WO2016171181A1 - 2-substituted fused pyrazole derivatives - Google Patents

2-substituted fused pyrazole derivatives Download PDF

Info

Publication number
WO2016171181A1
WO2016171181A1 PCT/JP2016/062536 JP2016062536W WO2016171181A1 WO 2016171181 A1 WO2016171181 A1 WO 2016171181A1 JP 2016062536 W JP2016062536 W JP 2016062536W WO 2016171181 A1 WO2016171181 A1 WO 2016171181A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
compound
ring
same
Prior art date
Application number
PCT/JP2016/062536
Other languages
French (fr)
Japanese (ja)
Inventor
英史 吉永
洋平 井熊
Original Assignee
大日本住友製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大日本住友製薬株式会社 filed Critical 大日本住友製薬株式会社
Publication of WO2016171181A1 publication Critical patent/WO2016171181A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a condensed pyrazole derivative having a selective dopamine D 4 receptor agonistic action and a salt thereof, and a therapeutic agent for central nervous system diseases comprising the derivative as an active ingredient.
  • Dopamine D 4 receptors G-protein coupled receptors (G protein-coupled receptors: GPCRs ) is one of, since it is highly expressed in prefrontal cortex associated with attention behavior and cognitive function, dopamine D 4 Receptor agonists are expected as therapeutic agents for central nervous system diseases related to higher brain functions such as attention deficit hyperactivity disorder (ADHD).
  • ADHD is one of the developmental disorders that develop in childhood with inattention, hyperactivity, and impulsivity as core symptoms. Core symptoms persist even in adulthood. It is known to do.
  • the central nervous system stimulant methylphenidate is used as a first-line drug in ADHD drug therapy.
  • methylphenidate has the risk of drug dependence and abuse, and the risk of side effects on the cardiovascular system such as palpitation, tachycardia, and blood pressure fluctuations.
  • the selective noradrenaline reuptake inhibitor atomoxetine which is a non-central nervous stimulant, is selected as an ADHD therapeutic agent with small drug dependence formation.
  • atomoxetine requires a sufficient administration period before the therapeutic effect is exhibited. For these reasons, it is desired to develop an ADHD therapeutic agent that can reduce the risk of drug dependence and cardiovascular side effects and exhibits rapid onset of efficacy.
  • the ADHD patient the mutation of the dopamine transporter gene and the dopamine D 4 receptor gene is observed has been reported (e.g., see Non-Patent Document 1).
  • the child with a genetic polymorphism of seven repeat sequence of 48bp in the third exon of the dopamine D 4 receptor gene developmental delay of the cerebral cortex has been observed (for example, see Non-Patent Document 3).
  • dopamine D 4 receptors are highly expressed in prefrontal cortex associated with attention behavior and cognitive function (e.g., see Non-Patent Document 2). From these facts, dopamine D 4 receptor is considered to be related to attention / cognitive function.
  • dopamine D 4 receptors are known to be not expressed in the nucleus accumbens involved in drug dependence. Based on the above, a drug that selectively exhibits an agonistic action on the dopamine D 4 receptor is a therapeutic agent for central nervous system diseases involving dopaminergic nerves, particularly ADHD and drug dependence. It is expected as a therapeutic agent for ADHD with reduced side effects.
  • a compound represented by the following formula can regulate the activity of a metabotropic glutamate receptor (mGluR5), and is useful for the treatment, prevention, and / or management of various disorders such as neuropathy. It is disclosed.
  • R 1 is aryl, heteroaryl, etc .
  • R 2 is aryl, heteroaryl, etc .
  • R 3 and R 4 are each independently hydrogen, halogen, lower alkyl, etc .
  • L 1 is a bond, —O—, —CR 5 R 6 — and the like
  • L 2 is a bond, —O—, —CR 5 R 6 — and the like
  • X is C or N
  • Y is O, S, N, etc .
  • Z is O, S, N, etc .
  • R 5 and R 6 are each independently hydrogen, halogen, or lower alkyl, or CR 5 R 6 is C ⁇ O; or R 5 and R 6 are taken together with the carbon atom to which they are attached. May form 3 to 7 member
  • Patent Document 1 does not specifically disclose a condensed pyrazole derivative.
  • An object of the present invention is to provide a novel selective dopamine D 4 receptor agonist useful as a therapeutic agent for central nervous system diseases.
  • the present inventors have found that the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary). Has been found to have an excellent selective dopamine D 4 receptor agonist activity, and the present invention has been completed.
  • the present invention is as follows.
  • n and m each independently represent 1 or 2; W 1 and W 2 each independently represent a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms); R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group, or together with the carbon atom to which they are attached, a 3-membered May form a ⁇ 8 membered cycloalkane ring; R 3 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group; Ring Q 1 represents an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered heteroaryl group; Ring Q 2 represents an optionally substituted 5-membered heteroaryl group, and the following compounds Or a pharmaceutically acceptable salt thereof.
  • n and m are each independently 1 or 2; W 1 and W 2 are each independently a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms); R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types).
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
  • Ring Q 1 is (1) a 5- to 10-membered heteroaryl group (the group is (A) a halogen atom, (B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups); (C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms), (D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types); (E) a cyano group, and (f)
  • Item [3] m is 1; The compound or a pharmaceutically acceptable salt thereof according to Item [1] or Item [2], wherein both W 1 and W 2 are a single bond.
  • n 1; The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [3], wherein R 1 and R 2 are both hydrogen atoms.
  • Ring Q 1 is a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms
  • the group is (A) a halogen atom, (B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups); (C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms), (D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types); (E) a cyano group, and (f) an amino group (the group is substituted with one or two groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) May be substituted with 1 to 4 groups of the same or different types selected from the group consisting of, and when two substitution of
  • Ring Q 1 is represented by the following formula (2a) or (2b): Wherein X 1 represents N or CR 12 ; R 11 represents a halogen atom, a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkyl group (the group includes a halogen atom and a hydroxy group). Which may be substituted with the same or different 1 to 3 groups selected from the group consisting of groups); R 12 , R 13 , R 14 and R 15 each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group (the group is substituted with 1 to 3 halogen atoms of the same or different types).
  • a C 2-6 alkenyl group (the group may be substituted with 1 to 4 halogen atoms of the same or different types), a C 1-6 alkoxy group (1 to 3 groups Or an amino group (the group may be substituted with the same or different 1 to 2 C 1-6 alkyl groups);
  • R 11 and R 12 , or R 11 and R 15 together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring, a 5- to 8-membered saturated heterocycle, or 5 Membered to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocyclic ring, or 5-membered to 8-membered cycloalkene ring includes a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) And may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of:
  • Item [9] The compound or a pharmaceutically acceptable salt thereof according to any one of Items [6] to [8], wherein X 1 is CR 12 .
  • R 11 and R 12 , or R 11 and R 15 together with the carbon atom to which they are attached, are a 5 to 8 membered cycloalkane ring, a 5 to 8 membered saturated heterocycle, or a 5 to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is composed of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. Or a compound thereof according to any one of items [6] to [9], which may be substituted with 1 to 4 groups of the same or different types selected from the group A pharmaceutically acceptable salt.
  • Item 11 The compound according to any one of Items [6] to [9] or a pharmaceutically acceptable salt thereof, wherein R 11 is a C 1-4 alkyl group optionally substituted with 1 to 3 fluorine atoms. Salt.
  • Ring Q 2 is The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types).
  • the oxazole group, isoxazole group, imidazole group, pyrazole group, oxadizazole group, triazole group, thiazole group, isothiazole group, or thiadiazole group that may be substituted with one or two groups of Item [11]
  • Ring Q 2 is The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types).
  • Ring Q 2 is represented by the following formula (3a), (3b) or (3c): (In the formula, X 2 represents O or NR 23 (R 23 represents a hydrogen atom or a C 1-6 alkyl group (the group may be substituted with the same or different 1 to 3 halogen atoms).) Represents); R 21 and R 22 each independently represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). To express. The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [13], which is a group represented by
  • Item [16] The compound or a pharmaceutically acceptable salt thereof according to Item [14] or Item [15], wherein X 2 is O.
  • Item [17] The compound or a pharmaceutically acceptable salt thereof according to any one of Items [14] to [16], wherein R 21 and R 22 are both hydrogen atoms.
  • Item [18] Item [1] to Item [17], wherein R 3 is a hydrogen atom or a C 1-6 alkyl group (this group may be substituted with the same or different 1 to 3 halogen atoms). Or a pharmaceutically acceptable salt thereof.
  • Item [19] The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [18], wherein R 3 is a C 1-4 alkyl group.
  • Item [22] A pharmaceutical comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item [23] Containing the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient, attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, A therapeutic agent for central nervous system diseases selected from the group consisting of mood disorders and cognitive impairments.
  • a therapeutic agent for attention deficit / hyperactivity disorder comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item [25] The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly caused by attention deficit (inattention).
  • Item [26] The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly having hyperactivity.
  • Item [28] A therapeutic agent for autism spectrum disorder, comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item [29] The therapeutic agent according to Item [28], wherein the autism spectrum disorder is a disorder whose main symptom is a persistent defect in social communication and social interaction.
  • Item [30] The therapeutic agent according to Item [28], wherein the autism spectrum disorder is a disorder whose main symptom is a repeated behavior, interest, or activity pattern with limited autism spectrum disorder.
  • Item [31] Lack of attention, characterized by administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof
  • a method for treating a central nervous system disease selected from the group consisting of hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive impairment.
  • Item [32] Item [1] to Item [1] for producing a therapeutic agent for central nervous system disease selected from the group consisting of attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction 21]
  • a therapeutic agent for central nervous system disease selected from the group consisting of attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction 21]
  • the present invention compounds exhibit strong agonistic effect on dopamine D 4 receptors.
  • bioavailability at the time of oral administration (bioavailability) is high, the ability to transfer to the brain is excellent, and the risk of hepatotoxicity is also low. Therefore, the compound of the present invention is highly safe and excellent in the treatment of central nervous system diseases (for example, lack of attention). It is useful as a therapeutic agent for hyperactivity disorder.
  • C 1-6 alkyl is synonymous with an alkyl group having 1 to 6 carbon atoms.
  • halogen atom include fluorine atom, chlorine atom, bromine atom or iodine atom.
  • C 1-6 alkyl group means a straight 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 2-6 alkenyl group means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 carbon-carbon double bonds.
  • a “C 2-4 alkenyl group” is preferable.
  • Specific examples of “C 2-6 alkenyl group” include, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • the “C 1-4 alkylene group” is a divalent saturated hydrocarbon containing a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms or a cyclic structure having 3 to 4 carbon atoms. Means group.
  • Specific examples of the linear or branched “C 1-4 alkylene group” include, for example, methylene, ethylene, propylene, butylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene. 2-methylethylene, 1-ethylethylene and the like, preferably methylene and ethylene.
  • Specific examples of the “C 1-4 alkylene group” containing a cyclic structure include, for example, groups represented by the following groups.
  • C 1-6 alkoxy group refers to a “C 1-6 alkyl-O— group”, and the “C 1-6 alkyl” portion has the same meaning as the above “C 1-6 alkyl”.
  • a “C 1-4 alkoxy group” is preferable.
  • Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 3-7 cycloalkyl group means a 3- to 7-membered monocyclic saturated or partially unsaturated hydrocarbon group.
  • Specific examples of “C 3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and the like.
  • “3- to 8-membered cycloalkane ring” means a 3- to 8-membered monocyclic saturated hydrocarbon ring. A 5-membered or 6-membered saturated hydrocarbon ring is preferred. Specific examples of the “3- to 8-membered cycloalkane ring” include, for example, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and the like.
  • C 6-10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is “C 6 aryl group” (phenyl). Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • the “C 6-10 aryl group” contains one or more (for example, 1 to 4) of the same or different heteroatoms selected from phenyl and 5- to 7-membered nitrogen, sulfur and oxygen atoms. Or a group condensed with a 5- to 7-membered saturated or partially unsaturated hydrocarbon ring (eg, cyclopentane, cyclopentene, cyclohexane, etc.). However, in the case of a polycyclic “C 6-10 aryl group” in which an aromatic ring and a non-aromatic ring are condensed, only the aromatic ring has a “group” bond. Specific examples of the group include groups represented by the following formulas.
  • heteroaryl group examples include a 5- to 10-membered monocyclic or polycyclic aromatic group, and the group is the same or selected from a nitrogen atom, a sulfur atom and an oxygen atom, 1 or more (for example, 1 to 4) heterogeneous heteroatoms are contained.
  • polycyclic heteroaryl group a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable.
  • the polycyclic heteroaryl group includes those in which the monocyclic heteroaryl group is condensed with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, piperidine, etc.).
  • Specific examples of the “heteroaryl group” include, for example, a group represented by the following formula.
  • the “5- to 10-membered heteroaryl group” in ring Q 1 is preferably a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms, A group represented by the following formula is more preferable, A group represented by the following formula is more preferable.
  • the “5-membered heteroaryl group” in ring Q 2 include, for example, an oxazole group, an isoxazole group, a pyrrole group, an imidazole group, a pyrazole group, an oxadizazole, a triazole group, a thiazole group, an isothiazole group, a thiadiazole group, Examples include tetrazole groups, and oxazole groups, isoxazole groups, imidazole groups, and pyrazole groups are preferable, and oxazole groups are more preferable.
  • the bond across the ring in the above formula means that the “group” is bonded at a substitutable position in the ring.
  • the following formula In the case of the heteroaryl group, it means a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group.
  • heteroaryl group is a polycyclic group, for example, the following formula In addition to 1-benzimidazolyl or 2-benzimidazolyl, 4-, 5-, 6- or 7-benzimidazolyl may be used.
  • the substituent in the group defined as “optionally substituted” can be substituted at a substitutable position within the substitutable number range.
  • the range of the number of substitutable substituents in the methyl group is 1 to 3.
  • the optionally substituted C 6-10 aryl group is a phenyl group
  • the number of substitutable substituents in the phenyl group ranges from 1 to 5.
  • there are a plurality of substituted groups they may be the same or different.
  • the description of each group also applies if the group is part of another group or a substituent.
  • Examples of the substituent in the “optionally substituted C 1-4 alkylene group” include a hydroxy group, a halogen atom, a C 3-7 cycloalkyl group, a C 1-6 alkoxy group, and the like, A fluorine atom is mentioned.
  • Examples of the substituent in the “optionally substituted C 1-6 alkyl group” include (1) a halogen atom, (2) a C 3-7 cycloalkyl group, (3) C 1-6 alkoxy group (this group may be substituted with 1 to 3 halogen atoms of the same or different types), (4) a cyano group, (5) Amino group (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) , (6) a hydroxy group, and (7) an aminocarbonyl group (the amino is a same or different 1-2 groups selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted).
  • Preferable examples include a fluorine atom, a hydroxy group, and a C 1-6 alkoxy group.
  • Examples of the substituent in the “optionally substituted aryl group” and “optionally substituted heteroaryl group” include (1) a halogen atom, (2) C 1-6 alkyl group (this group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups), (3) C 1-6 alkoxy group (this group may be substituted with 1 to 3 halogen atoms of the same or different types), (4) a cyano group, (5) Amino group (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) , (6) a hydroxy group, and (7) an aminocarbonyl group (the amino is a same or different 1-2 groups selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted).
  • a halogen atom a C 1-6 alkyl group, a C 1-6 alkoxy group, a cyano group, an amino group (the group is selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted with 1-2 groups of the same or different types.
  • R 1 and R 2 together with the carbon atoms to which they are bonded may form a 3- to 8-membered cycloalkane ring
  • R 1 and R 2 are the same carbon When attached to an atom and together with the carbon atom to which they are attached form a 3- to 8-membered spirocycloalkane ring, and (2) R 1 and R 2 are attached to an adjacent carbon atom. And the case where they form a 3- to 8-membered fused cycloalkane ring together with the carbon atom to which they are bonded.
  • ring Q 1 When two substituents of ring Q 1 are substituted by adjacent carbon atoms, they may be combined with the carbon atoms to which they are attached to form a 5- to 8-membered ring”. one of the substituents attached to two adjacent carbon atoms on the ring Q 1, if they form a ring of 5 to 8 membered together with partial ring Q 1 containing a carbon atom bonded Examples of the ring include a cycloalkane ring, a saturated heterocyclic ring, and a cycloalkene ring. Wherein heteroatom saturated heterocyclic ring derived from a hetero atom contained in the substituent of the ring Q 1 (the oxygen atom in the alkoxy group, such as a nitrogen atom in an amino group).
  • the cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. It may be substituted with 1 to 4 groups of the same or different types. Specific examples include “groups” represented by the following groups.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, solvates such as these hydrates or ethanol solvates are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) include, for example, hydrochloride, hydrobromide, sulfuric acid.
  • Inorganic acid salts such as salts, phosphates, nitrates; and acetates, propionates, oxalates, succinates, lactates, malates, tartrate, citrate, maleate, fumarate
  • organic acid salts such as methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate.
  • the compound represented by the formula (1) may exist as a tautomer. Therefore, this invention compound also includes the tautomer of the compound represented by Formula (1).
  • the compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds. When the compound represented by the formula (1) has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the compounds of the present invention include stereoisomers of these compounds, mixtures thereof and isolated ones. In addition, a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1). .
  • Boc group tert-butoxycarbonyl group
  • Cbz group benzyloxycarbonyl group
  • Alloc group allyloxycarbonyl group
  • Fmoc group 9-fluorenylmethyloxycarbonyl group
  • DMF N, N-dimethylformamide
  • the compound of the present invention can be produced, for example, by the methods shown in the following production methods 1 to 9. These production methods can be improved as appropriate based on the knowledge of those skilled in organic synthesis.
  • the compounds used as raw materials may be used as salts as necessary.
  • the desired product can be obtained by protecting the points other than the reaction point as necessary and deprotecting after completion of the reaction or after a series of reactions.
  • Protecting groups are described in literature (T. W. Greene and P. G. M.
  • amino protecting groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the like, and hydroxy groups
  • specific examples of the protection of can include, for example, trialkylsilyl, acetyl, benzyl and the like.
  • Manufacturing method 1 The compound represented by Formula (1) is manufactured by the method shown below, for example.
  • R 101 represents a Cbz group and a Boc group , Alloc group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group
  • LG represents a leaving group (for example, iodine atom, bromine atom, A chlorine atom, a substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like are represented.
  • R 101 represents a Cbz group and a Boc group , Alloc group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group
  • LG represents a leaving group (for example, iodine
  • Step 1-1 Preparation process of Compound (1-2) (1-2), using the compound (1-1) as a starting material, the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .) Etc.).
  • Step 1-2 Production Step of Compound (1)
  • Compound (1) is produced by reacting compound (1-2) with compound (1-3) in a suitable inert solvent.
  • the reaction may be performed in the presence of a base, if necessary, in the presence of a phase transfer catalyst.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium
  • phase transfer catalyst examples include, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether. Etc.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane
  • Lower alcohols such as methanol, ethanol, 2-propanol
  • Step 1-3 Production Step of Compound (1)
  • Compound (1) is reduced in a suitable inert solvent using compound (1-2) and an aldehyde represented by formula (1-4) and a reducing agent. It can also be produced by subjecting it to an amination reaction.
  • the reaction may be performed in the presence of a base, an acid, or other additives as necessary.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • the reducing agent include, for example, lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium tri (sec-butyl) borohydride, hydrogen Tri (sec-butyl) borohydride sodium, potassium tri (sec-butyl) borohydride, borane-dimethylsulfide complex, borane-tetrahydrofuran complex, lithium triethylborohydride, ammonium formate, palladium-carbon and palladium oxide
  • a metal catalyst such as
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc. It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphat
  • the acid examples include organic acids such as acetic acid, trifluoroacetic acid and methanesulfonic acid; inorganic acids such as hydrochloric acid and sulfuric acid.
  • additives include dehydrating agents such as tetramethyl orthosilicate and methyl orthoformate; zinc chloride, titanium tetrachloride, lanthanum sulfate, magnesium sulfate-pyridinium sulfate pyridinium, magnesium bromide, indium chloride, zirconium chloride,
  • dehydrating agents such as tetramethyl orthosilicate and methyl orthoformate
  • zinc chloride titanium tetrachloride, lanthanum sulfate, magnesium sulfate-pyridinium sulfate pyridinium, magnesium bromide, indium chloride, zirconium chloride
  • Lewis acids such as magnesium triflate, ytterbium (III) triflate, scandium triflate, alumina, copper sulfate, tetraisopropoxide titanate, and tetraethoxide titanate.
  • the solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like.
  • Ether solvents halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • 1,2-dimethoxyethane 1, tetrahydrofuran, 1,4-dioxane and the like.
  • Ether solvents include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like.
  • Ether solvents alcohol solvents such as methanol
  • Step 1-4 Production Step of Compound (1-6)
  • Compound (1-6) is a compound represented by formula (1-5) in the presence of a condensing agent in an inert solvent. It is produced by reacting with a carboxylic acid.
  • the reaction may be further performed in the presence of a base.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • condensing agent examples 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 (WSC ⁇ HCl) and dicyclohexylcarbodiimide (DCC); Triazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphide salt ( And phosphates such as HBTU); diphenylphosphonyl diamide (DPPA); N, N-carbonyl diimidazole (CDI) and the like.
  • DPPA diphenyl
  • N-hydroxysuccinimide HSu
  • 1-hydroxybenzotriazole HBt
  • 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine HOOBt
  • the additive can be added to carry out the reaction.
  • the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1, Ether solvents such as 4-dioxane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; aprotic polarities such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide A solvent; a basic solvent such as pyridine; and a mixed solvent thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • aromatic hydrocarbons such as benzene and toluene
  • phase transfer catalyst can be added as necessary.
  • phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
  • the compound (1-6) is obtained by adding a halogenating reagent (eg, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, pentachloride to the compound (1-5). It is also produced by reacting with a compound (1-2) in an inert solvent in the presence of a base as necessary.
  • a halogenating reagent eg, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, pentachloride
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform , Halogenated hydrocarbon solvents such as dichloroethane; ester solvents such as ethyl acetate and isopropyl acetate; ketone solvents such as methyl ethyl ketone and acetone; non-solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and hexamethylenephosphoamide A protic solvent is mentioned.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
  • hydrocarbon solvents such as
  • Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene. , Organic bases such as pyridine, dimethylaminopyridine, and picoline.
  • Step 1-5 Production Step of Compound (1)
  • Compound (1) can also be produced by reacting compound (1-6) with a reducing agent in an inert solvent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, reducing agent used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • the reducing agent examples include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, borane complex (borane-dimethylsulfide complex or borane-tetrahydrofuran complex) and the like.
  • the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; and mixed solvents thereof.
  • the compound represented by the formula (2-4) is produced, for example, by the method shown below.
  • R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, 4- It represents a methoxybenzyl group, a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, or an Fmoc group.
  • Step 2-1 Step of producing compound (2-2)
  • Compound (2-2) is produced by the same method as in step 1-5, using compound (2-1).
  • Step 2-2 Production Step of Compound (2-4)
  • Compound (2-4) is produced in the same manner as in step 1-1, using compound (2-2).
  • Step 2-3 Preparation process of Compound (2-3) (2-3), using the compound (2-1), the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) Etc.).
  • Step 2-4 Step of producing compound (3-3) Compound (2-4) is produced by the same method as in step 1-5 using compound (2-3).
  • the compound represented by the formula (3-2) is produced, for example, by the method shown below.
  • LG represents a leaving group (for example, an iodine atom , Bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like.
  • LG represents a leaving group (for example, an iodine atom , Bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like.
  • Step 3-1 Production Step of Compound (3-1)
  • Compound (3-1) is produced by the same method as in Step 1-2, using Compound (2-3) and Compound (1-3) as raw materials. Is done.
  • Step 2-2 Production Step of Compound (2-3)
  • Compound (3-2) is produced in the same manner as in step 1-5 using compound (3-1).
  • the compound represented by formula (4-3) is produced, for example, by the method shown below.
  • R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, and a 4-methoxybenzyl group. , 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group; both Z 1 and Z 2 represent a hydrogen atom, or Z 1 and Z 2 together represent a carbonyl group
  • R 3a represents a halogen atom
  • R 3b represents a C 1-6 alkyl group.
  • Step 4-1 Production Step of Compound (4-2)
  • Compound (4-2) is prepared by reacting Compound (4-1) with, for example, N-bromosuccinimide, N-chlorosuccinimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane It is produced by reacting with a halogenating agent such as bis (tetrafluoroborate).
  • a halogenating agent such as bis (tetrafluoroborate).
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used. While the reaction time varies depending on the reaction temperature, the halogenating agent used, the raw materials, the solvent and the like, it is usually 10 minutes to 48 hours.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; dimethylformamide and N-methyl And aprotic polar solvents such as -2-pyrrolidinone; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane
  • aprotic polar solvents such as -2-pyrrolidinone
  • Step 4-2 Production Step of Compound (4-3)
  • Compound (4-3) is prepared by reacting compound (4-2) with, for example, dimethylzinc in an appropriate inert solvent in the presence of a transition metal catalyst. Or an organoboron compound such as trimethylboroxine.
  • the reaction can be performed in the presence of a ligand, a base, an additive, or the like as necessary.
  • the reaction temperature is usually in the range from ⁇ 10 ° C. to the boiling point of the solvent used. Although depending on conditions such as reaction temperature, reagents used, raw materials and solvent, it is usually 10 minutes to 48 hours.
  • transition metal examples include, for example, palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) Palladium chloride (II), dichlorobis (tri-O-tolylphosphine) palladium (II), bis (tri-tert-butylphosphine) palladium (0), and [1,1′-bis (diphenylphosphino) ferrocene] Examples include dichloropalladium (II).
  • ligand examples include, for example, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1′-bis.
  • (Diphenylphosphino) ferrocene 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and the like.
  • the base include organic bases such as triethylamine and diisopropylethylamine; inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
  • organic bases such as triethylamine and diisopropylethylamine
  • inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
  • specific examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, copper (I) bromide, and the like.
  • compound (4-3) is obtained by reacting compound (4-2) with alkyllithium such as n-butyllithium in a suitable inert solvent and then reacting with alkyl halide such as methyl iodide. It is also produced by reacting.
  • alkyllithium such as n-butyllithium
  • alkyl halide such as methyl iodide
  • Step 5-1 Step of producing compound (5-4)
  • Compound (5-4) is compound (5-2) or compound (5-3) in a suitable inert solvent. It is manufactured by reacting with.
  • the reaction may be carried out in the presence of a base, if necessary, in the presence of a phase transfer catalyst.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium
  • phase transfer catalyst examples include, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether. Etc.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane
  • Lower alcohols such as methanol, ethanol, 2-propanol
  • compound (5-4) is produced by carrying out Mitsunobu reaction according to a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of triphenylphosphine and Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or using a cyanomethylenephosphorane reagent.
  • Mitsunobu reaction according to a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of triphenylphosphine and Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or using a cyanomethylenephosphorane reagent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; and mixed solvents thereof.
  • Step 5-2 Production Step of Compound (5-5)
  • Compound (5-5) is produced by reacting compound (5-4) with a reducing agent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • the reducing agent include, for example, lithium aluminum hydride, sodium borohydride, borane complex (borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, etc.) and the like.
  • the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, lower alcohols such as methanol, ethanol and 2-propanol, and mixed solvents thereof.
  • Step 5-3 Production Step of Compound (5-6)
  • LG has a methanesulfonyloxy group, a chloromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, p-toluenemethane
  • the compound (5-5) in an inert solvent in the presence of a base, methanesulfonyl chloride, methanesulfonic anhydride, chloromethanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, Produced by reacting with benzenesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonyl chloride, or p-toluenesulfonic
  • the reaction temperature is usually in the range from about ⁇ 40 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, reagent, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • the base is not particularly limited as long as it is used as a base in a normal reaction.
  • Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium Bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium-bis (trimethylsilyl) amide, lithium amide, n-butyllithium, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate And inorganic bases such as sodium hydroxide and sodium hydride.
  • the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylenephosphoamide and the like, and a mixed solvent thereof may be used.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
  • hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene
  • dichloromethane chloroform And halogenated hydrocarbon solvents
  • the compound (5-5) is chlorinated by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989)
  • compound (5-6) can be produced.
  • the chlorinating reagent oxalyl chloride, thionyl chloride, phosphorus oxychloride, sulfuryl chloride, cyanuryl trichloride, carbon tetrachloride, or N-chlorosuccinimide is preferably used.
  • LG represents a bromine atom
  • bromination of the compound (5-5) by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989, etc.)
  • compound (5-6) can be produced.
  • the bromination reagent phosphorus tribromide, carbon tetrabromide, bromine, or N-bromosuccinimide is preferably used.
  • compound (5-5) is iodinated by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989, etc.)
  • compound (5-6) can be produced.
  • the iodination reagent iodine, N-iodosuccinimide and the like are preferably used.
  • the compound (5-6) in which LG is halogen can also be produced by reacting the compound (5-6) in which LG is a substituted sulfonyloxy group with, for example, lithium bromide or lithium chloride in an inert solvent. Is done.
  • Step 5-4 Production Step of Compound (5-7)
  • Compound (5-7) is produced by reacting compound (5-6) with a base in a suitable inert solvent.
  • the reaction may be performed in the presence of a phase transfer catalyst as necessary.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium
  • phase transfer catalyst examples include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane
  • Aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2
  • n and R 3 are as defined above in [1];
  • R 102 represents an optionally substituted C 1-4 alkyl group;
  • R 103 represents a benzyl group, a 4-methoxybenzyl group, Represents a 2,4-dimethoxybenzyl group or a 3,4-dimethoxybenzyl group;
  • Y represents —W 2 -ring Q 2 (W 2 , ring Q 2 has the same meaning as in the above [1]),
  • C 1-4 represents an alkoxycarbonyl group, a halogen atom, or a nitro group;
  • LG 1 and LG 2 are the same or different and are a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom, a substituted sulfonyl group (for example, a methanesulfonyl group, p -Toluen
  • Step 6-1 Step for producing compound (6-3)
  • Compound (6-3) is compound (5-1) and compound (6-1) or (6-2), which is the same as step 5-1 It is manufactured by the method.
  • Step 6-2 Production Step of Compound (6-5)
  • Compound (6-5) is obtained by converting Compound (6-3) to Compound (6-) in an appropriate inert solvent and optionally in the presence of an additive. Produced by reacting with 4).
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • additives can be added as necessary.
  • examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide and the like.
  • the inert solvent include, for example, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane; lower alcohols such as methanol, ethanol, 2-propanol; acetonitrile, acetone, methyl ethyl ketone, dimethylformamide.
  • aprotic polar solvents such as N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.
  • Manufacturing method 7 The compound represented by the formula (7-4) is produced, for example, by the method shown below. [Wherein, n, R 1 , R 2 , R 3 , and ring Q 2 have the same meanings as the above [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, and a 4-methoxybenzyl group.
  • X represents a halogen atom
  • A represents the following formula (a), (b), (c), (d) Or (e); (Wherein M + represents a potassium ion, a sodium ion, or an ammonium ion, and X ′ represents a halogen atom); Z 1 and Z 2 both represent a hydrogen atom; Alternatively, Z 1 and Z 2 together represent a carbonyl group.
  • Step 7-1 Production Step of Compound (7-2)
  • the production can be carried out by the following production method (i. Or ii.).
  • Compound (7-2) is produced by reacting iron and compound (7-1) in an inert solvent.
  • the inert solvent include water, acetic acid, or alcohol solvents such as methanol, ethanol, or 2-propanol, and a mixed solvent thereof may be used.
  • the reaction temperature is usually in the range from about 30 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 96 hours.
  • Compound (7-2) can be produced by hydrogenating compound (7-1) in the presence of palladium on carbon or palladium hydroxide in an inert solvent. Moreover, an acid can also be added as needed.
  • the reaction temperature is usually in the range from about 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 96 hours.
  • the acid include hydrochloric acid water, hydrogen bromide water, sulfuric acid water, acetic acid, trifluoroacetic acid and the like.
  • the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; alcohol solvents such as ethanol, methanol and isopropanol, acetic acid and the like, and mixed solvents thereof may be used.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
  • hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene
  • dichloromethane chloroform And halogenated hydrocarbon solvents
  • alcohol solvents such as ethanol,
  • Step 7-2 Production Step of Compound (7-3)
  • Compound (7-3) is compound (7-2) as a starting material, and literature (for example, Tetrahedron Letters 38, 7963 (1997), Bioorg. Med. Chem. Lett. 12, 543 (2002), Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) and Tetrahedron Letters 42, 2201 (2001)).
  • literature for example, Tetrahedron Letters 38, 7963 (1997), Bioorg. Med. Chem. Lett. 12, 543 (2002), Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) and Tetrahedron Letters 42, 2201 (2001)).
  • Step 7-3 Step of producing compound (7-4)
  • Compound (7-4) is prepared by mixing compound (7-3) with an appropriate transition metal catalyst and an appropriate ligand in an inert solvent as necessary. In the presence of a base, it is produced by reacting with compound (6-5) in a suitable inert solvent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • transition metal catalyst and the ligand include, for example, the transition metal catalyst and the ligand used in Step 4-2.
  • the base include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, hydrogen Inorganic bases such as potassium iodide, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) ), Organometallic reagents such as amide, sodium bis (trimethylsilyl) amide, lithium amide, n-butyllithium, and the like.
  • potassium carbonate or cesium carbonate is used.
  • the inert solvent include acetone, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane.
  • ether solvents such as tert-butyl methyl ether and cyclopentyl methyl ether, lower alcohols such as methanol, ethanol and isopropanol, and aprotic polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide. These may be a mixed solvent.
  • toluene and N, N-dimethylformamide are used.
  • R 101 is a Cbz group, a Boc group, an Alloc group, a benzyl group, a 4-methoxybenzyl group, Represents a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, or an Fmoc group
  • R 104 represents a C 1-4 alkyl group
  • LG represents a leaving group (for example, an iodine atom, a bromine atom, Represents a chlorine atom, a substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.)
  • Z 1 and Z 2 both represent a hydrogen atom, or Z 1 and Z 2 together Represents a carbonyl group
  • Step 8-1 Preparation process of Compound (8-2) (8-2), the compound (8-1) a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .), Comprehensive Organic Transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.).
  • Step 8-2 Production Step of Compound (8-3) Compound (8-3) is produced by the same method as in Step 1-4 using Compound (8-2) and Compound (8-8) as raw materials. Is done.
  • Step 8-3 Production Step of Compound (8-4) Compound (8-4) is produced in the same manner as in step 5-3 using compound (8-3).
  • Step 8-4 Production Step of Compound (8-5)
  • Compound (8-5) uses compound (8-4) as a starting material, and literature (for example, Tetrahedron Letters, 53, 4409 (2012), JACS, 126 15195 (2004), Tetrahedron 58, 9853 (2002), Tetrahedron Letters 50, 6252 (2009), Angewandte Chemie, International Edition 51, 6480 (2012), etc.).
  • Step 8-5 Production Step of Compound (8-6)
  • Compound (8-6) uses Compound (8-5) as a raw material, and literature (for example, Organic Letters 13, 6256 (2011), Organic Letters, 12 , 4686 (2010), Tetrahedron Letters 51, 1822 (2010), Tetrahedron Letters 44, 3133 (2003), Synthesis 11, 873 (1989), Journal of Medicinal Chemistry 47, 1969 (2004), Tetrahedron Letters 44, 3133 (2003 ), Bioorganic & Medicinal Chemistry Letters 22, 4955 (2012), etc.).
  • Manufacturing method 9 The compound represented by the formula (9-4) is produced, for example, by the method shown below. [Wherein n, R 1 and R 2 have the same meanings as defined in [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, a 4-methoxybenzyl group, and 2,4-dimethoxybenzyl.
  • R 104 represents a C 1-4 alkyl group
  • R 105 is a C 1-4 alkyl group, or two OR 105 together And may be bonded to form a ring
  • both Z 1 and Z 2 represent a hydrogen atom, or Z 1 and Z 2 together represent a carbonyl group.
  • Step 9-1 Production Step of Compound (9-2)
  • Compound (9-2) is obtained from compound (8-1) and compound (9-1) based on literature (for example, Organic Letters 16, 2018, (2014), etc. ) In the same manner as described in).
  • Step 9-2 Preparation process of Compound (9-3) (9-3) in the literature from a compound (9-2) (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) , etc.) In the same manner as described in 1.
  • Step 9-3 Production Step of Compound (9-4)
  • Compound (9-4) is obtained from compound (9-3) in literature (for example, Journal of Medicinal Chemistry 45, 3905 (2002), Synlett 10, 1642 (1999). ), WO2012 / 168350, WO2004 / 113353, Organic Letters 4, 2665 (2002), Bioorg. Med. Chem. Lett. 21, 3404 (2011), Bioorg. Med. Chem. Lett. 24, 1681 (2014), etc.) In the same manner as described in 1.
  • the intermediates and target compounds in each of the above production methods are isolated by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be purified.
  • each intermediate can be subjected to the next reaction without any particular purification.
  • the optically active form of the compound of the present invention can be produced by using optically active starting materials and intermediates, or by optically resolving the final racemate.
  • Examples of the optical resolution method include a physical separation method using an optically active column and a chemical separation method such as a fractional crystallization method.
  • the diastereomer of the compound of the present invention is produced, for example, by a fractional crystallization method.
  • the pharmaceutically acceptable salt of the compound represented by the formula (1) is, for example, a compound represented by the formula (1) and a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, and acetone. It can be manufactured by mixing with.
  • the compound of the present invention is a dopamine D 4 receptor agonist, it is a central nervous disease that exhibits symptoms similar to ADHD, for example, autism spectrum disorder (diagnosis and statistical guide 5th edition of mental disorders (DSM- 5) Autism spectrum disorder in the conventional DSM-IV, which was classified as autism, Asperger syndrome, atypical pervasive developmental disorder, and childhood disintegrative disorder), ADHD-like It can be a therapeutic agent for schizophrenia, mood disorder, cognitive dysfunction and the like that show symptoms.
  • the compound of the present invention can be used in combination with a central nerve stimulant such as methylphenidate, a selective noradrenaline reuptake inhibitor such as atomoxetine, various schizophrenia therapeutic agents and the like.
  • One of the etiology hypotheses of autism spectrum disorder is the lack of neural network synchrony associated with the excitatory-inhibitory neurotransmitter imbalance in the cerebral cortex. It has been observed that amplification improves this imbalance.
  • Dopamine D 4 receptor agonists can be amplified ⁇ waves in the cerebral cortex it has been reported.
  • oxytocin a hormone produced in the hypothalamus, has been reported to be involved in social cognition, suggesting an association with autism. Since dopamine D 4 receptors are highly expressed in oxytocin-producing neurons expressed in the hypothalamic paraventricular nucleus, dopamine D 4 receptor agonists activate oxytocin-producing neurons and promote oxytocin release in the brain. It is expected. From the above, a dopamine D 4 receptor agonist can be a therapeutic agent for autism spectrum disorder through the ⁇ -wave amplification effect in the cerebral cortex and the oxytocin release promoting effect in the hypothalamus.
  • the compound of the present invention is ADHD (diagnosis name classified as attention deficit / hyperactivity disorder in conventional DSM-IV in ADHD in Diagnosis and Statistics Guide 5th Edition (DSM-5)) And preferably used for the treatment of autism spectrum disorder.
  • ADHD diagnosis name classified as attention deficit / hyperactivity disorder in conventional DSM-IV in ADHD in Diagnosis and Statistics Guide 5th Edition (DSM-5)
  • DSM-5 Diagnosis and Statistics Guide 5th Edition
  • autism spectrum disorder As a treatment for ADHD, it is particularly preferably used for ADHD whose main symptoms are attention, hyperactivity, and impulsivity.
  • the treatment of autism spectrum disorders includes, among other things, persistent deficits in social communication and social interaction, and autism spectrum disorders whose main symptoms are limited repetitive behaviors, interests and activities. Is preferably used.
  • the pharmaceutical compound After the pharmaceutical compound is taken into the living body, it undergoes metabolism to change its chemical structure, producing highly reactive intermediates, ie reactive metabolites, and toxicity (liver toxicity, allergy, tissue necrosis, mutagen) Sex, carcinogenicity, etc.).
  • One of the tests for easily evaluating the toxicity risk due to this reactive metabolite is a glutathione (GSH) trapping test using dansylated glutathione (dGSH).
  • GSH glutathione
  • dGSH dansylated glutathione
  • the compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal preparation, nasal preparation and the like.
  • topical administration agent examples include capsules, tablets, pills, powders, cachets, suppositories, and liquids.
  • injections include sterile solutions or suspensions.
  • topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
  • the above-mentioned dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives.
  • pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.
  • Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter Etc.
  • Capsules can be formulated by placing the compound of the present invention in a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.
  • injection solutions include solutions, suspensions, and emulsions. Examples thereof include an aqueous solution and a water-propylene glycol solution.
  • the solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water.
  • a solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary.
  • a solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous.
  • the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
  • the dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but usually 0.1 to 1000 mg of the compound of the present invention for an adult (50 kg body weight). / Day, preferably 0.1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.
  • Example 1 5-[(5-Methylpyridin-2-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
  • the compound of Reference Example 1 (43.9 mg, 0.231 mmol), commercially available 2- (chloromethyl) -5-methylpyridine hydrochloride (41.1 mg, 0.231 mmol), tetrabutylammonium bromide (7.5 mg, 0 0.0231 mmol), 50% aqueous potassium carbonate (255 mg), and THF (2.0 mL) were stirred at 80 ° C. overnight.
  • reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (22.4 mg, 33%).
  • Example 2 5-Benzyl-2- (1-methyl-1H-imidazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
  • a mixture of the compound of Reference Example 7 (101 mg, 0.497 mmol), potassium carbonate (103 mg, 0.746 mmol), benzyl bromide (85 mg, 0.497 mmol), and acetonitrile (2 mL) was stirred at 50 ° C. overnight.
  • the reaction solution was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 3 2- (1,3-oxazol-2-yl) -5- ⁇ [2- (trifluoromethyl) pyrimidin-5-yl] methyl ⁇ -4,5,6,7-tetrahydropyrazolo [1,5- a] Pyrazine
  • dichloromethane 2 mL
  • the compound of Reference Example 11 105 mg, 0.599 mmol
  • TFA 5.7 mg, 0.05 mmol
  • sodium triacetoxyborohydride 212 mg, 0.998 mmol
  • Examples 4-7 The compounds of Examples 4 to 7 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 2.
  • Examples 8-11 The compounds of Examples 8 to 11 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 3.
  • Examples 12-33 The compounds of Examples 12 to 36 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 1.
  • Examples 37-44 The compounds of Examples 37 to 44 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 3.
  • Examples 45-48 The compounds of Examples 45 to 48 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 1.
  • reaction solution was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (2.01 g, 59%).
  • the reaction solution was allowed to cool to room temperature, di-tert-butyl dicarbonate (10.99 g, 50.36 mmol) was added, and the mixture was stirred at room temperature for 1 hr. 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 anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (5.53 g, 49%).
  • Reference Example 7 2- (1-Methyl-1H-imidazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
  • dichloromethane 15 mL
  • hydrochloric acid-1,4-dioxane 15 mL
  • potassium carbonate 1.38 g, 10 mmol
  • water 30 mL
  • reaction solution was allowed to cool to room temperature, and the solvent was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain the title compound (2.09 g, 87%).
  • Reference Example 44 5- (2,4-Dimethoxybenzyl) -N-[(2S) -1-hydroxypropan-2-yl] -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide
  • a mixture of the compound of Reference Example 45 (515.6 mg, 1.435 mmol), L-alaninol (216 mg, 2.87 mmol), lanthanum trifluorosulfonate (84 mg, 0.143 mmol), and toluene (1 mL) was added at 70 ° C. for 24 hours. Stir for hours.
  • Reference Example 45 Ethyl 5- (2,4-dimethoxybenzyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate To a solution of the compound of Reference Example 46 (8.22 g, 25.12 mmol) in ethanol (6 mL) was added 2,4-dimethoxybenzylamine (4.62 g, 27.63 mmol) and potassium iodide (417 mg, 2.5 mmol). The mixture was stirred for 7 hours under heating and reflux. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure.
  • Reference Example 49 tert-Butyl 3-methyl-2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
  • the compound of Reference Example 50 (1.10 g, 3.0 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (367 mg, 0.45 mmol), sodium carbonate (1.27 g, 12 mmol) ), And DMF (5 mL) were added 2,4,6-trimethylboroxine (940 mg, 7.50 mmol) in an ice bath. The reaction mixture was stirred at 100 ° C.
  • Reference Example 54 5- (2,4-Dimethoxybenzyl) -4-oxo-N- (2-oxoethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide 1 mol / L hydrochloric acid (1.42 L) was added to an acetone (1.42 L) solution of the compound of Reference Example 55 (188.5 g, 0.423 mol), and the mixture was stirred at 65 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure.
  • Test Example 1 D 4 Evaluation of selectivity and agonist activity for the receptor Action of the compound of the present invention on the G protein-dependent pathway of the dopamine D 4 receptor
  • the G protein-dependent pathway is that G protein is activated by binding of G protein to guanosine triphosphate (GTP), It is a pathway that transmits signals into cells via second messengers.
  • GTP guanosine triphosphate
  • GPCRs When GPCRs are activated by a ligand, G protein binds to GPCRs, GTP binds to G ⁇ which is one of G protein subunits, and G ⁇ subunits dissociate.
  • the activated G ⁇ transmits a signal into the cell by adjusting intracellular cAMP concentration through activation and inhibition of adenylate cyclase and adjusting intracellular calcium concentration through activation of phospholipase C. Therefore, G protein-dependent pathway activity can be measured by measuring the amount of intracellular cAMP and the concentration of intracellular calcium. In this test, to measure the effect of the present invention compounds on G-protein-dependent pathway of dopamine D 4 receptors.
  • Expressing cell lines produced human brain-derived dopamine D 4 receptor gene (Gene Bank Accession No: NM_000797) , calcium-binding photoprotein aequorin, and G ⁇ 16 or to prepare a plasmid expressing a chimeric G protein such as Gqi5, these An expression cell line was prepared by introducing it into CHO cells (chinese hamster ovary cells) or HEK293 cells (human embryonic kidney 293 cells).
  • G protein-dependent agonist activity was measured as follows using intracellular calcium concentration as an index.
  • D 4 receptor gene was introduced was a CHO-K1 cell line or HEK293 cell lines were seeded in 384 well plates, 37 ° C. in a CO 2 incubator, after 24 hours of incubation, dissolved in DMSO to cells that have incorporated the pre coelenterazine The compound of the present invention was added, and the change in the amount of luminescence was measured with FDSS (manufactured by Hamamatsu Photonics).
  • the compound of the present invention is defined by setting the luminescence amount of a well not added with the compound of the present invention to 0% and the luminescence amount of a well added with 1 ⁇ M endogenous ligand (dopamine) instead of the compound of the present invention as 100%.
  • the maximum activity (Emax) was calculated.
  • the EC 50 value was calculated as a reaction concentration corresponding to 50% of the compound Emax of the present invention.
  • Test Example 2 Evaluation of bioavailability Rat PK Test
  • the pharmacokinetics of the compound of the present invention can be evaluated.
  • the SD compound or the WKY rat 7 weeks old is administered the compound of the present invention intravenously in a physiological saline solution or orally in a carboxymethylcellulose suspension or a methylcellulose suspension. Collected.
  • Intravenous administration 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration
  • Oral administration 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration
  • Plasma is obtained from the collected blood for 24 hours and the plasma drug concentration is measured by LC-MS. From this concentration transition, the area under the plasma concentration-time curve (AUC) was calculated and applied to the following formula to calculate the bioavailability.
  • Bioavailability (%) AUC after oral administration / AUC after intravenous administration ⁇ 100
  • Test Example 2 The results of Test Example 2 are shown in the table below.
  • Test Example 3 Evaluation of migration into the brain Rat Brain Translocation Test This test can evaluate the brain translocation of the compounds of the present invention.
  • the compound of the present invention is administered subcutaneously in a physiological saline solution or orally in a methylcellulose suspension solution to a SD or WKY 7-week-old rat, and plasma is administered 0.5 hour, 1 hour or 2 hours after administration. Then, brains were collected, and plasma and brain drug concentrations were measured by LC-MS. Serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis.
  • Kp, uu, brain (Brain compound concentration ⁇ (100 ⁇ protein binding rate in brain (%)) / 100) / (plasma compound concentration ⁇ (100 ⁇ protein binding rate in plasma (%)) / 100)
  • Test Example 3 The results of Test Example 3 are shown in the table below.
  • Test Example 4 Evaluation of pharmacological action on hyperactive behavior in SHR rats SHR rats in early childhood are widely recognized as highly valid ADHD models.
  • the compound of the present invention was orally administered to 6- or 7-week-old SHR rats, and the spontaneous movement for 90 minutes was evaluated after 30 minutes.
  • the measurement was performed using an open field of 900 mm ⁇ 900 mm ⁇ 420 mm, and the momentum was analyzed using a behavior analysis system LimeLight (ACTIMETRICS). Based on the solvent administration group, the cumulative exercise amount (cm) every 30 minutes of the compound administration group of the present invention was compared.
  • the compounds of Example 19 (10 mg / kg administration) and Example 22 (10 mg / kg administration) suppressed the hyperactivity behavior exhibited by SHR rats.
  • Test Example 5 Evaluation of pharmacological action on attention function in SHR rats
  • SHR rats a low spontaneous alternation behavior rate is observed in the Y-shaped maze test compared to the background animals WKY rats. Therefore, the compound of the present invention was pretreated and the effect on attention function was evaluated.
  • a Y-shaped maze device made of black acrylic: 450 mm ⁇ 100 mm ⁇ 420 mm, Horikawa Seisakusho
  • the compound of the present invention was orally administered to 6- or 7-week-old SHR rats, and the spontaneous alternation behavior rate was measured for 8 minutes from 30 minutes later. Based on the spontaneous alternation behavior rate of the vehicle administration group, the spontaneous alternation behavior rate (%) of the compound administration group was compared.
  • the compounds of Example 19 (10 mg / kg administration) and Example 22 (10 mg / kg administration) showed a significant effect of improving the spontaneous alternation behavior rate.
  • Test Example 6 Evaluation of pharmacological action against social disorder in rats treated with fetal valproic acid
  • the compound of the present invention can be pretreated to evaluate the improvement effect on social cognition. Rats exposed to valproic acid at 12.5 days of gestation are widely recognized as a highly relevant model of autism. In this rat, social cognitive impairment is observed in the three-chamber test, which is a social evaluation test. In the experiment, a social cage (600 mm ⁇ 400 mm ⁇ 220 mm, Muromachi Kikai Co., Ltd.) is used. The compound of the present invention was orally administered to a 3-week-old gestational valproic acid-treated rat, and after 30 minutes, the approach time to the rat or a new object was measured for 10 minutes. The ratio of the approach time to the rat when the approach time to the new object is taken as 100% is calculated, and the improvement rate (%) based on the result of the vehicle administration group is evaluated.
  • the compound of the present invention is a dopamine D 4 receptor agonist, it is useful as a therapeutic agent for central nervous system diseases (for example, a therapeutic agent for attention deficit hyperactivity disorder, etc.).

Abstract

Provided are fused pyrazole derivatives and pharmaceutically acceptable salts thereof that act at high selectivity on dopamine D4 receptors and are useful as agents for the treatment of attention deficit-hyperactivity disorder and the like, the fused pyrazole derivatives including a compound represented by formula (1): [in the formula, n and m each independently represent 1 or 2; W1 and W2 each independently represent a single bond or an optionally substituted C1-4 alkylene group; R1 and R2 each independently represent a hydrogen atom or the like; R3 represents a hydrogen atom, halogen atom, or the like; ring Q1 represents an optionally substituted C6-10 aryl group or the like; and ring Q2 represents an optionally substituted 5-membered heteroaryl group] or a pharmaceutically acceptable salt thereof.

Description

２位置換縮合ピラゾール誘導体2-substituted fused pyrazole derivatives
　本発明は、選択的ドパミンＤ４受容体アゴニスト作用を有する縮合ピラゾール誘導体およびその塩、並びに該誘導体を有効成分とする中枢神経系疾患治療剤に関する。 The present invention relates to a condensed pyrazole derivative having a selective dopamine D 4 receptor agonistic action and a salt thereof, and a therapeutic agent for central nervous system diseases comprising the derivative as an active ingredient.
　ドパミンＤ４受容体は、Ｇタンパク質共役受容体（G protein-coupled receptors: GPCRs）の一つであり、注意行動や認知機能に関連する前頭連合野で高発現していることから、ドパミンＤ４受容体アゴニストは、注意欠如多動性障害（attention deficit hyperactivity disorder: ADHD）等の高次脳機能に関わる中枢神経系疾患の治療薬として期待されている。ＡＤＨＤは、小児期に発症する、不注意行動（inattention）、多動性（hyperactivity）および衝動性（impulsivity）を中核症状とする発達障害の一つであり、成人期に至っても中核症状が持続することが知られている。そして、ＡＤＨＤの薬物療法における第一選択薬として、中枢神経刺激薬メチルフェニデートが用いられている。メチルフェニデートの治療効果は、神経伝達物質ドパミンの遊離に関わるドパミントランスポーターの機能調節に基づくと考えられており、即効性を示す。しかし、メチルフェニデートには、薬物依存や乱用のリスク、および動悸や頻脈、血圧変動等心臓血管系に対する副作用のリスクがある。薬物依存形成の小さいＡＤＨＤ治療剤としては、非中枢神経刺激薬である選択的ノルアドレナリン再取り込み阻害剤アトモキセチンが選択される。しかし、アトモキセチンは、治療効果の発現までに十分な投与期間が必要とされる。これらのことから、薬物依存リスクや心臓血管系副作用が軽減され、速やかな薬効発現を示すＡＤＨＤ治療剤の開発が望まれている。
　ＡＤＨＤ患者には、ドパミントランスポーター遺伝子やドパミンＤ４受容体遺伝子の変異が認められることが報告されている（例えば、非特許文献１を参照）。また、ドパミンＤ４受容体遺伝子の第３エクソン内の４８ｂｐの７回繰り返し配列の遺伝子多型を有する児童に、大脳皮質の発達遅延が認められている（例えば、非特許文献３を参照）。そして、ドパミンＤ４受容体は、注意行動や認知機能に関連する前頭連合野で高発現している（例えば、非特許文献２を参照）。これらのことから、ドパミンＤ４受容体が注意・認知機能に関連すると考えられている。加えて、ドパミンＤ４受容体は、薬物依存に関わる側坐核で発現していないことが知られている。
　以上のことから、ドパミンＤ４受容体に選択的にアゴニスト作用を示す薬剤は、ドパミン作動性神経が関わる中枢神経系疾患治療薬、殊にＡＤＨＤに対して速やかな薬効を示すと共に薬物依存性等の副作用が軽減されたＡＤＨＤ治療薬として期待されている。 Dopamine D 4 receptors, G-protein coupled receptors (G protein-coupled receptors: GPCRs ) is one of, since it is highly expressed in prefrontal cortex associated with attention behavior and cognitive function, dopamine D 4 Receptor agonists are expected as therapeutic agents for central nervous system diseases related to higher brain functions such as attention deficit hyperactivity disorder (ADHD). ADHD is one of the developmental disorders that develop in childhood with inattention, hyperactivity, and impulsivity as core symptoms. Core symptoms persist even in adulthood. It is known to do. The central nervous system stimulant methylphenidate is used as a first-line drug in ADHD drug therapy. The therapeutic effect of methylphenidate is thought to be based on the functional regulation of the dopamine transporter involved in the release of the neurotransmitter dopamine, and exhibits immediate effect. However, methylphenidate has the risk of drug dependence and abuse, and the risk of side effects on the cardiovascular system such as palpitation, tachycardia, and blood pressure fluctuations. The selective noradrenaline reuptake inhibitor atomoxetine, which is a non-central nervous stimulant, is selected as an ADHD therapeutic agent with small drug dependence formation. However, atomoxetine requires a sufficient administration period before the therapeutic effect is exhibited. For these reasons, it is desired to develop an ADHD therapeutic agent that can reduce the risk of drug dependence and cardiovascular side effects and exhibits rapid onset of efficacy.
The ADHD patient, the mutation of the dopamine transporter gene and the dopamine D 4 receptor gene is observed has been reported (e.g., see Non-Patent Document 1). Also, the child with a genetic polymorphism of seven repeat sequence of 48bp in the third exon of the dopamine D 4 receptor gene, developmental delay of the cerebral cortex has been observed (for example, see Non-Patent Document 3). Then, dopamine D 4 receptors are highly expressed in prefrontal cortex associated with attention behavior and cognitive function (e.g., see Non-Patent Document 2). From these facts, dopamine D 4 receptor is considered to be related to attention / cognitive function. In addition, dopamine D 4 receptors are known to be not expressed in the nucleus accumbens involved in drug dependence.
Based on the above, a drug that selectively exhibits an agonistic action on the dopamine D 4 receptor is a therapeutic agent for central nervous system diseases involving dopaminergic nerves, particularly ADHD and drug dependence. It is expected as a therapeutic agent for ADHD with reduced side effects.
　特許文献１には、下記式で表される化合物が代謝型グルタミン酸受容体（ｍＧｌｕＲ５）の活性を調整でき、神経障害等の種々の障害の治療、予防、および／または管理に有用であることが開示されている。
Figure JPOXMLDOC01-appb-C000005
 ［式中、Ｒ１は、アリール、ヘテロアリール等であり；
Ｒ２は、アリール、ヘテロアリール等であり；
Ｒ３およびＲ４はそれぞれ独立して水素、ハロゲン、低級アルキル等であり；
Ｌ１は、結合、－Ｏ－、－ＣＲ５Ｒ６－等であり；
Ｌ２は、結合、－Ｏ－、－ＣＲ５Ｒ６－等であり；
ＸはＣまたはＮであり；
ＹはＯ、Ｓ、Ｎ等であり；
ＺはＯ、Ｓ、Ｎ等であり；
Ｒ５およびＲ６はそれぞれ独立して水素、ハロゲン、または低級アルキルであるか、ＣＲ５Ｒ６はＣ＝Ｏであるか；あるいはＲ５およびＲ６はそれらが結合した炭素原子と一緒になって３から７員のシクロアルキルを形成してもよく；
ＧはＮまたはＣＨであり；
ｏは０、１、または２であり；
ｐは１または２である］ In Patent Document 1, a compound represented by the following formula can regulate the activity of a metabotropic glutamate receptor (mGluR5), and is useful for the treatment, prevention, and / or management of various disorders such as neuropathy. It is disclosed.
Figure JPOXMLDOC01-appb-C000005
 [Wherein R 1 is aryl, heteroaryl, etc .;
R 2 is aryl, heteroaryl, etc .;
R 3 and R 4 are each independently hydrogen, halogen, lower alkyl, etc .;
L 1 is a bond, —O—, —CR 5 R 6 — and the like;
L 2 is a bond, —O—, —CR 5 R 6 — and the like;
X is C or N;
Y is O, S, N, etc .;
Z is O, S, N, etc .;
R 5 and R 6 are each independently hydrogen, halogen, or lower alkyl, or CR 5 R 6 is C═O; or R 5 and R 6 are taken together with the carbon atom to which they are attached. May form 3 to 7 membered cycloalkyl;
G is N or CH;
o is 0, 1, or 2;
p is 1 or 2]
　しかしながら、特許文献１には縮合ピラゾール誘導体は具体的に開示されていない。 However, Patent Document 1 does not specifically disclose a condensed pyrazole derivative.
特表２０１２－５２２７９３号公報Special table 2012-522793 gazette
　本発明の課題は、中枢神経系疾患治療薬として有用な新規な選択的ドパミンＤ４受容体アゴニストを提供することにある。 An object of the present invention is to provide a novel selective dopamine D 4 receptor agonist useful as a therapeutic agent for central nervous system diseases.
　本発明者らは、上記課題を達成するために鋭意研究した結果、下記式（１）で表される化合物およびその薬学上許容される塩（以下必要に応じ「本発明化合物」と略称することがある。）が優れた選択的ドパミンＤ４受容体アゴニスト作用を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary). Has been found to have an excellent selective dopamine D 4 receptor agonist activity, and the present invention has been 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）：
Figure JPOXMLDOC01-appb-C000006
 （式中、ｎおよびｍは、それぞれ独立して、１または２を表し；
　Ｗ１およびＷ２は、それぞれ独立して、単結合、またはＣ１－４アルキレン基（該基は同種または異種の１～２個のハロゲン原子で置換されていてもよい。）を表し；
　Ｒ１およびＲ２は、それぞれ独立して、水素原子、ハロゲン原子、もしくは置換されていてもよいＣ１－６アルキル基であるか、またはそれらが結合する炭素原子と一緒になって、３員～８員のシクロアルカン環を形成してもよく；
　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アルキル基を表し；
　環Ｑ１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～１０員のヘテロアリール基を表し;
　環Ｑ２は、置換されていてもよい５員のヘテロアリール基を表すが、以下の化合物
Figure JPOXMLDOC01-appb-C000007
 を除く）で表される化合物またはその薬学上許容される塩。 Item [1]
Formula (1):
Figure JPOXMLDOC01-appb-C000006
 (In the formula, n and m each independently represent 1 or 2;
W 1 and W 2 each independently represent a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms);
R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group, or together with the carbon atom to which they are attached, a 3-membered May form a ˜8 membered cycloalkane ring;
R 3 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group;
Ring Q 1 represents an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered heteroaryl group;
Ring Q 2 represents an optionally substituted 5-membered heteroaryl group, and the following compounds
Figure JPOXMLDOC01-appb-C000007
 Or a pharmaceutically acceptable salt thereof.
項〔２〕
　ｎおよびｍが、それぞれ独立して、１または２であり；
　Ｗ１およびＷ２が、それぞれ独立して、単結合、またはＣ１－４アルキレン基（該基は同種または異種の１～２個のハロゲン原子で置換されていてもよい。）であり；
　Ｒ１およびＲ２が、それぞれ独立して、水素原子、ハロゲン原子、もしくはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）であるか、またはそれらが結合する炭素原子と一緒になって、３員～８員のシクロアルカン環を形成してもよく；
　Ｒ３が、水素原子、ハロゲン原子、シアノ基、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）であり；
　環Ｑ１が、
（１）５員～１０員のヘテロアリール基（該基は、
　（ａ）ハロゲン原子、
　（ｂ）Ｃ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）、
　（ｃ）Ｃ２－６アルケニル基（該基は同種または異種の１～４個のハロゲン原子で置換されていてもよい。）、
　（ｄ）Ｃ１－６アルコキシ基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、
　（ｅ）シアノ基、および
　（ｆ）アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）からなる群から選択される同種または異種の１～４個の基で置換されていてもよく、また２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環（該環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）、または
（２）Ｃ６－１０アリール基（該基は、本項中の前記（１）の（ａ）～（ｆ）からなる群から選択される同種または異種の１～４個の基で置換されていてもよく、また２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環（該環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）であり；
　環Ｑ２が、
　（ａ）ハロゲン原子、および
　（ｂ）Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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５員のヘテロアリール基である、項〔１〕に記載の化合物またはその薬学上許容される塩。 Item [2]
n and m are each independently 1 or 2;
W 1 and W 2 are each independently a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms);
R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). Or together with the carbon atom to which they are attached may form a 3- to 8-membered cycloalkane ring;
R 3 is a hydrogen atom, a halogen atom, a cyano group, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
Ring Q 1 is
(1) a 5- to 10-membered heteroaryl group (the group is
(A) a halogen atom,
(B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups);
(C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms),
(D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
(E) a cyano group, and (f) an amino group (the group is substituted with one or two groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) May be substituted with 1 to 4 groups of the same or different types selected from the group consisting of, and when two substituents are substituted with adjacent carbon atoms, A 5- to 8-membered ring together with the carbon atom to which is bonded (the ring is the same kind selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) Alternatively, it may be substituted with 1 to 4 different groups.). ), Or (2) a C 6-10 aryl group (this group is the same or different 1 to 4 groups selected from the group consisting of (a) to (f) of (1) in this section In the case where two substituents are substituted by adjacent carbon atoms, a 5- to 8-membered ring together with the carbon atoms to which they are bonded (the ring is a halogen atom) , A hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group may be substituted with the same or different 1 to 4 groups selected from the group consisting of .);
Ring Q 2 is
The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). The compound or a pharmaceutically acceptable salt thereof according to Item [1], wherein the compound is a 5-membered heteroaryl group optionally substituted by 1 to 2 groups.
項〔３〕
　ｍが１であり；
　Ｗ１およびＷ２がいずれも単結合である、項〔１〕または項〔２〕に記載の化合物またはその薬学上許容される塩。 Item [3]
m is 1;
The compound or a pharmaceutically acceptable salt thereof according to Item [1] or Item [2], wherein both W 1 and W 2 are a single bond.
項〔４〕
　ｎが１であり；
　Ｒ１およびＲ２がいずれも水素原子である、項〔１〕～項〔３〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [4]
n is 1;
The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [3], wherein R 1 and R 2 are both hydrogen atoms.
項〔５〕
　環Ｑ１が、１～３個の窒素原子を含有する５員～１０員のヘテロアリール基（該基は、
　（ａ）ハロゲン原子、
　（ｂ）Ｃ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）、
　（ｃ）Ｃ２－６アルケニル基（該基は同種または異種の１～４個のハロゲン原子で置換されていてもよい。）、
　（ｄ）Ｃ１－６アルコキシ基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、
　（ｅ）シアノ基、および
　（ｆ）アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）からなる群から選択される同種または異種の１～４個の基で置換されていてもよく、また２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環（該環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）である、項〔１〕～項〔４〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [5]
Ring Q 1 is a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms (the group is
(A) a halogen atom,
(B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups);
(C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms),
(D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
(E) a cyano group, and (f) an amino group (the group is substituted with one or two groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) May be substituted with 1 to 4 groups of the same or different types selected from the group consisting of, and when two substituents are substituted with adjacent carbon atoms, A 5- to 8-membered ring together with the carbon atom to which is bonded (the ring is the same kind selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) Alternatively, it may be substituted with 1 to 4 different groups.). The compound according to any one of Items [1] to [4] or a pharmaceutically acceptable salt thereof.
項〔６〕
　環Ｑ１が、下記式（２ａ）または（２ｂ）：
Figure JPOXMLDOC01-appb-C000008
 （式中、Ｘ１は、ＮまたはＣＲ１２を表し；
　Ｒ１１は、ハロゲン原子、Ｃ１－６アルコキシ基（該基は１～３個のハロゲン原子で置換されていてもよい。）、またはＣ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）を表し；
　Ｒ１２、Ｒ１３、Ｒ１４およびＲ１５は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、Ｃ２－６アルケニル基（該基は同種または異種の１～４個のハロゲン原子で置換されていてもよい。）、Ｃ１－６アルコキシ基（該基は１～３個のハロゲン原子で置換されていてもよい。）、またはアミノ基（該基は、同種または異種の１～２個のＣ１－６アルキル基で置換されていてもよい。）を表すか；
　または、Ｒ１１およびＲ１２、またはＲ１１およびＲ１５が、それらが結合する炭素原子と一緒になって、５員～８員のシクロアルカン環、５員～８員の飽和ヘテロ環、または５員～８員のシクロアルケン環（該シクロアルカン環、飽和ヘテロ環、または５員～８員のシクロアルケン環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）で表される基である、項〔１〕～項〔４〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [6]
Ring Q 1 is represented by the following formula (2a) or (2b):
Figure JPOXMLDOC01-appb-C000008
 Wherein X 1 represents N or CR 12 ;
R 11 represents a halogen atom, a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkyl group (the group includes a halogen atom and a hydroxy group). Which may be substituted with the same or different 1 to 3 groups selected from the group consisting of groups);
R 12 , R 13 , R 14 and R 15 each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group (the group is substituted with 1 to 3 halogen atoms of the same or different types). A C 2-6 alkenyl group (the group may be substituted with 1 to 4 halogen atoms of the same or different types), a C 1-6 alkoxy group (1 to 3 groups Or an amino group (the group may be substituted with the same or different 1 to 2 C 1-6 alkyl groups);
Or R 11 and R 12 , or R 11 and R 15 , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring, a 5- to 8-membered saturated heterocycle, or 5 Membered to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocyclic ring, or 5-membered to 8-membered cycloalkene ring includes a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) And may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of: The compound or a pharmaceutically acceptable salt thereof according to any one of items [1] to [4], which is a group represented by
項〔７〕
　環Ｑ１が、式（２ａ）で表される基である、項〔６〕に記載の化合物またはその薬学上許容される塩。 Item [7]
The compound according to item [6] or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is a group represented by formula (2a).
項〔８〕
　環Ｑ１が、式（２ｂ）で表される基である、項〔６〕に記載の化合物またはその薬学上許容される塩。 Item [8]
The compound or a pharmaceutically acceptable salt thereof according to Item [6], wherein Ring Q 1 is a group represented by Formula (2b).
項〔９〕
　Ｘ１がＣＲ１２である、項〔６〕～項〔８〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [9]
The compound or a pharmaceutically acceptable salt thereof according to any one of Items [6] to [8], wherein X 1 is CR 12 .
項〔１０〕
　Ｒ１１およびＲ１２、またはＲ１１およびＲ１５が、それらが結合する炭素原子と一緒になって、５員～８員のシクロアルカン環、５員～８員の飽和ヘテロ環、または５員～８員のシクロアルケン環（該シクロアルカン環、飽和ヘテロ環、または５員～８員のシクロアルケン環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成している、項〔６〕～項〔９〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [10]
R 11 and R 12 , or R 11 and R 15 , together with the carbon atom to which they are attached, are a 5 to 8 membered cycloalkane ring, a 5 to 8 membered saturated heterocycle, or a 5 to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is composed of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. Or a compound thereof according to any one of items [6] to [9], which may be substituted with 1 to 4 groups of the same or different types selected from the group A pharmaceutically acceptable salt.
項〔１１〕
　Ｒ１１が１～３個のフッ素原子で置換されていてもよいＣ１－４アルキル基である、項〔６〕～項〔９〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [11]
Item 11. The compound according to any one of Items [6] to [9] or a pharmaceutically acceptable salt thereof, wherein R 11 is a C 1-4 alkyl group optionally substituted with 1 to 3 fluorine atoms. Salt.
項〔１２〕
　環Ｑ２が、
　（ａ）ハロゲン原子、および
　（ｂ）Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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オキサゾール基、イソキサゾール基、イミダゾール基、ピラゾール基、オキサジザゾール基、トリアゾール基、チアゾール基、イソチアゾール基、またはチアジアゾール基である、項〔１〕～項〔１１〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [12]
Ring Q 2 is
The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). The oxazole group, isoxazole group, imidazole group, pyrazole group, oxadizazole group, triazole group, thiazole group, isothiazole group, or thiadiazole group that may be substituted with one or two groups of Item [11] The compound according to any one of [11] or a pharmaceutically acceptable salt thereof.
項〔１３〕
　環Ｑ２が、
　（ａ）ハロゲン原子、および
　（ｂ）Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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オキサゾール基、イソキサゾール基、イミダゾール基、またはピラゾール基である、項〔１２〕に記載の化合物またはその薬学上許容される塩。 Item [13]
Ring Q 2 is
The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). The compound or a pharmaceutically acceptable salt thereof according to Item [12], which is an oxazole group, an isoxazole group, an imidazole group, or a pyrazole group which may be substituted with 1 to 2 groups of
項〔１４〕
　環Ｑ２が、下記式（３ａ）、（３ｂ）または（３ｃ）：
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｘ２は、ＯまたはＮＲ２３（Ｒ２３は水素原子、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）を表す）を表し；
　Ｒ２１およびＲ２２は、それぞれ独立して、水素原子、ハロゲン原子、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）を表す。）で表される基である、項〔１〕～項〔１３〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [14]
Ring Q 2 is represented by the following formula (3a), (3b) or (3c):
Figure JPOXMLDOC01-appb-C000009
 (In the formula, X 2 represents O or NR 23 (R 23 represents a hydrogen atom or a C 1-6 alkyl group (the group may be substituted with the same or different 1 to 3 halogen atoms).) Represents);
R 21 and R 22 each independently represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). To express. The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [13], which is a group represented by
項〔１５〕
　環Ｑ２が、式（３ａ）で表される基である、項〔１４〕に記載の化合物またはその薬学上許容される塩。 Item [15]
The compound according to item [14] or a pharmaceutically acceptable salt thereof, wherein ring Q 2 is a group represented by formula (3a).
項〔１６〕
　Ｘ２がＯである、項〔１４〕または項〔１５〕に記載の化合物またはその薬学上許容される塩。 Item [16]
The compound or a pharmaceutically acceptable salt thereof according to Item [14] or Item [15], wherein X 2 is O.
項〔１７〕
　Ｒ２１およびＲ２２がいずれも水素原子である、項〔１４〕～項〔１６〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [17]
The compound or a pharmaceutically acceptable salt thereof according to any one of Items [14] to [16], wherein R 21 and R 22 are both hydrogen atoms.
項〔１８〕
　Ｒ３が、水素原子、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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学上許容される塩。 Item [18]
Item [1] to Item [17], wherein R 3 is a hydrogen atom or a C 1-6 alkyl group (this group may be substituted with the same or different 1 to 3 halogen atoms). Or a pharmaceutically acceptable salt thereof.
項〔１９〕
　Ｒ３がＣ１－４アルキル基である、項〔１〕～項〔１８〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [19]
The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [18], wherein R 3 is a C 1-4 alkyl group.
項〔２０〕
　下記式のいずれかで表される項〔１〕に記載の化合物、またはその薬学上許容される塩。
Figure JPOXMLDOC01-appb-C000010
 Item [20]
The compound according to item [1] represented by any one of the following formulas, or a pharmaceutically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000010
項〔２１〕
　下記式のいずれかで表される項〔１〕に記載の化合物、またはその薬学上許容される塩。
Figure JPOXMLDOC01-appb-C000011
 Item [21]
The compound according to item [1] represented by any one of the following formulas, or a pharmaceutically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000011
項〔２２〕
　項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する医薬。 Item [22]
A pharmaceutical comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
項〔２３〕
　項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する、注意欠如多動性障害、自閉症スペクトラム障害、統合失調症、気分障害、および認知機能障害からなる群から選ばれる中枢神経性疾患の治療剤。 Item [23]
Containing the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient, attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, A therapeutic agent for central nervous system diseases selected from the group consisting of mood disorders and cognitive impairments.
項〔２４〕
　項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する、注意欠如多動性障害の治療剤。 Item [24]
A therapeutic agent for attention deficit / hyperactivity disorder comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
項〔２５〕
　注意欠如多動性障害が注意欠如（inattention）を主症状とする障害である、項〔２４〕に記載の治療剤。 Item [25]
The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly caused by attention deficit (inattention).
項〔２６〕
　注意欠如多動性障害が多動性（hyperactivity）を主症状とする障害である、項〔２４〕に記載の治療剤。 Item [26]
The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly having hyperactivity.
項〔２７〕
　注意欠如多動性障害が衝動性（impulsivity）を主症状とする障害である、項〔２４〕に記載の治療剤。 [27]
The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly having impulsivity.
項〔２８〕
　項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する、自閉症スペクトラム障害の治療剤。 Item [28]
A therapeutic agent for autism spectrum disorder, comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
項〔２９〕
　自閉症スペクトラム障害が社会的コミュニケーションと社会的相互作用の持続的な欠陥を主症状とする障害である、項〔２８〕に記載の治療剤。 Item [29]
The therapeutic agent according to Item [28], wherein the autism spectrum disorder is a disorder whose main symptom is a persistent defect in social communication and social interaction.
項〔３０〕
　自閉症スペクトラム障害が制限された反復される行動や興味や活動の様式を主症状とする障害である、項〔２８〕に記載の治療剤。 Item [30]
The therapeutic agent according to Item [28], wherein the autism spectrum disorder is a disorder whose main symptom is a repeated behavior, interest, or activity pattern with limited autism spectrum disorder.
項〔３１〕
　項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩の治療上有効な量を、それが必要な患者に投与することを特徴とする、注意欠如多動性障害、自閉症スペクトラム障害、統合失調症、気分障害、および認知機能障害からなる群から選ばれる中枢神経性疾患の治療方法。 Item [31]
Lack of attention, characterized by administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof A method for treating a central nervous system disease selected from the group consisting of hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive impairment.
項〔３２〕
　注意欠如多動性障害、自閉症スペクトラム障害、統合失調症、気分障害、および認知機能障害からなる群から選ばれる中枢神経性疾患の治療剤を製造するための、項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩の使用。 Item [32]
Item [1] to Item [1] for producing a therapeutic agent for central nervous system disease selected from the group consisting of attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction 21] Use of the compound according to any one of [21] or a pharmaceutically acceptable salt thereof.
項〔３３〕
　注意欠如多動性障害、自閉症スペクトラム障害、統合失調症、気分障害、および認知機能障害からなる群から選ばれる中枢神経性疾患の治療に用いるための、項〔１〕～項〔２１〕のいずれか一項に記載の化合物またはその薬学上許容される塩。 Item [33]
Item [1] to Item [21] for use in the treatment of central nervous disease selected from the group consisting of attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive impairment Or a pharmaceutically acceptable salt thereof.
　本発明化合物は、ドパミンＤ４受容体に対して強いアゴニスト作用を示す。加えて、好ましい態様においては、経口投与時の生物学的利用率（バイオアベイラビリティー）が高く、脳移行性が優れており、さらに肝毒性リスクも低い。したがって、本発明化合物は、薬物依存性を持たず、心臓血管系の副作用が軽減され、低用量で速やかに薬効が発現する、安全性の高い優れた中枢神経系疾患治療薬（例えば、注意欠如多動性障害の治療薬等）として有用である。 The present invention compounds exhibit strong agonistic effect on dopamine D 4 receptors. In addition, in a preferred embodiment, the bioavailability at the time of oral administration (bioavailability) is high, the ability to transfer to the brain is excellent, and the risk of hepatotoxicity is also low. Therefore, the compound of the present invention is highly safe and excellent in the treatment of central nervous system diseases (for example, lack of attention). It is useful as a therapeutic agent for hyperactivity disorder.
実施例１９および実施例２２の化合物を投与した場合の、試験例４のＳＨＲラットにおける多動行動に対する薬理作用の評価結果である。It is an evaluation result of the pharmacological action with respect to hyperactivity behavior in the SHR rat of Test Example 4 when the compounds of Example 19 and Example 22 are administered. 実施例１９および実施例２２の化合物を投与した場合の、試験例５のＳＨＲラットにおける注意機能に対する薬理作用の評価結果である。It is an evaluation result of the pharmacological action with respect to the attention function in the SHR rat of Test Example 5 when the compounds of Example 19 and Example 22 are administered.
　以下に、本発明を詳細に説明する。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」等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のアルキル基と同義である。 The present invention is described in 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.
　「ハロゲン原子」の具体例としては、フッ素原子、塩素原子、臭素原子またはヨウ素原子が挙げられる。 Specific examples of “halogen atom” include fluorine atom, chlorine atom, bromine atom or iodine atom.
　「Ｃ１－６アルキル基」は、炭素数１～６個を有する直鎖状もしく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 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.
　「Ｃ２－６アルケニル基」は、１～３個の炭素－炭素二重結合を含有する、炭素数２～６個を有する直鎖状もしくは分枝状の不飽和炭化水素基を意味する。好ましくは「Ｃ２－４アルケニル基」である。「Ｃ２－６アルケニル基」の具体例としては、例えば、エテニル、プロペニル、ブテニル、ペンテニル、ヘキセニル等が挙げられる。 The “C 2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 carbon-carbon double bonds. A “C 2-4 alkenyl group” is preferable. Specific examples of “C 2-6 alkenyl group” include, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
　「Ｃ１－４アルキレン基」は、炭素数１～４個を有する直鎖状もしくは分枝状の飽和炭化水素基、または炭素数３～４個を有する環状構造を含む二価の飽和炭化水素基を意味する。
　直鎖状もしくは分枝状「Ｃ１－４アルキレン基」の具体例としては、例えば、メチレン、エチレン、プロピレン、ブチレン、１－メチルメチレン、１－エチルメチレン、１－プロピルメチレン、１－メチルエチレン、２－メチルエチレン、１－エチルエチレン等が挙げられ、好ましくは、メチレン、エチレンが挙げられる。
　環状構造を含む「Ｃ１－４アルキレン基」の具体例としては、例えば、下記群で表される基等が挙げられる。
Figure JPOXMLDOC01-appb-C000012
 The “C 1-4 alkylene group” is a divalent saturated hydrocarbon containing a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms or a cyclic structure having 3 to 4 carbon atoms. Means group.
Specific examples of the linear or branched “C 1-4 alkylene group” include, for example, methylene, ethylene, propylene, butylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene. 2-methylethylene, 1-ethylethylene and the like, preferably methylene and ethylene.
Specific examples of the “C 1-4 alkylene group” containing a cyclic structure include, for example, groups represented by the following groups.
Figure JPOXMLDOC01-appb-C000012
　「Ｃ１－６アルコキシ基」は「Ｃ１－６アルキル－Ｏ－基」を指し、その「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 alkoxy group” refers to a “C 1-6 alkyl-O— group”, and the “C 1-6 alkyl” portion has the same meaning as the above “C 1-6 alkyl”. A “C 1-4 alkoxy group” is preferable. Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
　「Ｃ３－７シクロアルキル基」は、３員～７員の単環式の飽和または部分不飽和の炭化水素基を意味する。「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、シクロヘプチル、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 3- to 7-membered monocyclic saturated or partially unsaturated hydrocarbon group. Specific examples of “C 3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and the like.
　「３員～８員のシクロアルカン環」は、３員～８員の単環式の飽和炭化水素環を意味する。好ましくは５員もしくは６員の飽和炭化水素環である。「３員～８員のシクロアルカン環」の具体例としては、例えば、シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロヘプタン環、シクロオクタン環等が挙げられる。 “3- to 8-membered cycloalkane ring” means a 3- to 8-membered monocyclic saturated hydrocarbon ring. A 5-membered or 6-membered saturated hydrocarbon ring is preferred. Specific examples of the “3- to 8-membered cycloalkane ring” include, for example, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring 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」（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. Preferred is “C 6 aryl group” (phenyl). 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、フェニルと５員～７員の窒素原子、硫黄原子および酸素原子から選択されるヘテロ原子を同一または異なって１個以上（例えば１～４個）含有するヘテロ環、または５員～７員の飽和もしくは部分不飽和の炭化水素環（例えば、シクロペンタン、シクロペンテン、シクロヘキサン等）と縮環した基も包含される。但し、芳香環と非芳香族環とが縮環する多環式「Ｃ６－１０アリール基」の場合には、芳香環のみが「基」の結合手を有する。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-C000013
 The “C 6-10 aryl group” contains one or more (for example, 1 to 4) of the same or different heteroatoms selected from phenyl and 5- to 7-membered nitrogen, sulfur and oxygen atoms. Or a group condensed with a 5- to 7-membered saturated or partially unsaturated hydrocarbon ring (eg, cyclopentane, cyclopentene, cyclohexane, etc.). However, in the case of a polycyclic “C 6-10 aryl group” in which an aromatic ring and a non-aromatic ring are condensed, only the aromatic ring has a “group” bond. Specific examples of the group include groups represented by the following formulas.
Figure JPOXMLDOC01-appb-C000013
　「ヘテロアリール基」としては、例えば、５員～１０員の単環式もしくは多環式の芳香族基等が挙げられ、該基は、窒素原子、硫黄原子および酸素原子から選択さ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。「多環式のヘテロアリール基」としては、２もしくは３環式の基が好ましく、２環式の基がより好ましい。多環式のヘテロアリール基には、前記単環式のへテロアリール基と芳香族環（ベンゼン、ピリジン等）または非芳香族環（シクロヘキシル、ピペリジン等）とが縮環したものも含む。「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等が挙げられる。
Figure JPOXMLDOC01-appb-C000014
 Examples of the “heteroaryl group” include a 5- to 10-membered monocyclic or polycyclic aromatic group, and the group is the same or selected from a nitrogen atom, a sulfur atom and an oxygen atom, 1 or more (for example, 1 to 4) heterogeneous heteroatoms are contained. As the “polycyclic heteroaryl group”, a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable. The polycyclic heteroaryl group includes those in which the monocyclic heteroaryl group is condensed with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, piperidine, etc.). Specific examples of the “heteroaryl group” include, for example, a group represented by the following formula.
Figure JPOXMLDOC01-appb-C000014
　環Ｑ１における「５員～１０員のヘテロアリール基」としては、１～３個の窒素原子を含有する５員～１０員のヘテロアリール基が好ましく、
下記式で表される基等がより好ましく、
Figure JPOXMLDOC01-appb-C000015
 下記式で表される基がさらに好ましい。
Figure JPOXMLDOC01-appb-C000016
 The “5- to 10-membered heteroaryl group” in ring Q 1 is preferably a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms,
A group represented by the following formula is more preferable,
Figure JPOXMLDOC01-appb-C000015
 A group represented by the following formula is more preferable.
Figure JPOXMLDOC01-appb-C000016
　環Ｑ２における「５員のヘテロアリール基」の具体例としては、例えば、オキサゾール基、イソキサゾール基、ピロール基、イミダゾール基、ピラゾール基、オキサジザゾール、トリアゾール基、チアゾール基、イソチアゾール基、チアジアゾール基、テトラゾール基等が挙げられ、オキサゾール基、イソキサゾール基、イミダゾール基、ピラゾール基が好ましく、オキサゾール基がより好ましい。 Specific examples of the “5-membered heteroaryl group” in ring Q 2 include, for example, an oxazole group, an isoxazole group, a pyrrole group, an imidazole group, a pyrazole group, an oxadizazole, a triazole group, a thiazole group, an isothiazole group, a thiadiazole group, Examples include tetrazole groups, and oxazole groups, isoxazole groups, imidazole groups, and pyrazole groups are preferable, and oxazole groups are more preferable.
　前記式において環を横切る結合手は、「基」が該環における置換可能な位置で結合することを意味する。例えば、下記式
Figure JPOXMLDOC01-appb-C000017
 のヘテロアリール基の場合には、２－ピリジル基、３-ピリジル基または４－ピリジル基であることを意味する。 The bond across the ring in the above formula means that the “group” is bonded at a substitutable position in the ring. For example, the following formula
Figure JPOXMLDOC01-appb-C000017
 In the case of the heteroaryl group, it means a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group.
　更に、「ヘテロアリール基」が多環式の基である場合において、例えば、下記式
Figure JPOXMLDOC01-appb-C000018
 で表される場合には、１－ベンゾイミダゾリル、または２－ベンゾイミダゾリルの他に、４－、５－、６－または７－ベンゾイミダゾリルであってもよい。 Further, when the “heteroaryl group” is a polycyclic group, for example, the following formula
Figure JPOXMLDOC01-appb-C000018
 In addition to 1-benzimidazolyl or 2-benzimidazolyl, 4-, 5-, 6- or 7-benzimidazolyl may be used.
　但し、芳香環と非芳香族環（シクロヘキサン環、ピペリジン環等）とが縮環する多環式へテロアリール基の場合には、芳香環のみが「基」の結合手を有する。例えば、下記式
Figure JPOXMLDOC01-appb-C000019
 で表される「多環式のヘテロアリール基」の場合には、「基」が２－、３－、または４－位で結合することを意味する。 However, in the case of a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (cyclohexane ring, piperidine ring, etc.) are condensed, only the aromatic ring has a “group” bond. For example, the following formula
Figure JPOXMLDOC01-appb-C000019
 In the case of the “polycyclic heteroaryl group” represented by the formula, it means that the “group” is bonded at the 2-, 3-, or 4-position.
　「置換されていてもよい」で定義される基における置換基は、特に数量に指定がない限り、置換可能な位置に、置換可能な数の範囲内で置換することができる。例えば、置換されていてもよいＣ１－６アルキル基がメチル基である場合、そのメチル基における置換可能な置換基数の範囲は１～３である。置換されていてもよいＣ６－１０アリール基がフェニル基である場合、そのフェニル基における置換可能な置換基数の範囲は１～５である。また、置換されている基が複数ある場合は、それらは同一でも異なっていてもよい。さらに、特に指示した場合を除き、各々の基の説明はその基が他の基の一部分または置換基である場合にも該当する。 Unless otherwise specified, the substituent in the group defined as “optionally substituted” can be substituted at a substitutable position within the substitutable number range. For example, when the optionally substituted C 1-6 alkyl group is a methyl group, the range of the number of substitutable substituents in the methyl group is 1 to 3. When the optionally substituted C 6-10 aryl group is a phenyl group, the number of substitutable substituents in the phenyl group ranges from 1 to 5. Further, when there are a plurality of substituted groups, they may be the same or different. Further, unless otherwise indicated, the description of each group also applies if the group is part of another group or a substituent.
　「置換されていてもよいＣ１－４アルキレン基」における置換基としては、例えば、ヒドロキシ基、ハロゲン原子、Ｃ３－７シクロアルキル基、Ｃ１－６アルコキシ基等が挙げられ、好ましくは、フッ素原子が挙げられる。 Examples of the substituent in the “optionally substituted C 1-4 alkylene group” include a hydroxy group, a halogen atom, a C 3-7 cycloalkyl group, a C 1-6 alkoxy group, and the like, A fluorine atom is mentioned.
　「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
（１）ハロゲン原子、
（２）Ｃ３－７シクロアルキル基、
（３）Ｃ１－６アルコキシ基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、
（４）シアノ基、
（５）アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）、
（６）ヒドロキシ基、および
（７）アミノカルボニル基（該アミノは、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）等が挙げられる。
　好ましくは、フッ素原子、ヒドロキシ基、Ｃ１－６アルコキシ基が挙げられる。 Examples of the substituent in the “optionally substituted C 1-6 alkyl group” include (1) a halogen atom,
(2) a C 3-7 cycloalkyl group,
(3) C 1-6 alkoxy group (this group may be substituted with 1 to 3 halogen atoms of the same or different types),
(4) a cyano group,
(5) Amino group (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) ,
(6) a hydroxy group, and (7) an aminocarbonyl group (the amino is a same or different 1-2 groups selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted).
Preferable examples include a fluorine atom, a hydroxy group, and a C 1-6 alkoxy group.
　「置換されていてもよいアリール基」、「置換されていてもよいヘテロアリール基」における置換基としては、例えば
（１）ハロゲン原子、
（２）Ｃ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）、
（３）Ｃ１－６アルコキシ基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、
（４）シアノ基、
（５）アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）、
（６）ヒドロキシ基、および
（７）アミノカルボニル基（該アミノは、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）等が挙げられる。
　好ましくは、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、シアノ基、アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）が挙げられる。 Examples of the substituent in the “optionally substituted aryl group” and “optionally substituted heteroaryl group” include (1) a halogen atom,
(2) C 1-6 alkyl group (this group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups),
(3) C 1-6 alkoxy group (this group may be substituted with 1 to 3 halogen atoms of the same or different types),
(4) a cyano group,
(5) Amino group (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) ,
(6) a hydroxy group, and (7) an aminocarbonyl group (the amino is a same or different 1-2 groups selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted).
Preferably, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a cyano group, an amino group (the group is selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted with 1-2 groups of the same or different types.
　「Ｒ１およびＲ２が、結合する炭素原子と一緒になって、３員～８員のシクロアルカン環を形成してもよい」とは、（１）Ｒ１およびＲ２が、同一の炭素原子に結合して、それらが結合する炭素原子と一緒になって３員～８員のスピロシクロアルカン環を形成する場合、および（２）Ｒ１およびＲ２が、隣接する炭素原子に結合して、それらが結合する炭素原子と一緒になって３員～８員の縮合シクロアルカン環を形成する場合が挙げられる。 “R 1 and R 2 together with the carbon atoms to which they are bonded may form a 3- to 8-membered cycloalkane ring” means that (1) R 1 and R 2 are the same carbon When attached to an atom and together with the carbon atom to which they are attached form a 3- to 8-membered spirocycloalkane ring, and (2) R 1 and R 2 are attached to an adjacent carbon atom. And the case where they form a 3- to 8-membered fused cycloalkane ring together with the carbon atom to which they are bonded.
　「環Ｑ１の２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環を形成してもよい」とは、２つの置換基が環Ｑ１上の隣接する２つの炭素原子にそれぞれ結合して、それらが結合する炭素原子を含む環Ｑ１の部分と一緒になって５員～８員の環を形成する場合が挙げられ、環としてはシクロアルカン環、飽和ヘテロ環、シクロアルケン環などが挙げられる。ここで飽和ヘテロ環のヘテロ原子は環Ｑ１の置換基に含まれるヘテロ原子（アルコキシ基中の酸素原子、アミノ基中の窒素原子など）に由来する。また、該シクロアルカン環、飽和ヘテロ環、または５員～８員のシクロアルケン環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。具体例としては、下記群で表わされる「基」等が挙げられる。
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
 “When two substituents of ring Q 1 are substituted by adjacent carbon atoms, they may be combined with the carbon atoms to which they are attached to form a 5- to 8-membered ring”. one of the substituents attached to two adjacent carbon atoms on the ring Q 1, if they form a ring of 5 to 8 membered together with partial ring Q 1 containing a carbon atom bonded Examples of the ring include a cycloalkane ring, a saturated heterocyclic ring, and a cycloalkene ring. Wherein heteroatom saturated heterocyclic ring derived from a hetero atom contained in the substituent of the ring Q 1 (the oxygen atom in the alkoxy group, such as a nitrogen atom in an amino group). The cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. It may be substituted with 1 to 4 groups of the same or different types. Specific examples include “groups” represented by the following groups.
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
　本発明化合物は、水和物および／または溶媒和物の形で存在することもあるので、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本発明化合物に含まれる。さらに、本発明化合物はあらゆる態様の結晶形のものも包含している。
　式（１）で表される化合物（以下必要に応じ「化合物（１）」と略称することがある。）の薬学上許容される塩としては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、硝酸塩等の無機酸塩；および酢酸塩、プロピオン酸塩、シュウ酸塩、コハク酸塩、乳酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、メタンスルホン酸塩、ｐ－トルエンスルホン酸塩、ベンゼンスルホン酸塩、アスコルビン酸塩等の有機酸塩等が具体例として挙げられる。 Since the compounds of the present invention may exist in the form of hydrates and / or solvates, solvates such as these hydrates or ethanol solvates are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) (hereinafter sometimes abbreviated as “compound (1)” if necessary) include, for example, hydrochloride, hydrobromide, sulfuric acid. Inorganic acid salts such as salts, phosphates, nitrates; and acetates, propionates, oxalates, succinates, lactates, malates, tartrate, citrate, maleate, fumarate Specific examples include organic acid salts such as methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate.
　式（１）で表される化合物は、互変異性体として存在する場合もあり得る。従って、本発明化合物は、式（１）で表される化合物の互変異性体も包含する。 The compound represented by the formula (1) may exist as a tautomer. Therefore, this invention compound also includes the tautomer of the compound represented by Formula (1).
　式（１）で表される化合物は、少なくとも一つの不斉炭素原子を有する場合もあり得る。従って、本発明化合物は、式（１）で表される化合物のラセミ体のみならず、これらの化合物の光学活性体も包含する。式（１）で表される化合物が２個以上の不斉炭素原子を有する場合、立体異性を生じる場合がある。従って、本発明化合物は、これらの化合物の立体異性体およびその混合物や単離されたものも包含する。
　また、式（１）で表される化合物のいずれか１つ又は２つ以上の１Ｈを２Ｈ（Ｄ）に変換した重水素変換体も式（１）で表される化合物に包含される。 The compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds. When the compound represented by the formula (1) has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the compounds of the present invention include stereoisomers of these compounds, mixtures thereof and isolated ones.
In addition, a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1). .
　以下に、本発明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。なお、本明細書において、記載の簡略化のために次の略語を使用することもある。
Ｂｏｃ基：ｔｅｒｔ－ブトキシカルボニル基
Ｃｂｚ基：ベンジルオキシカルボニル基
Ａｌｌｏｃ基：アリルオキシカルボニル基
Ｆｍｏｃ基：９－フルオレニルメチルオキシカルボニル基
ＴＨＦ：テトラヒドロフラン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド Hereinafter, the production method of the compound of the present invention will be described with reference to examples, but the present invention is not limited to these examples. In this specification, the following abbreviations may be used for the sake of simplicity.
Boc group: tert-butoxycarbonyl group Cbz group: benzyloxycarbonyl group Alloc group: allyloxycarbonyl group Fmoc group: 9-fluorenylmethyloxycarbonyl group THF: tetrahydrofuran DMF: N, N-dimethylformamide
製造法
　本発明化合物は、例えば、下記製造法１～９に示す方法によって製造することができる。これらの製造方法は、有機合成に習熟している者の知識に基づき、適宜改良され得る。原料として用いられる化合物は、必要に応じてそれぞれ塩として用いてもよい。 Production Method The compound of the present invention can be produced, for example, by the methods shown in the following production methods 1 to 9. These production methods can be improved as appropriate based on the knowledge of those skilled in organic synthesis. The compounds used as raw materials may be used as salts as necessary.
　下記製造法において、具体的に保護基の使用を明示した場合以外でも、反応点以外の何れかの官能基が説明した反応条件以外で変化する場合、または説明した方法を実施するのに不適切な場合には、反応点以外を必要に応じて保護し、反応終了後または一連の反応を行った後に脱保護することにより目的物を得ることができる。保護基としては、文献（T. W. Greene and P. G. M. Wuts,”Protective Groups in Organic Synthesis,”3rd Ed., John Wiley and Sons, inc., New York (1999)）等に記載されている通常の保護基を用いることができ、更に具体的には、アミノ基の保護基の具体例としては、例えば、ベンジルオキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、アセチル、ベンジル等を、またヒドロキシ基の保護の具体例としては、例えば、トリアルキルシリル、アセチル、ベンジル等をそれぞれ挙げることができる。 In the following production method, even when the use of a protecting group is not specifically stated, when any functional group other than the reactive site changes under the reaction conditions described, or inappropriate for carrying out the described method In such a case, the desired product can be obtained by protecting the points other than the reaction point as necessary and deprotecting after completion of the reaction or after a series of reactions. Protecting groups are described in literature (T. W. Greene and P. G. M. Wuts, ”Protective Groups in Organic Synthesis,” 3rd Ed., John Wiley and Sons, inc., New York (1999)) And, more specifically, specific examples of amino protecting groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the like, and hydroxy groups Specific examples of the protection of can include, for example, trialkylsilyl, acetyl, benzyl and the like.
　保護基の導入及び脱離は、有機合成化学で常用される方法（例えば、T. W. Greene and P. G. M. Wuts,”Protective Groups in Organic Synthesis,”3rd Ed., John Wiley and Sons, inc., New York (1999)に記載されている方法等）またはそれに準じた方法により行うことができる。 The introduction and removal of protecting groups are commonly used in organic synthetic chemistry (eg T. W. Greene and P. G. M. Wuts, ”Protective Groups in Organic Synthesis,” 3rd Ed., John Wiley and Sons , Inc., New York (1999)) or a similar method.
製造法１
　式（１）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000022
 〔式中、ｍ、ｎ、Ｗ１、Ｗ２、Ｒ１、Ｒ２、Ｒ３、環Ｑ１、環Ｑ２は、前記〔１〕と同義であり；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表し；ＬＧは、脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。〕 Manufacturing method 1
The compound represented by Formula (1) is manufactured by the method shown below, for example.
Figure JPOXMLDOC01-appb-C000022
 [Wherein, m, n, W 1 , W 2 , R 1 , R 2 , R 3 , ring Q 1 , and ring Q 2 have the same meanings as the above [1]; R 101 represents a Cbz group and a Boc group , Alloc group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group; LG represents a leaving group (for example, iodine atom, bromine atom, A chlorine atom, a substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like are represented. ]
工程１－１：化合物（１－２）の製造工程
　化合物（１－２）は、化合物（１－１）を原料として用い、文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)等）に記載されている方法と同様の方法により製造される。 Step 1-1: Preparation process of Compound (1-2) (1-2), using the compound (1-1) as a starting material, the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .) Etc.).
工程１－２：化合物（１）の製造工程
　化合物（１）は、適当な不活性溶媒中で化合物（１－２）を化合物（１－３）と反応させることにより製造される。 Step 1-2: Production Step of Compound (1) Compound (1) is produced by reacting compound (1-2) with compound (1-3) in a suitable inert solvent.
　当該反応は、必要に応じ塩基の存在下、さらには相間移動触媒の存在下で行ってもよい。反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲である。反応時間は、反応温度、使用される塩基、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction may be performed in the presence of a base, if necessary, in the presence of a phase transfer catalyst. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
　塩基の具体例としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の有機塩基；炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素カリウム、炭酸水素ナトリウム、リン酸二水素カリウム、リン酸水素二カリウム、リン酸カリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基；ナトリウムメトキシド、カリウムtert-ブトキシド等の金属アルコキシド等が挙げられる。 Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
　相間移動触媒の具体例としては、例えば、硫酸水素テトラブチルアンモニウム、テトラブチルアンモニウムヨージド、テトラブチルアンモニウムブロミド、ベンジルトリエチルアンモニウムブロミド等の四級アンモニウム塩、１８－クラウン－６－エーテル等のクラウンエーテル等が挙げられる。 Specific examples of the phase transfer catalyst include, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether. Etc.
　不活性溶媒の具体例としては、例えば、クロロホルム、ジクロロメタン等のハロゲン化炭化水素；ベンゼン、トルエン等の芳香族炭化水素；ジエチルエーテル、テトラヒドロフラン（THF）、１，４－ジオキサン等のエーテル系溶媒；メタノール、エタノール、２－プロパノール等の低級アルコール；アセトニトリル、アセトン、メチルエチルケトン、ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン、ジメチルスルホキシド等の非プロトン性極性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
工程１－３：化合物（１）の製造工程
　化合物（１）は、化合物（１－２）と式（１－４）で表されるアルデヒドおよび還元剤を用い、適当な不活性溶媒中で還元的アミノ化反応をすることによっても製造される。 Step 1-3: Production Step of Compound (1) Compound (1) is reduced in a suitable inert solvent using compound (1-2) and an aldehyde represented by formula (1-4) and a reducing agent. It can also be produced by subjecting it to an amination reaction.
　当該反応は必要に応じて塩基、酸、またはその他の添加剤の存在下で行ってもよい。反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲である。反応時間は、反応温度、使用される還元剤、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction may be performed in the presence of a base, an acid, or other additives as necessary. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
　還元剤の具体例としては、例えば、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化ジイソブチルアルミニウム、水素化トリ(sec-ブチル)ホウ素リチウム、水素化トリ(sec-ブチル)ホウ素ナトリウム、水素化トリ(sec-ブチル)ホウ素カリウム、ボラン-ジメチルスルフィド コンプレックス、ボラン-テトラヒドロフラン コンプレックス、水素化トリエチルホウ素リチウム、ギ酸アンモニウムが挙げられ、パラジウム－炭素や酸化パラジウム等の金属触媒を用いる水素添加反応も挙げられる。 Specific examples of the reducing agent include, for example, lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium tri (sec-butyl) borohydride, hydrogen Tri (sec-butyl) borohydride sodium, potassium tri (sec-butyl) borohydride, borane-dimethylsulfide complex, borane-tetrahydrofuran complex, lithium triethylborohydride, ammonium formate, palladium-carbon and palladium oxide A hydrogenation reaction using a metal catalyst such as
　塩基の具体例としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の有機塩基；炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素カリウム、炭酸水素ナトリウム、リン酸二水素カリウム、リン酸水素二カリウム、リン酸カリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基；ナトリウムメトキシド、カリウム tert-ブトキシド等の金属アルコキシド等が挙げられる。 Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc. It is done.
　酸の具体例としては、例えば、酢酸、トリフルオロ酢酸、メタンスルホン酸等の有機酸；塩酸、硫酸等の無機酸等が挙げられる。 Specific examples of the acid include organic acids such as acetic acid, trifluoroacetic acid and methanesulfonic acid; inorganic acids such as hydrochloric acid and sulfuric acid.
　その他の添加剤としては、オルトケイ酸テトラメチル、オルトギ酸メチル等の脱水剤；塩化亜鉛、四塩化チタン、硫酸ランタン、硫酸マグネシウム－p-トルエンスルホン酸ピリジニウム、臭化マグネシウム、塩化インジウム、塩化ジルコニウム、マグネシウムトリフラート、イッテルビウム(III)トリフラート、スカンジウムトリフラート、アルミナ、硫酸銅、チタン酸テトライソプロポキシド、チタン酸テトラエトキシドのようなルイス酸が挙げられる。 Other additives include dehydrating agents such as tetramethyl orthosilicate and methyl orthoformate; zinc chloride, titanium tetrachloride, lanthanum sulfate, magnesium sulfate-pyridinium sulfate pyridinium, magnesium bromide, indium chloride, zirconium chloride, Examples include Lewis acids such as magnesium triflate, ytterbium (III) triflate, scandium triflate, alumina, copper sulfate, tetraisopropoxide titanate, and tetraethoxide titanate.
　溶媒の具体例としては、例えば、水、アセトニトリルや、クロロホルム、ジクロロメタン等のハロゲン化炭化水素；ベンゼン、トルエン等の芳香族炭化水素；１，２－ジメトキシエタン、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；メタノール、エタノール、２－プロパノール等のアルコール系溶媒；ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等の非プロトン性極性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like. Ether solvents; alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone; and mixed solvents thereof.
工程１－４：化合物（１－６）の製造工程
　化合物（１－６）は、化合物（１－２）を、縮合剤の存在下、不活性溶媒中、式（１－５）で表されるカルボン酸と反応させることにより製造される。 Step 1-4: Production Step of Compound (1-6) Compound (1-6) is a compound represented by formula (1-5) in the presence of a condensing agent in an inert solvent. It is produced by reacting with a carboxylic acid.
　当該反応はさらに塩基の存在下で行ってもよい。反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲である。反応時間は、反応温度、使用される縮合剤、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction may be further performed in the presence of a base. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
　縮合剤としては、実験化学講座（日本化学会編、丸善）２２巻に記載されているもの等が挙げられる。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（ＷＳＣ・ＨＣｌ）、ジシクロヘキシルカルボジイミド（ＤＣＣ）等のカルボジイミド類；ベンゾトリアゾール－１－イル－トリス（ジメチルアミノ）ホスホニウム・ヘキサフルオロリン化物塩（ＢＯＰ）、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・ヘキサフルオロリン化物塩（ＨＢＴＵ）等のホスフェート類；ジフェニルホスホニルジアミド（ＤＰＰＡ）；Ｎ，Ｎ－カルボニルジミイダゾール（ＣＤＩ）等が挙げられる。必要に応じて、例えば、Ｎ－ヒドロキシスクシンイミド（ＨＯＳｕ）、１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、３－ヒドロキシ－４－オキソ－３，４－ジヒドロ－１，２，３－ベンゾトリアジン（ＨＯＯＢｔ）などの添加剤を加えて当該反応を行うことができる。 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 (WSC · HCl) and dicyclohexylcarbodiimide (DCC); Triazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphide salt ( And phosphates such as HBTU); diphenylphosphonyl diamide (DPPA); N, N-carbonyl diimidazole (CDI) and the like. If necessary, for example, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc. The additive can be added to carry out the reaction.
　不活性溶媒の具体例としては、例えば、クロロホルム、ジクロロメタン、ジクロロエタン等のハロゲン化炭化水素；ベンゼン、トルエン等の芳香族炭化水素；ジエチルエーテル、テトラヒドロフラン（THF）、１，２－ジメトキシエタン、１，４－ジオキサン等のエーテル系溶媒；ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒；アセトニトリル、アセトン、メチルエチルケトン、ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン、ジメチルスルホキシド等の非プロトン性極性溶媒；ピリジン等の塩基性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1, Ether solvents such as 4-dioxane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; aprotic polarities such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide A solvent; a basic solvent such as pyridine; and a mixed solvent thereof.
　本反応において、必要に応じて相間移動触媒を添加することもできる。相間移動触媒としては、例えば、テトラブチルアンモニウムブロミド、ベンジルトリエチルアンモニウムブロミド等の四級アンモニウム塩、１８－クラウン－６－エーテル等のクラウンエーテル等が挙げられる。 In this reaction, a phase transfer catalyst can be added as necessary. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
　また、化合物（１－６）は、化合物（１－５）にハロゲン化試薬（例えば、１－クロロ－Ｎ，Ｎ，２－トリメチルプロペニルアミン、オキシ塩化リン、三塩化リン、塩化チオニル、五塩化リン等が挙げられる。）を作用させて酸ハライドに導いた後、不活性溶媒中、必要に応じて塩基の存在下、化合物（１－２）と反応させることによっても製造される。 In addition, the compound (1-6) is obtained by adding a halogenating reagent (eg, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, pentachloride to the compound (1-5). It is also produced by reacting with a compound (1-2) in an inert solvent in the presence of a base as necessary.
　反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲である。反応時間は、反応温度、使用される縮合剤、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
　不活性溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒；ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒；ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化炭化水素系溶媒；酢酸エチル、酢酸イソプロピル等のエステル系溶媒；メチルエチルケトン、アセトン等のケトン系溶媒；アセトニトリル、N,N－ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチレンホスホアミド等の非プロトン性溶媒が挙げられる。 Examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform , Halogenated hydrocarbon solvents such as dichloroethane; ester solvents such as ethyl acetate and isopropyl acetate; ketone solvents such as methyl ethyl ketone and acetone; non-solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and hexamethylenephosphoamide A protic solvent is mentioned.
　塩基としては、例えば、Ｎ－メチルモルホリン、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、１，８－ジアザビシクロ[4.3.0]ノナ－５－エン、１，４－ジアザビシクロ[5.4.0]ウンデカ－７－エン、ピリジン、ジメチルアミノピリジン、ピコリン等の有機塩基が挙げられる。 Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene. , Organic bases such as pyridine, dimethylaminopyridine, and picoline.
工程１－５：化合物（１）の製造工程
　化合物（１）は、不活性溶媒中、化合物（１－６）を還元剤と反応させることによっても製造される。 Step 1-5: Production Step of Compound (1) Compound (1) can also be produced by reacting compound (1-6) with a reducing agent in an inert solvent.
　反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される還元剤、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reducing agent used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
　還元剤の具体例としては、例えば、水素化リチウムアルミニウム、水素化ビス(2-メトキシエトキシ)アルミニウムナトリウム、ボラン錯体（ボラン－ジメチルスルフィド錯体またはボラン－テトラヒドロフラン錯体等）等が挙げられる。 Specific examples of the reducing agent include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, borane complex (borane-dimethylsulfide complex or borane-tetrahydrofuran complex) and the like.
　不活性溶媒の具体例としては、例えば、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；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; and mixed solvents thereof.
製造法２
　式（１－２）で表される化合物のうち、式（２－４）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000023
 〔式中、ｎ、Ｒ１、Ｒ２、Ｒ３、Ｗ２、環Ｑ２は、前記〔１〕と同義であり；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表す。〕 Manufacturing method 2
Of the compounds represented by the formula (1-2), the compound represented by the formula (2-4) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000023
 [Wherein, n, R 1 , R 2 , R 3 , W 2 , and ring Q 2 have the same meanings as the above [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, 4- It represents a methoxybenzyl group, a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, or an Fmoc group. ]
工程２－１：化合物（２－２）の製造工程
　化合物（２－２）は、化合物（２－１）を用い、工程１－５と同様の方法により製造される。 Step 2-1: Step of producing compound (2-2) Compound (2-2) is produced by the same method as in step 1-5, using compound (2-1).
工程２－２：化合物（２－４）の製造工程
　化合物（２－４）は、化合物（２－２）を用い、工程１－１と同様の方法により製造される。 Step 2-2: Production Step of Compound (2-4) Compound (2-4) is produced in the same manner as in step 1-1, using compound (2-2).
工程２－３：化合物（２－３）の製造工程
　化合物（２－３）は、化合物（２－１）を用い、文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)等）に記載されている方法と同様の方法により製造される。 Step 2-3: Preparation process of Compound (2-3) (2-3), using the compound (2-1), the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) Etc.).
工程２－４：化合物（３－３）の製造工程
　化合物（２－４）は、化合物（２－３）を用い、工程１－５と同様の方法により製造される。 Step 2-4: Step of producing compound (3-3) Compound (2-4) is produced by the same method as in step 1-5 using compound (2-3).
製造法３
　式（１）で表される化合物のうち、式（３－２）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000024
〔式中、ｎ、Ｒ１、Ｒ２、Ｒ３、Ｗ１、Ｗ２、環Ｑ１、環Ｑ２は、前記〔１〕と同義であり；ＬＧは、脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。〕 Production method 3
Of the compounds represented by the formula (1), the compound represented by the formula (3-2) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000024
[Wherein, n, R 1 , R 2 , R 3 , W 1 , W 2 , ring Q 1 and ring Q 2 have the same meanings as the above [1]; LG represents a leaving group (for example, an iodine atom , Bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like. ]
工程３－１：化合物（３－１）の製造工程
　化合物（３－１）は、化合物（２－３）と化合物（１－３）を原料として用い、工程１－２と同様の方法により製造される。 Step 3-1: Production Step of Compound (3-1) Compound (3-1) is produced by the same method as in Step 1-2, using Compound (2-3) and Compound (1-3) as raw materials. Is done.
工程２－２：化合物（２－３）の製造工程
　化合物（３－２）は、化合物（３－１）を用い、工程１－５と同様の方法により製造される。 Step 2-2: Production Step of Compound (2-3) Compound (3-2) is produced in the same manner as in step 1-5 using compound (3-1).
製造法４
　式（１－１）で表される化合物のうち、式（４－３）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000025
 〔式中、ｎ、Ｒ１、Ｒ２、Ｗ２、環Ｑ２は、前記〔１〕と同義であり；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表し；Ｚ１およびＺ２はいずれも水素原子を表すか、あるいはＺ１およびＺ２が一緒になってカルボニル基を表し；Ｒ３ａは、ハロゲン原子を表し；Ｒ３ｂは、Ｃ１－６アルキル基を表す。〕 Manufacturing method 4
Of the compounds represented by formula (1-1), the compound represented by formula (4-3) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000025
 [Wherein, n, R 1 , R 2 , W 2 and ring Q 2 have the same meanings as the above [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, and a 4-methoxybenzyl group. , 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group; both Z 1 and Z 2 represent a hydrogen atom, or Z 1 and Z 2 together represent a carbonyl group R 3a represents a halogen atom; R 3b represents a C 1-6 alkyl group. ]
工程４－１：化合物（４－２）の製造工程
　化合物（４－２）は、適当な不活性溶媒中で、化合物（４－１）を、例えば、Ｎ－ブロモスクシンイミド、Ｎ－クロロスクシンイミド、１-クロロメチル-４-フルオロ-１，４-ジアゾニアビシクロ[２．２．２]オクタン ビス(テトラフルオロボラート)等のハロゲン化剤と作用させることにより製造される。 Step 4-1: Production Step of Compound (4-2) Compound (4-2) is prepared by reacting Compound (4-1) with, for example, N-bromosuccinimide, N-chlorosuccinimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane It is produced by reacting with a halogenating agent such as bis (tetrafluoroborate).
　反応温度は通常－２０℃から用いた溶媒の沸点までの範囲である。反応時間は、反応温度、使用されるハロゲン化剤、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. While the reaction time varies depending on the reaction temperature, the halogenating agent used, the raw materials, the solvent and the like, it is usually 10 minutes to 48 hours.
　不活性溶媒の具体例としては、例えば、クロロホルム、ジクロロメタン等のハロゲン化炭化水素；ジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒；ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等の非プロトン性極性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; dimethylformamide and N-methyl And aprotic polar solvents such as -2-pyrrolidinone; and mixed solvents thereof.
工程４－２：化合物（４－３）の製造工程
　化合物（４－３）は、遷移金属触媒の存在下、適当な不活性溶媒中で、化合物（４－２）を、例えば、ジメチル亜鉛等の有機亜鉛化合物；またはトリメチルボロキシン等の有機ホウ素化合物等とカップリング反応させることにより製造される。当該反応は、必要に応じて配位子、塩基、添加剤等の存在下で行うことができる。反応温度は通常－１０℃から用いた溶媒の沸点までの範囲である。反応温度、使用される試薬、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 Step 4-2: Production Step of Compound (4-3) Compound (4-3) is prepared by reacting compound (4-2) with, for example, dimethylzinc in an appropriate inert solvent in the presence of a transition metal catalyst. Or an organoboron compound such as trimethylboroxine. The reaction can be performed in the presence of a ligand, a base, an additive, or the like as necessary. The reaction temperature is usually in the range from −10 ° C. to the boiling point of the solvent used. Although depending on conditions such as reaction temperature, reagents used, raw materials and solvent, it is usually 10 minutes to 48 hours.
　遷移金属の具体例としては、例えば、酢酸パラジウム（II）、塩化パラジウム（II）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、テトラキス（トリフェニルホスフィン）パラジウム（０）、ビス（トリフェニルホスフィン）パラジウムクロリド（II）、ジクロロビス（トリ－O－トリルホスフィン）パラジウム（II）、ビス（トリ－tert－ブチルホスフィン）パラジウム（０）、および［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）等が挙げられる。 Specific examples of the transition metal include, for example, palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) Palladium chloride (II), dichlorobis (tri-O-tolylphosphine) palladium (II), bis (tri-tert-butylphosphine) palladium (0), and [1,1′-bis (diphenylphosphino) ferrocene] Examples include dichloropalladium (II).
　配位子の具体例としては、例えば、トリフェニルホスフィン、トリ－ｏ－トリルホスフィン、トリ－tert－ブチルホスフィン、トリ－２－フリルホスフィン、トリシクロヘキシルホスフィン、トリフェニルアルシン、１，１'－ビス（ジフェニルホスフィノ）フェロセン、２－ジシクロヘキシルホスフィノ－２',６'－ジメトキシビフェニル、２－ジシクロヘキシルホスフィノ－２',４',６'－トリイソプロピルビフェニル等が挙げられる。 Specific examples of the ligand include, for example, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1′-bis. (Diphenylphosphino) ferrocene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and the like.
　塩基の具体例としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン等の有機塩基；炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウム、リン酸カリウム等の無機塩基等が挙げられる。
　添加剤の具体例としては、例えば、塩化リチウム、フッ化セシウム、ヨウ化銅（I）、臭化銅（I）等の無機塩等が挙げられる。 Specific examples of the base include organic bases such as triethylamine and diisopropylethylamine; inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
Specific examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, copper (I) bromide, and the like.
　また、化合物（４－３）は、適当な不活性溶媒中で、化合物（４－２）をｎ－ブチルリチウム等のアルキルリチウムと作用させた後、例えばヨウ化メチル等のハロゲン化アルキル等と反応させることによっても製造される。 In addition, compound (4-3) is obtained by reacting compound (4-2) with alkyllithium such as n-butyllithium in a suitable inert solvent and then reacting with alkyl halide such as methyl iodide. It is also produced by reacting.
製造法５
　式（５－７）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000026
 〔式中、ｎ、Ｒ３は、前記〔１〕と同義であり；Ｒ１０２は、置換されてもよいＣ１－４アルキル基を表し；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表し；Ｙは－Ｗ２－環Ｑ２（Ｗ２、環Ｑ２は前記〔１〕と同義である）、Ｃ１－４アルコキシカルボニル基、ハロゲン原子、ニトロ基を表し；ＬＧは、脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。〕 Manufacturing method 5
The compound represented by the formula (5-7) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000026
 [Wherein, n and R 3 are as defined above in [1]; R 102 represents an optionally substituted C 1-4 alkyl group; R 101 represents a Cbz group, a Boc group, an Alloc group, Represents a benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group; Y represents —W 2 -ring Q 2 (W 2 , ring Q 2 represents the above [ 1], C 1-4 alkoxycarbonyl group, halogen atom, nitro group; LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyl group (eg, methanesulfonyl) Group, p-toluenesulfonyl group and the like)). ]
工程５－１：化合物（５－４）の製造工程
　化合物（５－４）は、適当な不活性溶媒中で化合物（５－２）、もしくは化合物（５－３）を化合物（５－１）と反応させることにより製造される。 Step 5-1: Step of producing compound (5-4) Compound (5-4) is compound (5-2) or compound (5-3) in a suitable inert solvent. It is manufactured by reacting with.
　化合物（５－２）を用いた場合、当該反応は、必要に応じ塩基の存在下、さらには相間移動触媒の存在下で行ってもよい。反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される塩基、原料、および溶媒等の条件によって異なるが、通常１０分間～４８時間である。 When the compound (5-2) is used, the reaction may be carried out in the presence of a base, if necessary, in the presence of a phase transfer catalyst. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
　塩基の具体例としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の有機塩基；炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素カリウム、炭酸水素ナトリウム、リン酸二水素カリウム、リン酸水素二カリウム、リン酸カリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基；ナトリウムメトキシド、カリウムtert-ブトキシド等の金属アルコキシド等が挙げられる。 Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
　相間移動触媒の具体例としては、例えば、硫酸水素テトラブチルアンモニウム、テトラブチルアンモニウムヨージド、テトラブチルアンモニウムブロミド、ベンジルトリエチルアンモニウムブロミド等の四級アンモニウム塩、１８－クラウン－６－エーテル等のクラウンエーテル等が挙げられる。 Specific examples of the phase transfer catalyst include, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether. Etc.
　不活性溶媒の具体例としては、例えば、クロロホルム、ジクロロメタン等のハロゲン化炭化水素；ベンゼン、トルエン等の芳香族炭化水素；ジエチルエーテル、テトラヒドロフラン（THF）、１，４－ジオキサン等のエーテル系溶媒；メタノール、エタノール、２－プロパノール等の低級アルコール；アセトニトリル、アセトン、メチルエチルケトン、ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン、ジメチルスルホキシド等の非プロトン性極性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
　化合物（５－３）を用いた場合、化合物（５－４）は、適当な不活性溶媒中で常法に従い光延反応させることにより製造される。具体的には、トリフェニルホスフィンとアゾジカルボン酸ジエチルやアゾジカルボン酸ジイソプロピル等の光延試薬の共存下行うか、あるいは、シアノメチレンホスホラン試薬を用いて行うことができる。 When compound (5-3) is used, compound (5-4) is produced by carrying out Mitsunobu reaction according to a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of triphenylphosphine and Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or using a cyanomethylenephosphorane reagent.
　反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される試薬、原料、および溶媒等の条件によって異なるが、通常１０分間～４８時間である。 The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
　不活性溶媒の具体例としては、例えば、ベンゼン、トルエン等の芳香族炭化水素；ジエチルエーテル、テトラヒドロフラン（THF）、１，４－ジオキサン等のエーテル系溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; and mixed solvents thereof.
工程５－２：化合物（５－５）の製造工程
　化合物（５－５）は、化合物（５－４）を還元剤と反応させることにより製造される。 Step 5-2: Production Step of Compound (5-5) Compound (5-5) is produced by reacting compound (5-4) with a reducing agent.
　反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される還元剤、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
　還元剤の具体例としては、例えば、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、ボラン錯体（ボラン－ジメチルスルフィド錯体またはボラン－テトラヒドロフラン錯体等）等が挙げられる。 Specific examples of the reducing agent include, for example, lithium aluminum hydride, sodium borohydride, borane complex (borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, etc.) and the like.
　不活性溶媒の具体例としては、例えば、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、メタノール、エタノール、２－プロパノール等の低級アルコール、およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, lower alcohols such as methanol, ethanol and 2-propanol, and mixed solvents thereof.
工程５－３：化合物（５－６）の製造工程
　化合物（５－６）は、ＬＧがメタンスルホニルオキシ基、クロロメタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、p-トルエンメタンスルホニルオキシ基を表す場合、化合物（５－５）を不活性溶媒中、塩基存在下、メタンスルホニルクロライド、メタンスルホン酸無水物、クロロメタンスルホニルクロライド、トリフルオロメタンスルホニルクロライド、トリフルオロメタンスルホン酸無水物、ベンゼンスルホニルクロライド、ベンゼンスルホン酸無水物、p-トルエンスルホニルクロライド、またはp-トルエンスルホン酸無水物と反応させることにより製造される。 Step 5-3: Production Step of Compound (5-6) In the compound (5-6), LG has a methanesulfonyloxy group, a chloromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, p-toluenemethane In the case of representing a sulfonyloxy group, the compound (5-5) in an inert solvent in the presence of a base, methanesulfonyl chloride, methanesulfonic anhydride, chloromethanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, Produced by reacting with benzenesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonyl chloride, or p-toluenesulfonic anhydride.
　反応温度は通常約－４０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される塩基、試薬、原料、および溶媒等の条件によって異なるが、通常１０分から４８時間である。 The reaction temperature is usually in the range from about −40 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, reagent, raw material, and solvent, but is usually 10 minutes to 48 hours.
　塩基としては、通常の反応において塩基として使用されるものであれば特に限定されないが、例えば、Ｎ－メチルモルホリン、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、１，８－ジアザビシクロ[4.3.0]ノナ－５－エン、１，４－ジアザビシクロ[5.4.0]ウンデカ－７－エン、ピリジン、ジメチルアミノピリジン、ピコリン等の有機塩基；ナトリウムメトキシド、ナトリウム ｔｅｒｔ－ブトキシド、カリウム ｔｅｒｔ－ブトキシド、リチウム ジイソプロピルアミド、リチウム ビス（トリメチルシリル）アミド、カリウム　ビス(トリメチルシリル)アミド、ナトリウム ビス(トリメチルシリル)アミド、リチウムアミド、ｎ―ブチルリチウム、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、水素化ナトリウム等の無機塩基等が挙げられる。 The base is not particularly limited as long as it is used as a base in a normal reaction. For example, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [4.3.0] non-5 Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium Bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium-bis (trimethylsilyl) amide, lithium amide, n-butyllithium, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate And inorganic bases such as sodium hydroxide and sodium hydride.
　不活性溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒；ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒；ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化炭化水素系溶媒；Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチレンホスホアミド等の非プロトン性溶媒が挙げられ、これらの混合溶媒であってもよい。 Examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylenephosphoamide and the like, and a mixed solvent thereof may be used.
　ＬＧが塩素原子を表す場合、化合物（５－５）を公知の方法（例えば、Comprehensive Organic transformation, R. C. ラロック著等、VCH publisher Inc., 1989等）と同様の方法で塩素化することにより化合物（５－６）を製造することができる。塩素化試薬としては、好ましくはオキサリルクロライド、塩化チオニル、オキシ塩化リン、塩化スルフリル、三塩化シアヌリル、四塩化炭素、またはＮ－クロロスクシンイミド等が用いられる。 When LG represents a chlorine atom, the compound (5-5) is chlorinated by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989) Thus, compound (5-6) can be produced. As the chlorinating reagent, oxalyl chloride, thionyl chloride, phosphorus oxychloride, sulfuryl chloride, cyanuryl trichloride, carbon tetrachloride, or N-chlorosuccinimide is preferably used.
　ＬＧが臭素原子を表す場合、化合物（５－５）を公知の方法（例えば、Comprehensive Organic transformation, R. C. ラロック著等、VCH publisher Inc., 1989等）と同様の方法で臭素化することにより化合物（５－６）を製造することができる。臭素化試薬としては、好ましくは三臭化リン、四臭化炭素、臭素、またはＮ－ブロモスクシンイミド等が用いられる。 When LG represents a bromine atom, bromination of the compound (5-5) by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989, etc.) Thus, compound (5-6) can be produced. As the bromination reagent, phosphorus tribromide, carbon tetrabromide, bromine, or N-bromosuccinimide is preferably used.
　ＬＧがヨウ素原子を表す場合、化合物（５－５）を公知の方法（例えば、Comprehensive Organic transformation, R. C. ラロック著等、VCH publisher Inc., 1989等）と同様の方法でヨウ素化することにより化合物（５－６）を製造することができる。ヨウ素化試薬としては、好ましくはヨウ素、Ｎ－ヨードスクシンイミド等が用いられる。 When LG represents an iodine atom, compound (5-5) is iodinated by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989, etc.) Thus, compound (5-6) can be produced. As the iodination reagent, iodine, N-iodosuccinimide and the like are preferably used.
　またＬＧがハロゲンである化合物（５－６）は、ＬＧが置換スルホニルオキシ基である化合物（５－６）を、不活性溶媒中で例えば臭化リチウムまたは塩化リチウム等と反応させることによっても製造される。 The compound (5-6) in which LG is halogen can also be produced by reacting the compound (5-6) in which LG is a substituted sulfonyloxy group with, for example, lithium bromide or lithium chloride in an inert solvent. Is done.
工程５－４：化合物（５－７）の製造工程
　化合物（５－７）は、適当な不活性溶媒中で化合物（５－６）を塩基と反応させることにより製造される。 Step 5-4: Production Step of Compound (5-7) Compound (5-7) is produced by reacting compound (5-6) with a base in a suitable inert solvent.
　当該反応は、必要に応じ相間移動触媒の存在下で行ってもよい。反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される塩基、原料、および溶媒等の条件によって異なるが、通常１０分間～４８時間である。 The reaction may be performed in the presence of a phase transfer catalyst as necessary. The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
　塩基の具体例としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の有機塩基；炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素カリウム、炭酸水素ナトリウム、リン酸二水素カリウム、リン酸水素二カリウム、リン酸カリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸ナトリウム、水酸化カリウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基；ナトリウムメトキシド、カリウムtert-ブトキシド等の金属アルコキシド等が挙げられる。 Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
　相間移動触媒の具体例としては、例えば、テトラブチルアンモニウムブロミド、ベンジルトリエチルアンモニウムブロミド等の四級アンモニウム塩、１８－クラウン－６－エーテル等のクラウンエーテル等が挙げられる。 Specific examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
　不活性溶媒の具体例としては、例えば、クロロホルム、ジクロロメタン等のハロゲン化炭化水素；ベンゼン、トルエン等の芳香族炭化水素；ジエチルエーテル、テトラヒドロフラン（THF）、１，４－ジオキサン等のエーテル系溶媒；；アセトニトリル、アセトン、メチルエチルケトン、ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン、ジメチルスルホキシド等の非プロトン性極性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
製造法６
　式（６－５）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000027
 〔式中、ｎ、Ｒ３は、前記〔１〕と同義であり；Ｒ１０２は、置換されてもよいＣ１－４アルキル基を表し；Ｒ１０３は、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、または３，４－ジメトキシベンジル基を表し；Ｙは－Ｗ２－環Ｑ２（Ｗ２、環Ｑ２は前記〔１〕と同義である）、Ｃ１－４アルコキシカルボニル基、ハロゲン原子、またはニトロ基を表し；ＬＧ１およびＬＧ２は、同一または異なって脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表す。〕 Manufacturing method 6
The compound represented by the formula (6-5) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000027
 [Wherein, n and R 3 are as defined above in [1]; R 102 represents an optionally substituted C 1-4 alkyl group; R 103 represents a benzyl group, a 4-methoxybenzyl group, Represents a 2,4-dimethoxybenzyl group or a 3,4-dimethoxybenzyl group; Y represents —W 2 -ring Q 2 (W 2 , ring Q 2 has the same meaning as in the above [1]), C 1-4 Represents an alkoxycarbonyl group, a halogen atom, or a nitro group; LG 1 and LG 2 are the same or different and are a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom, a substituted sulfonyl group (for example, a methanesulfonyl group, p -Toluenesulfonyl group and the like)). ]
工程６－１：化合物（６－３）の製造工程
　化合物（６－３）は、化合物（５－１）および化合物（６－１）もしくは（６－２）を用い、工程５－１と同様の方法により製造される。 Step 6-1: Step for producing compound (6-3) Compound (6-3) is compound (5-1) and compound (6-1) or (6-2), which is the same as step 5-1 It is manufactured by the method.
工程６－２：化合物（６－５）の製造工程
　化合物（６－５）は、適当な不活性溶媒中で、必要に応じて添加剤存在下、化合物（６－３）を化合物（６－４）と反応させることにより製造される。反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される塩基、原料、および溶媒等の条件によって異なるが、通常１０分間～４８時間である。 Step 6-2: Production Step of Compound (6-5) Compound (6-5) is obtained by converting Compound (6-3) to Compound (6-) in an appropriate inert solvent and optionally in the presence of an additive. Produced by reacting with 4). The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
　本反応において、必要に応じて添加剤を加えることもできる。添加剤としては、例えば、ヨウ化カリウム、ヨウ化ナトリウム、テトラブチルアンモニウムヨージド等が挙げられる。 In this reaction, additives can be added as necessary. Examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide and the like.
　不活性溶媒の具体例としては、例えば、ジエチルエーテル、テトラヒドロフラン（THF）、１，４－ジオキサン等のエーテル系溶媒；メタノール、エタノール、２－プロパノール等の低級アルコール；アセトニトリル、アセトン、メチルエチルケトン、ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン、ジメチルスルホキシド等の非プロトン性極性溶媒；およびこれらの混合溶媒等が挙げられる。 Specific examples of the inert solvent include, for example, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane; lower alcohols such as methanol, ethanol, 2-propanol; acetonitrile, acetone, methyl ethyl ketone, dimethylformamide. And aprotic polar solvents such as N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.
製造法７
　式（７－４）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000028
 〔式中、ｎ、Ｒ１、Ｒ２、Ｒ３、環Ｑ２は、前記〔１〕と同義であり；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表し；Ｘはハロゲン原子を表し；Ａは、下記式（ａ）、（ｂ）、（ｃ）、（ｄ）、または（ｅ）；
Figure JPOXMLDOC01-appb-C000029
 （式中、Ｍ＋はカリウムイオン、ナトリウムイオン、もしくはアンモニウムイオンを表し、Ｘ’はハロゲン原子を表す。）で表される基を表し；Ｚ１およびＺ２はいずれも水素原子を表すか、あるいはＺ１およびＺ２が一緒になってカルボニル基を表す。〕 Manufacturing method 7
The compound represented by the formula (7-4) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000028
 [Wherein, n, R 1 , R 2 , R 3 , and ring Q 2 have the same meanings as the above [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, and a 4-methoxybenzyl group. , 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group; X represents a halogen atom; A represents the following formula (a), (b), (c), (d) Or (e);
Figure JPOXMLDOC01-appb-C000029
 (Wherein M + represents a potassium ion, a sodium ion, or an ammonium ion, and X ′ represents a halogen atom); Z 1 and Z 2 both represent a hydrogen atom; Alternatively, Z 1 and Z 2 together represent a carbonyl group. ]
工程７－１：化合物（７－２）の製造工程
　例えば、下記に示す製造法（ｉ．またはｉｉ．）によって実施することができる。 Step 7-1: Production Step of Compound (7-2) For example, the production can be carried out by the following production method (i. Or ii.).
　ｉ．化合物（７－２）は、不活性溶媒中、鉄および化合物（７－１）を反応させることにより製造される。不活性溶媒としては、例えば、水、酢酸、またはメタノール、エタノール、もしくは２－プロパノール等のアルコール系溶媒等が挙げられ、これらの混合溶媒でもよい。反応温度は通常約３０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、原料、および溶媒等の条件によって異なるが、通常１０分間～９６時間である。 I. Compound (7-2) is produced by reacting iron and compound (7-1) in an inert solvent. Examples of the inert solvent include water, acetic acid, or alcohol solvents such as methanol, ethanol, or 2-propanol, and a mixed solvent thereof may be used. The reaction temperature is usually in the range from about 30 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 96 hours.
　ｉｉ．化合物（７－２）は、パラジウム炭素または水酸化パラジウム存在下、不活性溶媒中、化合物（７－１）を水素添加することにより製造することができる。また、必要に応じて酸を添加することもできる。反応温度は通常約２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、原料、および溶媒等の条件によって異なるが、通常１０分間～９６時間である。酸としては、例えば、塩酸水、臭化水素水、硫酸水、酢酸、トリフルオロ酢酸等が挙げられる。不活性溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒；ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒；ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化炭化水素系溶媒；エタノール、メタノール、イソプロパノール等のアルコール系溶媒、酢酸等が挙げられ、これらの混合溶媒であってもよい。 Ii. Compound (7-2) can be produced by hydrogenating compound (7-1) in the presence of palladium on carbon or palladium hydroxide in an inert solvent. Moreover, an acid can also be added as needed. The reaction temperature is usually in the range from about 20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 96 hours. Examples of the acid include hydrochloric acid water, hydrogen bromide water, sulfuric acid water, acetic acid, trifluoroacetic acid and the like. Examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; alcohol solvents such as ethanol, methanol and isopropanol, acetic acid and the like, and mixed solvents thereof may be used.
工程７－２：化合物（７－３）の製造工程
　化合物（７－３）は、化合物（７－２）を原料として用い、文献（例えば、Tetrahedron Letters 38, 7963 (1997), Bioorg. Med. Chem. Lett. 12, 543 (2002)、Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) およびTetrahedron Letters 42, 2201 (2001)等）に記載された方法と同様の方法により製造される。 Step 7-2: Production Step of Compound (7-3) Compound (7-3) is compound (7-2) as a starting material, and literature (for example, Tetrahedron Letters 38, 7963 (1997), Bioorg. Med. Chem. Lett. 12, 543 (2002), Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) and Tetrahedron Letters 42, 2201 (2001)). The
工程７－３：化合物（７－４）の製造工程
　化合物（７－４）は、化合物（７－３）を不活性溶媒中、適当な遷移金属触媒や適当な配位子と、必要に応じて塩基の存在下、適当な不活性溶媒中で化合物（６－５）と反応させることにより製造される。 Step 7-3: Step of producing compound (7-4) Compound (7-4) is prepared by mixing compound (7-3) with an appropriate transition metal catalyst and an appropriate ligand in an inert solvent as necessary. In the presence of a base, it is produced by reacting with compound (6-5) in a suitable inert solvent.
　反応温度は通常約－２０℃から用いた溶媒の沸点までの範囲の温度である。反応時間は、反応温度、使用される試薬、原料、および溶媒等の条件によって異なるが、通常１０分間～４８時間である。 The reaction temperature is usually in the range from about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
　遷移金属触媒および配位子の具体例としては、例えば、工程４－２で使用する遷移金属触媒および配位子が挙げられる。 Specific examples of the transition metal catalyst and the ligand include, for example, the transition metal catalyst and the ligand used in Step 4-2.
　塩基の具体例としては、例えばトリエチルアミン、Ｎ－メチルモルホリン、ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン等の有機塩基、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水素化ナトリウム、水素化カリウム、炭酸セシウム、炭酸ナトリウム、炭酸水素ナトリウム、リン酸カリウム等の無機塩基、ナトリウムメトキシド、ナトリウム ｔｅｒｔ－ブトキシド、カリウム ｔｅｒｔ－ブトキシド、リチウム ジイソプロピルアミド、リチウム ビス（トリメチルシリル）アミド、カリウム ビス(トリメチルシリル)アミド、ナトリウム ビス(トリメチルシリル)アミド、リチウムアミド、ｎ－ブチルリチウム、等の有機金属試薬等が挙げられる。好ましくは炭酸カリウム、もしくは、炭酸セシウムが挙げられる。 Specific examples of the base include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, hydrogen Inorganic bases such as potassium iodide, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) ), Organometallic reagents such as amide, sodium bis (trimethylsilyl) amide, lithium amide, n-butyllithium, and the like. Preferably, potassium carbonate or cesium carbonate is used.
　不活性溶媒の具体例としては、アセトン、アセトニトリル、例えばクロロホルム、ジクロロメタン等のハロゲン化炭化水素、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、ジメトキシエタン、ｔｅｒｔ－ブチルメチルエーテル、シクロペンチルメチルエーテル等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒が挙げられ、これらの混合溶媒であってもよい。好ましくは、トルエンやＮ，Ｎ－ジメチルホルムアミドが挙げられる。 Specific examples of the inert solvent include acetone, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane. And ether solvents such as tert-butyl methyl ether and cyclopentyl methyl ether, lower alcohols such as methanol, ethanol and isopropanol, and aprotic polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide. These may be a mixed solvent. Preferably, toluene and N, N-dimethylformamide are used.
製造法８
　式（８－６）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000030
 〔式中、ｎ、Ｒ１、Ｒ２、Ｒ２１、Ｒ２２は、前記〔１〕と同義であり；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表し；Ｒ１０４は、Ｃ１－４アルキル基を表し；ＬＧは、脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基等）等）を表し；Ｚ１およびＺ２はいずれも水素原子を表すか、あるいはＺ１およびＺ２が一緒になってカルボニル基を表す。〕 Manufacturing method 8
The compound represented by the formula (8-6) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000030
 [Wherein, n, R 1 , R 2 , R 21 , R 22 are as defined above [1]; R 101 is a Cbz group, a Boc group, an Alloc group, a benzyl group, a 4-methoxybenzyl group, Represents a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, or an Fmoc group; R 104 represents a C 1-4 alkyl group; LG represents a leaving group (for example, an iodine atom, a bromine atom, Represents a chlorine atom, a substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.); Z 1 and Z 2 both represent a hydrogen atom, or Z 1 and Z 2 together Represents a carbonyl group. ]
工程８－１：化合物（８－２）の製造工程
　化合物（８－２）は、化合物（８－１）を公知の方法（例えば、Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)、Comprehensive Organic Transformation, R. C. ラロック著等、VCH publisher Inc., 1989等）と同様の方法で加水分解することにより製造される。 Step 8-1: Preparation process of Compound (8-2) (8-2), the compound (8-1) a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .), Comprehensive Organic Transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.).
工程８－２：化合物（８－３）の製造工程
　化合物（８－３）は、化合物（８－２）と化合物（８－８）を原料として用い、工程１－４と同様の方法により製造される。 Step 8-2: Production Step of Compound (8-3) Compound (8-3) is produced by the same method as in Step 1-4 using Compound (8-2) and Compound (8-8) as raw materials. Is done.
工程８－３：化合物（８－４）の製造工程
　化合物（８－４）は、化合物（８－３）を用い、工程５－３と同様の方法により製造される。 Step 8-3: Production Step of Compound (8-4) Compound (8-4) is produced in the same manner as in step 5-3 using compound (8-3).
工程８－４：化合物（８－５）の製造工程
　化合物（８－５）は、化合物（８－４）を原料として用い、文献（例えば、Tetrahedron Letters, 53, 4409 (2012), JACS, 126, 15195 (2004), Tetrahedron 58, 9853 (2002), Tetrahedron Letters 50, 6252 (2009), Angewandte Chemie, International Edition 51, 6480 (2012)等）に記載された方法と同様の方法により製造される。 Step 8-4: Production Step of Compound (8-5) Compound (8-5) uses compound (8-4) as a starting material, and literature (for example, Tetrahedron Letters, 53, 4409 (2012), JACS, 126 15195 (2004), Tetrahedron 58, 9853 (2002), Tetrahedron Letters 50, 6252 (2009), Angewandte Chemie, International Edition 51, 6480 (2012), etc.).
工程８－５：化合物（８－６）の製造工程
　化合物（８－６）は、化合物（８－５）を原料として用い、文献（例えば、Organic Letters 13, 6256 (2011), Organic Letters, 12, 4686 (2010), Tetrahedron Letters 51, 1822 (2010), Tetrahedron Letters 44, 3133 (2003), Synthesis 11, 873 (1989), Journal of Medicinal Chemistry 47, 1969 (2004), Tetrahedron Letters 44, 3133 (2003), Bioorganic & Medicinal Chemistry Letters 22, 4955 (2012)等）に記載された方法と同様の方法により製造される。 Step 8-5: Production Step of Compound (8-6) Compound (8-6) uses Compound (8-5) as a raw material, and literature (for example, Organic Letters 13, 6256 (2011), Organic Letters, 12 , 4686 (2010), Tetrahedron Letters 51, 1822 (2010), Tetrahedron Letters 44, 3133 (2003), Synthesis 11, 873 (1989), Journal of Medicinal Chemistry 47, 1969 (2004), Tetrahedron Letters 44, 3133 (2003 ), Bioorganic & Medicinal Chemistry Letters 22, 4955 (2012), etc.).
製造法９
　式（９－４）で表される化合物は、例えば、下記に示す方法によって製造される。
Figure JPOXMLDOC01-appb-C000031
 〔式中、ｎ、Ｒ１、Ｒ２は、前記〔１〕と同義であり；Ｒ１０１は、Ｃｂｚ基、Ｂｏｃ基、Ａｌｌｏｃ基、ベンジル基、４－メトキシベンジル基、２，４－ジメトキシベンジル基、３，４－ジメトキシベンジル基、またはＦｍｏｃ基を表し；Ｒ１０４は、Ｃ１－４アルキル基を表し；Ｒ１０５は、Ｃ１－４アルキル基であるか、もしくは２つのＯＲ１０５が一緒になって結合して環を形成してもよく；Ｚ１およびＺ２はいずれも水素原子を表すか、あるいはＺ１およびＺ２が一緒になってカルボニル基を表す。〕 Manufacturing method 9
The compound represented by the formula (9-4) is produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000031
 [Wherein n, R 1 and R 2 have the same meanings as defined in [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, a 4-methoxybenzyl group, and 2,4-dimethoxybenzyl. Represents a group, 3,4-dimethoxybenzyl group or Fmoc group; R 104 represents a C 1-4 alkyl group; R 105 is a C 1-4 alkyl group, or two OR 105 together And may be bonded to form a ring; both Z 1 and Z 2 represent a hydrogen atom, or Z 1 and Z 2 together represent a carbonyl group. ]
工程９－１：化合物（９－２）の製造工程
　化合物（９－２）は、化合物（８－１）と化合物（９－１）から文献（例えば、Organic Letters 16, 2018, (2014)等）に記載された方法と同様の方法により製造される。 Step 9-1: Production Step of Compound (9-2) Compound (9-2) is obtained from compound (8-1) and compound (9-1) based on literature (for example, Organic Letters 16, 2018, (2014), etc. ) In the same manner as described in).
工程９－２：化合物（９－３）の製造工程
　化合物（９－３）は、化合物（９－２）から文献（Protective Groups in Organic Synthesis 3rd Edition (John Wiley & Sons, Inc.)等）に記載された方法と同様の方法により製造される。 Step 9-2: Preparation process of Compound (9-3) (9-3) in the literature from a compound (9-2) (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) , etc.) In the same manner as described in 1.
工程９－３：化合物（９－４）の製造工程
　化合物（９－４）は、化合物（９－３）から文献（例えば、Journal of Medicinal Chemistry 45, 3905 (2002), Synlett 10, 1642 (1999), WO2012/168350, WO2004/113353,Organic Letters 4, 2665 (2002), Bioorg. Med. Chem. Lett. 21, 3404 (2011), Bioorg. Med. Chem. Lett. 24, 1681 (2014)等）に記載された方法と同様の方法により製造される。 Step 9-3: Production Step of Compound (9-4) Compound (9-4) is obtained from compound (9-3) in literature (for example, Journal of Medicinal Chemistry 45, 3905 (2002), Synlett 10, 1642 (1999). ), WO2012 / 168350, WO2004 / 113353, Organic Letters 4, 2665 (2002), Bioorg. Med. Chem. Lett. 21, 3404 (2011), Bioorg. Med. Chem. Lett. 24, 1681 (2014), etc.) In the same manner as described in 1.
　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、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して単離精製することができる。また、各中間体においては、特に精製することなく次の反応に供することも可能である。 The intermediates and target compounds in each of the above production methods are isolated by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be purified. In addition, each intermediate can be subjected to the next reaction without any particular purification.
　光学活性な出発原料や中間体を用いることにより、あるいは最終品のラセミ体を光学分割することにより、本発明化合物の光学活性体を製造することができる。光学分割の方法としては、光学活性カラムを用いた物理的な分離方法、分別結晶化法等の化学的な分離方法が挙げられる。本発明化合物のジアステレオマーは、例えば、分別結晶化法によって製造される。 The optically active form of the compound of the present invention can be produced by using optically active starting materials and intermediates, or by optically resolving the final racemate. Examples of the optical resolution method include a physical separation method using an optically active column and a chemical separation method such as a fractional crystallization method. The diastereomer of the compound of the present invention is produced, for example, by a fractional crystallization method.
　式（１）で表される化合物の薬学上許容される塩は、例えば、水、メタノール、エタノール、アセトン等の溶媒中で、式（１）で表される化合物と、薬学上許容される酸と混合することで製造することができる。 The pharmaceutically acceptable salt of the compound represented by the formula (1) is, for example, a compound represented by the formula (1) and a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, and acetone. It can be manufactured by mixing with.
　本発明化合物は、ドパミンＤ４受容体アゴニストであることから、ＡＤＨＤと類似の症状を示す中枢神経性疾患、例えば、自閉症スペクトラム障害（精神障害の診断と統計の手引き第５版（ＤＳＭ－５）における自閉症スペクトラム障害であって、従来のＤＳＭ－ＩＶにおいて、自閉症、アスペルガー症候群、非定型広汎性発達障害、および小児崩壊性障害と分類されていた診断名）、ＡＤＨＤ様の症状を示す統合失調症、気分障害、認知機能障害等の治療剤になり得る。本発明化合物は、メチルフェニデート等の中枢神経刺激薬、アトモキセチン等の選択的ノルアドレナリン再取り込み阻害剤、種々の統合失調症治療剤等と組み合わせて用いることができる。 Since the compound of the present invention is a dopamine D 4 receptor agonist, it is a central nervous disease that exhibits symptoms similar to ADHD, for example, autism spectrum disorder (diagnosis and statistical guide 5th edition of mental disorders (DSM- 5) Autism spectrum disorder in the conventional DSM-IV, which was classified as autism, Asperger syndrome, atypical pervasive developmental disorder, and childhood disintegrative disorder), ADHD-like It can be a therapeutic agent for schizophrenia, mood disorder, cognitive dysfunction and the like that show symptoms. The compound of the present invention can be used in combination with a central nerve stimulant such as methylphenidate, a selective noradrenaline reuptake inhibitor such as atomoxetine, various schizophrenia therapeutic agents and the like.
　自閉症スペクトラム障害の病因仮説の一つとして、大脳皮質における興奮性－抑制性神経伝達物質の不均衡に伴う神経ネットワーク同調性の欠如が想定されており、高周波帯の脳波であるγ波の増幅がこの不均衡を改善することが認められている。ドパミンＤ４受容体アゴニストは大脳皮質においてγ波を増幅させることがこれまで報告されている。
　一方、視床下部において生成されるホルモンであるオキシトシンは、社会性認知に関与することが報告されており、自閉症との関連が示唆されている。ドパミンＤ４受容体は視床下部室傍核に発現するオキシトシン産生ニューロンに高発現していることから、ドパミンＤ４受容体アゴニストは、オキシトシン産生ニューロンを活性化し、脳内でオキシトシンの遊離を促進することが期待される。
　以上のことから、ドパミンＤ４受容体アゴニストは、大脳皮質におけるγ波の増幅作用、および視床下部におけるオキシトシン遊離促進作用を介した、自閉症スペクトラム障害の治療薬となり得る。 One of the etiology hypotheses of autism spectrum disorder is the lack of neural network synchrony associated with the excitatory-inhibitory neurotransmitter imbalance in the cerebral cortex. It has been observed that amplification improves this imbalance. Dopamine D 4 receptor agonists can be amplified γ waves in the cerebral cortex it has been reported.
On the other hand, oxytocin, a hormone produced in the hypothalamus, has been reported to be involved in social cognition, suggesting an association with autism. Since dopamine D 4 receptors are highly expressed in oxytocin-producing neurons expressed in the hypothalamic paraventricular nucleus, dopamine D 4 receptor agonists activate oxytocin-producing neurons and promote oxytocin release in the brain. It is expected.
From the above, a dopamine D 4 receptor agonist can be a therapeutic agent for autism spectrum disorder through the γ-wave amplification effect in the cerebral cortex and the oxytocin release promoting effect in the hypothalamus.
　本発明化合物は、ＡＤＨＤ（精神障害の診断と統計の手引き第５版（ＤＳＭ－５）におけるＡＤＨＤであって、従来のＤＳＭ－ＩＶにおいて、注意欠陥多動性障害と分類されていた診断名）および自閉症スペクトラム障害の治療に好適に用いられる。
　ＡＤＨＤの治療としては、特に、注意欠如（inattention）、多動性（hyperactivity）、および衝動性（impulsivity）を主症状とするＡＤＨＤに好適に用いられる。
　自閉症スペクトラム障害の治療としては、特に、社会的コミュニケーションと社会的相互作用の持続的な欠陥、および制限された反復される行動や興味や活動の様式を主症状とする自閉症スペクトラム障害に好適に用いられる。 The compound of the present invention is ADHD (diagnosis name classified as attention deficit / hyperactivity disorder in conventional DSM-IV in ADHD in Diagnosis and Statistics Guide 5th Edition (DSM-5)) And preferably used for the treatment of autism spectrum disorder.
As a treatment for ADHD, it is particularly preferably used for ADHD whose main symptoms are attention, hyperactivity, and impulsivity.
The treatment of autism spectrum disorders includes, among other things, persistent deficits in social communication and social interaction, and autism spectrum disorders whose main symptoms are limited repetitive behaviors, interests and activities. Is preferably used.
　医薬品化合物が生体内に取り込まれた後、代謝を受けることにより化学構造が変化し、反応性の高い中間体、すなわち反応性代謝物が生成し、毒性（肝毒性、アレルギー、組織壊死、変異原性やがん原性等）を発現させることがある。この反応性代謝物による毒性リスクを簡易に評価する試験の一つとして、ダンシル化されたグルタチオン（ｄＧＳＨ）を用いたグルタチオン（ＧＳＨ）トラッピング試験がある。ｄＧＳＨ共有結合量の値が高い化合物ほど、全身に曝露された場合、上記の毒性リスクが高まる。
　本発明化合物は、ｄＧＳＨ共有結合量の値が極めて低いことから（試験例４）、肝毒性等リスクが低く、長期にわたって安全に投与できることが期待される。 After the pharmaceutical compound is taken into the living body, it undergoes metabolism to change its chemical structure, producing highly reactive intermediates, ie reactive metabolites, and toxicity (liver toxicity, allergy, tissue necrosis, mutagen) Sex, carcinogenicity, etc.). One of the tests for easily evaluating the toxicity risk due to this reactive metabolite is a glutathione (GSH) trapping test using dansylated glutathione (dGSH). The higher the dGSH covalent bond value, the higher the toxicity risk when exposed to whole body.
Since the compound of the present invention has an extremely low dGSH covalent bond amount (Test Example 4), it is expected that the compound has low risk such as liver toxicity and can be safely administered over a long period of time.
　本発明化合物は経口的または非経口的に投与することができる。経口的に投与する場合、通常用いられる投与形態で投与することができる。非経口的には、局所投与剤、注射剤、経皮剤、経鼻剤等の形で投与することができる。経口剤または直腸投与剤としては、例えば、カプセル、錠剤、ピル、散剤、カシェ剤、坐剤、液剤等が挙げられる。注射剤としては、例えば、無菌の溶液または懸濁液等が挙げられる。局所投与剤としては、例えば、クリーム、軟膏、ロ－ション、経皮剤（通常のパッチ剤、マトリクス剤）等が挙げられる。 The compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal preparation, nasal preparation and the like. Examples of the oral agent or rectal administration agent include capsules, tablets, pills, powders, cachets, suppositories, and liquids. Examples of injections include sterile solutions or suspensions. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
　上記の剤形は通常の方法で、薬学的に許容される賦形剤、添加剤とともに製剤される。薬学的に許容される賦形剤、添加剤としては、担体、結合剤、香料、緩衝剤、増粘剤、着色剤、安定剤、乳化剤、分散剤、懸濁化剤、防腐剤等が挙げられる。
　薬学的に許容される担体としては、例えば、炭酸マグネシウム、ステアリン酸マグネシウム、タルク、砂糖、ラクトース、ペクチン、デキストリン、澱粉、ゼラチン、トラガント、メチルセルロース、ナトリウムカルボキシメチルセルロ－ス、低融点ワックス、カカオバター等が挙げられる。カプセルは、本発明化合物を薬学的に許容される担体と共に中に入れることにより製剤できる。本発明化合物は薬学的に許容される賦形剤と共に混合し、または賦形剤なしにカプセルの中に入れることができる。カシェ剤も同様の方法で製造できる。 The above-mentioned dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.
Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter Etc. Capsules can be formulated by placing the compound of the present invention in a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.
　注射用液剤としては、溶液、懸濁液、乳剤等が挙げられる。例えば、水溶液、水－プロピレングリコール溶液等が挙げられる。液剤は、水を含んでもよい、ポリエチレングリコールまたは／およびプロピレングリコールの溶液の形で製造することもできる。経口投与に適切な液剤は、本発明化合物を水に加え、着色剤、香料、安定化剤、甘味剤、溶解剤、増粘剤等を必要に応じて加え製造することができる。また経口投与に適切な液剤は、本発明化合物を分散剤とともに水に加え、粘稠にすることによっても製造できる。増粘剤としては、例えば、薬学的に許容される天然または合成ガム、レジン、メチルセルロース、ナトリウムカルボキシメチルセルロースまたは公知の懸濁化剤等が挙げられる。 Examples of injection solutions include solutions, suspensions, and emulsions. Examples thereof include an aqueous solution and a water-propylene glycol solution. The solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water. A solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. A solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous. Examples of the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
　用量は、個々の化合物により、また患者の疾患、年齢、体重、性別、症状、投与経路等により変化するが、通常は成人（体重５０ｋｇ）に対して、本発明化合物を、０．１～１０００ｍｇ／日、好ましくは０．１～３００ｍｇ／日を１日１回または２ないし３回に分けて投与する。また、数日～数週に１回投与することもできる。 The dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but usually 0.1 to 1000 mg of the compound of the present invention for an adult (50 kg body weight). / Day, preferably 0.1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.
　以下に本発明を、参考例、実施例および試験例により、更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、以下の参考例及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。なお、記載の簡略化のために略語を使用することもあるが、これらの略号は前記記載と同義である。
　化合物の同定はプロトン核磁気共鳴吸収スペクトル（1H-NMR）、ＬＣ－ＭＳ等を用いて行った。なお、参考例および実施例におけるアミノクロマトグラフィーは、山善株式会社製のアミノカラムを用いた。ＬＣ－ＭＳは下記表１に示す種々の条件を用いて測定を行った。リテンションタイム（Ｒ．Ｔ．）はＬＣ－ＭＳ測定におけるマススペクトルピークが現れた時間を表す。
Figure JPOXMLDOC01-appb-T000032
 Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. In addition, although abbreviations may be used for simplification of description, these abbreviations have the same meanings as described above.
The compound was identified using proton nuclear magnetic resonance absorption spectrum ( 1 H-NMR), LC-MS, and the like. In the reference examples and examples, amino columns manufactured by Yamazen Co., Ltd. were used. LC-MS was measured using various conditions shown in Table 1 below. Retention time (RT) represents the time at which a mass spectrum peak appeared in LC-MS measurement.
Figure JPOXMLDOC01-appb-T000032
　本明細書において次の略号を使用することもある。
　参考例ならびに実施例のＮＭＲデータにおいては以下の略号を使用する。
Ｍｅ基：メチル基
Ｅｔ基：エチル基
Ｂｏｃ基：ｔｅｒｔ－ブトキシカルボニル基
tert- ：ターシャリー
ｓ ： シングレット（singlet）
brs： ブロードシングレット（broad singlet）
ｄ ： ダブレット（doublet）
ｔ ： トリプレット（triplet）
ｍ ： マルチプレット（multiplet）
br ： ブロード（broad）
Ｊ ： カップリング定数（broad constant）
Ｈｚ：ヘルツ（Hertz）
ＣＤＣｌ３：重クロロホルム
ＤＭＳＯ－ｄ６：重ジメチルスルホキシド
ＴＨＦ：テトラヒドロフラン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＴＦＡ：トリフルオロ酢酸 In the present specification, the following abbreviations may be used.
The following abbreviations are used in the NMR data of Reference Examples and Examples.
Me group: methyl group Et group: ethyl group Boc group: tert-butoxycarbonyl group
tert-: tertiary s: singlet
brs: Broad singlet
d: Doublet
t: triplet
m: multiplet
br: broad
J: Coupling constant (broad constant)
Hz: Hertz
CDCl 3 : deuterated chloroform DMSO-d 6 : deuterated dimethyl sulfoxide THF: tetrahydrofuran DMF: N, N-dimethylformamide TFA: trifluoroacetic acid
実施例１
５－[(５-メチルピリジン-２－イル)メチル]-２-(１，３-オキサゾール-２-イル)-４，５，６，７-テトラヒドロピラゾロ[１，５－ａ]ピラジン
Figure JPOXMLDOC01-appb-C000033
 　参考例１の化合物（４３．９ｍｇ，０．２３１ｍｍｏｌ）、市販の２－（クロロメチル）－５－メチルピリジン 塩酸塩（４１．１ｍｇ，０．２３１ｍｍｏｌ）、テトラブチルアンモニウムブロマイド（７．５ｍｇ，０．０２３１ｍｍｏｌ）、５０％炭酸カリウム水溶液（２５５ｍｇ）、およびＴＨＦ（２．０ｍＬ）の混合物を８０℃で終夜撹拌した。反応溶液を室温まで放冷後、水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーにより精製することで表題化合物（２２．４ｍｇ，３３％）得た。
1H-NMR (400 MHz, CDCl3) δ: 2.34 (3H, s), 3.04 (2H, t, J = 5.5 Hz), 3.79 (2H, s), 3.86 (2H, s), 4.28 (2H, t, J = 5.5 Hz), 6.51 (1H, s), 7.19 (1H, s), 7.33 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.66 (1H, s), 8.43 (1H, s). Example 1
5-[(5-Methylpyridin-2-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000033
 The compound of Reference Example 1 (43.9 mg, 0.231 mmol), commercially available 2- (chloromethyl) -5-methylpyridine hydrochloride (41.1 mg, 0.231 mmol), tetrabutylammonium bromide (7.5 mg, 0 0.0231 mmol), 50% aqueous potassium carbonate (255 mg), and THF (2.0 mL) were stirred at 80 ° C. overnight. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (22.4 mg, 33%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.34 (3H, s), 3.04 (2H, t, J = 5.5 Hz), 3.79 (2H, s), 3.86 (2H, s), 4.28 (2H, t, J = 5.5 Hz), 6.51 (1H, s), 7.19 (1H, s), 7.33 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.66 (1H, s), 8.43 (1H, s).
実施例２
５－ベンジル－２－（１－メチル－１Ｈ－イミダゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000034
 　参考例７の化合物（１０１ｍｇ，０．４９７ｍｍｏｌ）、炭酸カリウム（１０３ｍｇ，０．７４６ｍｍｏｌ）、ベンジルブロマイド（８５ｍｇ，０．４９７ｍｍｏｌ）、およびアセトニトリル（２ｍＬ）の混合物を５０℃で終夜撹拌した。反応溶液を室温まで放冷後、反応混合物に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（３５ｍｇ，２４％）。
1H-NMR (400 MHz, CDCl3) δ: 3.00 (2H, t, J = 5.4 Hz), 3.76 (4H, s), 3.99 (3H, s), 4.23 (2H, t, J = 5.4 Hz), 6.51 (1H, s), 6.90 (1H, s), 7.07 (1H, s), 7.29-7.44 (5H, m). Example 2
5-Benzyl-2- (1-methyl-1H-imidazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000034
 A mixture of the compound of Reference Example 7 (101 mg, 0.497 mmol), potassium carbonate (103 mg, 0.746 mmol), benzyl bromide (85 mg, 0.497 mmol), and acetonitrile (2 mL) was stirred at 50 ° C. overnight. The reaction solution was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (35 mg, 24%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.00 (2H, t, J = 5.4 Hz), 3.76 (4H, s), 3.99 (3H, s), 4.23 (2H, t, J = 5.4 Hz) , 6.51 (1H, s), 6.90 (1H, s), 7.07 (1H, s), 7.29-7.44 (5H, m).
実施例３
２－（１，３－オキサゾール－２－イル）－５－｛［２－（トリフルオロメチル）ピリミジン－５－イル］メチル｝－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000035
 　参考例１の化合物（９５ｍｇ，０．４９９ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液に、参考例１１の化合物（１０５ｍｇ，０．５９９ｍｍｏｌ）、ＴＦＡ（５．７ｍｇ、０．０５ｍｍｏｌ）および水素化トリアセトキシホウ素ナトリウム（２１２ｍｇ，０．９９８ｍｍｏｌ）を加えた。室温で終夜攪拌後、反応溶液に飽和炭酸水素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後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（４８ｍｇ，２７％）。
1H-NMR (400 MHz, CDCl3) δ: 3.03 (2H, t, J = 5.5 Hz), 3.80 (2H, s), 3.86 (2H, s), 4.29 (2H, t, J = 5.5 Hz), 6.54 (1H, s), 7.19 (1H, s), 7.66 (1H, d, J = 0.9 Hz), 8.91 (2H, s). Example 3
2- (1,3-oxazol-2-yl) -5-{[2- (trifluoromethyl) pyrimidin-5-yl] methyl} -4,5,6,7-tetrahydropyrazolo [1,5- a] Pyrazine
Figure JPOXMLDOC01-appb-C000035
 To a solution of the compound of Reference Example 1 (95 mg, 0.499 mmol) in dichloromethane (2 mL), the compound of Reference Example 11 (105 mg, 0.599 mmol), TFA (5.7 mg, 0.05 mmol) and sodium triacetoxyborohydride (212 mg, 0.998 mmol) was added. After stirring at room temperature overnight, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography to obtain the title compound (48 mg, 27%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.03 (2H, t, J = 5.5 Hz), 3.80 (2H, s), 3.86 (2H, s), 4.29 (2H, t, J = 5.5 Hz) , 6.54 (1H, s), 7.19 (1H, s), 7.66 (1H, d, J = 0.9 Hz), 8.91 (2H, s).
実施例４～７
　対応する参考例の化合物より、実施例２記載方法に準じ、実施例４～７の化合物を合成した。
Figure JPOXMLDOC01-appb-T000036
 Examples 4-7
The compounds of Examples 4 to 7 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 2.
Figure JPOXMLDOC01-appb-T000036
実施例８～１１
　対応する参考例の化合物より、実施例３記載方法に準じ、実施例８～１１の化合物を合成した。
Figure JPOXMLDOC01-appb-T000037
 Examples 8-11
The compounds of Examples 8 to 11 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 3.
Figure JPOXMLDOC01-appb-T000037
実施例１２～３３
　対応する参考例の化合物より、実施例１記載方法に準じ、実施例１２～３６の化合物を合成した。
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-I000039

Figure JPOXMLDOC01-appb-I000040

Figure JPOXMLDOC01-appb-I000041

Figure JPOXMLDOC01-appb-I000042
 Examples 12-33
The compounds of Examples 12 to 36 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 1.
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-I000039

Figure JPOXMLDOC01-appb-I000040

Figure JPOXMLDOC01-appb-I000041

Figure JPOXMLDOC01-appb-I000042
実施例３７～４４
　対応する参考例の化合物より、実施例３記載方法に準じ、実施例３７～４４の化合物を合成した。
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-I000044
 Examples 37-44
The compounds of Examples 37 to 44 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 3.
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-I000044
実施例４５～４８
　対応する参考例の化合物より、実施例１記載方法に準じ、実施例４５～４８の化合物を合成した。
Figure JPOXMLDOC01-appb-T000045
 Examples 45-48
The compounds of Examples 45 to 48 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 1.
Figure JPOXMLDOC01-appb-T000045
参考例１
２－（１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾール［１，５－ａ］ピラジン 塩酸塩
Figure JPOXMLDOC01-appb-C000046
 　参考例２の化合物（２．０１ｇ，６．９２ｍｍｏｌ）の酢酸エチル溶液（３０ｍＬ）に４ｍｏｌ／Ｌ塩酸－１，４－ジオキサン（３０ｍＬ）を加え、室温で３時間撹拌した。反応溶液の溶媒を減圧留去することで表題の化合物を得た（１．８６ｇ，９８％）。
LC‐MS：Ｒ.Ｔ.= 0.50 min　ObsMS = 200 [M+1] Reference example 1
2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazole [1,5-a] pyrazine hydrochloride
Figure JPOXMLDOC01-appb-C000046
 To an ethyl acetate solution (30 mL) of the compound of Reference Example 2 (2.01 g, 6.92 mmol) was added 4 mol / L hydrochloric acid-1,4-dioxane (30 mL), and the mixture was stirred at room temperature for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (1.86 g, 98%).
LC-MS: RT = 0.50 min ObsMS = 200 [M + 1]
参考例２
ｔｅｒｔ－ブチル ２－（１，３－オキサゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000047
 　参考例３の化合物（４．０９ｇ，１１．７１ｍｍｏｌ）、２－(トリ－Ｎ－ブチルスタニル)オキサゾール（６．２９ｇ，１７．５６ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（１．３５ｇ，１．７１ｍｍｏｌ）のＤＭＦ（３０ｍＬ）溶液を８０℃で３時間撹拌した。反応溶液を室温まで放冷後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水で２回、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（２．０１ｇ，５９％）。
1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 3.90 (2H, t, J = 5.0 Hz), 4.24 (2H, t, J = 5.0 Hz), 4.68 (2H, s), 6.62 (1H, s), 7.20 (1H, s), 7.67 (1H, s). Reference example 2
tert-Butyl 2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000047
 The compound of Reference Example 3 (4.09 g, 11.71 mmol), 2- (tri-N-butylstannyl) oxazole (6.29 g, 17.56 mmol), tetrakis (triphenylphosphine) palladium (1.35 g, 1.71 mmol) ) In DMF (30 mL) was stirred at 80 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (2.01 g, 59%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47 (9H, s), 3.90 (2H, t, J = 5.0 Hz), 4.24 (2H, t, J = 5.0 Hz), 4.68 (2H, s) , 6.62 (1H, s), 7.20 (1H, s), 7.67 (1H, s).
参考例３
ｔｅｒｔ－ブチル ２－ヨード－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000048
 　参考例４の化合物（４．２９ｇ，１８．００ｍｍｏｌ）、亜硝酸イソアミル（２．７３ｇ，２３．３０ｍｍｏｌ）、ジヨードメタン（７．２３ｇ，２６．９９ｍｍｏｌ）のトルエン（５０ｍＬ）溶液を８０℃で２時間撹拌した。反応溶液を室温まで放冷後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（４．０９ｇ，６５％）。
LC-MS：Ｒ.Ｔ.= 1.730 min　ObsMS = 350 [M+1] Reference example 3
tert-Butyl 2-iodo-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000048
 A toluene (50 mL) solution of the compound of Reference Example 4 (4.29 g, 18.00 mmol), isoamyl nitrite (2.73 g, 23.30 mmol) and diiodomethane (7.23 g, 26.99 mmol) at 80 ° C. for 2 hours. Stir. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (4.09 g, 65%).
LC-MS: RT = 1.730 min ObsMS = 350 [M + 1]
参考例４
ｔｅｒｔ－ブチル ２－アミノ－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000049
 　参考例５の化合物（６．１４ｇ，２２．８９ｍｍｏｌ）のメタノール（７０ｍＬ）溶液にパラジウム－炭素（９３９ｍｇ）を加え、水素雰囲気下で２４時間撹拌した。反応溶液をセライトろ過し、減圧濃縮することで表題の化合物を得た（５．２９ｇ，９７％）。
LC‐MS：Ｒ.Ｔ.= 1.287 min　ObsMS = 239 [M+1] Reference example 4
tert-Butyl 2-amino-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000049
 Palladium-carbon (939 mg) was added to a methanol (70 mL) solution of the compound of Reference Example 5 (6.14 g, 22.89 mmol), and the mixture was stirred under a hydrogen atmosphere for 24 hours. The reaction solution was filtered through Celite and concentrated under reduced pressure to give the title compound (5.29 g, 97%).
LC-MS: RT = 1.287 min ObsMS = 239 [M + 1]
参考例５
ｔｅｒｔ－ブチル ２－ニトロ－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000050
 　参考例６の化合物（７．１８ｇ，４１．９６ｍｍｏｌ）、ｔｅｒｔ－ブチル Ｎ－（２－ブロモメチル）カルバメート（１０．３４ｇ，４６．１４ｍｍｏｌ）、炭酸カリウム（１１．６０ｇ，８３．９３ｍｍｏｌ）、およびＤＭＦ（８０ｍＬ）の混合物を室温で終夜撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を水で２回、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮することでメチル １－｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］エチル｝－３－ニトロ－１Ｈ－ピラゾール－５－カルボキシレートの粗生成物を得た（１４．３５ｇ）。
　得られたメチル １－｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］エチル｝－３－ニトロ－１Ｈ－ピラゾール－５－カルボキシレートの粗生成物をＴＨＦ（８０ｍＬ）に溶解し、室温で水素化ホウ素ナトリウム（３．１７ｇ，８３．８０ｍｍｏｌ）、メタノール（１３．４４ｇ，４１９ｍｍｏｌ）を加えた。反応混合物を３時間撹拌した後、氷浴下、濃塩酸（１１．９０ｇ，１１７．５ｍｍｏｌ）／水（１３０ｍＬ）を滴下した。氷浴下、５分間撹拌した後、水酸化ナトリウム（５．４５ｇ，１３６ｍｍｏｌ）／水（２０ｍＬ）を加えた。混合物を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮することでｔｅｒｔ－ブチル ｛２－［５－（ヒドロキシメチル）－３－ニトロ－１Ｈ－ピラゾール－１－イル］エチル｝カルバメートの粗生成物を得た（１４．１５ｇ）。
　得られたｔｅｒｔ－ブチル ｛２－［５－（ヒドロキシメチル）－３－ニトロ－１Ｈ－ピラゾール－１－イル］エチル｝カルバメートの粗生成物をジクロロメタン（８０ｍＬ）に溶かし、塩化チオニル（５．９９ｇ，５０．３５ｍｍｏｌ）を加えた。室温で２時間撹拌した後、反応溶液の溶媒を減圧留去することでｔｅｒｔ－ブチル ｛２－［５－（クロロメチル）－３－ニトロ－１Ｈ－ピラゾール－１－イル］エチル｝カルバメートの粗生成物を得た。
　得られたｔｅｒｔ－ブチル ｛２－［５－（クロロメチル）－３－ニトロ－１Ｈ－ピラゾール－１－イル］エチル｝カルバメートの粗生成物のＴＨＦ（５０ｍＬ）溶液に、４ｍｏｌ／Ｌ塩酸-酢酸エチル（８０ｍＬ）を加え、室温で２時間撹拌した。反応液の溶媒を減圧留去することで２－［５－（クロロメチル）－３－ニトロ－１Ｈ－ピラゾール－１－イル］エタンアミン 塩酸塩の粗生成物を得た。
　得られた２－［５－（クロロメチル）－３－ニトロ－１Ｈ－ピラゾール－１－イル］エタンアミン 塩酸塩の粗生成物のＴＨＦ（６０ｍＬ）／水（２０ｍＬ）溶液に、８０℃で炭酸水素ナトリウム（１４．１０ｇ）／水（２０ｍＬ）を滴下し、１．５時間撹拌した。反応溶液を室温まで放冷後、ジ－ｔｅｒｔ－ブチルジカーボネート（１０．９９ｇ，５０．３６ｍｍｏｌ）を加え、室温で１時間撹拌した。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、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（５．５３ｇ，４９％）。
1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 3.95 (2H, t, J = 5.5 Hz), 4.25 (2H, t, J = 5.5 Hz), 4.69 (2H, s), 6.71 (1H, s). Reference Example 5
tert-Butyl 2-nitro-6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000050
 The compound of Reference Example 6 (7.18 g, 41.96 mmol), tert-butyl N- (2-bromomethyl) carbamate (10.34 g, 46.14 mmol), potassium carbonate (11.60 g, 83.93 mmol), and DMF (80 mL) of the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 1- {2-[(tert-butoxycarbonyl) amino] ethyl} -3-nitro. A crude product of -1H-pyrazole-5-carboxylate was obtained (14.35 g).
The obtained methyl 1- {2-[(tert-butoxycarbonyl) amino] ethyl} -3-nitro-1H-pyrazole-5-carboxylate crude product was dissolved in THF (80 mL) and hydrogenated at room temperature. Sodium boron (3.17 g, 83.80 mmol) and methanol (13.44 g, 419 mmol) were added. After stirring the reaction mixture for 3 hours, concentrated hydrochloric acid (11.90 g, 117.5 mmol) / water (130 mL) was added dropwise in an ice bath. After stirring for 5 minutes in an ice bath, sodium hydroxide (5.45 g, 136 mmol) / water (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl {2- [5- (hydroxymethyl) -3-nitro- A crude product of 1H-pyrazol-1-yl] ethyl} carbamate was obtained (14.15 g).
The obtained crude product of tert-butyl {2- [5- (hydroxymethyl) -3-nitro-1H-pyrazol-1-yl] ethyl} carbamate was dissolved in dichloromethane (80 mL) and thionyl chloride (5.99 g) was dissolved. , 50.35 mmol). After stirring at room temperature for 2 hours, the solvent of the reaction solution was distilled off under reduced pressure to give crude tert-butyl {2- [5- (chloromethyl) -3-nitro-1H-pyrazol-1-yl] ethyl} carbamate. The product was obtained.
To a solution of the obtained crude product of tert-butyl {2- [5- (chloromethyl) -3-nitro-1H-pyrazol-1-yl] ethyl} carbamate in THF (50 mL) was added 4 mol / L hydrochloric acid-acetic acid. Ethyl (80 mL) was added and stirred at room temperature for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product of 2- [5- (chloromethyl) -3-nitro-1H-pyrazol-1-yl] ethanamine hydrochloride.
To the resulting 2- [5- (chloromethyl) -3-nitro-1H-pyrazol-1-yl] ethanamine hydrochloride crude product in THF (60 mL) / water (20 mL) solution at 80 ° C. with hydrogen carbonate Sodium (14.10 g) / water (20 mL) was added dropwise and stirred for 1.5 hours. The reaction solution was allowed to cool to room temperature, di-tert-butyl dicarbonate (10.99 g, 50.36 mmol) was added, and the mixture was stirred at room temperature for 1 hr. 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 anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (5.53 g, 49%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.50 (9H, s), 3.95 (2H, t, J = 5.5 Hz), 4.25 (2H, t, J = 5.5 Hz), 4.69 (2H, s) , 6.71 (1H, s).
参考例６
メチル ３－ニトロ－１Ｈ－ピラゾール－５－カルボキシレート
Figure JPOXMLDOC01-appb-C000051
 　５－ニトロ－３－ピラゾールカルボン酸（６．７９ｇ，４３．２２ｍｍｏｌ）のメタノール（８０ｍＬ）溶液に塩化チオニル（７．７１ｇ，６４．８３ｍｍｏｌ）を加え、加熱還流下、１．５時間撹拌した。反応溶液を室温まで放冷後、反応溶液の溶媒を減圧留去した。得られた残渣にヘキサンを加え、析出した固体をろ取することにより表題の化合物を得た（７．４０ｇ，９７％）。
1H-NMR (400 MHz, DMSO-d6) δ: 3.89 (3H, s), 7.52 (1H, s). Reference Example 6
Methyl 3-nitro-1H-pyrazole-5-carboxylate
Figure JPOXMLDOC01-appb-C000051
 To a solution of 5-nitro-3-pyrazolecarboxylic acid (6.79 g, 43.22 mmol) in methanol (80 mL) was added thionyl chloride (7.71 g, 64.83 mmol), and the mixture was stirred for 1.5 hours with heating under reflux. After allowing the reaction solution to cool to room temperature, the solvent of the reaction solution was distilled off under reduced pressure. Hexane was added to the resulting residue, and the precipitated solid was collected by filtration to give the title compound (7.40 g, 97%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.89 (3H, s), 7.52 (1H, s).
参考例７
２－（１－メチル－１Ｈ－イミダゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000052
 　参考例８の化合物（１．８２ｇ，５．００ｍｍｏｌ）のジクロロメタン（１５ｍＬ）溶液に４ｍｏｌ／Ｌ 塩酸－１，４－ジオキサン（１５ｍＬ）を加え、室温で４時間撹拌した。反応溶液に炭酸カリウム（１．３８ｇ，１０ｍｍｏｌ）／水（３０ｍＬ）を加え、４０℃で４時間撹拌した。反応溶液を室温まで放冷後、水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮することにより２－（１－メチル－１Ｈ－イミダゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－４（５Ｈ）－オンを得た。
　水素化アルミニウムリチウム（１９３ｍｇ，５．０８ｍｍｏｌ）のＴＨＦ（３ｍＬ）溶液の懸濁溶液に、６０℃で２－（１－メチル－１Ｈ－イミダゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－４（５Ｈ）－オン（５５２ｍｇ，２．５４ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液を滴下した。反応溶液を室温まで放冷し、１時間撹拌した。反応溶液に芒硝を加えて室温で終夜撹拌し、得られた懸濁液をセライトろ過した。ろ液を減圧濃縮することにより表題の化合物を得た（４９０ｍｇ，９５％）。
1H-NMR (400 MHz, DMSO-d6) δ: 2.51 (3H, s), 3.14 (2H, t, J = 5.6 Hz), 3.92 (2H, s), 4.02 (2H, t, J = 5.6 Hz), 6.34 (1H, s), 6.89 (1H, s), 7.16 (1H, s). Reference Example 7
2- (1-Methyl-1H-imidazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000052
 To a solution of the compound of Reference Example 8 (1.82 g, 5.00 mmol) in dichloromethane (15 mL) was added 4 mol / L hydrochloric acid-1,4-dioxane (15 mL), and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added potassium carbonate (1.38 g, 10 mmol) / water (30 mL), and the mixture was stirred at 40 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (1-methyl-1H-imidazol-2-yl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one was obtained.
To a suspension of lithium aluminum hydride (193 mg, 5.08 mmol) in THF (3 mL) at 60 ° C., 2- (1-methyl-1H-imidazol-2-yl) -6,7-dihydropyrazolo [ A solution of 1,5-a] pyrazin-4 (5H) -one (552 mg, 2.54 mmol) in THF (5 mL) was added dropwise. The reaction solution was allowed to cool to room temperature and stirred for 1 hour. To the reaction solution was added mirabilite and stirred at room temperature overnight, and the resulting suspension was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (490 mg, 95%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 2.51 (3H, s), 3.14 (2H, t, J = 5.6 Hz), 3.92 (2H, s), 4.02 (2H, t, J = 5.6 Hz), 6.34 (1H, s), 6.89 (1H, s), 7.16 (1H, s).
参考例８
エチル １－｛２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］エチル｝－３－（１－メチル－１Ｈ－イミダゾール－２－イル）－１Ｈ－ピラゾロ－５－カルボキシレート
Figure JPOXMLDOC01-appb-C000053
 　参考例９の化合物（１．７０ｇ，７．７４ｍｍｏｌ）のＤＭＦ（１５ｍＬ）溶液に炭酸カリウム（２．６７ｇ，１９．３５ｍｍｏｌ）、ｔｅｒｔ－ブチル Ｎ－（２－ブロモメチル）カルバメート（２．６０ｇ，１１．６１ｍｍｏｌ）を加え、５０℃で６時間撹拌した。反応溶液を室温まで放冷後、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、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（１．８０ｇ，６４％）。
1H-NMR (400 MHz, DMSO-d6) δ: 1.26-1.38 (12H, m), 3.94 (2H, m), 4.30-4.36 (2H, m), 4.57-4.60 (2H, m), 6.96 (1H, s), 7.13 (1H, s), 7.22 (1H, s). Reference Example 8
Ethyl 1- {2-[(tert-butoxycarbonyl) amino] ethyl} -3- (1-methyl-1H-imidazol-2-yl) -1H-pyrazolo-5-carboxylate
Figure JPOXMLDOC01-appb-C000053
 To a solution of the compound of Reference Example 9 (1.70 g, 7.74 mmol) in DMF (15 mL) was added potassium carbonate (2.67 g, 19.35 mmol), tert-butyl N- (2-bromomethyl) carbamate (2.60 g, 11 .61 mmol) was added and the mixture was stirred at 50 ° C. for 6 hours. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.80 g, 64%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.26-1.38 (12H, m), 3.94 (2H, m), 4.30-4.36 (2H, m), 4.57-4.60 (2H, m), 6.96 (1H, s), 7.13 (1H, s), 7.22 (1H, s).
参考例９
エチル ３－（１－メチル－１Ｈ－イミダゾール－２－イル）－１Ｈ－ピラゾール－５－カルボキシレート
Figure JPOXMLDOC01-appb-C000054
 　市販の２－アセチル－１－メチルイミダゾール（５．０ｇ，４０．３ｍｍｏｌ）のＴＨＦ（１００ｍＬ）溶液に１ｍｏｌ／Ｌ リチウム ビス（トリメチルシリル）アミドのＴＨＦ溶液（４０．３ｍＬ，４０．３ｍｍｏｌ）を－７８℃で滴下した。－７８℃で３０分間攪拌後、シュウ酸ジエチル（５．７ｍＬ，４２．３ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応溶液をろ過し、固体に水を加え、ｐＨ６になるまで１ｍｏｌ／Ｌ 塩酸を加え、酢酸エチルで３回で抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮することで、エチル ４－（１－メチル－１Ｈ－イミダゾール－２－イル）－２，４－ジオキソブタノエート（４．９ｇ，５４％）を得た。
　４－（１－メチル－１Ｈ－イミダゾール－２－イル）－２，４－ジオキソブタノエート（２．０８ｇ，９．３０ｍｍｏｌ）のエタノール（３０ｍＬ）溶液にヒドラジン・一水和物（４６６ｍｇ，９．３０ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応溶液を室温まで放冷後、反応溶液の溶媒を減圧留去し粗生成物を得た。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（１．７０ｇ，８３％）。
1H-NMR (400 MHz, CDCl3) δ: 1.42 (3H, t, J = 7.0 Hz), 3.94 (3H, s), 4.43 (2H, q, J = 7.0 Hz), 6.99 (1H, s), 7.18 (1H, s), 7.19 (1H, s). Reference Example 9
Ethyl 3- (1-methyl-1H-imidazol-2-yl) -1H-pyrazole-5-carboxylate
Figure JPOXMLDOC01-appb-C000054
 To a commercially available solution of 2-acetyl-1-methylimidazole (5.0 g, 40.3 mmol) in THF (100 mL) was added 1 mol / L lithium bis (trimethylsilyl) amide in THF (40.3 mL, 40.3 mmol) to -78. It was dripped at ° C. After stirring at −78 ° C. for 30 minutes, diethyl oxalate (5.7 mL, 42.3 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Filter the reaction solution, add water to the solid, add 1 mol / L hydrochloric acid until pH 6 is obtained, extract with ethyl acetate three times, dry the combined organic layer with anhydrous sodium sulfate, filter and concentrate. Gave ethyl 4- (1-methyl-1H-imidazol-2-yl) -2,4-dioxobutanoate (4.9 g, 54%).
To a solution of 4- (1-methyl-1H-imidazol-2-yl) -2,4-dioxobutanoate (2.08 g, 9.30 mmol) in ethanol (30 mL) was added hydrazine monohydrate (466 mg, 9.30 mmol) was added and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, and then the solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.70 g, 83%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.42 (3H, t, J = 7.0 Hz), 3.94 (3H, s), 4.43 (2H, q, J = 7.0 Hz), 6.99 (1H, s) , 7.18 (1H, s), 7.19 (1H, s).
参考例１０
２－（１－メチル－１Ｈ－ピラゾール－３－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン 塩酸塩
Figure JPOXMLDOC01-appb-C000055
 　上記参考例９、５、および参考例１に記載の方法に準じ、市販の１－（１－メチル－１Ｈ－ピラゾール－３－イル）エタン－１－オンから表題化合物を得た。
1H-NMR (400 MHz, DMSO-d6) δ: 3.65 (2H, m), 3.86 (3H, s), 4.34-4.40 (4H, m), 6.47-6.49 (2H, m), 7.71 (1H, s), 10.23 (2H, brs). Reference Example 10
2- (1-Methyl-1H-pyrazol-3-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine hydrochloride
Figure JPOXMLDOC01-appb-C000055
 The title compound was obtained from commercially available 1- (1-methyl-1H-pyrazol-3-yl) ethan-1-one according to the methods described in Reference Examples 9 and 5 and Reference Example 1.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.65 (2H, m), 3.86 (3H, s), 4.34-4.40 (4H, m), 6.47-6.49 (2H, m), 7.71 (1H , s), 10.23 (2H, brs).
参考例１１
２－（トリフルオロメチル）ピリミジン－５－カルバルデヒド
Figure JPOXMLDOC01-appb-C000056
 　参考例１２の化合物（５０．０ｍｇ，０．２２７ｍｍｏｌ）のトルエン（０．８ｍＬ）溶液に、－７８℃で１ｍｏｌ／Ｌ 水素化ジイソブチルアルミニウムのトルエン溶液（０．２５ｍＬ，０．２５ｍｍｏＬ）を加えた。－７８℃で１５分間撹拌後、反応溶液に飽和ロッシェル塩水溶液を加え、室温で１時間撹拌した。混合物を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、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（３０．０ｍｇ，７５％）を得た。
1H-NMR (400 MHz, CDCl3) δ: 9.33 (2H, s), 10.24 (1H, s). Reference Example 11
2- (Trifluoromethyl) pyrimidine-5-carbaldehyde
Figure JPOXMLDOC01-appb-C000056
 To a toluene (0.8 mL) solution of the compound of Reference Example 12 (50.0 mg, 0.227 mmol) was added 1 mol / L toluene solution of diisobutylaluminum hydride (0.25 mL, 0.25 mmol) at −78 ° C. . After stirring at −78 ° C. for 15 minutes, a saturated aqueous Rochelle salt solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (30.0 mg, 75%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 9.33 (2H, s), 10.24 (1H, s).
参考例１２
エチル ２－（トリフルオロメチル）ピリミジン－５－カルボキシレ－ト
Figure JPOXMLDOC01-appb-C000057
 　文献既知（例えば、ＷＯ２０１０／１２２９６８等）のエチル ４－クロロ－２－（トリフルオロメチル）ピリミジン－５－カルボキシレート（１．９９ｇ，７．８２ｍｍｏｌ）のエタノール（３０ ｍＬ）溶液にジイソプロピルエチルアミン（２．４３ｇ, １８．８ｍｍｏｌ）、１０％パラジウム－炭素（２００ｍｇ）を加え、水素雰囲気化、室温で３時間半撹拌した。反応混合物をセライトろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（１．３６ｇ，７９％）を得た。
1H-NMR (400 MHz, CDCl3) δ: 1.46 (3H, t, J = 7.2 Hz), 4.51 (2H, q, J = 7.2 Hz), 9.43 (2H, s). Reference Example 12
Ethyl 2- (trifluoromethyl) pyrimidine-5-carboxylate
Figure JPOXMLDOC01-appb-C000057
 Diisopropylethylamine (2 mL) was added to a solution of ethyl 4-chloro-2- (trifluoromethyl) pyrimidine-5-carboxylate (1.99 g, 7.82 mmol) known in the literature (for example, WO2010 / 122968) in ethanol (30 mL). (43 g, 18.8 mmol), 10% palladium-carbon (200 mg) was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 3.5 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (1.36 g, 79%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 (3H, t, J = 7.2 Hz), 4.51 (2H, q, J = 7.2 Hz), 9.43 (2H, s).
参考例１３
３－（クロロメチル）－５，６，７，８－テトラヒドロキノリン 塩酸塩
Figure JPOXMLDOC01-appb-C000058
 　参考例１４の化合物（７６５ｍｇ，４．７２ｍｍｏｌ）のジクロロメタン（１２ｍＬ）溶液に氷浴下、塩化チオニル（０．６３ｍＬ，８．６８ｍｍｏｌ）を加えた。室温で１時間撹拌後、反応溶液の溶媒を減圧留去した。得られた残渣にトルエン／ヘキサン（１：１）を加え、生じた固体をろ取することにより表題の化合物を得た（６９７ｍｇ，７３％）。
1H-NMR (400 MHz, DMSO-d6) δ: 1.76-1.83 (4H, m), 2.86 (2H, t, J = 6.2 Hz), 3.04 (2H, t, J = 6.2 Hz), 4.88 (2H, s), 8.30-8.30 (1H, m), 8.71-8.71 (1H, m). Reference Example 13
3- (Chloromethyl) -5,6,7,8-tetrahydroquinoline hydrochloride
Figure JPOXMLDOC01-appb-C000058
 To a solution of the compound of Reference Example 14 (765 mg, 4.72 mmol) in dichloromethane (12 mL) was added thionyl chloride (0.63 mL, 8.68 mmol) in an ice bath. After stirring at room temperature for 1 hour, the solvent of the reaction solution was distilled off under reduced pressure. Toluene / hexane (1: 1) was added to the obtained residue, and the resulting solid was collected by filtration to give the title compound (697 mg, 73%).
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.76-1.83 (4H, m), 2.86 (2H, t, J = 6.2 Hz), 3.04 (2H, t, J = 6.2 Hz), 4.88 ( 2H, s), 8.30-8.30 (1H, m), 8.71-8.71 (1H, m).
参考例１４
５，６，７，８－テトラヒドロキノリン－３－イルメタノール
Figure JPOXMLDOC01-appb-C000059
 　水素化アルミニウムリチウム（１７０ｍｇ，４．５０ｍｍｏｌ）とＴＨＦ（３ｍＬ）の懸濁溶液に、氷浴下、参考例１５の化合物（８６０ｍｇ，４．５０ｍｍｏｌ）のＴＨＦ（７ｍＬ）溶液を滴下した。氷浴下で１時間撹拌後、芒硝を加えて室温で３０分間で撹拌し、得られた懸濁液をセライトろ過した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（７０５ｍｇ，９６％）を得た。
1H-NMR (400 MHz, CDCl3) δ: 1.76-1.83 (2H, m), 1.84-1.91 (2H, m), 2.76 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 4.64 (2H, s), 7.40 (1H, d, J = 1.4 Hz), 8.24 (1H, d, J = 1.4 Hz). Reference Example 14
5,6,7,8-tetrahydroquinolin-3-ylmethanol
Figure JPOXMLDOC01-appb-C000059
 To a suspension of lithium aluminum hydride (170 mg, 4.50 mmol) and THF (3 mL) was added dropwise a THF (7 mL) solution of the compound of Reference Example 15 (860 mg, 4.50 mmol) in an ice bath. After stirring for 1 hour in an ice bath, sodium sulfate was added and stirred at room temperature for 30 minutes, and the resulting suspension was filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (705 mg, 96%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.76-1.83 (2H, m), 1.84-1.91 (2H, m), 2.76 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 4.64 (2H, s), 7.40 (1H, d, J = 1.4 Hz), 8.24 (1H, d, J = 1.4 Hz).
参考例１５
メチル ５，６，７，８－テトラヒドロキノリン－３－カルボキシレート
Figure JPOXMLDOC01-appb-C000060
 　市販のメチル キノリン－３－カルボキシレート（１．２０ｇ，６．４１ｍｍｏｌ）のＴＦＡ（２５ｍＬ）溶液に酸化白金 (１５０ｍｇ)を加え、水素雰囲気下、６０℃で５時間撹拌した。反応溶液を室温まで放冷後、セライトろ過し、ろ液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（８６０ｍｇ，７０％）。
LC‐MS：Ｒ.Ｔ.= 0.532 min　ObsMS = 192 [M+1] Reference Example 15
Methyl 5,6,7,8-tetrahydroquinoline-3-carboxylate
Figure JPOXMLDOC01-appb-C000060
 Platinum oxide (150 mg) was added to a solution of commercially available methyl quinoline-3-carboxylate (1.20 g, 6.41 mmol) in TFA (25 mL), and the mixture was stirred at 60 ° C. for 5 hours in a hydrogen atmosphere. The reaction solution was allowed to cool to room temperature, filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (860 mg, 70%).
LC-MS: RT = 0.532 min ObsMS = 192 [M + 1]
参考例１６
３－クロロ－５－（クロロメチル）－２－メチルピリジン 塩酸塩
Figure JPOXMLDOC01-appb-C000061
 　参考例１３と同様の方法で、参考例１７から表題化合物を得た。
1H-NMR (400 MHz, DMSO-d6) δ: 2.57 (3H, s), 4.81 (2H, s), 8.08 (1H, d, J = 1.8 Hz), 8.54 (1H, d, J = 1.8 Hz). Reference Example 16
3-Chloro-5- (chloromethyl) -2-methylpyridine hydrochloride
Figure JPOXMLDOC01-appb-C000061
 In the same manner as in Reference Example 13, the title compound was obtained from Reference Example 17.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 2.57 (3H, s), 4.81 (2H, s), 8.08 (1H, d, J = 1.8 Hz), 8.54 (1H, d, J = 1.8 Hz).
参考例１７
（５－クロロ－６－メチルピリジン－３－イル）メタノール
Figure JPOXMLDOC01-appb-C000062
 　参考例１８の化合物（７６６ｍｇ，３．８４ｍｍｏｌ）のＴＨＦ（１０ｍＬ）に－７８℃で水素化ジイソブチルアルミニウム（１１．５ｍＬ，１１．５ｍｍｏｌ，１．０Ｍトルエン溶液）を滴下した。－７８℃で３時間撹拌後、反応溶液に飽和ロッシェル塩を加え、室温まで加温し、２時間撹拌した。混合物を酢酸エチルで抽出し、有機層を飽和食塩水で浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（５０１．４ｍｇ，８３％）。
1H-NMR (400 MHz, CDCl3) δ: 2.59 (3H, s), 4.67 (2H, s), 7.67 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 1.8 Hz). Reference Example 17
(5-Chloro-6-methylpyridin-3-yl) methanol
Figure JPOXMLDOC01-appb-C000062
 Diisobutylaluminum hydride (11.5 mL, 11.5 mmol, 1.0 M toluene solution) was added dropwise to THF (10 mL) of the compound of Reference Example 18 (766 mg, 3.84 mmol) at −78 ° C. After stirring at −78 ° C. for 3 hours, saturated Rochelle salt was added to the reaction solution, warmed to room temperature, and stirred for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (501.4 mg, 83%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.59 (3H, s), 4.67 (2H, s), 7.67 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 1.8 Hz) .
参考例１８
エチル ５－クロロ－６－メチルピリジン－３－カルボキシレート
Figure JPOXMLDOC01-appb-C000063
 　市販のエチル ５，６－ジクロロニコチネート（１．２２ｇ，５．５３ｍｍｏｌ）のＴＨＦ（８ｍＬ）／Ｎ－メチルピロリドン（０．８ｍＬ）溶液に室温で鉄(III)アセチルアセトナート（９８ｍｇ，０．２７６ｍｍｏｌ）を加えた。続いて、反応混合物にメチルマグネシウムブロマイド（２．２１ｍＬ，６．６３ｍｍｏｌ、３．０ｍｏｌ／Ｌジエチルエーテル溶液）を加え、室温で３時間撹拌した。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。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（７８０ｍｇ，７０％）。
1H-NMR (400 MHz, CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 2.67 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 8.20 (1H, d, J = 1.8 Hz), 8.95 (1H, d, J = 1.8 Hz). Reference Example 18
Ethyl 5-chloro-6-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000063
 Commercially available ethyl 5,6-dichloronicotinate (1.22 g, 5.53 mmol) in THF (8 mL) / N-methylpyrrolidone (0.8 mL) at room temperature with iron (III) acetylacetonate (98 mg,. 276 mmol) was added. Subsequently, methylmagnesium bromide (2.21 mL, 6.63 mmol, 3.0 mol / L diethyl ether solution) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (780 mg, 70%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 2.67 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 8.20 (1H, d, J = 1.8 Hz), 8.95 (1H, d, J = 1.8 Hz).
参考例１９
５－（クロロメチル）－２－（ジフルオロメチル）ピリジン
Figure JPOXMLDOC01-appb-C000064
 　参考例２０の化合物（２７６ｍｇ，１．７４ｍｍｏｌ）のＴＨＦ溶液（５．０ｍＬ）にトリエチルアミン（０．８５ｍＬ，６．０９ｍｍｏｌ）とメタンスルホニルクロライド（０．３４ｍＬ，４．３５ｍｍｏｌ）を加え、１．５時間加熱還流下、撹拌した。反応溶液を室温まで放冷後、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。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題の化合物（２３１ｍｇ，７５％）を得た。
1H-NMR (400 MHz, CDCl3) δ: 4.63 (2H, s), 6.65 (1H, t, J = 55.4 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.90 (1H, dd, J = 2.0, 8.0 Hz), 8.66 (1H, d, J = 2.0 Hz). Reference Example 19
5- (Chloromethyl) -2- (difluoromethyl) pyridine
Figure JPOXMLDOC01-appb-C000064
 To a THF solution (5.0 mL) of the compound of Reference Example 20 (276 mg, 1.74 mmol), triethylamine (0.85 mL, 6.09 mmol) and methanesulfonyl chloride (0.34 mL, 4.35 mmol) were added, and 1.5. The mixture was stirred with heating under reflux for an hour. The reaction solution was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (231 mg, 75%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.63 (2H, s), 6.65 (1H, t, J = 55.4 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.90 (1H, dd, J = 2.0, 8.0 Hz), 8.66 (1H, d, J = 2.0 Hz).
参考例２０
［６－（ジフルオロメチル）ピリジン－３－イル］メタノール
Figure JPOXMLDOC01-appb-C000065
 　水素化リチウムアルミニウム（７７．９ｍｇ，２．２３ｍｍｏｌ）のＴＨＦ（６．０ｍＬ）懸濁液に、氷浴下、参考例２１の化合物（３４８ｍｇ，１．８６ｍｍｏｌ）のＴＨＦ（２．０ｍＬ）溶液を滴下した。０℃で１時間撹拌後、反応混合物に飽和ロッシェル塩水溶液を加え、室温で３時間撹拌した。混合物をクロロホルムで３回抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（２７６ｍｇ，９３％）を得た。
1H-NMR (400 MHz, CDCl3) δ: 4.80 (2H, s), 6.64 (1H, t, J = 55.4 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.86 (1H, dd, J = 1.7, 8.0 Hz), 8.61 (1H, d, J = 1.7 Hz). Reference Example 20
[6- (Difluoromethyl) pyridin-3-yl] methanol
Figure JPOXMLDOC01-appb-C000065
 To a suspension of lithium aluminum hydride (77.9 mg, 2.23 mmol) in THF (6.0 mL), a solution of the compound of Reference Example 21 (348 mg, 1.86 mmol) in THF (2.0 mL) was added in an ice bath. It was dripped. After stirring at 0 ° C. for 1 hour, a saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The mixture was extracted three times with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (276 mg, 93%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.80 (2H, s), 6.64 (1H, t, J = 55.4 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.86 (1H, dd, J = 1.7, 8.0 Hz), 8.61 (1H, d, J = 1.7 Hz).
参考例２１
メチル ６－（ジフルオロメチル）ピリジン－３－カルボキシレート
Figure JPOXMLDOC01-appb-C000066
 　市販のメチル ６－（ヒドロキシメチル)ニコチネート（５１１ｍｇ，３．０６ ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、二酸化マンガン（１．３３ｇ，１５．３ｍｍｏｌ）を加え、室温で４．５時間撹拌した。その後、反応混合物をセライトろ過し、ろ液を減圧濃縮することにより、メチル ６－ホルミルニコチネートを得た。得られたメチル ６－ホルミルニコチネートのジクロロメタン（５．０ｍＬ）溶液に、氷浴下、ジエチルアミノサルファートリフルオライド（１．６０ｍＬ，１２．２４ｍｍｏｌ）を加えた。氷浴下、１時間撹拌後、反応溶液に飽和炭酸水素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、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（３６１ｍｇ，６３％）を得た。
1H-NMR (400 MHz, CDCl3)δ: 3.99 (3H, s), 6.68 (1H, t, J = 55.2 Hz), 7.73 (1H, d, J = 8.1 Hz), 8.45 (1H, dd, J = 2.2, 8.1 Hz), 9.25 (1H, m). Reference Example 21
Methyl 6- (difluoromethyl) pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000066
 Manganese dioxide (1.33 g, 15.3 mmol) was added to a solution of commercially available methyl 6- (hydroxymethyl) nicotinate (511 mg, 3.06 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 4.5 hours. Thereafter, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain methyl 6-formylnicotinate. Diethylaminosulfur trifluoride (1.60 mL, 12.24 mmol) was added to a solution of the resulting methyl 6-formylnicotinate in dichloromethane (5.0 mL) in an ice bath. After stirring for 1 hour in an ice bath, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (361 mg, 63%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.99 (3H, s), 6.68 (1H, t, J = 55.2 Hz), 7.73 (1H, d, J = 8.1 Hz), 8.45 (1H, dd, J = 2.2, 8.1 Hz), 9.25 (1H, m).
参考例２２
２－（クロロメチル）－５，６，７，８－テトラヒドロキノリン 塩酸塩
Figure JPOXMLDOC01-appb-C000067
 　参考例１３と同様の方法により、参考例２３の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3)δ: 1.75-1.82 (2H, m), 1.84-1.91 (2H, m), 2.74 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 4.61 (2H, s), 7.17 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 7.8 Hz). Reference Example 22
2- (Chloromethyl) -5,6,7,8-tetrahydroquinoline hydrochloride
Figure JPOXMLDOC01-appb-C000067
 The title compound was obtained from the compound of Reference Example 23 by a method similar to that of Reference Example 13.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.75-1.82 (2H, m), 1.84-1.91 (2H, m), 2.74 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 4.61 (2H, s), 7.17 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 7.8 Hz).
参考例２３
５，６，７，８－テトラヒドロキノリン－２－イルメタノール
Figure JPOXMLDOC01-appb-C000068
 　参考例１４と同様の方法により、参考例２４の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3)δ: 1.77-1.82 (2H, m), 1.67-1.91 (2H, m), 2.75 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 4.67 (2H, s), 6.96 (1H, d, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz). Reference Example 23
5,6,7,8-tetrahydroquinolin-2-ylmethanol
Figure JPOXMLDOC01-appb-C000068
 In the same manner as in Reference Example 14, the title compound was obtained from the compound of Reference Example 24.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.77-1.82 (2H, m), 1.67-1.91 (2H, m), 2.75 (2H, t, J = 6.4 Hz), 2.89 (2H, t, J = 6.4 Hz), 4.67 (2H, s), 6.96 (1H, d, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz).
参考例２４
メチル ５，６，７，８－テトラヒドロキノリン－２－カルボキシレート
Figure JPOXMLDOC01-appb-C000069
 　参考例２５の化合物（２．００ｇ，１２．６ｍｍｏｌ）に濃塩酸（４０ｍＬ）を加え、加熱還流下、１時間撹拌した。反応溶液を室温まで放冷後、反応溶液を減圧濃縮することで５，６，７，８－テトラヒドロキノリン－２－カルボン酸を得た。
　得られた５，６，７，８－テトラヒドロキノリン－２－カルボン酸のメタノール（３０ｍＬ）溶液に塩化チオニル（１．８ｍＬ，２４．８ｍｍｏｌ）を加え、加熱還流下、終夜撹拌した。反応溶液を室温まで放冷後、溶媒を減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（２．０９ｇ，８７％）を得た。
1H-NMR (400 MHz, CDCl3)δ: 1.78-1.84 (2H, m), 1.86-1.92 (2H, m), 2.81 (2H, t, J = 6.4 Hz), 3.00 (2H, t, J = 6.4 Hz), 3.96 (3H, s), 7.46 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz). Reference Example 24
Methyl 5,6,7,8-tetrahydroquinoline-2-carboxylate
Figure JPOXMLDOC01-appb-C000069
 Concentrated hydrochloric acid (40 mL) was added to the compound of Reference Example 25 (2.00 g, 12.6 mmol), and the mixture was stirred for 1 hour with heating under reflux. The reaction solution was allowed to cool to room temperature, and the reaction solution was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroquinoline-2-carboxylic acid.
To a solution of the obtained 5,6,7,8-tetrahydroquinoline-2-carboxylic acid in methanol (30 mL) was added thionyl chloride (1.8 mL, 24.8 mmol), and the mixture was stirred overnight with heating under reflux. The reaction solution was allowed to cool to room temperature, and the solvent was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (2.09 g, 87%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.78-1.84 (2H, m), 1.86-1.92 (2H, m), 2.81 (2H, t, J = 6.4 Hz), 3.00 (2H, t, J = 6.4 Hz), 3.96 (3H, s), 7.46 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz).
参考例２５
５，６，７，８－テトラヒドロキノリン－２－カルボニトリル
Figure JPOXMLDOC01-appb-C000070
 　市販の５，６，７，８－テトラヒドロキノリン（３．５７ｇ，２６．８ｍｍｏｌ）のジクロロメタン（５０ｍＬ）／水（５０ｍＬ）溶液に氷浴下、炭酸水素ナトリウム（６．８ｇ，８０．９４ｍｍｏｌ）、メタ－クロロ過安息香酸（７．９ｇ，３２．２ｍｍｏｌ）を加えた。氷浴下、１８時間撹拌後、反応混合物に飽和チオ硫酸ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮することで粗生成物として５，６，７，８－テトラヒドロキノリン Ｎ－オキサイドを得た（４．２５ｇ）。
　得られた５，６，７，８－テトラヒドロキノリン Ｎ－オキサイドの粗生成物とトリメチルシリルシアニド（３．３２ｇ，３３．４６ｍｍｏｌ）のジクロロメタン（４０ｍＬ）溶液に、ジメチルカルバミルクロライド（３．６０ｇ，３３．４８ｍｍｏｌ）を加え、室温で２４時間撹拌した。反応混合物に１０％炭酸カリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（２．００ｇ，４７％）を得た。
LC‐MS：Ｒ.Ｔ.= 1.449 min　ObsMS = 159 [M+1] Reference Example 25
5,6,7,8-tetrahydroquinoline-2-carbonitrile
Figure JPOXMLDOC01-appb-C000070
 Sodium hydrogen carbonate (6.8 g, 80.94 mmol) in a dichloromethane (50 mL) / water (50 mL) solution of commercially available 5,6,7,8-tetrahydroquinoline (3.57 g, 26.8 mmol) in an ice bath, Meta-chloroperbenzoic acid (7.9 g, 32.2 mmol) was added. After stirring for 18 hours in an ice bath, a saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroquinoline N-oxide (4.25 g) as a crude product.
To a solution of the obtained 5,6,7,8-tetrahydroquinoline N-oxide crude product and trimethylsilylcyanide (3.32 g, 33.46 mmol) in dichloromethane (40 mL), dimethylcarbamyl chloride (3.60 g, 33.48 mmol) was added and stirred at room temperature for 24 hours. A 10% aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (2.00 g, 47%).
LC-MS: RT = 1.449 min ObsMS = 159 [M + 1]
参考例２６
２－（クロロメチル）－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン
Figure JPOXMLDOC01-appb-C000071
 　参考例２７の化合物（１０６ｍｇ，０．７１１ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に氷浴下、塩化チオニル（１６９ｍｇ，１．４２ｍｍｏｌ）を加えた。室温で１時間撹拌後、反応溶液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（１０２ｍｇ，８６％）を得た。
1H-NMR (400 MHz, CDCl3)δ: 2.12-2.17 (2H, m), 2.93 (2H, t, J = 7.6 Hz), 3.02 (2H, t, J = 7.8 Hz), 4.64 (2H, s), 7.18 (1H, d, J = 7.3 Hz), 7.50 (1H, d, J = 7.3 Hz). Reference Example 26
2- (Chloromethyl) -6,7-dihydro-5H-cyclopenta [b] pyridine
Figure JPOXMLDOC01-appb-C000071
 To a solution of the compound of Reference Example 27 (106 mg, 0.711 mmol) in dichloromethane (3 mL) was added thionyl chloride (169 mg, 1.42 mmol) in an ice bath. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (102 mg, 86%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.12-2.17 (2H, m), 2.93 (2H, t, J = 7.6 Hz), 3.02 (2H, t, J = 7.8 Hz), 4.64 (2H, s), 7.18 (1H, d, J = 7.3 Hz), 7.50 (1H, d, J = 7.3 Hz).
参考例２７
６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－２－イルメタノール
Figure JPOXMLDOC01-appb-C000072
 　参考例１４と同様の方法により、参考例２８の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3)δ: 2.11-2.14 (2H, m), 2.92 (2H, t, J = 7.6 Hz), 2.99 (2H, t, J = 7.8 Hz), 4.71 (2H, s), 7.00 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz). Reference Example 27
6,7-Dihydro-5H-cyclopenta [b] pyridin-2-ylmethanol
Figure JPOXMLDOC01-appb-C000072
 In the same manner as in Reference Example 14, the title compound was obtained from the compound of Reference Example 28.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.11-2.14 (2H, m), 2.92 (2H, t, J = 7.6 Hz), 2.99 (2H, t, J = 7.8 Hz), 4.71 (2H, s), 7.00 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz).
参考例２８
メチル ６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－２－カルボキシレート
Figure JPOXMLDOC01-appb-C000073
 　参考例２４と同様の方法により、参考例２９の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3)δ: 2.11-2.19 (2H, m), 2.97 (2H, t, J = 7.8 Hz), 3.08 (2H, t, J = 7.6 Hz), 3.97 (3H, s), 7.59 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 7.8 Hz). Reference Example 28
Methyl 6,7-dihydro-5H-cyclopenta [b] pyridine-2-carboxylate
Figure JPOXMLDOC01-appb-C000073
 In the same manner as in Reference Example 24, the title compound was obtained from the compound of Reference Example 29.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.11-2.19 (2H, m), 2.97 (2H, t, J = 7.8 Hz), 3.08 (2H, t, J = 7.6 Hz), 3.97 (3H, s), 7.59 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 7.8 Hz).
参考例２９
６，７－ジヒドロ－５Ｈ－シクロペンタ［ｂ］ピリジン－２－カルボニトリル
Figure JPOXMLDOC01-appb-C000074
 　参考例２５と同様の方法により、市販の２，３－シクロペンテノピリジンから表題化合物を得た。
1H-NMR (400 MHz, CDCl3) δ: 2.16-2.19 (2H, m), 3.01-3.05 (4H, m), 7.44 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz). Reference Example 29
6,7-Dihydro-5H-cyclopenta [b] pyridine-2-carbonitrile
Figure JPOXMLDOC01-appb-C000074
 In the same manner as in Reference Example 25, the title compound was obtained from commercially available 2,3-cyclopentenopyridine.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.16-2.19 (2H, m), 3.01-3.05 (4H, m), 7.44 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz).
参考例３０
３－（クロロメチル）－６，７－ジヒドロ－５Ｈ－シクロペンタ［ｃ］ピリジン
Figure JPOXMLDOC01-appb-C000075
 　参考例２６と同様の方法により、参考例３１の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3)δ: 2.09-2.16 (2H, m), 2.92-2.94 (4H, m), 4.66 (2H, s), 7.34 (1H, s), 8.41 (1H, s). Reference Example 30
3- (Chloromethyl) -6,7-dihydro-5H-cyclopenta [c] pyridine
Figure JPOXMLDOC01-appb-C000075
 In the same manner as in Reference Example 26, the title compound was obtained from the compound of Reference Example 31.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.09-2.16 (2H, m), 2.92-2.94 (4H, m), 4.66 (2H, s), 7.34 (1H, s), 8.41 (1H, s ).
参考例３１
６，７－ジヒドロ－５Ｈ－シクロペンタ［ｃ］ピリジン－３－イルメタノール
Figure JPOXMLDOC01-appb-C000076
 　参考例１４と同様の方法により、参考例３２の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3)δ: 2.06-2.14 (2H, m), 2.89-2.91 (4H, m), 4.69 (2H, s), 7.10 (1H, s), 8.36 (1H, s). Reference Example 31
6,7-Dihydro-5H-cyclopenta [c] pyridin-3-ylmethanol
Figure JPOXMLDOC01-appb-C000076
 The title compound was obtained from the compound of Reference Example 32 by a method similar to that of Reference Example 14.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.06-2.14 (2H, m), 2.89-2.91 (4H, m), 4.69 (2H, s), 7.10 (1H, s), 8.36 (1H, s ).
参考例３２
エチル ６，７－ジヒドロ－５Ｈ－シクロペンタ［ｃ］ピリジン－３－カルボキシレート
Figure JPOXMLDOC01-appb-C000077
 　エチルシアノホルメート（５６５ｍｇ，５．７０ｍｍｏｌ）の１，２－ジクロロエタン（５．６ｍＬ）溶液に、クロロ（１，５－シクロオクタジエン）(ペンタメチルシクロペンタジエニル)ルテニウム（II）（２８ｍｇ，０．０７３７ｍｍｏｌ）と１，６－ヘプタジイン（７８８ｍｇ，８．５５ｍｍｏｌ）の１，２－ジクロロエタン（５．６ｍＬ）溶液を滴下した。３時間撹拌後、反応混合物の溶媒を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（６２４ｍｇ，５７％）を得た。
LC‐MS：Ｒ.Ｔ.= 1.161 min　ObsMS = 192 [M+1] Reference Example 32
Ethyl 6,7-dihydro-5H-cyclopenta [c] pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000077
 To a solution of ethyl cyanoformate (565 mg, 5.70 mmol) in 1,2-dichloroethane (5.6 mL) was added chloro (1,5-cyclooctadiene) (pentamethylcyclopentadienyl) ruthenium (II) (28 mg, 0.0737 mmol) and 1,6-heptadiyne (788 mg, 8.55 mmol) in 1,2-dichloroethane (5.6 mL) were added dropwise. After stirring for 3 hours, the solvent of the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (624 mg, 57%).
LC-MS: RT = 1.161 min ObsMS = 192 [M + 1]
参考例３３
３－クロロ－２－（１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン 塩酸塩
Figure JPOXMLDOC01-appb-C000078
 　参考例１と同様の方法により、参考例３４の化合物から表題化合物を得た。
1H-NMR (400 MHz, DMSO-d6)δ: 3.68 (2H, t, J = 5.5 Hz), 4.42-4.45 (4H, m), 7.42 (1H, s), 8.26 (1H, s), 10.32 (2H, s). Reference Example 33
3-Chloro-2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine hydrochloride
Figure JPOXMLDOC01-appb-C000078
 The title compound was obtained from the compound of Reference Example 34 by a method similar to that of Reference Example 1.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.68 (2H, t, J = 5.5 Hz), 4.42-4.45 (4H, m), 7.42 (1H, s), 8.26 (1H, s), 10.32 (2H, s).
参考例３４
ｔｅｒｔ－ブチル ３－クロロ－２－（１，３－オキサゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000079
 　参考例２の化合物（４８１．５ｍｇ，１．６６ｍｍｏｌ）のＤＭＦ（４ｍＬ）溶液に、Ｎ－クロロスクシンイミド（２３３ｍｇ，１．７４ｍｍｏｌ）を加えた。６０℃で３時間撹拌後、反応溶液を室温まで放冷し、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。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（３６２．７ｍｇ，６７％）を得た。
1H-NMR (400 MHz, CDCl3)δ: 1.51 (9H, s), 3.93 (2H, t, J = 5.3 Hz), 4.23 (2H, t, J = 5.3 Hz), 4.64 (2H, s), 7.30 (1H, s), 7.73 (1H, s). Reference Example 34
tert-Butyl 3-chloro-2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000079
 N-chlorosuccinimide (233 mg, 1.74 mmol) was added to a DMF (4 mL) solution of the compound of Reference Example 2 (481.5 mg, 1.66 mmol). After stirring at 60 ° C. for 3 hours, the reaction solution was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (362.7 mg, 67%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51 (9H, s), 3.93 (2H, t, J = 5.3 Hz), 4.23 (2H, t, J = 5.3 Hz), 4.64 (2H, s) , 7.30 (1H, s), 7.73 (1H, s).
参考例３５
６－（クロロメチル）－３，４－ジヒドロ－２Ｈ－ピラノ［２，３－ｂ］ピリジン 塩酸塩
Figure JPOXMLDOC01-appb-C000080
 　参考例１３と同様の方法により、参考例３６の化合物から表題化合物を得た。
LC‐MS：Ｒ.Ｔ.= 1.353 min　ObsMS = 184 [M+1] Reference Example 35
6- (Chloromethyl) -3,4-dihydro-2H-pyrano [2,3-b] pyridine hydrochloride
Figure JPOXMLDOC01-appb-C000080
 In the same manner as in Reference Example 13, the title compound was obtained from the compound of Reference Example 36.
LC-MS: RT = 1.353 min ObsMS = 184 [M + 1]
参考例３６
３，４－ジヒドロ－２Ｈ－ピラノ［２，３－ｂ］ピリジン－６－イルメタノール
Figure JPOXMLDOC01-appb-C000081
 　市販の３，４－ジヒドロ－２Ｈ－ピラノ[２，３－ｂ]ピリジン－６－カルボアルデヒド（２６９．８ｍｇ，１．６５ｍｍｏｌ）のＴＨＦ（４ｍＬ）溶液に、室温で水素化ホウ素ナトリウム（６２．６ｍｇ，１．６５ｍｍｏｌ）を加えた。反応混合物を３時間撹拌した後、氷浴下、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。有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（１０１．６ｍｇ，３７％）を得た。
LC‐MS：Ｒ.Ｔ.= 1.226 min　ObsMS = 166 [M+1] Reference Example 36
3,4-dihydro-2H-pyrano [2,3-b] pyridin-6-ylmethanol
Figure JPOXMLDOC01-appb-C000081
 To a commercially available 3,4-dihydro-2H-pyrano [2,3-b] pyridine-6-carbaldehyde (269.8 mg, 1.65 mmol) solution in THF (4 mL) at room temperature, sodium borohydride (62. 6 mg, 1.65 mmol) was added. After stirring the reaction mixture for 3 hours, a saturated aqueous ammonium chloride solution was added in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (101.6 mg, 37%).
LC-MS: RT = 1.226 min ObsMS = 166 [M + 1]
参考例３７
６－（クロロメチル）－３，４－ジヒドロ－２Ｈ－ピラノ［２，３－ｃ］ピリジン 塩酸塩
Figure JPOXMLDOC01-appb-C000082
 　参考例１３と同様の方法により、市販の２Ｈ，３Ｈ，４Ｈ－ピラノ[２，３－ｃ]ピリジン－６－イルメタノールから表題化合物を得た。　　　
LC‐MS：Ｒ.Ｔ.= 1.026 min　ObsMS = 184 [M+1] Reference Example 37
6- (Chloromethyl) -3,4-dihydro-2H-pyrano [2,3-c] pyridine hydrochloride
Figure JPOXMLDOC01-appb-C000082
 In the same manner as in Reference Example 13, the title compound was obtained from commercially available 2H, 3H, 4H-pyrano [2,3-c] pyridin-6-ylmethanol.
LC-MS: RT = 1.026 min ObsMS = 184 [M + 1]
参考例３８
７－（クロロメチル）－２，３－ジヒドロ［１，４］ジオキシノ［２，３－ｂ］ピリジン塩酸塩
Figure JPOXMLDOC01-appb-C000083
 　参考例１３と同様の方法により、参考例３９の化合物から表題化合物を得た。
LC‐MS：Ｒ.Ｔ.= 1.484 min　ObsMS = 186 [M+1] Reference Example 38
7- (Chloromethyl) -2,3-dihydro [1,4] dioxino [2,3-b] pyridine hydrochloride
Figure JPOXMLDOC01-appb-C000083
 In the same manner as in Reference Example 13, the title compound was obtained from the compound of Reference Example 39.
LC-MS: RT = 1.484 min ObsMS = 186 [M + 1]
参考例３９
２，３－ジヒドロ［１，４］ジオキシノ［２，３－ｂ］ピリジン－７－イルメタノール
Figure JPOXMLDOC01-appb-C000084
 　参考例３６と同様の方法により、市販の２，３－ジヒドロ[１，４]ジオキシノ[２，３－ｂ]ピリジン－７－カルボアルデヒドから表題化合物を得た。
LC‐MS：Ｒ.Ｔ.= 0.395 min　ObsMS = 168 [M+1] Reference Example 39
2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-ylmethanol
Figure JPOXMLDOC01-appb-C000084
 In the same manner as in Reference Example 36, the title compound was obtained from commercially available 2,3-dihydro [1,4] dioxino [2,3-b] pyridine-7-carbaldehyde.
LC-MS: RT = 0.395 min ObsMS = 168 [M + 1]
参考例４０
２－（４－メチル－１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ]ピラジン
Figure JPOXMLDOC01-appb-C000085
 　参考例４１の化合物（７３．６ｍｇ，０．２０８ｍｍｏｌ）にＴＦＡ（２ｍＬ）を加え、８０℃で３時間撹拌した。反応溶液を室温まで放冷後、トリフルオロ酢酸を減圧留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（３６．５ｍｇ，８６％）を得た。
LC‐MS：Ｒ.Ｔ.= 0.461 min　ObsMS = 205 [M+1] Reference Example 40
2- (4-Methyl-1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000085
 TFA (2 mL) was added to the compound of Reference Example 41 (73.6 mg, 0.208 mmol), and the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and trifluoroacetic acid was distilled off under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (36.5 mg, 86%).
LC-MS: RT = 0.461 min ObsMS = 205 [M + 1]
参考例４１
５－（２，４－ジメトキシベンジル）－２－（４－メチル－１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000086
 　水素化リチウムアルミニウム（２２．８ｍｇ，０．６０１ｍｍｏｌ）、塩化アルミニウム（１０．０ｍｇ，０．０７５ｍｍｏｌ）のＴＨＦ（２．０ｍＬ）懸濁液に、氷浴下、参考例４２の化合物（９２．２ｍｇ，０．２５０ｍｍｏｌ）のＴＨＦ（５．０ｍＬ）溶液を滴下した。０℃で４時間撹拌後、反応混合物に飽和ロッシェル塩水溶液を加え、室温で１時間撹拌した。混合物をクロロホルム／エタノール（４：１）で抽出し、有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（７３．６ｍｇ，８３％）を得た。
LC‐MS：Ｒ.Ｔ.= 1.420 min　ObsMS = 355 [M+1] Reference Example 41
5- (2,4-Dimethoxybenzyl) -2- (4-methyl-1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000086
 To a suspension of lithium aluminum hydride (22.8 mg, 0.601 mmol) and aluminum chloride (10.0 mg, 0.075 mmol) in THF (2.0 mL) was added the compound of Reference Example 42 (92.2 mg) in an ice bath. , 0.250 mmol) in THF (5.0 mL) was added dropwise. After stirring at 0 ° C. for 4 hours, a saturated aqueous Rochelle salt solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with chloroform / ethanol (4: 1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (73.6 mg, 83%).
LC-MS: RT = 1.420 min ObsMS = 355 [M + 1]
参考例４２
５－（２，４－ジメトキシベンジル）－２－（４－メチル－１，３－オキサゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－４（５Ｈ）－オン
Figure JPOXMLDOC01-appb-C000087
 　参考例４３の化合物（３４．７ｍｇ，０．０９４ｍｍｏｌ）のトルエン（４ｍＬ）溶液に、３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（２７．６ｍｇ，０．１２２ｍｍｏｌ）を加え、４時間加熱還流下、撹拌した。反応溶液を室温まで放冷後、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（１１．５ｍｇ，３３％）を得た。
LC‐MS：Ｒ.Ｔ.= 1.573 min　ObsMS = 369 [M+1] Reference Example 42
5- (2,4-Dimethoxybenzyl) -2- (4-methyl-1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H)- on
Figure JPOXMLDOC01-appb-C000087
 To a solution of the compound of Reference Example 43 (34.7 mg, 0.094 mmol) in toluene (4 mL), 3-dichloro-5,6-dicyano-1,4-benzoquinone (27.6 mg, 0.122 mmol) was added. The mixture was stirred with heating under reflux for an hour. The reaction solution was allowed to cool to room temperature, 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (11.5 mg, 33%).
LC-MS: RT = 1.573 min ObsMS = 369 [M + 1]
参考例４３
５－（２，４－ジメトキシベンジル）－２－［（４Ｓ）－４－メチル－４，５－ジヒドロ－１，３－オキサゾール－２－イル］－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－４（５Ｈ）－オン
Figure JPOXMLDOC01-appb-C000088
 　参考例４４の化合物（１．７２ｇ，４．４３ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に室温で塩化チオニル（０．６４６ｍＬ，８．８６ｍｍｏｌ）を加え、加熱還流下、２時間撹拌した。反応溶液を室温まで放冷後、反応溶液の溶媒を減圧留去することで、粗生成物（１．６４ｇ）を得た。得られた粗生成物のエタノール（１０ｍＬ）溶液に１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１０ｍＬ）を加え、６０℃で１時間撹拌した。反応溶液を室温まで放冷後、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、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（１．２４ｇ，７６％）。
LC‐MS：Ｒ.Ｔ.= 1.570 min　ObsMS = 371 [M+1] Reference Example 43
5- (2,4-dimethoxybenzyl) -2-[(4S) -4-methyl-4,5-dihydro-1,3-oxazol-2-yl] -6,7-dihydropyrazolo [1,5 -A] pyrazin-4 (5H) -one
Figure JPOXMLDOC01-appb-C000088
 To a solution of the compound of Reference Example 44 (1.72 g, 4.43 mmol) in dichloromethane (10 mL) was added thionyl chloride (0.646 mL, 8.86 mmol) at room temperature, and the mixture was stirred with heating under reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and then the solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product (1.64 g). A 1 mol / L aqueous sodium hydroxide solution (10 mL) was added to a solution of the obtained crude product in ethanol (10 mL), and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.24 g, 76%).
LC-MS: RT = 1.570 min ObsMS = 371 [M + 1]
参考例４４
５－（２，４－ジメトキシベンジル）－Ｎ－［（２Ｓ）－１－ヒドロキシプロパン－２－イル］－４－オキソ－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン－２－カルボキシアミド
Figure JPOXMLDOC01-appb-C000089
 　参考例４５の化合物（５１５．６ｍｇ，１．４３５ｍｍｏｌ）とＬ－アラニノール（２１６ｍｇ，２．８７ｍｍｏｌ）、ランタントリフルオロスルホネート（８４ｍｇ，０．１４３ｍｍｏｌ）、およびトルエン（１ｍＬ）の混合物を７０℃で２４時間撹拌した。反応混合物を室温まで放冷後、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（５３７．１ｍｇ，９６％）。
1H-NMR (400 MHz, CDCl3)δ: 1.25 (3H, d, J = 6.9 Hz), 3.59-3.61 (1H, m), 3.71-3.72 (3H, m), 3.78 (3H, s), 3.80 (3H, s), 4.20-4.25 (3H, m), 4.65 (2H, d, J = 14.7 Hz), 4.69 (2H, d, J = 14.7 Hz), 6.44-6.45 (2H, m), 6.90 (1H, d, J = 7.8 Hz), 7.25-7.26 (1H, m), 7.29 (1H, s). Reference Example 44
5- (2,4-Dimethoxybenzyl) -N-[(2S) -1-hydroxypropan-2-yl] -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000089
 A mixture of the compound of Reference Example 45 (515.6 mg, 1.435 mmol), L-alaninol (216 mg, 2.87 mmol), lanthanum trifluorosulfonate (84 mg, 0.143 mmol), and toluene (1 mL) was added at 70 ° C. for 24 hours. Stir for hours. The reaction mixture was allowed to cool to room temperature, and the obtained residue was purified by silica gel column chromatography to give the title compound (537.1 mg, 96%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.25 (3H, d, J = 6.9 Hz), 3.59-3.61 (1H, m), 3.71-3.72 (3H, m), 3.78 (3H, s), 3.80 (3H, s), 4.20-4.25 (3H, m), 4.65 (2H, d, J = 14.7 Hz), 4.69 (2H, d, J = 14.7 Hz), 6.44-6.45 (2H, m), 6.90 (1H, d, J = 7.8 Hz), 7.25-7.26 (1H, m), 7.29 (1H, s).
参考例４５
エチル ５－（２，４－ジメトキシベンジル）－４－オキソ－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン－２－カルボキシレート
Figure JPOXMLDOC01-appb-C000090
 　参考例４６の化合物（８．２２ｇ，２５．１２ｍｍｏｌ）のエタノール（６ｍＬ）溶液に２，４－ジメトキシベンジルアミン（４．６２ｇ，２７．６３ｍｍｏｌ）、ヨウ化カリウム（４１７ｍｇ，２．５ｍｍｏｌ）を加え、加熱還流下、７時間撹拌した。反応溶液を室温まで放冷後、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（４．６８ｇ，５２％）を得た。
1H-NMR (400 MHz, CDCl3)δ: 1.39-1.41 (3H, m), 3.75 (2H, t, J = 5.7 Hz), 3.81 (3H, s), 3.83 (3H, s), 4.37-4.42 (4H, m), 4.70 (2H, s), 6.47 (2H, s), 7.26-7.30 (1H, m), 7.36 (1H, s). Reference Example 45
Ethyl 5- (2,4-dimethoxybenzyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate
Figure JPOXMLDOC01-appb-C000090
 To a solution of the compound of Reference Example 46 (8.22 g, 25.12 mmol) in ethanol (6 mL) was added 2,4-dimethoxybenzylamine (4.62 g, 27.63 mmol) and potassium iodide (417 mg, 2.5 mmol). The mixture was stirred for 7 hours under heating and reflux. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (4.68 g, 52%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.39-1.41 (3H, m), 3.75 (2H, t, J = 5.7 Hz), 3.81 (3H, s), 3.83 (3H, s), 4.37- 4.42 (4H, m), 4.70 (2H, s), 6.47 (2H, s), 7.26-7.30 (1H, m), 7.36 (1H, s).
参考例４６
ジエチル １－（２－ブロモエチル）－１Ｈ－ピラゾール－３，５－ジカルボキシレート
Figure JPOXMLDOC01-appb-C000091
 　市販のジエチル３，５－ピラゾールジカルボキシレート（５．３３ｇ，２５．１２ｍｍｏｌ）、２－ブロモエタノール（３．７７ｇ，３０．１７ｍｍｏｌ）、トリフェニルホスフィン（７．２５ｇ，２７．６４ｍｍｏｌ）のＴＨＦ（６０ｍＬ）に、氷浴下、ジイソプロピルアゾジカルボキシレート（５．５９ｇ，２７．６４ｍｍｏｌ）を加えた。室温で３時間撹拌後、反応溶液の溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製することにより、表題化合物（８．２２ｇ、定量的）を得た。
1H-NMR (400 MHz, CDCl3)δ: 1.40-1.41 (6H, m), 3.74 (2H, t, J = 6.9 Hz), 4.36-4.45 (4H, m), 5.04 (2H, t, J = 6.9 Hz), 7.36 (1H, s). Reference Example 46
Diethyl 1- (2-bromoethyl) -1H-pyrazole-3,5-dicarboxylate
Figure JPOXMLDOC01-appb-C000091
 Commercially available diethyl 3,5-pyrazole dicarboxylate (5.33 g, 25.12 mmol), 2-bromoethanol (3.77 g, 30.17 mmol), triphenylphosphine (7.25 g, 27.64 mmol) in THF ( 60 mL) was added diisopropyl azodicarboxylate (5.59 g, 27.64 mmol) in an ice bath. After stirring at room temperature for 3 hours, the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (8.22 g, quantitative).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40-1.41 (6H, m), 3.74 (2H, t, J = 6.9 Hz), 4.36-4.45 (4H, m), 5.04 (2H, t, J = 6.9 Hz), 7.36 (1H, s).
参考例４７
２－（５－メチル－１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000092
 　上記参考例４４，４３，４２，４１，および参考例４０に記載の方法に準じ、参考例４５の化合物と（Ｓ）－（＋）－１－アミノ－２－プロパノールからから表題化合物を得た。
LC‐MS：Ｒ.Ｔ.= 1.266 min　ObsMS = 205 [M+1] Reference Example 47
2- (5-Methyl-1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000092
 The title compound was obtained from the compound of Reference Example 45 and (S)-(+)-1-amino-2-propanol according to the method described in Reference Examples 44, 43, 42, 41 and Reference Example 40 above. .
LC-MS: RT = 1.266 min ObsMS = 205 [M + 1]
参考例４８
３－メチル－２－（１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾール［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000093
 　参考例１と同様の方法により、参考例４９の化合物から表題の化合物を得た。
1H NMR (400 MHz, CDCl3): 2.25 (3H, s), 3.29-3.32 (2H, m), 4.01 (2H, s), 4.14-4.17 (2H, m), 7.22 (1H, s), 7.67 (1H, s). Reference Example 48
3-Methyl-2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazole [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000093
 In the same manner as in Reference Example 1, the title compound was obtained from the compound of Reference Example 49.
1 H NMR (400 MHz, CDCl 3 ): 2.25 (3H, s), 3.29-3.32 (2H, m), 4.01 (2H, s), 4.14-4.17 (2H, m), 7.22 (1H, s), 7.67 (1H, s).
参考例４９
ｔｅｒｔ－ブチル ３－メチル－２－（１，３－オキサゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000094
 　参考例５０の化合物（１．１０ｇ，３．０ｍｍｏｌ）、［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)（３６７ｍｇ，０．４５ｍｍｏｌ）、炭酸ナトリウム（１．２７ｇ，１２ｍｍｏｌ）、およびＤＭＦ（５ｍＬ）の混合物に、氷浴下、２，４，６－トリメチルボロキシン（９４０ｍｇ，７．５０ｍｍｏｌ）を加えた。反応混合物を１００℃で１６時間撹拌後、室温まで放冷し、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、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（４５６ｍｇ，５０％）。
1H-NMR (400 MHz, CDCl3): 1.48 (9H, s), 2.27 (3H, s), 3.88-3.89 (2H, m), 4.18-4.21 (2H, m), 4.57 (2H, s), 7.20 (1H, s), 7.66 (1H, s). Reference Example 49
tert-Butyl 3-methyl-2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000094
 The compound of Reference Example 50 (1.10 g, 3.0 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (367 mg, 0.45 mmol), sodium carbonate (1.27 g, 12 mmol) ), And DMF (5 mL) were added 2,4,6-trimethylboroxine (940 mg, 7.50 mmol) in an ice bath. The reaction mixture was stirred at 100 ° C. for 16 hours, allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (456 mg, 50%).
1 H-NMR (400 MHz, CDCl 3 ): 1.48 (9H, s), 2.27 (3H, s), 3.88-3.89 (2H, m), 4.18-4.21 (2H, m), 4.57 (2H, s) , 7.20 (1H, s), 7.66 (1H, s).
参考例５０
ｔｅｒｔ－ブチル ３－ブロモ－２－（１，３－オキサゾール－２－イル）－６，７－ジヒドロピラゾロ［１，５－ａ］ピラジン－５（４Ｈ）－カルボキシレート
Figure JPOXMLDOC01-appb-C000095
 　参考例２の化合物（２．９０ｇ，１０ｍｍｏｌ）のジクロロメタン（４０ｍＬ）溶液にＮ－ブロモスクシンイミド（２．３１ｇ，１３ｍｍｏｌ）を加えた。反応溶液を室温で１６時間撹拌後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで表題の化合物を得た（２．２１ｇ，６０％）。
1H NMR (400 MHz, CDCl3): 2.76 (9H, s), 3.95 (2H, s), 4.24-4.25 (2H, m), 4.61 (2H, s), 7.32 (1H, s), 7.74 (1H, s). Reference Example 50
tert-Butyl 3-bromo-2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
Figure JPOXMLDOC01-appb-C000095
 N-bromosuccinimide (2.31 g, 13 mmol) was added to a solution of the compound of Reference Example 2 (2.90 g, 10 mmol) in dichloromethane (40 mL). The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (2.21 g, 60%).
1 H NMR (400 MHz, CDCl 3 ): 2.76 (9H, s), 3.95 (2H, s), 4.24-4.25 (2H, m), 4.61 (2H, s), 7.32 (1H, s), 7.74 ( 1H, s).
参考例５１
２－（１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000096
 　参考例５２の化合物（４．６ｇ，１３．５ｍｍｏｌ）にＴＦＡ（９５ｍＬ）を加え、加熱還流下、１時間撹拌した。反応溶液を室温まで放冷し、減圧濃縮した。得られた残渣に水を加え、水層を酢酸エチルで３回洗浄した。水層に炭酸水素ナトリウム水溶液を加え、ｐＨ １０として、クロロホルムで３回抽出した。得られた有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮することで表題の化合物を得た（２．１ｇ，８２％）。
1H-NMR (400 MHz, CDCl3): 3.33-3.36 (2H, t, J = 5.6 Hz), 4.12 (2H, s), 4.20-4.23 (2H, t, J = 5.6 Hz), 6.55 (1H, s), 7.21 (1H, s), 7.68 (1H, s). Reference Example 51
2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000096
 TFA (95 mL) was added to the compound of Reference Example 52 (4.6 g, 13.5 mmol), and the mixture was stirred for 1 hour with heating under reflux. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. Water was added to the obtained residue, and the aqueous layer was washed 3 times with ethyl acetate. Aqueous sodium hydrogen carbonate solution was added to the aqueous layer to adjust the pH to 10, and extracted with chloroform three times. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (2.1 g, 82%).
1 H-NMR (400 MHz, CDCl 3 ): 3.33-3.36 (2H, t, J = 5.6 Hz), 4.12 (2H, s), 4.20-4.23 (2H, t, J = 5.6 Hz), 6.55 (1H , s), 7.21 (1H, s), 7.68 (1H, s).
参考例５２
５－（２，４－ジメトキシベンジル）－２－（１，３－オキサゾール－２－イル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン
Figure JPOXMLDOC01-appb-C000097
 　参考例４１と同様の方法により、参考例５３の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3): δ 3.02 (2H, t, J = 5.4 Hz), 3.75 (2H, s), 3.77 (2H, s), 3.83 (6H, s), 4.72 (2H, t, J = 5.6 Hz), 6.49-6.52 (2H, m), 6.53 (1H, s), 7.21 (1H, s), 7.23-7.26 (1H, m), 7.67 (1H, s). Reference Example 52
5- (2,4-Dimethoxybenzyl) -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
Figure JPOXMLDOC01-appb-C000097
 The title compound was obtained from the compound of Reference Example 53 by a method similar to that of Reference Example 41.
1 H-NMR (400 MHz, CDCl 3 ): δ 3.02 (2H, t, J = 5.4 Hz), 3.75 (2H, s), 3.77 (2H, s), 3.83 (6H, s), 4.72 (2H, t, J = 5.6 Hz), 6.49-6.52 (2H, m), 6.53 (1H, s), 7.21 (1H, s), 7.23-7.26 (1H, m), 7.67 (1H, s).
参考例５３
５－（２，４－ジメトキシベンジル）－２－（１，３－オキサゾール－２－イル）－６,７－ジヒドロピラゾロ［１，５－ａ］ピラジン－４（５Ｈ）－オン
Figure JPOXMLDOC01-appb-C000098
 　ヘキサクロロエタン（５．０１ｇ，２１．１６ｍｍｏｌ）、トリフェニルホスフィン（５．５５ｇ，２１．１６ｍｍｏｌ）のアセトニトリル（５０ｍＬ）溶液に、参考例５４の化合物（３．９４ｇ，１０．５８ｍｍｏｌ）のアセトニトリル（５０ｍＬ）懸濁液を加え、室温で３０分間撹拌した。反応溶液にピリジン（３．４２ｍＬ，４２．３ｍｍｏｌ）を加え、室温で終夜撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣にメタノールを加え、室温で２時間撹拌し、固体をろ取することにより表題の化合物を得た（２．１０ｇ，５６％）。
1H-NMR (400 MHz, CDCl3) δ: 3.76-3.80 (5H, m), 3.83 (3H, s), 4.37-4.39 (2H, m), 4.72 (2H, s), 6.47-6.48 (2H, m), 7.26 (1H, s), 7.29-7.31 (1H, m), 7.35 (1H, s), 7.70 (1H, s). Reference Example 53
5- (2,4-Dimethoxybenzyl) -2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
Figure JPOXMLDOC01-appb-C000098
 To a solution of hexachloroethane (5.01 g, 21.16 mmol) and triphenylphosphine (5.55 g, 21.16 mmol) in acetonitrile (50 mL) was added acetonitrile (50 mL) of the compound of Reference Example 54 (3.94 g, 10.58 mmol). ) The suspension was added and stirred at room temperature for 30 minutes. Pyridine (3.42 mL, 42.3 mmol) was added to the reaction solution, and the mixture was stirred overnight at room temperature. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Methanol was added to the resulting residue, the mixture was stirred at room temperature for 2 hours, and the solid was collected by filtration to give the title compound (2.10 g, 56%).
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.76-3.80 (5H, m), 3.83 (3H, s), 4.37-4.39 (2H, m), 4.72 (2H, s), 6.47-6.48 (2H , m), 7.26 (1H, s), 7.29-7.31 (1H, m), 7.35 (1H, s), 7.70 (1H, s).
参考例５４
５－（２，４－ジメトキシベンジル）－４－オキソ－Ｎ－（２－オキソエチル）－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン－２－カルボキサミド
Figure JPOXMLDOC01-appb-C000099
 　参考例５５の化合物（１８８．５ｇ，０．４２３ｍｏｌ）のアセトン（１．４２Ｌ）溶液に１ｍｏｌ／Ｌ塩酸（１．４２Ｌ）を加え、６５℃で２時間撹拌した。反応溶液を室温まで放冷後、減圧濃縮した。得られた水層を酢酸エチルで抽出、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮することで表題の化合物を得た（１４２ｇ，９０％）。
1H-NMR (400 MHz, CDCl3): δ 3.77-3.80 (2H, m), 3.81 (6H, d, J = 10 Hz), 4.32 (2H, s), 4.38 (2H, d, J = 4.8 Hz), 4.70 (2H, s), 6.46-6.48(2H, m), 7.28-7.30 (1H, m), 7.40-7.50 (2H, m), 9.75 (1H, s). Reference Example 54
5- (2,4-Dimethoxybenzyl) -4-oxo-N- (2-oxoethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000099
 1 mol / L hydrochloric acid (1.42 L) was added to an acetone (1.42 L) solution of the compound of Reference Example 55 (188.5 g, 0.423 mol), and the mixture was stirred at 65 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (142 g, 90%).
1 H-NMR (400 MHz, CDCl 3 ): δ 3.77-3.80 (2H, m), 3.81 (6H, d, J = 10 Hz), 4.32 (2H, s), 4.38 (2H, d, J = 4.8 Hz), 4.70 (2H, s), 6.46-6.48 (2H, m), 7.28-7.30 (1H, m), 7.40-7.50 (2H, m), 9.75 (1H, s).
参考例５５
Ｎ－（２，２－ジエトキシエチル）－５－（２，４－ジメトキシベンジル）－４－オキソ－４，５，６，７－テトラヒドロピラゾロ［１，５－ａ］ピラジン－２－カルボキサミド
Figure JPOXMLDOC01-appb-C000100
 　参考例４４と同様の方法により、参考例４５の化合物から表題化合物を得た。
1H-NMR (400 MHz, CDCl3) δ: 1.20 (6H, t, J = 7.1 Hz), 3.53-3.56 (5H, m), 3.67-3.75 (5H, m), 3.77 (3H, s), 3.80 (3H, s), 4.26 (2H, dd, J = 6.6, 5.3 Hz), 4.56 (1H, t, J = 5.5 Hz), 4.67 (2H, s), 6.46-6.47 (2H, m), 7.00-7.02 (1H, m), 7.27-7.29 (1H, m), 7.33 (1H, s). Reference Example 55
N- (2,2-diethoxyethyl) -5- (2,4-dimethoxybenzyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000100
 In the same manner as in Reference Example 44, the title compound was obtained from the compound of Reference Example 45.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.20 (6H, t, J = 7.1 Hz), 3.53-3.56 (5H, m), 3.67-3.75 (5H, m), 3.77 (3H, s), 3.80 (3H, s), 4.26 (2H, dd, J = 6.6, 5.3 Hz), 4.56 (1H, t, J = 5.5 Hz), 4.67 (2H, s), 6.46-6.47 (2H, m), 7.00 -7.02 (1H, m), 7.27-7.29 (1H, m), 7.33 (1H, s).
試験例１：Ｄ ４ 受容体に対するアゴニスト活性と選択性の評価
ドパミンＤ ４ 受容体のＧ蛋白依存的経路に対する本発明化合物の作用
　Ｇ蛋白依存的経路は、Ｇ蛋白質にグアノシン三リン酸(Guanosine triphosphate：GTP)が結合することで、Ｇ蛋白質が活性化され、セカンドメッセンジャーを介して細胞内にシグナルを伝達する経路である。リガンドによりＧＰＣＲｓが活性化されると、Ｇ蛋白質がＧＰＣＲｓと結合し、Ｇ蛋白サブユニットの一つであるＧαにＧＴＰが結合並びにＧγβサブユニットの乖離がおこる。活性化されたＧαはアデニル酸シクラーゼの活性化及び抑制を介した細胞内ｃＡＭＰ濃度の調整、ホスホリパーゼＣの活性化を介した細胞内カルシウム濃度の調整により、シグナルを細胞内に伝達する。そのため、Ｇ蛋白依存的な経路の活性測定は、細胞内ｃＡＭＰ量の測定並びに細胞内カルシウム濃度の測定により行うことができる。
　本試験では、ドパミンＤ４受容体のＧ蛋白依存的経路に対する本発明化合物の作用を測定した。 Test Example 1: D 4 Evaluation of selectivity and agonist activity for the receptor
Action of the compound of the present invention on the G protein-dependent pathway of the dopamine D 4 receptor The G protein-dependent pathway is that G protein is activated by binding of G protein to guanosine triphosphate (GTP), It is a pathway that transmits signals into cells via second messengers. When GPCRs are activated by a ligand, G protein binds to GPCRs, GTP binds to Gα which is one of G protein subunits, and Gγβ subunits dissociate. The activated Gα transmits a signal into the cell by adjusting intracellular cAMP concentration through activation and inhibition of adenylate cyclase and adjusting intracellular calcium concentration through activation of phospholipase C. Therefore, G protein-dependent pathway activity can be measured by measuring the amount of intracellular cAMP and the concentration of intracellular calcium.
In this test, to measure the effect of the present invention compounds on G-protein-dependent pathway of dopamine D 4 receptors.
発現細胞株の作製
　ヒト脳由来のドパミンＤ４受容体遺伝子（Gene Bank Accession No: NM_000797）、カルシウム結合性発光蛋白質エクオリン、及びＧα１６もしくはＧｑｉ５等のキメラＧ蛋白を発現するプラスミドを作製し、これらをＣＨＯ細胞 (chinese hamster ovary cells) あるいはＨＥＫ２９３細胞 (human embryonic kidney 293 cells) に導入することにより発現細胞株を作製した。 Expressing cell lines produced human brain-derived dopamine D 4 receptor gene (Gene Bank Accession No: NM_000797) , calcium-binding photoprotein aequorin, and Gα16 or to prepare a plasmid expressing a chimeric G protein such as Gqi5, these An expression cell line was prepared by introducing it into CHO cells (chinese hamster ovary cells) or HEK293 cells (human embryonic kidney 293 cells).
Ｇ蛋白依存的な経路の活性測定
　Ｇ蛋白依存的なアゴニスト活性については細胞内カルシウム濃度を指標にして以下のとおり測定した。Ｄ４受容体遺伝子を導入したＣＨＯ－Ｋ１細胞株あるいはHEK293細胞株を３８４穴プレートに播種し、ＣＯ２インキュベータ内で３７℃、２４時間培養した後、予めセレンテラジンを取り込ませた細胞にＤＭＳＯに溶解した本発明化合物を添加し、発光量の変化をＦＤＳＳ(浜松フォトニクス社製)で測定した。アゴニスト活性については、本発明化合物を添加していないウェルの発光量を０％とし、本発明化合物の代わりに１μＭ内因性リガンド（ドパミン）を添加したウェルの発光量を１００％として、本発明化合物の最大活性（Ｅｍａｘ）を算出した。ＥＣ５０値は本発明化合物 Ｅｍａｘの５０％に相当する反応濃度として算出した。 Measurement of G protein-dependent pathway activity G protein-dependent agonist activity was measured as follows using intracellular calcium concentration as an index. D 4 receptor gene was introduced was a CHO-K1 cell line or HEK293 cell lines were seeded in 384 well plates, 37 ° C. in a CO 2 incubator, after 24 hours of incubation, dissolved in DMSO to cells that have incorporated the pre coelenterazine The compound of the present invention was added, and the change in the amount of luminescence was measured with FDSS (manufactured by Hamamatsu Photonics). With regard to agonist activity, the compound of the present invention is defined by setting the luminescence amount of a well not added with the compound of the present invention to 0% and the luminescence amount of a well added with 1 μM endogenous ligand (dopamine) instead of the compound of the present invention as 100%. The maximum activity (Emax) was calculated. The EC 50 value was calculated as a reaction concentration corresponding to 50% of the compound Emax of the present invention.
　試験例１の試験法を用いて得られた結果を下表に示す。
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
 The results obtained using the test method of Test Example 1 are shown in the table below.
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
試験例２：生物学的利用率の評価
ラットＰＫ試験
　本試験では本発明化合物の薬物動態を評価できる。ＳＤ系あるいはＷＫＹ系７週齢のラットに対して、本発明化合物を生理食塩水溶液にて静脈内投与またはカルボキシメチルセルロース懸濁液あるいはメチルセルロース懸濁液にて経口投与し、それぞれ以下の時間で血液を採取した。
静脈内投与：投与後５分、１５分、３０分、１時間、２時間、４時間、６時間および２４時間
経口投与：投与後１５分、３０分、１時間、２時間、４時間、６時間および２４時間
　採取した血液から血漿を得、ＬＣ－ＭＳにて血漿中薬物濃度を測定する。この濃度推移から血漿中濃度－時間曲線下面積（ＡＵＣ）を算出し、下記の式にあてはめることにより、生物学的利用率を算出した。
生物学的利用率（％）＝経口投与後のＡＵＣ／静脈内投与後のＡＵＣ×１００ Test Example 2: Evaluation of bioavailability
Rat PK Test In this test, the pharmacokinetics of the compound of the present invention can be evaluated. The SD compound or the WKY rat 7 weeks old is administered the compound of the present invention intravenously in a physiological saline solution or orally in a carboxymethylcellulose suspension or a methylcellulose suspension. Collected.
Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration Plasma is obtained from the collected blood for 24 hours and the plasma drug concentration is measured by LC-MS. From this concentration transition, the area under the plasma concentration-time curve (AUC) was calculated and applied to the following formula to calculate the bioavailability.
Bioavailability (%) = AUC after oral administration / AUC after intravenous administration × 100
　試験例２の結果を下表に示す。
Figure JPOXMLDOC01-appb-T000103
 The results of Test Example 2 are shown in the table below.
Figure JPOXMLDOC01-appb-T000103
試験例３：脳内移行性の評価
ラット脳内移行性試験
　本試験では本発明化合物の脳内移行性を評価できる。ＳＤ系あるいはＷＫＹ系７週齢のラットに対して、本発明化合物を生理食塩水溶液にて皮下投与またはメチルセルロース懸濁溶液にて経口投与し、投与後０．５時間、１時間あるいは２時間後に血漿及び脳を採取し、ＬＣ－ＭＳにて血漿中及び脳内薬物濃度を測定した。
　本発明化合物の血清及び脳内タンパク結合率を、平衡透析法を用いて測定した。
　上記の試験により得られた血漿中および脳内化合物濃度および血漿中および脳内タンパク結合率を下記の式にあてはめることにより、Ｋｐ，ｕｕ，ｂｒａｉｎ（脳／血漿間非結合型薬物濃度比）を算出した。
Ｋｐ，ｕｕ，ｂｒａｉｎ＝（脳内化合物濃度×（１００－脳内タンパク結合率（％））／１００）／（血漿中化合物濃度×（１００－血漿中タンパク結合率（％））／１００） Test Example 3: Evaluation of migration into the brain
Rat Brain Translocation Test This test can evaluate the brain translocation of the compounds of the present invention. The compound of the present invention is administered subcutaneously in a physiological saline solution or orally in a methylcellulose suspension solution to a SD or WKY 7-week-old rat, and plasma is administered 0.5 hour, 1 hour or 2 hours after administration. Then, brains were collected, and plasma and brain drug concentrations were measured by LC-MS.
Serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis.
By fitting the plasma and brain compound concentrations and plasma and brain protein binding rates obtained by the above test to the following equations, Kp, uu, brain (brain / plasma non-binding drug concentration ratio) Calculated.
Kp, uu, brain = (Brain compound concentration × (100−protein binding rate in brain (%)) / 100) / (plasma compound concentration × (100−protein binding rate in plasma (%)) / 100)
　試験例３の結果を下表に示す。
Figure JPOXMLDOC01-appb-T000104
 The results of Test Example 3 are shown in the table below.
Figure JPOXMLDOC01-appb-T000104
試験例４：ＳＨＲラットにおける多動行動に対する薬理作用評価
　幼若期のＳＨＲラットは、妥当性の高いＡＤＨＤモデルとして広く認知されている。本ラットにおけるオープンフィールド環境における多動行動に対して、本発明化合物を投与した際の抑制作用を評価した。６もしくは７週齢のＳＨＲラットに対して、本発明化合物を経口投与し、３０分後から９０分間の自発運動を評価した。測定は、９００ｍｍ×９００ｍm×４２０ｍｍのオープンフィールドを用いて実施し、その運動量を行動解析システムLimeLight（ACTIMETRICS）を用いて解析した。溶媒投与群を基準として、本発明化合物投与群の３０分ごとの累積運動量（ｃｍ）を比較した。
　図１に示すとおり、実施例１９（１０ｍｇ／ｋｇ投与）および実施例２２（１０ｍｇ／ｋｇ投与）の化合物は、ＳＨＲラットが示す多動行動を抑制した。 Test Example 4: Evaluation of pharmacological action on hyperactive behavior in SHR rats SHR rats in early childhood are widely recognized as highly valid ADHD models. The inhibitory action when the compound of the present invention was administered to the hyperactive behavior in the open field environment in the rat was evaluated. The compound of the present invention was orally administered to 6- or 7-week-old SHR rats, and the spontaneous movement for 90 minutes was evaluated after 30 minutes. The measurement was performed using an open field of 900 mm × 900 mm × 420 mm, and the momentum was analyzed using a behavior analysis system LimeLight (ACTIMETRICS). Based on the solvent administration group, the cumulative exercise amount (cm) every 30 minutes of the compound administration group of the present invention was compared.
As shown in FIG. 1, the compounds of Example 19 (10 mg / kg administration) and Example 22 (10 mg / kg administration) suppressed the hyperactivity behavior exhibited by SHR rats.
試験例５：ＳＨＲラットにおける注意機能に対する薬理作用評価
　ＳＨＲラットでは、バックグランド動物であるＷＫＹラットに対して、Ｙ字型迷路試験において低い自発交替行動率が認められる。そこで、本発明化合物を前処置し、注意機能に対する作用を評価した。実験にはＹ字型迷路装置（黒色アクリル製：４５０ｍｍ×１００ｍｍ×４２０ｍｍ、堀川製作所株式会社）を用いた。６もしくは７週齢のＳＨＲラットに対して、本発明化合物を経口投与し、３０分後から８分間の自発交替行動率を測定した。媒体投与群の自発交替行動率を基準として、本発明化合物投与群の自発交替行動率（％）を比較した。
　図２に示すとおり、実施例１９（１０ｍｇ／ｋｇ投与）および実施例２２（１０ｍｇ／ｋｇ投与）の化合物は、有意な自発交替行動率の改善作用を示した。 Test Example 5: Evaluation of pharmacological action on attention function in SHR rats In the SHR rats , a low spontaneous alternation behavior rate is observed in the Y-shaped maze test compared to the background animals WKY rats. Therefore, the compound of the present invention was pretreated and the effect on attention function was evaluated. For the experiment, a Y-shaped maze device (made of black acrylic: 450 mm × 100 mm × 420 mm, Horikawa Seisakusho) was used. The compound of the present invention was orally administered to 6- or 7-week-old SHR rats, and the spontaneous alternation behavior rate was measured for 8 minutes from 30 minutes later. Based on the spontaneous alternation behavior rate of the vehicle administration group, the spontaneous alternation behavior rate (%) of the compound administration group was compared.
As shown in FIG. 2, the compounds of Example 19 (10 mg / kg administration) and Example 22 (10 mg / kg administration) showed a significant effect of improving the spontaneous alternation behavior rate.
試験例６：胎生期バルプロ酸投与ラットにおける社会性障害に対する薬理作用評価
　本発明化合物を前処置し、社会性認知に対する改善作用を評価することができる。胎生期１２．５日齢にバルプロ酸に曝露されたラットは、妥当性の高い自閉症モデルとして広く認知されている。本ラットでは、社会性評価試験である３チャンバーテストにおいて、社会性認知障害が認められる。実験にはソーシャビリティーケージ（６００ｍｍ×４００ｍｍ×２２０ｍｍ、室町機械株式会社）を用いる。３週齢の胎生期バルプロ酸投与ラットに対して本発明化合物を経口投与し、３０分後から、ラットもしくは新規物体への接近時間を１０分間測定した。新規物体への接近時間を１００％とした時のラットへの接近時間の割合を算出し、媒体投与群の結果を基準とした改善率（％）を評価する。 Test Example 6: Evaluation of pharmacological action against social disorder in rats treated with fetal valproic acid The compound of the present invention can be pretreated to evaluate the improvement effect on social cognition. Rats exposed to valproic acid at 12.5 days of gestation are widely recognized as a highly relevant model of autism. In this rat, social cognitive impairment is observed in the three-chamber test, which is a social evaluation test. In the experiment, a social cage (600 mm × 400 mm × 220 mm, Muromachi Kikai Co., Ltd.) is used. The compound of the present invention was orally administered to a 3-week-old gestational valproic acid-treated rat, and after 30 minutes, the approach time to the rat or a new object was measured for 10 minutes. The ratio of the approach time to the rat when the approach time to the new object is taken as 100% is calculated, and the improvement rate (%) based on the result of the vehicle administration group is evaluated.
　以上で説明したように、本発明化合物は、ドパミンＤ４受容体アゴニストであることから、中枢神経系疾患治療薬（例えば注意欠如多動性障害等の治療剤等）として有用である。 As described above, since the compound of the present invention is a dopamine D 4 receptor agonist, it is useful as a therapeutic agent for central nervous system diseases (for example, a therapeutic agent for attention deficit hyperactivity disorder, etc.).

Claims (30)

  1. 　式（１）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、ｎおよびｍは、それぞれ独立して、１または２を表し；
    　Ｗ１およびＷ２は、それぞれ独立して、単結合、またはＣ１－４アルキレン基（該基は同種または異種の１～２個のハロゲン原子で置換されていてもよい。）を表し；
    　Ｒ１およびＲ２は、それぞれ独立して、水素原子、ハロゲン原子、もしくは置換されていてもよいＣ１－６アルキル基であるか、またはそれらが結合する炭素原子と一緒になって、３員～８員のシクロアルカン環を形成してもよく；
    　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アルキル基を表し；
    　環Ｑ１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～１０員のヘテロアリール基を表し;
    　環Ｑ２は、置換されていてもよい５員のヘテロアリール基を表すが、以下の化合物
    Figure JPOXMLDOC01-appb-C000002
     を除く）で表される化合物またはその薬学上許容される塩。     Formula (1):
    Figure JPOXMLDOC01-appb-C000001
     (In the formula, n and m each independently represent 1 or 2;
    W 1 and W 2 each independently represent a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms);
    R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group, or together with the carbon atom to which they are attached, a 3-membered May form a ˜8 membered cycloalkane ring;
    R 3 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group;
    Ring Q 1 represents an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered heteroaryl group;
    Ring Q 2 represents an optionally substituted 5-membered heteroaryl group, and the following compounds
    Figure JPOXMLDOC01-appb-C000002
     Or a pharmaceutically acceptable salt thereof.
  2. 　ｎおよびｍが、それぞれ独立して、１または２であり；
    　Ｗ１およびＷ２が、それぞれ独立して、単結合、またはＣ１－４アルキレン基（該基は同種または異種の１～２個のハロゲン原子で置換されていてもよい。）であり；
    　Ｒ１およびＲ２が、それぞれ独立して、水素原子、ハロゲン原子、もしくはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）であるか、またはそれらが結合する炭素原子と一緒になって、３員～８員のシクロアルカン環を形成してもよく；
    　Ｒ３が、水素原子、ハロゲン原子、シアノ基、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）であり；
    　環Ｑ１が、
    （１）５員～１０員のヘテロアリール基（該基は、
    　（ａ）ハロゲン原子、
    　（ｂ）Ｃ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）、
    　（ｃ）Ｃ２－６アルケニル基（該基は同種または異種の１～４個のハロゲン原子で置換されていてもよい。）、
    　（ｄ）Ｃ１－６アルコキシ基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、
    　（ｅ）シアノ基、および
    　（ｆ）アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）からなる群から選択される同種または異種の１～４個の基で置換されていてもよく、また２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環（該環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）、または
    （２）Ｃ６－１０アリール基（該基は、本項中の前記（１）の（ａ）～（ｆ）からなる群から選択される同種または異種の１～４個の基で置換されていてもよく、また２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環（該環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）であり；
    　環Ｑ２が、
    　（ａ）ハロゲン原子、および
    　（ｂ）Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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５員のヘテロアリール基である、請求項１に記載の化合物またはその薬学上許容される塩。     n and m are each independently 1 or 2;
    W 1 and W 2 are each independently a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms);
    R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). Or together with the carbon atom to which they are attached may form a 3- to 8-membered cycloalkane ring;
    R 3 is a hydrogen atom, a halogen atom, a cyano group, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
    Ring Q 1 is
    (1) a 5- to 10-membered heteroaryl group (the group is
    (A) a halogen atom,
    (B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups);
    (C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms),
    (D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
    (E) a cyano group, and (f) an amino group (the group is substituted with one or two groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) May be substituted with 1 to 4 groups of the same or different types selected from the group consisting of, and when two substituents are substituted with adjacent carbon atoms, A 5- to 8-membered ring together with the carbon atom to which is bonded (the ring is the same kind selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) Alternatively, it may be substituted with 1 to 4 different groups.). ), Or (2) a C 6-10 aryl group (this group is the same or different 1 to 4 groups selected from the group consisting of (a) to (f) of (1) in this section In the case where two substituents are substituted by adjacent carbon atoms, a 5- to 8-membered ring together with the carbon atoms to which they are bonded (the ring is a halogen atom) , A hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group may be substituted with the same or different 1 to 4 groups selected from the group consisting of .);
    Ring Q 2 is
    The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a 5-membered heteroaryl group which may be substituted with 1 to 2 groups.
  3. 　ｍが１であり；
    　Ｗ１およびＷ２がいずれも単結合である、請求項１または請求項２に記載の化合物またはその薬学上許容される塩。     m is 1;
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein both W 1 and W 2 are a single bond.
  4. 　ｎが１であり；
    　Ｒ１およびＲ２がいずれも水素原子である、請求項１～請求項３のいずれか一項に記載の化合物またはその薬学上許容される塩。     n is 1;
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 and R 2 are both hydrogen atoms.
  5. 　環Ｑ１が、１～３個の窒素原子を含有する５員～１０員のヘテロアリール基（該基は、
    　（ａ）ハロゲン原子、
    　（ｂ）Ｃ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）、
    　（ｃ）Ｃ２－６アルケニル基（該基は同種または異種の１～４個のハロゲン原子で置換されていてもよい。）、
    　（ｄ）Ｃ１－６アルコキシ基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、
    　（ｅ）シアノ基、および
    　（ｆ）アミノ基（該基は、Ｃ１－６アルキル基およびＣ３－７シクロ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１～２個の基で置換されていてもよい。）からなる群から選択される同種または異種の１～４個の基で置換されていてもよく、また２つの置換基が隣接する炭素原子に置換される場合は、それらが結合する炭素原子と一緒になって５員～８員の環（該環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）である、請求項１～請求項４のいずれか一項に記載の化合物またはその薬学上許容される塩。     Ring Q 1 is a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms (the group is
    (A) a halogen atom,
    (B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups);
    (C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms),
    (D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
    (E) a cyano group, and (f) an amino group (the group is substituted with one or two groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) May be substituted with 1 to 4 groups of the same or different types selected from the group consisting of, and when two substituents are substituted with adjacent carbon atoms, A 5- to 8-membered ring together with the carbon atom to which is bonded (the ring is the same kind selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) Alternatively, it may be substituted with 1 to 4 different groups.). The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
  6. 　環Ｑ１が、下記式（２ａ）または（２ｂ）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｘ１は、ＮまたはＣＲ１２を表し；
    　Ｒ１１は、ハロゲン原子、Ｃ１－６アルコキシ基（該基は１～３個のハロゲン原子で置換されていてもよい。）、またはＣ１－６アルキル基（該基は、ハロゲン原子およびヒドロキシ基からなる群から選択される同種または異種の１～３個の基で置換されていてもよい。）を表し；
    　Ｒ１２、Ｒ１３、Ｒ１４およびＲ１５は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）、Ｃ２－６アルケニル基（該基は同種または異種の１～４個のハロゲン原子で置換されていてもよい。）、Ｃ１－６アルコキシ基（該基は１～３個のハロゲン原子で置換されていてもよい。）、またはアミノ基（該基は、同種または異種の１～２個のＣ１－６アルキル基で置換されていてもよい。）を表すか；
    　または、Ｒ１１およびＲ１２、またはＲ１１およびＲ１５が、それらが結合する炭素原子と一緒になって、５員～８員のシクロアルカン環、５員～８員の飽和ヘテロ環、または５員～８員のシクロアルケン環（該シクロアルカン環、飽和ヘテロ環、または５員～８員のシクロアルケン環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成してもよい。）で表される基である、請求項１～請求項４のいずれか一項に記載の化合物またはその薬学上許容される塩。     Ring Q 1 is represented by the following formula (2a) or (2b):
    Figure JPOXMLDOC01-appb-C000003
     Wherein X 1 represents N or CR 12 ;
    R 11 represents a halogen atom, a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkyl group (the group includes a halogen atom and a hydroxy group). Which may be substituted with the same or different 1 to 3 groups selected from the group consisting of groups);
    R 12 , R 13 , R 14 and R 15 each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group (the group is substituted with 1 to 3 halogen atoms of the same or different types). A C 2-6 alkenyl group (the group may be substituted with 1 to 4 halogen atoms of the same or different types), a C 1-6 alkoxy group (1 to 3 groups Or an amino group (the group may be substituted with the same or different 1 to 2 C 1-6 alkyl groups);
    Or R 11 and R 12 , or R 11 and R 15 , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring, a 5- to 8-membered saturated heterocycle, or 5 Membered to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocyclic ring, or 5-membered to 8-membered cycloalkene ring includes a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) And may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of: The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a group represented by
  7. 　環Ｑ１が、式（２ａ）で表される基である、請求項６に記載の化合物またはその薬学上許容される塩。 The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is a group represented by formula (2a).
  8. 　環Ｑ１が、式（２ｂ）で表される基である、請求項６に記載の化合物またはその薬学上許容される塩。 The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein ring Q 1 is a group represented by formula (2b).
  9. 　Ｘ１がＣＲ１２である、請求項６～請求項８のいずれか一項に記載の化合物またはその薬学上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 8, wherein X 1 is CR 12 .
  10. 　Ｒ１１およびＲ１２、またはＲ１１およびＲ１５が、それらが結合する炭素原子と一緒になって、５員～８員のシクロアルカン環、５員～８員の飽和ヘテロ環、または５員～８員のシクロアルケン環（該シクロアルカン環、飽和ヘテロ環、または５員～８員のシクロアルケン環は、ハロゲン原子、ヒドロキシ基、Ｃ１－６アルキル基、およびＣ１－６アルコキシ基からなる群から選択される同種または異種の１～４個の基で置換されていてもよい。）を形成している、請求項６～請求項９のいずれか一項に記載の化合物またはその薬学上許容される塩。 R 11 and R 12 , or R 11 and R 15 , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring, a 5- to 8-membered saturated heterocycle, or a 5-membered to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is composed of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. Or a pharmaceutically acceptable compound thereof, which may be substituted with 1 to 4 groups of the same or different types selected from the group). Acceptable salt.
  11. 　Ｒ１１が１～３個のフッ素原子で置換されていてもよいＣ１－４アルキル基である、請求項６～請求項９のいずれか一項に記載の化合物またはその薬学上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein R 11 is a C 1-4 alkyl group which may be substituted with 1 to 3 fluorine atoms. .
  12. 　環Ｑ２が、
    　（ａ）ハロゲン原子、および
    　（ｂ）Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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オキサゾール基、イソキサゾール基、イミダゾール基、ピラゾール基、オキサジザゾール基、トリアゾール基、チアゾール基、イソチアゾール基、またはチアジアゾール基である、請求項１～請求項１１のいずれか一項に記載の化合物またはその薬学上許容される塩。     Ring Q 2 is
    The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). An oxazole group, an isoxazole group, an imidazole group, a pyrazole group, an oxadizazole group, a triazole group, a thiazole group, an isothiazole group, or a thiadiazole group, which may be substituted with one or two groups of Item 12. The compound according to any one of Items 11 or a pharmaceutically acceptable salt thereof.
  13. 　環Ｑ２が、
    　（ａ）ハロゲン原子、および
    　（ｂ）Ｃ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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オキサゾール基、イソキサゾール基、イミダゾール基、またはピラゾール基である、請求項１２に記載の化合物またはその薬学上許容される塩。     Ring Q 2 is
    The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). The compound or a pharmaceutically acceptable salt thereof according to claim 12, which is an oxazole group, an isoxazole group, an imidazole group, or a pyrazole group, which may be substituted with 1 to 2 groups.
  14. 　環Ｑ２が、下記式（３ａ）、（３ｂ）または（３ｃ）：
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｘ２は、ＯまたはＮＲ２３（Ｒ２３は水素原子、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）を表す）を表し；
    　Ｒ２１およびＲ２２は、それぞれ独立して、水素原子、ハロゲン原子、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）を表す。）で表される基である、請求項１～請求項１３のいずれか一項に記載の化合物またはその薬学上許容される塩。     Ring Q 2 is represented by the following formula (3a), (3b) or (3c):
    Figure JPOXMLDOC01-appb-C000004
     (In the formula, X 2 represents O or NR 23 (R 23 represents a hydrogen atom or a C 1-6 alkyl group (the group may be substituted with the same or different 1 to 3 halogen atoms).) Represents);
    R 21 and R 22 each independently represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). To express. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, which is a group represented by
  15. 　環Ｑ２が、式（３ａ）で表される基である、請求項１４に記載の化合物またはその薬学上許容される塩。 Ring Q 2 is a group represented by the formula (3a), a compound or a pharmaceutically acceptable salt thereof according to claim 14.
  16. 　Ｘ２がＯである、請求項１４または請求項１５に記載の化合物またはその薬学上許容される塩。 X 2 is O, and compound or a pharmaceutically acceptable salt thereof according to claim 14 or claim 15.
  17. 　Ｒ２１およびＲ２２がいずれも水素原子である、請求項１４～請求項１６のいずれか一項に記載の化合物またはその薬学上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 16, wherein R 21 and R 22 are both hydrogen atoms.
  18. 　Ｒ３が、水素原子、またはＣ１－６アルキル基（該基は同種または異種の１～３個のハロゲン原子で置換されていてもよい。）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学上許容される塩。 18. Any one of claims 1 to 17, wherein R 3 is a hydrogen atom or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). Or a pharmaceutically acceptable salt thereof.
  19. 　Ｒ３がＣ１－４アルキル基である、請求項１～請求項１８のいずれか一項に記載の化合物またはその薬学上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 3 is a C 1-4 alkyl group.
  20. 　下記式のいずれかで表される請求項１に記載の化合物、またはその薬学上許容される塩：
    5-[(6-メチルピリジン-3-イル)メチル]-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン、
    5-[(5-メチルピリジン-2-イル)メチル]-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン、
    3-{[2-(1,3-オキサゾール-2-イル)-6,7-ジヒドロピラゾロ [1,5-a]ピラジン-5(4H)-イル]メチル}-5,6,7,8-テトラヒドロキノリン、
    2-(1,3-オキサゾール-2-イル)-5-{[6-(トリフルオロメチル)ピリジン-3-イル]メチル}-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン、
    5-{[6-(ジフルオロメチル)ピリジン-3-イル]メチル}-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン、
    6-{[2-(1,3-オキサゾール-2-イル)-6,7-ジヒドロピラゾロ [1,5-a]ピラジン-5(4H)-イル]メチル}-3,4-ジヒドロ-2H-ピラノ [2,3-b]ピリジン。     The compound according to claim 1 represented by any one of the following formulas, or a pharmaceutically acceptable salt thereof:
    5-[(6-methylpyridin-3-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine,
    5-[(5-methylpyridin-2-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine,
    3-{[2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] methyl} -5,6,7, 8-tetrahydroquinoline,
    2- (1,3-oxazol-2-yl) -5-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -4,5,6,7-tetrahydropyrazolo [1,5- a] pyrazine,
    5-{[6- (Difluoromethyl) pyridin-3-yl] methyl} -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazine,
    6-{[2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] methyl} -3,4-dihydro- 2H-pyrano [2,3-b] pyridine.
  21. 　下記式のいずれかで表される請求項１に記載の化合物、またはその薬学上許容される塩：
    3-メチル-5-[(6-メチルピリジン-3-イル)メチル]-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン
    3-メチル-5-[(5-メチルピリジン-2-イル)メチル]-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン
    3-メチル-5-[(6-メチルピリジン-2-イル)メチル]-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン
    5-[(5-クロロ-6-メチルピリジン-3-イル)メチル]-3-メチル-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピラジン
    5-[(5,6-ジメチルピリジン-3-イル)メチル]-3-メチル-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン
    5-[(5-フルオロ-6-メチルピリジン-2-イル)メチル]-3-メチル-2-(1,3-オキサゾール-2-イル)-4,5,6,7-テトラヒドロピラゾロ [1,5-a]ピラジン。     The compound according to claim 1 represented by any one of the following formulas, or a pharmaceutically acceptable salt thereof:
    3-Methyl-5-[(6-methylpyridin-3-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5- a] pyrazine
    3-Methyl-5-[(5-methylpyridin-2-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5- a] pyrazine
    3-Methyl-5-[(6-methylpyridin-2-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5- a] pyrazine
    5-[(5-Chloro-6-methylpyridin-3-yl) methyl] -3-methyl-2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [ 1,5-a] pyrazine
    5-[(5,6-Dimethylpyridin-3-yl) methyl] -3-methyl-2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1, 5-a] pyrazine
    5-[(5-Fluoro-6-methylpyridin-2-yl) methyl] -3-methyl-2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [ 1,5-a] pyrazine.
  22. 　請求項１～請求項２１のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
  23. 　請求項１～請求項２１のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する、注意欠如多動性障害、自閉症スペクトラム障害、統合失調症、気分障害、および認知機能障害からなる群から選ばれる中枢神経性疾患の治療剤。 Attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient And a therapeutic agent for a central nervous system disease selected from the group consisting of cognitive impairment.
  24. 　請求項１～請求項２１のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する、注意欠如多動性障害の治療剤。 A therapeutic agent for attention-deficit / hyperactivity disorder comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
  25. 　注意欠如多動性障害が注意欠如（inattention）を主症状とする障害である、請求項２４に記載の治療剤。 The therapeutic agent according to claim 24, wherein the attention deficit hyperactivity disorder is a disorder mainly having an attention deficit (inattention).
  26. 　注意欠如多動性障害が多動性（hyperactivity）を主症状とする障害である、請求項２４に記載の治療剤。 The therapeutic agent according to claim 24, wherein the attention deficit hyperactivity disorder is a disorder mainly having hyperactivity.
  27. 　注意欠如多動性障害が衝動性（impulsivity）を主症状とする障害である、請求項２４に記載の治療剤。 The therapeutic agent according to claim 24, wherein the attention deficit hyperactivity disorder is a disorder whose main symptom is impulsivity.
  28. 　請求項１～請求項２１のいずれか一項に記載の化合物またはその薬学上許容される塩を有効成分として含有する、自閉症スペクトラム障害の治療剤。 A therapeutic agent for autism spectrum disorder, comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient.
  29. 　自閉症スペクトラム障害が社会的コミュニケーションと社会的相互作用の持続的な欠陥を主症状とする障害である、請求項２８に記載の治療剤。 The therapeutic agent according to claim 28, wherein the autism spectrum disorder is a disorder whose main symptom is a persistent defect in social communication and social interaction.
  30. 　自閉症スペクトラム障害が制限された反復される行動や興味や活動の様式を主症状とする障害である、請求項２８に記載の治療剤。 29. The therapeutic agent according to claim 28, wherein the autism spectrum disorder is a disorder whose main symptom is a repetitive behavior, interest, or activity pattern with limited autism spectrum disorder.
PCT/JP2016/062536 2015-04-21 2016-04-20 2-substituted fused pyrazole derivatives WO2016171181A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015-086709 2015-04-21
JP2015086709 2015-04-21

Publications (1)

Publication Number Publication Date
WO2016171181A1 true WO2016171181A1 (en) 2016-10-27

Family

ID=57143121

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/062536 WO2016171181A1 (en) 2015-04-21 2016-04-20 2-substituted fused pyrazole derivatives

Country Status (1)

Country Link
WO (1) WO2016171181A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110724151A (en) * 2019-11-18 2020-01-24 成都睿智化学研究有限公司 Synthesis method of (3, 4-dihydro-2H-pyrano [2,3-b ] pyridine-6-yl) methanol

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012522793A (en) * 2009-04-03 2012-09-27 大日本住友製薬株式会社 Compounds for the treatment of metabotropic glutamate receptor 5-mediated disorders and methods of use thereof
JP2013544891A (en) * 2010-12-08 2013-12-19 ヴァンダービルト ユニバーシティー Bicyclic pyrazole compounds as allosteric modulators of the mGLUR5 receptor
JP2015059118A (en) * 2013-09-20 2015-03-30 大日本住友製薬株式会社 Tetrahydropyrazolopyrazine derivatives
WO2015060348A1 (en) * 2013-10-23 2015-04-30 大日本住友製薬株式会社 Fused pyrazole derivative

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012522793A (en) * 2009-04-03 2012-09-27 大日本住友製薬株式会社 Compounds for the treatment of metabotropic glutamate receptor 5-mediated disorders and methods of use thereof
JP2013544891A (en) * 2010-12-08 2013-12-19 ヴァンダービルト ユニバーシティー Bicyclic pyrazole compounds as allosteric modulators of the mGLUR5 receptor
JP2015059118A (en) * 2013-09-20 2015-03-30 大日本住友製薬株式会社 Tetrahydropyrazolopyrazine derivatives
WO2015060348A1 (en) * 2013-10-23 2015-04-30 大日本住友製薬株式会社 Fused pyrazole derivative

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110724151A (en) * 2019-11-18 2020-01-24 成都睿智化学研究有限公司 Synthesis method of (3, 4-dihydro-2H-pyrano [2,3-b ] pyridine-6-yl) methanol
CN110724151B (en) * 2019-11-18 2022-03-04 成都睿智化学研究有限公司 Synthesis method of (3, 4-dihydro-2H-pyrano [2,3-b ] pyridine-6-yl) methanol

Similar Documents

Publication Publication Date Title
KR102179599B1 (en) New bicyclic derivatives
US8841299B2 (en) Substituted pyrrolo[1,2-a]pyrazines as tankyrase inhibitors
JP6800885B2 (en) Imidazopyrazine and pyrazolopyrimidine, and their use as AMPA receptor regulators
JP2021193099A (en) Substituted 4-azaindoles and their use as glun2b receptor modulators
KR20150126036A (en) NEW OCTAHYDRO-PYRROLO[3,4-c]-PYRROLE DERIVATIVES AND ANALOGS THEREOF AS AUTOTAXIN INHIBITORS
TW201726675A (en) 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor
JPWO2007040166A1 (en) Novel condensed pyrrole derivatives
JP2024020396A (en) Fused lactam derivatives
KR20220140710A (en) Triazolopyridazine derivatives, methods for their preparation, drug compositions and uses
JP2021512055A (en) TAM Family Kinase / and CSF1R Kinase Inhibitors and Their Applications
CN112805063A (en) Bicyclic derivatives as GABAA a5 receptor modulators
WO2015060348A1 (en) Fused pyrazole derivative
JP2023134749A (en) Macrolide derivatives, preparation method and application thereof
WO2016171181A1 (en) 2-substituted fused pyrazole derivatives
JP2016204374A (en) Medicine comprising condensed pyrazole derivative
US10745401B2 (en) Condensed lactam derivative
JP6370294B2 (en) Cyclic aminomethylpyrimidine derivatives
CA3191001A1 (en) Synthesis of quinazoline compounds
JP2013166727A (en) Dihydroimidazo pyrazinone derivative
JP2022554385A (en) WDR5 inhibitors and modulators
WO2018079628A1 (en) Pyrrole derivative with fused ring and pharmaceutical use thereof
JP2021119130A (en) Drug comprising fused lactam derivative
AU2015370697A1 (en) Novel heterocyclic compounds and the use thereof in medicine and in cosmetics

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16783202

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16783202

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP