WO2021066088A1 - Novel triazine derivative - Google Patents

Novel triazine derivative Download PDF

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Publication number
WO2021066088A1
WO2021066088A1 PCT/JP2020/037404 JP2020037404W WO2021066088A1 WO 2021066088 A1 WO2021066088 A1 WO 2021066088A1 JP 2020037404 W JP2020037404 W JP 2020037404W WO 2021066088 A1 WO2021066088 A1 WO 2021066088A1
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Prior art keywords
triazine
diamine
methylamino
pyrrolidine
methyl
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PCT/JP2020/037404
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French (fr)
Japanese (ja)
Inventor
佑太 藤原
聡志 一色
美紀 山内
鈴木　伸幸
渉吾 松本
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Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
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Publication of WO2021066088A1 publication Critical patent/WO2021066088A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • 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
    • C07D487/08—Bridged systems
    • 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to a novel triazine derivative, and more particularly to a novel compound which is a triazine derivative having a regulating action on histamine H4 receptor, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these.
  • 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. Expression is also observed in immune cells such as spheres and T 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. There is.
  • Patent Document 1 Non-Patent Document 4
  • Non-Patent Document 5 Non-Patent Document 5
  • Non-Patent Document 6 describe that a triazine derivative has a histamine H4 receptor-regulating action.
  • the present invention comprises 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 inventors showed histamine H4 receptor affinity for a compound which is a novel triazine derivative having a specific structure and a pharmacologically acceptable salt thereof. , Histamine H4 receptor regulatory action was found, and the present invention was completed.
  • the present invention includes the following inventions.
  • R 1 and R 2 may further contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded.
  • a non-aromatic nitrogen-containing heterocyclic group is formed, wherein the heterocyclic group is a monocyclic group, a fused bicyclic group, a crosslinked bicyclic group, or a spirobicyclic group, and the heterocyclic group is formed. May be substituted with one or more substituents selected from fluorine atoms, hydroxyl groups, —N (R 5) R 6 , C 1-6 alkyl groups, and C 1-6 aminoalkyl groups.
  • heterocyclic group is a heterocyclic group containing at least two nitrogen atoms, or is substituted with a group containing one nitrogen atom and containing at least one nitrogen atom.
  • Heterocyclic group R 5 and R 6 are independently selected from hydrogen atoms and C 1-6 alkyl groups, respectively, or R 5 and R 6 are 4- to 6-membered with the nitrogen atom to which they are attached.
  • Forming a non-aromatic nitrogen-containing heterocyclic group of R 3 is one or more of good C 3 ⁇ 7 cycloalkyl group optionally substituted with a halogen atom, one or more optionally substituted phenyl group with a halogen atom, a fluorine atom, a hydroxyl group, CF 3 , OCH 3 , Si (CH 3 ) 3 , cyclopropyl (dimethyl) silyl group, 1-methylsiloran-1-yl group, -S (O) 2 R 7 , -S (O) 2 N (H) R 8 , 5- to 6-membered aromatic heterocyclic group, 4- to 6-membered non-aromatic heterocyclic group, 5- to 7-membered bridged bicyclic group, and 9 to 10-membered bridged tricyclic group C 1-6 alkyl groups optionally substituted with one or more substituents selected from the groups; halogen atoms, methyl groups, CF 3 , CH 2
  • R 7 and R 8 are independently alkyl groups, respectively.
  • R 4 is an amino group or a hydrogen atom.
  • R 1 and R 2 form a 4- to 7-membered monocyclic non-aromatic nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, or. Forming 7-9 member condensed bicyclic non-aromatic nitrogen-containing heterocyclic groups, The compound according to [1] or a pharmacologically acceptable salt thereof.
  • the 4- to 7-membered monocyclic non-aromatic nitrogen-containing heterocyclic group is pyrrolidine, azetidine, piperazine, or diazepan. The compound according to [2] or a pharmacologically acceptable salt thereof.
  • R 3 is selected from C 3 to 7 cycloalkyl groups, which may be substituted with one or more halogen atoms, a fluorine atom, a hydroxyl group, CF 3 , and Si (CH 3 ) 3. one or more of which may be substituted with a substituent C 1 - 6 alkyl groups is, one or more of which may be substituted with halogen atoms C 3 - 7 cycloalkyl group; a 5- to 6-membered Aromatic heterocyclic group; 5- to 7-membered crosslinked bicyclic group; or 9 to 10-membered crosslinked tricyclic group.
  • the compound represented by the formula (1) is N 2 - (2,2-dimethylpropyl) -6 - [(3S) -3- methylpiperazin-l-yl] -1,3,5-triazine-2,4-diamine, N 2- (2,2-dimethylpropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine, N 2- (2,2-dimethylpropyl) -6- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine, 6- (1,4-Diazepan-1-yl) -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine, N 2- (2,2-dimethylpropyl
  • the pharmaceutical composition according to [6] which is a composition for regulating histamine H4 receptors.
  • Involvement of 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 [5] and a pharmacologically acceptable salt thereof.
  • the compounds of the present invention, pharmacologically acceptable salts thereof, and pharmaceutical compositions containing them can be used to treat and / or treat diseases or conditions (various allergies, inflammatory diseases, etc.) in which the histamine H4 receptor is involved.
  • diseases or conditions include, for example, COPD, inflammatory bowel disease, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, psoriatic arthritis, psoriasis vulgaris, and various other diseases.
  • Cancer colon cancer, lung cancer, blood cancer, brain tumor, etc.
  • metabolic disease diabetes, obesity, etc.
  • pain, etc. are included, but are not limited to these.
  • 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).
  • R 4 is an amino group or a hydrogen atom.
  • R 1 and R 2 may further contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded. It forms a 4- to 9-membered non-aromatic nitrogen-containing heterocyclic group.
  • the heterocyclic group may be a monocyclic group, a fused bicyclic group, a bridged bicyclic group, or a spiro dicyclic group, and more specifically, the heterocyclic group may be a monocyclic group or a fused bicyclic group. It is a bicyclic type, a bridged bicyclic type, or a spiro bicyclic type.
  • the heterocyclic group is substituted with one or more substituents selected from a fluorine atom, a hydroxyl group, an ⁇ N (R 5 ) R 6 , a C 1 to 6 alkyl group, and a C 1 to 6 amino alkyl group. It may have been done.
  • the heterocyclic group is a heterocyclic group containing at least two nitrogen atoms (that is, a ring is formed by an atom containing at least two nitrogen atoms), or one. It is a heterocyclic formula containing a nitrogen atom (that is, a ring is formed by an atom containing one nitrogen atom) and substituted with a group containing at least one nitrogen atom.
  • R 5 and R 6 are independently selected from a hydrogen atom and a C 1 to 6 alkyl group, or are 4- to 6-membered non-aromatics together with a nitrogen atom to which they are bonded. It forms a nitrogen-containing heterocyclic group.
  • R 3 is a C 3 to 7 cycloalkyl group which may be substituted with one or more (preferably one) halogen atoms, or one or more (preferably one).
  • R 7 and R 8 are independently alkyl groups.
  • Halogen atom means fluorine, chlorine, bromine and iodine.
  • alkyl group simply means a linear or branched alkyl group, and preferably has 1 to 6 carbon atoms.
  • 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 ⁇ 6 alkyl group (particularly, in the formula (1), C 1 ⁇ 6 alkyl group represented by R 5 and / or R 6) it will also contain deuterium isotopes.
  • the “C 1 to 6 aminoalkyl group” means a group in which one hydrogen atom of the C 1 to 6 alkyl group is substituted with an amino group.
  • 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.
  • the "aromatic heterocyclic group” means an aromatic heterocyclic group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the 5- to 6-membered aromatic heterocyclic group contained in R 3 is preferably a monocyclic group. Examples thereof include a group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a furanyl group and the like.
  • non-aromatic heterocyclic group means a saturated heterocyclic group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the non-aromatic heterocyclic group is preferably monocyclic, for example, azetidine, oxetane, thietan, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothio, which are 4 to 9 members.
  • Examples thereof include pyran, piperazine, morpholine, azepan, diazepan, oxetane, thiepan, azocan, oxocan, thiocan, azonan, oxonan, thionan and the like.
  • Examples of the 4- to 6-membered non-aromatic heterocyclic group contained in R 3 or indicated by R 3 include azetidine, oxetane, thietan, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiophene, and the like. Examples include piperidine and morpholine.
  • non-aromatic nitrogen-containing heterocyclic group means a saturated heterocyclic group containing a nitrogen atom.
  • the 4- to 9-membered non-aromatic nitrogen-containing heterocyclic group indicated by R 1 and R 2 is preferably a monocyclic group, for example, azetidine. Examples thereof include pyrrolidine, piperidine, piperazine, morpholine, azepane, diazepane, azocane and azonan.
  • it has 4 to 7 members, and examples thereof include azetidine, pyrrolidine, piperidine, piperazine, and diazepan, and more preferably, azetidine, pyrrolidine, piperazine, and diazepan.
  • Examples of the 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group indicated by R 5 and R 6 include azetidine, pyrrolidine, piperazine and the like.
  • the "condensed 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.
  • non-aromatic fused bicyclic groups include, for example, 5- to 9-membered bicyclo [2.1.0] pentane, bicyclo [3.1.0] hexane, and bicyclo [3.2.0]. Examples include heptane, bicyclo [3.3.0] octane, and bicyclo [4.3.0] nonane.
  • the number of members is 7 to 9, and examples thereof include diazabicyclo [3.2.0] heptane, diazabicyclo [3.3.0] octane, 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.
  • non-aromatic spirobicyclic groups include spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, and spiro [3. 3] Heptane, spiro [3.4] octane, spiro [4.4] nonane can be mentioned.
  • Azaspiro [2.2] pentane is a spirobicyclic non-aromatic nitrogen-containing heterocyclic group containing a nitrogen atom indicated by R 1 and R 2 (that is, ⁇ N (R 1 ) R 2). , Azaspiro [2.3] hexane, Azaspiro [2.4] heptane, diazaspiro [3.3] heptane, diazaspiro [3.4] octane, diazaspiro [4.4] nonane and the like, and preferably azaspiro [4.4] nonane.
  • Heptane can be mentioned.
  • Cross-linked bicyclic group means a group having two rings in which two atoms of a cyclic compound are linked by cross-linking.
  • the crosslinked bicyclic group is preferably non-aromatic, and is, for example, 4- to 9-membered bicyclo [1.1.1] pentane, bicyclo [2.1.1] hexane, bicyclo [2. 2.1] Heptane, diazabicyclo [3.2.1] octane, bicyclo [3.3.1] nonane can be mentioned.
  • bridged bicyclic groups those containing a nitrogen atom indicated by R 1 and R 2 (that is, -N (R 1 ) R 2 ) (bridged bicyclic non-aromatic nitrogen-containing heterocyclic group).
  • Examples include azabicyclo [1.1.1] pentane, azabicyclo [2.1.1] hexane, diazabicyclo [2.2.1] heptane, diazabicyclo [3.2.1] octane, and diazabicyclo [3.3.1].
  • Nonan is mentioned.
  • Preferred are bicyclo [1.1.1] pentane and bicyclo [2.2.1] heptane.
  • the "crosslinked tricyclic group” means a group having three rings in which one atom of each ring of the bicyclic compound is linked by cross-linking.
  • the crosslinking tricyclic group of 9-membered to 10-membered indicated or R 3 contained in R 3, is preferably a non-aromatic, for example, adamantane, hexahydro-2,5-methanopentalene the like.
  • “may be substituted” means that the group is not substituted and one or more hydrogen atoms of the group are substituted with an atom or a substituent. Means to include a group. If there are multiple substituted atoms or substituents, they may be the same or different from each other. The number of substituted atoms or substituents is preferably, for example, 1 to 3.
  • 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, 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 it may be a racemate.
  • the method for producing the triazine derivative of the present invention is not particularly limited, and can be synthesized by those skilled in the art using commercially available starting materials, precursors, reagents, solvents and the like, which can be synthesized by a method recognized by those skilled in the art. It can be produced by combining a wide variety of recognized synthetic methods and, if necessary, a method obtained by modifying the synthetic method. For example, it can be produced by the following typical methods.
  • R 1 , R 2 , and R 3 are synonymous with R 1 , R 2 , and R 3 in the equation (1), respectively, and X, Y, and Z are independent of each other. It is a leaving group.
  • the compound represented by the formula (1a) is subjected to the presence of a base of the compound represented by the formula (4) and an appropriate amine.
  • 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 with respect to 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 with respect to 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 and the like. , One of these may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (1a) is selected, for example, in the range of 100 to 200 ° C, preferably in the range of 130 to 180 ° C.
  • the reaction time is, for example, in the range of 30 minutes to 2 hours, preferably in the range of 1 hour to 90 minutes.
  • the compound represented by the formula (4) can be synthesized, for example, by reacting the compound represented by the formula (3) with an excess amount of ammonia.
  • the ammonia used in the synthesis reaction of the compound represented by the formula (4) may be an aqueous ammonia solution or a solution in which ammonia is dissolved in a solvent, and the amount thereof is preferably represented by the formula (3). It is in the range of 10 to 100 equivalents with respect to the compound.
  • the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like.
  • One of the above may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (4) 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 30 minutes to 6 hours, 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 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 (3) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (2).
  • Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents with respect to the compound represented by the formula (2).
  • Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (3) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (1a) can also be synthesized, for example, by reacting the compound represented by the formula (6) 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 (1a) from the compound represented by the formula (6) is preferably 1 to 1 to that of the compound represented by the formula (6). It is in the range of 3 equivalents.
  • 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 with respect to the compound represented by the formula (6).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (1a) from the compound represented by the formula (6) is selected, for example, in the range of 50 to 150 ° C., preferably in the range of 80 to 110 ° C. Is.
  • 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 (6) can be synthesized, for example, by reacting the compound represented by the formula (5) with an excess amount of ammonia.
  • the ammonia used in the synthesis reaction of the compound represented by the formula (6) may be an aqueous ammonia solution or a solution in which ammonia is dissolved in a solvent, and the amount thereof is preferably represented by the formula (5). It is in the range of 10 to 100 equivalents with respect to the compound.
  • the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like.
  • One of the above may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (6) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (5) can be synthesized, for example, by reacting the compound represented by the formula (2) 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 (5) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (2).
  • Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents with respect to the compound represented by the formula (2).
  • Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (5) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the leaving groups represented by X, Y, and Z are independently alternative leaving groups such as halogen atoms (eg chlorine), sulfonic acid esters (eg 4-methylphenyl sulfonic acid); sulfonyl groups.
  • halogen atoms eg chlorine
  • sulfonic acid esters eg 4-methylphenyl sulfonic acid
  • sulfonyl groups eg., methanesulfonyl or phenylsulfonyl
  • methanesulfonyl or phenylsulfonyl includes, but is not limited to, a sulfinyl group (eg, methanesulfinyl).
  • isolation or purification of the intermediate compound represented by the formula (3) is not always necessary, but additional amines (eg, diisopropylethylamine) are required so as to require the continuous addition of appropriate amines.
  • a tertiary amine such as triethylamine) or a solvent suitable for the compound represented by the above formula (2) for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N- With or without addition of dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone), with or without heating of the reaction mixture during the addition of the two amines.
  • solvent suitable for the compound represented by the above formula (2) for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N- With or without addition of dimethylacetamide, dimethylsulfoxide, N-methyl-2
  • protecting groups at any step in synthesizing the compound represented by the 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 Willey & Sons, Inc. Etc. (the methods for desorbing such groups are also described).
  • 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 triazine derivative of the present invention can also be produced, for example, by the method shown below.
  • R 1 , R 2 , and R 3 are synonymous with R 1 , R 2 , and R 3 in the equation (1), respectively, and X and Y are independent leaving groups, respectively. Is.
  • the compound represented by the formula (1b) among the compounds represented by the formula (1) is suitable for the compound represented by the formula (8) in the presence of a base in a solvent. It can be synthesized by reacting with an amine.
  • the amount of amine used in the synthetic reaction of the compound represented by the formula (1b) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (8).
  • the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents with respect to the compound represented by the formula (8).
  • the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (1b) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (8) can be synthesized, for example, by reacting the compound represented by the formula (7) 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 (8) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (7).
  • 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 with respect to the compound represented by the formula (7).
  • 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 and the like. , One of these may be used alone or in combination of two or more.
  • the temperature in the synthetic reaction of the compound represented by the formula (8) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
  • the compound represented by the formula (7) can be easily prepared by a method known in the literature or well known to those skilled in the art.
  • the triazine derivative of the present invention has an affinity for the histamine H4 receptor (hereinafter, also simply referred to as "H4 receptor" in some cases). Therefore, the triazine derivative 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 the H4 receptor include, for example, COPD, inflammatory bowel disease, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, psoriatic arthritis, psoriasis vulgaris, and the like.
  • Psoriasis colon cancer, lung cancer, blood cancer, brain tumor, etc.
  • metabolic diseases diabetes, obesity, etc.
  • pain etc., but are not limited to these.
  • the pharmaceutical composition of the present invention contains the triazine derivative 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 in an appropriate dosage form according to the administration route.
  • Specific examples of the dosage forms of the above-mentioned preparations include oral preparations such as tablets, pills, capsules, granules, powders, elixirs, suspensions, emulsions, and syrups, and injections.
  • Parenteral agents such as inhalants, enteral agents, suppositories, lotions, sprays, ointments, creams, patches, and sustained-release preparations.
  • These various preparations if necessary, contain 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 a pharmacologically acceptable additive and / or carrier.
  • the content of the triazine derivative of the present invention (in the case of a mixture of two or more kinds, the total content thereof) is appropriately adjusted according to the purpose of administration, the dosage form of the preparation, and the like. Therefore, although it cannot be said unconditionally, it is usually 0.01 to 70% by mass, preferably 0.05 to 0.05 to the total mass of the pharmaceutical composition in terms of the free form of the compound represented by the formula (1). It is 50% by mass.
  • the dose of the triazine derivative of the present invention (the total dose in the case of a mixture of two or more kinds) is determined in individual cases in consideration of the patient's age, weight, sex, difference in disease, degree of symptoms, etc. Although it cannot be unequivocally determined because it is appropriately determined according to the above, usually, in terms of free form of the compound represented by the formula (1), 0.01 to 1000 mg, preferably 0.1, per day for an adult. The dose is ⁇ 300 mg, which can be administered once a day or in several divided doses.
  • N-Benzyl-N-methylazepan-4-amine hydrochloride (500 mg) was suspended in dichloromethane (17 mL), followed by triethylamine (1.39 mL) and di-tert-butyl. Dicarbonate (1.09 g) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate ⁇ ethyl acetate: methanol) to obtain 701 mg of tert-butyl 4-oxazepan-1-carboxylate.
  • (2S) -1-methoxy-3-methylbutane-2-amine hydrochloride (a) (2S) -2-amino-3,3-dimethylbutane-1-ol (230 mg) was dissolved in dichloromethane (10 mL). After adding di-tert-butyldicarbonate (850 mg), the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture for extraction, and then the organic layer was dried over sodium sulfate.
  • Example 2 The compound (107.8 mg) obtained in Example 1 (a) was dissolved in chloroform (2.3 mL), trifluoroacetic acid (2.3 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. .. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 126.5 mg of the title compound.
  • the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue to neutralize the residue. After adding methanol to the mixture, the solvent was distilled off again under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 28.1 mg of the title compound.
  • Example 3 N 2- (2,2-dimethylpropyl) -6- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine
  • the tert in Example 2 (a) Using tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride instead of -butylmethyl [(3R) -pyrrolidine-3-yl] carbamate, the title compound was obtained in the same manner as in Example 2. ..
  • Example 4 6- (1,4-diazepan-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-in-triazine-2,4-diamine
  • Example 2 (a) tert-butyl
  • the title compound was obtained in the same manner as in Example 2 using tert-butyl 1,4-diazepan-1-carboxylate instead of methyl [(3R) -pyrrolidin-3-yl] carbamate.
  • Example 5 N 2 - (2,2-dimethylpropyl) -6- (piperazin-1-yl) -1,3,5-triazine-2,4-diamine
  • Example 2 in (a) tert-butyl methyl [(3R ) -Pyrrolidine-3-yl] tert-butylpiperazin-1-carboxylate was used instead of carbamate, and the title compound was obtained in the same manner as in Example 2.
  • Example 6 6- (4-amino-piperidin-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 in (a) tert-butyl ( 2S) Using tert-butyl piperidine-4-ylcarbamate instead of -2-methylpiperazin-1-carboxylate, the title compound was obtained in the same manner as in Example 1.
  • Example 7 6- (2,6-diazaspiro [3.3] heptan-2-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 (a ) In place of tert-butyl (2S) -2-methylpiperazin-1-carboxylate, tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate was used, as in Example 1. The title compound was obtained by the method.
  • Example 8 6- (3,8-diazabicyclo [3.2.1] octan-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 Example using tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in (a). The title compound was obtained in the same manner as in 1.
  • Example 9 6- (3,6-diazabicyclo [3.2.0] heptan-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 Example using tert-butyl 3,6-diazabicyclo [3.2.0] heptane-6-carboxylate instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate in (a). The title compound was obtained in the same manner as in 1.
  • Example 10 6-[(7R) -7-amino-5-azaspiro [2.4] heptane-5-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4- Diamine
  • Example 1 tert-butyl (7R) -5-azaspiro [2.4] heptane-7-ilcarbamate was used instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate.
  • the compound of the title was obtained in the same manner as in Example 1.
  • Example 11 6 - [(3S, 4S) -3- amino-4-fluoro-1-yl] -N 2 - (2,2- dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 11 using tert-butyl [(3S, 4S) -4-fluoropyrrolidine-3-yl] carbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in 1 (a).
  • the title compound was obtained in the same manner as in 1.
  • Example 12 6- (4-amino-3,3-difluoro-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 (a) but In the same manner as in Example 1, tert-butyl (4,4-difluoropyrrolidine-3-yl) carbamate was used instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in the title. Compound was obtained.
  • Example 13 6-[(1R, 5R) -3,6-diazabicyclo [3.2.0] heptane-3-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2, 4-Diamine
  • Example 1 (a) tert-butyl (1S, 5R) -3,6-diazabicyclo [3.2.0] instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate.
  • the title compound was obtained in the same manner as in Example 1 using heptane-6-carboxylate.
  • Example 14 6-[(1S, 5S) -3,6-diazabicyclo [3.2.0] heptane-3-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2, 4-Diamine
  • Example 1 (a) tert-butyl (1R, 5S) -3,6-diazabicyclo [3.2.0] instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate.
  • the title compound was obtained in the same manner as in Example 1 using heptane-6-carboxylate.
  • Example 15 6- (1,7-diazaspiro [4.4] nonan-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 (a ) In place of tert-butyl (2S) -2-methylpiperazine-1-carboxylate, tert-butyl 1,7-diazaspiro [4.4] nonane-7-carboxylate was used, as in Example 1. The title compound was obtained by the method.
  • Example 16 3- ⁇ 4-Amino-6-[(2,2-dimethylpropyl) amino] -1,3,5-triazine-2-yl ⁇ -3,7-diazabicyclo [3.3.1] Nonan-9- All In Example 1 (a), instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate, tert-butyl 9-hydroxy-3,7-diazabicyclo [3.3.1] nonane-3 -Using carboxylate, the title compound was obtained in the same manner as in Example 1.
  • Example 17 6- [3- (Aminomethyl) Azetidine-1-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • the tert in Example 1 (a) Using tert-butyl [(azetidine-3-yl) methyl] carbamate instead of -butyl (2S) -2-methylpiperazin-1-carboxylate, the title compound was obtained in the same manner as in Example 1. ..
  • Example 18 N 2- (2,2-Dimethylpropyl) -6- [3-Methyl-3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 1 (a) ), Using tert-butyl methyl (3-methylazetidine-3-yl) carbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate, in the same manner as in Example 1. The title compound was obtained.
  • Example 19 N 2- (2,2-Dimethylpropyl) -6- (4-Methyl-1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine
  • Example 1 (a) , Tert-Butyl (2S) -2-methylpiperazine-1-carboxylate was used instead of 1-methyl-1,4-diazepan, and the title compound was obtained in the same manner as in Example 1.
  • Example 20 6- (6-amino-3-azabicyclo [3.1.0] hexane-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine [
  • the title compound was obtained in the same manner as in 1.
  • Example 21 6 - in (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 1 (a) - [( 3R) -3- amino-1-yl] -N 2
  • the title compound was obtained in the same manner as in Example 1 using tert-butyl (3R) -pyrrolidine-3-ylcarbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate. ..
  • Example 23 N 2 - (2,2-dimethylpropyl) -6- (octahydro -6H- pyrrolo [3,4-b] pyridin-6-yl) -1,3,5-triazine-2,4-diamine
  • Example 1 Example using tert-butyl octahydro-1H-pyrrolo [3,4-b] pyridin-1-carboxylate instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate in (a). The title compound was obtained in the same manner as in 1.
  • Example 24 N 2 - (2,2-dimethylpropyl) -6-enantiomer of (octahydro -6H- pyrrolo [3,4-b] pyridin-6-yl) -1,3,5-triazine-2,4-diamine Body
  • Example 24-2) (isomer with long retention time) was obtained in an amount of 6.9 mg.
  • Example 25 N 2- (2,2-dimethylpropyl) -6- [3- (pyrrolidine-1-yl) azetidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 1 (a) The compound obtained in Reference Example 3 was used in place of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in the above, and the title compound was obtained in the same manner as in Example 1.
  • Example 26 N 2 - (2,2-dimethylpropyl) -6 - ⁇ (3R) -3 - [(2 H 3) - methylamino] pyrrolidin-1-yl ⁇ -1,3,5-triazine-2,4 Diamine
  • the compound obtained in Reference Example 4 was used instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in Example 1 (a).
  • Example 27 N 2- (2,2-dimethylpropyl) -6- [4- (methylamino) azepan-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 1 In place of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in, the compound obtained in Reference Example 5 was used, and 6- ⁇ 4- [benzyl (methyl)) was used in the same manner as in Example 1. ) Amino] Azepan-1-yl ⁇ -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine was obtained.
  • Example 28-1 (short retention time) was used in the same manner as in Example 27 (b).
  • Example 28-2) (Isomer with long retention time)] were obtained.
  • Example 29 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine
  • a Reference The compound (109.8 mg) obtained in Example 6 was suspended in 1,4-dioxane (1.67 mL), and N, N-diisopropylethylamine (114 ⁇ L) and 1- (1-methylcyclopentyl) methaneamine hydrochloride (50 mg) were suspended. ) was added, and the mixture was stirred at 150 ° C. for 1.5 hours under microwave irradiation.
  • Example 29 (B) The compound (106.4 mg) obtained in Example 29 (a) was dissolved in chloroform (1.3 mL), trifluoroacetic acid (1.3 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. .. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 63.2 mg of the title compound.
  • Example 30 ⁇ 1-[( ⁇ 4-Amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl ⁇ amino) methyl] cyclopentyl ⁇ methanol implementation [1- (Aminomethyl) cyclopentyl] methanol was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in Example 29 (a), and the title compound was obtained in the same manner as in Example 29.
  • Example 31 N 2- (2,2-difluoropropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) ), 2,2-Difluoropropane-1-amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
  • Example 32 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 - ⁇ [1- (trifluoromethyl) cyclopropyl] methyl ⁇ -1,3,5-triazine-2,4- Diamine
  • Example 29 (a) 1- [1- (trifluoromethyl) cyclopropyl] methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same method as in Example 29 was used. Obtained the title compound.
  • Example 33 3-( ⁇ 4-Amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl ⁇ amino) -2,2-dimethylpropane-
  • Example 29 (a) 3-amino-2,2-dimethylpropan-1-ol was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same method as in Example 29 was used. Obtained the title compound.
  • Example 34 N 2 -[(3,3-difluorocyclobutyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine implementation
  • Example 29 (a) 1- (3,3-difluorocyclobutyl) methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29.
  • Example 35 Examples of N 2 -[(4,4-difluorocyclohexyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • the title compound was obtained in the same manner as in Example 29 by using 1- (4,4-difluorocyclohexyl) methaneamine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in 29 (a).
  • Example 36 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclohexyl) methyl] -1,3,5-triazine-2,4-diamine
  • Example 29 The title compound was obtained in the same manner as in Example 29 by using 1- (1-methylcyclohexyl) methaneamine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in a).
  • Example 37 N 2 - (2-fluoro-2-methylpropyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 The compound prepared in Reference Example 7 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a), and the title compound was obtained in the same manner as in Example 29.
  • Example 38 N 2 -[(2S) -1-methoxy-3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5- Triazine-2,4-diamine
  • (2S) -1-methoxy-3-methylbutane-2-amine prepared in Reference Example 8 instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride Using hydrochloride, the title compound was obtained in the same manner as in Example 29.
  • Example 39 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- [1- (trifluoromethyl) cyclopentyl] -1,3,5-triazine-2,4-diamine
  • Example 29 In place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a), 1- (trifluoromethyl) cyclopentane-1-amine hydrochloride was used, and the title compound was prepared in the same manner as in Example 29. Obtained.
  • Example 40 N 2 -[(4-chlorophenyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) ), 1- (4-Chlorophenyl) methaneamine was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
  • Example 41 N 2 -[(furan-2-yl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 The title compound was obtained in the same manner as in Example 29 by using 1- (furan-2-yl) methaneamine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a).
  • Example 42 N 2- (4-Chlorophenyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) The title compound was obtained in the same manner as in Example 29 using 4-chloroaniline instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride.
  • Example 43 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 - ⁇ [1- (trifluoromethyl) cyclopentyl] methyl ⁇ -1,3,5-triazine-2,4-diamine
  • Example 29 (a) 1- [1- (trifluoromethyl) cyclopentyl] methaneamine hydrochloride prepared in Reference Example 9 was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same as in Example 29. The title compound was obtained in the same manner.
  • Example 44 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(3-methyloxetane-3-yl) methyl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) 1- (3-methyloxetane-3-yl) methaneamine was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29.
  • Example 45 N 2 - ⁇ [1- (fluoromethyl) cyclopropyl] methyl ⁇ -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 43 (a) 1- (fluoromethyl) cyclopropane-1-carboxylic acid was used instead of 1- (trifluoromethyl) cyclopentane-1-carboxylic acid, and the same method as in Example 43 was used. The title compound was obtained.
  • Example 46 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2 , 4-Diamine
  • Example 43 (a) 3,3,3-trifluoro-2,2-dimethylpropionic acid was used instead of 1- (trifluoromethyl) cyclopentane-1-carboxylic acid. The title compound was obtained in the same manner as in 43.
  • Example 47 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 - ⁇ [1- (trifluoromethyl) cyclobutyl] methyl ⁇ -1,3,5-triazine-2,4-diamine
  • Example 43 (a) 1- (trifluoromethyl) cyclobutane-1-carboxylic acid was used instead of 1- (trifluoromethyl) cyclopentane-1-carboxylic acid, and the same method as in Example 43 was used. The title compound was obtained.
  • Example 48 N 2- (cyclopropylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine 2 in Example 2 (a) , 2-Cyclopropylmethaneamine was used instead of 2-dimethylpropane-1-amine, and the title compound was obtained in the same manner as in Example 2.
  • Example 50 N 2 - cyclopentyl-6 - 2,2-dimethyl-in [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 2 (a) Using cyclopentylamine instead of propane-1-amine, the title compound was obtained in the same manner as in Example 2.
  • Example 51 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(oxolan-2-yl) methyl] -1,3,5-triazine-2,4-diamine
  • the compound obtained in Reference Example 2 (a) was dissolved in chloroform (7 mL), N, N-diisopropylethylamine (170 ⁇ L) and 1- (fran-3-yl) methaneamine (93 ⁇ L) were added, and then at room temperature. Stirred overnight.
  • Example 51 (C) The inside of the flask to which the compound (438.3 mg) obtained in Example 51 (b) was added was replaced with argon, and palladium hydroxide-activated carbon (88 mg) and methanol (8.6 mL) were added in this order. After suspension, the inside of the system was replaced with hydrogen, and the mixture was stirred at 40 ° C. overnight.
  • reaction solution was filtered through Celite, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate ⁇ ethyl acetate: methanol) to purify with tert-butyl [((developing solvent, hexane: ethyl acetate ⁇ ethyl acetate: methanol)).
  • Example 52 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(oxan-4-yl) methyl] -1,3,5-triazine-2,4-diamine
  • Example 2 The title compound was obtained in the same manner as in Example 2 by using 1- (oxane-4-yl) methaneamine instead of 2,2-dimethylpropane-1-amine in (a).
  • Example 53 N 2- (cyclopentylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine 2, in Example 2 (a)
  • the title compound was obtained in the same manner as in Example 2 using 1-cyclopentylmethaneamine instead of 2-dimethylpropane-1-amine.
  • Example 55 N 2 -[(2S) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-Diamine Using (2S) -3,3-dimethylbutane-2-amine instead of 2,2-dimethylpropan-1-amine in Example 2 (a), the title is the same as in Example 2. Compound was obtained.
  • Example 56 6 - in (2-methylpropyl) -1,3,5-triazine-2,4-diamine
  • Example 2 (a) - [(3R ) -3- ( methylamino) pyrrolidin-1-yl] -N 2 2-Methylpropane-1-amine was used instead of 2,2-dimethylpropane-1-amine, and the title compound was obtained in the same manner as in Example 2.
  • Example 57 N 2- (cyclobutylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine 2 in Example 2 (a) , 2-Cyclobutylmethaneamine was used instead of 2-dimethylpropane-1-amine, and the title compound was obtained in the same manner as in Example 2.
  • Example 58 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- [1- (2,2,2-trifluoroethyl) piperidine-4-yl] -1,3,5- Triazine-2,4-Diamine
  • Example 2 (a) 1- (2,2,2-trifluoroethyl) piperidine-4-amine was used instead of 2,2-dimethylpropan-1-amine. The title compound was obtained in the same manner as in 2.
  • Example 59 6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -N 2 - (2,2,2- trifluoroethyl) -1,3,5-triazine-2,4-diamine
  • 2,2,2-trifluoroethane-1-amine hydrochloride instead of 2,2-dimethylpropan-1-amine in 2 (a)
  • the title compound was obtained in the same manner as in Example 2. It was.
  • Example 60 N 2 - cyclopropyl -6 - in [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 2 (a) 2,2- Using cyclopropaneamine instead of dimethylpropane-1-amine, the title compound was obtained in the same manner as in Example 2.
  • Example 61 N 2 -[(2R) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-Diamine Using (2R) -3,3-dimethylbutane-2-amine instead of 2,2-dimethylpropan-1-amine in Example 2 (a), the title is the same as in Example 2. Compound was obtained.
  • Example 62 6- (1,4-Diazepan-1-yl) -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine
  • (a) The compound obtained in Reference Example 10 is 1 , 4-Dioxane (2.5 mL), N, N-diisopropylethylamine (128 ⁇ L) and 1- (trimethylsilyl) methaneamine (67 ⁇ L) were added, and the mixture was stirred at 150 ° C. for 1.5 hours under microwave irradiation. ..
  • Example 62 (a) The compound (136.9 mg) obtained in Example 62 (a) was dissolved in chloroform (1.7 mL), cooled to 0 ° C., trifluoroacetic acid (1.7 mL) was added, and 1 at room temperature. . Stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain 28.5 mg of the title compound.
  • Example 63 6- (1,4-Diazepan-1-yl) -N 2- (1-methylcyclopentyl) -1,3,5-triazine-2,4-diamine 1- (trimethylsilyl) methaneamine in Example 62 (a) In place of 1-methylcyclopentane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 62.
  • Example 64 6- (1,4-Diazepan-1-yl) -N 2- (2,2-difluoropropyl) -1,3,5-triazine-2,4-diamine 1- (trimethylsilyl) in Example 62 (a) ) 2,2-Difluoropropane-1-amine hydrochloride was used instead of methaneamine, and the title compound was obtained in the same manner as in Example 62.
  • Example 65 N 2- (bicyclo [1.1.1] pentane-1-yl) -6- (1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine
  • Example 62 Using bicyclo [1.1.1] pentane-1-amine hydrochloride instead of 1- (trimethylsilyl) methaneamine in a), the title compound was obtained in the same manner as in Example 62.
  • Example 66 6- (1,4-diazepan-1-yl) -N 2 - (2,2,2-trifluoroethyl) -1,3,5-triazine-2,4-diamine
  • Example 62 1 in (a) Using 2,2,2-trifluoroethane-1-amine hydrochloride instead of-(trimethylsilyl) methaneamine, the title compound was obtained in the same manner as in Example 62.
  • Example 68 6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine 1- in Example 62 (a) The title compound was obtained in the same manner as in Example 62, using 1- (1-methylcyclopropyl) methaneamine hydrochloride instead of (trimethylsilyl) methaneamine.
  • Example 69 6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine 1- (1 in Example 62 (a))
  • the title compound was obtained in the same manner as in Example 62, using 1- (1-methylcyclopentyl) methaneamine hydrochloride instead of trimethylsilyl) methaneamine.
  • Example 70 6- (1,4-Diazepan-1-yl) -N 2 - ⁇ [1- (trifluoromethyl) cyclopropyl] methyl ⁇ -1,3,5-triazine-2,4-diamine
  • Example 62 (a) 1- [1- (Trifluoromethyl) cyclopropyl] methaneamine hydrochloride was used in place of 1- (trimethylsilyl) methaneamine in ), and the title compound was obtained in the same manner as in Example 62.
  • Example 71 6- (1,4-Diazepan-1-yl) -N 2 -[(3-fluorophenyl) methyl] -1,3,5-triazine-2,4-diamine 1- (1 in Example 62 (a)) Using 1- (3-fluorophenyl) methaneamine instead of trimethylsilyl) methaneamine, the title compound was obtained in the same manner as in Example 62.
  • Example 72 2- ⁇ [4-Amino-6- (1,4-diazepan-1-yl) -1,3,5-triazine-2-yl] amino ⁇ -N- (cyclopropylmethyl) ethane-1-sulfonamide
  • 2-amino-N- (cyclopropylmethyl) ethane-1-sulfonamide prepared in Reference Example 11 was used in the same manner as in Example 62. Obtained the title compound.
  • Example 73 N 2- [1- (adamantane-1-yl) ethyl] -6- (1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine
  • Example 62 (a) The title compound was obtained in the same manner as in Example 62, using 1- (adamantane-1-yl) ethane-1-amine instead of 1- (trimethylsilyl) methaneamine.
  • Example 74 6- (1,4-Diazepan-1-yl) -N 2 -[(1-fluorocyclopentyl) methyl] -1,3,5-triazine-2,4-diamine 1- (1 in Example 62 (a))
  • the title compound was obtained in the same manner as in Example 62, using 1- (1-fluorocyclopentyl) methaneamine hydrochloride instead of trimethylsilyl) methaneamine.
  • Example 75 4- [3- (Methylamino) azetidine-1-yl] -N-[(thiophene-2-yl) methyl] -1,3,5-triazine-2-amine (a) 2,4-dichloro-1 , 3,5-Triazine (29.7 mg) was dissolved in THF (2 mL), cooled at -30 ° C, and then 1- (thiophen-2-yl) methaneamine (19.9 ⁇ L) dissolved in THF (1 mL). Was added, and the mixture was stirred at ⁇ 30 ° C. for 1 hour.
  • tert-butyl azetidine-3-yl (methyl) carbamate (44.5 mg) dissolved in THF (1 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the resulting residue was washed with ethyl acetate and tert-butyl [(3R) -1- ⁇ 4-[(2,2-difluoropropyl) amino] -1,3,5. -Triazine-2-yl ⁇ azetidine-3-yl] Methyl carbamate was obtained in an amount of 53 mg. The obtained crude product was used in the next step without purification.
  • Example 75 (B) The crude product (53 mg) in Example 75 (a) was dissolved in chloroform (1.4 mL), trifluoroacetic acid (321.6 ⁇ L) was added, and the mixture was stirred at room temperature for 30 minutes. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative TLC (developing solvent, chloroform: methanol) using an amino silica gel plate to obtain 5.7 mg of the title compound.
  • preparative TLC developing solvent, chloroform: methanol
  • tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate (120.2 mg) was added, and the mixture was stirred at room temperature for 2.5 hours.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate ⁇ ethyl acetate: methanol) to tert-butyl [(3R) -1- ⁇ 4-[(). 2,2-Difluoropropyl) amino] -1,3,5-triazine-2-yl ⁇ pyrrolidine-3-yl] methyl carbamate was obtained in an amount of 51.8 mg.
  • Example 76 (a) The compound obtained in Example 76 (a) was dissolved in chloroform (695 ⁇ L), cooled at 0 ° C., trifluoroacetic acid (695 ⁇ L) was added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the obtained residue was purified by amino silica gel column chromatography (developing solvent, hexane: ethyl acetate ⁇ ethyl acetate: methanol) to obtain 12.2 mg of the title compound.
  • Example 77 4- (1,4-Diazepan-1-yl) -N- (2,2-difluoropropyl) -1,3,5-triazine-2-amine tert-butyl methyl [(3R) in Example 76 (a) ) -Pyrrolidine-3-yl] tert-butyl 1,4-diazepan-1-carboxylate was used instead of carbamate to obtain the title compound in the same manner as in Example 76.
  • Example 78 N- (2,2-difluoropropyl) -4- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2-amine tert-butyl methyl in Example 76 (a) [ Using tert-butyl azetidine-3-yl (methyl) carbamate instead of (3R) -pyrrolidin-3-yl] carbamate, the title compound was obtained in the same manner as in Example 76.
  • Example 79 N-Butyl-4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1 in Example 76
  • Butane-1-amine was used instead of -amine hydrochloride, and the title compound was obtained in the same manner as in Example 76.
  • Example 80 N 2- (3,3-difluorocyclobutyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 In place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in a), 3,3-difluorocyclobutane-1-amine hydrochloride was used, and the title compound was obtained in the same manner as in Example 29.
  • Example 81 N 2 -[(2,2-difluorocyclopropyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine implementation
  • Example 29 (a) 1- (2,2-difluorocyclopropyl) methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29.
  • Example 82 N 2- (2,2-Dimethylpropyl) -6- (1,2,5-oxadiazepan-5-yl) -1,3,5-triazine-2,4-diamine tert in Example 1 (a) Using tert-butyl 1,2,5-oxadiazepan-2-carboxylate instead of -butyl (2S) -2-methylpiperazin-1-carboxylate, the title compound was obtained in the same manner as in Example 1. It was.
  • Example 83 N 2 -[(3,3-difluoro-1-methylcyclobutyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-Diamine
  • Example 29 (a) 1- (3,3-difluoro-1methylcyclobutyl) methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same as in Example 29. The title compound was obtained by the method of.
  • Example 84 N 2 - butyl - 6 - in [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) 1- (1 Butane-1-amine was used in place of -methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
  • Example 85 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- ⁇ [1- (trifluoromethyl) cyclopropyl] methyl ⁇ -1,3,5-triazine-2-amine
  • 1- [1- (trifluoromethyl) cyclopropyl] methaneamine hydrochloride instead of 2,2-difluoropropane-1-amine hydrochloride in 76 (a)
  • the title was given in the same manner as in Example 76. The compound was obtained.
  • Example 86 N- (Cyclopropylmethyl) -4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2,2- in Example 76
  • Example 76 Using 1-cyclopropylmethaneamine instead of difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
  • Example 87 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3-methylbutyl) -1,3,5-triazine-2-amine 2,2- in Example 76
  • Example 76 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3-methylbutyl) -1,3,5-triazine-2-amine 2,2- in Example 76
  • 3-methylbutane-1-amine instead of difluoropropane-1-amine hydrochloride
  • Example 88 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (2-methylpropyl) -1,3,5-triazine-2-amine 2,2 in Example 76
  • Example 76 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (2-methylpropyl) -1,3,5-triazine-2-amine 2,2 in Example 76
  • 2-methylpropane-1-amine instead of -difluoropropane-1-amine hydrochloride
  • Example 89 N-Butyl-4- (piperazine-1-yl) -1,3,5-triazine-2 -amine Butane-1 instead of 2,2-difluoropropane-1-amine hydrochloride in Example 76
  • (a) -Amine was tert-butyl piperazine-1-carboxylate instead of tert-butyl methyl [(3R) -pyrrolidine-3-yl] carbamate, and the title compound was obtained in the same manner as in Example 76. ..
  • Example 90 N-Butyl-4-[(3S) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1 in Example 76
  • Butane-1-amine instead of -amine hydrochloride, tert-butylmethyl [(3S) -pyrrolidin-3-yl] carbamate instead of tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate
  • the compound of the title was obtained in the same manner as in Example 76.
  • Example 91 N- (Butane-2-yl) -4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2, in Example 76 (a) Butane-2-amine was used in place of 2-difluoropropane-1-amine hydrochloride, and the title compound was obtained in the same manner as in Example 76.
  • Example 92 N-Butyl-4- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1-amine hydrochloride in Example 76
  • Butane-1-amine was used instead of tert-butylmethyl [(3R) -pyrrolidin-3-yl] carbamate, and tert-butyl azetidine-3-yl (methyl) carbamate was used in the same manner as in Example 76.
  • the title compound was obtained by the method.
  • Example 93 N 2- (adamantane-1-yl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) Adamantane-1-amine was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in the above, and the title compound was obtained in the same manner as in Example 29.
  • Example 94 N 2- (Hexahydro-2,5-methanopentalene-3a (1H) -yl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-
  • Example 29 (a) of 2,4-diamine hexahydro-2,5-methanopentalene-3a (1H) -amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride. The title compound was obtained in the same manner as in 29.
  • Example 95 N 2 - ⁇ [[1,1'-bi (cyclopropane)] -1-yl] methyl ⁇ -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5 -Triazine-2,4-diamine
  • Example 29 (a) 1-[[1,1'-bi (cyclopropane)] -1-yl] instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride] Using methaneamine hydrochloride, the title compound was obtained in the same manner as in Example 29.
  • Example 96 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine
  • Example 76 (a). Using (2S) -2-methylbutane-1-amine instead of 2,2-difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
  • Example 97 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2- Amine
  • the compound synthesized in Reference Example 12 was used in place of 2,2-difluoropropane-1-amine hydrochloride in Example 76 (a), and the title compound was obtained in the same manner as in Example 76.
  • Example 98 4- (1,4-Diazepan-1-yl) -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine 2,2-difluoropropane in Example 76 (a) Instead of -1-amine hydrochloride, (2S) -2-methylbutane-1-amine, tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate, tert-butyl 1,4-diazepan- The title compound was obtained in the same manner as in Example 76 using 1-carboxylate.
  • Example 99 N 2 - ⁇ [1- (difluoromethyl) cyclopropyl] methyl ⁇ -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • the compound synthesized in Reference Example 13 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in Example 29 (a), and the title compound was obtained in the same manner as in Example 29.
  • Example 100 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (4,4,5-trifluorobutyl) -1,3,5-triazine-2,4-diamine
  • Example 101 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoropropyl) -1,3,5-triazine-2,4-diamine
  • Example 101 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoropropyl) -1,3,5-triazine-2,4-diamine
  • 29 (a) 3,3,3-trifluoropropane-1-amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29.
  • Example 102 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine
  • Example 29 The title compound was obtained in the same manner as in Example 29 by using 1- (1-methylcyclopropyl) methaneamine hydrochloride instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a).
  • Example 103 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) 1- (Trimethylsilyl) methaneamine was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
  • Example 104 N 2 - (2-cyclopropylethyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) 2-Cyclopropylethane-1-amine hydrochloride was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in the above, and the title compound was obtained in the same manner as in Example 29.
  • Example 105 4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(trimethylsilyl) methyl] -1,3,5-triazine-2-amine 2,2 in Example 76 (a) Using 1- (trimethylsilyl) methaneamine instead of -difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
  • Example 106 4- (4-Ethylpiperazin-1-yl) -N-[(trimethylsilyl) methyl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1-amine in Example 76 (a) Using 1- (trimethylsilyl) methaneamine instead of the hydrochloride and 1-ethylpiperazine instead of tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate, in the same manner as in Example 76 (a). Obtained the title compound.
  • Example 10-7 N 2- [bis (trimethylsilyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) In place of 1- (1-methylcyclopentyl) methaneamine hydrochloride, 1,1-bis (trimethylsilyl) methaneamine was used in the above, and the title compound was obtained in the same manner as in Example 29.
  • Example 108 N 2- (3,3-difluorocyclopentyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • Example 29 (a) 3,3-Difluorocyclopentane-1-amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
  • Example 109 N 2 - (3,3-difluoro-cyclopentyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-enantiomer exemplary diamine
  • Example 110 6- [3- (Methylamino) azetidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine (a) tert-butyl 1 in Reference Example 10 , 4-Diazepan-1-carboxylate instead of tert-butyl azetidine-3-yl (methyl) carbamate, tert-butyl [1- (4-amino-6-chloro) in the same manner as in Reference Example 10. -1,3,5-triazin-2-yl) azetidine-3-yl] Methylcarbamate was obtained in an amount of 41.2 mg.
  • Example 62 (B) Instead of tert-butyl 4- (4-amino-6-chloro-1,3,5-triazine-2-yl) -1,4-diazepan-1-carboxylate in Example 62 (a) Using the compound obtained in Example 110 (a), the title compound was obtained in the same manner as in Example 62.
  • Example 111 6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylsiloran-1-yl) methyl] -1,3,5-triazine-2,4-diamine
  • the compound synthesized in Reference Example 14 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in Example 29 (a), and the title compound was obtained in the same manner as in Example 29.
  • Example 112 Examples of N 2 - ⁇ [cyclopropyl (dimethyl) silyl] methyl ⁇ -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine
  • the compound synthesized in Reference Example 15 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in 29 (a), and the title compound was obtained in the same manner as in Example 29.
  • 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.
  • the H4 receptor affinity is evaluated based on the histamine H4 receptor inhibition constant Ki value calculated by the above method, and the inhibition constant Ki value of 1000 nM or more and less than 5000 nM is A, and the inhibitory constant Ki value is 100 nM or more and less than 1000 nM. The one was designated as B, and the one less than 100 nM was designated as C. If the inhibition constant Ki value is less than 5000 nM, it indicates that it has an affinity for the H4 receptor.
  • the following table shows the evaluation results when the compounds obtained in each of the above examples were used as the test compounds.

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Abstract

Provided is a compound represented by the following formula (1) and a pharmacologically acceptable salt, which have a regulatory activity for a histamine H4 receptor and are useful for the treatment and/or prevention of diseases or conditions in which the histamine H4 receptor is involved; use of the same; and a pharmaceutical composition comprising the same.

Description

新規トリアジン誘導体New triazine derivative
　本発明は、新規トリアジン誘導体に関し、より詳しくは、ヒスタミンＨ４受容体の調節作用を有するトリアジン誘導体である新規化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物に関する。 The present invention relates to a novel triazine derivative, and more particularly to a novel compound which is a triazine derivative having a regulating action on histamine H4 receptor, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these.
　ヒスタミン受容体は、生体内の活性アミンの一つであるヒスタミンの受容体であり、Ｈ１～Ｈ４の４種のサブタイプが知られている。そのうち、ヒスタミンＨ４受容体は、Ｇαｉ／ｏタンパク質と結合するＧＰＣＲ（Ｇタンパク質共役受容体）で、胸腺、骨髄、脾臓などの免疫組織での発現が高く、マスト細胞、樹状細胞、好酸球、Ｔ細胞といった免疫細胞においても発現が認められている。ヒスタミン刺激によるこれら免疫細胞の遊走がヒスタミンＨ４受容体を介して行われていることなどから、ヒスタミンＨ４受容体は、炎症やアレルギーなどの免疫調節に関わっていると考えられている（非特許文献１）。そのため、ヒスタミンＨ４受容体の調節作用を有するヒスタミンＨ４受容体モジュレーターには、各種免疫炎症性疾患、例えばリウマチ、喘息、アトピー性皮膚炎、アレルギー性鼻炎などの治療薬としての可能性が期待されている。 The histamine receptor is a receptor for histamine, which is one of the active amines in the living body, and four subtypes of H1 to H4 are known. Of these, the histamine H4 receptor is a GPCR (G protein-conjugated receptor) that binds to the Gα 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. Expression is also observed in immune cells such as spheres and T cells. Since the migration of these immune cells by histamine stimulation is carried out via the histamine H4 receptor, it is considered that the histamine H4 receptor is involved in immune regulation such as inflammation and allergy (non-patent literature). 1). Therefore, the histamine H4 receptor modulator, which has a regulating action on the histamine H4 receptor, is expected to have potential as a therapeutic agent for various immunoinflammatory diseases such as rheumatism, asthma, atopic dermatitis, and allergic rhinitis. There is.
　近年、様々なヒスタミンＨ４受容体モジュレーターが報告されており、例えば、その進歩に関する概観は非特許文献２や非特許文献３に記載されている。また、例えば、特許文献１、非特許文献４、非特許文献５、非特許文献６には、トリアジン誘導体がヒスタミンＨ４受容体の調節作用を持つことが記載されている。 In recent years, various histamine H4 receptor modulators have been reported. For example, an overview of their progress is described in Non-Patent Document 2 and Non-Patent Document 3. Further, for example, Patent Document 1, Non-Patent Document 4, Non-Patent Document 5, and Non-Patent Document 6 describe that a triazine derivative has a histamine H4 receptor-regulating action.
国際公開第２００９／０３５６７１号International Publication No. 2009/035671
　本発明は、ヒスタミンＨ４受容体の調節作用を有し、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防に有用な、新規化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物を提供することを目的とする。 The present invention comprises novel compounds and pharmacologically acceptable salts thereof, which have a regulatory effect on the histamine H4 receptor and are useful for the treatment and / or prevention of diseases or conditions involving the histamine H4 receptor. It is an object of the present invention to provide a pharmaceutical composition containing these.
　本発明者らは、上記課題を解決すべく鋭意研究を行った結果、特定の構造を有する新規のトリアジン誘導体である化合物及びその薬理学的に許容される塩がヒスタミンＨ４受容体親和性を示し、ヒスタミンＨ４受容体調節作用を有することを見出し、本発明を完成した。 As a result of diligent research to solve the above problems, the present inventors showed histamine H4 receptor affinity for a compound which is a novel triazine derivative having a specific structure and a pharmacologically acceptable salt thereof. , Histamine H4 receptor regulatory action was found, and the present invention was completed.
　すなわち、本発明は、以下の発明を含包する。
［１］
　下記式（１）で表される化合物又はその薬理学的に許容される塩。 That is, the present invention includes the following inventions.
[1]
A compound represented by the following formula (1) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
［式（１）中、
　Ｒ１及びＲ２は、これらが結合している窒素原子と共に、窒素原子、酸素原子、及び硫黄原子から選択される１個又は複数のヘテロ原子をさらに含有してもよい４員～９員の非芳香族含窒素複素環式基を形成し、ここで、前記複素環式基は、単環式、縮合二環式、架橋二環式、若しくはスピロ二環式であり、前記複素環式基は、フッ素原子、水酸基、－Ｎ（Ｒ５）Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される１個又は複数の置換基で置換されていてもよく、ただし、前記複素環式基は、少なくとも２個の窒素原子を含有する複素環式基であるか、又は、１個の窒素原子を含有しかつ少なくとも１個の窒素原子を含有する基で置換された複素環式基であり、
　　Ｒ５及びＲ６は、それぞれ独立に、水素原子及びＣ１～６アルキル基から選択されるか、又は、Ｒ５及びＲ６は、これらが結合している窒素原子と共に、４員～６員の非芳香族含窒素複素環式基を形成しており、
　Ｒ３は、１個又は複数のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基、１個又は複数のハロゲン原子で置換されていてもよいフェニル基、フッ素原子、水酸基、ＣＦ３、ＯＣＨ３、Ｓｉ（ＣＨ３）３、シクロプロピル（ジメチル）シリル基、１－メチルシロラン－１－イル基、－Ｓ（Ｏ）２Ｒ７、－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ８、５員～６員の芳香族複素環式基、４員～６員の非芳香族複素環式基、５員～７員の架橋二環式基、及び９員～１０員の架橋三環式基から選択される１個又は複数の置換基で置換されていてもよいＣ１～６アルキル基；ハロゲン原子、メチル基、ＣＦ３、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、及びシクロプロピル基から選択される１個又は複数の置換基で置換されていてもよいＣ３～７シクロアルキル基；１個又は複数のハロゲン原子で置換されていてもよいフェニル基；５員～６員の芳香族複素環式基；４員～６員の非芳香族複素環式基；５員～７員の架橋二環式基；又は９員～１０員の架橋三環式基であり、
　　Ｒ７及びＲ８は、それぞれ独立に、アルキル基であり、
　Ｒ４は、アミノ基又は水素原子である。］
［２］
　前記式（１）中、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、４員～７員の単環式の非芳香族含窒素複素環式基を形成するか、又は、７員～９員の縮合二環式の非芳香族含窒素複素環式基を形成する、
［１］に記載の化合物又はその薬理学的に許容される塩。
［３］
　前記４員～７員の単環式の非芳香族含窒素複素環式基が、ピロリジン、アゼチジン、ピペラジン、又はジアゼパンである、
［２］に記載の化合物又はその薬理学的に許容される塩。
［４］
　前記式（１）中、Ｒ３が、１個又は複数のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基、フッ素原子、水酸基、ＣＦ３、及びＳｉ（ＣＨ３）３から選択される１個又は複数の置換基で置換されていてもよいＣ１～６アルキル基；１個又は複数のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基；５員～６員の芳香族複素環式基；５員～７員の架橋二環式基；又は９員～１０員の架橋三環式基である、
［１］～［３］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。
［５］
　前記式（１）で表される化合物が、
Ｎ２－（２，２－ジメチルプロピル）－６－［（３Ｓ）－３－メチルピペラジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－（ピペラジン－１－イル）－１，３，５－トリアジン－２，４－ジアミン、
６－（３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル）－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
６－［（１Ｓ，５Ｓ）－３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル］－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－［３－メチル－３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－（４－メチル－１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－アミノピロリジン－１－イル］－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－（オクタヒドロ－６Ｈ－ピロロ［３，４－ｂ］ピリジン－６－イル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－［３－（ピロリジン－１－イル）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－｛（３Ｒ）－３－［（２Ｈ３）－メチルアミノ］ピロリジン－１－イル｝－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２，２－ジメチルプロピル）－６－［４－（メチルアミノ）アゼパン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
｛１－［（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）メチル］シクロペンチル｝メタノール、
Ｎ２－（２，２－ジフルオロプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシクロヘキシル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（２－フルオロ－２－メチルプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［１－（トリフルオロメチル）シクロペンチル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－｛［１－（トリフルオロメチル）シクロペンチル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－｛［１－（フルオロメチル）シクロプロピル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－｛［１－（トリフルオロメチル）シクロブチル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（シクロプロピルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（ビシクロ［２．２．１］ヘプタン－２－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－シクロペンチル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（シクロペンチルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
（２Ｓ）－２－（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）－３，３－ジメチルブタン－１－オール、
Ｎ２－［（２Ｓ）－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－（２－メチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（シクロブチルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－（２，２，２－トリフルオロエチル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－シクロプロピル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－［（２Ｒ）－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－（１－メチルシクロペンチル）－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－（２，２－ジフルオロプロピル）－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－（ビシクロ［１．１．１］ペンタン－１－イル）－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン、
（２Ｓ）－２－｛［４－アミノ－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２－イル］アミノ｝－３，３－ジメチルブタン－１－オール、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（１－メチルシクロプロピル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（１－メチルシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（１－フルオロシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ－ブチル－４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン、
Ｎ２－（３，３－ジフルオロシクロブチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－［（２，２－ジフルオロシクロプロピル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－［（３，３－ジフルオロ－１－メチルシクロブチル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－ブチル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２、４－ジアミン、
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２－アミン、
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（２－メチルプロピル）－１，３，５－トリアジン－２－アミン、
Ｎ－ブチル－４－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２－アミン、
Ｎ２－（ヘキサヒドロ－２，５－メタノペンタレン－３ａ（１Ｈ）－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
Ｎ２－｛［［１，１’－ビ（シクロプロパン）］－１－イル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－［（２Ｓ）－２－メチルブチル］－１，３，５－トリアジン－２－アミン、
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－１，３，５－トリアジン－２－アミン、
４－（１，４－ジアゼパン－１－イル）－Ｎ－［（２Ｓ）－２－メチルブチル］－１，３，５－トリアジン－２－アミン、
Ｎ２－｛［１－（ジフルオロメチル）シクロプロピル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシクロプロピル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２－アミン、
Ｎ２－（３，３－ジフルオロシクロペンチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
６－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ２－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシロラン－１－イル）メチル］－１，３，５－トリアジン－２，４－ジアミン、又は
Ｎ２－｛［シクロプロピル（ジメチル）シリル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミンである、［１］に記載の化合物又はその薬理学的に許容される塩。
［６］
　［１］～［５］のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を含有する医薬組成物。
［７］
　ヒスタミンＨ４受容体調節用組成物である、［６］に記載の医薬組成物。
［８］
　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の組成物である、［６］に記載の医薬組成物。
［９］
　［１］～［５］のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を対象に投与する工程を含む、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防の方法。
［１０］
　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の医薬組成物の製造のための、［１］～［５］のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩の使用。 [In equation (1),
R 1 and R 2 may further contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded. A non-aromatic nitrogen-containing heterocyclic group is formed, wherein the heterocyclic group is a monocyclic group, a fused bicyclic group, a crosslinked bicyclic group, or a spirobicyclic group, and the heterocyclic group is formed. May be substituted with one or more substituents selected from fluorine atoms, hydroxyl groups, —N (R 5) R 6 , C 1-6 alkyl groups, and C 1-6 aminoalkyl groups. However, the heterocyclic group is a heterocyclic group containing at least two nitrogen atoms, or is substituted with a group containing one nitrogen atom and containing at least one nitrogen atom. Heterocyclic group
R 5 and R 6 are independently selected from hydrogen atoms and C 1-6 alkyl groups, respectively, or R 5 and R 6 are 4- to 6-membered with the nitrogen atom to which they are attached. Forming a non-aromatic nitrogen-containing heterocyclic group of
R 3 is one or more of good C 3 ~ 7 cycloalkyl group optionally substituted with a halogen atom, one or more optionally substituted phenyl group with a halogen atom, a fluorine atom, a hydroxyl group, CF 3 , OCH 3 , Si (CH 3 ) 3 , cyclopropyl (dimethyl) silyl group, 1-methylsiloran-1-yl group, -S (O) 2 R 7 , -S (O) 2 N (H) R 8 , 5- to 6-membered aromatic heterocyclic group, 4- to 6-membered non-aromatic heterocyclic group, 5- to 7-membered bridged bicyclic group, and 9 to 10-membered bridged tricyclic group C 1-6 alkyl groups optionally substituted with one or more substituents selected from the groups; halogen atoms, methyl groups, CF 3 , CH 2 OH, CH 2 F, CHF 2 , and cyclopropyl groups. one or more of which may be substituted with a substituent C 3 - 7 cycloalkyl group selected from; one or more phenyl group which may be substituted by a halogen atom; 5-membered to 6-membered aromatic Group heterocyclic groups; 4- to 6-membered non-aromatic heterocyclic groups; 5- to 7-membered crosslinked bicyclic groups; or 9 to 10-membered crosslinked tricyclic groups.
R 7 and R 8 are independently alkyl groups, respectively.
R 4 is an amino group or a hydrogen atom. ]
[2]
In the formula (1), R 1 and R 2 form a 4- to 7-membered monocyclic non-aromatic nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, or. Forming 7-9 member condensed bicyclic non-aromatic nitrogen-containing heterocyclic groups,
The compound according to [1] or a pharmacologically acceptable salt thereof.
[3]
The 4- to 7-membered monocyclic non-aromatic nitrogen-containing heterocyclic group is pyrrolidine, azetidine, piperazine, or diazepan.
The compound according to [2] or a pharmacologically acceptable salt thereof.
[4]
In the above formula (1), R 3 is selected from C 3 to 7 cycloalkyl groups, which may be substituted with one or more halogen atoms, a fluorine atom, a hydroxyl group, CF 3 , and Si (CH 3 ) 3. one or more of which may be substituted with a substituent C 1 - 6 alkyl groups is, one or more of which may be substituted with halogen atoms C 3 - 7 cycloalkyl group; a 5- to 6-membered Aromatic heterocyclic group; 5- to 7-membered crosslinked bicyclic group; or 9 to 10-membered crosslinked tricyclic group.
The compound according to any one of [1] to [3] or a pharmacologically acceptable salt thereof.
[5]
The compound represented by the formula (1) is
N 2 - (2,2-dimethylpropyl) -6 - [(3S) -3- methylpiperazin-l-yl] -1,3,5-triazine-2,4-diamine,
N 2- (2,2-dimethylpropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2- (2,2-dimethylpropyl) -6- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine,
6- (1,4-Diazepan-1-yl) -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine,
N 2- (2,2-dimethylpropyl) -6- (piperazine-1-yl) -1,3,5-triazine-2,4-diamine,
6- (3,6-diazabicyclo [3.2.0] heptan-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine,
6-[(1S, 5S) -3,6-diazabicyclo [3.2.0] heptane-3-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2, 4-diamine,
N 2- (2,2-dimethylpropyl) -6- [3-methyl-3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2- (2,2-dimethylpropyl) -6- (4-methyl-1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine,
6 - [(3R) -3- amino-1-yl] -N 2 - (2,2- dimethylpropyl) -1,3,5-triazine-2,4-diamine,
N 2 - (2,2-dimethylpropyl) -6- (octahydro -6H- pyrrolo [3,4-b] pyridin-6-yl) -1,3,5-triazine-2,4-diamine,
N 2- (2,2-dimethylpropyl) -6- [3- (pyrrolidin-1-yl) azetidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2 - (2,2-dimethylpropyl) -6 - {(3R) -3 - [(2 H 3) - methylamino] pyrrolidin-1-yl} -1,3,5-triazine-2,4 Diamine,
N 2- (2,2-dimethylpropyl) -6- [4- (methylamino) azepan-1-yl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine,
{1-[({4-Amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) methyl] cyclopentyl} methanol,
N 2- (2,2-difluoropropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2,4- Diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclohexyl) methyl] -1,3,5-triazine-2,4-diamine,
N 2 - (2-fluoro-2-methylpropyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- [1- (trifluoromethyl) cyclopentyl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclopentyl] methyl} -1,3,5-triazine-2,4-diamine ,
N 2 -{[1- (fluoromethyl) cyclopropyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine ,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2 , 4-Diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclobutyl] methyl} -1,3,5-triazine-2,4-diamine ,
N 2- (cyclopropylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2 - (bicyclo [2.2.1] heptan-2-yl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4 -Diamine,
N 2 -cyclopentyl-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2- (cyclopentyl methyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
(2S) -2-({4-amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) -3,3 -Dimethylbutane-1-ol,
N 2 -[(2S) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-diamine,
6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -N 2 - (2- methylpropyl) -1,3,5-triazine-2,4-diamine,
N 2- (cyclobutylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (2,2,2-trifluoroethyl) -1,3,5-triazine-2,4-diamine,
N 2 - cyclopropyl -6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine,
N 2 -[(2R) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-diamine,
6- (1,4-Diazepan-1-yl) -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine,
6- (1,4-Diazepan-1-yl) -N 2- (1-methylcyclopentyl) -1,3,5-triazine-2,4-diamine,
6- (1,4-Diazepan-1-yl) -N 2- (2,2-difluoropropyl) -1,3,5-triazine-2,4-diamine,
N 2- (bicyclo [1.1.1] pentane-1-yl) -6- (1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine,
(2S) -2-{[4-amino-6- (1,4-diazepan-1-yl) -1,3,5-triazine-2-yl] amino} -3,3-dimethylbutane-1- All,
6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine,
6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine,
6- (1,4-Diazepan-1-yl) -N 2 -{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2,4-diamine,
6- (1,4-Diazepan-1-yl) -N 2 -[(1-fluorocyclopentyl) methyl] -1,3,5-triazine-2,4-diamine,
N-Butyl-4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine,
N 2- (3,3-difluorocyclobutyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2 -[(2,2-difluorocyclopropyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
N 2 -[(3,3-difluoro-1-methylcyclobutyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-diamine,
N 2 - butyl -6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine,
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2-amine,
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (2-methylpropyl) -1,3,5-triazine-2-amine,
N-Butyl-4- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2-amine,
N 2- (Hexahydro-2,5-methanopentalene-3a (1H) -yl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine- 2,4-diamine,
N 2 -{[[1,1'-bi (cyclopropane)] -1-yl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5 -Triazine-2,4-diamine,
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine,
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2- Amine,
4- (1,4-Diazepan-1-yl) -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine,
N 2 -{[1- (difluoromethyl) cyclopropyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine ,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine,
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(trimethylsilyl) methyl] -1,3,5-triazine-2-amine,
N 2- (3,3-difluorocyclopentyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
6- [3- (methylamino) azetidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine,
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylsiloran-1-yl) methyl] -1,3,5-triazine-2,4-diamine, Or with N 2 -{[cyclopropyl (dimethyl) silyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine A compound according to [1] or a pharmaceutically acceptable salt thereof.
[6]
A pharmaceutical composition containing at least one selected from the compound according to any one of [1] to [5] and a pharmacologically acceptable salt thereof.
[7]
The pharmaceutical composition according to [6], which is a composition for regulating histamine H4 receptors.
[8]
The pharmaceutical composition according to [6], which is a composition for treating and / or preventing a disease or condition involving the histamine H4 receptor.
[9]
Involvement of 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 [5] and a pharmacologically acceptable salt thereof. A method of treating and / or preventing a disease or condition.
[10]
The compound according to any one of [1] to [5] or its pharmacology for producing a pharmaceutical composition for treating and / or preventing a disease or condition involving the histamine H4 receptor. Tolerable use of salt.
　本発明によれば、ヒスタミンＨ４受容体に対して優れた調節作用を有する新規化合物及びその薬理学的に許容される塩を提供することが可能となる。 According to the present invention, it is possible to provide a novel compound having an excellent regulatory action on the histamine H4 receptor and a pharmacologically acceptable salt thereof.
　本発明の化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物は、ヒスタミンＨ４受容体が関与する疾患若しくは状態（各種アレルギー、炎症性疾患等）の治療及び／又は予防に有用である。ヒスタミンＨ４受容体が関与する疾患若しくは状態としては、例えば、ＣＯＰＤ、炎症性腸疾患、リウマチ、アトピー性皮膚炎、掻痒性皮膚炎、アレルギー性結膜炎、鼻炎、関節症性乾癬、尋常性乾癬、各種がん（大腸がん、肺がん、血液がん、脳腫瘍など）、代謝性疾患（糖尿病、肥満など）、疼痛などが挙げられるが、これらのみに限定されるものではない。 The compounds of the present invention, pharmacologically acceptable salts thereof, and pharmaceutical compositions containing them can be used to treat and / or treat diseases or conditions (various allergies, inflammatory diseases, etc.) in which the histamine H4 receptor is involved. Useful for prevention. Diseases or conditions involving the histamine H4 receptor include, for example, COPD, inflammatory bowel disease, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, psoriatic arthritis, psoriasis vulgaris, and various other diseases. Cancer (colon cancer, lung cancer, blood cancer, brain tumor, etc.), metabolic disease (diabetes, obesity, etc.), pain, etc. are included, but are not limited to these.
　以下、本発明をその好適な実施形態に即して詳細に説明する。なお、以下の説明中、同一又は相当する要素には同一の記号を付し、重複する説明は省略する。 Hereinafter, the present invention will be described in detail according to its preferred embodiment. In the following description, the same or corresponding elements will be given the same symbol, and duplicate description will be omitted.
　１つの実施形態において、本発明は、下記式（１）で表される化合物及びその薬理学的に許容される塩を提供する。また１つの実施形態において、本発明は、下記式（１）で表される化合物及びその薬理学的に許容される塩のうちの少なくとも１種を含有する医薬組成物、好ましくは有効成分として含有する医薬組成物（免疫炎症性疾患治療剤等）を提供する。 In one embodiment, the present invention provides a compound represented by the following formula (1) and a pharmacologically acceptable salt thereof. Further, in one embodiment, the present invention contains a pharmaceutical composition containing at least one of a compound represented by the following formula (1) and a pharmacologically acceptable salt thereof, preferably as an active ingredient. To provide a pharmaceutical composition (such as a therapeutic agent for immunoinflammatory diseases).
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　式（１）中、Ｒ４はアミノ基又は水素原子である。 Wherein (1), R 4 is an amino group or a hydrogen atom.
　式（１）中、Ｒ１及びＲ２は、これらが結合している窒素原子と共に、窒素原子、酸素原子、及び硫黄原子から選択される１個又は複数のヘテロ原子をさらに含有してもよい４員～９員の非芳香族含窒素複素環式基を形成する。ここで、前記複素環式基は、単環式、縮合二環式、架橋二環式、スピロ二環式であってよく、より具体的に、前記複素環式基は、単環式、縮合二環式、架橋二環式、又はスピロ二環式である。前記複素環式基としては、フッ素原子、水酸基、－Ｎ（Ｒ５）Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される１個又は複数の置換基で置換されていてもよい。ただし、前記複素環式基は、少なくとも２個の窒素原子を含有する（すなわち、少なくとも２個の窒素原子を含む原子で環が形成される）複素環式基であるか、又は、１個の窒素原子を含有し（すなわち、１個の窒素原子を含む原子で環が形成され）、かつ、少なくとも１個の窒素原子を含有する基で置換された複素環式である。ここで、Ｒ５及びＲ６は、それぞれ独立に、水素原子及びＣ１～６アルキル基から選択されるか、又は、これらが結合している窒素原子と共に、４員～６員の非芳香族含窒素複素環式基を形成する。 In formula (1), R 1 and R 2 may further contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded. It forms a 4- to 9-membered non-aromatic nitrogen-containing heterocyclic group. Here, the heterocyclic group may be a monocyclic group, a fused bicyclic group, a bridged bicyclic group, or a spiro dicyclic group, and more specifically, the heterocyclic group may be a monocyclic group or a fused bicyclic group. It is a bicyclic type, a bridged bicyclic type, or a spiro bicyclic type. The heterocyclic group is substituted with one or more substituents selected from a fluorine atom, a hydroxyl group, an −N (R 5 ) R 6 , a C 1 to 6 alkyl group, and a C 1 to 6 amino alkyl group. It may have been done. However, the heterocyclic group is a heterocyclic group containing at least two nitrogen atoms (that is, a ring is formed by an atom containing at least two nitrogen atoms), or one. It is a heterocyclic formula containing a nitrogen atom (that is, a ring is formed by an atom containing one nitrogen atom) and substituted with a group containing at least one nitrogen atom. Here, R 5 and R 6 are independently selected from a hydrogen atom and a C 1 to 6 alkyl group, or are 4- to 6-membered non-aromatics together with a nitrogen atom to which they are bonded. It forms a nitrogen-containing heterocyclic group.
　前記式（１）中、Ｒ３は、１個又は複数（好ましくは１個）のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基、１個又は複数（好ましくは１個）のハロゲン原子で置換されていてもよいフェニル基、フッ素原子、水酸基、ＣＦ３、ＯＣＨ３、Ｓｉ（ＣＨ３）３、シクロプロピル（ジメチル）シリル基、１－メチルシロラン－１－イル基、－Ｓ（Ｏ）２Ｒ７、－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ８、５員～６員の芳香族複素環式基、４員～６員の非芳香族複素環式基、５員～７員の架橋二環式基、及び９員～１０員の架橋三環式基から選択される１個又は複数の置換基で置換されていてもよいＣ１～６アルキル基；ハロゲン原子（好ましくはフッ素原子）、メチル基、ＣＦ３、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、及びシクロプロピル基から選択される１個又は複数の置換基で置換されていてもよいＣ３～７シクロアルキル基；１個又は複数（好ましくは１個）のハロゲン原子で置換されていてもよいフェニル基；５員～６員の芳香族複素環式基；４員～６員の非芳香族複素環式基；５員～７員の架橋二環式基；又は９員～１０員の架橋三環式基である。ここで、Ｒ７及びＲ８は、それぞれ独立に、アルキル基である。 In the formula (1), R 3 is a C 3 to 7 cycloalkyl group which may be substituted with one or more (preferably one) halogen atoms, or one or more (preferably one). A phenyl group, a fluorine atom, a hydroxyl group, a CF 3 , OCH 3 , Si (CH 3 ) 3 , a cyclopropyl (dimethyl) silyl group, a 1-methylsiloran-1-yl group, which may be substituted with a halogen atom, -S ( O) 2 R 7 , -S (O) 2 N (H) R 8 , 5- to 6-membered aromatic heterocyclic group, 4- to 6-membered non-aromatic heterocyclic group, 5-member to 7 A C 1-6 alkyl group optionally substituted with one or more substituents selected from a membered crosslinked bicyclic group and a 9 to 10 membered crosslinked tricyclic group; a halogen atom (preferably a halogen atom). fluorine atom), a methyl group, CF 3, CH 2 OH, CH 2 F, CHF 2, and one or more of which may be substituted with a substituent C 3 ~ 7 cycloalkyl group selected from cyclopropyl A phenyl group optionally substituted with one or more (preferably one) halogen atoms; a 5- to 6-membered aromatic heterocyclic group; a 4- to 6-membered non-aromatic heterocyclic group. A 5- to 7-membered crosslinked bicyclic group; or a 9 to 10-membered crosslinked tricyclic group. Here, R 7 and R 8 are independently alkyl groups.
　本明細書中で用いる用語を以下に説明する。 The terms used in this specification will be described below.
　「ハロゲン原子」とは、フッ素、塩素、臭素及びヨウ素を意味する。本明細書中、単に「アルキル基」という場合には、直鎖状又は分岐鎖状のアルキル基を意味し、炭素数１～６であることが好ましい。 "Halogen atom" means fluorine, chlorine, bromine and iodine. In the present specification, the term "alkyl group" simply means a linear or branched alkyl group, and preferably has 1 to 6 carbon atoms.
　「Ｃ１～６アルキル基」とは、炭素数１～６の直鎖状又は分岐鎖状のアルキル基を意味し、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓ－ブチル基、ｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、２－メチルブチル基、２，２－ジメチルプロピル基、１－エチルプロピル基、ｎ－ヘキシル基、イソヘキシル基、４－メチルペンチル基、３－メチルペンチル基、２－メチルペンチル基、１－メチルペンチル基、３，３－ジメチルブチル基、２，２－ジメチルブチル基、１，１－ジメチルブチル基、１，２－ジメチルブチル基、１，３－ジメチルブチル基、２，３－ジメチルブチル基、１－エチルブチル基、２－エチルブチル基が挙げられ、好ましくは、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、２，２－ジメチルプロピル基、３，３－ジメチルブチル基、より好ましくは、メチル基、２，２－ジメチルプロピル基等が挙げられる。Ｃ１～６アルキル基（特に、式（１）中、Ｒ５及び／又はＲ６が示すＣ１～６アルキル基）には、重水素同位体も含む。 "C 1 to 6 alkyl groups" means linear or branched alkyl groups having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl. Group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 4-Methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1, Examples thereof include 2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group and 2-ethylbutyl group, preferably methyl group, ethyl group, n-propyl group and isopropyl. Groups, n-butyl groups, isobutyl groups, 2,2-dimethylpropyl groups, 3,3-dimethylbutyl groups, more preferably methyl groups, 2,2-dimethylpropyl groups and the like can be mentioned. C 1 ~ 6 alkyl group (particularly, in the formula (1), C 1 ~ 6 alkyl group represented by R 5 and / or R 6) it will also contain deuterium isotopes.
　「Ｃ１～６アミノアルキル基」とは、前記Ｃ１～６アルキル基の１つの水素原子がアミノ基に置換された基を意味する。 The “C 1 to 6 aminoalkyl group” means a group in which one hydrogen atom of the C 1 to 6 alkyl group is substituted with an amino group.
　「Ｃ３～７シクロアルキル基」とは、炭素数３～７の飽和炭素環基を意味する。Ｃ３～７シクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロへプチル基が挙げられ、好ましくは、炭素数３～６のＣ３～６シクロアルキル基であり、より好ましくは、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。 The “C 3 to 7 cycloalkyl group” means a saturated carbocyclic group having 3 to 7 carbon atoms. Examples of the C 3 to 7 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and a C 3 to 6 cycloalkyl group having 3 to 6 carbon atoms is preferable. Yes, more preferably, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like can be mentioned.
　「芳香族複素環式基」とは、酸素原子、窒素原子、及び硫黄原子から選択される１個以上のヘテロ原子を含む芳香族複素環基を意味する。Ｒ３に含まれる５員～６員の芳香族複素環式基としては、単環式であることが好ましく、例えば、オキサゾリル基、イソオキサゾリル基、オキサジアゾリル基、チアゾリル基、イソチアゾリル基、イミダゾリル基、ピラゾリル基、トリアゾリル基、テトラゾリル基、ピリジル基、ピリミジニル基、フラニル基等が挙げられる。 The "aromatic heterocyclic group" means an aromatic heterocyclic group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. The 5- to 6-membered aromatic heterocyclic group contained in R 3 is preferably a monocyclic group. Examples thereof include a group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a furanyl group and the like.
　「非芳香族複素環式基」とは、酸素原子、窒素原子、及び硫黄原子から選択される１個以上のヘテロ原子を含む飽和複素環基を意味する。前記非芳香族複素環式基としては、単環式であることが好ましく、例えば、４員～９員である、アゼチジン、オキセタン、チエタン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、テトラヒドロピラン、テトラヒドロチオピラン、ピペラジン、モルホリン、アゼパン、ジアゼパン、オキセパン、チエパン、アゾカン、オキソカン、チオカン、アゾナン、オキソナン、チオナン等が挙げられる。 The "non-aromatic heterocyclic group" means a saturated heterocyclic group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. The non-aromatic heterocyclic group is preferably monocyclic, for example, azetidine, oxetane, thietan, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothio, which are 4 to 9 members. Examples thereof include pyran, piperazine, morpholine, azepan, diazepan, oxetane, thiepan, azocan, oxocan, thiocan, azonan, oxonan, thionan and the like.
　Ｒ３に含まれる又はＲ３が示す４員～６員の非芳香族複素環式基としては、例えば、アゼチジン、オキセタン、チエタン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、テトラヒドロピラン、テトラヒドロチオピラン、ピペラジン、モルホリン等が挙げられる。 Examples of the 4- to 6-membered non-aromatic heterocyclic group contained in R 3 or indicated by R 3 include azetidine, oxetane, thietan, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiophene, and the like. Examples include piperidine and morpholine.
　「非芳香族複素環式基」のうち、「非芳香族含窒素複素環式基」とは、窒素原子を含む飽和複素環基を意味する。Ｒ１及びＲ２（すなわち、－Ｎ（Ｒ１）Ｒ２）が示す４員～９員の非芳香族含窒素複素環式基としては、単環式であることが好ましく、例えば、アゼチジン、ピロリジン、ピペリジン、ピペラジン、モルホリン、アゼパン、ジアゼパン、アゾカン、アゾナンが挙げられる。より好ましくは、４員～７員であり、アゼチジン、ピロリジン、ピペリジン、ピペラジン、ジアゼパン等が挙げられ、さらに好ましくは、アゼチジン、ピロリジン、ピペラジン、ジアゼパンが挙げられる。 Among the "non-aromatic heterocyclic groups", the "non-aromatic nitrogen-containing heterocyclic group" means a saturated heterocyclic group containing a nitrogen atom. The 4- to 9-membered non-aromatic nitrogen-containing heterocyclic group indicated by R 1 and R 2 (that is, −N (R 1 ) R 2) is preferably a monocyclic group, for example, azetidine. Examples thereof include pyrrolidine, piperidine, piperazine, morpholine, azepane, diazepane, azocane and azonan. More preferably, it has 4 to 7 members, and examples thereof include azetidine, pyrrolidine, piperidine, piperazine, and diazepan, and more preferably, azetidine, pyrrolidine, piperazine, and diazepan.
　Ｒ５及びＲ６（すなわち、－Ｎ（Ｒ５）Ｒ６）が示す４員～６員の非芳香族含窒素複素環式基としては、例えば、アゼチジン、ピロリジン、ピペラジン等が挙げられる。 Examples of the 4- to 6-membered non-aromatic nitrogen-containing heterocyclic group indicated by R 5 and R 6 (that is, −N (R 5 ) R 6) include azetidine, pyrrolidine, piperazine and the like.
　「縮合二環式基」とは、環状化合物同士が隣接する２か所の原子を共有した形で結合した、２つの環を有する基を意味する。非芳香族の縮合二環式基としては、例えば、５員～９員である、ビシクロ［２．１．０］ペンタン、ビシクロ［３．１．０］ヘキサン、ビシクロ［３．２．０］ヘプタン、ビシクロ［３．３．０］オクタン、ビシクロ［４．３．０］ノナンが挙げられる。Ｒ１及びＲ２（すなわち、－Ｎ（Ｒ１）Ｒ２）が示す窒素原子を含むもの（縮合二環式の非芳香族含窒素複素環式基）としては、アザビシクロ［２．１．０］ペンタン、アザビシクロ［３．１．０］ヘキサン、ジアザビシクロ［３．２．０］ヘプタン、ジアザビシクロ［３．３．０］オクタン、ジアザビシクロ［４．３．０］ノナン等が挙げられる。好ましくは、７員～９員であり、ジアザビシクロ［３．２．０］ヘプタン、ジアザビシクロ［３．３．０］オクタン、ジアザビシクロ［４．３．０］ノナンが挙げられる。 The "condensed 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. Examples of non-aromatic fused bicyclic groups include, for example, 5- to 9-membered bicyclo [2.1.0] pentane, bicyclo [3.1.0] hexane, and bicyclo [3.2.0]. Examples include heptane, bicyclo [3.3.0] octane, and bicyclo [4.3.0] nonane. As those containing a nitrogen atom (that is, -N (R 1 ) R 2 ) indicated by R 1 and R 2 (that is, a fused bicyclic non-aromatic nitrogen-containing heterocyclic group), azabicyclo [2.1.0] ] Pentane, azabicyclo [3.1.0] hexane, diazabicyclo [3.2.0] heptane, diazabicyclo [3.3.0] octane, diazabicyclo [4.3.0] nonane and the like. Preferably, the number of members is 7 to 9, and examples thereof include diazabicyclo [3.2.0] heptane, diazabicyclo [3.3.0] octane, and diazabicyclo [4.3.0] nonane.
　「スピロ二環式基」とは、環状化合物同士が１か所の原子を共有した形で結合した、２つの環を有する基を意味する。非芳香族のスピロ二環式基としては、例えば、５員～９員である、スピロ［２．２］ペンタン、スピロ［２．３］ヘキサン、スピロ［２．４］ヘプタン、スピロ［３．３］ヘプタン、スピロ［３．４］オクタン、スピロ［４．４］ノナンが挙げられる。Ｒ１及びＲ２（すなわち、－Ｎ（Ｒ１）Ｒ２）が示す窒素原子を含むもの（スピロ二環式の非芳香族含窒素複素環式基）としては、アザスピロ［２．２］ペンタン、アザスピロ［２．３］ヘキサン、アザスピロ［２．４］ヘプタン、ジアザスピロ［３．３］ヘプタン、ジアザスピロ［３．４］オクタン、ジアザスピロ［４．４］ノナン等が挙げられ、好ましくは、アザスピロ［２．４］ヘプタンが挙げられる。 The "spirobicyclic group" means a group having two rings in which cyclic compounds are bonded to each other in a form in which one atom is shared. Examples of non-aromatic spirobicyclic groups include spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, and spiro [3. 3] Heptane, spiro [3.4] octane, spiro [4.4] nonane can be mentioned. Azaspiro [2.2] pentane is a spirobicyclic non-aromatic nitrogen-containing heterocyclic group containing a nitrogen atom indicated by R 1 and R 2 (that is, −N (R 1 ) R 2). , Azaspiro [2.3] hexane, Azaspiro [2.4] heptane, diazaspiro [3.3] heptane, diazaspiro [3.4] octane, diazaspiro [4.4] nonane and the like, and preferably azaspiro [4.4] nonane. 2.4] Heptane can be mentioned.
　「架橋二環式基」とは、環状化合物の２か所の原子が架橋により連結された、２つの環を有する基を意味する。架橋二環式基としては、非芳香族であることが好ましく、例えば、４～９員である、ビシクロ［１．１．１］ペンタン、ビシクロ［２．１．１］ヘキサン、ビシクロ［２．２．１］ヘプタン、ジアザビシクロ［３．２．１］オクタン、ビシクロ［３．３．１］ノナンが挙げられる。 "Cross-linked bicyclic group" means a group having two rings in which two atoms of a cyclic compound are linked by cross-linking. The crosslinked bicyclic group is preferably non-aromatic, and is, for example, 4- to 9-membered bicyclo [1.1.1] pentane, bicyclo [2.1.1] hexane, bicyclo [2. 2.1] Heptane, diazabicyclo [3.2.1] octane, bicyclo [3.3.1] nonane can be mentioned.
　Ｒ３に含まれる又はＲ３が示す５員～７員の架橋二環式基としては、非芳香族であることが好ましく、例えば、ビシクロ［１．１．１］ペンタン、ビシクロ［２．１．１］ヘキサン、ビシクロ［２．２．１］ヘプタンが挙げられる。 The bridged bicyclic group having 5 to 7 membered indicated or R 3 contained in R 3, it is preferably a non-aromatic, for example, bicyclo [1.1.1] pentane, bicyclo [2.1 .1] Hexane and bicyclo [2.2.1] heptane can be mentioned.
　「架橋二環式基」のうち、Ｒ１及びＲ２（すなわち、－Ｎ（Ｒ１）Ｒ２）が示す窒素原子を含むもの（架橋二環式の非芳香族含窒素複素環式基）としては、アザビシクロ［１．１．１］ペンタン、アザビシクロ［２．１．１］ヘキサン、ジアザビシクロ［２．２．１］ヘプタン、ジアザビシクロ［３．２．１］オクタン、ジアザビシクロ［３．３．１］ノナンが挙げられる。好ましくは、ビシクロ［１．１．１］ペンタン、ビシクロ［２．２．１］ヘプタンが挙げられる。 Among "bridged bicyclic groups", those containing a nitrogen atom indicated by R 1 and R 2 (that is, -N (R 1 ) R 2 ) (bridged bicyclic non-aromatic nitrogen-containing heterocyclic group). Examples include azabicyclo [1.1.1] pentane, azabicyclo [2.1.1] hexane, diazabicyclo [2.2.1] heptane, diazabicyclo [3.2.1] octane, and diazabicyclo [3.3.1]. ] Nonan is mentioned. Preferred are bicyclo [1.1.1] pentane and bicyclo [2.2.1] heptane.
　「架橋三環式基」とは、二環性化合物の各環の１か所の原子が架橋により連結された、３つの環を有する基を意味する。Ｒ３に含まれる又はＲ３が示す９員～１０員の架橋三環式基としては、非芳香族であることが好ましく、例えば、アダマンタン、ヘキサヒドロ－２，５－メタノペンタレンが挙げられる。 The "crosslinked tricyclic group" means a group having three rings in which one atom of each ring of the bicyclic compound is linked by cross-linking. The crosslinking tricyclic group of 9-membered to 10-membered indicated or R 3 contained in R 3, is preferably a non-aromatic, for example, adamantane, hexahydro-2,5-methanopentalene the like.
　本発明において、各基が「置換されていてもよい」とは、当該基が、置換されていない基、並びに、当該基の１個又は複数の水素原子が原子又は置換基に置換されている基を含むことを意味する。置換された原子又は置換基が複数ある場合、それらは互いに同じであっても異なっていてもよい。また、置換された原子又は置換基の数としては、例えば、１～３であることが好ましい。 In the present invention, "may be substituted" means that the group is not substituted and one or more hydrogen atoms of the group are substituted with an atom or a substituent. Means to include a group. If there are multiple substituted atoms or substituents, they may be the same or different from each other. The number of substituted atoms or substituents is preferably, for example, 1 to 3.
　本発明において、前記式（１）で表される化合物は、遊離塩基の形態（遊離体）のほか、その薬理学的に許容される塩であってもよい。前記薬理学的に許容される塩としては、酸付加塩の形態であることが好ましく、前記酸付加塩の酸としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸などのハロゲン化水素酸塩；硫酸、硝酸、リン酸、炭酸などの無機酸塩；酢酸、トリクロロ酢酸、トリフルオロ酢酸、ヒドロキシ酢酸、乳酸、クエン酸、酒石酸、シュウ酸、安息香酸、マンデル酸、酪酸、マレイン酸、プロピオン酸、ギ酸、リンゴ酸などの有機カルボン酸塩；アスパラギン酸、グルタミン酸などの酸性アミノ酸；メタンスルホン酸などのアルキルスルホン酸；ｐ－トルエンスルホン酸などのアリールスルホン酸等が挙げられる。また、前記式（１）で表される化合物又はその薬理学的に許容される塩の範囲には、これらにそれぞれ対応する溶媒和物（例えば、水和物）も包含される。 In the present invention, the compound represented by the formula (1) may be a free base form (free form) or a pharmacologically acceptable salt thereof. The pharmacologically acceptable salt is preferably in the form of an acid addition salt, and the acid of the acid addition salt is, for example, hydrogen halide such as hydrochloric acid, hydrobromic acid, and hydroiodic acid. Acid salts; Inorganic acid salts such as sulfuric acid, nitrate, phosphoric acid, carbonic acid; acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid Organic carboxylates such as propionic acid, formic acid and malic acid; acidic amino acids such as aspartic acid and glutamate; alkylsulfonic acids such as methanesulfonic acid; arylsulfonic acids such as p-toluenesulfonic acid and the like. In addition, the range of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof also includes solvates (for example, hydrates) corresponding thereto.
　また、前記式（１）で表される化合物、その薬理学的に許容される塩、及びこれらの溶媒和物は、置換基の種類に応じて、１個又は２個以上の不斉炭素を有する場合があるが、これらの１個又は２個以上の不斉炭素に基づく光学活性体、ジアステレオ異性体、幾何異性体、互変異性体、それらの任意の混合物、ラセミ体などはいずれも、前記式（１）で表される化合物及びその薬理学的に許容される塩の範囲に包含される。 Further, the compound represented by the formula (1), a pharmacologically acceptable salt thereof, and a mixture thereof have one or two or more asymmetric carbons depending on the type of the substituent. Any of these one or more asymmetric carbon-based optically active compounds, diastereoisomers, geometric isomers, tautomers, any mixture thereof, racemates, etc. may be present. , The compound represented by the above formula (1) and the pharmaceutically acceptable salt thereof are included in the range.
　さらに、前記式（１）で表される化合物及びその薬理学的に許容される塩の範囲には、これらに対応する放射性同位体や非放射性同位体などの同位体でラベル化された化合物及びその溶媒和物も包含される。 Further, the range of the compound represented by the above formula (1) and its pharmacologically acceptable salt includes compounds labeled with isotopes such as radioactive isotopes and non-radioactive isotopes corresponding thereto. The solvate is also included.
　本明細書中において、上記の異性体や同位体等が存在する化合物であって、その名称において特に言及が無い場合、その化合物はこれらの異性体や同位体のうちの１種であっても、２種以上の混合物であっても、ラセミ体であってもよい。 In the present specification, a compound in which the above isomers, isotopes, etc. are present, and unless otherwise specified in the name, the compound may be one of these isomers, isotopes, etc. It may be a mixture of two or more kinds, or it may be a racemate.
　以下、前記式（１）で表される化合物及びその薬理学的に許容される塩（上記の溶媒和物、異性体、同位体等を含む）から選択される少なくとも１種を、「本発明のトリアジン誘導体」と総称する。 Hereinafter, at least one selected from the compound represented by the formula (1) and a pharmacologically acceptable salt thereof (including the above solvates, isomers, isotopes, etc.) is referred to as "the present invention. Triazine derivatives ".
　本発明のトリアジン誘導体の製造方法は特に制限されず、市販の入手可能な、又は当業者によって認知される方法により合成可能な、出発原料、前駆体、試薬及び溶媒などを用いて、当業者によって認知される幅広い様々な種類の合成法及び必要に応じて当該合成法に改良などを加えた方法などを組み合わせることによって製造できる。例えば、以下に示す代表的な方法により製造することができる。 The method for producing the triazine derivative of the present invention is not particularly limited, and can be synthesized by those skilled in the art using commercially available starting materials, precursors, reagents, solvents and the like, which can be synthesized by a method recognized by those skilled in the art. It can be produced by combining a wide variety of recognized synthetic methods and, if necessary, a method obtained by modifying the synthetic method. For example, it can be produced by the following typical methods.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　上記各式中、Ｒ１、Ｒ２、及びＲ３は、それぞれ、前記式（１）中のＲ１、Ｒ２、及びＲ３と同義であり、Ｘ、Ｙ、及びＺは、それぞれ独立に脱離基である。 In each of the above equations, R 1 , R 2 , and R 3 are synonymous with R 1 , R 2 , and R 3 in the equation (1), respectively, and X, Y, and Z are independent of each other. It is a leaving group.
　上記方法により、例えば、前記式（１）で表される化合物のうちの前記式（１ａ）で表される化合物を、前記式（４）で表される化合物と適切なアミンとを塩基存在下、溶媒中で、マイクロウェーブ照射下で反応させることにより合成することができる。 By the above method, for example, among the compounds represented by the formula (1), the compound represented by the formula (1a) is subjected to the presence of a base of the compound represented by the formula (4) and an appropriate amine. , Can be synthesized by reacting in a solvent under microwave irradiation.
　前記式（１ａ）で表される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（４）で表される化合物に対して１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（４）で表される化合物に対して２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (1a) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (4). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents with respect to the compound represented by the formula (4). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
　前記式（１ａ）で表される化合物の合成反応における温度は、例えば、１００～２００℃の範囲で選択され、好ましくは、１３０～１８０℃の範囲である。反応時間は、例えば、３０分～２時間の範囲であり、好ましくは、１時間～９０分の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (1a) is selected, for example, in the range of 100 to 200 ° C, preferably in the range of 130 to 180 ° C. The reaction time is, for example, in the range of 30 minutes to 2 hours, preferably in the range of 1 hour to 90 minutes.
　前記式（４）で表される化合物は、例えば、前記式（３）で表される化合物を過剰量のアンモニアと反応させることにより合成することができる。 The compound represented by the formula (4) can be synthesized, for example, by reacting the compound represented by the formula (3) with an excess amount of ammonia.
　前記式（４）で表される化合物の合成反応に用いられるアンモニアとしては、アンモニア水溶液、又はアンモニアを溶媒に溶解させた溶液でもよく、その量は、好ましくは、前記式（３）で表される化合物に対して１０～１００当量の範囲である。前記溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The ammonia used in the synthesis reaction of the compound represented by the formula (4) may be an aqueous ammonia solution or a solution in which ammonia is dissolved in a solvent, and the amount thereof is preferably represented by the formula (3). It is in the range of 10 to 100 equivalents with respect to the compound. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. One of the above may be used alone or in combination of two or more.
　前記式（４）で表される化合物の合成反応における温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは０～３０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは、１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (4) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（３）で表される化合物は、例えば、前記式（２）で表される化合物を塩基存在下、溶媒中で、適切なアミンと反応させることにより合成することができる。 The compound represented by the formula (3) can be synthesized, for example, by reacting the compound represented by the formula (2) with an appropriate amine in the presence of a base in a solvent.
　前記式（３）で表される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（２）で表される化合物に対して１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（２）で表される化合物に対して２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (3) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (2). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents with respect to the compound represented by the formula (2). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
　前記式（３）で表される化合物の合成反応における温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは、０～３０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (3) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（１ａ）で表される化合物は、例えば、前記式（６）で表される化合物を塩基存在下、溶媒中で、適切なアミンと反応させることによっても合成することができる。 The compound represented by the formula (1a) can also be synthesized, for example, by reacting the compound represented by the formula (6) with an appropriate amine in the presence of a base in a solvent.
　前記式（６）で表される化合物からの前記式（１ａ）で表される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（６）で示される化合物に対して１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（６）で表される化合物に対して２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (1a) from the compound represented by the formula (6) is preferably 1 to 1 to that of the compound represented by the formula (6). It is in the range of 3 equivalents. 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 with respect to the compound represented by the formula (6). 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 and the like. , One of these may be used alone or in combination of two or more.
　前記式（６）で表される化合物からの前記式（１ａ）で表される化合物の合成反応における温度は、例えば、５０～１５０℃の範囲で選択され、好ましくは、８０～１１０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは、１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (1a) from the compound represented by the formula (6) is selected, for example, in the range of 50 to 150 ° C., preferably in the range of 80 to 110 ° C. Is. The reaction time is, for example, in the range of 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（６）で表される化合物は、例えば、前記式（５）で表される化合物を過剰量のアンモニアと反応させることにより合成することができる。 The compound represented by the formula (6) can be synthesized, for example, by reacting the compound represented by the formula (5) with an excess amount of ammonia.
　前記式（６）で表される化合物の合成反応に用いられるアンモニアとしては、アンモニア水溶液、又はアンモニアを溶媒に溶解させた溶液でもよく、その量は、好ましくは、前記式（５）で表される化合物に対して１０～１００当量の範囲である。前記溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The ammonia used in the synthesis reaction of the compound represented by the formula (6) may be an aqueous ammonia solution or a solution in which ammonia is dissolved in a solvent, and the amount thereof is preferably represented by the formula (5). It is in the range of 10 to 100 equivalents with respect to the compound. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. One of the above may be used alone or in combination of two or more.
　前記式（６）で表される化合物の合成反応における温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは０～３０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは、１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (6) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（５）で表される化合物は、例えば、前記式（２）で表される化合物を塩基存在下、溶媒中で、適切なアミンと反応させることにより合成することができる。 The compound represented by the formula (5) can be synthesized, for example, by reacting the compound represented by the formula (2) with an appropriate amine in the presence of a base in a solvent.
　前記式（５）で表される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（２）で表される化合物に対して１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（２）で表される化合物に対して２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (5) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (2). Examples of the base used in the reaction include diisopropylethylamine and triethylamine, and the amount thereof is preferably in the range of 2 to 5 equivalents with respect to the compound represented by the formula (2). Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and the like. , One of these may be used alone or in combination of two or more.
　前記式（５）で表される化合物の合成反応における温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは、０～３０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (5) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　Ｘ、Ｙ、及びＺで示される脱離基には、それぞれ独立に、例えば、ハロゲン原子（例えば塩素）、スルホン酸エステル（例えばスルホン酸４－メチルフェニル）などの代替的脱離基；スルホニル基（例えばメタンスルホニル又はフェニルスルホニル）；スルフィニル基（例えばメタンスルフィニル）などを含むが、別段これに限定されるものではない。 The leaving groups represented by X, Y, and Z are independently alternative leaving groups such as halogen atoms (eg chlorine), sulfonic acid esters (eg 4-methylphenyl sulfonic acid); sulfonyl groups. (For example, methanesulfonyl or phenylsulfonyl); includes, but is not limited to, a sulfinyl group (eg, methanesulfinyl).
　上記方法において、前記式（３）で表される中間体化合物の単離又は精製は必ずしも要しないが、適切なアミンの連続的な添加を必要とするように、追加のアミン（例えば、ジイソプロピルエチルアミン、トリエチルアミン等の第３級アミン）又は溶媒を前記式（２）で表される化合物に適切な溶媒（例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、Ｎ－メチル－２－ピロリドン）の存在下に添加して、又は添加せずに、２種のアミンの添加の間に反応混合物を加熱して、又は加熱せずに、前記の変換を実施することができることは、当業者であれば認めるであろう。 In the above method, isolation or purification of the intermediate compound represented by the formula (3) is not always necessary, but additional amines (eg, diisopropylethylamine) are required so as to require the continuous addition of appropriate amines. , A tertiary amine such as triethylamine) or a solvent suitable for the compound represented by the above formula (2) (for example, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N- With or without addition of dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone), with or without heating of the reaction mixture during the addition of the two amines. Those skilled in the art will appreciate that the conversion can be carried out.
　当業者であれば、前記式（１）で表される化合物を合成する任意の段階で、分子中の１個又は複数の不安定な基を保護基で保護して、望ましくない副反応を防ぐことが必要であるか、望ましいことを認めるであろう。特に、アミノ基を保護することが必要であるか、望ましい。前記式（１）で表される化合物を合成する際に使用される保護基としては、例えば、Ｇｒｅｅｎｅ　Ｗｕｔｓ著，ＰＲＯＴＥＣＴＩＶＥ　ＧＲＯＵＰＳ　ｉｎ　ＯＲＧＡＮＩＣ　ＳＹＮＴＨＥＳＩＳ　ＴＨＩＲＤ　ＥＤＩＴＩＯＮ，Ｊｏｈｎ　Ｗｉｌｅｙ＆Ｓｏｎｓ，Ｉｎｃ．などに記載される基（そのような基を脱離するための方法も記載されている）を挙げることができる。 Those skilled in the art will protect one or more unstable groups in the molecule with protecting groups at any step in synthesizing the compound represented by the 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 Willey & Sons, Inc. Etc. (the methods for desorbing such groups are also described).
　前記式（２）で表される化合物は、文献で知られているか、当業者によく知られている方法により容易に調製することができる。 The compound represented by the formula (2) can be easily prepared by a method known in the literature or well known to those skilled in the art.
　本発明のトリアジン誘導体は、例えば、以下に示す方法によっても製造することができる。 The triazine derivative of the present invention can also be produced, for example, by the method shown below.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　上記各式中、Ｒ１、Ｒ２、及びＲ３は、それぞれ、前記式（１）中のＲ１、Ｒ２、及びＲ３と同義であり、Ｘ及びＹは、それぞれ独立に脱離基である。 In each of the above equations, R 1 , R 2 , and R 3 are synonymous with R 1 , R 2 , and R 3 in the equation (1), respectively, and X and Y are independent leaving groups, respectively. Is.
　上記方法により、例えば、前記式（１）で表される化合物のうちの式（１ｂ）で表される化合物を、式（８）で表される化合物を塩基存在下、溶媒中で、適切なアミンと反応させることにより合成することができる。 By the above method, for example, the compound represented by the formula (1b) among the compounds represented by the formula (1) is suitable for the compound represented by the formula (8) in the presence of a base in a solvent. It can be synthesized by reacting with an amine.
　前記式（１ｂ）で表される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（８）で表される化合物に対して１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（８）で表される化合物に対して２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (1b) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (8). 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 with respect to the compound represented by the formula (8). 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 and the like. , One of these may be used alone or in combination of two or more.
　前記式（１ｂ）で表される化合物の合成反応における温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは、０～３０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (1b) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（８）で表される化合物は、例えば、前記式（７）で表される化合物を塩基存在下、溶媒中で、適切なアミンと反応させることにより合成することができる。 The compound represented by the formula (8) can be synthesized, for example, by reacting the compound represented by the formula (7) with an appropriate amine in the presence of a base in a solvent.
　前記式（８）で表される化合物の合成反応に用いられるアミンの量は、好ましくは、前記式（７）で表される化合物に対して１～３当量の範囲である。前記反応に用いられる塩基としては、例えば、ジイソプロピルエチルアミン、トリエチルアミンが挙げられ、その量は、好ましくは、前記式（７）で表される化合物に対して２～５当量の範囲である。前記反応に用いられる溶媒としては、例えば、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、ジメチルスルホキシド、及びＮ－メチル－２－ピロリドン等が挙げられ、これらのうちの１種を単独であっても２種以上の組み合わせであってもよい。 The amount of amine used in the synthetic reaction of the compound represented by the formula (8) is preferably in the range of 1 to 3 equivalents with respect to the compound represented by the formula (7). 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 with respect to the compound represented by the formula (7). 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 and the like. , One of these may be used alone or in combination of two or more.
　前記式（８）で表される化合物の合成反応における温度は、例えば、－２０～５０℃の範囲で選択され、好ましくは、０～３０℃の範囲である。反応時間は、例えば、３０分～６時間の範囲であり、好ましくは１～３時間の範囲である。 The temperature in the synthetic reaction of the compound represented by the formula (8) 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 30 minutes to 6 hours, preferably in the range of 1 to 3 hours.
　前記式（７）で表される化合物は、文献で知られているか、当業者によく知られている方法により容易に調製することができる。 The compound represented by the formula (7) can be easily prepared by a method known in the literature or well known to those skilled in the art.
　本発明のトリアジン誘導体は、ヒスタミンＨ４受容体（以下、場合により、単に「Ｈ４受容体」ともいう）に対する親和性を有する。そのため、本発明のトリアジン誘導体は、そのまま、又はこれを含有する医薬組成物として、Ｈ４受容体の調節用、より具体的には、Ｈ４受容体が関与する疾患若しくは状態の治療及び／又は予防のために使用することができる。 The triazine derivative of the present invention has an affinity for the histamine H4 receptor (hereinafter, also simply referred to as "H4 receptor" in some cases). Therefore, the triazine derivative of the present invention can be used as it is, or as a pharmaceutical composition containing the same, for the regulation of the H4 receptor, more specifically, for the treatment and / or prevention of a disease or condition involving the H4 receptor. Can be used for.
　Ｈ４受容体が関与する疾患若しくは状態としては、例えば、ＣＯＰＤ、炎症性腸疾患、リウマチ、アトピー性皮膚炎、掻痒性皮膚炎、アレルギー性結膜炎、鼻炎、関節症性乾癬、尋常性乾癬、各種がん（大腸がん、肺がん、血液がん、脳腫瘍など）、代謝性疾患（糖尿病、肥満など）、疼痛などが挙げられるが、これらのみに限定されるものではない。 Diseases or conditions involving the H4 receptor include, for example, COPD, inflammatory bowel disease, rheumatism, atopic dermatitis, pruritic dermatitis, allergic conjunctivitis, rhinitis, psoriatic arthritis, psoriasis vulgaris, and the like. Psoriasis (colon cancer, lung cancer, blood cancer, brain tumor, etc.), metabolic diseases (diabetes, obesity, etc.), pain, etc., but are not limited to these.
　本発明の医薬組成物は、本発明のトリアジン誘導体を有効成分として含有する。本発明の医薬組成物は、経口又は非経口のいずれの投与経路で対象に投与してもよく、前記対象としては、ヒト又はヒト以外の動物が挙げられる。 The pharmaceutical composition of the present invention contains the triazine derivative of the present invention as an active ingredient. The pharmaceutical composition of the present invention may be administered to a subject by either an oral or parenteral route of administration, and the subject includes humans or animals other than humans.
　本発明の医薬組成物は、前記投与経路に応じて適当な剤型の製剤とすることができる。前記製剤の剤型の例としては、具体的には、錠剤、丸剤、カプセル剤、顆粒剤、散剤、エリキシル剤、懸濁剤、乳剤、及びシロップ剤などの経口剤、並びに、注射剤、吸入剤、直腸投与剤、坐剤、ローション剤、スプレー剤、軟膏剤、クリーム剤、貼付剤、及び徐放製剤などの非経口剤が挙げられる。これらの各種製剤は、必要に応じて、薬学の分野において通常用いられている賦形剤、崩壊剤、結合剤、滑沢剤、着色剤などの薬理学的に許容される添加剤や担体を用い、常法により製造することができる。そのため、本発明の医薬組成物としては、薬理学的に許容される添加剤及び／又は担体をさらに含有していてよい。 The pharmaceutical composition of the present invention can be prepared in an appropriate dosage form according to the administration route. Specific examples of the dosage forms of the above-mentioned preparations include oral preparations such as tablets, pills, capsules, granules, powders, elixirs, suspensions, emulsions, and syrups, and injections. Parenteral agents such as inhalants, enteral agents, suppositories, lotions, sprays, ointments, creams, patches, and sustained-release preparations. These various preparations, if necessary, contain 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 a pharmacologically acceptable additive and / or carrier.
　本発明の医薬組成物において、本発明のトリアジン誘導体の含有量（２種以上の混合物である場合にはその合計含有量）は、その投与目的や製剤の剤型などに応じて適宜調整するものであるため一概にはいえないが、通常、式（１）で表される化合物の遊離体換算で、医薬組成物の全質量に対して０．０１～７０質量％、好ましくは０．０５～５０質量％である。 In the pharmaceutical composition of the present invention, the content of the triazine derivative of the present invention (in the case of a mixture of two or more kinds, the total content thereof) is appropriately adjusted according to the purpose of administration, the dosage form of the preparation, and the like. Therefore, although it cannot be said unconditionally, it is usually 0.01 to 70% by mass, preferably 0.05 to 0.05 to the total mass of the pharmaceutical composition in terms of the free form of the compound represented by the formula (1). It is 50% by mass.
　本発明のトリアジン誘導体の投与量（２種以上の混合物である場合にはその合計投与量）は、患者の年齢、体重、性別、疾患の相違、症状の程度などを考慮して、個々の場合に応じて適宜決定されるものであるため一概にはいえないが、通常、式（１）で表される化合物の遊離体換算で、成人１日当り、０．０１～１０００ｍｇ、好ましくは０．１～３００ｍｇであり、これを１日１回又は数回に分けて投与することができる。 The dose of the triazine derivative of the present invention (the total dose in the case of a mixture of two or more kinds) is determined in individual cases in consideration of the patient's age, weight, sex, difference in disease, degree of symptoms, etc. Although it cannot be unequivocally determined because it is appropriately determined according to the above, usually, in terms of free form of the compound represented by the formula (1), 0.01 to 1000 mg, preferably 0.1, per day for an adult. The dose is ~ 300 mg, which can be administered once a day or in several divided doses.
　以下、本発明について、実施例を用いてより詳しく説明するが、本発明はこれら実施例に限定されるものではない。また、実施例で使用する原料化合物の製造法を参考例として説明するが、これらも本発明の実施について具体的に説明するための例示であって、当該例示によって本発明の範囲が制限されるものではなく、本発明の範囲を逸脱しない範囲で種々の応用、変形及び修正などが可能であることは自明のことである。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Further, the method for producing the raw material compound used in the examples will be described as a reference example, but these are also examples for specifically explaining the practice of the present invention, and the scope of the present invention is limited by the examples. It is self-evident that various applications, modifications and modifications can be made without departing from the scope of the present invention.
　以下、実施例及び参考例における略語は、下記の意味である。 Hereinafter, the abbreviations in the examples and reference examples have the following meanings.
　　Ｍ：ｍｏｌ／Ｌ
　　ＴＨＦ：テトラヒドロフラン
　　ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
　　ｔｅｒｔ：ターシャリー
　　ＬＣ－ＭＳ：液体クロマトグラフ質量分析
　　ＨＰＬＣ：高速液体クロマトグラフィー
　（参考例１）
６－クロロ－Ｎ－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　シアヌル酸クロリド（１．８４ｇ）をＴＨＦ（５０ｍＬ）に溶解し０℃で冷却した後、ネオペンチルアミン（１．８５ｇ）を加え、室温で１時間撹拌した。反応液に２８％アンモニア水（５０ｍＬ）を加えた後室温で１時間撹拌、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、表題の化合物を１．２７ｇ得た。
１Ｈ－ＮＭＲ　（４００　ＭＨｚ，ＣＤ３ＯＤ），δ：０．９２（９Ｈ，ｍ），３．２（２Ｈ，ｍ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　２１６　（Ｍ＋Ｈ）＋。 M: mol / L
THF: tetrahydrofuran DMF: N, N-dimethylformamide tert: tertiary LC-MS: liquid chromatograph mass analysis HPLC: high performance liquid chromatography (Reference Example 1)
After dissolving 6-chloro-N- (2,2-dimethylpropyl) -1,3,5-triazine-2,4- diaminecyanuric chloride (1.84 g) in THF (50 mL) and cooling at 0 ° C. , Neopentylamine (1.85 g) was added, and the mixture was stirred at room temperature for 1 hour. After adding 28% aqueous ammonia (50 mL) to the reaction mixture, the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to obtain 1.27 g of the title compound.
1 1 H-NMR (400 MHz, CD 3 OD), δ: 0.92 (9 H, m), 3.2 (2 H, m)
MS (ESI) m / z 216 (M + H) + .
　（参考例２）
６－クロロ－Ｎ ２ －（２，２－ジメチルプロピル）－Ｎ ４ －［（４－メトキシフェニル）メチル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）シアヌル酸クロリド（１．８４ｇ）をＴＨＦ（５０ｍＬ）に溶解し０℃で冷却した後、Ｎ，Ｎ－ジイソプロピルエチルアミン（２．６ｍＬ）、１－（４－メトキシフェニル）メタンアミン（１．３ｍＬ）の順に加え、０℃で４０分撹拌した。反応液をセライト濾過して得られた濾液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、４，６－ジクロロ－Ｎ－［（４－メトキシフェニル）メチル］－１，３，５－トリアジン－２－アミンを２．２９ｇ得た。
（ｂ）参考例２（ａ）で得られた化合物（２８５．１ｍｇ）をクロロホルムに溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（１７０μＬ）、２，２－ジメチルプロパン－１－アミン（１１８μＬ）の順に加え、室温で終夜撹拌した。反応液に蒸留水を加え、クロロホルムで抽出し、有機層（有機相）を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、表題の化合物を２５３．７ｍｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６），δ：０．８１－０．８７（９Ｈ，ｍ），３．０６－３．０８（２Ｈ，ｍ），３．７１（３Ｈ，ｍ），４．３２－４．４１（２Ｈ，ｍ），６．８５－６．８８（２Ｈ，ｍ），７．１８－７．２３（２Ｈ，ｍ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　３３６　（Ｍ＋Ｈ）＋。 (Reference example 2)
6-Chloro-N 2- (2,2-dimethylpropyl) -N 4 -[(4-Methoxyphenyl) methyl] -1,3,5-triazine-2,4-diamine (a) cyanuric chloride (1) .84 g) is dissolved in THF (50 mL) and cooled at 0 ° C., then N, N-diisopropylethylamine (2.6 mL) and 1- (4-methoxyphenyl) methaneamine (1.3 mL) are added in this order at 0 ° C. Was stirred for 40 minutes. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to purify 4,6-dichloro-N-[(4-methoxyphenyl) methyl] -1,3,5-triazine-2. -2.29 g of amine was obtained.
(B) The compound (285.1 mg) obtained in Reference Example 2 (a) was dissolved in chloroform in the order of N, N-diisopropylethylamine (170 μL) and 2,2-dimethylpropan-1-amine (118 μL). In addition, it was stirred overnight at room temperature. Distilled water was added to the reaction solution, the mixture was extracted with chloroform, and the organic layer (organic phase) was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to obtain 253.7 mg of the title compound.
1 1 H-NMR (400 MHz, DMSO-d 6 ), δ: 0.81-0.87 (9H, m), 3.06-3.08 (2H, m), 3.71 (3H, m), 4.32-4.41 (2H, m), 6.85-6.88 (2H, m), 7.18-7.23 (2H, m)
MS (ESI) m / z 336 (M + H) + .
　（参考例３）
１－（アゼチジン－３－イル）ピロリジントリフルオロ酢酸塩
（ａ）ピロリジン（１０３μＬ）を酢酸（１．２５ｍＬ）／メタノール（１２．５ｍＬ）の混液に溶解した後、ｔｅｒｔ－ブチル　３－オキソアゼチジン－１－カルボキシレート（１７１．２ｍｇ）と２－メチルピリジン－ボラン錯体（１０７．０ｍｇ）を加え７０℃で５時間撹拌した。減圧下で溶媒を留去した後、残留物をメタノール／クロロホルム（１／１０）の混液と水で抽出し、有機層を硫酸ナトリウムで乾燥させ、ｔｅｒｔ－ブチル　３－（ピロリジン－１－イル）アゼチジン－１－カルボキシレートを８２．２ｍｇ得た。
（ｂ）参考例３（ａ）で得られた化合物（７９．３ｍｇ）をクロロホルム（１．５ｍＬ）に溶解し０℃に冷却した後、トリフルオロ酢酸（１．５ｍＬ）を加え、室温で２．５時間撹拌した。減圧下で溶媒を留去し、表題の化合物を得た。
ＭＳ　（ＥＳＩ）　ｍ／ｚ　１２７　（Ｍ＋Ｈ）＋。 (Reference example 3)
1- (Azetidine-3-yl) Pyrrolidine Trifluoroacetic acid salt (a) Pyrrolidine (103 μL) is dissolved in a mixed solution of acetic acid (1.25 mL) / methanol (12.5 mL), and then tert-butyl 3-oxoazetidine-1. -Carboxylate (171.2 mg) and 2-methylpyridine-boran complex (107.0 mg) were added, and the mixture was stirred at 70 ° C. for 5 hours. After distilling off the solvent under reduced pressure, the residue was extracted with a mixed solution of methanol / chloroform (1/10) and water, the organic layer was dried over sodium sulfate, and tert-butyl 3- (pyrrolidin-1-yl). 82.2 mg of azetidine-1-carboxylate was obtained.
(B) The compound (79.3 mg) obtained in Reference Example 3 (a) was dissolved in chloroform (1.5 mL), cooled to 0 ° C., trifluoroacetic acid (1.5 mL) was added, and 2 at room temperature. . Stirred for 5 hours. The solvent was distilled off under reduced pressure to obtain the title compound.
MS (ESI) m / z 127 (M + H) + .
　（参考例４）
Ｎ－（ ２ Ｈ ３ ）メチル－２－ニトロ－Ｎ－［（３Ｒ）－ピロリジン－３－イル］ベンゼン－１－スルホンアミド
（ａ）ｔｅｒｔ－ブチル（３Ｒ）－３－アミノピロリジン－１－カルボキシレート（５５８．８ｍｇ）をジクロロメタン（１５ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（７６６μＬ）を加え０℃に冷却した。２－ニトロベンゼン－１－スルホニルクロライド（７９７．８ｍｇ）を加えた後、室温で５時間撹拌した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製、ｔｅｒｔ－ブチル（３Ｒ）－３－｛［（２－ニトロフェニル）スルホニル］アミノ｝ピロリジン－１－カルボキシレートを８８３．３ｍｇ得た。
（ｂ）参考例４（ａ）で得られた化合物（２２１．８ｍｇ）をＤＭＦ（３ｍＬ）に溶解し、炭酸カリウム（９９．０ｍｇ）とヨード（２Ｈ３）メタン（１２９．９μＬ）を加え、室温で４時間撹拌した。反応液に蒸留水を加え、酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、ｔｅｒｔ－ブチル（３Ｒ）－３－｛（２Ｈ３）メチル［（２－ニトロフェニル）スルホニル］アミノ｝ピロリジン－１－カルボキシレートを２１９．７ｍｇ得た。
（ｃ）参考例４（ｂ）で得られた化合物をクロロホルム（１．４ｍＬ）に溶解し、０℃でトリフルオロ酢酸（１．４ｍＬ）を加えた後、室温で１時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え中和した後、溶媒を減圧下で留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）で精製して、表題の化合物を５７．２ｍｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３），δ：１．６９－１．７４（１Ｈ，ｍ），１．９７－２．０２（１Ｈ，ｍ），２．７７－２．８１（１Ｈ，ｍ），２．８４－２．９１（１Ｈ，ｍ），２．９６－３．０２（１Ｈ，ｍ），３．０８－３．１３（１Ｈ，ｍ），４．４８－４．５５（１Ｈ，ｍ），７．６１－７．６８（１Ｈ，ｍ），７．６８－７．７１（２Ｈ，ｍ），８．０３－８．０６（１Ｈ，ｍ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　２８９　（Ｍ＋Ｈ）＋。 (Reference example 4)
N- (2 H 3) methyl-2-nitro -N - [(3R) - pyrrolidin-3-yl] benzene-1-sulfonamide (a) tert-butyl (3R) -3-amino-1-carboxy The rate (558.8 mg) was dissolved in dichloromethane (15 mL), N, N-diisopropylethylamine (766 μL) was added, and the mixture was cooled to 0 ° C. After adding 2-nitrobenzene-1-sulfonyl chloride (797.8 mg), the mixture was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate), tert-butyl (3R) -3-{[(2-nitrophenyl) sulfonyl] amino}. 883.3 mg of pyrrolidine-1-carboxylate was obtained.
(B) the compound obtained in Reference Example 4 (a) to (221.8mg) was dissolved in DMF (3 mL), was added potassium carbonate (99.0 mg) and iodine (2 H 3) methane (129.9μL) , Stirred at room temperature for 4 hours. Distilled water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to give, tert- butyl (3R) -3 - {(2 H 3) Methyl [(2 -Nitrophenyl) sulfonyl] amino} pyrrolidine-1-carboxylate was obtained in 219.7 mg.
(C) The compound obtained in Reference Example 4 (b) was dissolved in chloroform (1.4 mL), trifluoroacetic acid (1.4 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 57.2 mg of the title compound.
1 1 H-NMR (400 MHz, CDCl 3 ), δ: 1.69-1.74 (1 H, m), 1.97-2.02 (1 H, m), 2.77-2.81 (1 H, m) ), 2.84-2.91 (1H, m), 2.96-3.02 (1H, m), 3.08-3.13 (1H, m), 4.48-4.55 (1H) , M), 7.61-7.68 (1H, m), 7.68-7.71 (2H, m), 8.03-8.06 (1H, m)
MS (ESI) m / z 289 (M + H) + .
　（参考例５）
Ｎ－ベンジル－Ｎ－メチルアゼパン－４－アミン塩酸塩
（ａ）アゼパン－４－オン塩酸塩（５００ｍｇ）をジクロロメタン（１７ｍＬ）に懸濁させた後、トリエチルアミン（１．３９ｍＬ）とジ－ｔｅｒｔ－ブチル　ジカーボネート（１．０９ｇ）を加え、室温で３時間撹拌した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製して、ｔｅｒｔ－ブチル　４－オキサゼパン－１－カルボキシレートを７０１ｍｇ得た。
（ｂ）参考例５（ａ）で得られた化合物（４７７．６ｍｇ）を酢酸（２．８ｍＬ）／メタノール（１２８ｍＬ）の混液に溶解した後、Ｎ－メチル－１－フェニルメタンアミン（２３９．６ｍｇ）と２－メチルピリジン－ボラン錯体（２３９．６ｍｇ）を加え７０℃で５時間撹拌した。減圧下で溶媒を留去した後、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製して、ｔｅｒｔ－ブチル　４－［ベンジル（メチル）アミノ］アゼパン－１－カルボキシレートを１４３．８ｍｇ得た。
（ｃ）参考例５（ｂ）で得られた化合物（１４３．８ｍｇ）を４Ｍ塩酸／１，４－ジオキサン溶液（５６５μＬ）に懸濁させ、６０℃で１．５時間撹拌した。溶媒を減圧下で留去し、表題の化合物（１６５．２ｍｇ）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ），δ：１．７８－１．９３（２Ｈ，ｍ），２．１１－２．４２（４Ｈ，ｍ），２．７３（３Ｈ，ｓ），３．１６－３．２９（３Ｈ，ｍ），３．４９－３．６０（２Ｈ，ｍ），４．１９－４．２６（１Ｈ，ｍ），４．３９－４．４５（１Ｈ，ｍ），７．４５－７．４９（５Ｈ，ｍ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　２１９　（Ｍ＋Ｈ）＋。 (Reference example 5)
N-Benzyl-N-methylazepan-4-amine hydrochloride (a) Azepan-4-one hydrochloride (500 mg) was suspended in dichloromethane (17 mL), followed by triethylamine (1.39 mL) and di-tert-butyl. Dicarbonate (1.09 g) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate → ethyl acetate: methanol) to obtain 701 mg of tert-butyl 4-oxazepan-1-carboxylate. Obtained.
(B) The compound (477.6 mg) obtained in Reference Example 5 (a) was dissolved in a mixed solution of acetic acid (2.8 mL) / methanol (128 mL), and then N-methyl-1-phenylmethaneamine (239. 6 mg) and 2-methylpyridine-borane complex (239.6 mg) were added, and the mixture was stirred at 70 ° C. for 5 hours. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate → ethyl acetate: methanol) to tert-butyl 4- [benzyl (methyl) amino]. 143.8 mg of azepan-1-carboxylate was obtained.
(C) The compound (143.8 mg) obtained in Reference Example 5 (b) was suspended in a 4M hydrochloric acid / 1,4-dioxane solution (565 μL), and the mixture was stirred at 60 ° C. for 1.5 hours. The solvent was evaporated under reduced pressure to give the title compound (165.2 mg).
1 1 H-NMR (400 MHz, D 2 O), δ: 1.78-1.93 (2 H, m), 2.11-2.42 (4 H, m), 2.73 (3 H, s), 3 .16-3.29 (3H, m), 3.49-3.60 (2H, m), 4.19-4.26 (1H, m), 4.39-4.45 (1H, m) , 7.45-7.49 (5H, m)
MS (ESI) m / z 219 (M + H) + .
　（参考例６）
ｔｅｒｔ－ブチル［（３Ｒ）－１－（４－アミノ－６－クロロ－１，３，５－トリアジン－２－イル）ピロリジン－３－イル］メチルカーバメート
　シアヌル酸クロリド（６４５．４ｍｇ）をＴＨＦ（１５ｍＬ）に溶解し０℃で冷却した後、ＴＨＦ（２ｍＬ）に溶解させたｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメート（７０１ｍｇ）を加え、０℃で１時間撹拌した。反応液に２８％アンモニア水（１７．５ｍＬ）を加えた後室温で１時間撹拌、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、表題の化合物を１．０３ｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３），δ：１．４７（９Ｈ，ｄ，Ｊ＝２．５Ｈｚ），１．９９－２．１５（３Ｈ，ｍ），２．７９（３Ｈ，ｄ，Ｊ＝２．５Ｈｚ），３．３６－３．４７（２Ｈ，ｍ），３．７３－３．８０（２Ｈ，ｍ），５．１８（２Ｈ，ｂｒｓ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　３２９　（Ｍ＋Ｈ）＋。 (Reference example 6)
tert-Butyl [(3R) -1- (4-amino-6-chloro-1,3,5-triazine-2-yl) pyrrolidine-3-yl] methyl carbamate cyanuric chloride (645.4 mg) in THF ( After dissolving in 15 mL) and cooling at 0 ° C., tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate (701 mg) dissolved in THF (2 mL) was added, and the mixture was stirred at 0 ° C. for 1 hour. After adding 28% aqueous ammonia (17.5 mL) to the reaction mixture, the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to obtain 1.03 g of the title compound.
1 1 H-NMR (400 MHz, CDCl 3 ), δ: 1.47 (9H, d, J = 2.5 Hz), 1.99-2.15 (3H, m), 2.79 (3H, d, J) = 2.5Hz), 3.36-3.47 (2H, m), 3.73-3.80 (2H, m), 5.18 (2H, brs)
MS (ESI) m / z 329 (M + H) + .
　（参考例７）
２－フルオロ－２－メチルプロパン－１－アミントリフルオロ酢酸塩
　ｔｅｒｔ－ブチル（２－フルオロ－２－メチルプロピル）カーバメート（８０ｍｇ）をクロロホルム（２ｍＬ）に溶解し０℃で冷却した後、トリフルオロ酢酸（２ｍＬ）を添加し室温で１時間撹拌した。溶媒を減圧下で留去し、表題の化合物を得た。
ＭＳ（ＥＳＩ）　ｍ／ｚ　９２　（Ｍ＋Ｈ）＋。 (Reference example 7)
2-Fluoro-2-methylpropane-1-amine Trifluoroacetate tert-butyl (2-fluoro-2-methylpropyl) carbamate (80 mg) is dissolved in chloroform (2 mL), cooled at 0 ° C., and then trifluoro. Acetic acid (2 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give the title compound.
MS (ESI) m / z 92 (M + H) + .
　（参考例８）
（２Ｓ）－１－メトキシ－３－メチルブタン－２－アミン塩酸塩
（ａ）（２Ｓ）－２－アミノ－３，３－ジメチルブタン－１－オール（２３０ｍｇ）をジクロロメタン（１０ｍＬ）に溶解し、ジ－ｔｅｒｔ－ブチル　ジカーボネート（８５０ｍｇ）を加えた後、室温で終夜撹拌した。反応液に水と酢酸エチルを加え抽出した後、有機層を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製して、ｔｅｒｔ－ブチル［（２Ｓ）－１－ヒドロキシ－３，３－ジメチルブタン－２－イル］カーバメートを３３２ｍｇ得た。
（ｂ）参考例８（ａ）で得られた化合物（３２７．３ｍｇ）をアセトニトリル（１５ｍＬ）に溶解した後ヨードメタン（１．４ｍＬ）と酸化銀（ＩＩ）（５６０ｍｇ）を加え、還流条件で終夜撹拌した。室温にて冷却した反応液をセライト濾過し、得られた濾液を減圧下で濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、ｔｅｒｔ－ブチル［（２Ｓ）－１－メトキシ－３，３－ジメチルブタン－２－イル］カーバメートを２００ｍｇ得た。
（ｃ）参考例８（ｂ）で得られた化合物（１００ｍｇ）を１，４－ジオキサン（８６４μＬ）に懸濁させ０℃にて冷却した後、４Ｍ塩酸／１，４－ジオキサン溶液（４３２μＬ）を加え、室温で４時間撹拌した。溶媒を減圧下で留去し得られた残渣をエーテルで洗浄し、表題の化合物（６５ｍｇ）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３），δ：１．１３（９Ｈ，ｓ），３．０９－３．１２（１Ｈ，ｍ），３．４０（３Ｈ，ｓ），３．５９－３．６６（２Ｈ，ｍ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　１３２　（Ｍ＋Ｈ）＋。 (Reference example 8)
(2S) -1-methoxy-3-methylbutane-2-amine hydrochloride (a) (2S) -2-amino-3,3-dimethylbutane-1-ol (230 mg) was dissolved in dichloromethane (10 mL). After adding di-tert-butyldicarbonate (850 mg), the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture for extraction, and then the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, chloroform: methanol) with tert-butyl [(2S) -1-hydroxy-3,3-dimethylbutane-. 2-Il] 332 mg of carbamate was obtained.
(B) The compound (327.3 mg) obtained in Reference Example 8 (a) was dissolved in acetonitrile (15 mL), iodomethane (1.4 mL) and silver (II) oxide (560 mg) were added, and the mixture was added overnight under reflux conditions. Stirred. The reaction solution cooled at room temperature was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to obtain 200 mg of tert-butyl [(2S) -1-methoxy-3,3-dimethylbutane-2-yl] carbamate. It was.
(C) The compound (100 mg) obtained in Reference Example 8 (b) was suspended in 1,4-dioxane (864 μL), cooled at 0 ° C., and then 4M hydrochloric acid / 1,4-dioxane solution (432 μL). Was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and the resulting residue was washed with ether to give the title compound (65 mg).
1 1 H-NMR (400 MHz, CDCl 3 ), δ: 1.13 (9H, s), 3.09-3.12 (1H, m), 3.40 (3H, s), 3.59-3. 66 (2H, m)
MS (ESI) m / z 132 (M + H) + .
　（参考例９）
１－［１－（トリフルオロメチル）シクロペンチル］メタンアミン塩酸塩
（ａ）１－（トリフルオロメチル）シクロペンタンカルボン酸（３５５．２ｍｇ）をジクロロメタン（１５ｍＬ）に溶解した後、エタンジオイルジクロライド（２５２μＬ）、ＤＭＦ（１滴）を添加し、室温で１時間撹拌した。溶媒を減圧下で留去した後、残渣をＴＨＦ（５ｍＬ）に懸濁させ、ＴＨＦ（１０ｍＬ）と２８％アンモニア水（１．７ｍＬ）の混液を添加、室温で４．５時間撹拌した。反応液に水と酢酸エチルを加え抽出した後、有機層を飽和塩化ナトリウム水溶液で洗浄、続いて硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去し、１－（トリフルオロメチル）シクロペンタンカルボキサミドを２７６．３ｍｇ得た。
（ｂ）参考例９（ａ）で得られた化合物（９２．１ｍｇ）をＴＨＦ（３ｍＬ）に溶解した後、ボラン－ＴＨＦ錯体のＴＨＦ溶液（０．９２Ｍ，５．５ｍＬ）を加え、６５℃で２．５時間撹拌した。反応液にメタノール（５．５ｍＬ）を徐々に加えた後、溶媒を減圧下で留去した。残渣に再度メタノール（５．５ｍＬ）を加えた後に、３Ｍ塩酸水溶液（５．５ｍＬ）を徐々に添加し６５℃で４時間撹拌した。溶媒を減圧下で留去した後、２－プロパノールによる共沸処理を行い、表題の化合物を５８．５ｍｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６），δ：１．４０－１．４４（２Ｈ，ｍ），１．６４－１．６９（２Ｈ，ｍ），１．７８－１．８５（２Ｈ，ｍ），３．０４（１Ｈ，ｍ），３．３７－３．４６（２Ｈ，ｍ），４．３５－４．３８（１Ｈ，ｍ），８．１１（２Ｈ，ｂｒｓ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　２０４　（Ｍ＋Ｈ）＋。 (Reference example 9)
1- [1- (Trifluoromethyl) Cyclopentyl] methaneamine hydrochloride (a) 1- (Trifluoromethyl) cyclopentanecarboxylic acid (355.2 mg) is dissolved in dichloromethane (15 mL) and then ethanedioil dichloride (252 μL). ), DMF (1 drop) was added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was suspended in THF (5 mL), a mixed solution of THF (10 mL) and 28% aqueous ammonia (1.7 mL) was added, and the mixture was stirred at room temperature for 4.5 hours. Water and ethyl acetate were added to the reaction solution for extraction, and then the organic layer was washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 276.3 mg of 1- (trifluoromethyl) cyclopentanecarboxamide.
(B) After dissolving the compound (92.1 mg) obtained in Reference Example 9 (a) in THF (3 mL), a THF solution (0.92 M, 5.5 mL) of a borane-THF complex was added, and the temperature was 65 ° C. Was stirred for 2.5 hours. Methanol (5.5 mL) was gradually added to the reaction mixture, and then the solvent was distilled off under reduced pressure. After adding methanol (5.5 mL) to the residue again, 3M aqueous hydrochloric acid solution (5.5 mL) was gradually added, and the mixture was stirred at 65 ° C. for 4 hours. After distilling off the solvent under reduced pressure, azeotropic treatment with 2-propanol was carried out to obtain 58.5 mg of the title compound.
1 1 H-NMR (400 MHz, DMSO-d 6 ), δ: 1.40-1.44 (2H, m), 1.64-1.69 (2H, m), 1.78-1.85 (2H) , M), 3.04 (1H, m), 3.37-3.46 (2H, m), 4.35-4.38 (1H, m), 8.11 (2H, brs)
MS (ESI) m / z 204 (M + H) + .
　（参考例１０）
ｔｅｒｔ－ブチル　４－（４－アミノ－６－クロロ－１，３，５－トリアジン－２－イル）－１，４－ジアゼパン－１－カルボキシレート
　シアヌル酸クロリド（１．８４ｇ）をＴＨＦ（４０ｍＬ）に溶解しＮ，Ｎ－ジイソプロピルエチルアミン（２．５５ｍＬ）を加えた後０℃で冷却し、ＴＨＦ（１０ｍＬ）に溶解させたｔｅｒｔ－ブチル　１，４－ジアゼパン－１－カルボキシレート（２ｇ）を加え、０℃で２時間撹拌した。反応液に２８％アンモニア水（５０ｍＬ）を加えた後、室温で２時間撹拌、溶媒を減圧下で留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、表題の化合物を２．１ｇ得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３），δ：１．４６（９Ｈ，ｓ），１．９２（２Ｈ，ｍ），３．３０－３．５０（２Ｈ，ｍ），３．６６（２Ｈ，ｍ），３．７０－３．７２（２Ｈ，ｍ），３．７３－３．８３（２Ｈ，ｍ），５．１３（２Ｈ，ｂｒｓ）
ＭＳ（ＥＳＩ）　ｍ／ｚ　３２９　（Ｍ＋Ｈ）＋。 (Reference example 10)
tert-Butyl 4- (4-amino-6-chloro-1,3,5-triazine-2-yl) -1,4-diazepan-1-carboxylate cyanuric chloride (1.84 g) in THF (40 mL) After adding N, N-diisopropylethylamine (2.55 mL), the mixture was cooled at 0 ° C., and tert-butyl 1,4-diazepan-1-carboxylate (2 g) dissolved in THF (10 mL) was added. , Stirred at 0 ° C. for 2 hours. After adding 28% aqueous ammonia (50 mL) to the reaction mixture, the mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to obtain 2.1 g of the title compound.
1 1 H-NMR (400 MHz, CDCl 3 ), δ: 1.46 (9H, s), 1.92 (2H, m), 3.30-3.50 (2H, m), 3.66 (2H, 2H, m), 3.70-3.72 (2H, m), 3.73-3.83 (2H, m), 5.13 (2H, brs)
MS (ESI) m / z 329 (M + H) + .
　（参考例１１）
２－アミノ－Ｎ－（シクロプロピルメチル）エタン－１－スルホンアミド
（ａ）２－（１，３－ジオキソ－１，３－ジヒドロ－２Ｈ－イソインドール－２－イル）エタンスルホニルクロライド（２７３．７ｍｇ）をＴＨＦ（２ｍＬ）に溶解した後、１－シクロプロピルメタンアミン（１７２μＬ）を加え室温で２時間撹拌した。溶媒を減圧下で留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、Ｎ－（シクロプロピルメチル）－２－（１，３－ジオキソ－１，３－ジヒドロ－２Ｈ－イソインドール－２－イル）エタンスルホンアミドを２４１．１ｍｇ得た。
（ｂ）参考例１１（ａ）で得られた化合物（２４１．１ｍｇ）をエタノール（３．５ｍＬ）に溶解し、ヒドラジン一水和物（０．８６０ｍＬ）を加えた後、還流条件下４時間撹拌した。反応液を室温にて冷却後、溶媒を減圧下で留去し、得られた粗生成物をそのまま実施例７２の反応へ用いた。
ＭＳ（ＥＳＩ）　ｍ／ｚ　１７９　（Ｍ＋Ｈ）＋。 (Reference example 11)
2-Amino-N- (cyclopropylmethyl) ethane-1-sulfonamide (a) 2- (1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) ethanesulfonyl chloride (273. 7 mg) was dissolved in THF (2 mL), 1-cyclopropylmethaneamine (172 μL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to purify N- (cyclopropylmethyl) -2- (1,3-dioxo-1,3). 24-1.1 mg of 3-dihydro-2H-isoindole-2-yl) ethanesulfoneamide was obtained.
(B) The compound (241.1 mg) obtained in Reference Example 11 (a) was dissolved in ethanol (3.5 mL), hydrazine monohydrate (0.860 mL) was added, and then under reflux conditions for 4 hours. Stirred. After cooling the reaction solution at room temperature, the solvent was distilled off under reduced pressure, and the obtained crude product was used as it was for the reaction of Example 72.
MS (ESI) m / z 179 (M + H) + .
　（参考例１２）
３，３，３－トリフルオロ－２，２－ジメチルプロパン－１－アミン塩酸塩
　参考例９における１－（トリフルオロメチル）シクロペンタンカルボン酸の代わりに３，３，３－トリフルオロ－２，２－ジメチルプロパン酸を用い、参考例９と同様の方法にて表題の化合物を得た。
ＭＳ（ＥＳＩ）　ｍ／ｚ　１４２　（Ｍ＋Ｈ）＋。 (Reference example 12)
3,3,3-trifluoro-2,2-dimethylpropane-1-amine hydrochloride In place of 1- (trifluoromethyl) cyclopentanecarboxylic acid in Reference Example 9, 3,3,3-trifluoro-2, Using 2-dimethylpropanoic acid, the title compound was obtained in the same manner as in Reference Example 9.
MS (ESI) m / z 142 (M + H) + .
　（参考例１３）
１－［１－（トリフルオロメチル）シクロプロピル］メタンアミン塩酸塩
　参考例９における１－（トリフルオロメチル）シクロペンタンカルボン酸の代わりに１－（トリフルオロメチル）シクロプロパン－１－カルボン酸を用い、参考例９と同様の方法にて表題の化合物を得た。
ＭＳ（ＥＳＩ）　ｍ／ｚ　１４０　（Ｍ＋Ｈ）＋。 (Reference example 13)
1- [1- (Trifluoromethyl) Cyclopropyl] Methanamine Hydrochloride Use 1- (trifluoromethyl) cyclopropane-1-carboxylic acid instead of 1- (trifluoromethyl) cyclopentanecarboxylic acid in Reference Example 9. , The title compound was obtained in the same manner as in Reference Example 9.
MS (ESI) m / z 140 (M + H) + .
　（参考例１４）
１－（１－メチルシロラン－１－イル）メタンアミン塩酸塩
（ａ）削り状マグネシウム（７３２．９ｍｇ）をＴＨＦ（３２ｍＬ）に懸濁させ０℃にて冷却した後、１，４－ジブロモブタン（１．８６ｍＬ）を滴下した。室温で１時間攪拌した後、ジクロロ（クロロメチル）メチルシラン（１．６６ｍＬ）を滴下し室温で３時間攪拌した。反応液を氷水に注いだ後、メチル　ｔｅｒｔ－ブチルエーテルにて３回抽出し、得られた有機相を飽和食塩水で洗浄した。有機相を硫酸マグネシウムで乾燥後、減圧下で溶媒を留去し１－（クロロメチル）－１－メチルシロランを１．７７ｇ得た。
（ｂ）参考例１４（ａ）で得られた化合物（１．７７ｇ）をＤＭＦ（３５ｍＬ）に溶解し、フタルイミドカリウム（２．２ｇ）を加えたのち８０℃で６．５時間攪拌した。反応液に水を徐々に加えた後、メチル　ｔｅｒｔ－ブチルエーテルにて３回抽出し、得られた有機相を飽和食塩水で洗浄した。有機相を硫酸マグネシウムで乾燥後、減圧下で溶媒を留去、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製し、２－［（１－メチルシロラン－１－イル）メチル］－１Ｈ－イソインドール－１，３（２Ｈ）－ジオンを１．３７ｇ得た。
ＭＳ（ＥＳＩ）　ｍ／ｚ　２６０　（Ｍ＋Ｈ）＋。
（ｃ）参考例１４（ｂ）で得られた化合物（２７５．９ｍｇ）をエタノール（２．１ｍＬ）に溶解した後、ヒドラジン一水和物（５７μＬ）を加え、還流条件下１７時間撹拌した。反応液を室温で放置した後、氷浴にて冷却し、析出してきた固体をエタノールで洗浄しつつ濾過にて除去した。濾液を減圧下で濃縮した後、エタノール（２．１ｍＬ）に溶解し、２Ｍ塩酸水溶液（１．８ｍＬ）を添加し還流条件下３時間撹拌した。溶媒を減圧下で留去した後、表題の化合物を５８．５ｍｇ得た。
ＭＳ（ＥＳＩ）　ｍ／ｚ　１３０　（Ｍ＋Ｈ）＋。 (Reference example 14)
1- (1-Methylsiloran-1-yl) methaneamine hydrochloride (a) Shaving magnesium (732.9 mg) was suspended in THF (32 mL), cooled at 0 ° C., and then 1,4-dibromobutane (1). .86 mL) was added dropwise. After stirring at room temperature for 1 hour, dichloromethane (chloromethyl) methylsilane (1.66 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, extracted three times with methyl tert-butyl ether, and the obtained organic phase was washed with saturated brine. The organic phase was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.77 g of 1- (chloromethyl) -1-methylsilorane.
(B) The compound (1.77 g) obtained in Reference Example 14 (a) was dissolved in DMF (35 mL), phthalimide potassium (2.2 g) was added, and the mixture was stirred at 80 ° C. for 6.5 hours. After gradually adding water to the reaction mixture, the mixture was extracted 3 times with methyl tert-butyl ether, and the obtained organic phase was washed with saturated brine. The organic phase was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to 2-[(1-methylsiloran-1-yl). ) Methyl] -1H-isoindole-1,3 (2H) -dione was obtained in an amount of 1.37 g.
MS (ESI) m / z 260 (M + H) + .
(C) The compound (275.9 mg) obtained in Reference Example 14 (b) was dissolved in ethanol (2.1 mL), hydrazine monohydrate (57 μL) was added, and the mixture was stirred under reflux conditions for 17 hours. The reaction mixture was left at room temperature, cooled in an ice bath, and the precipitated solid was washed with ethanol and removed by filtration. The filtrate was concentrated under reduced pressure, dissolved in ethanol (2.1 mL), 2M aqueous hydrochloric acid solution (1.8 mL) was added, and the mixture was stirred under reflux conditions for 3 hours. After distilling off the solvent under reduced pressure, 58.5 mg of the title compound was obtained.
MS (ESI) m / z 130 (M + H) + .
　（参考例１５）
１－［シクロプロピル（ジメチル）シリル］メタンアミン塩酸塩
　参考例１４における１，４－ジブロモブタンの代わりにブロモシクロプロパンを用い、参考例１４と同様の方法にて表題の化合物を得た。
ＭＳ（ＥＳＩ）　ｍ／ｚ　１３０　（Ｍ＋Ｈ）＋。 (Reference example 15)
1- [Cyclopropyl (dimethyl) Cyril] Methanamine Hydrochloride Using bromocyclopropane instead of 1,4-dibromobutane in Reference Example 14, the title compound was obtained in the same manner as in Reference Example 14.
MS (ESI) m / z 130 (M + H) + .
　（実施例１）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［（３Ｓ）－３－メチルピペラジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）参考例１で得られた化合物（１０７．８ｍｇ）を１，４－ジオキサン（３．３ｍＬ）に溶解し、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレート（１００．２ｍｇ）及びＮ，Ｎ－ジイソプロピルエチルアミン（１２８μＬ）を加え１００℃で３時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した後、有機層を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル）で精製して、ｔｅｒｔ－ブチル（２Ｓ）－４－｛４－アミノ－６－［（２，２－ジメチルプロピル）アミノ］－１，３，５－トリアジン－２－イル｝－２－メチルピペラジン－１－カルボキシレートを１８４．２ｍｇ得た。
（ｂ）実施例１（ａ）で得られた化合物（１０７．８ｍｇ）をクロロホルム（２．３ｍＬ）に溶解し、０℃でトリフルオロ酢酸（２．３ｍＬ）を加え、室温で１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え中和した後、溶媒を減圧下で留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）で精製して、表題の化合物を１２６．５ｍｇ得た。 (Example 1)
N 2- (2,2-dimethylpropyl) -6-[(3S) -3-methylpiperazine-1-yl] -1,3,5-triazine-2,4-dioxane (a) Obtained in Reference Example 1. The compound (107.8 mg) was dissolved in 1,4-dioxane (3.3 mL) to tert-butyl (2S) -2-methylpiperazin-1-carboxylate (100.2 mg) and N, N-diisopropyl. Ethylamine (128 μL) was added and the mixture was stirred at 100 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) to tert-butyl (2S) -4- {4-amino-6-[(2,2-dimethylpropyl) amino] -1, 184.2 mg of 3,5-triazine-2-yl} -2-methylpiperazin-1-carboxylate was obtained.
(B) The compound (107.8 mg) obtained in Example 1 (a) was dissolved in chloroform (2.3 mL), trifluoroacetic acid (2.3 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. .. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 126.5 mg of the title compound.
　（実施例２）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）参考例２（ｂ）で得られた化合物を１，４－ジオキサン（４ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（２２２μＬ）、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメート（１３０．５ｍｇ）を加え、還流条件下２．５時間撹拌した。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、ｔｅｒｔ－ブチル［（３Ｒ）－１－（４－［（２，２－ジメチルプロピル）アミノ］－６－｛［（４－メトキシフェニル）メチル］アミノ｝－１，３，５－トリアジン－２－イル）ピロリジン－３－イル］メチルカーバメートを２６７．０ｍｇ得た。
（ｂ）実施例２（ａ）で得られた化合物（１３３ｍｇ）をトリフルオロ酢酸（２．６ｍＬ）に溶解し、６０℃で２．５時間撹拌した。減圧下で溶媒を留去し、残渣に飽和炭酸水素ナトリウム水溶液を加え中和した。混合物にメタノールを加えた後、再度溶媒を減圧下で留去し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）で精製、表題の化合物を２８．１ｍｇ得た。 (Example 2)
N 2- (2,2-dimethylpropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine (a) Reference example The compound obtained in 2 (b) was dissolved in 1,4-dioxane (4 mL), and N, N-diisopropylethylamine (222 μL), tert-butyl methyl [(3R) -pyrrolidine-3-yl] carbamate (130). 5.5 mg) was added, and the mixture was stirred under reflux conditions for 2.5 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) with tert-butyl [(3R) -1- (4-[(2,2-)). Dimethylpropyl) amino] -6-{[(4-methoxyphenyl) methyl] amino} -1,3,5-triazine-2-yl) pyrrolidine-3-yl] methyl carbamate was obtained in an amount of 267.0 mg.
(B) The compound (133 mg) obtained in Example 2 (a) was dissolved in trifluoroacetic acid (2.6 mL) and stirred at 60 ° C. for 2.5 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue to neutralize the residue. After adding methanol to the mixture, the solvent was distilled off again under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 28.1 mg of the title compound.
　（実施例３）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート塩酸塩を用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 3)
N 2- (2,2-dimethylpropyl) -6- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine The tert in Example 2 (a) Using tert-butyl azetidine-3-yl (methyl) carbamate hydrochloride instead of -butylmethyl [(3R) -pyrrolidine-3-yl] carbamate, the title compound was obtained in the same manner as in Example 2. ..
　（実施例４）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　１，４－ジアゼパン－１－カルボキシレートを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 4)
6- (1,4-diazepan-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-in-triazine-2,4-diamine Example 2 (a), tert-butyl The title compound was obtained in the same manner as in Example 2 using tert-butyl 1,4-diazepan-1-carboxylate instead of methyl [(3R) -pyrrolidin-3-yl] carbamate.
　（実施例５）
Ｎ ２ －（２，２－ジメチルプロピル）－６－（ピペラジン－１－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 5)
N 2 - (2,2-dimethylpropyl) -6- (piperazin-1-yl) -1,3,5-triazine-2,4-diamine Example 2 in (a), tert-butyl methyl [(3R ) -Pyrrolidine-3-yl] tert-butylpiperazin-1-carboxylate was used instead of carbamate, and the title compound was obtained in the same manner as in Example 2.
　（実施例６）
６－（４－アミノピペリジン－１－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　ピペリジン－４－イルカーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 6)
6- (4-amino-piperidin-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 in (a), tert-butyl ( 2S) Using tert-butyl piperidine-4-ylcarbamate instead of -2-methylpiperazin-1-carboxylate, the title compound was obtained in the same manner as in Example 1.
　（実施例７）
６－（２，６－ジアザスピロ［３．３］ヘプタン－２－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　２，６－ジアザスピロ［３．３］ヘプタン－２－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 7)
6- (2,6-diazaspiro [3.3] heptan-2-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 (a ) In place of tert-butyl (2S) -2-methylpiperazin-1-carboxylate, tert-butyl 2,6-diazaspiro [3.3] heptane-2-carboxylate was used, as in Example 1. The title compound was obtained by the method.
　（実施例８）
６－（３，８－ジアザビシクロ［３．２．１］オクタン－３－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　３，８－ジアザビシクロ［３．２．１］オクタン－８－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 8)
6- (3,8-diazabicyclo [3.2.1] octan-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 Example using tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in (a). The title compound was obtained in the same manner as in 1.
　（実施例９）
６－（３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　３，６－ジアザビシクロ［３．２．０］ヘプタン－６－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 9)
6- (3,6-diazabicyclo [3.2.0] heptan-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 Example using tert-butyl 3,6-diazabicyclo [3.2.0] heptane-6-carboxylate instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate in (a). The title compound was obtained in the same manner as in 1.
　（実施例１０）
６－［（７Ｒ）－７－アミノ－５－アザスピロ［２．４］ヘプタン－５－イル］－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル（７Ｒ）－５－アザスピロ［２．４］ヘプタン－７－イルカーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 10)
6-[(7R) -7-amino-5-azaspiro [2.4] heptane-5-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4- Diamine In Example 1 (a), tert-butyl (7R) -5-azaspiro [2.4] heptane-7-ilcarbamate was used instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate. The compound of the title was obtained in the same manner as in Example 1.
　（実施例１１）
６－［（３Ｓ，４Ｓ）－３－アミノ－４－フルオロピロリジン－１－イル］－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル［（３Ｓ，４Ｓ）－４－フルオロピロリジン－３－イル］カーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 11)
6 - [(3S, 4S) -3- amino-4-fluoro-1-yl] -N 2 - (2,2- dimethylpropyl) -1,3,5-triazine-2,4-diamine Example Example using tert-butyl [(3S, 4S) -4-fluoropyrrolidine-3-yl] carbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in 1 (a). The title compound was obtained in the same manner as in 1.
　（実施例１２）
６－（４－アミノ－３，３－ジフルオロピロリジン－１－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル（４，４－ジフルオロピロリジン－３－イル）カーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 12)
6- (4-amino-3,3-difluoro-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 (a) but In the same manner as in Example 1, tert-butyl (4,4-difluoropyrrolidine-3-yl) carbamate was used instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in the title. Compound was obtained.
　（実施例１３）
６－［（１Ｒ，５Ｒ）－３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル］－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル（１Ｓ，５Ｒ）－３，６－ジアザビシクロ［３．２．０］ヘプタン－６－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 13)
6-[(1R, 5R) -3,6-diazabicyclo [3.2.0] heptane-3-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2, 4-Diamine In Example 1 (a), tert-butyl (1S, 5R) -3,6-diazabicyclo [3.2.0] instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate. ] The title compound was obtained in the same manner as in Example 1 using heptane-6-carboxylate.
　（実施例１４）
６－［（１Ｓ，５Ｓ）－３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル］－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル（１Ｒ，５Ｓ）－３，６－ジアザビシクロ［３．２．０］ヘプタン－６－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 14)
6-[(1S, 5S) -3,6-diazabicyclo [3.2.0] heptane-3-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2, 4-Diamine In Example 1 (a), tert-butyl (1R, 5S) -3,6-diazabicyclo [3.2.0] instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate. ] The title compound was obtained in the same manner as in Example 1 using heptane-6-carboxylate.
　（実施例１５）
６－（１，７－ジアザスピロ［４．４］ノナン－１－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　１，７－ジアザスピロ［４．４］ノナン－７－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 15)
6- (1,7-diazaspiro [4.4] nonan-1-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 (a ) In place of tert-butyl (2S) -2-methylpiperazine-1-carboxylate, tert-butyl 1,7-diazaspiro [4.4] nonane-7-carboxylate was used, as in Example 1. The title compound was obtained by the method.
　（実施例１６）
３－｛４－アミノ－６－［（２，２－ジメチルプロピル）アミノ］－１，３，５－トリアジン－２－イル｝－３，７－ジアザビシクロ［３．３．１］ノナン－９－オール
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　９－ヒドロキシ－３，７－ジアザビシクロ［３．３．１］ノナン－３－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 16)
3- {4-Amino-6-[(2,2-dimethylpropyl) amino] -1,3,5-triazine-2-yl} -3,7-diazabicyclo [3.3.1] Nonan-9- All In Example 1 (a), instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate, tert-butyl 9-hydroxy-3,7-diazabicyclo [3.3.1] nonane-3 -Using carboxylate, the title compound was obtained in the same manner as in Example 1.
　（実施例１７）
６－［３－（アミノメチル）アゼチジン－１－イル］－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル［（アゼチジン－３－イル）メチル］カーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 17)
6- [3- (Aminomethyl) Azetidine-1-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine The tert in Example 1 (a). Using tert-butyl [(azetidine-3-yl) methyl] carbamate instead of -butyl (2S) -2-methylpiperazin-1-carboxylate, the title compound was obtained in the same manner as in Example 1. ..
　（実施例１８）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［３－メチル－３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　メチル（３－メチルアゼチジン－３－イル）カーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 18)
N 2- (2,2-Dimethylpropyl) -6- [3-Methyl-3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine Example 1 (a) ), Using tert-butyl methyl (3-methylazetidine-3-yl) carbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate, in the same manner as in Example 1. The title compound was obtained.
　（実施例１９）
Ｎ ２ －（２，２－ジメチルプロピル）－６－（４－メチル－１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりに１－メチル－１，４－ジアゼパンを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 19)
N 2- (2,2-Dimethylpropyl) -6- (4-Methyl-1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine In Example 1 (a) , Tert-Butyl (2S) -2-methylpiperazine-1-carboxylate was used instead of 1-methyl-1,4-diazepan, and the title compound was obtained in the same manner as in Example 1.
　（実施例２０）
６－（６－アミノ－３－アザビシクロ［３．１．０］ヘキサン－３－イル）－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　３－アザビシクロ［３．１．０］ヘキ－６－イル　カーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 20)
6- (6-amino-3-azabicyclo [3.1.0] hexane-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine [ Example using tert-butyl 3-azabicyclo [3.1.0] hex-6-ylcarbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in Example 1 (a). The title compound was obtained in the same manner as in 1.
　（実施例２１）
６－［（３Ｒ）－３－アミノピロリジン－１－イル］－Ｎ ２ －（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル（３Ｒ）－ピロリジン－３－イルカーバメートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 21)
6 - in (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine Example 1 (a), - [( 3R) -3- amino-1-yl] -N 2 The title compound was obtained in the same manner as in Example 1 using tert-butyl (3R) -pyrrolidine-3-ylcarbamate instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate. ..
　（実施例２２）
Ｎ ２ －（２，２－ジメチルプロピル）－６－（ヘキサヒドロピロロ［３，４－ｃ］ピロール－２（１Ｈ）－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　ヘキサヒドロピロロ［３，４－ｃ］ピロール－２（１Ｈ）－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 22)
N 2 - (2,2-dimethylpropyl) -6- (hexahydropyrrolo [3,4-c] pyrrol -2 (IH) - yl) -1,3,5-triazine-2,4-diamine Example Using tert-butyl hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate in 1 (a). The title compound was obtained in the same manner as in Example 1.
　（実施例２３）
Ｎ ２ －（２，２－ジメチルプロピル）－６－（オクタヒドロ－６Ｈ－ピロロ［３，４－ｂ］ピリジン－６－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　オクタヒドロ－１Ｈ－ピロロ［３，４－ｂ］ピリジン－１－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 23)
N 2 - (2,2-dimethylpropyl) -6- (octahydro -6H- pyrrolo [3,4-b] pyridin-6-yl) -1,3,5-triazine-2,4-diamine Example 1 Example using tert-butyl octahydro-1H-pyrrolo [3,4-b] pyridin-1-carboxylate instead of tert-butyl (2S) -2-methylpiperazine-1-carboxylate in (a). The title compound was obtained in the same manner as in 1.
　（実施例２４）
Ｎ ２ －（２，２－ジメチルプロピル）－６－（オクタヒドロ－６Ｈ－ピロロ［３，４－ｂ］ピリジン－６－イル）－１，３，５－トリアジン－２，４－ジアミンの光学異性体
　実施例２３にて得られた化合物（１９．７ｍｇ）をエタノール（８００μＬ）／クロロホルム（１００μＬ）の混液に溶解し、分取ＨＰＬＣ（カラム：ＣＨＩＲＡＬＰＡＫ　ＩＤ　２ｃｍ×２５ｃｍ、展開溶媒：ｎ－ヘキサン／エタノール＝４／１、流速：１９．８ｍＬ／ｍｉｎ、注入量：９００μＬ、室温）に付し、ｉｓｏｍｅｒ　Ａ（実施例２４－１）（保持時間の短い異性体）を８．１ｍｇ及びｉｓｏｍｅｒ　Ｂ（実施例２４－２）（保持時間の長い異性体）を６．９ｍｇ得た。 (Example 24)
N 2 - (2,2-dimethylpropyl) -6-enantiomer of (octahydro -6H- pyrrolo [3,4-b] pyridin-6-yl) -1,3,5-triazine-2,4-diamine Body The compound (19.7 mg) obtained in Example 23 was dissolved in a mixed solution of ethanol (800 μL) / chloroform (100 μL), and preparative HPLC (column: CHIRALPAK ID 2 cm × 25 cm, developing solvent: n-hexane / Soaked in ethanol = 4/1, flow velocity: 19.8 mL / min, injection volume: 900 μL, room temperature), isomer A (Example 24-1) (isomer with short retention time) of 8.1 mg and isomer B (isomer B). Example 24-2) (isomer with long retention time) was obtained in an amount of 6.9 mg.
　（実施例２５）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［３－（ピロリジン－１－イル）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりに参考例３で得られた化合物を用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 25)
N 2- (2,2-dimethylpropyl) -6- [3- (pyrrolidine-1-yl) azetidine-1-yl] -1,3,5-triazine-2,4-diamine Example 1 (a) The compound obtained in Reference Example 3 was used in place of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in the above, and the title compound was obtained in the same manner as in Example 1.
　（実施例２６）
Ｎ ２ －（２，２－ジメチルプロピル）－６－｛（３Ｒ）－３－［（ ２ Ｈ ３ ）－メチルアミノ］ピロリジン－１－イル｝－１，３，５－トリアジン－２，４－ジアミン
（ａ）実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりに参考例４で得られた化合物を用い、実施例１と同様の方法にてＮ－［（３Ｒ）－１－｛４－アミノ－６－［（２，２－ジメチルプロピル）アミノ］－１，３，５－トリアジン－２－イル｝ピロリジン－３－イル］－Ｎ－（２Ｈ３）メチル－２－ニトロベンゼン－１－スルホンアミドを得た。
（ｂ）実施例２６（ａ）で得られた化合物（２８．０ｍｇ）をＤＭＦ（１１０μＬ）に溶解した後、チオグリコール酸（４μＬ）と水酸化リチウム一水和物（５ｍｇ）を加え、室温で終夜撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した後、残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製して、表題の化合物を４．９ｍｇ得た。 (Example 26)
N 2 - (2,2-dimethylpropyl) -6 - {(3R) -3 - [(2 H 3) - methylamino] pyrrolidin-1-yl} -1,3,5-triazine-2,4 Diamine (a) In the same method as in Example 1, the compound obtained in Reference Example 4 was used instead of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in Example 1 (a). N-[(3R) -1- {4-amino-6-[(2,2-dimethylpropyl) amino] -1,3,5-triazine-2-yl} pyrrolidine-3-yl] -N- (2 H 3) to give methyl 2-nitrobenzene-1-sulfonamide.
(B) After dissolving the compound (28.0 mg) obtained in Example 26 (a) in DMF (110 μL), thioglycolic acid (4 μL) and lithium hydroxide monohydrate (5 mg) were added, and the temperature was changed to room temperature. Stirred overnight. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain 4.9 mg of the title compound.
　（実施例２７）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［４－（メチルアミノ）アゼパン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりに参考例５で得られた化合物を用い、実施例１と同様の方法にて６－｛４－［ベンジル（メチル）アミノ］アゼパン－１－イル｝－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミンを得た。
（ｂ）実施例２７（ａ）で得られた化合物（４２．６ｍｇ）を加えたフラスコ内をアルゴンで置換し、水酸化パラジウム－活性炭素（９ｍｇ）、メタノール（１．１ｍＬ）の順に加えて懸濁させた後、系内を水素で置換し室温で終夜撹拌した。反応液をセライト濾過して得られた濾液を減圧下で濃縮し、表題の化合物を２３．３ｍｇ得た。 (Example 27)
N 2- (2,2-dimethylpropyl) -6- [4- (methylamino) azepan-1-yl] -1,3,5-triazine-2,4-diamine (a) Example 1 (a) In place of tert-butyl (2S) -2-methylpiperazin-1-carboxylate in, the compound obtained in Reference Example 5 was used, and 6- {4- [benzyl (methyl)) was used in the same manner as in Example 1. ) Amino] Azepan-1-yl} -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine was obtained.
(B) The inside of the flask to which the compound (42.6 mg) obtained in Example 27 (a) was added was replaced with argon, and palladium hydroxide-activated carbon (9 mg) and methanol (1.1 mL) were added in this order. After suspension, the inside of the system was replaced with hydrogen, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure to obtain 23.3 mg of the title compound.
　（実施例２８）
Ｎ ２ －（２，２－ジメチルプロピル）－６－［４－（メチルアミノ）アゼパン－１－イル］－１，３，５－トリアジン－２，４－ジアミンの光学異性体
（ａ）６－｛４－［ベンジル（メチル）アミノ］アゼパン－１－イル｝－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミンの光学分割
　実施例２７（ａ）にて得られた化合物（４１．３ｍｇ）をエタノール（４．０ｍＬ）に溶解し、分取ＨＰＬＣ（カラム：ＣＨＩＲＡＬＰＡＫ　ＩＤ　２ｃｍ×２５ｃｍ、展開溶媒：ｎ－ヘキサン（０．１％ジエチルアミン含有）／エタノール＝９５／５、流速：１９．８ｍＬ／ｍｉｎ、注入量：１．０×４ｍＬ、室温）に付し、ｉｓｏｍｅｒ　Ａ（保持時間の短い異性体）を１４．２ｍｇ及びｉｓｏｍｅｒ　Ｂ（保持時間の長い異性体）を１２．３ｍｇ得た。
（ｂ）実施例２７（ｂ）における、６－｛４－［ベンジル（メチル）アミノ］アゼパン－１－イル｝－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミンの代わりに実施例２８（ａ）で得られた化合物を用い、実施例２７（ｂ）と同様の方法にて表題の化合物［（実施例２８－１）（保持時間の短い異性体）及び（実施例２８－２）（保持時間の長い異性体）］を得た。 (Example 28)
N 2 - (2,2-dimethylpropyl) -6- [4- (methylamino) azepan-1-yl] optical isomers of 1,3,5-triazine-2,4-diamine (a) 6- {4- [benzyl (methyl) amino] azepan-1-yl} -N 2 - (2,2-dimethylpropyl) -1,3,5-optical Resolution example triazine-2,4-diamine 27 (a ) Was dissolved in ethanol (4.0 mL) and preparative HPLC (column: CHIRALPAK ID 2 cm × 25 cm, developing solvent: n-hexane (containing 0.1% diethylamine) / Ethanol = 95/5, flow velocity: 19.8 mL / min, injection volume: 1.0 × 4 mL, room temperature), isomer A (isomer with short retention time) 14.2 mg and isomer B (retention time) (Long isomer) was obtained in an amount of 12.3 mg.
(B) in Example 27 (b), 6- {4- [ benzyl (methyl) amino] azepan-1-yl} -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine - Using the compound obtained in Example 28 (a) instead of 2,4-diamine, the title compound [(Example 28-1) (short retention time) was used in the same manner as in Example 27 (b). (Isomer) and (Example 28-2) (Isomer with long retention time)] were obtained.
　（実施例２９）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（１－メチルシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）参考例６で得られた化合物（１０９．８ｍｇ）を１，４－ジオキサン（１．６７ｍＬ）に懸濁し、Ｎ，Ｎ－ジイソプロピルエチルアミン（１１４μＬ）と１－（１－メチルシクロペンチル）メタンアミン塩酸塩（５０ｍｇ）を加え、マイクロウェーブ照射下１５０℃で１．５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製して、ｔｅｒｔ－ブチル［（３Ｒ）－１－（４－アミノ－６－｛［（１－メチルシクロペンチル）メチル］アミノ｝－１，３，５－トリアジン－２－イル）ピロリジン－３－イル］メチルカーバメートを１０６．４ｍｇ得た。
（ｂ）実施例２９（ａ）で得られた化合物（１０６．４ｍｇ）をクロロホルム（１．３ｍＬ）に溶解し、０℃でトリフルオロ酢酸（１．３ｍＬ）を加え、室温で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え中和した後、溶媒を減圧下で留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）で精製して、表題の化合物を６３．２ｍｇ得た。 (Example 29)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine (a) Reference The compound (109.8 mg) obtained in Example 6 was suspended in 1,4-dioxane (1.67 mL), and N, N-diisopropylethylamine (114 μL) and 1- (1-methylcyclopentyl) methaneamine hydrochloride (50 mg) were suspended. ) Was added, and the mixture was stirred at 150 ° C. for 1.5 hours under microwave irradiation. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate → ethyl acetate: methanol) and tert-butyl [(3R) -1- (4-amino). 106.4 mg of -6-{[(1-methylcyclopentyl) methyl] amino} -1,3,5-triazine-2-yl) pyrrolidine-3-yl] methyl carbamate was obtained.
(B) The compound (106.4 mg) obtained in Example 29 (a) was dissolved in chloroform (1.3 mL), trifluoroacetic acid (1.3 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. .. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 63.2 mg of the title compound.
　（実施例３０）
｛１－［（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）メチル］シクロペンチル｝メタノール
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに［１－（アミノメチル）シクロペンチル］メタノールを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 30)
{1-[({4-Amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) methyl] cyclopentyl} methanol implementation [1- (Aminomethyl) cyclopentyl] methanol was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in Example 29 (a), and the title compound was obtained in the same manner as in Example 29.
　（実施例３１）
Ｎ ２ －（２，２－ジフルオロプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに２，２－ジフルオロプロパン－１－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 31)
N 2- (2,2-difluoropropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a) ), 2,2-Difluoropropane-1-amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
　（実施例３２）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－［１－（トリフルオロメチル）シクロプロピル］メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 32)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2,4- Diamine In Example 29 (a), 1- [1- (trifluoromethyl) cyclopropyl] methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same method as in Example 29 was used. Obtained the title compound.
　（実施例３３）
３－（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）－２，２－ジメチルプロパン－１－オール
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに３－アミノ－２，２－ジメチルプロパン－１－オールを用い、実施例２９と同様の方法にて表題の化合物を得た。
（実施例３４）
Ｎ ２ －［（３，３－ジフルオロシクロブチル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（３，３－ジフルオロシクロブチル）メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 33)
3-({4-Amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) -2,2-dimethylpropane- In 1-all Example 29 (a), 3-amino-2,2-dimethylpropan-1-ol was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same method as in Example 29 was used. Obtained the title compound.
(Example 34)
N 2 -[(3,3-difluorocyclobutyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine implementation In Example 29 (a), 1- (3,3-difluorocyclobutyl) methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29. Got
　（実施例３５）
Ｎ ２ －［（４，４－ジフルオロシクロヘキシル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（４，４－ジフルオロシクロヘキシル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 35)
Examples of N 2 -[(4,4-difluorocyclohexyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine The title compound was obtained in the same manner as in Example 29 by using 1- (4,4-difluorocyclohexyl) methaneamine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in 29 (a).
　（実施例３６）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（１－メチルシクロヘキシル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（１－メチルシクロヘキシル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 36)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclohexyl) methyl] -1,3,5-triazine-2,4-diamine Example 29 ( The title compound was obtained in the same manner as in Example 29 by using 1- (1-methylcyclohexyl) methaneamine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in a).
　（実施例３７）
Ｎ ２ －（２－フルオロ－２－メチルプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに参考例７で調製した化合物を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 37)
N 2 - (2-fluoro-2-methylpropyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine Example 29 The compound prepared in Reference Example 7 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a), and the title compound was obtained in the same manner as in Example 29.
　（実施例３８）
Ｎ ２ －［（２Ｓ）－１－メトキシ－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに参考例８で調製した（２Ｓ）－１－メトキシ－３－メチルブタン－２－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 38)
N 2 -[(2S) -1-methoxy-3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5- Triazine-2,4-diamine In Example 29 (a), (2S) -1-methoxy-3-methylbutane-2-amine prepared in Reference Example 8 instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride Using hydrochloride, the title compound was obtained in the same manner as in Example 29.
　（実施例３９）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［１－（トリフルオロメチル）シクロペンチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（トリフルオロメチル）シクロペンタン－１－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 39)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- [1- (trifluoromethyl) cyclopentyl] -1,3,5-triazine-2,4-diamine Example 29 In place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a), 1- (trifluoromethyl) cyclopentane-1-amine hydrochloride was used, and the title compound was prepared in the same manner as in Example 29. Obtained.
　（実施例４０）
Ｎ ２ －［（４－クロロフェニル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（４－クロロフェニル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 40)
N 2 -[(4-chlorophenyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a) ), 1- (4-Chlorophenyl) methaneamine was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
　（実施例４１）
Ｎ ２ －［（フラン－２－イル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（フラン－２－イル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 41)
N 2 -[(furan-2-yl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 The title compound was obtained in the same manner as in Example 29 by using 1- (furan-2-yl) methaneamine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a).
　（実施例４２）
Ｎ ２ －（４－クロロフェニル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに４－クロロアニリンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 42)
N 2- (4-Chlorophenyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine In Example 29 (a), The title compound was obtained in the same manner as in Example 29 using 4-chloroaniline instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride.
　（実施例４３）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －｛［１－（トリフルオロメチル）シクロペンチル］メチル｝－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに参考例９で調製した１－［１－（トリフルオロメチル）シクロペンチル］メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 43)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclopentyl] methyl} -1,3,5-triazine-2,4-diamine In Example 29 (a), 1- [1- (trifluoromethyl) cyclopentyl] methaneamine hydrochloride prepared in Reference Example 9 was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same as in Example 29. The title compound was obtained in the same manner.
　（実施例４４）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（３－メチルオキセタン－３－イル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（３－メチルオキセタン－３－イル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 44)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(3-methyloxetane-3-yl) methyl] -1,3,5-triazine-2,4-diamine In Example 29 (a), 1- (3-methyloxetane-3-yl) methaneamine was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29. Got
　（実施例４５）
Ｎ ２ －｛［１－（フルオロメチル）シクロプロピル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例４３（ａ）における、１－（トリフルオロメチル）シクロペンタン－１－カルボン酸の代わりに１－（フルオロメチル）シクロプロパン－１－カルボン酸を用い、実施例４３と同様の方法にて表題の化合物を得た。 (Example 45)
N 2 -{[1- (fluoromethyl) cyclopropyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine In Example 43 (a), 1- (fluoromethyl) cyclopropane-1-carboxylic acid was used instead of 1- (trifluoromethyl) cyclopentane-1-carboxylic acid, and the same method as in Example 43 was used. The title compound was obtained.
　（実施例４６）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例４３（ａ）における、１－（トリフルオロメチル）シクロペンタン－１－カルボン酸の代わりに３，３，３－トリフルオロ－２，２－ジメチルプロピオン酸を用い、実施例４３と同様の方法にて表題の化合物を得た。 (Example 46)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2 , 4-Diamine In Example 43 (a), 3,3,3-trifluoro-2,2-dimethylpropionic acid was used instead of 1- (trifluoromethyl) cyclopentane-1-carboxylic acid. The title compound was obtained in the same manner as in 43.
　（実施例４７）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －｛［１－（トリフルオロメチル）シクロブチル］メチル｝－１，３，５－トリアジン－２，４－ジアミン
　実施例４３（ａ）における、１－（トリフルオロメチル）シクロペンタン－１－カルボン酸の代わりに１－（トリフルオロメチル）シクロブタン－１－カルボン酸を用い、実施例４３と同様の方法にて表題の化合物を得た。 (Example 47)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclobutyl] methyl} -1,3,5-triazine-2,4-diamine In Example 43 (a), 1- (trifluoromethyl) cyclobutane-1-carboxylic acid was used instead of 1- (trifluoromethyl) cyclopentane-1-carboxylic acid, and the same method as in Example 43 was used. The title compound was obtained.
　（実施例４８）
Ｎ ２ －（シクロプロピルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに１－シクロプロピルメタンアミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 48)
N 2- (cyclopropylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine 2 in Example 2 (a) , 2-Cyclopropylmethaneamine was used instead of 2-dimethylpropane-1-amine, and the title compound was obtained in the same manner as in Example 2.
　（実施例４９）
Ｎ ２ －（ビシクロ［２．２．１］ヘプタン－２－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりにビシクロ［２．２．１］ヘプタン－２－アミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 49)
N 2 - (bicyclo [2.2.1] heptan-2-yl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4 - using bicyclo [2.2.1] heptan-2-amine in place of 2,2-dimethyl-1-amine in the diamine example 2 (a), the title compound in the same manner as in example 2 Got
　（実施例５０）
Ｎ ２ －シクロペンチル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりにシクロペンチルアミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 50)
N 2 - cyclopentyl-6 - 2,2-dimethyl-in [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine Example 2 (a) Using cyclopentylamine instead of propane-1-amine, the title compound was obtained in the same manner as in Example 2.
　（実施例５１）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（オキソラン－２－イル）メチル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）参考例２（ａ）で得られた化合物をクロロホルム（７ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（１７０μＬ）と１－（フラン－３－イル）メタンアミン（９３μＬ）を加えた後、室温で終夜撹拌した。反応液にクロロホルムと水を加えて抽出し、有機層を硫酸ナトリウムで乾燥した後、溶媒を減圧下で留去し６－クロロ－Ｎ２－［（フラン－２－イル）メチル］－Ｎ４－［（４－メトキシフェニル）メチル］－１，３，５－トリアジン－２，４－ジアミンを３４１．９ｍｇ得た。
（ｂ）実施例５１（ａ）で得られた化合物（３４１．１ｍｇ）を１，４－ジオキサン（６ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（３３６μＬ）とｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメート（１９７．５ｍｇ）を加えた後、還流条件下２時間撹拌した。溶媒を減圧下で留去し得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、ｔｅｒｔ－ブチル［（３Ｒ）－１－（４－｛［（フラン－２－イル）メチル］アミノ｝－６－｛［（４－メトキシフェニル）メチル］アミノ｝－１，３，５－トリアジン－２－イル）ピロリジン－３－イル］メチルカーバメートを４３８．３ｍｇ得た。
（ｃ）実施例５１（ｂ）で得られた化合物（４３８．３ｍｇ）を加えたフラスコ内をアルゴンで置換し、水酸化パラジウム－活性炭素（８８ｍｇ）、メタノール（８．６ｍＬ）の順に加えて懸濁させた後、系内を水素で置換し４０℃で終夜撹拌した。反応液をセライト濾過して得られた濾液を減圧下で濃縮、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製して、ｔｅｒｔ－ブチル［（３Ｒ）－１－（４－｛［（４－メトキシフェニル）メチル］アミノ｝－６－｛［（オキソラン－２－イル）メチル］アミノ｝－１，３，５－トリアジン－２－イル）ピロリジン－３－イル］メチルカーバメートを１７８．２ｍｇ得た。
（ｄ）実施例５１（ｃ）で得られた化合物（１７８．２ｍｇ）をトリフルオロ酢酸（３．５ｍＬ）に溶解し、６０℃で撹拌した。減圧下で溶媒を留去し、残渣に飽和炭酸水素ナトリウム水溶液を加え中和した。混合物にメタノールを加えた後、再度溶媒を減圧下で留去し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）で精製、表題の化合物を２８．４ｍｇ得た。 (Example 51)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(oxolan-2-yl) methyl] -1,3,5-triazine-2,4-diamine (a) The compound obtained in Reference Example 2 (a) was dissolved in chloroform (7 mL), N, N-diisopropylethylamine (170 μL) and 1- (fran-3-yl) methaneamine (93 μL) were added, and then at room temperature. Stirred overnight. Chloroform and water are added to the reaction solution for extraction, the organic layer is dried with sodium sulfate, and the solvent is distilled off under reduced pressure to make 6-chloro-N 2 -[(furan-2-yl) methyl] -N 4 -[(4-Methoxyphenyl) methyl] -1,3,5-triazine-2,4-diamine was obtained in 341.9 mg.
(B) The compound (341.1 mg) obtained in Example 51 (a) was dissolved in 1,4-dioxane (6 mL), and N, N-diisopropylethylamine (336 μL) and tert-butyl methyl [(3R)) were dissolved. -Pyrrolidine-3-yl] carbamate (197.5 mg) was added, and the mixture was stirred under reflux conditions for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to purify tert-butyl [(3R) -1- (4-{[(furan-2)). -Il) methyl] amino} -6-{[(4-methoxyphenyl) methyl] amino} -1,3,5-triazine-2-yl) pyrrolidine-3-yl] methyl carbamate was obtained in an amount of 438.3 mg.
(C) The inside of the flask to which the compound (438.3 mg) obtained in Example 51 (b) was added was replaced with argon, and palladium hydroxide-activated carbon (88 mg) and methanol (8.6 mL) were added in this order. After suspension, the inside of the system was replaced with hydrogen, and the mixture was stirred at 40 ° C. overnight. The reaction solution was filtered through Celite, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate → ethyl acetate: methanol) to purify with tert-butyl [((developing solvent, hexane: ethyl acetate → ethyl acetate: methanol)). 3R) -1-(4-{[(4-methoxyphenyl) methyl] amino} -6-{[(oxolan-2-yl) methyl] amino} -1,3,5-triazine-2-yl) pyrrolidine -3-Il] 178.2 mg of methyl carbamate was obtained.
(D) The compound (178.2 mg) obtained in Example 51 (c) was dissolved in trifluoroacetic acid (3.5 mL) and stirred at 60 ° C. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue to neutralize the residue. After adding methanol to the mixture, the solvent was distilled off again under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (chloroform: methanol) to obtain 28.4 mg of the title compound.
　（実施例５２）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（オキサン－４－イル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに１－（オキサン－４－イル）メタンアミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 52)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(oxan-4-yl) methyl] -1,3,5-triazine-2,4-diamine Example 2 The title compound was obtained in the same manner as in Example 2 by using 1- (oxane-4-yl) methaneamine instead of 2,2-dimethylpropane-1-amine in (a).
　（実施例５３）
Ｎ ２ －（シクロペンチルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに１－シクロペンチルメタンアミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 53)
N 2- (cyclopentylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine 2, in Example 2 (a) The title compound was obtained in the same manner as in Example 2 using 1-cyclopentylmethaneamine instead of 2-dimethylpropane-1-amine.
　（実施例５４）
（２Ｓ）－２－（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）－３，３－ジメチルブタン－１－オール
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに（２Ｓ）－２－アミノ－３，３－ジメタルブタン－１－オールを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 54)
(2S) -2-({4-amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) -3,3 - using (2S)-2-amino-3,3 Jimetarubutan 1-ol in place of 2,2-dimethyl-1-amine in dimethyl butan-1-ol example 2 (a), example 2 The title compound was obtained in the same manner as in the above.
　（実施例５５）
Ｎ ２ －［（２Ｓ）－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに（２Ｓ）－３，３－ジメチルブタン－２－アミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 55)
N 2 -[(2S) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-Diamine Using (2S) -3,3-dimethylbutane-2-amine instead of 2,2-dimethylpropan-1-amine in Example 2 (a), the title is the same as in Example 2. Compound was obtained.
　（実施例５６）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －（２－メチルプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに２－メチルプロパン－１－アミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 56)
6 - in (2-methylpropyl) -1,3,5-triazine-2,4-diamine Example 2 (a) - [(3R ) -3- ( methylamino) pyrrolidin-1-yl] -N 2 2-Methylpropane-1-amine was used instead of 2,2-dimethylpropane-1-amine, and the title compound was obtained in the same manner as in Example 2.
　（実施例５７）
Ｎ ２ －（シクロブチルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに１－シクロブチルメタンアミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 57)
N 2- (cyclobutylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine 2 in Example 2 (a) , 2-Cyclobutylmethaneamine was used instead of 2-dimethylpropane-1-amine, and the title compound was obtained in the same manner as in Example 2.
　（実施例５８）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［１－（２，２，２－トリフルオロエチル）ピペリジン－４－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに１－（２，２，２－トリフルオロエチル）ピペリジン－４－アミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 58)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- [1- (2,2,2-trifluoroethyl) piperidine-4-yl] -1,3,5- Triazine-2,4-Diamine In Example 2 (a), 1- (2,2,2-trifluoroethyl) piperidine-4-amine was used instead of 2,2-dimethylpropan-1-amine. The title compound was obtained in the same manner as in 2.
　（実施例５９）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －（２，２，２－トリフルオロエチル）－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに２，２，２－トリフルオロエタン－１－アミン塩酸塩を用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 59)
6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -N 2 - (2,2,2- trifluoroethyl) -1,3,5-triazine-2,4-diamine Example Using 2,2,2-trifluoroethane-1-amine hydrochloride instead of 2,2-dimethylpropan-1-amine in 2 (a), the title compound was obtained in the same manner as in Example 2. It was.
　（実施例６０）
Ｎ ２ －シクロプロピル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりにシクロプロパンアミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 60)
N 2 - cyclopropyl -6 - in [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine Example 2 (a) 2,2- Using cyclopropaneamine instead of dimethylpropane-1-amine, the title compound was obtained in the same manner as in Example 2.
　（実施例６１）
Ｎ ２ －［（２Ｒ）－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２（ａ）における２，２－ジメチルプロパン－１－アミンの代わりに（２Ｒ）－３，３－ジメチルブタン－２－アミンを用い、実施例２と同様の方法にて表題の化合物を得た。 (Example 61)
N 2 -[(2R) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-Diamine Using (2R) -3,3-dimethylbutane-2-amine instead of 2,2-dimethylpropan-1-amine in Example 2 (a), the title is the same as in Example 2. Compound was obtained.
　（実施例６２）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン
（ａ）参考例１０で得られた化合物を１，４－ジオキサン（２．５ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（１２８μＬ）と１－（トリメチルシリル）メタンアミン（６７μＬ）を加えた後、マイクロウェーブ照射下１５０℃で１．５時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した後、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル）で精製して、ｔｅｒｔ－ブチル　４－（４－アミノ－６－｛［（トリメチルシリル）メチル］アミノ｝－１，３，５－トリアジン－２－イル）－１，４－ジアゼパン－１－カルボキシレートを１３８．６ｍｇ得た。
（ｂ）実施例６２（ａ）で得られた化合物（１３６．９ｍｇ）をクロロホルム（１．７ｍＬ）に溶解し、０℃に冷却した後トリフルオロ酢酸（１．７ｍＬ）を加え室温にて１．５時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え中和した後、溶媒を減圧下で留去した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、クロロホルム：メタノール）で精製して、表題の化合物を２８．５ｍｇ得た。 (Example 62)
6- (1,4-Diazepan-1-yl) -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine (a) The compound obtained in Reference Example 10 is 1 , 4-Dioxane (2.5 mL), N, N-diisopropylethylamine (128 μL) and 1- (trimethylsilyl) methaneamine (67 μL) were added, and the mixture was stirred at 150 ° C. for 1.5 hours under microwave irradiation. .. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate) to purify tert-butyl 4- (4-amino-6-{[(trimethylsilyl) methyl]. Amino} -1,3,5-triazine-2-yl) -1,4-diazepan-1-carboxylate was obtained in an amount of 138.6 mg.
(B) The compound (136.9 mg) obtained in Example 62 (a) was dissolved in chloroform (1.7 mL), cooled to 0 ° C., trifluoroacetic acid (1.7 mL) was added, and 1 at room temperature. . Stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for neutralization, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (developing solvent, chloroform: methanol) to obtain 28.5 mg of the title compound.
　（実施例６３）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －（１－メチルシクロペンチル）－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－メチルシクロペンタン－１－アミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 63)
6- (1,4-Diazepan-1-yl) -N 2- (1-methylcyclopentyl) -1,3,5-triazine-2,4-diamine 1- (trimethylsilyl) methaneamine in Example 62 (a) In place of 1-methylcyclopentane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 62.
　（実施例６４）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －（２，２－ジフルオロプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに２，２－ジフルオロプロパン－１－アミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 64)
6- (1,4-Diazepan-1-yl) -N 2- (2,2-difluoropropyl) -1,3,5-triazine-2,4-diamine 1- (trimethylsilyl) in Example 62 (a) ) 2,2-Difluoropropane-1-amine hydrochloride was used instead of methaneamine, and the title compound was obtained in the same manner as in Example 62.
　（実施例６５）
Ｎ ２ －（ビシクロ［１．１．１］ペンタン－１－イル）－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりにビシクロ［１．１．１］ペンタン－１－アミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 65)
N 2- (bicyclo [1.1.1] pentane-1-yl) -6- (1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine Example 62 ( Using bicyclo [1.1.1] pentane-1-amine hydrochloride instead of 1- (trimethylsilyl) methaneamine in a), the title compound was obtained in the same manner as in Example 62.
　（実施例６６）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －（２，２，２－トリフルオロエチル）－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに２，２，２－トリフルオロエタン－１－アミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 66)
6- (1,4-diazepan-1-yl) -N 2 - (2,2,2-trifluoroethyl) -1,3,5-triazine-2,4-diamine Example 62 1 in (a) Using 2,2,2-trifluoroethane-1-amine hydrochloride instead of-(trimethylsilyl) methaneamine, the title compound was obtained in the same manner as in Example 62.
　（実施例６７）
（２Ｓ）－２－｛［４－アミノ－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２－イル］アミノ｝－３，３－ジメチルブタン－１－オール
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに（２Ｓ）－２－アミノ－３，３－ジメタルブタン－１－オールを用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 67)
(2S) -2-{[4-amino-6- (1,4-diazepan-1-yl) -1,3,5-triazine-2-yl] amino} -3,3-dimethylbutane-1- All Using (2S) -2-amino-3,3-dimetalbutane-1-ol instead of 1- (trimethylsilyl) methaneamine in Example 62 (a), the title compound was prepared in the same manner as in Example 62. Obtained.
　（実施例６８）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －［（１－メチルシクロプロピル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－（１－メチルシクロプロピル）メタンアミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 68)
6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine 1- in Example 62 (a) The title compound was obtained in the same manner as in Example 62, using 1- (1-methylcyclopropyl) methaneamine hydrochloride instead of (trimethylsilyl) methaneamine.
　（実施例６９）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －［（１－メチルシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－（１－メチルシクロペンチル）メタンアミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 69)
6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine 1- (1 in Example 62 (a)) The title compound was obtained in the same manner as in Example 62, using 1- (1-methylcyclopentyl) methaneamine hydrochloride instead of trimethylsilyl) methaneamine.
　（実施例７０）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－［１－（トリフルオロメチル）シクロプロピル］メタンアミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 70)
6- (1,4-Diazepan-1-yl) -N 2 -{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2,4-diamine Example 62 (a) 1- [1- (Trifluoromethyl) cyclopropyl] methaneamine hydrochloride was used in place of 1- (trimethylsilyl) methaneamine in ), and the title compound was obtained in the same manner as in Example 62.
　（実施例７１）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －［（３－フルオロフェニル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－（３－フルオロフェニル）メタンアミンを用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 71)
6- (1,4-Diazepan-1-yl) -N 2 -[(3-fluorophenyl) methyl] -1,3,5-triazine-2,4-diamine 1- (1 in Example 62 (a)) Using 1- (3-fluorophenyl) methaneamine instead of trimethylsilyl) methaneamine, the title compound was obtained in the same manner as in Example 62.
　（実施例７２）
２－｛［４－アミノ－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２－イル］アミノ｝－Ｎ－（シクロプロピルメチル）エタン－１－スルホンアミド
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに参考例１１で調製した２－アミノ－Ｎ－（シクロプロピルメチル）エタン－１－スルホンアミドを用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 72)
2-{[4-Amino-6- (1,4-diazepan-1-yl) -1,3,5-triazine-2-yl] amino} -N- (cyclopropylmethyl) ethane-1-sulfonamide In place of 1- (trimethylsilyl) methaneamine in Example 62 (a), 2-amino-N- (cyclopropylmethyl) ethane-1-sulfonamide prepared in Reference Example 11 was used in the same manner as in Example 62. Obtained the title compound.
　（実施例７３）
Ｎ ２ －［１－（アダマンタン－１－イル）エチル］－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－（アダマンタン－１－イル）エタン－１－アミンを用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 73)
N 2- [1- (adamantane-1-yl) ethyl] -6- (1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine In Example 62 (a) The title compound was obtained in the same manner as in Example 62, using 1- (adamantane-1-yl) ethane-1-amine instead of 1- (trimethylsilyl) methaneamine.
　（実施例７４）
６－（１，４－ジアゼパン－１－イル）－Ｎ ２ －［（１－フルオロシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例６２（ａ）における１－（トリメチルシリル）メタンアミンの代わりに１－（１－フルオロシクロペンチル）メタンアミン塩酸塩を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 74)
6- (1,4-Diazepan-1-yl) -N 2 -[(1-fluorocyclopentyl) methyl] -1,3,5-triazine-2,4-diamine 1- (1 in Example 62 (a)) The title compound was obtained in the same manner as in Example 62, using 1- (1-fluorocyclopentyl) methaneamine hydrochloride instead of trimethylsilyl) methaneamine.
　（実施例７５）
４－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ－［（チオフェン－２－イル）メチル］－１，３，５－トリアジン－２－アミン
（ａ）２，４－ジクロロ－１，３，５－トリアジン（２９．７ｍｇ）をＴＨＦ（２ｍＬ）に溶解し－３０℃で冷却した後、ＴＨＦ（１ｍＬ）に溶解させた１－（チオフェン－２－イル）メタンアミン（１９．９μＬ）を加え、－３０℃で１時間撹拌した。反応液に、ＴＨＦ（１ｍＬ）に溶解させたｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメート（４４．５ｍｇ）を加え、室温で終夜撹拌した。溶媒を減圧下で留去し、得られた残渣を酢酸エチルで洗浄し、ｔｅｒｔ－ブチル［（３Ｒ）－１－｛４－［（２，２－ジフルオロプロピル）アミノ］－１，３，５－トリアジン－２－イル｝アゼチジン－３－イル］メチルカーバメートを５３ｍｇ得た。得られた粗生成物は精製することなく、次工程へ用いた。
（ｂ）実施例７５（ａ）における粗生成物（５３ｍｇ）をクロロホルム（１．４ｍＬ）に溶解し、トリフルオロ酢酸（３２１．６μＬ）を加えた後、室温で３０分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去した後、残渣をアミノシリカゲルプレートを用いたプレパラティブＴＬＣ（展開溶媒、クロロホルム：メタノール）で精製して、表題の化合物を５．７ｍｇ得た。 (Example 75)
4- [3- (Methylamino) azetidine-1-yl] -N-[(thiophene-2-yl) methyl] -1,3,5-triazine-2-amine (a) 2,4-dichloro-1 , 3,5-Triazine (29.7 mg) was dissolved in THF (2 mL), cooled at -30 ° C, and then 1- (thiophen-2-yl) methaneamine (19.9 μL) dissolved in THF (1 mL). Was added, and the mixture was stirred at −30 ° C. for 1 hour. To the reaction mixture, tert-butyl azetidine-3-yl (methyl) carbamate (44.5 mg) dissolved in THF (1 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the resulting residue was washed with ethyl acetate and tert-butyl [(3R) -1- {4-[(2,2-difluoropropyl) amino] -1,3,5. -Triazine-2-yl} azetidine-3-yl] Methyl carbamate was obtained in an amount of 53 mg. The obtained crude product was used in the next step without purification.
(B) The crude product (53 mg) in Example 75 (a) was dissolved in chloroform (1.4 mL), trifluoroacetic acid (321.6 μL) was added, and the mixture was stirred at room temperature for 30 minutes. After adding a saturated aqueous sodium hydrogen carbonate solution to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative TLC (developing solvent, chloroform: methanol) using an amino silica gel plate to obtain 5.7 mg of the title compound.
　（実施例７６）
Ｎ－（２，２－ジフルオロプロピル）－４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン
（ａ）２，４－ジクロロ－１，３，５－トリアジン（７５．０ｍｇ）をＴＨＦ（２．５ｍＬ）に溶解し、Ｎ，Ｎ－ジイソプロピルエチルアミン（２５５μＬ）を加えた後０℃に冷却し、２，２－ジフルオロプロパン－１－アミン塩酸塩（６５．８ｍｇ）を加え、室温で２時間撹拌した。反応液に、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメート（１２０．２ｍｇ）を加え、室温で２．５時間撹拌した。溶媒を減圧下で留去し、残留物をシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製して、ｔｅｒｔ－ブチル［（３Ｒ）－１－｛４－［（２，２－ジフルオロプロピル）アミノ］－１，３，５－トリアジン－２－イル｝ピロリジン－３－イル］メチルカーバメートを５１．８ｍｇ得た。
（ｂ）実施例７６（ａ）で得られた化合物をクロロホルム（６９５μＬ）に溶解し、０℃にて冷却した後トリフルオロ酢酸（６９５μＬ）を加え、室温で１時間撹拌した。溶媒を減圧下で留去した後得られた残留物をアミノシリカゲルカラムクロマトグラフィー（展開溶媒、ヘキサン：酢酸エチル→酢酸エチル：メタノール）で精製して、表題の化合物を１２．２ｍｇ得た。 (Example 76)
N- (2,2-difluoropropyl) -4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine (a) 2,4-dichloro -1,3,5-triazine (75.0 mg) is dissolved in THF (2.5 mL), N, N-diisopropylethylamine (255 μL) is added, and then cooled to 0 ° C., 2,2-difluoropropane- 1-Amine hydrochloride (65.8 mg) was added and stirred at room temperature for 2 hours. To the reaction mixture, tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate (120.2 mg) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, hexane: ethyl acetate → ethyl acetate: methanol) to tert-butyl [(3R) -1- {4-[(). 2,2-Difluoropropyl) amino] -1,3,5-triazine-2-yl} pyrrolidine-3-yl] methyl carbamate was obtained in an amount of 51.8 mg.
(B) The compound obtained in Example 76 (a) was dissolved in chloroform (695 μL), cooled at 0 ° C., trifluoroacetic acid (695 μL) was added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the obtained residue was purified by amino silica gel column chromatography (developing solvent, hexane: ethyl acetate → ethyl acetate: methanol) to obtain 12.2 mg of the title compound.
　（実施例７７）
４－（１，４－ジアゼパン－１－イル）－Ｎ－（２，２－ジフルオロプロピル）－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）におけるｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　１，４－ジアゼパン－１－カルボキシレートを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 77)
4- (1,4-Diazepan-1-yl) -N- (2,2-difluoropropyl) -1,3,5-triazine-2-amine tert-butyl methyl [(3R) in Example 76 (a) ) -Pyrrolidine-3-yl] tert-butyl 1,4-diazepan-1-carboxylate was used instead of carbamate to obtain the title compound in the same manner as in Example 76.
　（実施例７８）
Ｎ－（２，２－ジフルオロプロピル）－４－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）におけるｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメートを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 78)
N- (2,2-difluoropropyl) -4- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2-amine tert-butyl methyl in Example 76 (a) [ Using tert-butyl azetidine-3-yl (methyl) carbamate instead of (3R) -pyrrolidin-3-yl] carbamate, the title compound was obtained in the same manner as in Example 76.
　（実施例７９）
Ｎ－ブチル－４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりにブタン－１－アミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 79)
N-Butyl-4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1 in Example 76 (a) Butane-1-amine was used instead of -amine hydrochloride, and the title compound was obtained in the same manner as in Example 76.
　（実施例８０）
Ｎ ２ －（３，３－ジフルオロシクロブチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに３，３－ジフルオロシクロブタン－１－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 80)
N 2- (3,3-difluorocyclobutyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 ( In place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in a), 3,3-difluorocyclobutane-1-amine hydrochloride was used, and the title compound was obtained in the same manner as in Example 29.
　（実施例８１）
Ｎ ２ －［（２，２－ジフルオロシクロプロピル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（２，２－ジフルオロシクロプロピル）メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 81)
N 2 -[(2,2-difluorocyclopropyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine implementation In Example 29 (a), 1- (2,2-difluorocyclopropyl) methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29. Got
　（実施例８２）
Ｎ ２ －（２，２－ジメチルプロピル）－６－（１，２，５－オキサジアゼパン－５－イル）－１，３，５－トリアジン－２，４－ジアミン
　実施例１（ａ）における、ｔｅｒｔ－ブチル（２Ｓ）－２－メチルピペラジン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　１，２，５－オキサジアゼパン－２－カルボキシレートを用い、実施例１と同様の方法にて表題の化合物を得た。 (Example 82)
N 2- (2,2-Dimethylpropyl) -6- (1,2,5-oxadiazepan-5-yl) -1,3,5-triazine-2,4-diamine tert in Example 1 (a) Using tert-butyl 1,2,5-oxadiazepan-2-carboxylate instead of -butyl (2S) -2-methylpiperazin-1-carboxylate, the title compound was obtained in the same manner as in Example 1. It was.
　（実施例８３）
Ｎ ２ －［（３，３－ジフルオロ－１－メチルシクロブチル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（３，３－ジフルオロ－１メチルシクロブチル）メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 83)
N 2 -[(3,3-difluoro-1-methylcyclobutyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-Diamine In Example 29 (a), 1- (3,3-difluoro-1methylcyclobutyl) methaneamine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the same as in Example 29. The title compound was obtained by the method of.
　（実施例８４）
Ｎ ２ －ブチル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２、４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりにブタン－１－アミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 84)
N 2 - butyl - 6 - in [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a), 1- (1 Butane-1-amine was used in place of -methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
　（実施例８５）
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに１－［１－（トリフルオロメチル）シクロプロピル］メタンアミン塩酸塩を用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 85)
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2-amine Examples Using 1- [1- (trifluoromethyl) cyclopropyl] methaneamine hydrochloride instead of 2,2-difluoropropane-1-amine hydrochloride in 76 (a), the title was given in the same manner as in Example 76. The compound was obtained.
　（実施例８６）
Ｎ－（シクロプロピルメチル）－４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに１－シクロプロピルメタンアミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 86)
N- (Cyclopropylmethyl) -4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2,2- in Example 76 (a) Using 1-cyclopropylmethaneamine instead of difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
　（実施例８７）
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（３－メチルブチル）－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに３－メチルブタン－１－アミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 87)
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3-methylbutyl) -1,3,5-triazine-2-amine 2,2- in Example 76 (a) Using 3-methylbutane-1-amine instead of difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
　（実施例８８）
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（２－メチルプロピル）－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに２－メチルプロパン－１－アミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 88)
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (2-methylpropyl) -1,3,5-triazine-2-amine 2,2 in Example 76 (a) Using 2-methylpropane-1-amine instead of -difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
　（実施例８９）
Ｎ－ブチル－４－（ピペラジン－１－イル）－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりにブタン－１－アミンを、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　ピペラジン－１－カルボキシレートを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 89)
N-Butyl-4- (piperazine-1-yl) -1,3,5-triazine-2 -amine Butane-1 instead of 2,2-difluoropropane-1-amine hydrochloride in Example 76 (a) -Amine was tert-butyl piperazine-1-carboxylate instead of tert-butyl methyl [(3R) -pyrrolidine-3-yl] carbamate, and the title compound was obtained in the same manner as in Example 76. ..
　（実施例９０）
Ｎ－ブチル－４－［（３Ｓ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりにブタン－１－アミンを、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　メチル［（３Ｓ）－ピロリジン－３－イル］カーバメートを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 90)
N-Butyl-4-[(3S) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1 in Example 76 (a) Butane-1-amine instead of -amine hydrochloride, tert-butylmethyl [(3S) -pyrrolidin-3-yl] carbamate instead of tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate The compound of the title was obtained in the same manner as in Example 76.
　（実施例９１）
Ｎ－（ブタン－２－イル）－４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりにブタン－２－アミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 91)
N- (Butane-2-yl) -4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine 2, in Example 76 (a) Butane-2-amine was used in place of 2-difluoropropane-1-amine hydrochloride, and the title compound was obtained in the same manner as in Example 76.
　（実施例９２）
Ｎ－ブチル－４－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりにブタン－１－アミンを、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメートを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 92)
N-Butyl-4- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1-amine hydrochloride in Example 76 (a) Butane-1-amine was used instead of tert-butylmethyl [(3R) -pyrrolidin-3-yl] carbamate, and tert-butyl azetidine-3-yl (methyl) carbamate was used in the same manner as in Example 76. The title compound was obtained by the method.
　（実施例９３）
Ｎ ２ －（アダマンタン－１－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりにアダマンタン－１－アミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 93)
N 2- (adamantane-1-yl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a) Adamantane-1-amine was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in the above, and the title compound was obtained in the same manner as in Example 29.
　（実施例９４）
Ｎ ２ －（ヘキサヒドロ－２，５－メタノペンタレン－３ａ（１Ｈ）－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりにヘキサヒドロ－２，５－メタノペンタレン－３ａ（１Ｈ）－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 94)
N 2- (Hexahydro-2,5-methanopentalene-3a (1H) -yl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine- In Example 29 (a) of 2,4-diamine , hexahydro-2,5-methanopentalene-3a (1H) -amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride. The title compound was obtained in the same manner as in 29.
　（実施例９５）
Ｎ ２ －｛［［１，１’－ビ（シクロプロパン）］－１－イル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－［［１，１’－ビ（シクロプロパン）］－１－イル］メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 95)
N 2 -{[[1,1'-bi (cyclopropane)] -1-yl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5 -Triazine-2,4-diamine In Example 29 (a), 1-[[1,1'-bi (cyclopropane)] -1-yl] instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride] Using methaneamine hydrochloride, the title compound was obtained in the same manner as in Example 29.
　（実施例９６）
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－［（２Ｓ）－２－メチルブチル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに（２Ｓ）－２－メチルブタン－１－アミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 96)
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine In Example 76 (a). Using (2S) -2-methylbutane-1-amine instead of 2,2-difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
　（実施例９７）
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに参考例１２にて合成した化合物を用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 97)
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2- Amine The compound synthesized in Reference Example 12 was used in place of 2,2-difluoropropane-1-amine hydrochloride in Example 76 (a), and the title compound was obtained in the same manner as in Example 76.
　（実施例９８）
４－（１，４－ジアゼパン－１－イル）－Ｎ－［（２Ｓ）－２－メチルブチル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに（２Ｓ）－２－メチルブタン－１－アミンを、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりにｔｅｒｔ－ブチル　１，４－ジアゼパン－１－カルボキシレートを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 98)
4- (1,4-Diazepan-1-yl) -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine 2,2-difluoropropane in Example 76 (a) Instead of -1-amine hydrochloride, (2S) -2-methylbutane-1-amine, tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate, tert-butyl 1,4-diazepan- The title compound was obtained in the same manner as in Example 76 using 1-carboxylate.
　（実施例９９）
Ｎ ２ －｛［１－（ジフルオロメチル）シクロプロピル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに参考例１３で合成された化合物を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 99)
N 2 -{[1- (difluoromethyl) cyclopropyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine The compound synthesized in Reference Example 13 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in Example 29 (a), and the title compound was obtained in the same manner as in Example 29.
　（実施例１００）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －（４，４，４－トリフルオロブチル）－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに４，４，４－トリフルオロブタン－１－アミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 100)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (4,4,5-trifluorobutyl) -1,3,5-triazine-2,4-diamine Example Using 4,4,4-trifluorobutane-1-amine instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in 29 (a), the title compound was obtained in the same manner as in Example 29. It was.
　（実施例１０１）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －（３，３，３－トリフルオロプロピル）－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに３，３，３－トリフルオロプロパン－１－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 101)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoropropyl) -1,3,5-triazine-2,4-diamine Examples In 29 (a), 3,3,3-trifluoropropane-1-amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was used in the same manner as in Example 29. Got
　（実施例１０２）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（１－メチルシクロプロピル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（１－メチルシクロプロピル）メタンアミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 102)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine Example 29 The title compound was obtained in the same manner as in Example 29 by using 1- (1-methylcyclopropyl) methaneamine hydrochloride instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride in (a).
　（実施例１０３）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１－（トリメチルシリル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 103)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine In Example 29 (a). , 1- (Trimethylsilyl) methaneamine was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
　（実施例１０４）
Ｎ ２ －（２－シクロプロピルエチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに２－シクロプロピルエタン－１－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 104)
N 2 - (2-cyclopropylethyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a) 2-Cyclopropylethane-1-amine hydrochloride was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in the above, and the title compound was obtained in the same manner as in Example 29.
　（実施例１０５）
４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに１－（トリメチルシリル）メタンアミンを用い、実施例７６と同様の方法にて表題の化合物を得た。 (Example 105)
4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(trimethylsilyl) methyl] -1,3,5-triazine-2-amine 2,2 in Example 76 (a) Using 1- (trimethylsilyl) methaneamine instead of -difluoropropane-1-amine hydrochloride, the title compound was obtained in the same manner as in Example 76.
　（実施例１０６）
４－（４－エチルピペラジン－１－イル）－Ｎ－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２－アミン
　実施例７６（ａ）における２，２－ジフルオロプロパン－１－アミン塩酸塩の代わりに１－（トリメチルシリル）メタンアミンを、ｔｅｒｔ－ブチル　メチル［（３Ｒ）－ピロリジン－３－イル］カーバメートの代わりに１－エチルピペラジンを用い、実施例７６（ａ）と同様の方法にて表題の化合物を得た。 (Example 106)
4- (4-Ethylpiperazin-1-yl) -N-[(trimethylsilyl) methyl] -1,3,5-triazine-2-amine 2,2-difluoropropane-1-amine in Example 76 (a) Using 1- (trimethylsilyl) methaneamine instead of the hydrochloride and 1-ethylpiperazine instead of tert-butyl methyl [(3R) -pyrrolidin-3-yl] carbamate, in the same manner as in Example 76 (a). Obtained the title compound.
　（実施例１０７）
Ｎ ２ －［ビス（トリメチルシリル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに１，１－ビス（トリメチルシリル）メタンアミンを用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 107)
N 2- [bis (trimethylsilyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a) In place of 1- (1-methylcyclopentyl) methaneamine hydrochloride, 1,1-bis (trimethylsilyl) methaneamine was used in the above, and the title compound was obtained in the same manner as in Example 29.
　（実施例１０８）
Ｎ ２ －（３，３－ジフルオロシクロペンチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに３，３－ジフルオロシクロペンタン－１－アミン塩酸塩を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 108)
N 2- (3,3-difluorocyclopentyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine Example 29 (a) ), 3,3-Difluorocyclopentane-1-amine hydrochloride was used instead of 1- (1-methylcyclopentyl) methaneamine hydrochloride, and the title compound was obtained in the same manner as in Example 29.
　（実施例１０９）
Ｎ ２ －（３，３－ジフルオロシクロペンチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミンの光学異性体
　実施例１０８にて得られた化合物（１０．４ｍｇ）をエタノール（１ｍＬ）に溶解し、分取ＨＰＬＣ（カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ　２ｃｍ×２５ｃｍ、展開溶媒：０．１％ジエチルアミンのｎ－ヘキサン溶液／エタノール＝８５／１５、流速：１９．８ｍＬ／ｍｉｎ、注入量：９００μＬ、室温）に付し、ｉｓｏｍｅｒ　Ａ（実施例１０９－１）（保持時間の短い異性体）を２．８ｍｇ及びｉｓｏｍｅｒ　Ｂ（実施例１０９－２）（保持時間の長い異性体）を３．４ｍｇ得た。 (Example 109)
N 2 - (3,3-difluoro-cyclopentyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-enantiomer exemplary diamine The compound (10.4 mg) obtained in Example 108 was dissolved in ethanol (1 mL), and preparative HPLC (column: CHIRALPAK IC 2 cm × 25 cm, developing solvent: n-hexane solution of 0.1% diethylamine / ethanol = 85/15, flow velocity: 19.8 mL / min, injection volume: 900 μL, room temperature), isomer A (Example 109-1) (isomer with short retention time) 2.8 mg and isomer B (Example). 109-2) (an isomer with a long retention time) was obtained in an amount of 3.4 mg.
　（実施例１１０）
６－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ ２ －［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　（ａ）参考例１０におけるｔｅｒｔ－ブチル　１，４－ジアゼパン－１－カルボキシレートの代わりにｔｅｒｔ－ブチル　アゼチジン－３－イル（メチル）カーバメートを用い、参考例１０と同様の方法にてｔｅｒｔ－ブチル［１－（４－アミノ－６－クロロ－１，３，５－トリアジン－２－イル）アゼチジン－３－イル］メチルカーバメートを４１．２ｍｇ得た。
（ｂ）実施例６２（ａ）におけるｔｅｒｔ－ブチル　４－（４－アミノ－６－クロロ－１，３，５－トリアジン－２－イル）－１，４－ジアゼパン－１－カルボキシレートの代わりに実施例１１０（ａ）で得られた化合物を用い、実施例６２と同様の方法にて表題の化合物を得た。 (Example 110)
6- [3- (Methylamino) azetidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine (a) tert-butyl 1 in Reference Example 10 , 4-Diazepan-1-carboxylate instead of tert-butyl azetidine-3-yl (methyl) carbamate, tert-butyl [1- (4-amino-6-chloro) in the same manner as in Reference Example 10. -1,3,5-triazin-2-yl) azetidine-3-yl] Methylcarbamate was obtained in an amount of 41.2 mg.
(B) Instead of tert-butyl 4- (4-amino-6-chloro-1,3,5-triazine-2-yl) -1,4-diazepan-1-carboxylate in Example 62 (a) Using the compound obtained in Example 110 (a), the title compound was obtained in the same manner as in Example 62.
　（実施例１１１）
６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ ２ －［（１－メチルシロラン－１－イル）メチル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに参考例１４で合成された化合物を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 111)
6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylsiloran-1-yl) methyl] -1,3,5-triazine-2,4-diamine The compound synthesized in Reference Example 14 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in Example 29 (a), and the title compound was obtained in the same manner as in Example 29.
　（実施例１１２）
Ｎ ２ －｛［シクロプロピル（ジメチル）シリル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
　実施例２９（ａ）における、１－（１－メチルシクロペンチル）メタンアミン塩酸塩の代わりに参考例１５で合成された化合物を用い、実施例２９と同様の方法にて表題の化合物を得た。 (Example 112)
Examples of N 2 -{[cyclopropyl (dimethyl) silyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine The compound synthesized in Reference Example 15 was used in place of 1- (1-methylcyclopentyl) methaneamine hydrochloride in 29 (a), and the title compound was obtained in the same manner as in Example 29.
　上記実施例にて製造した化合物を下記表に示す。また下記表に、各化合物の１Ｈ－ＮＭＲ及びＥＳＩ－ＭＳによる分析結果を示す。 The compounds produced in the above examples are shown in the table below. The table below shows the analysis results of each compound by 1 H-NMR and ESI-MS.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
　（試験例　Ｈ４受容体親和性評価）
　ヒトヒスタミンＨ４受容体遺伝子組み換えＨＥＫ（ヒト胎児腎細胞）で得られた膜タンパク質、放射標識リガンド２０ｎＭ［３Ｈ］ヒスタミン（パーキンエルマー社）、及びＤＭＳＯに溶解した被験化合物を、９６ウェルプレート上、５０ｍＭ　トリス－塩酸、ｐＨ７．４、５．０ｍＭ　ＥＤＴＡ－２Ｎａを含む緩衝溶液中で、常温にて６０分間反応させた後、０．５％ポリエチレンイミンで前処理したＧＦ／Ｃフィルター（パーキンエルマー社）で濾過した。５０ｍＭ　トリス－塩酸、ｐＨ７．４緩衝溶液で５回洗浄し、５０℃にて２時間以上乾燥後、ＧＦ／Ｃフィルターにシンチレーションカクテル（ＭｉｃｒｏＳｃｉｎｔ２０：パーキンエルマー社）を添加し、９６ウェル用液体シンチレーションカウンター（ＴｏｐＣｏｕｎｔ：パーキンエルマー社）で各ウェルの放射活性を測定した。非特異的結合は５．０μＭヒスタミン存在下で評価した。阻害定数Ｋｉは、Ｃｈｅｎｇ　ａｎｄ　Ｐｒｕｓｏｆｆの式に従って、各試験から得られた５０％阻害濃度（ＩＣ５０値）とＳｃａｔｃｈａｒｄプロットで得られた放射性リガンド解離定数（Ｋｄ値）より算出した。上記方法により算出した、前記被験化合物におけるヒスタミンＨ４受容体の阻害定数Ｋｉ値によってＨ４受容体親和性を評価し、阻害定数Ｋｉ値が１０００ｎＭ以上～５０００ｎＭ未満のものをＡ、１００ｎＭ以上～１０００ｎＭ未満のものをＢ、１００ｎＭ未満のものをＣとした。阻害定数Ｋｉ値が５０００ｎＭ未満であればＨ４受容体に対する親和性を有することを示す。被験化合物として、上記の各実施例で得られた化合物を用いたときの評価結果を下記表に示す。 (Test Example H4 receptor affinity evaluation)
Membrane protein obtained from human histamine H4 receptor recombinant HEK (human fetal kidney cell), radiolabeled ligand 20 nM [ 3 H] histamine (PerkinElmer), and test compound dissolved in DMSO were placed on a 96-well plate. A GF / C filter (PerkinElmer) pretreated with 0.5% polyethyleneimine after reacting at room temperature for 60 minutes in a buffer solution containing 50 mM Tris-hydrochloric acid, pH 7.4, 5.0 mM EDTA-2Na. ) Was filtered. Wash 5 times with 50 mM Tris-hydrochloric acid and pH 7.4 buffer solution, dry at 50 ° C. for 2 hours or more, add scintillation cocktail (MicroScan20: PerkinElmer) to the GF / C filter, and liquid scintillation counter for 96 wells. (TopCount: PerkinElmer) measured the radioactivity of each well. Non-specific binding was evaluated in the presence of 5.0 μM histamine. The inhibition constant Ki was calculated from the 50% inhibition concentration (IC50 value) obtained from each test and the radioligand dissociation constant (Kd value) obtained by Scatchard plot according to the formula of Change and Prussoff. The H4 receptor affinity is evaluated based on the histamine H4 receptor inhibition constant Ki value calculated by the above method, and the inhibition constant Ki value of 1000 nM or more and less than 5000 nM is A, and the inhibitory constant Ki value is 100 nM or more and less than 1000 nM. The one was designated as B, and the one less than 100 nM was designated as C. If the inhibition constant Ki value is less than 5000 nM, it indicates that it has an affinity for the H4 receptor. The following table shows the evaluation results when the compounds obtained in each of the above examples were used as the test compounds.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　以上説明したように、本発明によれば、優れたヒスタミンＨ４受容体調節作用を有する新規化合物及びその薬理学的に許容される塩、並びに、これらを含有する医薬組成物を提供することが可能となる。 As described above, according to the present invention, it is possible to provide a novel compound having an excellent histamine H4 receptor regulating action, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing these. It becomes.

Claims (10)

  1. 　下記式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ［式（１）中、
    　Ｒ１及びＲ２は、これらが結合している窒素原子と共に、窒素原子、酸素原子、及び硫黄原子から選択される１個又は複数のヘテロ原子をさらに含有してもよい４員～９員の非芳香族含窒素複素環式基を形成し、ここで、前記複素環式基は、単環式、縮合二環式、架橋二環式、若しくはスピロ二環式であり、前記複素環式基は、フッ素原子、水酸基、－Ｎ（Ｒ５）Ｒ６、Ｃ１～６アルキル基、及びＣ１～６アミノアルキル基から選択される１個又は複数の置換基で置換されていてもよく、ただし、前記複素環式基は、少なくとも２個の窒素原子を含有する複素環式基であるか、又は、１個の窒素原子を含有しかつ少なくとも１個の窒素原子を含有する基で置換された複素環式であり、
    　　Ｒ５及びＲ６は、それぞれ独立に、水素原子及びＣ１～６アルキル基から選択されるか、又は、Ｒ５及びＲ６は、これらが結合している窒素原子と共に、４員～６員の非芳香族含窒素複素環式基を形成しており、
    　Ｒ３は、１個又は複数のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基、１個又は複数のハロゲン原子で置換されていてもよいフェニル基、フッ素原子、水酸基、ＣＦ３、ＯＣＨ３、Ｓｉ（ＣＨ３）３、シクロプロピル（ジメチル）シリル基、１－メチルシロラン－１－イル基、－Ｓ（Ｏ）２Ｒ７、－Ｓ（Ｏ）２Ｎ（Ｈ）Ｒ８、５員～６員の芳香族複素環式基、４員～６員の非芳香族複素環式基、５員～７員の架橋二環式基、及び９員～１０員の架橋三環式基から選択される１個又は複数の置換基で置換されていてもよいＣ１～６アルキル基；ハロゲン原子、メチル基、ＣＦ３、ＣＨ２ＯＨ、ＣＨ２Ｆ、ＣＨＦ２、及びシクロプロピル基から選択される１個又は複数の置換基で置換されていてもよいＣ３～７シクロアルキル基；１個又は複数のハロゲン原子で置換されていてもよいフェニル基；５員～６員の芳香族複素環式基；４員～６員の非芳香族複素環式基；５員～７員の架橋二環式基；又は９員～１０員の架橋三環式基であり、
    　　Ｒ７及びＲ８は、それぞれ独立に、アルキル基であり、
    　Ｒ４は、アミノ基又は水素原子である。］
    で表される化合物又はその薬理学的に許容される塩。     The following formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [In equation (1),
    R 1 and R 2 may further contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms, as well as the nitrogen atoms to which they are bonded. A non-aromatic nitrogen-containing heterocyclic group is formed, wherein the heterocyclic group is a monocyclic group, a fused bicyclic group, a crosslinked bicyclic group, or a spirobicyclic group, and the heterocyclic group is formed. May be substituted with one or more substituents selected from fluorine atoms, hydroxyl groups, —N (R 5) R 6 , C 1-6 alkyl groups, and C 1-6 aminoalkyl groups. However, the heterocyclic group is a heterocyclic group containing at least two nitrogen atoms, or is substituted with a group containing one nitrogen atom and containing at least one nitrogen atom. Heterocyclic
    R 5 and R 6 are independently selected from hydrogen atoms and C 1-6 alkyl groups, respectively, or R 5 and R 6 are 4- to 6-membered with the nitrogen atom to which they are attached. Forming a non-aromatic nitrogen-containing heterocyclic group of
    R 3 is one or more of good C 3 ~ 7 cycloalkyl group optionally substituted with a halogen atom, one or more optionally substituted phenyl group with a halogen atom, a fluorine atom, a hydroxyl group, CF 3 , OCH 3 , Si (CH 3 ) 3 , cyclopropyl (dimethyl) silyl group, 1-methylsiloran-1-yl group, -S (O) 2 R 7 , -S (O) 2 N (H) R 8 , 5- to 6-membered aromatic heterocyclic group, 4- to 6-membered non-aromatic heterocyclic group, 5- to 7-membered bridged bicyclic group, and 9 to 10-membered bridged tricyclic group C 1-6 alkyl groups optionally substituted with one or more substituents selected from the groups; halogen atoms, methyl groups, CF 3 , CH 2 OH, CH 2 F, CHF 2 , and cyclopropyl groups. one or more of which may be substituted with a substituent C 3 - 7 cycloalkyl group selected from; one or more phenyl group which may be substituted by a halogen atom; 5-membered to 6-membered aromatic Group heterocyclic groups; 4- to 6-membered non-aromatic heterocyclic groups; 5- to 7-membered crosslinked bicyclic groups; or 9 to 10-membered crosslinked tricyclic groups.
    R 7 and R 8 are independently alkyl groups, respectively.
    R 4 is an amino group or a hydrogen atom. ]
    A compound represented by or a pharmacologically acceptable salt thereof.
  2. 　前記式（１）中、Ｒ１及びＲ２が、これらが結合している窒素原子と共に、４員～７員の単環式の非芳香族含窒素複素環式基を形成するか、又は、７員～９員の縮合二環式の非芳香族含窒素複素環式基を形成する、
    請求項１に記載の化合物又はその薬理学的に許容される塩。     In the formula (1), R 1 and R 2 form a 4- to 7-membered monocyclic non-aromatic nitrogen-containing heterocyclic group together with the nitrogen atom to which they are bonded, or. Forming 7-9 member condensed bicyclic non-aromatic nitrogen-containing heterocyclic groups,
    The compound according to claim 1 or a pharmacologically acceptable salt thereof.
  3. 　前記４員～７員の単環式の非芳香族含窒素複素環式基が、ピロリジン、アゼチジン、ピペラジン、又はジアゼパンである、
    請求項２に記載の化合物又はその薬理学的に許容される塩。     The 4- to 7-membered monocyclic non-aromatic nitrogen-containing heterocyclic group is pyrrolidine, azetidine, piperazine, or diazepan.
    The compound according to claim 2 or a pharmacologically acceptable salt thereof.
  4. 　前記式（１）中、Ｒ３が、１個又は複数のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基、フッ素原子、水酸基、ＣＦ３、及びＳｉ（ＣＨ３）３から選択される１個又は複数の置換基で置換されていてもよいＣ１～６アルキル基；１個又は複数のハロゲン原子で置換されていてもよいＣ３～７シクロアルキル基；５員～６員の芳香族複素環式基；５員～７員の架橋二環式基；又は９員～１０員の架橋三環式基である、
    請求項１～３のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩。     In the above formula (1), R 3 is selected from C 3 to 7 cycloalkyl groups, which may be substituted with one or more halogen atoms, a fluorine atom, a hydroxyl group, CF 3 , and Si (CH 3 ) 3. one or more of which may be substituted with a substituent C 1 - 6 alkyl groups is, one or more of which may be substituted with halogen atoms C 3 - 7 cycloalkyl group; a 5- to 6-membered Aromatic heterocyclic group; 5- to 7-membered crosslinked bicyclic group; or 9 to 10-membered crosslinked tricyclic group.
    The compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof.
  5. 　前記式（１）で表される化合物が、
    Ｎ２－（２，２－ジメチルプロピル）－６－［（３Ｓ）－３－メチルピペラジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－（ピペラジン－１－イル）－１，３，５－トリアジン－２，４－ジアミン、
    ６－（３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル）－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（１Ｓ，５Ｓ）－３，６－ジアザビシクロ［３．２．０］ヘプタン－３－イル］－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－［３－メチル－３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－（４－メチル－１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－アミノピロリジン－１－イル］－Ｎ２－（２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－（オクタヒドロ－６Ｈ－ピロロ［３，４－ｂ］ピリジン－６－イル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－［３－（ピロリジン－１－イル）アゼチジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－｛（３Ｒ）－３－［（２Ｈ３）－メチルアミノ］ピロリジン－１－イル｝－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２，２－ジメチルプロピル）－６－［４－（メチルアミノ）アゼパン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ｛１－［（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）メチル］シクロペンチル｝メタノール、
    Ｎ２－（２，２－ジフルオロプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシクロヘキシル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（２－フルオロ－２－メチルプロピル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［１－（トリフルオロメチル）シクロペンチル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－｛［１－（トリフルオロメチル）シクロペンチル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－｛［１－（フルオロメチル）シクロプロピル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－｛［１－（トリフルオロメチル）シクロブチル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（シクロプロピルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（ビシクロ［２．２．１］ヘプタン－２－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－シクロペンチル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（シクロペンチルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    （２Ｓ）－２－（｛４－アミノ－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－イル｝アミノ）－３，３－ジメチルブタン－１－オール、
    Ｎ２－［（２Ｓ）－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－（２－メチルプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（シクロブチルメチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－（２，２，２－トリフルオロエチル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－シクロプロピル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－［（２Ｒ）－３，３－ジメチルブタン－２－イル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－（１－メチルシクロペンチル）－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－（２，２－ジフルオロプロピル）－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－（ビシクロ［１．１．１］ペンタン－１－イル）－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２，４－ジアミン、
    （２Ｓ）－２－｛［４－アミノ－６－（１，４－ジアゼパン－１－イル）－１，３，５－トリアジン－２－イル］アミノ｝－３，３－ジメチルブタン－１－オール、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（１－メチルシクロプロピル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（１－メチルシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２，４－ジアミン、
    ６－（１，４－ジアゼパン－１－イル）－Ｎ２－［（１－フルオロシクロペンチル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ－ブチル－４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２－アミン、
    Ｎ２－（３，３－ジフルオロシクロブチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－［（２，２－ジフルオロシクロプロピル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－［（３，３－ジフルオロ－１－メチルシクロブチル）メチル］－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－ブチル－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２、４－ジアミン、
    ４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－１，３，５－トリアジン－２－アミン、
    ４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（２－メチルプロピル）－１，３，５－トリアジン－２－アミン、
    Ｎ－ブチル－４－［３－（メチルアミノ）アゼチジン－１－イル］－１，３，５－トリアジン－２－アミン、
    Ｎ２－（ヘキサヒドロ－２，５－メタノペンタレン－３ａ（１Ｈ）－イル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    Ｎ２－｛［［１，１’－ビ（シクロプロパン）］－１－イル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン
    、
    ４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－［（２Ｓ）－２－メチルブチル］－１，３，５－トリアジン－２－アミン、
    ４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－（３，３，３－トリフルオロ－２，２－ジメチルプロピル）－１，３，５－トリアジン－２－アミン、
    ４－（１，４－ジアゼパン－１－イル）－Ｎ－［（２Ｓ）－２－メチルブチル］－１，３，５－トリアジン－２－アミン、
    Ｎ２－｛［１－（ジフルオロメチル）シクロプロピル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシクロプロピル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ４－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２－アミン、
    Ｎ２－（３，３－ジフルオロシクロペンチル）－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［３－（メチルアミノ）アゼチジン－１－イル］－Ｎ２－［（トリメチルシリル）メチル］－１，３，５－トリアジン－２，４－ジアミン、
    ６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－Ｎ２－［（１－メチルシロラン－１－イル）メチル］－１，３，５－トリアジン－２，４－ジアミン、又は
    Ｎ２－｛［シクロプロピル（ジメチル）シリル］メチル｝－６－［（３Ｒ）－３－（メチルアミノ）ピロリジン－１－イル］－１，３，５－トリアジン－２，４－ジアミンである、請求項１に記載の化合物又はその薬理学的に許容される塩。     The compound represented by the formula (1) is
    N 2 - (2,2-dimethylpropyl) -6 - [(3S) -3- methylpiperazin-l-yl] -1,3,5-triazine-2,4-diamine,
    N 2- (2,2-dimethylpropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2- (2,2-dimethylpropyl) -6- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine,
    N 2- (2,2-dimethylpropyl) -6- (piperazine-1-yl) -1,3,5-triazine-2,4-diamine,
    6- (3,6-diazabicyclo [3.2.0] heptan-3-yl) -N 2 - (2,2-dimethylpropyl) -1,3,5-triazine-2,4-diamine,
    6-[(1S, 5S) -3,6-diazabicyclo [3.2.0] heptane-3-yl] -N 2- (2,2-dimethylpropyl) -1,3,5-triazine-2, 4-diamine,
    N 2- (2,2-dimethylpropyl) -6- [3-methyl-3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2- (2,2-dimethylpropyl) -6- (4-methyl-1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine,
    6 - [(3R) -3- amino-1-yl] -N 2 - (2,2- dimethylpropyl) -1,3,5-triazine-2,4-diamine,
    N 2 - (2,2-dimethylpropyl) -6- (octahydro -6H- pyrrolo [3,4-b] pyridin-6-yl) -1,3,5-triazine-2,4-diamine,
    N 2- (2,2-dimethylpropyl) -6- [3- (pyrrolidin-1-yl) azetidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2 - (2,2-dimethylpropyl) -6 - {(3R) -3 - [(2 H 3) - methylamino] pyrrolidin-1-yl} -1,3,5-triazine-2,4 Diamine,
    N 2- (2,2-dimethylpropyl) -6- [4- (methylamino) azepan-1-yl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine,
    {1-[({4-Amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) methyl] cyclopentyl} methanol,
    N 2- (2,2-difluoropropyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2,4- Diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclohexyl) methyl] -1,3,5-triazine-2,4-diamine,
    N 2 - (2-fluoro-2-methylpropyl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- [1- (trifluoromethyl) cyclopentyl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclopentyl] methyl} -1,3,5-triazine-2,4-diamine ,
    N 2 -{[1- (fluoromethyl) cyclopropyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine ,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2 , 4-Diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -{[1- (trifluoromethyl) cyclobutyl] methyl} -1,3,5-triazine-2,4-diamine ,
    N 2- (cyclopropylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2 - (bicyclo [2.2.1] heptan-2-yl) -6 - [(3R) -3- ( methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4 -Diamine,
    N 2 -cyclopentyl-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2- (cyclopentyl methyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    (2S) -2-({4-amino-6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-yl} amino) -3,3 -Dimethylbutane-1-ol,
    N 2 -[(2S) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-diamine,
    6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -N 2 - (2- methylpropyl) -1,3,5-triazine-2,4-diamine,
    N 2- (cyclobutylmethyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2- (2,2,2-trifluoroethyl) -1,3,5-triazine-2,4-diamine,
    N 2 - cyclopropyl -6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2 -[(2R) -3,3-dimethylbutane-2-yl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2- (1-methylcyclopentyl) -1,3,5-triazine-2,4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2- (2,2-difluoropropyl) -1,3,5-triazine-2,4-diamine,
    N 2- (bicyclo [1.1.1] pentane-1-yl) -6- (1,4-diazepan-1-yl) -1,3,5-triazine-2,4-diamine,
    (2S) -2-{[4-amino-6- (1,4-diazepan-1-yl) -1,3,5-triazine-2-yl] amino} -3,3-dimethylbutane-1- All,
    6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2 -[(1-methylcyclopentyl) methyl] -1,3,5-triazine-2,4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2 -{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2,4-diamine,
    6- (1,4-Diazepan-1-yl) -N 2 -[(1-fluorocyclopentyl) methyl] -1,3,5-triazine-2,4-diamine,
    N-Butyl-4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2-amine,
    N 2- (3,3-difluorocyclobutyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2 -[(2,2-difluorocyclopropyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    N 2 -[(3,3-difluoro-1-methylcyclobutyl) methyl] -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2, 4-diamine,
    N 2 - butyl -6 - [(3R) -3- (methylamino) pyrrolidin-1-yl] -1,3,5-triazine-2,4-diamine,
    4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-{[1- (trifluoromethyl) cyclopropyl] methyl} -1,3,5-triazine-2-amine,
    4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (2-methylpropyl) -1,3,5-triazine-2-amine,
    N-Butyl-4- [3- (methylamino) azetidine-1-yl] -1,3,5-triazine-2-amine,
    N 2- (Hexahydro-2,5-methanopentalene-3a (1H) -yl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine- 2,4-diamine,
    N 2 -{[[1,1'-bi (cyclopropane)] -1-yl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5 -Triazine-2,4-diamine,
    4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine,
    4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N- (3,3,3-trifluoro-2,2-dimethylpropyl) -1,3,5-triazine-2- Amine,
    4- (1,4-Diazepan-1-yl) -N-[(2S) -2-methylbutyl] -1,3,5-triazine-2-amine,
    N 2 -{[1- (difluoromethyl) cyclopropyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine ,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylcyclopropyl) methyl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine,
    4-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N-[(trimethylsilyl) methyl] -1,3,5-triazine-2-amine,
    N 2- (3,3-difluorocyclopentyl) -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine,
    6- [3- (methylamino) azetidine-1-yl] -N 2 -[(trimethylsilyl) methyl] -1,3,5-triazine-2,4-diamine,
    6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -N 2 -[(1-methylsiloran-1-yl) methyl] -1,3,5-triazine-2,4-diamine, Or with N 2 -{[cyclopropyl (dimethyl) silyl] methyl} -6-[(3R) -3- (methylamino) pyrrolidine-1-yl] -1,3,5-triazine-2,4-diamine A compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  6. 　請求項１～５のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を含有する医薬組成物。 A pharmaceutical composition containing at least one selected from the compound according to any one of claims 1 to 5 and a pharmacologically acceptable salt thereof.
  7. 　ヒスタミンＨ４受容体調節用組成物である、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, which is a composition for regulating histamine H4 receptors.
  8. 　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の組成物である、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, which is a composition for treating and / or preventing a disease or condition in which the histamine H4 receptor is involved.
  9. 　請求項１～５のうちのいずれか一項に記載の化合物及びその薬理学的に許容される塩から選択される少なくとも１種を対象に投与する工程を含む、ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防の方法。 A disease involving a histamine H4 receptor, which comprises the step of administering to a subject at least one selected from the compound according to any one of claims 1 to 5 and a pharmacologically acceptable salt thereof. Or a method of treating and / or preventing the condition.
  10. 　ヒスタミンＨ４受容体が関与する疾患若しくは状態の治療及び／又は予防用の医薬組成物の製造のための、請求項１～５のうちのいずれか一項に記載の化合物又はその薬理学的に許容される塩の使用。 The compound according to any one of claims 1 to 5 or pharmacologically acceptable thereof for the production of a pharmaceutical composition for the treatment and / or prevention of a disease or condition involving the histamine H4 receptor. Use of salt to be done.
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