WO2021221097A1 - Novel bicyclic compound - Google Patents

Novel bicyclic compound Download PDF

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Publication number
WO2021221097A1
WO2021221097A1 PCT/JP2021/016942 JP2021016942W WO2021221097A1 WO 2021221097 A1 WO2021221097 A1 WO 2021221097A1 JP 2021016942 W JP2021016942 W JP 2021016942W WO 2021221097 A1 WO2021221097 A1 WO 2021221097A1
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amino
sulfonamide
ethane
triazine
pyrazolo
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PCT/JP2021/016942
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French (fr)
Japanese (ja)
Inventor
聡志 一色
佑太 藤原
淳史 山田
広太 村▲崎▼
美紀 山内
渉吾 松本
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Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
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Publication of WO2021221097A1 publication Critical patent/WO2021221097A1/en

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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 bicyclic compound, more specifically, a novel compound which is a bicyclic compound having a regulating action on histamine H4 receptor, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these. Regarding.
  • the histamine receptor is a receptor for histamine, which is one of the active amines in the living body, and four subtypes of H1 to H4 are known.
  • the histamine H4 receptor is a GPCR (G protein-conjugated receptor) that binds to the G ⁇ i / o protein and is highly expressed in immune tissues such as the thoracic gland, bone marrow, and spleen, and is highly expressed in mast cells, dendritic cells, and eosinophils.
  • T cells are also found to be expressed in immune cells.
  • the histamine H4 receptor modulator which has a regulating action on the histamine H4 receptor, is expected to have potential as a therapeutic agent for various immunoinflammatory diseases such as rheumatism, asthma, atopic dermatitis, and allergic rhinitis. ing.
  • Patent Document 1 Patent Document 2
  • Patent Document 2 Patent Document 3
  • Patent Document 1 Patent Document 2
  • Patent Document 2 describe that a heterobicyclic derivative has a histamine H4 receptor-regulating action.
  • the present invention presents with novel compounds and pharmacologically acceptable salts thereof, which have a regulatory effect on the histamine H4 receptor and are useful for the treatment and / or prevention of diseases or conditions involving the histamine H4 receptor. It is an object of the present invention to provide a pharmaceutical composition containing these.
  • the present invention includes the following inventions.
  • X 1 is a CH or nitrogen atom and X 2 is a halogen atom, C 1 ⁇ 6 alkyl group, NH 2, NHCH 3, N (CH 3) 2, NO 2, OH, and substituted with either one substituent selected from OCH 3 CH; or a nitrogen atom, which may be X 3 and X 4 are independently carbon or nitrogen atoms, respectively.
  • Ring A is a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms.
  • ring A may be substituted with at least one substituent selected from a halogen atom, CH 2 OH, CH 2 F, CHF 2 , and a cyclopropyl group; a C 1-6 alkyl group; a halogen atom.
  • R 1 and R 2 are 4- to 9-membered non-members which may further contain at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded.
  • the non-aromatic heterocyclic group is a monocyclic, fused bicyclic, crosslinked bicyclic, or spirobicyclic group and contains at least two nitrogen atoms.
  • it is a group containing one nitrogen atom and substituted with a group containing at least one nitrogen atom.
  • R 5 and R 6 are independently hydrogen atoms or C 1 to 6 alkyl groups, or 4- to 6-membered non-aromatics together with the nitrogen atom to which R 5 and R 6 are bonded.
  • R 3 is a hydrogen atom or a C 1-6 alkyl group.
  • R 4 is a phenyl group optionally substituted with a fluorine atom; -NR 7 R 8 ; or a C 1-6 alkyl group.
  • R 7 and R 8 are independently substituted with at least one substituent selected from a hydrogen atom; a hydroxyl group; a C 1 to 6 alkyl group; a halogen atom, a CN, a hydroxyl group, and CH 2 OH.
  • C 3 ⁇ 7 cycloalkyl group optionally; halogen atom, a hydroxyl group, and at least one substituent a phenyl group which may be substituted with a group selected from CF 3; 5-membered 6-membered aromatic heterocyclic ring A 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group, or a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group with a nitrogen atom to which R 7 and R 8 are bonded.
  • the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently substituted with at least one substituent selected from a fluorine atom; CF 3 ; a hydroxyl group; OCH 3 ; a fluorine atom and CF 3.
  • C 3 to 7 cycloalkyl groups which may be substituted; a phenyl group which may be substituted with at least one substituent selected from a halogen atom and CF 3; and 5 members which may be substituted with a halogen atom. May be substituted with one or more substituents selected from the 6-membered aromatic heterocyclic group.
  • n is an integer from 1 to 4.
  • R 1 and R 2 are a 4- to 7-membered monocyclic non-aromatic heterocyclic group and a 6- to 9-membered fused two, together with the nitrogen atom to which they are bonded.
  • R 1 and R 2 form a 4- to 7-membered monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and the 4-membered non-aromatic heterocyclic group is formed.
  • R 1 and R 2 form a 7- to 9-membered spirobicyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.
  • Spirobicyclic non-aromatic heterocyclic groups of 9 to 9 members are represented by the following formulas (e) to (h):
  • R 4 is ⁇ NR 7 R 8 , and R 7 and R 8 may be independently substituted with hydrogen atom; C 1 to 6 alkyl group; halogen atom , respectively.
  • the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently C 3 to 7 cycloalkyl groups which may be substituted with a fluorine atom; CF 3 ; a fluorine atom; a halogen atom and CF 3
  • the ring A is a 5-membered aromatic heterocycle containing 1 to 3 nitrogen atoms or a 6-membered aromatic heterocycle containing 2 to 3 nitrogen atoms.
  • a two-ring containing X 1 ⁇ X 4 and ring A structure :
  • the compound represented by the formula (1) is 2-( ⁇ 1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl ⁇ amino) -N- (propane-2-) Il) ethane-1-sulfonamide, N-Benzyl-2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1-sulfonamide, N-Cyclopropyl-2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1-sulfonamide ,
  • the pharmaceutical composition according to [10] which is a composition for regulating histamine H4 receptors.
  • Involved in the histamine H4 receptor which comprises the step of administering to the subject at least one selected from the compound according to any one of [1] to [9] and a pharmacologically acceptable salt thereof.
  • the compound according to any one of [1] to [9] or its pharmacology for producing a pharmaceutical composition for treating and / or preventing a disease or condition involving a histamine H4 receptor. Tolerable use of salt.
  • the compounds of the present invention, pharmacologically acceptable salts thereof, and pharmaceutical compositions containing them are useful for the treatment and / or prevention of diseases or conditions involving the histamine H4 receptor.
  • Diseases or conditions involving the histamine H4 receptor include, for example, various allergies, immunoinflammatory diseases (COPD, etc.), inflammatory bowel diseases, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, etc.
  • COPD immunoinflammatory diseases
  • inflammatory bowel diseases COPD, etc.
  • rheumatism atopic dermatitis
  • pruritic dermatitis atopic dermatitis
  • allergic conjunctivitis rhinitis, etc.
  • the present invention provides a compound represented by the following formula (1) and a pharmacologically acceptable salt thereof. Further, in one embodiment, the present invention contains a pharmaceutical composition containing at least one of a compound represented by the following formula (1) and a pharmacologically acceptable salt thereof, preferably as an active ingredient. To provide a pharmaceutical composition (such as a therapeutic agent for immunoinflammatory diseases).
  • X 1 is a CH or nitrogen atom.
  • X 2 is a halogen atom, C 1 ⁇ 6 alkyl group, NH 2, NHCH 3, N (CH 3) 2, NO 2, OH, and substituted with either one substituent selected from OCH 3 It may be a CH; or a nitrogen atom.
  • X 3 and X 4 are independently carbon atoms or nitrogen atoms, respectively.
  • the ring A is a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • ring A may be substituted with at least one substituent selected from a halogen atom, CH 2 OH, CH 2 F, CHF 2 , and a cyclopropyl group; a C 1-6 alkyl group; halogen.
  • the structure of a secondary ring containing X 1 - X 4, and ring A is preferably a structure represented by any one of the formulas (101) to (130) ..
  • R 1 and R 2 may further contain at least one hetero atom selected from nitrogen atom, oxygen atom, and sulfur atom together with the nitrogen atom to which they are bonded4. It forms a 9-membered non-aromatic heterocyclic group.
  • the non-aromatic heterocyclic group is a monocyclic group, a fused bicyclic group, a crosslinked bicyclic group, or a spiro bicyclic group.
  • the non-aromatic heterocyclic group is substituted with at least one substituent selected from a fluorine atom, a hydroxyl group, an ⁇ NR 5 R 6 , a C 1 to 6 alkyl group, and a C 1 to 6 amino alkyl group. May be.
  • R 5 and R 6 are independently hydrogen atoms or C 1 to 6 alkyl groups, or 4- to 6-membered non-aromatic heterocycles with nitrogen atoms to which R 5 and R 6 are attached. Form a formula group.
  • the non-aromatic heterocyclic group is a group containing at least two nitrogen atoms (including a nitrogen atom to which R 1 and R 2 are bonded), or one nitrogen atom (including a nitrogen atom to which R 1 and R 2 are bonded). That is, it is a group substituted with a group containing (a nitrogen atom to which R 1 and R 2 are bonded) and containing at least one nitrogen atom.
  • the non-aromatic heterocyclic groups containing R 1 and R 2 and the nitrogen atom to which they are bonded include 4- to 7-membered monocyclic non-aromatic heterocyclic groups, from 6-membered groups. It is preferably a 9-membered fused bicyclic non-aromatic heterocyclic group or a 7- to 9-membered spirobicyclic non-aromatic heterocyclic group, preferably an azetidine ring, a pyrrolidine ring, or a piperazine ring. , Piperidine ring, diazepan ring, or a group represented by any one of the above formulas (a) to (h) is more preferable. These groups may be substituted with the groups listed as the substituents of the non-aromatic heterocyclic groups containing R 1 and R 2 described above.
  • R 3 is a hydrogen atom or a C 1 to 6 alkyl group.
  • R 4 is a phenyl group optionally substituted with a fluorine atom; -NR 7 R 8 ; or a C 1-6 alkyl group.
  • n is an integer of any one of 1 to 4.
  • R 7 and R 8 are independently substituted with at least one substituent selected from a hydrogen atom; a hydroxyl group; a C 1 to 6 alkyl group; a halogen atom, a CN, a hydroxyl group, and CH 2 OH.
  • C 3 ⁇ 7 cycloalkyl group optionally; halogen atom, a hydroxyl group, and at least one substituent a phenyl group which may be substituted with a group selected from CF 3; 5-membered 6-membered aromatic heterocyclic ring Formula group; or a 4- to 6-membered non-aromatic heterocyclic group, or a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group with a nitrogen atom to which R 7 and R 8 are bonded.
  • the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently substituted with at least one substituent selected from a fluorine atom; CF 3 ; a hydroxyl group; OCH 3 ; a fluorine atom and CF 3.
  • C 3 to 7 cycloalkyl groups which may be substituted; a phenyl group which may be substituted with at least one substituent selected from a halogen atom and CF 3; and 5 members which may be substituted with a halogen atom. It may be substituted with one or more substituents selected from the 6-membered aromatic heterocyclic group.
  • R 7 and R 8 are each independently selected from a hydrogen atom; a C 1 to 6 alkyl group; a C 3 to 7 cycloalkyl group optionally substituted with a halogen atom; a halogen atom and at least one selected from CF 3. number of substituent a phenyl group which may be substituted with group; 5 6-membered membered aromatic heterocyclic group; or a non-aromatic heterocyclic group having 6 membered or 4-membered, or, R 7 and It is preferable that R 8 forms a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group together with the attached nitrogen atom.
  • the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently fluorine atoms; CF 3 ; C 3 to 7 cycloalkyl groups which may be substituted with fluorine atoms; halogen atoms and CF 3 respectively.
  • R 7 and R 8 are independently selected from a hydrogen atom; a C 1 to 6 alkyl group; a C 3 to 7 cycloalkyl group which may be substituted with a halogen atom; or a halogen atom and CF 3. More preferably, it is a phenyl group which may be substituted with at least one substituent.
  • the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently fluorine atoms; CF 3 ; C 3 to 7 cycloalkyl groups which may be substituted with fluorine atoms; halogen atoms and CF 3 respectively.
  • a phenyl group optionally substituted with at least one substituent selected from; and one or more selected from a 5- to 6-membered aromatic heterocyclic group optionally substituted with a halogen atom. It is preferably substituted with the number of substituents.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • alkyl group means a linear or branched alkyl group, and is preferably a C1 to 6 alkyl group.
  • C 1 to 6 alkyl groups means linear or branched alkyl groups having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl.
  • C 1 to 6 alkyl groups (particularly, in formula (1), non-aromatic heterocyclic groups containing R 1 and R 2 may have C 1 to 6 alkyl groups; R 5 and / or R 6 C 1 to 6 alkyl groups) also include heavy hydrogen isotopes.
  • C 2-3 alkenyl group means an alkenyl group having one linear or branched carbon-carbon double bond having 2 to 3 carbon atoms.
  • C 1 to 6 aminoalkyl group means a group in which one hydrogen atom of the C 1 to 6 alkyl group is substituted with an amino group.
  • the “C 3 to 7 cycloalkyl group” means a saturated carbocyclic group having 3 to 7 carbon atoms.
  • Examples of the C 3 to 7 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and a C 3 to 6 cycloalkyl group having 3 to 6 carbon atoms is preferable.
  • Yes more preferably, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like can be mentioned.
  • aromatic heterocycle means an aromatic heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and two adjacent atoms are combined with another ring. Includes shared and bonded forms and forms substituted with one or more substituents.
  • the aromatic heterocycle represented by ring A is a 5-membered aromatic heterocycle containing 1 to 3 nitrogen atoms or a 6-membered aromatic heterocycle containing 2 to 3 nitrogen atoms. It is preferable to have.
  • the "aromatic heterocyclic group” means a monovalent group of an aromatic heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom.
  • Indicated R 7 and / or R 8, or the aromatic heterocyclic group having 6 from 5 members to R 7 and / or R 8 is included in the group represented, is preferably a monocyclic, for example, Examples thereof include an oxazolyl group, an isooxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group and a furanyl group.
  • non-aromatic heterocyclic group means a monovalent group of a saturated heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom.
  • Said non-aromatic heterocyclic group, a fluorine atom, a hydroxyl group, -NR 5 R 6, C 1 ⁇ 6 alkyl group, and C 1 ⁇ 6 substituted by at least one substituent selected from aminoalkyl groups You may.
  • non-aromatic heterocyclic group examples include monocyclic, fused bicyclic, crosslinked bicyclic, and spirobicyclic groups.
  • non-aromatic heterocycle of a 4- to 9-membered non-aromatic heterocyclic group containing R 1 and R 2 examples include monocyclic.
  • Azocan ring, oxocan ring, thiocan ring, azonan ring, oxonan ring, thionan ring and the like preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a diazepan ring.
  • non-aromatic heterocycle of the 4- to 6-membered non-aromatic heterocyclic group containing R 5 and R 6 or indicated by R 7 and R 8 examples include azetidine, oxetane, thietane, pyrrolidine, and the like. Examples thereof include tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, piperazine, morpholine and the like.
  • non-aromatic nitrogen-containing heterocyclic group means a monovalent group of a saturated heterocycle containing a nitrogen atom.
  • non-aromatic heterocycle of a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group containing R 7 and R 8 include azetidine. , Pyrrolidine, piperazine and the like.
  • the "condensation bicyclic” group means a group having two rings in which cyclic compounds are bonded to each other in a shared manner at two adjacent atoms.
  • the ring of a fused bicyclic group of a non-aromatic heterocyclic group is 5 to 9 members, bicyclo [2.1.0] pentane, bicyclo [3.1.0] hexane, bicyclo. Examples thereof include [3.2.0] heptane, bicyclo [3.3.0] octane, and bicyclo [4.3.0] nonane.
  • Examples of those containing a nitrogen atom include azabicyclo [2.1.0] pentane, azabicyclo [3.1.0] hexane, and diazabicyclo [3.2. 0] Heptan, diazabicyclo [3.3.0] octane, diazabicyclo [4.3.0] nonane and the like can be mentioned.
  • Preferred are diazabicyclo [3.2.0] heptane and diazabicyclo [4.3.0] nonane.
  • the "spirobicyclic” group means a group having two rings in which cyclic compounds are bonded to each other in a form in which one atom is shared.
  • the rings of the spirobicyclic group of the non-aromatic heterocyclic group are 5 to 9 members, spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4]. ] Heptan, spiro [3.3] heptane, spiro [3.4] octane, spiro [4.4] nonane.
  • substances containing a nitrogen atom include azaspiro [2.2] pentane, azaspiro [2.3] hexane, azaspiro [2.4] heptane, and diazaspiro [ 3.3] Heptan, diazaspiro [3.4] octane, diazaspiro [4.4] nonane and the like can be mentioned, with preference given to azaspiro [2.4] heptane.
  • crosslinked bicyclic means a group having two rings in which two atoms of a cyclic compound are linked by crosslinks.
  • bridged bicyclic groups of non-aromatic heterocyclic groups include 4- to 9-membered bicyclo [1.1.1] pentane, bicyclo [2.1.1] hexane, and bicyclo. Examples thereof include [2.2.1] heptane, diazabicyclo [3.2.1] octane, and bicyclo [3.3.1] nonane.
  • Examples of those containing a nitrogen atom include azabicyclo [1.1.1] pentane, azabicyclo [2.1.1] hexane, and diazabicyclo [2.2. 1] Heptan, diazabicyclo [3.2.1] octane, diazabicyclo [3.3.1] nonane can be mentioned.
  • Bicyclo [1.1.1] pentane and bicyclo [2.2.1] heptane are preferable.
  • -S (O) 2 R 9 means a group formed by substituting one hydrogen atom of an alkyl group (R 9 ) with a divalent -S (O) 2- group
  • -S (“. “O) 2 N (H) R 10 means a group formed by substituting one hydrogen atom of NH 2 R 10 with a divalent —S (O) 2-group.
  • the alkyl groups indicated by R 9 and R 10 are preferably C 1 to 6 alkyl groups independently of each other.
  • each group "may be substituted” means that the group is not substituted and one or more hydrogen atoms of the group are substituted with an atom or a substituent.
  • the number of substituted atoms or substituents is preferably, for example, 1 to 3.
  • the compound represented by the formula (1) may be a free base form (free form) or a pharmacologically acceptable salt thereof.
  • the pharmacologically acceptable salt is preferably in the form of an acid addition salt, and the acid of the acid addition salt is, for example, hydrogen halide such as hydrochloric acid, hydrobromic acid, and hydroiodic acid.
  • Acid salts Inorganic acid salts such as sulfuric acid, nitrate, phosphoric acid, and carbonic acid; acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, Organic carboxylates such as propionic acid, formic acid and malic acid; acidic amino acids such as aspartic acid and glutamate; alkylsulfonic acids such as methanesulfonic acid; arylsulfonic acids such as p-toluenesulfonic acid and the like.
  • the range of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof also includes solvates (for example, hydrates) corresponding thereto.
  • the compound represented by the formula (1), a pharmacologically acceptable salt thereof, and a mixture thereof have one or two or more asymmetric carbons depending on the type of the substituent. Any of these one or more asymmetric carbon-based optically active compounds, diastereoisomers, geometric isomers, tautomers, any mixture thereof, racemates, etc. may be present. , The compound represented by the above formula (1) and the pharmaceutically acceptable salt thereof are included in the range.
  • the range of the compound represented by the above formula (1) and its pharmacologically acceptable salt includes compounds labeled with isotopes such as radioactive isotopes and non-radioactive isotopes corresponding thereto.
  • the solvate is also included.
  • a compound in which the above isomers, isotopes, etc. are present and unless otherwise specified in the name, the compound may be one of these isomers, isotopes, etc. It may be a mixture of two or more kinds, or may be a racemate.
  • the method for producing the bicyclic compound of the present invention is not particularly limited, and those skilled in the art can use starting materials, precursors, reagents, solvents, etc., which are commercially available or can be synthesized by a method recognized by those skilled in the art. It can be produced by combining a wide variety of synthetic methods recognized by the above and, if necessary, a method obtained by modifying the synthetic method. For example, it can be produced by the following typical methods.
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 7 , R 8 , and n are X 1 , X 2 , X 3 in the above formula (1), respectively.
  • X 4 , R 1 , R 2 , R 7 , R 8 , and n where R'is a hydrogen atom, a halogen atom, CF 3 , an optionally substituted C 1-6 alkyl group (halogen).
  • R 9 and R 10 are synonymous with R 9 and R 10 in the above formula (1), respectively.
  • Y and Z are independent leaving groups, respectively.
  • the compound represented by the formula (1a) is mixed with the compound represented by the formula (3) and an appropriate amine in the presence of a base as a solvent. It can be synthesized by reacting in.
  • the amount of amine used in the synthetic reaction of the compound represented by the formula (1a) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (3).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (3).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (1a) is selected, for example, in the range of 20 to 150 ° C., preferably in the range of 50 to 100 ° C.
  • the reaction time is, for example, in the range of 2 to 18 hours, preferably in the range of 2 to 6 hours. If the reaction is slow, it is possible to carry out the reaction under microwave irradiation.
  • the reaction temperature in this case is selected, for example, in the range of 100 to 200 ° C., preferably in the range of 120 to 150 ° C., for example, 130 to 150 ° C., and the reaction time in this case is, for example, 30 minutes to 20 hours. It is preferably in the range of 30 minutes to 5 hours, and more preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (3) can be synthesized, for example, by reacting the compound represented by the formula (2) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
  • the amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (3) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (2).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (2).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the above formula (3) is selected, for example, in the range of 0 to 60 ° C, preferably in the range of 20 to 40 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 1 to 3 hours.
  • the intermediate compound represented by the above formula (3) does not require isolation or purification thereof, but additional amines (preferably tertiary) are required so that appropriate continuous addition of amines is required.
  • Amine eg, diisopropylethylamine, triethylamine
  • the solvent is a suitable solvent for the compound represented by the formula (2) (eg, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N.
  • the compound represented by the formula (2) can be easily prepared by a method known in the literature or well known to those skilled in the art.
  • the bicyclic compound of the present invention can also be produced, for example, by the method shown below.
  • R 1, R 2, R 7, R 8, and n respectively, wherein R 1 in formula (1) in, R 2, R 7, R 8, and have the same meanings as n, Et Indicates an ethyl group.
  • the compound represented by the formula (1b), the compound represented by the formula (7) and triethyl orthoformate are used as a solvent in the presence of an acid. It can be synthesized by reacting in.
  • the amount of triethyl orthoformate used in the synthetic reaction of the compound represented by the formula (1b) is preferably in the range of 3 to 5 equivalents based on the compound represented by the formula (7).
  • the acid used in the reaction include acetic acid, and the amount thereof is preferably in the range of 3 to 5 equivalents based on the compound represented by the formula (7).
  • the solvent used in the reaction include ethanol, methanol and the like, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (1b) is selected, for example, in the range of 60 to 130 ° C., preferably in the range of 80 to 110 ° C.
  • the reaction time is, for example, in the range of 1 to 6 hours, preferably in the range of 2 to 3 hours.
  • the compound represented by the formula (7) can be synthesized, for example, by reacting the compound represented by the formula (6) with hydrazine monohydrate in a solvent.
  • the amount of hydrazine monohydrate used in the synthetic reaction of the compound represented by the formula (7) is preferably in the range of 1 to 1.5 equivalents based on the compound represented by the formula (6).
  • the solvent used in the reaction include ethanol, methanol and the like, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (7) is selected, for example, in the range of 40 to 100 ° C, preferably in the range of 60 to 80 ° C.
  • the reaction time is, for example, in the range of 2 to 6 hours, preferably in the range of 3 to 5 hours.
  • the compound represented by the formula (6) can be synthesized, for example, by reacting the compound represented by the formula (5) with an appropriate amine in the presence of a base in a solvent.
  • the amount of amine used in the synthetic reaction of the compound represented by the formula (6) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (5).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 3 equivalents based on the compound represented by the formula (5).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the above formula (6) is selected, for example, in the range of 0 to 60 ° C, preferably in the range of 20 to 40 ° C.
  • the reaction time is, for example, in the range of 1 to 18 hours, preferably in the range of 2 to 4 hours.
  • the compound represented by the formula (5) can be synthesized, for example, by reacting the compound represented by the formula (4) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
  • the amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (5) is preferably in the range of 1 to 1.5 equivalents based on the compound represented by the formula (4).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (4).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the above formula (5) is selected, for example, in the range of ⁇ 20 to 30 ° C., preferably in the range of 0 to 20 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the above formula (4) can be easily prepared by a method known in the literature or well known to those skilled in the art.
  • the bicyclic compound of the present invention can also be produced, for example, by the method shown below.
  • R 1, R 2, R 7, R 8 , and n respectively, R 1, R 2, R 7, R 8 in the formula (1), and has the same meaning as n
  • t Bu represents a t-butyl group.
  • the compound represented by the formula (1c) is mixed with the compound represented by the formula (12) and an appropriate amine in the presence of a base as a solvent. It can be synthesized by reacting in.
  • the amount of amine used in the synthetic reaction of the compound represented by the formula (1c) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (12).
  • Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (12).
  • Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (1c) is selected, for example, in the range of 40 to 120 ° C, preferably in the range of 60 to 90 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 1 to 3 hours. If the reaction is slow, it is possible to carry out the reaction under microwave irradiation.
  • the reaction temperature in this case is selected, for example, in the range of 100 to 200 ° C., preferably in the range of 130 to 150 ° C., and the reaction time in this case is, for example, in the range of 30 minutes to 5 hours, preferably in the range of 30 minutes to 5 hours. Is in the range of 1 to 3 hours.
  • the compound represented by the formula (12) can be synthesized, for example, by reacting the compound represented by the formula (11) with metachloroperbenzoic acid in a solvent.
  • the amount of meta-chloroperbenzoic acid used in the synthetic reaction of the compound represented by the formula (12) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (11).
  • the solvent used in the reaction include tetrahydrofuran, chloroform and the like, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (12) is selected, for example, in the range of ⁇ 20 to 50 ° C., preferably in the range of 0 to 30 ° C.
  • the reaction time is, for example, in the range of 2 to 6 hours, preferably in the range of 3 to 4 hours.
  • the compound represented by the formula (11) can be synthesized, for example, by reacting the compound represented by the formula (10) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
  • the amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (11) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (10).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (10).
  • the solvent used in the reaction include methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-. Examples thereof include 2-pyrrolidone and chloroform, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthesis reaction of the compound represented by the formula (11) is selected, for example, in the range of 0 to 100 ° C., preferably 0 to 60 ° C., and more preferably in the range of 20 to 40 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (10) can be synthesized, for example, by reacting the compound represented by the formula (9) with tert-butyl nitrite.
  • the amount of tert-butyl nitrite used in the synthesis reaction of the compound represented by the formula (10) is preferably in the range of 2 to 4 equivalents based on the compound represented by the formula (9).
  • Examples of the solvent used in the reaction include acetonitrile.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (10) is selected, for example, in the range of 40 to 100 ° C, preferably in the range of 60 to 80 ° C.
  • the reaction time is, for example, in the range of 1 to 6 hours, preferably in the range of 2 to 3 hours.
  • the compound represented by the formula (9) can be synthesized, for example, by reacting the compound represented by the formula (8) with tin (II) chloride dihydrate.
  • the amount of tin (II) chloride dihydrate used in the synthetic reaction of the compound represented by the formula (9) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (8). ..
  • the solvent used in the reaction include ethanol, methanol and the like, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (9) is selected, for example, in the range of 40 to 100 ° C, preferably in the range of 60 to 80 ° C.
  • the reaction time is, for example, in the range of 1 to 6 hours, preferably in the range of 2 to 3 hours.
  • the compound represented by the formula (8) can be easily prepared by a method known in the literature or well known to those skilled in the art.
  • the bicyclic compound of the present invention can also be produced, for example, by the method shown below.
  • R 1, R 2, R 7, R 8, and n respectively, R 1, R 2 in the formula (1), R 7, R 8, and is synonymous with n.
  • the compound represented by the formula (1d) is mixed with the compound represented by the formula (19) and pyridine hydrobromide in a solvent. It can be synthesized by reacting.
  • the amount of pyridine hydrobromide used in the synthesis reaction of the compound represented by the formula (1d) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (19).
  • the solvent used in the reaction include methanol / water, ethanol / water, 2-propanol / water and the like.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (1d) is selected, for example, in the range of 0 to 60 ° C, preferably in the range of 20 to 40 ° C.
  • the reaction time is, for example, in the range of 1 to 5 hours, preferably in the range of 2 to 3 hours.
  • the compound represented by the formula (19) can be synthesized, for example, by reacting the compound represented by the formula (18) with an aqueous glyoxal solution in a solvent.
  • the amount of the glyoxal aqueous solution used in the synthesis reaction of the compound represented by the formula (19) is preferably in the range of 4 to 10 equivalents based on the compound represented by the formula (18).
  • the solvent used in the reaction include ethanol, water and the like.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (19) is selected, for example, in the range of 50 to 150 ° C, preferably in the range of 70 to 100 ° C.
  • the reaction time is, for example, in the range of 1 to 5 hours, preferably in the range of 2 to 3 hours.
  • the compound represented by the formula (18) can be synthesized, for example, by reacting the compound represented by the formula (17) with an aqueous solution of basic ammonium in a solvent in the presence of zinc.
  • the amount of zinc used in the synthetic reaction of the compound represented by the formula (18) is preferably in the range of 4 to 10 equivalents based on the compound represented by the formula (17).
  • Examples of the solvent used in the reaction include methanol, ethanol, 2-propanol and the like, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (18) is selected, for example, in the range of 50 to 110 ° C, preferably in the range of 70 to 90 ° C.
  • the reaction time is, for example, in the range of 3 to 9 hours, preferably in the range of 4 to 5 hours.
  • the compound represented by the formula (17) can be synthesized, for example, by reacting the compound represented by the formula (16) with an appropriate amine in the presence of a base in a solvent.
  • the amount of amine used in the synthetic reaction of the compound represented by the formula (17) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (16).
  • Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (16).
  • Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthesis reaction of the compound represented by the formula (17) is selected, for example, in the range of 20 to 120 ° C., preferably 40 to 120 ° C., more preferably 40 to 90 ° C., still more preferably 60 to 90 ° C. It is in the range of ° C.
  • the reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (16) can be synthesized, for example, by reacting the compound represented by the formula (15) with metachloroperbenzoic acid in a solvent.
  • the amount of metachlorobenzoic acid used in the synthetic reaction of the compound represented by the formula (16) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (15).
  • Examples of the solvent used in the reaction include tetrahydrofuran, chloroform and the like, and one of them may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (16) is selected, for example, in the range of 0 to 50 ° C, preferably in the range of 15 to 35 ° C.
  • the reaction time is, for example, in the range of 2 to 6 hours, preferably in the range of 3 to 5 hours.
  • the compound represented by the formula (15) can be synthesized, for example, by reacting the compound represented by the formula (14) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
  • the amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (15) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (14).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (14).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (15) is selected, for example, in the range of 0 to 50 ° C, preferably in the range of 20 to 40 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (14) can be synthesized, for example, by reacting the compound represented by the formula (13) with an aqueous ammonia solution in a solvent in the presence of a base.
  • the amount of the aqueous ammonia solution used in the synthesis reaction of the compound represented by the formula (14) is preferably in the range of 1 to 1.5 equivalents based on the compound represented by the formula (13).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the above formula (13).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
  • the reaction temperature in the synthetic reaction of the compound represented by the formula (14) is selected, for example, in the range of 0 to 50 ° C, preferably in the range of 15 to 35 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (13) can be easily prepared by a method known in the literature or well known to those skilled in the art.
  • protecting groups at any step in synthesizing the compound of formula (1) to prevent unwanted side reactions. Will admit that it is necessary or desirable. In particular, it is necessary or desirable to protect the amino group.
  • Examples of the protecting group used when synthesizing the compound represented by the formula (1) include Greene Wuts, PROTECIVE GROUPs in ORGANIC SYNTHESIS THIRD EDITION, John Wiley & Sons, Inc. Etc. (the methods for desorbing such groups are also described).
  • the bicyclic compound of the present invention Since the bicyclic compound of the present invention has an affinity for the histamine H4 receptor (hereinafter, also simply referred to as "H4 receptor" in some cases), it has an action of regulating histamine H4 receptor activity. Therefore, the bicyclic compound of the present invention can be used as it is, or as a pharmaceutical composition containing the same, for the regulation of the H4 receptor, more specifically, for the treatment and / or prevention of a disease or condition involving the H4 receptor. Can be used for.
  • H4 receptor histamine H4 receptor
  • H4 receptors Diseases or conditions involving H4 receptors include, for example, various allergies, immunoinflammatory diseases (COPD, etc.), inflammatory bowel diseases, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, joints.
  • COPD immunoinflammatory diseases
  • inflammatory bowel diseases COPD, etc.
  • rheumatism atopic dermatitis
  • pruritic dermatitis atopic dermatitis
  • allergic conjunctivitis rhinitis
  • cancers colon cancer, lung cancer, blood cancer, brain tumor, etc.
  • metabolic diseases diabetes, obesity, etc.
  • the "regulatory action of H4 receptor activity” includes an antagonist action, an agonist action, a partial antagonist action, an inverse agonist action and / or a partial agonist action of the activity related to the H4 receptor.
  • it is an antagonist action or an inverse agonist action.
  • the ability of a compound to regulate H4 receptor function can be confirmed by binding assay, signaling assay, and / or cell response assay between the compound and H4 receptor.
  • the pharmaceutical composition of the present invention contains the bicyclic compound of the present invention as an active ingredient.
  • the pharmaceutical composition of the present invention may be administered to a subject by either an oral or parenteral route of administration, and the subject includes humans or animals other than humans.
  • the pharmaceutical composition of the present invention can be prepared into an appropriate dosage form according to the administration route.
  • Specific examples of the dosage form of the above-mentioned preparation include oral preparations such as tablets, suppositories, capsules, granules, powders, elixirs, suspensions, emulsions, and syrups, and injections.
  • Examples thereof include parenteral preparations such as inhalants, rectal administrations, suppositories, lotions, sprays, ointments, creams, patches, and sustained-release preparations.
  • These various formulations contain, as required, pharmacologically acceptable additives and carriers such as excipients, disintegrants, binders, lubricants and colorants commonly used in the field of pharmacy. It can be used and manufactured by a conventional method. Therefore, the pharmaceutical composition of the present invention may further contain these pharmacologically acceptable additives and / or carriers.
  • the content of the bicyclic compound of the present invention (when the bicyclic compound of the present invention is a combination of two or more kinds, the total content thereof) is determined by the purpose of administration and the preparation of the preparation. Although it cannot be said unconditionally because it is appropriately adjusted according to the type and the like, it is usually 0.01 to 0.01 to the total mass of the pharmaceutical composition in terms of the free form of the compound represented by the above formula (1). It is 70% by mass, preferably 0.05 to 50% by mass.
  • the dose of the dicyclic compound of the present invention is the age, weight, sex, difference in disease, and degree of symptoms of the patient. It cannot be said unconditionally because it is appropriately determined according to each individual case in consideration of the above, but usually, it is 0 per day for an adult in terms of the free form of the compound represented by the above formula (1). It is 0.01 to 1000 mg, preferably 0.1 to 300 mg, and this can be administered once a day or in several divided doses.
  • the solvent was distilled off under reduced pressure, ethanol (10.0 mL) and hydrazine monohydrate (1.0 mL) were added to the obtained residue, and the mixture was stirred under reflux for 2 hours. After confirming that the raw material had disappeared by LCMS, the mixture was stirred at 0 ° C. for 15 minutes. The precipitated solid was filtered, ethanol (10.0 mL) was added to the mother liquor, and the mixture was stirred at 0 ° C. for 15 minutes. The precipitated solid was filtered again and the solvent was evaporated under reduced pressure to give the title compound (186 mg).
  • Tables 1 and 2 below show the results of analysis of each compound by ESI-MS.
  • Example 1 2-( ⁇ 1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl ⁇ amino) -N- (propane-2-)
  • Example 2 N-Benzyl-2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1-sulfonamide
  • a) N-benzyl-2-[(5-chloro-1-methyl-1H-pyrazolo [4,3-"] in the same manner as in Example 1 (a) except that benzylamine was used instead of isopropylamine.
  • Pyrimidine-7-yl) amino] -N- (propane-2-yl) ethane-1-sulfonamide was obtained.
  • Example 3 N-Cyclopropyl-2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1-sulfonamide
  • A 2-[(5-Chloro-1-methyl-1H-pyrazolo [4,3-d]] in the same manner as in Example 1 (a) except that cyclopropaneamine was used instead of isopropylamine. Pyrimidine-7-yl) amino] -N- (propane-2-yl) cyclopropylethane-1-sulfonamide was obtained.
  • B The title compound was obtained from the compound obtained in (a) by the same method as in Example 2 (b).
  • Example 4 2- ⁇ [1-Methyl-5- (piperazine-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ -N- (propane-2-yl) ethane-1-
  • the title compound was obtained from the compound obtained in Example 1 (a) in the same manner as in Example 2 (b) except that piperazine was used instead of sulfoneamide (a) 1-methylpiperazine.
  • Example 5 2-( ⁇ 1-methyl-5-[(3S) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl ⁇ amino) -N-( Propane-2-yl) Same as in Example 2 (b) except that tert-butyl (3S) -pyrrolidin-3-ylcarbamate was used instead of ethane-1-sulfonamide (a) 1-methylpiperazine.
  • Example 6 N- (Cyclopropylmethyl) -2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1 -Sulfoneamide (a)
  • the title compound was obtained in the same manner as in Example 2 except that cyclopropylmethylamine was used instead of benzylamine in Example 2 (a).
  • Example 7 N- (Cyclobutylmethyl) -2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1 -Sulfone Amide (a)
  • the title compound was obtained in the same manner as in Example 2 except that cyclobutylmethylamine was used instead of the benzylamine in Example 2 (a).
  • Example 8 2-( ⁇ 1-methyl-5-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl ⁇ amino) -N-( Propane-2-yl) Same as in Example 2 (b) except that tert-butyl (3R) -pyrrolidin-3-ylcarbamate was used instead of ethane-1-sulfonamide (a) 1-methylpiperazine.
  • Example 9 2- ⁇ [1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ -N- (propane-2-yl) ethane -1-Sulfonamide (a)
  • the title compound was obtained in the same manner as in Example 2 except that isopropylamine was used instead of benzylamine in Example 2 (a).
  • Example 11 2- ⁇ [2- (4-Methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- (propane-2-yl) ethane -1-sulfonamide
  • a The compound (13.2 mg) obtained in Example 10 (d) was dissolved in methanol (2.0 mL), 5% palladium carbon (6.6 mg) was added, and the atmosphere was hydrogen. Was stirred for 16 hours. After confirming that the raw materials had disappeared by LCMS, the reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure to obtain the title compound (9.1 mg).
  • Example 12 N-cyclohexyl-2- ⁇ [2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ ethane-1-sulfonamide
  • 1-Il) Pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N-cyclohexylethane-1-sulfonamide was obtained.
  • B The title compound was obtained from the compound obtained in (a) by the same method as in Example 11 (a).
  • Example 13 2- ⁇ [7-Methyl-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- (propane-2) -Il) Ethan-1-sulfonamide
  • Example 10 except that 3-amino-5-methylpyrazole was used instead of 4-bromo-1H-pyrazole-5-amine in Example 10 (a). The title compound was obtained in the same manner as in.
  • Example 17 N-cyclopentyl-2- ⁇ [2- (4-methylpiperazin-1-yl) pyrrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ ethane-1-sulfonamide ( a)
  • the title compound was obtained in the same manner as in Example 16 except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1.
  • Example 20 N-cyclopentyl-2- ( ⁇ 2- [3- (methylamino) azetidine-1-yl] pyrrolo [2,1-f] [1,2,4] triazine-4-yl ⁇ amino) ethane-1- Sulfonamide
  • the compound (31.0 mg) obtained in Example 17 (a) was dissolved in 1,4-dioxane (0.9 mL) and water (0.1 mL), and then tert-butyl azetidine-3.
  • Example 21 N-cyclopentyl-2- ⁇ [2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ ethane-1-sulfonamide
  • a After dissolving a part of the residue obtained in Example 10 (c) and DIPEA (523 ⁇ L) in THF (6.0 mL), the compound (115 mg) synthesized in Reference Example 3 was added, and the mixture was added at room temperature for 1 hour. Stirred. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • Example 22 N-Cyclopentyl-2-( ⁇ 2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) ethane-1-
  • tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of the sulfonamide (a) 1-methylpiperazine.
  • Example 23 N-[(4-fluorophenyl) methyl] -2-( ⁇ 2- [3- (methylamino) azetidine-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4- Il ⁇ amino) ethane-1-sulfonamide
  • Example 16 The same method as in Example 16 (a), except that the compound synthesized in Reference Example 4 was used instead of the compound synthesized in Reference Example 1, 2- [(2-Chloropyrrolo [2,1-f] [1,2,4] triazine-4-yl) amino] -N-[(4-fluorophenyl) methyl] ethane-1-sulfonamide was obtained.
  • Example 24 2- ⁇ [2- (6-Methyl-2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇
  • Example 16 2-methyl-2,6-diazaspiro [3.3] heptane was used in place of -N- (propane-2-yl) ethane-1-sulfonamide (a) 1-methylpiperazine. The title compound was obtained in the same manner as in.
  • Example 25 2- ⁇ [2- (Piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ -N- (propane-2-yl) ethane-1-
  • the title compound was obtained in the same manner as in Example 16 except that piperazine was used instead of sulfonamide (a) 1-methylpiperazine.
  • Example 26 2- ⁇ [2- (2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ -N-( Example 16 except that tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate was used in place of propane-2-yl) ethane-1-sulfonamide (a) 1-methylpiperazine.
  • Example 27 2-( ⁇ 2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- (propane-2-)
  • Ethan-1-sulfonamide (a) 8-bromopyrazolo [1,5-a] [1,3,5] triazine-2,4-diol (69.0 mg) with phosphorus oxychloride (560 ⁇ L) and DIPEA ( 100 ⁇ L) was added in order, and the mixture was stirred at 100 ° C. for 2 hours.
  • Example 29 N-Cyclopentyl-2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1-sulfonamide ( a)
  • the title compound was obtained in the same manner as in Example 28 (b) except that 1-methylpiperazine was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
  • Example 30 2- ⁇ [7-Chloro-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- (propane-2) -Il) Ethan-1-sulfonamide (a) In Example 10 (a), except that 3-chloro-1H-pyrazole-5-amine was used instead of 4-bromo-1H-pyrazole-5-amine. Ethyl ⁇ [(3-chloro-1H-pyrazole-5-yl) carbamoyl] carbamate was obtained in the same manner.
  • Example 31 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( Same as in Example 21 (b) except that tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of propane-2-yl) ethane-1-sulfonamide (a) 1-methylpiperazine.
  • Example 32 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N-cyclopentyl Ethan-1-sulfonamide
  • Example 30 in the same manner as in Example 21 (a) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1.
  • 2-[(2,7-Dichloropyrazolo [1,5-a] [1,3,5] triazine-4-yl) amino] -N-cyclopentylethane-1-sulfonamide was obtained from the residue of ..
  • Example 33 2- ⁇ [1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ -N- (2-methylpropyl) ethane- 1-Sulfoneamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 5 was replaced with the tert-butyl azetidine-3-yl (methyl) in Example 28 (b). The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of carbamate hydrochloride.
  • Example 34 N-cyclopentyl-2- ⁇ [1-methyl-5-(6-methyl-2,6-diazaspiro [3.3] heptan-2-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino ⁇ ethane-1-sulfonamide (a) 2-[(5-chloro-1-methyl-1H-pyrazolo [4,3-d] pyrimidin-7) in the same manner as in Example 28 (a). -Il ⁇ amino)]-ethane-N-cyclopentylethane-1-sulfonamide was obtained.
  • Example 35 N-Cyclobutyl-2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ ethane-1-sulfonamide ( a) Except that 1-methylpiperazine was used in place of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride and the compound synthesized in Reference Example 6 was used instead of the compound synthesized in Reference Example 3. The title compound was obtained in the same manner as in Example 28.
  • Example 36 N- (3,3-difluorocyclobutyl) -2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ Etan-1-sulfonamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 7 was replaced with the compound synthesized in Reference Example 28 (b), tert-butyl azetidine-3-3. The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of yl (methyl) carbamate hydrochloride.
  • Example 37 N-[(3,3-difluorocyclobutyl) methyl] -2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino ⁇ ethane-1-sulfonamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 8 was replaced with the tert-butyl azetidine in Example 28 (b). The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of -3-yl (methyl) carbamate hydrochloride.
  • Example 38 N- (2,2-difluoropropyl) -2- ⁇ [1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino ⁇ Etan-1-sulfonamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 9 was replaced with the tert-butyl azetidine-3-yl in Example 28 (b). The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of (methyl) carbamate hydrochloride.
  • Example 40 2- ( ⁇ 2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N-cyclopentylethane-1-sulfonamide (a)
  • 2-N-cyclopentylethane-1-sulfonamide (a) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1.
  • Example 41 2-( ⁇ 7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( Propane-2-yl) ethane-1-sulfonamide
  • the title compound was obtained in the same manner as in Example 39 except that amine was used.
  • Example 44 2-( ⁇ 7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( 2-Methylpropyl) Etan-1-sulfonamide
  • 3- (Trifluoromethyl) -1H-pyrazole-5-amine was replaced with 3-bromo-1H-pyrazole-5-amine in Reference Example 1.
  • the title compound was obtained in the same manner as in Example 39, except that the compounds synthesized in Reference Example 5 were used instead of the compounds.
  • Example 46 2- ⁇ [6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino ⁇ -N- (propane-2-yl) ethane-1-sulfonamide
  • Example 47 N-cyclopentyl-2- ⁇ [2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino ⁇ ethane-1-sulfonamide (a) Synthesized in Reference Example 1 in Example 45 (b) The title compound was obtained in the same manner as in Example 45 except that the compound synthesized in Reference Example 3 was used instead of the compound.
  • Example 48 2- ⁇ [6-bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino ⁇ -N-cyclopentylethane-1-sulfonamide (a) Same as Example 46 (a) By technique, the title compound was obtained from the mixture obtained in Example 47.
  • Example 49 N-Cyclopentyl-2-( ⁇ 2- [3- (methylamino) azetidine-1-yl] pteridine-4-yl ⁇ amino) ethane-1-sulfonamide
  • Reference Example 1 in Example 45 (b) The compound synthesized in Reference Example 3 was used in place of the compound synthesized in Example 45 (c), except that tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of 1-methylpiperazin in Example 45 (c).
  • Example 52 2- ⁇ [7-Chloro-2- (1,4-diazepan-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N-cyclopentylethane-
  • 1,4-diazepan was used instead of 1-sulfonamide (a) piperidine-4-amine.
  • Example 53 2-( ⁇ 2-[(3S) -3-aminopyrrolidine-1-yl] -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N-cyclopentyl Tert-butyl [(3S)] in the same manner as in Example 51, except that tert-butyl (3S) -pyrrolidine-3-ylcarbamate was used instead of ethane-1-sulfonamide (a) piperidine-4-amine.
  • Example 54 2-( ⁇ 2-Bromo-5- [3- (methylamino) azetidine-1-yl] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] ⁇ Amino) -N-cyclopentylethane-1-sulfonamide
  • 3-Bromo-1H-1,2,4-triazole-5-amine was used instead of 4-bromo-1H-pyrazol-5-amine.
  • the title compound was obtained in the same manner as in Example 42 except that.
  • Example 55 2-( ⁇ 7-Cyano-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N-cyclopentyl Etan-1-sulfonamide (a)
  • the compound (154 mg) synthesized in Example 42 (e) was dissolved in THF (8.0 mL), metachloroperbenzoic acid (260 mg) was added, and the mixture was stirred at room temperature for 3 hours.
  • Example 56 2- ⁇ [6-cyano-2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino ⁇ -N-cyclopentylethane-1-sulfonamide
  • (a) Synthesized in Example 48 (a) Compound (31.5 mg), tetrakistriphenylphosphine palladium (0) (6.9 mg) and zinc cyanide (22.2 mg) were suspended in DMF (0.6 mL) at 120 ° C. using a microwave reactor. It was stirred for 1 hour. Unnecessary substances were removed by filtration through Celite, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC (acetonitrile / water) to give the title compound (11.1 mg).
  • Example 57 2- ( ⁇ 7-Chloro-2- [3-methyl-3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Except for the use of tert-butyl methyl (3-methylazetidine-3-yl) carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-yl carbamate. , The title compound was obtained in the same manner as in Example 53.
  • Example 58 N-Cyclopentyl-2- ⁇ [6-ethoxy-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino ⁇ ethane-1-sulfonamide
  • a Compound obtained in Example 48 ( 15 mg) was dissolved in methanol (1 mL), 0.5 M potassium hydroxide-ethanol solution (120 ⁇ L) was added, and the mixture was stirred at 140 ° C. for 40 minutes using a microwave reactor. After adding saturated aqueous ammonium chloride solution, the organic phase was extracted with chloroform / methanol (10/1), and the solvent was distilled off under reduced pressure to give the title compound (20.1 mg).
  • Example 59 2- ⁇ [7-Chloro-2- (2,6-diazabicyclo [3.2.0] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] Amino ⁇ -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-ylcarbamate instead of tert-butyl 2,6-diazabicyclo [3.2.0] heptane-2- The title compound was obtained in the same manner as in Example 53 except that carboxylate was used.
  • Example 60 2- ⁇ [2- (3-Amino-3-methylazetidine-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- Example 53, except that tert-butyl (3-methylazetidine-3-yl) carbamate was used instead of cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-yl carbamate. The title compound was obtained in the same manner as in.
  • Example 62 2- ⁇ [2- (3-Aminoazetidine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ -N-cyclopentylethane-1-sulfonamide
  • A 2-[(2-Chloropyrrolo [2,1-]) was carried out in the same manner as in Example 16 (a) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1.
  • f] [1,2,4] triazine-4-yl) amino] -N-cyclopentylethane-1-sulfonamide was obtained.
  • Example 63 2- ⁇ [2- (3-Aminoazetidine-1-yl) -7- (difluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- Cyclopentylethane-1-sulfonamide (a) 3- (difluoromethyl) -1H-pyrazol-5-amine instead of 3- (trifluoromethyl) -1H-pyrazol-5-amine, tert-butyl azetidine-3 The title compound was obtained in the same manner as in Example 39, except that tert-butyl azetidine-3-yl carbamate was used instead of -yl (methyl) carbamate hydrochloride.
  • Example 64 2- ⁇ [7-Bromo-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N-cyclopentylethane-1-sulfonamide (A)
  • the title compound was obtained in the same manner as in Example 42, except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
  • Example 65 2- ⁇ [7-Chloro-2- (1,6-diazaspiro [3.3] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N-Cyclopentylethane-1-sulfonamide
  • a tert-butyl (3S) -pyrrolidin-3-ylcarbamate instead of tert-butyl 1,6-diazaspiro [3.3] heptane-1-carboxylate
  • the title compound was obtained in the same manner as in Example 53, except that the compound was obtained.
  • Example 67 2- ⁇ [6-Bromo-2- (piperazine-1-yl) imidazo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ -N-cyclopentylethane-1-sulfonamide
  • A The title compound was obtained in the same manner as in Example 66, except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-ylcarbamate.
  • Example 68 2- ⁇ [2- (6-amino-3-azabicyclo [3.1.0] hexane-3-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino ⁇ -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidine-3-ylcarbamate instead of tert-butyl 3-azabicyclo [3.1.0] hexane-6-yl The title compound was obtained in the same manner as in Example 53 except that carbamate was used.
  • Example 69 4- ⁇ [2- (Cyclopentyl sulfamoyl) ethyl] amino ⁇ -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-7 -Carboxamide (a)
  • the compound (33 mg) obtained in Example 55 (b) was dissolved in trifluoroacetic acid (420 ⁇ L) and stirred at 140 ° C. for 90 minutes using a microwave reactor. After distilling off the solvent under reduced pressure, the obtained residue was purified by preparative HPLC (acetonitrile / water).
  • Example 70 N-cyclopentyl-2- ⁇ [2- (hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino ⁇ ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride instead of octahydropyrro [1,2-a] pyrazine, in the compound synthesized in Reference Example 1. The title compound was obtained in the same manner as in Example 27, except that the compound synthesized in Reference Example 3 was used instead.
  • Example 71 2-( ⁇ 7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( Oxolan-3-yl) ethane-1-sulfonamide (a)
  • the title compound was prepared in the same manner as in Example 42, except that the compound synthesized in Reference Example 10 was used instead of the compound synthesized in Reference Example 3. Obtained.
  • Example 72 2-( ⁇ 7-Bromo-2-[(3S) -3-methylpiperazin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- Performed except that tert-butyl (2S) -2-methylpiperazin-1-carboxylate was used in place of cyclopentylethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained in the same manner as in Example 42.
  • Example 74 N-cyclopentyl-2- ( ⁇ 2- [3- (methylamino) azetidine-1-yl] -7- (pyridin-3-yl) pyrazolo [1,5-a] [1,3,5] triazine-
  • the title compound was obtained using the same procedure as in Example 73, except that pyridine-3-ylboronic acid was used in place of 4-yl ⁇ amino) ethane-1-sulfonamide (a) phenylboronic acid.
  • Example 75 2- ⁇ [7-Cyano-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N-cyclopentylethane-1-sulfonamide (A)
  • the title compound was obtained in the same manner as in Example 55, except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
  • Example 76 2-( ⁇ 7-Chloro-2-[(1R, 5S) -6- (methylamino) -3-azabicyclo [3.1.0] hexane-3-yl] pyrazolo [1,5-a] [1 , 3,5] Triazine-4-yl ⁇ amino) -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-ylcarbamate instead of tert-butyl (1R, 5S) The title compound was obtained in the same manner as in Example 53, except that -3-azabicyclo [3.1.0] hexane-6-yl (methyl) carbamate was used.
  • Example 77 2-( ⁇ 7-Chloro-2-[(3R) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Except for the use of tert-butyl methyl [(3R) -pyrrolidine-3-yl] carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidine-3-yl carbamate. , The title compound was obtained in the same manner as in Example 53.
  • Example 79 N-Cyclopentyl-2- ⁇ [7- (difluoromethyl) -2- (piperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ ethane-1 -Sulfonamide
  • a 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of 3- (difluoromethyl) -1H-pyrazol-5-amine, tert-butyl azetidine-3-yl (methyl)
  • the title compound was obtained in the same manner as in Example 39, except that tert-butylpiperazin-1-carboxylate was used instead of carbamate hydrochloride.
  • Example 80 2-( ⁇ 7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( 2-methoxyethyl) Etan-1-sulfonamide
  • a 3- (Trifluoromethyl) -1H-pyrazole-5-amine was replaced with 3-bromo-1H-pyrazole-5-amine in Reference Example 1.
  • the title compound was obtained in the same manner as in Example 39, except that the compound synthesized in Reference Example 11 was used instead of the compound obtained.
  • Example 81 2-( ⁇ 7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- [ 1- (Hydroxymethyl) cyclopentyl] Ethan-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of 3-bromo-1H-pyrazol-5-amine, reference example The title compound was obtained in the same manner as in Example 39, except that the compound synthesized in Reference Example 12 was used instead of the compound synthesized in 1.
  • Example 82 2-( ⁇ 7-Chloro-2-[(3S) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Except for the use of tert-butyl methyl [(3S) -pyrrolidine-3-yl] carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidine-3-yl carbamate. , The title compound was obtained in the same manner as in Example 53.
  • Example 83 2- ⁇ [6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ -N- (2-methylpropyl) ethane -1-sulfonamide (a)
  • the title compound was obtained in the same manner as in Example 61 except that the compound synthesized in Reference Example 5 was used instead of the compound synthesized in Reference Example 3.
  • Example 84 N-cyclopentyl-2- ( ⁇ 2- [3- (methylamino) azetidine-1-yl] -7- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ Amino) Ethane-1-sulfonamide (a) Compound (200 mg) synthesized in Example 73 (a), Tris (dibenzilidenacetone) dipalladium (0) (31.9 mg), 4,5-bis ( After suspending diphenylphosphino) -9,9-dimethylxanthene (40.4 mg), sodium methanethiolate (48.9 mg) and DIPEA (183 ⁇ L) in 1,4-dioxane (350 ⁇ L), a microwave reactor was stirred at 130 ° C.
  • Example 85 2- ⁇ [7-Chloro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- (2-methylpropyl) ethane -1-sulfonamide
  • the title compound was obtained in the same manner as in Example 31 except that the compound synthesized in (1) was used.
  • Example 86 2- ⁇ [6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino ⁇ -N-cyclobutylethane-1-sulfone Amide (a) The title compound was obtained in the same manner as in Example 61, except that the compound synthesized in Reference Example 6 was used instead of the compound synthesized in Reference Example 3.
  • Potassium vinyl trifluoroborate (11.7 mg) was added to the mixture and stirred at 120 ° C. for an additional 30 minutes using a microwave reactor. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to extract the organic phase, and then the organic phase was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: hexane) and tert-butyl [1-(4- ⁇ [2- (cyclopentylsulfamoyl) ethyl] amino ⁇ -7-ethenylpyrazolo).
  • Example 88 N-cyclopentyl-2- ( ⁇ 2- [3- (methylamino) azetidine-1-yl] -7- (prop-1-en-2-yl) pyrazolo [1,5-a] [1,3, 5] Triazine-4-yl ⁇ amino) ethane-1-sulfonamide (a) The title compound in the same manner as in Example 87, except that potassium isopropenyl trifluoroborate was used instead of potassium vinyl trifluoroborate.
  • Example 89-1.2 2-( ⁇ 7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( Optical isomer of oxolan-3-yl) ethane-1-sulfonamide (a) Using the compound synthesized in Example 71, the title compound was obtained in the same manner as in Example 105 (b).
  • Example 90 2-( ⁇ 7-Chloro-2- [trans-3-fluoro-4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ Amino) -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyridine-3-ylcarbamate instead of tert-butyl (trans-3-fluoropiperidine-4-yl) methylcarbamate The title compound was obtained in the same manner as in Example 53, except that the compound was obtained.
  • Example 91 N-cyclopentyl-2- ( ⁇ 7-ethyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Ethane-1-sulfonamide (a)
  • the compound obtained in Example 87 (a) was suspended in (51.0 mg) and 10% palladium carbon (10.0 mg) in methanol (1 mL), followed by a hydrogen atmosphere. Stirred overnight below.
  • Example 92 N-cyclopentyl-2- ( ⁇ 2- [3- (methylamino) azetidine-1-yl] -7- (propane-2-yl) pyrazolo [1,5-a] [1,3,5] triazine-
  • the title compound was obtained in the same manner as in Example 91, except that potassium isopropenyl trifluoroborate was used in place of 4-yl ⁇ amino) ethane-1-sulfonamide (a) potassium vinyl trifluoroborate.
  • Example 93 2-( ⁇ 7-Cyano-2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N-cyclopentyl Same as in Example 55, except that tert-butylmethyl (piperidin-4-yl) carbamate was used instead of ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained by the procedure.
  • Example 94 2- ( ⁇ 7-Chloro-2- [4-methyl-4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Except for the use of tert-butyl methyl (4-methylpiperidin-4-yl) carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-yl carbamate. The title compound was obtained in the same manner as in Example 53.
  • Example 96 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( 1-Cyanocyclopropyl) Ethan-1-sulfonamide (a) In the same manner as in Example 95, except that 1-aminocyclopropane-1-carbonitrile hydrochloride was used instead of oxane-3-amine. The title compound was obtained.
  • Example 97 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- [ (1S, 2S) -2-Hydroxycyclopentyl]
  • Example 95 except that trans-2-aminocyclopentane-1-ol hydrochloride was used instead of ethane-1-sulfonamide (a) oxane-3-amine.
  • the title compound was obtained in the same manner as in the above.
  • Example 98 N-cyclopentyl-2- ( ⁇ 7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Same as in Example 39, except that 3-methoxy-1H-pyrazol-5-amine was used instead of ethane-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine. The title compound was obtained by the procedure.
  • Example 99 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( 2-Hydroxy-2-methylpropyl) Ethan-1-sulfonamide (a) Same as in Example 95 except that 1-amino-2-methylpropan-2-ol was used instead of oxane-3-amine. The title compound was obtained by the method.
  • Example 100 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( 3,3-Difluorocyclopentane) Ethane-1-sulfonamide (a) The same procedure as in Example 95, except that 3,3-difluorocyclopentane-1-amine hydrochloride was used instead of oxane-3-amine. The title compound was obtained in.
  • Example 101 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( Examples except that 2-amino-2-methylpropan-1-ol was used instead of 1-hydroxy-2-methylpropan-2-yl) ethane-1-sulfonamide (a) oxane-3-amine. The title compound was obtained in the same manner as in 95.
  • Example 102 2- ⁇ [7- (difluoromethyl) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ -N- (2-methyl Propyl) ethane-1-sulfonamide (a)
  • the title compound was obtained in the same manner as in Example 79, except that the compound synthesized in Reference Example 5 was used instead of the compound synthesized in Reference Example 3. ..
  • Example 103 N-cyclopentyl-2- ( ⁇ 7-fluoro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino)
  • Example 39 (a) except that 3-fluoro-1H-pyrazol-5-amine was used instead of ethane-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine.
  • 4-Chloro-7- (fluoro) -2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine was obtained from the above in the same manner as in (d).
  • Example 105-1 ⁇ 2 N- (butane-2-yl) -2-( ⁇ 7-chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-
  • Example 10-7 2-( ⁇ 7- (difluoromethyl) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino)- Synthesis of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride in place of N- (2-methylpropyl) ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl carbamate in Reference Example 3 The title compound was obtained in the same manner as in Example 63, except that the compound synthesized in Reference Example 5 was used instead of the compound obtained.
  • Example 109 2-( ⁇ 7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ⁇ Except for the use of 1- [1- (trifluoromethyl) cyclopropyl] methaneamine hydrochloride instead of [1- (trifluoromethyl) cyclopropyl] methyl ⁇ ethane-1-sulfonamide (a) oxane-3-amine. Obtained the title compound in the same manner as in Example 95.
  • Example 110 2-( ⁇ 7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide
  • 3-methoxy-1H-pyrazole-5-amine was synthesized in Reference Example 1 instead of 3- (trifluoromethyl) -1H-pyrazole-5-amine.
  • the title compound was obtained in the same manner as in Example 39, except that the compound synthesized in Reference Example 5 was used instead of the compound obtained.
  • Example 111 N-cyclopentyl-2- ⁇ [7-methoxy-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ ethane-1-sulfonamide
  • A instead of 3- (trifluoromethyl) -1H-pyrazol-5-amine, 3-methoxy-1H-pyrazol-5-amine, instead of tert-butylazetidine-3-yl (methyl) carbamate hydrochloride
  • the title compound was obtained in the same manner as in Example 39 except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1 for tert-butyl piperazine-1-carboxylate. ..
  • Example 112 N-cyclopentyl-2- ( ⁇ 7-methoxy-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) Etan-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of 3-methoxy-1H-pyrazol-5-amine, tert-butyl azetidine-3-yl (methyl) ) Same as Example 39 except that tert-butyl methyl (piperidine-4-yl) carbamate was used instead of carbamate hydrochloride and the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. The title compound was obtained by the method of.
  • Example 113 N-Cyclopentyl-2- ⁇ [7-fluoro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino ⁇ ethane-1-sulfonamide (A)
  • the title compound was obtained in the same manner as in Example 103 except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
  • Example 115 2-( ⁇ 7-Bromo-2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino) -N- ( Examples except that tert-butylmethyl (piperidin-4-yl) carbamate was used instead of 2-methylpropyl) ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained in the same manner as in 44.
  • Example 116 N-cyclopentyl-2- ( ⁇ 7-fluoro-2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl ⁇ amino)
  • tert-butylmethyl (piperidin-4-yl) carbamate was used instead of ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
  • the title compound was obtained in.
  • Example 117 N-Cyclopentyl-2-( ⁇ 7- (difluoromethoxy) -2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] ⁇ Amino) ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate
  • Example 104 except that tert-butyl methyl (piperidine-4-yl) carbamate was used instead of the hydrochloride salt. The title compound was obtained in a similar manner.
  • Example 118 6-bromo-N- [2- (methanesulfonyl) ethyl] -2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-amine
  • a 6-bromo After dissolving -2,4-dichloropyrido [2,3-d] pyrimidine (50 mg) in THF (1 mL), DIPEA (93 ⁇ L) and 2- (methanesulfonyl) ethane-1-amine hydrochloride (29 mg) were added. In addition, it was stirred overnight at room temperature.
  • Example 119 6-Bromo-2- [3- (methylamino) azetidine-1-yl] -N- [2- (morpholine-4-sulfonyl) ethyl] pyrido [2,3-d] pyrimidin-4-amine (a)
  • the title compound was obtained in the same manner as in Example 118, except that the compound synthesized in Reference Example 13 was used instead of 2- (methanesulfonyl) ethane-1-amine hydrochloride.
  • Example 120 2-( ⁇ 6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl ⁇ amino) -N- (4-fluorophenyl) ethane-
  • the title compound was obtained in the same manner as in Example 118, except that the compound synthesized in Reference Example 14 was used instead of 1-sulfonamide (a) 2- (methanesulfonyl) ethane-1-amine hydrochloride. ..
  • Example 121 2-( ⁇ 6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl ⁇ amino) -N-methyl-N-phenylethane-1
  • the title compound was obtained in the same manner as in Example 118, except that the compound synthesized in Reference Example 15 was used instead of the -sulfonamide (a) 2- (methanesulfonyl) ethane-1-amine hydrochloride.
  • Example 122 2- ⁇ [6-Bromo-2- (piperazine-1-yl) pyrido [2,3-d] pyrimidin-4-yl] amino ⁇ -N-methyl-N-phenylethane-1-sulfonamide
  • a instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride, tert-butyl piperazine-1-carboxylate was synthesized in Reference Example 15 instead of 2- (methanesulfonyl) ethane-1-amine hydrochloride. The title compound was obtained in the same manner as in Example 118 except that the compound was used.
  • Example 12-7 N- [2- (4-Fluorobenzene-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine (a) 2-(4 instead of aminoethanesulfonic acid)
  • the title compound was obtained in the same manner as in Examples 124 (a) to (d) except that 4-fluorobenzene-1-sulfonyl) ethane-1-amine hydrochloride was used.
  • Example 1228 N-cyclopentyl-2- ⁇ methyl [2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino ⁇ ethane-1-sulfonamide (a) 2-( instead of 2-aminoethanesulfonic acid)
  • the title compound was obtained in the same manner as in Example 124 except that cyclopentylamine was used instead of azetidine for methylamino) ethane-1-sulfonic acid.
  • Example 130 2-( ⁇ 6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl ⁇ amino) -N- [4- (trifluoromethyl) Phenyl] Ethane-1-sulfonamide
  • a 2- (methanesulfonyl) ethane-1-amine
  • the title was given in the same manner as in Example 118, except that the compound synthesized in Reference Example 17 was used instead of the ethane-1-amine hydrochloride. The compound was obtained.
  • Tables 3 to 19 The compounds produced in each of the above examples are shown in Tables 3 to 19 below. Tables 3 to 19 below also show the analysis results of each compound by 1 H-NMR and ESI-MS.
  • Membrane protein obtained from human histamine H4 receptor recombinant HEK (human fetal kidney cell), radiolabeled ligand 20 nM [ 3 H] histamine (PerkinElmer), and test compound dissolved in DMSO were placed on a 96-well plate.
  • GF / C filter PerkinElmer pretreated with 0.5% polyethyleneimine after reacting at room temperature for 60 minutes in a buffer solution containing 50 mM Tris-hydrochloric acid, pH 7.4, 5.0 mM EDTA-2Na. ) was filtered. Wash 5 times with 50 mM Tris-hydrochloric acid and pH 7.4 buffer solution, dry at 50 ° C.
  • test compounds were evaluated H4 receptor affinity by the inhibition constant K i values of histamine H4 receptor in inhibition constant Ki value A a of less than 1000nM than ⁇ 5000 nM, 100 nM or higher ⁇ 1000nM Those less than 100 nM were designated as B, and those less than 100 nM were designated as C. If the inhibition constant Ki value is less than 5000 nM, it indicates that it has an affinity for the H4 receptor.
  • Ki value A a of less than 1000nM than ⁇ 5000 nM, 100 nM or higher ⁇ 1000nM Those less than 100 nM were designated as B, and those less than 100 nM were designated as C. If the inhibition constant Ki value is less than 5000 nM, it indicates that it has an affinity for the H4 receptor.
  • Tables 20 to 21 The evaluation results when the compounds obtained in each of the above Examples were used as the test compounds are shown in Tables 20 to 21 below.

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Abstract

Provided are: a novel compound, and a pharmaceutically acceptable salt thereof, represented by formula (1), the compound having a histamine H4 receptor-regulating effect and being useful in the treatment and/or prevention of an illness or state in which histamine H4 receptor participates; the use of the same; and a medical composition containing the same.

Description

新規二環化合物New bicyclic compound
　本発明は、新規二環化合物に関し、より詳しくは、ヒスタミンＨ４受容体の調節作用を有する二環化合物である新規化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物に関する。 The present invention relates to a novel bicyclic compound, more specifically, a novel compound which is a bicyclic compound having a regulating action on histamine H4 receptor, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these. Regarding.
　ヒスタミン受容体は、生体内の活性アミンの一つであるヒスタミンの受容体であり、Ｈ１～Ｈ４の４種のサブタイプが知られている。そのうち、ヒスタミンＨ４受容体は、Ｇαｉ／ｏタンパク質と結合するＧＰＣＲ（Ｇタンパク質共役受容体）で、胸腺、骨髄、脾臓などの免疫組織での発現が高く、マスト細胞、樹状細胞、好酸球、Ｔ細胞といった免疫細胞においても発現が認められている。ヒスタミン刺激による、これら免疫細胞の遊走がヒスタミンＨ４受容体を介して行われていることなどから、ヒスタミンＨ４受容体は、炎症やアレルギーなどの免疫調節に関わっていると考えられている（非特許文献１）。そのため、ヒスタミンＨ４受容体の調節作用を有するヒスタミンＨ４受容体モジュレーターには、各種免疫炎症性疾患、例えば、リウマチ、喘息、アトピー性皮膚炎、アレルギー性鼻炎などの治療薬としての可能性が期待されている。 The histamine receptor is a receptor for histamine, which is one of the active amines in the living body, and four subtypes of H1 to H4 are known. Of these, the histamine H4 receptor is a GPCR (G protein-conjugated receptor) that binds to the Gαi / o protein and is highly expressed in immune tissues such as the thoracic gland, bone marrow, and spleen, and is highly expressed in mast cells, dendritic cells, and eosinophils. , T cells are also found to be expressed in immune cells. Since the migration of these immune cells by histamine stimulation is carried out via the histamine H4 receptor, it is considered that the histamine H4 receptor is involved in immune regulation such as inflammation and allergy (non-patented). Document 1). Therefore, the histamine H4 receptor modulator, which has a regulating action on the histamine H4 receptor, is expected to have potential as a therapeutic agent for various immunoinflammatory diseases such as rheumatism, asthma, atopic dermatitis, and allergic rhinitis. ing.
　近年、様々なヒスタミンＨ４受容体モジュレーターが報告されており、例えば、その進歩に関する概観は非特許文献２や非特許文献３に記載されている。また、例えば、特許文献１、特許文献２、及び特許文献３には、ヘテロ二環性誘導体がヒスタミンＨ４受容体の調節作用を有することが記載されている。 In recent years, various histamine H4 receptor modulators have been reported. For example, an overview of their progress is described in Non-Patent Document 2 and Non-Patent Document 3. Further, for example, Patent Document 1, Patent Document 2, and Patent Document 3 describe that a heterobicyclic derivative has a histamine H4 receptor-regulating action.
国際公開第２００９／０８３６０８号International Publication No. 2009/0836008 国際公開第２０１１／０７８１４３号International Publication No. 2011/078143 国際公開第２０２０／０２０９３９号International Publication No. 2020/20939
　本発明は、ヒスタミンＨ４受容体の調節作用を有し、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防に有用な、新規化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物を提供することを目的とする。 The present invention presents with novel compounds and pharmacologically acceptable salts thereof, which have a regulatory effect on the histamine H4 receptor and are useful for the treatment and / or prevention of diseases or conditions involving the histamine H4 receptor. It is an object of the present invention to provide a pharmaceutical composition containing these.
　本発明者らは、上記課題を解決すべく鋭意研究を行った結果、特定の構造を有する新規の二環化合物及びその薬理学的に許容される塩が、ヒスタミンＨ４受容体親和性を示し、優れたヒスタミンＨ４受容体調節作用を有することを見出し、本発明を完成するに至った。 As a result of diligent research to solve the above problems, the present inventors have shown that a novel bicyclic compound having a specific structure and a pharmacologically acceptable salt thereof show histamine H4 receptor affinity. They have found that they have an excellent histamine H4 receptor regulatory action, and have completed the present invention.
　すなわち、本発明は、以下の発明を包含する。
［１］
　下記一般式（１）で表される化合物又はその薬理学的に許容される塩。 That is, the present invention includes the following inventions.
[1]
A compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式（１）中、
　Ｘ１は、ＣＨ又は窒素原子であり、
　Ｘ２は、ハロゲン原子、Ｃ１～６アルキル基、ＮＨ２、ＮＨＣＨ３、Ｎ（ＣＨ３）２、ＮＯ２、ＯＨ、及びＯＣＨ３から選択されるいずれか１個の置換基で置換されていてもよいＣＨ；又は窒素原子であり、
　Ｘ３及びＸ４は、それぞれ独立に、炭素原子又は窒素原子であり、
　環Ａは、窒素原子、酸素原子、及び硫黄原子から選択される少なくとも１個のヘテロ原子を含有する５員又は６員の芳香族複素環であり、
　　ここで環Ａは、ハロゲン原子、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、及びシクロプロピル基から選択される少なくとも１個の置換基で置換されていてもよいＣ１～６アルキル基；ハロゲン原子；ＣＦ３；Ｃ２～３アルケニル基；水酸基；ＯＣＨ３；ＯＣＨＦ２；ＯＣＨ２ＣＨ３；ＣＮ；ＣＯＮＨ２；ＳＣＨ３；Ｓｉ（ＣＨ３）３；－Ｓ（Ｏ）２Ｒ９；－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ１０；フェニル基；及びピリジル基から選択される１個又は複数個の置換基で置換されていてもよく、Ｒ９及びＲ１０は、それぞれ独立にアルキル基であり、
　Ｒ１及びＲ２は、これらが結合している窒素原子と共に、さらに窒素原子、酸素原子、及び硫黄原子から選択される少なくとも１個のヘテロ原子を含有してもよい４員から９員の非芳香族複素環式基を形成しており、
　　ここで前記非芳香族複素環式基は、単環式、縮合二環式、架橋二環式、又はスピロ二環式の基であって、少なくとも２個の窒素原子を含有するであるか、又は、１個の窒素原子を含有しかつ少なくとも１個の窒素原子を含有する基で置換された基であり、
　　前記非芳香族複素環式基は、フッ素原子、水酸基、－ＮＲ５Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される少なくとも１個の置換基で置換されていてもよく、
　　　ここで、Ｒ５及びＲ６は、それぞれ独立に、水素原子若しくはＣ１～６アルキル基であるか、又は、Ｒ５及びＲ６が結合している窒素原子と共に４員から６員の非芳香族複素環式基を形成しており、
　Ｒ３は、水素原子又はＣ１～６アルキル基であり、
　Ｒ４は、フッ素原子で置換されてもよいフェニル基；－ＮＲ７Ｒ８；又はＣ１～６アルキル基であり、
　　ここで、Ｒ７及びＲ８は、それぞれ独立に、水素原子；水酸基；Ｃ１～６アルキル基；ハロゲン原子、ＣＮ、水酸基、及びＣＨ２ＯＨから選択される少なくとも１個の置換基で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子、水酸基、及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；５員から６員の芳香族複素環式基、若しくは４員から６員の非芳香族複素環式基であるか、又は、Ｒ７及びＲ８が結合している窒素原子と共に４員から６員の非芳香族含窒素複素環式基を形成しており、
　　ここで、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；水酸基；ＯＣＨ３；フッ素原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていてもよく、
　ｎは、１～４のうちの整数である。］
［２］
　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、４員から７員の単環式の非芳香族複素環式基、６員から９員の縮合二環式の非芳香族複素環式基、又は、７員から９員のスピロ二環式の非芳香族複素環式基を形成している、［１］に記載の化合物又はその薬理学的に許容される塩。
［３］
　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、４員から７員の単環式の非芳香族複素環式基を形成しており、前記４員から７員の単環式の非芳香族複素環が、アゼチジン環、ピロリジン環、ピペラジン環、ピペリジン環、又はジアゼパン環である、［２］に記載の化合物又はその薬理学的に許容される塩。
［４］
　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、６員から９員の縮合二環式の非芳香族複素環式基を形成しており、前記６員から９員の縮合二環式の非芳香族複素環式基が、下記式（ａ）～（ｄ）： [In equation (1),
X 1 is a CH or nitrogen atom and
X 2 is a halogen atom, C 1 ~ 6 alkyl group, NH 2, NHCH 3, N (CH 3) 2, NO 2, OH, and substituted with either one substituent selected from OCH 3 CH; or a nitrogen atom, which may be
X 3 and X 4 are independently carbon or nitrogen atoms, respectively.
Ring A is a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms.
Here, ring A may be substituted with at least one substituent selected from a halogen atom, CH 2 OH, CH 2 F, CHF 2 , and a cyclopropyl group; a C 1-6 alkyl group; a halogen atom. CF 3 ; C 2-3 alkenyl groups; hydroxyl groups; OCH 3 ; OCHF 2 ; OCH 2 CH 3 ; CN; CONH 2 ; SCH 3 ; Si (CH 3 ) 3 ; -S (O) 2 R 9 ; -S (O) 2 N (H) R 10 ; may be substituted with one or more substituents selected from a phenyl group; and a pyridyl group, with R 9 and R 10 being independently alkyl groups, respectively. can be,
R 1 and R 2 are 4- to 9-membered non-members which may further contain at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded. Forming an aromatic heterocyclic group,
Here, the non-aromatic heterocyclic group is a monocyclic, fused bicyclic, crosslinked bicyclic, or spirobicyclic group and contains at least two nitrogen atoms. Alternatively, it is a group containing one nitrogen atom and substituted with a group containing at least one nitrogen atom.
Said non-aromatic heterocyclic group, a fluorine atom, a hydroxyl group, -NR 5 R 6, C 1 ~ 6 alkyl group, and C 1 ~ 6 substituted by at least one substituent selected from aminoalkyl groups May be
Here, R 5 and R 6 are independently hydrogen atoms or C 1 to 6 alkyl groups, or 4- to 6-membered non-aromatics together with the nitrogen atom to which R 5 and R 6 are bonded. Forming a group heterocyclic group,
R 3 is a hydrogen atom or a C 1-6 alkyl group.
R 4 is a phenyl group optionally substituted with a fluorine atom; -NR 7 R 8 ; or a C 1-6 alkyl group.
Here, R 7 and R 8 are independently substituted with at least one substituent selected from a hydrogen atom; a hydroxyl group; a C 1 to 6 alkyl group; a halogen atom, a CN, a hydroxyl group, and CH 2 OH. good C 3 ~ 7 cycloalkyl group optionally; halogen atom, a hydroxyl group, and at least one substituent a phenyl group which may be substituted with a group selected from CF 3; 5-membered 6-membered aromatic heterocyclic ring A 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group, or a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group with a nitrogen atom to which R 7 and R 8 are bonded. Forming a group
Here, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently substituted with at least one substituent selected from a fluorine atom; CF 3 ; a hydroxyl group; OCH 3 ; a fluorine atom and CF 3. C 3 to 7 cycloalkyl groups which may be substituted; a phenyl group which may be substituted with at least one substituent selected from a halogen atom and CF 3; and 5 members which may be substituted with a halogen atom. May be substituted with one or more substituents selected from the 6-membered aromatic heterocyclic group.
n is an integer from 1 to 4. ]
[2]
In the above formula (1), R 1 and R 2 are a 4- to 7-membered monocyclic non-aromatic heterocyclic group and a 6- to 9-membered fused two, together with the nitrogen atom to which they are bonded. The compound according to [1] or pharmacologically thereof, which forms a cyclic non-aromatic heterocyclic group or a 7- to 9-membered spirobic non-aromatic heterocyclic group. Allowable salt.
[3]
In the formula (1), R 1 and R 2 form a 4- to 7-membered monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and the 4-membered non-aromatic heterocyclic group is formed. The compound according to [2] or a pharmacologically acceptable salt thereof, wherein the 7-membered monocyclic non-aromatic heterocycle is an azetidine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, or a diazepan ring. ..
[4]
In the formula (1), R 1 and R 2 form a 6- to 9-membered fused bicyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. Condensed bicyclic non-aromatic heterocyclic groups of 9 to 9 members are represented by the following formulas (a) to (d):
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
のうちのいずれか１種で表される基である、［２］に記載の化合物又はその薬理学的に許容される塩。
［５］
　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、７員から９員のスピロ二環式の非芳香族複素環式基を形成しており、前記７員から９員のスピロ二環式の非芳香族複素環式基が、下記式（ｅ）～（ｈ）： The compound according to [2] or a pharmacologically acceptable salt thereof, which is a group represented by any one of the above.
[5]
In the formula (1), R 1 and R 2 form a 7- to 9-membered spirobicyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. Spirobicyclic non-aromatic heterocyclic groups of 9 to 9 members are represented by the following formulas (e) to (h):
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
のうちのいずれか１種で表される基である、［２］に記載の化合物又はその薬理学的に許容される塩。
［６］
　前記式（１）において、Ｒ４が－ＮＲ７Ｒ８であり、Ｒ７及びＲ８が、それぞれ独立に、水素原子；Ｃ１～６アルキル基；ハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基；又はハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基であり、
　　ここで、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；フッ素原子で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていてもよい、
　［１］～［５］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。
［７］
　前記式（１）において、環Ａが、１～３個の窒素原子を含有する５員の芳香族複素環、又は２～３個の窒素原子を含有する６員の芳香族複素環である、［１］～［６］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。
［８］
　前記式（１）において、Ｘ１～Ｘ４及び環Ａを含む二環の構造： The compound according to [2] or a pharmacologically acceptable salt thereof, which is a group represented by any one of the above.
[6]
In the above formula (1), R 4 is −NR 7 R 8 , and R 7 and R 8 may be independently substituted with hydrogen atom; C 1 to 6 alkyl group; halogen atom , respectively. C 3 ~ 7 Cycloalkyl group; or a phenyl group optionally substituted with at least one substituent selected from a halogen atom and CF 3.
Here, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently C 3 to 7 cycloalkyl groups which may be substituted with a fluorine atom; CF 3 ; a fluorine atom; a halogen atom and CF 3 A phenyl group optionally substituted with at least one substituent selected from; and one or more selected from a 5- to 6-membered aromatic heterocyclic group optionally substituted with a halogen atom. May be substituted with 17 substituents,
The compound according to any one of [1] to [5] or a pharmacologically acceptable salt thereof.
[7]
In the formula (1), the ring A is a 5-membered aromatic heterocycle containing 1 to 3 nitrogen atoms or a 6-membered aromatic heterocycle containing 2 to 3 nitrogen atoms. The compound according to any one of [1] to [6] or a pharmacologically acceptable salt thereof.
[8]
In the formula (1), a two-ring containing X 1 ~ X 4 and ring A structure:
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
が、下記式（１０１）～（１３０）： However, the following equations (101) to (130):
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
のうちのいずれか１種で表される構造である、［１］～［７］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。
［９］
　前記式（１）で表される化合物が、
２－（｛１－メチル－５－［３－（メチルアミノ）アゼチジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
Ｎ－ベンジル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロプロピル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［１－メチル－５－（ピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－（｛１－メチル－５－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
Ｎ－（シクロプロピルメチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－（シクロブチルメチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
２－（｛１－メチル－５－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［８－ブロモ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－）エタン－１－スルホンアミド、
２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－）エタン－１－スルホンアミド、
Ｎ－シクロヘキシル－２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［７－メチル－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［７－（４－メチルピペラジン－１－イル）［１，２，４］トリアゾロ［４，３－ａ］［１，３，５］トリアジン－５－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［５－（４－メチルピペラジン－１－イル）－１Ｈ－［１，２，３］トリアゾロ［４，５－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［２－（４－メチルピペラジン－１－イル）フロ［３，２－ｄ］ピリミジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
Ｎ－［（４－フルオロフェニル）メチル］－２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－［（４－フルオロフェニル）メチル］－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－｛［２－（６－メチル－２，６－ジアザスピロ［３．３］ヘプタン－２－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［２－（２，６－ジアザスピロ［３．３］ヘプタン－２－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛１－メチル－５－［３－（メチルアミノ）アゼチジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［７－クロロ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［１－メチル－５－（６－メチル－２，６－ジアザスピロ［３．３］ヘプタン－２－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロブチル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－（３，３－ジフルオロシクロブチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－［（３，３－ジフルオロシクロブチル）メチル］－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－（２，２－ジフルオロプロピル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－）エタン－１－スルホンアミド、
２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［５－（４－メチルピペラジン－１－イル）［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル］アミノ｝エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］プテリジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［５－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［２－（４－アミノピペリジン－１－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［７－クロロ－２－（１，４－ジアゼパン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛２－［（３Ｓ）－３－アミノピロリジン－１－イル］－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛２－ブロモ－５－［３－（メチルアミノ）アゼチジン－１－イル］［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－シアノ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［６－シアノ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－メチル－３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［６－エトキシ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－｛［７－クロロ－２－（２，６－ジアザビシクロ［３．２．０］ヘプタン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［２－（３－アミノ－３－メチルアゼチジン－１－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［２－（３－アミノアゼチジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［２－（３－アミノアゼチジン－１－イル）－７－（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］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［７－ブロモ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［７－クロロ－２－（１，６－ジアザスピロ［３．３］ヘプタン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［２－（３－アミノアゼチジン－１－イル）－６－ブロモイミダゾ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（ピペラジン－１－イル）イミダゾ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［２－（６－アミノ－３－アザビシクロ［３．１．０］ヘキサン－３－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－７－カルボキサミド、
Ｎ－シクロペンチル－２－｛［２－（ヘキサヒドロピロロ［１，２－ａ］ピラジン－２（１Ｈ）－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［（３Ｓ）－３－メチルピペラジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－フェニルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（ピリジン－３－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－｛［７－シアノ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－クロロ－２－［（１Ｒ，５Ｓ）－６－（メチルアミノ）－３－アザビシクロ［３．１．０］ヘキサン－３－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－クロロ－２－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛６－シアノ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［７－（ジフルオロメチル）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メトキシエチル）エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－［１－（ヒドロキシメチル）シクロペンチル］エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－｛［７－クロロ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロブチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－エテニル－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（プロプ－１－エン－２－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［トランス－３－フルオロ－４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－エチル－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（プロパン－２－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－（｛７－シアノ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－クロロ－２－［４－メチル－４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキサン－３－イル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－シアノシクロプロピル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－［（１Ｓ，２Ｓ）－２－ヒドロキシシクロペンチル］エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－メトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－ヒドロキシ－２－メチルプロピル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（３，３－ジフルオロシクロペンチル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－ヒドロキシ－２－メチルプロパン－２－イル）エタン－１－スルホンアミド、
２－｛［７－（ジフルオロメチル）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－フルオロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－（ジフルオロメトキシ）－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－（ブタン－２－イル）－２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
２－（｛７－エトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
２－（｛７－（ジフルオロメチル）－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－シアノシクロペンチル）エタン－１－スルホンアミド、
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝エタン－１－スルホンアミド、
２－（｛７－メトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［７－メトキシ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－メトキシ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［７－フルオロ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［７－（ジフルオロメトキシ）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
２－（｛７－ブロモ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－フルオロ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－（｛７－（ジフルオロメトキシ）－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
６－ブロモ－Ｎ－［２－（メタンスルホニル）エチル］－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－アミン、
６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ－［２－（モルホリン－４－スルホニル）エチル］ピリド［２，３－ｄ］ピリミジン－４－アミン、
２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－（４－フルオロフェニル）エタン－１－スルホンアミド、
２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド、
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピリド［２，３－ｄ］ピリミジン－４－イル］アミノ｝－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド、
２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（ピリジン－２－イル）エタン－１－スルホンアミド、
Ｎ－［２－（アゼチジン－１－スルホニル）エチル］－２－（４－メチルピペラジン－１－イル）プテリジン－４－アミン、
２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（３，３－ジフルオロシクロブチル）エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［２－（ヘキサヒドロピロロ［１，２－ａ］ピラジン－２（１Ｈ）－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－［２－（４－フルオロベンゼン－１－スルホニル）エチル］－２－（４－メチルピペラジン－１－イル）プテリジン－４－アミン、
Ｎ－シクロペンチル－２－｛メチル［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
Ｎ－シクロペンチル－２－｛［７－（４－メチルピペラジン－１－イル）ピリミド［５，４－ｅ］［１，２，４］トリアジン－５－イル］アミノ｝エタン－１－スルホンアミド、又は
２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－［４－（トリフルオロメチル）フェニル］エタン－１－スルホンアミド
である、［１］～［８］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。
［１０］
　［１］～［９］のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を含有する医薬組成物。
［１１］
　ヒスタミンＨ４受容体調節用組成物である、［１０］に記載の医薬組成物。
［１２］
　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の組成物である、［１０］又は［１１］に記載の医薬組成物。
［１３］
　［１］～［９］のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を対象に投与する工程を含む、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防の方法。
［１４］
　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の医薬組成物の製造のための、［１］～［９］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩の使用。 The compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof, which is a structure represented by any one of the above.
[9]
The compound represented by the formula (1) is
2-({1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N- (propane-2-) Il) ethane-1-sulfonamide,
N-Benzyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
N-Cyclopropyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide ,
2-{[1-Methyl-5- (piperazine-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane-1- Sulfonamide,
2-({1-methyl-5-[(3S) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N-( Propane-2-yl) ethane-1-sulfonamide,
N- (cyclopropylmethyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1 -Sulfonamide,
N- (Cyclobutylmethyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1 -Sulfonamide,
2-({1-methyl-5-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N-( Propane-2-yl) ethane-1-sulfonamide,
2-{[1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane -1-sulfonamide,
2-{[8-Bromo-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -) Ethane-1-sulfonamide,
2-{[2- (4-Methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2-) ethane- 1-sulfonamide,
N-cyclohexyl-2-{[2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide,
2-{[7-Methyl-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) ethane-1-sulfonamide,
2-{[7- (4-Methylpiperazin-1-yl) [1,2,4] triazolo [4,3-a] [1,3,5] triazine-5-yl] amino} -N-( Propane-2-yl) ethane-1-sulfonamide,
2-{[5- (4-Methylpiperazin-1-yl) -1H- [1,2,3] triazolo [4,5-d] pyrimidin-7-yl] amino} -N- (propane-2-) Il) ethane-1-sulfonamide,
2-{[2- (4-Methylpiperazin-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (propane-2-yl) ethane -1-sulfonamide,
N-Cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pyrrolo [2,1-f] [1,2,4] triazine-4-yl] amino} ethane-1-sulfonamide,
2-{[2- (4-Methylpiperazin-1-yl) flo [3,2-d] pyrimidin-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide,
N-[(4-fluorophenyl) methyl] -2-{[2- (4-methylpiperazin-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino } Ethane-1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pyrrolo [2,1-f] [1,2,4] triazine-4-yl} amino) ethane-1- Sulfonamide,
N-Cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) ethane-1- Sulfonamide,
N-[(4-fluorophenyl) methyl] -2-({2- [3- (methylamino) azetidine-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4- Il} amino) ethane-1-sulfonamide,
2-{[2- (6-Methyl-2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (Propane-2-yl) ethane-1-sulfonamide,
2-{[2- (Piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (propane-2-yl) ethane-1- Sulfonamide,
2-{[2- (2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-( Propane-2-yl) ethane-1-sulfonamide,
2-({2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- (propane-2-) Il) ethane-1-sulfonamide,
N-cyclopentyl-2- ({1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) ethane-1- Sulfonamide,
N-Cyclopentyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
2-{[7-Chloro-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Propane-2-yl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
2-{[1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (2-methylpropyl) ethane- 1-sulfonamide,
N-Cyclopentyl-2-{[1-methyl-5-(6-methyl-2,6-diazaspiro [3.3] heptane-2-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino} ethane-1-sulfonamide,
N-Cyclobutyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
N- (3,3-difluorocyclobutyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino } Ethane-1-sulfonamide,
N-[(3,3-difluorocyclobutyl) methyl] -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino} ethane-1-sulfonamide,
N- (2,2-difluoropropyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} Ethane-1-sulfonamide,
2-({2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- (Propane-2-) ethane-1-sulfonamide,
2-({2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Propane-2-yl) ethane-1-sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
N-Cyclopentyl-2-{[5- (4-methylpiperazin-1-yl) [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] amino} Ethane-1-sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
2-{[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide,
2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide,
N-Cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide,
N-Cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pteridine-4-yl} amino) ethane-1-sulfonamide,
N-Cyclopentyl-2-{[5- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
2-{[2- (4-Aminopiperidin-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1- Sulfonamide,
2-{[7-Chloro-2- (1,4-diazepan-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane- 1-sulfonamide,
2-({2-[(3S) -3-aminopyrrolidine-1-yl] -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
2-({2-Bromo-5- [3- (methylamino) azetidine-1-yl] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] } Amino) -N-cyclopentylethane-1-sulfonamide,
2-({7-Cyano-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
2-{[6-Cyano-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide,
2- ({7-Chloro-2- [3-methyl-3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
N-Cyclopentyl-2-{[6-ethoxy-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
2-{[7-Chloro-2- (2,6-diazabicyclo [3.2.0] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] Amino} -N-cyclopentylethane-1-sulfonamide,
2-{[2- (3-Amino-3-methylazetidine-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- Cyclopentylethane-1-sulfonamide,
2-{[6-Bromo-2- (piperazine-1-yl) pyrrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
2-{[2- (3-Aminoazetidine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
2-{[2- (3-Aminoazetidine-1-yl) -7- (difluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- Cyclopentylethane-1-sulfonamide,
2-{[7-Bromo-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
2-{[7-Chloro-2- (1,6-diazaspiro [3.3] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide,
2-{[2- (3-Aminoazetidine-1-yl) -6-bromoimidazole [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane- 1-Sulfonamide,
2-{[6-Bromo-2- (piperazine-1-yl) imidazole [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
2-{[2- (6-amino-3-azabicyclo [3.1.0] hexane-3-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino} -N-cyclopentylethane-1-sulfonamide,
4-{[2- (Cyclopentyl sulfamoyl) ethyl] amino} -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-7 -Carboxamide,
N-Cyclopentyl-2-{[2- (hexahydropyrro [1,2-a] pyrazine-2 (1H) -yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino} ethane-1-sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxolan-3-yl) ethane-1-sulfonamide,
2-({7-Bromo-2-[(3S) -3-methylpiperazin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- Cyclopentylethane-1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7-phenylpyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino ) Ethane-1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (pyridin-3-yl) pyrazolo [1,5-a] [1,3,5] triazine- 4-yl} amino) ethane-1-sulfonamide,
2-{[7-Cyano-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
2-({7-Chloro-2-[(1R, 5S) -6- (methylamino) -3-azabicyclo [3.1.0] hexane-3-yl] pyrazolo [1,5-a] [1 , 3,5] Triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
2-({7-Chloro-2-[(3R) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
2-({6-cyano-2- [4- (methylamino) piperidine-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
N-Cyclopentyl-2-{[7- (difluoromethyl) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1 -Sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methoxyethyl) ethane-1-sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- [ 1- (Hydroxymethyl) cyclopentyl] ethane-1-sulfonamide,
2-({7-Chloro-2-[(3S) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
2-{[6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (2-methylpropyl) ethane -1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (methylsulfanilic) pyrazolo [1,5-a] [1,3,5] triazine-4-yl } Amino) ethane-1-sulfonamide,
2-{[7-Chloro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (2-methylpropyl) ethane -1-sulfonamide,
2-{[6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclobutylethane-1-sulfone Amide,
N-cyclopentyl-2- ({7-ethenyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (prop-1-en-2-yl) pyrazolo [1,5-a] [1,3, 5] Triazine-4-yl} amino) ethane-1-sulfonamide,
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxolan-3-yl) ethane-1-sulfonamide,
2-({7-Chloro-2- [trans-3-fluoro-4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} Amino) -N-cyclopentylethane-1-sulfonamide,
N-cyclopentyl-2- ({7-ethyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (propane-2-yl) pyrazolo [1,5-a] [1,3,5] triazine- 4-yl} amino) ethane-1-sulfonamide,
2-({7-Cyano-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
2- ({7-Chloro-2- [4-methyl-4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxan-3-yl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Cyanocyclopropyl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- [ (1S, 2S) -2-Hydroxycyclopentyl] ethane-1-sulfonamide,
N-cyclopentyl-2- ({7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Hydroxy-2-methylpropyl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 3,3-Difluorocyclopentyl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Hydroxy-2-methylpropan-2-yl) ethane-1-sulfonamide,
2-{[7- (difluoromethyl) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (2-methyl Propyl) ethane-1-sulfonamide,
N-cyclopentyl-2- ({7-fluoro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
N-cyclopentyl-2-({7- (difluoromethoxy) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] } Amino) ethane-1-sulfonamide,
N- (butane-2-yl) -2-({7-chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine- 4-yl} amino) ethane-1-sulfonamide,
2-({7-ethoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
2-({7- (difluoromethyl) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino)- N- (2-Methylpropyl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Cyanocyclopentyl) ethane-1-sulfonamide,
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- { [1- (Trifluoromethyl) cyclopropyl] methyl} ethane-1-sulfonamide,
2-({7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
N-Cyclopentyl-2-{[7-methoxy-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide ,
N-cyclopentyl-2- ({7-methoxy-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
N-Cyclopentyl-2-{[7-fluoro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide ,
N-Cyclopentyl-2-{[7- (difluoromethoxy) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1 -Sulfonamide,
2-({7-Bromo-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
N-cyclopentyl-2- ({7-fluoro-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
N-cyclopentyl-2-({7- (difluoromethoxy) -2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] } Amino) ethane-1-sulfonamide,
6-Bromo-N- [2- (Methanesulfonyl) Ethyl] -2- [3- (Methylamino) Azetidine-1-yl] Pyrid [2,3-d] Pyrimidine-4-amine,
6-Bromo-2- [3- (methylamino) azetidine-1-yl] -N- [2- (morpholine-4-sulfonyl) ethyl] pyrido [2,3-d] pyrimidin-4-amine,
2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N- (4-fluorophenyl) ethane- 1-Sulfonamide,
2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N-methyl-N-phenylethane-1 -Sulfonamide,
2-{[6-Bromo-2- (piperazine-1-yl) pyrido [2,3-d] pyrimidin-4-yl] amino} -N-methyl-N-phenylethane-1-sulfonamide,
2-{[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (pyridin-2-yl) ethane-1-sulfonamide,
N- [2- (azetidine-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine,
2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (3,3-difluorocyclobutyl) ethane-1-sulfonamide,
N-Cyclopentyl-2-{[2- (hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
N- [2- (4-Fluorobenzene-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine,
N-Cyclopentyl-2- {methyl [2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
N-cyclopentyl-2-{[7- (4-methylpiperazin-1-yl) pyrimide [5,4-e] [1,2,4] triazine-5-yl] amino} ethane-1-sulfonamide, Or 2- ({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N- [4- (trifluoromethyl) ) Phenyl] The compound according to any one of [1] to [8], which is an ethane-1-sulfonamide, or a pharmacologically acceptable salt thereof.
[10]
A pharmaceutical composition containing at least one selected from the compound according to any one of [1] to [9] and a pharmacologically acceptable salt thereof.
[11]
The pharmaceutical composition according to [10], which is a composition for regulating histamine H4 receptors.
[12]
The pharmaceutical composition according to [10] or [11], which is a composition for treating and / or preventing a disease or condition in which the histamine H4 receptor is involved.
[13]
Involved in the histamine H4 receptor, which comprises the step of administering to the subject at least one selected from the compound according to any one of [1] to [9] and a pharmacologically acceptable salt thereof. A method of treating and / or preventing a disease or condition.
[14]
The compound according to any one of [1] to [9] or its pharmacology for producing a pharmaceutical composition for treating and / or preventing a disease or condition involving a histamine H4 receptor. Tolerable use of salt.
　本発明によれば、ヒスタミンＨ４受容体に対して優れた調節作用を有する新規化合物及びその薬理学的に許容される塩を提供することが可能となる。 According to the present invention, it is possible to provide a novel compound having an excellent regulatory action on the histamine H4 receptor and a pharmacologically acceptable salt thereof.
　本発明の化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物は、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防に有用である。 The compounds of the present invention, pharmacologically acceptable salts thereof, and pharmaceutical compositions containing them are useful for the treatment and / or prevention of diseases or conditions involving the histamine H4 receptor.
　ヒスタミンＨ４受容体が関与する疾患若しくは状態としては、例えば、各種アレルギー、免疫炎症性疾患（ＣＯＰＤなど）、炎症性腸疾患、リウマチ、アトピー性皮膚炎、掻痒性皮膚炎、アレルギー性結膜炎、鼻炎、関節症性乾癬、尋常性乾癬、喘息、めまい、アレルギー性鼻炎、多発性硬化症、敗血症、アテローム性動脈硬化症、移植片拒絶、耳鳴り、蕁麻疹、難治性掻痒、皮膚そう痒症、皮脂欠乏性皮膚炎、多形滲出性紅斑、虫刺症、痒疹、副鼻腔炎、中耳炎、好酸球増多症、好酸球性肺炎、好酸球性心筋症、好酸球性食道炎、好酸球性胃炎、好酸球性腸炎、好酸球性肺大腸炎、疼痛等、各種がん（大腸がん、肺がん、血液がん、脳腫瘍など）、代謝性疾患（糖尿病、肥満など）等が挙げられるが、これらのみに限定されるものではない。 Diseases or conditions involving the histamine H4 receptor include, for example, various allergies, immunoinflammatory diseases (COPD, etc.), inflammatory bowel diseases, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, etc. Arthritis psoriasis, psoriasis vulgaris, asthma, dizziness, allergic rhinitis, multiple sclerosis, sepsis, atherosclerosis, transplant rejection, ear ringing, urticaria, refractory pruritus, cutaneous pruritus, sebum deficiency Atopic dermatitis, polymorphic exudative erythema, worm sting, pruritus, sinusitis, middle ear inflammation, eosinophilia, eosinophil pneumonia, eosinophil myocardium, eosinophil esophagitis, favor Various cancers (colon cancer, lung cancer, blood cancer, brain tumor, etc.), metabolic diseases (diabetes, obesity, etc.), etc. However, it is not limited to these.
　以下、本発明をその好適な実施形態に即して詳細に説明する。なお、以下の説明中、同一又は相当する要素には同一の記号を付し、重複する説明は省略する。 Hereinafter, the present invention will be described in detail according to its preferred embodiment. In the following description, the same or corresponding elements will be given the same symbol, and duplicate description will be omitted.
　１つの実施形態において、本発明は、下記式（１）で表される化合物及びその薬理学的に許容される塩を提供する。また１つの実施形態において、本発明は、下記式（１）で表される化合物及びその薬理学的に許容される塩のうちの少なくとも１種を含有する医薬組成物、好ましくは有効成分として含有する医薬組成物（免疫炎症性疾患治療剤等）を提供する。 In one embodiment, the present invention provides a compound represented by the following formula (1) and a pharmacologically acceptable salt thereof. Further, in one embodiment, the present invention contains a pharmaceutical composition containing at least one of a compound represented by the following formula (1) and a pharmacologically acceptable salt thereof, preferably as an active ingredient. To provide a pharmaceutical composition (such as a therapeutic agent for immunoinflammatory diseases).
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　式（１）中、Ｘ１は、ＣＨ又は窒素原子である。Ｘ２は、ハロゲン原子、Ｃ１～６アルキル基、ＮＨ２、ＮＨＣＨ３、Ｎ（ＣＨ３）２、ＮＯ２、ＯＨ、及びＯＣＨ３から選択されるいずれか１個の置換基で置換されていてもよいＣＨ；又は窒素原子である。また、Ｘ３及びＸ４は、それぞれ独立に、炭素原子又は窒素原子である。 In formula (1), X 1 is a CH or nitrogen atom. X 2 is a halogen atom, C 1 ~ 6 alkyl group, NH 2, NHCH 3, N (CH 3) 2, NO 2, OH, and substituted with either one substituent selected from OCH 3 It may be a CH; or a nitrogen atom. Further, X 3 and X 4 are independently carbon atoms or nitrogen atoms, respectively.
　また、式（１）中、環Ａは、窒素原子、酸素原子、及び硫黄原子から選択される少なくとも１個のヘテロ原子を含有する５員又は６員の芳香族複素環である。ここで、環Ａは、ハロゲン原子、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、及びシクロプロピル基から選択される少なくとも１個の置換基で置換されていてもよいＣ１～６アルキル基；ハロゲン原子；ＣＦ３；Ｃ２～３アルケニル基；水酸基；ＯＣＨ３；ＯＣＨＦ２；ＯＣＨ２ＣＨ３；ＣＮ；ＣＯＮＨ２；ＳＣＨ３；Ｓｉ（ＣＨ３）３；－Ｓ（Ｏ）２Ｒ９；－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ１０；フェニル基；及びピリジル基から選択される１個又は複数個の置換基で置換されていてもよく、ここで、Ｒ９及びＲ１０は、それぞれ独立に、アルキル基である。 Further, in the formula (1), the ring A is a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Here, ring A may be substituted with at least one substituent selected from a halogen atom, CH 2 OH, CH 2 F, CHF 2 , and a cyclopropyl group; a C 1-6 alkyl group; halogen. Atomic; CF 3 ; C 2-3 alkenyl group; hydroxyl group; OCH 3 ; OCHF 2 ; OCH 2 CH 3 ; CN; CONH 2 ; SCH 3 ; Si (CH 3 ) 3 ; -S (O) 2 R 9 ;- It may be substituted with one or more substituents selected from S (O) 2 N (H) R 10 ; phenyl group; and pyridyl group, where R 9 and R 10 are independent of each other. In addition, it is an alkyl group.
　前記式（１）において、Ｘ１～Ｘ４及び環Ａを含む二環の構造としては、前記式（１０１）～（１３０）のうちのいずれか１種で表される構造であることが好ましい。 In the formula (1), the structure of a secondary ring containing X 1 - X 4, and ring A, is preferably a structure represented by any one of the formulas (101) to (130) ..
　式（１）中、Ｒ１及びＲ２は、これらが結合している窒素原子と共に、さらに窒素原子、酸素原子、及び硫黄原子から選択される少なくとも１個のヘテロ原子を含有してもよい４員から９員の非芳香族複素環式基を形成している。 In formula (1), R 1 and R 2 may further contain at least one hetero atom selected from nitrogen atom, oxygen atom, and sulfur atom together with the nitrogen atom to which they are bonded4. It forms a 9-membered non-aromatic heterocyclic group.
　ここで、前記非芳香族複素環式基は、単環式、縮合二環式、架橋二環式、又はスピロ二環式の基である。前記非芳香族複素環式基としては、フッ素原子、水酸基、－ＮＲ５Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される少なくとも１個の置換基で置換されていてもよい。Ｒ５及びＲ６は、それぞれ独立に、水素原子若しくはＣ１～６アルキル基であるか、又は、Ｒ５及びＲ６が結合している窒素原子と共に４員から６員の非芳香族複素環式基を形成する。 Here, the non-aromatic heterocyclic group is a monocyclic group, a fused bicyclic group, a crosslinked bicyclic group, or a spiro bicyclic group. The non-aromatic heterocyclic group is substituted with at least one substituent selected from a fluorine atom, a hydroxyl group, an −NR 5 R 6 , a C 1 to 6 alkyl group, and a C 1 to 6 amino alkyl group. May be. R 5 and R 6 are independently hydrogen atoms or C 1 to 6 alkyl groups, or 4- to 6-membered non-aromatic heterocycles with nitrogen atoms to which R 5 and R 6 are attached. Form a formula group.
　さらに、前記非芳香族複素環式基は、少なくとも２個の窒素原子（Ｒ１及びＲ２が結合している窒素原子を含む）を含有する基であるか、又は、１個の窒素原子（すなわち、Ｒ１及びＲ２が結合している窒素原子）を含有しかつ少なくとも１個の窒素原子を含有する基で置換された基である。 Further, the non-aromatic heterocyclic group is a group containing at least two nitrogen atoms (including a nitrogen atom to which R 1 and R 2 are bonded), or one nitrogen atom (including a nitrogen atom to which R 1 and R 2 are bonded). That is, it is a group substituted with a group containing (a nitrogen atom to which R 1 and R 2 are bonded) and containing at least one nitrogen atom.
　Ｒ１及びＲ２、並びに、これらが結合している窒素原子を含む前記非芳香族複素環式基としては、４員から７員の単環式の非芳香族複素環式基、６員から９員の縮合二環式の非芳香族複素環式基、又は、７員から９員のスピロ二環式の非芳香族複素環式基であることが好ましく、アゼチジン環、ピロリジン環、ピペラジン環、ピペリジン環、ジアゼパン環、又は、前記式（ａ）～（ｈ）のうちのいずれか１種で表される基であることがより好ましい。これらの基は、上記のＲ１及びＲ２を含む非芳香族複素環式基の置換基として挙げた基で置換されていてよい。 The non-aromatic heterocyclic groups containing R 1 and R 2 and the nitrogen atom to which they are bonded include 4- to 7-membered monocyclic non-aromatic heterocyclic groups, from 6-membered groups. It is preferably a 9-membered fused bicyclic non-aromatic heterocyclic group or a 7- to 9-membered spirobicyclic non-aromatic heterocyclic group, preferably an azetidine ring, a pyrrolidine ring, or a piperazine ring. , Piperidine ring, diazepan ring, or a group represented by any one of the above formulas (a) to (h) is more preferable. These groups may be substituted with the groups listed as the substituents of the non-aromatic heterocyclic groups containing R 1 and R 2 described above.
　式（１）中、Ｒ３は、水素原子又はＣ１～６アルキル基である。Ｒ４は、フッ素原子で置換されてもよいフェニル基；－ＮＲ７Ｒ８；又はＣ１～６アルキル基である。また、ｎは、１～４のうちのいずれかの整数である。 In formula (1), R 3 is a hydrogen atom or a C 1 to 6 alkyl group. R 4 is a phenyl group optionally substituted with a fluorine atom; -NR 7 R 8 ; or a C 1-6 alkyl group. Further, n is an integer of any one of 1 to 4.
　ここで、Ｒ７及びＲ８は、それぞれ独立に、水素原子；水酸基；Ｃ１～６アルキル基；ハロゲン原子、ＣＮ、水酸基、及びＣＨ２ＯＨから選択される少なくとも１個の置換基で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子、水酸基、及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；５員から６員の芳香族複素環式基；若しくは４員から６員の非芳香族複素環式基であるか、又は、Ｒ７及びＲ８が結合している窒素原子と共に４員から６員の非芳香族含窒素複素環式基を形成する。 Here, R 7 and R 8 are independently substituted with at least one substituent selected from a hydrogen atom; a hydroxyl group; a C 1 to 6 alkyl group; a halogen atom, a CN, a hydroxyl group, and CH 2 OH. good C 3 ~ 7 cycloalkyl group optionally; halogen atom, a hydroxyl group, and at least one substituent a phenyl group which may be substituted with a group selected from CF 3; 5-membered 6-membered aromatic heterocyclic ring Formula group; or a 4- to 6-membered non-aromatic heterocyclic group, or a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group with a nitrogen atom to which R 7 and R 8 are bonded. Form a group.
　ここで、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；水酸基；ＯＣＨ３；フッ素原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていてもよい。 Here, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently substituted with at least one substituent selected from a fluorine atom; CF 3 ; a hydroxyl group; OCH 3 ; a fluorine atom and CF 3. C 3 to 7 cycloalkyl groups which may be substituted; a phenyl group which may be substituted with at least one substituent selected from a halogen atom and CF 3; and 5 members which may be substituted with a halogen atom. It may be substituted with one or more substituents selected from the 6-membered aromatic heterocyclic group.
　Ｒ７及びＲ８としては、それぞれ独立に、水素原子；Ｃ１～６アルキル基；ハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；５員から６員の芳香族複素環式基；若しくは４員から６員の非芳香族複素環式基であるか、又は、Ｒ７及びＲ８が結合している窒素原子と共に４員から６員の非芳香族含窒素複素環式基を形成していることが好ましい。この場合、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；フッ素原子で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていることが好ましい。 R 7 and R 8 are each independently selected from a hydrogen atom; a C 1 to 6 alkyl group; a C 3 to 7 cycloalkyl group optionally substituted with a halogen atom; a halogen atom and at least one selected from CF 3. number of substituent a phenyl group which may be substituted with group; 5 6-membered membered aromatic heterocyclic group; or a non-aromatic heterocyclic group having 6 membered or 4-membered, or, R 7 and It is preferable that R 8 forms a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group together with the attached nitrogen atom. In this case, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently fluorine atoms; CF 3 ; C 3 to 7 cycloalkyl groups which may be substituted with fluorine atoms; halogen atoms and CF 3 respectively. A phenyl group optionally substituted with at least one substituent selected from; and one or more selected from a 5- to 6-membered aromatic heterocyclic group optionally substituted with a halogen atom. It is preferably substituted with the number of substituents.
　また、Ｒ７及びＲ８としては、それぞれ独立に、水素原子；Ｃ１～６アルキル基；ハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基；又はハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基であることがより好ましい。この場合、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；フッ素原子で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていることが好ましい。 Further, R 7 and R 8 are independently selected from a hydrogen atom; a C 1 to 6 alkyl group; a C 3 to 7 cycloalkyl group which may be substituted with a halogen atom; or a halogen atom and CF 3. More preferably, it is a phenyl group which may be substituted with at least one substituent. In this case, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently fluorine atoms; CF 3 ; C 3 to 7 cycloalkyl groups which may be substituted with fluorine atoms; halogen atoms and CF 3 respectively. A phenyl group optionally substituted with at least one substituent selected from; and one or more selected from a 5- to 6-membered aromatic heterocyclic group optionally substituted with a halogen atom. It is preferably substituted with the number of substituents.
　本明細書中で用いる用語を以下に説明する。 The terms used in this specification will be described below.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、及びヨウ素原子を意味する。本明細書中、単に「アルキル基」という場合には、直鎖状又は分岐鎖状のアルキル基を意味し、Ｃ１～６アルキル基であることが好ましい。 "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present specification, the term "alkyl group" means a linear or branched alkyl group, and is preferably a C1 to 6 alkyl group.
　「Ｃ１～６アルキル基」とは、炭素数１～６の直鎖状又は分岐鎖状のアルキル基を意味し、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓ－ブチル基、ｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、２－メチルブチル基、２，２－ジメチルプロピル基、１－エチルプロピル基、ｎ－ヘキシル基、イソヘキシル基、４－メチルペンチル基、３－メチルペンチル基、２－メチルペンチル基、１－メチルペンチル基、３，３－ジメチルブチル基、２，２－ジメチルブチル基、１，１－ジメチルブチル基、１，２－ジメチルブチル基、１，３－ジメチルブチル基、２，３－ジメチルブチル基、１－エチルブチル基、２－エチルブチル基が挙げられ、好ましくは、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、２，２－ジメチルプロピル基、３，３－ジメチルブチル基、より好ましくは、メチル基、２，２－ジメチルプロピル基等が挙げられる。Ｃ１～６アルキル基（特に、式（１）中、Ｒ１及びＲ２を含む非芳香族複素環式基が有していてもよいＣ１～６アルキル基；Ｒ５及び／又はＲ６が示すＣ１～６アルキル基）には、重水素同位体も含む。 "C 1 to 6 alkyl groups" means linear or branched alkyl groups having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl. Group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 4-Methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1, Examples thereof include 2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group and 2-ethylbutyl group, preferably methyl group, ethyl group, n-propyl group and isopropyl. Groups, n-butyl groups, isobutyl groups, 2,2-dimethylpropyl groups, 3,3-dimethylbutyl groups, more preferably methyl groups, 2,2-dimethylpropyl groups and the like can be mentioned. C 1 to 6 alkyl groups (particularly, in formula (1), non-aromatic heterocyclic groups containing R 1 and R 2 may have C 1 to 6 alkyl groups; R 5 and / or R 6 C 1 to 6 alkyl groups) also include heavy hydrogen isotopes.
　「Ｃ２～３アルケニル基」とは、炭素数２～３の直鎖状又は分岐鎖状の炭素―炭素二重結合を１個有するアルケニル基を意味する。また、「Ｃ１～６アミノアルキル基」とは、前記Ｃ１～６アルキル基の１つの水素原子がアミノ基に置換された基を意味する。 The "C 2-3 alkenyl group" means an alkenyl group having one linear or branched carbon-carbon double bond having 2 to 3 carbon atoms. Further, the “C 1 to 6 aminoalkyl group” means a group in which one hydrogen atom of the C 1 to 6 alkyl group is substituted with an amino group.
　「Ｃ３～７シクロアルキル基」とは、炭素数３～７の飽和炭素環基を意味する。Ｃ３～７シクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロへプチル基が挙げられ、好ましくは、炭素数３～６のＣ３～６シクロアルキル基であり、より好ましくは、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。 The “C 3 to 7 cycloalkyl group” means a saturated carbocyclic group having 3 to 7 carbon atoms. Examples of the C 3 to 7 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and a C 3 to 6 cycloalkyl group having 3 to 6 carbon atoms is preferable. Yes, more preferably, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like can be mentioned.
　「芳香族複素環」とは、酸素原子、窒素原子、及び硫黄原子から選択される１個以上のヘテロ原子を含む芳香族複素環を意味し、隣接する２か所の原子を他の環と共有して結合した形態や、１個又は複数の置換基で置換された形態を含む。環Ａが示す芳香族複素環としては、１～３個の窒素原子を含有する５員の芳香族複素環であるか、２～３個の窒素原子を含有する６員の芳香族複素環であることが好ましい。 The "aromatic heterocycle" means an aromatic heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and two adjacent atoms are combined with another ring. Includes shared and bonded forms and forms substituted with one or more substituents. The aromatic heterocycle represented by ring A is a 5-membered aromatic heterocycle containing 1 to 3 nitrogen atoms or a 6-membered aromatic heterocycle containing 2 to 3 nitrogen atoms. It is preferable to have.
　「芳香族複素環式基」とは、酸素原子、窒素原子、及び硫黄原子から選択される１個以上のヘテロ原子を含む芳香族複素環の一価基を意味する。Ｒ７及び／又はＲ８が示す、又はＲ７及び／又はＲ８が示す基に含まれる５員から６員の芳香族複素環式基としては、単環式であることが好ましく、例えば、オキサゾリル基、イソオキサゾリル基、オキサジアゾリル基、チアゾリル基、イソチアゾリル基、イミダゾリル基、ピラゾリル基、トリアゾリル基、テトラゾリル基、ピリジル基、ピリミジニル基、フラニル基等が挙げられる。 The "aromatic heterocyclic group" means a monovalent group of an aromatic heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Indicated R 7 and / or R 8, or the aromatic heterocyclic group having 6 from 5 members to R 7 and / or R 8 is included in the group represented, is preferably a monocyclic, for example, Examples thereof include an oxazolyl group, an isooxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group and a furanyl group.
　「非芳香族複素環式基」とは、酸素原子、窒素原子、及び硫黄原子から選択される１個以上のヘテロ原子を含む飽和複素環の一価基を意味する。前記非芳香族複素環式基は、フッ素原子、水酸基、－ＮＲ５Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される少なくとも１個の置換基で置換されていてもよい。 The "non-aromatic heterocyclic group" means a monovalent group of a saturated heterocycle containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. Said non-aromatic heterocyclic group, a fluorine atom, a hydroxyl group, -NR 5 R 6, C 1 ~ 6 alkyl group, and C 1 ~ 6 substituted by at least one substituent selected from aminoalkyl groups You may.
　前記非芳香族複素環式基としては、単環式、縮合二環式、架橋二環式、及びスピロ二環式の基が挙げられる。Ｒ１及びＲ２が含まれる（すなわち、－Ｎ（Ｒ１）Ｒ２が含まれる）４員から９員の非芳香族複素環式基の非芳香族複素環としては、例えば、単環式では、アゼチジン環、オキセタン環、チエタン環、ピロリジン環、テトラヒドロフラン環、テトラヒドロチオフェン環、ピペリジン環、テトラヒドロピラン環、テトラヒドロチオピラン環、ピペラジン環、モルホリン環、アゼパン環、ジアゼパン環、オキセパン環、チエパン環、アゾカン環、オキソカン環、チオカン環、アゾナン環、オキソナン環、チオナン環等が挙げられるが、好ましくは、アゼチジン環、ピロリジン環、ピペリジン環、ピペラジン環、又はジアゼパン環である。 Examples of the non-aromatic heterocyclic group include monocyclic, fused bicyclic, crosslinked bicyclic, and spirobicyclic groups. Examples of the non-aromatic heterocycle of a 4- to 9-membered non-aromatic heterocyclic group containing R 1 and R 2 (ie, including −N (R 1 ) R 2) include monocyclic. Then, azetidine ring, oxetidine ring, thietan ring, pyrrolidine ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, tetrahydropyran ring, tetrahydrothiopyran ring, piperazine ring, morpholine ring, azepan ring, diazepan ring, oxepan ring, thiepan ring. , Azocan ring, oxocan ring, thiocan ring, azonan ring, oxonan ring, thionan ring and the like, preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a diazepan ring.
　Ｒ５及びＲ６が含まれる、又は、Ｒ７及びＲ８が示す４員から６員の非芳香族複素環式基の非芳香族複素環としては、例えば、アゼチジン、オキセタン、チエタン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、テトラヒドロピラン、テトラヒドロチオピラン、ピペラジン、モルホリン等が挙げられる。 Examples of the non-aromatic heterocycle of the 4- to 6-membered non-aromatic heterocyclic group containing R 5 and R 6 or indicated by R 7 and R 8 include azetidine, oxetane, thietane, pyrrolidine, and the like. Examples thereof include tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, piperazine, morpholine and the like.
　「非芳香族複素環式基」のうち、「非芳香族含窒素複素環式基」とは、窒素原子を含む飽和複素環の一価基を意味する。Ｒ７及びＲ８が含まれる（すなわち、－Ｎ（Ｒ７）Ｒ８が含まれる）４員から６員の非芳香族含窒素複素環式基の非芳香族複素環としては、例えば、アゼチジン、ピロリジン、ピペラジン等が挙げられる。 Among the "non-aromatic heterocyclic groups", the "non-aromatic nitrogen-containing heterocyclic group" means a monovalent group of a saturated heterocycle containing a nitrogen atom. Examples of the non-aromatic heterocycle of a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group containing R 7 and R 8 (ie, including −N (R 7 ) R 8) include azetidine. , Pyrrolidine, piperazine and the like.
　「縮合二環式」の基とは、環状化合物同士が隣接する２か所の原子を共有した形で結合した、２つの環を有する基を意味する。例えば、非芳香族複素環式基の縮合二環式の基の環としては、５員から９員である、ビシクロ［２．１．０］ペンタン、ビシクロ［３．１．０］ヘキサン、ビシクロ［３．２．０］ヘプタン、ビシクロ［３．３．０］オクタン、ビシクロ［４．３．０］ノナンが挙げられる。窒素原子を含むもの（縮合二環式の非芳香族含窒素複素環式基）としては、アザビシクロ［２．１．０］ペンタン、アザビシクロ［３．１．０］ヘキサン、ジアザビシクロ［３．２．０］ヘプタン、ジアザビシクロ［３．３．０］オクタン、ジアザビシクロ［４．３．０］ノナン等が挙げられる。好ましくはジアザビシクロ［３．２．０］ヘプタン、ジアザビシクロ［４．３．０］ノナンである。 The "condensation bicyclic" group means a group having two rings in which cyclic compounds are bonded to each other in a shared manner at two adjacent atoms. For example, the ring of a fused bicyclic group of a non-aromatic heterocyclic group is 5 to 9 members, bicyclo [2.1.0] pentane, bicyclo [3.1.0] hexane, bicyclo. Examples thereof include [3.2.0] heptane, bicyclo [3.3.0] octane, and bicyclo [4.3.0] nonane. Examples of those containing a nitrogen atom (condensed bicyclic non-aromatic nitrogen-containing heterocyclic group) include azabicyclo [2.1.0] pentane, azabicyclo [3.1.0] hexane, and diazabicyclo [3.2. 0] Heptan, diazabicyclo [3.3.0] octane, diazabicyclo [4.3.0] nonane and the like can be mentioned. Preferred are diazabicyclo [3.2.0] heptane and diazabicyclo [4.3.0] nonane.
　「スピロ二環式」の基とは、環状化合物同士が１か所の原子を共有した形で結合した、２つの環を有する基を意味する。例えば、非芳香族複素環式基のスピロ二環式の基の環としては、５員から９員である、スピロ［２．２］ペンタン、スピロ［２．３］ヘキサン、スピロ［２．４］ヘプタン、スピロ［３．３］ヘプタン、スピロ［３．４］オクタン、スピロ［４．４］ノナンが挙げられる。窒素原子を含むもの（スピロ二環式の非芳香族含窒素複素環式基）としては、アザスピロ［２．２］ペンタン、アザスピロ［２．３］ヘキサン、アザスピロ［２．４］ヘプタン、ジアザスピロ［３．３］ヘプタン、ジアザスピロ［３．４］オクタン、ジアザスピロ［４．４］ノナン等が挙げられ、好ましくはアザスピロ［２．４］ヘプタンである。 The "spirobicyclic" group means a group having two rings in which cyclic compounds are bonded to each other in a form in which one atom is shared. For example, the rings of the spirobicyclic group of the non-aromatic heterocyclic group are 5 to 9 members, spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4]. ] Heptan, spiro [3.3] heptane, spiro [3.4] octane, spiro [4.4] nonane. Examples of substances containing a nitrogen atom (spirobicyclic non-aromatic nitrogen-containing heterocyclic group) include azaspiro [2.2] pentane, azaspiro [2.3] hexane, azaspiro [2.4] heptane, and diazaspiro [ 3.3] Heptan, diazaspiro [3.4] octane, diazaspiro [4.4] nonane and the like can be mentioned, with preference given to azaspiro [2.4] heptane.
　「架橋二環式」の基とは、環状化合物の２か所の原子が架橋により連結された、２つの環を有する基を意味する。例えば、非芳香族複素環式基の架橋二環式の基の環としては、４員から９員である、ビシクロ［１．１．１］ペンタン、ビシクロ［２．１．１］ヘキサン、ビシクロ［２．２．１］ヘプタン、ジアザビシクロ［３．２．１］オクタン、ビシクロ［３．３．１］ノナンが挙げられる。窒素原子を含むもの（架橋二環式の非芳香族含窒素複素環式基）としては、アザビシクロ［１．１．１］ペンタン、アザビシクロ［２．１．１］ヘキサン、ジアザビシクロ［２．２．１］ヘプタン、ジアザビシクロ［３．２．１］オクタン、ジアザビシクロ［３．３．１］ノナンが挙げられる。好ましくはビシクロ［１．１．１］ペンタン、ビシクロ［２．２．１］ヘプタンである。 The "crosslinked bicyclic" group means a group having two rings in which two atoms of a cyclic compound are linked by crosslinks. For example, bridged bicyclic groups of non-aromatic heterocyclic groups include 4- to 9-membered bicyclo [1.1.1] pentane, bicyclo [2.1.1] hexane, and bicyclo. Examples thereof include [2.2.1] heptane, diazabicyclo [3.2.1] octane, and bicyclo [3.3.1] nonane. Examples of those containing a nitrogen atom (crosslinked bicyclic non-aromatic nitrogen-containing heterocyclic group) include azabicyclo [1.1.1] pentane, azabicyclo [2.1.1] hexane, and diazabicyclo [2.2. 1] Heptan, diazabicyclo [3.2.1] octane, diazabicyclo [3.3.1] nonane can be mentioned. Bicyclo [1.1.1] pentane and bicyclo [2.2.1] heptane are preferable.
　「－Ｓ（Ｏ）２Ｒ９」とは、アルキル基（Ｒ９）の１つの水素原子が二価の－Ｓ（Ｏ）２－基で置換されてなる基を意味し、「－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ１０」とは、ＮＨ２Ｒ１０の１つの水素原子が二価の－Ｓ（Ｏ）２－基で置換されてなる基を意味する。Ｒ９及びＲ１０が示すアルキル基としては、それぞれ独立に、Ｃ１～６アルキル基であることが好ましい。 "-S (O) 2 R 9 " means a group formed by substituting one hydrogen atom of an alkyl group (R 9 ) with a divalent -S (O) 2- group, and "-S (". "O) 2 N (H) R 10 " means a group formed by substituting one hydrogen atom of NH 2 R 10 with a divalent —S (O) 2-group. The alkyl groups indicated by R 9 and R 10 are preferably C 1 to 6 alkyl groups independently of each other.
　本発明において、各基が「置換されていてもよい」とは、当該基として、置換されていない基、並びに、当該基の１個又は複数の水素原子が原子又は置換基に置換されている基を含むことを意味する。置換された原子又は置換基が複数ある場合、それらは互いに同じであっても異なっていてもよい。また、置換された原子又は置換基の数としては、例えば、１～３であることが好ましい。 In the present invention, each group "may be substituted" means that the group is not substituted and one or more hydrogen atoms of the group are substituted with an atom or a substituent. Means to include a group. If there are multiple substituted atoms or substituents, they may be the same or different from each other. The number of substituted atoms or substituents is preferably, for example, 1 to 3.
　本発明において、前記式（１）で表される化合物は、遊離塩基の形態（遊離体）のほか、その薬理学的に許容される塩であってもよい。前記薬理学的に許容される塩としては、酸付加塩の形態であることが好ましく、前記酸付加塩の酸としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸などのハロゲン化水素酸塩；硫酸、硝酸、リン酸、炭酸などの無機酸塩；酢酸、トリクロロ酢酸、トリフルオロ酢酸、ヒドロキシ酢酸、乳酸、クエン酸、酒石酸、シュウ酸、安息香酸、マンデル酸、酪酸、マレイン酸、プロピオン酸、ギ酸、リンゴ酸などの有機カルボン酸塩；アスパラギン酸、グルタミン酸などの酸性アミノ酸；メタンスルホン酸などのアルキルスルホン酸；ｐ－トルエンスルホン酸などのアリールスルホン酸等が挙げられる。また、前記式（１）で表される化合物又はその薬理学的に許容される塩の範囲には、これらにそれぞれ対応する溶媒和物（例えば、水和物）も包含される。 In the present invention, the compound represented by the formula (1) may be a free base form (free form) or a pharmacologically acceptable salt thereof. The pharmacologically acceptable salt is preferably in the form of an acid addition salt, and the acid of the acid addition salt is, for example, hydrogen halide such as hydrochloric acid, hydrobromic acid, and hydroiodic acid. Acid salts; Inorganic acid salts such as sulfuric acid, nitrate, phosphoric acid, and carbonic acid; acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, Organic carboxylates such as propionic acid, formic acid and malic acid; acidic amino acids such as aspartic acid and glutamate; alkylsulfonic acids such as methanesulfonic acid; arylsulfonic acids such as p-toluenesulfonic acid and the like. In addition, the range of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof also includes solvates (for example, hydrates) corresponding thereto.
　さらに、前記式（１）で表される化合物、その薬理学的に許容される塩、及びこれらの溶媒和物は、置換基の種類に応じて、１個又は２個以上の不斉炭素を有する場合があるが、これらの１個又は２個以上の不斉炭素に基づく光学活性体、ジアステレオ異性体、幾何異性体、互変異性体、それらの任意の混合物、ラセミ体などはいずれも、前記式（１）で表される化合物及びその薬理学的に許容される塩の範囲に包含される。 Further, the compound represented by the formula (1), a pharmacologically acceptable salt thereof, and a mixture thereof have one or two or more asymmetric carbons depending on the type of the substituent. Any of these one or more asymmetric carbon-based optically active compounds, diastereoisomers, geometric isomers, tautomers, any mixture thereof, racemates, etc. may be present. , The compound represented by the above formula (1) and the pharmaceutically acceptable salt thereof are included in the range.
　また、前記式（１）で表される化合物及びその薬理学的に許容される塩の範囲には、これらに対応する放射性同位体や非放射性同位体などの同位体でラベル化された化合物及びその溶媒和物も包含される。 In addition, the range of the compound represented by the above formula (1) and its pharmacologically acceptable salt includes compounds labeled with isotopes such as radioactive isotopes and non-radioactive isotopes corresponding thereto. The solvate is also included.
　本明細書中において、上記の異性体や同位体等が存在する化合物であって、その名称において特に言及が無い場合、その化合物はこれらの異性体や同位体のうちの１種であっても、２種以上の混合物であっても、ラセミ体であってもよい。 In the present specification, a compound in which the above isomers, isotopes, etc. are present, and unless otherwise specified in the name, the compound may be one of these isomers, isotopes, etc. It may be a mixture of two or more kinds, or may be a racemate.
　以下、前記式（１）で表される化合物及びその薬理学的に許容される塩（上記の溶媒和物、異性体、同位体等を含む）から選択される少なくとも１種を、「本発明の二環化合物」と総称する。 Hereinafter, at least one selected from the compound represented by the formula (1) and a pharmacologically acceptable salt thereof (including the above solvates, isomers, isotopes, etc.) is referred to as "the present invention. Bicycle compound ".
　本発明の二環化合物の製造方法は特に制限されず、市販の入手可能な、又は当業者によって認知される方法により合成可能な、出発原料、前駆体、試薬及び溶媒などを用いて、当業者によって認知される幅広い様々な種類の合成法及び必要に応じて当該合成法に改良などを加えた方法などを組み合わせることによって製造できる。例えば、以下に示す代表的な方法により製造することができる。 The method for producing the bicyclic compound of the present invention is not particularly limited, and those skilled in the art can use starting materials, precursors, reagents, solvents, etc., which are commercially available or can be synthesized by a method recognized by those skilled in the art. It can be produced by combining a wide variety of synthetic methods recognized by the above and, if necessary, a method obtained by modifying the synthetic method. For example, it can be produced by the following typical methods.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　上記各式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｒ１、Ｒ２、Ｒ７、Ｒ８、及びｎは、それぞれ、前記式（１）中のＸ１、Ｘ２、Ｘ３、Ｘ４、Ｒ１、Ｒ２、Ｒ７、Ｒ８、及びｎと同義であり、Ｒ’は、水素原子、ハロゲン原子、ＣＦ３、置換されていてもよいＣ１～６アルキル基（ハロゲン原子、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、シクロプロピル基から選択される１個又は複数の置換基で置換されていてもよい）、Ｃ２～３アルケニル基、水酸基、ＯＣＨ３、ＯＣＨＦ２、ＯＣＨ２ＣＨ３、ＣＮ、ＣＯＮＨ２、ＳＣＨ３、Ｓｉ（ＣＨ３）３、－Ｓ（Ｏ）２Ｒ９、－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ１０、フェニル基、又はピリジル基である。Ｒ９及びＲ１０は、それぞれ、前記式（１）中のＲ９及びＲ１０と同義である。Ｙ及びＺは、それぞれ独立に脱離基である。 In each of the above formulas, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 7 , R 8 , and n are X 1 , X 2 , X 3 in the above formula (1), respectively. , X 4 , R 1 , R 2 , R 7 , R 8 , and n, where R'is a hydrogen atom, a halogen atom, CF 3 , an optionally substituted C 1-6 alkyl group (halogen). It may be substituted with one or more substituents selected from the atom, CH 2 OH, CH 2 F, CHF 2 , cyclopropyl group), C 2-3 alkenyl groups, hydroxyl groups, OCH 3 , OCHF 2 , OCH 2 CH 3 , CN, CONH 2 , SCH 3 , Si (CH 3 ) 3 , -S (O) 2 R 9 , -S (O) 2 N (H) R 10 , with phenyl or pyridyl groups be. R 9 and R 10 are synonymous with R 9 and R 10 in the above formula (1), respectively. Y and Z are independent leaving groups, respectively.
　上記方法により、例えば、前記式（１）で示される化合物のうちの前記式（１ａ）で示される化合物を、前記式（３）で示される化合物と適切なアミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 By the above method, for example, among the compounds represented by the formula (1), the compound represented by the formula (1a) is mixed with the compound represented by the formula (3) and an appropriate amine in the presence of a base as a solvent. It can be synthesized by reacting in.
　前記式（１ａ）で示される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（３）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（３）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン、及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (1a) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (3). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (3). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（１ａ）で示される化合物の合成反応における反応温度は、例えば、２０～１５０℃の範囲で選択され、好ましくは５０～１００℃の範囲である。反応時間は、例えば、２～１８時間の範囲であり、好ましくは２～６時間の範囲である。前記反応が遅い場合は、マイクロウェーブ照射下で反応を行う事も可能である。この場合の反応温度は、例えば、１００～２００℃の範囲で選択され、好ましくは１２０～１５０℃、例えば１３０～１５０℃の範囲であり、この場合の反応時間は、例えば、３０分～２０時間、好ましくは３０分～５時間の範囲であり、より好ましくは１～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (1a) is selected, for example, in the range of 20 to 150 ° C., preferably in the range of 50 to 100 ° C. The reaction time is, for example, in the range of 2 to 18 hours, preferably in the range of 2 to 6 hours. If the reaction is slow, it is possible to carry out the reaction under microwave irradiation. The reaction temperature in this case is selected, for example, in the range of 100 to 200 ° C., preferably in the range of 120 to 150 ° C., for example, 130 to 150 ° C., and the reaction time in this case is, for example, 30 minutes to 20 hours. It is preferably in the range of 30 minutes to 5 hours, and more preferably in the range of 1 to 3 hours.
　前記式（３）で示される化合物は、例えば、前記式（２）で示される化合物と適切なスルホンアミド含有アミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 The compound represented by the formula (3) can be synthesized, for example, by reacting the compound represented by the formula (2) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
　前記式（３）で示される化合物の合成反応に用いられるスルホンアミド含有アミンの量は、好ましくは、前記式（２）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（２）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン、及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (3) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (2). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (2). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（３）で示される化合物の合成反応における反応温度は、例えば、０～６０℃の範囲で選択され、好ましくは２０～４０℃の範囲である。反応時間は、例えば、３０分～１８時間、好ましくは３０分～６時間の範囲であり、より好ましくは１～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the above formula (3) is selected, for example, in the range of 0 to 60 ° C, preferably in the range of 20 to 40 ° C. The reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 1 to 3 hours.
　前記式（３）で示される中間体化合物については、その単離又は精製を必要としないが、適切なアミンの連続的な添加を必要とするように、追加のアミン（好ましくは、第３級アミン（例えば、ジイソプロピルエチルアミン、トリエチルアミン））又は前記溶媒を前記式（２）で示される化合物に適切な溶媒（例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン）の存在下に添加して、又は添加せずに、２種のアミンの添加の間に反応混合物を加熱して、又は加熱せずに、前記の変換を実施することができることは、当業者であれば認めるであろう。 The intermediate compound represented by the above formula (3) does not require isolation or purification thereof, but additional amines (preferably tertiary) are required so that appropriate continuous addition of amines is required. Amine (eg, diisopropylethylamine, triethylamine)) or the solvent is a suitable solvent for the compound represented by the formula (2) (eg, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N. -With or without addition of dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone) with or without heating of the reaction mixture between the addition of the two amines , The person skilled in the art will recognize that the above conversion can be carried out.
　前記式（２）で示される化合物は、文献で知られているか、当業者によく知られている方法により容易に調製することができる。 The compound represented by the formula (2) can be easily prepared by a method known in the literature or well known to those skilled in the art.
　本発明の二環化合物は、例えば、以下に示す方法によっても製造することができる。 The bicyclic compound of the present invention can also be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　上記各式中、Ｒ１、Ｒ２、Ｒ７、Ｒ８、及びｎは、それぞれ、前記式（１）中のＲ１、Ｒ２、Ｒ７、Ｒ８、及びｎと同義であり、Ｅｔはエチル基を示す。 In the above formulas, R 1, R 2, R 7, R 8, and n, respectively, wherein R 1 in formula (1) in, R 2, R 7, R 8, and have the same meanings as n, Et Indicates an ethyl group.
　上記方法により、例えば、前記式（１）で示される化合物のうちの前記式（１ｂ）で示される化合物を、前記式（７）で示される化合物とオルトギ酸トリエチルとを、酸存在下、溶媒中で反応させることにより合成することができる。 By the above method, for example, among the compounds represented by the formula (1), the compound represented by the formula (1b), the compound represented by the formula (7) and triethyl orthoformate are used as a solvent in the presence of an acid. It can be synthesized by reacting in.
　前記式（１ｂ）で示される化合物の合成反応に用いられるオルトギ酸トリエチルの量は、好ましくは、前記式（７）で示される化合物を基準に３～５当量の範囲である。前記反応に用いられる酸としては、例えば、酢酸が挙げられ、その量は、好ましくは、前記式（７）で示される化合物を基準に３～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、エタノール、メタノール等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of triethyl orthoformate used in the synthetic reaction of the compound represented by the formula (1b) is preferably in the range of 3 to 5 equivalents based on the compound represented by the formula (7). Examples of the acid used in the reaction include acetic acid, and the amount thereof is preferably in the range of 3 to 5 equivalents based on the compound represented by the formula (7). Examples of the solvent used in the reaction include ethanol, methanol and the like, and one of them may be used alone or in combination of two or more.
　前記式（１ｂ）で示される化合物の合成反応における反応温度は、例えば、６０～１３０℃の範囲で選択され、好ましくは８０～１１０℃の範囲である。反応時間は、例えば、１～６時間の範囲であり、好ましくは２～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (1b) is selected, for example, in the range of 60 to 130 ° C., preferably in the range of 80 to 110 ° C. The reaction time is, for example, in the range of 1 to 6 hours, preferably in the range of 2 to 3 hours.
　前記式（７）で示される化合物は、例えば、前記式（６）で示される化合物をヒドラジン一水和物と溶媒中で反応させることにより合成することができる。 The compound represented by the formula (7) can be synthesized, for example, by reacting the compound represented by the formula (6) with hydrazine monohydrate in a solvent.
　前記式（７）で示される化合物の合成反応に用いられるヒドラジン一水和物の量は、好ましくは、式（６）で示される化合物を基準に１～１．５当量の範囲である。前記反応に用いられる溶媒としては、例えば、エタノール、メタノール等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of hydrazine monohydrate used in the synthetic reaction of the compound represented by the formula (7) is preferably in the range of 1 to 1.5 equivalents based on the compound represented by the formula (6). Examples of the solvent used in the reaction include ethanol, methanol and the like, and one of them may be used alone or in combination of two or more.
　前記式（７）で示される化合物の合成反応における反応温度は、例えば、４０～１００℃の範囲で選択され、好ましくは６０～８０℃の範囲である。反応時間は、例えば、２～６時間の範囲であり、好ましくは３～５時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (7) is selected, for example, in the range of 40 to 100 ° C, preferably in the range of 60 to 80 ° C. The reaction time is, for example, in the range of 2 to 6 hours, preferably in the range of 3 to 5 hours.
　前記式（６）で示される化合物は、例えば、前記式（５）で示される化合物と適切なアミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 The compound represented by the formula (6) can be synthesized, for example, by reacting the compound represented by the formula (5) with an appropriate amine in the presence of a base in a solvent.
　前記式（６）で示される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（５）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基は、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（５）で示される化合物を基準に２～３当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン、及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (6) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (5). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 3 equivalents based on the compound represented by the formula (5). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（６）で示される化合物の合成反応における反応温度は、例えば、０～６０℃の範囲で選択され、好ましくは２０～４０℃の範囲である。反応時間は、例えば、１～１８時間の範囲であり、好ましくは２～４時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the above formula (6) is selected, for example, in the range of 0 to 60 ° C, preferably in the range of 20 to 40 ° C. The reaction time is, for example, in the range of 1 to 18 hours, preferably in the range of 2 to 4 hours.
　前記式（５）で示される化合物は、例えば、前記式（４）で示される化合物と適切なスルホンアミド含有アミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 The compound represented by the formula (5) can be synthesized, for example, by reacting the compound represented by the formula (4) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
　前記式（５）で示される化合物の合成反応に用いられるスルホンアミド含有アミンの量は、好ましくは、前記式（４）で示される化合物を基準に１～１．５当量の範囲である。前記反応に用いられる塩基は、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（４）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン、及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (5) is preferably in the range of 1 to 1.5 equivalents based on the compound represented by the formula (4). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (4). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（５）で示される化合物の合成反応における反応温度は、例えば、－２０～３０℃の範囲で選択され、好ましくは０～２０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the above formula (5) is selected, for example, in the range of −20 to 30 ° C., preferably in the range of 0 to 20 ° C. The reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（４）で示される化合物は、文献で知られているか、当業者によく知られている方法により容易に調製することができる。 The compound represented by the above formula (4) can be easily prepared by a method known in the literature or well known to those skilled in the art.
　本発明の二環化合物は、例えば、以下に示す方法によっても製造することができる。 The bicyclic compound of the present invention can also be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　上記各式中、Ｒ１、Ｒ２、Ｒ７、Ｒ８、及びｎは、それぞれ、前記式（１）中のＲ１、Ｒ２、Ｒ７、Ｒ８、及びｎと同義であり、ｔＢｕはｔ－ブチル基を示す。 In the above formulas, R 1, R 2, R 7, R 8 , and n, respectively, R 1, R 2, R 7, R 8 in the formula (1), and has the same meaning as n, t Bu represents a t-butyl group.
　上記方法により、例えば、前記式（１）で示される化合物のうちの前記式（１ｃ）で示される化合物を、前記式（１２）で示される化合物と適切なアミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 By the above method, for example, among the compounds represented by the formula (1), the compound represented by the formula (1c) is mixed with the compound represented by the formula (12) and an appropriate amine in the presence of a base as a solvent. It can be synthesized by reacting in.
　前記式（１ｃ）で示される化合物の合成反応に用いられるアミンの量は、好ましくは、式（１２）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（１２）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン、及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (1c) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (12). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (12). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（１ｃ）で示される化合物の合成反応における反応温度は、例えば、４０～１２０℃の範囲で選択され、好ましくは６０～９０℃の範囲である。反応時間は、例えば、３０分～１８時間の範囲であり、好ましくは１～３時間の範囲である。前記反応が遅い場合は、マイクロウェーブ照射下で反応を行う事も可能である。この場合の反応温度は、例えば、１００～２００℃の範囲で選択され、好ましくは１３０～１５０℃の範囲であり、この場合の反応時間は、例えば、３０分～５時間の範囲であり、好ましくは１～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (1c) is selected, for example, in the range of 40 to 120 ° C, preferably in the range of 60 to 90 ° C. The reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 1 to 3 hours. If the reaction is slow, it is possible to carry out the reaction under microwave irradiation. The reaction temperature in this case is selected, for example, in the range of 100 to 200 ° C., preferably in the range of 130 to 150 ° C., and the reaction time in this case is, for example, in the range of 30 minutes to 5 hours, preferably in the range of 30 minutes to 5 hours. Is in the range of 1 to 3 hours.
　前記式（１２）で示される化合物は、例えば、前記式（１１）で示される化合物をメタクロロ過安息香酸と溶媒中で反応させることにより合成することができる。 The compound represented by the formula (12) can be synthesized, for example, by reacting the compound represented by the formula (11) with metachloroperbenzoic acid in a solvent.
　前記式（１２）で示される化合物の合成反応に用いられるメタクロロ過安息香酸の量は、好ましくは、前記式（１１）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、クロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of meta-chloroperbenzoic acid used in the synthetic reaction of the compound represented by the formula (12) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (11). Examples of the solvent used in the reaction include tetrahydrofuran, chloroform and the like, and one of them may be used alone or in combination of two or more.
　前記式（１２）で示される化合物の合成反応における反応温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは０～３０℃の範囲である。反応時間は、例えば、２～６時間の範囲であり、好ましくは３～４時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (12) is selected, for example, in the range of −20 to 50 ° C., preferably in the range of 0 to 30 ° C. The reaction time is, for example, in the range of 2 to 6 hours, preferably in the range of 3 to 4 hours.
　前記式（１１）で示される化合物は、例えば、前記式（１０）で示される化合物と適切なスルホンアミド含有アミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 The compound represented by the formula (11) can be synthesized, for example, by reacting the compound represented by the formula (10) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
　前記式（１１）で示される化合物の合成反応に用いられるスルホンアミド含有アミンの量は、好ましくは、前記式（１０）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（１０）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、メタノール、エタノール、２－プロパノール、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (11) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (10). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (10). Examples of the solvent used in the reaction include methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-. Examples thereof include 2-pyrrolidone and chloroform, and one of them may be used alone or in combination of two or more.
　前記式（１１）で示される化合物の合成反応における反応温度は、例えば、０～１００℃、好ましくは０～６０℃の範囲で選択され、より好ましくは２０～４０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The reaction temperature in the synthesis reaction of the compound represented by the formula (11) is selected, for example, in the range of 0 to 100 ° C., preferably 0 to 60 ° C., and more preferably in the range of 20 to 40 ° C. The reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（１０）で示される化合物は、例えば、前記式（９）で示される化合物を亜硝酸　ｔｅｒｔ－ブチルと反応させることにより合成することができる。 The compound represented by the formula (10) can be synthesized, for example, by reacting the compound represented by the formula (9) with tert-butyl nitrite.
　前記式（１０）で示される化合物の合成反応に用いられる亜硝酸　ｔｅｒｔ－ブチルの量は、好ましくは、前記式（９）で示される化合物を基準に２～４当量の範囲である。前記反応に用いられる溶媒としては、アセトニトリルが挙げられる。 The amount of tert-butyl nitrite used in the synthesis reaction of the compound represented by the formula (10) is preferably in the range of 2 to 4 equivalents based on the compound represented by the formula (9). Examples of the solvent used in the reaction include acetonitrile.
　前記式（１０）で示される化合物の合成反応における反応温度は、例えば、４０～１００℃の範囲で選択され、好ましくは６０～８０℃の範囲である。反応時間は、例えば、１～６時間の範囲であり、好ましくは２～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (10) is selected, for example, in the range of 40 to 100 ° C, preferably in the range of 60 to 80 ° C. The reaction time is, for example, in the range of 1 to 6 hours, preferably in the range of 2 to 3 hours.
　前記式（９）で示される化合物は、例えば、前記式（８）で示される化合物を塩化すず（ＩＩ）二水和物と反応させることにより合成することができる。 The compound represented by the formula (9) can be synthesized, for example, by reacting the compound represented by the formula (8) with tin (II) chloride dihydrate.
　前記式（９）で示される化合物の合成反応に用いられる塩化すず（ＩＩ）二水和物の量は、好ましくは前記式（８）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、エタノール、メタノール等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of tin (II) chloride dihydrate used in the synthetic reaction of the compound represented by the formula (9) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (8). .. Examples of the solvent used in the reaction include ethanol, methanol and the like, and one of them may be used alone or in combination of two or more.
　前記式（９）で示される化合物の合成反応における反応温度は、例えば、４０～１００℃の範囲で選択され、好ましくは６０～８０℃の範囲である。反応時間は、例えば、１～６時間の範囲であり、好ましくは２～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (9) is selected, for example, in the range of 40 to 100 ° C, preferably in the range of 60 to 80 ° C. The reaction time is, for example, in the range of 1 to 6 hours, preferably in the range of 2 to 3 hours.
　前記式（８）で示される化合物は、文献で知られているか、当業者によく知られている方法により容易に調製することができる。 The compound represented by the formula (8) can be easily prepared by a method known in the literature or well known to those skilled in the art.
　本発明の二環化合物は、例えば、以下に示す方法によっても製造することができる。 The bicyclic compound of the present invention can also be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　上記各式中、Ｒ１、Ｒ２、Ｒ７、Ｒ８、及びｎは、それぞれ、前記式（１）中のＲ１、Ｒ２、Ｒ７、Ｒ８、及びｎと同義である。 In the above formulas, R 1, R 2, R 7, R 8, and n, respectively, R 1, R 2 in the formula (1), R 7, R 8, and is synonymous with n.
　上記方法により、例えば、前記式（１）で示される化合物のうちの前記式（１ｄ）で示される化合物を、前記式（１９）で示される化合物とピリジン臭化水素酸塩とを溶媒中で反応させることにより合成することができる。 By the above method, for example, among the compounds represented by the formula (1), the compound represented by the formula (1d) is mixed with the compound represented by the formula (19) and pyridine hydrobromide in a solvent. It can be synthesized by reacting.
　前記式（１ｄ）で示される化合物の合成反応に用いられるピリジン臭化水素酸塩の量は、好ましくは、前記式（１９）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、メタノール／水、エタノール／水、２－プロパノール／水等が挙げられる。 The amount of pyridine hydrobromide used in the synthesis reaction of the compound represented by the formula (1d) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (19). Examples of the solvent used in the reaction include methanol / water, ethanol / water, 2-propanol / water and the like.
　前記式（１ｄ）で示される化合物の合成反応における反応温度は、例えば、０～６０℃の範囲で選択され、好ましくは２０～４０℃の範囲である。反応時間は、例えば、１～５時間の範囲であり、好ましくは２～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (1d) is selected, for example, in the range of 0 to 60 ° C, preferably in the range of 20 to 40 ° C. The reaction time is, for example, in the range of 1 to 5 hours, preferably in the range of 2 to 3 hours.
　前記式（１９）で示される化合物は、例えば、前記式（１８）で示される化合物をグリオキサール水溶液と溶媒中で反応させることにより合成することができる。 The compound represented by the formula (19) can be synthesized, for example, by reacting the compound represented by the formula (18) with an aqueous glyoxal solution in a solvent.
　前記式（１９）で示される化合物の合成反応に用いられるグリオキサール水溶液の量は、好ましくは、前記式（１８）で示される化合物を基準に４～１０当量の範囲である。前記反応に用いられる溶媒としては、例えば、エタノール、水等が挙げられる。 The amount of the glyoxal aqueous solution used in the synthesis reaction of the compound represented by the formula (19) is preferably in the range of 4 to 10 equivalents based on the compound represented by the formula (18). Examples of the solvent used in the reaction include ethanol, water and the like.
　前記式（１９）で示される化合物の合成反応における反応温度は、例えば、５０～１５０℃の範囲で選択され、好ましくは７０～１００℃の範囲である。反応時間は、例えば、１～５時間の範囲であり、好ましくは２～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (19) is selected, for example, in the range of 50 to 150 ° C, preferably in the range of 70 to 100 ° C. The reaction time is, for example, in the range of 1 to 5 hours, preferably in the range of 2 to 3 hours.
　前記式（１８）で示される化合物は、例えば、前記式（１７）で示される化合物を亜鉛存在下、溶媒中で、塩基アンモニウム水溶液と反応させることにより合成することができる。 The compound represented by the formula (18) can be synthesized, for example, by reacting the compound represented by the formula (17) with an aqueous solution of basic ammonium in a solvent in the presence of zinc.
　前記式（１８）で示される化合物の合成反応に用いられる亜鉛の量は、好ましくは、前記式（１７）で示される化合物を基準に４～１０当量の範囲である。前記反応に用いられる溶媒としては、例えば、メタノール、エタノール、２－プロパノール等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of zinc used in the synthetic reaction of the compound represented by the formula (18) is preferably in the range of 4 to 10 equivalents based on the compound represented by the formula (17). Examples of the solvent used in the reaction include methanol, ethanol, 2-propanol and the like, and one of them may be used alone or in combination of two or more.
　前記式（１８）で示される化合物の合成反応における反応温度は、例えば、５０～１１０℃の範囲で選択され、好ましくは７０～９０℃の範囲である。反応時間は、例えば、３～９時間の範囲であり、好ましくは４～５時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (18) is selected, for example, in the range of 50 to 110 ° C, preferably in the range of 70 to 90 ° C. The reaction time is, for example, in the range of 3 to 9 hours, preferably in the range of 4 to 5 hours.
　前記式（１７）で示される化合物は、例えば、前記式（１６）で示される化合物と適切なアミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 The compound represented by the formula (17) can be synthesized, for example, by reacting the compound represented by the formula (16) with an appropriate amine in the presence of a base in a solvent.
　前記式（１７）で示される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（１６）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（１６）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (17) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (16). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (16). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（１７）で示される化合物の合成反応における反応温度は、例えば、２０～１２０℃、好ましくは４０～１２０℃の範囲で選択され、より好ましくは４０～９０℃、さらに好ましくは６０～９０℃の範囲である。反応時間は、例えば、３０分～１８時間の範囲であり、好ましくは１～３時間の範囲である。 The reaction temperature in the synthesis reaction of the compound represented by the formula (17) is selected, for example, in the range of 20 to 120 ° C., preferably 40 to 120 ° C., more preferably 40 to 90 ° C., still more preferably 60 to 90 ° C. It is in the range of ° C. The reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 1 to 3 hours.
　前記式（１６）で示される化合物は、例えば、式（１５）で示される化合物をメタクロロ過安息香酸と溶媒中で反応させることにより合成することができる。 The compound represented by the formula (16) can be synthesized, for example, by reacting the compound represented by the formula (15) with metachloroperbenzoic acid in a solvent.
　前記式（１６）で示される化合物の合成反応に用いられるメタクロロ安息香酸の量は、好ましくは、前記式（１５）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、クロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of metachlorobenzoic acid used in the synthetic reaction of the compound represented by the formula (16) is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (15). Examples of the solvent used in the reaction include tetrahydrofuran, chloroform and the like, and one of them may be used alone or in combination of two or more.
　前記式（１６）で示される化合物の合成反応における反応温度は、例えば、０～５０℃の範囲で選択され、好ましくは１５～３５℃の範囲である。反応時間は、例えば、２～６時間の範囲であり、好ましくは３～５時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (16) is selected, for example, in the range of 0 to 50 ° C, preferably in the range of 15 to 35 ° C. The reaction time is, for example, in the range of 2 to 6 hours, preferably in the range of 3 to 5 hours.
　前記式（１５）で示される化合物は、例えば、前記式（１４）で示される化合物と適切なスルホンアミド含有アミンとを、塩基存在下、溶媒中で反応させることにより合成することができる。 The compound represented by the formula (15) can be synthesized, for example, by reacting the compound represented by the formula (14) with an appropriate sulfonamide-containing amine in the presence of a base in a solvent.
　前記式（１５）で示される化合物の合成反応に用いられるスルホンアミド含有アミンの量は、好ましくは、前記式（１４）で示される化合物を基準に１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（１４）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン、及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of the sulfonamide-containing amine used in the synthesis reaction of the compound represented by the formula (15) is preferably in the range of 1 to 3 equivalents based on the compound represented by the formula (14). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the formula (14). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（１５）で示される化合物の合成反応における反応温度は、例えば、０～５０℃の範囲で選択され、好ましくは２０～４０℃の範囲である。反応時間は、例えば、３０分～１８時間、好ましくは３０分～６時間の範囲であり、より好ましくは１～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (15) is selected, for example, in the range of 0 to 50 ° C, preferably in the range of 20 to 40 ° C. The reaction time is, for example, in the range of 30 minutes to 18 hours, preferably in the range of 30 minutes to 6 hours, and more preferably in the range of 1 to 3 hours.
　前記式（１４）で示される化合物は、例えば、前記式（１３）で示される化合物を塩基存在下、溶媒中でアンモニア水溶液と反応させることにより合成することができる。 The compound represented by the formula (14) can be synthesized, for example, by reacting the compound represented by the formula (13) with an aqueous ammonia solution in a solvent in the presence of a base.
　前記式（１４）で示される化合物の合成反応に用いられるアンモニア水溶液の量は、好ましくは、前記式（１３）で示される化合物を基準に１～１．５当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（１３）で示される化合物を基準に２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン及びクロロホルム等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of the aqueous ammonia solution used in the synthesis reaction of the compound represented by the formula (14) is preferably in the range of 1 to 1.5 equivalents based on the compound represented by the formula (13). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents based on the compound represented by the above formula (13). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, chloroform and the like. One of these may be used alone or in combination of two or more.
　前記式（１４）で示される化合物の合成反応における反応温度は、例えば、０～５０℃の範囲で選択され、好ましくは１５～３５℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The reaction temperature in the synthetic reaction of the compound represented by the formula (14) is selected, for example, in the range of 0 to 50 ° C, preferably in the range of 15 to 35 ° C. The reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（１３）で示される化合物は、文献で知られているか、当業者によく知られている方法により容易に調製することができる。 The compound represented by the formula (13) can be easily prepared by a method known in the literature or well known to those skilled in the art.
　当業者であれば、前記式（１）で表される化合物を合成する任意の段階で、分子中の１個又は複数の不安定な基を保護基で保護して、望ましくない副反応を防ぐことが必要であるか、望ましいことを認めるであろう。特に、アミノ基を保護することが必要であるか、望ましい。前記式（１）で表される化合物を合成する際に使用される保護基としては、例えば、Ｇｒｅｅｎｅ　Ｗｕｔｓ著，ＰＲＯＴＥＣＴＩＶＥ　ＧＲＯＵＰＳ　ｉｎ　ＯＲＧＡＮＩＣ　ＳＹＮＴＨＥＳＩＳ　ＴＨＩＲＤ　ＥＤＩＴＩＯＮ，Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，Ｉｎｃ．などに記載される基（そのような基を脱離するための方法も記載されている）を挙げることができる。 Those skilled in the art will protect one or more unstable groups in the molecule with protecting groups at any step in synthesizing the compound of formula (1) to prevent unwanted side reactions. Will admit that it is necessary or desirable. In particular, it is necessary or desirable to protect the amino group. Examples of the protecting group used when synthesizing the compound represented by the formula (1) include Greene Wuts, PROTECIVE GROUPs in ORGANIC SYNTHESIS THIRD EDITION, John Wiley & Sons, Inc. Etc. (the methods for desorbing such groups are also described).
　本発明の二環化合物は、ヒスタミンＨ４受容体（以下、場合により、単に「Ｈ４受容体」ともいう）に対する親和性を有するため、ヒスタミンＨ４受容体活性の調節作用を有する。そのため、本発明の二環化合物は、そのまま、又はこれを含有する医薬組成物として、Ｈ４受容体の調節用、より具体的には、Ｈ４受容体が関与する疾患若しくは状態の治療及び／又は予防のために使用することができる。 Since the bicyclic compound of the present invention has an affinity for the histamine H4 receptor (hereinafter, also simply referred to as "H4 receptor" in some cases), it has an action of regulating histamine H4 receptor activity. Therefore, the bicyclic compound of the present invention can be used as it is, or as a pharmaceutical composition containing the same, for the regulation of the H4 receptor, more specifically, for the treatment and / or prevention of a disease or condition involving the H4 receptor. Can be used for.
　Ｈ４受容体が関与する疾患若しくは状態としては、例えば、各種アレルギー、免疫炎症性疾患（ＣＯＰＤなど）、炎症性腸疾患、リウマチ、アトピー性皮膚炎、掻痒性皮膚炎、アレルギー性結膜炎、鼻炎、関節症性乾癬、尋常性乾癬、喘息、めまい、アレルギー性鼻炎、多発性硬化症、敗血症、アテローム性動脈硬化症、移植片拒絶、耳鳴り、蕁麻疹、難治性掻痒、皮膚そう痒症、皮脂欠乏性皮膚炎、多形滲出性紅斑、虫刺症、痒疹、副鼻腔炎、中耳炎、好酸球増多症、好酸球性肺炎、好酸球性心筋症、好酸球性食道炎、好酸球性胃炎、好酸球性腸炎、好酸球性肺大腸炎、疼痛等、各種がん（大腸がん、肺がん、血液がん、脳腫瘍など）、代謝性疾患（糖尿病、肥満など）等が挙げられるが、これらのみに限定されるものではない。 Diseases or conditions involving H4 receptors include, for example, various allergies, immunoinflammatory diseases (COPD, etc.), inflammatory bowel diseases, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, joints. Symptomatic psoriasis, psoriasis vulgaris, asthma, dizziness, allergic rhinitis, multiple sclerosis, sepsis, atherosclerosis, transplant rejection, ear ringing, urticaria, refractory pruritus, dermatitis, sebum deficiency Dermatitis, polymorphic exudative erythema, worm sting, pruritus, sinusitis, middle ear inflammation, eosinophilia, eosinophil pneumonia, eosinophil cardiomyopathy, eosinophil esophagitis, eosinophils Various cancers (colon cancer, lung cancer, blood cancer, brain tumor, etc.), metabolic diseases (diabetes, obesity, etc.), etc. However, it is not limited to these.
　本発明において、「Ｈ４受容体活性の調節作用」には、Ｈ４受容体に関連する活性のアンタゴニスト作用、アゴニスト作用、部分アンタゴニスト作用、インバースアゴニスト作用及び／又は部分アゴニスト作用を包含する。好ましくは、アンタゴニスト作用又はインバースアゴニスト作用である。Ｈ４受容体の機能を調節する化合物の能力は、該化合物とＨ４受容体との間の結合アッセイ、シグナル伝達アッセイ、及び／又は細胞応答アッセイにより確認することができる。 In the present invention, the "regulatory action of H4 receptor activity" includes an antagonist action, an agonist action, a partial antagonist action, an inverse agonist action and / or a partial agonist action of the activity related to the H4 receptor. Preferably, it is an antagonist action or an inverse agonist action. The ability of a compound to regulate H4 receptor function can be confirmed by binding assay, signaling assay, and / or cell response assay between the compound and H4 receptor.
　本発明の医薬組成物は、本発明の二環化合物を有効成分として含有する。本発明の医薬組成物は、経口又は非経口のいずれの投与経路で対象に投与してもよく、前記対象としては、ヒト又はヒト以外の動物が挙げられる。 The pharmaceutical composition of the present invention contains the bicyclic compound of the present invention as an active ingredient. The pharmaceutical composition of the present invention may be administered to a subject by either an oral or parenteral route of administration, and the subject includes humans or animals other than humans.
　本発明の医薬組成物は、前記投与経路に応じて適当な剤型の製剤とすることができる。前記製剤の剤型の例としては、具体的には、錠剤、丸剤、カプセル剤、顆粒剤、散剤、エリキシル剤、懸濁剤、乳剤、及びシロップ剤などの経口剤、並びに、注射剤、吸入剤、直腸投与剤、坐剤、ローション剤、スプレー剤、軟膏剤、クリーム剤、貼付剤、及び徐放製剤などの非経口剤が挙げられる。これらの各種製剤は、必要に応じて、薬学の分野において通常用いられている賦形剤、崩壊剤、結合剤、滑沢剤、着色剤などの薬理学的に許容される添加剤や担体を用い、常法により製造することができる。そのため、本発明の医薬組成物としては、これら薬理学的に許容される添加剤及び／又は担体をさらに含有していてよい。 The pharmaceutical composition of the present invention can be prepared into an appropriate dosage form according to the administration route. Specific examples of the dosage form of the above-mentioned preparation include oral preparations such as tablets, suppositories, capsules, granules, powders, elixirs, suspensions, emulsions, and syrups, and injections. Examples thereof include parenteral preparations such as inhalants, rectal administrations, suppositories, lotions, sprays, ointments, creams, patches, and sustained-release preparations. These various formulations contain, as required, pharmacologically acceptable additives and carriers such as excipients, disintegrants, binders, lubricants and colorants commonly used in the field of pharmacy. It can be used and manufactured by a conventional method. Therefore, the pharmaceutical composition of the present invention may further contain these pharmacologically acceptable additives and / or carriers.
　本発明の医薬組成物において、本発明の二環化合物の含有量（本発明の二環化合物が２種以上の組み合わせである場合にはそれらの合計含有量）は、その投与目的や製剤の剤型などに応じて適宜調整するものであるため一概にはいえないが、通常、前記式（１）で表される化合物の遊離体換算で、医薬組成物の全質量を基準として０．０１～７０質量％、好ましくは０．０５～５０質量％である。 In the pharmaceutical composition of the present invention, the content of the bicyclic compound of the present invention (when the bicyclic compound of the present invention is a combination of two or more kinds, the total content thereof) is determined by the purpose of administration and the preparation of the preparation. Although it cannot be said unconditionally because it is appropriately adjusted according to the type and the like, it is usually 0.01 to 0.01 to the total mass of the pharmaceutical composition in terms of the free form of the compound represented by the above formula (1). It is 70% by mass, preferably 0.05 to 50% by mass.
　本発明の二環化合物の投与量（本発明の二環化合物が２種以上の組み合わせである場合にはそれらの合計投与量）は、患者の年齢、体重、性別、疾患の相違、症状の程度などを考慮して、個々の場合に応じて適宜決定されるものであるため一概にはいえないが、通常、前記式（１）で表される化合物の遊離体換算で、成人１日当り、０．０１～１０００ｍｇ、好ましくは０．１～３００ｍｇであり、これを１日１回又は数回に分けて投与することができる。 The dose of the dicyclic compound of the present invention (or the total dose of the bicyclic compound of the present invention when two or more kinds are combined) is the age, weight, sex, difference in disease, and degree of symptoms of the patient. It cannot be said unconditionally because it is appropriately determined according to each individual case in consideration of the above, but usually, it is 0 per day for an adult in terms of the free form of the compound represented by the above formula (1). It is 0.01 to 1000 mg, preferably 0.1 to 300 mg, and this can be administered once a day or in several divided doses.
　以下、本発明について、実施例を用いてより詳しく説明するが、本発明はこれら実施例に限定されるものではない。また、実施例で使用する原料化合物の製造法を参考例として説明するが、これらも本発明の実施について具体的に説明するための例示であって、当該例示によって本発明の範囲が制限されるものではなく、本発明の範囲を逸脱しない範囲で種々の応用、変形及び修正などが可能であることは自明のことである。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Further, the method for producing the raw material compound used in the examples will be described as a reference example, but these are also examples for specifically explaining the practice of the present invention, and the scope of the present invention is limited by the examples. It is self-evident that various applications, modifications and modifications can be made without departing from the scope of the present invention.
　以下、実施例及び参考例における略語は、下記の意味である。 Hereinafter, the abbreviations in the examples and reference examples have the following meanings.
　　Ｍ：ｍｏｌ／Ｌ
　　ＴＨＦ：テトラヒドロフラン
　　ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
　　ｔｅｒｔ：ターシャリー
　　ＬＣ－ＭＳ：液体クロマトグラフ質量分析
　　ＨＰＬＣ：高速液体クロマトグラフィー
　　ＤＩＰＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン。 M: mol / L
THF: tetrahydrofuran DMF: N, N-dimethylformamide tert: tertiary LC-MS: liquid chromatograph mass spectrometry HPLC: high performance liquid chromatography DIPEA: N, N-diisopropylethylamine.
　（参考例１）
２－アミノ－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）２－フタルイミドエタンスルホニルクロリド（４００ｍｇ）にクロロホルム（７．３ｍＬ）とＤＩＰＥＡ（１．３ｍＬ）を加えた後に、イソプロピルアミン（１７９μＬ）を加え室温で２時間攪拌した。ＬＣＭＳで目的物が生成したことを確認した後に、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。減圧下で溶媒を留去し、得られた残留物にエタノール（１０．０ｍＬ）とヒドラジン一水和物（１．０ｍＬ）を加え、還流下で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、０℃で１５分攪拌した。析出した固体をろ過し母液にエタノール（１０．０ｍＬ）を加え、０℃で１５分攪拌した。析出した固体を再びろ過し、減圧下で溶媒を留去し表題の化合物（１８６ｍｇ）を得た。 (Reference example 1)
After adding chloroform (7.3 mL) and DIPEA (1.3 mL) to 2-amino-N- (propane-2-yl) ethane-1-sulfonamide (a) 2-phthalimide ethanesulfonyl chloride (400 mg), Isopropylamine (179 μL) was added and the mixture was stirred at room temperature for 2 hours. After confirming that the desired product was produced by LCMS, an aqueous ammonium chloride solution was added and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, ethanol (10.0 mL) and hydrazine monohydrate (1.0 mL) were added to the obtained residue, and the mixture was stirred under reflux for 2 hours. After confirming that the raw material had disappeared by LCMS, the mixture was stirred at 0 ° C. for 15 minutes. The precipitated solid was filtered, ethanol (10.0 mL) was added to the mother liquor, and the mixture was stirred at 0 ° C. for 15 minutes. The precipitated solid was filtered again and the solvent was evaporated under reduced pressure to give the title compound (186 mg).
　（参考例２）
２－アミノ－Ｎ－シクロヘキシルエタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにシクロヘキシルアミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 2)
2-Amino-N-cyclohexylethane-1-sulfonamide (a) The title compound was obtained in the same manner as in Reference Example 1 except that cyclohexylamine was used instead of isopropylamine.
　（参考例３）
２－アミノ－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにシクロペンチルアミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 3)
2-Amino-N-cyclopentylethane-1-sulfonamide (a) The title compound was obtained in the same manner as in Reference Example 1 except that cyclopentylamine was used instead of isopropylamine.
　（参考例４）
２－アミノ－Ｎ－［（４－フルオロフェニル）メチル］エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに４－フルオロベンジルアミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 4)
2-Amino-N-[(4-fluorophenyl) methyl] ethane-1-sulfonamide (a) The title is the same as in Reference Example 1 except that 4-fluorobenzylamine was used instead of isopropylamine. The compound was obtained.
　（参考例５）
２－アミノ－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにイソブチルアミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 5)
The title compound was obtained in the same manner as in Reference Example 1 except that isobutylamine was used instead of 2-amino-N- (2-methylpropyl) ethane-1-sulfonamide (a) isopropylamine.
　（参考例６）
２－アミノ－Ｎ－シクロブチルエタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにアミノシクロブタンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 6)
2-Amino-N-cyclobutylethane-1-sulfonamide (a) The title compound was obtained in the same manner as in Reference Example 1 except that aminocyclobutane was used instead of isopropylamine.
　（参考例７）
２－アミノ－Ｎ－（３，３－ジフルオロシクロブチル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに３，３－ジフルオロシクロブタン－１－アミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 7)
2-Amino-N- (3,3-difluorocyclobutyl) ethane-1-sulfonamide (a) Same as Reference Example 1 except that 3,3-difluorocyclobutane-1-amine was used instead of isopropylamine. The title compound was obtained by the method of.
　（参考例８）
２－アミノ－Ｎ－［（３，３－ジフルオロシクロブチル）メチル］エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに（３，３－ジフルオロシクロブチル）メタンアミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 8)
Reference example except that (3,3-difluorocyclobutyl) methaneamine was used instead of 2-amino-N-[(3,3-difluorocyclobutyl) methyl] ethane-1-sulfonamide (a) isopropylamine. The title compound was obtained in the same manner as in 1.
　（参考例９）
２－アミノ－Ｎ－（２，２－ジフルオロプロピル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに２，２－ジフルオロプロパン－１－アミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 9)
2-Amino-N- (2,2-difluoropropyl) ethane-1-sulfonamide (a) Same as Reference Example 1 except that 2,2-difluoropropane-1-amine was used instead of isopropylamine. The title compound was obtained by the procedure.
　（参考例１０）
２－アミノ－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにオキソラン－３－アミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 10)
2-Amino-N- (oxolan-3-yl) ethane-1-sulfonamide (a) The title compound was prepared in the same manner as in Reference Example 1 except that oxolan-3-amine was used instead of isopropylamine. Obtained.
　（参考例１１）
２－アミノ－Ｎ－（２－メトキシエチル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに２－メトキシエタン－１－アミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 11)
2-Amino-N- (2-Methoxyethyl) ethane-1-sulfonamide (a) The title is the same as in Reference Example 1 except that 2-methoxyethane-1-amine was used instead of isopropylamine. The compound was obtained.
　（参考例１２）
２－アミノ－Ｎ－［１－（ヒドロキシメチル）シクロペンチル］エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに（１－アミノシクロペンチル）メタノールを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 12)
2-Amino-N- [1- (hydroxymethyl) cyclopentyl] Ethane-1-sulfonamide (a) In the same manner as in Reference Example 1 except that (1-aminocyclopentyl) methanol was used instead of isopropylamine. The title compound was obtained.
　（参考例１３）
２－（モルホリン－４－スルホニル）エタン－１－アミン
（ａ）イソプロピルアミンの代わりにモルホリンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 13)
2- (Morpholine-4-sulfonyl) ethane-1-amine (a) The title compound was obtained in the same manner as in Reference Example 1 except that morpholine was used instead of isopropylamine.
　（参考例１４）
２－アミノ－Ｎ－（４－フルオロフェニル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに４－フルオロアニリンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 14)
The title compound was obtained in the same manner as in Reference Example 1 except that 4-fluoroaniline was used instead of 2-amino-N- (4-fluorophenyl) ethane-1-sulfonamide (a) isopropylamine. ..
　（参考例１５）
２－アミノ－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにＮ－メチルアニリンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 15)
The title compound was obtained in the same manner as in Reference Example 1 except that N-methylaniline was used instead of 2-amino-N-methyl-N-phenylethane-1-sulfonamide (a) isopropylamine.
　（参考例１６）
２－アミノ－Ｎ－（ピリジン－２－イル）エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにピリジン－２－アミンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 16)
2-Amino-N- (pyridin-2-yl) ethane-1-sulfonamide (a) The title compound was prepared in the same manner as in Reference Example 1 except that pyridine-2-amine was used instead of isopropylamine. Obtained.
　（参考例１７）
２－アミノ－Ｎ－［４－（トリフルオロメチル）フェニル］エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりに４－（トリフルオロメチル）アニリンを用いた以外は、参考例１と同様の手法で表題の化合物を得た。 (Reference example 17)
2-Amino-N- [4- (trifluoromethyl) phenyl] ethane-1-sulfonamide (a) Same as Reference Example 1 except that 4- (trifluoromethyl) aniline was used instead of isopropylamine. The title compound was obtained by the procedure.
　上記各参考例にて製造した化合物を下記表１～２に示す。また、下記表１～２には、各化合物のＥＳＩ－ＭＳによる分析結果も示す。 The compounds produced in each of the above reference examples are shown in Tables 1 and 2 below. Tables 1 and 2 below also show the results of analysis of each compound by ESI-MS.
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
　（実施例１）
２－（｛１－メチル－５－［３－（メチルアミノ）アゼチジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）５，７－ジクロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン（３００ｍｇ）とＤＩＰＥＡ（９２０μＬ）をアセトニトリル／水＝１０／１（３．３ｍＬ）に溶解した後、タウリン（２２０ｍｇ）を加えマイクロウェーブ反応装置を用いて１３０℃で３０分反応させた。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をジクロロメタン（６．０ｍＬ）に溶解し、０℃でオキサリルクロリド（３８０μＬ）とＤＭＦ（６０．０μＬ）を加え、５分攪拌した後に、室温で３時間攪拌した。減圧下で溶媒を留去し、得られた残留物をアセトニトリル（６．０ｍＬ）に溶解し、０℃でイソプロピルアミン（１９０μＬ）とＤＩＰＥＡ（６４０μＬ）を加え、０℃で５分攪拌した後に、室温で３０分攪拌した。ＴＬＣで原料の消失を確認した後水を加えジクロロメタンで抽出した。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（５－クロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル）アミノ］－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（１６０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（５０．０ｍｇ）とＤＩＰＥＡ（２６．０μＬ）をイソプロパノール（５．０ｍＬ）に溶解した後、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（８０．０ｍｇ）を加えマイクロウェーブ反応装置を用いて１００℃で２０時間反応させた。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ジクロロメタン：メタノール）で精製し、ｔｅｒｔ－ブチル　メチル｛１－［１－メチル－７－（｛２－［（プロパン－２－イル）スルファモイル］エチル｝アミノ）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－５－イル］アゼチジン－３－イル｝カーバメート（３０．０ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（６０．０ｍｇ）をジクロロメタン（２．０ｍＬ）に溶解し、トリフルオロ酢酸（１８０μＬ）を加え室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、炭酸水素ナトリウム水溶液を加え、ジクロロメタン／メタノール＝１０／１で抽出した。減圧下で溶媒を留去し、表題の化合物（４０．０ｍｇ）を得た。 (Example 1)
2-({1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N- (propane-2-) Il) Ethane-1-sulfonamide (a) 5,7-dichloro-1-methyl-1H-pyrazolo [4,3-d] pyrimidine (300 mg) and DIPEA (920 μL) acetonitrile / water = 10/1 (3) After dissolving in (3 mL), taurine (220 mg) was added and reacted at 130 ° C. for 30 minutes using a microwave reactor. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (6.0 mL), oxalyl chloride (380 μL) and DMF (60.0 μL) were added at 0 ° C., and the mixture was stirred for 5 minutes and then at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the obtained residue was dissolved in acetonitrile (6.0 mL), isopropylamine (190 μL) and DIPEA (640 μL) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 5 minutes. The mixture was stirred at room temperature for 30 minutes. After confirming the disappearance of the raw material by TLC, water was added and the mixture was extracted with dichloromethane. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-[(5-chloro-1-methyl-1H-pyrazolo [4]. , 3-d] pyrimidin-7-yl) amino] -N- (propane-2-yl) ethane-1-sulfonamide (160 mg) was obtained.
(B) After dissolving the compound (50.0 mg) obtained in (a) and DIPEA (26.0 μL) in isopropanol (5.0 mL), tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride ( 80.0 mg) was added and reacted at 100 ° C. for 20 hours using a microwave reactor. After confirming that the raw materials had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, dichloromethane: methanol), and tert-butyl methyl {1- [1-methyl-7- ({2). -[(Propane-2-yl) sulfamoyl] ethyl} amino) -1H-pyrazolo [4,5-d] pyrimidin-5-yl] azetidine-3-yl} carbamate (30.0 mg) was obtained.
(C) The compound (60.0 mg) obtained in (b) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (180 μL) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane / methanol = 10/1. The solvent was distilled off under reduced pressure to obtain the title compound (40.0 mg).
　（実施例２）
Ｎ－ベンジル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにベンジルアミンを用いた以外は、実施例１（ａ）と同様の手法でＮ－ベンジル－２－［（５－クロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル）アミノ］－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミドを得た。
（ｂ）（ａ）で得られた化合物（１５０ｍｇ）とＤＩＰＥＡ（１７２μＬ）をＮＭＰ（４．０ｍＬ）に溶解した後、１－メチルピペラジン（８７．９μＬ）を加えマイクロウェーブ反応装置を用いて１５０℃で１時間反応させた。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ジクロロメタン：メタノール）で精製し、表題の化合物（１１０ｍｇ）を得た。 (Example 2)
N-Benzyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide ( a) N-benzyl-2-[(5-chloro-1-methyl-1H-pyrazolo [4,3-"] in the same manner as in Example 1 (a) except that benzylamine was used instead of isopropylamine. d] Pyrimidine-7-yl) amino] -N- (propane-2-yl) ethane-1-sulfonamide was obtained.
(B) After dissolving the compound (150 mg) obtained in (a) and DIPEA (172 μL) in NMP (4.0 mL), 1-methylpiperazin (87.9 μL) was added and 150 using a microwave reactor. The reaction was carried out at ° C. for 1 hour. After confirming that the raw material had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, dichloromethane: methanol) to obtain the title compound (110 mg).
　（実施例３）
Ｎ－シクロプロピル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）イソプロピルアミンの代わりにシクロプロパンアミンを用いた以外は、実施例１（ａ）と同様の手法で２－［（５－クロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル）アミノ］－Ｎ－（プロパン－２－イル）シクロプロピルエタン－１－スルホンアミドを得た。
（ｂ）実施例２（ｂ）と同様の手法で、（ａ）で得られた化合物から表題の化合物を得た。 (Example 3)
N-Cyclopropyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide (A) 2-[(5-Chloro-1-methyl-1H-pyrazolo [4,3-d]] in the same manner as in Example 1 (a) except that cyclopropaneamine was used instead of isopropylamine. Pyrimidine-7-yl) amino] -N- (propane-2-yl) cyclopropylethane-1-sulfonamide was obtained.
(B) The title compound was obtained from the compound obtained in (a) by the same method as in Example 2 (b).
　（実施例４）
２－｛［１－メチル－５－（ピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにピペラジンを用いた以外は、実施例２（ｂ）と同様の手法で、実施例１（ａ）で得られた化合物から表題の化合物を得た。 (Example 4)
2-{[1-Methyl-5- (piperazine-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane-1- The title compound was obtained from the compound obtained in Example 1 (a) in the same manner as in Example 2 (b) except that piperazine was used instead of sulfoneamide (a) 1-methylpiperazine.
　（実施例５）
２－（｛１－メチル－５－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートを用いた以外は、実施例２（ｂ）と同様の手法で、実施例１（ａ）で得られた化合物からｔｅｒｔ－ブチル　メチル｛（３Ｓ）－１－［１－メチル－７－（｛２－［（プロパン－２－イル）スルファモイル］エチル｝アミノ）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－５－イル］ピロリジン－３－イル｝カーバメートを得た。
（ｂ）実施例１（ｃ）と同様の手法で、（ａ）で得られた化合物から表題の化合物を得た。 (Example 5)
2-({1-methyl-5-[(3S) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N-( Propane-2-yl) Same as in Example 2 (b) except that tert-butyl (3S) -pyrrolidin-3-ylcarbamate was used instead of ethane-1-sulfonamide (a) 1-methylpiperazine. By the method, from the compound obtained in Example 1 (a), tert-butyl methyl {(3S) -1- [1-methyl-7- ({2-[(propane-2-yl) sulfamoyl] ethyl} amino ) -1H-pyrazolo [4,5-d] pyrimidin-5-yl] pyrrolidine-3-yl} carbamate was obtained.
(B) The title compound was obtained from the compound obtained in (a) by the same method as in Example 1 (c).
　（実施例６）
Ｎ－（シクロプロピルメチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例２（ａ）におけるベンジルアミンの代わりにシクロプロピルメチルアミンを用いた以外は、実施例２と同様の手法で表題の化合物を得た。 (Example 6)
N- (Cyclopropylmethyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1 -Sulfoneamide (a) The title compound was obtained in the same manner as in Example 2 except that cyclopropylmethylamine was used instead of benzylamine in Example 2 (a).
　（実施例７）
Ｎ－（シクロブチルメチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例２（ａ）におけるベンジルアミンの代わりにシクロブチルメチルアミンを用いた以外は、実施例２と同様の手法で表題の化合物を得た。 (Example 7)
N- (Cyclobutylmethyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1 -Sulfone Amide (a) The title compound was obtained in the same manner as in Example 2 except that cyclobutylmethylamine was used instead of the benzylamine in Example 2 (a).
　（実施例８）
２－（｛１－メチル－５－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　（３Ｒ）－ピロリジン－３－イルカーバメートを用いた以外は、実施例２（ｂ）と同様の手法で、実施例１（ａ）で得られた化合物からｔｅｒｔ－ブチル　メチル｛（３Ｒ）－１－［１－メチル－７－（｛２－［（プロパン－２－イル）スルファモイル］エチル｝アミノ）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－５－イル］ピロリジン－３－イル｝カーバメートを得た。
（ｂ）実施例１（ｃ）と同様の手法で、（ａ）で得られた化合物から表題の化合物を得た。 (Example 8)
2-({1-methyl-5-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N-( Propane-2-yl) Same as in Example 2 (b) except that tert-butyl (3R) -pyrrolidin-3-ylcarbamate was used instead of ethane-1-sulfonamide (a) 1-methylpiperazine. By the method, from the compound obtained in Example 1 (a), tert-butyl methyl {(3R) -1- [1-methyl-7- ({2-[(propane-2-yl) sulfamoyl] ethyl} amino ) -1H-pyrazolo [4,5-d] pyrimidin-5-yl] pyrrolidine-3-yl} carbamate was obtained.
(B) The title compound was obtained from the compound obtained in (a) by the same method as in Example 1 (c).
　（実施例９）
２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）実施例２（ａ）におけるベンジルアミンの代わりにイソプロピルアミンを用いた以外は、実施例２と同様の手法で表題の化合物を得た。 (Example 9)
2-{[1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane -1-Sulfonamide (a) The title compound was obtained in the same manner as in Example 2 except that isopropylamine was used instead of benzylamine in Example 2 (a).
　（実施例１０）
２－｛［８－ブロモ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）４－ブロモ－１Ｈ－ピラゾール－５－アミン（１．６ｇ）をＤＭＦ（３０ｍＬ）に溶解し０℃で冷却した後、イソシアン酸エトキシカルボニル（１．２ｍＬ）を滴下して、１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、冷水（７５ｍＬ）を加え０℃で３０分攪拌した。得られた固体を濾過し、エチル［（４－ブロモ－１Ｈ－ピラゾール－５－イル）カルバモイル］カーバメート（１．９ｇ）を得た。
（ｂ）（ａ）で得られた化合物（１．９ｇ）にＴＨＦ（３５．０ｍＬ）を加え０℃で攪拌した。カリウム　ｔｅｒｔ－ブトキシド（２．０ｇ）を加え、６０℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、水酸化ナトリウム水溶液を加え固体を溶解させた。その後、塩酸を加えてｐＨを４以下に調整し１５分攪拌した。得られた固体を濾過し、８－ブロモピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオール（１．３ｇ）を得た。
（ｃ）（ｂ）で得られた化合物（２３１ｍｇ）にオキシ塩化リン（１．９ｍＬ）とＤＩＰＥＡ（１７０μＬ）を順に加え、１００℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、トルエンを加え共沸し得られた残留物を次の反応に使用した。
（ｄ）（ｃ）で得られた残留物の一部とＤＩＰＥＡ（１３０μＬ）をＴＨＦ（３．０ｍＬ）に溶解した後、参考例１で合成した化合物（２５．０ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、１－メチルピペラジン（５０．０μＬ）とＤＩＰＥＡ（７８．０μＬ）を加え、６０℃で１６時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（１６．４ｍｇ）を得た。 (Example 10)
2-{[8-Bromo-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) Ethan-1-sulfonamide (a) 4-bromo-1H-pyrazol-5-amine (1.6 g) was dissolved in DMF (30 mL) and cooled at 0 ° C., and then ethoxycarbonyl isocyanate (1. 2 mL) was added dropwise, and the mixture was stirred for 1 hour. After confirming that the raw material had disappeared by LCMS, cold water (75 mL) was added, and the mixture was stirred at 0 ° C. for 30 minutes. The obtained solid was filtered to obtain ethyl [(4-bromo-1H-pyrazole-5-yl) carbamoyl] carbamate (1.9 g).
(B) THF (35.0 mL) was added to the compound (1.9 g) obtained in (a), and the mixture was stirred at 0 ° C. Potassium tert-butoxide (2.0 g) was added, and the mixture was stirred at 60 ° C. for 2 hours. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydroxide solution was added to dissolve the solid. Then, hydrochloric acid was added to adjust the pH to 4 or less, and the mixture was stirred for 15 minutes. The obtained solid was filtered to obtain 8-bromopyrazolo [1,5-a] [1,3,5] triazine-2,4-diol (1.3 g).
(C) To the compound (231 mg) obtained in (b), phosphorus oxychloride (1.9 mL) and DIPEA (170 μL) were added in that order, and the mixture was stirred at 100 ° C. for 2 hours. After confirming that the raw material had disappeared by LCMS, toluene was added and the residue obtained by azeotrope was used for the next reaction.
(D) After dissolving a part of the residue obtained in (c) and DIPEA (130 μL) in THF (3.0 mL), the compound (25.0 mg) synthesized in Reference Example 1 was added, and the mixture was added at room temperature for 1 hour. Stirred. After confirming that the raw materials had disappeared by LCMS, 1-methylpiperazine (50.0 μL) and DIPEA (78.0 μL) were added, and the mixture was stirred at 60 ° C. for 16 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (16.4 mg).
　（実施例１１）
２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）実施例１０（ｄ）で得られた化合物（１３．２ｍｇ）をメタノール（２．０ｍＬ）に溶解し、５％パラジウムカーボン（６．６ｍｇ）を加え、水素雰囲気下で１６時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、反応溶液をセライトで濾過した。減圧下で溶媒を留去し、表題の化合物（９．１ｍｇ）を得た。 (Example 11)
2-{[2- (4-Methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2-yl) ethane -1-sulfonamide (a) The compound (13.2 mg) obtained in Example 10 (d) was dissolved in methanol (2.0 mL), 5% palladium carbon (6.6 mg) was added, and the atmosphere was hydrogen. Was stirred for 16 hours. After confirming that the raw materials had disappeared by LCMS, the reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure to obtain the title compound (9.1 mg).
　（実施例１２）
Ｎ－シクロヘキシル－２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに参考例２で合成した化合物を用いた以外は、実施例１０と同様の手法で、２－｛［８－ブロモ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロヘキシルエタン－１－スルホンアミドを得た。
（ｂ）実施例１１（ａ）と同様の手法で、（ａ）で得られた化合物から表題の化合物を得た。 (Example 12)
N-cyclohexyl-2-{[2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide ( a) 2-{[8-Bromo-2- (4-methylpiperazin-) in the same manner as in Example 10 except that the compound synthesized in Reference Example 2 was used instead of the compound synthesized in Reference Example 1. 1-Il) Pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclohexylethane-1-sulfonamide was obtained.
(B) The title compound was obtained from the compound obtained in (a) by the same method as in Example 11 (a).
　（実施例１３）
２－｛［７－メチル－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）実施例１０（ａ）における４－ブロモ－１Ｈ－ピラゾール－５－アミンの代わりに３－アミノ－５－メチルピラゾールを用いた以外は、実施例１０と同様の手法で表題の化合物を得た。 (Example 13)
2-{[7-Methyl-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) Ethan-1-sulfonamide (a) Example 10 except that 3-amino-5-methylpyrazole was used instead of 4-bromo-1H-pyrazole-5-amine in Example 10 (a). The title compound was obtained in the same manner as in.
　（実施例１４）
２－｛［７－（４－メチルピペラジン－１－イル）［１，２，４］トリアゾロ［４，３－ａ］［１，３，５］トリアジン－５－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）シアヌル酸クロリド（１８４ｍｇ）とＤＩＰＥＡ（１９４μＬ）をＴＨＦ（５．０ｍＬ）に溶解し０℃で冷却した後、参考例１で合成した化合物（１６６ｍｇ）を加え、室温で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（４，６－ジクロロ－１，３，５－トリアジン－２－イル）アミノ］－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（２９０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（２９０ｍｇ）とＤＩＰＥＡ（１６０μＬ）をＴＨＦ（５．０ｍＬ）に溶解し、１－メチルピペラジン（１０２μＬ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、２－｛［４－クロロ－６－（４－メチルピペラジン－１－イル）－１，３，５－トリアジン－２－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（２９０ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（２９０ｍｇ）とヒドラジン一水和物（１１２μＬ）をエタノール（８．０ｍＬ）に溶解し、６０℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、溶媒を留去して２－｛［４－ヒドラジンイル－６－（４－メチルピペラジン－１－イル）－１，３，５－トリアジン－２－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（３１０ｍｇ）を混合物として得た。
（ｄ）（ｃ）で得られた化合物（３７．０ｍｇ）と酢酸（１８．０ｍｇ）とオルトギ酸トリエチル（４４．０ｍｇ）をエタノール（１．０ｍＬ）に溶解し、還流下で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、室温まで冷却した後、得られた固体をろ取し、エタノールで洗浄し表題の化合物（１４．０ｍｇ）を得た。 (Example 14)
2-{[7- (4-Methylpiperazin-1-yl) [1,2,4] triazolo [4,3-a] [1,3,5] triazine-5-yl] amino} -N-( Propane-2-yl) Ethan-1-sulfonamide (a) The compound synthesized in Reference Example 1 after dissolving cyanuric chloride (184 mg) and DIPEA (194 μL) in THF (5.0 mL) and cooling at 0 ° C. (166 mg) was added, and the mixture was stirred at room temperature for 2 hours. After confirming that the raw materials had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-[(4,6-dichloro-1,3,5-). Triazine-2-yl) amino] -N- (propane-2-yl) ethane-1-sulfonamide (290 mg) was obtained.
(B) The compound (290 mg) obtained in (a) and DIPEA (160 μL) were dissolved in THF (5.0 mL), 1-methylpiperazine (102 μL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw materials had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) and 2-{[4-chloro-6- (4-methylpiperazin-1). -Il) -1,3,5-triazine-2-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (290 mg) was obtained.
(C) The compound (290 mg) obtained in (b) and hydrazine monohydrate (112 μL) were dissolved in ethanol (8.0 mL) and stirred at 60 ° C. for 2 hours. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off and 2-{[4-hydrazineyl-6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2-yl) was confirmed. ] Amino} -N- (propane-2-yl) ethane-1-sulfonamide (310 mg) was obtained as a mixture.
(D) The compound (37.0 mg) obtained in (c), acetic acid (18.0 mg) and triethyl orthoformate (44.0 mg) were dissolved in ethanol (1.0 mL) and stirred under reflux for 3 hours. .. After confirming that the raw materials had disappeared by LCMS and cooling to room temperature, the obtained solid was collected by filtration and washed with ethanol to obtain the title compound (14.0 mg).
　（実施例１５）
２－｛［５－（４－メチルピペラジン－１－イル）－１Ｈ－［１，２，３］トリアゾロ［４，５－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）６－クロロ－２－（メチルスルファニル）－５－ニトロピリミジン－４－アミン（２６８　ｍｇ）をエタノール（６．０ｍＬ）に溶解し、塩化すず（ＩＩ）二水和物（１．１ｇ）を加え還流下で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、６－クロロ－２－（メチルスルファニル）ピリミジン－４，５－ジアミン（１６９ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（１６７ｍｇ）と亜硝酸　ｔｅｒｔ－ブチル（２９０μＬ）をアセトニトリル（４．３ｍＬ）に溶解し、６５℃で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、７－クロロ－５－（メチルスルファニル）－１Ｈ－［１，２，３］トリアゾロ［４，５－ｄ］ピリミジン（１１７　ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（３７．８ｍｇ）と参考例１で合成した化合物（３１．１ｍｇ）とＤＩＰＥＡ（４８．０μＬ）をエタノール（１．０ｍＬ）に溶解し、還流下で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－｛［５－（メチルスルファニル）－１Ｈ－［１，２，３］トリアゾロ［４，５－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（４１．８ｍｇ）を得た。
（ｄ）（ｃ）で得られた化合物（４０．３ｍｇ）をＴＨＦ（２．４ｍＬ）に溶解し、メタクロロ過安息香酸（７５．２ｍｇ）を加え、室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、チオ硫酸ナトリウム水溶液を加え反応を停止し、クロロホルムで抽出した。有機層を減圧下で留去した後、得られた残留物を２－プロパノール（６１０μＬ）に溶解し、１－メチルピペラジン（２７．０μＬ）を加え、マイクロウェーブ反応装置を用いて１４０℃で１時間反応させた。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、酢酸エチル：メタノール）で精製し、表題の化合物（１１．３ｍｇ）を得た。 (Example 15)
2-{[5- (4-Methylpiperazin-1-yl) -1H- [1,2,3] triazolo [4,5-d] pyrimidin-7-yl] amino} -N- (propane-2-) Il) Ethane-1-sulfonamide (a) 6-chloro-2- (methylsulfanilic) -5-nitropyrimidine-4-amine (268 mg) was dissolved in ethanol (6.0 mL) and tin chloride (II). Dihydrate (1.1 g) was added and stirred under reflux for 3 hours. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After distilling off the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to purify 6-chloro-2- (methylsulfanyl) pyrimidine-4,5-. Diamine (169 mg) was obtained.
(B) The compound (167 mg) obtained in (a) and tert-butyl nitrite (290 μL) were dissolved in acetonitrile (4.3 mL) and stirred at 65 ° C. for 1 hour. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After distilling off the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate), and 7-chloro-5- (methylsulfanyl) -1H- [1, 2,3] Triazolo [4,5-d] pyrimidine (117 mg) was obtained.
(C) The compound (37.8 mg) obtained in (b), the compound (31.1 mg) synthesized in Reference Example 1 and DIPEA (48.0 μL) were dissolved in ethanol (1.0 mL) under reflux. Stirred for 2 hours. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After distilling off the organic layer under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-{[5- (methylsulfanyl) -1H- [1, 2,3] Triazolo [4,5-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (41.8 mg) was obtained.
(D) The compound (40.3 mg) obtained in (c) was dissolved in THF (2.4 mL), metachloroperbenzoic acid (75.2 mg) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw material had disappeared by LCMS, an aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted with chloroform. After distilling off the organic layer under reduced pressure, the obtained residue was dissolved in 2-propanol (610 μL), 1-methylpiperazine (27.0 μL) was added, and 1 at 140 ° C. using a microwave reactor. Reacted for time. After confirming that the raw material had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: methanol) to obtain the title compound (11.3 mg).
　（実施例１６）
２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）２，４－ジクロロピロロ［２，１－ｆ］［１，２，４］トリアジン（１９．０ｍｇ）とＤＩＰＥＡ（２６．０μＬ）をＴＨＦ（１．０ｍＬ）に溶解した後、参考例１で合成した化合物（１７．０ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（２－クロロピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（３２．０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（３２．０ｍｇ）とＤＩＰＥＡ（２６．０μＬ）を１－ブタノール（１．０ｍＬ）に溶解した後、１－メチルピペラジン（２２．０μＬ）を加えマイクロウェーブ反応装置を用いて２００℃で１０時間反応させた。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（１８．０ｍｇ）を得た。 (Example 16)
2-{[2- (4-Methylpiperazin-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (propane-2-yl) ethane -1-sulfonamide (a) 2,4-dichloropyrrolo [2,1-f] [1,2,4] Triazine (19.0 mg) and DIPEA (26.0 μL) are dissolved in THF (1.0 mL). After that, the compound (17.0 mg) synthesized in Reference Example 1 was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-[(2-chloropyrrolo [2,1-f] [1,2,4] triazine-4-yl]. Amino} -N- (propane-2-yl) ethane-1-sulfonamide (32.0 mg) was obtained.
(B) The compound (32.0 mg) obtained in (a) and DIPEA (26.0 μL) are dissolved in 1-butanol (1.0 mL), and then 1-methylpiperazine (22.0 μL) is added to microwave. The reaction was carried out at 200 ° C. for 10 hours using a reactor. After confirming that the raw material had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (18.0 mg).
　（実施例１７）
Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例１６と同様の手法で表題の化合物を得た。 (Example 17)
N-cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pyrrolo [2,1-f] [1,2,4] triazine-4-yl] amino} ethane-1-sulfonamide ( a) The title compound was obtained in the same manner as in Example 16 except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1.
　（実施例１８）
２－｛［２－（４－メチルピペラジン－１－イル）フロ［３，２－ｄ］ピリミジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）２，４－ジクロロフロ［３，２－ｄ］ピリミジン（３０．０ｍｇ）とＤＩＰＥＡ（４１．０μＬ）をＴＨＦ（１．０ｍＬ）に溶解した後、参考例１で合成した化合物（２６．０ｍｇ）を加え室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（２－クロロフロ［３，２－ｄ］ピリミジン－４－イル）アミノ］－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（３２．０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（３５．０ｍｇ）とＤＩＰＥＡ（５７．０μＬ）を１－ブタノール（１．０ｍＬ）に溶解した後、１－メチルピペラジン（３６．０μＬ）を加えマイクロウェーブ反応装置を用いて２００℃で２時間反応させた。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（２５．０ｍｇ）を得た。 (Example 18)
2-{[2- (4-Methylpiperazin-1-yl) flo [3,2-d] pyrimidine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (a) ) 2,4-Dichloroflo [3,2-d] Pyrimidine (30.0 mg) and DIPEA (41.0 μL) dissolved in THF (1.0 mL), and then the compound synthesized in Reference Example 1 (26.0 mg). Was added and stirred at room temperature for 3 hours. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-[(2-chloroflo [3,2-d] pyrimidin-4-yl) amino] -N- (propane). -2-Il) Ethane-1-sulfonamide (32.0 mg) was obtained.
(B) The compound (35.0 mg) obtained in (a) and DIPEA (57.0 μL) are dissolved in 1-butanol (1.0 mL), and then 1-methylpiperazine (36.0 μL) is added to microwave. The reaction was carried out at 200 ° C. for 2 hours using a reactor. After confirming that the raw material had disappeared by LCMS, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (25.0 mg).
　（実施例１９）
Ｎ－［（４－フルオロフェニル）メチル］－２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに参考例４で合成した化合物を用いた以外は、実施例１６と同様の手法で、表題の化合物を得た。 (Example 19)
N-[(4-fluorophenyl) methyl] -2-{[2- (4-methylpiperazin-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino } Ethane-1-sulfonamide (a) The title compound was obtained in the same manner as in Example 16 except that the compound synthesized in Reference Example 4 was used instead of the compound synthesized in Reference Example 1.
　（実施例２０）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）実施例１７（ａ）で得られた化合物（３１．０ｍｇ）を１，４－ジオキサン（０．９ｍＬ）と水（０．１ｍＬ）に溶解した後、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（４０．０ｍｇ）とトリス（ジベンジリデンアセトン）ジパラジウム（０）（８．２ｍｇ）と２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル（８．６ｍｇ）と炭酸セシウム（５９．０ｍｇ）を加え、マイクロウェーブ反応装置を用いて１５０℃で１時間反応させた。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、ｔｅｒｔ－ブチル　［１－（４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピロロ［２，１－ｆ］［１，２，４］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメート（３５．０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（３５．０ｍｇ）に、２Ｍ塩化水素メタノール溶液（１．０ｍＬ）を加え、室温で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（１０．０ｍｇ）を得た。 (Example 20)
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pyrrolo [2,1-f] [1,2,4] triazine-4-yl} amino) ethane-1- Sulfonamide (a) The compound (31.0 mg) obtained in Example 17 (a) was dissolved in 1,4-dioxane (0.9 mL) and water (0.1 mL), and then tert-butyl azetidine-3. -Il (methyl) carbamate hydrochloride (40.0 mg), tris (dibenzylideneacetone) dipalladium (0) (8.2 mg) and 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl ( 8.6 mg) and cesium carbonate (59.0 mg) were added, and the mixture was reacted at 150 ° C. for 1 hour using a microwave reactor. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and tert-butyl [1-(4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrrolo [2. 1-f] [1,2,4] triazine-2-yl) azetidine-3-yl] methyl carbamate (35.0 mg) was obtained.
(B) A 2M hydrogen chloride methanol solution (1.0 mL) was added to the compound (35.0 mg) obtained in (a), and the mixture was stirred at room temperature for 2 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (10.0 mg).
　（実施例２１）
Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例１０（ｃ）で得られた残留物の一部とＤＩＰＥＡ（５２３μＬ）をＴＨＦ（６．０ｍＬ）に溶解した後、参考例３で合成した化合物（１１５ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、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。減圧下で溶媒を留去し、得られた残留物を次の反応に使用した。
（ｂ）（ａ）で得られた化合物をジオキサン（２．０ｍＬ）に溶解し、１－メチルピペラジン（６７．０μＬ）とＤＩＰＥＡ（１０５μＬ）を加え、マイクロウェーブ反応装置を用いて１２０℃で３０分反応させた。ＬＣＭＳで原料が消失したことを確認し、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。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、２－｛［８－ブロモ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｃ）実施例１１（ａ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 21)
N-cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide ( a) After dissolving a part of the residue obtained in Example 10 (c) and DIPEA (523 μL) in THF (6.0 mL), the compound (115 mg) synthesized in Reference Example 3 was added, and the mixture was added at room temperature for 1 hour. Stirred. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure and the obtained residue was used for the next reaction.
(B) The compound obtained in (a) is dissolved in dioxane (2.0 mL), 1-methylpiperazine (67.0 μL) and DIPEA (105 μL) are added, and 30 at 120 ° C. using a microwave reactor. It was reacted for a minute. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to 2-{[8-bromo-2- (4-methylpiperazin-1-yl). ) Pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide was obtained.
(C) The title compound was obtained from the compound obtained in (b) by the same method as in Example 11 (a).
　（実施例２２）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩を用いた以外は、実施例２１（ｂ）と同様の手法で、ｔｅｒｔ－ブチル　［１－（８－ブロモ－４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメートを得た。
（ｂ）実施例１１（ａ）と同様の手法で、（ａ）で得られた化合物からｔｅｒｔ－ブチル　［１－（４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメートの残留物を得た。
（ｃ）実施例１（ｃ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 22)
N-Cyclopentyl-2-({2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) ethane-1- In the same manner as in Example 21 (b), tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of the sulfonamide (a) 1-methylpiperazine. (8-Bromo-4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrazolo [1,5-a] [1,3,5] triazine-2-yl) azetidine-3-yl] methylcarbamate Got
(B) In the same manner as in Example 11 (a), tert-butyl [1-(4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrazolo [1] was obtained from the compound obtained in (a). , 5-a] [1,3,5] triazine-2-yl) Azetidine-3-yl] A residue of methyl carbamate was obtained.
(C) The title compound was obtained from the compound obtained in (b) by the same method as in Example 1 (c).
　（実施例２３）
Ｎ－［（４－フルオロフェニル）メチル］－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに参考例４で合成した化合物を用いた以外は、実施例１６（ａ）と同様の手法で、２－［（２－クロロピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル）アミノ］－Ｎ－［（４－フルオロフェニル）メチル］エタン－１－スルホンアミドを得た。
（ｂ）実施例２０（ａ）と同様の手法で、（ａ）で得られた化合物からｔｅｒｔ－ブチル　（１－｛４－［（２－｛［（４－フルオロフェニル）メチル］スルファモイル｝エチル）アミノ］ピロロ［２，１－ｆ］［１，２，４］トリアジン－２－イル｝アゼチジン－３－イル）メチルカーバメートを得た。
（ｃ）実施例２０（ｂ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 23)
N-[(4-fluorophenyl) methyl] -2-({2- [3- (methylamino) azetidine-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4- Il} amino) ethane-1-sulfonamide (a) The same method as in Example 16 (a), except that the compound synthesized in Reference Example 4 was used instead of the compound synthesized in Reference Example 1, 2- [(2-Chloropyrrolo [2,1-f] [1,2,4] triazine-4-yl) amino] -N-[(4-fluorophenyl) methyl] ethane-1-sulfonamide was obtained.
(B) tert-Butyl (1- {4-[(2-{[(4-fluorophenyl) methyl] sulfamoyl} ethyl) from the compound obtained in (a) in the same manner as in Example 20 (a). ) Amino] pyrolo [2,1-f] [1,2,4] triazine-2-yl} azetidine-3-yl) Methyl carbamate was obtained.
(C) The title compound was obtained from the compound obtained in (b) in the same manner as in Example 20 (b).
　（実施例２４）
２－｛［２－（６－メチル－２，６－ジアザスピロ［３．３］ヘプタン－２－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりに２－メチル－２，６－ジアザスピロ［３．３］ヘプタンを用いた以外は、実施例１６と同様の手法で表題の化合物を得た。 (Example 24)
2-{[2- (6-Methyl-2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} Example 16 except that 2-methyl-2,6-diazaspiro [3.3] heptane was used in place of -N- (propane-2-yl) ethane-1-sulfonamide (a) 1-methylpiperazine. The title compound was obtained in the same manner as in.
　（実施例２５）
２－｛［２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにピペラジンを用いた以外は、実施例１６と同様の手法で表題の化合物を得た。 (Example 25)
2-{[2- (Piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (propane-2-yl) ethane-1- The title compound was obtained in the same manner as in Example 16 except that piperazine was used instead of sulfonamide (a) 1-methylpiperazine.
　（実施例２６）
２－｛［２－（２，６－ジアザスピロ［３．３］ヘプタン－２－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　２，６－ジアザスピロ［３．３］ヘプタン－２－カルボキシレートを用いた以外は、実施例１６（ｂ）と同様の手法で、ｔｅｒｔ－ブチル　６－［４－（｛２－［（プロパン－２－イル）スルファモイル］エチル｝アミノ）ピロロ［２，１－ｆ］［１，２，４］トリアジン－２－イル］－２，６－ジアザスピロ［３．３］ヘプタン－２－カルボキシレートを得た。
（ｂ）（ａ）で得られた化合物（３４．０ｍｇ）をジクロロメタン（０．５ｍＬ）に溶解した後、トリフルオロ酢酸（０．５ｍＬ）を加え、室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（２７．０ｍｇ）を得た。 (Example 26)
2-{[2- (2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-( Example 16 except that tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate was used in place of propane-2-yl) ethane-1-sulfonamide (a) 1-methylpiperazine. In the same manner as in (b), tert-butyl 6- [4-({2-[(propane-2-yl) sulfamoyl] ethyl} amino) pyrolo [2,1-f] [1,2,4] Triazine-2-yl] -2,6-diazaspiro [3.3] heptane-2-carboxylate was obtained.
(B) The compound (34.0 mg) obtained in (a) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (27.0 mg).
　（実施例２７）
２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）８－ブロモピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオール（６９．０ｍｇ）にオキシ塩化リン（５６０μＬ）とＤＩＰＥＡ（１００μＬ）を順に加え、１００℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、トルエンを加え共沸した。得られた残留物とＤＩＰＥＡ（２６０μＬ）をＴＨＦ（３．０ｍＬ）に溶解した後、参考例１で合成した化合物（５０．０ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（８－ブロモ－２－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）アミノ］－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（６３．０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（６３．０ｍｇ）とＤＩＰＥＡ（８３．０μＬ）を１，４－ジオキサン（０．５ｍＬ）とエタノール（０．５ｍＬ）に溶解した後、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（１０７ｍｇ）を加えマイクロウェーブ反応装置を用いて１２０℃で１時間反応させた。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、ｔｅｒｔ－ブチル　｛１－［８－ブロモ－４－（｛２－［（プロパン－２－イル）スルファモイル］エチル｝アミノ）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］アゼチジン－３－イル｝メチルカーバメート（８５．０ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（８５．０ｍｇ）をメタノール（２．０ｍＬ）とクロロホルム（１．０ｍＬ）に溶解した後、５％パラジウムカーボン（１０．０ｍｇ）を加え、水素雰囲気下、室温で１６時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、セライト濾過し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、酢酸エチル：メタノール）で精製し、ｔｅｒｔ－ブチル　メチル｛１－［４－（｛２－［（プロパン－２－イル）スルファモイル］エチル｝アミノ）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］アゼチジン－３－イル｝カーバメート（４３．０ｍｇ）を得た。
（ｄ）実施例２６（ｂ）と同様の手法で、（ｃ）で得られた化合物から表題の化合物を得た。 (Example 27)
2-({2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- (propane-2-) Il) Ethan-1-sulfonamide (a) 8-bromopyrazolo [1,5-a] [1,3,5] triazine-2,4-diol (69.0 mg) with phosphorus oxychloride (560 μL) and DIPEA ( 100 μL) was added in order, and the mixture was stirred at 100 ° C. for 2 hours. After confirming that the raw material had disappeared by LCMS, toluene was added and azeotropically boiled. The obtained residue and DIPEA (260 μL) were dissolved in THF (3.0 mL), the compound (50.0 mg) synthesized in Reference Example 1 was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-[(8-bromo-2-chloropyrazolo [1,5-a)). ] [1,3,5] Triazine-4-yl) amino] -N- (propane-2-yl) ethane-1-sulfonamide (63.0 mg) was obtained.
(B) The compound (63.0 mg) and DIPEA (83.0 μL) obtained in (a) were dissolved in 1,4-dioxane (0.5 mL) and ethanol (0.5 mL), and then tert-butyl azetidine. -3-Il (methyl) carbamate hydrochloride (107 mg) was added and reacted at 120 ° C. for 1 hour using a microwave reactor. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and tert-butyl {1- [8-bromo-4- ({2- [(propane-2-yl) sulfamoyl]]. Ethyl} amino) pyrazolo [1,5-a] [1,3,5] triazine-2-yl] azetidine-3-yl} methyl carbamate (85.0 mg) was obtained.
(C) The compound (85.0 mg) obtained in (b) was dissolved in methanol (2.0 mL) and chloroform (1.0 mL), and then 5% palladium carbon (10.0 mg) was added under a hydrogen atmosphere. , Stirred at room temperature for 16 hours. After confirming that the raw material had disappeared by LCMS, the mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: methanol) to purify tert-butyl methyl {1- [4-({2-[(propane-2-yl) sulfamoyl] ethyl} amino). ) Pyrazolo [1,5-a] [1,3,5] triazine-2-yl] azetidine-3-yl} carbamate (43.0 mg) was obtained.
(D) The title compound was obtained from the compound obtained in (c) by the same method as in Example 26 (b).
　（実施例２８）
Ｎ－シクロペンチル－２－（｛１－メチル－５－［３－（メチルアミノ）アゼチジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）エタン－１－スルホンアミド
（ａ）５，７－ジクロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン（１００　ｍｇ）とＤＩＰＥＡ（１２７μＬ）をＴＨＦ（５．０ｍＬ）に溶解した後、参考例３で合成した化合物（９５．０ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（５－クロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）］－エタン－Ｎ－シクロペンチルエタン－１－スルホンアミド（９４．０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（３０．０ｍｇ）とＤＩＰＥＡ（２９．０μＬ）を１－ブタノール（１．０ｍＬ）に溶解した後、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（３７．０ｍｇ）を加えマイクロウェーブ反応装置を用いて２００℃で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（１４．０ｍｇ）を得た。 (Example 28)
N-cyclopentyl-2- ({1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) ethane-1- After dissolving sulfoneamide (a) 5,7-dichloro-1-methyl-1H-pyrazolo [4,3-d] pyrimidin (100 mg) and DIPEA (127 μL) in THF (5.0 mL), Reference Example 3 The compound synthesized in (95.0 mg) was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-[(5-chloro-1-methyl-1H-pyrazolo [4,3-d] pyrimidin-7-yl). } Amino)]-ethane-N-cyclopentylethane-1-sulfonamide (94.0 mg) was obtained.
(B) After dissolving the compound (30.0 mg) obtained in (a) and DIPEA (29.0 μL) in 1-butanol (1.0 mL), tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride Salt (37.0 mg) was added and the mixture was stirred at 200 ° C. for 1 hour using a microwave reactor. After confirming that the raw material had disappeared by LCMS, the obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (14.0 mg).
　（実施例２９）
Ｎ－シクロペンチル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりに１－メチルピペラジンを用いた以外は、実施例２８（ｂ）と同様の手法で表題の化合物を得た。 (Example 29)
N-Cyclopentyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide ( a) The title compound was obtained in the same manner as in Example 28 (b) except that 1-methylpiperazine was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
　（実施例３０）
２－｛［７－クロロ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）４－ブロモ－１Ｈ－ピラゾール－５－アミンの代わりに３－クロロ－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例１０（ａ）と同様の手法でエチル｛［（３－クロロ－１Ｈ－ピラゾール－５－イル）カルバモイル］カーバメートを得た。
（ｂ）実施例１０（ｂ）と同様の手法で、（ａ）で得られた化合物から７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－２，４－ジオールを得た。
（ｃ）実施例１０（ｃ）と同様の手法で、（ｂ）で得られた化合物から２，４，７－トリクロロピラゾロ［１，５－ａ］［１，３，５］トリアジンの残留物を得た。
（ｄ）参考例３で合成した化合物の代わりに参考例１で合成した化合物を用いた以外は、実施例２１（ａ）と同様の手法で、（ｃ）で得られた残留物から２－［（２，７－ジクロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）アミノ］－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミドを得た。
（ｅ）実施例２１（ｂ）と同様の手法で、（ｄ）で得られた化合物から表題の化合物を得た。 (Example 30)
2-{[7-Chloro-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) Ethan-1-sulfonamide (a) In Example 10 (a), except that 3-chloro-1H-pyrazole-5-amine was used instead of 4-bromo-1H-pyrazole-5-amine. Ethyl {[(3-chloro-1H-pyrazole-5-yl) carbamoyl] carbamate was obtained in the same manner.
(B) 7-Chloropyrazolo [1,5-a] [1,3,5] triazine-2,4-diol is obtained from the compound obtained in (a) by the same method as in Example 10 (b). rice field.
(C) Residue of 2,4,7-trichloropyrazolo [1,5-a] [1,3,5] triazine from the compound obtained in (b) by the same method as in Example 10 (c). I got something.
(D) From the residue obtained in (c), 2-in the same manner as in Example 21 (a), except that the compound synthesized in Reference Example 1 was used instead of the compound synthesized in Reference Example 3. [(2,7-Dichloropyrazolo [1,5-a] [1,3,5] triazine-4-yl) amino] -N- (propane-2-yl) ethane-1-sulfonamide was obtained. ..
(E) The title compound was obtained from the compound obtained in (d) by the same method as in Example 21 (b).
　（実施例３１）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩を用いた以外は、実施例２１（ｂ）と同様の手法で、実施例３０（ｄ）で得られた化合物からｔｅｒｔ－ブチル　［１－（７－クロロ－４－｛［２－Ｎ－（プロパン－２－イル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメートを得た。
（ｂ）実施例２２（ｃ）と同様の手法で、（ａ）で得られた化合物から表題の化合物を得た。 (Example 31)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Same as in Example 21 (b) except that tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of propane-2-yl) ethane-1-sulfonamide (a) 1-methylpiperazine. From the compound obtained in Example 30 (d) by the method of tert-butyl [1- (7-chloro-4-{[2-N- (propane-2-yl) ethyl] amino} pyrazolo [1, 5-a] [1,3,5] triazine-2-yl) azetidine-3-yl] methyl carbamate was obtained.
(B) The title compound was obtained from the compound obtained in (a) by the same method as in Example 22 (c).
　（実施例３２）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例２１（ａ）と同様の手法で、実施例３０（ｃ）の残留物から２－［（２，７－ジクロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル）アミノ］－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｂ）１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩を用いた以外は、実施例２１（ｂ）と同様の手法で、（ａ）で得られた化合物からｔｅｒｔ－ブチル　［１－（７－クロロ－４－｛［２－Ｎ－シクロペンチルエチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメートを得た。
（ｃ）実施例２２（ｃ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 32)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethan-1-sulfonamide (a) Example 30 (c) in the same manner as in Example 21 (a) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. 2-[(2,7-Dichloropyrazolo [1,5-a] [1,3,5] triazine-4-yl) amino] -N-cyclopentylethane-1-sulfonamide was obtained from the residue of ..
(B) The compound obtained in (a) in the same manner as in Example 21 (b) except that tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of 1-methylpiperazin. From tert-butyl [1- (7-chloro-4-{[2-N-cyclopentylethyl] amino} pyrazolo [1,5-a] [1,3,5] triazine-2-yl) azetidine-3- Il] Methyl carbamate was obtained.
(C) The title compound was obtained from the compound obtained in (b) in the same manner as in Example 22 (c).
　（実施例３３）
２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）実施例２８（ａ）における参考例３で合成した化合物の代わりに参考例５で合成した化合物を、実施例２８（ｂ）におけるｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりに１－メチルピペラジンを用いた以外は、実施例２８と同様の手法で表題の化合物を得た。 (Example 33)
2-{[1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (2-methylpropyl) ethane- 1-Sulfoneamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 5 was replaced with the tert-butyl azetidine-3-yl (methyl) in Example 28 (b). The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of carbamate hydrochloride.
　（実施例３４）
Ｎ－シクロペンチル－２－｛［１－メチル－５－（６－メチル－２，６－ジアザスピロ［３．３］ヘプタン－２－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例２８（ａ）と同様の手法で、２－［（５－クロロ－１－メチル－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）］－エタン－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｂ）（ａ）で得られた化合物（３０．０ｍｇ）を１，４－ジオキサン（０．９ｍＬ）と水（０．１ｍＬ）に溶解した後、２－メチル－２，６－ジアザスピロ［３．３］ヘプタン（３８．０ｍｇ）とトリス（ジベンジリデンアセトン）ジパラジウム（０）（７．７ｍｇ）と２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル（８．０ｍｇ）と炭酸セシウム（１０９ｍｇ）を加え、マイクロウェーブ反応装置を用いて１５０℃で１時間反応させた。ＬＣＭＳで原料が消失したことを確認し、減圧下で溶媒を留去した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（１５．０ｍｇ）を得た。 (Example 34)
N-cyclopentyl-2-{[1-methyl-5-(6-methyl-2,6-diazaspiro [3.3] heptan-2-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino} ethane-1-sulfonamide (a) 2-[(5-chloro-1-methyl-1H-pyrazolo [4,3-d] pyrimidin-7) in the same manner as in Example 28 (a). -Il} amino)]-ethane-N-cyclopentylethane-1-sulfonamide was obtained.
(B) The compound (30.0 mg) obtained in (a) was dissolved in 1,4-dioxane (0.9 mL) and water (0.1 mL), and then 2-methyl-2,6-diazaspiro [3]. .3] Heptane (38.0 mg), tris (dibenzylideneacetone) dipalladium (0) (7.7 mg) and 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl (8.0 mg) And cesium carbonate (109 mg) were added, and the mixture was reacted at 150 ° C. for 1 hour using a microwave reactor. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (15.0 mg).
　（実施例３５）
Ｎ－シクロブチル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりに１－メチルピペラジンを、参考例３で合成した化合物の代わりに参考例６で合成した化合物を、それぞれ用いた以外は、実施例２８と同様の手法で表題の化合物を得た。 (Example 35)
N-Cyclobutyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide ( a) Except that 1-methylpiperazine was used in place of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride and the compound synthesized in Reference Example 6 was used instead of the compound synthesized in Reference Example 3. The title compound was obtained in the same manner as in Example 28.
　（実施例３６）
Ｎ－（３，３－ジフルオロシクロブチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例２８（ａ）における参考例３で合成した化合物の代わりに参考例７で合成した化合物を、実施例２８（ｂ）におけるｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりに１－メチルピペラジンを用いた以外は、実施例２８と同様の手法で表題の化合物を得た。 (Example 36)
N- (3,3-difluorocyclobutyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino } Etan-1-sulfonamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 7 was replaced with the compound synthesized in Reference Example 28 (b), tert-butyl azetidine-3-3. The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of yl (methyl) carbamate hydrochloride.
　（実施例３７）
Ｎ－［（３，３－ジフルオロシクロブチル）メチル］－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例２８（ａ）における参考例３で合成した化合物の代わりに参考例８で合成した化合物を、実施例２８（ｂ）におけるｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりに１－メチルピペラジンを用いた以外は、実施例２８と同様の手法で表題の化合物を得た。 (Example 37)
N-[(3,3-difluorocyclobutyl) methyl] -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino} ethane-1-sulfonamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 8 was replaced with the tert-butyl azetidine in Example 28 (b). The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of -3-yl (methyl) carbamate hydrochloride.
　（実施例３８）
Ｎ－（２，２－ジフルオロプロピル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例２８（ａ）における参考例３で合成した化合物の代わりに参考例９で合成した化合物を、実施例２８（ｂ）におけるｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりに１－メチルピペラジンを用いた以外は、実施例２８と同様の手法で表題の化合物を得た。 (Example 38)
N- (2,2-difluoropropyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} Etan-1-sulfonamide (a) Instead of the compound synthesized in Reference Example 3 in Example 28 (a), the compound synthesized in Reference Example 9 was replaced with the tert-butyl azetidine-3-yl in Example 28 (b). The title compound was obtained in the same manner as in Example 28, except that 1-methylpiperazine was used instead of (methyl) carbamate hydrochloride.
　（実施例３９）
２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）４－ブロモ－１Ｈ－ピラゾール－５－アミンの代わりに３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例１０（ａ）と同様の手法でエチル｛［（３－トリフルオロメチル－１Ｈ－ピラゾール－５－イル）カルバモチオイル］カーバメート（９５８ｍｇ）を得た。
（ｂ）実施例１０（ｂ）と同様の手法で、（ａ）で得られた化合物から２－スルファニル－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オール（５８６ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（５８６ｍｇ）をエタノール（１５．０ｍＬ）と１Ｍ水酸化ナトリウム水溶液（５．０ｍＬ）に溶解し、ヨウ化メチル（１５５μＬ）を加え、室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、塩酸を加えてｐＨを４に調整し１５分攪拌した。得られた固体を濾過し、２－（メチルスルファニル）－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－オール（３９９ｍｇ）を得た。
（ｄ）（ｃ）で得られた化合物（１７５ｍｇ）にオキシ塩化リン（１．３ｍＬ）とＤＩＰＥＡ（２４４μＬ）を順に加え、１００℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、トルエンを加え共沸し得られた残留物を次の反応に使用した。
（ｅ）（ｄ）で得られた残留物の一部とＤＩＰＥＡ（３０５μＬ）をＴＨＦ（４．０ｍＬ）に溶解した後、参考例１で合成した化合物（５８．２ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－｛［２－（メチルスルファニル）－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（７７．５ｍｇ）を得た。
（ｆ）（ｅ）で得られた化合物（７７．５ｍｇ）をＴＨＦ（４．０ｍＬ）に溶解し、メタクロロ過安息香酸（１２９ｍｇ）を加え、室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、ＤＩＰＥＡ（１９９μＬ）とｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（８６．５ｍｇ）を加え６０℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、クロロホルム（２．０ｍＬ）とトリフルオロ酢酸（７６７μＬ）を加え、室温で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（７６．１ｍｇ）を得た。 (Example 39)
2-({2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} Use 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of -N- (propane-2-yl) ethane-1-sulfonamide (a) 4-bromo-1H-pyrazole-5-amine Ethyl {[(3-trifluoromethyl-1H-pyrazol-5-yl) carbamotioil] carbamate (958 mg) was obtained in the same manner as in Example 10 (a).
(B) 2-Sulfanyl-7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] from the compound obtained in (a) in the same manner as in Example 10 (b). Triazine-4-ol (586 mg) was obtained.
(C) The compound (586 mg) obtained in (b) was dissolved in ethanol (15.0 mL) and a 1 M aqueous sodium hydroxide solution (5.0 mL), methyl iodide (155 μL) was added, and the mixture was stirred at room temperature for 1 hour. bottom. After confirming that the raw material had disappeared by LCMS, hydrochloric acid was added to adjust the pH to 4, and the mixture was stirred for 15 minutes. The resulting solid was filtered to give 2- (methylsulfanyl) -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-ol (399 mg).
(D) To the compound (175 mg) obtained in (c), phosphorus oxychloride (1.3 mL) and DIPEA (244 μL) were added in order, and the mixture was stirred at 100 ° C. for 2 hours. After confirming that the raw material had disappeared by LCMS, toluene was added and the residue obtained by azeotrope was used for the next reaction.
(E) After dissolving a part of the residue obtained in (d) and DIPEA (305 μL) in THF (4.0 mL), the compound (58.2 mg) synthesized in Reference Example 1 was added, and the mixture was added at room temperature for 1 hour. Stirred. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-{[2- (methylsulfanyl) -7- (trifluoromethyl). ) Pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (77.5 mg) was obtained.
(F) The compound (77.5 mg) obtained in (e) was dissolved in THF (4.0 mL), metachloroperbenzoic acid (129 mg) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw materials had disappeared by LCMS, DIPEA (199 μL) and tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride (86.5 mg) were added, and the mixture was stirred at 60 ° C. for 2 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, chloroform (2.0 mL) and trifluoroacetic acid (767 μL) were added, and the mixture was stirred at room temperature for 2 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (76.1 mg).
　（実施例４０）
２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例３９（ｅ）と同様の手法で、２－｛［２－（メチルスルファニル）－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｂ）実施例３９（ｆ）と同様の手法で、（ａ）で得られた化合物から表題の化合物を得た。 (Example 40)
2- ({2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide (a) In the same manner as in Example 39 (e), 2-N-cyclopentylethane-1-sulfonamide (a), except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. {[2- (Methylsulfanyl) -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide Obtained.
(B) The title compound was obtained from the compound obtained in (a) by the same method as in Example 39 (f).
　（実施例４１）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）実施例３９（ａ）における３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 41)
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Propane-2-yl) ethane-1-sulfonamide (a) 3-bromo-1H-pyrazol-5-instead of 3- (trifluoromethyl) -1H-pyrazole-5-amine in Example 39 (a) The title compound was obtained in the same manner as in Example 39 except that amine was used.
　（実施例４２）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成した化合物の代わりに参考例３で合成した化合物を、それぞれ用いた以外は、実施例３９（ａ）から（ｅ）と同様の手法で２－｛［７－ブロモ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンタン－１－スルホンアミドを得た。
（ｂ）（ａ）で合成した化合物を用いて、実施例３９（ｆ）と同様の手法で表題の化合物を得た。 (Example 42)
2-({7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Instead of ethane-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine, 3-bromo-1H-pyrazol-5-amine was used instead of the compound synthesized in Reference Example 1. 2-{[7-Bromo-2- (methylsulfanyl) pyrazolo [1,5-] by the same method as in Examples 39 (a) to (e) except that the compounds synthesized in Reference Example 3 were used respectively. a] [1,3,5] Triazine-4-yl] amino} -N-cyclopentane-1-sulfonamide was obtained.
(B) Using the compound synthesized in (a), the title compound was obtained in the same manner as in Example 39 (f).
　（実施例４３）
Ｎ－シクロペンチル－２－｛［５－（４－メチルピペラジン－１－イル）［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）１Ｈ－１，２，４－トリアゾール－５－アミン（５２１ｍｇ）をＤＭＦ（７．０ｍＬ）に溶解し０℃で冷却した後、エトキシカルボニルイソチオシアナート（０．７ｍＬ）を滴下して、１６時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、冷水（７５ｍＬ）を加え反応を停止し、酢酸エチルで抽出した。有機層を濃縮してエチル［（１Ｈ－１，２，４－トリアゾール－５－イル）カルバモチオイル］カーバメート（１．１ｇ）を混合物として得た。
（ｂ）（ａ）で得られた化合物（１．０ｇ）をエタノール（１８．０ｍＬ）に溶解し、２Ｍ水酸化ナトリウム水溶液（５．３ｍＬ）を加え還流下で３０分攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、室温で３０分攪拌した。得られた固体をろ取した後、水（２９．０ｍＬ）と２Ｍ塩酸（９．７ｍＬ）を加えて室温で１０分攪拌した。得られた固体を濾過し、５－スルファニル［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－オール（５９９ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（８０９ｍｇ）をＴＨＦ（３．２ｍＬ）に溶解し、０．５Ｍナトリウムメトキシドメタノール溶液（１０．０ｍＬ）を加え室温で２分攪拌した。その後、ヨウ化メチル（３１２μＬ）を加え、室温で１時間攪拌し、ＬＣＭＳで原料が消失したことを確認した後に、溶媒を留去し、水（３０．０ｍＬ）を加えた。室温で１５分攪拌した後に、得られた固体をろ取し、５－（メチルスルファニル）［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－オール（５３９ｍｇ）を得た。
（ｄ）（ｃ）で得られた化合物（２６９ｍｇ）にオキシ塩化リン（２．７ｍＬ）とＤＩＰＥＡ（１．７５ｍＬ）を順に加え、１００℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、トルエンを加え共沸し得られた残留物を次の反応に使用した。
（ｅ）（ｄ）で得られた残留物の一部とＤＩＰＥＡ（１．８ｍＬ）をＴＨＦ（１７．０ｍＬ）に溶解した後、参考例３で合成した化合物（２８３ｍｇ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、炭酸水素ナトリウム水溶液を加え反応を停止した後に、クロロホルムで抽出した。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、Ｎ－シクロペンチル－２－｛［５－（メチルスルファニル）［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル］アミノ｝エタン－１－スルホンアミド（２４１ｍｇ）を得た。
（ｆ）（ｅ）で得られた化合物（８９．３ｍｇ）をＴＨＦ（２．５ｍＬ）に溶解し、メタクロロ過安息香酸（６７．８ｍｇ）を加え、室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、ＤＩＰＥＡ（１２８μＬ）と１－メチルピペラジン（５５．０μＬ）を加え６０℃で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、チオ硫酸ナトリウムを加え反応を停止し、クロロホルムで抽出した。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、酢酸エチル：メタノール）で精製し、表題の化合物（７６．５ｍｇ）を得た。 (Example 43)
N-cyclopentyl-2-{[5- (4-methylpiperazin-1-yl) [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] amino} Ethan-1-sulfonamide (a) 1H-1,2,4-triazole-5-amine (521 mg) was dissolved in DMF (7.0 mL) and cooled at 0 ° C., and then ethoxycarbonylisothiocyanate (0. 7 mL) was added dropwise, and the mixture was stirred for 16 hours. After confirming that the raw material had disappeared by LCMS, cold water (75 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give ethyl [(1H-1,2,4-triazole-5-yl) carbamoti oil] carbamate (1.1 g) as a mixture.
(B) The compound (1.0 g) obtained in (a) was dissolved in ethanol (18.0 mL), a 2 M aqueous sodium hydroxide solution (5.3 mL) was added, and the mixture was stirred under reflux for 30 minutes. After confirming that the raw material had disappeared by LCMS, the mixture was stirred at room temperature for 30 minutes. The obtained solid was collected by filtration, water (29.0 mL) and 2M hydrochloric acid (9.7 mL) were added, and the mixture was stirred at room temperature for 10 minutes. The obtained solid was filtered to obtain 5-sulfanyl [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-ol (599 mg).
(C) The compound (809 mg) obtained in (b) was dissolved in THF (3.2 mL), a 0.5 M sodium methoxide methanol solution (10.0 mL) was added, and the mixture was stirred at room temperature for 2 minutes. Then, methyl iodide (312 μL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw material had disappeared by LCMS, the solvent was distilled off and water (30.0 mL) was added. After stirring at room temperature for 15 minutes, the obtained solid was collected by filtration and 5- (methylsulfanyl) [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-ol. (539 mg) was obtained.
(D) To the compound (269 mg) obtained in (c), phosphorus oxychloride (2.7 mL) and DIPEA (1.75 mL) were added in this order, and the mixture was stirred at 100 ° C. for 2 hours. After confirming that the raw material had disappeared by LCMS, toluene was added and the residue obtained by azeotrope was used for the next reaction.
(E) After dissolving a part of the residue obtained in (d) and DIPEA (1.8 mL) in THF (17.0 mL), the compound (283 mg) synthesized in Reference Example 3 was added, and the mixture was added at room temperature for 1 hour. Stirred. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and then the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and N-cyclopentyl-2-{[5- (methylsulfanyl) [1, 2,4] Triazolo [1,5-a] [1,3,5] triazine-7-yl] amino} ethane-1-sulfonamide (241 mg) was obtained.
(F) The compound (89.3 mg) obtained in (e) was dissolved in THF (2.5 mL), metachloroperbenzoic acid (67.8 mg) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw materials had disappeared by LCMS, DIPEA (128 μL) and 1-methylpiperazine (55.0 μL) were added, and the mixture was stirred at 60 ° C. for 3 hours. After confirming that the raw materials had disappeared by LCMS, sodium thiosulfate was added to stop the reaction, and extraction was performed with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: methanol) to obtain the title compound (76.5 mg).
　（実施例４４）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成した化合物の代わりに参考例５で合成した化合物を、それぞれ用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 44)
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) Etan-1-sulfonamide (a) 3- (Trifluoromethyl) -1H-pyrazole-5-amine was replaced with 3-bromo-1H-pyrazole-5-amine in Reference Example 1. The title compound was obtained in the same manner as in Example 39, except that the compounds synthesized in Reference Example 5 were used instead of the compounds.
　（実施例４５）
２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）４，６－ジクロロ－２－（メチルスルファニル）－５－ニトロピリミジン（９６０ｍｇ）をＴＨＦ（８．０ｍＬ）に溶解し、０℃でトリエチルアミン（６１３μＬ）と２Ｍアンモニアエタノール溶液（３．０ｍＬ）を加え、室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去し６－クロロ－２－（メチルスルファニル）－５－ニトロピリミジン－４－アミンを混合物として得た。
（ｂ）（ａ）で得られた混合物（６６２ｍｇ）をＴＨＦ（１５．０ｍＬ）に溶解し、参考例１で合成した化合物（５０６ｍｇ）とＤＩＰＥＡ（１．０ｍＬ）を加え、４０℃で１８時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去し２－｛［６－アミノ－２－（メチルスルファニル）－５－ニトロピリミジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミドを混合物として得た。
（ｃ）（ｂ）で得られた混合物（１．０ｇ）をＴＨＦ（３０．０ｍＬ）に溶解し、メタクロロ過安息香酸（２．０ｇ）を加え、室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、１－メチルピペラジン（９９８μＬ）とＤＩＰＥＡ（１．６ｍＬ）を加え、室温で１時間反応させた。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、２－｛［６－アミノ－２－（４－メチルピペラジン－１－イル）－５－ニトロピリミジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド（１．１ｇ）を得た。
（ｄ）（ｃ）で得られた化合物（５９２ｍｇ）と亜鉛（４９０ｍｇ）をエタノール（１５．０ｍＬ）と飽和塩化アンモニウム水溶液（７．５ｍＬ）の混液に加え、１００℃で５時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、１．０Ｍ　グリオキサール水溶液（５．０ｍＬ）を加え１００℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、炭酸水素ナトリウム水溶液を加え反応を停止し、セライトろ過をした後、クロロホルム／メタノールで抽出した。有機層を減圧下で留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（１２５ｍｇ）を得た。 (Example 45)
2-{[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (a) 4,6-dichloro-2 -(Methyl sulfanyl) -5-nitropyrimidine (960 mg) was dissolved in THF (8.0 mL), triethylamine (613 μL) and 2M ammonia ethanol solution (3.0 mL) were added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. .. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was distilled off under reduced pressure to obtain 6-chloro-2- (methylsulfanyl) -5-nitropyrimidine-4-amine as a mixture.
(B) The mixture (662 mg) obtained in (a) was dissolved in THF (15.0 mL), the compound (506 mg) synthesized in Reference Example 1 and DIPEA (1.0 mL) were added, and the mixture was added at 40 ° C. for 18 hours. Stirred. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was distilled off under reduced pressure and 2-{[6-amino-2- (methylsulfanilic) -5-nitropyrimidine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfone. The amide was obtained as a mixture.
(C) The mixture (1.0 g) obtained in (b) was dissolved in THF (30.0 mL), metachloroperbenzoic acid (2.0 g) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw materials had disappeared by LCMS, 1-methylpiperazine (998 μL) and DIPEA (1.6 mL) were added, and the mixture was reacted at room temperature for 1 hour. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to 2-{[6-amino-2- (4-methylpiperazin-1-). Ill) -5-nitropyrimidine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (1.1 g) was obtained.
(D) The compound (592 mg) obtained in (c) and zinc (490 mg) were added to a mixed solution of ethanol (15.0 mL) and saturated aqueous ammonium chloride solution (7.5 mL), and the mixture was stirred at 100 ° C. for 5 hours. After confirming that the raw material had disappeared by LCMS, a 1.0 M aqueous glyoxal solution (5.0 mL) was added, and the mixture was stirred at 100 ° C. for 2 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, filtration through Celite was performed, and then extraction was performed with chloroform / methanol. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (125 mg).
　（実施例４６）
２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド
（ａ）実施例４５で得られた化合物をエタノール／水＝４／１（２．５ｍＬ）に溶解し、ピリジン　臭化水素酸塩（１５．９ｍｇ）を加え室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、分取ＨＰＬＣ（アセトニトリル／水）で精製した。得られた分画に炭酸水素ナトリウム水溶液を加え、クロロホルム／メタノールで抽出した。有機層を減圧下で留去し、表題の化合物（４．５ｍｇ）を得た。 (Example 46)
2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide (a) Example 45 The compound obtained in (1) was dissolved in ethanol / water = 4/1 (2.5 mL), pyridine hydrobromide (15.9 mg) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw materials had disappeared by LCMS, the mixture was purified by preparative HPLC (acetonitrile / water). An aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with chloroform / methanol. The organic layer was distilled off under reduced pressure to obtain the title compound (4.5 mg).
　（実施例４７）
Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例４５（ｂ）における参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例４５と同様の手法で表題の化合物を得た。 (Example 47)
N-cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide (a) Synthesized in Reference Example 1 in Example 45 (b) The title compound was obtained in the same manner as in Example 45 except that the compound synthesized in Reference Example 3 was used instead of the compound.
　（実施例４８）
２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）実施例４６（ａ）と同様の手法で、実施例４７で得られた混合物から表題の化合物を得た。 (Example 48)
2-{[6-bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (a) Same as Example 46 (a) By technique, the title compound was obtained from the mixture obtained in Example 47.
　（実施例４９）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］プテリジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）実施例４５（ｂ）における参考例１で合成した化合物の代わりに参考例３で合成した化合物を、実施例４５（ｃ）における１－メチルピペラジンの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩を用いた以外は、実施例４５と同様の手法でｔｅｒｔ－ブチル　［１－（４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝プテリジン－２－イル）アゼチジン－３－イル］メチルカーバメートを得た。
（ｂ）実施例１（ｃ）と同様の手法により、表題の化合物（４９．７ｍｇ）を得た。 (Example 49)
N-Cyclopentyl-2-({2- [3- (methylamino) azetidine-1-yl] pteridine-4-yl} amino) ethane-1-sulfonamide (a) Reference Example 1 in Example 45 (b) The compound synthesized in Reference Example 3 was used in place of the compound synthesized in Example 45 (c), except that tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride was used instead of 1-methylpiperazin in Example 45 (c). Methyl carbamate of tert-butyl [1-(4-{[2- (cyclopentyl sulfamoyl) ethyl] amino} pteridine-2-yl) azetidine-3-yl] was obtained in the same manner as in Example 45.
(B) The title compound (49.7 mg) was obtained by the same method as in Example 1 (c).
　（実施例５０）
Ｎ－シクロペンチル－２－｛［５－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド
（ａ）３－ブロモ－５，７－ジクロロピラゾロ［１，５－ａ］ピリミジン（８０．１ｍｇ）をＴＨＦ（３．０ｍＬ）に溶解し、ＤＩＰＥＡ（７９μＬ）を加え０℃で冷却した。参考例３で合成した化合物（５７．７ｍｇ）を加えた後、室温に昇温しＬＣＭＳで原料が消失するまで攪拌した。炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を減圧下で留去し、得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、２－［（３－ブロモ－５－クロロピラゾロ［１，５－ａ］ピリミジン－７－イル）アミノ］－Ｎ－シクロペンチルエタン－１－スルホンアミド（９１．７ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（６１．１ｍｇ）を１，４－ジオキサン（２ｍＬ）に溶解しＤＩＰＥＡ（７５μＬ）と１－メチルピペラジン（４８μＬ）を加えた後、１２０℃に昇温しＬＣＭＳで原料が消失するまで攪拌した。炭酸水素ナトリウム水溶液を加え反応を停止し、クロロホルムで抽出した。有機層を減圧下で留去し、得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、２－｛［３－ブロモ－５－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］ピリミジン－７－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド（５３．５　ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（４３．０ｍｇ）と水酸化パラジウム（４．３ｍｇ）をメタノール（２ｍＬ）に懸濁した後、水素雰囲気下ＬＣＭＳで原料が消失するまで攪拌した。混合物をセライト濾過した後、得られた有機層を減圧下で留去し、残留物をシリカゲルカラムクロマトグラフィーで精製することで表題の化合物（２４．８ｍｇ）を得た。 (Example 50)
N-cyclopentyl-2-{[5- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] pyrimidine-7-yl] amino} ethane-1-sulfonamide (a) 3-bromo-5 , 7-Dichloropyrazolo [1,5-a] pyrimidine (80.1 mg) was dissolved in THF (3.0 mL), DIPEA (79 μL) was added, and the mixture was cooled at 0 ° C. After adding the compound (57.7 mg) synthesized in Reference Example 3, the temperature was raised to room temperature and the mixture was stirred by LCMS until the raw materials disappeared. An aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to 2-[(3-bromo-5-chloropyrazolo [1,5-a] pyrimidin-7-yl) amino]. -N-Cyclopentylethane-1-sulfonamide (91.7 mg) was obtained.
(B) The compound (61.1 mg) obtained in (a) was dissolved in 1,4-dioxane (2 mL), DIPEA (75 μL) and 1-methylpiperazine (48 μL) were added, and then the temperature was raised to 120 ° C. The mixture was stirred by LCMS until the raw materials disappeared. An aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 2-{[3-bromo-5- (4-methylpiperazin-1-yl) pyrazolo [1,5-]. a] Pirimidine-7-yl] amino} -N-cyclopentylethane-1-sulfonamide (53.5 mg) was obtained.
(C) The compound (43.0 mg) obtained in (b) and palladium hydroxide (4.3 mg) were suspended in methanol (2 mL), and then stirred by LCMS under a hydrogen atmosphere until the raw materials disappeared. After filtering the mixture by Celite, the obtained organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (24.8 mg).
　（実施例５１）
２－｛［２－（４－アミノピペリジン－１－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－クロロ－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例３９（ａ）から（ｅ）と同様の手法で２－｛［７－クロロ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｂ）（ａ）で得られた化合物（６２．５ｍｇ）をＴＨＦ（０．８ｍＬ）に溶解し、メタクロロ過安息香酸（６９ｍｇ）を加え、室温で２時間攪拌した。ＤＩＰＥＡ（１３９．２μＬ）とピペリジン－４－アミン（２５．４μＬ）を加え６０℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（２５．２ｍｇ）を得た。 (Example 51)
2-{[2- (4-Aminopiperidin-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1- Examples 39 (a) to (e) except that 3-chloro-1H-pyrazole-5-amine was used instead of sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazole-5-amine. 2-{[7-Chloro-2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1- A sulfonamide was obtained.
(B) The compound (62.5 mg) obtained in (a) was dissolved in THF (0.8 mL), metachloroperbenzoic acid (69 mg) was added, and the mixture was stirred at room temperature for 2 hours. DIPEA (139.2 μL) and piperidine-4-amine (25.4 μL) were added, and the mixture was stirred at 60 ° C. for 2 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (25.2 mg).
　（実施例５２）
２－｛［７－クロロ－２－（１，４－ジアゼパン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ピペリジン－４－アミンの代わりに１，４－ジアゼパンを用いた以外は、実施例５１と同様の手法で表題の化合物を得た。 (Example 52)
2-{[7-Chloro-2- (1,4-diazepan-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane- The title compound was obtained in the same manner as in Example 51, except that 1,4-diazepan was used instead of 1-sulfonamide (a) piperidine-4-amine.
　（実施例５３）
２－（｛２－［（３Ｓ）－３－アミノピロリジン－１－イル］－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ピペリジン－４－アミンの代わりにｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートを用いた以外は、実施例５１と同様の手法でｔｅｒｔ－ブチル　［（３Ｓ）－１－（７－クロロ－４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）ピロリジン－３－イル］カーバメートを得た。
（ｂ）（ａ）で得られた化合物（９２．３ｍｇ）をクロロホルム（０．８７ｍＬ）に溶解し、トリフルオロ酢酸（０．８７ｍＬ）を加えた後室温で１．５時間攪拌した。減圧下で溶媒を留去した後、残留物に飽和炭酸水素ナトリウム水溶液を加えて攪拌し、再度溶媒を減圧下で除去した。残留物をアミノシリカゲルクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（２２．４ｍｇ）を得た。 (Example 53)
2-({2-[(3S) -3-aminopyrrolidine-1-yl] -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Tert-butyl [(3S)] in the same manner as in Example 51, except that tert-butyl (3S) -pyrrolidine-3-ylcarbamate was used instead of ethane-1-sulfonamide (a) piperidine-4-amine. ) -1- (7-Chloro-4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrazolo [1,5-a] [1,3,5] triazine-2-yl) pyrrolidine-3- Il] I got a carbamate.
(B) The compound (92.3 mg) obtained in (a) was dissolved in chloroform (0.87 mL), trifluoroacetic acid (0.87 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. After distilling off the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue and stirred, and the solvent was removed again under reduced pressure. The residue was purified by amino silica gel chromatography (developing solvent, chloroform: methanol) to give the title compound (22.4 mg).
　（実施例５４）
２－（｛２－ブロモ－５－［３－（メチルアミノ）アゼチジン－１－イル］［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）４－ブロモ－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－１，２，４－トリアゾール－５－アミンを用いた以外は、実施例４２と同様の手法で表題の化合物を得た。 (Example 54)
2-({2-Bromo-5- [3- (methylamino) azetidine-1-yl] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] } Amino) -N-cyclopentylethane-1-sulfonamide (a) 3-Bromo-1H-1,2,4-triazole-5-amine was used instead of 4-bromo-1H-pyrazol-5-amine. The title compound was obtained in the same manner as in Example 42 except that.
　（実施例５５）
２－（｛７－シアノ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）実施例４２（ｅ）で合成した化合物（１５４ｍｇ）をＴＨＦ（８．０ｍＬ）に溶解し、メタクロロ過安息香酸（２６０ｍｇ）を加え、室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、ＤＩＰＥＡ（４００μＬ）とｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（１７２ｍｇ）を加え６０℃で２時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後、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。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、ｔｅｒｔ－ブチル［１－（７－ブロモ－４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメート（１５２ｍｇ）を得た。
（ｂ）（ａ）で合成した化合物（１２３ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（２０ｍｇ）、亜鉛（４．０ｍｇ）、シアン化亜鉛（５０ｍｇ）、１，１’－ビス（ジフェニルホスフィノ）フェロセン（２４ｍｇ）をＤＭＡ（１．４ｍＬ）に加えマイクロウェーブ反応装置を用い１５０℃で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認し、不要物をセライト濾過で除き、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。減圧下で溶媒を留去し、得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、ｔｅｒｔ－ブチル［１－（７－シアノ－４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメート（１０２ｍｇ）を得た。
（ｃ）実施例１（ｃ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 55)
2-({7-Cyano-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Etan-1-sulfonamide (a) The compound (154 mg) synthesized in Example 42 (e) was dissolved in THF (8.0 mL), metachloroperbenzoic acid (260 mg) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the raw materials had disappeared by LCMS, DIPEA (400 μL) and tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride (172 mg) were added, and the mixture was stirred at 60 ° C. for 2 hours. After confirming that the raw materials had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) and tert-butyl [1- (7-bromo-4-{[2- ( Cyclopentylsulfamoyl) ethyl] amino} pyrazolo [1,5-a] [1,3,5] triazine-2-yl) azetidine-3-yl] methyl carbamate (152 mg) was obtained.
(B) Compound (123 mg) synthesized in (a), tris (dibenzylideneacetone) dipalladium (0) (20 mg), zinc (4.0 mg), zinc cyanide (50 mg), 1,1'-bis ( Diphenylphosphino) ferrocene (24 mg) was added to DMA (1.4 mL), and the mixture was stirred at 150 ° C. for 3 hours using a microwave reactor. After confirming that the raw materials had disappeared by LCMS, unnecessary substances were removed by filtration through Celite, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (developing solvent, hexane: ethyl acetate) with tert-butyl [1- (7-cyano-4-{[2-]. (Cyclopentyl sulfamoyl) ethyl] amino} pyrazolo [1,5-a] [1,3,5] triazine-2-yl) azetidine-3-yl] methyl carbamate (102 mg) was obtained.
(C) The title compound was obtained from the compound obtained in (b) by the same method as in Example 1 (c).
　（実施例５６）
２－｛［６－シアノ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）実施例４８（ａ）で合成した化合物（３１．５ｍｇ）とテトラキストリフェニルホスフィンパラジウム（０）（６．９ｍｇ）、シアン化亜鉛（２２．２ｍｇ）をＤＭＦ（０．６ｍＬ）に懸濁させ、マイクロウェーブ反応装置を用い１２０℃で１時間攪拌した。不要物をセライト濾過で除き、減圧下で溶媒を留去、得られた残留物を分取ＨＰＬＣ（アセトニトリル／水）で精製することで表題の化合物（１１．１ｍｇ）を得た。 (Example 56)
2-{[6-cyano-2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (a) Synthesized in Example 48 (a) Compound (31.5 mg), tetrakistriphenylphosphine palladium (0) (6.9 mg) and zinc cyanide (22.2 mg) were suspended in DMF (0.6 mL) at 120 ° C. using a microwave reactor. It was stirred for 1 hour. Unnecessary substances were removed by filtration through Celite, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC (acetonitrile / water) to give the title compound (11.1 mg).
　（実施例５７）
２－（｛７－クロロ－２－［３－メチル－３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　メチル（３－メチルアゼチジン－３－イル）カーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 57)
2- ({7-Chloro-2- [3-methyl-3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Except for the use of tert-butyl methyl (3-methylazetidine-3-yl) carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-yl carbamate. , The title compound was obtained in the same manner as in Example 53.
　（実施例５８）
Ｎ－シクロペンチル－２－｛［６－エトキシ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）実施例４８で得られた化合物（１５ｍｇ）をメタノール（１ｍＬ）に溶解した後、０．５Ｍ　水酸化カリウム－エタノール溶液（１２０μＬ）を加えマイクロウェーブ反応装置を用い１４０℃で４０分攪拌した。飽和塩化アンモニウム水溶液を加えた後、クロロホルム／メタノール（１０／１）で有機相を抽出し、溶媒を減圧下で留去することで表題の化合物（２０．１ｍｇ）を得た。 (Example 58)
N-Cyclopentyl-2-{[6-ethoxy-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide (a) Compound obtained in Example 48 ( 15 mg) was dissolved in methanol (1 mL), 0.5 M potassium hydroxide-ethanol solution (120 μL) was added, and the mixture was stirred at 140 ° C. for 40 minutes using a microwave reactor. After adding saturated aqueous ammonium chloride solution, the organic phase was extracted with chloroform / methanol (10/1), and the solvent was distilled off under reduced pressure to give the title compound (20.1 mg).
　（実施例５９）
２－｛［７－クロロ－２－（２，６－ジアザビシクロ［３．２．０］ヘプタン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　２，６－ジアザビシクロ［３．２．０］ヘプタン－２－カルボキシレートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 59)
2-{[7-Chloro-2- (2,6-diazabicyclo [3.2.0] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] Amino} -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-ylcarbamate instead of tert-butyl 2,6-diazabicyclo [3.2.0] heptane-2- The title compound was obtained in the same manner as in Example 53 except that carboxylate was used.
　（実施例６０）
２－｛［２－（３－アミノ－３－メチルアゼチジン－１－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　（３－メチルアゼチジン－３－イル）カーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 60)
2-{[2- (3-Amino-3-methylazetidine-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- Example 53, except that tert-butyl (3-methylazetidine-3-yl) carbamate was used instead of cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-yl carbamate. The title compound was obtained in the same manner as in.
　（実施例６１）
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）メチル　４－ブロモ－１Ｈ－ピロール－２－カルボキシレート（２．０４ｇ）をＤＭＦに溶解し、０℃にて冷却した後、水素化ナトリウム（６５４．５ｍｇ）とＯ－（２，４－ジニトロフェニル）ヒドロキシルアミン（２．３９ｇ）を加え室温で２時間攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで有機相を抽出し、減圧下で溶媒を留去することで得られた残留物をシリカゲルクロマトグラフィーで精製することでメチル　１－アミノ－４－ブロモ－１Ｈ－ピロール－２－カルボキシレートを定量的に得た。
（ｂ）（ａ）で得られた化合物を用いて実施例１０（ａ）から（ｃ）と同様の手法により、６－ブロモ－４－クロロ－２－（メチルスルファニル）ピロロ［２，１－ｆ］［１，２，４］トリアジンを得た。
（ｃ）（ｂ）で得られた化合物を用いて実施例３９（ｅ）と同様の手法により、２－｛［６－ブロモ－２－（メチルスルファニル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンタン－１－スルホンアミドを得た。
（ｄ）（ｃ）で合成された化合物（６０ｍｇ）をＴＨＦ（１．３８ｍＬ）に溶解し０℃にて冷却した。メタクロロ過安息香酸（１０２ｍｇ）を加えた後、５０℃で４５分攪拌し、再び０℃にて冷却した。飽和チオ硫酸ナトリウム水溶液と飽和炭酸水素ナトリウム水溶液を加えて攪拌した後、酢酸エチルで有機相を抽出し、減圧下で溶媒を留去することで得られた粗生成物を次の反応に用いた。
（ｅ）（ｄ）で合成された粗生成物（１７．５ｍｇ）をＮＭＰ（３８０μＬ）に溶解し、ＤＩＰＥＡ（３２．８μＬ）を加え、ピペラジン（１６．２ｍｇ）を攪拌開始前、１時間後、３．５時間後と添加しつつ、マイクロウェーブ反応装置を用い２００℃で攪拌した。酢酸エチルと水を加え有機相を抽出し、減圧下で溶媒を留去、得られた残留物を分取ＨＰＬＣ（アセトニトリル／水）で精製することで表題の化合物（１０．３ｍｇ）を得た。 (Example 61)
2-{[6-Bromo-2- (piperazin-1-yl) pyrrole [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (A) Methyl 4-bromo-1H-pyrrole-2-carboxylate (2.04 g) was dissolved in DMF, cooled at 0 ° C., and then sodium hydride (654.5 mg) and O- (2,4). -Dinitrophenyl) Hydroxylamine (2.39 g) was added and stirred at room temperature for 2 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the organic phase is extracted with ethyl acetate, and the residue obtained by distilling off the solvent under reduced pressure is purified by silica gel chromatography to obtain methyl 1-amino-4-. Bromo-1H-pyrrole-2-carboxylate was quantitatively obtained.
(B) Using the compound obtained in (a), 6-bromo-4-chloro-2- (methylsulfanyl) pyrrolo [2,1-" was used in the same manner as in Examples 10 (a) to (c). f] [1,2,4] Triazine was obtained.
(C) Using the compound obtained in (b), 2-{[6-bromo-2- (methylsulfanyl) pyrolo [2,1-f] [1] was carried out in the same manner as in Example 39 (e). , 2,4] Triazine-4-yl] amino} -N-cyclopentane-1-sulfonamide was obtained.
(D) The compound (60 mg) synthesized in (c) was dissolved in THF (1.38 mL) and cooled at 0 ° C. After adding metachloroperbenzoic acid (102 mg), the mixture was stirred at 50 ° C. for 45 minutes and cooled again at 0 ° C. After adding saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution and stirring, the organic phase was extracted with ethyl acetate, and the crude product obtained by distilling off the solvent under reduced pressure was used for the next reaction. ..
(E) The crude product (17.5 mg) synthesized in (d) was dissolved in NMP (380 μL), DIPEA (32.8 μL) was added, and piperazine (16.2 mg) was added 1 hour before the start of stirring. After 3.5 hours, the mixture was stirred at 200 ° C. using a microwave reactor. Ethyl acetate and water were added to extract the organic phase, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative HPLC (acetonitrile / water) to give the title compound (10.3 mg). ..
　（実施例６２）
２－｛［２－（３－アミノアゼチジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）参考例１で合成した化合物の代わりに、参考例３で合成した化合物を用いた以外は、実施例１６（ａ）と同様の手法により２－［（２－クロロピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル）アミノ］－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｂ）実施例３４（ａ）で合成した化合物の代わりに（ａ）で合成した化合物を、２－メチル－２，６－ジアザスピロ［３．３］ヘプタンの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イルカーバメートを用いた以外は実施例３４（ｂ）と同様の手法によりｔｅｒｔ－ブチル［１－（４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピロロ［２，１－ｆ］［１，２，４］トリアジン－２－イル）アゼチジン－３－イル］カーバメートを得た。
（ｃ）（ｂ）で合成した化合物（１０．４ｍｇ）をジクロロメタン（４４０μＬ）に溶解し、トリメチルシリル　トリフルオロメタンスルホネート（１５．７μＬ）と２，６－ルチジン（１２．６μＬ）を加えた後室温で１．５時間攪拌した。混合物を０℃で冷却し、飽和塩化アンモニウム水溶液を加えた後酢酸エチル添加、有機相を抽出した。有機相を飽和炭酸水素ナトリウム水溶液で洗浄し、溶媒を減圧下で留去した。残留物を分取ＨＰＬＣ（アセトニトリル／水）で精製することで表題の化合物（６．８ｍｇ）を得た。 (Example 62)
2-{[2- (3-Aminoazetidine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (A) 2-[(2-Chloropyrrolo [2,1-]) was carried out in the same manner as in Example 16 (a) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. f] [1,2,4] triazine-4-yl) amino] -N-cyclopentylethane-1-sulfonamide was obtained.
(B) Instead of the compound synthesized in Example 34 (a), the compound synthesized in (a) was replaced with tert-butyl azetidine-3- instead of 2-methyl-2,6-diazaspiro [3.3] heptane. Tert-Butyl [1-(4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrrolo [2,1-f] [ 1,2,4] Triazine-2-yl) Azetidine-3-yl] Carbamate was obtained.
(C) The compound (10.4 mg) synthesized in (b) was dissolved in dichloromethane (440 μL), trimethylsilyl trifluoromethanesulfonate (15.7 μL) and 2,6-lutidine (12.6 μL) were added, and then at room temperature. The mixture was stirred for 1.5 hours. The mixture was cooled at 0 ° C., saturated aqueous ammonium chloride solution was added, ethyl acetate was added, and the organic phase was extracted. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile / water) to give the title compound (6.8 mg).
　（実施例６３）
２－｛［２－（３－アミノアゼチジン－１－イル）－７－（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］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－（ジフルオロメチル）－１Ｈ－ピラゾール－５－アミンを、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　アゼチジン－３－イルカーバメートを用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 63)
2-{[2- (3-Aminoazetidine-1-yl) -7- (difluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- Cyclopentylethane-1-sulfonamide (a) 3- (difluoromethyl) -1H-pyrazol-5-amine instead of 3- (trifluoromethyl) -1H-pyrazol-5-amine, tert-butyl azetidine-3 The title compound was obtained in the same manner as in Example 39, except that tert-butyl azetidine-3-yl carbamate was used instead of -yl (methyl) carbamate hydrochloride.
　（実施例６４）
２－｛［７－ブロモ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用いた以外は、実施例４２と同様の手法で表題の化合物を得た。 (Example 64)
2-{[7-Bromo-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (A) The title compound was obtained in the same manner as in Example 42, except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
　（実施例６５）
２－｛［７－クロロ－２－（１，６－ジアザスピロ［３．３］ヘプタン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　１，６－ジアザスピロ［３．３］ヘプタン－１－カルボキシレートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 65)
2-{[7-Chloro-2- (1,6-diazaspiro [3.3] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-Cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-ylcarbamate instead of tert-butyl 1,6-diazaspiro [3.3] heptane-1-carboxylate The title compound was obtained in the same manner as in Example 53, except that the compound was obtained.
　（実施例６６）
２－｛［２－（３－アミノアゼチジン－１－イル）－６－ブロモイミダゾ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）エチル　１－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－１Ｈ－イミダゾール－２－カルボキシレート（１．２ｇ）をＤＭＦ（１０ｍＬ）に溶解した後、Ｎ－ブロモスクシンイミド（８０７ｍｇ）を加えて室温で３時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。減圧下で溶媒を留去した後、得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、エチル　４－ブロモ－１－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－１Ｈ－イミダゾール－２－カルボキシレート（１１６ｍｇ）を得た。
（ｂ）実施例１（ｃ）と同様の手法で、エチル　１－アミノ－４－ブロモ－１Ｈ－イミダゾール－２－カルボキシレートを得た。
（ｃ）実施例３９（ａ）と同様の手法で（ｂ）で得られた化合物からエチル　４－ブロモ－１－｛［（エトキシカルボニル）カルバモチオイル］アミノ｝－１Ｈ－イミダゾール－２－カルボキシレートを得た。
（ｄ）実施例３９（ｂ）と同様の手法で、（ｃ）で得られた化合物から６－ブロモ－２－スルファニルイミダゾロ［２，１－ｆ］［１，２，４］トリアジン－４－オールを得た。
（ｅ）ヨウ化メチルの代わりに２，２，２－トリフルオロエチル　ヨージドを用いた以外は、実施例３９（ｃ）と同様の手法で、（ｄ）で得られた化合物から６－ブロモ－２－［（２，２，２－トルフルオロエチル）スルファニル］イミダゾロ［２，１－ｆ］［１，２，４］トリアジン－４－オールを得た。
（ｆ）実施例３９（ｄ）と同様の手法で、（ｅ）で得られた化合物から６－ブロモ－４－クロロ－２－［（２，２，２－トルフルオロエチル）スルファニル］イミダゾロ［２，１－ｆ］［１，２，４］トリアジンを得た。
（ｇ）参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例３９（ｅ）と同様の手法で（ｆ）で得られた化合物から２－（｛６－ブロモ－２－［（２，２，２－トルフルオロエチル）スルファニル］イミダゾロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｈ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　アゼチジン－３－イルカーバメートを用いた以外は、実施例３９（ｆ）と同様の手法で、（ｇ）で得られた化合物から表題の化合物を得た。 (Example 66)
2-{[2- (3-Aminoazetidine-1-yl) -6-bromoimidazole [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane- 1-Sulfonamide (a) Ethyl 1-[(tert-butoxycarbonyl) amino] -1H-imidazole-2-carboxylate (1.2 g) was dissolved in DMF (10 mL) and then N-bromosuccinimide (807 mg). Was added and stirred at room temperature for 3 hours. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate), and ethyl 4-bromo-1-[(tert-butoxycarbonyl) amino]-. 1H-imidazole-2-carboxylate (116 mg) was obtained.
(B) Ethyl 1-amino-4-bromo-1H-imidazol-2-carboxylate was obtained in the same manner as in Example 1 (c).
(C) Ethyl 4-bromo-1-{[(ethoxycarbonyl) carbamoti oil] amino} -1H-imidazol-2-carboxy from the compound obtained in (b) in the same manner as in Example 39 (a). Got a rate.
(D) 6-Bromo-2-sulfanylimidazolo [2,1-f] [1,2,4] triazine-4 from the compound obtained in (c) in the same manner as in Example 39 (b). -I got an oar.
(E) 6-Bromo- from the compound obtained in (d) in the same manner as in Example 39 (c) except that 2,2,2-trifluoroethyl iodide was used instead of methyl iodide. 2-[(2,2,2-tolufluoroethyl) sulfanyl] imidazolo [2,1-f] [1,2,4] triazine-4-ol was obtained.
(F) 6-Bromo-4-chloro-2-[(2,2,2-torfluoroethyl) sulfanyl] imidazolo [ 2,1-f] [1,2,4] Triazine was obtained.
(G) From the compound obtained in (f) by the same method as in Example 39 (e), 2- ({{ 6-Bromo-2-[(2,2,2-torfluoroethyl) sulfanyl] imidazolo [2,1-f] [1,2,4] triazine-4-yl} amino} -N-cyclopentylethane-1 -Sulfonamide was obtained.
(H) In the same manner as in Example 39 (f), except that tert-butyl azetidine-3-yl carbamate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride, (g) The title compound was obtained from the compound obtained in.
　（実施例６７）
２－｛［６－ブロモ－２－（ピペラジン－１－イル）イミダゾ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用いた以外は、実施例６６と同様の手法で表題の化合物を得た。 (Example 67)
2-{[6-Bromo-2- (piperazine-1-yl) imidazo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (A) The title compound was obtained in the same manner as in Example 66, except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-ylcarbamate.
　（実施例６８）
２－｛［２－（６－アミノ－３－アザビシクロ［３．１．０］ヘキサン－３－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　３－アザビシクロ［３．１．０］ヘキサン－６－イルカーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 68)
2-{[2- (6-amino-3-azabicyclo [3.1.0] hexane-3-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino} -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidine-3-ylcarbamate instead of tert-butyl 3-azabicyclo [3.1.0] hexane-6-yl The title compound was obtained in the same manner as in Example 53 except that carbamate was used.
　（実施例６９）
４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－７－カルボキサミド
（ａ）実施例５５（ｂ）で得られた化合物（３３ｍｇ）をトリフルオロ酢酸（４２０μＬ）に溶解し、マイクロウェーブ反応装置を用い１４０℃で９０分攪拌した。減圧下で溶媒を留去した後、得られた残留物を分取ＨＰＬＣ（アセトニトリル／水）で精製した。得られた分画に炭酸水素ナトリウム水溶液を加え、クロロホルム／メタノールで抽出した。有機層を減圧下で留去することで、表題の化合物と４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝－２－｛３－［メチル（トリフルオロアセチル）アミノ］アゼチジン－１－イル｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－７－カルボキサミドが混合物として得られた。
（ｂ）（ａ）で得られた混合物（１９ｍｇ）をメタノール（２６３μＬ）に溶解した後、４Ｎ水酸化ナトリウム水溶液（８７．５μＬ）を加え室温で４時間攪拌した。水と酢酸エチルを加え抽出し、有機層を減圧下で留去することで表題の化合物を得た。 (Example 69)
4-{[2- (Cyclopentyl sulfamoyl) ethyl] amino} -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-7 -Carboxamide (a) The compound (33 mg) obtained in Example 55 (b) was dissolved in trifluoroacetic acid (420 μL) and stirred at 140 ° C. for 90 minutes using a microwave reactor. After distilling off the solvent under reduced pressure, the obtained residue was purified by preparative HPLC (acetonitrile / water). An aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with chloroform / methanol. By distilling off the organic layer under reduced pressure, the title compound and 4-{[2- (cyclopentylsulfamoyl) ethyl] amino} -2-{3- [methyl (trifluoroacetyl) amino] azetidine-1 -Il} pyrazolo [1,5-a] [1,3,5] triazine-7-carboxamide was obtained as a mixture.
(B) The mixture (19 mg) obtained in (a) was dissolved in methanol (263 μL), 4N aqueous sodium hydroxide solution (87.5 μL) was added, and the mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added and extracted, and the organic layer was distilled off under reduced pressure to obtain the title compound.
　（実施例７０）
Ｎ－シクロペンチル－２－｛［２－（ヘキサヒドロピロロ［１，２－ａ］ピラジン－２（１Ｈ）－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにオクタヒドロピロロ［１，２－ａ］ピラジンを、参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例２７と同様の手法で表題の化合物を得た。 (Example 70)
N-cyclopentyl-2-{[2- (hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino} ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride instead of octahydropyrro [1,2-a] pyrazine, in the compound synthesized in Reference Example 1. The title compound was obtained in the same manner as in Example 27, except that the compound synthesized in Reference Example 3 was used instead.
　（実施例７１）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミド
（ａ）参考例３で合成した化合物に代えて参考例１０で合成した化合物を用いた以外は、実施例４２と同様の手法で表題の化合物を得た。 (Example 71)
2-({7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxolan-3-yl) ethane-1-sulfonamide (a) The title compound was prepared in the same manner as in Example 42, except that the compound synthesized in Reference Example 10 was used instead of the compound synthesized in Reference Example 3. Obtained.
　（実施例７２）
２－（｛７－ブロモ－２－［（３Ｓ）－３－メチルピペラジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　（２Ｓ）－２－メチルピペラジン－１－カルボキシレートを用いた以外は、実施例４２と同様の手法で表題の化合物を得た。 (Example 72)
2-({7-Bromo-2-[(3S) -3-methylpiperazin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- Performed except that tert-butyl (2S) -2-methylpiperazin-1-carboxylate was used in place of cyclopentylethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained in the same manner as in Example 42.
　（実施例７３）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－フェニルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例３９と同様の手法でｔｅｒｔ－ブチル　［１－（７－ブロモ－４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメートを得た。
（ｂ）（ａ）で得た化合物（１１４ｍｇ）を１，４－ジオキサン（２．０ｍＬ）に溶解した後、フェニルボロン酸（４８．８ｍｇ）、炭酸カリウム（５５．２ｍｇ）、ジクロロ［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）ジクロロメタン錯体（１４．６ｍｇ）を加えてマイクロウェーブ反応装置を用い１２０℃で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、炭酸水素ナトリウム水溶液を加え反応を停止し、クロロホルムで抽出した。減圧下で溶媒を留去した後、得られた残留物をクロロホルム（１．０ｍＬ）に溶解し、トリフルオロ酢酸（６００μＬ）を加え室温で１時間攪拌した。ＬＣＭＳで原料が消失したことを確認した後に、炭酸水素ナトリウム水溶液を加え反応を停止し、クロロホルムで抽出した。減圧下で溶媒を留去した後、シリカゲルカラムクロマトグラフィー（展開溶媒、酢酸エチル：メタノール）で精製し、表題の化合物（８．１ｍｇ）を得た。 (Example 73)
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7-phenylpyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino ) Etan-1-sulfonamide (a) Instead of 3- (trifluoromethyl) -1H-pyrazol-5-amine, 3-bromo-1H-pyrazol-5-amine was used instead of the compound synthesized in Reference Example 1. In the same manner as in Example 39, tert-butyl [1- (7-bromo-4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrazolo) was used, except that the compound synthesized in Reference Example 3 was used. [1,5-a] [1,3,5] Triazine-2-yl) Azetidine-3-yl] Methyl carbamate was obtained.
(B) After dissolving the compound (114 mg) obtained in (a) in 1,4-dioxane (2.0 mL), phenylboronic acid (48.8 mg), potassium carbonate (55.2 mg), and dichloromethane [1, 1'-Bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane complex (14.6 mg) was added, and the mixture was stirred at 120 ° C. for 1 hour using a microwave reactor. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the obtained residue was dissolved in chloroform (1.0 mL), trifluoroacetic acid (600 μL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming that the raw material had disappeared by LCMS, an aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: methanol) to obtain the title compound (8.1 mg).
　（実施例７４）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（ピリジン－３－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）フェニルボロン酸の代わりにピリジン－３－イルボロン酸を用いた以外は、実施例７３と同様の手法を用いて表題の化合物を得た。 (Example 74)
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (pyridin-3-yl) pyrazolo [1,5-a] [1,3,5] triazine- The title compound was obtained using the same procedure as in Example 73, except that pyridine-3-ylboronic acid was used in place of 4-yl} amino) ethane-1-sulfonamide (a) phenylboronic acid.
　（実施例７５）
２－｛［７－シアノ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用いた以外は、実施例５５と同様の手法で表題の化合物を得た。 (Example 75)
2-{[7-Cyano-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide (A) The title compound was obtained in the same manner as in Example 55, except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
　（実施例７６）
２－（｛７－クロロ－２－［（１Ｒ，５Ｓ）－６－（メチルアミノ）－３－アザビシクロ［３．１．０］ヘキサン－３－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　（１Ｒ，５Ｓ）－３－アザビシクロ［３．１．０］ヘキサン－６－イル（メチル）カーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 76)
2-({7-Chloro-2-[(1R, 5S) -6- (methylamino) -3-azabicyclo [3.1.0] hexane-3-yl] pyrazolo [1,5-a] [1 , 3,5] Triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-ylcarbamate instead of tert-butyl (1R, 5S) The title compound was obtained in the same manner as in Example 53, except that -3-azabicyclo [3.1.0] hexane-6-yl (methyl) carbamate was used.
　（実施例７７）
２－（｛７－クロロ－２－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 77)
2-({7-Chloro-2-[(3R) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Except for the use of tert-butyl methyl [(3R) -pyrrolidine-3-yl] carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidine-3-yl carbamate. , The title compound was obtained in the same manner as in Example 53.
　（実施例７８）
２－（｛６－シアノ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）出発物として実施例６１（ｄ）で合成した化合物を用いた以外は、実施例５５（ａ）と同様の手法により２－｛［６－シアノ－２－（メタンスルホニル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミドを得た。
（ｂ）（ａ）で合成した化合物を用い、ピペラジンの代わりにｔｅｒｔ－ブチル　メチル（ピペリジン－４－イル）カーバメートを用いた以外は、実施例６１（ｅ）と同様の手法によりｔｅｒｔ－ブチル　［１－（６－シアノ－４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝ピロロ［２，１－ｆ］［１，２，４］トリアジン－２－イル）ピペリジン－４－イル］メチルカーバメートを得た。
（ｃ）実施例５３（ｂ）と同様の手法により表題の化合物を得た。 (Example 78)
2-({6-cyano-2- [4- (methylamino) piperidin-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4-yl} amino) -N-cyclopentyl Ethan-1-sulfonamide (a) 2-{[6-cyano-2-(6-cyano-2-( Methansulfonyl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide was obtained.
(B) The compound synthesized in (a) was used, and tert-butyl methyl (piperidine-4-yl) carbamate was used instead of piperazine, except that tert-butyl methyl (piperidine-4-yl) carbamate was used in the same manner as in Example 61 (e). 1- (6-cyano-4-{[2- (cyclopentylsulfamoyl) ethyl] amino} pyrrolo [2,1-f] [1,2,4] triazine-2-yl) piperidine-4-yl] Methyl carbamate was obtained.
(C) The title compound was obtained by the same method as in Example 53 (b).
　（実施例７９）
Ｎ－シクロペンチル－２－｛［７－（ジフルオロメチル）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－（ジフルオロメチル）－１Ｈ－ピラゾール－５－アミンを、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 79)
N-Cyclopentyl-2-{[7- (difluoromethyl) -2- (piperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1 -Sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of 3- (difluoromethyl) -1H-pyrazol-5-amine, tert-butyl azetidine-3-yl (methyl) The title compound was obtained in the same manner as in Example 39, except that tert-butylpiperazin-1-carboxylate was used instead of carbamate hydrochloride.
　（実施例８０）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メトキシエチル）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成された化合物の代わりに参考例１１で合成された化合物を用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 80)
2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-methoxyethyl) Etan-1-sulfonamide (a) 3- (Trifluoromethyl) -1H-pyrazole-5-amine was replaced with 3-bromo-1H-pyrazole-5-amine in Reference Example 1. The title compound was obtained in the same manner as in Example 39, except that the compound synthesized in Reference Example 11 was used instead of the compound obtained.
　（実施例８１）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－［１－（ヒドロキシメチル）シクロペンチル］エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－ブロモ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成された化合物の代わりに参考例１２で合成された化合物を用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 81)
2-({7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- [ 1- (Hydroxymethyl) cyclopentyl] Ethan-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of 3-bromo-1H-pyrazol-5-amine, reference example The title compound was obtained in the same manner as in Example 39, except that the compound synthesized in Reference Example 12 was used instead of the compound synthesized in 1.
　（実施例８２）
２－（｛７－クロロ－２－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　メチル［（３Ｓ）－ピロリジン－３－イル］カーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 82)
2-({7-Chloro-2-[(3S) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Except for the use of tert-butyl methyl [(3S) -pyrrolidine-3-yl] carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidine-3-yl carbamate. , The title compound was obtained in the same manner as in Example 53.
　（実施例８３）
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）参考例３で合成した化合物に代えて参考例５で合成した化合物を用いた以外は、実施例６１と同様の手法で表題の化合物を得た。 (Example 83)
2-{[6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (2-methylpropyl) ethane -1-sulfonamide (a) The title compound was obtained in the same manner as in Example 61 except that the compound synthesized in Reference Example 5 was used instead of the compound synthesized in Reference Example 3.
　（実施例８４）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）実施例７３（ａ）で合成された化合物（２００ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（３１．９ｍｇ）、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（４０．４ｍｇ）、ナトリウムメタンチオレート（４８．９ｍｇ）、ＤＩＰＥＡ（１８３μＬ）を１，４－ジオキサン（３５０μＬ）に懸濁した後、マイクロウェーブ反応装置を用い１３０℃で１時間攪拌した。飽和炭酸水素ナトリウム水溶液と酢酸エチルを加えセライト濾過した後、有機相を抽出した。減圧下で有機相を留去し得られた残留物（３１７ｍｇ）の一部を次の反応に用いた。
（ｂ）（ａ）で得られた残留物（５３．８ｍｇ）をクロロホルム（６６７μＬ）に溶解し、トリフルオロ酢酸（３３３μＬ）を加え室温で１時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え反応を停止し、クロロホルム／メタノールで抽出した。減圧下で溶媒を留去した後、アミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）と分取ＨＰＬＣ（アセトニトリル／水）で精製し、表題の化合物（１０．７ｍｇ）を得た。 (Example 84)
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl } Amino) Ethane-1-sulfonamide (a) Compound (200 mg) synthesized in Example 73 (a), Tris (dibenzilidenacetone) dipalladium (0) (31.9 mg), 4,5-bis ( After suspending diphenylphosphino) -9,9-dimethylxanthene (40.4 mg), sodium methanethiolate (48.9 mg) and DIPEA (183 μL) in 1,4-dioxane (350 μL), a microwave reactor Was stirred at 130 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the mixture was filtered through Celite, and then the organic phase was extracted. A part of the residue (317 mg) obtained by distilling off the organic phase under reduced pressure was used for the next reaction.
(B) The residue (53.8 mg) obtained in (a) was dissolved in chloroform (667 μL), trifluoroacetic acid (333 μL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform / methanol. After distilling off the solvent under reduced pressure, purification was performed by amino silica gel column chromatography (developing solvent, chloroform: methanol) and preparative HPLC (acetonitrile / water) to obtain the title compound (10.7 mg).
　（実施例８５）
２－｛［７－クロロ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを、参考例１で合成された化合物の代わりに参考例５で合成された化合物を用いた以外は、実施例３１と同様の手法で表題の化合物を得た。 (Example 85)
2-{[7-Chloro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (2-methylpropyl) ethane -1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride instead of tert-butyl piperazine-1-carboxylate, reference example 5 instead of the compound synthesized in Reference Example 1. The title compound was obtained in the same manner as in Example 31 except that the compound synthesized in (1) was used.
　（実施例８６）
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロブチルエタン－１－スルホンアミド
（ａ）参考例３で合成した化合物の代わりに参考例６で合成した化合物を用いた以外は、実施例６１と同様の手法で表題の化合物を得た。 (Example 86)
2-{[6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclobutylethane-1-sulfone Amide (a) The title compound was obtained in the same manner as in Example 61, except that the compound synthesized in Reference Example 6 was used instead of the compound synthesized in Reference Example 3.
　（実施例８７）
Ｎ－シクロペンチル－２－（｛７－エテニル－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）実施例７３（ａ）で合成された化合物（１００ｍｇ）、カリウムビニルトリフルオロボラート（４６．７ｍｇ）テトラキストリフェニルホスフィンパラジウム（０）（２０．２ｍｇ）、炭酸セシウム（１７０ｍｇ）を１，４－ジオキサン（２．３ｍＬ）と蒸留水（０．２３ｍＬ）に懸濁した後、マイクロウェーブ反応装置を用い１２０℃で１時間攪拌した。混合物にカリウムビニルトリフルオロボラート（１１．７ｍｇ）を添加し、マイクロウェーブ反応装置を用い１２０℃でさらに３０分攪拌した。飽和炭酸水素ナトリウム水溶液とクロロホルムを加え有機相を抽出した後、減圧下で有機相を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、酢酸エチル：ヘキサン）で精製し、ｔｅｒｔ－ブチル　［１－（４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝－７－エテニルピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメート（６６．８ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（１５ｍｇ）をクロロホルム（３８７μＬ）に溶解し、トリフルオロ酢酸（１９３μＬ）を加え室温で１時間攪拌した。飽和炭酸水素ナトリウム水溶液を加え反応を停止し、クロロホルム／メタノールで抽出した。減圧下で溶媒を留去し、表題の化合物（１２．０ｍｇ）を得た。 (Example 87)
N-cyclopentyl-2- ({7-ethenyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Etan-1-sulfonamide (a) Compound (100 mg) synthesized in Example 73 (a), potassium vinyltrifluoroborate (46.7 mg) tetraxtriphenylphosphine palladium (0) (20.2 mg), cesium carbonate (170 mg) was suspended in 1,4-dioxane (2.3 mL) and distilled water (0.23 mL), and then stirred at 120 ° C. for 1 hour using a microwave reactor. Potassium vinyl trifluoroborate (11.7 mg) was added to the mixture and stirred at 120 ° C. for an additional 30 minutes using a microwave reactor. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to extract the organic phase, and then the organic phase was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: hexane) and tert-butyl [1-(4-{[2- (cyclopentylsulfamoyl) ethyl] amino} -7-ethenylpyrazolo). [1,5-a] [1,3,5] triazine-2-yl) azetidine-3-yl] methyl carbamate (66.8 mg) was obtained.
(B) The compound (15 mg) obtained in (a) was dissolved in chloroform (387 μL), trifluoroacetic acid (193 μL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with chloroform / methanol. The solvent was distilled off under reduced pressure to obtain the title compound (12.0 mg).
　（実施例８８）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（プロプ－１－エン－２－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）カリウムビニルトリフルオロボラートに代えてカリウムイソプロペニルトリフルオロボラートを用いた以外は、実施例８７と同様の手法で表題の化合物を得た。 (Example 88)
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (prop-1-en-2-yl) pyrazolo [1,5-a] [1,3, 5] Triazine-4-yl} amino) ethane-1-sulfonamide (a) The title compound in the same manner as in Example 87, except that potassium isopropenyl trifluoroborate was used instead of potassium vinyl trifluoroborate. Got
　（実施例８９－１・２）
２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミドの光学異性体
（ａ）実施例７１で合成した化合物を用いて、実施例１０５（ｂ）と同様の手法により表題の化合物を得た。 (Example 89-1.2)
2-({7-bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Optical isomer of oxolan-3-yl) ethane-1-sulfonamide (a) Using the compound synthesized in Example 71, the title compound was obtained in the same manner as in Example 105 (b).
　（実施例９０）
２－（｛７－クロロ－２－［トランス－３－フルオロ－４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　（トランス－３－フルオロピペリジン－４－イル）メチルカーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 90)
2-({7-Chloro-2- [trans-3-fluoro-4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} Amino) -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyridine-3-ylcarbamate instead of tert-butyl (trans-3-fluoropiperidine-4-yl) methylcarbamate The title compound was obtained in the same manner as in Example 53, except that the compound was obtained.
　（実施例９１）
Ｎ－シクロペンチル－２－（｛７－エチル－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）実施例８７（ａ）で得られた化合物を（５１．０ｍｇ）と１０％パラジウム炭素（１０．０　ｍｇ）をメタノール（１ｍＬ）に懸濁した後、水素雰囲気下で終夜攪拌した。混合物をセライト濾過した後、得られた有機層を減圧下で留去し、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、酢酸エチル：ヘキサン）で精製することでｔｅｒｔ－ブチル　［１－（４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝－７－エチルピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメート（３６．６ｍｇ）を得た。
（ｂ）実施例８７（ｂ）と同様の手法で表題の化合物を得た。 (Example 91)
N-cyclopentyl-2- ({7-ethyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide (a) The compound obtained in Example 87 (a) was suspended in (51.0 mg) and 10% palladium carbon (10.0 mg) in methanol (1 mL), followed by a hydrogen atmosphere. Stirred overnight below. After filtering the mixture by Celite, the obtained organic layer was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: hexane) to obtain tert-butyl [1- (4- (4- (4- (4- (4-)]. {[2- (Cyclopentyl sulfamoyl) ethyl] amino} -7-ethylpyrazolo [1,5-a] [1,3,5] triazine-2-yl) azetidine-3-yl] methyl carbamate (36.6 mg) ) Was obtained.
(B) The title compound was obtained in the same manner as in Example 87 (b).
　（実施例９２）
Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（プロパン－２－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）カリウムビニルトリフルオロボラートに代えてカリウムイソプロペニルトリフルオロボラートを用いた以外は、実施例９１と同様の手法で表題の化合物を得た。 (Example 92)
N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (propane-2-yl) pyrazolo [1,5-a] [1,3,5] triazine- The title compound was obtained in the same manner as in Example 91, except that potassium isopropenyl trifluoroborate was used in place of 4-yl} amino) ethane-1-sulfonamide (a) potassium vinyl trifluoroborate.
　（実施例９３）
２－（｛７－シアノ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　メチル（ピペリジン－４－イル）カーバメートを用いた以外は、実施例５５と同様の手法で表題の化合物を得た。 (Example 93)
2-({7-Cyano-2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Same as in Example 55, except that tert-butylmethyl (piperidin-4-yl) carbamate was used instead of ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained by the procedure.
　（実施例９４）
２－（｛７－クロロ－２－［４－メチル－４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　（３Ｓ）－ピロリジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　メチル（４－メチルピペリジン－４－イル）カーバメートを用いた以外は、実施例５３と同様の手法で表題の化合物を得た。 (Example 94)
2- ({7-Chloro-2- [4-methyl-4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Except for the use of tert-butyl methyl (4-methylpiperidin-4-yl) carbamate instead of -N-cyclopentylethane-1-sulfonamide (a) tert-butyl (3S) -pyrrolidin-3-yl carbamate. The title compound was obtained in the same manner as in Example 53.
　（実施例９５）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキサン－３－イル）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－クロロ－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例３９（ａ）から（ｄ）と同様の手法で４，７－ジクロロ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジンを得た。
（ｂ）（ａ）で得られた化合物（１．６５ｇ）、２－アミノエタンスルホン酸（９７６ｍｇ）、ＤＩＰＥＡ（２．４ｍＬ）を１，４－ジオキサン（７ｍＬ）に懸濁させ、マイクロウェーブ反応装置を用い１２０℃で３０分攪拌した。混合物に水酸化ナトリウム水溶液を加えた後、クロロホルムで有機相を抽出した。水相をクロロホルム－メタノール（４／１）にて再度抽出、得られた有機相を減圧下で濃縮した。残留物をＴＨＦ／酢酸エチル（１／３）で洗浄することで２－｛［７－クロロ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホン酸（１．１２ｇ）を得た。
（ｃ）（ｂ）で得られた化合物（９７１ｍｇ）をジクロロメタン（３０ｍＬ）に懸濁させ、ＤＭＦ（１０４μＬ）を加えたのち０℃にて冷却した。塩化オキサリル（１．３ｍＬ）を加えた後、室温で終夜攪拌した。溶媒を減圧下で留去した後、残留物を酢酸エチルで洗浄し室温下乾燥させることで２－｛［７－クロロ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホニル　クロライド（７４４ｍｇ）を得た。
（ｄ）（ｃ）で得られた化合物（５０ｍｇ）をジクロロメタン（０．７３ｍＬ）に溶解させ、ＤＩＰＥＡ（１２８μＬ）とオキサン－３－アミン（２９．５ｍｇ）を加えた後室温で２時間攪拌した。飽和塩化アンモニウム水溶液とクロロホルムを加えた後、有機相を抽出、溶媒を留去した。得られた残留物をシリカゲルクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製することで２－｛［７－クロロ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（オキサン－３－イル）エタン－１－スルホンアミド（２８．７ｍｇ）を得た。
（ｅ）（ｄ）で得られた化合物（２８．７ｍｇ）をＴＨＦ（３５５μＬ）に溶解し、メタクロロ過安息香酸（４３．９ｍｇ）を加え、室温で１時間攪拌した。ＤＩＰＥＡ（６２μＬ）とｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（３１．６ｍｇ）とを加え６０℃で終夜攪拌した。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。減圧下で溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、ｔｅｒｔ－ブチル　｛１－［７－クロロ－４－（｛２－［（オキサン－３－イル）スルファモイル］エチル｝アミノ）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－２－イル］アゼチジン－３－イル｝メチルカーバメート（２７．２ｍｇ）を得た。
（ｆ）（ｅ）で得られた化合物（２７．２ｍｇ）をクロロホルム（０．２５ｍＬ）に溶解しトリフルオロ酢酸（０．２５ｍＬ）を加えた後、室温で１時間攪拌した。減圧下で溶媒を留去し得られた残留物に飽和炭酸水素ナトリウム水溶液を加え、再度溶媒を留去した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（２２．２ｍｇ）を得た。 (Example 95)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Except for the use of 3-chloro-1H-pyrazole-5-amine instead of oxane-3-yl) ethane-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazole-5-amine. 4,7-Dichloro-2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine was obtained in the same manner as in Examples 39 (a) to (d).
(B) The compound (1.65 g) obtained in (a), 2-aminoethanesulfonic acid (976 mg), and DIPEA (2.4 mL) were suspended in 1,4-dioxane (7 mL) and subjected to a microwave reaction. The device was used to stir at 120 ° C. for 30 minutes. After adding an aqueous sodium hydroxide solution to the mixture, the organic phase was extracted with chloroform. The aqueous phase was extracted again with chloroform-methanol (4/1), and the obtained organic phase was concentrated under reduced pressure. By washing the residue with THF / ethyl acetate (1/3), 2-{[7-chloro-2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine-4- Il] amino} ethane-1-sulfonic acid (1.12 g) was obtained.
(C) The compound (971 mg) obtained in (b) was suspended in dichloromethane (30 mL), DMF (104 μL) was added, and the mixture was cooled at 0 ° C. After adding oxalyl chloride (1.3 mL), the mixture was stirred overnight at room temperature. After distilling off the solvent under reduced pressure, the residue was washed with ethyl acetate and dried at room temperature to 2-{[7-chloro-2- (methylsulfanyl) pyrazolo [1,5-a] [1,3. , 5] Triazine-4-yl] amino} ethane-1-sulfonyl chloride (744 mg) was obtained.
(D) The compound (50 mg) obtained in (c) was dissolved in dichloromethane (0.73 mL), DIPEA (128 μL) and oxane-3-amine (29.5 mg) were added, and the mixture was stirred at room temperature for 2 hours. .. After adding saturated aqueous ammonium chloride solution and chloroform, the organic phase was extracted and the solvent was distilled off. The obtained residue was purified by silica gel chromatography (developing solvent, chloroform: methanol) to 2-{[7-chloro-2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5. ] Triazine-4-yl] amino} -N- (oxan-3-yl) ethane-1-sulfonamide (28.7 mg) was obtained.
(E) The compound (28.7 mg) obtained in (d) was dissolved in THF (355 μL), metachloroperbenzoic acid (43.9 mg) was added, and the mixture was stirred at room temperature for 1 hour. DIPEA (62 μL) and tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride (31.6 mg) were added and stirred at 60 ° C. overnight. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent, chloroform: methanol), and tert-butyl {1- [7-chloro-4- ({2- [(oxane)). -3-Il) Sulfamoyl] ethyl} amino) pyrazolo [1,5-a] [1,3,5] triazine-2-yl] azetidine-3-yl} methyl carbamate (27.2 mg) was obtained.
(F) The compound (27.2 mg) obtained in (e) was dissolved in chloroform (0.25 mL), trifluoroacetic acid (0.25 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by distilling off the solvent under reduced pressure, and the solvent was distilled off again. The obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (22.2 mg).
　（実施例９６）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－シアノシクロプロピル）エタン－１－スルホンアミド
（ａ）オキサン－３－アミンに代えて１－アミノシクロプロパン－１－カルボニトリル塩酸塩を用いた以外は、実施例９５と同様の手法にて表題の化合物を得た。 (Example 96)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Cyanocyclopropyl) Ethan-1-sulfonamide (a) In the same manner as in Example 95, except that 1-aminocyclopropane-1-carbonitrile hydrochloride was used instead of oxane-3-amine. The title compound was obtained.
　（実施例９７）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－［（１Ｓ，２Ｓ）－２－ヒドロキシシクロペンチル］エタン－１－スルホンアミド
（ａ）オキサン－３－アミンに代えてトランス－２－アミノシクロペンタン－１－オール塩酸塩を用いた以外は、実施例９５と同様の手法にて表題の化合物を得た。 (Example 97)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- [ (1S, 2S) -2-Hydroxycyclopentyl] Example 95, except that trans-2-aminocyclopentane-1-ol hydrochloride was used instead of ethane-1-sulfonamide (a) oxane-3-amine. The title compound was obtained in the same manner as in the above.
　（実施例９８）
Ｎ－シクロペンチル－２－（｛７－メトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－メトキシ－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 98)
N-cyclopentyl-2- ({7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Same as in Example 39, except that 3-methoxy-1H-pyrazol-5-amine was used instead of ethane-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine. The title compound was obtained by the procedure.
　（実施例９９）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－ヒドロキシ－２－メチルプロピル）エタン－１－スルホンアミド
（ａ）オキサン－３－アミンに代えて１－アミノ－２－メチルプロパン－２－オールを用いた以外は、実施例９５と同様の手法にて表題の化合物を得た。 (Example 99)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Hydroxy-2-methylpropyl) Ethan-1-sulfonamide (a) Same as in Example 95 except that 1-amino-2-methylpropan-2-ol was used instead of oxane-3-amine. The title compound was obtained by the method.
　（実施例１００）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（３，３－ジフルオロシクロペンチル）エタン－１－スルホンアミド
（ａ）オキサン－３－アミンに代えて３，３－ジフルオロシクロペンタン－１－アミン塩酸塩を用いた以外は、実施例９５と同様の手法にて表題の化合物を得た。 (Example 100)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 3,3-Difluorocyclopentane) Ethane-1-sulfonamide (a) The same procedure as in Example 95, except that 3,3-difluorocyclopentane-1-amine hydrochloride was used instead of oxane-3-amine. The title compound was obtained in.
　（実施例１０１）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－ヒドロキシ－２－メチルプロパン－２－イル）エタン－１－スルホンアミド
（ａ）オキサン－３－アミンに代えて２－アミノ－２－メチルプロパン－１－オールを用いた以外は、実施例９５と同様の手法にて表題の化合物を得た。 (Example 101)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Examples except that 2-amino-2-methylpropan-1-ol was used instead of 1-hydroxy-2-methylpropan-2-yl) ethane-1-sulfonamide (a) oxane-3-amine. The title compound was obtained in the same manner as in 95.
　（実施例１０２）
２－｛［７－（ジフルオロメチル）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）参考例３で合成された化合物の代わりに参考例５で合成された化合物を用いた以外は、実施例７９と同様の手法で表題の化合物を得た。 (Example 102)
2-{[7- (difluoromethyl) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (2-methyl Propyl) ethane-1-sulfonamide (a) The title compound was obtained in the same manner as in Example 79, except that the compound synthesized in Reference Example 5 was used instead of the compound synthesized in Reference Example 3. ..
　（実施例１０３）
Ｎ－シクロペンチル－２－（｛７－フルオロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－フルオロ－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例３９（ａ）から（ｄ）と同様の手法で４－クロロ－７－（フルオロ）－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジンを得た。
（ｂ）参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例３９（ｅ）と同様の手法で、（ａ）で得られた化合物からＮ－シクロペンチル－２－｛［７－（フルオロ）－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ}エタン－１－スルホンアミドを得た。
（ｃ）実施例３９（ｆ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 103)
N-cyclopentyl-2- ({7-fluoro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Example 39 (a), except that 3-fluoro-1H-pyrazol-5-amine was used instead of ethane-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine. 4-Chloro-7- (fluoro) -2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine was obtained from the above in the same manner as in (d).
(B) N-cyclopentyl from the compound obtained in (a) by the same method as in Example 39 (e) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. -2-{[7- (fluoro) -2- (methylsulfanilic) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide was obtained.
(C) The title compound was obtained from the compound obtained in (b) in the same manner as in Example 39 (f).
　（実施例１０４）
Ｎ－シクロペンチル－２－（｛７－（ジフルオロメトキシ）－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－（ジリフルオロメトキシ）－１Ｈ－ピラゾール－５－アミンを用いた以外は、実施例３９（ａ）から（ｄ）と同様の手法で４－クロロ－７－（ジフルオロメトキシ）－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジンを得た。
（ｂ）参考例１で合成した化合物の代わりに参考例３で合成した化合物を用いた以外は、実施例３９（ｅ）と同様の手法で、（ａ）で得られた化合物からＮ－シクロペンチル－２－｛［７－（ジフルオロメトキシ）－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミドを得た。
（ｃ）実施例３９（ｆ）と同様の手法で、（ｂ）で得られた化合物から表題の化合物を得た。 (Example 104)
N-cyclopentyl-2- ({7- (difluoromethoxy) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] } Amino) Etan-1-sulfonamide (a) 3- (difluoromethoxy) -1H-pyrazol-5-amine instead of 3- (trifluoromethyl) -1H-pyrazol-5-amine , 4-Chloro-7- (difluoromethoxy) -2- (methylsulfanyl) pyrazolo [1,5-a] [1,3,5] triazine in the same manner as in Examples 39 (a) to (d). Obtained.
(B) N-cyclopentyl from the compound obtained in (a) by the same method as in Example 39 (e) except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. -2-{[7- (difluoromethoxy) -2- (methylsulfanilic) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide was obtained. ..
(C) The title compound was obtained from the compound obtained in (b) in the same manner as in Example 39 (f).
　（実施例１０５－１・２）
Ｎ－（ブタン－２－イル）－２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミドの光学異性体
（ａ）オキサン－３－アミンに代えてブタン－２－アミンを用いた以外は、実施例９５と同様の手法にて表題の化合物のラセミ体を得た。
（ｂ）（ａ）で得られた化合物（２０ｍｇ）をエタノールに溶解し、Ｍｕｌｔｉｐｌｅ　ｐｒｅｐａｒａｔｉｖｅ　ＨＰＬＣ　ＬＣ－ｆｏｒｔｅ／Ｒを用いて（カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ　２ｃｍ×２５ｃｍ、展開溶媒：ｎ－ヘキサン（０．１％ジエチルアミン含有）／エタノール＝６５／３５、流速：２０ｍＬ／ｍｉｎ、注入量：１．０×４ｍＬ、室温）、表題の化合物［（実施例１０５－１）（保持時間の短い異性体）を７．７ｍｇ及び（実施例１０５－２）（保持時間の長い異性体）］を７．１ｍｇ得た。 (Example 105-1 ・ 2)
N- (butane-2-yl) -2-({7-chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine- The compound of the title in the same manner as in Example 95, except that the optical isomer of 4-yl} amino) ethane-1-sulfonamide (a) butane-2-amine was used instead of oxane-3-amine. I got the lamellar body of.
(B) The compound (20 mg) obtained in (a) was dissolved in ethanol, and using Multiple preparative HPLC LC-forte / R (column: CHIRALPAK IC 2 cm × 25 cm, developing solvent: n-hexane (0.1). % Ethylamine-containing) / ethanol = 65/35, flow velocity: 20 mL / min, injection volume: 1.0 × 4 mL, room temperature), the title compound [(Example 105-1) (isomer with short retention time) 7 7. mg and (Example 105-2) (isomer with long retention time)] were obtained at 7.1 mg.
　（実施例１０６）
２－（｛７－エトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－メトキシ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成された化合物の代わりに参考例５で合成された化合物を用いた以外は、実施例３９（ａ）から（ｅ）と同様の手法で２－｛［７－メトキシ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミドを得た。
（ｂ）（ａ）で得られた化合物（６６．１ｍｇ）をジクロロメタン（８８３μＬ）に溶解させた後に１Ｍ　３臭化ホウ素のジクロロメタン溶液（８８３μＬ）を加え、５０℃で終夜攪拌した。室温で冷却後、飽和塩化アンモニウム水溶液を加え酢酸エチルで有機相を抽出した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－｛［７－ヒドロキシ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド（６３．６ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（４１．２ｍｇ）をアセトニトリル（７６０μＬ）に溶解させた後、炭酸カリウム（３１．６ｍｇ）とヨウ化エチル（９．７μＬ）を加え室温で終夜攪拌した。混合物にクロロホルム／メタノールを加え有機相を抽出し、溶媒を減圧下で留去して得られた残留物（３１．０ｍｇ）を次の反応に用いた。
（ｄ）実施例３９（ｅ）で得られた化合物の代わりに（ｃ）で得られた化合物を用いた以外は、実施例３９（ｆ）と同様の手法で表題の化合物を得た。 (Example 106)
2-({7-ethoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide (a) 3-methoxy-1H-pyrazole-5-amine was synthesized in Reference Example 1 instead of 3- (trifluoromethyl) -1H-pyrazole-5-amine. 2-{[7-methoxy-2- (methylsulfanyl) pyrazolo in the same manner as in Examples 39 (a) to (e), except that the compound synthesized in Reference Example 5 was used instead of the compound obtained. [1,5-a] [1,3,5] Triazine-4-yl] amino} -N- (2-methylpropyl) ethane-1-sulfonamide was obtained.
(B) The compound (66.1 mg) obtained in (a) was dissolved in dichloromethane (883 μL), a dichloromethane solution (883 μL) of 1M3 boron tribromide was added, and the mixture was stirred at 50 ° C. overnight. After cooling at room temperature, a saturated aqueous solution of ammonium chloride was added, and the organic phase was extracted with ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and 2-{[7-hydroxy-2- (methylsulfanyl) pyrazolo [1,5-]. a] [1,3,5] Triazine-4-yl] amino} -N- (2-methylpropyl) ethane-1-sulfonamide (63.6 mg) was obtained.
(C) The compound (41.2 mg) obtained in (b) was dissolved in acetonitrile (760 μL), potassium carbonate (31.6 mg) and ethyl iodide (9.7 μL) were added, and the mixture was stirred overnight at room temperature. .. Chloroform / methanol was added to the mixture to extract the organic phase, and the solvent was distilled off under reduced pressure, and the obtained residue (31.0 mg) was used in the next reaction.
(D) The title compound was obtained in the same manner as in Example 39 (f) except that the compound obtained in (c) was used instead of the compound obtained in Example 39 (e).
　（実施例１０７）
２－（｛７－（ジフルオロメチル）－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イルカーバメートの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩を、参考例３で合成された化合物の代わりに参考例５で合成された化合物を用いた以外は、実施例６３と同様の手法で表題の化合物を得た。 (Example 107)
2-({7- (difluoromethyl) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino)- Synthesis of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride in place of N- (2-methylpropyl) ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl carbamate in Reference Example 3 The title compound was obtained in the same manner as in Example 63, except that the compound synthesized in Reference Example 5 was used instead of the compound obtained.
　（実施例１０８）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－シアノシクロペンチル）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－クロロ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成された化合物の代わりに２－アミノエタン－１－スルホンアミドを用いた以外は、実施例３９（ａ）から（ｅ）と同様の手法で　２－｛［７－クロロ－２－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミドを得た。
（ｂ）（ａ）で得られた化合物（８０ｍｇ）を１，４－ジオキサン（９９２μＬ）に溶解させ、シクロペンタノン（３２．９μＬ）とオルトチタン酸テトライソプロピル（２１８μＬ）を加えた後、マイクロウェーブ反応装置を用い２００℃で２時間攪拌した。混合物にトリメチルシランカルボニトリル（３６．９ｍｇ）とオルトチタン酸テトライソプロピル（２１８μＬ）を加えた後、室温でさらに終夜攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルを用いてセライト濾過、有機相を抽出した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、（８６．３ｍｇ）を得た。
（ｃ）実施例３９（ｅ）で得られた化合物の代わりに（ｂ）で得られた化合物を用い、実施例３９（ｆ）と同様の手法で表題の化合物を得た。 (Example 108)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Cyanocyclopentyl) Etan-1-sulfonamide (a) 3- (Trifluoromethyl) -1H-pyrazole-5-amine was replaced with 3-chloro-1H-pyrazole-5-amine in Reference Example 1. 2-{[7-Chloro-2- (methylsulfanyl) pyrazolo in the same manner as in Examples 39 (a) to (e), except that 2-aminoethane-1-sulfonamide was used in place of the compound. [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide was obtained.
(B) The compound (80 mg) obtained in (a) was dissolved in 1,4-dioxane (992 μL), cyclopentanone (32.9 μL) and tetraisopropyl orthotitanium (218 μL) were added, and then micro. The mixture was stirred at 200 ° C. for 2 hours using a wave reactor. Trimethylsilanecarbonitrile (36.9 mg) and tetraisopropyl orthotitanium (218 μL) were added to the mixture, followed by further stirring overnight at room temperature. After adding a saturated aqueous sodium hydrogen carbonate solution, the organic phase was extracted by filtration through Celite using ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to obtain (86.3 mg).
(C) The compound obtained in (b) was used in place of the compound obtained in Example 39 (e), and the title compound was obtained in the same manner as in Example 39 (f).
　（実施例１０９）
２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝エタン－１－スルホンアミド
（ａ）オキサン－３－アミンに代えて１－［１－（トリフルオロメチル）シクロプロピル］メタンアミン塩酸塩を用いた以外は、実施例９５と同様の手法にて表題の化合物を得た。 (Example 109)
2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- { Except for the use of 1- [1- (trifluoromethyl) cyclopropyl] methaneamine hydrochloride instead of [1- (trifluoromethyl) cyclopropyl] methyl} ethane-1-sulfonamide (a) oxane-3-amine. Obtained the title compound in the same manner as in Example 95.
　（実施例１１０）
２－（｛７－メトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－メトキシ－１Ｈ－ピラゾール－５－アミンを、参考例１で合成された化合物の代わりに参考例５で合成された化合物を用いた以外は、実施例３９と同様の手法で表題の化合物を得た。 (Example 110)
2-({7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide (a) 3-methoxy-1H-pyrazole-5-amine was synthesized in Reference Example 1 instead of 3- (trifluoromethyl) -1H-pyrazole-5-amine. The title compound was obtained in the same manner as in Example 39, except that the compound synthesized in Reference Example 5 was used instead of the compound obtained.
　（実施例１１１）
Ｎ－シクロペンチル－２－｛［７－メトキシ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－メトキシ－１Ｈ－ピラゾール－５－アミンを、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを、参考例１で合成された化合物の代わりに参考例３で合成された化合物を用いた以外は実施例３９と同様の手法で表題の化合物を得た。 (Example 111)
N-cyclopentyl-2-{[7-methoxy-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide (A) Instead of 3- (trifluoromethyl) -1H-pyrazol-5-amine, 3-methoxy-1H-pyrazol-5-amine, instead of tert-butylazetidine-3-yl (methyl) carbamate hydrochloride The title compound was obtained in the same manner as in Example 39 except that the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1 for tert-butyl piperazine-1-carboxylate. ..
　（実施例１１２）
Ｎ－シクロペンチル－２－（｛７－メトキシ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）３－（トリフルオロメチル）－１Ｈ－ピラゾール－５－アミンの代わりに３－メトキシ－１Ｈ－ピラゾール－５－アミンを、ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　メチル（ピペリジン－４－イル）カーバメートを、参考例１で合成された化合物の代わりに参考例３で合成された化合物を用いた以外は実施例３９と同様の手法で表題の化合物を得た。 (Example 112)
N-cyclopentyl-2- ({7-methoxy-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Etan-1-sulfonamide (a) 3- (trifluoromethyl) -1H-pyrazol-5-amine instead of 3-methoxy-1H-pyrazol-5-amine, tert-butyl azetidine-3-yl (methyl) ) Same as Example 39 except that tert-butyl methyl (piperidine-4-yl) carbamate was used instead of carbamate hydrochloride and the compound synthesized in Reference Example 3 was used instead of the compound synthesized in Reference Example 1. The title compound was obtained by the method of.
　（実施例１１３）
Ｎ－シクロペンチル－２－｛［７－フルオロ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用いた以外は実施例１０３と同様の手法で表題の化合物を得た。 (Example 113)
N-Cyclopentyl-2-{[7-fluoro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide (A) The title compound was obtained in the same manner as in Example 103 except that tert-butyl piperazine-1-carboxylate was used instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride.
　（実施例１１４）
Ｎ－シクロペンチル－２－｛［７－（ジフルオロメトキシ）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用いた以外は実施例１０４と同様の手法で表題の化合物を得た。 (Example 114)
N-cyclopentyl-2-{[7- (difluoromethoxy) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1 - give the sulfonamide (a) tert- butyl azetidin-3-yl (methyl) the title compound was prepared in a similar manner as in example 104 except using tert- butyl piperazine-1-carboxylate in place of carbamate hydrochloride rice field.
　（実施例１１５）
２－（｛７－ブロモ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　メチル（ピペリジン－４－イル）カーバメートを用いた以外は実施例４４と同様の手法で表題の化合物を得た。 (Example 115)
2-({7-Bromo-2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Examples except that tert-butylmethyl (piperidin-4-yl) carbamate was used instead of 2-methylpropyl) ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained in the same manner as in 44.
　（実施例１１６）
Ｎ－シクロペンチル－２－（｛７－フルオロ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　メチル（ピペリジン－４－イル）カーバメートを用いた以外は実施例１０３と同様の手法で表題の化合物を得た。 (Example 116)
N-cyclopentyl-2- ({7-fluoro-2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) The same procedure as in Example 103 except that tert-butylmethyl (piperidin-4-yl) carbamate was used instead of ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride. The title compound was obtained in.
　（実施例１１７）
Ｎ－シクロペンチル－２－（｛７－（ジフルオロメトキシ）－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　メチル（ピペリジン－４－イル）カーバメートを用いた以外は実施例１０４と同様の手法で表題の化合物を得た。 (Example 117)
N-Cyclopentyl-2-({7- (difluoromethoxy) -2- [4- (methylamino) piperidin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] } Amino) ethane-1-sulfonamide (a) tert-butyl azetidine-3-yl (methyl) carbamate Example 104 except that tert-butyl methyl (piperidine-4-yl) carbamate was used instead of the hydrochloride salt. The title compound was obtained in a similar manner.
　（実施例１１８）
６－ブロモ－Ｎ－［２－（メタンスルホニル）エチル］－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－アミン
（ａ）６－ブロモ－２，４－ジクロロピリド［２，３－ｄ］ピリミジン（５０ｍｇ）をＴＨＦ（１ｍＬ）に溶解させた後、ＤＩＰＥＡ（９３μＬ）と２－（メタンスルホニル）エタン－１－アミン塩酸塩（２９ｍｇ）を加え室温で終夜攪拌した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、６－ブロモ－２－クロロ－Ｎ－［２－（メタンスルホニル）エチル］ピリド［２，３－ｄ］ピリミジン－４－アミン（５８．０ｍｇ）を得た。
（ｂ）（ａ）で得られた化合物（５８．０ｍｇ）をＴＨＦ（２ｍＬ）に溶解させた後、ＤＩＰＥＡ（１１０μＬ）とｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩（７１ｍｇ）を加え、マイクロウェーブ反応装置を用い１５０℃で１時間攪拌した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、ｔｅｒｔ－ブチル　［１－（６－ブロモ－４－｛［２－（メタンスルホニル）エチル］アミノ｝ピリド［２，３－ｄ］ピリミジン－２－イル）アゼチジン－３－イル］メチルカーバメート（６７．０ｍｇ）を得た。
（ｃ）（ｂ）で得られた化合物（６７ｍｇ）をジクロロメタン（５００μＬ）に溶解し、トリフルオロ酢酸（５００μＬ）を加え室温で２時間攪拌した。減圧下で溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、表題の化合物（４４．１ｍｇ）を得た。 (Example 118)
6-bromo-N- [2- (methanesulfonyl) ethyl] -2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-amine (a) 6-bromo After dissolving -2,4-dichloropyrido [2,3-d] pyrimidine (50 mg) in THF (1 mL), DIPEA (93 μL) and 2- (methanesulfonyl) ethane-1-amine hydrochloride (29 mg) were added. In addition, it was stirred overnight at room temperature. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) and 6-bromo-2-chloro-N- [2- (methanesulfonyl) ethyl] pyride [ 2,3-d] Pyrimidine-4-amine (58.0 mg) was obtained.
(B) After dissolving the compound (58.0 mg) obtained in (a) in THF (2 mL), DIPEA (110 μL) and tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride (71 mg) were added. In addition, the mixture was stirred at 150 ° C. for 1 hour using a microwave reactor. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) and tert-butyl [1- (6-bromo-4-{[2- (methanesulfonyl)). Ethyl] amino} pyrido [2,3-d] pyrimidin-2-yl) azetidine-3-yl] methyl carbamate (67.0 mg) was obtained.
(C) The compound (67 mg) obtained in (b) was dissolved in dichloromethane (500 μL), trifluoroacetic acid (500 μL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain the title compound (44.1 mg).
　（実施例１１９）
６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ－［２－（モルホリン－４－スルホニル）エチル］ピリド［２，３－ｄ］ピリミジン－４－アミン
（ａ）２－（メタンスルホニル）エタン－１－アミン塩酸塩の代わりに参考例１３で合成した化合物を用いた以外は、実施例１１８と同様の手法で表題の化合物を得た。 (Example 119)
6-Bromo-2- [3- (methylamino) azetidine-1-yl] -N- [2- (morpholine-4-sulfonyl) ethyl] pyrido [2,3-d] pyrimidin-4-amine (a) The title compound was obtained in the same manner as in Example 118, except that the compound synthesized in Reference Example 13 was used instead of 2- (methanesulfonyl) ethane-1-amine hydrochloride.
　（実施例１２０）
２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－（４－フルオロフェニル）エタン－１－スルホンアミド
（ａ）２－（メタンスルホニル）エタン－１－アミン塩酸塩の代わりに参考例１４で合成した化合物を用いた以外は、実施例１１８と同様の手法で表題の化合物を得た。 (Example 120)
2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N- (4-fluorophenyl) ethane- The title compound was obtained in the same manner as in Example 118, except that the compound synthesized in Reference Example 14 was used instead of 1-sulfonamide (a) 2- (methanesulfonyl) ethane-1-amine hydrochloride. ..
　（実施例１２１）
２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド
（ａ）２－（メタンスルホニル）エタン－１－アミン塩酸塩の代わりに参考例１５で合成した化合物を用いた以外は、実施例１１８と同様の手法で表題の化合物を得た。 (Example 121)
2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N-methyl-N-phenylethane-1 The title compound was obtained in the same manner as in Example 118, except that the compound synthesized in Reference Example 15 was used instead of the -sulfonamide (a) 2- (methanesulfonyl) ethane-1-amine hydrochloride.
　（実施例１２２）
２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピリド［２，３－ｄ］ピリミジン－４－イル］アミノ｝－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩の代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを、２－（メタンスルホニル）エタン－１－アミン塩酸塩の代わりに参考例１５で合成した化合物を用いた以外は、実施例１１８と同様の手法で表題の化合物を得た。 (Example 122)
2-{[6-Bromo-2- (piperazine-1-yl) pyrido [2,3-d] pyrimidin-4-yl] amino} -N-methyl-N-phenylethane-1-sulfonamide (a) Instead of tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride, tert-butyl piperazine-1-carboxylate was synthesized in Reference Example 15 instead of 2- (methanesulfonyl) ethane-1-amine hydrochloride. The title compound was obtained in the same manner as in Example 118 except that the compound was used.
　（実施例１２３）
２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（ピリジン－２－イル）エタン－１－スルホンアミド
（ａ）プテリジン－２，４－ジオール（２０６．５ｍｇ）をオキシ塩化リン（２ｍＬ）に懸濁し、５塩化リン（１．０２ｇ）を加えて還流条件で２時間攪拌した。室温にて冷却した後、トルエンを加え減圧下で溶媒を留去する操作を３回繰り返した。残留物をＴＨＦ（６ｍＬ）に懸濁し、参考例１６で合成した化合物（２４５．２ｍｇ）とＤＩＰＥＡ（１２８μＬ）を加え室温で終夜攪拌した。減圧下で溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→メタノール：酢酸エチル）で精製し、２－［（２－クロロプテリジン－４－イル）アミノ］－Ｎ－（ピリジン－２－イル）エタン－１－スルホンアミド（５７．７ｍｇ）を得た。
（ｂ）（ａ）で合成した化合物（５７ｍｇ）を１，４－ジオキサン（１．６ｍＬ）に懸濁し、１－メチルピペラジン（３５μＬ）とＤＩＰＥＡ（８１μＬ）を加え６０℃で１．５時間攪拌した。室温にて冷却した後、減圧下で溶媒を留去し残留物を分取ＨＰＬＣ（アセトニトリル／水）にて精製し、表題の化合物（２９．８ｍｇ）を得た。 (Example 123)
2-{[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (pyridin-2-yl) ethane-1-sulfonamide (a) pteridine-2,4-diol (206.5 mg) was suspended in phosphorus oxychloride (2 mL), phosphorus pentachloride (1.02 g) was added, and the mixture was stirred under reflux conditions for 2 hours. After cooling at room temperature, the operation of adding toluene and distilling off the solvent under reduced pressure was repeated three times. The residue was suspended in THF (6 mL), the compound (245.2 mg) synthesized in Reference Example 16 and DIPEA (128 μL) were added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate → methanol: ethyl acetate) and 2-[(2-chloropteridine-4-yl) amino]-. N- (pyridine-2-yl) ethane-1-sulfonamide (57.7 mg) was obtained.
(B) The compound (57 mg) synthesized in (a) was suspended in 1,4-dioxane (1.6 mL), 1-methylpiperazine (35 μL) and DIPEA (81 μL) were added, and the mixture was stirred at 60 ° C. for 1.5 hours. bottom. After cooling at room temperature, the solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile / water) to give the title compound (29.8 mg).
　（実施例１２４）
Ｎ－［２－（アゼチジン－１－スルホニル）エチル］－２－（４－メチルピペラジン－１－イル）プテリジン－４－アミン
（ａ）５，６－ジアミノ－２－スルファニルピリミジン－４－オール（１ｇ）を蒸留水（２７ｍＬ）と３９％グリオキサール水溶液（３．６ｍＬ）に溶解し、水酸化カリウム（７０９ｍｇ）を加えた後室温で２時間攪拌した。５Ｎ塩酸水溶液を加えた後に沈殿している固体を濾過、さらに固体を蒸留水とメタノールで洗浄した。室温・減圧下で乾燥し、２－スルファニルプテリジン－４－オール（１．５８ｇ）を得た。
（ｂ）（ａ）で合成した化合物（１．５８ｇ）をＤＭＦ（１６ｍＬ）に溶解し、０℃で冷却した後、水素化ナトリウム（６０％、流動パラフィンに分散）（３１４．８ｍｇ）、次いでヨウ化メチル（５４４μＬ）を加えて０℃で４時間攪拌した。１Ｎ　塩酸水溶液を加えてｐＨ＝３に調整した後、クロロホルム／メタノールで有機相を抽出、溶媒を減圧下で留去した。残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、２－（メチルスルファニル）プテリジン－４－オール（８７９．６ｍｇ）を得た。
（ｃ）（ｂ）で合成した化合物（３５９．５　ｍｇ）を２－プロパノール（６．２ｍＬ）に溶解し、１－メチルピペラジン（４１１μＬ）を加えマイクロウェーブ反応装置を用い１８０℃で１時間攪拌した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製し、２－（４－メチルピペラジン－１－イル）プテリジン－４－オール（３４７．９ｍｇ）を得た。
（ｄ）（ｃ）で合成した化合物（２２９．０ｍｇ）と２－アミノエタンスルホン酸（１３５．２ｍｇ）をＤＭＦ（５ｍＬ）に溶解し、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（５１０．２ｍｇ）次いで１，８－ジアザビシクロ［５．４．０］－７－ウンデセン（２２８μＬ）を加え室温で終夜攪拌した。メタノールを加え攪拌した後、沈殿している固体をクロロホルムとメタノールで洗浄し、固体を室温・減圧下で乾燥して２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホン酸（１７５．４ｍｇ）を得た。
（ｅ）実施例９５（ｂ）で合成した化合物の代わりに（ｄ）で合成した化合物を、オキサン－３－アミンの代わりにアゼチジンを用いた以外は実施例９５（ｃ）から（ｄ）と同様の手法で表題の化合物を得た。 (Example 124)
N- [2- (azetidine-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine (a) 5,6-diamino-2-sulfanylpyrimidine-4-ol ( 1 g) was dissolved in distilled water (27 mL) and a 39% aqueous glyoxal solution (3.6 mL), potassium hydroxide (709 mg) was added, and the mixture was stirred at room temperature for 2 hours. After adding the 5N aqueous hydrochloric acid solution, the precipitated solid was filtered, and the solid was washed with distilled water and methanol. Drying at room temperature under reduced pressure gave 2-sulfanilpteridine-4-ol (1.58 g).
(B) The compound (1.58 g) synthesized in (a) was dissolved in DMF (16 mL), cooled at 0 ° C., sodium hydride (60%, dispersed in liquid paraffin) (314.8 mg), and then. Methyl iodide (544 μL) was added and the mixture was stirred at 0 ° C. for 4 hours. After adjusting the pH to 3 by adding a 1N aqueous hydrochloric acid solution, the organic phase was extracted with chloroform / methanol, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) to obtain 2- (methylsulfanyl) pteridine-4-ol (879.6 mg).
(C) The compound (359.5 mg) synthesized in (b) was dissolved in 2-propanol (6.2 mL), 1-methylpiperazine (411 μL) was added, and the mixture was stirred at 180 ° C. for 1 hour using a microwave reactor. bottom. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) and 2- (4-methylpiperazin-1-yl) pteridine-4-ol (347.9 mg). ) Was obtained.
(D) The compound (229.0 mg) synthesized in (c) and 2-aminoethanesulfonic acid (135.2 mg) were dissolved in DMF (5 mL), and O- (7-azabenzotriazole-1-yl)-. N, N, N', N'-tetramethyluronium hexafluorophosphate (510.2 mg) was then added, 1,8-diazabicyclo [5.4.0] -7-undecene (228 μL) was added, and the mixture was stirred overnight at room temperature. .. After adding methanol and stirring, the precipitated solid was washed with chloroform and methanol, and the solid was dried at room temperature under reduced pressure to 2-{[2- (4-methylpiperazin-1-yl) pteridine-4-. Il] amino} ethane-1-sulfonic acid (175.4 mg) was obtained.
(E) From Examples 95 (c) to (d) except that the compound synthesized in (d) was used in place of the compound synthesized in Example 95 (b) and azetidine was used instead of oxane-3-amine. The title compound was obtained in a similar manner.
　（実施例１２５）
２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（３，３－ジフルオロシクロブチル）エタン－１－スルホンアミド
（ａ）２－アミノエタンスルホン酸の代わりに参考例７で合成した化合物を用いた以外は、実施例１２６（ａ）から（ｄ）と同様の手法でＮ－（３，３－ジフルオロシクロブチル）－２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミドを得た。
（ｂ）（ａ）で合成した化合物（２７ｍｇ）をエタノール／蒸留水（７５２μＬ／１８８μＬ）に懸濁した後、室温で攪拌した。ピリジン　臭化水素酸塩（２３４ｍｇ）を４回に分け５時間で添加した後、さらに室温で１．５時間攪拌した。溶媒を減圧下で留去し、残留物をシリカゲルプレートを用いたプレパラティブＴＬＣ（展開溶媒，クロロホルム／メタノール）で精製し、表題の化合物（４．５ｍｇ）を得た。 (Example 125)
2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (3,3-difluorocyclobutyl) ethane-1-sulfonamide (a) 2 -N- (3,3-difluorocyclobutyl) -2- in the same manner as in Examples 126 (a) to (d) except that the compound synthesized in Reference Example 7 was used instead of aminoethanesulfonic acid. {[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide was obtained.
(B) The compound (27 mg) synthesized in (a) was suspended in ethanol / distilled water (752 μL / 188 μL) and then stirred at room temperature. Pyridine hydrobromide (234 mg) was added in 4 portions for 5 hours, and then the mixture was further stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (developing solvent, chloroform / methanol) using a silica gel plate to obtain the title compound (4.5 mg).
　（実施例１２６）
Ｎ－シクロペンチル－２－｛［２－（ヘキサヒドロピロロ［１，２－ａ］ピラジン－２（１Ｈ）－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）１－メチルピペラジンの代わりにオクタヒドロピロロ［１，２－ａ］ピラジンを用いた以外は、実施例４７と同様の手法で表題の化合物を得た。 (Example 126)
N-cyclopentyl-2-{[2- (hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) pteridine-4-yl] amino} ethane-1-sulfonamide (a) 1-methyl The title compound was obtained in the same manner as in Example 47, except that octahydropyrrolo [1,2-a] pyrazine was used instead of piperazine.
　（実施例１２７）
Ｎ－［２－（４－フルオロベンゼン－１－スルホニル）エチル］－２－（４－メチルピペラジン－１－イル）プテリジン－４－アミン
（ａ）２－アミノエタンスルホン酸に代えて２－（４－フルオロベンゼン－１－スルホニル）エタン－１－アミン塩酸塩を用いた以外は、実施例１２４（ａ）から（ｄ）と同様の手法で表題の化合物を得た。 (Example 127)
N- [2- (4-Fluorobenzene-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine (a) 2-(4 instead of aminoethanesulfonic acid) The title compound was obtained in the same manner as in Examples 124 (a) to (d) except that 4-fluorobenzene-1-sulfonyl) ethane-1-amine hydrochloride was used.
　（実施例１２８）
Ｎ－シクロペンチル－２－｛メチル［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド
（ａ）２－アミノエタンスルホン酸の代わりに２－（メチルアミノ）エタン－１－スルホン酸を、アゼチジンの代わりにシクロペンチルアミンを用いた以外は実施例１２４と同様の方法で表題の化合物を得た。 (Example 128)
N-cyclopentyl-2- {methyl [2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide (a) 2-( instead of 2-aminoethanesulfonic acid) The title compound was obtained in the same manner as in Example 124 except that cyclopentylamine was used instead of azetidine for methylamino) ethane-1-sulfonic acid.
　（実施例１２９）
Ｎ－シクロペンチル－２－｛［７－（４－メチルピペラジン－１－イル）ピリミド［５，４－ｅ］［１，２，４］トリアジン－５－イル］アミノ｝エタン－１－スルホンアミド
（ａ）４，６－ジクロロ－２－（メチルスルファニル）－５－ニトロピリミジン（３０ｍｇ）をＴＨＦ（０．６ｍＬ）に溶解し、－７８℃にて冷却した。参考例３で合成した化合物（２４．４ｍｇ）とＤＩＰＥＡ（６５μＬ）を加え、－７８℃で１．５時間攪拌した。その後室温にて終夜攪拌し、ヒドラジン一水和物（６μＬ）を加え室温で終夜攪拌した。クロロホルム／メタノール（１０／１）と水を加え有機相を抽出した後、減圧下で溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、Ｎ－シクロペンチル－２－｛［６－ヒドラジニル－２－（メチルスルファニル）－５－ニトロピリミジン－４－イル］アミノ｝エタン－１－スルホンアミド（１６．８ｍｇ）を得た。
（ｂ）（ａ）で合成した化合物（１５．８ｍｇ）をＤＭＦ（０．４ｍＬ）に懸濁した後、二塩化スズ（２４．２ｍｇ）を加え８０℃で終夜攪拌した。減圧下で溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－｛［５－アミノ－６－ヒドラジニル－２－（メチルスルファニル）ピリミジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド（５．０ｍｇ）を得た。
（ｃ）実施例５１（ａ）で合成した化合物に代えて（ｂ）で合成した化合物を用いた以外は、実施例５１（ｂ）と同様の手法で表題の化合物を得た。 (Example 129)
N-cyclopentyl-2-{[7- (4-methylpiperazin-1-yl) pyrimidine [5,4-e] [1,2,4] triazine-5-yl] amino} ethane-1-sulfonamide ( a) 4,6-Dichloro-2- (methylsulfanyl) -5-nitropyrimidine (30 mg) was dissolved in THF (0.6 mL) and cooled at −78 ° C. The compound (24.4 mg) synthesized in Reference Example 3 and DIPEA (65 μL) were added, and the mixture was stirred at −78 ° C. for 1.5 hours. Then, the mixture was stirred overnight at room temperature, hydrazine monohydrate (6 μL) was added, and the mixture was stirred overnight at room temperature. Chloroform / methanol (10/1) and water were added to extract the organic phase, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) and N-cyclopentyl-2-{[6-hydrazinyl-2- (methylsulfanyl) -5-nitropyrimidine-4-yl] amino}. Ethane-1-sulfonamide (16.8 mg) was obtained.
(B) The compound (15.8 mg) synthesized in (a) was suspended in DMF (0.4 mL), tin dichloride (24.2 mg) was added, and the mixture was stirred at 80 ° C. overnight. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate), and 2-{[5-amino-6-hydrazinyl-2- (methylsulfanyl) pyrimidin-4. -Il] amino} -N-cyclopentylethane-1-sulfonamide (5.0 mg) was obtained.
(C) The title compound was obtained in the same manner as in Example 51 (b) except that the compound synthesized in (b) was used instead of the compound synthesized in Example 51 (a).
　（実施例１３０）
２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－［４－（トリフルオロメチル）フェニル］エタン－１－スルホンアミド
（ａ）２－（メタンスルホニル）エタン－１－アミン塩酸塩の代わりに参考例１７で合成した化合物を用いた以外は、実施例１１８と同様の手法で表題の化合物を得た。 (Example 130)
2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N- [4- (trifluoromethyl) Phenyl] Ethane-1-sulfonamide (a) 2- (methanesulfonyl) ethane-1-amine The title was given in the same manner as in Example 118, except that the compound synthesized in Reference Example 17 was used instead of the ethane-1-amine hydrochloride. The compound was obtained.
　上記各実施例にて製造した化合物を下記表３～１９に示す。また、下記表３～１９には、各化合物の１Ｈ－ＮＭＲ及びＥＳＩ－ＭＳによる分析結果も示す。 The compounds produced in each of the above examples are shown in Tables 3 to 19 below. Tables 3 to 19 below also show the analysis results of each compound by 1 H-NMR and ESI-MS.
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
　（試験例　Ｈ４受容体親和性評価）
　ヒトヒスタミンＨ４受容体遺伝子組み換えＨＥＫ（ヒト胎児腎細胞）で得られた膜タンパク質、放射標識リガンド２０ｎＭ［３Ｈ］ヒスタミン（パーキンエルマー社）、及びＤＭＳＯに溶解した被験化合物を、９６ウェルプレート上、５０ｍＭ　トリス－塩酸、ｐＨ７．４、５．０ｍＭ　ＥＤＴＡ－２Ｎａを含む緩衝溶液中で、常温にて６０分間反応させた後、０．５％ポリエチレンイミンで前処理したＧＦ／Ｃフィルター（パーキンエルマー社）で濾過した。５０ｍＭ　トリス－塩酸、ｐＨ７．４緩衝溶液で５回洗浄し、５０℃にて２時間以上乾燥後、ＧＦ／Ｃフィルターにシンチレーションカクテル（ＭｉｃｒｏＳｃｉｎｔ２０：パーキンエルマー社）を添加し、９６ウェル用液体シンチレーションカウンター（ＴｏｐＣｏｕｎｔ：パーキンエルマー社）で各ウェルの放射活性を測定した。非特異的結合は５．０μＭヒスタミン存在下で評価した。阻害定数Ｋｉは、Ｃｈｅｎｇ　ａｎｄ　Ｐｒｕｓｏｆｆの式に従って、各試験から得られた５０％阻害濃度（ＩＣ５０値）とＳｃａｔｃｈａｒｄプロットで得られた放射性リガンド解離定数（Ｋｄ値）より算出した。上記の方法により算出した、前記被験化合物におけるヒスタミンＨ４受容体の阻害定数Ｋｉ値によってＨ４受容体親和性を評価し、阻害定数Ｋｉ値が１０００ｎＭ以上～５０００ｎＭ未満のものをＡ、１００ｎＭ以上～１０００ｎＭ未満のものをＢ、１００ｎＭ未満のものをＣとした。阻害定数Ｋｉ値が５０００ｎＭ未満であればＨ４受容体に対する親和性を有することを示す。被験化合物として、上記の各実施例で得られた化合物を用いたときの評価結果を下記表２０～２１に示す。 (Test Example H4 receptor affinity evaluation)
Membrane protein obtained from human histamine H4 receptor recombinant HEK (human fetal kidney cell), radiolabeled ligand 20 nM [ 3 H] histamine (PerkinElmer), and test compound dissolved in DMSO were placed on a 96-well plate. GF / C filter (PerkinElmer) pretreated with 0.5% polyethyleneimine after reacting at room temperature for 60 minutes in a buffer solution containing 50 mM Tris-hydrochloric acid, pH 7.4, 5.0 mM EDTA-2Na. ) Was filtered. Wash 5 times with 50 mM Tris-hydrochloric acid and pH 7.4 buffer solution, dry at 50 ° C. for 2 hours or more, add scintillation cocktail (MicroScan20: PerkinElmer) to the GF / C filter, and liquid scintillation counter for 96 wells. (TopCount: PerkinElmer) measured the radioactivity of each well. Non-specific binding was assessed in the presence of 5.0 μM histamine. The inhibition constant K i, according to equation Cheng and Prusoff, was calculated from the 50% inhibitory concentrations obtained from each test (IC 50 values) and the resulting radioligand dissociation constants Scatchard plots (K d value). Was calculated by the above method, the test compounds were evaluated H4 receptor affinity by the inhibition constant K i values of histamine H4 receptor in inhibition constant Ki value A a of less than 1000nM than ~ 5000 nM, 100 nM or higher ~ 1000nM Those less than 100 nM were designated as B, and those less than 100 nM were designated as C. If the inhibition constant Ki value is less than 5000 nM, it indicates that it has an affinity for the H4 receptor. The evaluation results when the compounds obtained in each of the above Examples were used as the test compounds are shown in Tables 20 to 21 below.
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
　以上説明したように、本発明によれば、優れたヒスタミンＨ４受容体調節作用を有する新規化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物を提供することが可能となる。 As described above, according to the present invention, it is possible to provide a novel compound having an excellent histamine H4 receptor regulating action, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these. It becomes.

Claims (14)

  1. 　下記一般式（１）で表される化合物又はその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     ［式（１）中、
    　Ｘ１は、ＣＨ又は窒素原子であり、
    　Ｘ２は、ハロゲン原子、Ｃ１～６アルキル基、ＮＨ２、ＮＨＣＨ３、Ｎ（ＣＨ３）２、ＮＯ２、ＯＨ、及びＯＣＨ３から選択されるいずれか１個の置換基で置換されていてもよいＣＨ；又は窒素原子であり、
    　Ｘ３及びＸ４は、それぞれ独立に、炭素原子又は窒素原子であり、
    　環Ａは、窒素原子、酸素原子、及び硫黄原子から選択される少なくとも１個のヘテロ原子を含有する５員又は６員の芳香族複素環であり、
    　　ここで環Ａは、ハロゲン原子、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、及びシクロプロピル基から選択される少なくとも１個の置換基で置換されていてもよいＣ１～６アルキル基；ハロゲン原子；ＣＦ３；Ｃ２～３アルケニル基；水酸基；ＯＣＨ３；ＯＣＨＦ２；ＯＣＨ２ＣＨ３；ＣＮ；ＣＯＮＨ２；ＳＣＨ３；Ｓｉ（ＣＨ３）３；－Ｓ（Ｏ）２Ｒ９；－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ１０；フェニル基；及びピリジル基から選択される１個又は複数個の置換基で置換されていてもよく、Ｒ９及びＲ１０は、それぞれ独立に、アルキル基であり、
    　Ｒ１及びＲ２は、これらが結合している窒素原子と共に、さらに窒素原子、酸素原子、及び硫黄原子から選択される少なくとも１個のヘテロ原子を含有してもよい４員から９員の非芳香族複素環式基を形成しており、
    　　ここで前記非芳香族複素環式基は、単環式、縮合二環式、架橋二環式、又はスピロ二環式の基であって、少なくとも２個の窒素原子を含有する基であるか、又は、１個の窒素原子を含有しかつ少なくとも１個の窒素原子を含有する基で置換された基であり、
    　　前記非芳香族複素環式基は、フッ素原子、水酸基、－ＮＲ５Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される少なくとも１個の置換基で置換されていてもよく、
    　　　ここで、Ｒ５及びＲ６は、それぞれ独立に、水素原子若しくはＣ１～６アルキル基であるか、又は、Ｒ５及びＲ６が結合している窒素原子と共に４員から６員の非芳香族複素環式基を形成しており、
    　Ｒ３は、水素原子又はＣ１～６アルキル基であり、
    　Ｒ４は、フッ素原子で置換されてもよいフェニル基；－ＮＲ７Ｒ８；又はＣ１～６アルキル基であり、
    　　ここで、Ｒ７及びＲ８は、それぞれ独立に、水素原子；水酸基；Ｃ１～６アルキル基；ハロゲン原子、ＣＮ、水酸基、及びＣＨ２ＯＨから選択される少なくとも１個の置換基で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子、水酸基、及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；５員から６員の芳香族複素環式基；若しくは４員から６員の非芳香族複素環式基であるか、又は、Ｒ７及びＲ８が結合している窒素原子と共に４員から６員の非芳香族含窒素複素環式基を形成しており、
    　　ここで、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；水酸基；ＯＣＨ３；フッ素原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていてもよく、
    　ｎは、１～４のうちの整数である。］     A compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     [In equation (1),
    X 1 is a CH or nitrogen atom and
    X 2 is a halogen atom, C 1 ~ 6 alkyl group, NH 2, NHCH 3, N (CH 3) 2, NO 2, OH, and substituted with either one substituent selected from OCH 3 CH; or a nitrogen atom, which may be
    X 3 and X 4 are independently carbon or nitrogen atoms, respectively.
    Ring A is a 5- or 6-membered aromatic heterocycle containing at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms.
    Here, ring A may be substituted with at least one substituent selected from a halogen atom, CH 2 OH, CH 2 F, CHF 2 , and a cyclopropyl group; a C 1-6 alkyl group; a halogen atom. CF 3 ; C 2-3 alkenyl groups; hydroxyl groups; OCH 3 ; OCHF 2 ; OCH 2 CH 3 ; CN; CONH 2 ; SCH 3 ; Si (CH 3 ) 3 ; -S (O) 2 R 9 ; -S (O) 2 N (H) R 10 ; may be substituted with one or more substituents selected from a phenyl group; and a pyridyl group, with R 9 and R 10 being independently alkyl groups, respectively. And
    R 1 and R 2 are 4- to 9-membered non-members which may further contain at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded. Forming an aromatic heterocyclic group,
    Here, is the non-aromatic heterocyclic group a monocyclic, fused bicyclic, crosslinked bicyclic, or spirobicyclic group containing at least two nitrogen atoms? , Or a group substituted with a group containing one nitrogen atom and containing at least one nitrogen atom.
    Said non-aromatic heterocyclic group, a fluorine atom, a hydroxyl group, -NR 5 R 6, C 1 ~ 6 alkyl group, and C 1 ~ 6 substituted by at least one substituent selected from aminoalkyl groups May be
    Here, R 5 and R 6 are independently hydrogen atoms or C 1 to 6 alkyl groups, or 4- to 6-membered non-aromatics together with the nitrogen atom to which R 5 and R 6 are bonded. Forming a group heterocyclic group,
    R 3 is a hydrogen atom or a C 1-6 alkyl group.
    R 4 is a phenyl group optionally substituted with a fluorine atom; -NR 7 R 8 ; or a C 1-6 alkyl group.
    Here, R 7 and R 8 are independently substituted with at least one substituent selected from a hydrogen atom; a hydroxyl group; a C 1 to 6 alkyl group; a halogen atom, a CN, a hydroxyl group, and CH 2 OH. good C 3 ~ 7 cycloalkyl group optionally; halogen atom, a hydroxyl group, and at least one substituent a phenyl group which may be substituted with a group selected from CF 3; 5-membered 6-membered aromatic heterocyclic ring Formula group; or a 4- to 6-membered non-aromatic heterocyclic group, or a 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group with a nitrogen atom to which R 7 and R 8 are bonded. Forming a group
    Here, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently substituted with at least one substituent selected from a fluorine atom; CF 3 ; a hydroxyl group; OCH 3 ; a fluorine atom and CF 3. C 3 to 7 cycloalkyl groups which may be substituted; a phenyl group which may be substituted with at least one substituent selected from a halogen atom and CF 3; and 5 members which may be substituted with a halogen atom. May be substituted with one or more substituents selected from the 6-membered aromatic heterocyclic group.
    n is an integer from 1 to 4. ]
  2. 　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、４員から７員の単環式の非芳香族複素環式基、６員から９員の縮合二環式の非芳香族複素環式基、又は、７員から９員のスピロ二環式の非芳香族複素環式基を形成している、請求項１に記載の化合物又はその薬理学的に許容される塩。 In the above formula (1), R 1 and R 2 are a 4- to 7-membered monocyclic non-aromatic heterocyclic group and a 6- to 9-membered fused two, together with the nitrogen atom to which they are bonded. The compound according to claim 1 or pharmacologically thereof, which forms a cyclic non-aromatic heterocyclic group or a 7- to 9-membered spirobic non-aromatic heterocyclic group. Allowable salt.
  3. 　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、４員から７員の単環式の非芳香族複素環式基を形成しており、前記４員から７員の単環式の非芳香族複素環が、アゼチジン環、ピロリジン環、ピペラジン環、ピペリジン環、又はジアゼパン環である、請求項２に記載の化合物又はその薬理学的に許容される塩。 In the formula (1), R 1 and R 2 form a 4- to 7-membered monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and the 4-membered non-aromatic heterocyclic group is formed. The compound according to claim 2 or a pharmacologically acceptable salt thereof, wherein the 7-membered monocyclic non-aromatic heterocycle is an azetidine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, or a diazepan ring. ..
  4. 　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、６員から９員の縮合二環式の非芳香族複素環式基を形成しており、前記６員から９員の縮合二環式の非芳香族複素環式基が、下記式（ａ）～（ｄ）：
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
     のうちのいずれか１種で表される基である、請求項２に記載の化合物又はその薬理学的に許容される塩。     In the formula (1), R 1 and R 2 form a 6- to 9-membered fused bicyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. Condensed bicyclic non-aromatic heterocyclic groups of 9 to 9 members are represented by the following formulas (a) to (d):
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
     The compound according to claim 2, which is a group represented by any one of the above, or a pharmacologically acceptable salt thereof.
  5. 　前記式（１）において、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、７員から９員のスピロ二環式の非芳香族複素環式基を形成しており、前記７員から９員のスピロ二環式の非芳香族複素環式基が、下記式（ｅ）～（ｈ）：
    Figure JPOXMLDOC01-appb-C000006
    Figure JPOXMLDOC01-appb-C000007
    Figure JPOXMLDOC01-appb-C000008
    Figure JPOXMLDOC01-appb-C000009
     のうちのいずれか１種で表される基である、請求項２に記載の化合物又はその薬理学的に許容される塩。     In the formula (1), R 1 and R 2 form a 7- to 9-membered spirobicyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. Spirobicyclic non-aromatic heterocyclic groups of 9 to 9 members are represented by the following formulas (e) to (h):
    Figure JPOXMLDOC01-appb-C000006
    Figure JPOXMLDOC01-appb-C000007
    Figure JPOXMLDOC01-appb-C000008
    Figure JPOXMLDOC01-appb-C000009
     The compound according to claim 2, which is a group represented by any one of the above, or a pharmacologically acceptable salt thereof.
  6. 　前記式（１）において、Ｒ４が－ＮＲ７Ｒ８であり、Ｒ７及びＲ８が、それぞれ独立に、水素原子；Ｃ１～６アルキル基；ハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基；又はハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基であり、
    　　ここで、Ｒ７及びＲ８が示すＣ１～６アルキル基は、それぞれ独立に、フッ素原子；ＣＦ３；フッ素原子で置換されていてもよいＣ３～７シクロアルキル基；ハロゲン原子及びＣＦ３から選択される少なくとも１個の置換基で置換されていてもよいフェニル基；及びハロゲン原子で置換されていてもよい５員から６員の芳香族複素環式基から選択される１個又は複数個の置換基で置換されていてもよい、
    　請求項１～５のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。     In the above formula (1), R 4 is −NR 7 R 8 , and R 7 and R 8 may be independently substituted with hydrogen atom; C 1 to 6 alkyl group; halogen atom , respectively. C 3 ~ 7 Cycloalkyl group; or a phenyl group optionally substituted with at least one substituent selected from a halogen atom and CF 3.
    Here, the C 1 to 6 alkyl groups indicated by R 7 and R 8 are independently C 3 to 7 cycloalkyl groups which may be substituted with a fluorine atom; CF 3 ; a fluorine atom; a halogen atom and CF 3 A phenyl group optionally substituted with at least one substituent selected from; and one or more selected from a 5- to 6-membered aromatic heterocyclic group optionally substituted with a halogen atom. May be substituted with 17 substituents,
    The compound according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof.
  7. 　前記式（１）において、環Ａが、１～３個の窒素原子を含有する５員の芳香族複素環、又は２～３個の窒素原子を含有する６員の芳香族複素環である、請求項１～６のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。 In the formula (1), the ring A is a 5-membered aromatic heterocycle containing 1 to 3 nitrogen atoms or a 6-membered aromatic heterocycle containing 2 to 3 nitrogen atoms. The compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.
  8. 　前記式（１）において、Ｘ１～Ｘ４及び環Ａを含む二環の構造：
    Figure JPOXMLDOC01-appb-C000010
     が、下記式（１０１）～（１３０）：
    Figure JPOXMLDOC01-appb-C000011
     のうちのいずれか１種で表される構造である、請求項１～７のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。     In the formula (1), a two-ring containing X 1 ~ X 4 and ring A structure:
    Figure JPOXMLDOC01-appb-C000010
     However, the following equations (101) to (130):
    Figure JPOXMLDOC01-appb-C000011
     The compound according to any one of claims 1 to 7, which is a structure represented by any one of the above, or a pharmacologically acceptable salt thereof.
  9. 　前記式（１）で表される化合物が、
    ２－（｛１－メチル－５－［３－（メチルアミノ）アゼチジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    Ｎ－ベンジル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロプロピル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［１－メチル－５－（ピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－（｛１－メチル－５－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    Ｎ－（シクロプロピルメチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－（シクロブチルメチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    ２－（｛１－メチル－５－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［８－ブロモ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－）エタン－１－スルホンアミド、
    ２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－）エタン－１－スルホンアミド、
    Ｎ－シクロヘキシル－２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［７－メチル－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［７－（４－メチルピペラジン－１－イル）［１，２，４］トリアゾロ［４，３－ａ］［１，３，５］トリアジン－５－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［５－（４－メチルピペラジン－１－イル）－１Ｈ－［１，２，３］トリアゾロ［４，５－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［２－（４－メチルピペラジン－１－イル）フロ［３，２－ｄ］ピリミジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    Ｎ－［（４－フルオロフェニル）メチル］－２－｛［２－（４－メチルピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－［（４－フルオロフェニル）メチル］－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－｛［２－（６－メチル－２，６－ジアザスピロ［３．３］ヘプタン－２－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［２－（２，６－ジアザスピロ［３．３］ヘプタン－２－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛１－メチル－５－［３－（メチルアミノ）アゼチジン－１－イル］－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［７－クロロ－２－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［１－メチル－５－（６－メチル－２，６－ジアザスピロ［３．３］ヘプタン－２－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロブチル－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－（３，３－ジフルオロシクロブチル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－［（３，３－ジフルオロシクロブチル）メチル］－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－（２，２－ジフルオロプロピル）－２－｛［１－メチル－５－（４－メチルピペラジン－１－イル）－１Ｈ－ピラゾロ［４，３－ｄ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    ２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－）エタン－１－スルホンアミド、
    ２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（トリフルオロメチル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［５－（４－メチルピペラジン－１－イル）［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    ２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（プロパン－２－イル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］プテリジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［５－（４－メチルピペラジン－１－イル）ピラゾロ［１，５－ａ］ピリミジン－７－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［２－（４－アミノピペリジン－１－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［７－クロロ－２－（１，４－ジアゼパン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛２－［（３Ｓ）－３－アミノピロリジン－１－イル］－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛２－ブロモ－５－［３－（メチルアミノ）アゼチジン－１－イル］［１，２，４］トリアゾロ［１，５－ａ］［１，３，５］トリアジン－７－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－シアノ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［６－シアノ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－メチル－３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［６－エトキシ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－｛［７－クロロ－２－（２，６－ジアザビシクロ［３．２．０］ヘプタン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［２－（３－アミノ－３－メチルアゼチジン－１－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［２－（３－アミノアゼチジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［２－（３－アミノアゼチジン－１－イル）－７－（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］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［７－ブロモ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［７－クロロ－２－（１，６－ジアザスピロ［３．３］ヘプタン－６－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［２－（３－アミノアゼチジン－１－イル）－６－ブロモイミダゾ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（ピペラジン－１－イル）イミダゾ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［２－（６－アミノ－３－アザビシクロ［３．１．０］ヘキサン－３－イル）－７－クロロピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ４－｛［２－（シクロペンチルスルファモイル）エチル］アミノ｝－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－７－カルボキサミド、
    Ｎ－シクロペンチル－２－｛［２－（ヘキサヒドロピロロ［１，２－ａ］ピラジン－２（１Ｈ）－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［（３Ｓ）－３－メチルピペラジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－フェニルピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（ピリジン－３－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－｛［７－シアノ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［（１Ｒ，５Ｓ）－６－（メチルアミノ）－３－アザビシクロ［３．１．０］ヘキサン－３－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛６－シアノ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［７－（ジフルオロメチル）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メトキシエチル）エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－［１－（ヒドロキシメチル）シクロペンチル］エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（メチルスルファニル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－｛［７－クロロ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピロロ［２，１－ｆ］［１，２，４］トリアジン－４－イル］アミノ｝－Ｎ－シクロブチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－エテニル－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（プロプ－１－エン－２－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキソラン－３－イル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［トランス－３－フルオロ－４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－エチル－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛２－［３－（メチルアミノ）アゼチジン－１－イル］－７－（プロパン－２－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－（｛７－シアノ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［４－メチル－４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－シクロペンチルエタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（オキサン－３－イル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－シアノシクロプロピル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－［（１Ｓ，２Ｓ）－２－ヒドロキシシクロペンチル］エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－メトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－ヒドロキシ－２－メチルプロピル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（３，３－ジフルオロシクロペンチル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－ヒドロキシ－２－メチルプロパン－２－イル）エタン－１－スルホンアミド、
    ２－｛［７－（ジフルオロメチル）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－フルオロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－（ジフルオロメトキシ）－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－（ブタン－２－イル）－２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ２－（｛７－エトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    ２－（｛７－（ジフルオロメチル）－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（１－シアノシクロペンチル）エタン－１－スルホンアミド、
    ２－（｛７－クロロ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝エタン－１－スルホンアミド、
    ２－（｛７－メトキシ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［７－メトキシ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－メトキシ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［７－フルオロ－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［７－（ジフルオロメトキシ）－２－（ピペラジン－１－イル）ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    ２－（｛７－ブロモ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）－Ｎ－（２－メチルプロピル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－フルオロ－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－（｛７－（ジフルオロメトキシ）－２－［４－（メチルアミノ）ピペリジン－１－イル］ピラゾロ［１，５－ａ］［１，３，５］トリアジン－４－イル｝アミノ）エタン－１－スルホンアミド、
    ６－ブロモ－Ｎ－［２－（メタンスルホニル）エチル］－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－アミン、
    ６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ－［２－（モルホリン－４－スルホニル）エチル］ピリド［２，３－ｄ］ピリミジン－４－アミン、
    ２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－（４－フルオロフェニル）エタン－１－スルホンアミド、
    ２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド、
    ２－｛［６－ブロモ－２－（ピペラジン－１－イル）ピリド［２，３－ｄ］ピリミジン－４－イル］アミノ｝－Ｎ－メチル－Ｎ－フェニルエタン－１－スルホンアミド、
    ２－｛［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（ピリジン－２－イル）エタン－１－スルホンアミド、
    Ｎ－［２－（アゼチジン－１－スルホニル）エチル］－２－（４－メチルピペラジン－１－イル）プテリジン－４－アミン、
    ２－｛［６－ブロモ－２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝－Ｎ－（３，３－ジフルオロシクロブチル）エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［２－（ヘキサヒドロピロロ［１，２－ａ］ピラジン－２（１Ｈ）－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－［２－（４－フルオロベンゼン－１－スルホニル）エチル］－２－（４－メチルピペラジン－１－イル）プテリジン－４－アミン、
    Ｎ－シクロペンチル－２－｛メチル［２－（４－メチルピペラジン－１－イル）プテリジン－４－イル］アミノ｝エタン－１－スルホンアミド、
    Ｎ－シクロペンチル－２－｛［７－（４－メチルピペラジン－１－イル）ピリミド［５，４－ｅ］［１，２，４］トリアジン－５－イル］アミノ｝エタン－１－スルホンアミド、又は
    ２－（｛６－ブロモ－２－［３－（メチルアミノ）アゼチジン－１－イル］ピリド［２，３－ｄ］ピリミジン－４－イル｝アミノ）－Ｎ－［４－（トリフルオロメチル）フェニル］エタン－１－スルホンアミド
    である、請求項１～８のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。     The compound represented by the formula (1) is
    2-({1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N- (propane-2-) Il) ethane-1-sulfonamide,
    N-Benzyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
    N-Cyclopropyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide ,
    2-{[1-Methyl-5- (piperazine-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane-1- Sulfonamide,
    2-({1-methyl-5-[(3S) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N-( Propane-2-yl) ethane-1-sulfonamide,
    N- (cyclopropylmethyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1 -Sulfonamide,
    N- (Cyclobutylmethyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1 -Sulfonamide,
    2-({1-methyl-5-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) -N-( Propane-2-yl) ethane-1-sulfonamide,
    2-{[1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (propane-2-yl) ethane -1-sulfonamide,
    2-{[8-Bromo-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -) Ethane-1-sulfonamide,
    2-{[2- (4-Methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2-) ethane- 1-sulfonamide,
    N-cyclohexyl-2-{[2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide,
    2-{[7-Methyl-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) ethane-1-sulfonamide,
    2-{[7- (4-Methylpiperazin-1-yl) [1,2,4] triazolo [4,3-a] [1,3,5] triazine-5-yl] amino} -N-( Propane-2-yl) ethane-1-sulfonamide,
    2-{[5- (4-Methylpiperazin-1-yl) -1H- [1,2,3] triazolo [4,5-d] pyrimidin-7-yl] amino} -N- (propane-2-) Il) ethane-1-sulfonamide,
    2-{[2- (4-Methylpiperazin-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (propane-2-yl) ethane -1-sulfonamide,
    N-Cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pyrrolo [2,1-f] [1,2,4] triazine-4-yl] amino} ethane-1-sulfonamide,
    2-{[2- (4-Methylpiperazin-1-yl) flo [3,2-d] pyrimidin-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide,
    N-[(4-fluorophenyl) methyl] -2-{[2- (4-methylpiperazin-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino } Ethane-1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pyrrolo [2,1-f] [1,2,4] triazine-4-yl} amino) ethane-1- Sulfonamide,
    N-Cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) ethane-1- Sulfonamide,
    N-[(4-fluorophenyl) methyl] -2-({2- [3- (methylamino) azetidine-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4- Il} amino) ethane-1-sulfonamide,
    2-{[2- (6-Methyl-2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (Propane-2-yl) ethane-1-sulfonamide,
    2-{[2- (Piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (propane-2-yl) ethane-1- Sulfonamide,
    2-{[2- (2,6-diazaspiro [3.3] heptane-2-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-( Propane-2-yl) ethane-1-sulfonamide,
    2-({2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- (propane-2-) Il) ethane-1-sulfonamide,
    N-cyclopentyl-2- ({1-methyl-5- [3- (methylamino) azetidine-1-yl] -1H-pyrazolo [4,3-d] pyrimidin-7-yl} amino) ethane-1- Sulfonamide,
    N-Cyclopentyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
    2-{[7-Chloro-2- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (propane-2) -Il) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Propane-2-yl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
    2-{[1-Methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} -N- (2-methylpropyl) ethane- 1-sulfonamide,
    N-Cyclopentyl-2-{[1-methyl-5-(6-methyl-2,6-diazaspiro [3.3] heptane-2-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino} ethane-1-sulfonamide,
    N-Cyclobutyl-2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
    N- (3,3-difluorocyclobutyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino } Ethane-1-sulfonamide,
    N-[(3,3-difluorocyclobutyl) methyl] -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7- Il] amino} ethane-1-sulfonamide,
    N- (2,2-difluoropropyl) -2-{[1-methyl-5- (4-methylpiperazin-1-yl) -1H-pyrazolo [4,3-d] pyrimidin-7-yl] amino} Ethane-1-sulfonamide,
    2-({2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- (Propane-2-) ethane-1-sulfonamide,
    2-({2- [3- (methylamino) azetidine-1-yl] -7- (trifluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Propane-2-yl) ethane-1-sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[5- (4-methylpiperazin-1-yl) [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] amino} Ethane-1-sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
    2-{[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide,
    2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (propane-2-yl) ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
    2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide,
    N-Cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] pteridine-4-yl} amino) ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[5- (4-methylpiperazin-1-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} ethane-1-sulfonamide,
    2-{[2- (4-Aminopiperidin-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1- Sulfonamide,
    2-{[7-Chloro-2- (1,4-diazepan-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane- 1-sulfonamide,
    2-({2-[(3S) -3-aminopyrrolidine-1-yl] -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
    2-({2-Bromo-5- [3- (methylamino) azetidine-1-yl] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-yl] } Amino) -N-cyclopentylethane-1-sulfonamide,
    2-({7-Cyano-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
    2-{[6-Cyano-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide,
    2- ({7-Chloro-2- [3-methyl-3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
    N-Cyclopentyl-2-{[6-ethoxy-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
    2-{[7-Chloro-2- (2,6-diazabicyclo [3.2.0] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] Amino} -N-cyclopentylethane-1-sulfonamide,
    2-{[2- (3-Amino-3-methylazetidine-1-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- Cyclopentylethane-1-sulfonamide,
    2-{[6-Bromo-2- (piperazine-1-yl) pyrrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
    2-{[2- (3-Aminoazetidine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
    2-{[2- (3-Aminoazetidine-1-yl) -7- (difluoromethyl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- Cyclopentylethane-1-sulfonamide,
    2-{[7-Bromo-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
    2-{[7-Chloro-2- (1,6-diazaspiro [3.3] heptane-6-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide,
    2-{[2- (3-Aminoazetidine-1-yl) -6-bromoimidazole [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane- 1-Sulfonamide,
    2-{[6-Bromo-2- (piperazine-1-yl) imidazole [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
    2-{[2- (6-amino-3-azabicyclo [3.1.0] hexane-3-yl) -7-chloropyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino} -N-cyclopentylethane-1-sulfonamide,
    4-{[2- (Cyclopentyl sulfamoyl) ethyl] amino} -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-7 -Carboxamide,
    N-Cyclopentyl-2-{[2- (hexahydropyrro [1,2-a] pyrazine-2 (1H) -yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl ] Amino} ethane-1-sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxolan-3-yl) ethane-1-sulfonamide,
    2-({7-Bromo-2-[(3S) -3-methylpiperazin-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- Cyclopentylethane-1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7-phenylpyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino ) Ethane-1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (pyridin-3-yl) pyrazolo [1,5-a] [1,3,5] triazine- 4-yl} amino) ethane-1-sulfonamide,
    2-{[7-Cyano-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N-cyclopentylethane-1-sulfonamide ,
    2-({7-Chloro-2-[(1R, 5S) -6- (methylamino) -3-azabicyclo [3.1.0] hexane-3-yl] pyrazolo [1,5-a] [1 , 3,5] Triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
    2-({7-Chloro-2-[(3R) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
    2-({6-cyano-2- [4- (methylamino) piperidine-1-yl] pyrolo [2,1-f] [1,2,4] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[7- (difluoromethyl) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1 -Sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methoxyethyl) ethane-1-sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- [ 1- (Hydroxymethyl) cyclopentyl] ethane-1-sulfonamide,
    2-({7-Chloro-2-[(3S) -3- (methylamino) pyrrolidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
    2-{[6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N- (2-methylpropyl) ethane -1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (methylsulfanilic) pyrazolo [1,5-a] [1,3,5] triazine-4-yl } Amino) ethane-1-sulfonamide,
    2-{[7-Chloro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (2-methylpropyl) ethane -1-sulfonamide,
    2-{[6-Bromo-2- (piperazine-1-yl) pyrolo [2,1-f] [1,2,4] triazine-4-yl] amino} -N-cyclobutylethane-1-sulfone Amide,
    N-cyclopentyl-2- ({7-ethenyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (prop-1-en-2-yl) pyrazolo [1,5-a] [1,3, 5] Triazine-4-yl} amino) ethane-1-sulfonamide,
    2-({7-Bromo-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxolan-3-yl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [trans-3-fluoro-4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} Amino) -N-cyclopentylethane-1-sulfonamide,
    N-cyclopentyl-2- ({7-ethyl-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
    N-cyclopentyl-2- ({2- [3- (methylamino) azetidine-1-yl] -7- (propane-2-yl) pyrazolo [1,5-a] [1,3,5] triazine- 4-yl} amino) ethane-1-sulfonamide,
    2-({7-Cyano-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentyl Ethane-1-sulfonamide,
    2- ({7-Chloro-2- [4-methyl-4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N-cyclopentylethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( Oxan-3-yl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Cyanocyclopropyl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- [ (1S, 2S) -2-Hydroxycyclopentyl] ethane-1-sulfonamide,
    N-cyclopentyl-2- ({7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Hydroxy-2-methylpropyl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 3,3-Difluorocyclopentyl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Hydroxy-2-methylpropan-2-yl) ethane-1-sulfonamide,
    2-{[7- (difluoromethyl) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} -N- (2-methyl Propyl) ethane-1-sulfonamide,
    N-cyclopentyl-2- ({7-fluoro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
    N-cyclopentyl-2-({7- (difluoromethoxy) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] } Amino) ethane-1-sulfonamide,
    N- (butane-2-yl) -2-({7-chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine- 4-yl} amino) ethane-1-sulfonamide,
    2-({7-ethoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
    2-({7- (difluoromethyl) -2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino)- N- (2-Methylpropyl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 1-Cyanocyclopentyl) ethane-1-sulfonamide,
    2-({7-Chloro-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- { [1- (Trifluoromethyl) cyclopropyl] methyl} ethane-1-sulfonamide,
    2-({7-methoxy-2- [3- (methylamino) azetidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[7-methoxy-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide ,
    N-cyclopentyl-2- ({7-methoxy-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[7-fluoro-2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1-sulfonamide ,
    N-Cyclopentyl-2-{[7- (difluoromethoxy) -2- (piperazine-1-yl) pyrazolo [1,5-a] [1,3,5] triazine-4-yl] amino} ethane-1 -Sulfonamide,
    2-({7-Bromo-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) -N- ( 2-Methylpropyl) ethane-1-sulfonamide,
    N-cyclopentyl-2- ({7-fluoro-2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl} amino) Ethane-1-sulfonamide,
    N-cyclopentyl-2-({7- (difluoromethoxy) -2- [4- (methylamino) piperidine-1-yl] pyrazolo [1,5-a] [1,3,5] triazine-4-yl] } Amino) ethane-1-sulfonamide,
    6-Bromo-N- [2- (Methanesulfonyl) Ethyl] -2- [3- (Methylamino) Azetidine-1-yl] Pyrid [2,3-d] Pyrimidine-4-amine,
    6-Bromo-2- [3- (methylamino) azetidine-1-yl] -N- [2- (morpholine-4-sulfonyl) ethyl] pyrido [2,3-d] pyrimidin-4-amine,
    2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N- (4-fluorophenyl) ethane- 1-Sulfonamide,
    2-({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N-methyl-N-phenylethane-1 -Sulfonamide,
    2-{[6-Bromo-2- (piperazine-1-yl) pyrido [2,3-d] pyrimidin-4-yl] amino} -N-methyl-N-phenylethane-1-sulfonamide,
    2-{[2- (4-Methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (pyridin-2-yl) ethane-1-sulfonamide,
    N- [2- (azetidine-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine,
    2-{[6-Bromo-2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} -N- (3,3-difluorocyclobutyl) ethane-1-sulfonamide,
    N-Cyclopentyl-2-{[2- (hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
    N- [2- (4-Fluorobenzene-1-sulfonyl) ethyl] -2- (4-methylpiperazin-1-yl) pteridine-4-amine,
    N-Cyclopentyl-2- {methyl [2- (4-methylpiperazin-1-yl) pteridine-4-yl] amino} ethane-1-sulfonamide,
    N-cyclopentyl-2-{[7- (4-methylpiperazin-1-yl) pyrimide [5,4-e] [1,2,4] triazine-5-yl] amino} ethane-1-sulfonamide, Or 2- ({6-bromo-2- [3- (methylamino) azetidine-1-yl] pyrido [2,3-d] pyrimidin-4-yl} amino) -N- [4- (trifluoromethyl) ) Phenyl] The compound according to any one of claims 1 to 8, which is an ethane-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
  10. 　請求項１～９のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を含有する医薬組成物。 A pharmaceutical composition containing at least one selected from the compound according to any one of claims 1 to 9 and a pharmacologically acceptable salt thereof.
  11. 　ヒスタミンＨ４受容体調節用組成物である、請求項１０に記載の医薬組成物。 The pharmaceutical composition according to claim 10, which is a composition for regulating histamine H4 receptors.
  12. 　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の組成物である、請求項１０又は１１に記載の医薬組成物。 The pharmaceutical composition according to claim 10 or 11, which is a composition for treating and / or preventing a disease or condition in which the histamine H4 receptor is involved.
  13. 　請求項１～９のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を対象に投与する工程を含む、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防の方法。 A disease involving a histamine H4 receptor, which comprises the step of administering to a subject at least one selected from the compound according to any one of claims 1 to 9 and a pharmacologically acceptable salt thereof. Or a method of treating and / or preventing the condition.
  14. 　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の医薬組成物の製造のための、請求項１～９のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩の使用。 The compound according to any one of claims 1 to 9 or pharmacologically acceptable thereof for the production of a pharmaceutical composition for the treatment and / or prevention of a disease or condition involving the histamine H4 receptor. Use of salt to be done.
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WO2023139164A1 (en) * 2022-01-20 2023-07-27 Origenis Gmbh Cdk9 inhibitors

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WO2009083608A1 (en) * 2008-01-02 2009-07-09 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg Quinazolines and related heterocyclic compounds, and their therapeutic use
WO2011078143A1 (en) * 2009-12-22 2011-06-30 塩野義製薬株式会社 Pyrimidine derivatives and pharmaceutical composition containing same
WO2020020939A1 (en) * 2018-07-25 2020-01-30 Faes Farma, S.A. Pyridopyrimidines as histamine h4-receptor inhibitors

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Publication number Priority date Publication date Assignee Title
WO2009083608A1 (en) * 2008-01-02 2009-07-09 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg Quinazolines and related heterocyclic compounds, and their therapeutic use
WO2011078143A1 (en) * 2009-12-22 2011-06-30 塩野義製薬株式会社 Pyrimidine derivatives and pharmaceutical composition containing same
WO2020020939A1 (en) * 2018-07-25 2020-01-30 Faes Farma, S.A. Pyridopyrimidines as histamine h4-receptor inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023139164A1 (en) * 2022-01-20 2023-07-27 Origenis Gmbh Cdk9 inhibitors

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