WO2017069270A1 - Nitrogen-containing condensed heterocyclic compound - Google Patents

Nitrogen-containing condensed heterocyclic compound Download PDF

Info

Publication number
WO2017069270A1
WO2017069270A1 PCT/JP2016/081355 JP2016081355W WO2017069270A1 WO 2017069270 A1 WO2017069270 A1 WO 2017069270A1 JP 2016081355 W JP2016081355 W JP 2016081355W WO 2017069270 A1 WO2017069270 A1 WO 2017069270A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
group
formula
atom
Prior art date
Application number
PCT/JP2016/081355
Other languages
French (fr)
Japanese (ja)
Inventor
梨絵 下野
大輔 松田
誠治 増田
修資 山本
Original Assignee
大正製薬株式会社
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 大正製薬株式会社 filed Critical 大正製薬株式会社
Publication of WO2017069270A1 publication Critical patent/WO2017069270A1/en

Links

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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines 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 novel compound having a positive allosteric modulator (PAM) action on the GABAB receptor of ⁇ -aminobutyric acid (GABA) receptor, or a pharmaceutically acceptable salt thereof, and effective Autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety disorder, dementia, pain, drug / alcoholism, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord Treatment of diseases such as paralysis, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, essential tremor, overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease or It relates to preventive drugs.
  • PAM positive allosteric modulator
  • GABA ⁇ -aminobutyric acid
  • GABAA receptor GABAA receptor
  • GABAB receptor GABAB receptor
  • GABAC receptor GABAA receptor selective antagonist
  • the GABAB receptor is composed of two subunits, GABAB1 (GB1) and GABAB2 (GB2), but GB2 has no ability to bind to a ligand, and forms a heterodimer with GB1 to activate G protein activity by GABA. It functions as a GABAB receptor, such as activation and activation of an inwardly rectifying K + channel (GIRK) (Non-patent Documents 7, 8 and 9).
  • GIRK inwardly rectifying K + channel
  • Non-patent Document 10 quantitative reduction of GABA in the patient's frontal lobe
  • Non-patent Document 11 decrease in the expression level of GABA synthase GAD65 in the patient's postmortem cerebellum, etc.
  • Non-patent Document 11 A postmortem brain analysis of patients with autism spectrum disorder has also reported a decrease in the expression levels of GB1 and GB2 in the anterior cingulate cortex, cerebral cortex, and cerebellum.
  • Non-patent Document 14 In a model mouse (Fmr1 KO mouse) with fragile X syndrome, a decrease in the protein level of Gabbr1 has been observed (Non-patent Document 14). In addition, decreased expression of GB1a was observed in patients with schizophrenia, and decreased expression of GB1a / b and GB2 was also observed in patients with bipolar disorder (Non-patent Document 15). Reports showing the involvement of GABAB receptors and prepulse inhibition disorders (Non-patent Documents 16 and 17), reports that GABAB receptor-related compounds show effects in amphetamine-induced hyperkinetic tests and MK801-induced hyperkinetic tests ( Non-patent document 18) is also available.
  • Non-Patent Documents 19, 20 and 21 there has been a background that has attracted attention as a target for anxiolytic drugs and antidepressant drugs through pharmacological analysis using knockout mice and GABAB receptor-related compounds.
  • Non-Patent Documents 22, 20 and 21 the involvement of GABAB receptors in diseases such as dementia, pain, drug / alcoholism, and convulsions has been suggested (Non-patent Documents 22 and 23), and research on GABAB receptor ligands as targets for these diseases Is underway.
  • Baclofen a GABAB receptor agonist
  • Baclofen also has an analgesic effect, and analgesic action against neuropathic pain in humans has been reported for a long time. Recently, there are clinical reports that R-baclofen was effective in improving symptoms in patients with autism spectrum disorder and fragile X syndrome.
  • baclofen is limited in use because it can cause rapid tolerance and various side effects (such as drowsiness, dizziness, sedation, nausea, muscle weakness, hypotension, hypothermia, mental confusion).
  • PAMs positive allosteric modulators
  • PAM itself does not exhibit agonism activity and enhances the potency and effectiveness of the receptor by actions such as increasing the affinity of the endogenous ligand for the receptor.
  • side effects caused by baclofen are not observed in administration of GABAB receptor PAM compounds in the therapeutic dose range (Non-patent Document 24).
  • Non-Patent Literature a GABAB receptor PAM compound
  • PAM compounds for GABAB receptors can prevent or reduce the side effects that can occur with the use of baclofen, while autism spectrum disorders, schizophrenia, bipolar disorder, depression, anxiety disorders, addictions, etc. It may be effective in the treatment and prevention of neurological diseases such as psychiatric disorders, convulsions, spinal cord palsy, multiple sclerosis, amyotrophic lateral sclerosis.
  • Patent Document 1 and Non-Patent Document 26 disclose PAM compounds for a GABAB receptor having a nitrogen-containing fused heterocyclic ring, but do not disclose the nitrogen-containing fused heterocyclic compound described in the present application.
  • the object of the present invention is to find a novel compound having a positive allosteric modulator (PAM) action on the GABAB receptor and to detect autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety Disorder, dementia, pain, drug / alcohol dependence, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, essential tremor
  • An object of the present invention is to provide a therapeutic or prophylactic agent for diseases such as overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease.
  • the present inventors have found that GABAB excellent in certain nitrogen-containing condensed heterocyclic compounds represented by the following formulas
  • the present invention was completed by finding that there is a PAM action on the receptor.
  • the embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
  • R N1 Indicates a hydrogen atom
  • R N2 Is adamantyl (which may be substituted with one hydroxy)
  • C 5-6 Cycloalkyl the C 5-6 Cycloalkyls may be substituted with one hydroxy and may be further substituted between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • R N1 And R N2 Is a 4- to 7-membered saturated heterocyclic ring that may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom together with the adjacent nitrogen atom (the 4- to 7-membered ring).
  • the saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl.
  • C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl.
  • C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), Formula triazolyl-Y-, C 3-6 Cycloalkylcarbonylamino (the C 3-6 Cycloalkylcarbonylamino may be substituted with one hydroxy.
  • Oxoimidazolidinyl (wherein the oxoimidazolidinyl represents one C 1-6 It may be substituted with alkyl. ), 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl, C 1-6 Alkylsulfonylamino, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino represents 1 to 2 C 1-6 It may be substituted with alkyl.
  • Amino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkylamino and guadinino, and further, C between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH—
  • R 2 Is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring.
  • C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl.
  • C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl.
  • R Three Is a hydrogen atom, methyl (the methyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), difluoroethyl, methoxy, difluoromethoxy, cyclopropyl, cyano or acetyl
  • X is CR Four in the case of, R 1 Is phenyl (the phenyl is C 2-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkanoylamino, hydroxymethyl and methoxy. ), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy (the C 3-6 Cycloalkoxy may be substituted with one oxo.
  • R N3 Represents a hydrogen atom, methyl, isopropyl, cyclopropyl or cyclobutyl, R N4 Is C 4-6 Cycloalkyl, phenyl, 2-methyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridin-6-yl, Or the following formula (III): (Where R C4 And R C5 Are the same or different and are hydrogen atoms or C 1-6 Indicates alkyl or Or R C4 And R C5 Together with adjacent
  • 4- to 6-membered cyclic ether or 4- to 6-membered cyclic amine (the 4- to 6-membered cyclic amine is one methyl, C 2-6 Alkanoyl or C 1-6 Substituted with alkoxycarbonyl.
  • R C6 Is a hydrogen atom, a halogen atom, hydroxy, phenyl, pyridyl, pyrimidyl, pyrazolyl, triazolyl, methyloxadiazolyl, cyclohexyl, amino, C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is amino and C 1-6 It may be substituted with one substituent selected from the group consisting of alkylsulfonyl. ) Or C 1-6 Represents alkoxycarbonylamino, p represents an integer of 0 to 1, q represents an integer of 0 to 3.
  • R N3 And R N4 Is a 4- to 7-membered saturated heterocyclic ring which may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms in addition to the nitrogen atom in the ring together with the adjacent nitrogen atom (the 4-7
  • the membered saturated heterocycle is hydroxy, C 1-6 Alkyl (the C 1-6 Alkyl is hydroxy, C 1-6 Alkoxy, carbamoyl, C 1-6 Alkoxycarbonyl, pyrazolyl, piperidinocarbonyl, dimethylaminocarbonyl and C 1-6 It may be substituted with one substituent selected from the group consisting of alkoxycarbonyloxy.
  • C 3-6 Cycloalkyl C 2-6 Alkanoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoylamino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, oxo, and amino, and the 4- to 7-membered saturated heterocyclic ring is between two different carbon atoms in the ring.
  • C 1-6 May be bridged with alkylene, or one carbon atom in the ring of the 4-7 membered saturated heterocyclic ring may be replaced by a 4-6 membered cyclic ether, or the 4-7 membered saturated
  • the heterocyclic ring may be condensed with one ring selected from the group consisting of benzene, pyridine, isoxazole or imidazole to form a condensed ring), or 2-oxa-6-azaadamantan-6-yl, 3 , 4-Dihydroquinolin-1 (2H) -yl or 2-oxoquinoxalin-1 (2H) -yl, wherein the 2-oxoquinoxalin-1 (2H) -yl may be substituted with one halogen atom .) May be formed, R 2 N-propyl (wherein n-propyl is substituted with 1 to 3 halogen atoms), n-butyl (wherein n-butyl is selected from the group consist
  • Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring may replace 1,3-dioxolane. ), C 4-6 Cycloalkenyl (the C 4-6 Cycloalkenyl may be substituted with one halogen atom.
  • Cyclopropylethyl, phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one substituent selected from the group consisting of a halogen atom, cyano and difluoromethyl), pyridyloxymethyl (the pyridyloxy Methyl pyridyl may be substituted by one trifluoromethyl)), piperidinocarbonyl, phenoxycarbonyl, propoxy, or cyclopropylethynyl;
  • R Three Is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy, cyano, ethoxycarbonyl, hydroxyisopropyl, pyrazolyl or methyl Oxadiazolyl,
  • X is a nitrogen atom and R 1 Is the formula NR N1 R N2 And R N1 And R N2 Are formed together with the adjacent nitrogen atom to form a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom, 4- to 7-membered saturated heterocycles are hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl.
  • C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl.
  • C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), Formula triazolyl-Y-, C 3-6 Cycloalkylcarbonylamino (the C 3-6 Cycloalkylcarbonylamino may be substituted with one hydroxy.
  • Oxoimidazolidinyl (wherein the oxoimidazolidinyl represents one C 1-6 It may be substituted with alkyl. ), 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, C 1-6 Alkylsulfonylamino, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino represents 1 to 2 C 1-6 It may be substituted with alkyl.
  • Amino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkylamino and guadinino, and further, C between two different carbon atoms in the ring. 1-6 May be cross-linked with alkylene, Except for the above case, the nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1), which is as described in (1). (3) In the formula (I), The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein X is a nitrogen atom.
  • R 1 Is tetrahydropyranyl, piperidinyl (which may be substituted with one substituent selected from the group consisting of carbamoyl, tert-butylcarbonyl, acetyl and methylsulfonyl), or Formula NR N1 R N2 And R N1 Is a hydrogen atom, R N2 Is adamantyl (which may be substituted with one hydroxy), C 5-6 Cycloalkyl (the C 5-6 Cycloalkyls may be substituted with one hydroxy and may be further substituted between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom (the 4- to 7-membered member)
  • the saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl.
  • C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl.
  • C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl.
  • mono C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkylamino and guadinino, and further, C between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH— R 2 N-propyl, n-butyl, n-pentyl (wherein the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring.
  • C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl.
  • C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl.
  • R 1 Is tetrahydropyranyl, piperidinyl (which may be substituted with one carbamoyl), or Formula NR N1 R N2 And R N1 Is a hydrogen atom
  • R N2 Is the following formula (II): (Where R C1 Is a hydrogen atom or methyl, R C2 Is methyl or isopropyl, Or R C1 And R C2 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane, R C3 Is a halogen atom, hydroxy, methylsulfonyl, carbamoyl (the carbamoyl represents 1 to 2 C 1-6 It may be substituted with alkyl.
  • n is an integer of 0 to 3.
  • R N1 And R N2 Together with the adjacent nitrogen atom, a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom (the 4- to 7-membered member)
  • the saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl.
  • C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl.
  • C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl.
  • C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl.
  • C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl.
  • the nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (3) or (4).
  • R 1 Is the formula NR N1 R N2 And R N1 Is a hydrogen atom
  • R N2 Is the following formula (II): (Where R C1 Is a hydrogen atom or methyl, R C2 Is methyl or isopropyl, Or R C1 And R C2 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane, R C3 Is hydroxy, methylsulfonyl, or carbamoyl (wherein the carbamoyl is one C 1-6 It may be substituted with alkyl. ) And n is an integer of 1 to 3.
  • a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom (the 4- to 7-membered member)
  • the saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl and carboxy.
  • C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 The alkanoylamino may be substituted with one hydroxy. ), Carbamoyl (the carbamoyl is one C 1-6 It may be substituted with alkyl.
  • 5-oxo-1H-1,2,4-triazol-4 (5H) -yl and may be substituted with 1 to 2 groups selected from the group consisting of two different carbons in the ring C between atoms 1-6 It may be bridged with alkylene.
  • Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH— R 2 N-propyl, n-butyl, n-pentyl (wherein the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring.
  • C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl.
  • C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl.
  • R Three The nitrogen-containing fused heterocyclic compound or a pharmaceutical thereof according to any one of (3) to (5), wherein is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano Top acceptable salt.
  • R 1 Is the formula NR N1 R N2 And R N1 Is a hydrogen atom
  • R N2 Is the following formula (II): (Where R C1 Is a hydrogen atom or methyl, R C2 Is methyl or isopropyl, Or R C1 And R C2 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane, R C3 Is hydroxy, methylsulfonyl, or carbamoyl (wherein the carbamoyl is one C 1-6 It may be substituted with alkyl. ) And n is an integer of 1 to 3.
  • R 1 Is the following formula (IV), (Where R C7 Is a hydrogen atom or hydroxy, R C8 Is a hydrogen atom, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, carbamoyl, and C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl. ), Carbamoyl (the carbamoyl is one C 1-6 It may be substituted with alkyl. ), Pyrazolyl (the pyrazolyl is one C 1-6 It may be substituted with alkyl. ) Or C 1-6 Alkoxycarbonylamino, r is an integer of 2 to 3.
  • R 1 Is the following formula (V), (Where R N3 But C 1-6 Alkyl (the C 1-6 Alkyl is carbamoyl and C 1-6 It may be substituted with one group selected from the group consisting of alkylaminocarbonyl. ) Or carbamoyl (the carbamoyl is one C 1-6 It may be substituted with alkyl. ).
  • R 1 Is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 3-thia-8-azabicyclo [3 2.1] one group selected from octane-3,3-dione-8-yl and 2-oxa-6-azaadamantan-6-yl; R 2 N-butyl, C 4-6 Cycloalkyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, 4-fluorobicyclo [2.2.2] octa- 1-yl, 2- (3,3-difluorocyclobutyl) ethyl, or cyclobutylmethoxy; R Three The nitrogen-containing fused heterocyclic compound or a pharmaceutical thereof according to any one of (3) to (6), wherein is methyl, mono
  • X is CR Four The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1) or (2).
  • R 1 Is phenyl (the phenyl is C 2-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkanoylamino, hydroxymethyl and methoxy. ), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy (the C 3-6 Cycloalkoxy may be substituted with one oxo.
  • R C6 Is a halogen atom, hydroxy, phenyl, pyridyl, pyrimidyl, pyrazolyl, triazolyl, methyloxadiazolyl, cyclohexanyl, amino, C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is a single amino or C 1-6 It may be substituted with alkylsulfonyl.
  • R N3 And R N4 Is a 4- to 7-membered saturated heterocyclic ring which may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms in addition to the nitrogen atom in the ring together with the adjacent nitrogen atom (the 4-7
  • the membered saturated heterocycle is hydroxy, C 1-6 Alkyl (the C 1-6 Alkyl is hydroxy, C 1-6 Alkoxy, carbamoyl, C 1-6 Alkoxycarbonyl, pyrazolyl, piperidinocarbonyl, dimethylaminocarbonyl and C 1-6 It may be substituted with one substituent selected from the group consisting of alkoxycarbonyloxy.
  • C 3-6 Cycloalkyl C 2-6 Alkanoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoylamino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, oxo, and amino, and the 4- to 7-membered saturated heterocyclic ring is between two different carbon atoms in the ring.
  • C 1-6 May be bridged with alkylene, or one carbon atom in the ring of the 4-7 membered saturated heterocyclic ring may be replaced by a 4-6 membered cyclic ether, or the 4-7 membered saturated
  • the heterocyclic ring may be condensed with one ring selected from the group consisting of benzene, pyridine, isoxazole or imidazole to form a condensed ring.
  • Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring may replace 1,3-dioxolane. ), C 4-6 Cycloalkenyl (the C 4-6 Cycloalkenyl may be substituted with one halogen atom.
  • Cyclopropylethyl, phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one substituent selected from the group consisting of a halogen atom, cyano and difluoromethyl), pyridyloxymethyl (the pyridyloxy The methyl pyridyl may be substituted with one trifluoromethyl.
  • a nitrogen-containing fused heterocyclic compound according to (8) which is piperidinocarbonyl, phenoxycarbonyl, propoxy, or cyclopropylethynyl; Its pharmaceutically acceptable salt.
  • R 1 Is phenyl (the phenyl is C 2-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkanoylamino, hydroxymethyl and methoxy. ), C 3-6 Cycloalkyl, or Formula NR N3 R N4 And R N3 Is a hydrogen atom, methyl, isopropyl or cyclobutyl, R N4 But C 4-6 Cycloalkyl, or the following formula (III): (Where R C4 And R C5 Both represent a hydrogen atom or methyl, Or R C4 And R C5 Together with adjacent carbon atoms, C 4-6 Cycloalkane (the C 4-6 The cycloalkane may be substituted with 1 to 2 halogen atoms.
  • R C6 Is a halogen atom, hydroxy, phenyl, pyridyl, pyrazolyl, triazolyl, p is 0, q is an integer of 0 to 3.
  • R N3 And R N4 4-6 membered saturated heterocycle which may contain one oxygen atom in addition to the nitrogen atom together with the adjacent nitrogen atom
  • the 4-6 membered saturated heterocycle is Hydroxy, C 1-6 Alkyl (the C 1-6 Alkyl is one hydroxy, C 1-6 Alkoxy, carbamoyl, C 1-6 It may be substituted with alkoxycarbonyl or pyrazolyl.
  • C 3-6 Cycloalkyl C 2-6 Alkanoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoylamino and C 1-6
  • the 4- to 6-membered saturated heterocyclic ring may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, and the 4- to 6-membered saturated heterocyclic ring is C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • a 4- to 6-membered saturated heterocycle containing one nitrogen atom in addition to the nitrogen atom in the ring (the 4- to 6-membered saturated heterocycle is C 2-6 Alkanoyl and C 1-6 Substituted with one substituent selected from the group consisting of alkoxycarbonyl, the 4- to 6-membered saturated heterocycle is C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • C 4-6 Cycloalkenyl (the C 4-8 Cycloalkenyl may be substituted with one halogen atom. )
  • Cyclopropylethyl or phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one halogen atom, cyano or difluoromethyl)
  • R Three Is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy or cyano
  • R 1 Is the formula NR N3 R N4 And R N3 Is a hydrogen atom
  • R N4 Is the following formula (III): (Where R C4 And R C5 Are both methyl or Or R C4 And R C5 Together with adjacent carbon atoms, C 4-6 A cycloalkane or a 4-6 membered cyclic ether may be formed, R C6 Is a halogen atom or hydroxy, p is 0, q is an integer of 1 to 3. ), Or R N3 And R N4 , Together with the adjacent nitrogen atom, may contain one oxygen atom in addition to the nitrogen atom in the ring.
  • the 4- to 6-membered saturated heterocyclic ring (the 4- to 6-membered saturated heterocyclic ring is , Hydroxy, C 1-6 Alkyl, C 2-6 Alkanoylamino and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, and a C atom between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • R 2 Is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene.
  • R 1 Is the formula NR N3 R N4 And R N3 Is a hydrogen atom
  • R N4 Is the following formula (III): (Where R C4 And R C5 Are both methyl or Or R C4 And R C5 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane, R C6 Is a halogen atom or hydroxy, p is 0, q is an integer of 1 to 3.
  • R 1 Is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 2-oxa-6-azaadamantane From -6-yl, 8-azabicyclo [3.2.1] octane-3-ol-8-yl, and 3-methyl-8-azabicyclo [3.2.1] octane-3-ol-8-yl
  • R 2 N-butyl, C 4-6 Cycloalkyl, cyclopropylethyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, or 4-fluorobicyclo [2.2 .2] oct-1-yl
  • R 3 Is methyl, difluoromethyl, methoxy or cyano
  • R 4 The nitrogen-containing fused heterocyclic
  • a medicament comprising, as an active ingredient, the nitrogen-containing fused heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (13).
  • the nitrogen-containing fused heterocyclic compound of the present invention acts on the activity-regulating site of GABAB receptor and enhances receptor stimulation by physiological ligand (GABA).
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl means linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl.
  • C 2-6 alkanoyl means linear or branched alkanoyl having 2 to 6 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
  • C 1-6 alkoxy means linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy and the like.
  • C 1-6 alkoxycarbonyl means a group in which the above “C 1-6 alkoxy” is bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl. Tert-butoxycarbonyl, pentyloxycarbonyl and the like.
  • C 1-6 alkoxycarbonylamino means a group in which the above “C 1-6 alkoxycarbonyl” and amino are bonded, and examples thereof include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, Examples include butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino and the like.
  • C 1-6 alkoxycarbonyloxy means a group in which the above “C 1-6 alkoxycarbonyl” is bonded to an oxygen atom.
  • methoxycarbonyloxy methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy Butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy and the like.
  • C 1-6 alkylamino means a group in which one or two identical or different “C 1-6 alkyl” and amino are combined, and examples thereof include methylamino, ethylamino, propylamino, Butylamino, pentylamino, hexylamino, isopropylamino, isobutylamino, tert-butylamino, isopentylamino, 1-ethylpropylamino, isohexylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino , Ethylpropylamino and the like.
  • C 1-6 alkylaminocarbonyl means a group in which the above “C 1-6 alkylamino” is bonded to a carbonyl group, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, Pentylaminocarbonyl, hexylaminocarbonyl, isopropylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, isopentylaminocarbonyl, 1-ethylpropylaminocarbonyl, isohexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di
  • a group having one C 1-6 alkyl is referred to as “mono C 1-6 alkylaminocarbonyl”, and a group having the same or different two C 1-6 alkyls is referred to as “di-C 1-6 alkylaminocarbonyl”.
  • C 1-6 alkylsulfonyl means a group in which the above “C 1-6 alkyl” is bonded to sulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert- Examples thereof include butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
  • C 1-6 alkylsulfonylamino means a group in which amino is bonded to the above “C 1-6 alkylsulfonyl”, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonyl Amino, isobutylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino and the like can be mentioned.
  • C 2-6 alkanoyloxy means a group in which the above “C 2-6 alkanoyl” is bonded to an oxygen atom, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, Examples include pivaloyloxy.
  • C 2-6 alkanoylamino means a group in which the above “C 1-6 alkanoyl” is bound to amino, such as acetamido, propionylamido, butyrylamide, isobutyrylamide, valerylamide, isovalerylamide, pivaloylamide.
  • C 3-6 cycloalkyl means cyclic alkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 4-6 cycloalkyl means cyclic alkyl having 4 to 6 carbon atoms, and examples thereof include cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 5-6 cycloalkyl means cyclic alkyl having 5 to 6 carbon atoms, and examples thereof include cyclopentyl and cyclohexyl.
  • two different carbon atoms in a C 4-6 cycloalkyl or C 5-6 cycloalkyl ring may be bridged with C 1-6 alkylene, and Examples are bicyclo [3.1.0] hex-3-yl, bicyclo [3.1.0] hex-6-yl, and bicyclo [2.2.2] oct-1-yl.
  • C 3-6 cycloalkylcarbonylamino means a group in which the above “C 3-6 cycloalkyl” and carbonylamino are bonded together, such as cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino.
  • C 3-6 cycloalkane means a cyclic alkane having 3 to 6 carbon atoms, and examples thereof include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • C 3-6 cycloalkoxy means a group in which the above “C 3-6 cycloalkyl” is bonded to an oxygen atom, and examples thereof include cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
  • C 1-6 alkylene means a divalent group obtained by removing one hydrogen atom from the “C 1-6 alkyl”, and includes methylene, ethylene, methylmethylene, trimethylene, methylethylene, tetramethylene, ethylethylene. And pentamethylene.
  • a 4 to 7-membered saturated heterocyclic ring which may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom together with the adjacent nitrogen atom means azetidine, pyrrolidine , Piperidine, piperazine, morpholine, thiomorpholine, azepane, 1,4-diazepane and the like.
  • Examples of the “4- to 6-membered cyclic ether” include oxetane, tetrahydrofuran, and tetrahydropyran.
  • Examples of the “4- to 6-membered cyclic amine” include azetidine, pyrrolidine, and piperidine.
  • C 4-6 cycloalkenyl means cyclic alkenyl having 4 to 6 carbon atoms, and examples thereof include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • a 4-6 membered saturated heterocyclic ring which may contain one oxygen atom in addition to the nitrogen atom together with the adjacent nitrogen atom means azetidine, pyrrolidine, piperidine, piperazine, morpholine Etc. Examples of the “4- to 6-membered saturated heterocyclic ring containing one nitrogen atom in addition to the nitrogen atom together with the adjacent nitrogen atom” include piperazine and the like.
  • two different carbon atoms in the 4 to 7 membered saturated heterocyclic ring and the 4 to 6 membered saturated heterocyclic ring may be bridged with C 1-6 alkylene.
  • bridged heterocycles are 8-azabicyclo [3.2.1] octane-8-yl, 9-azabicyclo [3.3.1] nonane-9-yl, 3,8-diazabicyclo [3.2.1].
  • the term “may be replaced” means that a particular chemical moiety may be replaced with another chemical moiety. For example, when the 4-position carbon atom of a piperidinyl group is replaced with oxetane, 2-oxa-7-azaspiro [3.5] non-7-yl is obtained.
  • “pharmaceutically acceptable salt” refers to a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, or acetic acid, benzoic acid, oxalic acid, lactic acid, apple Acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
  • a salt with an organic acid such as camphorsulfonic acid, naphthalene-2-sulfonic acid, lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, or one or more metal ions Salt, ammonia,
  • One preferred embodiment is a compound in which X is a nitrogen atom.
  • X is a nitrogen atom
  • Compounds in which R 1 is of the formula NR N1 R N2 are preferred
  • a compound in which R N1 is a hydrogen atom is preferable,
  • the compound whose RN2 is a following formula (II) is preferable.
  • R C1 is a hydrogen atom or methyl
  • R C2 is methyl or isopropyl
  • R C1 and R C2 together with an adjacent carbon atom form a C 4-6 cycloalkane is preferable, and a compound in which cyclopentane is formed is more preferable.
  • R C3 is hydroxy, methylsulfonyl, or carbamoyl (the carbamoyl may be substituted with one C 1-6 alkyl) is preferable, and a compound in which R C3 is hydroxy is more preferable.
  • R N1 and R N2 together with the adjacent nitrogen atom may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom in the ring.
  • a ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl and 1 to 3 groups selected from the group consisting of carboxy may be substituted.), C 1-6 alkoxy (the C 1-6 alkoxy is 1 selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl) May be substituted with ⁇ 3 groups), C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted with 1 hydroxy), carbamoyl (the carbamoyl is 1 C Optionally substituted with 1-6 alkyl), C 1-6 alkoxycarbonylamino, ureido (which may be substituted with 1 C 1-6 alkyl), pyrazolyl-Y— The pyrazolyl
  • C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted by one hydroxy. )
  • Carbamoyl the carbamoyl may be substituted with 1 C 1-6 alkyl
  • C 1-6 alkoxycarbonylamino (the ureido is substituted with 1 C 1-6 alkyl)
  • the pyrazolyl-Y— (wherein the pyrazolyl of the formula pyrazolyl-Y— may be substituted with one C 1-6 alkyl), the formula triazolyl-Y—, cyclopropylcarbonylamino Cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxoimidazolidinyl may be substituted with one C 1-6 alkyl) and 5- And may be substituted with 1 to 2 groups selected from the group consisting of oxo-1H-1,2,4-trifluoride, ureido is substitute
  • R 2 is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 cyclo Alkyl (the C 4-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and the C 4-6 cycloalkyl is different two between the carbon atoms may be cross-linked with a single bond or C 1-6 alkylene, or one carbon atom in the ring of the C 3-6 cycloalkane, C 3-6 cycloalkane of And C 3-6 cycloalkylethyl (the C 3-6 cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl).
  • C 3-6 cycloalkylmethoxy (the C 3-6 cycloalkyl Methoxy is optionally substituted with one C 1-6 alkyl.) And is preferably n-butyl, 3,3-difluorobutyl, cyclobutyl, 3,3-difluorocyclobutyl, 3,3- Dimethylcyclobutyl, 3-fluoro-3-methylcyclobutyl, cyclohexyl, 4-fluorocyclohexyl, bicyclo [3.1.0] hex-3-yl, 6,6-difluorobicyclo [3.1.0] hexa- 3-yl, spiro [2.3] hex-5-yl, 3,3-difluorobicyclo [3.1.0] hex-6-yl, 4-fluorobicyclo [2.2.2] oct-1- Yl, 2- (3,3-difluorocyclobutyl) ethyl, 2- (1-fluorocycl
  • R 3 is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano are preferred.
  • the 4- to 7-membered saturated heterocyclic ring is preferably hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl).
  • 1 to 3 groups selected from the group consisting of carboxy and C 1-6 alkoxy (the C 1-6 alkoxy is selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl) 1 to 3 groups may be substituted), C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted with 1 hydroxy), carbamoyl (the carbamoyl is 1 C 1-6 alkyl may be substituted.), C 1-6 alkoxycarbonylamino, ureido (the ureido may be substituted with one C 1-6 alkyl), wherein pyrazol -Y- (the pyrazolyl of the pyrazolyl-Y- may be substituted with one C 1-6 alkyl), formula triazolyl-Y-, cyclopropylcarbonylamino (the cyclopropylcarbonylamino is 1 May be substituted with 1 hydroxy), oxoimidazolidiny
  • R 1 is of the formula NR N1 R N2
  • R N1 is a hydrogen atom
  • R N2 is the following formula (II): (Where R C1 is a hydrogen atom or methyl; R C2 is methyl or isopropyl, Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane, R C3 is hydroxy, methylsulfonyl, or carbamoyl (which may be substituted with one C 1-6 alkyl); n is an integer of 1 to 3.
  • R 1 is the following formula (IV): (Where R C7 is a hydrogen atom or hydroxy, R C8 is a hydrogen atom, C 1-6 alkyl (the C 1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxy, carbamoyl, and C 1-6 alkylaminocarbonyl) may be.), carbamoyl (said carbamoyl may be substituted with one C 1-6 alkyl.), pyrazolyl (the pyrazolyl is optionally substituted with one C 1-6 alkyl Or C 1-6 alkoxycarbonylamino; r is an integer of 2 to 3.
  • R 1 is the following formula (V), (Where R N3 is C 1-6 alkyl (the C 1-6 alkyl may be substituted with one group selected from the group consisting of carbamoyl and C 1-6 alkylaminocarbonyl), or carbamoyl ( The carbamoyl may be substituted with one C 1-6 alkyl).
  • R 1 is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 3-thia-8 -One group selected from azabicyclo [3.2.1] octane-3,3-dione-8-yl and 2-oxa-6-azaadamantan-6-yl;
  • R 2 is n-butyl, C 4-6 cycloalkyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, 4 -Fluorobicyclo [2.2.2] oct-1-yl, 2- (3,3-difluorocyclobutyl) ethyl, or cyclobutylmethoxy;
  • a compound wherein R 3 is methyl, monofluoromethyl, difluoromethyl, difluoro
  • X is a compound of formula CR 4 . If X is the formula CR 4 , Compounds in which R 1 is of formula NR N3 R N4 are preferred Compounds in which RN3 is a hydrogen atom are preferred, The compound whose RN4 is a following formula (III) is preferable.
  • a compound in which R C4 and R C5 both represent methyl is preferred. Or a compound in which R C4 and R C5 are taken together with an adjacent carbon atom to form a C 4-6 cycloalkane or a 4- to 6-membered cyclic ether, and a C 4-6 cycloalkane is more preferable. More preferred are compounds that form pentane.
  • a compound in which R C6 is a halogen atom or hydroxy is preferable, and a compound in which R C6 is hydroxy is more preferable.
  • a compound in which p is 0 is preferable.
  • a compound in which q is an integer of 1 to 3 is preferred, a compound of 1 to 2 is more preferred, and a compound of 1 is more preferred.
  • R N3 and R N4 together with the adjacent nitrogen atom may contain a 4- to 6-membered saturated heterocyclic ring that may contain one oxygen atom in addition to the nitrogen atom (the 4-6 1 to 2 membered saturated heterocycles are selected from the group consisting of hydroxy, C 1-6 alkyl, C 2-6 alkanoylamino and C 1-6 alkoxycarbonylamino.
  • the compound formed is preferably a piperidine bridged by C 1-6 alkylene between two different carbon atoms in the ring (the piperidine is selected from the group consisting of hydroxy and C 1-6 alkyl).
  • 3-oxa-8-azabisic, which may be substituted with a group) [3.2.1] oct-8-yl, or a compound to form a 2-oxa-6-aza-adamantan-6-yl is more preferred.
  • R 2 is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 cycloalkyl (the C 4- The 6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and further the C 4-6 cycloalkyl is two different carbons in the ring.
  • the C 4-6 cycloalkyl may be bridged between two different carbon atoms in the ring by a single bond or C 1-6 alkylene.
  • a compound which is cyclopropylethyl is more preferable, n-butyl, 3-methylbutyl, 3,3-dimethylbutyl, 3,3-difluorobutyl, cyclopentane, cyclohexane, 4,4-difluorocyclohexane, 4-fluorocyclohexane, 6,6-difluorobicyclo [3.1.
  • a compound which is hexa-3-yl, 3,3-difluorobicyclo [3.1.0] hex-6-yl, cyclopropylethyl or 4-fluorobicyclo [2.2.2] oct-1-yl Is more preferable.
  • R 3 is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy, cyano, ethoxycarbonyl, hydroxyisopropyl, pyrazolyl Or a compound which is methyl oxadiazolyl, preferably a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy or cyano. Certain compounds are more preferred, and compounds that are methyl, difluoromethyl, methoxy or cyano are even more preferred.
  • R 4 is a hydrogen atom, a fluorine atom or methyl
  • X is of formula CR 4
  • R 1 is of the formula NR N3 R N4
  • R N3 is a hydrogen atom
  • R N4 is the following formula (III):
  • R C4 and R C5 both represent methyl, Or R C4 and R C5 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane, R C6 is a halogen atom or hydroxy, p is 0, q is an integer of 1 to 3.
  • R 1 is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 2-oxa- 6-azaadamantan-6-yl, 8-azabicyclo [3.2.1] octane-3-ol-8-yl, and 3-methyl-8-azabicyclo [3.2.1] octane-3-ol- One group selected from 8-yl, R 2 is n-butyl, C 4-6 cycloalkyl, cyclopropylethyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexa-3 -Yl, or 4-fluorobicyclo [2.2.2] oct-1-yl, R 3 is methyl, difluoromethyl, methoxy or cyano; R 4 is a compound that is a hydrogen
  • the preferred pyrazolyl used in the compounds of the present invention is 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 1H-pyrazol-5-yl.
  • a preferred methylpyrazolyl used in the compounds of the present invention is 1H-1-methylpyrazol-3-yl, 1H-1-methylpyrazol-4-yl, or 1H-1-methylpyrazol-5-yl.
  • Preferred triazolyls used in the compounds of the present invention are 1H-1,2,4-triazol-3-yl, 1H-1,2,3-triazol-1-yl, or 2H-1,2,3-triazole- 2-yl.
  • a preferred optionally substituted oxoimidazolidinyl used in the compounds of the present invention is imidazolidin-2-one-1-yl or 3-methylimidazolidin-2-one-1-yl.
  • this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention.
  • pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
  • the compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
  • the compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and halogen atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
  • the compound according to the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
  • These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose).
  • the compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day.
  • the dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be synthesized, for example, by the method shown below, but the production method of the compound of the present invention is not limited thereto.
  • “Inert solvent” means, for example, aromatic solvents such as benzene, toluene, xylene, pyridine; hydrocarbon solvents such as hexane, pentane, cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.
  • Halogenated hydrocarbon solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; methanol, ethanol, isopropyl alcohol, tert- Alcohol solvents such as butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfos such as dimethyl sulfoxide Sid solvents; acetonitrile, nitriles and water, such as propionitrile, and also these homogeneous and heterogeneous mixed solvents.
  • inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.
  • Examples of the “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or
  • bases are appropriately selected according to various reaction conditions known to those skilled in the art.
  • the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and the like.
  • Lewis acids such as organic acids, zinc (II) chloride, aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate, and the like. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • the compound (I) of the present invention can be produced, for example, by the method shown below.
  • the compound of the present invention represented by the formula (I-1) can be produced by the method of the following scheme 1.
  • R 2 , R 3 , X, R N1 and R N2 are as defined above.
  • L 1 represents a leaving group such as chlorine atom, bromine atom, iodine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.) or hydroxy.
  • Step 1 When L 1 represents a leaving group, the compound of the present invention represented by the formula (I-1) is reacted with the compound represented by the formula (1) in an inert solvent in the presence or absence of a base. It can manufacture by reaction of the compound represented by Formula (2).
  • the compound represented by the formula (1) and the compound represented by the formula (2) can be produced in an inert solvent by a reaction using various condensing agents (J. Org. Chem. 2007, 72, 10194-10210).
  • benzotriazol-1-yloxy-trisdimethylaminophosphonium salt BOP
  • hexafluorophosphoric acid benzotriazol-1-yloxy
  • tripyrrolidinophosphonium PyBOP
  • bromotri (pyrrolidino) phosphonium hexafluorophosphate PyBrOP
  • the compounds represented by formula (1) and formula (2) commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis techniques known to those skilled in the art are used. Can do.
  • the palladium catalyst examples include palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium acetate (II), bis (triphenylphosphine) palladium chloride (II), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine Palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), allyl palladium (II) chloride, bis (acetonitrile) palladium (II) Examples of the child are triphenylphosphine, 2,2-bis (diphenyl
  • the copper catalyst is, for example, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I) tristriphenylphosphine complex, copper trifluoromethanesulfonate.
  • the ligand is a ligand known to those skilled in the art in a coupling reaction using a copper catalyst, such as N, N′-dimethylethylenediamine, 1,2- Examples include cyclohexanediamine, 2-aminopyridine, 1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, and picolinic acid.
  • the compound of the present invention represented by the formula (I) can be produced by the method of the following scheme 2.
  • R 2 , R 3 and X are as defined above.
  • L 2 represents a leaving group such as chlorine atom, bromine atom, iodine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.).
  • M represents a metal atom or metal atomic group used in the coupling reaction, and examples of the compound represented by the formula (4) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, Tin reactive agent etc. are mentioned.
  • Step 2 The compound of the present invention represented by the formula (I) is prepared by using a transition metal catalyst such as a palladium catalyst or an iron catalyst in an inert solvent, in the presence or absence of a base, and optionally using a ligand. It can manufacture by the coupling reaction of the compound represented by (3), and the compound represented by Formula (4).
  • examples of the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, ⁇ Comprehensive Organic Transformations Second Edition ⁇ , 1999, John Willy and Sons (John Wiley & Sons, INC.) ⁇ Or the like, a method based thereon, or a combination of these with conventional methods.
  • the compounds represented by formula (3) and formula (4) are commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis methods known to those skilled in the art. Can do.
  • the iron catalyst include tris (2,4-pentanedionato) iron (III).
  • the compound of the present invention represented by the formula (I) can be produced by the method of the following scheme 3.
  • Step 3 The compound of the present invention represented by the formula (I) can be produced from the compound represented by the formula (5) and the compound represented by the formula (6) by the same method as in the step 2 in Scheme 2.
  • the compounds represented by the formulas (5) and (6) commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis methods known to those skilled in the art are used. Can do.
  • An intermediate of the compound of the present invention represented by the formula (12) can be produced by the method of the following scheme 4.
  • R 2 , R 3 , R 4 and L 2 are as defined above.
  • PG and PG 1 represent a carboxy protecting group, and examples thereof include a methyl group, an ethyl group, and a benzyl group.
  • Process 4 The compound represented by Formula (8) can be manufactured by making the reagent prepared from acetonitrile and a base react with Formula (7) in an inert solvent.
  • a base for example, an organic lithium reagent such as n-butyllithium and sec-butyllithium, an alkali metal or alkaline earth metal lower alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hydride, hydrogen, etc.
  • the compound represented by Formula (9) can be manufactured by reaction of Formula (8) and hydrazine in the presence or absence of a base or an acid in an inert solvent. Hydrazine may be used in the form of a hydrate, hydrochloric acid, acetic acid or the like.
  • Process 6 The compound represented by Formula (11) is manufactured by reaction of the compound represented by Formula (9) and the compound represented by Formula (10) in the presence or absence of an acid in an inert solvent. can do.
  • the compound represented by the formula (10) a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.
  • Step 7 The compound represented by the formula (12) can convert the hydroxyl group in the formula (11) into a leaving group by using various organic synthesis methods known to those skilled in the art. For example, when L2 is a chloro atom, the compound represented by the formula (12) can be produced by using oxalyl chloride, thionyl chloride or the like in an inert solvent in the presence or absence of a base.
  • the intermediate of the compound of the present invention represented by the formula (16) can be produced by the method of the following scheme 5.
  • R 2 , R 3 and L 2 are as defined above.
  • PG 2 represents a protecting group, and examples thereof include a methyl group, an ethyl group, and a benzyl group.
  • Process 8 The compound represented by Formula (14) is a reaction of the compound represented by Formula (9) and the compound represented by Formula (13) in the presence or absence of a base or an acid in an inert solvent. Can be manufactured.
  • the compound represented by the formula (13) a commercially available compound, a known compound or a compound synthesized from a known compound by using various organic synthesis methods known to those skilled in the art can be used.
  • Step 9 The compound represented by the formula (15) is used in an inert solvent in the presence or absence of a base with respect to the formula (14) using a reagent such as carbonyldiimidazole, triphosgene, diethyl carbonate or the like. It can be produced by carrying out a cyclization reaction.
  • Step 10 The compound represented by the formula (16) can be produced from the compound represented by the formula (15) by the same method as in the step 7 in the scheme 4.
  • the compound of the present invention represented by the formula (I-2) can be produced by the method of the following scheme 6.
  • R 1 , R 2 and L 1 are as defined above.
  • R 5 represents C 3-6 alkyl or C 3-6 cycloalkylmethyl (the C 3-6 cycloalkylmethyl may be substituted with one C 1-6 alkyl).
  • Process 11 The compound represented by Formula (19) can be manufactured by reaction of the compound represented by Formula (17) and the compound represented by Formula (18).
  • L 1 in formula (18) is a leaving group such as chlorine atom, bromine atom, iodine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.)
  • the reaction can be performed in an inert solvent in the presence or absence of a base under the conditions of an alkylation reaction generally used by those skilled in the art.
  • L 1 in formula (18) is a hydroxyl group
  • the reaction can be carried out in an inert solvent in the presence or absence of a base under the conditions of Mitsunobu reaction generally used by those skilled in the art.
  • Step 12 The compound represented by the formula (I-2) can be produced from the compound represented by the formula (19).
  • the compound represented by Formula (19) may be subjected to the same reaction as in Step 6 and Step 7, and then the obtained product may be subjected to the same reaction as in Step 1 or 2.
  • the obtained product may be subjected to the same reaction as in Step 1 or 2.
  • MS mass spectra
  • NMR nuclear magnetic resonance spectra
  • MS mass spectrometry
  • ESI electrospray ionization
  • APCI atmospheric pressure chemical ionization
  • RT retention time
  • NMR nuclear magnetic resonance spectroscopy
  • H proton
  • J coupling constant
  • DMSO- d6 deuterated dimethyl sulfoxide
  • a salt may be formed using various acids under various reaction conditions known to those skilled in the art.
  • Tables 1-1 to 1-8 show the structural formulas, compound names, and instrument data of intermediates shown in Production Examples 1 to 17 and intermediates synthesized by the same method.
  • the numbers described in the column of production examples in the table indicate which of the above production examples 1 to 17 was synthesized by the same method as in the above production examples.
  • Tables 2-1 to 2-2 show the structural formulas, compound names and instrument data of the compounds shown in Reference Examples 1 and 2 and compounds synthesized by the same methods as in Reference Examples 1 and 2 and the examples described below. Shown in The numbers in the column of Examples / Reference Examples in the table indicate which compounds were synthesized by the same method as in Reference Examples 1-2 and Examples 1-60 above. is there.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water. After drying the organic layer with anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure.
  • N- (3-butyl-1H-pyrazol-5-yl) ethanimidoamide (100 mg), tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (409 mg), sodium ethoxide / ethanol solution (about 20 %, 1 mL) and ethanol (1 mL) were stirred at 85 ° C. for 4 days.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator.
  • the obtained solid was dissolved in tetrahydrofuran (5 mL), ice-cooled, sodium hydride (about 60% / oil, 10.6 mg) was added, and the mixture was stirred for 30 min. After stirring at room temperature for 2 hours and at 40 ° C. for 2 hours, water was added and the mixture was extracted with chloroform.
  • the organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure.
  • Tables 3-1 to 3-25 and Tables 4-1 to 4-30 show the structural formulas, compound names, and instrument data of the compounds shown in Examples 1 to 60 and compounds synthesized by the same method.
  • the number described in the column of the example in the table indicates which of the above Examples 1 to 60 was synthesized by the same method as in the above Examples.
  • an example of the invention is the following compound or a pharmaceutically acceptable salt thereof: 2 (6,6-Difluorobicyclo [3.1.0] hexane-3-yl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine (A136), 2 ( ⁇ 2-[(1R, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -5-methylpyrazolo [1,5-a] pyrimidin-7-yl ⁇ amino) -2-methylpropan-1-ol (A180), 3-( ⁇ 2-[(1R, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -5-methylpyrazolo [1,5-a] pyrimidin-7-yl ⁇ amino ) -3-Methylbutan-1-ol (A136), 2
  • Test example Evaluation of PAM activity using cells expressing stable expression of human GABA (B) receptor as an indicator of changes in intracellular Ca 2+ concentration CHO that stably expresses human GABAB1A (Accession No. -K1 cells were used to evaluate the PAM activity of each test compound under GABA stimulation using changes in intracellular Ca 2+ concentration as an index when the fluorescent probe Fluo4-AM was used as a Ca 2+ indicator.
  • the aforementioned human GABA (B) receptor stably expressing cells were grown in Ham's F-12 medium containing 10% fetal bovine serum, 400 ⁇ g / mL Geneticin, 5 ⁇ g / mL Blasticidin, 250 ⁇ g / mL Zeocin.
  • the buffer containing Flou-4 AM was removed from each well, 36 ⁇ L of Assay buffer containing each test compound at a concentration of about 1.33 times the final concentration was added, and the mixture was allowed to stand at light-shielded room temperature for about 30 minutes. Thereafter, 12 ⁇ L of Assay buffer containing 4 times the final concentration of GABA was added, and the change in fluorescence accompanying changes in intracellular Ca 2+ concentration was measured over time. A series of measurement work was performed using FDSS6000 (Hamamatsu Photonics Co., Ltd.).
  • the compound of the present invention was shown to have a GABAB receptor PAM action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for diseases modulated by GABAB receptor PAM action such as autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety. Disorder, dementia, pain, drug / alcoholism, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, essential tremor It can be used as a therapeutic or prophylactic agent for diseases such as overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease.
  • diseases modulated by GABAB receptor PAM action such as autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety. Disorder, dementia, pain, drug / alcoholism, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Provided is a novel compound or a pharmaceutically acceptable salt thereof that is useful for treating or preventing, on the basis of the PAM effects of the GABAB receptor, diseases such as autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety disorder, dementia, pain, drug/alcohol addiction, convulsion, cerebrovascular disorder, cerebral palsy, spinal palsy, external-injury posttraumatic complication, multiple sclerosis, amyotrophic lateral sclerosis, stiff-person syndrome, essential tremor, overactive bladder, gastroesophageal reflux disease, Charcot-Marie-Tooth disease, and so forth. Specifically, provided is a compound indicated by formula (I) or a pharmaceutically acceptable salt thereof.

Description

含窒素縮合複素環化合物Nitrogen-containing fused heterocyclic compounds
　本発明は、γ-アミノ酪酸（γ－ａｍｉｎｏｂｕｔｙｒｉｃ　ａｃｉｄ，　ＧＡＢＡ）受容体のＧＡＢＡＢ受容体に対してポジティブアロステリックモジュレーター（ＰＡＭ）作用を有する新規な化合物又はその医薬上許容される塩、並びにそれらを有効成分として含有する自閉症スペクトラム障害、脆弱性Ｘ症候群、統合失調症、双極性障害、うつ病、不安障害、認知症、疼痛、薬物・アルコール依存症、痙攣、脳血管障害、脳性麻痺、脊髄麻痺、外傷後遺症、多発性硬化症、筋萎縮性側索硬化症、ｓｔｉｆｆ－ｍａｎ症候群、本態性振戦、過活動膀胱、胃食道逆流性疾患又はＣｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病等の疾患の治療又は予防薬に関する。 The present invention relates to a novel compound having a positive allosteric modulator (PAM) action on the GABAB receptor of γ-aminobutyric acid (GABA) receptor, or a pharmaceutically acceptable salt thereof, and effective Autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety disorder, dementia, pain, drug / alcoholism, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord Treatment of diseases such as paralysis, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, essential tremor, overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease or It relates to preventive drugs.
　γ－アミノ酪酸（γ－ａｍｉｎｏｂｕｔｙｒｉｃ　ａｃｉｄ，　ＧＡＢＡ）は、ＧＡＢＡＡ受容体、ＧＡＢＡＢ受容体、ＧＡＢＡＣ受容体の３種の受容体に作用する抑制性の神経伝達物質である（非特許文献１）。これら受容体のうちＧＡＢＡＢ受容体は、ＧＡＢＡＡ受容体選択的アンタゴニストであるｂｉｃｕｃｕｌｌｉｎｅに非感受性であり、ＧＡＢＡ誘導体であるバクロフェンを選択的アゴニストとするＧＡＢＡ受容体として同定された（非特許文献２、３及び４）。ＧＡＢＡＡおよびＧＡＢＡＣ受容体がイオンチャネルを形成するのに対し、ＧＡＢＡＢ受容体はＧｉ／Ｇｏタンパク質と共役する代謝調節型ＧＰＣＲである（非特許文献５及び６）。ＧＡＢＡＢ受容体はＧＡＢＡＢ１（ＧＢ１）およびＧＡＢＡＢ２（ＧＢ２）の２つのサブユニットから構成されるが、ＧＢ２はリガンドとの結合能力は無く、ＧＢ１とヘテロ２量体を形成することでＧＡＢＡによるＧタンパク活性化や内向き整流性Ｋ+チャネル（ＧＩＲＫ）の活性化といったＧＡＢＡＢ受容体としての機能を発現する（非特許文献７、８及び９）。 γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter that acts on three types of receptors, GABAA receptor, GABAB receptor, and GABAC receptor (Non-patent Document 1). Among these receptors, the GABAB receptor has been identified as a GABA receptor having a selective agonist of baclofen, which is a GABA derivative, which is insensitive to biculculline, a GABAA receptor selective antagonist (Non-patent Documents 2 and 3). And 4). GABAA and GABAC receptors form ion channels, whereas GABAB receptors are metabolically regulated GPCRs that couple to Gi / Go proteins (Non-Patent Documents 5 and 6). The GABAB receptor is composed of two subunits, GABAB1 (GB1) and GABAB2 (GB2), but GB2 has no ability to bind to a ligand, and forms a heterodimer with GB1 to activate G protein activity by GABA. It functions as a GABAB receptor, such as activation and activation of an inwardly rectifying K + channel (GIRK) (Non-patent Documents 7, 8 and 9).
　幾つかの精神疾患とＧＡＢＡおよびＧＡＢＡＢ受容体との関連が示唆されている。自閉症スペクトラム障害に関しては、患者前頭葉におけるＧＡＢＡの量的な減少（非特許文献１０）、患者死後小脳におけるＧＡＢＡ合成酵素ＧＡＤ６５の発現量の低下などが報告されている（非特許文献１１）。自閉症スペクトラム障害患者の死後脳解析からは、前帯状皮質、大脳皮質、小脳におけるＧＢ１およびＧＢ２の発現量の低下も報告されている（非特許文献１２及び１３）。脆弱性Ｘ症候群のモデルマウス（Ｆｍｒ１　ＫＯマウス）ではＧａｂｂｒ１のタンパク質レベルで低下が認められている（非特許文献１４）。また、統合失調症患者においてはＧＢ１ａの発現低下が、双極性障害患者においてもＧＢ１ａ／ｂおよびＧＢ２の発現低下が認められている（非特許文献１５）。ＧＡＢＡＢ受容体とプレパルスインヒビション障害の関与を示す報告（非特許文献１６及び１７）、ＧＡＢＡＢ受容体関連化合物がアンフェタミン誘発性運動亢進試験、ＭＫ８０１誘発性運動亢進試験において効果を示すとの報告（非特許文献１８）などもある。さらに、ノックアウトマウスやＧＡＢＡＢ受容体関連化合物を用いた薬理学的解析を通じて、抗不安薬および抗うつ薬の標的として注目されてきた経緯がある（非特許文献１９、２０及び２１）。その他、認知症、疼痛、薬物・アルコール依存症、痙攣などの疾患に対するＧＡＢＡＢ受容体の関与も示唆されており（非特許文献２２及び２３）、これら疾患治療薬の標的としてＧＡＢＡＢ受容体リガンドの研究が進められている。 , It has been suggested that some mental illnesses are related to GABA and GABAB receptors. Regarding autism spectrum disorder, quantitative reduction of GABA in the patient's frontal lobe (Non-patent Document 10), decrease in the expression level of GABA synthase GAD65 in the patient's postmortem cerebellum, etc. have been reported (Non-patent Document 11). A postmortem brain analysis of patients with autism spectrum disorder has also reported a decrease in the expression levels of GB1 and GB2 in the anterior cingulate cortex, cerebral cortex, and cerebellum (Non-patent Documents 12 and 13). In a model mouse (Fmr1 KO mouse) with fragile X syndrome, a decrease in the protein level of Gabbr1 has been observed (Non-patent Document 14). In addition, decreased expression of GB1a was observed in patients with schizophrenia, and decreased expression of GB1a / b and GB2 was also observed in patients with bipolar disorder (Non-patent Document 15). Reports showing the involvement of GABAB receptors and prepulse inhibition disorders (Non-patent Documents 16 and 17), reports that GABAB receptor-related compounds show effects in amphetamine-induced hyperkinetic tests and MK801-induced hyperkinetic tests ( Non-patent document 18) is also available. Furthermore, there has been a background that has attracted attention as a target for anxiolytic drugs and antidepressant drugs through pharmacological analysis using knockout mice and GABAB receptor-related compounds (Non-Patent Documents 19, 20 and 21). In addition, the involvement of GABAB receptors in diseases such as dementia, pain, drug / alcoholism, and convulsions has been suggested (Non-patent Documents 22 and 23), and research on GABAB receptor ligands as targets for these diseases Is underway.
ＧＡＢＡＢ受容体アゴニストであるバクロフェンは主に脳血管障害、脳性麻痺、痙性脊髄麻痺、外傷後遺症などに伴う痙性麻痺の治療薬として臨床現場で古くから用いられてきた。現在では、多発性硬化症、筋萎縮性側索硬化症、ｓｔｉｆｆ－ｍａｎ症候群などの治療にも適用され、重症の患者には髄腔内注射として使用される。またバクロフェンは鎮痛効果も有しており、ヒトにおける神経因性疼痛に対する鎮痛作用なども古くから報告されている。最近では、Ｒ－バクロフェンが自閉症スペクトラム障害および脆弱性Ｘ症候群の患者の症状改善に有効であったとの臨床報告がある。しかしながら、バクロフェンは急速な耐性を生じ得ること、また様々な副作用（眠気、目眩、鎮静、吐き気、筋脱力、低血圧、体温低下、精神錯乱など）が生じ得ることなどの理由により使用は制限される。ＧＡＢＡＢ受容体に対するポジティブアロステリックモジュレーター（ＰＡＭ）に関する報告が複数ある。ＰＡＭは、それ自体はアゴニス卜活性を示さず、内在性リガンドの受容体への親和性を高めるなどの作用によって受容体の効力および効果を高める。げっ歯動物を用いた実験では、薬効用量域のＧＡＢＡＢ受容体ＰＡＭ化合物の投与ではバクロフェンによって生じる副作用を認めないとする報告が複数ある（非特許文献２４）。ＧＡＢＡＢ受容体ＰＡＭ化合物であるＧＳ３９７８３は、運動機能障害、学習記憶障害、体温低下、催眠作用を示すことなく、高架式十字迷路試験などにおいて抗不安作用を示す事が報告されている（非特許文献２５）。このように、ＧＡＢＡＢ受容体に対するＰＡＭ化合物は、バクロフェンの使用で生じる得る副作用を回避もしくは軽減しながら、自閉症スペクトラム障害、統合失調症、双極性障害、うつ病、不安障害、依存症などの精神疾患、痙攣、脊髄麻痺、多発性硬化症、筋萎縮性側索硬化症などの神経疾患の治療および予防に有効である可能性がある。
　特許文献１及び非特許文献２６には、含窒素縮合複素環を有するＧＡＢＡＢ受容体に対するＰＡＭ化合物が開示されているが、本願記載の含窒素縮合複素環化合物についての開示はない。 Baclofen, a GABAB receptor agonist, has long been used in clinical settings as a therapeutic agent for spastic paralysis mainly associated with cerebrovascular disorders, cerebral palsy, spastic spinal cord palsy, and traumatic sequelae. At present, it is also applied to the treatment of multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, etc., and used as an intrathecal injection for severe patients. Baclofen also has an analgesic effect, and analgesic action against neuropathic pain in humans has been reported for a long time. Recently, there are clinical reports that R-baclofen was effective in improving symptoms in patients with autism spectrum disorder and fragile X syndrome. However, baclofen is limited in use because it can cause rapid tolerance and various side effects (such as drowsiness, dizziness, sedation, nausea, muscle weakness, hypotension, hypothermia, mental confusion). The There are several reports on positive allosteric modulators (PAMs) for GABAB receptors. PAM itself does not exhibit agonism activity and enhances the potency and effectiveness of the receptor by actions such as increasing the affinity of the endogenous ligand for the receptor. In experiments using rodents, there are multiple reports that side effects caused by baclofen are not observed in administration of GABAB receptor PAM compounds in the therapeutic dose range (Non-patent Document 24). GS39783, a GABAB receptor PAM compound, has been reported to exhibit anxiolytic activity in elevated plus maze tests and the like without exhibiting motor dysfunction, learning memory impairment, hypothermia, and hypnosis (Non-Patent Literature). 25). Thus, PAM compounds for GABAB receptors can prevent or reduce the side effects that can occur with the use of baclofen, while autism spectrum disorders, schizophrenia, bipolar disorder, depression, anxiety disorders, addictions, etc. It may be effective in the treatment and prevention of neurological diseases such as psychiatric disorders, convulsions, spinal cord palsy, multiple sclerosis, amyotrophic lateral sclerosis.
Patent Document 1 and Non-Patent Document 26 disclose PAM compounds for a GABAB receptor having a nitrogen-containing fused heterocyclic ring, but do not disclose the nitrogen-containing fused heterocyclic compound described in the present application.
WO2015/056771WO2015 / 056771
　本発明の目的は、ＧＡＢＡＢ受容体に対してポジティブアロステリックモジュレーター（ＰＡＭ）作用を有する新規な化合物を見出し、自閉症スペクトラム障害、脆弱性Ｘ症候群、統合失調症、双極性障害、うつ病、不安障害、認知症、疼痛、薬物・アルコール依存症、痙攣、脳血管障害、脳性麻痺、脊髄麻痺、外傷後遺症、多発性硬化症、筋萎縮性側索硬化症、ｓｔｉｆｆ－ｍａｎ症候群、本態性振戦、過活動膀胱、胃食道逆流性疾患又はＣｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病等の疾患の治療又は予防薬を提供することにある。 The object of the present invention is to find a novel compound having a positive allosteric modulator (PAM) action on the GABAB receptor and to detect autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety Disorder, dementia, pain, drug / alcohol dependence, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, essential tremor An object of the present invention is to provide a therapeutic or prophylactic agent for diseases such as overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease.
　本発明者らはＧＡＢＡＢ受容体に対してポジティブアロステリックモジュレーター（ＰＡＭ）作用を有する新規な化合物につき鋭意検討した結果、下記に示す式で表されるある種の含窒素縮合複素環化合物に優れたＧＡＢＡＢ受容体に対するＰＡＭ作用があることを見出し、本発明を完成した。
本発明の態様（以下、「本発明化合物」という）は以下に示すものである。
（１）式（Ｉ）
Figure JPOXMLDOC01-appb-C000014
 （式中、
Ｘは、窒素原子又は式ＣＲ4を示し、
Ｘが、窒素原子の場合、
Ｒ1は、テトラヒドロピラニル、ピペリジニル（該ピペリジニルは、カルバモイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイル及びＣ1-6アルキルスルホニルからなる群から選ばれる１個の置換基で置換されてもよい。）、又は、
式ＮＲN1ＲN2を示し、
ＲN1は水素原子を示し、
ＲN2は、アダマンチル（該アダマンチルは、１個のヒドロキシで置換されてもよい。）、Ｃ5-6シクロアルキル（該Ｃ5-6シクロアルキルは、１個のヒドロキシで置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は、
下記式（ＩＩ）を示し、
Figure JPOXMLDOC01-appb-C000015
 （式中、
ＲC1は、水素原子又はＣ1-6アルキルを示し、
ＲC2は、Ｃ1-6アルキルを示すか、
又は、ＲC1及びＲC2は、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカンを形成してもよく、
ＲC3は、ハロゲン原子、ヒドロキシ、Ｃ1-6アルキルスルホニル、カルバモイル（該カルバモイルは、１～２個のＣ1-6アルキルで置換されてもよい。）、トリアゾリル、又はカルボキシを示し、
ｎは、０～３の整数を示す。）
又は、ＲN1及びＲN2は、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、Ｃ3-6シクロアルキルカルボニルアミノ（該Ｃ3-6シクロアルキルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－１－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）、アミノ、Ｃ1-6アルキルアミノ及びグアジニノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
Ｒ2は、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）を示し、
Ｒ3は、水素原子、メチル（該メチルは、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル、シアノ又はアセチルを示し、
Ｘが、式ＣＲ4の場合、
Ｒ1は、フェニル（該フェニルは、Ｃ2-6アルカノイルアミノ、ヒドロキシメチル及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ3-6シクロアルコキシ（該Ｃ3-6シクロアルコキシは、１個のオキソで置換されてもよい。）、シアノ、ピリジル、ピリミジル、ピラゾリル、イソオキサゾリル（該ピラゾリル及びイソオキサゾリルは、１～２個のメチルで置換されてもよい。）、イソプロピル、イソブチル、Ｃ3-6シクロアルキルメトキシ、フェノキシ、ピペリジノカルボニル、ジヒドロピラニル、又は、
式ＮＲN3ＲN4を示し、
ＲN3は、水素原子、メチル、イソプロピル、シクロプロピル又はシクロブチルを示し、
ＲN4は、Ｃ4-6シクロアルキル、フェニル、２－メチル－５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［１，５－ａ］ピリジン－６－イル、
又は下記式（ＩＩＩ）を示し、
Figure JPOXMLDOC01-appb-C000016
 （式中、
ＲC4及びＲC5は、同一又は異なって水素原子又はＣ1-6アルキルを示すか、
又はＲC4及びＲC5は、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカン（該Ｃ3-6シクロアルカンは、ハロゲン原子及びヒドロキシからなる群より選ばれる１～２個の基で置換されてもよい。）、４～６員の環状エーテル、又は４～６員の環状アミン（該４～６員の環状アミンは、１個のメチル、Ｃ2-6アルカノイル又はＣ1-6アルコキシカルボニルで置換されている。）を形成してもよく、
ＲC6は、水素原子、ハロゲン原子、ヒドロキシ、フェニル、ピリジル、ピリミジル、ピラゾリル、トリアゾリル、メチルオキサジアゾリル、シクロヘキシル、アミノ、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、アミノ及びＣ1-6アルキルスルホニルからなる群より選ばれる１個の置換基で置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノを示し、
ｐは、０～１の整数を示し、
ｑは、０～３の整数を示す。）、
又はＲN3及びＲN4は、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１つ以上の窒素原子、酸素原子若しくは硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ヒドロキシ、Ｃ1-6アルコキシ、カルバモイル、Ｃ1-6アルコキシカルボニル、ピラゾリル、ピペリジノカルボニル、ジメチルアミノカルボニル及びＣ1-6アルコキシカルボニルオキシからなる群より選ばれる１個の置換基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ2-6アルカノイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイルアミノ、Ｃ1-6アルコキシカルボニルアミノ、オキソ、及びアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに該４～７員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよく、又は該４～７員の飽和複素環の環中の１個の炭素原子が、４～６員の環状エーテルで置き換わってもよく、又は該４～７員の飽和複素環が、ベンゼン、ピリジン、イソオキサゾール又はイミダゾールからなる群より選ばれる１つの環と縮合し、縮合環を形成してもよい）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イル、３，４‐ジヒドロキノリン‐１（２Ｈ）‐イル又は２‐オキソキノキサリン‐１（２Ｈ）‐イル（該２‐オキソキノキサリン‐１（２Ｈ）‐イルは、１個のハロゲン原子で置換されてもよい。）を形成してもよく、
Ｒ2は、ｎ－プロピル（該ｎ－プロピルは、１～３個のハロゲン原子で置換されている。）、ｎ‐ブチル（該ｎ‐ブチルは、メチル、ハロゲン原子、ヒドロキシ及びオキソからなる群より選ばれる１～３個の基で置換されてもよい。）、ｔｅｒｔ－ブチル、Ｃ3-6シクロアルキル（該Ｃ3-6シクロアルキルは、ハロゲン原子、Ｃ1-6アルキル、ヒドロキシ、オキソ及びトリフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ3-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、１，３‐ジオキソランと置き換わってもよい。）、Ｃ4-6シクロアルケニル（該Ｃ4-6シクロアルケニルは、１個のハロゲン原子で置換されてもよい。）、シクロプロピルエチル、フェノキシメチル（該フェノキシメチルのフェニル基は、ハロゲン原子、シアノ及びジフロロメチルからなる群より選ばれる１個の置換基で置換されてもよい。）、ピリジルオキシメチル（該ピリジルオキシメチルのピリジルは、１個のトリフロロメチルで置換されてもよい。）、ピペリジノカルボニル、フェノキシカルボニル、プロポキシ、又はシクロプロピルエチニルを示し、
Ｒ3は、ハロゲン原子、メチル（該メチル基は、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、メトキシ、シアノ、エトキシカルボニル、ヒドロキシイソプロピル、ピラゾリル又はメチルオキサジアゾリルであり、
Ｒ4は、水素原子、フッ素原子、メチル（該メチルは、ヒドロキシ及びメトキシからなる群より選ばれる１個の置換基で置換されてもよい。）、又はエトキシカルボニルを示す。）
で表される含窒素縮合複素環化合物又はその医薬上許容される塩。
（２）Ｘが窒素原子であり、Ｒ1が式ＮＲN1ＲN2を示し、かつＲN1及びＲN2が隣接する窒素原子と一緒になって環中に前記窒素原子以外にさらに１個の窒素原子、酸素原子若しくは硫黄原子を含んでもよい４～７員の飽和複素環を形成する場合には、該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、Ｃ3-6シクロアルキルカルボニルアミノ（該Ｃ3-6シクロアルキルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）、アミノ、Ｃ1-6アルキルアミノ及びグアジニノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよく、
前記の場合以外については（１）に記載のとおりである、（１）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（３）式（Ｉ）において、
Ｘが、窒素原子である、（１）又は（２）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（４）式（Ｉ）において、
Ｒ1が、テトラヒドロピラニル、ピペリジニル（該ピペリジニルは、カルバモイル、ｔｅｒｔ－ブチルカルボニル、アセチル及びメチルスルホニルからなる群から選ばれる１個の置換基で置換されてもよい。）、又は
式ＮＲN1ＲN2であり、
ＲN1が水素原子であり、
ＲN2が、アダマンチル（該アダマンチルは、１個のヒドロキシで置換されてもよい）、Ｃ5-6シクロアルキル（該Ｃ5-6シクロアルキルは、１個のヒドロキシで置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は下記式（ＩＩ）であり、
Figure JPOXMLDOC01-appb-C000017
 （式中、
ＲC1が、水素原子又はメチルであり、
ＲC2が、メチル又はイソプロピルであるか、
又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカンを形成してもよく、
ＲC3が、ハロゲン原子、ヒドロキシ、メチルスルホニル、カルバモイル（該カルバモイルは、１～２個のＣ1-6アルキルで置換されてもよい。）、トリアゾリル、又はカルボキシであり、
ｎが、０～３の整数である。）、
又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、　５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）及びアミノ、モノＣ1-6アルキルアミノ、グアジニノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
Ｒ2が、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）である、（３）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（５）式（Ｉ）において、
Ｒ1が、テトラヒドロピラニル、ピペリジニル（該ピペリジニルは、１個のカルバモイルで置換されてもよい。）、又は
式ＮＲN1ＲN2であり、
ＲN1が、水素原子であり、
ＲN2が、下記式（ＩＩ）であり、
Figure JPOXMLDOC01-appb-C000018
 （式中、
ＲC1が、水素原子又はメチルであり、
ＲC2が、メチル又はイソプロピルであるか、
又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
ＲC3が、ハロゲン原子、ヒドロキシ、メチルスルホニル、カルバモイル（該カルバモイルは、１～２個のＣ1-6アルキルで置換されてもよい。）、又はトリアゾリルであり、
ｎが、０～３の整数である。）、
又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）からなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
Ｒ2が、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）である、（３）又は（４）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（６）式（Ｉ）において、
Ｒ1が、式ＮＲN1ＲN2であり、
ＲN1が、水素原子であり、
ＲN2が、下記式（ＩＩ）であり、
Figure JPOXMLDOC01-appb-C000019
 （式中、
ＲC1が、水素原子又はメチルであり、
ＲC2が、メチル又はイソプロピルであるか、
又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
ＲC3が、ヒドロキシ、メチルスルホニル、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）であり、
ｎが、１～３の整数である。）、
又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル及びカルボキシからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のヒドロキシで置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）及び５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イルからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
Ｒ2が、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）であり、
Ｒ3が、メチル、モノフルオロメチル、ジフルオロメチル、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル又はシアノである、（３）～（５）のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（７）式（Ｉ）において、
Ｒ1が、式ＮＲN1ＲN2であり、
ＲN1が、水素原子であり、
ＲN2が、下記式（ＩＩ）であり、
Figure JPOXMLDOC01-appb-C000020
 （式中、
ＲC1が、水素原子又はメチルであり、
ＲC2が、メチル又はイソプロピルであるか、
又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
ＲC3が、ヒドロキシ、メチルスルホニル、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）であり、
ｎが、１～３の整数である。）、
又は、Ｒ1が下記式（ＩＶ）であり、
Figure JPOXMLDOC01-appb-C000021
 （式中、
ＲC７が、水素原子又はヒドロキシであり、
ＲC８が、水素原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、カルバモイル、及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１～３個の基で置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、ピラゾリル（該ピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノであり、
ｒが、２～３の整数である。）、
又は、Ｒ1が下記式（Ｖ）であり、
Figure JPOXMLDOC01-appb-C000022
 （式中、
ＲN３が、Ｃ1-6アルキル（該Ｃ1-6アルキルは、カルバモイル、及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１個の基で置換されてもよい。）、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）である。）、
又は、Ｒ1が３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、３－チア－８－アザビシクロ［３．２．１］オクタン－３，３－ジオン－８－イル、及び２‐オキサ‐６‐アザアダマンタン‐６‐イルから選ばれる１つの基であり、
Ｒ２が、ｎ‐ブチル、Ｃ4-6シクロアルキル、３，３－ジフルオロブチル、（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、４－フルオロビシクロ［２．２．２］オクタ－１－イル、２－（３，３－ジフルオロシクロブチル)エチル、又はシクロブチルメトキシであり、
Ｒ3が、メチル、モノフルオロメチル、ジフルオロメチル、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル又はシアノである、（３）～（６）のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（８）式（Ｉ）において、
Ｘが、式ＣＲ4である、（１）又は（２）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（９）式（Ｉ）において、
Ｒ1が、フェニル（該フェニルは、Ｃ2-6アルカノイルアミノ、ヒドロキシメチル及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ3-6シクロアルコキシ（該Ｃ3-6シクロアルコキシは、１個のオキソで置換されてもよい。）、シアノ、ピリジル、ピリミジル、ピラゾリル、イソオキサゾリル（該ピラゾリル及びイソオキサゾリルは、１～２個のメチルで置換されてもよい。）、イソプロピル、イソブチル、Ｃ3-6シクロアルキルメトキシ、フェノキシ、ピペリジノカルボニル、ジヒドロピラニル、又は、
式ＮＲN3ＲN4であり、
ＲN3が、水素原子、メチル、イソプロピル、シクロプロピル又はシクロブチルであり、
ＲN4が、Ｃ4-6シクロアルキル、フェニル又は２－メチル－５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［１，５－ａ］ピリジン－６－イル、又は下記式（ＩＩＩ）であり、
Figure JPOXMLDOC01-appb-C000023
 （式中、
ＲC4及びＲC5は、同一又は異なって水素原子又はＣ1-6アルキルを示すか、
又はＲC4及びＲC5は、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカン（該Ｃ3-6シクロアルカンは、ハロゲン原子及びヒドロキシからなる群より選ばれる１～２個の基で置換されてもよい。）、４～６員の環状エーテル、又は４～６員の環状アミン（該４～６員の環状アミンは、１個のメチル、Ｃ2-6アルカノイル又はＣ1-6アルコキシカルボニルで置換されている。）を形成してもよく、
ＲC6が、ハロゲン原子、ヒドロキシ、フェニル、ピリジル、ピリミジル、ピラゾリル、トリアゾリル、メチルオキサジアゾリル、シクロヘキサニル、アミノ、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のアミノ又はＣ1-6アルキルスルホニルで置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノであり、
ｐが、０～１の整数であり、
ｑが、０～３の整数である。）、
又はＲN3及びＲN4は、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１つ以上の窒素原子、酸素原子若しくは硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ヒドロキシ、Ｃ1-6アルコキシ、カルバモイル、Ｃ1-6アルコキシカルボニル、ピラゾリル、ピペリジノカルボニル、ジメチルアミノカルボニル及びＣ1-6アルコキシカルボニルオキシからなる群より選ばれる１個の置換基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ2-6アルカノイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイルアミノ、Ｃ1-6アルコキシカルボニルアミノ、オキソ、及びアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに該４～７員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよく、又は該４～７員の飽和複素環の環中の１個の炭素原子が、４～６員の環状エーテルで置き換わってもよく、又は該４～７員の飽和複素環が、ベンゼン、ピリジン、イソオキサゾール又はイミダゾールからなる群より選ばれる１つの環と縮合し、縮合環を形成してもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イル、３，４‐ジヒドロキノリン‐１（２Ｈ）‐イル又は２‐オキソキノキサリン‐１（２Ｈ）‐イル（該２‐オキソキノキサリン‐１（２Ｈ）‐イルは、１個のハロゲン原子で置換されてもよい。）を形成してもよく、
Ｒ2が、ｎ－プロピル（該ｎ－プロピルは、１～３個のハロゲン原子で置換されている。）、ｎ‐ブチル（該ｎ‐ブチルは、メチル、ハロゲン原子、ヒドロキシ及びオキソからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ3-6シクロアルキル（該Ｃ3-6シクロアルキルは、ハロゲン原子、Ｃ1-6アルキル、ヒドロキシ、オキソ及びトリフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ3-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、１，３‐ジオキソランと置き換わってもよい。）、Ｃ4-6シクロアルケニル（該Ｃ4-6シクロアルケニルは、１個のハロゲン原子で置換されてもよい。）、シクロプロピルエチル、フェノキシメチル（該フェノキシメチルのフェニル基は、ハロゲン原子、シアノ及びジフロロメチルからなる群より選ばれる１個の置換基で置換されてもよい。）、ピリジルオキシメチル（該ピリジルオキシメチルのピリジルは、１個のトリフロロメチルで置換されてもよい。）、ピペリジノカルボニル、フェノキシカルボニル、プロポキシ、又はシクロプロピルエチニルである、（８）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（１０）式（Ｉ）において、
Ｒ1が、フェニル（該フェニルは、Ｃ2-6アルカノイルアミノ、ヒドロキシメチル及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、Ｃ3-6シクロアルキル、又は
式ＮＲN3ＲN4であり、
ＲN3が、水素原子、メチル、イソプロピル又はシクロブチルであり、
ＲN4が、Ｃ4-6シクロアルキル、又は下記式（ＩＩＩ）であり、
Figure JPOXMLDOC01-appb-C000024
 （式中、
ＲC4及びＲC5は、共に水素原子又はメチルを示すか、
又はＲC4及びＲC5は、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカン（該Ｃ4-6シクロアルカンは、１～２個のハロゲン原子で置換されてもよい。）又は４～６員の環状エーテルを形成してもよく、
ＲC6が、ハロゲン原子、ヒドロキシ、フェニル、ピリジル、ピラゾリル、トリアゾリルであり、
ｐが、０であり、
ｑが、０～３の整数である。）、
又はＲN3及びＲN4が、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１個の酸素原子を含んでもよい４～６員の飽和複素環（該４～６員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ、Ｃ1-6アルコキシ、カルバモイル、Ｃ1-6アルコキシカルボニル又はピラゾリルで置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ2-6アルカノイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイルアミノ及びＣ1-6アルコキシカルボニルアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに該４～６員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、環中に前記窒素原子の他に１個の窒素原子を含む４～６員の飽和複素環（該４～６員の飽和複素環は、Ｃ2-6アルカノイル及びＣ1-6アルコキシカルボニルからなる群より選ばれる１個の置換基で置換されており、さらに該４～６員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イル、３，４‐ジヒドロキノリン‐１（２Ｈ）‐イル若しくは２‐オキソキノキサリン‐１（２Ｈ）‐イルを形成してもよく、
Ｒ2が、ｎ‐ブチル（該ｎ‐ブチルは、メチル又はハロゲン原子からなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよい。）、Ｃ4-6シクロアルケニル（該Ｃ4-8シクロアルケニルは、１個のハロゲン原子で置換されてもよい。）、シクロプロピルエチル又はフェノキシメチル（該フェノキシメチルのフェニル基は、１個のハロゲン原子、シアノ又はジフロロメチルで置換されてもよい。）であり、
Ｒ3が、ハロゲン原子、メチル（該メチル基は、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、メトキシ又はシアノであり、
Ｒ4が、水素原子、フッ素原子又はメチル（該メチル基は、１個のメトキシで置換されてもよい。）である、（８）又は（９）に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（１１）式（Ｉ）において、
Ｒ1が、式ＮＲN3ＲN4であり、
ＲN3が水素原子であり、
ＲN4が、下記式（ＩＩＩ）であり、
Figure JPOXMLDOC01-appb-C000025
 （式中、
ＲC4及びＲC5が、共にメチルを示すか、
又はＲC4及びＲC5が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカン又は４～６員の環状エーテルを形成してもよく、
ＲC6が、ハロゲン原子又はヒドロキシであり、
ｐが、０であり、
ｑが、１～３の整数である。）、
又は、ＲN3及びＲN4が、隣接する窒素原子と一緒になって、環中に前記窒素原子の他にさらに１個の酸素原子を含んでもよい４～６員の飽和複素環（該４～６員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル、Ｃ2-6アルカノイルアミノ及びＣ1-6アルコキシカルボニルアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
Ｒ2が、ｎ‐ブチル（該ｎ‐ブチルは、メチル又はハロゲン原子からなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよい。）、シクロプロピルエチル又はジフロロメチルフェノキシメチルであり、
Ｒ3が、メチル、ジフロロメチル、メトキシ又はシアノであり、
Ｒ4が、水素原子、フッ素原子又はメチルである（８）～（１０）のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（１２）式（Ｉ）において、
Ｒ1が、式ＮＲN3ＲN4であり、
ＲN3が、水素原子であり、
ＲN4が、下記式（ＩＩＩ）であり、
Figure JPOXMLDOC01-appb-C000026
 （式中、
ＲC4及びＲC5が、共にメチルを示すか、
又はＲC4及びＲC5が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
ＲC6が、ハロゲン原子又はヒドロキシであり、
ｐが、０であり、
ｑが、１～３の整数である。）、
又は、Ｒ1が、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、２‐オキサ‐６‐アザアダマンタン‐６‐イル、８－アザビシクロ［３．２．１］オクタン－3－オール－８－イル、及び３－メチル－８－アザビシクロ［３．２．１］オクタン－3－オール－８－イルから選ばれる１つの基であり、
Ｒ2が、ｎ‐ブチル、Ｃ4-6シクロアルキル、シクロプロピルエチル、３，３－ジフルオロブチル、（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、又は４－フルオロビシクロ［２．２．２］オクタ－１－イルであり、
Ｒ３が、メチル、ジフロロメチル、メトキシ又はシアノであり、
Ｒ４が、水素原子又はフッ素原子である（８）～（１１）のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。
（１３）前記（１）に記載される下記化合物からなる群から選択される化合物、又はその医薬上許容される塩。
２－ブチル－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン、
６－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
２－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン、
６－（２－シクロペンチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
６－｛２－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル｝－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
７－ブチル－２－メチル－４－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン、
６－（７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
６－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－オール、
２－（｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－２－メチルプロパン－１-オール、
６－｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
７－（３，３－ジフルオロブチル）－４－（３，３－ジオキシド－３－チア－８－アザビシクロ［３．２．１］オクタ－８－イル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン、
８－｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝－３－チア－８－アザビシクロ［３．２．１］オクタン－３，３－ジオン。
（１４）前記（１）～（１３）のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩を有効成分として含有する医薬。
（１５）前記（１）～（１３）のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬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、脆弱性Ｘ症候群、統合失調症、双極性障害、うつ病、不安障害、認知症、疼痛、薬物・アルコール依存症、痙攣、脳血管障害、脳性麻痺、脊髄麻痺、外傷後遺症、多発性硬化症、筋萎縮性側索硬化症、ｓｔｉｆｆ－ｍａｎ症候群、本態性振戦、過活動膀胱、胃食道逆流性疾患又はＣｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病等の治療又は予防薬。 As a result of intensive studies on a novel compound having a positive allosteric modulator (PAM) action on a GABAB receptor, the present inventors have found that GABAB excellent in certain nitrogen-containing condensed heterocyclic compounds represented by the following formulas The present invention was completed by finding that there is a PAM action on the receptor.
The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1) Formula (I)
Figure JPOXMLDOC01-appb-C000014
 (Where
X is a nitrogen atom or the formula CR Four Indicate
When X is a nitrogen atom,
R 1 Is tetrahydropyranyl, piperidinyl (the piperidinyl is carbamoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoyl and C 1-6 It may be substituted with one substituent selected from the group consisting of alkylsulfonyl. ) Or
Formula NR N1 R N2 Indicate
R N1 Indicates a hydrogen atom,
R N2 Is adamantyl (which may be substituted with one hydroxy), C 5-6 Cycloalkyl (the C 5-6 Cycloalkyls may be substituted with one hydroxy and may be further substituted between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. ) Or
The following formula (II) is shown,
Figure JPOXMLDOC01-appb-C000015
 (Where
R C1 Is a hydrogen atom or C 1-6 Indicates alkyl,
R C2 Is C 1-6 Indicates alkyl or
Or R C1 And R C2 Together with adjacent carbon atoms, C 3-6 May form a cycloalkane,
R C3 Is a halogen atom, hydroxy, C 1-6 Alkylsulfonyl, carbamoyl (wherein the carbamoyl is 1-2 C 1-6 It may be substituted with alkyl. ), Triazolyl or carboxy,
n represents an integer of 0 to 3. )
Or R N1 And R N2 Is a 4- to 7-membered saturated heterocyclic ring that may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom together with the adjacent nitrogen atom (the 4- to 7-membered ring). The saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl. ), C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl. ), C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), Formula triazolyl-Y-, C 3-6 Cycloalkylcarbonylamino (the C 3-6 Cycloalkylcarbonylamino may be substituted with one hydroxy. ), Oxoimidazolidinyl (wherein the oxoimidazolidinyl represents one C 1-6 It may be substituted with alkyl. ), 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl, C 1-6 Alkylsulfonylamino, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino represents 1 to 2 C 1-6 It may be substituted with alkyl. ), Amino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkylamino and guadinino, and further, C between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. Or 2-oxa-6-azaadamantan-6-yl,
Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH—
R 2 Is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring is C 3-6 It may be replaced with cycloalkane. ), C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl. Or C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl. )
R Three Is a hydrogen atom, methyl (the methyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), difluoroethyl, methoxy, difluoromethoxy, cyclopropyl, cyano or acetyl Indicate
X is CR Four in the case of,
R 1 Is phenyl (the phenyl is C 2-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkanoylamino, hydroxymethyl and methoxy. ), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy (the C 3-6 Cycloalkoxy may be substituted with one oxo. ), Cyano, pyridyl, pyrimidyl, pyrazolyl, isoxazolyl (the pyrazolyl and isoxazolyl may be substituted with 1 to 2 methyls), isopropyl, isobutyl, C 3-6 Cycloalkylmethoxy, phenoxy, piperidinocarbonyl, dihydropyranyl, or
Formula NR N3 R N4 Indicate
R N3 Represents a hydrogen atom, methyl, isopropyl, cyclopropyl or cyclobutyl,
R N4 Is C 4-6 Cycloalkyl, phenyl, 2-methyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridin-6-yl,
Or the following formula (III):
Figure JPOXMLDOC01-appb-C000016
 (Where
R C4 And R C5 Are the same or different and are hydrogen atoms or C 1-6 Indicates alkyl or
Or R C4 And R C5 Together with adjacent carbon atoms, C 3-6 Cycloalkane (the C 3-6 The cycloalkane may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and hydroxy. ) 4- to 6-membered cyclic ether, or 4- to 6-membered cyclic amine (the 4- to 6-membered cyclic amine is one methyl, C 2-6 Alkanoyl or C 1-6 Substituted with alkoxycarbonyl. )
R C6 Is a hydrogen atom, a halogen atom, hydroxy, phenyl, pyridyl, pyrimidyl, pyrazolyl, triazolyl, methyloxadiazolyl, cyclohexyl, amino, C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is amino and C 1-6 It may be substituted with one substituent selected from the group consisting of alkylsulfonyl. ) Or C 1-6 Represents alkoxycarbonylamino,
p represents an integer of 0 to 1,
q represents an integer of 0 to 3. ),
Or R N3 And R N4 Is a 4- to 7-membered saturated heterocyclic ring which may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms in addition to the nitrogen atom in the ring together with the adjacent nitrogen atom (the 4-7 The membered saturated heterocycle is hydroxy, C 1-6 Alkyl (the C 1-6 Alkyl is hydroxy, C 1-6 Alkoxy, carbamoyl, C 1-6 Alkoxycarbonyl, pyrazolyl, piperidinocarbonyl, dimethylaminocarbonyl and C 1-6 It may be substituted with one substituent selected from the group consisting of alkoxycarbonyloxy. ), C 3-6 Cycloalkyl, C 2-6 Alkanoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoylamino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, oxo, and amino, and the 4- to 7-membered saturated heterocyclic ring is between two different carbon atoms in the ring. C 1-6 May be bridged with alkylene, or one carbon atom in the ring of the 4-7 membered saturated heterocyclic ring may be replaced by a 4-6 membered cyclic ether, or the 4-7 membered saturated The heterocyclic ring may be condensed with one ring selected from the group consisting of benzene, pyridine, isoxazole or imidazole to form a condensed ring), or 2-oxa-6-azaadamantan-6-yl, 3 , 4-Dihydroquinolin-1 (2H) -yl or 2-oxoquinoxalin-1 (2H) -yl, wherein the 2-oxoquinoxalin-1 (2H) -yl may be substituted with one halogen atom .) May be formed,
R 2 N-propyl (wherein n-propyl is substituted with 1 to 3 halogen atoms), n-butyl (wherein n-butyl is selected from the group consisting of methyl, halogen atom, hydroxy and oxo) Optionally substituted with 1 to 3 groups), tert-butyl, C 3-6 Cycloalkyl (the C 3-6 Cycloalkyl is a halogen atom, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, hydroxy, oxo and trifluoromethyl. 3-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring may replace 1,3-dioxolane. ), C 4-6 Cycloalkenyl (the C 4-6 Cycloalkenyl may be substituted with one halogen atom. ), Cyclopropylethyl, phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one substituent selected from the group consisting of a halogen atom, cyano and difluoromethyl), pyridyloxymethyl (the pyridyloxy Methyl pyridyl may be substituted by one trifluoromethyl)), piperidinocarbonyl, phenoxycarbonyl, propoxy, or cyclopropylethynyl;
R Three Is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy, cyano, ethoxycarbonyl, hydroxyisopropyl, pyrazolyl or methyl Oxadiazolyl,
R Four Represents a hydrogen atom, a fluorine atom, methyl (the methyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy), or ethoxycarbonyl. )
Or a pharmaceutically acceptable salt thereof.
(2) X is a nitrogen atom and R 1 Is the formula NR N1 R N2 And R N1 And R N2 Are formed together with the adjacent nitrogen atom to form a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom, 4- to 7-membered saturated heterocycles are hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl. ), C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl. ), C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), Formula triazolyl-Y-, C 3-6 Cycloalkylcarbonylamino (the C 3-6 Cycloalkylcarbonylamino may be substituted with one hydroxy. ), Oxoimidazolidinyl (wherein the oxoimidazolidinyl represents one C 1-6 It may be substituted with alkyl. ), 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, C 1-6 Alkylsulfonylamino, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino represents 1 to 2 C 1-6 It may be substituted with alkyl. ), Amino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkylamino and guadinino, and further, C between two different carbon atoms in the ring. 1-6 May be cross-linked with alkylene,
Except for the above case, the nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1), which is as described in (1).
(3) In the formula (I),
The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein X is a nitrogen atom.
(4) In formula (I),
R 1 Is tetrahydropyranyl, piperidinyl (which may be substituted with one substituent selected from the group consisting of carbamoyl, tert-butylcarbonyl, acetyl and methylsulfonyl), or
Formula NR N1 R N2 And
R N1 Is a hydrogen atom,
R N2 Is adamantyl (which may be substituted with one hydroxy), C 5-6 Cycloalkyl (the C 5-6 Cycloalkyls may be substituted with one hydroxy and may be further substituted between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. Or the following formula (II):
Figure JPOXMLDOC01-appb-C000017
 (Where
R C1 Is a hydrogen atom or methyl,
R C2 Is methyl or isopropyl,
Or R C1 And R C2 Together with adjacent carbon atoms, C 3-6 May form a cycloalkane,
R C3 Is a halogen atom, hydroxy, methylsulfonyl, carbamoyl (the carbamoyl represents 1 to 2 C 1-6 It may be substituted with alkyl. ), Triazolyl, or carboxy,
n is an integer of 0 to 3. ),
Or R N1 And R N2 Together with the adjacent nitrogen atom, a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom (the 4- to 7-membered member) The saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl. ), C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl. ), C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), The formula triazolyl-Y—, cyclopropylcarbonylamino (the cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxoimidazolidinyl is one C 1-6 It may be substituted with alkyl. ), 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, C 1-6 Alkylsulfonylamino, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino represents 1 to 2 C 1-6 It may be substituted with alkyl. ) And amino, mono C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkylamino and guadinino, and further, C between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. Or 2-oxa-6-azaadamantan-6-yl,
Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH—
R 2 N-propyl, n-butyl, n-pentyl (wherein the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring is C 3-6 It may be replaced with cycloalkane. ), C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl. Or C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl. The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (3).
(5) In the formula (I),
R 1 Is tetrahydropyranyl, piperidinyl (which may be substituted with one carbamoyl), or
Formula NR N1 R N2 And
R N1 Is a hydrogen atom,
R N2 Is the following formula (II):
Figure JPOXMLDOC01-appb-C000018
 (Where
R C1 Is a hydrogen atom or methyl,
R C2 Is methyl or isopropyl,
Or R C1 And R C2 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane,
R C3 Is a halogen atom, hydroxy, methylsulfonyl, carbamoyl (the carbamoyl represents 1 to 2 C 1-6 It may be substituted with alkyl. ), Or triazolyl,
n is an integer of 0 to 3. ),
Or R N1 And R N2 Together with the adjacent nitrogen atom, a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom (the 4- to 7-membered member) The saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl. ), C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is hydroxy, C 2-6 It may be substituted with one substituent selected from the group consisting of alkanoyloxy, pyrazolyl and triazolyl. ), Carbamoyl (the carbamoyl is C 1-6 Alkyl, pyrazolyl C 1-6 Alkyl and triazolyl C 1-6 It may be substituted with 1 to 2 substituents selected from the group consisting of alkyl. ), C 1-6 Alkoxycarbonylamino (the C 1-6 Alkoxycarbonylamino is a C 1-6 It may be substituted with alkyl. ), Ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), The formula triazolyl-Y—, cyclopropylcarbonylamino (the cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxoimidazolidinyl is one C 1-6 It may be substituted with alkyl. ), 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, C 1-6 Alkylsulfonylamino, C 1-6 Alkoxycarbonyl, C 1-6 Alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino represents 1 to 2 C 1-6 It may be substituted with alkyl. ) May be substituted with 1 to 2 groups selected from the group consisting of 1-6 It may be bridged with alkylene. Or 2-oxa-6-azaadamantan-6-yl,
Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH—
R 2 N-propyl, n-butyl, n-pentyl (wherein the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring is C 3-6 It may be replaced with cycloalkane. ), C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl. Or C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl. The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (3) or (4).
(6) In the formula (I),
R 1 Is the formula NR N1 R N2 And
R N1 Is a hydrogen atom,
R N2 Is the following formula (II):
Figure JPOXMLDOC01-appb-C000019
 (Where
R C1 Is a hydrogen atom or methyl,
R C2 Is methyl or isopropyl,
Or R C1 And R C2 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane,
R C3 Is hydroxy, methylsulfonyl, or carbamoyl (wherein the carbamoyl is one C 1-6 It may be substituted with alkyl. ) And
n is an integer of 1 to 3. ),
Or R N1 And R N2 Together with the adjacent nitrogen atom, a 4- to 7-membered saturated heterocyclic ring which may further contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom (the 4- to 7-membered member) The saturated heterocycle of is hydroxy, oxo, carboxy, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl and carboxy. ), C 1-6 Alkoxy (the C 1-6 Alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl. ), C 2-6 Alkanoylamino (the C 2-6 The alkanoylamino may be substituted with one hydroxy. ), Carbamoyl (the carbamoyl is one C 1-6 It may be substituted with alkyl. ), C 1-6 Alkoxycarbonylamino, ureido (the ureido is one C 1-6 Optionally substituted with alkyl), a pyrazolyl-Y— of the formula (wherein the pyrazolyl of the formula pyrazolyl-Y— represents one C 1-6 It may be substituted with alkyl. ), The formula triazolyl-Y—, cyclopropylcarbonylamino (the cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxoimidazolidinyl is one C 1-6 It may be substituted with alkyl. ) And 5-oxo-1H-1,2,4-triazol-4 (5H) -yl, and may be substituted with 1 to 2 groups selected from the group consisting of two different carbons in the ring C between atoms 1-6 It may be bridged with alkylene. Or 2-oxa-6-azaadamantan-6-yl,
Y is a single bond, formula —O—, formula —NH—, formula —SO 2 -, Formula -SO 2 NH— or the formula —CONH—
R 2 N-propyl, n-butyl, n-pentyl (wherein the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring is C 3-6 It may be replaced with cycloalkane. ), C 3-6 Cycloalkylethyl (the C 3-6 Cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl. Or C 3-6 Cycloalkylmethoxy (the C 3-6 Cycloalkylmethoxy is one C 1-6 It may be substituted with alkyl. ) And
R Three The nitrogen-containing fused heterocyclic compound or a pharmaceutical thereof according to any one of (3) to (5), wherein is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano Top acceptable salt.
(7) In the formula (I),
R 1 Is the formula NR N1 R N2 And
R N1 Is a hydrogen atom,
R N2 Is the following formula (II):
Figure JPOXMLDOC01-appb-C000020
 (Where
R C1 Is a hydrogen atom or methyl,
R C2 Is methyl or isopropyl,
Or R C1 And R C2 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane,
R C3 Is hydroxy, methylsulfonyl, or carbamoyl (wherein the carbamoyl is one C 1-6 It may be substituted with alkyl. ) And
n is an integer of 1 to 3. ),
Or R 1 Is the following formula (IV),
Figure JPOXMLDOC01-appb-C000021
 (Where
R C7 Is a hydrogen atom or hydroxy,
R C8 Is a hydrogen atom, C 1-6 Alkyl (the C 1-6 Alkyl is a halogen atom, hydroxy, carbamoyl, and C 1-6 It may be substituted with 1 to 3 groups selected from the group consisting of alkylaminocarbonyl. ), Carbamoyl (the carbamoyl is one C 1-6 It may be substituted with alkyl. ), Pyrazolyl (the pyrazolyl is one C 1-6 It may be substituted with alkyl. ) Or C 1-6 Alkoxycarbonylamino,
r is an integer of 2 to 3. ),
Or R 1 Is the following formula (V),
Figure JPOXMLDOC01-appb-C000022
 (Where
R N3 But C 1-6 Alkyl (the C 1-6 Alkyl is carbamoyl and C 1-6 It may be substituted with one group selected from the group consisting of alkylaminocarbonyl. ) Or carbamoyl (the carbamoyl is one C 1-6 It may be substituted with alkyl. ). ),
Or R 1 Is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 3-thia-8-azabicyclo [3 2.1] one group selected from octane-3,3-dione-8-yl and 2-oxa-6-azaadamantan-6-yl;
R 2 N-butyl, C 4-6 Cycloalkyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, 4-fluorobicyclo [2.2.2] octa- 1-yl, 2- (3,3-difluorocyclobutyl) ethyl, or cyclobutylmethoxy;
R Three The nitrogen-containing fused heterocyclic compound or a pharmaceutical thereof according to any one of (3) to (6), wherein is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano Top acceptable salt.
(8) In the formula (I),
X is CR Four The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to (1) or (2).
(9) In the formula (I),
R 1 Is phenyl (the phenyl is C 2-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkanoylamino, hydroxymethyl and methoxy. ), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy (the C 3-6 Cycloalkoxy may be substituted with one oxo. ), Cyano, pyridyl, pyrimidyl, pyrazolyl, isoxazolyl (the pyrazolyl and isoxazolyl may be substituted with 1 to 2 methyls), isopropyl, isobutyl, C 3-6 Cycloalkylmethoxy, phenoxy, piperidinocarbonyl, dihydropyranyl, or
Formula NR N3 R N4 And
R N3 Is a hydrogen atom, methyl, isopropyl, cyclopropyl or cyclobutyl,
R N4 But C 4-6 Cycloalkyl, phenyl or 2-methyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridin-6-yl, or the following formula (III):
Figure JPOXMLDOC01-appb-C000023
 (Where
R C4 And R C5 Are the same or different and are hydrogen atoms or C 1-6 Indicates alkyl or
Or R C4 And R C5 Together with adjacent carbon atoms, C 3-6 Cycloalkane (the C 3-6 The cycloalkane may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and hydroxy. ) 4- to 6-membered cyclic ether, or 4- to 6-membered cyclic amine (the 4- to 6-membered cyclic amine is one methyl, C 2-6 Alkanoyl or C 1-6 Substituted with alkoxycarbonyl. )
R C6 Is a halogen atom, hydroxy, phenyl, pyridyl, pyrimidyl, pyrazolyl, triazolyl, methyloxadiazolyl, cyclohexanyl, amino, C 2-6 Alkanoylamino (the C 2-6 Alkanoylamino is a single amino or C 1-6 It may be substituted with alkylsulfonyl. ) Or C 1-6 Alkoxycarbonylamino,
p is an integer from 0 to 1,
q is an integer of 0 to 3. ),
Or R N3 And R N4 Is a 4- to 7-membered saturated heterocyclic ring which may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms in addition to the nitrogen atom in the ring together with the adjacent nitrogen atom (the 4-7 The membered saturated heterocycle is hydroxy, C 1-6 Alkyl (the C 1-6 Alkyl is hydroxy, C 1-6 Alkoxy, carbamoyl, C 1-6 Alkoxycarbonyl, pyrazolyl, piperidinocarbonyl, dimethylaminocarbonyl and C 1-6 It may be substituted with one substituent selected from the group consisting of alkoxycarbonyloxy. ), C 3-6 Cycloalkyl, C 2-6 Alkanoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoylamino, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, oxo, and amino, and the 4- to 7-membered saturated heterocyclic ring is between two different carbon atoms in the ring. C 1-6 May be bridged with alkylene, or one carbon atom in the ring of the 4-7 membered saturated heterocyclic ring may be replaced by a 4-6 membered cyclic ether, or the 4-7 membered saturated The heterocyclic ring may be condensed with one ring selected from the group consisting of benzene, pyridine, isoxazole or imidazole to form a condensed ring. ), Or 2-oxa-6-azaadamantan-6-yl, 3,4-dihydroquinolin-1 (2H) -yl or 2-oxoquinoxalin-1 (2H) -yl (the 2-oxoquinoxaline-1 ( 2H) -yl may be substituted with one halogen atom)),
R 2 N-propyl (wherein n-propyl is substituted with 1 to 3 halogen atoms), n-butyl (wherein n-butyl is selected from the group consisting of methyl, halogen atom, hydroxy and oxo) Optionally substituted with 1 to 3 groups), C 3-6 Cycloalkyl (the C 3-6 Cycloalkyl is a halogen atom, C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, hydroxy, oxo and trifluoromethyl. 3-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene or the C 3-6 One carbon atom in the cycloalkane ring may replace 1,3-dioxolane. ), C 4-6 Cycloalkenyl (the C 4-6 Cycloalkenyl may be substituted with one halogen atom. ), Cyclopropylethyl, phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one substituent selected from the group consisting of a halogen atom, cyano and difluoromethyl), pyridyloxymethyl (the pyridyloxy The methyl pyridyl may be substituted with one trifluoromethyl.), A nitrogen-containing fused heterocyclic compound according to (8), which is piperidinocarbonyl, phenoxycarbonyl, propoxy, or cyclopropylethynyl; Its pharmaceutically acceptable salt.
(10) In the formula (I),
R 1 Is phenyl (the phenyl is C 2-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkanoylamino, hydroxymethyl and methoxy. ), C 3-6 Cycloalkyl, or
Formula NR N3 R N4 And
R N3 Is a hydrogen atom, methyl, isopropyl or cyclobutyl,
R N4 But C 4-6 Cycloalkyl, or the following formula (III):
Figure JPOXMLDOC01-appb-C000024
 (Where
R C4 And R C5 Both represent a hydrogen atom or methyl,
Or R C4 And R C5 Together with adjacent carbon atoms, C 4-6 Cycloalkane (the C 4-6 The cycloalkane may be substituted with 1 to 2 halogen atoms. ) Or a 4-6 membered cyclic ether,
R C6 Is a halogen atom, hydroxy, phenyl, pyridyl, pyrazolyl, triazolyl,
p is 0,
q is an integer of 0 to 3. ),
Or R N3 And R N4 4-6 membered saturated heterocycle which may contain one oxygen atom in addition to the nitrogen atom together with the adjacent nitrogen atom (the 4-6 membered saturated heterocycle is Hydroxy, C 1-6 Alkyl (the C 1-6 Alkyl is one hydroxy, C 1-6 Alkoxy, carbamoyl, C 1-6 It may be substituted with alkoxycarbonyl or pyrazolyl. ), C 3-6 Cycloalkyl, C 2-6 Alkanoyl, C 1-6 Alkoxycarbonyl, C 2-6 Alkanoylamino and C 1-6 The 4- to 6-membered saturated heterocyclic ring may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, and the 4- to 6-membered saturated heterocyclic ring is C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. ), A 4- to 6-membered saturated heterocycle containing one nitrogen atom in addition to the nitrogen atom in the ring (the 4- to 6-membered saturated heterocycle is C 2-6 Alkanoyl and C 1-6 Substituted with one substituent selected from the group consisting of alkoxycarbonyl, the 4- to 6-membered saturated heterocycle is C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. Or 2-oxa-6-azaadamantan-6-yl, 3,4-dihydroquinolin-1 (2H) -yl or 2-oxoquinoxalin-1 (2H) -yl,
R 2 Is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. ), C 4-6 Cycloalkenyl (the C 4-8 Cycloalkenyl may be substituted with one halogen atom. ), Cyclopropylethyl or phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one halogen atom, cyano or difluoromethyl),
R Three Is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy or cyano,
R Four Is a hydrogen atom, a fluorine atom or methyl (the methyl group may be substituted with one methoxy), or a nitrogen-containing fused heterocyclic compound according to (8) or (9) or a pharmaceutically acceptable salt thereof Acceptable salt.
(11) In the formula (I),
R 1 Is the formula NR N3 R N4 And
R N3 Is a hydrogen atom,
R N4 Is the following formula (III):
Figure JPOXMLDOC01-appb-C000025
 (Where
R C4 And R C5 Are both methyl or
Or R C4 And R C5 Together with adjacent carbon atoms, C 4-6 A cycloalkane or a 4-6 membered cyclic ether may be formed,
R C6 Is a halogen atom or hydroxy,
p is 0,
q is an integer of 1 to 3. ),
Or R N3 And R N4 , Together with the adjacent nitrogen atom, may contain one oxygen atom in addition to the nitrogen atom in the ring. The 4- to 6-membered saturated heterocyclic ring (the 4- to 6-membered saturated heterocyclic ring is , Hydroxy, C 1-6 Alkyl, C 2-6 Alkanoylamino and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkoxycarbonylamino, and a C atom between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. Or 2-oxa-6-azaadamantan-6-yl,
R 2 Is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 Cycloalkyl (the C 4-6 Cycloalkyl is a halogen atom and C 1-6 It may be substituted with 1 to 2 groups selected from the group consisting of alkyl, and 4-6 Cycloalkyl is a single bond or C 2 between two different carbon atoms in the ring. 1-6 It may be bridged with alkylene. ), Cyclopropylethyl or difluoromethylphenoxymethyl,
R Three Is methyl, difluoromethyl, methoxy or cyano,
R Four The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (8) to (10), wherein is a hydrogen atom, a fluorine atom or methyl.
(12) In the formula (I),
R 1 Is the formula NR N3 R N4 And
R N3 Is a hydrogen atom,
R N4 Is the following formula (III):
Figure JPOXMLDOC01-appb-C000026
 (Where
R C4 And R C5 Are both methyl or
Or R C4 And R C5 Together with adjacent carbon atoms, C 4-6 May form a cycloalkane,
R C6 Is a halogen atom or hydroxy,
p is 0,
q is an integer of 1 to 3. ),
Or R 1 Is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 2-oxa-6-azaadamantane From -6-yl, 8-azabicyclo [3.2.1] octane-3-ol-8-yl, and 3-methyl-8-azabicyclo [3.2.1] octane-3-ol-8-yl One group chosen,
R 2 N-butyl, C 4-6 Cycloalkyl, cyclopropylethyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, or 4-fluorobicyclo [2.2 .2] oct-1-yl,
R 3 Is methyl, difluoromethyl, methoxy or cyano,
R 4 The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (8) to (11), wherein is a hydrogen atom or a fluorine atom.
(13) A compound selected from the group consisting of the following compounds described in (1) above, or a pharmaceutically acceptable salt thereof.
2-butyl-5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine,
6- (2-Butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) -2-oxa-6-azatricyclo [3.3.1.1] 3,7 ] Deccan,
2-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexan-3-yl] -5-methyl-7- (3-oxa-8-azabicyclo [3.2. 1] octane-8-yl) pyrazolo [1,5-a] pyrimidine,
6- (2-Cyclopentyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) -2-oxa-6-azatricyclo [3.3.1.1] 3,7 ] Deccan,
6- {2-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -5-methylpyrazolo [1,5-a] pyrimidin-7-yl} -2-Oxa-6-azatricyclo [3.3.1.1 3,7 ] Deccan,
7-butyl-2-methyl-4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] [1,3,5] triazine,
6- (7-Butyl-2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl) -2-oxa-6-azatricyclo [3.3.1.1] 3,7 ] Deccan,
6- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3. 1.1 3,7 ] Deccan,
(3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Octane-3-ol,
2-({7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -2-methylpyrazolo [1,5-a] [1,3, 5] triazin-4-yl} amino) -2-methylpropan-1-ol,
6- {7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -2-methylpyrazolo [1,5-a] [1,3,5 ] Triazin-4-yl} -2-oxa-6-azatricyclo [3.3.1.1] 3,7 ] Deccan,
7- (3,3-Difluorobutyl) -4- (3,3-dioxide-3-thia-8-azabicyclo [3.2.1] oct-8-yl) -2-methylpyrazolo [1,5-a ] [1, 3, 5] triazine,
8- {7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -2-methylpyrazolo [1,5-a] [1,3,5 ] Triazin-4-yl} -3-thia-8-azabicyclo [3.2.1] octane-3,3-dione.
(14) A medicament comprising, as an active ingredient, the nitrogen-containing fused heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (13).
(15) A nitrogenous fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (13) as an active ingredient, autistic spectrum disorder, fragile X syndrome, Schizophrenia, bipolar disorder, depression, anxiety disorder, dementia, pain, drug / alcohol dependence, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis, amyotrophic lateral cord A therapeutic or prophylactic agent for sclerosis, stiff-man syndrome, essential tremor, overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease.
　本発明の含窒素縮合複素環化合物はＧＡＢＡＢ受容体の活性調節部位に作用して生理的リガンド（ＧＡＢＡ）による受容体刺激を増強させることが明らかになった。 It has been clarified that the nitrogen-containing fused heterocyclic compound of the present invention acts on the activity-regulating site of GABAB receptor and enhances receptor stimulation by physiological ligand (GABA).
本明細書において用いる用語は、以下の意味である。
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。
「Ｃ1-6アルキル」とは、直鎖状又は分岐鎖状の炭素数１～６個のアルキルを意味し、例えばメチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１－エチルプロピル、ｎ－ヘキシル、イソヘキシル、ネオヘキシル等を挙げることができる。
「Ｃ2-6アルカノイル」とは、直鎖状又は分岐鎖状の炭素数２～６個のアルカノイルを意味し、例えばアセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル等を挙げることができる。
「Ｃ1-6アルコキシ」とは、直鎖状又は分岐鎖状の炭素数１～６個のアルコキシを意味し、例えばメトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ｔｅｒｔ－ペンチルオキシ、１－エチルプロポキシ、ｎ－ヘキシルオキシ等を挙げることができる。
「Ｃ1-6アルコキシカルボニル」とは、前記「Ｃ1-6アルコキシ」とカルボニルが結合した基を意味し、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ペンチルオキシカルボニル等を挙げることができる。
「Ｃ1-6アルコキシカルボニルアミノ」とは、前記「Ｃ1-6アルコキシカルボニル」とアミノが結合した基を意味し、例えば、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、イソプロポキシカルボニルアミノ、ブトキシカルボニルアミノ、イソブトキシカルボニルアミノ、ｔｅｒｔ－ブトキシカルボニルアミノ、ペンチルオキシカルボニルアミノ等を挙げることができる。
「Ｃ1-6アルコキシカルボニルオキシ」とは、前記「Ｃ1-6アルコキシカルボニル」と酸素原子が結合した基を意味し、例えば、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、イソプロポキシカルボニルオキシ、ブトキシカルボニルオキシ、イソブトキシカルボニルオキシ、ｔｅｒｔ－ブトキシカルボニルオキシ、ペンチルオキシカルボニルオキシ等を挙げることができる。
「Ｃ1-6アルキルアミノ」とは、１個あるいは同一又は異なった２個の前記「Ｃ1-6アルキル」とアミノが結合した基を意味し、例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ブチルアミノ、ペンチルアミノ、ヘキシルアミノ、イソプロピルアミノ、イソブチルアミノ、ｔｅｒｔ－ブチルアミノ、イソペンチルアミノ、１－エチルプロピルアミノ、イソヘキシルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ、メチルプロピルアミノ、エチルプロピルアミノ等が挙げられる。１個のＣ1-6アルキルを有する基を「モノＣ1-6アルキルアミノ」、同一又は異なった２個のＣ1-6アルキルを有する基を「ジＣ1-6アルキルアミノ」と記すこともある。
「Ｃ1-6アルキルアミノカルボニル」とは、前記「Ｃ1-6アルキルアミノ」とカルボニル基が結合した基を意味し、例えば、メチルアミノカルボニル、エチルアミノカルボニル、プロピルアミノカルボニル、ブチルアミノカルボニル、ペンチルアミノカルボニル、ヘキシルアミノカルボニル、イソプロピルアミノカルボニル、イソブチルアミノカルボニル、ｔｅｒｔ－ブチルアミノカルボニル、イソペンチルアミノカルボニル、１－エチルプロピルアミノカルボニル、イソヘキシルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル、ジプロピルアミノカルボニル、エチルメチルアミノカルボニル、メチルプロピルアミノカルボニル、エチルプロピルアミノカルボニル等を挙げることができる。１個のＣ1-6アルキルを有する基を「モノＣ1-6アルキルアミノカルボニル」、同一又は異なった２個のＣ1-6アルキルを有する基を「ジＣ1-6アルキルアミノカルボニル」と記すこともある。
「Ｃ1-6アルキルスルホニル」とは、前記「Ｃ1-6アルキル」とスルホニルが結合した基を意味し、例えばメチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、イソブチルスルホニル、ｔｅｒｔ－ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニル等を挙げることができる。
「Ｃ1-6アルキルスルホニルアミノ」とは、前記「Ｃ1-6アルキルスルホニル」とアミノが結合した基を意味し、例えばメチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、ペンチルスルホニルアミノ、ヘキシルスルホニルアミノ等を挙げることができる。
「Ｃ2-6アルカノイルオキシ」とは、前記「Ｃ2-6アルカノイル」と酸素原子が結合した基を意味し、例えばアセトキシ、プロピオニルオキシ、ブチリルオキシ、イソブチリルオキシ、バレリルオキシ、イソバレリルオキシ、ピバロイルオキシ等を挙げることができる。
「Ｃ2-6アルカノイルアミノ」とは、前記「Ｃ1-6アルカノイル」とアミノが結合した基を意味し、例えばアセトアミド、プロピオニルアミド、ブチリルアミド、イソブチリルアミド、バレリルアミド、イソバレリルアミド、ピバロイルアミド等を挙げることができる。
「Ｃ3-6シクロアルキル」とは、炭素数３～６個の環状のアルキルを意味し、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルを挙げることができる。
「Ｃ4-6シクロアルキル」とは、炭素数４～６個の環状のアルキルを意味し、シクロブチル、シクロペンチル、シクロヘキシルを挙げることができる。
「Ｃ5-6シクロアルキル」とは、炭素数５～６個の環状のアルキルを意味し、シクロペンチル、シクロヘキシルを挙げることができる。
本発明においては、Ｃ4-6シクロアルキル又はＣ5-6シクロアルキル環中の異なる２個の炭素原子の間は、Ｃ1-6アルキレンで架橋されてもよく、そのような架橋シクロアルキルの例は、ビシクロ［３．１．０］ヘキサ－３－イル、ビシクロ［３．１．０］ヘキサ－６－イル、及びビシクロ［２．２．２］オクタ－１－イルである。
「Ｃ3-6シクロアルキルカルボニルアミノ」とは、前記「Ｃ3-6シクロアルキル」とカルボニルアミノが結合した基を意味し、シクロプロピルカルボニルアミノ、シクロブチルカルボニルアミノ、シクロペンチルカルボニルアミノ、シクロヘキシルカルボニルアミノを挙げることができる。
「Ｃ3-6シクロアルカン」とは、炭素数３～６個の環状のアルカンを意味し、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサンを挙げることができる。
「Ｃ3-6シクロアルコキシ」とは、前記「Ｃ3-6シクロアルキル」と酸素原子が結合した基を意味し、シクロプロポキシ、シクロブトキシ、シクロペンチルオキシ、シクロヘキシルオキシを挙げることができる。
「Ｃ1-6アルキレン」とは、前記「Ｃ1-6アルキル」から水素原子を１個除した二価基を意味し、メチレン、エチレン、メチルメチレン、トリメチレン、メチルエチレン、テトラメチレン、エチルエチレン、ペンタメチレン等を挙げることができる。
「隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環」とは、アゼチジン、ピロリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、アゼパン、１、４－ジアゼパン等を挙げることができる。
「４～６員の環状エーテル」とは、オキセタン、テトラヒドロフラン、テトラヒドロピランを挙げることができる。
「４～６員の環状アミン」とは、アゼチジン、ピロリジン、ピペリジンを挙げることができる。
「Ｃ4-6シクロアルケニル」とは、炭素数４～６個の環状のアルケニルを意味し、シクロブテニル、シクロペンテニル、シクロヘキセニルを挙げることができる。
「隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１個の酸素原子を含んでもよい４～６員の飽和複素環」とは、アゼチジン、ピロリジン、ピペリジン、ピペラジン、モルホリン等を挙げることができる。
「隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１個の窒素原子を含む４～６員の飽和複素環」とは、ピペラジン等を挙げることができる。
本発明においては、前記の４～７員の飽和複素環、及び４～６員の飽和複素環における異なる２個の炭素原子の間はＣ1-6アルキレンで架橋されてもよく、そのような架橋複素環の例は、８－アザビシクロ［３．２．１］オクタン－８－イル、９－アザビシクロ［３．３．１］ノナン－９－イル、３，８－ジアザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、８－オキサ－３－アザビシクロ［３．２．１］オクタ－３－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、３－チア－８－アザビシクロ［３．２．１］オクタン－８－イル、２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル、２，５－ジアザビシクロ［２．２．２］オクタン－２－イル、２，５－ジアザビシクロ［２．２．１］ヘプタン－２－イル、及び７－アザビシクロ［２．２．１］ヘプタ－７－イルである。
Ｃ1-6アルコキシカルボニルアミノ基、Ｃ1-6アルキルスルホニルアミノ基、Ｃ2-6アルカノイルアミノ基、又はＣ3-6シクロアルキルカルボニルアミノ基は、具体的に明示される場合には置換基を有していてもよいが、確認のために記載すると、そのような場合、当該置換基は、それぞれの基のアルキル部分（例えば、Ｃ1-6アルキルスルホニルアミノ基のアルキル部分）に結合する。
用語「置き換わってもよい」は、特定の化学部分が、別の化学部分に置き換えられ（replace）てもよいことを意味する。例えば、ピペリジニル基の４位の炭素原子がオキセタンに置き換えられると、２－オキサ－７－アザスピロ［３．５］ノナ－７－イルになる。 The terms used in the present specification have the following meanings.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“C 1-6 alkyl” means linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. Tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl and the like.
“C 2-6 alkanoyl” means linear or branched alkanoyl having 2 to 6 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like. .
“C 1-6 alkoxy” means linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy and the like.
“C 1-6 alkoxycarbonyl” means a group in which the above “C 1-6 alkoxy” is bonded to carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl. Tert-butoxycarbonyl, pentyloxycarbonyl and the like.
“C 1-6 alkoxycarbonylamino” means a group in which the above “C 1-6 alkoxycarbonyl” and amino are bonded, and examples thereof include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, Examples include butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino and the like.
“C 1-6 alkoxycarbonyloxy” means a group in which the above “C 1-6 alkoxycarbonyl” is bonded to an oxygen atom. For example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy Butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy and the like.
The “C 1-6 alkylamino” means a group in which one or two identical or different “C 1-6 alkyl” and amino are combined, and examples thereof include methylamino, ethylamino, propylamino, Butylamino, pentylamino, hexylamino, isopropylamino, isobutylamino, tert-butylamino, isopentylamino, 1-ethylpropylamino, isohexylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, methylpropylamino , Ethylpropylamino and the like. Be referred to a group having one C 1-6 alkyl "mono-C 1-6 alkylamino", the same or different two C 1-6 groups having an alkyl and "di-C 1-6 alkylamino" There is also.
“C 1-6 alkylaminocarbonyl” means a group in which the above “C 1-6 alkylamino” is bonded to a carbonyl group, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, Pentylaminocarbonyl, hexylaminocarbonyl, isopropylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, isopentylaminocarbonyl, 1-ethylpropylaminocarbonyl, isohexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl , Ethylmethylaminocarbonyl, methylpropylaminocarbonyl, ethylpropylaminocarbonyl and the like. A group having one C 1-6 alkyl is referred to as “mono C 1-6 alkylaminocarbonyl”, and a group having the same or different two C 1-6 alkyls is referred to as “di-C 1-6 alkylaminocarbonyl”. Sometimes written.
“C 1-6 alkylsulfonyl” means a group in which the above “C 1-6 alkyl” is bonded to sulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert- Examples thereof include butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
“C 1-6 alkylsulfonylamino” means a group in which amino is bonded to the above “C 1-6 alkylsulfonyl”, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonyl Amino, isobutylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino and the like can be mentioned.
“C 2-6 alkanoyloxy” means a group in which the above “C 2-6 alkanoyl” is bonded to an oxygen atom, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, Examples include pivaloyloxy.
“C 2-6 alkanoylamino” means a group in which the above “C 1-6 alkanoyl” is bound to amino, such as acetamido, propionylamido, butyrylamide, isobutyrylamide, valerylamide, isovalerylamide, pivaloylamide. Etc.
“C 3-6 cycloalkyl” means cyclic alkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
“C 4-6 cycloalkyl” means cyclic alkyl having 4 to 6 carbon atoms, and examples thereof include cyclobutyl, cyclopentyl, and cyclohexyl.
“C 5-6 cycloalkyl” means cyclic alkyl having 5 to 6 carbon atoms, and examples thereof include cyclopentyl and cyclohexyl.
In the present invention, two different carbon atoms in a C 4-6 cycloalkyl or C 5-6 cycloalkyl ring may be bridged with C 1-6 alkylene, and Examples are bicyclo [3.1.0] hex-3-yl, bicyclo [3.1.0] hex-6-yl, and bicyclo [2.2.2] oct-1-yl.
“C 3-6 cycloalkylcarbonylamino” means a group in which the above “C 3-6 cycloalkyl” and carbonylamino are bonded together, such as cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino. Can be mentioned.
“C 3-6 cycloalkane” means a cyclic alkane having 3 to 6 carbon atoms, and examples thereof include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
“C 3-6 cycloalkoxy” means a group in which the above “C 3-6 cycloalkyl” is bonded to an oxygen atom, and examples thereof include cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
“C 1-6 alkylene” means a divalent group obtained by removing one hydrogen atom from the “C 1-6 alkyl”, and includes methylene, ethylene, methylmethylene, trimethylene, methylethylene, tetramethylene, ethylethylene. And pentamethylene.
“A 4 to 7-membered saturated heterocyclic ring which may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom together with the adjacent nitrogen atom” means azetidine, pyrrolidine , Piperidine, piperazine, morpholine, thiomorpholine, azepane, 1,4-diazepane and the like.
Examples of the “4- to 6-membered cyclic ether” include oxetane, tetrahydrofuran, and tetrahydropyran.
Examples of the “4- to 6-membered cyclic amine” include azetidine, pyrrolidine, and piperidine.
“C 4-6 cycloalkenyl” means cyclic alkenyl having 4 to 6 carbon atoms, and examples thereof include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
“A 4-6 membered saturated heterocyclic ring which may contain one oxygen atom in addition to the nitrogen atom together with the adjacent nitrogen atom” means azetidine, pyrrolidine, piperidine, piperazine, morpholine Etc.
Examples of the “4- to 6-membered saturated heterocyclic ring containing one nitrogen atom in addition to the nitrogen atom together with the adjacent nitrogen atom” include piperazine and the like.
In the present invention, two different carbon atoms in the 4 to 7 membered saturated heterocyclic ring and the 4 to 6 membered saturated heterocyclic ring may be bridged with C 1-6 alkylene. Examples of bridged heterocycles are 8-azabicyclo [3.2.1] octane-8-yl, 9-azabicyclo [3.3.1] nonane-9-yl, 3,8-diazabicyclo [3.2.1]. ] Octane-8-yl, 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 8-oxa-3-azabicyclo [3.2.1] oct-3-yl, 3-oxa -9-azabicyclo [3.3.1] nonane-9-yl, 3-thia-8-azabicyclo [3.2.1] octane-8-yl, 2-oxa-5-azabicyclo [2.2.1] ] Heptane-5-yl, 2,5-diazabicyclo [2.2.2] octa N-2-yl, 2,5-diazabicyclo [2.2.1] heptan-2-yl, and 7-azabicyclo [2.2.1] hept-7-yl.
A C 1-6 alkoxycarbonylamino group, a C 1-6 alkylsulfonylamino group, a C 2-6 alkanoylamino group, or a C 3-6 cycloalkylcarbonylamino group, when specifically indicated, has a substituent. May be included, but for verification purposes, in such cases, the substituent is attached to the alkyl portion of the respective group (eg, the alkyl portion of a C 1-6 alkylsulfonylamino group).
The term “may be replaced” means that a particular chemical moiety may be replaced with another chemical moiety. For example, when the 4-position carbon atom of a piperidinyl group is replaced with oxetane, 2-oxa-7-azaspiro [3.5] non-7-yl is obtained.
本明細書中における「医薬上許容される塩」とは、硫酸、塩酸、臭化水素酸、リン酸、硝酸等の無機酸との塩、或いは、酢酸、安息香酸、シュウ酸、乳酸、リンゴ酸、酒石酸、フマル酸、マレイン酸、クエン酸、マロン酸、マンデル酸、グルコン酸、ガラクタル酸、グルコヘプトン酸、グリコール酸、グルタミン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、カンファースルホン酸、ナフタレン－２－スルホン酸等の有機酸との塩、リチウムイオン、ナトリウムイオン、カリウムイオン、カルシウムイオン、マグネシウムイオン、亜鉛イオン、アルミニウムイオン等の１種又は複数の金属イオンとの塩、アンモニア、アルギニン、リシン、ピペラジン、コリン、ジエチルアミン、４－フェニルシクロヘキシルアミン、２－アミノエタノール、ベンザチン等のアミンとの塩が含まれる。遊離体から当該塩への変換は従来の方法で行うことができる。 As used herein, “pharmaceutically acceptable salt” refers to a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, or acetic acid, benzoic acid, oxalic acid, lactic acid, apple Acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid A salt with an organic acid such as camphorsulfonic acid, naphthalene-2-sulfonic acid, lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, or one or more metal ions Salt, ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylsilane B hexylamine, 2-aminoethanol, salts with amines such as benzathine. Conversion from the educt to the salt can be performed by conventional methods.
本発明化合物において、好ましい態様を以下にあげる。
一つの好ましい態様は、Ｘが窒素原子である化合物である。
Ｘが窒素原子の場合、
Ｒ1が、式ＮＲN1ＲN2である化合物が好ましく、
ＲN1が、水素原子である化合物が好ましく、
ＲN2が、下記式（ＩＩ）である化合物が好ましい。 Preferred embodiments of the compound of the present invention are listed below.
One preferred embodiment is a compound in which X is a nitrogen atom.
When X is a nitrogen atom,
Compounds in which R 1 is of the formula NR N1 R N2 are preferred
A compound in which R N1 is a hydrogen atom is preferable,
The compound whose RN2 is a following formula (II) is preferable.
Figure JPOXMLDOC01-appb-C000027
 （式中、
ＲC1が、水素原子又はメチルである化合物が好ましく、メチルである化合物がより好ましい。
ＲC2が、メチル又はイソプロピルである化合物が好ましい。
又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成した化合物が好ましく、シクロペンタンを形成した化合物がより好ましい。
ＲC3が、ヒドロキシ、メチルスルホニル、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）である化合物が好ましく、ヒドロキシである化合物がより好ましい。
ｎが、１～３の整数である化合物が好ましく、１～２である化合物がより好ましく、１である化合物がさらに好ましい。）
又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル及びカルボキシからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のヒドロキシで置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－１－イル、及び５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イルからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成した化合物が好ましく、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋したピペリジン（該ピペリジンは、ヒドロキシ、オキソ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のヒドロキシで置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）及び５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イルからなる群より選ばれる１～２個の基で置換されても良い）、３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル、３，３－ジオキシド－３－チア－８－アザビシクロ［３．２．１］オクタ－８－イル、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成した化合物がより好ましく、
Ｙが、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－である化合物が好ましい。
Ｒ2がｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）である化合物が好ましく、ｎ‐ブチル、３，３－ジフルオロブチル、シクロブチル、３，３－ジフルオロシクロブチル、３，３－ジメチルシクロブチル、３－フルオロ－３－メチルシクロブチル、シクロヘキシル、４－フルオロシクロヘキシル、ビシクロ［３．１．０］ヘキサ－３－イル、６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、スピロ［２．３］ヘキサ－５－イル、３，３－ジフルオロビシクロ［３．１．０］ヘキサ－６－イル、４－フルオロビシクロ［２．２．２］オクタ－１－イル、２－（３，３－ジフルオロシクロブチル）エチル、２－（１－フルオロシクロプロピル）エチル、２－［１－（ジフルオロメチル）シクロプロピル］エチルを形成する化合物又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）である化合物がより好ましい。
Ｒ3がメチル、モノフルオロメチル、ジフルオロメチル、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル又はシアノである化合物が好ましい。
　該４～７員の飽和複素環は、好ましくは、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル及びカルボキシからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のヒドロキシで置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、及び５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イルからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。
　Ｘが窒素原子である化合物の他の好ましい例は、式（Ｉ）において、
Ｒ1が、式ＮＲN1ＲN2であり、
ＲN1が、水素原子であり、
ＲN2が、下記式（ＩＩ）であり、
Figure JPOXMLDOC01-appb-C000028
 （式中、
ＲC1が、水素原子又はメチルであり、
ＲC2が、メチル又はイソプロピルであるか、
又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
ＲC3が、ヒドロキシ、メチルスルホニル、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）であり、
ｎが、１～３の整数である。）、
又は、Ｒ1が下記式（ＩＶ）であり、
Figure JPOXMLDOC01-appb-C000029
 （式中、
ＲC７が、水素原子又はヒドロキシであり、
ＲC８が、水素原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、カルバモイル、及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１～３個の基で置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、ピラゾリル（該ピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノであり、
ｒが、２～３の整数である。）、
又は、Ｒ1が下記式（Ｖ）であり、
Figure JPOXMLDOC01-appb-C000030
 （式中、
ＲN３が、Ｃ1-6アルキル（該Ｃ1-6アルキルは、カルバモイル、及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１個の基で置換されてもよい。）、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）である。）、
又は、Ｒ1が３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、３－チア－８－アザビシクロ［３．２．１］オクタン－３，３－ジオン－８－イル、及び２‐オキサ‐６‐アザアダマンタン‐６‐イルから選ばれる１つの基であり、
Ｒ２が、ｎ‐ブチル、Ｃ4-6シクロアルキル、３，３－ジフルオロブチル、（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、４－フルオロビシクロ［２．２．２］オクタ－１－イル、２－（３，３－ジフルオロシクロブチル)エチル、又はシクロブチルメトキシであり、
Ｒ3が、メチル、モノフルオロメチル、ジフルオロメチル、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル又はシアノである、化合物である。
　式（ＩＶ）の基は、より好ましくは、８－アザビシクロ［３．２．１］オクタン－３－オール－８－イル、又は３－メチル－８－アザビシクロ［３．２．１］オクタン－３－オール－８－イルである。
Figure JPOXMLDOC01-appb-C000027
 (Where
A compound in which R C1 is a hydrogen atom or methyl is preferable, and a compound in which methyl is methyl is more preferable.
Compounds in which R C2 is methyl or isopropyl are preferred.
Alternatively, a compound in which R C1 and R C2 together with an adjacent carbon atom form a C 4-6 cycloalkane is preferable, and a compound in which cyclopentane is formed is more preferable.
A compound in which R C3 is hydroxy, methylsulfonyl, or carbamoyl (the carbamoyl may be substituted with one C 1-6 alkyl) is preferable, and a compound in which R C3 is hydroxy is more preferable.
A compound in which n is an integer of 1 to 3 is preferred, a compound of 1 to 2 is more preferred, and a compound of 1 is more preferred. )
Alternatively, R N1 and R N2 together with the adjacent nitrogen atom may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom in the ring. A ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl and 1 to 3 groups selected from the group consisting of carboxy may be substituted.), C 1-6 alkoxy (the C 1-6 alkoxy is 1 selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl) May be substituted with ˜3 groups), C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted with 1 hydroxy), carbamoyl (the carbamoyl is 1 C Optionally substituted with 1-6 alkyl), C 1-6 alkoxycarbonylamino, ureido (which may be substituted with 1 C 1-6 alkyl), pyrazolyl-Y— The pyrazolyl of pyrazolyl-Y— may be substituted with one C 1-6 alkyl.), The formula triazolyl-Y—, cyclopropylcarbonylamino, wherein the cyclopropylcarbonylamino is substituted with one hydroxy ), Oxoimidazolidinyl (which may be substituted with 1 C 1-6 alkyl), 5-oxo-4,5-dihydro-1H-1,2 , 4-triazol-1-yl, and 5-oxo-1H-1,2,4-triazol-4 (5H) -yl may be substituted with one or two groups selected from the group consisting of 2 different pieces in the ring Between the carbon atoms may be crosslinked by C 1-6 alkylene.), Or 2-oxa-6-aza-adamantan-6-yl compound form is preferred, for two carbon atoms of different in the ring A piperidine bridged with C 1-6 alkylene (the piperidine is hydroxy, oxo, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl and C 1-6 alkylaminocarbonyl) 1 to 3 groups selected from the group consisting of C 1-6 alkoxy (wherein the C 1-6 alkoxy is selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl). may be substituted with number of groups.), C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted by one hydroxy. ), Carbamoyl (the carbamoyl may be substituted with 1 C 1-6 alkyl), C 1-6 alkoxycarbonylamino, ureido (the ureido is substituted with 1 C 1-6 alkyl) The pyrazolyl-Y— (wherein the pyrazolyl of the formula pyrazolyl-Y— may be substituted with one C 1-6 alkyl), the formula triazolyl-Y—, cyclopropylcarbonylamino Cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxoimidazolidinyl may be substituted with one C 1-6 alkyl) and 5- And may be substituted with 1 to 2 groups selected from the group consisting of oxo-1H-1,2,4-triazol-4 (5H) -yl), 3-oxa-8-azabicyclo [3.2. 1] Octa More preferred are compounds that form 8-yl, 3,3-dioxide-3-thia-8-azabicyclo [3.2.1] oct-8-yl, or 2-oxa-6-azaadamantan-6-yl. ,
Preferred are compounds wherein Y is a single bond, formula —O—, formula —NH—, formula —SO 2 —, formula —SO 2 NH—, or formula —CONH—.
R 2 is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 cyclo Alkyl (the C 4-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and the C 4-6 cycloalkyl is different two between the carbon atoms may be cross-linked with a single bond or C 1-6 alkylene, or one carbon atom in the ring of the C 3-6 cycloalkane, C 3-6 cycloalkane of And C 3-6 cycloalkylethyl (the C 3-6 cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl). ) Or C 3-6 cycloalkylmethoxy (the C 3-6 cycloalkyl Methoxy is optionally substituted with one C 1-6 alkyl.) And is preferably n-butyl, 3,3-difluorobutyl, cyclobutyl, 3,3-difluorocyclobutyl, 3,3- Dimethylcyclobutyl, 3-fluoro-3-methylcyclobutyl, cyclohexyl, 4-fluorocyclohexyl, bicyclo [3.1.0] hex-3-yl, 6,6-difluorobicyclo [3.1.0] hexa- 3-yl, spiro [2.3] hex-5-yl, 3,3-difluorobicyclo [3.1.0] hex-6-yl, 4-fluorobicyclo [2.2.2] oct-1- Yl, 2- (3,3-difluorocyclobutyl) ethyl, 2- (1-fluorocyclopropyl) ethyl, 2- [1- (difluoromethyl) cyclopropyl] ethyl More preferred is a compound which is a compound or C 3-6 cycloalkylmethoxy (wherein the C 3-6 cycloalkylmethoxy may be substituted with one C 1-6 alkyl).
Compounds in which R 3 is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano are preferred.
The 4- to 7-membered saturated heterocyclic ring is preferably hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl). And 1 to 3 groups selected from the group consisting of carboxy and C 1-6 alkoxy (the C 1-6 alkoxy is selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl) 1 to 3 groups may be substituted), C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted with 1 hydroxy), carbamoyl (the carbamoyl is 1 C 1-6 alkyl may be substituted.), C 1-6 alkoxycarbonylamino, ureido (the ureido may be substituted with one C 1-6 alkyl), wherein pyrazol -Y- (the pyrazolyl of the pyrazolyl-Y- may be substituted with one C 1-6 alkyl), formula triazolyl-Y-, cyclopropylcarbonylamino (the cyclopropylcarbonylamino is 1 May be substituted with 1 hydroxy), oxoimidazolidinyl (which may be substituted with 1 C 1-6 alkyl), and 5-oxo-1H-1, It may be substituted with 1 to 2 groups selected from the group consisting of 2,4-triazol-4 (5H) -yl, and a C 1-6 alkylene group between two different carbon atoms in the ring. It may be cross-linked.
Another preferred example of the compound in which X is a nitrogen atom is
R 1 is of the formula NR N1 R N2
R N1 is a hydrogen atom,
R N2 is the following formula (II):
Figure JPOXMLDOC01-appb-C000028
 (Where
R C1 is a hydrogen atom or methyl;
R C2 is methyl or isopropyl,
Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane,
R C3 is hydroxy, methylsulfonyl, or carbamoyl (which may be substituted with one C 1-6 alkyl);
n is an integer of 1 to 3. ),
Or R 1 is the following formula (IV):
Figure JPOXMLDOC01-appb-C000029
 (Where
R C7 is a hydrogen atom or hydroxy,
R C8 is a hydrogen atom, C 1-6 alkyl (the C 1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxy, carbamoyl, and C 1-6 alkylaminocarbonyl) may be.), carbamoyl (said carbamoyl may be substituted with one C 1-6 alkyl.), pyrazolyl (the pyrazolyl is optionally substituted with one C 1-6 alkyl Or C 1-6 alkoxycarbonylamino;
r is an integer of 2 to 3. ),
Or, R 1 is the following formula (V),
Figure JPOXMLDOC01-appb-C000030
 (Where
R N3 is C 1-6 alkyl (the C 1-6 alkyl may be substituted with one group selected from the group consisting of carbamoyl and C 1-6 alkylaminocarbonyl), or carbamoyl ( The carbamoyl may be substituted with one C 1-6 alkyl). ),
Or R 1 is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 3-thia-8 -One group selected from azabicyclo [3.2.1] octane-3,3-dione-8-yl and 2-oxa-6-azaadamantan-6-yl;
R 2 is n-butyl, C 4-6 cycloalkyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, 4 -Fluorobicyclo [2.2.2] oct-1-yl, 2- (3,3-difluorocyclobutyl) ethyl, or cyclobutylmethoxy;
A compound wherein R 3 is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano.
The group of formula (IV) is more preferably 8-azabicyclo [3.2.1] octane-3-ol-8-yl or 3-methyl-8-azabicyclo [3.2.1] octane-3 -All-8-yl.
別の好ましい態様は、Ｘが式ＣＲ4の化合物である。
Ｘが式ＣＲ4の場合、
Ｒ1が、式ＮＲN3ＲN4である化合物が好ましく、
ＲN3が水素原子である化合物が好ましく、
ＲN4が、下記式（ＩＩＩ）である化合物が好ましい。 Another preferred embodiment is where X is a compound of formula CR 4 .
If X is the formula CR 4 ,
Compounds in which R 1 is of formula NR N3 R N4 are preferred
Compounds in which RN3 is a hydrogen atom are preferred,
The compound whose RN4 is a following formula (III) is preferable.
Figure JPOXMLDOC01-appb-C000031
 （式中、
ＲC4及びＲC5が、共にメチルを示す化合物が好ましい。
又はＲC4及びＲC5が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカン又は４～６員の環状エーテルを形成した化合物が好ましく、Ｃ4-6シクロアルカンがより好ましく、シクロペンタンを形成した化合物がさらに好ましい。
ＲC6が、ハロゲン原子又はヒドロキシである化合物が好ましく、ヒドロキシである化合物がより好ましい。
ｐが、０である化合物が好ましい。
ｑが、１～３の整数である化合物が好ましく、１～２である化合物がより好ましく、１である化合物がさらに好ましい。）
又は、ＲN3及びＲN4が、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１個の酸素原子を含んでもよい４～６員の飽和複素環（該４～６員の飽和複素環は、該４～６員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル、Ｃ2-6アルカノイルアミノ及びＣ1-6アルコキシカルボニルアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成した化合物が好ましく、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋したピペリジン（該ピペリジンは、ヒドロキシ、Ｃ1-6アルキルからなる群より選ばれる１～２個の基で置換されても良い）、３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成した化合物がより好ましい。
Ｒ2が、ｎ‐ブチル（該ｎ‐ブチルは、メチル又はハロゲン原子からなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよい。）、シクロプロピルエチル又はジフロロメチルフェノキシメチルである化合物が好ましく、ｎ‐ブチル（該ｎ‐ブチルは、メチル又はハロゲン原子からなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよい。）又はシクロプロピルエチルである化合物がより好ましく、ｎ‐ブチル、３－メチルブチル、３，３－ジメチルブチル、３，３－ジフルオロブチル、シクロペンタン、シクロヘキサン、４，４－ジフルオロシクロヘキサン、４－フルオロシクロヘキサン、６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、３，３－ジフルオロビシクロ［３．１．０］ヘキサ－６－イル、シクロプロピルエチル又は４－フルオロビシクロ［２．２．２］オクタ－１－イルである化合物がさらに好ましい。
Ｒ3が、ハロゲン原子、メチル（該メチル基は、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、メトキシ、シアノ、エトキシカルボニル、ヒドロキシイソプロピル、ピラゾリル又はメチルオキサジアゾリルである化合物が好ましく、ハロゲン原子、メチル（該メチル基は、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、メトキシ又はシアノである化合物がより好ましく、メチル、ジフロロメチル、メトキシ又はシアノである化合物がさらに好ましい。
Ｒ4が、水素原子、フッ素原子又はメチルである化合物が好ましい。
　Ｘが式ＣＲ4である化合物の他の例は、式（Ｉ）において、
Ｒ1が、式ＮＲN3ＲN4であり、
ＲN3が、水素原子であり、
ＲN4が、下記式（ＩＩＩ）であり、
Figure JPOXMLDOC01-appb-C000031
 (Where
A compound in which R C4 and R C5 both represent methyl is preferred.
Or a compound in which R C4 and R C5 are taken together with an adjacent carbon atom to form a C 4-6 cycloalkane or a 4- to 6-membered cyclic ether, and a C 4-6 cycloalkane is more preferable. More preferred are compounds that form pentane.
A compound in which R C6 is a halogen atom or hydroxy is preferable, and a compound in which R C6 is hydroxy is more preferable.
A compound in which p is 0 is preferable.
A compound in which q is an integer of 1 to 3 is preferred, a compound of 1 to 2 is more preferred, and a compound of 1 is more preferred. )
Alternatively, R N3 and R N4 together with the adjacent nitrogen atom may contain a 4- to 6-membered saturated heterocyclic ring that may contain one oxygen atom in addition to the nitrogen atom (the 4-6 1 to 2 membered saturated heterocycles are selected from the group consisting of hydroxy, C 1-6 alkyl, C 2-6 alkanoylamino and C 1-6 alkoxycarbonylamino. Or may be bridged with C 1-6 alkylene between two different carbon atoms in the ring), or 2-oxa-6-azaadamantan-6-yl The compound formed is preferably a piperidine bridged by C 1-6 alkylene between two different carbon atoms in the ring (the piperidine is selected from the group consisting of hydroxy and C 1-6 alkyl). 3-oxa-8-azabisic, which may be substituted with a group) [3.2.1] oct-8-yl, or a compound to form a 2-oxa-6-aza-adamantan-6-yl is more preferred.
R 2 is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 cycloalkyl (the C 4- The 6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and further the C 4-6 cycloalkyl is two different carbons in the ring. A compound which may be bridged with a single bond or C 1-6 alkylene between atoms), cyclopropylethyl or difluoromethylphenoxymethyl is preferred, and n-butyl (wherein n-butyl is a methyl or halogen atom) Or a C 4-6 cycloalkyl (the C 4-6 cycloalkyl is selected from the group consisting of a halogen atom and C 1-6 alkyl). Optionally substituted with 1 to 2 groups Further, the C 4-6 cycloalkyl may be bridged between two different carbon atoms in the ring by a single bond or C 1-6 alkylene.) Or a compound which is cyclopropylethyl is more preferable, n-butyl, 3-methylbutyl, 3,3-dimethylbutyl, 3,3-difluorobutyl, cyclopentane, cyclohexane, 4,4-difluorocyclohexane, 4-fluorocyclohexane, 6,6-difluorobicyclo [3.1. 0] A compound which is hexa-3-yl, 3,3-difluorobicyclo [3.1.0] hex-6-yl, cyclopropylethyl or 4-fluorobicyclo [2.2.2] oct-1-yl Is more preferable.
R 3 is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy, cyano, ethoxycarbonyl, hydroxyisopropyl, pyrazolyl Or a compound which is methyl oxadiazolyl, preferably a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy or cyano. Certain compounds are more preferred, and compounds that are methyl, difluoromethyl, methoxy or cyano are even more preferred.
A compound in which R 4 is a hydrogen atom, a fluorine atom or methyl is preferable.
Other examples of compounds where X is of formula CR 4 are those in formula (I):
R 1 is of the formula NR N3 R N4 ,
R N3 is a hydrogen atom,
R N4 is the following formula (III):
Figure JPOXMLDOC01-appb-C000032
 （式中、
ＲC4及びＲC5が、共にメチルを示すか、
又はＲC4及びＲC5が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
ＲC6が、ハロゲン原子又はヒドロキシであり、
ｐが、０であり、
ｑが、１～３の整数である。）、
又は、Ｒ1が、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、２‐オキサ‐６‐アザアダマンタン‐６‐イル、８－アザビシクロ［３．２．１］オクタン－3－オール－８－イル、及び３－メチル－８－アザビシクロ［３．２．１］オクタン－3－オール－８－イルから選ばれる１つの基であり、
Ｒ2が、ｎ‐ブチル、Ｃ4-6シクロアルキル、シクロプロピルエチル、３，３－ジフルオロブチル、（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、又は４－フルオロビシクロ［２．２．２］オクタ－１－イルであり、
Ｒ３が、メチル、ジフロロメチル、メトキシ又はシアノであり、
Ｒ４が、水素原子又はフッ素原子である化合物である。
　本発明の化合物において用いられる好ましいピラゾリルは、１Ｈ－ピラゾール－１－イル、１Ｈ－ピラゾール－３－イル、１Ｈ－ピラゾール－４－イル、又は１Ｈ－ピラゾール－５－イルである。
　本発明の化合物において用いられる好ましいメチルピラゾリルは、１Ｈ－１－メチルピラゾール－３－イル、１Ｈ－１－メチルピラゾール－４－イル、又は１Ｈ－１－メチルピラゾール－５－イルである。
　本発明の化合物において用いられる好ましいトリアゾリルは、１Ｈ－１，２，４－トリアゾール－３－イル、１Ｈ－１，２，３－トリアゾール－１－イル、又は２Ｈ－１，２，３－トリアゾール－２－イルである。
　本発明の化合物において用いられる、好ましい置換されていてもよいオキソイミダゾリジニルは、イミダゾリジン－２－オン－１－イル、又は３－メチルイミダゾリジン－２－オン－１－イルである。
　なお、本発明化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。同様に、本発明化合物の水和物又は溶媒和物の医薬上許容される塩も本発明の範囲内に含まれる。
Figure JPOXMLDOC01-appb-C000032
 (Where
R C4 and R C5 both represent methyl,
Or R C4 and R C5 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane,
R C6 is a halogen atom or hydroxy,
p is 0,
q is an integer of 1 to 3. ),
Or R 1 is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 2-oxa- 6-azaadamantan-6-yl, 8-azabicyclo [3.2.1] octane-3-ol-8-yl, and 3-methyl-8-azabicyclo [3.2.1] octane-3-ol- One group selected from 8-yl,
R 2 is n-butyl, C 4-6 cycloalkyl, cyclopropylethyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexa-3 -Yl, or 4-fluorobicyclo [2.2.2] oct-1-yl,
R 3 is methyl, difluoromethyl, methoxy or cyano;
R 4 is a compound that is a hydrogen atom or a fluorine atom.
The preferred pyrazolyl used in the compounds of the present invention is 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 1H-pyrazol-5-yl.
A preferred methylpyrazolyl used in the compounds of the present invention is 1H-1-methylpyrazol-3-yl, 1H-1-methylpyrazol-4-yl, or 1H-1-methylpyrazol-5-yl.
Preferred triazolyls used in the compounds of the present invention are 1H-1,2,4-triazol-3-yl, 1H-1,2,3-triazol-1-yl, or 2H-1,2,3-triazole- 2-yl.
A preferred optionally substituted oxoimidazolidinyl used in the compounds of the present invention is imidazolidin-2-one-1-yl or 3-methylimidazolidin-2-one-1-yl.
In addition, when this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
本発明の化合物は、エナンチオマー、ジアステレオマー、平衡化合物、これらの任意の割合の混合物、ラセミ体等を全て含む。
本発明に係る化合物には、一つ以上の水素原子、炭素原子、窒素原子、酸素原子、ハロゲン原子が放射性同位元素や安定同位元素と置換された化合物も含まれる。これらの標識化合物は、代謝や薬物動態研究、受容体のリガンド等として生物学的分析等に有用である。
本発明に係る化合物は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、皮膚貼付剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術（例えば、第１５改正日本薬局方に規定する方法等）によって製造することができる。これらの投与剤型は、患者の症状、年齢、体重、及び治療の目的に応じて適宜選択することができる。
これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤（例えば、結晶セルロース、デンプン、乳糖、マンニトール）、結合剤（例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン）、滑沢剤（例えば、ステアリン酸マグネシウム、タルク）、崩壊剤（例えば、カルボキシメチルセルロースカルシウム）、その他薬理学的に許容される各種添加剤を配合し、製造することができる。
本発明の化合物は、成人患者に対して１回の投与量として０．００１～５００ｍｇを１日１回又は数回に分けて経口又は非経口で投与することが可能である。なお、この投与量は治療対象となる疾病の種類、患者の年齢、体重、症状等により適宜増減することができる。 The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
The compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and halogen atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
The compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
本発明化合物（Ｉ）及びその医薬上許容される塩は、例えば、以下に示す方法によって合成することができるが、本発明の化合物の製造方法はこれらに限定されるものではない。 The compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be synthesized, for example, by the method shown below, but the production method of the compound of the present invention is not limited thereto.
　「不活性溶媒」とは例えば、ベンゼン、トルエン、キシレン、ピリジン等の芳香族系溶媒；ヘキサン、ペンタン、シクロヘキサン等の炭化水素系溶媒；ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒；テトラヒドロフラン、ジエチルエーテル、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；酢酸エチル、ギ酸エチル等のエステル系溶媒；メタノール、エタノール、イソプロピルアルコール、ｔｅｒｔ－ブチルアルコール、エチレングリコール等のアルコール系溶媒；アセトン、メチルエチルケトン等のケトン系溶媒；Ｎ、Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、Ｎ、Ｎ－ジメチルアセトアミド等のアミド系溶媒；ジメチルスルホキシド等のスルホキシド系溶媒；アセトニトリル、プロピオニトリル等のニトリル系溶媒及び水であり、並びにこれらの均一系及び不均一系混合溶媒等である。これらの不活性溶媒は当業者に公知である種々の反応条件に応じて適宜選択される。 “Inert solvent” means, for example, aromatic solvents such as benzene, toluene, xylene, pyridine; hydrocarbon solvents such as hexane, pentane, cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc. Halogenated hydrocarbon solvents; ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; methanol, ethanol, isopropyl alcohol, tert- Alcohol solvents such as butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfos such as dimethyl sulfoxide Sid solvents; acetonitrile, nitriles and water, such as propionitrile, and also these homogeneous and heterogeneous mixed solvents. These inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.
　「塩基」とは例えば、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム等のアルカリ金属又はアルカリ土類金属の水素化物；リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等のアルカリ金属又はアルカリ土類金属のアミド；ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシド等のアルカリ金属又はアルカリ土類金属の低級アルコキシド；ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウム等のアルキルリチウム；水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウム等のアルカリ金属又はアルカリ土類金属の水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸セシウム等のアルカリ金属又はアルカリ土類金属の炭酸塩；炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属又はアルカリ土類金属の炭酸水素塩；トリエチルアミン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノン－５－エン（ＤＢＮ）、Ｎ，Ｎ－ジメチルアニリン等のアミン；フッ化テトラ-n-ブチルアンモニウム、ベンジルトリメチルアンモニウムヒドロキシド等の４級アンモニウム塩；ピリジン、イミダゾール、２，６－ルチジン等の塩基性複素環化合物等である。これらの塩基は当業者に公知である種々の反応条件に応じて適宜選択される。
　「酸」とは例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の無機酸、10-カンファースルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、ギ酸、酢酸等の有機酸、塩化亜鉛（ＩＩ）、塩化アルミニウム（ＩＩＩ）、塩化チタン（ＩＶ）、三フッ化ホウ素ジエチルエーテル錯体、三臭化ホウ素、トリメチルシリルヨージド、トリフルオロメタンスルホン酸トリメチルシリル等のルイス酸である。これらの酸は当業者に公知である種々の反応条件に応じて適宜選択される。 Examples of the “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or alkaline earth metal carbonate; Sodium hydrogen carbonate, potassium hydrogen carbonate or other alkali metal or alkaline earth Metal bicarbonates: triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3 0.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; quaternary ammonium salts such as tetra-n-butylammonium fluoride and benzyltrimethylammonium hydroxide; pyridine, imidazole, 2,6 -Basic heterocyclic compounds such as lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 10-camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid and the like. Lewis acids such as organic acids, zinc (II) chloride, aluminum (III) chloride, titanium (IV) chloride, boron trifluoride diethyl ether complex, boron tribromide, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate, and the like. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
　本発明化合物（Ｉ）は、例えば下記に示す方法によって製造することができる。
　式（Ｉ-1）で示される本発明化合物は下記スキーム１の方法にて製造することができる。 The compound (I) of the present invention can be produced, for example, by the method shown below.
The compound of the present invention represented by the formula (I-1) can be produced by the method of the following scheme 1.
スキーム１
Figure JPOXMLDOC01-appb-C000033
 　式中Ｒ2、Ｒ3、Ｘ、ＲN1、ＲN2は前記と同義である。L1は塩素原子、臭素原子、ヨウ素原子若しくは有機スルホニルオキシ（メタンスルホニルオキシ、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）等の脱離基又はヒドロキシを示す。
工程１：Ｌ1が脱離基を示す場合、式（Ｉ－１）で示される本発明化合物は不活性溶媒中、塩基の存在下もしくは非存在下、式（１）で表される化合物と式（２）で表される化合物の反応により製造することができる。また必要に応じてパラジウム触媒や銅触媒などの金属触媒および配位子を用いて製造することもできる。Ｌ1が水酸基を示す場合、不活性溶媒中、式（１）で表される化合物および式（２）で表される化合物を種々の縮合剤を用いた反応により製造することができる（Ｊ．　Ｏｒｇ．　Ｃｈｅｍ．　２００７，　７２，　１０１９４－１０２１０）。縮合剤としてはベンゾトリアゾール－１－イルオキシ－トリスジメチルアミノホスホニウム塩（ＢＯＰ）、ヘキサフルオロリン酸（ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウム（ＰｙＢＯＰ）、ブロモトリ（ピロリジノ）ホスホニウム　ヘキサフルオロリン酸塩（ＰｙＢｒＯＰ）などを挙げることができる。ここで、式（１）及び式（２）で表わされる化合物は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここでパラジウム触媒とは、例えば酢酸パラジウム（ＩＩ）、塩化パラジウム（ＩＩ）、ビス（トリフェニルホスフィン）酢酸パラジウム（ＩＩ）、ビス（トリフェニルホスフィン）塩化パラジウム（ＩＩ）、(1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾリデン)(3-クロロピリジル)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）、ビス(ジベンジリデンアセトン)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）、塩化〔１，１’－ビス（ジフェニルホスフィノ）フェロセン〕パラジウム（ＩＩ）、塩化アリルパラジウム（ＩＩ）、ビス（アセトニトリル）塩化パラジウム（ＩＩ）等を挙げることができ、配位子とは例えばトリフェニルホスフィン、２，２－ビス（ジフェニルホスフィノ）－１，１－ビナフチル（ＢＩＮＡＰ）、２－（ジ－ｔｅｒｔ－ブチルホスフィノ）ビフェニル、９，９－ジメチル－４，５－ビス（ジフェニルホスフィノ）キサンテン（Ｘａｎｔｐｈｏｓ）等を挙げることができる。またここで銅触媒とは例えば、銅（０）、ヨウ化銅（Ｉ）、塩化銅（Ｉ）、酸化銅（Ｉ）、臭化銅（Ｉ）トリストリフェニルホスフィン錯体、トリフルオロメタンスルホン酸銅（Ｉ）ベンゼン錯体等が挙げることができ、配位子とは、銅触媒を用いたカップリング反応で当業者に公知な配位子、例えば、Ｎ，Ｎ’－ジメチルエチレンジアミン、１，２－シクロヘキサンジアミン、２－アミノピリジン、１，１０－フェナントロリン、２－ヒドロキシベンズアルデヒドオキシム、エチレングリコール、ピコリン酸等が挙げられる Scheme 1
Figure JPOXMLDOC01-appb-C000033
 In the formula, R 2 , R 3 , X, R N1 and R N2 are as defined above. L 1 represents a leaving group such as chlorine atom, bromine atom, iodine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.) or hydroxy.
Step 1: When L 1 represents a leaving group, the compound of the present invention represented by the formula (I-1) is reacted with the compound represented by the formula (1) in an inert solvent in the presence or absence of a base. It can manufacture by reaction of the compound represented by Formula (2). Moreover, it can also manufacture using metal catalysts, such as a palladium catalyst and a copper catalyst, and a ligand as needed. When L 1 represents a hydroxyl group, the compound represented by the formula (1) and the compound represented by the formula (2) can be produced in an inert solvent by a reaction using various condensing agents (J. Org. Chem. 2007, 72, 10194-10210). As condensing agents, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP), hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP), bromotri (pyrrolidino) phosphonium hexafluorophosphate (PyBrOP). Here, as the compounds represented by formula (1) and formula (2), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis techniques known to those skilled in the art are used. Can do. Examples of the palladium catalyst include palladium (II) acetate, palladium (II) chloride, bis (triphenylphosphine) palladium acetate (II), bis (triphenylphosphine) palladium chloride (II), (1,3-bis (2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine Palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), allyl palladium (II) chloride, bis (acetonitrile) palladium (II) Examples of the child are triphenylphosphine, 2,2-bis (diphenylphosphino) 1,1-binaphthyl (BINAP), 2-(di -tert- butylphosphino) biphenyl, 9,9-dimethyl-4,5-bis (diphenylphosphino) can be exemplified xanthene (Xantphos) or the like. Here, the copper catalyst is, for example, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper bromide (I) tristriphenylphosphine complex, copper trifluoromethanesulfonate. (I) benzene complexes and the like can be mentioned, and the ligand is a ligand known to those skilled in the art in a coupling reaction using a copper catalyst, such as N, N′-dimethylethylenediamine, 1,2- Examples include cyclohexanediamine, 2-aminopyridine, 1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, and picolinic acid.
　式（Ｉ）で示される本発明化合物は下記スキーム２の方法にて製造することができる。 The compound of the present invention represented by the formula (I) can be produced by the method of the following scheme 2.
スキーム２
Figure JPOXMLDOC01-appb-C000034
 　式中Ｒ2、Ｒ3、Ｘは前記と同義である。L2は塩素原子、臭素原子、ヨウ素原子又は有機スルホニルオキシ（メタンスルホニルオキシ、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）等の脱離基を示す。Ｍはカップリング反応で用いられる金属原子又は金属原子団を示し、式（４）で表される化合物の例としてマグネシウム反応剤、亜鉛反応剤、ホウ酸又はホウ酸エステルが結合したホウ素反応剤、スズ反応剤等が挙げられる。
　工程２：式（Ｉ）で示される本発明化合物は不活性溶媒中、塩基存在下又は非存在下、パラジウム触媒や鉄触媒などの遷移金属触媒及び必要に応じて配位子を用いて、式（３）で表される化合物と式（４）で表される化合物のカップリング反応により製造することができる。ここでカップリング反応としては、当業者に公知なカップリング反応の条件が挙げられ、例えば、｛コンプリヘンシブオーガニックトランスフォーメーションズセカンドエディション｛Comprehensive Organic Transformations Second Edition）１９９９年、ジョンウィリーアンドサンズ（John Wiley & Sons, INC.）｝等に記載の方法、それに準じた方法、又はこれらと常法とを組み合わせることにより実施することができる。ここで式（３）及び式（４）で表される化合物は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで鉄触媒としてトリス（２，４－ペンタンジオナト）鉄（ＩＩＩ）などが挙げられる。 Scheme 2
Figure JPOXMLDOC01-appb-C000034
 In the formula, R 2 , R 3 and X are as defined above. L 2 represents a leaving group such as chlorine atom, bromine atom, iodine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.). M represents a metal atom or metal atomic group used in the coupling reaction, and examples of the compound represented by the formula (4) include a magnesium reactant, a zinc reactant, a boron reactant to which boric acid or a borate ester is bonded, Tin reactive agent etc. are mentioned.
Step 2: The compound of the present invention represented by the formula (I) is prepared by using a transition metal catalyst such as a palladium catalyst or an iron catalyst in an inert solvent, in the presence or absence of a base, and optionally using a ligand. It can manufacture by the coupling reaction of the compound represented by (3), and the compound represented by Formula (4). Here, examples of the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, {Comprehensive Organic Transformations Second Edition}, 1999, John Willy and Sons (John Wiley & Sons, INC.)} Or the like, a method based thereon, or a combination of these with conventional methods. The compounds represented by formula (3) and formula (4) are commercially available compounds, known compounds, or compounds synthesized from commercially available compounds or known compounds using various organic synthesis methods known to those skilled in the art. Can do. Examples of the iron catalyst include tris (2,4-pentanedionato) iron (III).
　式（Ｉ）で示される本発明化合物は下記スキーム３の方法にて製造することができる。 The compound of the present invention represented by the formula (I) can be produced by the method of the following scheme 3.
スキーム３
Figure JPOXMLDOC01-appb-C000035
 　式中Ｒ1、Ｒ2、Ｒ3、Ｘ、Ｌ2、Ｍは前記と同義である。
　工程３：式（Ｉ）で示される本発明化合物はスキーム２中の工程２と同様の方法により、式（５）で表わされる化合物と式（６）で表わされる化合物から製造することができる。ここで、式（５）及び式（６）で表わされる化合物は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。 Scheme 3
Figure JPOXMLDOC01-appb-C000035
 In the formula, R 1 , R 2 , R 3 , X, L 2 and M are as defined above.
Step 3: The compound of the present invention represented by the formula (I) can be produced from the compound represented by the formula (5) and the compound represented by the formula (6) by the same method as in the step 2 in Scheme 2. Here, as the compounds represented by the formulas (5) and (6), commercially available compounds, known compounds, or compounds synthesized from known compounds using various organic synthesis methods known to those skilled in the art are used. Can do.
　式（１２）で示される本発明化合物の中間体は下記スキーム４の方法にて製造することができる。 An intermediate of the compound of the present invention represented by the formula (12) can be produced by the method of the following scheme 4.
スキーム４
Figure JPOXMLDOC01-appb-C000036
 　式中Ｒ2、Ｒ3、Ｒ4、Ｌ2は前記と同義である。ＰＧ、ＰＧ1はカルボキシの保護基を示し、例えばメチル基、エチル基、ベンジル基などが挙げられる。
　工程４：式（８）で表される化合物は不活性溶媒中、式（７）に対してアセトニトリルおよび塩基から調整された試薬を反応させることにより製造することができる。ここで塩基として例えばｎ－ブチルリチウム、ｓｅｃ－ブチルリチウムなどの有機リチウム試薬やナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシド等のアルカリ金属又はアルカリ土類金属の低級アルコキシド、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム等のアルカリ金属又はアルカリ土類金属の水素化物等が挙げられる。ここで、式（７）で表される化合物は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて合成した化合物を用いることができる。
　工程５：式（９）で表される化合物は不活性溶媒中、塩基もしくは酸の存在下又は非存在下、式（８）とヒドラジンの反応によって製造することができる。ヒドラジンは水和物や塩酸、酢酸などの塩を形成したものを使用することができる。
　工程６：式（１１）で表される化合物は不活性溶媒中、酸の存在下又は非存在下、式（９）で表される化合物と式（１０）で表される化合物の反応により製造することができる。ここで、式（１０）で表わされる化合物は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。
　工程７：式（１２）で表される化合物は当業者に公知である種々の有機合成手法を用いて式（１１）中の水酸基を脱離基に変換することができる。例えばL2がクロロ原子の場合、不活性溶媒中、塩基の存在下又は非存在下、塩化オキサリルや塩化チオニルなどを用いることで式（１２）で表される化合物の製造が可能である。 Scheme 4
Figure JPOXMLDOC01-appb-C000036
 In the formula, R 2 , R 3 , R 4 and L 2 are as defined above. PG and PG 1 represent a carboxy protecting group, and examples thereof include a methyl group, an ethyl group, and a benzyl group.
Process 4: The compound represented by Formula (8) can be manufactured by making the reagent prepared from acetonitrile and a base react with Formula (7) in an inert solvent. Here, as a base, for example, an organic lithium reagent such as n-butyllithium and sec-butyllithium, an alkali metal or alkaline earth metal lower alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hydride, hydrogen, etc. Examples thereof include alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride. Here, as the compound represented by the formula (7), a commercially available compound, a known compound, or a compound synthesized using various organic synthesis techniques known to those skilled in the art can be used.
Process 5: The compound represented by Formula (9) can be manufactured by reaction of Formula (8) and hydrazine in the presence or absence of a base or an acid in an inert solvent. Hydrazine may be used in the form of a hydrate, hydrochloric acid, acetic acid or the like.
Process 6: The compound represented by Formula (11) is manufactured by reaction of the compound represented by Formula (9) and the compound represented by Formula (10) in the presence or absence of an acid in an inert solvent. can do. Here, as the compound represented by the formula (10), a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis techniques known to those skilled in the art can be used.
Step 7: The compound represented by the formula (12) can convert the hydroxyl group in the formula (11) into a leaving group by using various organic synthesis methods known to those skilled in the art. For example, when L2 is a chloro atom, the compound represented by the formula (12) can be produced by using oxalyl chloride, thionyl chloride or the like in an inert solvent in the presence or absence of a base.
　式（１６）で示される本発明化合物の中間体は下記スキーム５の方法にて製造することができる。 The intermediate of the compound of the present invention represented by the formula (16) can be produced by the method of the following scheme 5.
スキーム５
Figure JPOXMLDOC01-appb-C000037
 　式中Ｒ2、Ｒ3、Ｌ2は前記と同義である。ＰＧ2は保護基を示し、例えばメチル基、エチル基、ベンジル基などが挙げられる。
　工程８：式（１４）で表される化合物は不活性溶媒中、塩基もしくは酸の存在下又は非存在下、式（９）で表される化合物と式（１３）で表される化合物の反応により製造することができる。ここで、式（１３）で表される化合物は、市販化合物、公知化合物或いは当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。
　工程９：式（１５）で表される化合物は不活性溶媒中、塩基の存在下又は非存在下、式（１４）に対して、例えばカルボニルジイミダゾール、トリホスゲン、炭酸ジエチル等の試薬を用いて、環化反応を行うことにより製造することができる。
　工程１０：式（１６）で表される化合物はスキーム４中の工程７と同様の方法により、式（１５）で表わされる化合物から製造することができる。 Scheme 5
Figure JPOXMLDOC01-appb-C000037
 In the formula, R 2 , R 3 and L 2 are as defined above. PG 2 represents a protecting group, and examples thereof include a methyl group, an ethyl group, and a benzyl group.
Process 8: The compound represented by Formula (14) is a reaction of the compound represented by Formula (9) and the compound represented by Formula (13) in the presence or absence of a base or an acid in an inert solvent. Can be manufactured. Here, as the compound represented by the formula (13), a commercially available compound, a known compound or a compound synthesized from a known compound by using various organic synthesis methods known to those skilled in the art can be used.
Step 9: The compound represented by the formula (15) is used in an inert solvent in the presence or absence of a base with respect to the formula (14) using a reagent such as carbonyldiimidazole, triphosgene, diethyl carbonate or the like. It can be produced by carrying out a cyclization reaction.
Step 10: The compound represented by the formula (16) can be produced from the compound represented by the formula (15) by the same method as in the step 7 in the scheme 4.
　式（Ｉ－２）で示される本発明化合物は下記スキーム６の方法にて製造することができる。 The compound of the present invention represented by the formula (I-2) can be produced by the method of the following scheme 6.
スキーム６
Figure JPOXMLDOC01-appb-C000038
 　式中Ｒ1、Ｒ2、Ｌ1は前記と同義である。Ｒ5はＣ3-6アルキル又はＣ3-6シクロアルキルメチル（該Ｃ3-6シクロアルキルメチルは、１個のＣ1-6アルキルで置換されてもよい。）を示す。
　工程１１：式（１９）で表される化合物は式（１７）で表される化合物と式（１８）で表される化合物との反応により製造することができる。式（１８）中のＬ1が塩素原子、臭素原子、ヨウ素原子又は有機スルホニルオキシ（メタンスルホニルオキシ、ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）等の脱離基の場合、不活性溶媒中、塩基の存在下又は非存在下、同業者が一般的に用いるアルキル化反応の条件で反応を行うことができる。式（１８）中のＬ1が水酸基の場合、不活性溶媒中、塩基の存在下又は非存在下、同業者が一般的に用いる光延反応の条件で反応を行うことができる。光延反応の条件として、例えば、トリフェニルホスフィン、トリブチルホスフィン等の有機リン化合物とアゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル、アゾジカルボン酸ジ－ｔｅｒｔ－ブチル等のアゾ化合物を用いる方法、又はシアノメチルトリブチルホスホラン等のリンイリド試薬を用いる方法が挙げられる（Ｃｈｅｍ． Ｒｅｖ． ２００９． １０９，２５５１－２６５１参照）
　工程１２：式（Ｉ－２）で表される化合物は、式（１９）で表される化合物から製造することができる。具体的には、式（１９）で表される化合物を、工程６及び工程７と同様の反応に付した後、得られた生成物を工程１又は２と同様の反応に付せばよい。或いは、式（１９）で表される化合物を、工程８～１０と同様の反応に付した後、得られた生成物を工程１又は２と同様の反応に付せばよい。 Scheme 6
Figure JPOXMLDOC01-appb-C000038
 In the formula, R 1 , R 2 and L 1 are as defined above. R 5 represents C 3-6 alkyl or C 3-6 cycloalkylmethyl (the C 3-6 cycloalkylmethyl may be substituted with one C 1-6 alkyl).
Process 11: The compound represented by Formula (19) can be manufactured by reaction of the compound represented by Formula (17) and the compound represented by Formula (18). When L 1 in formula (18) is a leaving group such as chlorine atom, bromine atom, iodine atom or organic sulfonyloxy (methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.) The reaction can be performed in an inert solvent in the presence or absence of a base under the conditions of an alkylation reaction generally used by those skilled in the art. When L 1 in formula (18) is a hydroxyl group, the reaction can be carried out in an inert solvent in the presence or absence of a base under the conditions of Mitsunobu reaction generally used by those skilled in the art. As conditions for the Mitsunobu reaction, for example, a method using an organic phosphorus compound such as triphenylphosphine and tributylphosphine and an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, or cyanomethyltributyl Examples include a method using a phosphorus ylide reagent such as phosphorane (see Chem. Rev. 2009. 109, 2551-2651).
Step 12: The compound represented by the formula (I-2) can be produced from the compound represented by the formula (19). Specifically, the compound represented by Formula (19) may be subjected to the same reaction as in Step 6 and Step 7, and then the obtained product may be subjected to the same reaction as in Step 1 or 2. Alternatively, after the compound represented by the formula (19) is subjected to the same reaction as in Steps 8 to 10, the obtained product may be subjected to the same reaction as in Step 1 or 2.
以下の製造例及び実施例においてカラムクロマトグラフィーを使用して精製した際にはＢｉｏｔａｇｅ社ＳＮＡＰＣａｒｔｒｉｄｇｅ（登録商標）　Ｕｌｔｒａ、ＫＰ－Ｓｉｌ、Ｉｓｏｌｕｔｅ　ＮＨ２、ＧＲＡＣＥ社Ｒｅｖｅｒｅｌｉｓ　Ｆｌａｓｈ　Ｃａｒｔｒｉｄｇｅｓ（登録商標）　ｓｉｌｉｃａおよびａｍｉｎｏを用いた。
以下の製造例及び実施例の後処理操作の際の「ＩＳＯＬＵＴＥ　Ｐｈａｓｅ　Ｓｅｐａｒａｔｏｒ」にはＢｉｏｔａｇｅ社ＩＳＯＬＵＴＥ　Ｐｈａｓｅ　Ｓｅｐａｒａｔｏｒ（登録商標）を使用した。
以下の製造例および実施例において、薄層クロマトグラフィー（ＰＴＬＣ）による精製はＳｉｌｉｃａ　ｇｅｌ　６０Ｆ２５４（メルク社製）を使用した。
以下の製造例および実施例において、分取高速液体クロマトグラフィー（ＨＰＬＣ）による精製は以下の条件により行った。ただし、塩基性官能基を有する化合物の場合、本操作でトリフルオロ酢酸を用いたときには、フリー体を得るための中和操作等を行う場合がある。
機械：Ｇｉｌｓｏｎ社　ＴｒｉｌｕｔｉｏｎＬＣ
カラム：Ｗａｔｅｒｓ社　ＳｕｎＦｉｒｅ　ｐｒｅｐ　Ｃ１８　ＯＢＤ　５．０μｍ　３０ｘ５０ｍｍ　又はＹＭＣ社　ＹＭＣ－Ａｃｔｕｓ　Ｔｒｉａｎｔ　５．０μｍ　５０ｘ３０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル、もしくはＡ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝９０／１０）、１１分（Ａ液／Ｂ液＝２０／８０）、１２～１３．５分（Ａ液／Ｂ液＝５／９５）
流速：４０ｍＬ／ｍｉｎ
検出法：ＵＶ　２５４ｎｍ
以下の製造例および実施例において、高速液体クロマトグラフィーマススペクトル（ＬＣＭＳ）は以下の条件により測定した。
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ２９００及びＡｇｉｌｅｎｔ６１５０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８　１．７μｍ　２．１ｘ５０ｍｍ　
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝８０／２０）、１．２～１．４分（Ａ液／Ｂ液＝１／９９）
流速：０．８ｍＬ／ｍｉｎ、検出法：ＵＶ　２５４ｎｍ
イオン化法：電子衝撃イオン化法（ＥＳＩ：Ｅｌｅｃｔｒｏｎ　Ｓｐｒａｙ　Ｉｏｎｉｚａｔｉｏｎ）
以下の製造例および実施例において、マススペクトル（ＭＳ）および核磁気共鳴スペクトル（ＮＭＲ）は以下の条件により測定した。
ＭＳスペクトル：ＬＣＭＳ－２０１０ＥＶ（島津製作所）、ＬＣＭＳ－ＩＴ－ＴＯＦ（島津製作所）、ｍｉｃｒｏｍａｓｓ　Ｐｌａｔｆｏｒｍ　ＬＣ又はｍｉｃｒｏｍａｓｓ　ＧＣＴ、Ａｇｉｌｅｎｔ　２９００及びＡｇｉｌｅｎｔ　６１５０
ＮＭＲスペクトル：日本電子社ＪＮＭ－ＥＣＡ６００（６００ＭＨｚ）、日本電子社ＪＮＭ－ＥＣＡ５００（５００ＭＨｚ）、Ｂｒｕｋｅｒ社ＡＶＡＮＣＥＩＩＩ ＨＤ ４００（４００ＭＨｚ）、Ｖａｒｉａｎ社ＧＥＭＩＮＩ２０００／２００（２００ＭＨｚ）
以下の製造例および実施例において、マイクロウェーブ反応装置はＩｎｉｔｉａｔｏｒ（Ｂｉｏｔａｇｅ　ＡＢ）を用いて実施した。
以下の製造例および実施例において、化合物名はＡＣＤ／Ｎａｍｅ　（ＡＣＤ／Ｌａｂｓ　２０１５，　Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．）により命名した。
以下の製造例および実施例中において使用した略語を以下に示す。
MS（質量分析）、ESI（エレクトロスプレーイオン化）、APCI（大気圧化学イオン化）、ＲＴ（保持時間）、NMR（核磁気共鳴分光法）、H（プロトン）、J（カップリング定数）、DMSO-d6（重水素化ジメチルスルホキシド）、br. s（ブロードシングレット）、s（シングレット）、d（ダブレット）、t（トリプレット）、q（カルテット）、dd（ダブルダブレット）、ddd（ダブルダブルダブレット）、dt（ダブルトリプレット）、td（トリプルダブレット）、m（マルチプレット）、v/v（容量／容量）、 v/v/v（容量／容量／容量）。
以下の製造例及び実施例において塩基性官能基を有する化合物の場合、当業者に公知である種々の反応条件により各種酸を用いて塩とする場合がある。 When purifying using column chromatography in the following preparation examples and examples, use Biotage SNAPartridge (registered trademark) Ultra, KP-Sil, Isolute NH2, GRACE Reverelis Flash Cartridges (registered trademark) silica and amino. It was.
Biotage's ISOLUTE Phase Separator (registered trademark) was used for “ISOLUTE Phase Separator” in the post-processing operations of the following production examples and examples.
In the following production examples and examples, Silica gel 60F254 (manufactured by Merck) was used for purification by thin layer chromatography (PTLC).
In the following production examples and examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson TritionLC
Column: Waters SunFire prep C18 OBD 5.0 μm 30 × 50 mm or YMC YMC-Actus Trian 5.0 μm 50 × 30 mm
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile, or A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile Gradient: 0 minutes (A liquid / B liquid = 90/10), 11 minutes (A liquid / B liquid = 20/80), 12 to 13.5 minutes (A liquid / B liquid = 5/95)
Flow rate: 40 mL / min
Detection method: UV 254 nm
In the following production examples and examples, high performance liquid chromatography mass spectrum (LCMS) was measured under the following conditions.
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 80/20), 1.2 to 1.4 minutes (A solution / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Impact Ionization (ESI: Electron Spray Ionization)
In the following production examples and examples, mass spectra (MS) and nuclear magnetic resonance spectra (NMR) were measured under the following conditions.
MS spectrum: LCMS-2010EV (Shimadzu Corporation), LCMS-IT-TOF (Shimadzu Corporation), micromass Platform LC or micromass GCT, Agilent 2900 and Agilent 6150
NMR spectrum: JEOL JNM-ECA600 (600 MHz), JEOL JNM-ECA500 (500 MHz), Bruker AVANCE III HD 400 (400 MHz), Varian GEMINI 2000/200 (200 MHz)
In the following production examples and examples, the microwave reaction apparatus was implemented using an initiator (Biotage AB).
In the following production examples and examples, the compound names were named by ACD / Name (ACD / Labs 2015, Advanced Chemistry Development Inc.).
Abbreviations used in the following production examples and examples are shown below.
MS (mass spectrometry), ESI (electrospray ionization), APCI (atmospheric pressure chemical ionization), RT (retention time), NMR (nuclear magnetic resonance spectroscopy), H (proton), J (coupling constant), DMSO- d6 (deuterated dimethyl sulfoxide), br. s (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), ddd (double double doublet), dt (double triplet), td (triple doublet), m (multiplet), v / v (capacity / capacity), v / v / v (capacity / capacity / capacity).
In the following production examples and examples, in the case of a compound having a basic functional group, a salt may be formed using various acids under various reaction conditions known to those skilled in the art.
製造例１　３－ブチル－１Ｈ－ピラゾール－５－アミンの合成 Production Example 1 Synthesis of 3-butyl-1H-pyrazol-5-amine
Figure JPOXMLDOC01-appb-C000039
 　窒素雰囲気下、アセトニトリル（２１．５ｍL）のテトラヒドロフラン（３００ｍＬ）溶液を－７８℃に冷却し、ｎ－ブチルリチウム（２．６５Ｍ／ｎ－ヘキサン溶液，１６０ｍＬ）を滴下した。３０分間撹拌した後、吉草酸メチル（２５．０ｇ）のテトラヒドロフラン（５０ｍＬ）溶液を滴下し、－４０℃で２時間撹拌した。反応液を－７８℃に冷却した後、１０％塩酸を滴下し室温に戻した。液性を酸性にした後、酢酸エチルで抽出し、有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮した。残渣をエタノール（５００ｍＬ）に溶かし、ヒドラジン１水和物（１６．１５ｇ）を加え、８０℃で７時間撹拌した。反応液に水を加えた後、エタノールを減圧下留去した。得られた水層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、フェーズセパレーターで有機層を分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ，クロロホルム：メタノール＝９９：１～９０：１０）にて精製し、表題化合物（２２．０７ｇ）を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000039
 Under a nitrogen atmosphere, a solution of acetonitrile (21.5 mL) in tetrahydrofuran (300 mL) was cooled to −78 ° C., and n-butyllithium (2.65 M / n-hexane solution, 160 mL) was added dropwise. After stirring for 30 minutes, a solution of methyl valerate (25.0 g) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was stirred at −40 ° C. for 2 hours. The reaction mixture was cooled to −78 ° C., and 10% hydrochloric acid was added dropwise to return to room temperature. The solution was acidified and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (500 mL), hydrazine monohydrate (16.15 g) was added, and the mixture was stirred at 80 ° C. for 7 hr. After adding water to the reaction solution, ethanol was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting aqueous layer, extracted with chloroform, and the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 90:10) to obtain the title compound (22.07 g) as a yellow oil.
製造例２　２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－オールの合成 Production Example 2 Synthesis of 2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-ol
Figure JPOXMLDOC01-appb-C000040
 　製造例１で得た３－ブチル－１Ｈ－ピラゾール－５－アミン（１９．０ｇ）およびエチルアセトアセテート（１９．５ｇ）の酢酸（１４０ｍＬ）溶液を１１０℃で１時間撹拌した。反応液を室温に戻し、飽和炭酸水素ナトリウム水溶液を少しずつ加えて中性にした後、クロロホルムで抽出した。有機層をフェーズセパレーターで分離し、溶媒を減圧下留去した。残渣をイソプロピルエーテルで洗浄し、表題化合物（２１．８ｇ）を淡黄色固体として得た。
Figure JPOXMLDOC01-appb-C000040
 A solution of 3-butyl-1H-pyrazol-5-amine (19.0 g) and ethyl acetoacetate (19.5 g) obtained in Production Example 1 in acetic acid (140 mL) was stirred at 110 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The residue was washed with isopropyl ether to give the title compound (21.8 g) as a pale yellow solid.
製造例３　７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オールの合成 Production Example 3 Synthesis of 7-butyl-2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-ol
Figure JPOXMLDOC01-appb-C000041
 　製造例１で得た３－ブチル－１Ｈ－ピラゾール－５－アミン（５．００ｇ）およびエチルアセトイミデート塩酸塩（４．８８ｇ）のアセトニトリル（５０ｍＬ）懸濁液に酢酸（２．１ｍＬ）を加え、室温で１６時間撹拌した。析出物をろ取、アセトニトリル洗浄し、無色固体（５．３７ｇ）を得た。この無色固体および炭酸ジエチル（１８ｍＬ）に２０％ナトリウムエトキシド／エタノール溶液（７５ｍＬ）を加え、加熱還流下２時間撹拌した。反応液に２０％硫酸水素カリウム水溶液を加え、酸性にした後、クロロホルムで抽出した。フェーズセパレーターで有機層を分離した後、溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝９９：１～９０：１０）にて精製し、表題化合物（３．２４ｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000041
 Acetic acid (2.1 mL) was added to a suspension of 3-butyl-1H-pyrazol-5-amine (5.00 g) and ethylacetimidate hydrochloride (4.88 g) obtained in Preparation Example 1 in acetonitrile (50 mL). The mixture was further stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with acetonitrile to obtain a colorless solid (5.37 g). A 20% sodium ethoxide / ethanol solution (75 mL) was added to the colorless solid and diethyl carbonate (18 mL), and the mixture was stirred for 2 hours under heating to reflux. A 20% aqueous potassium hydrogen sulfate solution was added to the reaction solution to make it acidic, followed by extraction with chloroform. After separating the organic layer with a phase separator, the solvent was distilled off, and the residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 90:10) to give the title compound (3.24 g). Obtained as a colorless solid.
製造例３（別法）　７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オールの合成 Production Example 3 (Alternative Method) Synthesis of 7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-ol
Figure JPOXMLDOC01-appb-C000042
  
製造例１に準じた方法で得た３－（３，３－ジフルオロブチル）－１Ｈ－ピラゾール－５－アミン（３．００ｇ）、エチルアセトイミデート塩酸塩（３．１７ｇ）および酢酸ナトリウム（２．１１ｇ）のアセトニトリル（３０ｍＬ）懸濁液を室温で１時間撹拌した。反応液を減圧下濃縮し、残渣をエタノール（３０ｍＬ）に溶解した後、炭酸ジエチル（１０ｍＬ）および２０％ナトリウムエトキシド／エタノール溶液（２９ｇ）を加え、８０℃で２時間撹拌した。反応液をクロロホルムで希釈し、水で洗浄した。水層に４Ｍ塩酸を加えｐＨを４程度にし、クロロホルムで抽出した。有機層をフェーズセパレーターで分離し、減圧下濃縮した。残渣をジイソプロピルエーテルで洗浄し、固体をろ取した。表題化合物（２．０８ｇ）を淡褐色固体として得た。
Figure JPOXMLDOC01-appb-C000042
3- (3,3-Difluorobutyl) -1H-pyrazol-5-amine (3.00 g), ethylacetimidate hydrochloride (3.17 g) and sodium acetate (2) obtained by the method according to Production Example 1 .11 g) in acetonitrile (30 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol (30 mL), diethyl carbonate (10 mL) and 20% sodium ethoxide / ethanol solution (29 g) were added, and the mixture was stirred at 80 ° C. for 2 hr. The reaction solution was diluted with chloroform and washed with water. 4M hydrochloric acid was added to the aqueous layer to adjust the pH to about 4, and the mixture was extracted with chloroform. The organic layer was separated with a phase separator and concentrated under reduced pressure. The residue was washed with diisopropyl ether, and the solid was collected by filtration. The title compound (2.08 g) was obtained as a light brown solid.
製造例４　５－メチル－２－プロポキシピラゾロ［１，５－ａ］ピリミジン－７－オールの合成 Production Example 4 Synthesis of 5-methyl-2-propoxypyrazolo [1,5-a] pyrimidin-7-ol
Figure JPOXMLDOC01-appb-C000043
 （１）５－アミノ－１，２－ジヒドロ－３Ｈ－ピラゾール－３－オン（３００ｍｇ）のｎ－プロパノール（９１１ｍｇ）懸濁液に硫酸（６５３ｍｇ）を加え、１００℃で３時間撹拌した。反応液に２Ｍ水酸化ナトリウム水溶液を加えて中和した後、飽和炭酸水素ナトリウム水溶液を加えて塩基性にした後、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、溶媒を減圧下留去し、３－プロポキシ－１Ｈ－ピラゾール－５－アミンを含む褐色油状物（８５ｍｇ）を得た。
MS (ESI) m/z 142 [M+H]+
（２）３－プロポキシ－１Ｈ－ピラゾール－５－アミンの粗精製物（８５ｍｇ）を酢酸（３ｍＬ）に溶解し、エチルアセトアセテート（７８ｍｇ）を加え、９０℃で３時間撹拌した。反応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、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し残渣を分取ＨＰＬＣにて精製し、表題化合物（８ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000043
 (1) To a suspension of 5-amino-1,2-dihydro-3H-pyrazol-3-one (300 mg) in n-propanol (911 mg) was added sulfuric acid (653 mg), and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was neutralized with 2M aqueous sodium hydroxide solution, basified with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to give a brown oil (85 mg) containing 3-propoxy-1H-pyrazol-5-amine.
MS (ESI) m / z 142 [M + H] +
(2) A crude product of 3-propoxy-1H-pyrazol-5-amine (85 mg) was dissolved in acetic acid (3 mL), ethyl acetoacetate (78 mg) was added, and the mixture was stirred at 90 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (8 mg) as a colorless solid.
製造例５　２－メチル－７－［（１－メチルシクロプロピル）メトキシ］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オールの合成 Production Example 5 Synthesis of 2-methyl-7-[(1-methylcyclopropyl) methoxy] pyrazolo [1,5-a] [1,3,5] triazin-4-ol
Figure JPOXMLDOC01-appb-C000044
 （１）５－アミノ－１，２－ジヒドロ－３Ｈ－ピラゾール－３－オン（３００ｍｇ）のクロロホルム（６ｍＬ）懸濁液を－２０℃に冷却し、トリフェニルホスフィン（９５４ｍｇ）およびアゾジカルボン酸ジイソプロピル（７３５ｍｇ）を加え、０℃にて１時間撹拌した。１－メチルシクロプロパンメタノール（３１３ｍｇ）を加え、室温にて６０時間撹拌した。反応液に１Ｍ塩酸を加えて酸性にし、クロロホルムで水層を２回洗浄した。水層に２Ｍ水酸化ナトリウム水溶液を加えて塩基性にした後、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、減圧下溶媒を留去し、３－［（１－メチルシクロプロピル）メトキシ］－１Ｈ－ピラゾール－５－アミン（８６ｍｇ）を無色油状物として得た。
MS (ESI) m/z 168 [M+H]+
（２）製造例３と同様の方法により、３－［（１－メチルシクロプロピル）メトキシ］－１Ｈ－ピラゾール－５－アミン（８６ｍｇ）から表題化合物（６ｍｇ）を得た。
Figure JPOXMLDOC01-appb-C000044
 (1) A suspension of 5-amino-1,2-dihydro-3H-pyrazol-3-one (300 mg) in chloroform (6 mL) was cooled to −20 ° C., triphenylphosphine (954 mg) and diisopropyl azodicarboxylate (735 mg) was added, and the mixture was stirred at 0 ° C. for 1 hr. 1-Methylcyclopropanemethanol (313 mg) was added, and the mixture was stirred at room temperature for 60 hours. The reaction solution was acidified with 1M hydrochloric acid, and the aqueous layer was washed twice with chloroform. The aqueous layer was basified with 2M aqueous sodium hydroxide solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 3-[(1-methylcyclopropyl) methoxy] -1H-pyrazol-5-amine (86 mg) as a colorless oil.
MS (ESI) m / z 168 [M + H] +
(2) By the same method as in Production Example 3, the title compound (6 mg) was obtained from 3-[(1-methylcyclopropyl) methoxy] -1H-pyrazol-5-amine (86 mg).
製造例６　エチル　３－（３，３－ジフルオロシクロブチル）プロパノアートの合成 Production Example 6 Synthesis of ethyl 3- (3,3-difluorocyclobutyl) propanoate
Figure JPOXMLDOC01-appb-C000045
 エチル　３－（３－オキソシクロブチル）プロパノアート（２．２８ｇ）のクロロホルム（１３ｍＬ）溶液を０℃に冷却し、三フッ化ジエチルアミノ硫黄（４．３９ｍＬ）を加え、室温にて８．５時間撹拌した。０℃に冷却した後、飽和炭酸水素ナトリウム水溶液を加えて反応を停止した。クロロホルムで抽出し、飽和食塩水で洗浄した。フェーズセパレーターで有機層を分離した後、溶媒を減圧下留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９８：２～８０：２０）にて精製を行い、表題化合物（１．６５ｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000045
 A solution of ethyl 3- (3-oxocyclobutyl) propanoate (2.28 g) in chloroform (13 mL) is cooled to 0 ° C., diethylaminosulfur trifluoride (4.39 mL) is added, and the mixture is stirred at room temperature for 8.5 hours. did. After cooling to 0 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The mixture was extracted with chloroform and washed with saturated brine. After separating the organic layer with a phase separator, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 98: 2 to 80:20) to give the title compound (1.65 g) as a colorless oil.
製造例７　ベンジル　３－（１－フルオロシクロプロピル）プロパノアートの合成 Production Example 7 Synthesis of benzyl 3- (1-fluorocyclopropyl) propanoate
Figure JPOXMLDOC01-appb-C000046
 （１）ジイソプロピルアミン（４．２７ｇ）のテトラヒドロフラン（１７６ｍＬ）溶液にｎ－ブチルリチウム（２．６５Ｍ／ｎ－ヘキサン溶液，１５．９ｍＬ）を加え、１５分かけて０℃に昇温した。－７８℃にてｔｅｒｔ‐ブチルシクロプロパンカルボキシラート（５．００ｇ）を加え、同温にて３０分間撹拌した。アクリル酸エチル（４．２２ｇ）を加え、同温にて１時間攪拌した。反応液に１Ｍ塩酸を加え反応を停止した後、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝２０：１～１０：１）にて精製し、ｔｅｒｔ‐ブチル１－(３－エトキシ－３－オキソプロピル)シクロプロパンカルボキシラート（２．６４ｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.62 - 0.71 (m, 2 H), 1.09 - 1.19 (m, 2 H), 1.26 (t, J=7.0 Hz, 3 H), 1.44 (s, 9 H), 1.78 - 1.84 (m, 2 H), 2.47 - 2.57 (m, 2 H), 4.13 (q, J=7.0 Hz, 2 H)
（２）ｔｅｒｔ－ブチル １－(３－エトキシ－３－オキソプロピル)シクロプロパンカルボキシラート（２．６４ｇ）のメタノール（１０．９ｍＬ）溶液に水酸化カリウム（６１１ｍｇ）を加え、室温で１５時間撹拌した。反応液に水を加え、ジエチルエーテルで水層を洗浄した。水層に１Ｍ塩酸を加えて中性にした後、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した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。得られた黄色油状物（１．７２ｇ）をＤＭＦ（１６．１ｍＬ）に溶解した後、０℃に冷却し、炭酸カリウム（１．３３ｇ）およびベンジルブロミド（１．６５ｇ）を順次加えた。室温にて１５時間撹拌した後、反応液に水を加え、ヘキサン-酢酸エチル（１：２）にて抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９０：１０～８０：２０）にて精製し、ｔｅｒｔ－ブチル１－［３－(ベンジルオキシ)－３－オキソプロピル］シクロプロパンカルボキシラート（２．２４ｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.64 - 0.66 (m, 2 H), 1.12 - 1.14 (m, 2 H), 1.42 (s, 9 H), 1.82 - 1.86 (m, 2 H), 2.57 - 2.60 (m, 2 H), 5.12 (s, 2 H), 7.31 - 7.39 (m, 5 H)
（３）ｔｅｒｔ－ブチル １－［３－(ベンジルオキシ)－３－オキソプロピル］シクロプロパンカルボキシラート（２．２４ｇ）にクロロホルム（７．３６ｍＬ）、トリフルオロ酢酸（１４．７ｍＬ)を加え、室温にて３時間撹拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝２：１～２：３）にて精製し、１－［３－(ベンジルオキシ)－３－オキソプロピル］シクロプロパンカルボン酸（１．８３ｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.79 - 0.85 (m, 2 H), 1.28 - 1.33 (m, 2 H), 1.85 - 1.91 (m, 2 H), 2.58 - 2.66 (m, 2 H), 5.12 (s, 2 H), 6.03 (br s, 1 H), 7.31 - 7.41 (m, 5 H)
（４）１－［３－(ベンジルオキシ)－３－オキソプロピル］シクロプロパンカルボン酸（１．００ｇ）のアセトン（２０．１ｍＬ）溶液に硝酸銀（６８４ｍｇ）、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）（１．４３ｇ）を加え、５５℃で２時間撹拌した。反応液に水を加え、クロロホルムで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮した。残渣をクロロホルムで希釈し、飽和炭酸水素ナトリウム水溶液で２回洗浄し、有機層を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１０：１～３：１）にて精製し、表題化合物（１６０ｍｇ）を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000046
 (1) To a solution of diisopropylamine (4.27 g) in tetrahydrofuran (176 mL) was added n-butyllithium (2.65 M / n-hexane solution, 15.9 mL), and the temperature was raised to 0 ° C. over 15 minutes. Tert-butylcyclopropanecarboxylate (5.00 g) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Ethyl acrylate (4.22 g) was added and stirred at the same temperature for 1 hour. 1M hydrochloric acid was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 20: 1-10: 1), and tert-butyl 1- (3-ethoxy-3-oxopropyl) cyclopropanecarboxylate (2.64 g). ) Was obtained as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.62-0.71 (m, 2 H), 1.09-1.19 (m, 2 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.44 (s, 9 H ), 1.78-1.84 (m, 2 H), 2.47-2.57 (m, 2 H), 4.13 (q, J = 7.0 Hz, 2 H)
(2) Potassium hydroxide (611 mg) was added to a solution of tert-butyl 1- (3-ethoxy-3-oxopropyl) cyclopropanecarboxylate (2.64 g) in methanol (10.9 mL) and stirred at room temperature for 15 hours. did. Water was added to the reaction solution, and the aqueous layer was washed with diethyl ether. The aqueous layer was neutralized with 1M hydrochloric acid, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained yellow oil (1.72 g) was dissolved in DMF (16.1 mL), cooled to 0 ° C., and potassium carbonate (1.33 g) and benzyl bromide (1.65 g) were sequentially added. After stirring at room temperature for 15 hours, water was added to the reaction mixture, and the mixture was extracted with hexane-ethyl acetate (1: 2). The organic layer was washed with water and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10 to 80:20), and tert-butyl 1- [3- (benzyloxy) -3-oxopropyl] cyclopropanecarboxylate ( 2.24 g) was obtained as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.64-0.66 (m, 2 H), 1.12-1.14 (m, 2 H), 1.42 (s, 9 H), 1.82-1.86 (m, 2 H), 2.57 -2.60 (m, 2 H), 5.12 (s, 2 H), 7.31-7.39 (m, 5 H)
(3) tert-Butyl 1- [3- (benzyloxy) -3-oxopropyl] cyclopropanecarboxylate (2.24 g) was added chloroform (7.36 mL) and trifluoroacetic acid (14.7 mL), and For 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 2: 1 to 2: 3), and 1- [3- (benzyloxy) -3-oxopropyl] Cyclopropanecarboxylic acid (1.83 g) was obtained as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.79-0.85 (m, 2 H), 1.28-1.33 (m, 2 H), 1.85-1.91 (m, 2 H), 2.58-2.66 (m, 2 H) , 5.12 (s, 2 H), 6.03 (br s, 1 H), 7.31-7.41 (m, 5 H)
(4) To a solution of 1- [3- (benzyloxy) -3-oxopropyl] cyclopropanecarboxylic acid (1.00 g) in acetone (20.1 mL), silver nitrate (684 mg), 1-chloromethyl-4-fluoro- 1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) (1.43 g) was added, and the mixture was stirred at 55 ° C. for 2 hours. Water was added to the reaction solution and extracted with chloroform, and then the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was diluted with chloroform, washed twice with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 10: 1-3: 1) to give the title compound (160 mg) as a yellow oil.
製造例８　ベンジル　３－［１－（ジフルオロメチル）シクロプロピル］プロパノアートの合成 Production Example 8 Synthesis of benzyl 3- [1- (difluoromethyl) cyclopropyl] propanoate
Figure JPOXMLDOC01-appb-C000047
 （１）［１－（ジフルオロメチル）シクロプロピル］メタノールのクロロホルム（４０ｍＬ）溶液を０℃に冷却し、１，１，１－トリアセトキシ－１，１－ジヒドロ－１，２－ベンゾヨードキソール－３－（１Ｈ）－オン（２．０９ｇ）を加え、０℃にて３０分撹拌、室温にて１時間撹拌した。ベンジル(トリフェニルホスホラニリデン)酢酸（２．５２ｇ）を加え、室温にて１５時間撹拌した。反応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、有機層を飽和食塩水で洗浄した。フェーズセパレーターで有機層を分離した後、溶媒を減圧下留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９８：２～８０：２０）にて精製し、ベンジル　（２Ｅ）－３－［１－（ジフルオロメチル）シクロプロピル］プロパ－２－エノアート（３３８mｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.94 - 1.02 (m, 2 H) 1.22 - 1.30 (m, 2 H) 5.19 (s, 2 H) 5.64 - 5.86 (m, 1 H) 5.95 (d, J=16.10 Hz, 1 H) 6.81 (d, J=16.10 Hz, 1 H) 7.34 - 7.40 (m, 5 H)
（２）ベンジル　（２Ｅ）－３－［１－（ジフルオロメチル）シクロプロピル］プロパ－２－エノアート（３３８ｍｇ）のメタノール（１０ｍＬ）にジフェニルスルフィド（２．２５μＬ）および１０％パラジウム炭素（３４ｍｇ）を加え、系内を水素ガスで置換した。水素雰囲気下、室温で１７時間撹拌した後、セライト（登録商標）を用いて不溶物をろ別し、ろ液を減圧下濃縮した。表題化合物（２０５ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000047
 (1) A solution of [1- (difluoromethyl) cyclopropyl] methanol in chloroform (40 mL) was cooled to 0 ° C., and 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol -3- (1H) -one (2.09 g) was added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. Benzyl (triphenylphosphoranylidene) acetic acid (2.52 g) was added and stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. After separating the organic layer with a phase separator, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 98: 2 to 80:20), and benzyl (2E) -3- [1- (difluoromethyl) cyclopropyl] prop-2-enoate ( 338 mg) was obtained as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δppm 0.94-1.02 (m, 2 H) 1.22-1.30 (m, 2 H) 5.19 (s, 2 H) 5.64-5.86 (m, 1 H) 5.95 (d, J = 16.10 Hz, 1 H) 6.81 (d, J = 16.10 Hz, 1 H) 7.34-7.40 (m, 5 H)
(2) Benzyl (2E) -3- [1- (difluoromethyl) cyclopropyl] prop-2-enoate (338 mg) in methanol (10 mL) with diphenyl sulfide (2.25 μL) and 10% palladium carbon (34 mg) In addition, the system was replaced with hydrogen gas. After stirring for 17 hours at room temperature under a hydrogen atmosphere, insolubles were filtered off using Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The title compound (205 mg) was obtained as a colorless oil.
製造例９　２－ブチル－５，７－ジクロロピラゾロ［１，５－ａ］ピリミジンの合成 Production Example 9 Synthesis of 2-butyl-5,7-dichloropyrazolo [1,5-a] pyrimidine
Figure JPOXMLDOC01-appb-C000048
 （１）３－ブチル－１Ｈ－ピラゾール－５－アミン（３．０ｇ）のエタノール（３０ｍＬ）溶液にマロン酸ジエチル（４．２７ｇ）および２．６Ｍナトリウムエトキシド／エタノール溶液（２０．７ｍＬ）を加え、１００℃で１２時間、室温で１６時間撹拌した。減圧下溶媒を留去した後、残渣に水を加え、濃塩酸でｐＨを２に調整した。析出物をろ取し、２－ブチルピラゾロ［１，５－ａ］ピリミジン－５，７－ジオール（５．８ｇ，無機塩を含む）を無色固体として得た。
MS (ESI) m/z 208 [M+H]+
（２）２－ブチルピラゾロ［１，５－ａ］ピリミジン－５，７－ジオール（５．８ｇ）のアセトニトリル溶液に塩化ホスホリル（２６．１ｍＬ）を滴下し、６０℃にて撹拌した。氷冷下、ジエチルアニリン（１３．４ｍＬ）を滴下し、さらに８０℃で撹拌した。飽和炭酸水素ナトリウム水溶液に反応液を移し、クロロホルムで抽出した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（３．０４ｇ）を得た。
Figure JPOXMLDOC01-appb-C000048
 (1) To a solution of 3-butyl-1H-pyrazol-5-amine (3.0 g) in ethanol (30 mL) was added diethyl malonate (4.27 g) and 2.6 M sodium ethoxide / ethanol solution (20.7 mL). The mixture was further stirred at 100 ° C. for 12 hours and at room temperature for 16 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the pH was adjusted to 2 with concentrated hydrochloric acid. The precipitate was collected by filtration to give 2-butylpyrazolo [1,5-a] pyrimidine-5,7-diol (5.8 g, containing inorganic salt) as a colorless solid.
MS (ESI) m / z 208 [M + H] +
(2) Phosphoryl chloride (26.1 mL) was added dropwise to an acetonitrile solution of 2-butylpyrazolo [1,5-a] pyrimidine-5,7-diol (5.8 g), and the mixture was stirred at 60 ° C. Diethylaniline (13.4 mL) was added dropwise under ice cooling, and the mixture was further stirred at 80 ° C. The reaction solution was transferred to a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50) to obtain the title compound (3.04 g).
製造例１０　７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオールの合成 Production Example 10 Synthesis of 7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazine-2,4-diol
Figure JPOXMLDOC01-appb-C000049
 （１）３－（３，３－ジフルオロブチル）－１Ｈ－ピラゾール－５－アミン（３．５４ｇ）のＮ，Ｎ－ジメチルホルムアミド（２０ｍＬ）溶液を０℃に冷却し、イソシアナトギ酸エチル（２．５ｍＬ）を滴下し、室温で１時間撹拌した。反応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した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～０：１００）にて精製し、エチル　｛［３－（３，３－ジフルオロブチル）－１Ｈ－ピラゾール－５－イル］カルバモイル｝カルバマート（１．７５ｇ）を無色固体として得た。
MS (ESI) m/z 291 [M+H]+
（２）エチル　｛［３－（３，３－ジフルオロブチル）－１Ｈ－ピラゾール－５－イル］カルバモイル｝カルバマート（１．７５ｇ）のエタノール（３０ｍＬ）溶液にナトリウムエトキシド（２０％エタノール溶液，４．６ｍＬ）を加え、１００℃で２時間撹拌した。氷冷した後、析出物をろ取し、固体を減圧下乾燥した。得られた固体を水（１５ｍＬ）に溶解し、０℃に冷却した後、濃塩酸（２ｍＬ）を加えてｐＨを２に調整した。１時間撹拌し、析出物をろ取、乾燥の後、表題化合物（１．３７ｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000049
 (1) A solution of 3- (3,3-difluorobutyl) -1H-pyrazol-5-amine (3.54 g) in N, N-dimethylformamide (20 mL) was cooled to 0 ° C., and ethyl isocyanatoformate (2. 5 mL) was added dropwise and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 0: 100), and ethyl {[3- (3,3-difluorobutyl) -1H-pyrazol-5-yl] carbamoyl. } Carbamate (1.75 g) was obtained as a colorless solid.
MS (ESI) m / z 291 [M + H] +
(2) Ethyl {[3- (3,3-difluorobutyl) -1H-pyrazol-5-yl] carbamoyl} carbamate (1.75 g) in ethanol (30 mL) solution in sodium ethoxide (20% ethanol solution, 4 6 mL) and stirred at 100 ° C. for 2 hours. After cooling with ice, the precipitate was collected by filtration and the solid was dried under reduced pressure. The obtained solid was dissolved in water (15 mL), cooled to 0 ° C., and concentrated hydrochloric acid (2 mL) was added to adjust the pH to 2. After stirring for 1 hour, the precipitate was collected by filtration and dried to give the title compound (1.37 g) as a colorless solid.
製造例１１　７－シクロヘキシルピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオールの合成 Production Example 11 Synthesis of 7-cyclohexylpyrazolo [1,5-a] [1,3,5] triazine-2,4-diol
Figure JPOXMLDOC01-appb-C000050
 （１）製造例１０に準じた方法で合成した７－ブロモピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオール（５００ｍｇ）、１－シクロヘキセン－１－イルボロン酸（４０９ｍｇ）および炭酸カリウム（８９７ｍｇ）のトルエン／エタノール／水（２：１：１）懸濁液（１０ｍＬ）にテトラキストリフェニルホスフィンパラジウム（０）（２５０ｍｇ）を加え、１００℃で１時間撹拌した。ＤＭＦ（２０ｍＬ）を加え、１００℃で４時間撹拌した。室温に戻した後、析出物をろ別した。ろ液に１Ｍ塩酸を加え、室温で１時間撹拌した、生じた析出物をろ取、乾燥し、７－（シクロヘキサ－１－エン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオール（４４７ｍｇ）を淡黄色固体として得た。
1H NMR (600 MHz, DMSO-d6) δppm 1.57 - 1.69 (m, 4 H), 2.14 - 2.20 (m, 2 H), 2.33 - 2.40 (m, 2 H), 5.92 (s, 1 H), 6.41 - 6.50 (m, 1 H), 11.46 (s, 1 H), 11.81 (s, 1 H)
（２）７－（シクロヘキサ－１－エン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオール（４４７ｍｇ）のメタノール（４０ｍＬ）懸濁液に５％パラジウム炭素（９０ｍｇ）を加え、水素雰囲気下、室温で６０時間撹拌した。不溶物をセライト（登録商標）を用いてろ別した後、ろ液を減圧下濃縮し、表題化合物（３９４ｍｇ）を淡黄色固体として得た。
Figure JPOXMLDOC01-appb-C000050
 (1) 7-bromopyrazolo [1,5-a] [1,3,5] triazine-2,4-diol (500 mg), 1-cyclohexen-1-ylboronic acid (500 mg) synthesized by a method according to Preparation Example 10 409 mg) and potassium carbonate (897 mg) in toluene / ethanol / water (2: 1: 1) suspension (10 mL) were added tetrakistriphenylphosphine palladium (0) (250 mg) and stirred at 100 ° C. for 1 hour. DMF (20 mL) was added and stirred at 100 ° C. for 4 hours. After returning to room temperature, the precipitate was filtered off. 1M hydrochloric acid was added to the filtrate and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and dried to give 7- (cyclohex-1-en-1-yl) pyrazolo [1,5-a] [1, 3,5] triazine-2,4-diol (447 mg) was obtained as a pale yellow solid.
1H NMR (600 MHz, DMSO-d6) δppm 1.57-1.69 (m, 4 H), 2.14-2.20 (m, 2 H), 2.33-2.40 (m, 2 H), 5.92 (s, 1 H), 6.41 -6.50 (m, 1 H), 11.46 (s, 1 H), 11.81 (s, 1 H)
(2) To a suspension of 7- (cyclohex-1-en-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-2,4-diol (447 mg) in methanol (40 mL) 5% Palladium carbon (90 mg) was added, and the mixture was stirred at room temperature for 60 hours under a hydrogen atmosphere. The insoluble material was filtered off using Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give the title compound (394 mg) as a pale yellow solid.
製造例１２　２－メチル－４－（１Ｈ－ピラゾール－１－イル）ブタン－２－アミン　トリフルオロ酢酸塩の合成 Production Example 12 Synthesis of 2-methyl-4- (1H-pyrazol-1-yl) butan-2-amine trifluoroacetate
Figure JPOXMLDOC01-appb-C000051
 （１）ｔｅｒｔ－ブチル　（４－ヒドロキシ－２－メチルブタン－２－イル）カルバマート（４００ｍｇ）のトルエン（１２ｍＬ）溶液にピラゾール（２０１ｍｇ）およびシアノメチレントリブチルホスホラン（７１２ｍｇ）を加え、１００℃にて２．５時間撹拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８８：１２～０：１００）にて精製し、ｔｅｒｔ－ブチル　［２－メチル－４－（１Ｈ－ピラゾール－１－イル）ブタン－２－イル］カルバマートの粗精製物（１２９ｍｇ）を橙色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.28 (s, 6 H) 1.45 (s, 9 H) 2.25 - 2.33 (m, 2 H) 4.16 - 4.21 (m, 2 H) 4.51 (br s, 1 H) 6.22 - 6.26 (m, 1 H) 7.38 - 7.41 (m, 1 H) 7.47 - 7.51 (m, 1 H)
（２）ｔｅｒｔ－ブチル　［２－メチル－４－（１Ｈ－ピラゾール－１－イル）ブタン－２－イル］カルバマートの粗精製物（１２９ｍｇ）のクロロホルム（２．５０ｍＬ）溶液にトリフルオロ酢酸（２．５０ｍＬ）を加え、室温で２時間攪拌した。反応液を減圧下濃縮した後、トルエン（４ｍＬ）を加えて減圧下留去する操作を３回行った。表題化合物（１７０ｍｇ）を橙色油状物として得た。
Figure JPOXMLDOC01-appb-C000051
 (1) Pyrazole (201 mg) and cyanomethylenetributylphosphorane (712 mg) were added to a toluene (12 mL) solution of tert-butyl (4-hydroxy-2-methylbutan-2-yl) carbamate (400 mg) at 100 ° C. Stir for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 88: 12-0: 100), and tert-butyl [2-methyl-4- (1H-pyrazole- A crude product of 1-yl) butan-2-yl] carbamate (129 mg) was obtained as an orange oil.
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.28 (s, 6 H) 1.45 (s, 9 H) 2.25-2.33 (m, 2 H) 4.16-4.21 (m, 2 H) 4.51 (br s, 1 H ) 6.22-6.26 (m, 1 H) 7.38-7.41 (m, 1 H) 7.47-7.51 (m, 1 H)
(2) tert-Butyl [2-Methyl-4- (1H-pyrazol-1-yl) butan-2-yl] carbamate crude product (129 mg) in chloroform (2.50 mL) in trifluoroacetic acid (2 .50 mL) was added and stirred at room temperature for 2 hours. After concentrating the reaction solution under reduced pressure, an operation of adding toluene (4 mL) and evaporating under reduced pressure was performed three times. The title compound (170 mg) was obtained as an orange oil.
製造例１３　２－［（３－ｅｘｏ）－８－アザビシクロ［３．２．１］オクタ－３－イル］プロパン－２－オール塩酸塩の合成 Production Example 13 Synthesis of 2-[(3-exo) -8-azabicyclo [3.2.1] oct-3-yl] propan-2-ol hydrochloride
Figure JPOXMLDOC01-appb-C000052
 （１）メチル　（３－ｅｘｏ）－８－ベンジル－８－アザビシクロ［３．２．１］オクタン－３－カルボキシラート（１．００ｇ）のテトラヒドロフラン（１２ｍＬ）溶液を氷冷し、およそ３Ｍメチルマグネシウムブロミド／テトラヒドロフラン溶液（６．４ｍＬ）を加え、室温で１時間撹した。反応液に飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９０：１０～５０：５０）にて精製し、２－［（３－ｅｘｏ）－８－ベンジル－８－アザビシクロ［３．２．１］オクタ－３－イル］プロパン－２－オール（６４９ｍｇ）を淡黄色固体として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.17 (s, 6 H), 1.23 (s, 1 H), 1.39 - 1.50 (m, 2 H), 1.54 - 1.70 (m, 5 H), 1.96 - 2.03 (m, 2 H), 3.20 - 3.27 (m, 2 H), 3.56 (s, 2 H), 7.21 - 7.25 (m, 1 H), 7.28 - 7.33 (m, 2 H), 7.35 - 7.42 (m, 2 H)
（２）２－［（３－ｅｘｏ）－８－ベンジル－８－アザビシクロ［３．２．１］オクタ－３－イル］プロパン－２－オール（６４９ｍｇ）のメタノール（１３ｍＬ）溶液に２０％水酸化パラジウム炭素（６５ｍｇ）を加え、水素雰囲気下、室温で１８時間撹拌した。不溶物をセライト（登録商標）を用いてろ別し、ろ液を減圧下濃縮した。得られた残渣を酢酸エチルで溶解し、４Ｍ塩酸／酢酸エチル溶液を加え、室温で３０分撹拌した。析出物をろ取し、表題化合物（４５５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000052
 (1) A solution of methyl (3-exo) -8-benzyl-8-azabicyclo [3.2.1] octane-3-carboxylate (1.00 g) in tetrahydrofuran (12 mL) is ice-cooled, and about 3 M methylmagnesium A bromide / tetrahydrofuran solution (6.4 mL) was added and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 90: 10 to 50:50), and 2-[(3-exo) -8-benzyl-8-azabicyclo [3.2. 1] Oct-3-yl] propan-2-ol (649 mg) was obtained as a pale yellow solid.
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.17 (s, 6 H), 1.23 (s, 1 H), 1.39-1.50 (m, 2 H), 1.54-1.70 (m, 5 H), 1.96-2.03 (m, 2 H), 3.20-3.27 (m, 2 H), 3.56 (s, 2 H), 7.21-7.25 (m, 1 H), 7.28-7.33 (m, 2 H), 7.35-7.42 (m , 2 H)
(2) 20% water in a solution of 2-[(3-exo) -8-benzyl-8-azabicyclo [3.2.1] oct-3-yl] propan-2-ol (649 mg) in methanol (13 mL) Palladium oxide carbon (65 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The insoluble material was filtered off using Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, 4M hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration to give the title compound (455 mg) as a colorless solid.
製造例１４　（３－ｅｎｄｏ）－３－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－オール塩酸塩の合成 Production Example 14 Synthesis of (3-endo) -3- (1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octane-3-ol hydrochloride
Figure JPOXMLDOC01-appb-C000053
 （１）１－（２－テトラヒドロピラニル）－１Ｈ－ピラゾール（０．２０ｇ）のテトラヒドロフラン（３．５ｍＬ）溶液を－７８℃に冷却し、ｎ－ブチルリチウム（２．５５Ｍ、０．５１ｍＬ）を加え、１時間撹拌した。ｔｅｒｔ－ブチル　３－オキソ－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．２０ｇ）のテトラヒドロフラン（１ｍＬ）溶液を滴下し、０℃で１時間、室温で一晩撹拌した。水（１ｍＬ）を加えた後、酢酸エチルで抽出し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、ｔｅｒｔ－ブチル　（３－ｅｎｄｏ）－３－ヒドロキシ－３－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－５－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．３１２ｇ）を無色油状物として得た。
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.46 (s, 9 H), 1.66 - 1.76 (m, 2 H), 1.91 - 2.57 (m, 12 H), 2.90 - 3.13 (m, 1 H), 3.65 - 3.72 (m, 1 H), 4.01 (br d, J=10.3 Hz, 1 H), 4.20 - 4.30 (m, 1 H), 4.30 - 4.41 (m, 1 H), 5.81 (br s, 1 H), 6.06 (br s, 1 H), 7.40 - 7.42 (m, 1 H)
MS (ESI/APCI dual) m/z 400 [M+Na]+
（２）ｔｅｒｔ－ブチル　（３－ｅｎｄｏ）－３－ヒドロキシ－３－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ピラゾール－５－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．３１２ｇ）の酢酸エチル（１．７ｍＬ）溶液に４Ｍ塩酸／酢酸エチル（８．３ｍＬ）を加え、室温で一晩撹拌した。生じた固体をろ取し、（３－ｅｎｄｏ）－３－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－オール塩酸塩（０．１８６ｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000053
 (1) A solution of 1- (2-tetrahydropyranyl) -1H-pyrazole (0.20 g) in tetrahydrofuran (3.5 mL) was cooled to −78 ° C., and n-butyllithium (2.55 M, 0.51 mL) Was added and stirred for 1 hour. A solution of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (0.20 g) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. . Water (1 mL) was added, followed by extraction with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100), and tert-butyl (3-endo) -3-hydroxy-3- [1- (tetrahydro-2H -Pyran-2-yl) -1H-pyrazol-5-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate (0.312 g) was obtained as a colorless oil.
1H NMR (600 MHz, CHLOROFORM-d) δppm 1.46 (s, 9 H), 1.66-1.76 (m, 2 H), 1.91-2.57 (m, 12 H), 2.90-3.13 (m, 1 H), 3.65 -3.72 (m, 1 H), 4.01 (br d, J = 10.3 Hz, 1 H), 4.20-4.30 (m, 1 H), 4.30-4.41 (m, 1 H), 5.81 (br s, 1 H ), 6.06 (br s, 1 H), 7.40-7.42 (m, 1 H)
MS (ESI / APCI dual) m / z 400 [M + Na] +
(2) tert-Butyl (3-endo) -3-hydroxy-3- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] -8-azabicyclo [3.2. 1] To a solution of octane-8-carboxylate (0.312 g) in ethyl acetate (1.7 mL) was added 4M hydrochloric acid / ethyl acetate (8.3 mL), and the mixture was stirred overnight at room temperature. The resulting solid was collected by filtration, and (3-endo) -3- (1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octane-3-ol hydrochloride (0.186 g) was colorless. Obtained as a solid.
製造例１５　（３－ｅｎｄｏ）－Ｎ－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－アミン塩酸塩の合成 Production Example 15 Synthesis of (3-endo) -N- (1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octane-3-amine hydrochloride
Figure JPOXMLDOC01-appb-C000054
 （１）ｔｅｒｔ－ブチル　３－オキソ－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．２２ｇ）のテトラヒドロフラン（２．０ｍＬ）溶液に１Ｈ－ピラゾール－５－アミン（０．０８９ｇ）および酢酸（０．１１ｍＬ）を加え、室温で１時間撹拌した。水素化トリアセトキシホウ素ナトリウム（０．２５ｇ）を加え、室温で一晩撹拌した。反応液に少量の水を加え、減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（ＮＨシリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、ｔｅｒｔ－ブチル　（３－ｅｎｄｏ）－３－（１Ｈ－ピラゾール－５－イルアミノ）－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．１２８ｇ）を無色油状物として得た。
MS (ESI/APCI dual) m/z 293 [M+H]+
（２）ｔｅｒｔ－ブチル　（３－ｅｎｄｏ）－３－（１Ｈ－ピラゾール－５－イルアミノ）－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．１２８ｇ）の酢酸エチル（１．７ｍＬ）溶液に４Ｍ塩酸／酢酸エチル（２．２ｍＬ）を加え、室温で一晩撹拌した。生じた固体をろ取し、（３－ｅｎｄｏ）－Ｎ－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－アミン塩酸塩（０．０５８ｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000054
 (1) tert-Butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (0.22 g) in tetrahydrofuran (2.0 mL) in 1H-pyrazol-5-amine (0. 089 g) and acetic acid (0.11 mL) were added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.25 g) was added and stirred at room temperature overnight. A small amount of water was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (NH silica gel cartridge, hexane: ethyl acetate = 80: 20 to 0: 100), and tert-butyl. (3-endo) -3- (1H-pyrazol-5-ylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (0.128 g) was obtained as a colorless oil.
MS (ESI / APCI dual) m / z 293 [M + H] +
(2) tert-butyl (3-endo) -3- (1H-pyrazol-5-ylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (0.128 g) in ethyl acetate (1 .7 mL) solution was added 4M hydrochloric acid / ethyl acetate (2.2 mL) and stirred at room temperature overnight. The resulting solid was collected by filtration, and (3-endo) -N- (1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octane-3-amine hydrochloride (0.058 g) was colorless. Obtained as a solid.
製造例１６　（１Ｒ，５Ｓ）－３－（１Ｈ－ピラゾール－３－イルオキシ）－８－アザビシクロ［３．２．１］オクタン塩酸塩（ｃｉｓ体、ｔｒａｎｓ体の混合物）の合成 Production Example 16 Synthesis of (1R, 5S) -3- (1H-pyrazol-3-yloxy) -8-azabicyclo [3.2.1] octane hydrochloride (mixture of cis isomer and trans isomer)
Figure JPOXMLDOC01-appb-C000055
 （１）１－（３－ヒドロキシ－１Ｈ－ピラゾール－１－イル）エタノン（０．６７ｇ）のクロロホルム（８．８ｍＬ）溶液にトリフェニルホスフィン（１．５０ｇ）、ジイソプロピルアゾジカルボキシラート（１．９Ｍ／トルエン）を加え、室温で２時間撹拌した。ｔｅｒｔ－ブチル　（３－ｅｎｄｏ）－３－ヒドロキシ－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（１．０ｇ）を加え、室温で１時間撹拌した。反応液に水（３ｍＬ）を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、ｔｅｒｔ－ブチル　（１Ｒ，５Ｓ）－３－［（１－アセチル－１Ｈ－ピラゾール－３－イル）オキシ］－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（ｃｉｓ体、ｔｒａｎｓ体の混合物、０．７３ｇ）を淡黄色油状物として得た。
MS (ESI/APCI dual) m/z 358 [M+Na]+
（２）ｔｅｒｔ－ブチル　（１Ｒ，５Ｓ）－３－［（１－アセチル－１Ｈ－ピラゾール－３－イル）オキシ］－８－アザビシクロ［３．２．１］オクタン－８－カルボキシラート（０．７３ｇ）の酢酸エチル（９ｍＬ）溶液に４Ｎ塩酸／酢酸エチル（１１ｍＬ）を加え、室温で一晩撹拌した。生じた固体をろ取し、（１Ｒ，５Ｓ）－３－（１Ｈ－ピラゾール－３－イルオキシ）－８－アザビシクロ［３．２．１］オクタン塩酸塩（ｃｉｓ体、ｔｒａｎｓ体の混合物、０．３３ｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000055
 (1) A solution of 1- (3-hydroxy-1H-pyrazol-1-yl) ethanone (0.67 g) in chloroform (8.8 mL) was added to triphenylphosphine (1.50 g) and diisopropyl azodicarboxylate (1. 9M / toluene) was added and stirred at room temperature for 2 hours. Tert-butyl (3-endo) -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (1.0 g) was added, and the mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. After drying the organic layer with anhydrous sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100), and tert-butyl (1R, 5S) -3-[(1-acetyl-1H-pyrazole-3 -Yl) oxy] -8-azabicyclo [3.2.1] octane-8-carboxylate (a mixture of cis and trans isomers, 0.73 g) was obtained as a pale yellow oil.
MS (ESI / APCI dual) m / z 358 [M + Na] +
(2) tert-butyl (1R, 5S) -3-[(1-acetyl-1H-pyrazol-3-yl) oxy] -8-azabicyclo [3.2.1] octane-8-carboxylate (0. To a solution of 73 g) in ethyl acetate (9 mL) was added 4N hydrochloric acid / ethyl acetate (11 mL), and the mixture was stirred overnight at room temperature. The resulting solid was collected by filtration, and (1R, 5S) -3- (1H-pyrazol-3-yloxy) -8-azabicyclo [3.2.1] octane hydrochloride (a mixture of cis form and trans form). 33 g) was obtained as a colorless solid.
製造例１７　（１Ｒ，５Ｓ，６ｒ）－６－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］ビシクロ［３．１．０］ヘキサン－３－オンの合成 Production Example 17 (1R, 5S, 6r) -6- [5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine Synthesis of -2-yl] bicyclo [3.1.0] hexane-3-one
Figure JPOXMLDOC01-appb-C000056
 （１）製造例１と同様の方法により、（１Ｒ，５Ｓ，６ｒ）－３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサン－６－カルボン酸エチル（cis, trans体の混合物、４．６５ｇ）から３－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサ－６－イル）－１Ｈ－ピラゾール－５－アミン（cis, trans体の混合物、２．４２ｇ）を得た。
MS (ESI) m/z 294 [M+H]+
（２）製造例２と同様の方法により、３－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサ－６－イル）－１Ｈ－ピラゾール－５－アミン（cis, trans体の混合物、１．００ｇ）から２－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサ－６－イル）－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－オール（cis, trans体の混合物、０．９６ｇ）を得た。
MS (ESI) m/z 360 [M+H]+
（３）２－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサ－６－イル）－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－オール（cis, trans体の混合物、２００ｍｇ）、３－オキサ－８－アザビシクロ［３．２．１］オクタン塩酸塩（１６７ｍｇ）、ブロモトリピロリジノホスホニウムヘキサフルオロホスファート（３８９ｍｇ）およびジイソプロピルエチルアミン（３５９ｍｇ）のジオキサン（５．５ｍＬ）懸濁液を室温で１５時間撹拌した。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、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別の後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝５０：５０～０：１００、およびＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝５０：５０～２０：８０）にて精製し、２－［（１Ｒ，５Ｓ，６ｒ）－３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサン－６－イル］－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（cis, trans体の混合物、１８３ｍｇ）を無色固体として得た。
MS (ESI) m/z 455 [M+H]+
（４）２－［（１Ｒ，５Ｓ，６ｒ）－３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝ビシクロ［３．１．０］ヘキサン－６－イル］－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（cis, trans体の混合物、１８３ｍｇ）のテトラヒドロフラン（２ｍＬ）溶液にテトラブチルアンモニウムフルオリド（１Ｍテトラヒドロフラン溶液、０．６ｍＬ）を加え、室温で８０時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣を分取ＨＰＬＣにて精製を行い、（１Ｒ，５Ｓ，６ｒ）－６－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］ビシクロ［３．１．０］ヘキサン－３－オール（異性体１：７１ｍｇ、異性体２：２６ｍｇ）を得た。このうち異性体１をクロロホルム（３．１ｍＬ）に溶かし、１，１，１－トリアセトキシ－１，１－ジヒドロ－１，２－ベンゾヨードキソール－３－（１Ｈ）－オン（１０６ｍｇ）を加え、室温で２時間撹拌した。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後、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、酢酸エチル：メタノール＝１００：０～９０：１０）にて精製を行い、表題化合物（５２ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000056
 (1) In the same manner as in Production Example 1, (1R, 5S, 6r) -3-{[tert-butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] ethyl hexane-6-carboxylate ( Mixture of cis, trans isomers, 4.65 g) to 3- (3-{[tert-butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] hex-6-yl) -1H-pyrazole-5 An amine (mixture of cis and trans isomers, 2.42 g) was obtained.
MS (ESI) m / z 294 [M + H] +
(2) In the same manner as in Production Example 2, 3- (3-{[tert-butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] hex-6-yl) -1H-pyrazole-5- Amine (mixture of cis, trans isomers, 1.00 g) to 2- (3-{[tert-butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] hex-6-yl) -5-methylpyrazolo [ 1,5-a] pyrimidin-7-ol (a mixture of cis and trans isomers, 0.96 g) was obtained.
MS (ESI) m / z 360 [M + H] +
(3) 2- (3-{[tert-Butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] hex-6-yl) -5-methylpyrazolo [1,5-a] pyrimidin-7-ol (Mixture of cis, trans form, 200 mg), 3-oxa-8-azabicyclo [3.2.1] octane hydrochloride (167 mg), bromotripyrrolidinophosphonium hexafluorophosphate (389 mg) and diisopropylethylamine (359 mg) Of dioxane (5.5 mL) was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel cartridge, hexane: ethyl acetate = 50: 50 to 0: 100, and NH type silica gel cartridge, hexane: ethyl acetate = 50 : 50 to 20:80) and purified by 2-[(1R, 5S, 6r) -3-{[tert-butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] hexane-6-yl ] -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine (cis, trans mixture, 183 mg) Obtained as a solid.
MS (ESI) m / z 455 [M + H] +
(4) 2-[(1R, 5S, 6r) -3-{[tert-Butyl (dimethyl) silyl] oxy} bicyclo [3.1.0] hexane-6-yl] -5-methyl-7- ( To a solution of 3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine (cis, trans isomer, 183 mg) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride. (1M tetrahydrofuran solution, 0.6 mL) was added, and the mixture was stirred at room temperature for 80 hours. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was dried over chloroform. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC, and (1R, 5S, 6r) -6- [5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] bicyclo [3.1.0] hexane-3-ol (isomer 1:71 mg, isomer 2:26 mg) was obtained. Among them, isomer 1 was dissolved in chloroform (3.1 mL), and 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (106 mg) was dissolved. The mixture was further stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform, and then the organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, ethyl acetate: methanol = 100: 0 to 90:10) to give the title compound (52 mg). Obtained as a colorless solid.
製造例１～１７で示した中間体と、同様の方法で合成した中間体の構造式、化合物名及びそれらの機器データを表１－１～１－８に示す。表中の製造例の欄に記載された数字は、その中間体が上記製造例１～１７の内、どの製造例と同様な方法で合成されたかを示したものである。 Tables 1-1 to 1-8 show the structural formulas, compound names, and instrument data of intermediates shown in Production Examples 1 to 17 and intermediates synthesized by the same method. The numbers described in the column of production examples in the table indicate which of the above production examples 1 to 17 was synthesized by the same method as in the above production examples.
Figure JPOXMLDOC01-appb-T000057
  　 
Figure JPOXMLDOC01-appb-T000057
  　 
Figure JPOXMLDOC01-appb-T000058
  　 
Figure JPOXMLDOC01-appb-T000058
  　 
Figure JPOXMLDOC01-appb-T000059
  　 
Figure JPOXMLDOC01-appb-T000059
  　 
Figure JPOXMLDOC01-appb-T000060
  　 
Figure JPOXMLDOC01-appb-T000060
  　 
Figure JPOXMLDOC01-appb-T000061
  　 
Figure JPOXMLDOC01-appb-T000061
  　 
Figure JPOXMLDOC01-appb-T000062
  　 
Figure JPOXMLDOC01-appb-T000062
  　 
Figure JPOXMLDOC01-appb-T000063
  　 
Figure JPOXMLDOC01-appb-T000063
  　 
Figure JPOXMLDOC01-appb-T000064
  　 
Figure JPOXMLDOC01-appb-T000064
  　 
参考例１　化合物C１の光学分割（化合物Ｃ２および化合物Ｃ３の合成）
　２－［１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－2－イル］エタン－1－オール（４０ｍｇ、化合物Ｃ１）をセミ分取カラム（CHIRAL PAC ＯＺ-H、ヘキサン：イソプロパノール＝９０：１０、流速１ｍＬ／分）にて精製を行い、化合物C２（短保持時間、２１ｍｇ、無色固体）および化合物C３（長保持時間、１５ｍｇ、無色固体）をそれぞれ得た。 Reference Example 1 Optical Resolution of Compound C1 (Synthesis of Compound C2 and Compound C3)
2- [1- (2-Butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-2-yl] ethane-1-ol (40 mg, compound C1) was added to a semi-preparative column (CHIRAL Purification was performed using PAC OZ-H, hexane: isopropanol = 90: 10, flow rate 1 mL / min), and compound C2 (short retention time, 21 mg, colorless solid) and compound C3 (long retention time, 15 mg, colorless solid) were obtained. I got each.
参考例２　５－メチル－７－（３－オキサ－８－アザビシクロ［３，２，１］オクタン－８－イル）－２－フェニルピラゾロ［１，５－ａ］ピリミジン（化合物Ｃ１２）の合成 Reference Example 2 Synthesis of 5-methyl-7- (3-oxa-8-azabicyclo [3,2,1] octane-8-yl) -2-phenylpyrazolo [1,5-a] pyrimidine (Compound C12)
Figure JPOXMLDOC01-appb-C000065
 ２－ブロモ－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（２０ｍｇ）のトルエン/エタノール/水（１．０/０．５/０．５ｍＬ）溶液にフェニルボロン酸（１１ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（１４ｍｇ）、炭酸カリウム（２６ｍｇ）を加え、１００℃で８時間撹拌した。不溶物をセライト（登録商標）を用いてろ別後、ろ液を分取ＨＰＬＣにて精製を行い、表題化合物（１３ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000065
 2-Bromo-5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine (20 mg) in toluene / ethanol / water ( To the 1.0 / 0.5 / 0.5 mL solution, phenylboronic acid (11 mg), tetrakis (triphenylphosphine) palladium (0) (14 mg), and potassium carbonate (26 mg) were added and stirred at 100 ° C. for 8 hours. . The insoluble material was filtered off using Celite (registered trademark), and the filtrate was purified by preparative HPLC to give the title compound (13 mg) as a colorless solid.
参考例１～２で示した化合物と、参考例１～２及び下述の実施例と同様の方法で合成した化合物の構造式、化合物名及びそれらの機器データを表２－１～２－２に示す。表中の実施例/参考例の欄に記載された数字は、その化合物が上記参考例１～２及び実施例１～６０の内、どの例と同様な方法で合成されたかを示したものである。 Tables 2-1 to 2-2 show the structural formulas, compound names and instrument data of the compounds shown in Reference Examples 1 and 2 and compounds synthesized by the same methods as in Reference Examples 1 and 2 and the examples described below. Shown in The numbers in the column of Examples / Reference Examples in the table indicate which compounds were synthesized by the same method as in Reference Examples 1-2 and Examples 1-60 above. is there.
Figure JPOXMLDOC01-appb-T000066
 
Figure JPOXMLDOC01-appb-T000066
 
Figure JPOXMLDOC01-appb-T000067
 
Figure JPOXMLDOC01-appb-T000067
 
実施例１Ａ　２－ブチル－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１４）の合成 Example 1A Synthesis of 2-butyl-5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (Compound A14)
Figure JPOXMLDOC01-appb-C000068
 （１）２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－オール（１．００ｇ）のアセトニトリル（２０ｍＬ）溶液にオキシ塩化リン（０．６８５ｍＬ）を加え、８０℃で５時間、室温で２日間撹拌した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９２：８～４０：６０）にて精製を行い、２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（０．９５ｇ）を黄色油状物として得た。
（２）２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（５０ｍｇ）、３－オキサ－８－アザビシクロ［３．２．１］オクタン（３８ｍｇ）およびジイソプロピルエチルアミン（１１７μＬ）のエタノール（１ｍＬ）溶液を封管中１００℃で３．５時間撹拌した。反応液を室温に戻した後、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。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝７０：３０～３０：７０）にて精製を行った。表題化合物（５１ｍｇ）を淡緑色固体として得た。
Figure JPOXMLDOC01-appb-C000068
 (1) To a solution of 2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-ol (1.00 g) in acetonitrile (20 mL) was added phosphorus oxychloride (0.685 mL), and the mixture was heated at 80 ° C. for 5 hours. And stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 92: 8-40: 60) to give 2-butyl-7-chloro-5-methylpyrazolo [1, 5-a] pyrimidine (0.95 g) was obtained as a yellow oil.
(2) 2-butyl-7-chloro-5-methylpyrazolo [1,5-a] pyrimidine (50 mg), 3-oxa-8-azabicyclo [3.2.1] octane (38 mg) and diisopropylethylamine (117 μL) Of ethanol (1 mL) was stirred in a sealed tube at 100 ° C. for 3.5 hours. After returning the reaction solution to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30 to 30:70). The title compound (51 mg) was obtained as a pale green solid.
実施例１Ｂ　６－［２－（ｔｒａｎｓ－４－フルオロシクロヘキシル）－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ａ１９７）の合成 Example 1B 6- [2- (trans-4-fluorocyclohexyl) -5-methylpyrazolo [1,5-a] pyrimidin-7-yl] -2-oxa-6-azatricyclo [3.3.1.1 3 , 7 ] Synthesis of decane (compound A197)
Figure JPOXMLDOC01-appb-C000069
 　２－（ｔｒａｎｓ－４－フルオロシクロヘキシル）－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－オール（２０ｍｇ）、２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン塩酸塩（２２ｍｇ）、ブロモトリピロリジノホスホニウムヘキサフルオロホスファート（５６ｍｇ）およびジイソプロピルエチルアミン（４２μＬ）のジオキサン（１ｍＬ）懸濁液を室温で１５時間撹拌した。反応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、有機層をフェーズセパレーターで分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８５：１５～５０：５０）にて精製し、表題化合物（８ｍｇ）を無色アモルファスとして得た。
Figure JPOXMLDOC01-appb-C000069
 2- (trans-4-fluorocyclohexyl) -5-methylpyrazolo [1,5-a] pyrimidin-7-ol (20 mg), 2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane A suspension of hydrochloride (22 mg), bromotripyrrolidinophosphonium hexafluorophosphate (56 mg) and diisopropylethylamine (42 μL) in dioxane (1 mL) was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 85: 15-50: 50) to give the title compound (8 mg) as a colorless amorphous product.
実施例２Ａ　７－ブチル－２－メチル－４－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン（化合物Ｂ１）の合成 Example 2A 7-Butyl-2-methyl-4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] [1,3,5] triazine Synthesis of (Compound B1)
Figure JPOXMLDOC01-appb-C000070
 （１）７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オール（３１９ｍｇ）のアセトニトリル（３ｍＬ）溶液に、氷冷下、オキシ塩化リン（３５６ｍｇ）およびＮ，Ｎ－ジエチルアニリン（３４６ｍｇ）を加え、室温で１０分撹拌した。８０℃で４時間撹拌した後、反応液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、７－ブチル－４－クロロ－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン（３１０ｍｇ）を得た。
（２）７－ブチル－４－クロロ－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン（６０ｍｇ）のイソプロパノール（１ｍＬ）溶液に３－オキサ－８－アザビシクロ［３．２．１］オクタン（６６ｍｇ）およびジイソプロピルエチルアミン（６９ｍｇ）を加え、８０℃で１時間、室温で１６時間撹拌した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９５：５）にて精製し、表題化合物（２１ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000070
 (1) 7-butyl-2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-ol (319 mg) in a solution of acetonitrile (3 mL) under ice-cooling, phosphorus oxychloride (356 mg) And N, N-diethylaniline (346 mg) was added and stirred at room temperature for 10 minutes. After stirring at 80 ° C. for 4 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50), and 7-butyl-4-chloro-2-methylpyrazolo [1,5-a] [1,3, 5] Triazine (310 mg) was obtained.
(2) 7-butyl-4-chloro-2-methylpyrazolo [1,5-a] [1,3,5] triazine (60 mg) in isopropanol (1 mL) was added to 3-oxa-8-azabicyclo [3.2 .1] Octane (66 mg) and diisopropylethylamine (69 mg) were added, and the mixture was stirred at 80 ° C. for 1 hour and at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 95: 5) to obtain the title compound (21 mg) as a colorless solid.
実施例２Ｂ　６－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ８）の合成 Example 2B 6- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3 .3.1.1 3,7 ] Synthesis of decane (compound B8)
Figure JPOXMLDOC01-appb-C000071
 ７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オール（１．５０ｇ）、２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン塩酸塩（１．３０ｇ）、ブロモトリピロリジノホスホニウムヘキサフルオロホスファート（３．４６ｇ）およびジイソプロピルエチルアミン（４．３ｍＬ）のジオキサン（１５ｍＬ）懸濁液を８０℃で３時間撹拌した。反応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後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８８：１２～０：１００）にて精製した後、ヘキサン／酢酸エチル（＝２：１）の混合溶媒にて再結晶を行い、表題化合物（１．４０ｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000071
 7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-ol (1.50 g), 2-oxa-6-azatricyclo [3.3 .1.1 3,7] decane hydrochloride (1.30 g), dioxane (15 mL) suspension 80 ° C. of bromotripyrrolidinophosphonium hexafluorophosphate (3.46 g) and diisopropylethylamine (4.3 mL) For 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 88: 12 to 0: 100), and then recrystallized with a mixed solvent of hexane / ethyl acetate (= 2: 1). The title compound (1.40 g) was obtained as a colorless solid.
実施例３　２－ブチル－５－メチル－７－［（２Ｒ）－２－（１Ｈ－ピラゾール－１－イルメチル）ピペリジン－１－イル］ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１００）の合成 Example 3 Synthesis of 2-butyl-5-methyl-7-[(2R) -2- (1H-pyrazol-1-ylmethyl) piperidin-1-yl] pyrazolo [1,5-a] pyrimidine (Compound A100)
Figure JPOXMLDOC01-appb-C000072
 （１）ｔｅｒｔ－ブチル　［１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－３－イル］カルバマート（２８５ｍｇ）のクロロホルム（３ｍＬ）溶液にトリフルオロ酢酸（３ｍＬ）を加え、室温で２０時間撹拌した。反応液を減圧下濃縮した後、クロロホルムで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層をフェーズセパレーターで分離した後、減圧下溶媒を留去し、１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－３－アミン（２２０ｍｇ）を無色油状物として得た。
（２）１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－３－アミン（５０ｍｇ）のクロロホルム（１ｍＬ）溶液にトリエチルアミン（３１μＬ）、塩化アセチル（２３μＬ）を加え、室温で２時間撹拌した。反応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、有機層をフェーズセパレーターで分離した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、酢酸エチル１００％～クロロホルム：メタノール＝１００：０～９５：５）にて精製し、表題化合物（４０ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000072
 (1) tert-butyl [1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-3-yl] carbamate (285 mg) in chloroform (3 mL) in trifluoroacetic acid (3 mL) was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate solution. After separating the organic layer with a phase separator, the solvent was distilled off under reduced pressure to give 1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-3-amine (220 mg). Obtained as a colorless oil.
(2) Triethylamine (31 μL) and acetyl chloride (23 μL) were added to a solution of 1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-3-amine (50 mg) in chloroform (1 mL). ) And stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was separated with a phase separator. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, ethyl acetate 100% to chloroform: methanol = 100: 0 to 95: 5) to obtain the title compound (40 mg) as a colorless solid. .
実施例４　［１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－３－イル］カルバミン酸メチル（化合物Ａ１２１）の合成 Example 4 Synthesis of methyl [1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-3-yl] carbamate (Compound A121)
Figure JPOXMLDOC01-appb-C000073
 　１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－３－アミン（３０ｍｇ）のクロロホルム（１ｍＬ）溶液にトリエチルアミン（２５μＬ）およびクロロギ酸メチル（２０μＬ）を加え、室温で１時間撹拌した。トリエチルアミン（２５μＬ）およびクロロギ酸メチル（２０μＬ）を追加し、３０分撹拌した後、反応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。有機層をフェーズセパレーターで分離し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、酢酸エチル１００％～クロロホルム：メタノール＝１００：０～９０：１０）にて精製し、表題化合物（４０ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000073
 Triethylamine (25 μL) and methyl chloroformate (20 μL) were added to a solution of 1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-3-amine (30 mg) in chloroform (1 mL). The mixture was further stirred at room temperature for 1 hour. Triethylamine (25 μL) and methyl chloroformate (20 μL) were added, and the mixture was stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, ethyl acetate 100% to chloroform: methanol = 100: 0 to 90:10) to obtain the title compound (40 mg) as a colorless solid.
実施例５　２－ブチル－５－メチル－７－［（３Ｓ）－３－（１Ｈ－ピラゾール－１－イルメチル）ピペリジン－１－イル］ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ９９）の合成 Example 5 Synthesis of 2-butyl-5-methyl-7-[(3S) -3- (1H-pyrazol-1-ylmethyl) piperidin-1-yl] pyrazolo [1,5-a] pyrimidine (Compound A99)
Figure JPOXMLDOC01-appb-C000074
 （１）２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（１００ｍｇ）のエタノール懸濁液にジイソプロピルエチルアミン（２３４μＬ）および（（Ｓ）－ピペリジン－３－イル）メタノール塩酸塩（１０２ｍｇ）を加え、マイクロ波照射下、１５０℃で３０分撹拌した。反応液を減圧下濃縮し、カラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝７０：３０～３０：７０）にて精製を行い、［（３Ｓ）－１－（７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）ピペリジン－３－イル］メタノール（１４４ｍｇ）を淡黄色油状物として得た。
（２）［（３Ｓ）－１－（７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）ピペリジン－３－イル］メタノール（５２ｍｇ）のトルエン（１ｍＬ）溶液にピラゾール（２３ｍｇ）およびシアノメチレントリブチルホスホラン（８３ｍｇ）を加え、１００℃で２．５時間撹拌した。反応液を減圧下濃縮し、カラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝７０：３０～３５：６５）にて精製を行い、表題化合物（５２ｍｇ）を淡橙色油状物として得た。
Figure JPOXMLDOC01-appb-C000074
 (1) Dibutylethylamine (234 μL) and ((S) -piperidin-3-yl) methanol hydrochloride in an ethanol suspension of 2-butyl-7-chloro-5-methylpyrazolo [1,5-a] pyrimidine (100 mg) Salt (102 mg) was added, and the mixture was stirred at 150 ° C. for 30 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30 to 30:70), and [[3S) -1- (7-butyl-2-methylpyrazolo [ 1,5-a] [1,3,5] triazin-4-yl) piperidin-3-yl] methanol (144 mg) was obtained as a pale yellow oil.
(2) Toluene of [(3S) -1- (7-butyl-2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl) piperidin-3-yl] methanol (52 mg) To the (1 mL) solution were added pyrazole (23 mg) and cyanomethylenetributylphosphorane (83 mg), and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 70: 30 to 35:65) to give the title compound (52 mg) as a pale orange oil.
実施例６　２－［（２Ｒ）－１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－２－イル］－Ｎ，Ｎ－ジメチルアセトアミド（化合物Ａ１４２）の合成 Example 6 2-[(2R) -1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-2-yl] -N, N-dimethylacetamide (Compound A142) Synthesis of
Figure JPOXMLDOC01-appb-C000075
 （１）［（２Ｒ）－１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－２－イル］酢酸エチル（１２５ｍｇ）のメタノール（１ｍＬ）溶液に水酸化リチウム（１Ｍメタノール溶液、１ｍＬ）および水（１ｍＬ）を加え、室温で１時間撹拌した。反応液に１０％クエン酸水溶液を加えてｐＨを４に調整した後、クロロホルムで抽出し、有機層をフェーズセパレーターにて分離した。減圧下溶媒を留去し、分取ＴＬＣ（クロロホルム：メタノール＝９５：５）にて精製し、［（２Ｒ）－１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－２－イル］酢酸（５１ｍｇ）を無色固体として得た。
（２）［（２Ｒ）－１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）ピペリジン－２－イル］酢酸（２５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）溶液に１－ヒドロキシベンゾトリアゾール１水和物（１４ｍｇ）、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（２０ｍｇ）およびジメチルアミン（９．５Ｍ水溶液、１０μＬ）を加え、室温で１．５時間撹拌した。ジメチルアミン水溶液（１０μＬ）を追加し、さらに２．５時間撹拌した。反応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、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９５：５～０：１００）にて精製を行い、表題化合物（１１ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000075
 (1) [(2R) -1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-2-yl] ethyl acetate (125 mg) in methanol (1 mL) in water Lithium oxide (1M methanol solution, 1 mL) and water (1 mL) were added, and the mixture was stirred at room temperature for 1 hr. A 10% aqueous citric acid solution was added to the reaction solution to adjust the pH to 4, followed by extraction with chloroform, and the organic layer was separated with a phase separator. The solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (chloroform: methanol = 95: 5), and [(2R) -1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidine-7. -Iyl) piperidin-2-yl] acetic acid (51 mg) was obtained as a colorless solid.
(2) [(2R) -1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) piperidin-2-yl] acetic acid (25 mg) in N, N-dimethylformamide (0 5 mL) solution was added 1-hydroxybenzotriazole monohydrate (14 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (20 mg) and dimethylamine (9.5 M aqueous solution, 10 μL). And stirred at room temperature for 1.5 hours. Dimethylamine aqueous solution (10 μL) was added, and the mixture was further stirred for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5 to 0: 100) to give the title compound (11 mg) as a colorless oil.
実施例７　｛１－［（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）アミノ］シクロブチル｝メタノール（化合物Ａ１４４）の合成 Example 7 Synthesis of {1-[(2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) amino] cyclobutyl} methanol (Compound A144)
Figure JPOXMLDOC01-appb-C000076
 （１）実施例１Ａ工程（２）と同様の方法により、２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（１００ｍｇ）より１－［（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）アミノ］シクロブタン－１－カルボン酸エチル（４１ｍｇ）を無色固体として得た。
（２）１－［（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）アミノ］シクロブタン－１－カルボン酸エチル（４０ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液を氷冷し、水素化リチウムアルミニウム（１４ｍｇ）を加え、氷冷下１時間撹拌した。反応液に硫酸ナトリウム１０水和物を加え、室温で３．５時間撹拌した。不溶物をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８４：１６～０：１００）にて精製し、表題化合物（２７ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000076
 (1) In the same manner as in Example 1A step (2), 1-[(2-butyl-5-methylpyrazolo) was prepared from 2-butyl-7-chloro-5-methylpyrazolo [1,5-a] pyrimidine (100 mg). Ethyl [1,5-a] pyrimidin-7-yl) amino] cyclobutane-1-carboxylate (41 mg) was obtained as a colorless solid.
(2) A solution of ethyl 1-[(2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) amino] cyclobutane-1-carboxylate (40 mg) in tetrahydrofuran (1 mL) was ice-cooled, Lithium aluminum hydride (14 mg) was added, and the mixture was stirred for 1 hour under ice-cooling. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred at room temperature for 3.5 hours. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 84: 16-0: 100) to give the title compound (27 mg) as a colorless solid.
実施例８　２－ブチル－５－メトキシ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ７３）の合成 Example 8 Synthesis of 2-butyl-5-methoxy-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (Compound A73)
Figure JPOXMLDOC01-appb-C000077
 （１）２－ブチル－５，７－ジクロロピラゾロ［１，５－ａ］ピリミジン（１．０ｇ）、３－オキサ－８－アザビシクロ［３．２．１］オクタン（５５６ｍｇ）およびジイソプロピルエチルアミン（７９４ｍｇ）の２－プロパノール（１０ｍＬ）溶液を８０℃にて５時間撹拌した。飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出し、有機層を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製を行い、２－ブチル－５－クロロ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（１．１７ｇ）を無色固体として得た。
（２）メタノール（１ｍＬ）に水素化ナトリウム（約６０％／オイル、７．５ｍｇ）を加え、室温で１０分撹拌した後、２－ブチル－５－クロロ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（２０ｍｇ）を加え、室温で６時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、有機層を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製を行い、表題化合物（１４ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000077
 (1) 2-butyl-5,7-dichloropyrazolo [1,5-a] pyrimidine (1.0 g), 3-oxa-8-azabicyclo [3.2.1] octane (556 mg) and diisopropylethylamine ( (794 mg) in 2-propanol (10 mL) was stirred at 80 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with chloroform, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50), and 2-butyl-5-chloro-7- (3-oxa-8-azabicyclo [3.2 .1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (1.17 g) was obtained as a colorless solid.
(2) Sodium hydride (about 60% / oil, 7.5 mg) was added to methanol (1 mL) and stirred at room temperature for 10 minutes, and then 2-butyl-5-chloro-7- (3-oxa-8- Azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (20 mg) was added and stirred at room temperature for 6 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (14 mg) as a colorless oil.
実施例９　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）－５－（１Ｈ－ピラゾール－１－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ５３）の合成 Example 9 2-Butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -5- (1H-pyrazol-1-yl) pyrazolo [1,5-a] Synthesis of pyrimidine (compound A53)
Figure JPOXMLDOC01-appb-C000078
 　ピラゾール（６．４ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に水素化ナトリウム（約６０％／オイル、７．５ｍｇ）を加え、室温で５分撹拌した。２－ブチル－５－クロロ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（２０ｍｇ）を加え、１００℃で５時間撹拌した。室温に戻した後、飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出し、有機層を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製を行い、表題化合物（１６ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000078
 To a solution of pyrazole (6.4 mg) in N, N-dimethylformamide (1 mL) was added sodium hydride (about 60% / oil, 7.5 mg), and the mixture was stirred at room temperature for 5 minutes. Add 2-butyl-5-chloro-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (20 mg) and add 5 at 100 ° C. Stir for hours. After returning to room temperature, a saturated aqueous ammonium chloride solution was added, followed by extraction with chloroform, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (16 mg) as a colorless oil.
実施例１０　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルボニトリル（化合物Ａ１０８）の合成 Example 10 Synthesis of 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine-5-carbonitrile (Compound A108)
Figure JPOXMLDOC01-appb-C000079
 　２－ブチル－５－クロロ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（５０ｍｇ）、シアン化亜鉛（２８ｍｇ）、亜鉛（２ｍｇ）、Ｐｄ（ＴＦＡ）2（５．２ｍｇ）および２－（ジ－ｔ－ブチルホスフィノ）－１，１’－ビナフチル（６．２ｍｇ）のＮ，Ｎ－ジメチルアセトアミド（１ｍＬ）溶液を８０℃で５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、有機層を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９５：５）にて精製し、得られた固体をヘキサンにて洗浄し、表題化合物（７．２ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000079
 2-butyl-5-chloro-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (50 mg), zinc cyanide (28 mg) , Zinc (2 mg), Pd (TFA) 2 (5.2 mg) and 2- (di-t-butylphosphino) -1,1′-binaphthyl (6.2 mg) in N, N-dimethylacetamide (1 mL) The solution was stirred at 80 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 95: 5), and the obtained solid was washed with hexane to obtain the title compound (7.2 mg) as a colorless solid. .
実施例１１　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１０４）の合成 Example 11 Synthesis of 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (Compound A104)
Figure JPOXMLDOC01-appb-C000080
 　２－ブチル－５－クロロ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（３０ｍｇ）のメタノール（５ｍＬ）溶液に１０％パラジウム炭素（２５ｍｇ）を加え、系内を水素ガスで置換した。水素雰囲気下、室温で１６時間撹拌した後、不溶物をセライト（登録商標）を用いてろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１０：０～１：９）にて精製し、表題化合物（６．８ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000080
 To a solution of 2-butyl-5-chloro-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (30 mg) in methanol (5 mL) 10% palladium carbon (25 mg) was added, and the inside of the system was replaced with hydrogen gas. After stirring at room temperature for 16 hours under a hydrogen atmosphere, the insoluble material was filtered off using Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 10: 0 to 1: 9) to give the title compound (6.8 mg) as a colorless oil.
実施例１２　２－ブチル－５－（メトキシメチル）－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ８１）の合成 Example 12 2-Butyl-5- (methoxymethyl) -7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (Compound A81) Synthesis of
Figure JPOXMLDOC01-appb-C000081
 （１）一酸化炭素雰囲気下、２－ブチル－５－クロロ－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（１００ｍｇ）、１，３－ビス（ジフェニルホスフィノ）プロパン（２６ｍｇ）、酢酸パラジウム（ＩＩ）（７．０ｍｇ）および炭酸カリウム（６５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（７ｍＬ）／エタノール（１ｍＬ）溶液を９０℃にて５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、エチル　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルボキシラート（１１０ｍｇ）を黄色固体として得た。
（２）エチル　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルボキシラート（１５０ｍｇ）のエタノール（１．５ｍＬ）溶液を氷冷し、水素化ホウ素ナトリウム（３２ｍｇ）を加え、室温にて１時間、加熱還流下１時間撹拌した。反応液に水を加え、クロロホルムで抽出し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９５：５）にて精製を行い、［２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－イル］メタノール（１２１ｍｇ）を無色固体として得た。
（３）［２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－イル］メタノール（２５ｍｇ）のテトラヒドロフラン（０．５ｍＬ）溶液を氷冷し、水素化ナトリウム（約６０％／オイル、３．５ｍｇ）を加え、１５分撹拌した。ヨードメタン（１７ｍｇ）を加え、室温で５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（２２ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000081
 (1) In a carbon monoxide atmosphere, 2-butyl-5-chloro-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine ( 100 mg), 1,3-bis (diphenylphosphino) propane (26 mg), palladium (II) acetate (7.0 mg) and potassium carbonate (65 mg) in N, N-dimethylformamide (7 mL) / ethanol (1 mL) Was stirred at 90 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50), and ethyl 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] octa -8-yl) pyrazolo [1,5-a] pyrimidine-5-carboxylate (110 mg) was obtained as a yellow solid.
(2) Ethyl 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine-5-carboxylate (150 mg) in ethanol (1.5 mL) The solution was ice-cooled, sodium borohydride (32 mg) was added, and the mixture was stirred at room temperature for 1 hr and with heating under reflux for 1 hr. Water was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 95: 5), and [2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] octa -8-yl) pyrazolo [1,5-a] pyrimidin-5-yl] methanol (121 mg) was obtained as a colorless solid.
(3) of [2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-5-yl] methanol (25 mg) The tetrahydrofuran (0.5 mL) solution was ice-cooled, sodium hydride (about 60% / oil, 3.5 mg) was added, and the mixture was stirred for 15 min. Iodomethane (17 mg) was added and stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (22 mg) as a colorless oil.
実施例１３　２－ブチル－５－（３－メチル－１，２，４－オキサジアゾール－５－イル）－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ７５）の合成 Example 13 2-Butyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -7- (3-oxa-8-azabicyclo [3.2.1] oct-8- Il) Synthesis of pyrazolo [1,5-a] pyrimidine (Compound A75)
Figure JPOXMLDOC01-appb-C000082
 エチル　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルボキシラート（５０ｍｇ）およびＮ－ヒドロキシエタンイミドアミド（１１ｍｇ）のエタノール（０．５ｍＬ）溶液に２．７Ｍナトリウムエトキシド／エタノール溶液（５７μＬ）を加え、封管中１００℃で７時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９５：５）にて精製を行い、表題化合物（２３ｍｇ）を黄色固体として得た。
Figure JPOXMLDOC01-appb-C000082
 Ethyl 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine-5-carboxylate (50 mg) and N-hydroxyethane To a solution of imidoamide (11 mg) in ethanol (0.5 mL) was added 2.7 M sodium ethoxide / ethanol solution (57 μL), and the mixture was stirred in a sealed tube at 100 ° C. for 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 95: 5) to obtain the title compound (23 mg) as a yellow solid.
実施例１４　２－［２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－イル］プロパン－２－オール（化合物Ａ５４）の合成 Example 14 2- [2-Butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-5-yl] propane-2 -Synthesis of all (compound A54)
Figure JPOXMLDOC01-appb-C000083
 　エチル　２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルボキシラート（２０ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液を氷冷し、メチルマグネシウムブロミド（３．０Ｍ／ジエチルエーテル、０．４２ｍＬ）を加え、室温にて１６時間撹拌した。飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～０：１００）にて精製を行い、表題化合物（１２ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000083
 Ethyl 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine-5-carboxylate (20 mg) in tetrahydrofuran (1 mL) The solution was ice-cooled, methylmagnesium bromide (3.0 M / diethyl ether, 0.42 mL) was added, and the mixture was stirred at room temperature for 16 hr. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with chloroform, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 0: 100) to give the title compound (12 mg) as a colorless oil.
実施例１５　２－ブチル－５－（ジフルオロメチル）－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ７４）の合成 Example 15 2-Butyl-5- (difluoromethyl) -7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (Compound A74) Synthesis of
Figure JPOXMLDOC01-appb-C000084
 （１）［２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－イル］メタノール（５０ｍｇ）のクロロホルム（１．５ｍＬ）溶液に１，１，１－トリアセトキシ－１，１－ジヒドロ－１，２－ベンゾヨードキソール－３－（１Ｈ）－オン（１０１ｍｇ）を加え、室温で５時間撹拌した。反応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後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製を行い、２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルバルデヒド（４９ｍｇ）を黄色油状物として得た。
（２）２－ブチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－５－カルバルデヒド（４９ｍｇ）のクロロホルム（１ｍＬ）溶液を氷冷し、三フッ化Ｎ，Ｎ－ジエチルアミノ硫黄（７５ｍｇ）を滴下し、室温で６時間撹拌した。氷冷下、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出した後、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製を行い、表題化合物（３１ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000084
 (1) of [2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-5-yl] methanol (50 mg) To a chloroform (1.5 mL) solution was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3- (1H) -one (101 mg), and the mixture was stirred at room temperature for 5 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50), and 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] octane -8-yl) pyrazolo [1,5-a] pyrimidine-5-carbaldehyde (49 mg) was obtained as a yellow oil.
(2) 2-butyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine-5-carbaldehyde (49 mg) in chloroform ( (1 mL) The solution was ice-cooled, N, N-diethylaminosulfur trifluoride (75 mg) was added dropwise, and the mixture was stirred at room temperature for 6 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (31 mg) as a colorless oil.
実施例１６　６－［７－（３，３－ジフルオロブチル）－２－メトキシピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ４６）の合成 Example 16 6- [7- (3,3-Difluorobutyl) -2-methoxypyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo Synthesis of [3.3.1.1 3,7 ] decane (Compound B46)
Figure JPOXMLDOC01-appb-C000085
 （１）７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオール（１００ｍｇ）に塩化ホスホリル（７６１μＬ）およびＮ，Ｎ－ジエチルアニリン（１６３μＬ）を加え、７０℃で２時間撹拌した。反応液を減圧下濃縮し、残渣を２－プロパノール（３ｍＬ）に溶解させた後、２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（１０８ｍｇ）およびジイソプロピルエチルアミン（３５７μＬ）を加えた。７０℃で２時間撹拌した後、反応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。フェーズセパレーターで有機層を分離し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～５０：５０、クロロホルム：メタノール＝９０：１０）にて精製を行い、６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（４５ｍｇ）を黄色アモルファスとして得た。また７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－オール（７２ｍｇ）を副生成物として得た。
（２）６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（２０ｍｇ）のメタノール（１ｍＬ）溶液に２８％ナトリウムメトキシド／メタノール溶液（０．２ｍＬ）を加え、室温で一晩撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、フェーズセパレーターで有機層を分離し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～２０：８０）にて精製し、表題化合物（１３．９ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000085
 (1) 7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazine-2,4-diol (100 mg) and phosphoryl chloride (761 μL) and N, N-diethyl Aniline (163 μL) was added and stirred at 70 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 2-propanol (3 mL), then 2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane (108 mg) and diisopropylethylamine (357 μL). ) Was added. After stirring at 70 ° C. for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50, chloroform: methanol = 90: 10), and 6- [2-chloro-7- (3,3- Difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane (45 mg) yellow Obtained as amorphous. 7- (3,3-difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decan-6-yl) pyrazolo [1,5-a] [1 , 3,5] triazin-2-ol (72 mg) was obtained as a by-product.
(2) 6- [2-Chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [ 3.3.1.1 3,7 ] To a solution of decane (20 mg) in methanol (1 mL) was added 28% sodium methoxide / methanol solution (0.2 mL), and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. Then, the organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-20: 80) to give the title compound (13.9 mg) as a colorless solid.
実施例１７　６－［７－（３，３－ジフルオロブチル）－２－（メチルスルホニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ７０）の合成 Example 17 6- [7- (3,3-Difluorobutyl) -2- (methylsulfonyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6 Synthesis of azatricyclo [3.3.1.1 3,7 ] decane (compound B70)
Figure JPOXMLDOC01-appb-C000086
 　６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（２６ｍｇ）のＤＭＳＯ（１．５ｍＬ）溶液にメタンスルフィン酸ナトリウム（２１ｍｇ）、ヨウ化銅（Ｉ）（２．６ｍｇ）、Ｌ－プロリン（３．１ｍｇ）、炭酸ナトリウム（２．９ｍｇ）を加え、マイクロウェーブ照射下、８０℃で９０分間撹拌した。不溶物をろ別した後、ろ液を分取ＨＰＬＣにて精製し、表題化合物（１２．５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000086
 6- [2-Chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3 .1.1 3,7] DMSO (1.5mL) was added sodium sulfinate decane (26mg) (21mg), copper iodide (I) (2.6mg), L- proline (3.1 mg), Sodium carbonate (2.9 mg) was added, and the mixture was stirred at 80 ° C. for 90 minutes under microwave irradiation. The insoluble material was filtered off, and the filtrate was purified by preparative HPLC to give the title compound (12.5 mg) as a colorless solid.
実施例１８　７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－カルボニトリル（化合物Ｂ９５）の合成 Example 18 7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a] Synthesis of [1,3,5] triazine-2-carbonitrile (Compound B95)
Figure JPOXMLDOC01-appb-C000087
 　６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（３０ｍｇ）のＤＭＳＯ溶液にシアン化カリウム（１７ｍｇ）を加え、マイクロ波照射下、１２０℃で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行った。表題化合物（２２．４ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000087
 6- [2-Chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3 .1.1 3,7] potassium cyanide (17 mg) was added to the DMSO solution of decane (30 mg), under microwave irradiation, the mixture was stirred for 1 hour at 120 ° C.. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20 to 0: 100). The title compound (22.4 mg) was obtained as a colorless solid.
実施例１９　６－［７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ４４）の合成 Example 19 6- [7- (3,3-Difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3. 1.1 3,7 ] Synthesis of decane (compound B44)
Figure JPOXMLDOC01-appb-C000088
 　６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（３５ｍｇ）のメタノール（１ｍＬ）溶液に１０％パラジウム炭素（１０ｍｇ）、トリエチルアミン（１３μＬ）を加え、水素雰囲気下４時間撹拌した。不溶物をセライト（登録商標）を用いてろ別した後、ろ液を減圧下濃縮し、残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９５：５）にて精製を行い、表題化合物（１７ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000088
 6- [2-Chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3 .1.1 3,7] decane in methanol (35mg) (1mL) was added 10% palladium-carbon (10 mg), triethylamine (13 [mu] L) was added, followed by stirring in a hydrogen atmosphere for 4 hours. The insoluble material was filtered off using Celite (registered trademark), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 95: 5). Compound (17 mg) was obtained as a colorless solid.
実施例２０　６－［２－シクロプロピル－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ８７）の合成 Example 20 6- [2-Cyclopropyl-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo Synthesis of [3.3.1.1 3,7 ] decane (Compound B87)
Figure JPOXMLDOC01-appb-C000089
 　６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（３０ｍｇ）、シクロプロパンボロン酸（３４ｍｇ）、リン酸カリウム（５０ｍｇ）、酢酸パラジウム（ＩＩ）（１．８ｍｇ）、トリシクロヘキシルホスフィン（０．６Ｍ／トルエン溶液、０．３ｍＬ）のトルエン（１ｍＬ）／水（０．１ｍＬ）溶液を、封管中１２０℃で一晩撹拌した。不溶物をろ別した後、ろ液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）および分取ＨＰＬＣにて精製を行い、表題化合物（３．５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000089
 6- [2-Chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3 .1.1 3,7] decane (30 mg), cyclopropane boronic acid (34 mg), potassium phosphate (50 mg), palladium acetate (II) (1.8mg), tricyclohexylphosphine (0.6M / toluene solution, A solution of 0.3 mL) in toluene (1 mL) / water (0.1 mL) was stirred overnight at 120 ° C. in a sealed tube. Insoluble material was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) and preparative HPLC to obtain the title compound (3.5 mg) as a colorless solid.
実施例２１　１－［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］エタノール（化合物Ｂ９８）の合成 Example 21 1- [7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5 -A] Synthesis of [1,3,5] triazin-2-yl] ethanol (Compound B98)
Figure JPOXMLDOC01-appb-C000090
 （１）６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（１９６ｍｇ）、トリブチル（１－エトキシビニル）スズ（２２４μＬ）およびビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（７２ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３ｍＬ）溶液を、マイクロ波照射下、１００℃で６０分撹拌した。不溶物をろ別した後、ろ液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去した。残渣をテトラヒドロフラン（５ｍＬ）に溶解し、２Ｍ塩酸（２．６ｍＬ）を加え、室温で一晩撹拌した。１Ｍ水酸化ナトリウム水溶液で中和した後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣を１０％フッ化カリウム／シリカゲルに吸着した後、カラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、１－［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］エタノン（７７ｍｇ）を無色固体として得た。
（２）１－［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］エタノン（３９ｍｇ）のエタノール（１０ｍＬ）溶液に水素化ホウ素ナトリウム（７．５ｍｇ）を加え、室温で１時間撹拌した。反応液にシリカゲルを加え、減圧下溶媒を留去した。カラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～８０：２０）にて精製を行い、表題化合物（１４．４ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000090
 (1) 6- [2-Chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [ 3.3.1.1 3,7 ] decane (196 mg), tributyl (1-ethoxyvinyl) tin (224 μL) and bis (triphenylphosphine) palladium (II) dichloride (72 mg) in N, N-dimethylformamide (72 mg) The 3 mL) solution was stirred at 100 ° C. for 60 minutes under microwave irradiation. Insoluble material was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), 2M hydrochloric acid (2.6 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was neutralized with 1M aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was adsorbed on 10% potassium fluoride / silica gel and purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20 to 0: 100) to give 1- [7- (3,3- Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-2 -Il] ethanone (77 mg) was obtained as a colorless solid.
(2) 1- [7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5 -A] Sodium borohydride (7.5 mg) was added to a solution of [1,3,5] triazin-2-yl] ethanone (39 mg) in ethanol (10 mL) and stirred at room temperature for 1 hour. Silica gel was added to the reaction solution, and the solvent was distilled off under reduced pressure. Purification was performed by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 80:20) to obtain the title compound (14.4 mg) as a colorless solid.
実施例２２　６－［７－（３，３－ジフルオロブチル）－２－（１，１－ジフルオロエチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ１０６）の合成 Example 22 6- [7- (3,3-Difluorobutyl) -2- (1,1-difluoroethyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2 -Oxa-6-azatricyclo [3.3.1.1 3,7 ] decane (compound B106) synthesis
Figure JPOXMLDOC01-appb-C000091
 　１－［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］エタノン（２１ｍｇ）に三フッ化Ｎ，Ｎ－ジエチルアミノ硫黄（２１３μＬ）、エタノール（６μＬ）およびクロロホルム（１ｍＬ）を加え、室温で４時間撹拌した。反応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。フェーズセパレーターで有機層を分離した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～０：１００）及び分取ＨＰＬＣにて精製を行った。表題化合物（１０．６ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000091
 1- [7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a] To [1,3,5] triazin-2-yl] ethanone (21 mg) were added N, N-diethylaminosulfur trifluoride (213 μL), ethanol (6 μL) and chloroform (1 mL), and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. After separating the organic layer with a phase separator, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 0: 100) and preparative HPLC. . The title compound (10.6 mg) was obtained as a colorless solid.
実施例２３　６－［７－（３，３－ジフルオロブチル）－２－（ジフルオロメトキシ）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ６７）の合成 Example 23 6- [7- (3,3-Difluorobutyl) -2- (difluoromethoxy) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6 Synthesis of azatricyclo [3.3.1.1 3,7 ] decane (compound B67)
Figure JPOXMLDOC01-appb-C000092
 　７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－オール（２８ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液にクロロジフルオロ酢酸ナトリウム（１８ｍｇ）および炭酸セリウム（４１ｍｇ）を加え、９０℃で１時間撹拌した。水を加え、酢酸エチルで抽出した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～０：１００）および分取ＨＰＬＣにて精製を行い、表題化合物（８．０ｍｇ）を得た。また副生成物として７－（３，３－ジフルオロブチル）－１－（ジフルオロメチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２（１Ｈ）－オン（８．５ｍｇ）を得た。
Figure JPOXMLDOC01-appb-C000092
 7- (3,3-difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decan-6-yl) pyrazolo [1,5-a] [1, To a solution of 3,5] triazin-2-ol (28 mg) in N, N-dimethylformamide (1 mL) was added sodium chlorodifluoroacetate (18 mg) and cerium carbonate (41 mg), and the mixture was stirred at 90 ° C. for 1 hour. Water was added and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 0: 100) and preparative HPLC to give the title compound (8.0 mg) was obtained. 7- (3,3-difluorobutyl) -1- (difluoromethyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl as a by-product ) Pyrazolo [1,5-a] [1,3,5] triazin-2 (1H) -one (8.5 mg) was obtained.
実施例２４　６－［７－（３，３－ジフルオロブチル）－２－（メトキシメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ５５）の合成 Example 24 6- [7- (3,3-Difluorobutyl) -2- (methoxymethyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6 Synthesis of azatricyclo [3.3.1.1 3,7 ] decane (compound B55)
Figure JPOXMLDOC01-appb-C000093
 （１）一酸化炭素雰囲気下、６－［２－クロロ－７－（３，３－ジフルオロブチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（２２２ｍｇ）、１，３－ビス（ジフェニルホスフィノ）プロパン（９５ｍｇ）、酢酸パラジウム（ＩＩ）（２６ｍｇ）および炭酸カリウム（１６０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３ｍＬ）／エタノール（１ｍＬ）溶液を７０℃にて５時間撹拌した。反応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後、有機層を水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～３０：７０）にて精製し、エチル　７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－カルボキシラート（１６５ｍｇ）を無色固体として得た。
（２）エチル　７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－カルボキシラート（１２６ｍｇ）のエタノール（１０ｍＬ）溶液に水素化ホウ素ナトリウム（２３ｍｇ）を加え、７０℃で３０分撹拌した。反応液にシリカゲルを加え、減圧下溶媒を留去した。カラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～８０：２０）にて精製を行い、［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］メタノール（１１４ｍｇ）を無色固体として得た。
（３）［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］メタノール（２０ｍｇ）のテトラヒドロフラン（１ｍＬ）に水素化ナトリウム（約６０％／オイル、３．１ｍｇ）を加え、１５分間撹拌した。ヨードメタン（６．６μＬ）を加え、室温で３時間、５０℃で１時間撹拌した。反応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後、フェーズセパレーターで有機層を分離した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、表題化合物（１０．１ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000093
 (1) Under a carbon monoxide atmosphere, 6- [2-chloro-7- (3,3-difluorobutyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2- Oxa-6-azatricyclo [3.3.1.1 3,7 ] decane (222 mg), 1,3-bis (diphenylphosphino) propane (95 mg), palladium (II) acetate (26 mg) and potassium carbonate (160 mg ) In N, N-dimethylformamide (3 mL) / ethanol (1 mL) was stirred at 70 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water. After drying the organic layer with anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 30:70), and ethyl 7- (3,3-difluorobutyl) -4- (2-oxa-6-azatricyclo [ 3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-2-carboxylate (165 mg) was obtained as a colorless solid.
(2) Ethyl 7- (3,3-difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a [1,3,5] Triazine-2-carboxylate (126 mg) in ethanol (10 mL) was added sodium borohydride (23 mg), and the mixture was stirred at 70 ° C. for 30 min. Silica gel was added to the reaction solution, and the solvent was distilled off under reduced pressure. Purification was performed by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 80:20), and [7- (3,3-difluorobutyl) -4- (2-oxa-6-azatricyclo [3. 3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a] [1,3,5] triazin-2-yl] methanol (114 mg) was obtained as a colorless solid.
(3) [7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a ] [1,3,5] Triazin-2-yl] methanol (20 mg) in tetrahydrofuran (1 mL) was added sodium hydride (about 60% / oil, 3.1 mg) and stirred for 15 minutes. Iodomethane (6.6 μL) was added, and the mixture was stirred at room temperature for 3 hours and at 50 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give the title compound (10.1 mg) as a colorless oil. .
実施例２５　６－［７－（３，３－ジフルオロブチル）－２－（フルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ６８）の合成 Example 25 6- [7- (3,3-Difluorobutyl) -2- (fluoromethyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6 Synthesis of azatricyclo [3.3.1.1 3,7 ] decane (compound B68)
Figure JPOXMLDOC01-appb-C000094
 　［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］メタノール（２１ｍｇ）のクロロホルム（２ｍＬ）溶液に三フッ化Ｎ，Ｎ－ジエチルアミノ硫黄（２２μＬ）を加え、室温で９０分間撹拌した。反応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後、フェーズセパレーターで有機層を分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、表題化合物（１２ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000094
 [7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a] [1 , 3,5] triazin-2-yl] methanol (21 mg) in chloroform (2 mL) was added N, N-diethylaminosulfur trifluoride (22 μL) and stirred at room temperature for 90 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give the title compound (12 mg) as a colorless solid.
実施例２６　６－［７－（３，３－ジフルオロブチル）－２－（ジフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ５６）の合成 Example 26 6- [7- (3,3-Difluorobutyl) -2- (difluoromethyl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6 Synthesis of azatricyclo [3.3.1.1 3,7 ] decane (compound B56)
Figure JPOXMLDOC01-appb-C000095
 （１）［７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカ－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］メタノール（４５．６ｍｇ）のクロロホルム（３ｍＬ）溶液に１，１，１－トリアセトキシ－１，１－ジヒドロ－１，２－ベンゾヨードキソール－３－（１Ｈ）－オン（１２７ｍｇ）を加え、室温で１時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液および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後、フェーズセパレーターにて有機層を分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－カルバルデヒド（５４ｍｇ）を無色油状物として得た。
（２）７－（３，３－ジフルオロブチル）－４－（２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－カルバルデヒド（４５．３ｍｇ）のクロロホルム（１ｍＬ）溶液に三フッ化Ｎ，Ｎ－ジエチルアミノ硫黄（４８μＬ）を加え、室温で３０分間撹拌した。反応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後、フェーズセパレーターで有機層を分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、表題化合物（３３ｍｇ）を無色アモルファスとして得た。
Figure JPOXMLDOC01-appb-C000095
 (1) [7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] dec-6-yl) pyrazolo [1,5-a ] [1,3,5] triazin-2-yl] methanol (45.6 mg) in chloroform (3 mL) in 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol -3- (1H) -one (127 mg) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the reaction solution, followed by extraction with chloroform, and then the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100), and 7- (3,3-difluorobutyl) -4- (2-Oxa-6-azatricyclo [3.3.1.1 3,7 ] decan-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-2-carbaldehyde (54 mg) Was obtained as a colorless oil.
(2) 7- (3,3-Difluorobutyl) -4- (2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decan-6-yl) pyrazolo [1,5-a] To a solution of [1,3,5] triazine-2-carbaldehyde (45.3 mg) in chloroform (1 mL) was added N, N-diethylaminosulfur trifluoride (48 μL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give the title compound (33 mg) as a colorless amorphous product.
実施例２７　１－メチル－４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサノール（化合物Ａ４７および化合物Ａ４８）の合成 Example 27 1-methyl-4- [5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl Synthesis of cyclohexanol (compound A47 and compound A48)
Figure JPOXMLDOC01-appb-C000096
 （１）２－（１，４－ジオキサスピロ［４．５］デカ－８－イル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（１６０ｍｇ）の酢酸（２ｍＬ）／水（０．５ｍＬ）溶液を１００℃で３時間撹拌した。反応液を減圧下濃縮した後、残渣をクロロホルムに溶解し、飽和炭酸水素ナトリウム水溶液で洗浄した。フェーズセパレーターで有機層を分離した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝９８：２～８０：２０）にて精製を行い、４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサノン（１４５ｍｇ）を無色固体として得た。
（２）４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサノン（２０ｍｇ）のテトラヒドロフラン（０．５ｍＬ）溶液にメチルマグネシウムブロミド（３Ｍ／ジエチルエーテル溶液、６０μＬ）を加え、室温で３０分撹拌した。反応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後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、残渣を分取ＨＰＬＣにて精製を行い、表題化合物の２つの幾何異性体を得た。保持時間の短い異性体（６．０９ｍｇ、化合物Ａ４７）と保持時間の長い異性体（１２．８６ｍｇ、化合物Ａ４８）をそれぞれ無色固体として得た。
Figure JPOXMLDOC01-appb-C000096
 (1) 2- (1,4-Dioxaspiro [4.5] dec-8-yl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) A solution of pyrazolo [1,5-a] pyrimidine (160 mg) in acetic acid (2 mL) / water (0.5 mL) was stirred at 100 ° C. for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with a saturated aqueous sodium bicarbonate solution. After separating the organic layer with a phase separator, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 98: 2 to 80:20) to give 4- [5- Methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] cyclohexanone (145 mg) was obtained as a colorless solid.
(2) 4- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] cyclohexanone (20 mg ) In tetrahydrofuran (0.5 mL) was added methylmagnesium bromide (3 M / diethyl ether solution, 60 μL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain two geometric isomers of the title compound. An isomer with a short retention time (6.09 mg, compound A47) and an isomer with a long retention time (12.86 mg, compound A48) were obtained as colorless solids, respectively.
実施例２８　４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］－１－（トリフルオロメチル）シクロヘキサノール（化合物Ａ４９および化合物Ａ５０）の合成 Example 28 4- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] -1- Synthesis of (trifluoromethyl) cyclohexanol (Compound A49 and Compound A50)
Figure JPOXMLDOC01-appb-C000097
 　４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサノン（３０ｍｇ）のテトラヒドロフラン（０．５ｍＬ）溶液にトリフルオロメチルトリメチルシラン（３７ｍｇ）およびテトラブチルアンモニウムフルオリド（約１Ｍ／テトラヒドロフラン溶液、１８０μＬ）を加え、室温で３０分撹拌した。テトラブチルアンモニウムフルオリド（１００μＬ）を追加し、さらに１時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。有機層をフェーズセパレーターで分離した後、減圧下溶媒を留去し、残渣を分取ＬＣ／ＭＳにて精製を行った。表題化合物の２つの幾何異性体を得た。保持時間の短い異性体（１６．０ｍｇ、化合物Ａ４９）と保持時間の長い異性体（７．９０ｍｇ、化合物Ａ５０）をそれぞれ無色固体として得た。
Figure JPOXMLDOC01-appb-C000097
 4- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] cyclohexanone (30 mg) in tetrahydrofuran (0.5 mL) solution was added with trifluoromethyltrimethylsilane (37 mg) and tetrabutylammonium fluoride (about 1 M / tetrahydrofuran solution, 180 μL), and stirred at room temperature for 30 minutes. Tetrabutylammonium fluoride (100 μL) was added, and the mixture was further stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. After separating the organic layer with a phase separator, the solvent was distilled off under reduced pressure, and the residue was purified by preparative LC / MS. Two geometric isomers of the title compound were obtained. An isomer with a short retention time (16.0 mg, compound A49) and an isomer with a long retention time (7.90 mg, compound A50) were obtained as colorless solids, respectively.
実施例２９　２－（２－シクロプロピルエチル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ２０３）の合成 Example 29 2- (2-cyclopropylethyl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine ( Synthesis of compound A203)
Figure JPOXMLDOC01-appb-C000098
 （１）２－ブロモ－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（５０ｍｇ）のアセトニトリル（１ｍＬ）溶液にエチニルシクロプロパン（１３μＬ）、トリエチルアミン（６５μＬ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物（１ｍｇ）、ヨウ化銅（Ｉ）（０．３ｍｇ）を加え、室温で１時間、８５℃で２時間撹拌した。エチニルシクロプロパン（１２０μＬ）、トリエチルアミン（３６８μＬ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物（３２ｍｇ）、ヨウ化銅（Ｉ）（８．５ｍｇ）を追加し、８５℃で３時間撹拌した。不溶物をセライト（登録商標）を用いてろ別後、ろ液を分取ＨＰＬＣにて精製を行い、２－（シクロプロピルエチニル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（１９ｍｇ）を橙色油状物として得た。
（２）２－（シクロプロピルエチニル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（１１ｍｇ）のメタノール（０．５ｍＬ）溶液に１０％パラジウム炭素（２ｍｇ）を加え、系内を水素ガスで置換した後、水素雰囲気下、室温で２時間撹拌した。不溶物をセライト（登録商標）を用いてろ別後、ろ液を分取ＨＰＬＣにて精製を行い、得られた固体をヘキサンで洗浄した。表題化合物（１．６ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000098
 (1) 2-Bromo-5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine (50 mg) in acetonitrile (1 mL ) Ethynylcyclopropane (13 μL), triethylamine (65 μL), bis (triphenylphosphine) palladium (II) dichloride (1 mg), copper (I) iodide (0.3 mg) were added to the solution, and the mixture was stirred at room temperature for 1 hour. And stirred at 85 ° C. for 2 hours. Ethinylcyclopropane (120 μL), triethylamine (368 μL), bis (triphenylphosphine) palladium (II) dichloride (32 mg), copper (I) iodide (8.5 mg) were added, and the mixture was stirred at 85 ° C. for 3 hours. did. The insoluble material was filtered off using Celite (registered trademark), and the filtrate was purified by preparative HPLC, and 2- (cyclopropylethynyl) -5-methyl-7- (3-oxa-8-azabicyclo [3 2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (19 mg) was obtained as an orange oil.
(2) 2- (Cyclopropylethynyl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (11 mg) After adding 10% palladium carbon (2 mg) to a methanol (0.5 mL) solution and replacing the system with hydrogen gas, the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was filtered off using Celite (registered trademark), the filtrate was purified by preparative HPLC, and the resulting solid was washed with hexane. The title compound (1.6 mg) was obtained as a colorless solid.
実施例３０　５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）－２－（フェノキシメチル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ９２）の合成 Example 30 5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -2- (phenoxymethyl) pyrazolo [1,5-a] pyrimidine (Compound A92) Synthesis of
Figure JPOXMLDOC01-appb-C000099
 （１）５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－カルボン酸エチル（２００ｍｇ）のテトラヒドロフラン（５ｍＬ）溶液を氷冷し、水素化リチウムアルミニウム（７２ｍｇ）を加え、氷冷下２．５時間、室温で２．５時間撹拌した。反応液に硫酸ナトリウム１０水和物を加え、室温で一晩撹拌した後、不溶物をセライト（登録商標）を用いてろ別した後。ろ液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～１５：８５）にて精製を行い、［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］メタノール（１３８ｍｇ）を無色固体として得た。
（２）［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］メタノール（２０ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液にフェノール（１０ｍｇ）、アゾジカルボン酸エチル（２．２Ｍ／トルエン溶液、５０μＬ）およびトリフェニルホスフィン（２９ｍｇ）を加え、室温で２０時間撹拌した。反応液に珪藻土を加え、減圧下溶媒を留去した後、カラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８５：１５～４０：６０）および分取ＨＰＬＣにて精製を行った。表題化合物（１０ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000099
 (1) Tetrahydrofuran of ethyl 5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine-2-carboxylate (200 mg) (5 mL) The solution was ice-cooled, lithium aluminum hydride (72 mg) was added, and the mixture was stirred under ice-cooling for 2.5 hours and at room temperature for 2.5 hours. After adding sodium sulfate decahydrate to the reaction solution and stirring overnight at room temperature, the insoluble material was filtered off using Celite (registered trademark). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-15: 85), and [5-methyl-7- (3-oxa-8- Azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] methanol (138 mg) was obtained as a colorless solid.
(2) of [5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] methanol (20 mg) To a tetrahydrofuran (1 mL) solution were added phenol (10 mg), ethyl azodicarboxylate (2.2 M / toluene solution, 50 μL) and triphenylphosphine (29 mg), and the mixture was stirred at room temperature for 20 hours. Diatomaceous earth was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 85: 15 to 40:60) and preparative HPLC. The title compound (10 mg) was obtained as a colorless solid.
実施例３１　５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）－２－（｛［２－（トリフルオロメチル）ピリジン－４－イル］オキシ｝メチル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１６２）の合成 Example 31 5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -2-({[2- (trifluoromethyl) pyridin-4-yl] oxy } Methyl) pyrazolo [1,5-a] pyrimidine (Compound A162)
Figure JPOXMLDOC01-appb-C000100
 　［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］メタノール（３０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）溶液に水素化ナトリウム（約６０％／オイル、６．６ｍｇ）を加え、３０分撹拌した。ここに４－ブロモ－２－（トリフルオロメチル）ピリジン（７４ｍｇ）を加え、室温で１．５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、フェーズセパレーターで有機層を分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９５：５～１０：９０）にて精製を行い、表題化合物（１４ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000100
 [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] methanol (30 mg) in N, N Sodium hydride (about 60% / oil, 6.6 mg) was added to a dimethylformamide (2 mL) solution and stirred for 30 minutes. 4-Bromo-2- (trifluoromethyl) pyridine (74 mg) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5 to 10:90) to give the title compound (14 mg) as a colorless solid.
実施例３２　２－（１，１－ジフルオロブチル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１６７）の合成 Example 32 2- (1,1-difluorobutyl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine Synthesis of (Compound A167)
Figure JPOXMLDOC01-appb-C000101
 　１－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］ブタン－１－オン（３０ｍｇ）にクロロホルム（２０μＬ）および三フッ化Ｎ，Ｎ－ジエチルアミノ硫黄（２３ｍｇ）を加え、室温で５時間、５０℃で２．５時間、さらに室温で３日間撹拌した。氷冷した後、反応液をクロロホルムで希釈し、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。有機層を乾燥した後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～５０：５０）にて精製を行い、表題化合物（３ｍｇ）を淡黄色固体として得た。
Figure JPOXMLDOC01-appb-C000101
 1- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] butan-1-one ( 30 mg) was added chloroform (20 μL) and N, N-diethylaminosulfur trifluoride (23 mg), and the mixture was stirred at room temperature for 5 hours, at 50 ° C. for 2.5 hours, and further at room temperature for 3 days. After cooling with ice, the reaction mixture was diluted with chloroform, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-50: 50) to give the title compound (3 mg) as a pale product. Obtained as a yellow solid.
実施例３３　２－（３－フルオロプロピル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１４０）の合成 Example 33 2- (3-Fluoropropyl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine (compound A140)
Figure JPOXMLDOC01-appb-C000102
 　３－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］プロパン－１－オール（６０ｍｇ）のクロロホルム（２ｍＬ）溶液を氷冷し、ビス（２－メトキシエチル）アミノ硫黄三フッ化物（８８ｍｇ）を加え、室温で１５時間撹拌した。反応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後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別の後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝３４：６６～０：１００）にて精製を行い、表題化合物（２５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000102
 3- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] propan-1-ol ( 60 mg) in chloroform (2 mL) was ice-cooled, bis (2-methoxyethyl) aminosulfur trifluoride (88 mg) was added, and the mixture was stirred at room temperature for 15 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 34: 66-0: 100) to give the title compound (25 mg). Obtained as a colorless solid.
実施例３４　５－メチル－２－（３－メチルシクロブチル）－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１９６）の合成 Example 34 5-Methyl-2- (3-methylcyclobutyl) -7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine ( Synthesis of compound A196)
Figure JPOXMLDOC01-appb-C000103
 　実施例１と同様の方法により５－メチル－２－（３－メチリデンシクロブチル）ピラゾロ［１，５－ａ］ピリミジン－７－オール（不純物として５－メチル－２－（３－メチルシクロブチル）ピラゾロ［１，５－ａ］ピリミジン－７－オールを含む、１１５ｍｇ）より５－メチル－２－（３－メチリデンシクロブチル）－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（４０ｍｇ、無色固体）および表題化合物（１０ｍｇ、無色固体）を得た。
Figure JPOXMLDOC01-appb-C000103
 5-Methyl-2- (3-methylidenecyclobutyl) pyrazolo [1,5-a] pyrimidin-7-ol (5-methyl-2- (3-methylcyclobutyl as an impurity) was prepared in the same manner as in Example 1. ) From pyrazolo [1,5-a] pyrimidin-7-ol, 115 mg) from 5-methyl-2- (3-methylidenecyclobutyl) -7- (3-oxa-8-azabicyclo [3.2. 1] Octane-8-yl) pyrazolo [1,5-a] pyrimidine (40 mg, colorless solid) and the title compound (10 mg, colorless solid) were obtained.
実施例３５　６－［７－（３，３－ジメチルシクロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（化合物Ｂ５９）の合成 Example 35 6- [7- (3,3-Dimethylcyclobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [ 3.3.1.1 3,7 ] Synthesis of decane (compound B59)
Figure JPOXMLDOC01-appb-C000104
 　６－［２－メチル－７－（スピロ［２．３］ヘキサ－５－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１3,7］デカン（２５ｍｇ）の酢酸（３．５ｍＬ）／水（１．８ｍＬ）溶液に１０％Ｐｔ‐活性炭素（１０ｍｇ）を加え、水素雰囲気下、室温で１２０時間撹拌した。不溶物をセライト（登録商標）を用いてろ別後、ろ液を減圧下濃縮し、残渣を分取ＨＰＬＣにて精製し、表題化合物（４ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000104
 6- [2-Methyl-7- (spiro [2.3] hex-5-yl) pyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6- To a solution of azatricyclo [3.3.1.1 3,7 ] decane (25 mg) in acetic acid (3.5 mL) / water (1.8 mL) was added 10% Pt-activated carbon (10 mg), and a hydrogen atmosphere at room temperature was added. For 120 hours. The insoluble material was filtered off using Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (4 mg) as a colorless solid.
実施例３６　ｔｅｒｔ－ブチル　３－（７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）ピペリジン－１－カルボキシラート（化合物Ｂ２３）の合成 Example 36 Synthesis of tert-butyl 3- (7-butyl-2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl) piperidine-1-carboxylate (Compound B23)
Figure JPOXMLDOC01-appb-C000105
 　Ｎ－（３－ブチル－１Ｈ－ピラゾール－５－イル）エタンイミドアミド（１００ｍｇ）、ｔｅｒｔ－ブチル　３－エチル　ピペリジン－１，３－ジカルボキシラート（４０９ｍｇ）、ナトリウムエトキシド／エタノール溶液（約２０％、１ｍＬ）およびエタノール（１ｍＬ）の混合物を８５℃で４日間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した後、フェーズセパレーターで有機層を分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９５：５～５０：５０）にて精製を行い、表題化合物（６７ｍｇ）を淡黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000105
 N- (3-butyl-1H-pyrazol-5-yl) ethanimidoamide (100 mg), tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (409 mg), sodium ethoxide / ethanol solution (about 20 %, 1 mL) and ethanol (1 mL) were stirred at 85 ° C. for 4 days. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 95: 5 to 50:50) to give the title compound (67 mg) as a pale yellow oil. .
実施例３７　Ｎ－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝アセトアミド（化合物Ｂ７７）の合成 Example 37 N-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} acetamide (Compound B77)
Figure JPOXMLDOC01-appb-C000106
 （１）ｔｅｒｔ－ブチル　｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝カルバマート（２６０ｍｇ）の酢酸エチル（３ｍＬ）溶液に４ＭＨＣｌ／酢酸エチル溶液（１．４ｍＬ）を加え、室温で１時間撹拌した。反応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後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮し、残渣を再結晶（ヘキサン：酢酸エチル＝１：１）にて精製を行い、（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（９２ｍｇ）を無色固体として得た。
（２）（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（２０ｍｇ）のクロロホルム（０．１９ｍＬ）溶液に無水酢酸（６μＬ）を加え、室温で２時間撹拌した。反応液を減圧下濃縮した後、残渣を再結晶（ヘキサン：酢酸エチル＝１：１）にて精製を行い、表題化合物（１８．５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000106
 (1) tert-butyl {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] To a solution of −8-azabicyclo [3.2.1] oct-3-yl} carbamate (260 mg) in ethyl acetate (3 mL) was added 4M HCl / ethyl acetate solution (1.4 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by recrystallization (hexane: ethyl acetate = 1: 1) to give (3-exo) -8- [7- (3, 3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] octane-3-amine (92 mg) colorless Obtained as a solid.
(2) (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo Acetic anhydride (6 μL) was added to a solution of [3.2.1] octane-3-amine (20 mg) in chloroform (0.19 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by recrystallization (hexane: ethyl acetate = 1: 1) to give the title compound (18.5 mg) as a colorless solid.
実施例３８　Ｎ－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝尿素（化合物Ｂ７８）の合成 Example 38 N-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} urea (Compound B78)
Figure JPOXMLDOC01-appb-C000107
 　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（２０ｍｇ）の２－プロパノール（０．１１ｍＬ）溶液にトリメチルシリルイソシアネート（１１μＬ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣を再結晶（ヘキサン：酢酸エチル＝１：１）にて精製を行い、表題化合物（１０ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000107
 (3-exo) -8- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Trimethylsilyl isocyanate (11 μL) was added to a solution of octane-3-amine (20 mg) in 2-propanol (0.11 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by recrystallization (hexane: ethyl acetate = 1: 1) to give the title compound (10 mg) as a colorless solid.
実施例３９　｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝カルバミン酸メチル（化合物Ｂ８５）の合成 Example 39 {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8- Synthesis of methyl azabicyclo [3.2.1] oct-3-yl} carbamate (Compound B85)
Figure JPOXMLDOC01-appb-C000108
 　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（３３ｍｇ）のクロロホルム（０．３８ｍＬ）溶液にトリエチルアミン（４２μＬ）およびクロロギ酸メチル（１５μＬ）を加え、室温で２時間撹拌した。反応液をクロロホルムで希釈した後、水で洗浄し、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、表題化合物（３１ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000108
 (3-exo) -8- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Triethylamine (42 μL) and methyl chloroformate (15 μL) were added to a solution of octane-3-amine (33 mg) in chloroform (0.38 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give the title compound (31 mg). Obtained as a colorless solid.
実施例４０　４－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝－２，４－ジヒドロ－３Ｈ－１，２，４－トリアゾール－３－オン（化合物Ｂ１８４）の合成 Example 40 4-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} -2,4-dihydro-3H-1,2,4-triazol-3-one (Compound B184)
Figure JPOXMLDOC01-appb-C000109
 　トリホスゲン（５．６ｍｇ）のクロロホルム（０．５ｍＬ）溶液に、氷冷下、（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（０．０２０ｇ）およびトリエチルアミン（１６μＬ）を加え、室温で１時間撹拌した。氷冷下、ホルミルヒドラジン（５，１ｍｇ）およびトリエチルアミン（１６μＬ）を加え、室温で一晩撹拌した。反応液を減圧下濃縮した後、残渣に水酸化カリウム（１０ｍｇ）の１Ｍメタノール溶液を加え、マイクロ波照射下、９０℃で１時間撹拌した。反応液を１．２Ｍ塩酸で酸性にした後、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝９９：１～９８：２）にて精製を行い、表題化合物（１０．６ｍｇ）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000109
 To a solution of triphosgene (5.6 mg) in chloroform (0.5 mL) under ice-cooling, (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] Triazin-4-yl] -8-azabicyclo [3.2.1] octane-3-amine (0.020 g) and triethylamine (16 μL) were added, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, formylhydrazine (5, 1 mg) and triethylamine (16 μL) were added, and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, a 1M methanol solution of potassium hydroxide (10 mg) was added to the residue, and the mixture was stirred at 90 ° C. for 1 hour under microwave irradiation. The reaction mixture was acidified with 1.2M hydrochloric acid and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 99: 1 to 98: 2) to give the title compound (10.6 mg) as a colorless oil.
実施例４１　Ｎ－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝メタンスルホンアミド（化合物Ｂ８６）の合成 Example 41 N-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} methanesulfonamide (Compound B86)
Figure JPOXMLDOC01-appb-C000110
 　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（３３ｍｇ）のクロロホルム（０．３８ｍＬ）溶液を氷冷した後、トリエチルアミン（３９μＬ）およびメタンスルホニルクロリド（８μＬ）を加え、室温で２時間撹拌した。反応液に水を加え、クロロホルムで抽出した後、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧下濃縮し、残渣を再結晶（ヘキサン：酢酸エチル＝１：１）にて精製を行い、表題化合物（２５．７ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000110
 (3-exo) -8- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] A solution of octane-3-amine (33 mg) in chloroform (0.38 mL) was ice-cooled, triethylamine (39 μL) and methanesulfonyl chloride (8 μL) were added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution and extracted with chloroform, and then the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by recrystallization (hexane: ethyl acetate = 1: 1) to obtain the title compound (25.7 mg) as a colorless solid.
実施例４２　１－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝－３－メチルイミダゾリジン－２－オン（化合物Ｂ１８２）の合成 Example 42 1-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} -3-methylimidazolidin-2-one (Compound B182)
Figure JPOXMLDOC01-appb-C000111
 （１）（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－アミン（３０ｍｇ）の２－プロパノール（１ｍＬ）溶液に2－クロロエチルイソシアネート（１０μＬ）を加え、室温で３０分撹拌した。反応液を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、無色固体（４０ｍｇ）を得た。得られた固体をテトラヒドロフラン（５ｍＬ）に溶解し、氷冷した後、水素化ナトリウム（約６０％／オイル、１０．６ｍｇ）を加え、３０分撹拌した。室温で２時間、４０℃で２時間撹拌した後、水を加え、クロロホルムで抽出した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）および分取ＨＰＬＣにて精製を行い、１－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝イミダゾリジン－２－オン（１５．７ｍｇ）を無色固体として得た。
（２）１－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝イミダゾリジン－２－オン（９．０ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液を氷冷し、水素化ナトリウム（約６０％／オイル、４．３ｍｇ）を加え、３０分撹拌した。ヨードメタン（１５．２ｍｇ）を加え、室温で２時間撹拌した後、反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝１００：０～０：１００）にて精製を行い、表題化合物（６．６ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000111
 (1) (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo 2-Chloroethyl isocyanate (10 μL) was added to a solution of [3.2.1] octane-3-amine (30 mg) in 2-propanol (1 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give a colorless solid (40 mg). The obtained solid was dissolved in tetrahydrofuran (5 mL), ice-cooled, sodium hydride (about 60% / oil, 10.6 mg) was added, and the mixture was stirred for 30 min. After stirring at room temperature for 2 hours and at 40 ° C. for 2 hours, water was added and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) and preparative HPLC, and 1-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] octa -3-yl} imidazolidin-2-one (15.7 mg) was obtained as a colorless solid.
(2) 1-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- A solution of 8-azabicyclo [3.2.1] oct-3-yl} imidazolidin-2-one (9.0 mg) in tetrahydrofuran (1 mL) is ice-cooled and sodium hydride (about 60% / oil, 4. 3 mg) was added and stirred for 30 minutes. After adding iodomethane (15.2 mg) and stirring at room temperature for 2 hours, water was added to the reaction solution and extracted with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 100: 0 to 0: 100) to obtain the title compound (6.6 mg) as a colorless solid.
実施例４３　７－（３，３－ジフルオロブチル）－４－［（３－ｅｎｄｏ）－３－メトキシ－８－アザビシクロ［３．２．１］オクタ－８－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン（化合物Ｂ６５）の合成 Example 43 7- (3,3-difluorobutyl) -4-[(3-endo) -3-methoxy-8-azabicyclo [3.2.1] oct-8-yl] -2-methylpyrazolo [1, Synthesis of 5-a] [1,3,5] triazine (Compound B65)
Figure JPOXMLDOC01-appb-C000112
 　（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－オール（化合物Ｂ９、１８ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）溶液に水素化ナトリウム（約６０％／オイル、４．１ｍｇ）を加え、室温で３０分撹拌した。ヨードメタン（６μＬ）を加え、室温で４時間撹拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣を分取ＨＰＬＣにて精製を行い、表題化合物（１０ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000112
 (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Sodium hydride (approximately 60% / oil, 4.1 mg) was added to a solution of octan-3-ol (Compound B9, 18 mg) in N, N-dimethylformamide (0.5 mL), and the mixture was stirred at room temperature for 30 minutes. Stir. Iodomethane (6 μL) was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10 mg) as a colorless solid.
実施例４４　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボキサミド（化合物Ｂ９９）の合成 Example 44 (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] Synthesis of octane-3-carboxamide (Compound B99)
Figure JPOXMLDOC01-appb-C000113
 （１）７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オール（１００ｍｇ）、メチル　（３－ｅｘｏ）－８－アザビシクロ［３．２．１］オクタン－３－カルボキシラート（１４０ｍｇ）およびジイソプロピルエチルアミン（０．２２ｍＬ）の１，４－ジオキサン溶液にブロモトリピロリジノホスホニウムヘキサフルオロホスファート（２８９ｍｇ）を加え、７０℃で３時間撹拌した。反応液をクロロホルムで希釈した後、飽和炭酸水素ナトリウム水溶液で洗浄し、有機層をフェーズセパレーターで分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、メチル　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボキシラート（１１５ｍｇ）を無色固体として得た。
（２）メチル　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボキシラート（１１５ｍｇ）のメタノール（２ｍＬ）溶液に４Ｍ水酸化ナトリウム水溶液（０．２２ｍＬ）を加え、室温で３時間撹拌した。反応液に１Ｍ塩酸を加えて酸性にした後、酢酸エチルにて抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別した後、減圧下溶媒を留去し、（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボン酸（１０７ｍｇ）を無色固体として得た。
（３）（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボン酸（３５ｍｇ）２８％アンモニア水（９μＬ）、１－ヒドロキシベンゾトリアゾール１水和物（２１ｍｇ）および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（２７ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液を室温で１７時間撹拌した。反応液をろ過した後、ろ液を分取ＨＰＬＣにて精製を行い、表題化合物（２４ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000113
 (1) 7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-ol (100 mg), methyl (3-exo) -8-azabicyclo [3.2.1] Bromotripyrrolidinophosphonium hexafluorophosphate (289 mg) was added to a 1,4-dioxane solution of octane-3-carboxylate (140 mg) and diisopropylethylamine (0.22 mL) at 70 ° C. Stir for 3 hours. The reaction solution was diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100), and methyl (3-exo) -8- [7- ( 3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] octane-3-carboxylate (115 mg ) Was obtained as a colorless solid.
(2) Methyl (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8- To a solution of azabicyclo [3.2.1] octane-3-carboxylate (115 mg) in methanol (2 mL) was added 4M aqueous sodium hydroxide solution (0.22 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3 , 5] triazin-4-yl] -8-azabicyclo [3.2.1] octane-3-carboxylic acid (107 mg) was obtained as a colorless solid.
(3) (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] Octane-3-carboxylic acid (35 mg) 28% aqueous ammonia (9 μL), 1-hydroxybenzotriazole monohydrate (21 mg) and 1-ethyl-3- (3-dimethylaminopropyl) A solution of carbodiimide hydrochloride (27 mg) in N, N-dimethylformamide (1 mL) was stirred at room temperature for 17 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to give the title compound (24 mg) as a colorless solid.
実施例４５　Ｎ－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝－２－ヒドロキシアセトアミド（化合物Ｂ１０５）の合成 Example 45 N-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} -2-hydroxyacetamide (Compound B105)
Figure JPOXMLDOC01-appb-C000114
 　２－（｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝アミノ）－２－オキソエチル　アセタート（１３ｍｇ）のメタノール（０．５８ｍＬ）溶液に炭酸カリウム（４．０ｍｇ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣を飽和食塩水で希釈し、クロロホルムで抽出した。有機層をフェーズセパレーターで分離し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製し、表題化合物（９，４ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000114
 2-({(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8- To a solution of azabicyclo [3.2.1] oct-3-yl} amino) -2-oxoethyl acetate (13 mg) in methanol (0.58 mL) was added potassium carbonate (4.0 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated brine and extracted with chloroform. The organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give the title compound (9.4 mg) as a colorless solid.
実施例４６　１－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝－１－メチル尿素（化合物Ｂ１２１）の合成 Example 46 1-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} -1-methylurea (Compound B121)
Figure JPOXMLDOC01-appb-C000115
 （１）ｔｅｒｔ－ブチル　｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝カルバマート（２０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．４４ｍＬ）溶液に水素化ナトリウム（約６０％／オイル、２．３ｍｇ）を加え、室温で１５分間撹拌した。ヨードメタン（０．０１ｍＬ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製し、｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝メチルカルバミン酸ｔｅｒｔ－ブチル（１９．１ｍｇ、化合物Ｂ１０８）を無色固体として得た。
（２）｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝メチルカルバミン酸ｔｅｒｔ－ブチル（１５ｍｇ）の酢酸エチル（０．３２ｍＬ）溶液に４ＭＨＣｌ／酢酸エチル溶液（０．１６ｍＬ）を加え、室温で３時間撹拌した。反応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後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－Ｎ－メチル－８－アザビシクロ［３．２．１］オクタン－３－アミン（１１．９ｍｇ、化合物Ｂ１１６）を無色油状物として得た。
（３）（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－Ｎ－メチル－８－アザビシクロ［３．２．１］オクタン－３－アミン（９．９ｍｇ）の２－プロパノール（１ｍＬ）溶液にトリメチルシリルイソシアネート（５．１μＬ）を加え、室温で１時間撹拌した。反応液を減圧下濃縮した後、残渣を再結晶（ジエチルエーテル）にて精製し、表題化合物（５．９ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000115
 (1) tert-butyl {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] Sodium hydride (approximately 60% / oil, 2.3 mg) was added to a solution of -8-azabicyclo [3.2.1] oct-3-yl} carbamate (20 mg) in N, N-dimethylformamide (0.44 mL). In addition, the mixture was stirred at room temperature for 15 minutes. Iodomethane (0.01 mL) was added and stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100), and {(3-exo) -8- [7- (3 , 3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] oct-3-yl} methylcarbamic acid tert -Butyl (19.1 mg, compound B108) was obtained as a colorless solid.
(2) {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8- To a solution of tert-butyl azabicyclo [3.2.1] oct-3-yl} methylcarbamate (15 mg) in ethyl acetate (0.32 mL) was added 4M HCl / ethyl acetate solution (0.16 mL), and the mixture was stirred at room temperature for 3 hours. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was removed under reduced pressure. (3-exo) -8- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -N-methyl-8- Azabicyclo [3.2.1] octane-3-amine (11.9 mg, compound B116) was obtained as a colorless oil.
(3) (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -N-methyl Trimethylsilyl isocyanate (5.1 μL) was added to a solution of −8-azabicyclo [3.2.1] octane-3-amine (9.9 mg) in 2-propanol (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by recrystallization (diethyl ether) to give the title compound (5.9 mg) as a colorless solid.
実施例４７　２－［（３－ｅｘｏ）－８－｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝－８－アザビシクロ［３．２．１］オクタ－３－イル］－２，４－ジヒドロ－３Ｈ－１，２，４－トリアゾール－３－オン（化合物Ｂ２３０）および７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－２－メチル－４－［（３－ｅｘｏ）－３－（４Ｈ－１，２，４－トリアゾール－３－イルオキシ）－８－アザビシクロ［３．２．１］オクタ－８－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン（化合物Ｂ２２９）の合成 Example 47 2-[(3-exo) -8- {7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -2-methylpyrazolo [ 1,5-a] [1,3,5] triazin-4-yl} -8-azabicyclo [3.2.1] oct-3-yl] -2,4-dihydro-3H-1,2,4 -Triazol-3-one (compound B230) and 7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -2-methyl-4-[( 3-exo) -3- (4H-1,2,4-triazol-3-yloxy) -8-azabicyclo [3.2.1] oct-8-yl] pyrazolo [1,5-a] [1, 3,5] Synthesis of triazine (compound B229)
Figure JPOXMLDOC01-appb-C000116
 　（３－ｅｎｄｏ）－８－｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝－８－アザビシクロ［３．２．１］オクタン－３－オール（５９ｍｇ）のトルエン（０．５ｍＬ）溶液に４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－５－オン（２０ｍｇ）およびシアノメチレントリブチルホスホラン（６６μＬ）を加え、１００℃で４時間撹拌した。４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－５－オン（２０ｍｇ）を追加し、さらに２時間撹拌した。減圧下反応液を濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００、クロロホルム：メタノール＝９０：１０）および分取ＨＰＬＣにて精製を行い、化合物Ｂ２３０（５．７ｍｇ，無色固体）および化合物Ｂ２２９（１５ｍｇ，無色固体）をそれぞれ得た。
Figure JPOXMLDOC01-appb-C000116
 (3-endo) -8- {7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexan-3-yl] -2-methylpyrazolo [1,5-a] [1,3,5] Triazin-4-yl} -8-azabicyclo [3.2.1] octan-3-ol (59 mg) in toluene (0.5 mL) in 4,5-dihydro-1H-1 , 2,4-triazol-5-one (20 mg) and cyanomethylenetributylphosphorane (66 μL) were added, and the mixture was stirred at 100 ° C. for 4 hours. 4,5-Dihydro-1H-1,2,4-triazol-5-one (20 mg) was added, and the mixture was further stirred for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100, chloroform: methanol = 90: 10) and preparative HPLC to give a compound. B230 (5.7 mg, colorless solid) and compound B229 (15 mg, colorless solid) were obtained, respectively.
実施例４８　２－｛８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－３，８－ジアザビシクロ［３．２．１］オクタ－３－イル｝アセトアミド（化合物Ｂ１３５）の合成 Example 48 2- {8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -3,8-diazabicyclo [ 3.2.1] Synthesis of Oct-3-yl} acetamide (Compound B135)
Figure JPOXMLDOC01-appb-C000117
 　４－（３，８－ジアザビシクロ［３．２．１］オクタン－８－イル）－７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン２塩酸塩（５０ｍｇ）、ジイソプロピルエチルアミン（０．１１ｍＬ）およびヨウ化カリウム（触媒量）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に２－ブロモアセトアミド（２５ｍｇ）を加え、６０℃で１時間撹拌した。反応液をろ過した後、ろ液を分取ＨＰＬＣにて精製し、表題化合物（３９ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000117
 4- (3,8-diazabicyclo [3.2.1] octane-8-yl) -7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] 2-Bromoacetamide (25 mg) was added to a solution of triazine dihydrochloride (50 mg), diisopropylethylamine (0.11 mL) and potassium iodide (catalytic amount) in N, N-dimethylformamide (1 mL) at 60 ° C. for 1 hour. Stir. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to give the title compound (39 mg) as a colorless solid.
実施例４９　（１Ｒ，５Ｓ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－Ｎ－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－アミン（化合物Ｂ１５６）および（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－Ｎ－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－アミン（化合物Ｂ２２１）の合成 Example 49 (1R, 5S) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -N- ( 1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octane-3-amine (compound B156) and (3-exo) -8- [7- (3,3-difluorobutyl) -2 -Methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -N- (1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octane-3-amine Synthesis of (Compound B221)
Figure JPOXMLDOC01-appb-C000118
 　８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－オン（化合物Ｂ２５、６４ｍｇ）のテトラヒドロフラン（０．５３ｍＬ）溶液に１Ｈ－ピラゾール－５－アミン（１６．８ｍｇ）および酢酸（２１μＬ）を加えた。室温で３０分撹拌した後、水素化トリアセトキシホウ素ナトリウム（４６．８ｍｇ）を加え、室温で一晩撹拌した。反応液を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～０：１００）にて精製を行い、表題化合物の異性体混合物を得た。これをセミ分取カラム（CHIRAL PAC OZ-H、ヘキサン：エタノール＝８０：２０、流速１ｍＬ／分）にて精製を行い、化合物Ｂ１５６（長保持時間、２１．６ｍｇ、無色油状物）および化合物Ｂ２２１（短保持時間、２．４ｍｇ、無色固体）をそれぞれ得た。
Figure JPOXMLDOC01-appb-C000118
 8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] octane- To a solution of 3-one (Compound B25, 64 mg) in tetrahydrofuran (0.53 mL) was added 1H-pyrazol-5-amine (16.8 mg) and acetic acid (21 μL). After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (46.8 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20-0: 100) to give the isomer mixture of the title compounds. This was purified with a semi-preparative column (CHIRAL PAC OZ-H, hexane: ethanol = 80: 20, flow rate 1 mL / min), and compound B156 (long retention time 21.6 mg, colorless oil) and compound B221 (Short retention time, 2.4 mg, colorless solid) was obtained.
実施例５０　（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボキサミド（化合物Ｂ１５８）の合成 Example 50 (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] Synthesis of octane-3-carboxamide (Compound B158)
Figure JPOXMLDOC01-appb-C000119
 （１）（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－オール（化合物Ｂ５４、１００ｍｇ）およびトリエチルアミン（０．０５９ｍＬ）のクロロホルム（１．５ｍＬ）溶液にメタンスルホニルクロリド（０．０３３ｍＬ）を加え、室温で１時間撹拌した。反応液をクロロホルムで希釈した後、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層をフェーズセパレーターで分離し、減圧下溶媒を留去した。得られた残渣をジメチルスルホキシド（１．５ｍＬ）に溶解し、シアン化ナトリウム（７０ｍｇ）を加え、１００℃で８時間撹拌した。室温に戻した後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～２０：８０）で精製した。（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボニトリル（６８ｍｇ）を無色固体として得た。
（２）（３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボニトリル（６８ｍｇ）および炭酸カリウム（５２ｍｇ）のジメチルスルホキシド（２ｍＬ）懸濁液に３０％過酸化水素水（０．２ｍＬ）を加え、室温で１時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルで希釈後、飽和塩化アンモニウム水溶液および飽和食塩水にて洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９０：１０）にて精製し、表題化合物（４３ｍｇ）を無色アモルファスとして得た。
Figure JPOXMLDOC01-appb-C000119
 (1) (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] Methanesulfonyl chloride (0.033 mL) was added to a chloroform (1.5 mL) solution of octan-3-ol (Compound B54, 100 mg) and triethylamine (0.059 mL), and the mixture was stirred at room temperature for 1 hour. did. The reaction solution was diluted with chloroform and then washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated with a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dimethyl sulfoxide (1.5 mL), sodium cyanide (70 mg) was added, and the mixture was stirred at 100 ° C. for 8 hr. After returning to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20 to 20:80). (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Octane-3-carbonitrile (68 mg) was obtained as a colorless solid.
(2) (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] 30% aqueous hydrogen peroxide (0.2 mL) was added to a suspension of octane-3-carbonitrile (68 mg) and potassium carbonate (52 mg) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for 1 hour. Stir. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, diluted with ethyl acetate, and washed with a saturated aqueous ammonium chloride solution and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 90:10) to give the title compound (43 mg) as a colorless amorphous.
実施例５１　２－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝－Ｎ－メチルアセトアミド（化合物Ｂ１６５）の合成 Example 51 2-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Synthesis of 8-azabicyclo [3.2.1] oct-3-yl} -N-methylacetamide (Compound B165)
Figure JPOXMLDOC01-appb-C000120
 （１）メチル　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－カルボキシラート（４０ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液を氷冷し、水素化リチウムアルミニウム（７．７ｍｇ）を加え、氷冷下２時間撹拌した。反応液に硫酸ナトリウム１０水和物を加え、室温で２時間撹拌した後、不溶物をろ別した。減圧下溶媒を留去し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８０：２０～３５：６５）にて精製を行い、さらにヘキサンより結晶化を行い、｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝メタノール（１６ｍｇ、化合物Ｂ１０３）を無色固体として得た。
（２）実施例５０（１）と同様の方法により、｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝メタノール（１２５ｍｇ）より｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝アセトニトリル（１０４ｍｇ、化合物Ｂ１６１）を無色固体として得た。
（３）実施例５０（２）と同様の方法により、｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝アセトニトリル（８０ｍｇ）より２－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝アセトアミド（７３ｍｇ、化合物Ｂ１６２）を無色固体として得た。
（４）２－｛（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタ－３－イル｝アセトアミド（４０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に水素化ナトリウム（約６０％／オイル、４．５ｍＬ）を加え、室温で３０分撹拌した。ヨードメタン（８μＬ）を加え、室温で３時間撹拌した。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後、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム：メタノール＝１００：０～９０：１０）にて精製を行い、表題化合物（１１ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000120
 (1) Methyl (3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8- A solution of azabicyclo [3.2.1] octane-3-carboxylate (40 mg) in tetrahydrofuran (1 mL) was ice-cooled, lithium aluminum hydride (7.7 mg) was added, and the mixture was stirred under ice-cooling for 2 hr. Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours, and then insoluble matters were filtered off. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 80: 20 to 35:65), further crystallized from hexane, {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] octa -3-yl} methanol (16 mg, compound B103) was obtained as a colorless solid.
(2) In the same manner as in Example 50 (1), {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3 , 5] triazin-4-yl] -8-azabicyclo [3.2.1] oct-3-yl} methanol (125 mg), {(3-exo) -8- [7- (3,3-difluorobutyl ) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] oct-3-yl} acetonitrile (104 mg, compound B161). Obtained as a colorless solid.
(3) In the same manner as in Example 50 (2), {(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3 , 5] triazin-4-yl] -8-azabicyclo [3.2.1] oct-3-yl} acetonitrile (80 mg) from 2-{(3-exo) -8- [7- (3,3- Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3.2.1] oct-3-yl} acetamide (73 mg, compound B162 ) Was obtained as a colorless solid.
(4) 2-{(3-exo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl]- Sodium hydride (about 60% / oil, 4.5 mL) was added to a solution of 8-azabicyclo [3.2.1] oct-3-yl} acetamide (40 mg) in N, N-dimethylformamide (1 mL) at room temperature. For 30 minutes. Iodomethane (8 μL) was added and stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform: methanol = 100: 0 to 90:10) to obtain the title compound (11 mg) as a colorless solid.
実施例５２　７－（３，３－ジフルオロブチル）－２－メチル－４－［（３－ｅｘｏ）－３－（１Ｈ－ピラゾール－１－イル）－８－アザビシクロ［３．２．１］オクタ－８－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン（化合物Ｂ１７３）の合成 Example 52 7- (3,3-Difluorobutyl) -2-methyl-4-[(3-exo) -3- (1H-pyrazol-1-yl) -8-azabicyclo [3.2.1] octa Synthesis of -8-yl] pyrazolo [1,5-a] [1,3,5] triazine (Compound B173)
Figure JPOXMLDOC01-appb-C000121
 　（３－ｅｘｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－オール（６０ｍｇ、化合物Ｂ９）のクロロホルム（０．８５ｍＬ）溶液にトリエチルアミン（３６μＬ）およびメタンスルホニルクロリド（２０μＬ）を加え、室温で１時間撹拌した。反応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後、減圧下溶媒を留去した。得られた残渣（４２９ｍｇ）のうち、１４３ｍｇをＮ，Ｎ－ジメチルホルムアミド（０．２９ｍＬ）に溶かし、水素化ナトリウム（約６０％／オイル、１１ｍｇ）を加え、室温で１５分撹拌した。ピラゾール（１９ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液を加え、８０℃で３時間撹拌した。反応液に水を加え、クロロホルムで抽出した後、減圧下溶媒を留去した。残渣を分取ＨＰＬＣにて精製し、表題化合物（１１ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000121
 (3-exo) -8- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Triethylamine (36 μL) and methanesulfonyl chloride (20 μL) were added to a solution of octan-3-ol (60 mg, compound B9) in chloroform (0.85 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure. Of the obtained residue (429 mg), 143 mg was dissolved in N, N-dimethylformamide (0.29 mL), sodium hydride (about 60% / oil, 11 mg) was added, and the mixture was stirred at room temperature for 15 min. A solution of pyrazole (19 mg) in N, N-dimethylformamide was added, and the mixture was stirred at 80 ° C. for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform, and then the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC to give the title compound (11 mg) as a colorless solid.
実施例５３　７－（３，３－ジフルオロブチル）－２－メチル－４－［（３－ｅｎｄｏ）－３－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタ－８－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン（化合物Ｂ１８３）の合成 Example 53 7- (3,3-Difluorobutyl) -2-methyl-4-[(3-endo) -3- (1H-pyrazol-5-yl) -8-azabicyclo [3.2.1] octa Synthesis of -8-yl] pyrazolo [1,5-a] [1,3,5] triazine (Compound B183)
Figure JPOXMLDOC01-appb-C000122
 （３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－３－（１Ｈ－ピラゾール－５－イル）－８－アザビシクロ［３．２．１］オクタン－３－オール（化合物Ｂ１７０、１９ｍｇ）にトリフルオロ酢酸（１ｍＬ）を加え、７０℃で６時間撹拌した。反応液を減圧下濃縮した後、残渣にエタノール（１ｍＬ）、１．２Ｍ塩酸（０．２ｍＬ）および１０％パラジウム炭素（１０ｍｇ）を加えた。水素雰囲気下、室温で３時間撹拌した後、不溶物をろ別し、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣにて精製を行い、表題化合物（４．５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000122
 (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -3- (1H-pyrazole Trifluoroacetic acid (1 mL) was added to -5-yl) -8-azabicyclo [3.2.1] octan-3-ol (Compound B170, 19 mg), and the mixture was stirred at 70 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 mL), 1.2 M hydrochloric acid (0.2 mL) and 10% palladium carbon (10 mg) were added to the residue. After stirring at room temperature for 3 hours under a hydrogen atmosphere, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (4.5 mg) as a colorless solid.
実施例５４　２－ブチル－５－メチル－７－フェニルピラゾロ［１，５－ａ］ピリミジン（化合物Ａ２１２）の合成 Example 54 Synthesis of 2-butyl-5-methyl-7-phenylpyrazolo [1,5-a] pyrimidine (Compound A212)
Figure JPOXMLDOC01-appb-C000123
 ２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（５０ｍｇ）、フェニルボロン酸（３３ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（２６ｍｇ）および炭酸ナトリウム（４７ｍｇ）のジオキサン／水（２：１，１ｍＬ）溶液を８０℃で２時間撹拌した。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後、無水硫酸マグネシウムで乾燥した。ろ過、濃縮の後、残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９５：５～６０：４０）にて精製を行い、表題化合物（４６ｍｇ）を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000123
 Of 2-butyl-7-chloro-5-methylpyrazolo [1,5-a] pyrimidine (50 mg), phenylboronic acid (33 mg), tetrakis (triphenylphosphine) palladium (0) (26 mg) and sodium carbonate (47 mg) The dioxane / water (2: 1, 1 mL) solution was stirred at 80 ° C. for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 95: 5 to 60:40) to give the title compound (46 mg) as a yellow oil.
実施例５５　２－ブチル－７－シクロペンチル－５－メチルピラゾロ［１，５－ａ］ピリミジン（化合物Ａ２２６）の合成 Example 55 Synthesis of 2-butyl-7-cyclopentyl-5-methylpyrazolo [1,5-a] pyrimidine (Compound A226)
Figure JPOXMLDOC01-appb-C000124
 ２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（５０ｍｇ）およびトリス（２，４－ペンタンジオナト）鉄（ＩＩＩ）（７．９ｍｇ）のテトラヒドロフラン／Ｎ－メチルピロリドン（９：１，１ｍＬ）溶液を氷冷し、シクロペンチルマグネシウムブロミド（０．６ｍＬ）を加え、室温で１．５時間撹拌した。２Ｎ塩酸を加え、クロロホルムで抽出した後、無水硫酸マグネシウムで乾燥した。ろ過、濃縮の後、残渣を分取ＨＰＬＣにて精製を行い、表題化合物（５．３ｍｇ）を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000124
 2-butyl-7-chloro-5-methylpyrazolo [1,5-a] pyrimidine (50 mg) and tris (2,4-pentanedionato) iron (III) (7.9 mg) in tetrahydrofuran / N-methylpyrrolidone ( 9: 1, 1 mL) was ice-cooled, cyclopentylmagnesium bromide (0.6 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. 2N hydrochloric acid was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by preparative HPLC to give the title compound (5.3 mg) as a yellow oil.
実施例５６　２－ブチル－７－（シクロペンチルオキシ）－５－メチルピラゾロ［１，５－ａ］ピリミジン（化合物Ａ２３８）の合成 Example 56 Synthesis of 2-butyl-7- (cyclopentyloxy) -5-methylpyrazolo [1,5-a] pyrimidine (Compound A238)
Figure JPOXMLDOC01-appb-C000125
 ２－ブチル－７－ヒドロキシ－５－メチルピラゾロ［１，５－ａ］ピリミジン（５０ｍｇ）、シクロペンタノール（３１ｍｇ）、アゾジカルボン酸ジイソプロピル (１．９M／トルエン溶液、０．１９ｍL)およびトリフェニルホスフィン（９６ｍｇ）のテトラヒドロフラン（１ｍＬ）溶液を２時間撹拌した。反応液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン：酢酸エチル＝９０：１０～３０：７０）にて精製を行い、表題化合物（５３ｍｇ）を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000125
 2-butyl-7-hydroxy-5-methylpyrazolo [1,5-a] pyrimidine (50 mg), cyclopentanol (31 mg), diisopropyl azodicarboxylate (1.9 M / toluene solution, 0.19 mL) and triphenylphosphine A solution of (96 mg) in tetrahydrofuran (1 mL) was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-30: 70) to give the title compound (53 mg) as a yellow oil.
実施例５７　１－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）－３，４－ジヒドロキノキサリン－２（１Ｈ）－オン（化合物Ａ２３３）の合成 Example 57 Synthesis of 1- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) -3,4-dihydroquinoxalin-2 (1H) -one (Compound A233)
Figure JPOXMLDOC01-appb-C000126
 　２－ブチル－７－クロロ－５－メチルピラゾロ［１，５－ａ］ピリミジン（４０ｍｇ）、３，４－ジヒドロ－１Ｈ－キノキサリン－２－オン（４０ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（１６ｍｇ）４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（３１ｍｇ）および炭酸セシウム（１１７ｍｇ）のジオキサン（１ｍＬ）溶液を、封管中、１００℃で８時間撹拌した。クロロホルムで希釈した後、ＮＨ型シリカゲルカートリッジを通し、溶出液を減圧下濃縮した。残渣を分取ＨＰＬＣにて精製を行い、表題化合物（１８ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000126
 2-butyl-7-chloro-5-methylpyrazolo [1,5-a] pyrimidine (40 mg), 3,4-dihydro-1H-quinoxalin-2-one (40 mg), tris (dibenzylideneacetone) dipalladium (0 ) (16 mg) 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (31 mg) and a solution of cesium carbonate (117 mg) in dioxane (1 mL) were stirred in a sealed tube at 100 ° C. for 8 hours. After dilution with chloroform, the solution was passed through an NH type silica gel cartridge, and the eluate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (18 mg) as a colorless solid.
実施例５８　２－（ｃｉｓ－４－フルオロシクロヘキシル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン（化合物Ａ１５４）の合成 Example 58 2- (cis-4-fluorocyclohexyl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine Synthesis of (Compound A154)
Figure JPOXMLDOC01-appb-C000127
 （１）４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサン－１－オン（７０ｍｇ）のテトラヒドロフラン（２ｍＬ）溶液を氷冷し、水素化リチウムアルミニウム（８．０ｍｇ）を加え、同温にて３０分撹拌した。硫酸ナトリウム１０水和物を加え、室温で２時間撹拌した後、不溶物をろ別し、減圧下溶媒を留去した。残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８８：１２～０：１００）および分取ＨＰＬＣにて精製を行い、ｔｒａｎｓ－４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサン－１－オール（４４ｍｇ）を黄色固体として得た。
（２）ｔｒａｎｓ－４－［５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン－２－イル］シクロヘキサン－１－オール（２０ｍｇ）のクロロホルム（１ｍＬ）溶液を氷冷し、三フッ化Ｎ，Ｎ－ジエチルアミノ硫黄（１４μＬ）を加え、同温にて３０分撹拌した。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後、有機層をフェーズセパレーターで分離した。減圧下溶媒を留去した後、残渣をカラムクロマトグラフィー（ＮＨ型シリカゲルカートリッジ、ヘキサン：酢酸エチル＝８８：１２～０：１００）および分取ＨＰＬＣにて精製を行い、表題化合物（３．５ｍｇ）を無色固体として得た。
Figure JPOXMLDOC01-appb-C000127
 (1) 4- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] cyclohexane-1 A solution of -one (70 mg) in tetrahydrofuran (2 mL) was ice-cooled, lithium aluminum hydride (8.0 mg) was added, and the mixture was stirred at the same temperature for 30 min. Sodium sulfate decahydrate was added, and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 88: 12 to 0: 100) and preparative HPLC, and trans-4- [5-methyl-7- (3-oxa- 8-Azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] cyclohexane-1-ol (44 mg) was obtained as a yellow solid.
(2) trans-4- [5-Methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidin-2-yl] cyclohexane A solution of -1-ol (20 mg) in chloroform (1 mL) was ice-cooled, N, N-diethylaminosulfur trifluoride (14 μL) was added, and the mixture was stirred at the same temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform, and then the organic layer was separated with a phase separator. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (NH type silica gel cartridge, hexane: ethyl acetate = 88: 12 to 0: 100) and preparative HPLC to give the title compound (3.5 mg) Was obtained as a colorless solid.
実施例５９　化合物Ｂ１３１の光学分割（化合物Ｂ１５９および化合物Ｂ１６０）の合成
　５－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－Ｎ－（プロパン－２－イル）－２，５－ジアザビシクロ［２．２．２］オクタン－２－カルボキサミド（１０ｍｇ、化合物１３１）をセミ分取カラム（CHIRAL PAC ＡＳ-H、ヘキサン：エタノール＝２０：８０、流速１ｍＬ／分）にて精製を行い、化合物Ｂ１５９（短保持時間、４．１ｍｇ、無色アモルファス）および化合物Ｂ１６０（長保持時間、４．３ｍｇ、無色アモルファス）をそれぞれ得た。 Example 59 Synthesis of Optical Resolution of Compound B131 (Compound B159 and Compound B160) 5- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazine- 4-yl] -N- (propan-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxamide (10 mg, compound 131) was prepared using a semi-preparative column (CHIRAL PAC AS-H, Purification with hexane: ethanol = 20: 80, flow rate 1 mL / min) and compound B159 (short retention time, 4.1 mg, colorless amorphous) and compound B160 (long retention time, 4.3 mg, colorless amorphous), respectively Obtained.
実施例６０　化合物Ｂ１２６の光学分割（化合物Ｂ１６３および化合物Ｂ１６４）の合成
　５－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２，５－ジアザビシクロ［２．２．２］オクタン－２－カルボキサミド（７ｍｇ、化合物１２６）をセミ分取カラム（CHIRAL PAC ＡＳ-H、ヘキサン：エタノール＝２０：８０、流速１ｍＬ／分）にて精製を行い、化合物Ｂ１６３（短保持時間、２．５ｍｇ、無色アモルファス）および化合物Ｂ１６４（長保持時間、１．５ｍｇ、無色アモルファス）をそれぞれ得た。 Example 60 Synthesis of Optical Resolution of Compound B126 (Compound B163 and Compound B164) 5- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazine- 4-yl] -2,5-diazabicyclo [2.2.2] octane-2-carboxamide (7 mg, compound 126) in semi-preparative column (CHIRAL PAC AS-H, hexane: ethanol = 20: 80, flow rate 1 mL) / Min) to obtain Compound B163 (short retention time, 2.5 mg, colorless amorphous) and Compound B164 (long retention time, 1.5 mg, colorless amorphous), respectively.
実施例１～６０で示した化合物と、同様の方法で合成した化合物の構造式、化合物名及びそれらの機器データを表３－１～３－２５及び表４－１～４－３０に示す。表中の実施例の欄に記載された数字は、その化合物が上記実施例１～６０の内、どの実施例と同様な方法で合成されたかを示したものである。 Tables 3-1 to 3-25 and Tables 4-1 to 4-30 show the structural formulas, compound names, and instrument data of the compounds shown in Examples 1 to 60 and compounds synthesized by the same method. The number described in the column of the example in the table indicates which of the above Examples 1 to 60 was synthesized by the same method as in the above Examples.
Figure JPOXMLDOC01-appb-T000128
  　 
Figure JPOXMLDOC01-appb-T000128
  　 
Figure JPOXMLDOC01-appb-T000129
  　 
Figure JPOXMLDOC01-appb-T000129
  　 
Figure JPOXMLDOC01-appb-T000130
  　 
Figure JPOXMLDOC01-appb-T000130
  　 
Figure JPOXMLDOC01-appb-T000131
  　 
Figure JPOXMLDOC01-appb-T000131
  　 
Figure JPOXMLDOC01-appb-T000132
  　 
Figure JPOXMLDOC01-appb-T000132
  　 
Figure JPOXMLDOC01-appb-T000133
  　 
Figure JPOXMLDOC01-appb-T000133
  　 
Figure JPOXMLDOC01-appb-T000134
  　 
Figure JPOXMLDOC01-appb-T000134
  　 
Figure JPOXMLDOC01-appb-T000135
  　 
Figure JPOXMLDOC01-appb-T000135
  　 
Figure JPOXMLDOC01-appb-T000136
  　 
Figure JPOXMLDOC01-appb-T000136
  　 
Figure JPOXMLDOC01-appb-T000137
  　 
Figure JPOXMLDOC01-appb-T000137
  　 
Figure JPOXMLDOC01-appb-T000138
  　 
Figure JPOXMLDOC01-appb-T000138
  　 
Figure JPOXMLDOC01-appb-T000139
  　 
Figure JPOXMLDOC01-appb-T000139
  　 
Figure JPOXMLDOC01-appb-T000140
  　 
Figure JPOXMLDOC01-appb-T000140
  　 
Figure JPOXMLDOC01-appb-T000141
  　 
Figure JPOXMLDOC01-appb-T000141
  　 
Figure JPOXMLDOC01-appb-T000142
  　 
Figure JPOXMLDOC01-appb-T000142
  　 
Figure JPOXMLDOC01-appb-T000143
  　 
Figure JPOXMLDOC01-appb-T000143
  　 
Figure JPOXMLDOC01-appb-T000144
  　 
Figure JPOXMLDOC01-appb-T000144
  　 
Figure JPOXMLDOC01-appb-T000145
  　 
Figure JPOXMLDOC01-appb-T000145
  　 
Figure JPOXMLDOC01-appb-T000146
  　 
Figure JPOXMLDOC01-appb-T000146
  　 
Figure JPOXMLDOC01-appb-T000147
  　 
Figure JPOXMLDOC01-appb-T000147
  　 
Figure JPOXMLDOC01-appb-T000148
  　 
Figure JPOXMLDOC01-appb-T000148
  　 
Figure JPOXMLDOC01-appb-T000149
  　 
Figure JPOXMLDOC01-appb-T000149
  　 
Figure JPOXMLDOC01-appb-T000150
  　 
Figure JPOXMLDOC01-appb-T000150
  　 
Figure JPOXMLDOC01-appb-T000151
  　 
Figure JPOXMLDOC01-appb-T000151
  　 
Figure JPOXMLDOC01-appb-T000152
  　 
Figure JPOXMLDOC01-appb-T000152
  　 
Figure JPOXMLDOC01-appb-T000153
   
  　 
Figure JPOXMLDOC01-appb-T000153
   
  　 
Figure JPOXMLDOC01-appb-T000154
  　 
Figure JPOXMLDOC01-appb-T000154
  　 
Figure JPOXMLDOC01-appb-T000155
  　 
Figure JPOXMLDOC01-appb-T000155
  　 
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
  　 
Figure JPOXMLDOC01-appb-T000157
  　 
Figure JPOXMLDOC01-appb-T000158
  　 
Figure JPOXMLDOC01-appb-T000158
  　 
Figure JPOXMLDOC01-appb-T000159
  　 
Figure JPOXMLDOC01-appb-T000159
  　 
Figure JPOXMLDOC01-appb-T000160
  　 
Figure JPOXMLDOC01-appb-T000160
  　 
Figure JPOXMLDOC01-appb-T000161
  　 
Figure JPOXMLDOC01-appb-T000161
  　 
Figure JPOXMLDOC01-appb-T000162
  　 
Figure JPOXMLDOC01-appb-T000162
  　 
Figure JPOXMLDOC01-appb-T000163
  　 
Figure JPOXMLDOC01-appb-T000163
  　 
Figure JPOXMLDOC01-appb-T000164
  　 
Figure JPOXMLDOC01-appb-T000164
  　 
Figure JPOXMLDOC01-appb-T000165
  　 
Figure JPOXMLDOC01-appb-T000165
  　 
Figure JPOXMLDOC01-appb-T000166
  　 
Figure JPOXMLDOC01-appb-T000166
  　 
Figure JPOXMLDOC01-appb-T000167
  　 
Figure JPOXMLDOC01-appb-T000167
  　 
Figure JPOXMLDOC01-appb-T000168
  　 
Figure JPOXMLDOC01-appb-T000168
  　 
Figure JPOXMLDOC01-appb-T000169
  　 
Figure JPOXMLDOC01-appb-T000169
  　 
Figure JPOXMLDOC01-appb-T000170
  　 
Figure JPOXMLDOC01-appb-T000170
  　 
Figure JPOXMLDOC01-appb-T000171
  　 
Figure JPOXMLDOC01-appb-T000171
  　 
Figure JPOXMLDOC01-appb-T000172
  　 
Figure JPOXMLDOC01-appb-T000172
  　 
Figure JPOXMLDOC01-appb-T000173
  　 
Figure JPOXMLDOC01-appb-T000173
  　 
Figure JPOXMLDOC01-appb-T000174
  　 
Figure JPOXMLDOC01-appb-T000174
  　 
Figure JPOXMLDOC01-appb-T000175
  　 
Figure JPOXMLDOC01-appb-T000175
  　 
Figure JPOXMLDOC01-appb-T000176
  　 
Figure JPOXMLDOC01-appb-T000176
  　 
Figure JPOXMLDOC01-appb-T000177
  　 
Figure JPOXMLDOC01-appb-T000177
  　 
Figure JPOXMLDOC01-appb-T000178
  　 
Figure JPOXMLDOC01-appb-T000178
  　 
Figure JPOXMLDOC01-appb-T000179
  　 
Figure JPOXMLDOC01-appb-T000179
  　 
Figure JPOXMLDOC01-appb-T000180
  　 
Figure JPOXMLDOC01-appb-T000180
  　 
Figure JPOXMLDOC01-appb-T000181
  　 
Figure JPOXMLDOC01-appb-T000181
  　 
Figure JPOXMLDOC01-appb-T000182
 
一態様において、本発明の例は以下の化合物又はその医薬上許容される塩である。
２（６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（Ａ１３６）、
２（｛２－［（１Ｒ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル｝アミノ）－２－メチルプロパン－１－オール（Ａ１８０）、
３－（｛２－［（１Ｒ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル｝アミノ）－３－メチルブタン－１－オール（Ａ１８１）、
（３－ｅｎｄｏ）－８－｛２－［（１Ｒ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル］－８－アザビシクロ［３．２．１］オクタン－３－オール（Ａ１８２）、
２－（３，３－ジフルオロビシクロ［３．１．０］ヘキサン－６－イル）－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン（Ａ１９４）、
２－（｛７－３，３－ジフルオロビシクロ［３．１．０］ヘキサン－６－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－２－メチルプロパン－１－オール（Ｂ７１）、および
（３－ｅｎｄｏ）－９－｛７－（３，３－ジフルオロビシクロ［３．１．０］ヘキサン－６－イル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－３－メチル－９－アザビシクロ［３．３．１］ノナン－３－オール（Ｂ７２）。
Figure JPOXMLDOC01-appb-T000182

In one aspect, an example of the invention is the following compound or a pharmaceutically acceptable salt thereof:
2 (6,6-Difluorobicyclo [3.1.0] hexane-3-yl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) pyrazolo [1,5-a] pyrimidine (A136),
2 ({2-[(1R, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -5-methylpyrazolo [1,5-a] pyrimidin-7-yl} amino) -2-methylpropan-1-ol (A180),
3-({2-[(1R, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -5-methylpyrazolo [1,5-a] pyrimidin-7-yl} amino ) -3-Methylbutan-1-ol (A181),
(3-endo) -8- {2-[(1R, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -5-methylpyrazolo [1,5-a] pyrimidine- 7-yl] -8-azabicyclo [3.2.1] octan-3-ol (A182),
2- (3,3-Difluorobicyclo [3.1.0] hexane-6-yl) -5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] octane-8-yl) Pyrazolo [1,5-a] pyrimidine (A194),
2-({7-3,3-difluorobicyclo [3.1.0] hexane-6-yl] -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl} amino ) -2-Methylpropan-1-ol (B71), and (3-endo) -9- {7- (3,3-difluorobicyclo [3.1.0] hexane-6-yl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -3-methyl-9-azabicyclo [3.3.1] nonan-3-ol (B72).
試験例　（ＧＡＢＡＢ受容体ＰＡＭ活性の測定）
ヒトGABA(B)受容体安定発現細胞を用いた細胞内Ca2+濃度変化を指標としたPAM活性評価
ヒトGABAB1A (Accession No. CAA09939.1)、GABAB2 (NP_005449)およびGα16を安定に発現するCHO-K1細胞を用いて、蛍光プローブFluo4-AMをCa2+指示薬としたときの細胞内Ca2+濃度変化を指標に、GABA刺激下における各被験化合物のPAM活性を評価した。
上述のヒトGABA(B)受容体安定発現細胞は、10%ウシ胎児血清、400 μg/mL Geneticin、5 μg/mL Blasticidin、250 μg/mL Zeocinを含むHam’s F-12培地中で増殖させた。試験前日、上記培地のうち選択薬剤を含まない培地を用いて、poly-D-lysineコートされた384-well Black/Clear Flat Bottomマイクロプレートに5,000細胞/wellとなるよう細胞を播種した。細胞内Ca2+濃度変化測定試験には、10 mM HEPES, 0.1% BSA, 2.5 mM Probenecidを含むHank's Balanced Salt Solution（pH 7.4）を基本組成とするAssayバッファーを用いた。試験当日、各wellの培地を除いた後、2.5 μM Flou-4 AM, 0.02% Pluronic F-127を含むAssayバッファーを50 μL/well添加して、37 ℃のCO2インキュベーター内で約1時間静置した。各wellからFlou-4 AMを含むバッファーを取り除き、最終濃度の約1.33倍濃度の各被験化合物を含むAssayバッファーを36 μL添加した後、遮光・室温で約30分間静置した。その後、最終濃度の4倍濃度のGABAを含むAssayバッファーを12 μL添加して細胞内Ca2+濃度変化に伴う蛍光変化を経時的に測定した。一連の測定作業はFDSS6000（浜松ホトニクス株式会社）を用いて行った。
1 mM GABAが存在するときの反応を最大応答（100%）、GABAおよび被験化合物が存在しないときの反応を基礎応答（0%）としたとき、約20％の応答を引き起こすGABA（500  nM）で刺激して各被験化合物のPAM活性（EC50値）を算出した。また、最高濃度を30 μMまで評価した際の最大応答をPAM効果（％）とした。
本発明化合物の活性値を表５及び表６に示す。 Test example (GABAB receptor PAM activity measurement)
Evaluation of PAM activity using cells expressing stable expression of human GABA (B) receptor as an indicator of changes in intracellular Ca 2+ concentration CHO that stably expresses human GABAB1A (Accession No. -K1 cells were used to evaluate the PAM activity of each test compound under GABA stimulation using changes in intracellular Ca 2+ concentration as an index when the fluorescent probe Fluo4-AM was used as a Ca 2+ indicator.
The aforementioned human GABA (B) receptor stably expressing cells were grown in Ham's F-12 medium containing 10% fetal bovine serum, 400 μg / mL Geneticin, 5 μg / mL Blasticidin, 250 μg / mL Zeocin. On the day before the test, cells were seeded on a poly-D-lysine-coated 384-well Black / Clear Flat Bottom microplate at 5,000 cells / well using a medium that did not contain a selective drug. In the intracellular Ca 2+ concentration change measurement test, an Assay buffer having a basic composition of Hank's Balanced Salt Solution (pH 7.4) containing 10 mM HEPES, 0.1% BSA, and 2.5 mM Probenecid was used. On the day of the test, after removing the medium in each well, add 50 μL / well of assay buffer containing 2.5 μM Flou-4 AM, 0.02% Pluronic F-127, and leave it still in a CO 2 incubator at 37 ° C for about 1 hour. I put it. The buffer containing Flou-4 AM was removed from each well, 36 μL of Assay buffer containing each test compound at a concentration of about 1.33 times the final concentration was added, and the mixture was allowed to stand at light-shielded room temperature for about 30 minutes. Thereafter, 12 μL of Assay buffer containing 4 times the final concentration of GABA was added, and the change in fluorescence accompanying changes in intracellular Ca 2+ concentration was measured over time. A series of measurement work was performed using FDSS6000 (Hamamatsu Photonics Co., Ltd.).
GABA causing a response of about 20% when the response in the presence of 1 mM GABA is the maximum response (100%) and the response in the absence of GABA and the test compound is the basal response (0%) (500 nM) The PAM activity (EC 50 value) of each test compound was calculated. The maximum response when the maximum concentration was evaluated up to 30 μM was defined as the PAM effect (%).
The activity values of the compounds of the present invention are shown in Tables 5 and 6.
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
　本発明化合物は、ＧＡＢＡＢ受容体ＰＡＭ作用を有することが示された。従って、本発明化合物又はその医薬上許容される塩は、ＧＡＢＡＢ受容体ＰＡＭ作用によって調節される疾患、例えば自閉症スペクトラム障害、脆弱性Ｘ症候群、統合失調症、双極性障害、うつ病、不安障害、認知症、疼痛、薬物・アルコール依存症、痙攣、脳血管障害、脳性麻痺、脊髄麻痺、外傷後遺症、多発性硬化症、筋萎縮性側索硬化症、ｓｔｉｆｆ－ｍａｎ症候群、本態性振戦、過活動膀胱、胃食道逆流性疾患又はＣｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病等の疾患の治療又は予防薬として使用することが可能である。
 
 
  The compound of the present invention was shown to have a GABAB receptor PAM action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for diseases modulated by GABAB receptor PAM action such as autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar disorder, depression, anxiety. Disorder, dementia, pain, drug / alcoholism, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man syndrome, essential tremor It can be used as a therapeutic or prophylactic agent for diseases such as overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease.


Claims (15)

  1. 式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
     （式中、
    Ｘは、窒素原子又は式ＣＲ4を示し、
    Ｘが、窒素原子の場合、
    Ｒ1は、テトラヒドロピラニル、ピペリジニル（該ピペリジニルは、カルバモイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイル及びＣ1-6アルキルスルホニルからなる群から選ばれる１個の置換基で置換されてもよい。）、又は、
    式ＮＲN1ＲN2を示し、
    ＲN1は水素原子を示し、
    ＲN2は、アダマンチル（該アダマンチルは、１個のヒドロキシで置換されてもよい。）、Ｃ5-6シクロアルキル（該Ｃ5-6シクロアルキルは、１個のヒドロキシで置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は、
    下記式（ＩＩ）を示し、
    Figure JPOXMLDOC01-appb-C000002
     （式中、
    ＲC1は、水素原子又はＣ1-6アルキルを示し、
    ＲC2は、Ｃ1-6アルキルを示すか、
    又は、ＲC1及びＲC2は、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカンを形成してもよく、
    ＲC3は、ハロゲン原子、ヒドロキシ、Ｃ1-6アルキルスルホニル、カルバモイル（該カルバモイルは、１～２個のＣ1-6アルキルで置換されてもよい。）、トリアゾリル、又はカルボキシを示し、
    ｎは、０～３の整数を示す。）
    又は、ＲN1及びＲN2は、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、Ｃ3-6シクロアルキルカルボニルアミノ（該Ｃ3-6シクロアルキルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、５－オキソ－４，５－ジヒドロ－１Ｈ－１，２，４－トリアゾール－１－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）、アミノ、Ｃ1-6アルキルアミノ及びグアジニノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
    Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
    Ｒ2は、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）を示し、
    Ｒ3は、水素原子、メチル（該メチルは、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル、シアノ又はアセチルを示し、
    Ｘが、式ＣＲ4の場合、
    Ｒ1は、フェニル（該フェニルは、Ｃ2-6アルカノイルアミノ、ヒドロキシメチル及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ3-6シクロアルコキシ（該Ｃ3-6シクロアルコキシは、１個のオキソで置換されてもよい。）、シアノ、ピリジル、ピリミジル、ピラゾリル、イソオキサゾリル（該ピラゾリル及びイソオキサゾリルは、１～２個のメチルで置換されてもよい。）、イソプロピル、イソブチル、Ｃ3-6シクロアルキルメトキシ、フェノキシ、ピペリジノカルボニル、ジヒドロピラニル、又は、
    式ＮＲN3ＲN4を示し、
    ＲN3は、水素原子、メチル、イソプロピル、シクロプロピル又はシクロブチルを示し、
    ＲN4は、Ｃ4-6シクロアルキル、フェニル、２－メチル－５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［１，５－ａ］ピリジン－６－イル、
    又は下記式（ＩＩＩ）を示し、
    Figure JPOXMLDOC01-appb-C000003
     （式中、
    ＲC4及びＲC5は、同一又は異なって水素原子又はＣ1-6アルキルを示すか、
    又はＲC4及びＲC5は、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカン（該Ｃ3-6シクロアルカンは、ハロゲン原子及びヒドロキシからなる群より選ばれる１～２個の基で置換されてもよい。）、４～６員の環状エーテル、又は４～６員の環状アミン（該４～６員の環状アミンは、１個のメチル、Ｃ2-6アルカノイル又はＣ1-6アルコキシカルボニルで置換されている。）を形成してもよく、
    ＲC6は、水素原子、ハロゲン原子、ヒドロキシ、フェニル、ピリジル、ピリミジル、ピラゾリル、トリアゾリル、メチルオキサジアゾリル、シクロヘキシル、アミノ、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、アミノ及びＣ1-6アルキルスルホニルからなる群より選ばれる１個の置換基で置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノを示し、
    ｐは、０～１の整数を示し、
    ｑは、０～３の整数を示す。）、
    又はＲN3及びＲN4は、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１つ以上の窒素原子、酸素原子若しくは硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ヒドロキシ、Ｃ1-6アルコキシ、カルバモイル、Ｃ1-6アルコキシカルボニル、ピラゾリル、ピペリジノカルボニル、ジメチルアミノカルボニル及びＣ1-6アルコキシカルボニルオキシからなる群より選ばれる１個の置換基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ2-6アルカノイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイルアミノ、Ｃ1-6アルコキシカルボニルアミノ、オキソ、及びアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに該４～７員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよく、又は該４～７員の飽和複素環の環中の１個の炭素原子が、４～６員の環状エーテルで置き換わってもよく、又は該４～７員の飽和複素環が、ベンゼン、ピリジン、イソオキサゾール又はイミダゾールからなる群より選ばれる１つの環と縮合し、縮合環を形成してもよい）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イル、３，４‐ジヒドロキノリン‐１（２Ｈ）‐イル又は２‐オキソキノキサリン‐１（２Ｈ）‐イル（該２‐オキソキノキサリン‐１（２Ｈ）‐イルは、１個のハロゲン原子で置換されてもよい。）を形成してもよく、
    Ｒ2は、ｎ－プロピル（該ｎ－プロピルは、１～３個のハロゲン原子で置換されている。）、ｎ‐ブチル（該ｎ‐ブチルは、メチル、ハロゲン原子、ヒドロキシ及びオキソからなる群より選ばれる１～３個の基で置換されてもよい。）、ｔｅｒｔ－ブチル、Ｃ3-6シクロアルキル（該Ｃ3-6シクロアルキルは、ハロゲン原子、Ｃ1-6アルキル、ヒドロキシ、オキソ及びトリフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ3-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、１，３‐ジオキソランと置き換わってもよい。）、Ｃ4-6シクロアルケニル（該Ｃ4-6シクロアルケニルは、１個のハロゲン原子で置換されてもよい。）、シクロプロピルエチル、フェノキシメチル（該フェノキシメチルのフェニル基は、ハロゲン原子、シアノ及びジフロロメチルからなる群より選ばれる１個の置換基で置換されてもよい。）、ピリジルオキシメチル（該ピリジルオキシメチルのピリジルは、１個のトリフロロメチルで置換されてもよい。）、ピペリジノカルボニル、フェノキシカルボニル、プロポキシ、又はシクロプロピルエチニルを示し、
    Ｒ3は、ハロゲン原子、メチル（該メチル基は、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、メトキシ、シアノ、エトキシカルボニル、ヒドロキシイソプロピル、ピラゾリル又はメチルオキサジアゾリルであり、
    Ｒ4は、水素原子、フッ素原子、メチル（該メチルは、ヒドロキシ及びメトキシからなる群より選ばれる１個の置換基で置換されてもよい。）、又はエトキシカルボニルを示す。）
    で表される含窒素縮合複素環化合物又はその医薬上許容される塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
     (Where
    X represents a nitrogen atom or the formula CR 4 ,
    When X is a nitrogen atom,
    R 1 is tetrahydropyranyl, piperidinyl (the piperidinyl is substituted with one substituent selected from the group consisting of carbamoyl, C 1-6 alkoxycarbonyl, C 2-6 alkanoyl and C 1-6 alkylsulfonyl). Or)
    Shows the formula NR N1 R N2 ,
    R N1 represents a hydrogen atom,
    R N2 is adamantyl (the adamantyl may be substituted with one hydroxy.), C 5-6 cycloalkyl (said C 5-6 cycloalkyl may be substituted with one hydroxy, Furthermore, it may be bridged with C 1-6 alkylene between two different carbon atoms in the ring), or
    The following formula (II) is shown,
    Figure JPOXMLDOC01-appb-C000002
     (Where
    R C1 represents a hydrogen atom or C 1-6 alkyl;
    R C2 represents C 1-6 alkyl,
    Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 3-6 cycloalkane;
    R C3 represents a halogen atom, hydroxy, C 1-6 alkylsulfonyl, carbamoyl (which may be substituted with 1 to 2 C 1-6 alkyl), triazolyl, or carboxy;
    n represents an integer of 0 to 3. )
    Alternatively, R N1 and R N2 , together with the adjacent nitrogen atom, may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom in the ring, and a 4-7 membered saturated complex. A ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl, May be substituted with 1 to 3 groups selected from the group consisting of carboxy, pyrazolyl and methylpyrazolyl), C 1-6 alkoxy (the C 1-6 alkoxy is composed of a halogen atom, pyrazolyl and methylpyrazolyl) may be substituted with 1 to 3 substituents selected from the group.), C 2-6 alkanoylamino (the C 2-6 alkanoylamino, hydroxy, C 2-6 alkanoyloxy, pyrazolyl及In one substituent group selected from the group consisting of triazolyl may be substituted.), Carbamoyl (said carbamoyl, C 1-6 alkyl, from the group consisting of pyrazolyl C 1-6 alkyl and triazolyl C 1-6 alkyl 1 to 2 selected substituents may be substituted.), C 1-6 alkoxycarbonylamino (the C 1-6 alkoxycarbonylamino may be substituted with one C 1-6 alkyl) ), Ureido (the ureido may be substituted with 1 C 1-6 alkyl), pyrazolyl-Y— (wherein the pyrazolyl of the formula pyrazolyl-Y— is 1 C 1-6 alkyl may be substituted.), wherein triazolyl -Y-, C 3-6 cycloalkyl carbonyl amino (said C 3-6 cycloalkyl carbonyl amino may be substituted by one hydroxy.), oxo imidazolidinylidene (The oxo imidazolidinyl may be substituted with one C 1-6 alkyl.), 5-oxo-1H-1,2,4-triazole -4 (5H) - yl, 5-oxo - 4,5-dihydro-1H-1,2,4-triazol-1-yl, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino May be substituted with 1 to 2 C 1-6 alkyls), may be substituted with 1 to 2 groups selected from the group consisting of amino, C 1-6 alkylamino and guanidino, Further, it may be bridged with C 1-6 alkylene between two different carbon atoms in the ring. Or 2-oxa-6-azaadamantan-6-yl,
    Y represents a single bond, a formula —O—, a formula —NH—, a formula —SO 2 —, a formula —SO 2 NH—, or a formula —CONH—,
    R 2 is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and the C 4-6 cycloalkyl is a ring; two between the carbon atoms of different medium may be cross-linked with a single bond or C 1-6 alkylene, or one carbon atom in the ring of the C 3-6 cycloalkane, C 3-6 cycloalkyl Alkane may be substituted.), C 3-6 cycloalkylethyl (the C 3-6 cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl) .) or C 3-6 cycloalkyl-methoxy (said C 3-6 cycloalkyl Rumethoxy may be substituted with one C 1-6 alkyl).
    R 3 is a hydrogen atom, methyl (the methyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), difluoroethyl, methoxy, difluoromethoxy, cyclopropyl, cyano Or acetyl,
    When X is the formula CR 4
    R 1 is phenyl (the phenyl may be substituted with 1 to 2 groups selected from the group consisting of C 2-6 alkanoylamino, hydroxymethyl and methoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy (the C 3-6 cycloalkoxy may be substituted with one oxo), cyano, pyridyl, pyrimidyl, pyrazolyl, isoxazolyl (the pyrazolyl and isoxazolyl are one to two methyl groups) ), Isopropyl, isobutyl, C 3-6 cycloalkylmethoxy, phenoxy, piperidinocarbonyl, dihydropyranyl, or
    Shows the formula NR N3 R N4 ,
    R N3 represents a hydrogen atom, methyl, isopropyl, cyclopropyl or cyclobutyl,
    R N4 represents C 4-6 cycloalkyl, phenyl, 2-methyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridin-6-yl,
    Or the following formula (III):
    Figure JPOXMLDOC01-appb-C000003
     (Where
    R C4 and R C5 are the same or different and each represents a hydrogen atom or C 1-6 alkyl,
    Or R C4 and R C5 together with an adjacent carbon atom are C 3-6 cycloalkane (the C 3-6 cycloalkane is a group of 1 to 2 selected from the group consisting of a halogen atom and hydroxy) 4-6 membered cyclic ether, or 4-6 membered cyclic amine (wherein the 4-6 membered cyclic amine is one methyl, C 2-6 alkanoyl or C 1- Substituted with 6 alkoxycarbonyl).
    R C6 represents a hydrogen atom, a halogen atom, hydroxy, phenyl, pyridyl, pyrimidyl, pyrazolyl, triazolyl, methyloxadiazolyl, cyclohexyl, amino, C 2-6 alkanoylamino (the C 2-6 alkanoylamino is amino and C 1-6 alkylsulfonyl, which may be substituted with one substituent selected from the group consisting of 1-6 alkylsulfonyl), or C 1-6 alkoxycarbonylamino,
    p represents an integer of 0 to 1,
    q represents an integer of 0 to 3. ),
    Or R N3 and R N4 together with the adjacent nitrogen atom may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms in addition to the nitrogen atom in the ring; Ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, C 1-6 alkyl (the C 1-6 alkyl is hydroxy, C 1-6 alkoxy, carbamoyl, C 1-6 alkoxycarbonyl, pyrazolyl, piperidyl And optionally substituted with one substituent selected from the group consisting of nocarbonyl, dimethylaminocarbonyl and C 1-6 alkoxycarbonyloxy), C 3-6 cycloalkyl, C 2-6 alkanoyl, C 1- It may be substituted with 1 to 2 groups selected from the group consisting of 6 alkoxycarbonyl, C 2-6 alkanoylamino, C 1-6 alkoxycarbonylamino, oxo, and amino. A saturated heterocycle may be bridged with C 1-6 alkylene between two different carbon atoms in the ring, or one carbon atom in the ring of the 4-7 membered saturated heterocycle is It may be replaced by a 4-6 membered cyclic ether, or the 4-7 membered saturated heterocyclic ring is condensed with one ring selected from the group consisting of benzene, pyridine, isoxazole or imidazole to form a condensed ring Or 2-oxa-6-azaadamantan-6-yl, 3,4-dihydroquinolin-1 (2H) -yl or 2-oxoquinoxalin-1 (2H) -yl (the 2-oxo Quinoxalin-1 (2H) -yl may be substituted with one halogen atom),
    R 2 is n-propyl (the n-propyl is substituted with 1 to 3 halogen atoms), n-butyl (the n-butyl is a group consisting of methyl, halogen atom, hydroxy and oxo) 1 to 3 groups selected from the above), tert-butyl, C 3-6 cycloalkyl (the C 3-6 cycloalkyl is a halogen atom, C 1-6 alkyl, hydroxy, oxo And C 2-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of trifluoromethyl and a single bond or C 1 between two different carbon atoms in the ring. -6 alkylene may be bridged, or one carbon atom in the ring of the C 3-6 cycloalkane may be replaced by 1,3-dioxolane), C 4-6 cycloalkenyl C 4-6 cycloalkenyl is one halogen atom A cyclopropylethyl, phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one substituent selected from the group consisting of a halogen atom, cyano and difluoromethyl). , Pyridyloxymethyl (where the pyridyloxymethyl pyridyl may be substituted with one trifluoromethyl), piperidinocarbonyl, phenoxycarbonyl, propoxy, or cyclopropylethynyl;
    R 3 represents a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy, cyano, ethoxycarbonyl, hydroxyisopropyl, pyrazolyl Or methyl oxadiazolyl,
    R 4 represents a hydrogen atom, a fluorine atom, methyl (the methyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy), or ethoxycarbonyl. )
    Or a pharmaceutically acceptable salt thereof.
  2. Ｘが窒素原子であり、Ｒ1が式ＮＲN1ＲN2を示し、かつＲN1及びＲN2が隣接する窒素原子と一緒になって環中に前記窒素原子以外にさらに１個の窒素原子、酸素原子若しくは硫黄原子を含んでもよい４～７員の飽和複素環を形成する場合には、該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、Ｃ3-6シクロアルキルカルボニルアミノ（該Ｃ3-6シクロアルキルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）、アミノ、Ｃ1-6アルキルアミノ及びグアジニノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよく、
    前記の場合以外については請求項１に記載のとおりである、請求項１に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     X is a nitrogen atom, R 1 represents the formula NR N1 R N2 , and R N1 and R N2 together with the adjacent nitrogen atom, in addition to the nitrogen atom, one more nitrogen atom, oxygen When forming a 4- to 7-membered saturated heterocyclic ring which may contain an atom or a sulfur atom, the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1- 6 alkyl may be substituted with 1 to 3 groups selected from the group consisting of halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl, carboxy, pyrazolyl and methylpyrazolyl), C 1. -6 alkoxy (the C 1-6 alkoxy may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl), C 2-6 alkanoylamino (the C 2 -6 Alcano Ilamino may be substituted with one substituent selected from the group consisting of hydroxy, C 2-6 alkanoyloxy, pyrazolyl and triazolyl), carbamoyl (the carbamoyl is C 1-6 alkyl, pyrazolyl C 1). -6 alkyl and triazolyl may be substituted with 1 to 2 substituents selected from the group consisting of C 1-6 alkyl), C 1-6 alkoxycarbonylamino (the C 1-6 alkoxycarbonylamino is May be substituted with one C 1-6 alkyl.), Ureido (the ureido may be substituted with one C 1-6 alkyl), the formula pyrazolyl-Y— (the formula pyrazolyl-Y -. is pyrazolyl, optionally substituted by one C 1-6 alkyl), wherein triazolyl -Y-, C 3-6 cycloalkyl carbonyl amino (said C 3-6 cycloalkyl carbonyl amino May be substituted with one hydroxy.), Oxo imidazolidinyl (the oxo imidazolidinyl may be substituted with one C 1-6 alkyl.), 5-oxo-1H-1 , 2,4-triazol-4 (5H) -yl, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, aminosulfonylamino the C 1-6 alkyl may be substituted.), amino may be substituted with 1-2 substituents selected from the group consisting of C 1-6 alkylamino and guanidino, different further of the ring 2 May be bridged with C 1-6 alkylene between carbon atoms,
    The nitrogen-containing fused heterocyclic compound or the pharmaceutically acceptable salt thereof according to claim 1, which is as described in claim 1 except for the above case.
  3. 式（Ｉ）において、
    Ｘが、窒素原子である、請求項１又は２に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is a nitrogen atom.
  4. 式（Ｉ）において、
    Ｒ1が、テトラヒドロピラニル、ピペリジニル（該ピペリジニルは、カルバモイル、ｔｅｒｔ－ブチルカルボニル、アセチル及びメチルスルホニルからなる群から選ばれる１個の置換基で置換されてもよい。）、又は
    式ＮＲN1ＲN2であり、
    ＲN1が水素原子であり、
    ＲN2が、アダマンチル（該アダマンチルは、１個のヒドロキシで置換されてもよい）、Ｃ5-6シクロアルキル（該Ｃ5-6シクロアルキルは、１個のヒドロキシで置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は下記式（ＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000004
     （式中、
    ＲC1が、水素原子又はメチルであり、
    ＲC2が、メチル又はイソプロピルであるか、
    又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカンを形成してもよく、
    ＲC3が、ハロゲン原子、ヒドロキシ、メチルスルホニル、カルバモイル（該カルバモイルは、１～２個のＣ1-6アルキルで置換されてもよい。）、トリアゾリル、又はカルボキシであり、
    ｎが、０～３の整数である。）、
    又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、　５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）及びアミノ、モノＣ1-6アルキルアミノ、グアジニノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
    Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
    Ｒ2が、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）である、請求項３に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is tetrahydropyranyl, piperidinyl (the piperidinyl may be substituted with one substituent selected from the group consisting of carbamoyl, tert-butylcarbonyl, acetyl and methylsulfonyl), or the formula NR N1 R N2 and
    R N1 is a hydrogen atom,
    R N2 is adamantyl (the adamantyl may be substituted with one hydroxy), C 5-6 cycloalkyl (said C 5-6 cycloalkyl may be substituted with one hydroxy, further Between two different carbon atoms in the ring may be bridged with C 1-6 alkylene), or the following formula (II):
    Figure JPOXMLDOC01-appb-C000004
     (Where
    R C1 is a hydrogen atom or methyl;
    R C2 is methyl or isopropyl,
    Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 3-6 cycloalkane;
    R C3 is a halogen atom, hydroxy, methylsulfonyl, carbamoyl (which may be substituted with 1 to 2 C 1-6 alkyl), triazolyl, or carboxy;
    n is an integer of 0 to 3. ),
    Alternatively, R N1 and R N2 together with the adjacent nitrogen atom may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom in the ring. A ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl, May be substituted with 1 to 3 groups selected from the group consisting of carboxy, pyrazolyl and methylpyrazolyl), C 1-6 alkoxy (the C 1-6 alkoxy is composed of a halogen atom, pyrazolyl and methylpyrazolyl) may be substituted with 1 to 3 substituents selected from the group.), C 2-6 alkanoylamino (the C 2-6 alkanoylamino, hydroxy, C 2-6 alkanoyloxy, pyrazolyl及With 1 substituent selected from the group consisting of triazolyl may be substituted.), Carbamoyl (said carbamoyl, C 1-6 alkyl, from the group consisting of pyrazolyl C 1-6 alkyl and triazolyl C 1-6 alkyl 1 to 2 selected substituents may be substituted.), C 1-6 alkoxycarbonylamino (the C 1-6 alkoxycarbonylamino may be substituted with one C 1-6 alkyl) ), Ureido (the ureido may be substituted with 1 C 1-6 alkyl), pyrazolyl-Y— (wherein the pyrazolyl of the formula pyrazolyl-Y— is 1 C 1-6 alkyl May be substituted), the formula triazolyl-Y—, cyclopropylcarbonylamino (the cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxy Imidazolidinyl may be substituted with one C 1-6 alkyl), 5-oxo-1H-1,2,4-triazole -4 (5H) -.-Yl, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino may be substituted with 1-2 C 1-6 alkyl) and amino, mono C 1-6 alkyl And may be substituted with 1 to 2 groups selected from the group consisting of amino and guanidino, and may be further bridged with C 1-6 alkylene between two different carbon atoms in the ring), or 2-oxa-6-azaadamantan-6-yl may be formed,
    Y represents a single bond, a formula —O—, a formula —NH—, a formula —SO 2 —, a formula —SO 2 NH—, or a formula —CONH—,
    R 2 is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and the C 4-6 cycloalkyl is a ring; two between the carbon atoms of different medium may be cross-linked with a single bond or C 1-6 alkylene, or one carbon atom in the ring of the C 3-6 cycloalkane, C 3-6 cycloalkyl Alkane may be substituted.), C 3-6 cycloalkylethyl (the C 3-6 cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl) .) or C 3-6 cycloalkyl-methoxy (said C 3-6 cycloalkyl 4. The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein rumethoxy may be substituted with one C 1-6 alkyl.
  5. 式（Ｉ）において、
    Ｒ1が、テトラヒドロピラニル、ピペリジニル（該ピペリジニルは、１個のカルバモイルで置換されてもよい。）、又は
    式ＮＲN1ＲN2であり、
    ＲN1が、水素原子であり、
    ＲN2が、下記式（ＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000005
     （式中、
    ＲC1が、水素原子又はメチルであり、
    ＲC2が、メチル又はイソプロピルであるか、
    又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
    ＲC3が、ハロゲン原子、ヒドロキシ、メチルスルホニル、カルバモイル（該カルバモイルは、１～２個のＣ1-6アルキルで置換されてもよい。）、又はトリアゾリルであり、
    ｎが、０～３の整数である。）、
    又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル、カルボキシ、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、ヒドロキシ、Ｃ2-6アルカノイルオキシ、ピラゾリル及びトリアゾリルからなる群より選ばれる１個の置換基で置換されてもよい。）、カルバモイル（該カルバモイルは、Ｃ1-6アルキル、ピラゾリルＣ1-6アルキル及びトリアゾリルＣ1-6アルキルからなる群より選ばれる１～２個の置換基で置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ（該Ｃ1-6アルコキシカルボニルアミノは、１個のＣ1-6アルキルで置換されてもよい。）、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）、５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イル、Ｃ1-6アルキルスルホニルアミノ、Ｃ1-6アルコキシカルボニル、Ｃ1-6アルキルスルホニル、アミノスルホニルアミノ（該アミノスルホニルアミノは、１～２個のＣ1-6アルキルで置換されてもよい。）からなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
    Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
    Ｒ2が、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）である、請求項３又は４に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is tetrahydropyranyl, piperidinyl (which may be substituted with one carbamoyl), or the formula NR N1 R N2 ;
    R N1 is a hydrogen atom,
    R N2 is the following formula (II):
    Figure JPOXMLDOC01-appb-C000005
     (Where
    R C1 is a hydrogen atom or methyl;
    R C2 is methyl or isopropyl,
    Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane,
    R C3 is a halogen atom, hydroxy, methylsulfonyl, carbamoyl (which may be substituted with 1 to 2 C 1-6 alkyl), or triazolyl;
    n is an integer of 0 to 3. ),
    Alternatively, R N1 and R N2 together with the adjacent nitrogen atom may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom in the ring. A ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl, May be substituted with 1 to 3 groups selected from the group consisting of carboxy, pyrazolyl and methylpyrazolyl), C 1-6 alkoxy (the C 1-6 alkoxy is composed of a halogen atom, pyrazolyl and methylpyrazolyl) may be substituted with 1 to 3 substituents selected from the group.), C 2-6 alkanoylamino (the C 2-6 alkanoylamino, hydroxy, C 2-6 alkanoyloxy, pyrazolyl及With 1 substituent selected from the group consisting of triazolyl may be substituted.), Carbamoyl (said carbamoyl, C 1-6 alkyl, from the group consisting of pyrazolyl C 1-6 alkyl and triazolyl C 1-6 alkyl 1 to 2 selected substituents may be substituted.), C 1-6 alkoxycarbonylamino (the C 1-6 alkoxycarbonylamino may be substituted with one C 1-6 alkyl) ), Ureido (the ureido may be substituted with 1 C 1-6 alkyl), pyrazolyl-Y— (wherein the pyrazolyl of the formula pyrazolyl-Y— is 1 C 1-6 alkyl May be substituted), the formula triazolyl-Y—, cyclopropylcarbonylamino (the cyclopropylcarbonylamino may be substituted with one hydroxy), oxoimidazolidinyl (the oxy Imidazolidinyl may be substituted with one C 1-6 alkyl), 5-oxo-1H-1,2,4-triazole -4 (5H) -.-Yl, C 1-6 alkylsulfonylamino, C 1 to 2 selected from the group consisting of 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, aminosulfonylamino (the aminosulfonylamino may be substituted with 1 to 2 C 1-6 alkyl) Or may be bridged with C 1-6 alkylene between two different carbon atoms in the ring.), Or 2-oxa-6-azaadamantan-6-yl May form,
    Y represents a single bond, a formula —O—, a formula —NH—, a formula —SO 2 —, a formula —SO 2 NH—, or a formula —CONH—,
    R 2 is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and the C 4-6 cycloalkyl is a ring; two between the carbon atoms of different medium may be cross-linked with a single bond or C 1-6 alkylene, or one carbon atom in the ring of the C 3-6 cycloalkane, C 3-6 cycloalkyl Alkane may be substituted.), C 3-6 cycloalkylethyl (the C 3-6 cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl) .) or C 3-6 cycloalkyl-methoxy (said C 3-6 cycloalkyl The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein rumethoxy may be substituted with one C 1-6 alkyl.
  6. 式（Ｉ）において、
    Ｒ1が、式ＮＲN1ＲN2であり、
    ＲN1が、水素原子であり、
    ＲN2が、下記式（ＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000006
     （式中、
    ＲC1が、水素原子又はメチルであり、
    ＲC2が、メチル又はイソプロピルであるか、
    又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
    ＲC3が、ヒドロキシ、メチルスルホニル、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）であり、
    ｎが、１～３の整数である。）、
    又は、ＲN1及びＲN2が、隣接する窒素原子と一緒になって、環中に該窒素原子以外にさらに１個の窒素原子、酸素原子又は硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、オキソ、カルボキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、シアノ、カルバモイル、Ｃ1-6アルキルアミノカルボニル及びカルボキシからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、ハロゲン原子、ピラゾリル及びメチルピラゾリルからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のヒドロキシで置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ1-6アルコキシカルボニルアミノ、ウレイド（該ウレイドは、１個のＣ1-6アルキルで置換されてもよい）、式ピラゾリル－Ｙ－（該式ピラゾリル－Ｙ－のピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、式トリアゾリル－Ｙ－、シクロプロピルカルボニルアミノ（該シクロプロピルカルボニルアミノは、１個のヒドロキシで置換されてもよい。）、オキソイミダゾリジニル（該オキソイミダゾリジニルは、１個のＣ1-6アルキルで置換されてもよい。）及び５－オキソ－１Ｈ－１，２，４－トリアゾール－４（５Ｈ）－イルからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
    Ｙは、単結合、式－Ｏ－、式－ＮＨ－、式－ＳＯ2－、式－ＳＯ2ＮＨ－、又は式－ＣＯＮＨ－を示し、
    Ｒ2が、ｎ‐プロピル、ｎ‐ブチル、ｎ‐ペンチル（該ｎ‐プロピル、ｎ‐ブチル及びｎ‐ペンチルは、１～３個のハロゲン原子で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、Ｃ3-6シクロアルカンと置き換わってもよい。）、Ｃ3-6シクロアルキルエチル（該Ｃ3-6シクロアルキルエチルは、ハロゲン原子及びジフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよい。）又はＣ3-6シクロアルキルメトキシ（該Ｃ3-6シクロアルキルメトキシは、１個のＣ1-6アルキルで置換されてもよい。）であり、
    Ｒ3が、メチル、モノフルオロメチル、ジフルオロメチル、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル又はシアノである、請求項３～５のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is of the formula NR N1 R N2
    R N1 is a hydrogen atom,
    R N2 is the following formula (II):
    Figure JPOXMLDOC01-appb-C000006
     (Where
    R C1 is a hydrogen atom or methyl;
    R C2 is methyl or isopropyl,
    Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane,
    R C3 is hydroxy, methylsulfonyl, or carbamoyl (which may be substituted with one C 1-6 alkyl);
    n is an integer of 1 to 3. ),
    Alternatively, R N1 and R N2 together with the adjacent nitrogen atom may contain one nitrogen atom, oxygen atom or sulfur atom in addition to the nitrogen atom in the ring. A ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, oxo, carboxy, C 1-6 alkyl (the C 1-6 alkyl is a halogen atom, hydroxy, cyano, carbamoyl, C 1-6 alkylaminocarbonyl and 1 to 3 groups selected from the group consisting of carboxy may be substituted.), C 1-6 alkoxy (the C 1-6 alkoxy is 1 selected from the group consisting of a halogen atom, pyrazolyl and methylpyrazolyl) May be substituted with ˜3 groups), C 2-6 alkanoylamino (the C 2-6 alkanoylamino may be substituted with 1 hydroxy), carbamoyl (the carbamoyl is 1 C Optionally substituted with 1-6 alkyl), C 1-6 alkoxycarbonylamino, ureido (which may be substituted with 1 C 1-6 alkyl), pyrazolyl-Y— The pyrazolyl of the formula pyrazolyl-Y— may be substituted with one C 1-6 alkyl.), The formula triazolyl-Y—, cyclopropylcarbonylamino (the cyclopropylcarbonylamino is substituted with one hydroxy) ), Oxoimidazolidinyl (which may be substituted with 1 C 1-6 alkyl) and 5-oxo-1H-1,2,4-triazole- It may be substituted with 1 to 2 groups selected from the group consisting of 4 (5H) -yl, and may be further bridged with C 1-6 alkylene between two different carbon atoms in the ring. Or 2-oxa-6 May form a aza-adamantane-6-yl,
    Y represents a single bond, a formula —O—, a formula —NH—, a formula —SO 2 —, a formula —SO 2 NH—, or a formula —CONH—,
    R 2 is n-propyl, n-butyl, n-pentyl (the n-propyl, n-butyl and n-pentyl may be substituted with 1 to 3 halogen atoms), C 4-6 Cycloalkyl (the C 4-6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and the C 4-6 cycloalkyl is a ring; two between the carbon atoms of different medium may be cross-linked with a single bond or C 1-6 alkylene, or one carbon atom in the ring of the C 3-6 cycloalkane, C 3-6 cycloalkyl Alkane may be substituted.), C 3-6 cycloalkylethyl (the C 3-6 cycloalkylethyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and difluoromethyl) .) or C 3-6 cycloalkyl-methoxy (said C 3-6 cycloalkyl Rumethoxy may be substituted with one C 1-6 alkyl).
    6. The nitrogen-containing fused heterocyclic compound or pharmaceutical thereof according to claim 3 , wherein R 3 is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano. Top acceptable salt.
  7. 式（Ｉ）において、
    Ｒ1が、式ＮＲN1ＲN2であり、
    ＲN1が、水素原子であり、
    ＲN2が、下記式（ＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000007
     （式中、
    ＲC1が、水素原子又はメチルであり、
    ＲC2が、メチル又はイソプロピルであるか、
    又はＲC1及びＲC2が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
    ＲC3が、ヒドロキシ、メチルスルホニル、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）であり、
    ｎが、１～３の整数である。）、
    又は、Ｒ1が下記式（ＩＶ）であり、
    Figure JPOXMLDOC01-appb-C000008
     （式中、
    ＲC７が、水素原子又はヒドロキシであり、
    ＲC８が、水素原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ハロゲン原子、ヒドロキシ、カルバモイル、及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１～３個の基で置換されてもよい。）、カルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）、ピラゾリル（該ピラゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノであり、
    ｒが、２～３の整数である。）、
    又は、Ｒ1が下記式（Ｖ）であり、
    Figure JPOXMLDOC01-appb-C000009
     （式中、
    ＲN３が、Ｃ1-6アルキル（該Ｃ1-6アルキルは、カルバモイル、及びＣ1-6アルキルアミノカルボニルからなる群より選ばれる１個の基で置換されてもよい。）、又はカルバモイル（該カルバモイルは、１個のＣ1-6アルキルで置換されてもよい。）である。）、
    又は、Ｒ1が３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、３－チア－８－アザビシクロ［３．２．１］オクタン－３，３－ジオン－８－イル、及び２‐オキサ‐６‐アザアダマンタン‐６‐イルから選ばれる１つの基であり、
    Ｒ２が、ｎ‐ブチル、Ｃ4-6シクロアルキル、３，３－ジフルオロブチル、（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、４－フルオロビシクロ［２．２．２］オクタ－１－イル、２－（３，３－ジフルオロシクロブチル)エチル、又はシクロブチルメトキシであり、
    Ｒ3が、メチル、モノフルオロメチル、ジフルオロメチル、ジフルオロエチル、メトキシ、ジフルオロメトキシ、シクロプロピル又はシアノである、請求項３～６のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is of the formula NR N1 R N2
    R N1 is a hydrogen atom,
    R N2 is the following formula (II):
    Figure JPOXMLDOC01-appb-C000007
     (Where
    R C1 is a hydrogen atom or methyl;
    R C2 is methyl or isopropyl,
    Or R C1 and R C2 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane,
    R C3 is hydroxy, methylsulfonyl, or carbamoyl (which may be substituted with one C 1-6 alkyl);
    n is an integer of 1 to 3. ),
    Or R 1 is the following formula (IV):
    Figure JPOXMLDOC01-appb-C000008
     (Where
    R C7 is a hydrogen atom or hydroxy,
    R C8 is a hydrogen atom, C 1-6 alkyl (the C 1-6 alkyl is substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxy, carbamoyl, and C 1-6 alkylaminocarbonyl) may be.), carbamoyl (said carbamoyl may be substituted with one C 1-6 alkyl.), pyrazolyl (the pyrazolyl is optionally substituted with one C 1-6 alkyl Or C 1-6 alkoxycarbonylamino;
    r is an integer of 2 to 3. ),
    Or, R 1 is the following formula (V),
    Figure JPOXMLDOC01-appb-C000009
     (Where
    R N3 is C 1-6 alkyl (the C 1-6 alkyl may be substituted with one group selected from the group consisting of carbamoyl and C 1-6 alkylaminocarbonyl), or carbamoyl ( The carbamoyl may be substituted with one C 1-6 alkyl). ),
    Or R 1 is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 3-thia-8 -One group selected from azabicyclo [3.2.1] octane-3,3-dione-8-yl and 2-oxa-6-azaadamantan-6-yl;
    R 2 is n-butyl, C 4-6 cycloalkyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl, 4 -Fluorobicyclo [2.2.2] oct-1-yl, 2- (3,3-difluorocyclobutyl) ethyl, or cyclobutylmethoxy;
    The nitrogen-containing fused heterocyclic compound or a pharmaceutical thereof according to any one of claims 3 to 6, wherein R 3 is methyl, monofluoromethyl, difluoromethyl, difluoroethyl, methoxy, difluoromethoxy, cyclopropyl or cyano. Top acceptable salt.
  8. 式（Ｉ）において、
    Ｘが、式ＣＲ4である、請求項１又は２に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    X is a formula CR 4, fused nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2.
  9. 式（Ｉ）において、
    Ｒ1が、フェニル（該フェニルは、Ｃ2-6アルカノイルアミノ、ヒドロキシメチル及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ3-6シクロアルコキシ（該Ｃ3-6シクロアルコキシは、１個のオキソで置換されてもよい。）、シアノ、ピリジル、ピリミジル、ピラゾリル、イソオキサゾリル（該ピラゾリル及びイソオキサゾリルは、１～２個のメチルで置換されてもよい。）、イソプロピル、イソブチル、Ｃ3-6シクロアルキルメトキシ、フェノキシ、ピペリジノカルボニル、ジヒドロピラニル、又は、
    式ＮＲN3ＲN4であり、
    ＲN3が、水素原子、メチル、イソプロピル、シクロプロピル又はシクロブチルであり、
    ＲN4が、Ｃ4-6シクロアルキル、フェニル又は２－メチル－５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［１，５－ａ］ピリジン－６－イル、又は下記式（ＩＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000010
     （式中、
    ＲC4及びＲC5は、同一又は異なって水素原子又はＣ1-6アルキルを示すか、
    又はＲC4及びＲC5は、隣接する炭素原子と一緒になって、Ｃ3-6シクロアルカン（該Ｃ3-6シクロアルカンは、ハロゲン原子及びヒドロキシからなる群より選ばれる１～２個の基で置換されてもよい。）、４～６員の環状エーテル、又は４～６員の環状アミン（該４～６員の環状アミンは、１個のメチル、Ｃ2-6アルカノイル又はＣ1-6アルコキシカルボニルで置換されている。）を形成してもよく、
    ＲC6が、ハロゲン原子、ヒドロキシ、フェニル、ピリジル、ピリミジル、ピラゾリル、トリアゾリル、メチルオキサジアゾリル、シクロヘキサニル、アミノ、Ｃ2-6アルカノイルアミノ（該Ｃ2-6アルカノイルアミノは、１個のアミノ又はＣ1-6アルキルスルホニルで置換されてもよい。）、又はＣ1-6アルコキシカルボニルアミノであり、
    ｐが、０～１の整数であり、
    ｑが、０～３の整数である。）、
    又はＲN3及びＲN4は、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１つ以上の窒素原子、酸素原子若しくは硫黄原子を含んでもよい４～７員の飽和複素環（該４～７員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、ヒドロキシ、Ｃ1-6アルコキシ、カルバモイル、Ｃ1-6アルコキシカルボニル、ピラゾリル、ピペリジノカルボニル、ジメチルアミノカルボニル及びＣ1-6アルコキシカルボニルオキシからなる群より選ばれる１個の置換基で置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ2-6アルカノイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイルアミノ、Ｃ1-6アルコキシカルボニルアミノ、オキソ、及びアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに該４～７員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよく、又は該４～７員の飽和複素環の環中の１個の炭素原子が、４～６員の環状エーテルで置き換わってもよく、又は該４～７員の飽和複素環が、ベンゼン、ピリジン、イソオキサゾール又はイミダゾールからなる群より選ばれる１つの環と縮合し、縮合環を形成してもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イル、３，４‐ジヒドロキノリン‐１（２Ｈ）‐イル又は２‐オキソキノキサリン‐１（２Ｈ）‐イル（該２‐オキソキノキサリン‐１（２Ｈ）‐イルは、１個のハロゲン原子で置換されてもよい。）を形成してもよく、
    Ｒ2が、ｎ－プロピル（該ｎ－プロピルは、１～３個のハロゲン原子で置換されている。）、ｎ‐ブチル（該ｎ‐ブチルは、メチル、ハロゲン原子、ヒドロキシ及びオキソからなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ3-6シクロアルキル（該Ｃ3-6シクロアルキルは、ハロゲン原子、Ｃ1-6アルキル、ヒドロキシ、オキソ及びトリフルオロメチルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ3-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよく、又は該Ｃ3-6シクロアルカンの環中の１個の炭素原子が、１，３‐ジオキソランと置き換わってもよい。）、Ｃ4-6シクロアルケニル（該Ｃ4-6シクロアルケニルは、１個のハロゲン原子で置換されてもよい。）、シクロプロピルエチル、フェノキシメチル（該フェノキシメチルのフェニル基は、ハロゲン原子、シアノ及びジフロロメチルからなる群より選ばれる１個の置換基で置換されてもよい。）、ピリジルオキシメチル（該ピリジルオキシメチルのピリジルは、１個のトリフロロメチルで置換されてもよい。）、ピペリジノカルボニル、フェノキシカルボニル、プロポキシ、又はシクロプロピルエチニルである、請求項８に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is phenyl (which may be substituted with 1 to 2 groups selected from the group consisting of C 2-6 alkanoylamino, hydroxymethyl and methoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy (the C 3-6 cycloalkoxy may be substituted with one oxo), cyano, pyridyl, pyrimidyl, pyrazolyl, isoxazolyl (the pyrazolyl and isoxazolyl are one to two methyl groups) ), Isopropyl, isobutyl, C 3-6 cycloalkylmethoxy, phenoxy, piperidinocarbonyl, dihydropyranyl, or
    The formula NR N3 R N4 ,
    R N3 is a hydrogen atom, methyl, isopropyl, cyclopropyl or cyclobutyl,
    R N4 is C 4-6 cycloalkyl, phenyl or 2-methyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyridin-6-yl, or Formula (III)
    Figure JPOXMLDOC01-appb-C000010
     (Where
    R C4 and R C5 are the same or different and each represents a hydrogen atom or C 1-6 alkyl,
    Or R C4 and R C5 together with an adjacent carbon atom are C 3-6 cycloalkane (the C 3-6 cycloalkane is a group of 1 to 2 selected from the group consisting of a halogen atom and hydroxy) 4-6 membered cyclic ether, or 4-6 membered cyclic amine (wherein the 4-6 membered cyclic amine is one methyl, C 2-6 alkanoyl or C 1- Substituted with 6 alkoxycarbonyl).
    R C6 is a halogen atom, hydroxy, phenyl, pyridyl, pyrimidyl, pyrazolyl, triazolyl, methyloxadiazolyl, cyclohexanyl, amino, C 2-6 alkanoylamino (the C 2-6 alkanoylamino is one amino group) Or may be substituted with C 1-6 alkylsulfonyl), or C 1-6 alkoxycarbonylamino,
    p is an integer from 0 to 1,
    q is an integer of 0 to 3. ),
    Or R N3 and R N4 together with the adjacent nitrogen atom may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms in addition to the nitrogen atom in the ring; Ring (the 4- to 7-membered saturated heterocyclic ring is hydroxy, C 1-6 alkyl (the C 1-6 alkyl is hydroxy, C 1-6 alkoxy, carbamoyl, C 1-6 alkoxycarbonyl, pyrazolyl, piperidyl And optionally substituted with one substituent selected from the group consisting of nocarbonyl, dimethylaminocarbonyl and C 1-6 alkoxycarbonyloxy), C 3-6 cycloalkyl, C 2-6 alkanoyl, C 1- It may be substituted with 1 to 2 groups selected from the group consisting of 6 alkoxycarbonyl, C 2-6 alkanoylamino, C 1-6 alkoxycarbonylamino, oxo, and amino. A saturated heterocycle may be bridged with C 1-6 alkylene between two different carbon atoms in the ring, or one carbon atom in the ring of the 4-7 membered saturated heterocycle is It may be replaced by a 4-6 membered cyclic ether, or the 4-7 membered saturated heterocyclic ring is condensed with one ring selected from the group consisting of benzene, pyridine, isoxazole or imidazole to form a condensed ring Or 2-oxa-6-azaadamantan-6-yl, 3,4-dihydroquinolin-1 (2H) -yl or 2-oxoquinoxalin-1 (2H) -yl (the 2- Oxoquinoxalin-1 (2H) -yl may be substituted with one halogen atom),
    R 2 is n-propyl (the n-propyl is substituted with 1 to 3 halogen atoms), n-butyl (the n-butyl is a group consisting of methyl, halogen atom, hydroxy and oxo) A C 3-6 cycloalkyl (the C 3-6 cycloalkyl is a halogen atom, C 1-6 alkyl, hydroxy, oxo and trifluoromethyl). The C 3-6 cycloalkyl may be substituted with a single bond or C 1-6 alkylene between two different carbon atoms in the ring. May be bridged, or one carbon atom in the ring of the C 3-6 cycloalkane may be replaced by 1,3-dioxolane), C 4-6 cycloalkenyl (the C 4-6 Cycloalkenyl may be substituted with one halogen atom. Cyclopropylethyl, phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one substituent selected from the group consisting of a halogen atom, cyano and difluoromethyl), pyridyloxymethyl (the 9. The nitrogen-containing fused heterocycle according to claim 8, wherein pyridyl of pyridyloxymethyl is optionally substituted by one trifluoromethyl), piperidinocarbonyl, phenoxycarbonyl, propoxy, or cyclopropylethynyl. A compound or a pharmaceutically acceptable salt thereof.
  10. 式（Ｉ）において、
    Ｒ1が、フェニル（該フェニルは、Ｃ2-6アルカノイルアミノ、ヒドロキシメチル及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、Ｃ3-6シクロアルキル、又は
    式ＮＲN3ＲN4であり、
    ＲN3が、水素原子、メチル、イソプロピル又はシクロブチルであり、
    ＲN4が、Ｃ4-6シクロアルキル、又は下記式（ＩＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000011
     （式中、
    ＲC4及びＲC5は、共に水素原子又はメチルを示すか、
    又はＲC4及びＲC5は、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカン（該Ｃ4-6シクロアルカンは、１～２個のハロゲン原子で置換されてもよい。）又は４～６員の環状エーテルを形成してもよく、
    ＲC6が、ハロゲン原子、ヒドロキシ、フェニル、ピリジル、ピラゾリル、トリアゾリルであり、
    ｐが、０であり、
    ｑが、０～３の整数である。）、
    又はＲN3及びＲN4が、隣接する窒素原子と一緒になって、環中に前記窒素原子以外にさらに１個の酸素原子を含んでもよい４～６員の飽和複素環（該４～６員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ、Ｃ1-6アルコキシ、カルバモイル、Ｃ1-6アルコキシカルボニル又はピラゾリルで置換されてもよい。）、Ｃ3-6シクロアルキル、Ｃ2-6アルカノイル、Ｃ1-6アルコキシカルボニル、Ｃ2-6アルカノイルアミノ及びＣ1-6アルコキシカルボニルアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに該４～６員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、環中に前記窒素原子の他に１個の窒素原子を含む４～６員の飽和複素環（該４～６員の飽和複素環は、Ｃ2-6アルカノイル及びＣ1-6アルコキシカルボニルからなる群より選ばれる１個の置換基で置換されており、さらに該４～６員の飽和複素環は、環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イル、３，４‐ジヒドロキノリン‐１（２Ｈ）‐イル若しくは２‐オキソキノキサリン‐１（２Ｈ）‐イルを形成してもよく、
    Ｒ2が、ｎ‐ブチル（該ｎ‐ブチルは、メチル又はハロゲン原子からなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよい。）、Ｃ4-6シクロアルケニル（該Ｃ4-8シクロアルケニルは、１個のハロゲン原子で置換されてもよい。）、シクロプロピルエチル又はフェノキシメチル（該フェノキシメチルのフェニル基は、１個のハロゲン原子、シアノ又はジフロロメチルで置換されてもよい。）であり、
    Ｒ3が、ハロゲン原子、メチル（該メチル基は、ハロゲン原子及びメトキシからなる群より選ばれる１～２個の基で置換されてもよい。）、メトキシ又はシアノであり、
    Ｒ4が、水素原子、フッ素原子又はメチル（該メチル基は、１個のメトキシで置換されてもよい。）である、請求項８又は９に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is phenyl (which may be substituted with 1 to 2 groups selected from the group consisting of C 2-6 alkanoylamino, hydroxymethyl and methoxy), C 3-6 cycloalkyl, or The formula NR N3 R N4 ,
    R N3 is a hydrogen atom, methyl, isopropyl or cyclobutyl,
    R N4 is C 4-6 cycloalkyl, or the following formula (III),
    Figure JPOXMLDOC01-appb-C000011
     (Where
    R C4 and R C5 both represent a hydrogen atom or methyl,
    Or R C4 and R C5 taken together with adjacent carbon atoms are C 4-6 cycloalkanes (the C 4-6 cycloalkanes may be substituted with 1 to 2 halogen atoms) or 4-6 membered cyclic ethers may be formed,
    R C6 is a halogen atom, hydroxy, phenyl, pyridyl, pyrazolyl, triazolyl,
    p is 0,
    q is an integer of 0 to 3. ),
    Or R N3 and R N4 , together with the adjacent nitrogen atom, may contain one oxygen atom in addition to the nitrogen atom in the ring, and a 4-6 membered saturated heterocyclic ring (the 4-6 membered) The saturated heterocycle of is substituted with hydroxy, C 1-6 alkyl (wherein the C 1-6 alkyl is 1 hydroxy, C 1-6 alkoxy, carbamoyl, C 1-6 alkoxycarbonyl or pyrazolyl). ), C 3-6 cycloalkyl, C 2-6 alkanoyl, C 1-6 alkoxycarbonyl, C 2-6 alkanoylamino and C 1-6 alkoxycarbonylamino are substituted with 1 to 2 groups And the 4-6 membered saturated heterocycle may be bridged with C 1-6 alkylene between two different carbon atoms in the ring.) In addition, a 4- to 6-membered saturated heterocyclic ring containing one nitrogen atom (the 4- The 6-membered saturated heterocyclic ring is substituted with one substituent selected from the group consisting of C 2-6 alkanoyl and C 1-6 alkoxycarbonyl, and the 4- to 6-membered saturated heterocyclic ring is a ring. Between two different carbon atoms may be bridged with C 1-6 alkylene), or 2-oxa-6-azaadamantan-6-yl, 3,4-dihydroquinoline-1 (2H) -Yl or 2-oxoquinoxalin-1 (2H) -yl may be formed,
    R 2 is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 cycloalkyl (the C 4- The 6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and further the C 4-6 cycloalkyl is two different carbons in the ring. The atoms may be bridged with a single bond or C 1-6 alkylene.), C 4-6 cycloalkenyl (the C 4-8 cycloalkenyl may be substituted with one halogen atom.) , Cyclopropylethyl or phenoxymethyl (the phenyl group of the phenoxymethyl may be substituted with one halogen atom, cyano or difluoromethyl),
    R 3 is a halogen atom, methyl (the methyl group may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and methoxy), methoxy or cyano;
    The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable thereof according to claim 8 or 9, wherein R 4 is a hydrogen atom, a fluorine atom or methyl (the methyl group may be substituted with one methoxy). Acceptable salt.
  11. 式（Ｉ）において、
    Ｒ1が、式ＮＲN3ＲN4であり、
    ＲN3が水素原子であり、
    ＲN4が、下記式（ＩＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000012
     （式中、
    ＲC4及びＲC5が、共にメチルを示すか、
    又はＲC4及びＲC5が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカン又は４～６員の環状エーテルを形成してもよく、
    ＲC6が、ハロゲン原子又はヒドロキシであり、
    ｐが、０であり、
    ｑが、１～３の整数である。）、
    又は、ＲN3及びＲN4が、隣接する窒素原子と一緒になって、環中に前記窒素原子の他にさらに１個の酸素原子を含んでもよい４～６員の飽和複素環（該４～６員の飽和複素環は、ヒドロキシ、Ｃ1-6アルキル、Ｃ2-6アルカノイルアミノ及びＣ1-6アルコキシカルボニルアミノからなる群より選ばれる１～２個の基で置換されてもよく、さらに環中の異なる２個の炭素原子の間をＣ1-6アルキレンで架橋されてもよい。）、又は２‐オキサ‐６‐アザアダマンタン‐６‐イルを形成してもよく、
    Ｒ2が、ｎ‐ブチル（該ｎ‐ブチルは、メチル又はハロゲン原子からなる群より選ばれる１～３個の基で置換されてもよい。）、Ｃ4-6シクロアルキル（該Ｃ4-6シクロアルキルは、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる１～２個の基で置換されてもよく、さらに該Ｃ4-6シクロアルキルは、環中の異なる２個の炭素原子の間を単結合又はＣ1-6アルキレンで架橋されてもよい。）、シクロプロピルエチル又はジフロロメチルフェノキシメチルであり、
    Ｒ3が、メチル、ジフロロメチル、メトキシ又はシアノであり、
    Ｒ4が、水素原子、フッ素原子又はメチルである請求項８～１０のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is of the formula NR N3 R N4 ,
    R N3 is a hydrogen atom,
    R N4 is the following formula (III):
    Figure JPOXMLDOC01-appb-C000012
     (Where
    R C4 and R C5 both represent methyl,
    Or R C4 and R C5 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane or a 4-6 membered cyclic ether;
    R C6 is a halogen atom or hydroxy,
    p is 0,
    q is an integer of 1 to 3. ),
    Alternatively, R N3 and R N4 , together with the adjacent nitrogen atom, may contain one oxygen atom in addition to the nitrogen atom in the ring, and a 4-6 membered saturated heterocyclic ring (the 4- The 6-membered saturated heterocyclic ring may be substituted with 1 to 2 groups selected from the group consisting of hydroxy, C 1-6 alkyl, C 2-6 alkanoylamino and C 1-6 alkoxycarbonylamino, May be bridged with C 1-6 alkylene between two different carbon atoms in the ring), or may form 2-oxa-6-azaadamantan-6-yl,
    R 2 is n-butyl (the n-butyl may be substituted with 1 to 3 groups selected from the group consisting of methyl or halogen atoms), C 4-6 cycloalkyl (the C 4- The 6 cycloalkyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, and further the C 4-6 cycloalkyl is two different carbons in the ring. Between atoms may be bridged with a single bond or C 1-6 alkylene)), cyclopropylethyl or difluoromethylphenoxymethyl;
    R 3 is methyl, difluoromethyl, methoxy or cyano;
    The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 10, wherein R 4 is a hydrogen atom, a fluorine atom or methyl.
  12. 式（Ｉ）において、
    Ｒ1が、式ＮＲN3ＲN4であり、
    ＲN3が、水素原子であり、
    ＲN4が、下記式（ＩＩＩ）であり、
    Figure JPOXMLDOC01-appb-C000013
     （式中、
    ＲC4及びＲC5が、共にメチルを示すか、
    又はＲC4及びＲC5が、隣接する炭素原子と一緒になって、Ｃ4-6シクロアルカンを形成してもよく、
    ＲC6が、ハロゲン原子又はヒドロキシであり、
    ｐが、０であり、
    ｑが、１～３の整数である。）、
    又は、Ｒ1が、３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル、３－オキサ－９－アザビシクロ［３．３．１］ノナン－９－イル、２‐オキサ‐６‐アザアダマンタン‐６‐イル、８－アザビシクロ［３．２．１］オクタン－3－オール－８－イル、及び３－メチル－８－アザビシクロ［３．２．１］オクタン－3－オール－８－イルから選ばれる１つの基であり、
    Ｒ2が、ｎ‐ブチル、Ｃ4-6シクロアルキル、シクロプロピルエチル、３，３－ジフルオロブチル、（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル、又は４－フルオロビシクロ［２．２．２］オクタ－１－イルであり、
    Ｒ３が、メチル、ジフロロメチル、メトキシ又はシアノであり、
    Ｒ４が、水素原子又はフッ素原子である請求項８～１１のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬上許容される塩。     In formula (I):
    R 1 is of the formula NR N3 R N4 ,
    R N3 is a hydrogen atom,
    R N4 is the following formula (III):
    Figure JPOXMLDOC01-appb-C000013
     (Where
    R C4 and R C5 both represent methyl,
    Or R C4 and R C5 may be taken together with adjacent carbon atoms to form a C 4-6 cycloalkane,
    R C6 is a halogen atom or hydroxy,
    p is 0,
    q is an integer of 1 to 3. ),
    Or R 1 is 3-oxa-8-azabicyclo [3.2.1] octane-8-yl, 3-oxa-9-azabicyclo [3.3.1] nonane-9-yl, 2-oxa- 6-azaadamantan-6-yl, 8-azabicyclo [3.2.1] octane-3-ol-8-yl, and 3-methyl-8-azabicyclo [3.2.1] octane-3-ol- One group selected from 8-yl,
    R 2 is n-butyl, C 4-6 cycloalkyl, cyclopropylethyl, 3,3-difluorobutyl, (1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexa-3 -Yl, or 4-fluorobicyclo [2.2.2] oct-1-yl,
    R 3 is methyl, difluoromethyl, methoxy or cyano;
    The nitrogen-containing fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 11, wherein R 4 is a hydrogen atom or a fluorine atom.
  13. 請求項１に記載される下記化合物からなる群から選択される化合物、又はその医薬上許容される塩。
    ２－ブチル－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］ピリミジン、
    ６－（２－ブチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
    ２－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－５－メチル－７－（３－オキサ－８－アザビシクロ［３．２．１］オクタン－８－イル）ピラゾロ［１，５－ａ］ピリミジン、
    ６－（２－シクロペンチル－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル）－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
    ６－｛２－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－５－メチルピラゾロ［１，５－ａ］ピリミジン－７－イル｝－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
    ７－ブチル－２－メチル－４－（３－オキサ－８－アザビシクロ［３．２．１］オクタ－８－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン、
    ６－（７－ブチル－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
    ６－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
    （３－ｅｎｄｏ）－８－［７－（３，３－ジフルオロブチル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］－８－アザビシクロ［３．２．１］オクタン－３－オール、
    ２－（｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－２－メチルプロパン－１-オール、
    ６－｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサ－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝－２－オキサ－６－アザトリシクロ［３．３．１．１３，７］デカン、
    ７－（３，３－ジフルオロブチル）－４－（３，３－ジオキシド－３－チア－８－アザビシクロ［３．２．１］オクタ－８－イル）－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン、
    ８－｛７－［（１Ｒ，３ｓ，５Ｓ）－６，６－ジフルオロビシクロ［３．１．０］ヘキサン－３－イル］－２－メチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝－３－チア－８－アザビシクロ［３．２．１］オクタン－３，３－ジオン。     A compound selected from the group consisting of the following compounds according to claim 1, or a pharmaceutically acceptable salt thereof.
    2-butyl-5-methyl-7- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] pyrimidine,
    6- (2-butyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) -2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane,
    2-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexan-3-yl] -5-methyl-7- (3-oxa-8-azabicyclo [3.2. 1] octane-8-yl) pyrazolo [1,5-a] pyrimidine,
    6- (2-cyclopentyl-5-methylpyrazolo [1,5-a] pyrimidin-7-yl) -2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane,
    6- {2-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -5-methylpyrazolo [1,5-a] pyrimidin-7-yl} -2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane,
    7-butyl-2-methyl-4- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) pyrazolo [1,5-a] [1,3,5] triazine,
    6- (7-Butyl-2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl) -2-oxa-6-azatricyclo [3.3.1.1 3,7 ] Deccan,
    6- [7- (3,3-Difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -2-oxa-6-azatricyclo [3.3. 1.1 3,7 ] decane,
    (3-endo) -8- [7- (3,3-difluorobutyl) -2-methylpyrazolo [1,5-a] [1,3,5] triazin-4-yl] -8-azabicyclo [3. 2.1] Octane-3-ol,
    2-({7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -2-methylpyrazolo [1,5-a] [1,3, 5] triazin-4-yl} amino) -2-methylpropan-1-ol,
    6- {7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hex-3-yl] -2-methylpyrazolo [1,5-a] [1,3,5 ] Triazin-4-yl} -2-oxa-6-azatricyclo [3.3.1.1 3,7 ] decane,
    7- (3,3-Difluorobutyl) -4- (3,3-dioxide-3-thia-8-azabicyclo [3.2.1] oct-8-yl) -2-methylpyrazolo [1,5-a ] [1, 3, 5] triazine,
    8- {7-[(1R, 3s, 5S) -6,6-difluorobicyclo [3.1.0] hexane-3-yl] -2-methylpyrazolo [1,5-a] [1,3,5 ] Triazin-4-yl} -3-thia-8-azabicyclo [3.2.1] octane-3,3-dione.
  14. 請求項１～１３のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬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 nitrogen-containing fused heterocyclic compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
  15. 請求項１～１３のいずれか１項に記載の含窒素縮合複素環化合物又はその医薬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、脆弱性Ｘ症候群、統合失調症、双極性障害、うつ病、不安障害、認知症、疼痛、薬物・アルコール依存症、痙攣、脳血管障害、脳性麻痺、脊髄麻痺、外傷後遺症、多発性硬化症、筋萎縮性側索硬化症、ｓｔｉｆｆ－ｍａｎ症候群、本態性振戦、過活動膀胱、胃食道逆流性疾患又はＣｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病の治療又は予防薬。
          Autism spectrum disorder, fragile X syndrome, schizophrenia, bipolar, comprising the nitrogen-containing fused heterocyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 as an active ingredient Disorder, depression, anxiety disorder, dementia, pain, drug / alcoholism, convulsions, cerebrovascular disorder, cerebral palsy, spinal cord palsy, traumatic sequelae, multiple sclerosis, amyotrophic lateral sclerosis, stiff-man A therapeutic or prophylactic agent for syndrome, essential tremor, overactive bladder, gastroesophageal reflux disease or Charcot-Marie-Tooth disease.
PCT/JP2016/081355 2015-10-22 2016-10-21 Nitrogen-containing condensed heterocyclic compound WO2017069270A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015208431A JP2018199623A (en) 2015-10-22 2015-10-22 Nitrogen-containing condensation heterocyclic compound
JP2015-208431 2015-10-22

Publications (1)

Publication Number Publication Date
WO2017069270A1 true WO2017069270A1 (en) 2017-04-27

Family

ID=58557173

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/081355 WO2017069270A1 (en) 2015-10-22 2016-10-21 Nitrogen-containing condensed heterocyclic compound

Country Status (2)

Country Link
JP (1) JP2018199623A (en)
WO (1) WO2017069270A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018167630A1 (en) * 2017-03-13 2018-09-20 Richter Gedeon Nyrt. PHARMACOLOGICALLY ACTIVE ALICYCLIC-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
US11155560B2 (en) 2018-10-30 2021-10-26 Kronos Bio, Inc. Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activity
WO2022020890A1 (en) * 2020-07-27 2022-02-03 Esfam Biotech Pty Ltd Treatment of veterinary conditions associated with cd151
WO2022020887A1 (en) * 2020-07-27 2022-02-03 Esfam Biotech Pty Ltd Treatment of cd151 related disorders
WO2022029666A1 (en) 2020-08-05 2022-02-10 Richter Gedeon Nyrt. PHARMACOLOGICALLY ACTIVE HETEROCYCLIC-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
CN115023427A (en) * 2019-12-11 2022-09-06 拜耳公司 Pyrazolotriazines

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220017995A (en) * 2019-06-05 2022-02-14 광조우 조요 파마테크 컴퍼니 리미티드 Pyrrolopyrimidine compounds and uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5019769A (en) * 1973-05-22 1975-03-01
WO2000044754A1 (en) * 1999-01-29 2000-08-03 Sumitomo Chemical Company, Limited Fat accumulation inhibitory agents
WO2001077111A1 (en) * 2000-04-07 2001-10-18 Merck Sharp & Dohme Limited Pyrazolo-triazine derivatives as ligands for gaba receptors
WO2005084439A1 (en) * 2004-03-02 2005-09-15 Dov Pharmaceutical, Inc. 2-pyridinyl[7-(substituted-pyridin-4-yl) pyrazolo[1,5-a]pyrimidin-3-yl]methanones
WO2006136530A1 (en) * 2005-06-21 2006-12-28 Ferrer Internacional, S.A. Halogenated pyrazolo [1,5-a]pyrimidines, processes, uses as gaba-a receptors ligand, compositions and intermediates
CN101147741A (en) * 2007-07-19 2008-03-26 袁才尉 Medicine for giving up drug
WO2016169995A1 (en) * 2015-04-20 2016-10-27 AbbVie Deutschland GmbH & Co. KG Substituted pyrazolopyrimidines and method of use

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5019769A (en) * 1973-05-22 1975-03-01
WO2000044754A1 (en) * 1999-01-29 2000-08-03 Sumitomo Chemical Company, Limited Fat accumulation inhibitory agents
WO2001077111A1 (en) * 2000-04-07 2001-10-18 Merck Sharp & Dohme Limited Pyrazolo-triazine derivatives as ligands for gaba receptors
WO2005084439A1 (en) * 2004-03-02 2005-09-15 Dov Pharmaceutical, Inc. 2-pyridinyl[7-(substituted-pyridin-4-yl) pyrazolo[1,5-a]pyrimidin-3-yl]methanones
WO2006136530A1 (en) * 2005-06-21 2006-12-28 Ferrer Internacional, S.A. Halogenated pyrazolo [1,5-a]pyrimidines, processes, uses as gaba-a receptors ligand, compositions and intermediates
CN101147741A (en) * 2007-07-19 2008-03-26 袁才尉 Medicine for giving up drug
WO2016169995A1 (en) * 2015-04-20 2016-10-27 AbbVie Deutschland GmbH & Co. KG Substituted pyrazolopyrimidines and method of use

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [o] 14 January 2014 (2014-01-14), retrieved from STN Database accession no. 1519911-04-6 *
DATABASE REGISTRY 1 December 2013 (2013-12-01), Database accession no. 1484039-79-3 *
DATABASE REGISTRY 1 December 2013 (2013-12-01), Database accession no. 1484599-58-7 *
DATABASE REGISTRY 1 December 2013 (2013-12-01), Database accession no. 1484987- 46-3 *
DATABASE REGISTRY 11 December 2013 (2013-12-11), Database accession no. 1492372-93-6 *
DATABASE REGISTRY 11 December 2013 (2013-12-11), Database accession no. 1492766-46-7 *
DATABASE REGISTRY 12 December 2013 (2013-12-12), Database accession no. 1493322-46-5 *
DATABASE REGISTRY 13 December 2013 (2013-12-13), Database accession no. 1494260- 86-4 *
DATABASE REGISTRY 16 September 2008 (2008-09-16), Database accession no. 1049630- 51-4 *
DATABASE REGISTRY 17 December 2013 (2013-12-17), Database accession no. 1497361-86-0 *
DATABASE REGISTRY 17 January 2014 (2014-01-17), Database accession no. 1523122- 13-5 *
DATABASE REGISTRY 18 December 2013 (2013-12-18), Database accession no. 1497829-26-1 *
DATABASE REGISTRY 19 December 2013 (2013-12-19), Database accession no. 1498609-59-8 *
DATABASE REGISTRY 2 August 2009 (2009-08-02), Database accession no. 1171376-04-7 *
DATABASE REGISTRY 2 December 2013 (2013-12-02), Database accession no. 1485323-27-0 *
DATABASE REGISTRY 21 November 2013 (2013-11-21), Database accession no. 1478173-34-0 *
DATABASE REGISTRY 22 November 2013 (2013-11-22), Database accession no. 1478667-23-0 *
DATABASE REGISTRY 23 October 2013 (2013-10-23), Database accession no. 1462825-63-3 *
DATABASE REGISTRY 24 December 2013 (2013-12-24), Database accession no. 1502095- 66-0 *
DATABASE REGISTRY 24 November 2013 (2013-11-24), Database accession no. 1479520-43-8 *
DATABASE REGISTRY 25 November 2013 (2013-11-25), Database accession no. 1480240-96-7 *
DATABASE REGISTRY 25 November 2013 (2013-11-25), Database accession no. 1480540- 87-1 *
DATABASE REGISTRY 25 November 2013 (2013-11-25), Database accession no. 1480720-75-9 *
DATABASE REGISTRY 26 November 2013 (2013-11-26), Database accession no. 1481343-81-0 *
DATABASE REGISTRY 28 November 2013 (2013-11-28), Database accession no. 1483288- 46-5 *
DATABASE REGISTRY 29 November 2013 (2013-11-29), Database accession no. 1483721-43-2 *
DATABASE REGISTRY 29 November 2013 (2013-11-29), Database accession no. 1483825-47-3 *
DATABASE REGISTRY 29 October 2013 (2013-10-29), Database accession no. 1465595-13-4 *
DATABASE REGISTRY 3 December 2013 (2013-12-03), Database accession no. 1485876-77-4 *
DATABASE REGISTRY 3 November 2013 (2013-11-03), Database accession no. 1467906- 43-9 *
DATABASE REGISTRY 30 December 2013 (2013-12-30), Database accession no. 1506728-84-2 *
DATABASE REGISTRY 30 October 2013 (2013-10-30), Database accession no. 1466036-01-0 *
DATABASE REGISTRY 5 July 2015 (2015-07-05), Database accession no. 1793872-48-6 *
DATABASE REGISTRY 6 December 2013 (2013-12-06), Database accession no. 1489099-90-2 *
DATABASE REGISTRY 6 January 2014 (2014-01-06), Database accession no. 1512098-93-9 *
DATABASE REGISTRY 7 September 2008 (2008-09-07), Database accession no. 1046882-83-0 *
DATABASE REGISTRY 8 December 2013 (2013-12-08), Database accession no. 1490162- 01-0 *
DATABASE REGISTRY 9 December 2013 (2013-12-09), Database accession no. 1490726-27-6 *
PERDONA E. ET AL.: "In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4- chlorophenyl)-5-methylpyrazolo[1,5-a] pyrimidin-7-yl]-2-piperidinyl}ethanol(CMPPE)", NEUROPHARMACOLOGY, vol. 61, 2011, pages 957 - 66, XP028268260, ISSN: 0028-3908 *
SORBERA L.A. ET AL.: "Indiplon: Treatment of insomnia GABA-A agonist", DRUGS OF THE FUTURE, vol. 28, no. 8, 2003, pages 739 - 46, XP008045127, ISSN: 0377-8282 *
ZHANG X. ET AL.: "Highly facile and regio-selective synthesis of pyrazolo[1,5-a] pyrimidines via reactions of 1,2-allenic ketones with aminopyrazoles", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 12, 2014, pages 2099 - 107, XP055377462, ISSN: 1477-0520 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018167630A1 (en) * 2017-03-13 2018-09-20 Richter Gedeon Nyrt. PHARMACOLOGICALLY ACTIVE ALICYCLIC-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
CN110431142A (en) * 2017-03-13 2019-11-08 吉瑞工厂 Alicyclic substituted pyrazolo [1,5-a] pyrimidine derivatives of pharmacological activity
US11026946B2 (en) 2017-03-13 2021-06-08 Richter Gedeon Nyrt. Pharmacologically active alicyclic-substituted pyrazolo[1,5-a]pyrimidine derivatives
AU2018235266B2 (en) * 2017-03-13 2021-09-30 Richter Gedeon Nyrt. Pharmacologically active alicyclic-substituted pyrazolo[1,5-a]pyrimidine derivatives
EA038756B1 (en) * 2017-03-13 2021-10-14 Рихтер Гедеон Нирт. PHARMACOLOGICALLY ACTIVE ALICYCLIC-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
US11155560B2 (en) 2018-10-30 2021-10-26 Kronos Bio, Inc. Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activity
US11845754B2 (en) 2018-10-30 2023-12-19 Kronos Bio, Inc. Substituted pyrazolo[1,5-a]pyrimidines for modulating CDK9 activity
CN115023427A (en) * 2019-12-11 2022-09-06 拜耳公司 Pyrazolotriazines
WO2022020890A1 (en) * 2020-07-27 2022-02-03 Esfam Biotech Pty Ltd Treatment of veterinary conditions associated with cd151
WO2022020887A1 (en) * 2020-07-27 2022-02-03 Esfam Biotech Pty Ltd Treatment of cd151 related disorders
WO2022029666A1 (en) 2020-08-05 2022-02-10 Richter Gedeon Nyrt. PHARMACOLOGICALLY ACTIVE HETEROCYCLIC-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES
CN116075514A (en) * 2020-08-05 2023-05-05 吉瑞工厂 Pharmacologically active heterocyclic substituted pyrazolo [1,5-a ] pyrimidine derivatives

Also Published As

Publication number Publication date
JP2018199623A (en) 2018-12-20

Similar Documents

Publication Publication Date Title
WO2017069270A1 (en) Nitrogen-containing condensed heterocyclic compound
US20230043959A1 (en) Piperidin-4-yl azetidine derivatives as jak1 inhibitors
KR102179599B1 (en) New bicyclic derivatives
RU2679609C1 (en) Imidazopyridazine derivatives as modulators of tnf activity
IL273079A (en) Heterocyclylamines as pi3k inhibitors
JP6338601B2 (en) Novel compounds as dual inhibitors of phosphodiesterase and histone deacetylase
WO2018178338A1 (en) 2-oxo-thiazole derivatives as a2a inhibitors and compounds for use in the treatment of cancers
JP6356671B2 (en) 4-Methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
TWI419889B (en) A pyrazolo [1,5-a] pyrimidine compound
US20110059951A1 (en) HETEROCYCLIC DERIVATIVES OF PYRAZOL-4-YL-PYRROLO[2,3-d]PYRIMIDINES AS JANUS KINASE INHIBITORS
EP3601296B1 (en) 2-oxo-thiazole derivatives as a2a inhibitors and compounds for use in the treatment of cancers
JP2016539967A (en) Condensed tricyclic benzimidazole derivatives as modulators of TNF activity
WO2013026025A1 (en) Cyclohexyl azetidine derivatives as jak inhibitors
KR20150013554A (en) Heterocyclyl pyrimidine analogues as tyk2 inhibitors
KR20140019300A (en) Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
AU2013329097B2 (en) Urea and amide derivatives of aminoalkylpiperazines and use thereof
MX2011005119A (en) Alkylcyclohexylethers of dihydrotetraazabenzoazulenes.
KR20200046061A (en) Spirocycle compounds and methods of making and using them
US20230098694A1 (en) Non brain penetrant a2a inhibitors and methods for use in the treatment of cancers
US20180222868A1 (en) Indazole Derivatives as Modulators of TNF Activity
EA036289B1 (en) Fused tricyclic imidazo pyrazines as modulators of tnf activity
JP6477484B2 (en) Sulfur-containing bicyclic compound
US20150216867A1 (en) Compounds for use in gastric complication
WO2021210586A1 (en) Condensed heterocyclic compound
US9771351B2 (en) Wnt signaling inhibitor

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: 16857583

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: 16857583

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP