＡ－アセトニトリル＝８５／１５から５／９５）で精製し、表題化合物ＶＩ（１５３．４９ｍｇ）を得た。 Step (iv):
Compound IV (139.4 mg) obtained in step (iii), DMF (5 mL), Compound V (0.12 g, reference WO2009020137), WSC · HCl (0.3 g), HOBt · H 2 O (0. 3 g) and triethylamine (1 mL) were stirred at room temperature overnight. To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1). The resulting product was purified by reverse phase chromatography (elution solvent: 0.05% TFA-water / 0.035% TFA-acetonitrile = 85/15 to 5/95) to give the title compound VI (153.49 mg). It was.
1H-NMR (CDCl3)δ 1.47 (s, 1H), 1.54-1.57 (m, 2H), 1.79-1.82 (m, 4H), 1.87-1.94 (m, 4H), 2.20-2.24 (m, 3H), 3.26 (s, 3H), 3.57 (s, 3H), 4.20 (brs, 1H), 6.59 (s, 1H), 6.64 (m, 2H), 6.89 (m, 1H), 7.15 (m, 1H), 7.24 (m, 2H) 1 H-NMR (CDCl 3 ) δ 1.47 (s, 1H), 1.54-1.57 (m, 2H), 1.79-1.82 (m, 4H), 1.87-1.94 (m, 4H), 2.20-2.24 (m, 3H ), 3.26 (s, 3H), 3.57 (s, 3H), 4.20 (brs, 1H), 6.59 (s, 1H), 6.64 (m, 2H), 6.89 (m, 1H), 7.15 (m, 1H) , 7.24 (m, 2H)
実施例２～実施例２２：
　実施例１と同様の製造方法により実施例２から実施例２２を製造した。 Examples 2 to 22:
Examples 2 to 22 were produced by the same production method as in Example 1.
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-I000054
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-I000054
Figure JPOXMLDOC01-appb-I000055
Figure JPOXMLDOC01-appb-I000056
Figure JPOXMLDOC01-appb-I000055
Figure JPOXMLDOC01-appb-I000056
Figure JPOXMLDOC01-appb-I000057
Figure JPOXMLDOC01-appb-I000058
Figure JPOXMLDOC01-appb-I000057
Figure JPOXMLDOC01-appb-I000058
実施例２３：４－クロロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－［メチル（４－メチルフェニル）アミノ］－１Ｈ－ピラゾール－３－カルボキサミド Example 23: 4-Chloro-N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- [methyl (4-methylphenyl) amino] -1H-pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
工程（ｉ）：
　室温の化合物Ｉ（０．５０ｇ；実施例３の合成中間体）のＴＨＦ（１０ｍＬ）溶液に、Ｎ－クロロスクシンイミド（０．２７ｇ）を加え、終夜攪拌した。反応溶液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、化合物ＩＩ（０．５１ｇ）を得た。 Step (i):
N-chlorosuccinimide (0.27 g) was added to a THF (10 mL) solution of Compound I (0.50 g; synthesis intermediate of Example 3) at room temperature, and the mixture was stirred overnight. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1) to obtain Compound II (0.51 g).
工程（ｉｉ）：
　室温の化合物ＩＩ（２７０．４ｍｇ）、エタノール（８ｍＬ）および２Ｍ水酸化リチウム水溶液（０．８ｍＬ）の混合物を５日間攪拌した。減圧濃縮し、化合物ＩＩＩを得た。 Step (ii):
A mixture of Compound II (270.4 mg), ethanol (8 mL) and 2M aqueous lithium hydroxide solution (0.8 mL) at room temperature was stirred for 5 days. Concentration under reduced pressure gave compound III.
工程（ｉｉｉ）：
　工程（ｉｉ）で得られた化合物ＩＩＩ、ＤＭＦ（１０ｍＬ）、化合物ＩＶ（０．２１ｇ）、ＷＳＣ・ＨＣｌ（０．３５ｇ）、ＨＯＢｔ・Ｈ２Ｏ（０．３５ｇ）およびトリエチルアミン（０．６３ｍＬ）の混合物を室温で終夜攪拌した。反応溶液に２Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。成績体を逆相系クロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ－水／０．０３５％ＴＦＡ－アセトニトリル＝８０／２０から５／９５）で精製し、表題化合物Ｖ（２５７．２ｍｇ）を得た。 Step (iii):
Compound III, DMF (10 mL) obtained in step (ii), Compound IV (0.21 g), WSC · HCl (0.35 g), HOBt · H 2 O (0.35 g) and triethylamine (0.63 mL) The mixture was stirred at room temperature overnight. To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 10/1). The resulting product was purified by reverse phase chromatography (elution solvent: 0.05% TFA-water / 0.035% TFA-acetonitrile = 80/20 to 5/95) to give the title compound V (257.2 mg). It was.
1H-NMR (CDCl3)δ 1.42 (s, 1H), 1.54-1.57 (m, 2H), 1.79-1.96 (m, 8H), 2.20-2.27 (m, 6H), 3.29 (s, 3H), 3.63 (s, 3H), 4.22 (brs, 1H), 6.49 (m, 2H), 7.05-7.07 (m, 3H) 1 H-NMR (CDCl 3 ) δ 1.42 (s, 1H), 1.54-1.57 (m, 2H), 1.79-1.96 (m, 8H), 2.20-2.27 (m, 6H), 3.29 (s, 3H), 3.63 (s, 3H), 4.22 (brs, 1H), 6.49 (m, 2H), 7.05-7.07 (m, 3H)
実施例２４～３４：
　実施例２３と同様の製造方法により、実施例２４から実施例３４を製造した。 Examples 24-34:
Example 24 to Example 34 were manufactured by the same manufacturing method as Example 23.
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-I000061
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-I000061
Figure JPOXMLDOC01-appb-I000062
Figure JPOXMLDOC01-appb-I000063
Figure JPOXMLDOC01-appb-I000062
Figure JPOXMLDOC01-appb-I000063
実施例３５：４－クロロ－５－［（５－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド Example 35: 4-Chloro-5-[(5-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole -3-Carboxamide
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　化合物Ｉ（４０．２ｍｇ；実施例４７）のＴＨＦ（３ｍＬ）溶液に、Ｎ－クロロスクシンイミド（１７．１ｍｇ）を加え、室温で終夜攪拌した。反応溶液を減圧濃縮後、残渣を逆相カラムクロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ－水／０．０３５％ＴＦＡ－アセトニトリル＝８５／１５から５／９５）で精製し、表題化合物ＩＩ（３９．３ｍｇ）を得た。 N-chlorosuccinimide (17.1 mg) was added to a THF (3 mL) solution of Compound I (40.2 mg; Example 47), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (elution solvent: 0.05% TFA-water / 0.035% TFA-acetonitrile = 85/15 to 5/95) to give the title compound II ( 39.3 mg) was obtained.
1H-NMR (CDCl3)δ 1.41 (s, 1H), 1.55-1.58 (m, 2H), 1.79-1.96 (m, 8H), 2.23 (m, 3H), 3.38 (s, 3H), 3.69 (s, 3H), 4.22 (brs, 1H), 6.29 (m, 1H), 7.07 (m, 1H), 7.26 (m, 1H), 8.10 (m, 1H) 1 H-NMR (CDCl 3 ) δ 1.41 (s, 1H), 1.55-1.58 (m, 2H), 1.79-1.96 (m, 8H), 2.23 (m, 3H), 3.38 (s, 3H), 3.69 ( s, 3H), 4.22 (brs, 1H), 6.29 (m, 1H), 7.07 (m, 1H), 7.26 (m, 1H), 8.10 (m, 1H)
実施例３６～実施例４４：
　実施例３５と同様の製造方法により実施例３６から実施例４４を製造した。 Example 36 to Example 44:
Example 36 to Example 44 were manufactured by the same manufacturing method as Example 35.
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-I000066
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-I000066
Figure JPOXMLDOC01-appb-I000067
Figure JPOXMLDOC01-appb-I000067
実施例４５：Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－［メチル（２－ピリジニル）アミノ］－１Ｈ－ピラゾール－３－カルボキサミド Example 45: N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- [methyl (2-pyridinyl) amino] -1H-pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
工程（ｉ）：
　化合物Ｉ（２０．０７ｇ；参考例８の化合物ＩＩＩ）、ＴＨＦ（１８０ｍＬ）、ピリジン（２０ｍＬ）、Ｎ－メチルヒドラジン（４．４ｍｌ）およびＬａｗｅｓｓｏｎ試薬（３３．３７ｇ）の混合物を６０℃で終夜攪拌した。反応溶液に１．２Ｍ塩酸を加え、酢酸エチルで抽出し、飽和重曹水、飽和食塩水で順に洗浄した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩ（８．０９ｇ）を得た。 Step (i):
A mixture of Compound I (20.07 g; Compound III of Reference Example 8), THF (180 mL), pyridine (20 mL), N-methylhydrazine (4.4 ml) and Lawesson's reagent (33.37 g) was stirred at 60 ° C. overnight. did. To the reaction solution was added 1.2 M hydrochloric acid, extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound II (8.09 g).
工程（ｉｉ）：
　化合物ＩＩ（８．０９ｇ）、メタノール（１４０ｍＬ）、酢酸（１０ｍＬ）および２０％Ｐｄ（ＯＨ）２－カーボン（９．３９ｇ、６０％水分）の混合物を、水素雰囲気下（４ａｔｍ）に室温で４日間攪拌した。反応混合物をセライトろ過し、ろ液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／３）で精製し、化合物ＩＩＩ（３．３３ｇ）を得た。 Step (ii):
A mixture of Compound II (8.09 g), methanol (140 mL), acetic acid (10 mL) and 20% Pd (OH) 2 -carbon (9.39 g, 60% moisture) was added at room temperature under a hydrogen atmosphere (4 atm) at room temperature. Stir for days. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3) to give Compound III (3.33 g).
工程（ｉｉｉ）：
　氷冷した化合物ＩＩＩ（５２９．９ｍｇ）、２－クロロピリジン（１ｍＬ）とＤＭＦ（５ｍＬ）の混合物に、水素化ナトリウム（０．１４ｇ）を加えた。その後、９０℃で終夜攪拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／５）で精製し、化合物ＩＶ（２２１ｍｇ）を得た。 Step (iii):
Sodium hydride (0.14 g) was added to a mixture of ice-cooled compound III (529.9 mg), 2-chloropyridine (1 mL) and DMF (5 mL). Then, it stirred at 90 degreeC overnight. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/5) to give Compound IV (221 mg).
工程（ｖｉ）：
　化合物ＩＶ（５９．６ｍｇ）、エタノール（５ｍＬ）、２Ｍ水酸化リチウム水溶液（０．５ｍＬ）の混合物を室温で終夜攪拌した。反応混合物を減圧濃縮し、残渣を得た。この残渣、ＤＭＦ（５ｍＬ）、化合物Ｖ（５０ｍｇ）、ＷＳＣ・ＨＣｌ（１００ｍｇ）、ＨＯＢｔ・Ｈ２Ｏ（１００ｍｇ）およびトリエチルアミン（０．１６ｍＬ）の混合物を、室温で３日間攪拌した。反応混合物に２Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。成績体を逆相系クロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ－水／０．０３５％ＴＦＡ－アセトニトリル＝９９／１から５／９５）で精製し、表題化合物ＶＩ（７３．５７ｍｇ）を得た。 Step (vi):
A mixture of Compound IV (59.6 mg), ethanol (5 mL), 2M aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain a residue. A mixture of this residue, DMF (5 mL), compound V (50 mg), WSC · HCl (100 mg), HOBt · H 2 O (100 mg) and triethylamine (0.16 mL) was stirred at room temperature for 3 days. To the reaction mixture was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 10/1). The resulting product was purified by reverse phase chromatography (elution solvent: 0.05% TFA-water / 0.035% TFA-acetonitrile = 99/1 to 5/95) to give the title compound VI (73.57 mg). It was.
1H-NMR (CDCl3)δ 1.45 (s, 1H), 1.54-1.59 (m, 2H), 1.79-1.96 (m, 8H) 2.21-2.24 (m, 3H), 3.38 (s, 3H), 3.65 (s, 3H), 4.20 (brs, 1H), 6.30 (m, 1H), 6.65 (s, 1H), 6.74 (m, 1H), 7.16 (m, 1H), 7.44 (m, 1H), 8.24 (m, 1H) 1 H-NMR (CDCl 3 ) δ 1.45 (s, 1H), 1.54-1.59 (m, 2H), 1.79-1.96 (m, 8H) 2.21-2.24 (m, 3H), 3.38 (s, 3H), 3.65 (s, 3H), 4.20 (brs, 1H), 6.30 (m, 1H), 6.65 (s, 1H), 6.74 (m, 1H), 7.16 (m, 1H), 7.44 (m, 1H), 8.24 ( m, 1H)
実施例４６～実施例７７：
　実施例４５と同様の製造方法により実施例４６から実施例７７を製造した。 Examples 46-77:
Example 46 to Example 77 were manufactured by the same manufacturing method as Example 45.
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-I000070
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-I000070
Figure JPOXMLDOC01-appb-I000071
Figure JPOXMLDOC01-appb-I000072
Figure JPOXMLDOC01-appb-I000071
Figure JPOXMLDOC01-appb-I000072
Figure JPOXMLDOC01-appb-I000073
Figure JPOXMLDOC01-appb-I000074
Figure JPOXMLDOC01-appb-I000073
Figure JPOXMLDOC01-appb-I000074
Figure JPOXMLDOC01-appb-I000075
Figure JPOXMLDOC01-appb-I000076
Figure JPOXMLDOC01-appb-I000075
Figure JPOXMLDOC01-appb-I000076
Figure JPOXMLDOC01-appb-I000077
Figure JPOXMLDOC01-appb-I000078
Figure JPOXMLDOC01-appb-I000077
Figure JPOXMLDOC01-appb-I000078
Figure JPOXMLDOC01-appb-I000079
Figure JPOXMLDOC01-appb-I000080
Figure JPOXMLDOC01-appb-I000079
Figure JPOXMLDOC01-appb-I000080
実施例７８～実施例８９：
　参考例９を用いて実施例４５と同様の製造方法により実施例７８から実施例８９を製造した。 Examples 78-89:
Example 78 to Example 89 were produced by the same production method as in Example 45 using Reference Example 9.
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-I000082
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-I000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-I000084
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-I000084
実施例９０～実施例９１：
　参考例１０を用いて実施例４５と同様の製造方法により実施例９０から実施例９１を製造した。 Examples 90-91:
Example 90 to Example 91 were produced by the same production method as in Example 45 using Reference Example 10.
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
実施例９２：Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－｛メチル［４－（トリフルオロメチルｌ）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド Example 92: N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- {methyl [4- (trifluoromethyll) -2-pyridinyl] amino} -1H-pyrazole- 3-carboxamide
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
工程（ｉ）：
　化合物Ｉ（０．５ｇ；実施例４５の化合物Ｖ）、メタノール（８ｍＬ）および２Ｍ水酸化リチウム水溶液（１．５ｍＬ）の混合物を７０℃で終夜攪拌した。反応溶液を減圧濃縮し、化合物ＩＩを得た。 Step (i):
A mixture of Compound I (0.5 g; Compound V of Example 45), methanol (8 mL) and 2M aqueous lithium hydroxide (1.5 mL) was stirred at 70 ° C. overnight. The reaction solution was concentrated under reduced pressure to obtain Compound II.
工程（ｉｉ）：
　工程（ｉ）で得られた化合物ＩＩ、ＤＭＦ（２０ｍＬ）、化合物ＩＩＩ（０．５ｇ）、ＷＳＣ・ＨＣｌ（０．９５ｇ）、ＨＯＢｔ・Ｈ２Ｏ（１．０２ｇ）およびトリエチルアミン（１０ｍＬ）の混合物を室温で３日間攪拌した。反応混合物に２Ｍ水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。得られた固体をジエチルエーテルでリパルプ洗浄し、化合物ＩＶ（３３２．７ｍｇ）を得た。 Step (ii):
Compound II, DMF (20 mL), compound III (0.5 g), WSC.HCl (0.95 g), HOBt.H 2 O (1.02 g) and triethylamine (10 mL) obtained in step (i) Was stirred at room temperature for 3 days. 2M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 10/1). The obtained solid was repulp washed with diethyl ether to obtain Compound IV (332.7 mg).
工程（ｉｉｉ）：
　化合物ＩＶ（０．１０ｇ）、ＤＭＦ（３ｍＬ）、２－クロロ－４－トリフルオロピリジン（０．０８ｇ）および水素化ナトリウム（５１ｍｇ）の混合物を７０℃で終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製し、表題化合物Ｖ（６９．４ｍｇ）を得た。 Step (iii):
A mixture of Compound IV (0.10 g), DMF (3 mL), 2-chloro-4-trifluoropyridine (0.08 g) and sodium hydride (51 mg) was stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to give the title compound V (69.4 mg). Got.
1H-NMR (CDCl3)δ 1.42 (s, 1H), 1.56-1.60 (m, 2H), 1.80-1.97 (m, 8H), 2.24 (m, 3H), 3.42 (s, 3H), 3.66 (s, 3H), 4.21 (brs, 1H), 6.49 (s, 1H), 6.69 (m, 1H), 6.95 (m, 1H), 7.18 (m, 1H), 8.39 (m, 1H) 1 H-NMR (CDCl 3 ) δ 1.42 (s, 1H), 1.56-1.60 (m, 2H), 1.80-1.97 (m, 8H), 2.24 (m, 3H), 3.42 (s, 3H), 3.66 ( s, 3H), 4.21 (brs, 1H), 6.49 (s, 1H), 6.69 (m, 1H), 6.95 (m, 1H), 7.18 (m, 1H), 8.39 (m, 1H)
実施例９３：５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－メチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド Example 93: 5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1-methyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
工程（ｉ）：
　化合物Ｉ（２００ｍｇ；実施例４５の化合物Ｖ）、Ｎ，Ｎ－ジメチルホルムアミド（４ｍＬ）、トリスジベンジリデンアセトンジパラジウム（２７８ｍｇ）、Ｘｈａｎｔｐｈｏｓ（１７０ｍｇ；４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン）、炭酸セシウム（６５７ｍｇ）および２，４－ジクロロピリジン（２２１ｍｇ）の混合物を１００℃で終夜撹拌した。反応混合物をセライトろ過し、酢酸エチルでケーキを洗浄後、ろ液を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩ（５６ｍｇ）を得た。 Step (i):
Compound I (200 mg; Compound V of Example 45), N, N-dimethylformamide (4 mL), trisdibenzylideneacetone dipalladium (278 mg), Xhantphos (170 mg; 4,5-bis (diphenylphosphino) -9, A mixture of 9-dimethylxanthene), cesium carbonate (657 mg) and 2,4-dichloropyridine (221 mg) was stirred at 100 ° C. overnight. The reaction mixture was filtered through celite, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound II (56 mg).
工程（ｉｉ）：
　化合物ＩＩ（５６ｍｇ）、エタノール（３ｍＬ）および２Ｍ水酸化ナトリウム水溶液（０．２ｍＬ）の混合物を終夜撹拌した。反応混合物を減圧濃縮し、残渣にクエン酸水溶液を加えた後、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮し、化合物ＩＩＩ（６１ｍｇ）を得た。 Step (ii):
A mixture of Compound II (56 mg), ethanol (3 mL) and 2M aqueous sodium hydroxide (0.2 mL) was stirred overnight. The reaction mixture was concentrated under reduced pressure, an aqueous citric acid solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain Compound III (61 mg).
工程（ｉｉｉ）：
　化合物ＩＩＩ（６１ｍｇ）、ＴＨＦ（５ｍＬ）、１－クロロ－２－メチルピリジニウムヨージド（５５ｍｇ）、化合物ＩＶ（３６ｍｇ）およびトリエチルアミン（７５μＬ）の混合物を室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：クロロホルム／酢酸エチル＝１／１）で精製し、表題化合物Ｖ（３３ｍｇ）を得た。 Step (iii):
A mixture of Compound III (61 mg), THF (5 mL), 1-chloro-2-methylpyridinium iodide (55 mg), Compound IV (36 mg) and triethylamine (75 μL) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform / ethyl acetate = 1/1) to give the title compound V (33 mg).
1H-NMR (CDCl3)δ 1.84-1.98 (m, 11H), 2.26 (ddd, 3H, J = 13.8, 7.6, 3.0 Hz), 3.40 (s, 3H), 3.67 (s, 3H), 4.21-4.23 (m, 1H), 6.32 (d, 1H, J = 1.7 Hz), 6.68 (s, 1H), 6.77-6.78 (m, 1H), 7.17 (d, 1H, J = 8.1 Hz), 8.15 (d, 1H, J = 5.5 Hz) 1 H-NMR (CDCl 3 ) δ 1.84-1.98 (m, 11H), 2.26 (ddd, 3H, J = 13.8, 7.6, 3.0 Hz), 3.40 (s, 3H), 3.67 (s, 3H), 4.21- 4.23 (m, 1H), 6.32 (d, 1H, J = 1.7 Hz), 6.68 (s, 1H), 6.77-6.78 (m, 1H), 7.17 (d, 1H, J = 8.1 Hz), 8.15 (d , 1H, J = 5.5 Hz)
実施例９４～１２１：
　実施例９３と同様の製造方法により実施例９４から実施例１２１を製造した。 Examples 94-121:
Example 94 to Example 121 were manufactured by the same manufacturing method as Example 93.
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-I000089
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-I000089
Figure JPOXMLDOC01-appb-I000090
Figure JPOXMLDOC01-appb-I000091
Figure JPOXMLDOC01-appb-I000092
Figure JPOXMLDOC01-appb-I000090
Figure JPOXMLDOC01-appb-I000091
Figure JPOXMLDOC01-appb-I000092
Figure JPOXMLDOC01-appb-I000093
Figure JPOXMLDOC01-appb-I000094
Figure JPOXMLDOC01-appb-I000093
Figure JPOXMLDOC01-appb-I000094
Figure JPOXMLDOC01-appb-I000095
Figure JPOXMLDOC01-appb-I000096
Figure JPOXMLDOC01-appb-I000095
Figure JPOXMLDOC01-appb-I000096
Figure JPOXMLDOC01-appb-I000097
Figure JPOXMLDOC01-appb-I000097
実施例１２２：４－クロロ－５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド Example 122: 4-chloro-5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole -3-Carboxamide
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
工程（ｉ）：
　化合物Ｉ（２００ｍｇ）、トルエン（５ｍＬ）、酢酸パラジウム（４６ｍｇ）、ｒａｃ－ＢＩＮＡＰ（１２６ｍｇ）、炭酸セシウム（４９３ｍｇ）および２，４－ジクロロピリジン（２２４ｍｇ）の混合物を１００℃で終夜撹拌した。反応混合物をセライトろ過し、酢酸エチルでケーキを洗浄後、ろ液を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩ（７０ｍｇ）を得た。 Step (i):
A mixture of Compound I (200 mg), toluene (5 mL), palladium acetate (46 mg), rac-BINAP (126 mg), cesium carbonate (493 mg) and 2,4-dichloropyridine (224 mg) was stirred at 100 ° C. overnight. The reaction mixture was filtered through celite, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound II (70 mg).
工程（ｉｉ）：
　化合物ＩＩ（７０ｍｇ）、Ｎ－クロロスクシンイミド（３３ｍｇ）およびＴＨＦ（３ｍＬ）の混合物を室温で２日間撹拌した。反応混合物を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩＩ（４２ｍｇ）を得た。 Step (ii):
A mixture of Compound II (70 mg), N-chlorosuccinimide (33 mg) and THF (3 mL) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound III (42 mg).
工程（ｉｉｉ）：
　工程（ｉｉ）のようにして得られた化合物ＩＩＩ（３２２ｍｇ）、エタノール（４ｍＬ）および２Ｍ水酸化ナトリウム水溶液（１ｍＬ）の混合物を終夜撹拌した。反応混合物を減圧濃縮し、残渣にクエン酸水溶液を加えた後、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮し、化合物ＩＶ（４５　ｍｇ）を得た。 Step (iii):
A mixture of compound III (322 mg) obtained as in step (ii), ethanol (4 mL) and 2M aqueous sodium hydroxide (1 mL) was stirred overnight. The reaction mixture was concentrated under reduced pressure, an aqueous citric acid solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound IV (45 mg).
工程（ｉｖ）：
　化合物ＩＶ（４５ｍｇ）、ＴＨＦ（５ｍＬ）、１－クロロ－２－メチルピリジニウムヨージド（３７ｍｇ）、化合物Ｖ（２４ｍｇ）およびトリエチルアミン（０．０５１ｍＬ）の混合物を室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：クロロホルム／酢酸エチル＝１／１）で精製し、表題化合物ＶＩ（３９ｍｇ）を得た。 Step (iv):
A mixture of Compound IV (45 mg), THF (5 mL), 1-chloro-2-methylpyridinium iodide (37 mg), Compound V (24 mg) and triethylamine (0.051 mL) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform / ethyl acetate = 1/1) to give the title compound VI (39 mg).
1H-NMR (CDCl3)δ 1.41 (t, 3H, J = 6.3 Hz), 1.55-1.57 (m, 3H), 1.77-1.89 (m, 6H), 1.93-1.96 (m, 2H), 2.15-2.32 (m, 3H), 3.37-3.39 (m, 3H), 3.90-4.03 (m, 2H), 4.19-4.30 (m, 1H), 6.29 (d, 1H, J = 1.5 Hz), 6.79 (dd, 1H, J = 5.5, 1.6 Hz), 7.09 (d, 1H, J = 7.8 Hz), 8.14 (d, 1H, J = 5.4 Hz) 1 H-NMR (CDCl 3 ) δ 1.41 (t, 3H, J = 6.3 Hz), 1.55-1.57 (m, 3H), 1.77-1.89 (m, 6H), 1.93-1.96 (m, 2H), 2.15- 2.32 (m, 3H), 3.37-3.39 (m, 3H), 3.90-4.03 (m, 2H), 4.19-4.30 (m, 1H), 6.29 (d, 1H, J = 1.5 Hz), 6.79 (dd, 1H, J = 5.5, 1.6 Hz), 7.09 (d, 1H, J = 7.8 Hz), 8.14 (d, 1H, J = 5.4 Hz)
実施例１２３～１２６：
　実施例１２２と同様の製造方法により、実施例１２３から実施例１２６を製造した。 Examples 123-126:
Example 123 to Example 126 were manufactured by the same manufacturing method as Example 122.
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-I000100
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-I000100
実施例１２７～１３２：
　参考例１０または１３を用いて、実施例９３と同様の製造方法により、実施例１２７から実施例１３２を製造した。 Examples 127-132:
Example 127 to Example 132 were produced by the same production method as in Example 93 using Reference Example 10 or 13.
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-I000102
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-I000102
実施例１３３：５－［（４－フルオロフェニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１，４－ジメチル－１Ｈ－ピラゾール－３－カルボキサミド Example 133: 5-[(4-fluorophenyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1,4-dimethyl-1H-pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
工程（ｉ）：
　化合物Ｉ（７３８．２ｍｇ；実施例１０の合成中間体）、ＴＨＦ（２５ｍＬ）およびＮ－ブロモスクシンイミド（０．５０ｇ）の混合物を室温で終夜攪拌した。反応混合物を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、化合物ＩＩ（０．８６ｇ）を得た。 Step (i):
A mixture of Compound I (738.2 mg; synthesis intermediate of Example 10), THF (25 mL) and N-bromosuccinimide (0.50 g) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give Compound II (0.86 g).
工程（ｉｉ）：
　窒素雰囲気下の化合物ＩＩ（０．８６ｇ）、ＴＨＦ（１８ｍＬ）およびＰｄ（ｔ－Ｂｕ３Ｐ）２（０．１５ｇ）の混合物に、メチルジンククロリド－ヘキサン溶液（７ｍＬ、２．０Ｍ）を滴下した。室温で終夜攪拌後、反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩＩ（０．２０ｇ）を得た。 Step (ii):
To a mixture of Compound II (0.86 g), THF (18 mL) and Pd (t-Bu 3 P) 2 (0.15 g) under a nitrogen atmosphere, a methylzinc chloride-hexane solution (7 mL, 2.0 M) was added dropwise. did. After stirring at room temperature overnight, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound III (0.20 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（１０２．９ｍｇ）、エタノール（５ｍＬ）および２Ｍ水酸化リチウム水溶液（１．２ｍＬ）の混合物を５０℃で終夜攪拌した。反応混合物を減圧濃縮し、化合物ＩＶを得た。 Step (iii):
A mixture of Compound III (102.9 mg), ethanol (5 mL) and 2M aqueous lithium hydroxide (1.2 mL) was stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure to give compound IV.
工程（ｉｖ）：
　工程（ｉｉｉ）で得られた化合物ＩＶ、ＤＭＦ（５ｍＬ）、化合物Ｖ（７５ｍｇ）、ＷＳＣ・ＨＣｌ（０．１３ｇ）、ＨＯＢｔ・Ｈ２Ｏ（０．１３ｇ）およびトリエチルアミン（０．２５ｍＬ）の混合物を室温で終夜攪拌した。反応溶液に２Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。成績体を逆相系クロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ－水／０．０３５％ＴＦＡ－アセトニトリル＝８０／２０から５／９５）で精製し、表題化合物ＶＩ（１０７．０３ｍｇ）を得た。 Step (iv):
Compound IV, DMF (5 mL), Compound V (75 mg), WSC · HCl (0.13 g), HOBt · H 2 O (0.13 g) and triethylamine (0.25 mL) obtained in step (iii) Was stirred at room temperature overnight. To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1). The resulting product was purified by reverse phase chromatography (elution solvent: 0.05% TFA-water / 0.035% TFA-acetonitrile = 80/20 to 5/95) to give the title compound VI (107.03 mg). It was.
1H-NMR (CDCl3)δ 1.45 (s, 1H), 1.54-1.57 (m, 2H), 1.79-1.96 (m, 8H), 2.11 (s, 3H), 2.21-2.24 (m, 3H), 3.22(s, 3H), 3.60(s, 3H),4.21 (brs, 1H), 6.48 (m, 2H), 6.98 (m, 2H), 7.19 (brs, 1H) 1 H-NMR (CDCl 3 ) δ 1.45 (s, 1H), 1.54-1.57 (m, 2H), 1.79-1.96 (m, 8H), 2.11 (s, 3H), 2.21-2.24 (m, 3H), 3.22 (s, 3H), 3.60 (s, 3H), 4.21 (brs, 1H), 6.48 (m, 2H), 6.98 (m, 2H), 7.19 (brs, 1H)
実施例１３４：
　実施例１３３と同様の製造方法により実施例１３４を製造した。 Example 134:
Example 134 was produced by the same production method as in Example 133.
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
実施例１３５：Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１，４－ジメチル－５－［メチル（４－メチルフェニル）アミノ］－１Ｈ－ピラゾール－３－カルボキサミド Example 135: N-[(E) -5-hydroxyadamantan-2-yl] -1,4-dimethyl-5- [methyl (4-methylphenyl) amino] -1H-pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
工程（ｉ）：
　化合物Ｉ（３．５０ｇ）の無水プロピオン酸（１０．０ｇ）溶液を９０℃で終夜攪拌した。反応混合物にメタノール（３０ｍＬ）と２Ｍ水酸化ナトリウム水溶液（５０ｍＬ）を加えた後、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝３／１）で精製し、化合物ＩＩ（４．９８ｇ）を得た。 Step (i):
A solution of compound I (3.50 g) in propionic anhydride (10.0 g) was stirred at 90 ° C. overnight. Methanol (30 mL) and 2M aqueous sodium hydroxide solution (50 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give Compound II (4.98 g).
工程（ｉｉ）：
　氷冷したカリウム　ｔｅｒｔ－ブトキシド（６．８３ｇ）のＴＨＦ（１５０ｍＬ）溶液に、化合物ＩＩ（４．９８ｇ）およびシュウ酸ジエチル（８．３０ｇ）のＴＨＦ（５０ｍＬ）溶液を滴下した。滴下終了後、室温で終夜攪拌した。反応溶液に１．２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で順に洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮し、化合物ＩＩＩ（７．６２ｇ）を得た。 Step (ii):
A solution of compound II (4.98 g) and diethyl oxalate (8.30 g) in THF (50 mL) was added dropwise to a solution of ice-cooled potassium tert-butoxide (6.83 g) in THF (150 mL). After completion of dropping, the mixture was stirred overnight at room temperature. To the reaction solution was added 1.2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give compound III (7.62 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（７．６２ｇ）、ＴＨＦ（１３３ｍＬ）、ピリジン（７ｍＬ）、Ｎ－メチルヒドラジン（１．６ｍＬ）およびＬａｗｅｓｓｏｎ試薬（１２ｇ）の混合物を６０℃で終夜攪拌した。反応溶液に１．２Ｍ塩酸を加え、酢酸エチルで抽出し、飽和重曹水、飽和食塩水で順に洗浄した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＶ（３．５８ｇ）を得た。 Step (iii):
A mixture of Compound III (7.62 g), THF (133 mL), pyridine (7 mL), N-methylhydrazine (1.6 mL) and Lawesson's reagent (12 g) was stirred at 60 ° C. overnight. To the reaction solution was added 1.2 M hydrochloric acid, extracted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound IV (3.58 g).
工程（ｉｖ）：
　化合物ＩＶ（１０１ｍｇ）、エタノール（５ｍＬ）、２Ｍ水酸化リチウム水溶液（０．４ｍＬ）の混合物を５０℃で終夜攪拌した。反応混合物を減圧濃縮し、化合物Ｖを得た。 Step (iv):
A mixture of Compound IV (101 mg), ethanol (5 mL), 2M aqueous lithium hydroxide solution (0.4 mL) was stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure to obtain Compound V.
工程（ｖ）：
　工程（ｉｖ）で得られた化合物Ｖ、ＤＭＦ（５ｍＬ）、化合物ＶＩＩ（７５ｍｇ）、ＷＳＣ・ＨＣｌ（０．１３ｇ）、ＨＯＢｔ・Ｈ２Ｏ（０．１３ｇ）およびトリエチルアミン（０．２５ｍＬ）の混合物を、室温で終夜攪拌した。反応混合物に２Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。成績固体をジエチルエーテルで洗浄することにより、表題化合物ＶＩ（１０７ｍｇ）を得た。 Step (v):
Compound V, DMF (5 mL), Compound VII (75 mg), WSC · HCl (0.13 g), HOBt · H 2 O (0.13 g) and triethylamine (0.25 mL) obtained in step (iv) Was stirred at room temperature overnight. To the reaction mixture was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1). The resulting solid was washed with diethyl ether to give the title compound VI (107 mg).
1H-NMR (CDCl3)δ 1.42 (s, 1H), 1.54-1.58(m, 2H), 1.79-1.96 (m, 8H), 2.01 (s, 3H), 2.20-2.26 (m, 6H), 3.22 (s, 3H), 3.59 (s, 3H), 4.21 (brs, 1H), 6.46(m, 2H), 7.03 (m, 2H), 7.20 (brs, 1H) 1 H-NMR (CDCl 3 ) δ 1.42 (s, 1H), 1.54-1.58 (m, 2H), 1.79-1.96 (m, 8H), 2.01 (s, 3H), 2.20-2.26 (m, 6H), 3.22 (s, 3H), 3.59 (s, 3H), 4.21 (brs, 1H), 6.46 (m, 2H), 7.03 (m, 2H), 7.20 (brs, 1H)
実施例１３６：
　実施例１３５と同様の製造方法により実施例１３６を製造した。 Example 136:
Example 136 was manufactured by the same manufacturing method as Example 135.
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
実施例１３７：５－［（５－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１，４－ジメチル－１Ｈ－ピラゾール－３－カルボキサミド Example 137: 5-[(5-Fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1,4-dimethyl-1H-pyrazole-3 -Carboxamide
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　化合物Ｉ（６０．２ｍｇ；実施例４７）のＴＨＦ（４ｍＬ）溶液に、Ｎ－ブロモスクシンイミド（３２．２ｍｇ）を加え、室温で４時間攪拌した。この反応溶液に２Ｍメチルジンククロリド－ＴＨＦ溶液（０．５ｍＬ）を滴下し、ついでＰｄ（ｔＢｕ３Ｐ）２（２６．７ｍｇ）を加え、室温で終夜攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、残渣を逆相カラムクロマトグラフィーで精製（溶出溶媒：０．０５％ＴＦＡ水／０．０３５％ＴＦＡアセトニトリル＝８６／１４→５／９５）し、表題化合物ＩＩ（１６．５ｍｇ）を得た。 N-bromosuccinimide (32.2 mg) was added to a solution of compound I (60.2 mg; Example 47) in THF (4 mL), and the mixture was stirred at room temperature for 4 hours. It was added dropwise 2M methyl zinc chloride -THF solution (0.5 mL) to the reaction solution, followed by Pd a (t Bu 3 P) 2 ( 26.7mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (elution solvent: 0.05% TFA water / 0.035% TFA acetonitrile = 86/14 → 5/95) to give the title compound II (16. 5 mg) was obtained.
1H-NMR (CDCl3)δ 1.43 (s, 1H), 1.55-1.57 (m, 2H), 1.79-1.96 (m, 8H), 2.12 (s, 3H), 2.23 (m, 3H), 3.34 (s, 3H), 3.63 (s, 3H), 4.19 (brs, 1H), 6.14 (m, 1H), 7.19 (m, 2H), 8.10 (m, 1H) 1 H-NMR (CDCl 3 ) δ 1.43 (s, 1H), 1.55-1.57 (m, 2H), 1.79-1.96 (m, 8H), 2.12 (s, 3H), 2.23 (m, 3H), 3.34 ( s, 3H), 3.63 (s, 3H), 4.19 (brs, 1H), 6.14 (m, 1H), 7.19 (m, 2H), 8.10 (m, 1H)
実施例１３８：５－［（４，５－ジフルオロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド Example 138: 5-[(4,5-difluoro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3 -Carboxamide
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
工程（ｉ）：
　化合物Ｉ（４６４．８ｍｇ；実施例１１２の合成中間体）、スルホラン（５ｍＬ）、フッ化カリウム（１．７１ｇ）および１８－クラウン－６（０．８１ｇ）の混合物を１８０℃で終夜攪拌した。反応混合物に飽和重曹水を加え、酢酸エチルで抽出し、水、飽和食塩水の順に洗浄した。有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物Ｉと化合物ＩＩの混合物（８８．４ｍｇ）を得た。 Step (i):
A mixture of Compound I (464.8 mg; synthesis intermediate of Example 112), sulfolane (5 mL), potassium fluoride (1.71 g) and 18-crown-6 (0.81 g) was stirred at 180 ° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to obtain a mixture (88.4 mg) of Compound I and Compound II.
工程（ｉｉ）：
　工程（ｉ）で得られた化合物Ｉと化合物ＩＩの混合物（８８．４ｍｇ）、エタノール（１０ｍＬ）および２Ｍ水酸化ナトリウム水溶液（３ｍＬ）の混合物を室温で終夜攪拌した。反応混合物を濃縮し、１．２Ｍ塩酸を加え、酢酸エチルで抽出し化合物ＩＩＩ（８７．７ｍｇ）を得た。 Step (ii):
A mixture of compound I and compound II obtained in step (i) (88.4 mg), ethanol (10 mL) and 2M aqueous sodium hydroxide solution (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, 1.2 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate to obtain Compound III (87.7 mg).
工程（ｉｉｉ）：
　工程（ｉｉ）で得られた化合物ＩＩＩ（８７．７ｍｇ）、テトラヒドロフラン（１０ｍＬ）、化合物ＩＶ（７７ｍｇ）、２－クロロ－１－メチルピリジニウムアイオダイド（０．１５ｇ）およびトリエチルアミン（２ｍＬ）の混合物を室温で終夜攪拌した。減圧濃縮後、残渣に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製した。得られた固体を逆相クロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ水／０．０５％ＭｅＯＨ＝８７／１３から５／９５）で精製し、表題化合物Ｖ（４７．７ｍｇ）を得た。 Step (iii):
A mixture of compound III (87.7 mg), tetrahydrofuran (10 mL), compound IV (77 mg), 2-chloro-1-methylpyridinium iodide (0.15 g) and triethylamine (2 mL) obtained in step (ii) was obtained. Stir at room temperature overnight. After concentration under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1). The obtained solid was purified by reverse phase chromatography (elution solvent: 0.05% TFA water / 0.05% MeOH = 87/13 to 5/95) to give the title compound V (47.7 mg).
1H-NMR (CDCl3)δ 1.40-1.43 (m, 4H), 1.55-1.59 (m, 2H), 1.80-1.97 (m, 8H), 2.24 (m, 3H), 3.34 (s, 3H), 3.94 (m, 2H), 4.20 (brs, 1H), 6.08 (m, 1H), 6.64 (m, 1H), 7.18 (m, 1H), 8.13 (m, 1H) 1 H-NMR (CDCl 3 ) δ 1.40-1.43 (m, 4H), 1.55-1.59 (m, 2H), 1.80-1.97 (m, 8H), 2.24 (m, 3H), 3.34 (s, 3H), 3.94 (m, 2H), 4.20 (brs, 1H), 6.08 (m, 1H), 6.64 (m, 1H), 7.18 (m, 1H), 8.13 (m, 1H)
実施例１３９：
　実施例１３８と同様の製造方法により、実施例１３９を製造した。 Example 139:
Example 139 was produced by the same production method as in Example 138.
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
実施例１４０：５－［（５－クロロ－１，３－チアゾール－２－イル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド Example 140: 5-[(5-chloro-1,3-thiazol-2-yl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H -Pyrazole-3-carboxamide
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　化合物Ｉ（６０ｍｇ）のＴＨＦ（５ｍＬ）溶液に、Ｎ－クロロスクシンイミド（１６ｍｇ）を加え、室温で終夜攪拌した。反応溶液を減圧濃縮後、残渣を逆相カラムクロマトグラフィー（溶出溶媒：０．０５％ＴＦＡ－水／０．０３５％ＴＦＡ－アセトニトリル＝８２／１８から５／９５）で精製し、表題化合物ＩＩ（２５．１ｍｇ）を得た。 N-chlorosuccinimide (16 mg) was added to a THF (5 mL) solution of Compound I (60 mg), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (elution solvent: 0.05% TFA-water / 0.035% TFA-acetonitrile = 82/18 to 5/95) to give the title compound II ( 25.1 mg) was obtained.
1H-NMR (CDCl3) δ1.40 (s, 1H), 1.46 (m, 3H), 1.55-1.58 (m, 2H), 1.79-1.96 (m, 8H), 2.23 (m, 3H), 3.38 (s, 3H), 4.03 (m, 2H), 4.19 (brs, 1H), 6.74 (s, 1H), 7.05 (s, 1H), 7.16 (m, 1H) 1 H-NMR (CDCl 3 ) δ1.40 (s, 1H), 1.46 (m, 3H), 1.55-1.58 (m, 2H), 1.79-1.96 (m, 8H), 2.23 (m, 3H), 3.38 (s, 3H), 4.03 (m, 2H), 4.19 (brs, 1H), 6.74 (s, 1H), 7.05 (s, 1H), 7.16 (m, 1H)
実施例１４１：５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド Example 141: 5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole -3-Carboxamide
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
工程（ｉ）：
　氷冷した化合物Ｉ（２．５３ｇ；実施例１４３の化合物ＩＩ）のアセトニトリル（２５ｍＬ）溶液に、Ｓｅｌｅｃｔｆｌｕｏｒ（登録商標、アルドリッチ製品、４．０５ｇ）を加えた後、室温で２時間撹拌した。Ｓｅｌｅｃｔｆｌｕｏｒ（６５０ｍｇ）を室温で加え、３時間撹拌した。反応混合物をろ過し、ケーキを酢酸エチルで洗浄し、ろ液を減圧濃縮した。残渣に重曹水を加えて、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝４／１）で精製し、化合物ＩＩ（１．２６ｇ）を得た。 Step (i):
Selectfluor (registered trademark, Aldrich product, 4.05 g) was added to a solution of ice-cooled compound I (2.53 g; compound II of Example 143) in acetonitrile (25 mL), and the mixture was stirred at room temperature for 2 hours. Selectfluor (650 mg) was added at room temperature and stirred for 3 hours. The reaction mixture was filtered, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. Sodium bicarbonate water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 4/1) to give Compound II (1.26 g).
工程（ｉｉ）：
　化合物ＩＩ（１．２６ｇ）、メタノール（２０ｍＬ）、２０％パラジウム－カーボン（６００ｍｇ、４０％水分）の混合物を水素雰囲気下（４ａｔｍ）に室温で終夜撹拌した。反応混合物をセライトろ過し、ケーキをメタノールで洗浄した。ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／１）で精製し、化合物ＩＩＩ（６９８ｍｇ）を得た。 Step (ii):
A mixture of Compound II (1.26 g), methanol (20 mL) and 20% palladium-carbon (600 mg, 40% moisture) was stirred overnight at room temperature under a hydrogen atmosphere (4 atm). The reaction mixture was filtered through celite, and the cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1) to give Compound III (698 mg).
工程（ｉｉｉ）：
　化合物ＩＩＩ（４０２ｍｇ）、トルエン（６ｍＬ）、酢酸パラジウム（１２５ｍｇ）、ｒａｃ－ＢＩＮＡＰ（３４９ｍｇ）、炭酸セシウム（１．２１ｇ）および２，４－ジクロロピリジン（３０４ｍｇ）の混合物を１００℃で終夜撹拌した。反応混合物をセライトろ過し、ケーキを酢酸エチルで洗浄後、ろ液を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＶ（１７３ｍｇ）を得た。 Step (iii):
A mixture of Compound III (402 mg), toluene (6 mL), palladium acetate (125 mg), rac-BINAP (349 mg), cesium carbonate (1.21 g) and 2,4-dichloropyridine (304 mg) was stirred at 100 ° C. overnight. . The reaction mixture was filtered through Celite, the cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound IV (173 mg).
工程（ｉｖ）：
　化合物ＩＶ（１７３ｍｇ）、エタノール（５ｍＬ）および２Ｍ水酸化ナトリウム水溶液（０．５３ｍＬ）の混合物を室温で終夜撹拌した。反応混合物を減圧濃縮し、クエン酸水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、化合物Ｖ（１７１ｍｇ）をえた。 Step (iv):
A mixture of Compound IV (173 mg), ethanol (5 mL) and 2M aqueous sodium hydroxide (0.53 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, aqueous citric acid solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound V (171 mg).
工程（ｖ）：
　化合物Ｖ（１７１ｍｇ）、ＴＨＦ（１０ｍＬ）、１－クロロ－２－メチルピリジニウムヨージド（２０２ｍｇ）、化合物ＶＩ（３６ｍｇ）およびトリエチルアミン（７５μＬ）の混合物を、室温で終夜撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：クロロホルム／酢酸エチル＝１／１）で精製し、表題化合物ＶＩＩ（２１２ｍｇ）を得た。 Step (v):
A mixture of Compound V (171 mg), THF (10 mL), 1-chloro-2-methylpyridinium iodide (202 mg), Compound VI (36 mg) and triethylamine (75 μL) was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform / ethyl acetate = 1/1) to give the title compound VII (212 mg).
1H-NMR (CDCl3) δ 1.40 (t, 3H, J = 7.3 Hz), 1.56-1.59 (m, 3H), 1.81-1.84 (m, 6H), 1.93-1.96 (m, 2H), 2.20-2.25 (m, 3H), 3.39 (s, 3H), 3.92 (q, 2H, J = 7.3 Hz), 4.22-4.23 (m, 1H), 6.37 (d, 1H, J = 1.5 Hz), 6.79 (dd, 1H, J = 5.4, 1.7 Hz), 6.92 (d, 1H, J = 8.0 Hz), 8.13 (d, 1H, J = 5.4 Hz) 1 H-NMR (CDCl 3 ) δ 1.40 (t, 3H, J = 7.3 Hz), 1.56-1.59 (m, 3H), 1.81-1.84 (m, 6H), 1.93-1.96 (m, 2H), 2.20- 2.25 (m, 3H), 3.39 (s, 3H), 3.92 (q, 2H, J = 7.3 Hz), 4.22-4.23 (m, 1H), 6.37 (d, 1H, J = 1.5 Hz), 6.79 (dd , 1H, J = 5.4, 1.7 Hz), 6.92 (d, 1H, J = 8.0 Hz), 8.13 (d, 1H, J = 5.4 Hz)
実施例１４２：
　実施例１４１と同様の方法で実施例１４２を製造した。 Example 142:
Example 142 was produced in the same manner as in Example 141.
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
実施例１４３：１－エチル－５－［（４－フルオロフェニル）（メチル）アミノ］－Ｎ－［（２ｓ，５ｒ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド Example 143: 1-ethyl-5-[(4-fluorophenyl) (methyl) amino] -N-[(2s, 5r) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3 -Carboxamide
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
工程（ｉ）：
　化合物Ｉ（７０．２ｇ；参考例８の化合物ＩＩＩ）、エチルヒドラジン塩酸塩（５０．５ｇ）、ＴＨＦ（４００ｍＬ）の混合物にトリエチルアミン（８７．０ｇ）を室温にて滴下し、滴下終了後、室温にて終夜攪拌した。析出物をろ別し、ろ液にＬａｗｅｓｓｏｎ試薬（１２３．３５ｇ）およびピリジン（１００ｍＬ）を加え、６０℃にて９時間攪拌した。濃縮後、酢酸エチルを加え飽和重曹水、１．２Ｍ塩酸水の順に洗浄した。有機層を減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝２／１）で精製し、化合物ＩＩ（３５．４７ｇ）を得た。 Step (i):
Triethylamine (87.0 g) was added dropwise to a mixture of Compound I (70.2 g; Compound III of Reference Example 8), ethylhydrazine hydrochloride (50.5 g), and THF (400 mL) at room temperature. And stirred overnight. The precipitate was filtered off, Lawesson's reagent (123.35 g) and pyridine (100 mL) were added to the filtrate, and the mixture was stirred at 60 ° C. for 9 hours. After concentration, ethyl acetate was added and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and 1.2M aqueous hydrochloric acid. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give Compound II (35.47 g).
工程（ｉｉ）：
　化合物ＩＩ（３５．４７ｇ）、メタノール（３００ｍＬ）、２Ｍ水酸化ナトリウム水溶液（１５０ｍＬ）の混合物を５０℃で終夜撹拌した。濃縮後、１．２Ｍ塩酸水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、減圧濃縮し、化合物ＩＩＩ（２９．１２ｇ）を得た。 Step (ii):
A mixture of Compound II (35.47 g), methanol (300 mL), 2M aqueous sodium hydroxide solution (150 mL) was stirred at 50 ° C. overnight. After concentration, 1.2M aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain Compound III (29.12 g).
工程（ｉｉｉ）：
　化合物ＩＩＩ（５．０１ｇ）、ＤＭＦ（６４ｍＬ）、化合物ＩＶ（２．８８ｇ；参考例１４の化合物ＶＩＩ）、ＷＳＣ・ＨＣｌ（５．６０ｇ）、ＨＯＢｔ・Ｈ２Ｏ（５．２５ｇ）およびトリエチルアミン（３０ｍＬ）の混合物を室温で終夜攪拌した。反応溶液に２Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水の順で洗浄し、硫酸マグネシウムで乾燥した。減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／クロロホルム＝１／４）で精製し、化合物Ｖ（３．９１ｇ）を得た。 Step (iii):
Compound III (5.01 g), DMF (64 mL), Compound IV (2.88 g; Compound VII of Reference Example 14), WSC · HCl (5.60 g), HOBt · H 2 O (5.25 g) and triethylamine ( 30 mL) was stirred at room temperature overnight. To the reaction solution was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane / chloroform = 1/4) to obtain Compound V (3.91 g).
工程（ｉｖ）：
　化合物Ｖ（３．９１ｇ）、メタノール（４０ｍＬ）、ＴＨＦ（２０ｍＬ）、１０％パラジウム－カーボン（３．８８ｇ、５０％ウェット）の混合物を水素雰囲気下（３ａｔｍ）、室温で終夜撹拌した。反応混合物をセライト濾過し、化合物ＶＩ（３．１３ｇ）を得た。 Step (iv):
A mixture of Compound V (3.91 g), methanol (40 mL), THF (20 mL), 10% palladium-carbon (3.88 g, 50% wet) was stirred at room temperature overnight under a hydrogen atmosphere (3 atm). The reaction mixture was filtered through Celite to obtain Compound VI (3.13 g).
工程（ｖ）：
　化合物ＶＩ（１００ｍｇ）、トルエン（１．３ｍＬ）、４－フルオロブロモベンゼン（４３μＬ）、酢酸パラジウム（１２ｍｇ）、ＢＩＮＡＰ（３５ｍｇ）および炭酸セシウム（２５７ｍｇ）の混合物を、８０℃で終夜撹拌した。反応混合物をセライトろ過し、ろ液を減圧濃縮した。残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル＝１／４）で精製し、表題化合物ＶＩＩ（２８ｍｇ）を得た。 Step (v):
A mixture of Compound VI (100 mg), toluene (1.3 mL), 4-fluorobromobenzene (43 μL), palladium acetate (12 mg), BINAP (35 mg) and cesium carbonate (257 mg) was stirred at 80 ° C. overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/4) to give the title compound VII (28 mg).
1H-NMR (CDCl3) δ: 1.34 (t, 3H, J = 7.2 Hz), 1.66-1.69 (m, 2H), 1.99-2.02 (m, 2H), 2.10-2.25 (m, 7H), 2.35 (br s, 2H), 2.78 (s, 3H), 3.22 (s, 3H), 3.87 (q, 2H, J = 7.2 Hz), 4.23 (d, 1H, J = 7.2 Hz), 6.58-6.63 (m, 3H), 6.91-6.96 (m, 2H), 7.21 (d, 1H, J = 7.6 Hz) 1 H-NMR (CDCl 3 ) δ: 1.34 (t, 3H, J = 7.2 Hz), 1.66-1.69 (m, 2H), 1.99-2.02 (m, 2H), 2.10-2.25 (m, 7H), 2.35 (br s, 2H), 2.78 (s, 3H), 3.22 (s, 3H), 3.87 (q, 2H, J = 7.2 Hz), 4.23 (d, 1H, J = 7.2 Hz), 6.58-6.63 (m , 3H), 6.91-6.96 (m, 2H), 7.21 (d, 1H, J = 7.6 Hz)
実施例１４４～１５５：
　実施例１４３と同様の方法で実施例１４４から実施例１５５を製造した。 Examples 144-155:
In the same manner as in Example 143, Examples 144 to 155 were manufactured.
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-I000115
Figure JPOXMLDOC01-appb-I000116
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-I000115
Figure JPOXMLDOC01-appb-I000116
　上記実施例化合物に加えて、下記表に例示される化合物１～５１も本発明に包含される。 In addition to the above example compounds, compounds 1 to 51 exemplified in the following table are also included in the present invention.
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
試験例１：培養ヒト脂肪細胞のコルチゾン還元活性に対する阻害活性試験
　４８穴細胞培養プレートに正常ヒト前駆脂肪細胞（ＨＰｒＡＤ－ｖｉｓ、Ｃａｍｂｒｅｘ社製）を播種し、キット添付のプロトコールに従って分化誘導を行った。分化誘導９－１１日目の細胞の培地を、１００ｎＭ　［１，２－３Ｈ］コルチゾン（１μＣｉ／ウェル、室町薬品社製）、０．５％　ＤＭＳＯ、被検化合物（被験物質添加区、被験物質無添加区についてはＤＭＳＯのみ）を含む０．２ｍｌのＤ－ＭＥＭ培地（ギブコ社製）に交換した。３７℃で３時間培養後、培地を全量回収した。バックグラウンド区として、細胞に添加していない培地を使用した。培地をエッペンドルフチューブ中で０．１ｍｌの酢酸エチルと混合した。この混合液をボルテックス後、５，０００ｒｐｍ×１分、室温にて遠心分離することにより、酢酸エチル（上層）を分離した。酢酸エチル１０μｌを薄層クロマトグラフィー用アルミプレート（シリカゲル６０オングストローム、メルク社；以下、「ＴＬＣプレート」とも称する）上にスポットした。密閉容器にクロロホルム／メタノール（９０：１０、ｖ／ｖ）の展開溶媒を入れてＴＬＣプレートを展開した後、ＴＬＣプレートを室温で乾燥した。乾燥されたＴＬＣプレートにイメージングプレート（ＴＲ－２０４０、富士フィルム社）を１６時間以上露光させた。露光終了後、イメージングプレートをバイオイメージアナライザー（ＢＡＳ２５００、富士フィルム社）で分析し、ＴＬＣプレート上のコルチゾールの展開位置に相当する部分の［３Ｈ］放射活性を測定した。被験物質のコルチゾン還元活性阻害活性を以下のように算出した。
　（阻害活性（％））＝１００×（（被験物質無添加区）－（被験物質添加区））／（（被験物質無添加区）－（バックグラウンド区）） Test example 1: Inhibitory activity test on cortisone reducing activity of cultured human adipocytes Normal human preadipocytes (HPrAD-vis, manufactured by Cambrex) were seeded on a 48-well cell culture plate, and differentiation was induced according to the protocol attached to the kit. . Cell culture medium on differentiation induction day 9-11 is 100 nM [1,2-3H] cortisone (1 μCi / well, manufactured by Muromachi Yakuhin), 0.5% DMSO, test compound (test substance addition group, test substance) In the non-added section, the medium was replaced with 0.2 ml of D-MEM medium (Gibco) containing only DMSO. After culturing at 37 ° C. for 3 hours, the whole medium was recovered. As a background section, a medium not added to the cells was used. The medium was mixed with 0.1 ml of ethyl acetate in an Eppendorf tube. The mixture was vortexed and centrifuged at 5,000 rpm for 1 minute at room temperature to separate ethyl acetate (upper layer). 10 μl of ethyl acetate was spotted on an aluminum plate for thin layer chromatography (silica gel 60 Å, Merck; hereinafter also referred to as “TLC plate”). A TLC plate was developed by putting a developing solvent of chloroform / methanol (90:10, v / v) in a sealed container, and then the TLC plate was dried at room temperature. The dried TLC plate was exposed to an imaging plate (TR-2040, Fuji Film) for at least 16 hours. After completion of the exposure, the imaging plate was analyzed with a bioimage analyzer (BAS 2500, Fuji Film Co., Ltd.), and [3H] radioactivity in a portion corresponding to the development position of cortisol on the TLC plate was measured. The cortisone reduction activity inhibitory activity of the test substance was calculated as follows.
(Inhibitory activity (%)) = 100 × ((No test substance added group) − (Test substance added group)) / ((Test substance non-added group) − (Background group))
　ＩＣ５０値は、阻害活性が５０％付近の値を示す２点のデータを用い、検体濃度の対数値と阻害活性値を一次回帰させることにより算出した。本発明化合物のヒト脂肪細胞コルチゾン還元活性に対するＩＣ５０値は、通常０．０１－１０００ｎＭの範囲に存在する。下記の本発明化合物のヒト脂肪細胞コルチゾン還元活性に対するＩＣ５０値を測定した。
　その結果を表１９に示す。 The IC 50 value was calculated by linearly regressing the logarithmic value of the analyte concentration and the inhibitory activity value using two points of data showing the inhibitory activity around 50%. The IC 50 value for human adipocyte cortisone reducing activity of the compound of the present invention is usually in the range of 0.01 to 1000 nM. The IC 50 value for human adipocyte cortisone reduction activity of the following compounds of the present invention was measured.
The results are shown in Table 19.
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
　表１９の試験結果より、本化合物群は標的臓器であるヒト脂肪細胞において１１βＨＳＤ１活性を阻害し、コルチゾール産生を抑制することが期待される。 From the test results in Table 19, it is expected that this compound group inhibits 11βHSD1 activity and suppresses cortisol production in human adipocytes, which are target organs.
試験例２：マウス脂肪初代培養細胞のコルチゾン還元活性に対する阻害活性試験
　９～１１週齢のＩＣＲ系雄マウス（日本エスエルシー社）１０匹分の腸間膜および睾丸周囲に付着した脂肪組織（以下、「内臓脂肪組織」と記す。）を、リン酸緩衝液（０．２０ｇ／Ｌ　ＫＣｌ、０．２０ｇ／Ｌ　ＫＨ２ＰＯ４、８．００ｇ／Ｌ　ＮａＣｌ、２．１６ｇ／Ｌ　Ｎａ２ＨＰＯ４・７Ｈ２Ｏ、１００ユニット／ｍｌペニシリン（ギブコ社）、１００μｇ／ｍｌストレプトマイシン（ギブコ社）、２５０ｎｇ／ｍｌアンフォテリシン（ギブコ社））約１００ｍｌに浸し、室温で洗浄した。
　上記で摘出された内臓脂肪組識を、コラゲナーゼ（タイプＩＩ、シグマ社）、ペニシリン（ギブコ社）、ストレプトマイシン（ギブコ社）及びアンフォテリシン（ギブコ社）をそれぞれ終濃度１ｍｇ／ｍｌ、１００ユニット／ｍｌ、１００μｇ／ｍｌ及び２５０ｎｇ／ｍｌとなるように添加したダルベッコ改変イーグル培地（４．５ｇ／Ｌ　Ｄ－グルコース及び５８４ｍｇ／Ｌ　Ｌ－グルタミン含有、ギブコ社）約５０ｍｌ中でハサミを用いて約５ｍｍ角に細断した。次いで、これを３７℃で３０分間振とう（約１７０ｒｐｍ）し、ナイロンメッシュ（８０Ｓ［目の大きさが２５０μｍ］、三紳工業社）で濾過し、濾液（細胞懸濁液）を回収した。当該濾液を室温で１８００ｒｐｍ、５分間遠心分離した後、液層をデカンテーションにより静かに除去し、沈査を得た。この沈査を、ウシ胎児血清（以下、「ＦＢＳ」と記す。）（ギブコ社）、アスコルビン酸（和光純薬工業社）、ペニシリン（ギブコ社）、ストレプトマイシン（ギブコ社）及びアンフォテリシン（ギブコ社）をそれぞれ終濃度１０％、２００μＭ、１００ユニット／ｍｌ、１００μｇ／ｍｌ及び２５０ｎｇ／ｍｌとなるように添加したダルベッコ改変イーグル培地（４．５ｇ／Ｌ　Ｄ－グルコース及び５８４ｍｇ／Ｌ　Ｌ－グルタミン含有、ギブコ社、以下、「ＦＢＳ含有培地」と記すこともある。）３０ｍｌに懸濁し、懸濁液をナイロンメッシュ（４２０Ｓ［目の大きさが２５μｍ］、三紳工業社）で濾過した。濾液を回収し、室温で１８００ｒｐｍ、５分間遠心分離した後、液層をデカンテーションにより静かに除去し、沈査を再度ＦＢＳ含有培地３０ｍｌに懸濁した。当該懸濁液について、遠心分離、液層除去、ＦＢＳ含有培地に懸濁するという操作を更に２回、前記と同様に行い、懸濁液９０ｍｌを調製した。当該懸濁液を細胞培養用フラスコ（接着細胞用Ｔ１５０、岩城硝子社）に３０ｍｌずつ分注し、３７℃、５％ＣＯ２存在下で培養した。培養開始５～６時間後に培地を除き、フラスコの器壁を１５ｍｌの前記リン酸緩衝液で洗浄した。洗液を除き、当該洗浄操作を再度行った後、リン酸緩衝液を除き、３０ｍｌのＦＢＳ含有培地をフラスコに添加し、３７℃、５％ＣＯ２存在下で培養した。培養開始１日あるいは２日後に培地を除き、１５ｍｌのリン酸緩衝液でフラスコの器壁を１回洗浄した後、当該フラスコにトリプシン－エチレンジアミン四酢酸（以下、「トリプシン－ＥＤＴＡ」と記す。）溶液（０．０５％トリプシン、０．５３ｍＭ　ＥＤＴＡ・４Ｎａ、ギブコ社）を細胞が浸る程度に添加し、３７℃で５分放置した。これに、ＦＢＳ含有培地をトリプシン－ＥＤＴＡ溶液の約１０倍量添加し、細胞懸濁液を得た。 Test Example 2: Inhibitory activity test for cortisone reducing activity of primary cultured mouse fat cells Adipose tissue adhering to the mesentery and testicles of 10 ICR male mice (Japan SLC) 9-11 weeks old , Referred to as “visceral adipose tissue”) is phosphate buffer (0.20 g / L KCl, 0.20 g / L KH 2 PO 4 , 8.00 g / L NaCl, 2.16 g / L Na 2 HPO 4). 7H 2 O, 100 units / ml penicillin (Gibco), 100 μg / ml streptomycin (Gibco), 250 ng / ml amphotericin (Gibco)) was immersed in about 100 ml and washed at room temperature.
Visceral fat tissues extracted above were collagenase (type II, Sigma), penicillin (Gibco), streptomycin (Gibco) and amphotericin (Gibco), respectively, at final concentrations of 1 mg / ml, 100 units / ml, Dulbecco's modified Eagle's medium (containing 4.5 g / L D-glucose and 584 mg / L L-glutamine, Gibco) added to 100 μg / ml and 250 ng / ml to about 5 mm square using scissors Shredded. Next, this was shaken at 37 ° C. for 30 minutes (about 170 rpm), filtered through a nylon mesh (80S [eye size is 250 μm], Sangen Industrial Co., Ltd.), and the filtrate (cell suspension) was recovered. The filtrate was centrifuged at 1800 rpm for 5 minutes at room temperature, and then the liquid layer was gently removed by decantation to obtain a precipitate. This sedimentation was determined using fetal bovine serum (hereinafter referred to as “FBS”) (Gibco), ascorbic acid (Wako Pure Chemical Industries), penicillin (Gibco), streptomycin (Gibco) and amphotericin (Gibco). Dulbecco's modified Eagle's medium (containing 4.5 g / L D-glucose and 584 mg / L L-glutamine, Gibco) added to final concentrations of 10%, 200 μM, 100 units / ml, 100 μg / ml and 250 ng / ml, respectively. Hereinafter, it may be referred to as “FBS-containing medium”.) The suspension was suspended in 30 ml, and the suspension was filtered through a nylon mesh (420S [eye size is 25 μm], Sangen Industrial Co., Ltd.). The filtrate was collected, centrifuged at 1800 rpm for 5 minutes at room temperature, the liquid layer was gently removed by decantation, and the sediment was suspended again in 30 ml of FBS-containing medium. The suspension was centrifuged, liquid layer removed, and suspended in an FBS-containing medium two more times in the same manner as described above to prepare 90 ml of the suspension. 30 ml of the suspension was dispensed into a cell culture flask (T150 for adherent cells, Iwaki Glass Co., Ltd.) and cultured in the presence of 37 ° C. and 5% CO 2 . After 5 to 6 hours from the start of the culture, the medium was removed, and the wall of the flask was washed with 15 ml of the phosphate buffer. After removing the washing solution and performing the washing operation again, the phosphate buffer solution was removed, 30 ml of FBS-containing medium was added to the flask, and cultured in the presence of 37 ° C. and 5% CO 2 . One or two days after the start of the culture, the medium was removed, and the wall of the flask was washed once with 15 ml of phosphate buffer, and then trypsin-ethylenediaminetetraacetic acid (hereinafter referred to as “trypsin-EDTA”) in the flask. A solution (0.05% trypsin, 0.53 mM EDTA · 4Na, Gibco) was added to such an extent that the cells were immersed, and left at 37 ° C. for 5 minutes. To this, about 10 times the amount of trypsin-EDTA solution was added to the FBS-containing medium to obtain a cell suspension.
　細胞懸濁液中の細胞数を血球計算盤を用いて測定し、１．４×１０５細胞／ｍｌになるようにＦＢＳ含有培地を加えることにより当該細胞懸濁液を希釈した。このようにして得られた希釈液を４８穴プレート（接着細胞培養用、岩城硝子社）に１ウェルあたり３００μｌずつ分注し、５％ＣＯ２存在下、３７℃にて１～２日間培養した。４８穴プレートの各ウェルから培地を除き、１０μｇ／ｍｌインスリン（シグマ社）、０．２５μＭデキサメサゾン（和光純薬工業社）、０．５ｍＭ　３－イソブチル－１－メチル－キサンチン（シグマ社）及び５μＭ　１５－デオキシ－Δ１２，１４－プロスタグランジンＪ２（Ｃａｙｍａｎ社）を含むＦＢＳ含有培地３００μｌを各ウェルに添加して５％ＣＯ２存在下、３７℃にて３日間培養した。次いで、各ウェルの培地を除き、１０μｇ／ｍｌインスリン及び５μＭ　１５－デオキシ－Δ１２，１４－プロスタグランジンＪ２を含むＦＢＳ含有培地３００μｌを各ウェルに添加し、２日間培養した。更に各ウェルの培地を除き、１０μｇ／ｍｌインスリン及び５μＭ　１５－デオキシ－Δ１２，１４－プロスタグランジンＪ２を含むＦＢＳ含有培地３００μｌを各ウェルに添加し、２日間培養した。 The number of cells in the cell suspension was measured using a hemocytometer, and the cell suspension was diluted by adding an FBS-containing medium to 1.4 × 10 5 cells / ml. The diluted solution thus obtained was dispensed into a 48-well plate (for adherent cell culture, Iwaki Glass Co., Ltd.) at 300 μl per well and cultured at 37 ° C. for 1 to 2 days in the presence of 5% CO 2 . . The medium was removed from each well of the 48-well plate, 10 μg / ml insulin (Sigma), 0.25 μM dexamethasone (Wako Pure Chemical Industries), 0.5 mM 3-isobutyl-1-methyl-xanthine (Sigma) and 5 μM 300 μl of FBS-containing medium containing 15-deoxy-Δ12,14-prostaglandin J2 (Cayman) was added to each well and cultured at 37 ° C. for 3 days in the presence of 5% CO 2 . Next, the medium in each well was removed, and 300 μl of FBS-containing medium containing 10 μg / ml insulin and 5 μM 15-deoxy-Δ12,14-prostaglandin J2 was added to each well and cultured for 2 days. Further, the medium in each well was removed, and 300 μl of FBS-containing medium containing 10 μg / ml insulin and 5 μM 15-deoxy-Δ12,14-prostaglandin J2 was added to each well and cultured for 2 days.
　上記のとおり分化誘導を行った脂肪細胞の培地を、１００ｎＭ　［１，２－３Ｈ］コルチゾン（１μＣｉ／ウェル、室町薬品社）、０．５％　ＤＭＳＯ、被検化合物（被験物質添加区、被験物質無添加区についてはＤＭＳＯのみ）を含む０．２ｍｌのＤ－ＭＥＭ培地（ギブコ社）に交換した。３７℃で３時間培養後、培地を全量回収した。バックグラウンド区として、細胞に添加していない培地を使用した。培地をエッペンドルフチューブ中で０．１ｍｌの酢酸エチルと混合した。この混合液をボルテックス後、５，０００ｒｐｍ×１分、室温にて遠心分離することにより、酢酸エチル（上層）を分離した。酢酸エチル１０μｌを薄層クロマトグラフィー用アルミプレート（シリカゲル６０オングストローム、メルク社；以下、「ＴＬＣプレート」とも称する）上にスポットした。密閉容器にクロロホルム／メタノール（９０：１０、ｖ／ｖ）の展開溶媒を入れてＴＬＣプレートを展開した後、ＴＬＣプレートを室温で乾燥した。乾燥されたＴＬＣプレートにイメージングプレート（ＴＲ－２０４０、富士フィルム社）を１６時間以上露光させた。露光終了後、イメージングプレートをバイオイメージアナライザー（ＢＡＳ２５００、富士フィルム社）で分析し、ＴＬＣプレート上のコルチゾールの展開位置に相当する部分の［３Ｈ］放射活性を測定した。被験物質のコルチゾン還元活性阻害活性を以下のように算出した。
　（阻害活性（％））＝１００×（（被験物質無添加区）－（被験物質添加区））／（（被験物質無添加区）－（バックグラウンド区）） The adipocyte culture medium in which differentiation was induced as described above was prepared using 100 nM [1,2-3H] cortisone (1 μCi / well, Muromachi Pharmaceutical), 0.5% DMSO, test compound (test substance addition group, test substance) The medium was replaced with 0.2 ml of D-MEM medium (Gibco) containing DMSO for the additive-free group. After culturing at 37 ° C. for 3 hours, the whole medium was recovered. As a background section, a medium not added to the cells was used. The medium was mixed with 0.1 ml of ethyl acetate in an Eppendorf tube. The mixture was vortexed and centrifuged at 5,000 rpm for 1 minute at room temperature to separate ethyl acetate (upper layer). 10 μl of ethyl acetate was spotted on an aluminum plate for thin layer chromatography (silica gel 60 Å, Merck; hereinafter also referred to as “TLC plate”). A TLC plate was developed by putting a developing solvent of chloroform / methanol (90:10, v / v) in a sealed container, and then the TLC plate was dried at room temperature. The dried TLC plate was exposed to an imaging plate (TR-2040, Fuji Film) for at least 16 hours. After completion of the exposure, the imaging plate was analyzed with a bioimage analyzer (BAS 2500, Fuji Film Co., Ltd.), and [3H] radioactivity in a portion corresponding to the development position of cortisol on the TLC plate was measured. The cortisone reduction activity inhibitory activity of the test substance was calculated as follows.
(Inhibitory activity (%)) = 100 × ((No test substance added group) − (Test substance added group)) / ((Test substance non-added group) − (Background group))
　ＩＣ５０値は、阻害活性が５０％付近の値を示す２点のデータを用い、検体濃度の対数値と阻害活性値を一次回帰させることにより算出した。本発明化合物のマウス脂肪細胞コルチゾン還元活性に対するＩＣ５０値は、通常０．０１－１０００ｎＭの範囲に存在する。下記の本発明化合物のマウス脂肪細胞コルチゾン還元活性に対するＩＣ５０値を測定した。その結果を表２０に示す。 The IC 50 value was calculated by linearly regressing the logarithmic value of the analyte concentration and the inhibitory activity value using two points of data showing the inhibitory activity around 50%. The IC 50 value for mouse adipocyte cortisone reducing activity of the compound of the present invention is usually in the range of 0.01 to 1000 nM. IC 50 values for mouse adipocyte cortisone reduction activity of the following compounds of the present invention were measured. The results are shown in Table 20.
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
試験例３：糖尿病／肥満モデルマウスへの１１βＨＳＤ１阻害剤の投与
　実施例記載の方法で得ることができる１１βＨＳＤ１阻害剤の糖尿病／肥満モデルマウスに対する薬理評価は、以下の方法により行うことができる。
　Ｃ５７ＢＬ／６Ｊマウス（日本クレア社）に高脂肪食（Ｄ－１２４９２、リサーチダイエット社）を２週間から８ヶ月間負荷すると、高血糖、高インスリン、耐糖能異常、および肥満が誘導される。このようにして作製した糖尿病／肥満モデルマウスに対して、１ｋｇ体重あたり０．１－１００ｍｇの１１βＨＳＤ１阻害剤を、０．５％メチルセルロース♯４００溶液（ナカライテスク社製）を溶媒として、１日１回あるいは２回経口ゾンデを用いて投与する。投与１－８週間後に被験マウスの静脈血を採取し、血清あるいは血漿中に含まれる糖、インスリンの濃度を測定する。経口糖負荷試験を実施する際には、１８時間以上絶食したマウスに２０－３０％グルコース溶液を１ｋｇ体重あたり１０ｍＬの用量で経口投与し、投与１５分から３時間まで経時的に尾静脈から採血する。血液中に含まれる糖、インスリン濃度の経時変化から、曲線下面積値（ＡＵＣ）を計算する。対照群として、前記１１βＨＳＤ１阻害剤を含むメチルセルロース溶液の代わりにメチルセルロース溶液のみを投与した群についても同様な試験を行う。供試化合物投与群における血糖値、インスリン値、ＡＵＣ値が、対照群と比較して統計学的に有意に低いことを確認することによって、当該供試化合物が糖尿病改善作用、インスリン抵抗性改善作用を有することが判定できる。 Test Example 3 Administration of 11βHSD1 Inhibitor to Diabetes / Obesity Model Mice Pharmacological evaluation of 11βHSD1 inhibitor obtainable by the method described in the Examples on diabetes / obesity model mice can be performed by the following method.
When C57BL / 6J mice (CLEA Japan) are loaded with a high fat diet (D-12492, Research Diet) for 2 weeks to 8 months, hyperglycemia, high insulin, impaired glucose tolerance, and obesity are induced. Diabetes / obesity model mice prepared in this manner were treated with 0.1-100 mg / kg body weight of 11βHSD1 inhibitor and 0.5% methylcellulose # 400 solution (manufactured by Nacalai Tesque) as a solvent once a day. Administer once or twice using an oral sonde. One to eight weeks after administration, venous blood is collected from the test mouse, and the concentrations of sugar and insulin contained in the serum or plasma are measured. When conducting an oral glucose tolerance test, mice fasted for 18 hours or more are orally administered with a 20-30% glucose solution at a dose of 10 mL per kg body weight, and blood is collected from the tail vein over time from 15 minutes to 3 hours after administration. . The area under the curve (AUC) is calculated from changes over time in the sugar and insulin concentrations contained in the blood. As a control group, the same test is performed for a group administered with only the methylcellulose solution instead of the methylcellulose solution containing the 11βHSD1 inhibitor. By confirming that the blood glucose level, insulin level, and AUC level in the test compound administration group are statistically significantly lower than those in the control group, the test compound improves diabetes and improves insulin resistance. Can be determined.
　また、投与期間中の被験マウスの体重を測定し、供試化合物投与群における体重が、対照群と比較して統計学的に有意に低いことを確認することによって、当該供試化合物が抗肥満作用を有することが判定できる。
　さらに、投与終了後の被験マウスの内臓脂肪、具体的には腸間膜脂肪、副睾丸周囲脂肪および後腹膜脂肪の重量を測定する。供試化合物投与群における各脂肪重量が、対照群と比較して統計学的に有意に低いことを確認することによって、当該供試化合物が内臓脂肪蓄積抑制作用、または内臓脂肪減少作用を有することが判定できる。 In addition, by measuring the body weight of the test mice during the administration period and confirming that the body weight in the test compound administration group is statistically significantly lower than that in the control group, the test compound is anti-obesity It can be determined that it has an action.
Furthermore, the weights of the visceral fat, specifically mesenteric fat, epididymal fat and retroperitoneal fat of the test mice after the administration are measured. By confirming that each fat weight in the test compound administration group is statistically significantly lower than that in the control group, the test compound has a visceral fat accumulation-inhibiting action or a visceral fat reducing action. Can be determined.
試験例４：マウス尾懸垂試験
　１１βＨＳＤ１阻害剤の抗うつ作用に対する薬理評価は、以下の方法により行うことができる。
　２５－３５ｇの雄性Ｃｒｌｊ：ＣＤ１（ＩＣＲ）マウス（日本チャールズリバー）を用いた尾懸垂試験において、マウスの尾を吊り下げ、逆さ釣り状態における６分間の逃避行動（もがき反応）時間を測定する。
　逃避行動の減少は、行動的絶望状態を意味しており、うつ症状と類似している。そこで本発明化合物を試験前に単回あるいは複数回投与し、試験中の逃避行動時間を測定することにより抗うつ作用（うつ病、躁うつ病）を評価する。 Test Example 4: Mouse tail suspension test The pharmacological evaluation of the 11βHSD1 inhibitor against the antidepressant action can be performed by the following method.
In a tail suspension test using 25-35 g male Crlj: CD1 (ICR) mice (Charles River Japan), the mouse's tail is suspended and the escape behavior (postcard reaction) time for 6 minutes in the inverted fishing state is measured.
A decrease in escape behavior implies behavioral despair and is similar to depressive symptoms. Therefore, the compound of the present invention is administered once or multiple times before the test, and the antidepressant action (depression, manic depression) is evaluated by measuring the escape behavior time during the test.
試験例５：マウス物体認識試験における認知機能増強作用
　１３－１５ｇのＳｌｃ：ｄｄＹマウス（雄性、日本エスエルシー）を用いた新奇物体認識試験において、第一試行（トレーニング）と第二試行（テスト）の間隔時間依存的に、既知物体に対する記憶低下が認められ、２４時間後に第二試行を行った場合、顕著な忘却が認められる。そこで本発明化合物を第一試行前に投与し、第二試行における記憶増強作用を評価する。 Test Example 5: Cognitive function enhancing action in mouse object recognition test First trial (training) and second trial (test) in a novel object recognition test using 13-15 g of Slc: ddY mice (male, SLC Japan) Depending on the interval time, a decrease in memory for a known object is observed, and when the second trial is performed 24 hours later, significant forgetting is observed. Therefore, the compound of the present invention is administered before the first trial, and the memory enhancing action in the second trial is evaluated.
　本発明化合物は、１１βＨＳＤ１阻害薬として有用である。 The compound of the present invention is useful as an 11βHSD1 inhibitor.

Claims (29)

  1. 　式（１）で表される化合物、またはその薬理学上許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    　Ｒ１は、置換されていてもよいＣ６－１０アリール基、または置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基であり；
    　Ｒ２は、置換されていてもよいＣ１－６アルキル基、置換されていてもよいＣ３－７シクロアルキル基、または置換されていてもよい複素環基であり；
    　Ｒ３は水素原子、ハロゲン原子、シアノ基、または置換されていてもよいＣ１－６アルキル基であり；
    　Ｒ４は、置換されていてもよいＣ１－６アルキル基、または置換されていてもよいＣ３－７シクロアルキル基であり；および
    　Ｒ５は、水酸基、アミノカルボニル基、フッ素原子またはメチルスルホニル基である。］     A compound represented by formula (1) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    R 1 is an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group;
    R 2 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, or an optionally substituted heterocyclic group;
    R 3 is a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group;
    R 4 is an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-7 cycloalkyl group; and R 5 is a hydroxyl group, an aminocarbonyl group, a fluorine atom or methylsulfonyl It is a group. ]
  2. 　Ｒ１における置換されていてもよいＣ６－１０アリール基、および置換されていてもよい５員～１２員の単環式もしくは多環式ヘテロアリール基の置換基が、
    （１）重水素原子、
    （２）ハロゲン原子、
    （３）水酸基、
    （４）シアノ基、
    （５）複素環基、
    （６）Ｃ３－７シクロアルキル基、
    （７）Ｃ３－７シクロアルキルオキシ基、
    （８）Ｃ１－４アルキル基（該アルキル基は、
    　（ａ）１～３個のハロゲン原子、
    　（ｂ）ヒドロキシ、
    　（ｃ）Ｃ３－６シクロアルキルオキシ、
    　（ｄ）Ｃ１－４アルコキシ（該アルコキシは、
    　　　　１～３個のハロゲン原子、
    　　　　Ｃ１－４アルコキシ、または
    　　　　ヒドロキシで置換されていてもよい。）、
    　（ｅ）Ｃ３－６シクロアルキル、
    　（ｆ）アミノ（該アミノは、Ｃ１－６アルキル、およびＣ３－６シクロアルキルからなる群から選択される同種または異種の１～２個の基で置換されていてもよい。）、または
    　（ｇ）４員～７員の環状アミノで置換されていてもよい。）、
    （９）Ｃ１－４アルコキシ基（該アルコキシ基は、
    　（ａ）１～３個のハロゲン原子、
    　（ｂ）ヒドロキシ、
    　（ｃ）Ｃ１－４アルコキシ、
    　（ｄ）Ｃ３－６シクロアルキルオキシ、または
    　（ｅ）Ｃ３－６シクロアルキルで置換されていてもよい。）、
    （１０）Ｃ１－６アルキルカルボニル基（該アルキルは、
    　（ａ）ヒドロキシ、
    　（ｂ）１～３個のハロゲン原子、
    　（ｃ）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
    　（ｄ）Ｃ３－６シクロアルコキシ、または
    　（ｅ）Ｃ３－６シクロアルキルで置換されていてもよい。）、
    （１１）Ｃ３－６シクロアルキルカルボニル基（該シクロアルキルは、
    　（ａ）ヒドロキシ、
    　（ｂ）１～３個のハロゲン原子、
    　（ｃ）Ｃ１－４アルコキシ（該アルコキシは、１～３個のハロゲン原子で置換されていてもよい。）、
    　（ｄ）Ｃ３－６シクロアルコキシ、
    　（ｅ）Ｃ１－４アルキル、または
    　（ｆ）Ｃ３－６シクロアルキルで置換されていてもよい。）、
    （１２）Ｃ６－１０アリール基（該アリール基は、
    　（ａ）ハロゲン原子、
    　（ｂ）Ｃ１－４アルコキシ、
    　（ｃ）Ｃ３－７シクロアルキル、または
    　（ｄ）Ｃ１－４アルキルで置換されていてもよい。）、
    （１３）５員～１２員の単環式もしくは多環式のヘテロアリール基（該へテロアリール基は、
    　（ａ）ハロゲン原子、
    　（ｂ）Ｃ１－４アルキル（該アルキルは、１～３個のハロゲン原子で置換されていてもよい。）、または
    　（ｃ）Ｃ３－６シクロアルキルで置換されていてもよい。）、および
    （１４）Ｃ１－４アルキルスルホニル基
    からなる群から選択される基である、請求項１に記載の化合物、またはその薬理学上許容される塩。     The optionally substituted C 6-10 aryl group in R 1 and the optionally substituted 5- to 12-membered monocyclic or polycyclic heteroaryl group substituent are
    (1) deuterium atom,
    (2) a halogen atom,
    (3) hydroxyl group,
    (4) a cyano group,
    (5) a heterocyclic group,
    (6) a C 3-7 cycloalkyl group,
    (7) C 3-7 cycloalkyloxy group,
    (8) C 1-4 alkyl group (the alkyl group is
    (A) 1 to 3 halogen atoms,
    (B) hydroxy,
    (C) C 3-6 cycloalkyloxy,
    (D) C 1-4 alkoxy (the alkoxy is
    1 to 3 halogen atoms,
    It may be substituted with C 1-4 alkoxy or hydroxy. ),
    (E) C 3-6 cycloalkyl,
    (F) amino (the amino may be substituted with 1 to 2 groups of the same or different types selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl), or (G) It may be substituted with a 4- to 7-membered cyclic amino. ),
    (9) C 1-4 alkoxy group (the alkoxy group is
    (A) 1 to 3 halogen atoms,
    (B) hydroxy,
    (C) C 1-4 alkoxy,
    (D) C 3-6 cycloalkyloxy, or (e) C 3-6 optionally substituted by cycloalkyl. ),
    (10) C 1-6 alkylcarbonyl group (the alkyl is
    (A) hydroxy,
    (B) 1 to 3 halogen atoms,
    (C) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
    (D) C 3-6 cycloalkoxy, or (e) C 3-6 optionally substituted by cycloalkyl. ),
    (11) C 3-6 cycloalkylcarbonyl group (the cycloalkyl is
    (A) hydroxy,
    (B) 1 to 3 halogen atoms,
    (C) C 1-4 alkoxy (the alkoxy may be substituted with 1 to 3 halogen atoms),
    (D) C 3-6 cycloalkoxy,
    (E) optionally substituted with C 1-4 alkyl, or (f) C 3-6 cycloalkyl. ),
    (12) C 6-10 aryl group (the aryl group is
    (A) a halogen atom,
    (B) C 1-4 alkoxy,
    (C) C 3-7 cycloalkyl, or (d) C 1-4 alkyl may be substituted. ),
    (13) a 5- to 12-membered monocyclic or polycyclic heteroaryl group (the heteroaryl group is
    (A) a halogen atom,
    (B) C 1-4 alkyl (which may be substituted with 1 to 3 halogen atoms), or (c) optionally substituted with C 3-6 cycloalkyl. ), And (14) a compound selected from the group consisting of C 1-4 alkylsulfonyl groups, or a pharmacologically acceptable salt thereof.
  3. 　Ｒ１が、Ｃ６－１０アリール基（該アリール基は、
    （１）ハロゲン原子、
    （２）Ｃ３－７シクロアルキル基、
    （３）Ｃ１－４アルキル基（該アルキル基は、
    　（ａ）１～３個のフッ素原子、
    　（ｂ）Ｃ１－４アルコキシ、
    　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
    　（ｄ）４員～７員の環状アミノで置換されていてもよい。）、
    （４）Ｃ１－４アルコキシ基（該アルコキシ基は、
    　（ａ）１～３個のフッ素原子、または
    　（ｂ）Ｃ１－４アルコキシで置換されていてもよい。）、および
    （５）Ｃ１－４アルキルカルボニル基からなる群から選択される同種または異種の１～５個の基で置換されていてもよい。）である、請求項１または請求項２のいずれか一項に記載の化合物、またはその薬理学上許容される塩。     R 1 is a C 6-10 aryl group (the aryl group is
    (1) a halogen atom,
    (2) a C 3-7 cycloalkyl group,
    (3) C 1-4 alkyl group (the alkyl group is
    (A) 1 to 3 fluorine atoms,
    (B) C 1-4 alkoxy,
    (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ),
    (4) C 1-4 alkoxy group (the alkoxy group is
    (A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. And (5) 1 to 5 groups of the same or different types selected from the group consisting of C 1-4 alkylcarbonyl groups. Or a pharmacologically acceptable salt thereof according to any one of claims 1 and 2.
  4. 　Ｒ１が、Ｃ６－１０アリール基（該アリール基は、
    （１）ハロゲン原子、
    （２）Ｃ１－４アルキル（該アルキル基は、１～３個のフッ素原子で置換されていてもよい。）、および
    （３）Ｃ１－４アルコキシからなる群から選択される同種または異種の１～５個の基で置換されていてもよい。）である、請求項３に記載の化合物、またはその薬理学上許容される塩。     R 1 is a C 6-10 aryl group (the aryl group is
    (1) a halogen atom,
    (2) C 1-4 alkyl (the alkyl group may be substituted with 1 to 3 fluorine atoms), and (3) the same or different selected from the group consisting of C 1-4 alkoxy May be substituted with 1 to 5 groups. Or a pharmacologically acceptable salt thereof.
  5. 　Ｒ１が、５員もしくは６員の単環式ヘテロアリール基（該ヘテロアリール基は、
    （１）ハロゲン原子、
    （２）Ｃ３－７シクロアルキル基、
    （３）Ｃ１－４アルキル基（該アルキル基は、
    　（ａ）１～３個のフッ素原子、
    　（ｂ）Ｃ１－４アルコキシ、
    　（ｃ）アミノ（該アミノは、１～２個のＣ１－６アルキルで置換されていてもよい。）、または
    　（ｄ）４員～７員の環状アミノで置換されていてもよい。）、
    （４）Ｃ１－４アルコキシ基（該アルコキシ基は、
    　（ａ）１～３個のフッ素原子、または
    　（ｂ）Ｃ１－４アルコキシで置換されていてもよい。）、および
    （５）Ｃ１－４アルキルカルボニル基からなる群から選択される同種または異種の少なくとも１以上の置換基で置換されていてもよい。）である、請求項２に記載の化合物、またはその薬理学上許容される塩。     R 1 is a 5- or 6-membered monocyclic heteroaryl group (the heteroaryl group is
    (1) a halogen atom,
    (2) a C 3-7 cycloalkyl group,
    (3) C 1-4 alkyl group (the alkyl group is
    (A) 1 to 3 fluorine atoms,
    (B) C 1-4 alkoxy,
    (C) amino (the amino may be substituted with 1 to 2 C 1-6 alkyl), or (d) optionally substituted with 4 to 7 membered cyclic amino. ),
    (4) C 1-4 alkoxy group (the alkoxy group is
    (A) It may be substituted with 1 to 3 fluorine atoms, or (b) C 1-4 alkoxy. ), And (5) may be substituted with at least one or more substituents selected from the group consisting of C 1-4 alkylcarbonyl groups. The compound according to claim 2, or a pharmacologically acceptable salt thereof.
  6. 　Ｒ１が、５員もしくは６員の単環式ヘテロアリール基（該ヘテロアリール基は、
    （１）ハロゲン原子、および
    （２）Ｃ１－４アルキル基からなる群から選択される同種または異種の少なくとも１以上の置換基で置換されていてもよい。）である、請求項５に記載の化合物、またはその薬理学上許容される塩。     R 1 is a 5- or 6-membered monocyclic heteroaryl group (the heteroaryl group is
    It may be substituted with at least one or more substituents selected from the group consisting of (1) a halogen atom, and (2) a C 1-4 alkyl group. Or the pharmacologically acceptable salt thereof.
  7. 　Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ａ）～（ｄ）
    Figure JPOXMLDOC01-appb-C000002
     ［ここに、（ａ）～（ｄ）は請求項５または請求項６のいずれか一項にて定義される置換基で置換されていてもよい。］
    で表されるいずれか一つの基である、請求項５または請求項６のいずれか一項に記載の化合物、またはその薬理学上許容される塩。     The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a) to (d):
    Figure JPOXMLDOC01-appb-C000002
     [Wherein (a) to (d) may be substituted with a substituent defined in any one of claims 5 and 6. ]
    The compound as described in any one of Claim 5 or Claim 6 which is any one group represented by these, or its pharmacologically acceptable salt.
  8. 　Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ａ）
    Figure JPOXMLDOC01-appb-C000003
     ［ここに、（ａ）は請求項５または請求項６のいずれか一項にて定義される置換基で置換されていてもよい。］
    で表される基である、請求項７に記載の化合物、またはその薬理学上許容される塩。     The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a):
    Figure JPOXMLDOC01-appb-C000003
     [Wherein (a) may be substituted with a substituent defined in any one of claims 5 and 6]. ]
    The compound of Claim 7 which is group represented by these, or its pharmacologically acceptable salt.
  9. 　Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ａ１）
    Figure JPOXMLDOC01-appb-C000004
     ［ここに、（ａ１）は請求項５または請求項６のいずれか一項にて定義される置換基で置換されていてもよい。］
    で表される基である、請求項８に記載の化合物、またはその薬理学上許容される塩。     The 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (a1):
    Figure JPOXMLDOC01-appb-C000004
     [Wherein (a1) may be substituted with a substituent defined in any one of claims 5 and 6]. ]
    The compound of Claim 8 which is group represented by these, or its pharmacologically acceptable salt.
  10. 　Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ｂ）
    Figure JPOXMLDOC01-appb-C000005
     ［ここに、（ｂ）は請求項５または請求項６のいずれか一項にて定義される置換基で置換されていてもよい。］
    で表される基である、請求項７に記載の化合物、またはその薬理学上許容される塩。     A 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (b):
    Figure JPOXMLDOC01-appb-C000005
     [Here, (b) may be substituted with a substituent defined in any one of claims 5 and 6. ]
    The compound of Claim 7 which is group represented by these, or its pharmacologically acceptable salt.
  11. 　Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ｃ）
    Figure JPOXMLDOC01-appb-C000006
     ［ここに、（ｃ）は請求項５または請求項６のいずれか一項にて定義される置換基で置換されていてもよい。］
    で表される基である、請求項７に記載の化合物、またはその薬理学上許容される塩。     A 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (c):
    Figure JPOXMLDOC01-appb-C000006
     [Wherein (c) may be substituted with a substituent defined in any one of claims 5 and 6]. ]
    The compound of Claim 7 which is group represented by these, or its pharmacologically acceptable salt.
  12. 　Ｒ１における５員もしくは６員の単環式へテロアリール基が、下記（ｄ）
    Figure JPOXMLDOC01-appb-C000007
     ［ここに、（ｄ）は請求項５または請求項６のいずれか一項にて定義される置換基で置換されていてもよい。］
    で表される基である、請求項７に記載の化合物、またはその薬理学上許容される塩。     A 5-membered or 6-membered monocyclic heteroaryl group in R 1 is represented by the following (d):
    Figure JPOXMLDOC01-appb-C000007
     [Wherein (d) may be substituted with a substituent defined in any one of claims 5 and 6]. ]
    The compound of Claim 7 which is group represented by these, or its pharmacologically acceptable salt.
  13. 　Ｒ２が、Ｃ１－６アルキル基（該基は、
    （１）１～５個のハロゲン原子、
    （２）Ｃ３－６シクロアルキル、または
    （３）Ｃ１－４アルコキシで置換されていてもよい。）である、請求項１～請求項１２のいずれか一項に記載の化合物、またはその薬理学上許容される塩。     R 2 is a C 1-6 alkyl group (the group is
    (1) 1 to 5 halogen atoms,
    It may be substituted with (2) C 3-6 cycloalkyl or (3) C 1-4 alkoxy. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
  14. 　Ｒ２が、メチル基またはエチル基である、請求項１３に記載の化合物、またはその薬理学上許容される塩。 The compound according to claim 13, or a pharmacologically acceptable salt thereof, wherein R 2 is a methyl group or an ethyl group.
  15. 　Ｒ３が、
    （１）水素原子、
    （２）ハロゲン原子、または
    （３）Ｃ１－６アルキル基（該基は、
    　（ａ）１～３個のハロゲン原子、
    　（ｂ）Ｃ３－６シクロアルキル、または
    　（ｃ）Ｃ１－４アルコキシで置換されていてもよい。）である、請求項１～請求項１４のいずれか一項に記載の化合物、またはその薬理学上許容される塩。     R 3 is
    (1) a hydrogen atom,
    (2) a halogen atom, or (3) a C 1-6 alkyl group (the group is
    (A) 1 to 3 halogen atoms,
    (B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. The compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof.
  16. 　Ｒ３が、水素原子、塩素原子、フッ素原子またはメチル基である、請求項１～請求項１５のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15, wherein R 3 is a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group.
  17. 　Ｒ３が、水素原子である、請求項１６に記載の化合物、またはその薬理学上許容される塩。 The compound according to claim 16, or a pharmacologically acceptable salt thereof, wherein R 3 is a hydrogen atom.
  18. 　Ｒ４が、
    （１）Ｃ１－６アルキル基（該基は、
    　（ａ）１～３個のハロゲン原子、
    　（ｂ）Ｃ３－６シクロアルキル、または
    　（ｃ）Ｃ１－４アルコキシで置換されていてもよい。）、または
    （２）Ｃ３－６シクロアルキル基である、請求項１～請求項１７のいずれか一項に記載の化合物、またはその薬理学上許容される塩。     R 4 is
    (1) C 1-6 alkyl group (the group is
    (A) 1 to 3 halogen atoms,
    (B) optionally substituted with C 3-6 cycloalkyl, or (c) C 1-4 alkoxy. Or (2) a compound of any one of claims 1 to 17, which is a C 3-6 cycloalkyl group, or a pharmaceutically acceptable salt thereof.
  19. 　Ｒ４が、メチル基、２，２－ジフルオロエチル基、２，２，２－トリフルオロエチル基、またはエチル基である、請求項１８に記載の化合物、またはその薬理学上許容される塩。 19. The compound according to claim 18, or a pharmacologically acceptable salt thereof, wherein R 4 is a methyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, or an ethyl group.
  20. 　Ｒ４が、エチル基である、請求項１９に記載の化合物、またはその薬理学上許容される塩。 The compound according to claim 19, or a pharmacologically acceptable salt thereof, wherein R 4 is an ethyl group.
  21. 　Ｒ５が、水酸基である、請求項１～請求項２０のいずれか一項に記載の化合物、またはその薬理学上許容される塩。 The compound according to any one of claims 1 to 20, or a pharmacologically acceptable salt thereof, wherein R 5 is a hydroxyl group.
  22. 　Ｒ５が、アミノカルボニル基である、請求項１～請求項２０のいずれか一項に記載の化合物、またはその薬理学的に許容される塩。 The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 is an aminocarbonyl group.
  23. 　Ｒ５が、メチルスルホニル基である、請求項１～請求項２０のいずれか一項に記載の化合物、またはその薬理学的に許容される塩。 The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 5 is a methylsulfonyl group.
  24. 　以下の化合物群：
    ４－クロロ－５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
    ４－クロロ－５－［（３－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
    ４－クロロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－メチル－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－５－｛［３－フルオロ－５－（トリフルオロメチル）－２－ピリジニル］（メチル）アミノ｝－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ４－クロロ－５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－５－［（３－フルオロ－５－メチル－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－５－［（４－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－４－メチル－１Ｈ－ピラゾール－３－カルボキサミド、
    ４－クロロ－１－エチル－５－［（４－フルオロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－４－フルオロ－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－５－［（４－フルオロフェニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、および
    ５－［（４－クロロ－２－フルオロフェニル）（メチル）アミノ］－１－エチル－Ｎ－［（２ｓ，５ｒ）－５－（メチルスルホニル）アダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド
    から選択される化合物である、請求項１に記載の化合物、またはその薬理学上許容される塩。     The following compound groups:
    4-chloro-5-[(5-chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide ,
    5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
    5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
    1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3-carboxamide;
    4-chloro-5-[(3-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-1H-pyrazole-3-carboxamide ,
    4-Chloro-N-[(E) -5-hydroxyadamantan-2-yl] -1-methyl-5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3 -Carboxamide,
    1-ethyl-5-{[3-fluoro-5- (trifluoromethyl) -2-pyridinyl] (methyl) amino} -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole -3-carboxamide,
    4-chloro-5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
    1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
    1-ethyl-5-[(4-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -4-methyl-1H-pyrazole-3-carboxamide ,
    4-Chloro-1-ethyl-5-[(4-fluoro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
    5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
    5-[(5-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
    5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
    5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1-ethyl-4-fluoro-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
    1-ethyl-5-[(4-fluorophenyl) (methyl) amino] -N-[(E) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3-carboxamide, and 5- [(4-Chloro-2-fluorophenyl) (methyl) amino] -1-ethyl-N-[(2s, 5r) -5- (methylsulfonyl) adamantan-2-yl] -1H-pyrazole-3-carboxamide The compound according to claim 1, which is a compound selected from: or a pharmacologically acceptable salt thereof.
  25. 　以下の化合物群：
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－５－｛メチル［４－（トリフルオロメチル）－２－ピリジニル］アミノ｝－１Ｈ－ピラゾール－３－カルボキサミド、
    １－エチル－５－［（３－フルオロ－５－メチル－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２，２－ジフルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（４－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－カルボキサミド、および
    ５－［（５－クロロ－２－ピリジニル）（メチル）アミノ］－１－（２－フルオロエチル）－Ｎ－［（Ｅ）－５－ヒドロキシアダマンタン－２－イル］－１Ｈ－ピラゾール－３－カルボキサミド
    から選択される化合物である、請求項１に記載の化合物、またはその薬理学上許容される塩。     The following compound groups:
    5-[(5-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
    5-[(4-chloro-2-pyridinyl) (methyl) amino] -1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide;
    1-ethyl-N-[(E) -5-hydroxyadamantan-2-yl] -5- {methyl [4- (trifluoromethyl) -2-pyridinyl] amino} -1H-pyrazole-3-carboxamide;
    1-ethyl-5-[(3-fluoro-5-methyl-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3-carboxamide ,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole-3- Carboxamide,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
    5-[(5-Chloro-2-pyridinyl) (methyl) amino] -1- (2,2-difluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl] -1H-pyrazole- 3-carboxamide,
    5-[(4-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazole-3-carboxamide,
    5-[(5-Chloro-2-pyridinyl) (methyl) amino] -N-[(E) -5-hydroxyadamantan-2-yl] -1- (2,2,2-trifluoroethyl) -1H -Pyrazol-3-carboxamide, and 5-[(5-chloro-2-pyridinyl) (methyl) amino] -1- (2-fluoroethyl) -N-[(E) -5-hydroxyadamantan-2-yl The compound according to claim 1, which is a compound selected from 1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
  26. 　請求項１～請求項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof.
  27. 　請求項１～請求項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩を有効成分として含有するＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、脂質代謝異常症、高血圧、動脈硬化、血管狭窄、肥満、クッシング症候群、サブクリニカルクッシング症候群、緑内障、骨粗鬆症、メタボリックシンドローム、心血管疾患、アテローム性動脈硬化、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療剤。 A type II diabetes, glucose intolerance, hyperglycemia, insulin resistance, dyslipidemia containing the compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient , Hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atherosclerosis, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or depression Therapeutic agent for diseases.
  28. 　ＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、脂質代謝異常症、高血圧、動脈硬化、血管狭窄、肥満、クッシング症候群、サブクリニカルクッシング症候群、緑内障、骨粗鬆症、メタボリックシンドローム、心血管疾患、アテローム性動脈硬化、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療剤を製造するための、請求項１～請求項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩の使用。 Type II diabetes, impaired glucose tolerance, hyperglycemia, insulin resistance, dyslipidemia, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atheroma The compound according to any one of claims 1 to 25 or a pharmacologically thereof for producing a therapeutic agent for atherosclerosis, cognitive impairment, dementia, Alzheimer's disease, depression, anxiety or manic depression Use of acceptable salt.
  29. 　請求項１～請求項２５のいずれか一項に記載の化合物またはその薬理学上許容される塩の有効量をそれを必要とする対象に投与することを含む、ＩＩ型糖尿病、耐糖能異常、高血糖、インスリン抵抗性、脂質代謝異常症、高血圧、動脈硬化、血管狭窄、肥満、クッシング症候群、サブクリニカルクッシング症候群、緑内障、骨粗鬆症、メタボリックシンドローム、心血管疾患、アテローム性動脈硬化、認知障害、認知症、アルツハイマー症、うつ、不安または躁うつ病の治療方法。 A type II diabetes, impaired glucose tolerance comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof, Hyperglycemia, insulin resistance, dyslipidemia, hypertension, arteriosclerosis, vascular stenosis, obesity, Cushing syndrome, subclinical Cushing syndrome, glaucoma, osteoporosis, metabolic syndrome, cardiovascular disease, atherosclerosis, cognitive impairment, cognition Of treatment for Alzheimer's disease, Alzheimer's disease, depression, anxiety or manic depression.
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