WO2021221097A1 - Nouveau composé bicyclique - Google Patents

Nouveau composé bicyclique 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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English (en)
Japanese (ja)
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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/fr

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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

L'invention concerne : un nouveau composé, et un sel pharmaceutiquement acceptable de celui-ci, représenté par la formule (1), le composé ayant un effet de régulation du récepteur H4 de l'histamine et étant utile dans le traitement et/ou la prévention d'une maladie ou d'un état dans lequel le récepteur de l'histamine H4 joue un rôle ; l'utilisation de celui-ci ; et une composition médicale le contenant.
PCT/JP2021/016942 2020-04-28 2021-04-28 Nouveau composé bicyclique WO2021221097A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2023139164A1 (fr) * 2022-01-20 2023-07-27 Origenis Gmbh Inhibiteurs de cdk9

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009083608A1 (fr) * 2008-01-02 2009-07-09 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg Quinazolines et leurs composés hétérocycliques associés, et leur utilisation thérapeutique
WO2011078143A1 (fr) * 2009-12-22 2011-06-30 塩野義製薬株式会社 Dérivés de pyrimidine et composition pharmaceutique les contenant
WO2020020939A1 (fr) * 2018-07-25 2020-01-30 Faes Farma, S.A. Pyridopyrimidines en tant qu'inhibiteurs du récepteur h4 de l'histamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009083608A1 (fr) * 2008-01-02 2009-07-09 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg Quinazolines et leurs composés hétérocycliques associés, et leur utilisation thérapeutique
WO2011078143A1 (fr) * 2009-12-22 2011-06-30 塩野義製薬株式会社 Dérivés de pyrimidine et composition pharmaceutique les contenant
WO2020020939A1 (fr) * 2018-07-25 2020-01-30 Faes Farma, S.A. Pyridopyrimidines en tant qu'inhibiteurs du récepteur h4 de l'histamine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023139164A1 (fr) * 2022-01-20 2023-07-27 Origenis Gmbh Inhibiteurs de cdk9

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