WO2014017569A1 - Pharmaceutical product for lowering blood ldl - Google Patents

Pharmaceutical product for lowering blood ldl Download PDF

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Publication number
WO2014017569A1
WO2014017569A1 PCT/JP2013/070128 JP2013070128W WO2014017569A1 WO 2014017569 A1 WO2014017569 A1 WO 2014017569A1 JP 2013070128 W JP2013070128 W JP 2013070128W WO 2014017569 A1 WO2014017569 A1 WO 2014017569A1
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amino
methyl
ethyl
trifluoromethyl
ethoxy
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PCT/JP2013/070128
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French (fr)
Japanese (ja)
Inventor
忠明 扇谷
浩市 山▲崎▼
健之介 松田
敏明 渡部
崇司 前島
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興和株式会社
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Priority to JP2014526986A priority Critical patent/JPWO2014017569A1/en
Publication of WO2014017569A1 publication Critical patent/WO2014017569A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
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    • 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

Definitions

  • the present invention includes a pyrimidine compound having a proprotein convertase subtilisin / kexin type 9 (PCSK9: Proprotein convertase subtilisin / kexin 9) mRNA expression inhibitory activity as an active ingredient, and can reduce blood LDL. It relates to medicine.
  • PCSK9 Proprotein convertase subtilisin / kexin type 9
  • LDL low density lipoprotein
  • statins HMG-CoA reductase inhibitors
  • statins strongly lower LDL cholesterol, but heart accidents due to cardiovascular diseases and the reduction in mortality are only about 30%. It is thought that the risk of death from cardiovascular disease can be further reduced by further reducing LDL cholesterol, but statins have the problem that high doses cannot be administered due to the increased risk of rhabdomyolysis Yes. Therefore, there is a demand for the development of a drug having a mechanism of action different from that of statins and having a stronger action mechanism of LDL cholesterol when used in combination with statins.
  • PCs proprotein convertases
  • PCSK9 Protein convertase subtilisin / kexin type 9
  • LDL receptor LDL receptor on the surface of the liver cell membrane. And promotes the intracellular translocation of the LDL receptor. LDL receptors that have migrated into cells undergo degradation in intracellular organs.
  • Non-patent Document 2 Since the LDL receptor has a function of transporting lipoproteins containing cholesterol from the circulating blood to the liver, the expression of the PCSK9 protein inhibits the uptake of LDL cholesterol into the liver, resulting in blood LDL cholesterol. To raise. Actually, the blood LDL cholesterol level of a human having a loss-of-function mutation in the PCSK9 gene is kept low (Non-patent Document 2). On the other hand, a gain-of-function mutation has been reported for the PCSK9 gene, and the human LDL cholesterol level in humans having this mutation is high, and is known to be associated with autosomal dominant hypercholesterolemia (non-native). Patent Document 3). Moreover, it has been shown that LDL cholesterol in mice lacking PCSK9 in the liver is low at the animal level (Non-patent Document 4).
  • Non-Patent Documents 5 to 7 As a low molecular weight compound, berberine reports that PCSK9 mRNA and protein levels in HepG2 cells are reduced (Non-patent Document 8), and annexin A2 activator 5-azacytidine is a PCSK9 protein and annexin.
  • Patent Document 1 There is a report that promotes the binding of A2 and suppresses the degradation of the LDL receptor (Patent Document 1).
  • PCSK9 protein function inhibitors or PCSK9 protein production inhibitors of low molecular weight compounds are hardly reported in addition to those described above.
  • Patent Documents 2 to 5 disclose pyrimidine compounds having a dibenzylamine structure that exhibit strong inhibitory activity against cholesterol ester transfer protein (CETP) and have a strong blood HDL cholesterol increasing action. It is taught that a drug containing as an active ingredient is useful for the prevention and / or treatment of hyper-LDLemia, but this teaching increases HDL by inhibiting CETP, In other words, hyper-DLLemia can be prevented and / or treated by relatively increasing the HDL level, and does not teach that it has an action of directly reducing LDL.
  • CETP cholesterol ester transfer protein
  • Non-patent Document 9 PCs are attracting attention as targets for cancer treatment because they affect the growth, movement, adhesion, and invasion of cancer cells.
  • PCs are also involved in obesity, diabetes, arteriosclerosis, Alzheimer's disease, and diseases such as acquired immune deficiency syndrome (AIDS) and severe acute respiratory syndrome (SARS). Is known (Non-Patent Documents 10 and 11). Therefore, a compound having a PCSK9 protein level-reducing action or a function-inhibiting action can be expected to be used as an active ingredient of a medicine for the above diseases.
  • AIDS acquired immune deficiency syndrome
  • SARS severe acute respiratory syndrome
  • An object of the present invention is to provide a medicament capable of reducing blood LDL by containing, as an active ingredient, a low molecular weight compound having an action of suppressing the expression of PCSK9 mRNA, reducing the amount of PCSK9 protein, and increasing the amount of LDL receptor. It is to provide.
  • R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkylthio C 1-6 alkoxy group, a C 1-6 alkylsulfinyl C 1-6 alkoxy group, a C 1-6 alkylsulfonyl C 1 A -6 alkoxy group, an optionally substituted C 6-10 aryl C 1-6 alkoxy group, a hydroxyl group, a C 1-6 alkylamino group, a di C 1-6 alkylamino group, a C 1-6 alkylthio C 1-6 alkylamino group, C 1-6 alkylsulfinyl C 1-6 alkylamino group, C 1-6 alkylsulfonyl C 1-6 alkylamino group, C 6-10 arylamino group, hetero atoms in the ring
  • An optionally substituted amino C 1-6 alkyl group, an optionally substituted carbamoyl C 1-6 alkyl group, a C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl C 1 Represents a -6 alkyl group, a C 6-10 aryl group, an optionally substituted C 6-10 aryl C 1-6 alkyl group, or a C 3-8 cycloalkyl group, or R 2 and R 3 may form a cyclic amino group which may have a substituent together with the adjacent nitrogen atom or may have a hetero atom in the ring constituent atom, R is a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, an amino C 1-6 alkyl group which may have a substituent, or a substituent.
  • a medicament for reducing LDL in blood which comprises the compound represented by the general formula (I), a salt thereof, or a solvate thereof as an active ingredient.
  • the medicament and the pharmaceutical composition reduce blood LDL cholesterol, thereby causing diseases caused by high blood LDL cholesterol (for example, hyper LDL dysfunction, dyslipidemia (hyperlipidemia), arteriosclerosis, Atherosclerosis, peripheral vascular disease, hypercholesterolemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic re It can be used as a medicament for the prevention and / or treatment of stenosis, hypertension, etc.
  • the present invention relates to a compound represented by the above general formula (I) or a salt thereof for producing a medicament for the prevention and / or treatment of a disease caused by a high blood LDL cholesterol state, or a salt thereof, Use of a solvate; providing a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for use in the prevention and / or treatment of a disease caused by high blood LDL cholesterol status To do.
  • a PCSK9 production inhibitor containing a salt thereof or a solvate thereof as an active ingredient is provided.
  • Use of the compound represented by the above general formula (I), or a salt thereof, or a solvate thereof for the production of a PCSK9 mRNA expression inhibitor; represented by the above general formula (I) for use in suppressing PCSK9 mRNA expression Or a salt thereof, or a solvate thereof is also provided by the present invention.
  • the present invention provides a PCSK9 protein amount reducing agent comprising the compound represented by the general formula (I) or a salt thereof, or a solvate thereof as an active ingredient; represented by the general formula (I) PCSK9 protein production inhibitor comprising a compound, or a salt thereof, or a solvate thereof as an active ingredient; and a compound represented by the general formula (I), or a salt thereof, or a solvate thereof as an active ingredient
  • the present invention provides an agent for increasing the amount of LDL receptor.
  • the present invention provides a compound represented by the above general formula (I) for producing a PCSK9 protein amount reducing agent, a PCSK9 protein production inhibitor or an LDL receptor amount increasing agent, or a salt thereof, or their Use of a solvate; and a compound represented by the above general formula (I) or a salt thereof, or a solvate thereof for use in reducing PCSK9 protein amount, inhibiting PCSK9 protein production, or increasing LDL receptor amount Is to provide.
  • the present invention relates to a disease associated with PCs (cancer, obesity, diabetes, Alzheimer's disease, or the like, comprising the compound represented by the above general formula (I), a salt thereof, or a solvate thereof as an active ingredient.
  • the present invention provides a medicament for the prevention and / or treatment of viral infections and the like.
  • the present invention relates to the use of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for the manufacture of a medicament for the prevention and / or treatment of diseases involving PCs.
  • the present invention provides an HMG-CoA reductase mRNA expression inhibitor comprising as an active ingredient the compound represented by the general formula (I), or a salt thereof, or a solvate thereof; HMG-CoA reductase production inhibitor comprising a compound represented by formula (I), or a salt thereof, or a solvate thereof as an active ingredient; and a compound represented by general formula (I), or a compound thereof Diseases caused by expression of HMG-CoA reductase mRNA containing a salt of glycerin or a solvate thereof as an active ingredient (eg inflammation, cancer, Alzheimer's disease, osteoporosis, prostatic hypertrophy, glomerular disease, parasitic infection, viral infection , Psoriasis, macular degeneration, and the like).
  • HMG-CoA reductase mRNA expression inhibitor comprising as an active ingredient the compound represented by the general formula (I), or a salt thereof, or a solvate thereof
  • the present invention also provides an HMG-CoA reductase mRNA expression inhibitor, an HMG-CoA reductase production inhibitor, or a medicament for the prevention and / or treatment of diseases caused by HMG-CoA reductase mRNA expression.
  • the present invention also relates to a method for suppressing the expression of PCSK9 mRNA in vivo in mammals including humans, wherein the compound represented by the general formula (I), a salt thereof, or an effective solvate thereof is used.
  • a method comprising a step of administering an amount to a mammal including a human; a method for reducing the amount of PCSK9 protein in a living body of a mammal including a human, the compound represented by the general formula (I), or a method thereof
  • a method comprising a step of administering an effective amount of a salt or a solvate thereof to a mammal including a human; a method for suppressing the production of PCSK9 protein in a living body of a mammal including a human, wherein the general formula
  • a method comprising administering an effective amount of a compound represented by (I) or a salt thereof, or a solvate thereof to a mammal including a human;
  • the present invention also relates to a method for preventing and / or treating a disease caused by high blood LDL cholesterol status in mammals including humans, the compound represented by the general formula (I), or a salt thereof, or The present invention provides a method comprising the step of administering an effective amount of these solvates to mammals including humans.
  • the present invention is a method for preventing and / or treating diseases (cancer, obesity, diabetes, Alzheimer's disease, viral infection, etc.) involving PCs in mammals including humans, wherein the general formula (I) And a salt thereof, or a solvate thereof, is administered to mammals including humans.
  • diseases cancer, obesity, diabetes, Alzheimer's disease, viral infection, etc.
  • the present invention provides a method for suppressing the expression of HMG-CoA reductase mRNA in the living body of mammals including humans, comprising the compound represented by the general formula (I), or a salt thereof, A method comprising the step of administering an effective amount of a solvate of the above to a mammal including a human; a method of suppressing the production of HMG-CoA reductase in a living body of a mammal including a human, wherein the general formula ( A method comprising administering an effective amount of a compound represented by I) or a salt thereof, or a solvate thereof to a mammal including a human; and HMG-CoA reductase in a mammal including a human; Diseases resulting from mRNA expression (eg inflammation, cancer, Alzheimer's disease, osteoporosis, enlarged prostate, glomerular disease, parasitic infection, viral infection, psoriasis, macular degeneration, etc.) A method for preventing
  • the compound represented by the general formula (I) of the present invention exhibits a strong expression inhibitory action on PCSK9 mRNA, as specifically disclosed in Examples described later. Since it shows suppression of PCSK9 protein production, it can be preferably used as an active ingredient of a prophylactic and / or therapeutic agent for diseases based on PCSK9 protein production, and particularly preferably used as an active ingredient of a medicine that lowers blood LDL. Can do.
  • C 1-6 alkyl group halo C 1-6 alkyl group, C 3-8 cycloalkyl C 1-6 alkyl group, C 6-10 aryl C 1-6 alkyl group, carboxy C 1-6 alkyl group in the present invention as the C 1-6 alkyl group in C 1-6 alkoxycarbonyl C 1-6 alkyl group, straight chain or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n- propyl group Isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group and the like.
  • the C 2-6 alkenyl group includes a straight or branched alkenyl group having 2 to 6 carbon atoms having a carbon-carbon double bond at any one or more positions on the alkyl chain, such as vinyl.
  • C 1-6 alkoxy group halo C 1-6 alkoxy group, C 1-6 alkylthio C 1-6 alkoxy group, C 1-6 alkylsulfinyl C 1-6 alkoxy group, C 1-6 alkylsulfonyl C in the present invention 1-6 alkoxy group, C 6-10 aryl C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkylamino group, hydroxy C 1-6 alkoxy group Carboxy C 1-6 alkoxy group, amino C 1-6 alkoxy group, C 1-6 alkylamino C 1-6 alkoxy group, di-C 1-6 alkylamino C 1-6 alkoxy group, C 1-6 alkoxycarbonyl C 1-6 alkoxy group, phenylthio C 1-6 alkoxy group, phenylsulfinyl C 1-6 alkoxy group, phenyl sulfoni Le C 1-6 alkoxy group, the
  • C 1-6 alkylthio group in the present invention C 1-6 alkylthio C 1-6 alkoxy group, the C 1-6 alkylthio group in the C 1-6 alkylthio-C 1-6 alkylamino group, a straight-chain or branched-chain C1-C6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, n-pentylthio, 2-methylbutylthio Group, 2,2-dimethylpropylthio group and the like.
  • the C 1-6 alkylsulfinyl group, the C 1-6 alkylsulfinyl C 1-6 alkoxy group, the C 1-6 alkylsulfinyl C 1-6 alkylamino group, the C 1-6 alkylsulfinyl group includes Chain or branched alkyl sulfinyl group having 1 to 6 carbon atoms, for example, methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, t-butylsulfinyl group N-pentylsulfinyl group, 2-methylbutylsulfinyl group, 2,2-dimethylpropylsulfinyl group and the like.
  • C 1-6 alkylsulfonyl group C 1-6 alkylsulfonyl C 1-6 alkoxy group, a C 1-6 alkylsulfonyl group in C 1-6 alkylsulfonyl-C 1-6 alkylamino group, a straight Chain or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, t-butylsulfonyl group N-pentylsulfonyl group, 2-methylbutylsulfonyl group, 2,2-dimethylpropylsulfonyl group and the like.
  • a linear or branched alkylcarbonyl group having 1 to 6 carbon atoms such as a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group
  • Examples thereof include n-butylcarbonyl group, isobutylcarbonyl group, t-butylcarbonyl group, n-pentylcarbonyl group, 2-methylbutylcarbonyl group, 2,2-dimethylpropylcarbonyl group and the like.
  • C 1-6 alkoxycarbonyl group C 1-6 alkoxy
  • C 1-6 alkoxycarbonyl group straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms
  • Examples include a carbonyl group and a 2,2-dimethylpropoxycarbonyl group.
  • the C 1-6 acylamino group is a linear or branched acylamino group having 1 to 6 carbon atoms, such as formylamino group, acetylamino group, n-propionylamino group, isopropionylamino group, butyrylamino. Group, isobutyrylamino group, t-butyrylamino group, n-pentanoylamino group, 2-methylbutyrylamino group, 2,2-dimethylpropionylamino group and the like.
  • a C 1-6 alkylamino group a C 1-6 alkylthio C 1-6 alkylamino group, a C 1-6 alkylsulfinyl C 1-6 alkylamino group, a C 1-6 alkylsulfonyl C 1-6 alkyl amino group, C 1-6 alkoxy-C 1-6 alkylamino group, hydroxy-C 1-6 alkylamino group, the C 1-6 alkylamino group in C 1-6 alkylamino C 1-6 alkoxy group, a straight-chain Or a branched alkylamino group having 1 to 6 carbon atoms, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, t-butylamino group, Examples thereof include an n-pentylamino group, a 2-methylbutyl
  • di-C 1-6 alkylamino group a di C 1-6 alkylamino group in di-C 1-6 alkylamino C 1-6 alkoxy group, the carbon number of the same or different straight-chain or branched-chain
  • C 1-6 alkylsulfonylamino group the C 1-6 alkylsulfonylamino group in halo C 1-6 alkylsulfonylamino group, a linear or branched alkylsulfonylamino group having 1 to 6 carbon atoms
  • a C 3-8 cycloalkyl group C 3-8
  • the C 3-8 cycloalkyl group in the cycloalkyl C 1-6 alkyl group, a cycloalkyl group of cyclic 3 carbon atoms to 8, for example, cyclo A propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned.
  • a C 6-10 aryl group a C 6-10 aryl C 1-6 alkyl group, a C 6-10 aryl C 1-6 alkoxy group, a C 6-10 arylamino group, a C 6-10 arylsulfonylamino
  • Examples of the C 6-10 aryl group in the group include aryl groups having 6 to 10 carbon atoms, such as a phenyl group and a naphthyl group.
  • examples of the halogen atom in the halogen atom, halo C 1-6 alkyl group, and halo C 1-6 alkoxy group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are preferably a C 1-6 alkyl group, preferably a methyl group or an ethyl group.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11, the R 12, and R 13 is more preferably a methyl group.
  • halo C 1-6 alkyl group in 15 is, for example, C 1 substituted with a chemically possible number of halogen atoms such as trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group and the like. -6 alkyl group and the like can be mentioned, and a trifluoromethyl group is preferable.
  • Examples of the C 1-6 alkoxy group include a C 1-6 alkoxy substituted with a chemically possible number of halogen atoms such as a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a pentafluoroethoxy group, and the like. Group, and a trifluoromethoxy group is preferable.
  • R 4 in the general formulas (i), (ii), and (iii), in R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 , R 14 , and R 15
  • substituent in the amino group that may have a substituent include a C 1-6 alkyl group, a halo C 1-6 alkyl group, and a C 6-10 aryl group.
  • the amino group which may have a substituent may be the same or different and may have one or two substituents.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, a carboxyl group Or a C 1-6 alkoxycarbonyl group, and R 10 , R 11 , R 12 , and R 13 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C A 1-6 alkyl group, a C 1-6 alkoxy group, wherein R 14 and R 15 are the same or different and each represents a
  • examples of the C 1-6 alkylthio C 1-6 alkoxy group in R 1 include a methylthiomethoxy group, a 2-methylthioethoxy group, a 3-methylthiopropoxy group, and the like. Groups are preferred.
  • examples of the C 1-6 alkylsulfinyl C 1-6 alkoxy group in R 1 include a methylsulfinylmethoxy group, a 2-methylsulfinylethoxy group, and a 3-methylsulfinylpropoxy group.
  • a 2-methylsulfinylethoxy group is preferred.
  • examples of the C 1-6 alkylsulfonyl C 1-6 alkoxy group in R 1 include a methylsulfonylmethoxy group, a 2-methylsulfonylethoxy group, a 3-methylsulfonylpropoxy group, and the like.
  • a 2-methylsulfonylethoxy group is preferred.
  • examples of the substituent in the C 6-10 aryl C 1-6 alkoxy group which may have a substituent in R 1 include a halogen atom, a C 1-6 alkyl group, and halo C 1. Examples include a -6 alkyl group and a cyano group.
  • substitution position of these substituents is not particularly limited, in the present invention, substitution on the aryl ring of a C 6-10 aryl C 1-6 alkoxy group is preferable.
  • Examples of such a group include a phenyl C 1-6 alkoxy group which may have a halogen atom, a halo C 1-6 alkyl group, or a cyano group as a substituent on the phenyl group, such as 3-cyano-5- Examples thereof include a trifluoromethylbenzyloxy group and a 2,3-difluorobenzyloxy group.
  • examples of the cyclic amino group which may have a hetero atom in the ring constituent atom in R 1 include a pyrrolidinyl group, a morpholinyl group, a piperidinyl group and the like, and a morpholino group and a piperidino group are preferable. .
  • examples of the C 1-6 alkoxycarbonyl C 1-6 alkoxy group in R 1 include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, a methoxycarbonylethoxy group, an ethoxycarbonylethoxy group, and a methoxycarbonylpropoxy group.
  • Group, ethoxycarbonylpropoxy group and the like, and ethoxycarbonylpropoxy group is preferable.
  • examples of the carboxy C 1-6 alkoxy group in R 1 include a carboxymethoxy group, a carboxyethoxy group, a carboxypropoxy group, and the like, and a carboxypropoxy group is preferable.
  • examples of the phenylthio C 1-6 alkoxy group in R 1 include a phenylthiomethoxy group, a phenylthioethoxy group, a phenylthiopropoxy group, and the like, and a phenylthioethoxy group is preferable.
  • examples of the phenylsulfinyl C 1-6 alkoxy group represented by R 1 include a phenylsulfinylmethoxy group, a phenylsulfinylethoxy group, and a phenylsulfinylpropoxy group, and a phenylsulfinylethoxy group is preferable.
  • examples of the phenylsulfonyl C 1-6 alkoxy group in R 1 include a phenylsulfonylmethoxy group, a phenylsulfonylethoxy group, a phenylsulfonylpropoxy group, and the like, and a phenylsulfonylethoxy group is preferable.
  • examples of the phenoxy C 1-6 alkoxy group in R 1 include a phenoxymethoxy group, a phenoxyethoxy group, a phenoxypropoxy group, and the like, and a phenoxyethoxy group is preferable.
  • examples of the carboxy C 1-6 alkyl group in R, R 2 , and R 3 include a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, and the like.
  • R is a carboxymethyl group
  • R 2 and R 3 are more preferably a carboxyethyl group.
  • the C 1-6 alkoxycarbonyl C 1-6 alkyl group in R, R 2 , and R 3 includes a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, and isopropoxycarbonylmethyl.
  • a methyl group and a methoxycarbonylethyl group are preferable.
  • a methoxycarbonylmethyl group is more preferable
  • R 2 and R 3 a methoxycarbonylethyl group is more preferable.
  • examples of the C 2-6 alkenyl group in R 2 and R 3 include a vinyl group, an allyl group, a 3-buten-1-yl group, and the like, and an allyl group is preferable.
  • examples of the substituent in the C 3-8 cycloalkyl C 1-6 alkyl group which may have a substituent in R 2 and R 3 include a C 1-6 alkyl group, halo Examples thereof include a C 1-6 alkyl group, a carboxy group, a C 1-6 alkoxycarbonyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group and the like. Further, substitution positions of these substituents are not particularly limited, in the present invention, preferably substituted on C 3-8 cycloalkyl group a C 3-8 cycloalkyl C 1-6 alkyl group.
  • Such groups cycloalkyl carboxy as a substituent on the C 1-6 alkyl group or C 1-6 alkoxycarbonyl C 1-6 which may have an alkyl group C 3-8 cycloalkyl C 1-
  • Examples include 6 alkyl groups such as 4-carboxymethylcyclohexylmethyl group, 4-methoxycarbonylmethylcyclohexylmethyl group, 4-ethoxycarbonylmethylcyclohexylmethyl group, 4-isopropoxycarbonylmethylcyclohexylmethyl group and the like.
  • Examples of the C 3-8 cycloalkyl C 1-6 alkyl group include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and the like.
  • R a cyclopropylmethyl group is preferable.
  • examples of the substituent in the C 6-10 aryl C 1-6 alkyl group which may have a substituent in R 2 and R 3 include a halogen atom and a C 1-6 alkyl group.
  • substitution position of these substituents is not particularly limited, in the present invention, substitution on the aryl ring of a C 6-10 aryl C 1-6 alkyl group is preferable. Examples of such a group include a phenyl C 1-6 alkyl group which may have a C 1-6 alkoxy group as a substituent on the phenyl group, such as a 4-methoxybenzyl group.
  • a substituent in a cyclic amino group which may have a substituent together with the adjacent nitrogen atom in R 2 and R 3 or may have a hetero atom in the ring constituent atom
  • examples include a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, or a cyano group.
  • substitution position of these substituents is not specifically limited, In this invention, it is preferable to substitute on the carbon atom of a nitrogen-containing saturated heterocyclic ring.
  • Examples of such a group include a nitrogen-containing saturated heterocyclic group which may have a C 1-6 alkyl group as a substituent on the nitrogen-containing saturated heterocyclic ring, such as 4-methylpiperidino group, 2,6-dimethylmorpholine. Nyl group is mentioned.
  • the ring-constituting atoms may have at least one nitrogen atom, and may further have a plurality of heteroatoms such as nitrogen atom, oxygen atom, sulfur atom and the like. Examples of such monocyclic heterocycles include: Etc.
  • bicyclic heterocycle having 6 to 10 ring atoms and at least one of the ring atoms being a nitrogen atom may have at least one unsaturated bond
  • Bicyclic heterocycles having an aromaticity and bicyclic heterocycles not having aromaticity are included, but at least one of the two condensed rings is preferably an aromatic ring.
  • the ring-constituting atoms may have at least one nitrogen atom, and may further have a plurality of heteroatoms such as nitrogen atom, oxygen atom, sulfur atom and the like. Examples of such bicyclic heterocycles include: Etc.
  • R 14 and R 15 The above bonding position is not particularly limited, but for example, (In this case, R 14 and R 15 are the same as above, but R 14 and R 15 are the same or different and are each preferably a hydrogen atom or a C 1-6 alkyl group. 14 is a hydrogen atom or a C 1-6 alkyl group, and R 15 is more preferably a C 1-6 alkyl group). (In this case, R 14 and R 15 are the same as described above, but R 14 and R 15 are the same or different and are preferably a hydrogen atom, a hydroxyl group, or a C 1-6 alkoxy group.
  • R 14 is preferably a hydroxyl group or a C 1-6 alkoxy group, and R 15 is more preferably a hydrogen atom).
  • R 14 and R 15 are the same as described above, but R 14 and R 15 are preferably hydrogen atoms).
  • R 14 and R 15 are the same as above, but R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group.
  • R 14 is a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group
  • R 15 is More preferably a hydrogen atom).
  • R 14 and R 15 are the same as described above, but R 14 and R 15 are preferably C 1-6 alkyl groups).
  • R 4 , R 5 , R 6 , R 7 , and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group.
  • R 9 is a hydrogen atom, or a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group
  • R 2, and R 3 are the same or different, a hydrogen atom, C 1-6 alkyl group, a carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl groups, C 2-6 alkenyl group, a carboxy C 1-6 alkyl group, or a C 1-6 alkoxycarbonyl C 1-6 alkyl group which may have a C 3-8 cycloalkyl C 1-6 alkyl group as a substituent on the cycloalkyl group, or showing a C 1-6 optionally C 6-10 aryl C 1-6 alkyl group which may have
  • R 14 , and R 15 are the same or different, a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl group, C 1-6 alkoxy group, or a hydroxyl group, But It is preferable that In formula (I), Represents the formula (ii) R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and each is a hydrogen atom or a haloC 1-6 alkyl group, R 9 is a hydrogen atom or a C 1-6 alkyl group, R 2, and R 3 are the same or different, a hydrogen atom, C 1-6 alkyl group, C 2-6 alkenyl group, a carboxy C 1-6 alkyl group as a substituent on the cycloalkyl group, or C 1 -6 alkoxycarbonyl C 1-6 alkyl group a C 3-8 cycloalkyl C 1-6 alkyl group which may have a, which may have a C 1-6
  • R 4 , R 5 , R 6 , R 7 , and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group.
  • R 9 is a hydrogen atom or a C 1-6 alkyl group
  • R 2, and R 3 are the same or different, a hydrogen atom, C 1-6 alkyl group, a carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl groups, C 2-6 alkenyl group, a carboxy C 1-6 alkyl group, or a C 1-6 alkoxycarbonyl C 1-6 alkyl group which may have a C 3-8 cycloalkyl C 1-6 alkyl group as a substituent on the cycloalkyl group, or showing a C 1-6 optionally C 6-10 aryl C 1-6 alkyl group which may have an alkoxy group as a substituent on the aryl ring, or R 2, and the nitrogen atom to which R 3 is adjacent together Together with a pyrrolidino group, R 1 is
  • R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkoxy group, or a hydroxyl group).
  • R 14 and R 15 are hydrogen atoms
  • R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group
  • R 14 and R 15 are C 1-6 alkyl groups.
  • Examples of the salt of the compound represented by the general formula (I) include acid addition salts and base addition salts, and are not particularly limited as long as they are pharmaceutically acceptable salts.
  • acid addition salts acid addition salts with mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, methanesulfonate Acid addition salts with organic acids such as ethane sulfonate, ethane disulfonate, benzene sulfonate, p-toluene sulfonate, maleate, fumarate, tartrate, citrate, acetate Can be mentioned.
  • a base addition salt a base addition salt with a metal such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt; amine salt such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine; lysine, arginine And base addition salts with organic bases such as histidine.
  • a metal such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt
  • amine salt such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine
  • lysine, arginine base addition salts with organic bases such as histidine.
  • Examples of the solvent constituting the solvate of the compound represented by the general formula (I) or a salt thereof include, for example, water and physiologically acceptable organic solvents such as ethanol, hexane, and ethyl acetate. However, it is not limited to these.
  • the compounds represented by the above general formula (I) of the present invention include all compounds that are metabolized in vivo and converted into the compounds represented by the above general formula (I) of the present invention, so-called prodrugs. Is included.
  • prodrugs As a group that forms a prodrug of the compound of the present invention, “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161, Examples include the groups described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, pp. 163-198.
  • the compound represented by the above general formula (I), or a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited.
  • the manufacturing method is not limited to this.
  • functional groups other than the reaction site may be protected in advance if necessary, and may be deprotected at an appropriate stage.
  • the reaction may be carried out by a commonly performed method, and isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, chromatography and the like.
  • R is In which R 9 is a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group, (WO2008 / 111604 pamphlet, WO2008 / 129951 pamphlet, Japan published patent publication 2010-077116) and the like.
  • R is R 9 represents a hydrogen atom, and But, Can be produced by a method described in a known patent document (WO 2008/018529 pamphlet) or the like.
  • R is R 9 represents a hydrogen atom
  • Compound (Ia) is a leaving group W represented by general formula (IV) to an amine compound represented by general formula (III), which can be produced by the method described in the pamphlet of International Publication No. 2008/129951. It can be produced by reacting a compound having 1 with a base.
  • This reaction path is represented by the chemical reaction formula as follows. (Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 are the same as those in the general formula (I). And W 1 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an arylsulfonyloxy group.)
  • the reaction of the amine compound represented by the general formula (III) and the compound (IV) having a leaving group W 1 can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited, and for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used alone or in combination as a base.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metals such as metal lithium, metal sodium and metal potassium
  • lithium hydroxide sodium hydroxide
  • Alkali metal hydroxides such as potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate
  • lithium diisopropylamide sodium diisopropylamide
  • potassium diisopropylamide lithium hexamethyldisi Zido
  • sodium hexamethyldisilazide potassium hexamethyldisilazide
  • t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium n-butyl lithium, s-butyl lithium, t- Butyl lithium or the like can be used.
  • R is Compound (Ib) in which R 9 represents a hydrogen atom
  • R 9 represents a hydrogen atom
  • It can be produced by reacting a compound having the leaving group W 2 represented by the general formula (V) with a benzylaminopyrimidine derivative represented by the general formula (VI) with a base.
  • This reaction path is represented by the chemical reaction formula as follows. (Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and Is synonymous with that in the general formula (I), and W 2 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an arylsulfonyloxy group. )
  • the reaction of the compound (V) having a leaving group W 2 and the benzylaminopyrimidine derivative (VI) can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metals such as lithium metal, sodium metal and potassium
  • lithium hydroxide sodium hydroxide and potassium hydroxide.
  • Alkali metal hydroxides lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
  • the benzylaminopyrimidine derivative (VI) is produced by reacting a pyrimidine-2-amine derivative represented by the general formula (VII) with a compound having a leaving group W 1 represented by the general formula (IV) with a base. can do.
  • the benzylaminopyrimidine derivative (VI) is produced by reacting the pyrimidine-2-amine derivative represented by the general formula (VII) with the aldehyde derivative represented by the general formula (VIII) using a reductive amination method. can do.
  • This reaction path is represented by the chemical reaction formula as follows. (Wherein R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 have the same meanings as those in the general formula (I), and W 1 represents a halogen atom, an alkylsulfonyloxy group, a haloalkyl. Represents a sulfonyloxy group or an arylsulfonyloxy group.)
  • the reaction of the pyrimidine-2-amine (VII) derivative and the compound (IV) having a leaving group W 1 can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metals such as lithium metal, sodium metal and potassium
  • lithium hydroxide sodium hydroxide and potassium hydroxide.
  • Alkali metal hydroxides lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
  • the reaction of the pyrimidine-2-amine (VII) derivative and the aldehyde derivative (VIII) can be carried out in a solvent using a reducing reagent in the presence or absence of an acid.
  • the dehydration operation may be performed using a Dean-Stark apparatus or the like.
  • the solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination.
  • Lewis acids such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. .
  • a reducing reagent for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride,
  • borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used.
  • a hydrogen source for catalytic reduction for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.
  • R has a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, and a substituent.
  • Compound (Ic) which may be an amino C 1-6 alkyl group, a carbamoyl C 1-6 alkyl group which may have a substituent, or a C 3-8 cycloalkyl C 1-6 alkyl group is disclosed in known patents.
  • An amine compound represented by the general formula (IX) that can be produced by a method described in literatures (International Publication No. 2008/111604, Pamphlet of International Publication No. 2008/129951) is represented by General Formula (X). It can be produced by reacting a compound having a leaving group W 3 with a base.
  • This reaction path is represented by the chemical reaction formula as follows. (Wherein R 1 , R 2 , R 3 , and Is as defined in the general formula (I), W 3 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or a C 6-10 arylsulfonyloxy group, and R 16 represents a C 1-6 alkyl.
  • the reaction of the amine compound represented by the general formula (IX) and the compound (X) having a leaving group W 3 can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited, and for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used alone or in combination as a base.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metals such as metal lithium, metal sodium and metal potassium
  • lithium hydroxide sodium hydroxide
  • Alkali metal hydroxides such as potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate
  • lithium diisopropylamide sodium diisopropylamide
  • potassium diisopropylamide lithium hexamethyldisi Zido
  • sodium hexamethyldisilazide potassium hexamethyldisilazide
  • t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium n-butyl lithium, s-butyl lithium, t- Butyl lithium or the like can be used.
  • R has a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, and a substituent.
  • Compound (Ic) showing an optionally amino C 1-6 alkyl group, an optionally substituted carbamoyl C 1-6 alkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group is known.
  • This reaction path is represented by the chemical reaction formula as follows.
  • W 2 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an arylsulfonyloxy group
  • R 16 represents a C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, optionally substituted amino C 1-6 alkyl group, optionally substituted carbamoyl C 1-6 alkyl group Or a C 3-8 cycloalkyl C 1-6 alkyl group.
  • the reaction of the compound (V) having a leaving group and the alkylaminopyrimidine derivative (XI) can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metals such as lithium metal, sodium metal and potassium
  • lithium hydroxide sodium hydroxide and potassium hydroxide.
  • Alkali metal hydroxides lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
  • the alkylaminopyrimidine derivative (XI) is produced by reacting a pyrimidine-2-amine derivative represented by the general formula (VII) with a compound having a leaving group W 3 represented by the general formula (X) with a base. can do.
  • the alkylaminopyrimidine derivative (XI) is a reductive reaction of the pyrimidine-2-amine derivative represented by the general formula (VII) to the aldehyde derivative represented by the general formula (XII) or the ketone derivative represented by the general formula (XIII). It can manufacture by making it react using the method of amination.
  • R 1 have the same meanings as those explained for the general formula (I)
  • W 3 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or a C 6-10 arylsulfonyloxy group
  • R 16 Has a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, an amino C 1-6 alkyl group which may have a substituent, and a substituent
  • R 17 represents an atomic group in which R 17 —CH 2 — represents R 16
  • R 18 and R 19 represent (R 18 ) (R 19 ) CH— represents an atomic group in which R 16 is represented.
  • the reaction of the pyrimidine-2-amine (VII) derivative and the compound (X) having a leaving group can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metals such as lithium metal, sodium metal and potassium
  • lithium hydroxide sodium hydroxide and potassium hydroxide.
  • Alkali metal hydroxides lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
  • the reaction between the pyrimidine-2-amine (VII) derivative and the aldehyde derivative (XII) or ketone derivative (XIII) can be carried out in a solvent using a reducing reagent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like.
  • the solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination.
  • Lewis acids such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. .
  • a reducing reagent for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride,
  • borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used.
  • a hydrogen source for catalytic reduction for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.
  • various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers.
  • a racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography.
  • a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography.
  • the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • the active ingredient itself may be administered as the medicament of the present invention, but it can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art.
  • the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
  • the pharmaceutical composition suitable for parenteral administration includes Examples include injections such as intravenous injections and intramuscular injections, drops, suppositories, inhalants, eye drops, nasal drops, transdermal absorbents, transmucosal absorbents, etc. It is not limited to.
  • the above pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives.
  • pharmacologically and pharmaceutically acceptable additives include, for example, excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, Examples include, but are not limited to, flavoring agents, fragrances, coating agents, and diluents.
  • the dosage of the pharmaceutical agent of the present invention is not particularly limited, and can be appropriately selected according to the type of disease, the purpose of prevention or treatment, the type of active ingredient, etc., and the patient's weight and age, symptoms, administration route, etc. It can be increased or decreased as appropriate according to various factors that should be normally considered.
  • the weight of active ingredient per day for an adult can be used in the range of about 0.1 mg to 500 mg, but the dosage can be appropriately selected by those skilled in the art and is limited to the above range. None happen.
  • Example 7 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl ⁇ -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 11 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl ⁇ -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 13 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl ⁇ -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 16 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl ⁇ -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 21 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl ⁇ -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 22 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl ⁇ -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 25 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl ⁇ -5- [2- (methylthio) ) Ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 26 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl ⁇ -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 30 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 31 [1-( ⁇ 2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) ethyl] Production of -5- (trifluoromethyl) benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 32 3- [1-( ⁇ 2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) ethyl ] -5- (Trifluoromethyl) benzonitrile production: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 35 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine- 2-Amine production: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 36 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylsulfonyl) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine -2- Production of amines: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 37 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine- 2-Amine production: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 38 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylsulfonyl) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine -2- Production of amines: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 42 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 43 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino ) Preparation of methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 44 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino ) Preparation of methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetic acid: It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
  • Example 45 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfinyl) ethoxy] pyrimidine- 2-Il ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetic acid: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ obtained by the method described in the pamphlet of International Publication No.
  • Example 48 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ Preparation of amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate: It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
  • Example 49 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4 Preparation of-(trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetic acid: It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
  • Step 1 Preparation of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde
  • 2-Fluoro-5- (trifluoromethyl) benzaldehyde (500 mg, 2.60 mmol) in dimethyl sulfoxide-water (2: 1 mixed solution) , 15 mL) solution was added diallylamine (319 mg, 3.28 mmol) and sodium carbonate (828 mg, 7.81 mmol), and the mixture was stirred at 100 ° C. for 2 hours.
  • diallylamine 158 mg, 1.63 mmol
  • the reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene.
  • Step 2 Preparation of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (diallyl obtained in Step 1 Amino) -5- (trifluoromethyl) benzaldehyde (200 mg, 0.74 mmol) and 5- [2- (methylthio) ethoxy synthesized by the method of Example 1 described in the patent literature (WO 2008/129951 pamphlet) Acetic acid (45 mg, 0.75 mmol) was added to a solution of pyrimidine-2-amine (165 mg, 89 mmol) in toluene (5 mL), and the mixture was heated to reflux for 5 hours using a Dean-Stark apparatus.
  • Step 3 (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5
  • [2- (methylthio) ethoxy] pyrimidin-2-amine N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (138 mg, 0.31 mmol) was converted to N, N-dimethylformamide ( 4 mL), sodium hydride (50% in oil: 45 mg, 0.94 mmol) was added at ⁇ 20 ° C., and the mixture was stirred at the same temperature for 1 hour.
  • Example 54 (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine: (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine (6.47 mg, 8.66 mmol) is dissolved in 1,2-dichloroethane (6.3 mL), and anisole (9.31 g, 86.1 mmol) is added to the solution in an ice bath.
  • Example 56 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate: The reaction and treatment were conducted in a similar manner to Example 50 using 2- (trans-4- ⁇ [(4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate in place of diallylamine, and the title compound was obtained as a tan oil. It was.
  • Example 60 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (phenylthio) ethoxy] pyrimidine-2 Preparation of -yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate:
  • Step 1 Production of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide N- (5-hydroxy) synthesized by the method of Example 1 described in the patent document (WO 2008/129951 pamphlet) Pyrimidin-2-yl) hexanamide (3.00 g, 14.3 mmol) was dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (2.97 g, 21.5 mmol) and 1-bromo-2-chloroethane were dissolved at room temperature. (4.12 g, 28.7 mmol) was added, and the mixture was stirred at 60 ° C. for 20 hours.
  • Step 2 Preparation of N- ⁇ 5- [2- (phenylthio) ethoxy] pyrimidin-2-yl ⁇ hexanamide
  • Thiophenol (486 mg, 4.41 mmol) was dissolved in N, N-dimethylformamide (5 mL).
  • Sodium hydride (50% in oil: 265 mg, 5.52 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 15 minutes.
  • N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (1.00 g, 3.68 mmol) obtained in Step 1 was added to N, N-dimethylformamide (2 mL) in an ice bath.
  • Step 3 Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine N- ⁇ 5- [2- (phenylthio) ethoxy] pyrimidin-2-yl ⁇ hexanamide (400 mg) obtained in Step 2 , 1.16 mmol) was dissolved in methanol (2.8 mL), sodium methoxide (25.1 mg, 2.32 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 4 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (phenylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino )
  • Acetic acid (115 mg, 1.92 mmol) was added to a toluene (4 mL) solution, and the mixture was stirred for 3.5 hours using a Dean-Stark apparatus.
  • the reaction solution was allowed to cool to room temperature, and while stirring in an ice bath, trifluoroacetic acid (108 mg, 0.95 mmol) and sodium triacetoxyborohydride (394 mg, 1.86 mmol) were added, and the mixture was stirred at room temperature for 1 hour. .
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
  • Step 5 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (phenylthio) ethoxy] Preparation of pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate N- [2- (diallylamino) -5- (trifluoromethyl) 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (phenylthio) ethoxy] pyrimidine-2 instead of benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine -Il ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] cyclohexyl ⁇ ethyl
  • Example 63 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate preparation: The reaction and treatment were conducted in a similar manner to Example 60 using phenol instead of thiophenol, and the title compound was obtained as a pale-yellow oil.
  • Example 64 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ [5- (2-phenoxyethoxy) pyrimidin-2-yl) Preparation of amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetic acid: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate instead of 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ ( S) -1- [3,5-bis (
  • Example 65 2- [trans-4-( ⁇ [2- ⁇ [ ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ (5-methoxypyrimidin-2-yl) amino] methyl ⁇ Preparation of -4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate:
  • Step 1 2- [trans-4-( ⁇ ethyl [2- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate
  • the reaction and treatment were carried out in the same manner as in Step 4 of Example 60 using 5-methoxypyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, and 2- [trans- 4-( ⁇ Ethyl [2- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] acetic acid ethyl ester
  • the title compound was obtained as a colorless solid.
  • Step 2 2- [trans-4-( ⁇ [2- ⁇ [ ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ (5-methoxypyrimidin-2-yl) amino ] Preparation of methyl ⁇ -4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2 2- [trans-4-( ⁇ ethyl [2- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) instead of-(methylthio) ethoxy] pyrimidin-2-amine ) Phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate was used in the same manner as in Step 3 of Example 50 to give the title compound as a pale yellow
  • Step 1 2- [trans-4-( ⁇ [2- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl]
  • 2- [trans-4-( ⁇ [2- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] Preparation of ethyl acetate Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 4 of Example 60 was carried out.
  • Step 2 2- [trans-4-( ⁇ [2- ⁇ [ ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ (5-ethoxypyrimidin-2-yl) amino ] Preparation of ethyl ⁇ -4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2 2- (trans-4-( ⁇ [2- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) instead of-(methylthio) ethoxy] pyrimidin-2-amine Phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate was used for the reaction and treatment in the same manner as in Step 3 of Example 50 to obtain
  • Step 1 Preparation of 2- [trans-4-( ⁇ [2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate 2-Fluoro-5- ( Trans- ⁇ 4- [trifluoromethyl) benzaldehyde (1.00 g, 4.60 mmol) synthesized in a dimethyl sulfoxide-water (4: 1 mixed solution, 6.25 mL) solution by the method described in WO 2004/020393 pamphlet.
  • Step 2 2- (trans-4- ⁇ [ ⁇ 2-Chloro-6-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) Preparation of ethyl phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetate 2- [trans-4-( ⁇ [2]) obtained in Step 1 instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde -Chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate was reacted and treated in the same manner as in Step 2 of Example 50 to give 2- (trans-4 — ⁇ [ ⁇ 2-Chloro-6-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4
  • Step 3 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] Preparation of pyrimidin-2-yl ⁇ amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate N- [2- (diallylamino) -5- ( 2- (trans-4- ⁇ [ ⁇ 2-Chloro-6-[( ⁇ chloromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine obtained in Step 2 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl)
  • Example 70 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl ⁇ amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetic acid: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate instead of 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (
  • Example 72 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5-methoxy
  • Patent Literature Japanese Published Patent Application 2010-077116
  • Example 74 4-( ⁇ 2-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ ) Production of ethyl amino] pyrimidin-5-yl ⁇ oxy) butyrate: It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
  • Example 75 4-( ⁇ 2-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ ) Amino] pyrimidin-5-yl ⁇ oxy) butyric acid: It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
  • Step 1 Production of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Synthesized by the method described in Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) (3-bromo-6 -Methoxypyridin-2-yl) methanol (10.6 g, 48.6 mmol) in dichloromethane (150 mL) under ice-cooling, N, N-diisopropylethylamine (31.4 g, 243 mmol) and chloromethyl methyl ether (13.3 g) , 165 mmol) was added dropwise.
  • reaction mixture was cooled, filtered through celite, and washed with ethyl acetate.
  • -3-Amine (954 mg, 74%) was obtained as a yellow oil.
  • N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine (8.39 g, 27.2 mmol) in dioxane (400 mL) -water (100 mL) Concentrated hydrochloric acid (20 mL) was added dropwise thereto, and the mixture was stirred at 50 ° C. for 19 hours. The reaction mixture was basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 Preparation of N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5 -[2- (methylthio) ethoxy] pyrimidin-2-amine (1.03 g, 5.55 mmol) and 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde (1.60 g, A solution of 6.10 mmol) in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (1.24 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
  • Step 3 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇
  • sodium hydride 50% in oil, 24 mg, 1.4 mmol
  • Step 1 Preparation of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl- 1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N- (cyclopentylmethyl) -N-ethylamine produced by the method described in WO 2006/079773 (11.70 g, 92.0 mmol) were mixed and stirred at 100 ° C. for 8 hours under an argon atmosphere.
  • Step 2 N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo
  • 3,4-b] pyridin-6-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3 -Dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was reacted and treated in the same manner as in Step 2 of Example 76 to obtain N- (cyclopentylmethyl) -N-ethyl-1,3.
  • Step 3 5-[( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- ( Preparation of cyclopentylmethyl) -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6- Methoxypyridin-2-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (Methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4-b] pyri
  • Example 80 5-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl )
  • Example 81 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl) Production of —N-ethylquinolin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 82 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl )
  • Preparation of —N-ethylquinolin-2-amine It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 83 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl)
  • Preparation of —N-ethyl-6-methoxyquinolin-2-amine It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 84 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl )
  • Preparation of —N-ethyl-6-methoxyquinolin-2-amine It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 85 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl)
  • Example 86 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl Preparation of —N-ethyl-6- (trifluoromethyl) quinolin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 88 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl )
  • Preparation of —N-ethyl-6-methylquinolin-2-amine It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 90 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N-( ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl ⁇ methyl)- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 95 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] propyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl) Production of —N-ethylquinolin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 96 3-[( ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] propyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -N- (cyclopentylmethyl )
  • Preparation of —N-ethylquinolin-2-amine It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 97 3- ⁇ 1-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) ⁇ 5- [2 Preparation of-(Methylthio) ethoxy] pyrimidin-2-yl ⁇ amino] ethyl ⁇ -5- (trifluoromethyl) benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 98 3- ⁇ 1-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) ⁇ 5- [2 Preparation of-(Methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino] ethyl ⁇ -5- (trifluoromethyl) benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 100 N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl ⁇ methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
  • Example 104 Preparation of N-benzyl-N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine : It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 105 N-benzyl-N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine Manufacturing: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 106 Of N-benzyl-N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine Manufacturing: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 107 3- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino] methyl ⁇ -5- (Trifluoromethyl) benzonitrile production: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 108 3-[( ⁇ 2-[[3-Cyano-5- (trifluoromethyl) benzyl] ( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) amino] Preparation of Pyrimidin-5-yl ⁇ oxy) methyl] -5- (trifluoromethyl) benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 109 3- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl ⁇ amino] Production of methyl ⁇ -5- (trifluoromethyl) benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 110 3- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino] Production of methyl ⁇ -5- (trifluoromethyl) benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 111 N- [3,5-bis (trifluoromethyl) benzyl] -N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 112 N- [3,5-bis (trifluoromethyl) benzyl] -N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- Preparation of (methylsulfinyl) ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 114 3- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino] methyl ⁇
  • Production of benzonitrile It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 115 3- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl ⁇ amino] Production of methyl ⁇ benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 118 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylthio) ethoxy]
  • pyrimidine-2-amine It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 120 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfonyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 121 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 122 N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 124 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 126 N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethoxy) Preparation of [benzyl] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 129 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylthio) ethoxy]
  • pyrimidine-2-amine It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 130 N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 132 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 135 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 136 N-( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 138 N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (2,3-difluorobenzyl) -5-[(2,3-difluorobenzyl ) Preparation of oxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 139 N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 140 5- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino] methyl ⁇
  • isophthalonitrile It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 141 5- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl ⁇ amino] Production of methyl ⁇ isophthalonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 142 5- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino] Production of methyl ⁇ isophthalonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 146 N- [3,5-bis (trifluoromethyl) benzyl] -5-bromo-N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) pyrimidine- 2-Amine production: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 147 N- [3,5-bis (trifluoromethyl) benzyl] -N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5-morpholinopyrimidine- 2-Amine production: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 148 N- [3,5-bis (trifluoromethyl) benzyl] -N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) -5-piperidino Preparation of pyrimidine-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 150 N- [3,5-bis (trifluoromethyl) benzyl] -N- ⁇ [6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl ⁇ -5- [2- (methylsulfinyl) ) Preparation of ethoxy] pyrimidin-2-amine: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 152 6-[([3,5-bis (trifluoromethyl) benzyl] ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -5-[(cyclopentylmethyl) (ethyl) Production of amino] pyridin-2-ol: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 153 4- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino] methyl ⁇
  • Production of benzonitrile It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 154 4- ⁇ [( ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methyl) ⁇ 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl ⁇ amino] Production of methyl ⁇ benzonitrile: It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
  • Example 156 N- [3,5-bis (trifluoromethyl) benzyl] -N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) Preparation of [Ethoxy] pyrimidin-2-amine: N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of WO 2008/129951 N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared according to (R) Reaction and treatment in the same manner as in Step 3 of Example 50 using 3,5-bis (trifluoromethyl) benzyl bromide instead of -1- (1-bromoeth
  • Example 158 2- [trans-4-( ⁇ [2-( ⁇ [3,5-bis (trifluoromethyl) benzyl] ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino ⁇ methyl) -4 Preparation of-(trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate: N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of WO 2008/129951 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino prepared according to ) Methyl] cyclohexyl ⁇ ethyl acetate, and
  • Sodium hydride (60% in oil, 5.2 mg, 0.13) while stirring a solution of N, N-dimethylformamide (0.5 mL) in pyridine-6-amine (25.4 mg, 0.054 mmol) at -15 ° C mmol) and stirred at room temperature for 30 minutes.
  • Step 1 N- (cyclopentylmethyl) -N-ethyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine
  • 6-amine 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4] instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde -B] Similar to Step 2 of Example 50 using pyridine-5-carbaldehyde and using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine.
  • Step 2 N- (Cyclopentylmethyl) -N-ethyl-5- ⁇ [(5-methoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4 b]
  • Pyridin-6-amine N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl ] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of N- (cyclopentylmethyl) -N-ethyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -
  • the reaction and treatment were conducted in a similar manner to Example 161 using 1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6-amine, and the title compound was obtained as
  • Step 1 N- (cyclopentylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine
  • 6-amine 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4] instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde -B] Similar to Step 2 of Example 50 using pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine.
  • Step 2 N- (Cyclopentylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4 b]
  • Pyridin-6-amine N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl ] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of N- (cyclopentylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N-ethyl-
  • the reaction and treatment were conducted in a similar manner to Example 161 using 1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6-amine, and the title compound was obtained
  • Example 164 N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 4-b] Preparation of pyridine-6-amine: N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4 -B] While stirring a solution of pyridine-6-amine (26.3 mg, 0.056 mmol) in N, N-dimethylformamide (0.5 mL) at -15 ° C, sodium hydride (60% in oil, 5.4 mg, 0.14 mmol) and stirred at room temperature for 30 minutes.
  • Example 165 N- (cyclopentylmethyl) -N-ethyl-5- ⁇ [ethyl (5-methoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4 -B] N- (cyclopentylmethyl) -N-ethyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo instead of pyridine-6-amine
  • the reaction and treatment were conducted in the same manner as in Example 164 using [3,4-b] pyridin-6-amine to give the title compound
  • Example 166 N- (cyclopentylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) (ethyl) amino] methyl ⁇ -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine
  • Production of -6-amine N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4 -B] N- (cyclopentylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N-ethyl-1,3-dimethyl-1H-pyrazolo instead of pyridine-6-amine
  • the reaction and treatment were conducted in the same manner as in Example 164 using [3,4-b] pyridin-6-amine to give the title
  • Example 167 2- (trans-4- ⁇ [ ⁇ 1,3-dimethyl-5-[(methyl ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4 -B] Preparation of pyridin-6-yl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate: Step 1: Preparation of 2- (trans-4- ⁇ [ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl ⁇ cyclohexyl) ethyl acetate
  • Step 2 2- (trans-4- ⁇ [ ⁇ 1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3 , 4-b] pyridin-6-yl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate preparation 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (trans- Step 2 of Example 76 with ethyl 4- ⁇ [ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl ⁇ cyclohexyl) acetate The reaction and treatment were conducted in the same manner to give 2- (trans-4- ⁇ [ ⁇ 1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyr
  • Step 3 2- (trans-4- ⁇ [ ⁇ 1,3-dimethyl-5-[(methyl ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [ Preparation of 3,4-b] pyridin-6-yl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [ Instead of 2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine, 2- (trans-4- ⁇ [ ⁇ 1,3- Dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-y
  • Step 1 Preparation of ethyl 4-[(2-hexaneamidopyrimidin-5-yl) oxy] butanoate N- (5-hydroxypyrimidin-2-yl) hexanoic acid amide (3.0 g, 14.3 mmol) N, N -Ethyl 4-bromobutanoate (3.35 g, 17.2 mmol) and potassium carbonate (3.0 g, 21.5 mmol) were added to a dimethylformamide (15 mL) solution, and the mixture was stirred at 60 ° C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 2 Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butanoate
  • Sodium ethoxide (421 mg, 6.19 mmol) was added to an ethanol (4 mL) solution, and the mixture was heated to reflux for 5 hours. After allowing to cool, concentrated sulfuric acid (835 mg, 8.51 mmol) was added, and the mixture was heated to reflux for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino ]
  • 3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine
  • 4-[(2-aminopyridine- 5- (yl) oxy] butanoic acid ethyl was used for the reaction and treatment in the same manner as in Step 2 of Example 76 to give 4-( ⁇ 2-[(
  • Step 4 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) ( Preparation of methyl) amino] pyrimidin-5-yl ⁇ oxy) butanoate N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidine -2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of 4-( ⁇ 2-[( ⁇ 6-[(cyclopentylmethyl) (ethyl) amino]- 1,3-Dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino] pyrimidin-5-yl ⁇ oxy) reacted and treated in the same manner as in
  • Example 170 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) (methyl) amino ] Pyrimidin-5-yl ⁇ oxy) butanoic acid: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate instead of 4-( ⁇ 2-[( ⁇ 6-[(cyclopentylmethyl) (Ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b]
  • Step 1 Preparation of methyl 2-( ⁇ [6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ amino) amino acetate 6- (diethylamino)- While stirring a solution of 1,3-dimethyl-1H-pyrazolo [3,4, -b] pyridine-5-carbaldehyde (200 mg, 0.81 mmol) in methanol (3.2 mL) at 0 ° C., glycine methyl ester hydrochloride Salt (153 mg, 1.22 mmol) and triethylamine (123 mg, 1.22 mmol) were added, and the mixture was stirred at room temperature for 16 hours.
  • 1,3-dimethyl-1H-pyrazolo [3,4, -b] pyridine-5-carbaldehyde 200 mg, 0.81 mmol
  • methanol 3.2 mL
  • reaction solution was cooled to 0 ° C., sodium borohydride (61.4 mg, 1.62 mmol) was added, and the mixture was stirred for 4 hours while warming to room temperature.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 2 2-[(5-Bromopyrimidin-2-yl) ⁇ [6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ amino]
  • methyl acetate 2-( ⁇ [6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ amino) methyl acetate (130 mg, 0.41 mmol)
  • 5-bromo-2-chloropyrimidine 94.5 mg, 0.49 mmol
  • diisopropylethylamine 63 mg, 0.49 mmol
  • Step 3 2-( ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine -2-yl ⁇ amino) Production of methyl acetate 2-[(5-bromopyrimidin-2-yl) ⁇ [6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- To a solution of methyl 5-yl] methyl ⁇ amino] acetate (158 mg, 82%) (150 mg, 0.32 mmol) in dioxane, copper iodide (6.0 mg, 0.03 mmol), N, N-dimethylethylenediamine (6.8 ⁇ L, 0.06 mmol) and sodium iodide (94.4 mg, 0.63 mmol) were added, and the mixture was heated to reflux for 16 hours.
  • Example 172 2-( ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2- Il ⁇ amino) acetic acid production: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate instead of 2-( ⁇ [6- (diethylamino) -1,3-dimethyl -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ ⁇ 5- [
  • Example 173 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] Production of methyl propionate: Step 1: Preparation of methyl 3- (methylamino) propionate N-methylbenzylamine (17.1 mL, 0.13 mmol) was added to a methanol solution (50 mL) of methyl acrylate (10 mL, 0.12 mmol) at room temperature. Stir for 15 hours.
  • Step 2 Preparation of methyl 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate N- (cyclopentylmethyl)-
  • the reaction and treatment were conducted in the same manner as in Step 1 of Example 79 using methyl 3- (methylamino) propionate instead of N-ethylamine to give 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [ Methyl 3,4-b] pyridin-6-yl) (methyl) amino] propionate was obtained as a brown oil.
  • Step 3 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Preparation of methyl] amino] propionate 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4] instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde -B] Performed using methyl pyridin-6-yl) (methyl) amino] propionate using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine
  • the reaction and treatment were conducted in the same manner as in Step 2 of Example 76 to give 3-[(5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazol
  • Step 4 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl ) Preparation of methyl (methyl) amino] propionate N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino ) Methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of 3-[(5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl
  • the reaction and treatment were conducted in a similar manner to Example 161 using -1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate, to give the title compound as a pale yellow
  • Example 175 3- ⁇ [5-( ⁇ [Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino ⁇ methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- Preparation of methyl 6-yl] (methyl) amino ⁇ propionate: 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] A solution of methyl propionate (156 mg, 0.38 mmol) in DMF (1.5 mL) was cooled to ⁇ 60 ° C., sodium hydride (30.4 mg, 0.76 mmol) was added, and the mixture was stirred for 15 minutes, followed by tetrabutylammonium iodide ( 140 mg, 0.38 mmol) and 3,5-bis (trifluoromethyl) benz
  • Example 176 3- ⁇ [5-( ⁇ [Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino ⁇ methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- Preparation of 6-yl] (methyl) amino ⁇ propionic acid: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate instead of 3- ⁇ [5-( ⁇ [bis (trifluoromethyl) benzyl] ] (5-Ethoxypyrimidin-2-yl) amino ⁇ methyl) -1,3-dimethyl
  • Example 177 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Production of methyl propionate: 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Dissolve methyl propionate (157 mg, 0.38 mmol) in a mixed solvent of DMF (2 mL) and toluene (1 mL), add sodium t-pentoxide (83.4 mg, 0.76 mmol) at -40 ° C, and stir for 3 hours.
  • Example 178 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Manufacturing: Step 1: Preparation of 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine Reaction and treatment were conducted in the same manner as in Step 1 of Example 79 to obtain 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
  • Step 2 5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
  • 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, reaction and treatment in the same manner as in Step 2 of Example 76, and 5- ⁇ [ (5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine as a pale yellow
  • Step 3 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6
  • amine 5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine (30 mg, 0.08 mmol) in DMF (1.5 mL) was cooled to ⁇ 15 ° C., sodium hydride (6.5 mg, 0.16 mmol) was added, and the mixture was stirred for 30 min, then methyl iodide (15.2 ⁇ L, 0.24 mmol) ) And stirred for 24 hours while gradually warming to room temperature.
  • Example 179 3- ⁇ [ ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ Production of methyl benzoate: The reaction and treatment were conducted in a similar manner to Example 178 using methyl 3- (bromomethyl) benzoate instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 180 4- ⁇ [ ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ Production of methyl benzoate: The reaction and treatment were conducted in a similar manner to Example 178 using methyl 4- (bromomethyl) benzoate instead of methyl iodide, and the title compound was obtained as a white solid.
  • Example 182 4- ⁇ [ ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ (5-ethoxypyrimidin-2-yl) amino] methyl ⁇
  • Example 183 Preparation of 5- ⁇ [benzyl (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: The reaction and treatment were conducted in a similar manner to Example 178 using benzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 184 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (4-fluorobenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 4-fluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 185 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) isopropyl acetate: 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-Bis () synthesized by the method described in Patent Document (International Publication No.
  • the reaction mixture was cooled, neutralized with saturated aqueous sodium hydrogen carbonate solution (5 mL), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 186 2- (trans-4- ⁇ [ ⁇ 2-[( ⁇ (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidine- Preparation of methyl 2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ (ethyl) amino] methyl ⁇ cyclohexyl) acetate: The reaction was conducted in the same manner as in Example 185 using methanol instead of 2-propanol to obtain the title compound as a white amorphous.
  • Example 188 5- ⁇ [(3,5-difluorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Production of -6-amine: The reaction and treatment were conducted in a similar manner to Example 178 using 3,5-difluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 189 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (2-fluorobenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 2-fluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 190 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (3-fluorobenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 3-fluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 191 5- ⁇ [(2-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 2-chlorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 192 5- ⁇ [(3-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 3-chlorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 193 5- ⁇ [(4-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 4-chlorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 194 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (2-methylbenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 2-methylbenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 195 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (4-methylbenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 4-methylbenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 196 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (3-methylbenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 3-methylbenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 197 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (4-methoxybenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 4-methoxybenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 198 4- ⁇ [ ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ Production of benzonitrile: The reaction and treatment were conducted in a similar manner to Example 178 using 4-cyanobenzyl bromide instead of methyl iodide, and the title compound was obtained as a white solid.
  • Example 199 5- ⁇ [(Cyclopropylmethyl) (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production: The reaction and treatment were conducted in a similar manner to Example 178 using (bromomethyl) cyclopropane in place of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 200 2- ⁇ trans-4-[(ethyl ⁇ 2-[(ethyl ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl
  • cyclohexyl ⁇ ethyl acetate N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1,3-dimethyl-1H-pyrazolo [3
  • 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthiol)]] was prepared according to the method described in WO2008 / 129951.
  • Example 201 5- ⁇ [(5-Ethoxypyrimidin-2-yl) (3-methoxybenzyl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines: The reaction and treatment were conducted in a similar manner to Example 178 using 3-methoxybenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
  • Example 202 2- ⁇ [ ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ Production of benzonitrile: The reaction and treatment were conducted in a similar manner to Example 178 using 2-cyanobenzyl bromide instead of methyl iodide, and the title compound was obtained as a white solid.
  • Example 203 3- ⁇ [ ⁇ [6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ (5-ethoxypyrimidin-2-yl) amino] methyl ⁇ Production of benzonitrile: The reaction and treatment were conducted in a similar manner to Example 178 using 3-cyanobenzyl bromide instead of methyl iodide, and the title compound was obtained as a white solid.
  • the compounds obtained in the above examples are shown in Table 1.
  • the compounds of Examples 45, 50-71, and 156-203 are novel compounds. Accordingly, the present invention provides a compound selected from the group consisting of the compounds of Examples 45, 50-71, and 156-203, or a salt thereof, or a solvate thereof.
  • Test example 1 A test compound was added to HepG2 cells, a human hepatoma cell line, and the expression level of PCSK9 mRNA after 24 hours of culture was measured by quantitative real-time PCR. That is, HepG2 cells are seeded in a 24-well plate at a concentration of 3 ⁇ 10 5 cells / well, cultured for 3 nights, and the test compound dissolved in dimethyl sulfoxide (DMSO) is 1/1000 times the volume of the culture solution. added. After culturing at 37 ° C. for 24 hours in a CO 2 incubator, 500 ⁇ L of ISOGEN (Nippon Gene, catalog number 31-02501) was added, and total RNA was extracted.
  • DMSO dimethyl sulfoxide
  • CDNA was synthesized from the extracted total RNA using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, catalog number 4368813).
  • the expression level of human PCSK9 mRNA was determined using primers specific to human PCSK9 (Kourimate S. et.al., J Biol Chem. Vol.283, p9666) and Fast SYBR Green master mix (Applied Biosystems, catalog number 4385614). It was measured.
  • the measuring instrument was a 7900HT Fast Realtime PCR system.
  • the measured value was corrected by the expression level of ⁇ -Actin-mRNA, and the PCSK9 mRNA expression level of the cells to which DMSO alone was added was 1, and the PCSK9 mRNA expression level of the cells to which the test compound was added was calculated as a relative value.
  • Table 2 As can be seen from Table 2, the compound of the present invention was confirmed to suppress the expression level of PCSK9 mRNA.
  • Test Example 2 Measurement of PCSK9 Protein Production Amount of Compound on HepG2 Cells
  • a test compound was added to HepG2 cells, a human hepatoma cell line, and the amount of PCSK9 protein in the culture supernatant after 48 hours of culture was measured using Enzyme-Linked Immunosorbent Assay.
  • ELISA Enzyme-Linked Immunosorbent Assay
  • the cells were cultured for 48 hours at 37 ° C. in a CO 2 incubator, and then the cell culture supernatant was collected. The collected cell culture supernatant was centrifuged at 3000 ⁇ g, and the supernatant was collected and used as a cell culture supernatant sample.
  • Capture Antibody was dissolved at 2.0 ⁇ g / mL in Phosphate Buffered Saline (PBS), and 100 ⁇ L each was added to a 96-well plate and allowed to stand overnight at room temperature. did. The plate plate supernatant was washed and washed 3 times with 400 ⁇ L of wash buffer (0.05% Tween 20 in PBS, pH 7.2-7.4). Add 300 ⁇ L of Reagent Diluent Buffer (1% Bovine serum albumin (BSA) in PBS, pH 7.2-7.4, 0.2 ⁇ m filtered) and let stand at room temperature for 1 hour, then 3 times with Wash buffer Washed.
  • PBS Phosphate Buffered Saline
  • the prepared cell culture supernatant sample was diluted 50- to 100-fold with Reagent Diluent Buffer, added 100 ⁇ L to a 96-well plate, and allowed to stand at room temperature for 2 hours. After washing with Wash buffer three times, detection antibody diluted with Reagent Diluent 100 ⁇ L each was added, and allowed to stand at 4 ° C. for 18 hours. After washing with Wash buffer three times, 100 ⁇ L of Streptavidin-Horseadish peroxidase (HRP) diluted 50-fold with Reagent Diluent was added and allowed to stand at room temperature for 20 minutes.
  • HRP Streptavidin-Horseadish peroxidase
  • the compound of the present invention or a salt thereof, or a solvate thereof has a strong PCSK9 mRNA expression inhibitory action and PCSK9 protein production inhibitory action, and a disease involving PCSK9 mRNA expression and PCSK9 protein.
  • dyslipidemia hyperlipidemia
  • arteriosclerosis arteriosclerosis
  • atherosclerosis peripheral vascular disease
  • hyper-LDL hypo-HDL
  • hypercholesterolemia hyper-triglyceridemia
  • familial high Cholesterolemia cardiovascular disorder
  • angina pectoris ischemia
  • cardiac ischemia thrombosis
  • myocardial infarction reperfusion injury
  • angiogenic restenosis hypertension, cancer, obesity, diabetes, Alzheimer's disease or viral infection, etc. It became clear that it can be used suitably as an active ingredient of a therapeutic or prophylactic agent.
  • the compound represented by the general formula (I) of the present invention has a PCSK9 mRNA expression-inhibiting action, a PCSK9 protein production-inhibiting action, and an action to increase the amount of LDL receptor, and an effective pharmaceutical for reducing LDL Besides being usable as a component, it can be suitably used as an active ingredient such as a PCSK9 mRNA expression inhibitor, a PCSK9 protein production inhibitor, and a drug that increases the amount of LDL receptor. Furthermore, since the LDL cholesterol lowering action in the statin drugs can be enhanced, a high LDL cholesterol lowering action can be achieved by combining with the statin drugs.

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Abstract

A pharmaceutical product for lowering blood LDL, which is a pharmaceutical product that contains a compound represented by formula (I) as an active ingredient, said compound having actions of inhibiting the expression of PCSK9mRNA, lowering the amount of PCSK9 protein, and increasing the amount of an LDL receptor. (In formula (I), R1 represents a hydrogen atom, a hydroxyl group, a C1-6 alkoxy group or the like; R represents a C1-6 alkyl group or the like; the ring structure Q represents a phenyl group or a monocyclic or bicyclic heterocyclic ring; and each of R2 and R3 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C3-8 cycloalkyl C1-6 alkyl group or the like.)

Description

血中ＬＤＬを低下させるための医薬Medicine for lowering blood LDL
　本発明は、プロタンパク質コンバターゼサブチリシン／ケキシン９型（ＰＣＳＫ９：Ｐｒｏｐｒｏｔｅｉｎ　ｃｏｎｖｅｒｔａｓｅ　ｓｕｂｔｉｌｉｓｉｎ／ｋｅｘｉｎ　９）ｍＲＮＡの発現抑制作用などを有するピリミジン化合物を有効成分として含み、血中ＬＤＬを低下させることができる医薬に関する。 The present invention includes a pyrimidine compound having a proprotein convertase subtilisin / kexin type 9 (PCSK9: Proprotein convertase subtilisin / kexin 9) mRNA expression inhibitory activity as an active ingredient, and can reduce blood LDL. It relates to medicine.
　近年、生活水準の向上に伴う高カロリー、高コレステロール型食への変化、肥満、運動不足、高齢化等により脂質異常症（高脂血症）及びこれに起因する動脈硬化性疾患が急増している。低比重リポタンパク質（ＬＤＬ）コレステロール値及びトリグリセリド値が心疾患の発症率に正相関することはフラミンガム・スタディの研究を始めとする多くの疫学研究からも明らかにされており、それ故に脂質異常症及び動脈硬化症の薬物治療はＬＤＬを低下させることに重点が置かれている（非特許文献１）。 In recent years, dyslipidemia (hyperlipidemia) and arteriosclerotic diseases resulting from it have increased rapidly due to changes in high calorie, high cholesterol type diet, obesity, lack of exercise, aging, etc. accompanying the improvement of living standards Yes. A number of epidemiological studies, including those in the Framingham study, have shown that low density lipoprotein (LDL) cholesterol and triglyceride levels are positively correlated with the incidence of heart disease. In addition, drug treatment for arteriosclerosis is focused on reducing LDL (Non-patent Document 1).
　高ＬＤＬコレステロール血症は心血管疾患の強力な危険因子の一つであるが、その治療方法はＨＭＧ－ＣｏＡ還元酵素阻害薬（スタチン）の登場とともに飛躍的に進歩した。しかし、スタチンは強力にＬＤＬコレステロールを低下させるが、心血管疾患による心事故、死亡率の低下は約３０％にとどまる。ＬＤＬコレステロールをさらに低下させることにより、心血管疾患による死亡リスクをより低減できると考えられるが、スタチンは横紋筋融解症のリスクが高まるため高用量を投与することができないという問題を有している。そこで、スタチンとは作用機序が異なり、かつ、スタチンよりも強力な、またはスタチンと併用することで強力なＬＤＬコレステロール低下作用を有する作用機序の異なる薬剤の開発が求められている。 High LDL cholesterolemia is one of the powerful risk factors for cardiovascular disease, but its treatment method has made great strides with the advent of HMG-CoA reductase inhibitors (statins). However, statins strongly lower LDL cholesterol, but heart accidents due to cardiovascular diseases and the reduction in mortality are only about 30%. It is thought that the risk of death from cardiovascular disease can be further reduced by further reducing LDL cholesterol, but statins have the problem that high doses cannot be administered due to the increased risk of rhabdomyolysis Yes. Therefore, there is a demand for the development of a drug having a mechanism of action different from that of statins and having a stronger action mechanism of LDL cholesterol when used in combination with statins.
　一方、プロタンパク質コンバターゼ（ＰＣｓ）は哺乳類のセリンプロテアーゼファミリーのメンバーであり、細菌におけるサブチリシンや酵母におけるケキシンと相同性が認められている。ＰＣｓの一つであるＰＣＳＫ９（プロタンパク質コンバターゼサブチリシン／ケキシン９型：Ｐｒｏｐｒｏｔｅｉｎ　ｃｏｎｖｅｒｔａｓｅ　ｓｕｂｔｉｌｉｓｉｎ／ｋｅｘｉｎ　９)は、主に肝臓で発現して細胞外に分泌され、肝細胞膜表面上でＬＤＬ受容体と結合し、ＬＤＬ受容体の細胞内移行を促進する。細胞内に移行したＬＤＬ受容体は細胞内器官で分解を受ける。ＬＤＬ受容体はコレステロールを含むリポ蛋白を循環血液中から肝臓へと輸送する機能を有しているため、ＰＣＳＫ９タンパクの発現は肝臓へのＬＤＬコレステロールの取り込みを阻害し、結果として、血中ＬＤＬコレステロールを上昇させる。実際に、ＰＣＳＫ９遺伝子に機能喪失変異を有するヒトの血中ＬＤＬコレステロールレベルは低く維持されている（非特許文献２）。一方、ＰＣＳＫ９遺伝子には機能獲得型変異が報告されており、この変異を有するヒトの血中ＬＤＬコレステロールレベルは高く、常染色体優性高コレステロール血症と関連していることが知られている（非特許文献３）。また、動物レベルでは、肝臓のＰＣＳＫ９を欠損させたマウスのＬＤＬコレステロールは低値であることが示されている（非特許文献４）。 On the other hand, proprotein convertases (PCs) are members of the mammalian serine protease family and have been found to be homologous to subtilisins in bacteria and kexins in yeast. One of the PCs, PCSK9 (Proprotein convertase subtilisin / kexin type 9) is mainly expressed in the liver and secreted outside the cell, and is an LDL receptor on the surface of the liver cell membrane. And promotes the intracellular translocation of the LDL receptor. LDL receptors that have migrated into cells undergo degradation in intracellular organs. Since the LDL receptor has a function of transporting lipoproteins containing cholesterol from the circulating blood to the liver, the expression of the PCSK9 protein inhibits the uptake of LDL cholesterol into the liver, resulting in blood LDL cholesterol. To raise. Actually, the blood LDL cholesterol level of a human having a loss-of-function mutation in the PCSK9 gene is kept low (Non-patent Document 2). On the other hand, a gain-of-function mutation has been reported for the PCSK9 gene, and the human LDL cholesterol level in humans having this mutation is high, and is known to be associated with autosomal dominant hypercholesterolemia (non-native). Patent Document 3). Moreover, it has been shown that LDL cholesterol in mice lacking PCSK9 in the liver is low at the animal level (Non-patent Document 4).
　以上のことより、ＰＣＳＫ９タンパクの産生抑制等によりその量を低減することやＰＣＳＫ９タンパクの機能を阻害することは、ＬＤＬ受容体量の増加につながり、ひいては強力なＬＤＬコレステロール低下作用に結びつくものと考えられる。 Based on the above, it is considered that reducing the amount of PCSK9 protein by inhibiting the production thereof or inhibiting the function of PCSK9 protein leads to an increase in the amount of LDL receptor, which in turn leads to a strong LDL cholesterol lowering action. It is done.
　このような背景から、最近、ＰＣＳＫ９タンパクの機能阻害や産生抑制に関する研究が活発に行われている。例えば、抗体やアンチセンスオリゴヌクレオチドを用いるものとしては、ＰＣＳＫ９のモノクローナル抗体によるＰＣＳＫ９タンパクの機能阻害やＲＮＡ干渉によるＰＣＳＫ９タンパクの産生抑制などが報告されている（非特許文献５～７）。また、低分子化合物を用いるものとしては、ベルベリンがＨｅｐＧ２細胞におけるＰＣＳＫ９のｍＲＮＡとタンパクレベルを低下させるという報告（非特許文献８）や、アネキシンＡ２活性化剤である５－アザシチジンがＰＣＳＫ９タンパクとアネキシンＡ２の結合を促進し、ＬＤＬ受容体の分解を抑制するという報告がある（特許文献１）。しかし、低分子化合物のＰＣＳＫ９タンパク機能阻害剤又はＰＣＳＫ９タンパク産生抑制剤は前記したものの他にはほとんど報告がない。 Against this background, research on the inhibition of the function and production of PCSK9 protein has been actively conducted recently. For example, as a method using an antibody or an antisense oligonucleotide, inhibition of PCSK9 protein function by a PCSK9 monoclonal antibody and suppression of PCSK9 protein production by RNA interference have been reported (Non-Patent Documents 5 to 7). In addition, as a low molecular weight compound, berberine reports that PCSK9 mRNA and protein levels in HepG2 cells are reduced (Non-patent Document 8), and annexin A2 activator 5-azacytidine is a PCSK9 protein and annexin. There is a report that promotes the binding of A2 and suppresses the degradation of the LDL receptor (Patent Document 1). However, PCSK9 protein function inhibitors or PCSK9 protein production inhibitors of low molecular weight compounds are hardly reported in addition to those described above.
　なお、特許文献２～５にはコレステロールエステル転送タンパク（ＣＥＴＰ）に対して強い阻害活性を示し、強い血中ＨＤＬコレステロール増加作用を有するジベンジルアミン構造を有するピリミジン化合物が開示されており、当該化合物を有効成分として含む医薬が高ＬＤＬ血症の予防及び／又は治療に有用であることが教示されているが、この教示は、当該医薬がＣＥＴＰを阻害することによりＨＤＬを上昇させ、ＬＤＬに対して相対的にＨＤＬレベルを高めることにより高ＬＤＬ血症を予防及び／又は治療することができるということにあり、ＬＤＬを直接的に低下させる作用を有することを教示しているわけではない。 Patent Documents 2 to 5 disclose pyrimidine compounds having a dibenzylamine structure that exhibit strong inhibitory activity against cholesterol ester transfer protein (CETP) and have a strong blood HDL cholesterol increasing action. It is taught that a drug containing as an active ingredient is useful for the prevention and / or treatment of hyper-LDLemia, but this teaching increases HDL by inhibiting CETP, In other words, hyper-DLLemia can be prevented and / or treated by relatively increasing the HDL level, and does not teach that it has an action of directly reducing LDL.
　また、次の一般式（ａ）：
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ｙはアルキル基等で置換されてもよいメチレン基等を示し、Ａは置換されてもよい複素環等を示し、Ｂは置換されてもよいフェニル基を示し、Ｒ１は水素原子又は置換されてもよいアルキル基を示し、Ｒ２は置換されてもよいアルキル基等を示す］で表されるピリミジン誘導体が報告されている（特許文献６）。しかしながら、当該文献に記載された化合物は、ＣＥＴＰ阻害活性に基づく動脈硬化性疾患、高脂血症、脂質異常症の予防又は治療薬として有用であることは記載されているものの、ＰＣＳＫ９タンパクの阻害やＰＣＳＫ９タンパクの発現抑制に関する記載や示唆はない。 Moreover, the following general formula (a):
Figure JPOXMLDOC01-appb-C000008
 [Wherein Y represents a methylene group which may be substituted with an alkyl group, etc., A represents a heterocyclic ring which may be substituted, B represents a phenyl group which may be substituted, and R 1 represents hydrogen. An atom or an alkyl group that may be substituted, and R 2 represents an alkyl group that may be substituted, etc.] has been reported (Patent Document 6). However, although the compounds described in the literature are described as being useful as preventive or therapeutic agents for arteriosclerotic diseases, hyperlipidemia, and dyslipidemia based on CETP inhibitory activity, they inhibit PCSK9 protein. There is no description or suggestion regarding the expression suppression of PCSK9 protein.
　ＰＣｓは癌細胞の増殖、運動、接着、侵襲に影響を与えることから、癌治療の標的として注目されている（非特許文献９）。その他、ＰＣｓは、肥満、糖尿病、動脈硬化症、アルツハイマー病との関連や、後天性免疫不全症候群（ＡＩＤＳ）や重症急性呼吸器症候群（ＳＡＲＳ）等のウイルス感染症等の疾患にも関与することが知られている（非特許文献１０及び１１）。従って、ＰＣＳＫ９タンパク量の低下作用や機能阻害作用を有する化合物は、上記疾患に対する医薬の有効成分としての利用も期待できる。 PCs are attracting attention as targets for cancer treatment because they affect the growth, movement, adhesion, and invasion of cancer cells (Non-patent Document 9). PCs are also involved in obesity, diabetes, arteriosclerosis, Alzheimer's disease, and diseases such as acquired immune deficiency syndrome (AIDS) and severe acute respiratory syndrome (SARS). Is known (Non-Patent Documents 10 and 11). Therefore, a compound having a PCSK9 protein level-reducing action or a function-inhibiting action can be expected to be used as an active ingredient of a medicine for the above diseases.
国際公開第２００９／１４３６３３号パンフレットInternational Publication No. 2009/143633 Pamphlet 国際公開第２００８／０１８５２９号パンフレットInternational Publication No. 2008/018529 Pamphlet 国際公開第２００８／１１１６０４号パンフレットInternational Publication No. 2008/111604 Pamphlet 国際公開第２００８／１２９９５１号パンフレットInternational Publication No. 2008/129951 Pamphlet 特開２０１０－０７７１１６号公報JP 2010-077116 A 国際公開第２００７／０８８９９６号パンフレットInternational Publication No. 2007/088996 Pamphlet
　本発明の課題は、ＰＣＳＫ９ｍＲＮＡの発現を抑制し、ＰＣＳＫ９タンパク量を低下させ、ＬＤＬ受容体量を増加させる作用を有する低分子化合物を有効成分として含み、血中ＬＤＬを低下させることができる医薬を提供することにある。 An object of the present invention is to provide a medicament capable of reducing blood LDL by containing, as an active ingredient, a low molecular weight compound having an action of suppressing the expression of PCSK9 mRNA, reducing the amount of PCSK9 protein, and increasing the amount of LDL receptor. It is to provide.
　本発明者らは、上記目的を達成するため鋭意研究を続けた結果、次の一般式（I）：
Figure JPOXMLDOC01-appb-C000009
 （式中、
Ｒ１は、水素原子、ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、置換基を有してもよいＣ６－１０アリールＣ１－６アルコキシ基、水酸基、Ｃ１－６アルキルアミノ基、ジＣ１－６アルキルアミノ基、Ｃ１－６アルキルチオＣ１－６アルキルアミノ基、Ｃ１－６アルキルスルフィニルＣ１－６アルキルアミノ基、Ｃ１－６アルキルスルホニルＣ１－６アルキルアミノ基、Ｃ６－１０アリールアミノ基、環構成原子にヘテロ原子を有してもよい環状アミノ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルキルアミノ基、ヒドロキシＣ１－６アルコキシ基、ヒドロキシＣ１－６アルキルアミノ基、Ｃ１－６アシルアミノ基、Ｃ１－６アルキルスルホニルアミノ基、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ基、カルボキシＣ１－６アルコキシ基、アミノＣ１－６アルコキシ基、Ｃ１－６アルキルアミノＣ１－６アルコキシ基、ジＣ１－６アルキルアミノＣ１－６アルコキシ基、フェニルチオＣ１－６アルコキシ基、フェニルスルフィニルＣ１－６アルコキシ基、フェニルスルホニルＣ１－６アルコキシ基、及びフェノキシＣ１－６アルコキシ基を示し、
Ｒ２、及びＲ３は、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、Ｃ２－６アルケニル基、置換基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基、Ｃ６－１０アリール基、置換基を有してもよいＣ６－１０アリールＣ１－６アルキル基、若しくはＣ３－８シクロアルキル基を示すか、又はＲ２、及びＲ３が一緒になって隣接する窒素原子とともに置換基を有してもよく環構成原子にヘテロ原子を有してもよい環状アミノ基を形成してもよく、
ＲはＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基または次式（i）：
Figure JPOXMLDOC01-appb-C000010
 （ここでＲ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８は、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、水酸基、シアノ基、ニトロ基、Ｃ１－６アルキルチオ基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、ハロＣ１－６アルキルスルホニルアミノ基、Ｃ６－１０アリールスルホニルアミノ基、置換基を有してもよいアミノ基、カルボキシル基、Ｃ１－６アルキルカルボニル基、又はＣ１－６アルコキシカルボニル基を示し、
Ｒ９は、水素原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を示す）を示し、
式（I）中、
Figure JPOXMLDOC01-appb-C000011
 は、次式（ii）：
Figure JPOXMLDOC01-appb-C000012
 （ここでＲ１０、Ｒ１１、Ｒ１２、及びＲ１３は、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、水酸基、シアノ基、ニトロ基、Ｃ１－６アルキルチオ基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、ハロＣ１－６アルキルスルホニルアミノ基、Ｃ６－１０アリールスルホニルアミノ基、置換基を有してもよいアミノ基、カルボキシル基、Ｃ１－６アルキルカルボニル基、又はＣ１－６アルコキシカルボニル基を示す）
または次式（iii）：
Figure JPOXMLDOC01-appb-C000013
 （ここでＲ１４及びＲ１５は、同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、水酸基、シアノ基、ニトロ基、Ｃ１－６アルキルチオ基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、スルホンアミド基、置換基を有してもよいアミノ基、カルボキシル基、Ｃ１－６アルキルカルボニル基、又はＣ１－６アルコキシカルボニル基を示し、
Figure JPOXMLDOC01-appb-C000014
 は、環構成原子が６～１０個であり、環構成原子の少なくとも一つが窒素原子である単環性又は二環性の複素環を示す）を示し、
さらに一般式（I）は個々の鏡像異性体、及びその混合物の両方を示す。但し、２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸（II）
Figure JPOXMLDOC01-appb-C000015
 の個々の鏡像異性体、及びその混合物を除く。）
で表される化合物、若しくはその塩、又はそれらの溶媒和物がＰＣＳＫ９ｍＲＮＡに対して優れた発現抑制作用、ＰＣＳＫ９タンパクの産生抑制作用を示すことを見出した。ＰＣＳＫ９ｍＲＮＡ発現抑制作用、ＰＣＳＫ９タンパクの産生抑制作用はＬＤＬ受容体の分解を抑制し、血中ＬＤＬを低下させる作用につながるものである。本発明はこの知見を基にして完成された。 As a result of continuing intensive studies to achieve the above object, the present inventors have obtained the following general formula (I):
Figure JPOXMLDOC01-appb-C000009
 (Where
R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkylthio C 1-6 alkoxy group, a C 1-6 alkylsulfinyl C 1-6 alkoxy group, a C 1-6 alkylsulfonyl C 1 A -6 alkoxy group, an optionally substituted C 6-10 aryl C 1-6 alkoxy group, a hydroxyl group, a C 1-6 alkylamino group, a di C 1-6 alkylamino group, a C 1-6 alkylthio C 1-6 alkylamino group, C 1-6 alkylsulfinyl C 1-6 alkylamino group, C 1-6 alkylsulfonyl C 1-6 alkylamino group, C 6-10 arylamino group, hetero atoms in the ring atoms cyclic amino group which may have, C 1-6 alkoxy C 1-6 alkoxy group, C 1-6 alkoxy-C 1-6 alkylamino group, hydroxy C 1-6 a Kokishi group, hydroxy-C 1-6 alkylamino group, C 1-6 acylamino group, C 1-6 alkylsulfonylamino group, C 1-6 alkoxycarbonyl C 1-6 alkoxy group, a carboxy C 1-6 alkoxy group, an amino C 1-6 alkoxy group, C 1-6 alkylamino C 1-6 alkoxy group, di-C 1-6 alkylamino C 1-6 alkoxy group, phenylthio C 1-6 alkoxy group, phenylsulfinyl C 1-6 alkoxy group , Phenylsulfonyl C 1-6 alkoxy group, and phenoxy C 1-6 alkoxy group,
R 2 and R 3 are the same or different and each has a hydrogen atom, a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, or a substituent. An optionally substituted amino C 1-6 alkyl group, an optionally substituted carbamoyl C 1-6 alkyl group, a C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl C 1 Represents a -6 alkyl group, a C 6-10 aryl group, an optionally substituted C 6-10 aryl C 1-6 alkyl group, or a C 3-8 cycloalkyl group, or R 2 and R 3 may form a cyclic amino group which may have a substituent together with the adjacent nitrogen atom or may have a hetero atom in the ring constituent atom,
R is a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, an amino C 1-6 alkyl group which may have a substituent, or a substituent. An optionally substituted carbamoyl C 1-6 alkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group or the following formula (i):
Figure JPOXMLDOC01-appb-C000010
 (Wherein R 4 , R 5 , R 6 , R 7 , and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1- 6 alkoxy, halo C 1-6 alkoxy group, a hydroxyl group, a cyano group, a nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino Group, halo C 1-6 alkylsulfonylamino group, C 6-10 arylsulfonylamino group, optionally substituted amino group, carboxyl group, C 1-6 alkylcarbonyl group, or C 1-6 alkoxycarbonyl Group,
R 9 represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group).
In formula (I),
Figure JPOXMLDOC01-appb-C000011
 Is the following formula (ii):
Figure JPOXMLDOC01-appb-C000012
 (Wherein R 10 , R 11 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl group. C 1-6 alkyl group, halo C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group, hydroxyl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, C 6-10 arylsulfonylamino group And an optionally substituted amino group, carboxyl group, C 1-6 alkylcarbonyl group, or C 1-6 alkoxycarbonyl group)
Or the following formula (iii):
Figure JPOXMLDOC01-appb-C000013
 Wherein R 14 and R 15 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group, a halo C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group, hydroxyl group, cyano group, nitro group, C 1-6 alkylthio group, C A 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, a sulfonamide group, an optionally substituted amino group, a carboxyl group, a C 1-6 alkylcarbonyl group, or a C 1-6 alkoxycarbonyl group Show
Figure JPOXMLDOC01-appb-C000014
 Represents a monocyclic or bicyclic heterocycle having 6 to 10 ring atoms and at least one of the ring atoms being a nitrogen atom),
Furthermore, general formula (I) represents both the individual enantiomers and mixtures thereof. However, 2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine-2- Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid (II)
Figure JPOXMLDOC01-appb-C000015
 Individual enantiomers, and mixtures thereof. )
It has been found that the compound represented by the formula (1) or a salt thereof, or a solvate thereof exhibits an excellent expression inhibitory action on PCSK9 mRNA and a PCSK9 protein production inhibitory action. PCSK9 mRNA expression-suppressing action and PCSK9 protein production-suppressing action suppress the degradation of LDL receptor and lead to the action of lowering blood LDL. The present invention has been completed based on this finding.
　すなわち、本発明により、血中ＬＤＬを低下させる医薬であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬が提供される。 That is, according to the present invention, there is provided a medicament for reducing LDL in blood, which comprises the compound represented by the general formula (I), a salt thereof, or a solvate thereof as an active ingredient.
　当該医薬及び医薬組成物は、血中ＬＤＬコレステロールを低下させることにより、高血中ＬＤＬコレステロール状態に起因する疾患（例えば、高ＬＤＬ血症、脂質異常症（高脂血症）、動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、高コレステロール血症、家族性高コレステロール血症、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧等）の予防及び／又は治療のための医薬として用いることができる。 The medicament and the pharmaceutical composition reduce blood LDL cholesterol, thereby causing diseases caused by high blood LDL cholesterol (for example, hyper LDL dysfunction, dyslipidemia (hyperlipidemia), arteriosclerosis, Atherosclerosis, peripheral vascular disease, hypercholesterolemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic re It can be used as a medicament for the prevention and / or treatment of stenosis, hypertension, etc.
　さらに、本発明は、高血中ＬＤＬコレステロール状態に起因する疾患の予防及び／又は治療のための医薬を製造するための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用；高血中ＬＤＬコレステロール状態に起因する疾患の予防及び／又は治療に用いるための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を提供するものである。 Furthermore, the present invention relates to a compound represented by the above general formula (I) or a salt thereof for producing a medicament for the prevention and / or treatment of a disease caused by a high blood LDL cholesterol state, or a salt thereof, Use of a solvate; providing a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for use in the prevention and / or treatment of a disease caused by high blood LDL cholesterol status To do.
　また、本発明により、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むＰＣＳＫ９ｍＲＮＡ発現抑制剤；前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むＰＣＳＫ９産生抑制剤が提供される。ＰＣＳＫ９ｍＲＮＡ発現抑制剤の製造のための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用；ＰＣＳＫ９ｍＲＮＡ発現抑制に用いるための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物も本発明により提供される。 In addition, according to the present invention, a compound represented by the general formula (I), a salt thereof, or a PCSK9 mRNA expression inhibitor containing the solvate as an active ingredient; a compound represented by the general formula (I), Alternatively, a PCSK9 production inhibitor containing a salt thereof or a solvate thereof as an active ingredient is provided. Use of the compound represented by the above general formula (I), or a salt thereof, or a solvate thereof for the production of a PCSK9 mRNA expression inhibitor; represented by the above general formula (I) for use in suppressing PCSK9 mRNA expression Or a salt thereof, or a solvate thereof is also provided by the present invention.
　さらに、本発明は、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とするＰＣＳＫ９タンパク量の低下剤；前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とするＰＣＳＫ９タンパク産生抑制剤；及び前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とするＬＤＬ受容体量の増加剤を提供するものである。 Furthermore, the present invention provides a PCSK9 protein amount reducing agent comprising the compound represented by the general formula (I) or a salt thereof, or a solvate thereof as an active ingredient; represented by the general formula (I) PCSK9 protein production inhibitor comprising a compound, or a salt thereof, or a solvate thereof as an active ingredient; and a compound represented by the general formula (I), or a salt thereof, or a solvate thereof as an active ingredient The present invention provides an agent for increasing the amount of LDL receptor.
　また、本発明は、ＰＣＳＫ９タンパク量の低下剤、ＰＣＳＫ９タンパク産生抑制剤又はＬＤＬ受容体量の増加剤を製造するための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用；及びＰＣＳＫ９タンパク量の低下、ＰＣＳＫ９タンパク産生抑制又はＬＤＬ受容体量の増加に用いるための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を提供するものである。 Further, the present invention provides a compound represented by the above general formula (I) for producing a PCSK9 protein amount reducing agent, a PCSK9 protein production inhibitor or an LDL receptor amount increasing agent, or a salt thereof, or their Use of a solvate; and a compound represented by the above general formula (I) or a salt thereof, or a solvate thereof for use in reducing PCSK9 protein amount, inhibiting PCSK9 protein production, or increasing LDL receptor amount Is to provide.
　さらに、本発明は、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とする、ＰＣｓの関与する疾患（癌、肥満、糖尿病、アルツハイマー病、又はウイルス感染症等）の予防及び／又は治療のための医薬を提供するものである。 Furthermore, the present invention relates to a disease associated with PCs (cancer, obesity, diabetes, Alzheimer's disease, or the like, comprising the compound represented by the above general formula (I), a salt thereof, or a solvate thereof as an active ingredient. The present invention provides a medicament for the prevention and / or treatment of viral infections and the like.
　さらに、本発明は、ＰＣｓの関与する疾患の予防及び／又は治療のための医薬を製造するための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用；及びＰＣｓの関与する疾患の予防及び／又は治療に用いるための前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を提供するものである。 Furthermore, the present invention relates to the use of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for the manufacture of a medicament for the prevention and / or treatment of diseases involving PCs. And a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for use in the prevention and / or treatment of diseases involving PCs.
　さらに別の観点から、本発明は、前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を有効成分とするＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現抑制剤；前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を有効成分とするＨＭＧ－ＣｏＡ還元酵素産生抑制剤；及び前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を有効成分とするＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現に起因する疾患（例えば、炎症、癌、アルツハイマー病、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染、ウイルス感染、乾癬、黄斑変性など）の予防及び／又は治療のための医薬を提供するものである。 From still another aspect, the present invention provides an HMG-CoA reductase mRNA expression inhibitor comprising as an active ingredient the compound represented by the general formula (I), or a salt thereof, or a solvate thereof; HMG-CoA reductase production inhibitor comprising a compound represented by formula (I), or a salt thereof, or a solvate thereof as an active ingredient; and a compound represented by general formula (I), or a compound thereof Diseases caused by expression of HMG-CoA reductase mRNA containing a salt of glycerin or a solvate thereof as an active ingredient (eg inflammation, cancer, Alzheimer's disease, osteoporosis, prostatic hypertrophy, glomerular disease, parasitic infection, viral infection , Psoriasis, macular degeneration, and the like).
　また、本発明は、ＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現抑制剤、ＨＭＧ－ＣｏＡ還元酵素産生抑制剤、又はＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現に起因する疾患の予防及び／又は治療のための医薬を製造するための前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の使用；及びＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現抑制剤、ＨＭＧ－ＣｏＡ還元酵素産生抑制剤、又はＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現に起因する疾患の予防及び／又は治療のための医薬の有効成分として使用するための前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を提供するものである。 The present invention also provides an HMG-CoA reductase mRNA expression inhibitor, an HMG-CoA reductase production inhibitor, or a medicament for the prevention and / or treatment of diseases caused by HMG-CoA reductase mRNA expression. And the use of a compound represented by the general formula (I), or a salt thereof, or a solvate thereof; and an HMG-CoA reductase mRNA expression inhibitor, an HMG-CoA reductase production inhibitor, or an HMG -A compound represented by the above general formula (I), or a salt thereof, or a solvation thereof for use as an active ingredient of a medicament for the prevention and / or treatment of diseases caused by CoA reductase mRNA expression It provides things.
　また、本発明は、ヒトを含む哺乳類動物の生体内においてＰＣＳＫ９ｍＲＮＡの発現を抑制する方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法；ヒトを含む哺乳類動物の生体内においてＰＣＳＫ９タンパク量を低下させる方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法；ヒトを含む哺乳類動物の生体内においてＰＣＳＫ９タンパクの産生を抑制する方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法；ヒトを含む哺乳類動物の生体内においてＬＤＬ受容体量を増加する方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法；及び、ヒトを含む哺乳類動物の血中ＬＤＬを低下させる方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。 The present invention also relates to a method for suppressing the expression of PCSK9 mRNA in vivo in mammals including humans, wherein the compound represented by the general formula (I), a salt thereof, or an effective solvate thereof is used. A method comprising a step of administering an amount to a mammal including a human; a method for reducing the amount of PCSK9 protein in a living body of a mammal including a human, the compound represented by the general formula (I), or a method thereof A method comprising a step of administering an effective amount of a salt or a solvate thereof to a mammal including a human; a method for suppressing the production of PCSK9 protein in a living body of a mammal including a human, wherein the general formula A method comprising administering an effective amount of a compound represented by (I) or a salt thereof, or a solvate thereof to a mammal including a human; A method for increasing the amount of LDL receptor in vivo, wherein an effective amount of the compound represented by the general formula (I), a salt thereof, or a solvate thereof is administered to mammals including humans And a method for reducing LDL in blood of mammals including humans, which is an effective amount of the compound represented by the general formula (I), or a salt thereof, or a solvate thereof Is provided to mammals including humans.
　また、本発明は、ヒトを含む哺乳類動物における高血中ＬＤＬコレステロール状態に起因する疾患の予防及び／又は治療方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。 The present invention also relates to a method for preventing and / or treating a disease caused by high blood LDL cholesterol status in mammals including humans, the compound represented by the general formula (I), or a salt thereof, or The present invention provides a method comprising the step of administering an effective amount of these solvates to mammals including humans.
　さらに、本発明は、ヒトを含む哺乳類動物におけるＰＣｓの関与する疾患（癌、肥満、糖尿病、アルツハイマー病、又はウイルス感染症等）の予防及び／又は治療方法であって、前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。 Furthermore, the present invention is a method for preventing and / or treating diseases (cancer, obesity, diabetes, Alzheimer's disease, viral infection, etc.) involving PCs in mammals including humans, wherein the general formula (I) And a salt thereof, or a solvate thereof, is administered to mammals including humans.
　さらに、本発明は、ヒトを含む哺乳類動物の生体内においてＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡの発現を抑制する方法であって、前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法；ヒトを含む哺乳類動物の生体内においてＨＭＧ－ＣｏＡ還元酵素の産生を抑制する方法であって、前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法；及び、ヒトを含む哺乳類動物においてＨＭＧ－ＣｏＡ還元酵素ｍＲＮＡ発現に起因する疾患（例えば、炎症、癌、アルツハイマー病、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染、ウイルス感染、乾癬、黄斑変性など）を予防及び／又は治療する方法であって、前記一般式（I）で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。　 Furthermore, the present invention provides a method for suppressing the expression of HMG-CoA reductase mRNA in the living body of mammals including humans, comprising the compound represented by the general formula (I), or a salt thereof, A method comprising the step of administering an effective amount of a solvate of the above to a mammal including a human; a method of suppressing the production of HMG-CoA reductase in a living body of a mammal including a human, wherein the general formula ( A method comprising administering an effective amount of a compound represented by I) or a salt thereof, or a solvate thereof to a mammal including a human; and HMG-CoA reductase in a mammal including a human; Diseases resulting from mRNA expression (eg inflammation, cancer, Alzheimer's disease, osteoporosis, enlarged prostate, glomerular disease, parasitic infection, viral infection, psoriasis, macular degeneration, etc.) A method for preventing and / or treating, comprising a step of administering an effective amount of the compound represented by the general formula (I), or a salt thereof, or a solvate thereof to mammals including humans. A method is provided. *
　さらに別の観点からは、本発明により、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸、
２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［エチル（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（エチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチル、
４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸、
２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチル、
２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸、
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチル、
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸、
３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸メチル、
３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸、
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］プロピオン酸メチル、
５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
５－｛［ベンジル（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（４－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸イソプロピル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸メチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
５－｛［（３，５－ジフルオロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（２－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（３－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（２－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（３－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（４－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（２－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（４－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（３－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（４－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
５－｛［（シクロプロピルメチル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－｛ｔｒａｎｓ－４－［（エチル｛２－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチル、
５－｛［（５－エトキシピリミジン－２－イル）（３－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、及び
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
並びにそれらの塩、及びそれらの溶媒和物が新規物質として提供される。 From another point of view, according to the present invention,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid,
2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino} methyl)- 4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[ethyl (5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (ethyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) ethyl butanoate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) butanoic acid,
2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Yl} amino) methyl acetate,
2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Il} amino) acetic acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] propionic acid,
3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} methyl propionate,
3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} propionic acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl propionate,
5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
5-{[benzyl (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-Ethoxypyrimidin-2-yl) (4-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) isopropyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) methyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
5-{[(3,5-difluorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-Ethoxypyrimidin-2-yl) (2-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (3-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(2-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(3-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(4-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (2-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (4-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (3-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (4-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile,
5-{[(Cyclopropylmethyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
2- {trans-4-[(ethyl {2-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
5-{[(5-Ethoxypyrimidin-2-yl) (3-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
2-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile and 3-{[{[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) Amino] methyl} benzonitrile,
And their salts and their solvates are provided as novel substances.
　本発明の前記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物は、後述する実施例に具体的に開示されている通り、ＰＣＳＫ９ｍＲＮＡに対し強い発現抑制作用を示し、ＰＣＳＫ９タンパクの産生抑制を示すことから、ＰＣＳＫ９タンパク産生に基づく疾患の予防及び／又は治療剤の有効成分として好適に使用でき、血中ＬＤＬを低下させる医薬の有効成分として特に好適に使用することができる。 The compound represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof exhibits a strong expression inhibitory action on PCSK9 mRNA, as specifically disclosed in Examples described later. Since it shows suppression of PCSK9 protein production, it can be preferably used as an active ingredient of a prophylactic and / or therapeutic agent for diseases based on PCSK9 protein production, and particularly preferably used as an active ingredient of a medicine that lowers blood LDL. Can do.
　本発明におけるＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基、Ｃ６－１０アリールＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基におけるＣ１－６アルキル基としては、直鎖又は分岐鎖の炭素数１～６のアルキル基、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、ｔ－ブチル基、ｎ－ペンチル基、２－メチルブチル基、２，２－ジメチルプロピル基等が挙げられる。 C 1-6 alkyl group, halo C 1-6 alkyl group, C 3-8 cycloalkyl C 1-6 alkyl group, C 6-10 aryl C 1-6 alkyl group, carboxy C 1-6 alkyl group in the present invention as the C 1-6 alkyl group in C 1-6 alkoxycarbonyl C 1-6 alkyl group, straight chain or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n- propyl group Isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group and the like.
　本明細書におけるＣ２－６アルケニル基としては、アルキル鎖上のいずれか１カ所以上に炭素－炭素二重結合を有する炭素数２～６の直鎖、又は分岐鎖のアルケニル基、例えば、ビニル基、アリル基、１－プロペニル基、イソプロペニル基、ブタ－１－エン－１－イル基、ブタ－２－エン－１－イル基、ブタ－３－エン－１－イル基、ブタ－１－エン－２－イル基、ブタ－３－エン－２－イル基、ペンタ－１－エン－１－イル基、ペンタ－４－エン－１－イル基、ペンタ－１－エン－２－イル基、ペンタ－４－エン－２－イル基、３－メチル－ブタ－１－エン－１－イル基、ヘキサ－１－エン－１－イル基、ヘキサ－５－エン－１－イル基等が挙げられる。 In the present specification, the C 2-6 alkenyl group includes a straight or branched alkenyl group having 2 to 6 carbon atoms having a carbon-carbon double bond at any one or more positions on the alkyl chain, such as vinyl. Group, allyl group, 1-propenyl group, isopropenyl group, but-1-en-1-yl group, but-2-en-1-yl group, but-3-en-1-yl group, buta-1 -En-2-yl group, but-3-en-2-yl group, penta-1-en-1-yl group, penta-4-en-1-yl group, penta-1-en-2-yl Group, penta-4-en-2-yl group, 3-methyl-but-1-en-1-yl group, hexa-1-en-1-yl group, hexa-5-en-1-yl group, etc. Is mentioned.
　本発明におけるＣ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、Ｃ６－１０アリールＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルキルアミノ基、ヒドロキシＣ１－６アルコキシ基、カルボキシＣ１－６アルコキシ基、アミノＣ１－６アルコキシ基、Ｃ１－６アルキルアミノＣ１－６アルコキシ基、ジＣ１－６アルキルアミノＣ１－６アルコキシ基、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ基、フェニルチオＣ１－６アルコキシ基、フェニルスルフィニルＣ１－６アルコキシ基、フェニルスルホニルＣ１－６アルコキシ基、フェノキシＣ１－６アルコキシ基におけるＣ１－６アルコキシ基としては、直鎖又は分岐鎖の炭素数１～６のアルコキシ基、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｔ－ブトキシ基、ｎ－ペンチルオキシ基、２－メチルブトキシ基、２，２－ジメチルプロポキシ基等が挙げられる。 C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkylthio C 1-6 alkoxy group, C 1-6 alkylsulfinyl C 1-6 alkoxy group, C 1-6 alkylsulfonyl C in the present invention 1-6 alkoxy group, C 6-10 aryl C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkylamino group, hydroxy C 1-6 alkoxy group Carboxy C 1-6 alkoxy group, amino C 1-6 alkoxy group, C 1-6 alkylamino C 1-6 alkoxy group, di-C 1-6 alkylamino C 1-6 alkoxy group, C 1-6 alkoxycarbonyl C 1-6 alkoxy group, phenylthio C 1-6 alkoxy group, phenylsulfinyl C 1-6 alkoxy group, phenyl sulfoni Le C 1-6 alkoxy group, the C 1-6 alkoxy group in the phenoxy C 1-6 alkoxy group, a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, e.g., methoxy, ethoxy, n- Examples thereof include a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a t-butoxy group, an n-pentyloxy group, a 2-methylbutoxy group, and a 2,2-dimethylpropoxy group.
　本発明におけるＣ１－６アルキルチオ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルキルアミノ基におけるＣ１－６アルキルチオ基としては、直鎖又は分岐鎖の炭素数１～６のアルキルチオ基、例えば、メチルチオ基、エチルチオ基、ｎ－プロピルチオ基、イソプロピルチオ基、ｎ－ブチルチオ基、イソブチルチオ基、ｔ－ブチルチオ基、ｎ－ペンチルチオ基、２－メチルブチルチオ基、２，２－ジメチルプロピルチオ基等が挙げられる。 C 1-6 alkylthio group in the present invention, C 1-6 alkylthio C 1-6 alkoxy group, the C 1-6 alkylthio group in the C 1-6 alkylthio-C 1-6 alkylamino group, a straight-chain or branched-chain C1-C6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, n-pentylthio, 2-methylbutylthio Group, 2,2-dimethylpropylthio group and the like.
　本発明における、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルキルアミノ基におけるＣ１－６アルキルスルフィニル基としては、直鎖又は分岐鎖の炭素数１～６のアルキルスルフィニル基、例えば、メチルスルフィニル基、エチルスルフィニル基、ｎ－プロピルスルフィニル基、イソプロピルスルフィニル基、ｎ－ブチルスルフィニル基、イソブチルスルフィニル基、ｔ－ブチルスルフィニル基、ｎ－ペンチルスルフィニル基、２－メチルブチルスルフィニル基、２，２－ジメチルプロピルスルフィニル基等が挙げられる。 In the present invention, the C 1-6 alkylsulfinyl group, the C 1-6 alkylsulfinyl C 1-6 alkoxy group, the C 1-6 alkylsulfinyl C 1-6 alkylamino group, the C 1-6 alkylsulfinyl group includes Chain or branched alkyl sulfinyl group having 1 to 6 carbon atoms, for example, methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, t-butylsulfinyl group N-pentylsulfinyl group, 2-methylbutylsulfinyl group, 2,2-dimethylpropylsulfinyl group and the like.
　本発明における、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルキルアミノ基におけるＣ１－６アルキルスルホニル基としては、直鎖又は分岐鎖の炭素数１～６のアルキルスルホニル基、例えば、メチルスルホニル基、エチルスルホニル基、ｎ－プロピルスルホニル基、イソプロピルスルホニル基、ｎ－ブチルスルホニル基、イソブチルスルホニル基、ｔ－ブチルスルホニル基、ｎ－ペンチルスルホニル基、２－メチルブチルスルホニル基、２，２－ジメチルプロピルスルホニル基等が挙げられる。 In the present invention, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonyl C 1-6 alkoxy group, a C 1-6 alkylsulfonyl group in C 1-6 alkylsulfonyl-C 1-6 alkylamino group, a straight Chain or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, t-butylsulfonyl group N-pentylsulfonyl group, 2-methylbutylsulfonyl group, 2,2-dimethylpropylsulfonyl group and the like.
　本発明における、Ｃ１－６アルキルカルボニル基としては、直鎖又は分岐鎖の炭素数１～６のアルキルカルボニル基、例えば、メチルカルボニル基、エチルカルボニル基、ｎ－プロピルカルボニル基、イソプロピルカルボニル基、ｎ－ブチルカルボニル基、イソブチルカルボニル基、ｔ－ブチルカルボニル基、ｎ－ペンチルカルボニル基、２－メチルブチルカルボニル基、２，２－ジメチルプロピルカルボニル基等が挙げられる。 As the C 1-6 alkylcarbonyl group in the present invention, a linear or branched alkylcarbonyl group having 1 to 6 carbon atoms, such as a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, Examples thereof include n-butylcarbonyl group, isobutylcarbonyl group, t-butylcarbonyl group, n-pentylcarbonyl group, 2-methylbutylcarbonyl group, 2,2-dimethylpropylcarbonyl group and the like.
　本発明における、Ｃ１－６アルコキシカルボニル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基におけるＣ１－６アルコキシカルボニル基としては、直鎖又は分岐鎖の炭素数１～６のアルコキシカルボニル基、例えば、メトキシカルボニル基、エトキシカルボニル基、ｎ－プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ－ブトキシカルボニル基、イソブトキシカルボニル基、ｔ－ブトキシカルボニル基、ｎ－ペンチルオキシカルボニル基、２－メチルブトキシカルボニル基、２，２－ジメチルプロポキシカルボニル基等が挙げられる。 In the present invention, C 1-6 alkoxycarbonyl group, C 1-6 alkoxy As the C 1-6 alkoxycarbonyl group in the carbonylation C 1-6 alkyl group, straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms For example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group, 2-methylbutoxy Examples include a carbonyl group and a 2,2-dimethylpropoxycarbonyl group.
　本発明における、Ｃ１－６アシルアミノ基としては、直鎖又は分岐鎖の炭素数１～６のアシルアミノ基、例えば、ホルミルアミノ基、アセチルアミノ基、ｎ－プロピオニルアミノ基、イソプロピオニルアミノ基、ブチリルアミノ基、イソブチリルアミノ基、ｔ－ブチリルアミノ基、ｎ－ペンタノイルアミノ基、２－メチルブチリルアミノ基、２，２－ジメチルプロピオニルアミノ基等が挙げられる。 In the present invention, the C 1-6 acylamino group is a linear or branched acylamino group having 1 to 6 carbon atoms, such as formylamino group, acetylamino group, n-propionylamino group, isopropionylamino group, butyrylamino. Group, isobutyrylamino group, t-butyrylamino group, n-pentanoylamino group, 2-methylbutyrylamino group, 2,2-dimethylpropionylamino group and the like.
　本発明における、Ｃ１－６アルキルアミノ基、Ｃ１－６アルキルチオＣ１－６アルキルアミノ基、Ｃ１－６アルキルスルフィニルＣ１－６アルキルアミノ基、Ｃ１－６アルキルスルホニルＣ１－６アルキルアミノ基、Ｃ１－６アルコキシＣ１－６アルキルアミノ基、ヒドロキシＣ１－６アルキルアミノ基、Ｃ１－６アルキルアミノＣ１－６アルコキシ基におけるＣ１－６アルキルアミノ基としては、直鎖又は分岐鎖の炭素数１～６のアルキルアミノ基、例えば、メチルアミノ基、エチルアミノ基、ｎ－プロピルアミノ基、イソプロピルアミノ基、ｎ－ブチルアミノ基、イソブチルアミノ基、ｔ－ブチルアミノ基、ｎ－ペンチルアミノ基、２－メチルブチルアミノ基、２，２－ジメチルプロピルアミノ基等が挙げられる。 In the present invention, a C 1-6 alkylamino group, a C 1-6 alkylthio C 1-6 alkylamino group, a C 1-6 alkylsulfinyl C 1-6 alkylamino group, a C 1-6 alkylsulfonyl C 1-6 alkyl amino group, C 1-6 alkoxy-C 1-6 alkylamino group, hydroxy-C 1-6 alkylamino group, the C 1-6 alkylamino group in C 1-6 alkylamino C 1-6 alkoxy group, a straight-chain Or a branched alkylamino group having 1 to 6 carbon atoms, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, t-butylamino group, Examples thereof include an n-pentylamino group, a 2-methylbutylamino group, and a 2,2-dimethylpropylamino group.
　本発明における、ジＣ１－６アルキルアミノ基、ジＣ１－６アルキルアミノＣ１－６アルコキシ基におけるジＣ１－６アルキルアミノ基としては、それぞれ同一又は異なる直鎖又は分岐鎖の炭素数１～６のアルキル基が２個置換したアミノ基、例えば、メチルエチルアミノ基、ｎ－プロピルイソプロピルアミノ基、ｎ－ブチルイソブチルアミノ基、ｔ－ブチル－ｎ－ペンチルアミノ基、２－メチルブチル－２，２－ジメチルプロピルアミノ基等が挙げられる。 In the present invention, di-C 1-6 alkylamino group, a di C 1-6 alkylamino group in di-C 1-6 alkylamino C 1-6 alkoxy group, the carbon number of the same or different straight-chain or branched-chain An amino group substituted with two alkyl groups of 1 to 6, for example, methylethylamino group, n-propylisopropylamino group, n-butylisobutylamino group, t-butyl-n-pentylamino group, 2-methylbutyl-2 , 2-dimethylpropylamino group and the like.
　本発明における、Ｃ１－６アルキルスルホニルアミノ基、ハロＣ１－６アルキルスルホニルアミノ基におけるＣ１－６アルキルスルホニルアミノ基としては、直鎖又は分岐鎖の炭素数１～６のアルキルスルホニルアミノ基、例えば、メチルスルホニルアミノ基、エチルスルホニルアミノ基、ｎ－プロピルスルホニルアミノ基、イソプロピルスルホニルアミノ基、ｎ－ブチルスルホニルアミノ基、イソブチルスルホニルアミノ基、ｔ－ブチルスルホニルアミノ基、ｎ－ペンチルスルホニルアミノ基、２－メチルブチルスルホニルアミノ基、２，２－ジメチルプロピルスルホニルアミノ基等が挙げられる。 In the present invention, C 1-6 alkylsulfonylamino group, the C 1-6 alkylsulfonylamino group in halo C 1-6 alkylsulfonylamino group, a linear or branched alkylsulfonylamino group having 1 to 6 carbon atoms For example, methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, isopropylsulfonylamino group, n-butylsulfonylamino group, isobutylsulfonylamino group, t-butylsulfonylamino group, n-pentylsulfonylamino group 2-methylbutylsulfonylamino group, 2,2-dimethylpropylsulfonylamino group and the like.
　本発明における、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基におけるＣ３－８シクロアルキル基としては、環状の炭素数３～８のシクロアルキル基、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、シクロへキシル基等が挙げられる。 In the present invention, a C 3-8 cycloalkyl group, C 3-8 The C 3-8 cycloalkyl group in the cycloalkyl C 1-6 alkyl group, a cycloalkyl group of cyclic 3 carbon atoms to 8, for example, cyclo A propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned.
　本発明における、Ｃ６－１０アリール基、Ｃ６－１０アリールＣ１－６アルキル基、Ｃ６－１０アリールＣ１－６アルコキシ基、Ｃ６－１０アリールアミノ基、Ｃ６－１０アリールスルホニルアミノ基におけるＣ６－１０アリール基としては、炭素数６～１０のアリール基、例えば、フェニル基、ナフチル基等が挙げられる。 In the present invention, a C 6-10 aryl group, a C 6-10 aryl C 1-6 alkyl group, a C 6-10 aryl C 1-6 alkoxy group, a C 6-10 arylamino group, a C 6-10 arylsulfonylamino Examples of the C 6-10 aryl group in the group include aryl groups having 6 to 10 carbon atoms, such as a phenyl group and a naphthyl group.
　本発明における、ハロゲン原子、ハロＣ１－６アルキル基、ハロＣ１－６アルコキシ基におけるハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。 In the present invention, examples of the halogen atom in the halogen atom, halo C 1-6 alkyl group, and halo C 1-6 alkoxy group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　一般式（I）、（i）、（ii）中、Ｒ１、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３におけるハロゲン原子としては、フッ素原子、塩素原子、臭素原子が好ましく、Ｒ１においては、臭素原子が、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８においては、フッ素原子、塩素原子がより好ましい。 In general formula (I), (i), (ii), as a halogen atom in R < 1 >, R < 4 >, R < 5 >, R < 6 >, R < 7 >, R < 8 >, R < 10 >, R <11> , R < 12 >, and R < 13 > , A fluorine atom, a chlorine atom, and a bromine atom are preferable. In R 1 , a bromine atom is preferable, and in R 4 , R 5 , R 6 , R 7 , and R 8 , a fluorine atom and a chlorine atom are more preferable.
　一般式（I）、（i）、（ii）、（iii）中、Ｒ、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、及びＲ１５におけるＣ１－６アルキル基としては、メチル基、エチル基が好ましく、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３においては、メチル基がより好ましい。 In the general formulas (I), (i), (ii), and (iii), R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are preferably a C 1-6 alkyl group, preferably a methyl group or an ethyl group. R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11, the R 12, and R 13 is more preferably a methyl group.
　一般式（I）、（i）、（ii）、（iii）中、Ｒ１、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、及びＲ１５におけるＣ１－６アルコキシ基としては、メトキシ基、エトキシ基が好ましく、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、及びＲ１５においては、メトキシ基がより好ましい。 In the general formulas (I), (i), (ii) and (iii), R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R As the C 1-6 alkoxy group in 14 and R 15 , a methoxy group and an ethoxy group are preferable, and R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , In R 14 and R 15 , a methoxy group is more preferable.
　一般式（i）、（ii）、（iii）中、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、及びＲ１５におけるハロＣ１－６アルキル基としては、例えば、トリフルオロメチル基、２，２，２－トリフルオロエチル基、ペンタフルオロエチル基等の化学的に可能な数のハロゲン原子が置換したＣ１－６アルキル基等が挙げられ、トリフルオロメチル基が好ましい。 In the general formulas (i), (ii) and (iii), R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R The halo C 1-6 alkyl group in 15 is, for example, C 1 substituted with a chemically possible number of halogen atoms such as trifluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group and the like. -6 alkyl group and the like can be mentioned, and a trifluoromethyl group is preferable.
　一般式（i）、（ii）、（iii）中、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、及びＲ１５におけるハロＣ１－６アルコキシ基としては、例えば、トリフルオロメトキシ基、２，２，２－トリフルオロエトキシ基、ペンタフルオロエトキシ基等の化学的に可能な数のハロゲン原子が置換したＣ１－６アルコキシ基が挙げられ、トリフルオロメトキシ基が好ましい。 In general formulas (i), (ii), and (iii), halo in R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 Examples of the C 1-6 alkoxy group include a C 1-6 alkoxy substituted with a chemically possible number of halogen atoms such as a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a pentafluoroethoxy group, and the like. Group, and a trifluoromethoxy group is preferable.
　一般式（i）、（ii）、（iii）中、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３、Ｒ１４、及びＲ１５における、置換基を有してもよいアミノ基における置換基としては、例えば、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ６－１０アリール基等が挙げられる。置換基を有してもよいアミノ基は、置換基をそれぞれ同一又は異なって、１又は２個有していてもよい。 In the general formulas (i), (ii), and (iii), in R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 , R 14 , and R 15 Examples of the substituent in the amino group that may have a substituent include a C 1-6 alkyl group, a halo C 1-6 alkyl group, and a C 6-10 aryl group. The amino group which may have a substituent may be the same or different and may have one or two substituents.
　一般式（i）、（ii）、（iii）中、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４、及びＲ１５としては、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、水酸基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、シアノ基、カルボキシル基、又はＣ１－６アルコキシカルボニル基であることが好ましく、Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基であり、Ｒ１４、及びＲ１５が、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、水酸基、又はＣ１－６アルコキシ基であり、Ｒ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、シアノ基、カルボキシル基、又はＣ１－６アルコキシカルボニル基であることが特に好ましい。 In the general formulas (i), (ii), and (iii), as R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 , Are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, a carboxyl group Or a C 1-6 alkoxycarbonyl group, and R 10 , R 11 , R 12 , and R 13 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C A 1-6 alkyl group, a C 1-6 alkoxy group, wherein R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a hydroxyl group, or C 1-6 Al An alkoxy group, R 4, R 5, R 6, R 7, and R 8 are the same or different, a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl groups, C A 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, a carboxyl group, or a C 1-6 alkoxycarbonyl group is particularly preferable.
　一般式（I）中、Ｒ１におけるＣ１－６アルキルチオＣ１－６アルコキシ基としては、例えば、メチルチオメトキシ基、２－メチルチオエトキシ基、３－メチルチオプロポキシ基等が挙げられ、２－メチルチオエトキシ基が好ましい。 In the general formula (I), examples of the C 1-6 alkylthio C 1-6 alkoxy group in R 1 include a methylthiomethoxy group, a 2-methylthioethoxy group, a 3-methylthiopropoxy group, and the like. Groups are preferred.
　一般式（I）中、Ｒ１におけるＣ１－６アルキルスルフィニルＣ１－６アルコキシ基としては、例えば、メチルスルフィニルメトキシ基、２－メチルスルフィニルエトキシ基、３－メチルスルフィニルプロポキシ基等が挙げられ、２－メチルスルフィニルエトキシ基が好ましい。 In the general formula (I), examples of the C 1-6 alkylsulfinyl C 1-6 alkoxy group in R 1 include a methylsulfinylmethoxy group, a 2-methylsulfinylethoxy group, and a 3-methylsulfinylpropoxy group. A 2-methylsulfinylethoxy group is preferred.
　一般式（I）中、Ｒ１におけるＣ１－６アルキルスルホニルＣ１－６アルコキシ基としては、例えば、メチルスルホニルメトキシ基、２－メチルスルホニルエトキシ基、３－メチルスルホニルプロポキシ基等が挙げられ、２－メチルスルホニルエトキシ基が好ましい。 In the general formula (I), examples of the C 1-6 alkylsulfonyl C 1-6 alkoxy group in R 1 include a methylsulfonylmethoxy group, a 2-methylsulfonylethoxy group, a 3-methylsulfonylpropoxy group, and the like. A 2-methylsulfonylethoxy group is preferred.
　一般式（I）中、Ｒ１における置換基を有してもよいＣ６－１０アリールＣ１－６アルコキシ基における置換基としては、例えば、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、シアノ基等が挙げられる。また、これらの置換基の置換位置は特に限定されないが、本発明においては、Ｃ６－１０アリールＣ１－６アルコキシ基のアリール環上に置換することが好ましい。このような基としては、フェニル基上に置換基としてハロゲン原子、ハロＣ１－６アルキル基、又はシアノ基を有してもよいフェニルＣ１－６アルコキシ基、例えば、３－シアノ－５－トリフルオロメチルベンジルオキシ基、２，３－ジフルオロベンジルオキシ基等が挙げられる。 In general formula (I), examples of the substituent in the C 6-10 aryl C 1-6 alkoxy group which may have a substituent in R 1 include a halogen atom, a C 1-6 alkyl group, and halo C 1. Examples include a -6 alkyl group and a cyano group. In addition, although the substitution position of these substituents is not particularly limited, in the present invention, substitution on the aryl ring of a C 6-10 aryl C 1-6 alkoxy group is preferable. Examples of such a group include a phenyl C 1-6 alkoxy group which may have a halogen atom, a halo C 1-6 alkyl group, or a cyano group as a substituent on the phenyl group, such as 3-cyano-5- Examples thereof include a trifluoromethylbenzyloxy group and a 2,3-difluorobenzyloxy group.
　一般式（I）中、Ｒ１における環構成原子にヘテロ原子を有してもよい環状アミノ基としては、例えば、ピロリジニル基、モルホリニル基、ピペリジニル基等が挙げられ、モルホリノ基、ピペリジノ基が好ましい。 In the general formula (I), examples of the cyclic amino group which may have a hetero atom in the ring constituent atom in R 1 include a pyrrolidinyl group, a morpholinyl group, a piperidinyl group and the like, and a morpholino group and a piperidino group are preferable. .
　一般式（I）中、Ｒ１におけるＣ１－６アルコキシカルボニルＣ１－６アルコキシ基としては、例えば、メトキシカルボニルメトキシ基、エトキシカルボニルメトキシ基、メトキシカルボニルエトキシ基、エトキシカルボニルエトキシ基、メトキシカルボニルプロポキシ基、エトキシカルボニルプロポキシ基等が挙げられ、エトキシカルボニルプロポキシ基が好ましい。 In the general formula (I), examples of the C 1-6 alkoxycarbonyl C 1-6 alkoxy group in R 1 include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, a methoxycarbonylethoxy group, an ethoxycarbonylethoxy group, and a methoxycarbonylpropoxy group. Group, ethoxycarbonylpropoxy group and the like, and ethoxycarbonylpropoxy group is preferable.
　一般式（I）中、Ｒ１におけるカルボキシＣ１－６アルコキシ基としては、例えば、カルボキシメトキシ基、カルボキシエトキシ基、カルボキシプロポキシ基等が挙げられ、カルボキシプロポキシ基が好ましい。 In general formula (I), examples of the carboxy C 1-6 alkoxy group in R 1 include a carboxymethoxy group, a carboxyethoxy group, a carboxypropoxy group, and the like, and a carboxypropoxy group is preferable.
　一般式（I）中、Ｒ１におけるフェニルチオＣ１－６アルコキシ基としては、例えば、フェニルチオメトキシ基、フェニルチオエトキシ基、フェニルチオプロポキシ基等が挙げられ、フェニルチオエトキシ基が好ましい。 In the general formula (I), examples of the phenylthio C 1-6 alkoxy group in R 1 include a phenylthiomethoxy group, a phenylthioethoxy group, a phenylthiopropoxy group, and the like, and a phenylthioethoxy group is preferable.
　一般式（I）中、Ｒ１におけるフェニルスルフィニルＣ１－６アルコキシ基としては、例えば、フェニルスルフィニルメトキシ基、フェニルスルフィニルエトキシ基、フェニルスルフィニルプロポキシ基等が挙げられ、フェニルスルフィニルエトキシ基が好ましい。 In the general formula (I), examples of the phenylsulfinyl C 1-6 alkoxy group represented by R 1 include a phenylsulfinylmethoxy group, a phenylsulfinylethoxy group, and a phenylsulfinylpropoxy group, and a phenylsulfinylethoxy group is preferable.
　一般式（I）中、Ｒ１におけるフェニルスルホニルＣ１－６アルコキシ基としては、例えば、フェニルスルホニルメトキシ基、フェニルスルホニルエトキシ基、フェニルスルホニルプロポキシ基等が挙げられ、フェニルスルホニルエトキシ基が好ましい。 In general formula (I), examples of the phenylsulfonyl C 1-6 alkoxy group in R 1 include a phenylsulfonylmethoxy group, a phenylsulfonylethoxy group, a phenylsulfonylpropoxy group, and the like, and a phenylsulfonylethoxy group is preferable.
　一般式（I）中、Ｒ１におけるフェノキシＣ１－６アルコキシ基としては、例えば、フェノキシメトキシ基、フェノキシエトキシ基、フェノキシプロポキシ基等が挙げられ、フェノキシエトキシ基が好ましい。 In general formula (I), examples of the phenoxy C 1-6 alkoxy group in R 1 include a phenoxymethoxy group, a phenoxyethoxy group, a phenoxypropoxy group, and the like, and a phenoxyethoxy group is preferable.
　一般式（I）中、Ｒ、Ｒ２、及びＲ３におけるカルボキシＣ１－６アルキル基としては、カルボキシメチル基、カルボキシエチル基、カルボキシプロピル基等が挙げられ、カルボキシメチル基、カルボキシエチル基が好ましく、Ｒにおいては、カルボキシメチル基が、Ｒ２、及びＲ３においては、カルボキシエチル基がより好ましい。 In general formula (I), examples of the carboxy C 1-6 alkyl group in R, R 2 , and R 3 include a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, and the like. Preferably, R is a carboxymethyl group, and R 2 and R 3 are more preferably a carboxyethyl group.
　一般式（I）中、Ｒ、Ｒ２、及びＲ３におけるＣ１－６アルコキシカルボニルＣ１－６アルキル基としては、メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、イソプロポキシカルボニルメチル基、メトキシカルボニルエチル基、エトキシカルボニルエチル基、プロポキシカルボニルエチル基、イソプロポキシカルボニルエチル基、メトキシカルボニルプロピル基、エトキシカルボニルプロピル基、プロポキシカルボニルプロピル基、イソプロポキシカルボニルプロピル基等が挙げられ、メトキシカルボニルメチル基、メトキシカルボニルエチル基が好ましく、Ｒにおいては、メトキシカルボニルメチル基が、Ｒ２、及びＲ３においては、メトキシカルボニルエチル基がより好ましい。 In the general formula (I), the C 1-6 alkoxycarbonyl C 1-6 alkyl group in R, R 2 , and R 3 includes a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, and isopropoxycarbonylmethyl. Group, methoxycarbonylethyl group, ethoxycarbonylethyl group, propoxycarbonylethyl group, isopropoxycarbonylethyl group, methoxycarbonylpropyl group, ethoxycarbonylpropyl group, propoxycarbonylpropyl group, isopropoxycarbonylpropyl group, etc. A methyl group and a methoxycarbonylethyl group are preferable. In R, a methoxycarbonylmethyl group is more preferable, and in R 2 and R 3 , a methoxycarbonylethyl group is more preferable.
　一般式（I）中、Ｒ２、及びＲ３におけるＣ２－６アルケニル基としては、例えば、ビニル基、アリル基、３－ブテン－１－イル基等が挙げられ、アリル基が好ましい。 In the general formula (I), examples of the C 2-6 alkenyl group in R 2 and R 3 include a vinyl group, an allyl group, a 3-buten-1-yl group, and the like, and an allyl group is preferable.
　一般式（I）中、Ｒ２、及びＲ３における置換基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基における置換基としては、例えば、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、カルボキシ基、Ｃ１－６アルコキシカルボニル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基等が挙げられる。また、これらの置換基の置換位置は特に限定されないが、本発明においては、Ｃ３－８シクロアルキルＣ１－６アルキル基のＣ３－８シクロアルキル基上に置換するのが好ましい。このような基としては、シクロアルキル基上に置換基としてカルボキシＣ１－６アルキル基又はＣ１－６アルコキシカルボニルＣ１－６アルキル基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基、例えば４－カルボキシメチルシクロヘキシルメチル基、４－メトキシカルボニルメチルシクロヘキシルメチル基、４－エトキシカルボニルメチルシクロヘキシルメチル基、４－イソプロポキシカルボニルメチルシクロヘキシルメチル基等が挙げられる。 In the general formula (I), examples of the substituent in the C 3-8 cycloalkyl C 1-6 alkyl group which may have a substituent in R 2 and R 3 include a C 1-6 alkyl group, halo Examples thereof include a C 1-6 alkyl group, a carboxy group, a C 1-6 alkoxycarbonyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group and the like. Further, substitution positions of these substituents are not particularly limited, in the present invention, preferably substituted on C 3-8 cycloalkyl group a C 3-8 cycloalkyl C 1-6 alkyl group. Such groups, cycloalkyl carboxy as a substituent on the C 1-6 alkyl group or C 1-6 alkoxycarbonyl C 1-6 which may have an alkyl group C 3-8 cycloalkyl C 1- Examples include 6 alkyl groups such as 4-carboxymethylcyclohexylmethyl group, 4-methoxycarbonylmethylcyclohexylmethyl group, 4-ethoxycarbonylmethylcyclohexylmethyl group, 4-isopropoxycarbonylmethylcyclohexylmethyl group and the like.
　一般式（I）中、Ｒ、Ｒ２、及びＲ３における置換基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基又はＣ３－８シクロアルキルＣ１－６アルキル基におけるＣ３－８シクロアルキルＣ１－６アルキル基としては、例えば、シクロプロピルメチル基、シクロペンチルメチル基、シクロヘキシルメチル基等が挙げられ、Ｒにおいては、シクロプロピルメチル基が好ましい。 In the general formula (I), in the C 3-8 cycloalkyl C 1-6 alkyl group or C 3-8 cycloalkyl C 1-6 alkyl group which may have a substituent in R, R 2 , and R 3 Examples of the C 3-8 cycloalkyl C 1-6 alkyl group include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and the like. In R, a cyclopropylmethyl group is preferable.
　一般式（I）中、Ｒ２、及びＲ３における置換基を有してもよいＣ６－１０アリールＣ１－６アルキル基における置換基としては、例えば、ハロゲン原子、Ｃ１－６アルキル基、ハロ低Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、又はシアノ基等が挙げられる。また、これらの置換基の置換位置は特に限定されないが、本発明においては、Ｃ６－１０アリールＣ１－６アルキル基のアリール環上に置換することが好ましい。このような基としては、フェニル基上に置換基としてＣ１－６アルコキシ基を有してもよいフェニルＣ１－６アルキル基、例えば、４－メトキシベンジル基等が挙げられる。 In the general formula (I), examples of the substituent in the C 6-10 aryl C 1-6 alkyl group which may have a substituent in R 2 and R 3 include a halogen atom and a C 1-6 alkyl group. A halo low C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, and the like. In addition, although the substitution position of these substituents is not particularly limited, in the present invention, substitution on the aryl ring of a C 6-10 aryl C 1-6 alkyl group is preferable. Examples of such a group include a phenyl C 1-6 alkyl group which may have a C 1-6 alkoxy group as a substituent on the phenyl group, such as a 4-methoxybenzyl group.
　一般式（I）中、Ｒ２、及びＲ３における一緒になって隣接する窒素原子とともに含窒素飽和複素環としては、例えば、ピロリジノ基、ピペリジノ基、ホモピペリジノ基、モルホリノ基、Ｎ－Ｃ１－６アルキルピペラジノ基、ピペラジニル基等が挙げられ、ピロリジニル基、モルホリノ基、ピペリジノ基が好ましい。 In the general formula (I), R 2, and as the nitrogen-containing saturated heterocyclic ring together with the adjacent nitrogen atom together in R 3, for example, pyrrolidino group, piperidino group, homopiperidino group, morpholino group, N-C 1- 6- alkyl piperazino group, piperazinyl group and the like can be mentioned, and pyrrolidinyl group, morpholino group and piperidino group are preferable.
　一般式（I）中、Ｒ２、及びＲ３における一緒になって隣接する窒素原子とともに置換基を有してもよく環構成原子にヘテロ原子を有してもよい環状アミノ基における置換基としては、例えば、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、又はシアノ基等が挙げられる。また、これらの置換基の置換位置は特に限定されないが、本発明においては、含窒素飽和複素環の炭素原子上に置換することが好ましい。このような基としては、含窒素飽和複素環上に置換基としてＣ１－６アルキル基を有してもよい含窒素飽和複素環基、例えば、４－メチルピペリジノ基、２，６－ジメチルモルホリニル基が挙げられる。 In general formula (I), as a substituent in a cyclic amino group which may have a substituent together with the adjacent nitrogen atom in R 2 and R 3 or may have a hetero atom in the ring constituent atom Examples include a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, or a cyano group. Moreover, although the substitution position of these substituents is not specifically limited, In this invention, it is preferable to substitute on the carbon atom of a nitrogen-containing saturated heterocyclic ring. Examples of such a group include a nitrogen-containing saturated heterocyclic group which may have a C 1-6 alkyl group as a substituent on the nitrogen-containing saturated heterocyclic ring, such as 4-methylpiperidino group, 2,6-dimethylmorpholine. Nyl group is mentioned.
　一般式（iii）中、
Figure JPOXMLDOC01-appb-C000016
 で表される、環構成原子が６～１０個であり、環構成原子の少なくとも一つが窒素原子である単環性の複素環は、少なくとも１つの不飽和結合を有していればよく、芳香族性を有する単環性の複素環も芳香族性を有しない単環性の複素環も含まれるが、芳香族性を有する単環性の複素環が好ましい。また、環構成原子としては、少なくとも一つ窒素原子を有していればよく、さらに他に窒素原子、酸素原子、硫黄原子等のヘテロ原子を複数有していてもよい。こうした単環性の複素環としては、例えば、
Figure JPOXMLDOC01-appb-C000017
 等が挙げられる。 In general formula (iii),
Figure JPOXMLDOC01-appb-C000016
 The monocyclic heterocycle having 6 to 10 ring atoms and at least one of the ring atoms being a nitrogen atom, as long as it has at least one unsaturated bond, A monocyclic heterocycle having an aromaticity and a monocyclic heterocycle having no aromaticity are included, but a monocyclic heterocycle having an aromaticity is preferred. Further, the ring-constituting atoms may have at least one nitrogen atom, and may further have a plurality of heteroatoms such as nitrogen atom, oxygen atom, sulfur atom and the like. Examples of such monocyclic heterocycles include:
Figure JPOXMLDOC01-appb-C000017
 Etc.
　一般式（iii）中、
Figure JPOXMLDOC01-appb-C000018
 で表される、環構成原子が６～１０個であり、環構成原子の少なくとも一つが窒素原子である二環性の複素環は、少なくとも１つの不飽和結合を有していればよく、芳香族性を有する二環性の複素環も芳香族性を有しない二環性の複素環も含まれるが、縮合する二個の環のうち少なくとも一方が芳香族性を有する環であるのが好ましい。また、環構成原子としては、少なくとも一つ窒素原子を有していればよく、さらに他に窒素原子、酸素原子、硫黄原子等のヘテロ原子を複数有していてもよい。こうした二環性の複素環としては、例えば、
Figure JPOXMLDOC01-appb-C000019
 等が挙げられる。 In general formula (iii),
Figure JPOXMLDOC01-appb-C000018
 And the bicyclic heterocycle having 6 to 10 ring atoms and at least one of the ring atoms being a nitrogen atom may have at least one unsaturated bond, Bicyclic heterocycles having an aromaticity and bicyclic heterocycles not having aromaticity are included, but at least one of the two condensed rings is preferably an aromatic ring. . Further, the ring-constituting atoms may have at least one nitrogen atom, and may further have a plurality of heteroatoms such as nitrogen atom, oxygen atom, sulfur atom and the like. Examples of such bicyclic heterocycles include:
Figure JPOXMLDOC01-appb-C000019
 Etc.
　上記一般式（iii）中、
Figure JPOXMLDOC01-appb-C000020
 としては、
Figure JPOXMLDOC01-appb-C000021
 が好ましく、
Figure JPOXMLDOC01-appb-C000022
 がより好ましい。 In the general formula (iii),
Figure JPOXMLDOC01-appb-C000020
 as,
Figure JPOXMLDOC01-appb-C000021
 Is preferred,
Figure JPOXMLDOC01-appb-C000022
 Is more preferable.
　一般式（iii）中、Ｒ１４、及びＲ１５の
Figure JPOXMLDOC01-appb-C000023
 上の結合位置は、特に限定されるものではないが、例えば
Figure JPOXMLDOC01-appb-C000024
 （この場合において、Ｒ１４、及びＲ１５は上記と同様であるが、Ｒ１４、及びＲ１５は、それぞれ同一又は異なって、水素原子、又はＣ１－６アルキル基であることが好ましく、Ｒ１４は、水素原子、又はＣ１－６アルキル基であり、Ｒ１５は、Ｃ１－６アルキル基であるのがより好ましい。）、
Figure JPOXMLDOC01-appb-C000025
 （この場合において、Ｒ１４、及びＲ１５は上記と同様であるが、Ｒ１４、及びＲ１５は、それぞれ同一又は異なって、水素原子、水酸基、又はＣ１－６アルコキシ基であることが好ましく、Ｒ１４は、水酸基、又はＣ１－６アルコキシ基であり、Ｒ１５は、水素原子であるのがより好ましい。）、
Figure JPOXMLDOC01-appb-C000026
 （この場合において、Ｒ１４、及びＲ１５は上記と同様であるが、Ｒ１４、及びＲ１５は、水素原子であるのが好ましい。）、
Figure JPOXMLDOC01-appb-C000027
 （この場合において、Ｒ１４、及びＲ１５は上記と同様であるが、Ｒ１４、及びＲ１５は、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、又はＣ１－６アルコキシ基であることが好ましく、Ｒ１４は、水素原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、又はＣ１－６アルコキシ基であり、Ｒ１５は、水素原子であるのがより好ましい。）、
Figure JPOXMLDOC01-appb-C000028
 （この場合において、Ｒ１４、及びＲ１５は上記と同様であるが、Ｒ１４、及びＲ１５は、Ｃ１－６アルキル基であるのが好ましい。）等が挙げられる。 In the general formula (iii), R 14 and R 15
Figure JPOXMLDOC01-appb-C000023
 The above bonding position is not particularly limited, but for example,
Figure JPOXMLDOC01-appb-C000024
 (In this case, R 14 and R 15 are the same as above, but R 14 and R 15 are the same or different and are each preferably a hydrogen atom or a C 1-6 alkyl group. 14 is a hydrogen atom or a C 1-6 alkyl group, and R 15 is more preferably a C 1-6 alkyl group).
Figure JPOXMLDOC01-appb-C000025
 (In this case, R 14 and R 15 are the same as described above, but R 14 and R 15 are the same or different and are preferably a hydrogen atom, a hydroxyl group, or a C 1-6 alkoxy group. R 14 is preferably a hydroxyl group or a C 1-6 alkoxy group, and R 15 is more preferably a hydrogen atom).
Figure JPOXMLDOC01-appb-C000026
 (In this case, R 14 and R 15 are the same as described above, but R 14 and R 15 are preferably hydrogen atoms).
Figure JPOXMLDOC01-appb-C000027
 (In this case, R 14 and R 15 are the same as above, but R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group. Or a C 1-6 alkoxy group, R 14 is a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group, and R 15 is More preferably a hydrogen atom).
Figure JPOXMLDOC01-appb-C000028
 (In this case, R 14 and R 15 are the same as described above, but R 14 and R 15 are preferably C 1-6 alkyl groups).
　上記一般式（I）、（i）、（ii）、（iii）における、置換基の好ましい組合せとしては、
Ｒ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、シアノ基、カルボキシル基、又はＣ１－６アルコキシカルボニル基であり、
Ｒ９が、水素原子、又はＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基であり、
Ｒ２ 、及びＲ３が、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、Ｃ２－６アルケニル基、シクロアルキル基上に置換基としてカルボキシＣ１－６アルキル基、又はＣ１－６アルコキシカルボニルＣ１－６アルキル基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基、アリール環上に置換基としてＣ１－６アルコキシ基を有してもよいＣ６－１０アリールＣ１－６アルキル基を示すか、又はＲ２ 、及びＲ３が一緒になって隣接する窒素原子とともにピロリジノ基、Ｃ１－６アルキル基を有してもよいピペリジニル基、又はＣ１－６アルキル基を有してもよいモルホリニル基を形成するものであり、
Ｒ１が、ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、Ｃ６－１０アリールＣ１－６アルコキシ基（当該Ｃ６－１０アリールＣ１－６アルコキシ基のアリール環上に置換基としてハロゲン原子、ハロＣ１－６アルキル基、又はシアノ基を有してもよい）、水酸基、モルホリニル基、ピペリジニル基、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ基、カルボキシＣ１－６アルコキシ基、フェニルチオＣ１－６アルコキシ基、フェニルスルフィニルＣ１－６アルコキシ基、フェニルスルホニルＣ１－６アルコキシ基、又はフェノキシＣ１－６アルコキシ基であり、
Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、又はＣ１－６アルコキシ基であり、
Ｒ１４ 、及びＲ１５が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、又は水酸基であり、
Figure JPOXMLDOC01-appb-C000029
 が
Figure JPOXMLDOC01-appb-C000030
 であることが好ましく、
式（I）中、
Figure JPOXMLDOC01-appb-C000031
 が、式（ii）を示すとき、
Ｒ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８が、それぞれ同一又は異なって、水素原子、又はハロＣ１－６アルキル基であり、
Ｒ９が、水素原子、又はＣ１－６アルキル基であり、
Ｒ２ 、及びＲ３が、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、シクロアルキル基上に置換基としてカルボキシＣ１－６アルキル基、又はＣ１－６アルコキシカルボニルＣ１－６アルキル基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基、アリール環上に置換基としてＣ１－６アルコキシ基を有してもよいＣ６－１０アリールＣ１－６アルキル基を示すか、又はＲ２ 、及びＲ３が一緒になって隣接する窒素原子とともにピロリジノ基、Ｃ１－６アルキル基を有してもよいピペリジニル基、又はＣ１－６アルキル基を有してもよいモルホリニル基を形成するものであり、
Ｒ１が、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、水酸基、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ基、カルボキシＣ１－６アルコキシ基、フェニルチオＣ１－６アルコキシ基、フェニルスルフィニルＣ１－６アルコキシ基、フェニルスルホニルＣ１－６アルコキシ基、又はフェノキシＣ１－６アルコキシ基であり、
Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、又はＣ１－６アルコキシ基であることがより好ましく、
あるいは式（I）中、
Figure JPOXMLDOC01-appb-C000032
 が、式（iii）を示すとき、
Ｒ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、シアノ基、カルボキシル基、又はＣ１－６アルコキシカルボニル基であり、
Ｒ９が、水素原子、又はＣ１－６アルキル基であり、
Ｒ２ 、及びＲ３が、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、Ｃ２－６アルケニル基、シクロアルキル基上に置換基としてカルボキシＣ１－６アルキル基、又はＣ１－６アルコキシカルボニルＣ１－６アルキル基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基、アリール環上に置換基としてＣ１－６アルコキシ基を有してもよいＣ６－１０アリールＣ１－６アルキル基を示すか、又はＲ２ 、及びＲ３が一緒になって隣接する窒素原子とともにピロリジノ基を形成するものであり、
Ｒ１が、ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、Ｃ６－１０アリールＣ１－６アルコキシ基（当該Ｃ６－１０アリールＣ１－６アルコキシ基のアリール環上に置換基としてハロゲン原子、ハロＣ１－６アルキル基、又はシアノ基を有してもよい）、モルホリニル基、ピペリジニル基、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ基、又はカルボキシＣ１－６アルコキシ基であり、
Ｒ１４ 、及びＲ１５が、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、又は水酸基であり、
Figure JPOXMLDOC01-appb-C000033
 が
Figure JPOXMLDOC01-appb-C000034
 であることがより好ましく、
Figure JPOXMLDOC01-appb-C000035
 が
Figure JPOXMLDOC01-appb-C000036
 （Ｒ１４、及びＲ１５は、それぞれ同一又は異なって、水素原子、又はＣ１－６アルキル基である。）、
Figure JPOXMLDOC01-appb-C000037
 （Ｒ１４、及びＲ１５は、それぞれ同一又は異なって、水素原子、Ｃ１－６アルコキシ基、又は水酸基である。）、
Figure JPOXMLDOC01-appb-C000038
 （Ｒ１４、及びＲ１５は、水素原子である。）、
Figure JPOXMLDOC01-appb-C000039
 （Ｒ１４、及びＲ１５は、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、又はＣ１－６アルコキシ基である。）、又は
Figure JPOXMLDOC01-appb-C000040
 （Ｒ１４、及びＲ１５は、Ｃ１－６アルキル基である。）
であることが特に好ましい。 In the above general formulas (I), (i), (ii) and (iii), preferred combinations of substituents are as follows:
R 4 , R 5 , R 6 , R 7 , and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group. Halo C 1-6 alkoxy group, cyano group, carboxyl group, or C 1-6 alkoxycarbonyl group,
R 9 is a hydrogen atom, or a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group,
R 2, and R 3 are the same or different, a hydrogen atom, C 1-6 alkyl group, a carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl groups, C 2-6 alkenyl group, a carboxy C 1-6 alkyl group, or a C 1-6 alkoxycarbonyl C 1-6 alkyl group which may have a C 3-8 cycloalkyl C 1-6 alkyl group as a substituent on the cycloalkyl group, or showing a C 1-6 optionally C 6-10 aryl C 1-6 alkyl group which may have an alkoxy group as a substituent on the aryl ring, or R 2, and the nitrogen atom to which R 3 is adjacent together with pyrrolidino group, which form a C 1-6 piperidinyl group which may have an alkyl group, or a C 1-6 optionally morpholinyl group which may have an alkyl group,
R 1 is a halogen atom, a C 1-6 alkoxy group, C 1-6 alkylthio C 1-6 alkoxy group, C 1-6 alkylsulfinyl C 1-6 alkoxy group, C 1-6 alkylsulfonyl C 1-6 alkoxy A C 6-10 aryl C 1-6 alkoxy group (having a halogen atom, halo C 1-6 alkyl group, or cyano group as a substituent on the aryl ring of the C 6-10 aryl C 1-6 alkoxy group) Hydroxyl group, morpholinyl group, piperidinyl group, C 1-6 alkoxycarbonyl C 1-6 alkoxy group, carboxy C 1-6 alkoxy group, phenylthio C 1-6 alkoxy group, phenylsulfinyl C 1-6 alkoxy A phenylsulfonyl C 1-6 alkoxy group, or a phenoxy C 1-6 alkoxy group,
R 10 , R 11 , R 12 , and R 13 are the same or different and each is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group. ,
R 14, and R 15 are the same or different, a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl group, C 1-6 alkoxy group, or a hydroxyl group,
Figure JPOXMLDOC01-appb-C000029
 But
Figure JPOXMLDOC01-appb-C000030
 It is preferable that
In formula (I),
Figure JPOXMLDOC01-appb-C000031
 Represents the formula (ii)
R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and each is a hydrogen atom or a haloC 1-6 alkyl group,
R 9 is a hydrogen atom or a C 1-6 alkyl group,
R 2, and R 3 are the same or different, a hydrogen atom, C 1-6 alkyl group, C 2-6 alkenyl group, a carboxy C 1-6 alkyl group as a substituent on the cycloalkyl group, or C 1 -6 alkoxycarbonyl C 1-6 alkyl group a C 3-8 cycloalkyl C 1-6 alkyl group which may have a, which may have a C 1-6 alkoxy group as a substituent on the aryl ring C 6 -10 aryl C 1-6 represents an alkyl group, or R 2, and R 3 is a pyrrolidino group together with the adjacent nitrogen atom together, C 1-6 piperidinyl group which may have an alkyl group, or a C Forming a morpholinyl group which may have a 1-6 alkyl group,
R 1 is a C 1-6 alkoxy group, a C 1-6 alkylthio C 1-6 alkoxy group, a C 1-6 alkylsulfinyl C 1-6 alkoxy group, a C 1-6 alkylsulfonyl C 1-6 alkoxy group, a hydroxyl group C 1-6 alkoxycarbonyl C 1-6 alkoxy group, carboxy C 1-6 alkoxy group, phenylthio C 1-6 alkoxy group, phenylsulfinyl C 1-6 alkoxy group, phenylsulfonyl C 1-6 alkoxy group, or phenoxy A C 1-6 alkoxy group,
R 10 , R 11 , R 12 , and R 13 are the same or different and each is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group. More preferably,
Or in formula (I):
Figure JPOXMLDOC01-appb-C000032
 Represents formula (iii)
R 4 , R 5 , R 6 , R 7 , and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group. Halo C 1-6 alkoxy group, cyano group, carboxyl group, or C 1-6 alkoxycarbonyl group,
R 9 is a hydrogen atom or a C 1-6 alkyl group,
R 2, and R 3 are the same or different, a hydrogen atom, C 1-6 alkyl group, a carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl groups, C 2-6 alkenyl group, a carboxy C 1-6 alkyl group, or a C 1-6 alkoxycarbonyl C 1-6 alkyl group which may have a C 3-8 cycloalkyl C 1-6 alkyl group as a substituent on the cycloalkyl group, or showing a C 1-6 optionally C 6-10 aryl C 1-6 alkyl group which may have an alkoxy group as a substituent on the aryl ring, or R 2, and the nitrogen atom to which R 3 is adjacent together Together with a pyrrolidino group,
R 1 is a halogen atom, a C 1-6 alkoxy group, C 1-6 alkylthio C 1-6 alkoxy group, C 1-6 alkylsulfinyl C 1-6 alkoxy group, C 1-6 alkylsulfonyl C 1-6 alkoxy A C 6-10 aryl C 1-6 alkoxy group (having a halogen atom, halo C 1-6 alkyl group, or cyano group as a substituent on the aryl ring of the C 6-10 aryl C 1-6 alkoxy group) May be a morpholinyl group, a piperidinyl group, a C 1-6 alkoxycarbonyl C 1-6 alkoxy group, or a carboxy C 1-6 alkoxy group,
R 14, and R 15 are the same or different, a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl group, C 1-6 alkoxy group, or a hydroxyl group,
Figure JPOXMLDOC01-appb-C000033
 But
Figure JPOXMLDOC01-appb-C000034
 More preferably,
Figure JPOXMLDOC01-appb-C000035
 But
Figure JPOXMLDOC01-appb-C000036
 (R 14 and R 15 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group).
Figure JPOXMLDOC01-appb-C000037
 (R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkoxy group, or a hydroxyl group).
Figure JPOXMLDOC01-appb-C000038
 (R 14 and R 15 are hydrogen atoms),
Figure JPOXMLDOC01-appb-C000039
 (R 14 and R 15 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 1-6 alkoxy group), or
Figure JPOXMLDOC01-appb-C000040
 (R 14 and R 15 are C 1-6 alkyl groups.)
It is particularly preferred that
　本発明の医薬において好ましい有効成分として使用される化合物、若しくはその塩、又はそれらの溶媒和物としては、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メトキシベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メトキシベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－３，５－ジフルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－３，５－ジフルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メチルベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メチルベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－フルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－フルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－メトキシベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－メトキシベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－クロロ－６－［（シクロペンチルメチル）（エチル）アミノ］－３－メチルベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－クロロ－６－［（シクロペンチルメチル）（エチル）アミノ］－３－メチルベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４，５－ジフルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４，５－ジフルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－クロロ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－クロロ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－フルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－フルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛５－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛５－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
３－［１－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）エチル］－５－（トリフルオロメチル）ベンゾニトリル、
３－［１－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）エチル］－５－（トリフルオロメチル）ベンゾニトリル、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］－Ｎ－［２－ピペリジノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［２－ピペリジノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］－Ｎ－［２－モルホリノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［２－モルホリノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（４－メチルピペリジノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（４－メチルピペリジノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（cis－２，６－ジメチルモルホリノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（cis－２，６－ジメチルモルホリノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
Ｎ－｛２－［ビス（シクロプロピルメチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛２－［ビス（シクロプロピルメチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（ヒドロキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸、
２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－メトキシピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－ヒドロキシピリミジン－２－アミン、
４－（｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝）アミノ］ピリミジン－５－イル｝オキシ）酪酸エチル、
４－（｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝）アミノ］ピリミジン－５－イル｝オキシ）酪酸、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシキノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシキノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－（トリフルオロメチル）キノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－（トリフルオロメチル）キノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メチルキノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メチルキノリン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－メチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－メチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－エチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－エチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５，６－ジメチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５，６－ジメチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
３－｛１－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］エチル｝－５－（トリフルオロメチル）ベンゾニトリル、
３－｛１－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］エチル｝－５－（トリフルオロメチル）ベンゾニトリル、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］ピラジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］ピラジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン）、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリル、
３－［（｛２－［［３－シアノ－５－（トリフルオロメチル）ベンジル］（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）アミノ］ピリミジン－５－イル｝オキシ）メチル］－５－（トリフルオロメチル）ベンゾニトリル、
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリル、
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリル、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
Ｎ－［２，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－［２，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジクロロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジクロロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメチルベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメチルベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，４－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，４－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，５－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，５－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，６－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，６－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［（２，３－ジフルオロベンジル）オキシ］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリル、
５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリル、
５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリル、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－５－ブロモ－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－モルホリノピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－ピペリジノピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
６－［（［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－５－［（シクロペンチルメチル）（エチル）アミノ］ピリジン－２－オール、
４－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
４－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［エチル（４－メトキシベンジル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［エチル（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（エチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチル、
４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸、
２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチル、
２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸、
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチル、
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸、
３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸メチル、
３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸、
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］プロピオン酸メチル、
５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
５－｛［ベンジル（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（４－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸イソプロピル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸メチル、
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
５－｛［（３，５－ジフルオロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（２－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（３－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（２－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（３－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（４－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（２－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（４－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（３－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
５－｛［（５－エトキシピリミジン－２－イル）（４－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
５－｛［（シクロプロピルメチル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－｛ｔｒａｎｓ－４－［（エチル｛２－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチル、
５－｛［（５－エトキシピリミジン－２－イル）（３－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
２－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、及び
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル
からなる群から選ばれる化合物若しくはその塩、又はそれらの溶媒和物を挙げることができるが、本発明の医薬の有効成分として好適に使用される化合物若しくはその塩、又はそれらの溶媒和物の範囲はこれらに限定されることはない。 As a compound used as a preferable active ingredient in the medicament of the present invention, or a salt thereof, or a solvate thereof,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidine -2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylsulfonyl) ethoxy] Pyrimidine-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
3- [1-({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) ethyl] -5- (trifluoromethyl) benzonitrile,
3- [1-({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) ethyl ] -5- (trifluoromethyl) benzonitrile,
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine- 2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine -2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine- 2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine -2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -5- (trifluoromethyl) benzyl} -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {2- [bis (cyclopropylmethyl) amino] -5- (trifluoromethyl) benzyl} -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4 -(Trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid,
2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5-methoxy Pyrimidine-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5-hydroxy Pyrimidine-2-amine,
4-({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl}) Amino] pyrimidin-5-yl} oxy) ethyl butyrate,
4-({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl}) Amino] pyrimidin-5-yl} oxy) butyric acid,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
5-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethylquinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethylquinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-6-methoxyquinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-6-methoxyquinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-6- (trifluoromethyl) quinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-6- (trifluoromethyl) quinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-6-methylquinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-6-methylquinolin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl ) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl ) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethylquinolin-2-amine,
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethylquinolin-2-amine,
3- {1-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) {5- [2 -(Methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile,
3- {1-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) Benzyl] pyrimidin-2-amine),
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [3- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [3- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } -5- (trifluoromethyl) benzonitrile,
3-[({2-[[3-Cyano-5- (trifluoromethyl) benzyl] ({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) amino] Pyrimidin-5-yl} oxy) methyl] -5- (trifluoromethyl) benzonitrile,
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} -5- (trifluoromethyl) benzonitrile,
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Methyl} -5- (trifluoromethyl) benzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Benzonitrile,
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} benzonitrile,
N- [2,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- [2,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylsulfinyl) ethoxy] pyrimidin-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfonyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfonyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethoxy) Benzyl] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [3- (trifluoromethoxy ) Benzyl] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [3- (trifluoromethoxy ) Benzyl] pyrimidin-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,5-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,5-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5-[(2,3-difluorobenzyl ) Oxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
5-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Isophthalonitrile,
5-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} isophthalonitrile,
5-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Methyl} isophthalonitrile,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [4- (trifluoromethyl) Benzyl] pyrimidin-2-amine,
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [4- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [4- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5-bromo-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) pyrimidine- 2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5-morpholinopyrimidine- 2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5-piperidino Pyrimidine-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylsulfinyl) ) Ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
6-[([3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -5-[(cyclopentylmethyl) (ethyl) Amino] pyridin-2-ol,
4-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Benzonitrile,
4-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} benzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino} methyl)- 4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[ethyl (5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (ethyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) ethyl butanoate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) butanoic acid,
2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Yl} amino) methyl acetate,
2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Il} amino) acetic acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] propionic acid,
3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} methyl propionate,
3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} propionic acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl propionate,
5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
5-{[benzyl (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-Ethoxypyrimidin-2-yl) (4-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) isopropyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) methyl acetate,
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
5-{[(3,5-difluorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-Ethoxypyrimidin-2-yl) (2-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (3-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(2-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(3-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(4-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (2-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (4-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (3-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
5-{[(5-Ethoxypyrimidin-2-yl) (4-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile,
5-{[(Cyclopropylmethyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
2- {trans-4-[(ethyl {2-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
5-{[(5-Ethoxypyrimidin-2-yl) (3-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
2-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile, and
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile
A compound selected from the group consisting of: Is not limited to these.
　一般式（I）で表される化合物の塩としては、酸付加塩および塩基付加塩等が挙げられ、医薬として許容される塩であれば特に制限されない。例えば、酸付加塩であれば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩のような鉱酸との酸付加塩；安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、エタンジスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、酢酸塩等の有機酸との酸付加塩が挙げられる。また、塩基付加塩であればナトリウム塩、カリウム塩、リチウム塩、カルシウム塩、マグネシウム塩等の金属との塩基付加塩；アンモニア、トリメチルアミン、トリエチルアミン、ピリジン、コリジン、ルチジン等のアミン塩；リシン、アルギニン、ヒスチジン等の有機塩基との塩基付加塩等が挙げられる。 Examples of the salt of the compound represented by the general formula (I) include acid addition salts and base addition salts, and are not particularly limited as long as they are pharmaceutically acceptable salts. For example, in the case of acid addition salts, acid addition salts with mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, methanesulfonate Acid addition salts with organic acids such as ethane sulfonate, ethane disulfonate, benzene sulfonate, p-toluene sulfonate, maleate, fumarate, tartrate, citrate, acetate Can be mentioned. In addition, if it is a base addition salt, a base addition salt with a metal such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt; amine salt such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine; lysine, arginine And base addition salts with organic bases such as histidine.
　一般式（I）で表される化合物、又はその塩の溶媒和物を構成する溶媒としては、例えば、水のほか、生理学的に許容される有機溶媒、例えばエタノール、ヘキサン、酢酸エチルなどを挙げることができるが、これらに限定されることはない。 Examples of the solvent constituting the solvate of the compound represented by the general formula (I) or a salt thereof include, for example, water and physiologically acceptable organic solvents such as ethanol, hexane, and ethyl acetate. However, it is not limited to these.
　なお、本発明の上記一般式（I）で表される化合物には、生体内において代謝されて本発明の上記一般式（I）で表される化合物に変換される化合物、いわゆるプロドラッグもすべて包含される。本発明化合物のプロドラッグを形成する基としては、「プログレス・イン・メディシン（Progress in Medicine）」、ライフサイエンス・メディカ社、1985年、5巻、2157-2161ページに記載されている基や、廣川書店1990年刊「医薬品の開発」第7巻 分子設計163-198ページに記載されている基が挙げられる。 The compounds represented by the above general formula (I) of the present invention include all compounds that are metabolized in vivo and converted into the compounds represented by the above general formula (I) of the present invention, so-called prodrugs. Is included. As a group that forms a prodrug of the compound of the present invention, “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161, Examples include the groups described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, pp. 163-198.
　上記一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物は種々の公知の方法で製造することができ、特に制限されるものではなく、例えば、次の反応工程に従い製造することができるが、その製造方法はこれに限定されるものではない。また、下記反応を行う際において、反応部位以外の官能基については必要に応じてあらかじめ保護しておき、適当な段階においてこれを脱保護してもよい。さらに、各工程において、反応は通常行われる方法で行えばよく、単離精製は結晶化、再結晶化、クロマトグラフィー等の慣用される方法を適宜選択し、又は組み合わせて行えばよい。 The compound represented by the above general formula (I), or a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, according to the following reaction step Although it can manufacture, the manufacturing method is not limited to this. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance if necessary, and may be deprotected at an appropriate stage. Further, in each step, the reaction may be carried out by a commonly performed method, and isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, chromatography and the like.
　上記一般式（I）で表される化合物のうち、Ｒが
Figure JPOXMLDOC01-appb-C000041
 を示し、Ｒ９がＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基のものは、公知の特許文献（国際公開第２００８／１１１６０４号パンフレット、国際公開第２００８／１２９９５１号パンフレット、日本国公開特許公報２０１０－０７７１１６）等に記載の方法により製造することができる。 Of the compounds represented by the general formula (I), R is
Figure JPOXMLDOC01-appb-C000041
 In which R 9 is a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group, (WO2008 / 111604 pamphlet, WO2008 / 129951 pamphlet, Japan published patent publication 2010-077116) and the like.
　上記一般式（I）で表される化合物のうち、Ｒが
Figure JPOXMLDOC01-appb-C000042
 を示し、Ｒ９が水素原子を示し、かつ
Figure JPOXMLDOC01-appb-C000043
 が、
Figure JPOXMLDOC01-appb-C000044
 を示す化合物は公知の特許文献（国際公開第２００８／０１８５２９号パンフレット）等に記載の方法により製造することができる。 Of the compounds represented by the general formula (I), R is
Figure JPOXMLDOC01-appb-C000042
 R 9 represents a hydrogen atom, and
Figure JPOXMLDOC01-appb-C000043
 But,
Figure JPOXMLDOC01-appb-C000044
 Can be produced by a method described in a known patent document (WO 2008/018529 pamphlet) or the like.
　上記一般式（I）で表される化合物のうち、Ｒが
Figure JPOXMLDOC01-appb-C000045
 を示し、Ｒ９が水素原子を示し、かつ
Figure JPOXMLDOC01-appb-C000046
 が、
Figure JPOXMLDOC01-appb-C000047
 を示す化合物（Ia）は、国際公開第２００８／１２９９５１号パンフレット記載の方法により製造することができる一般式（III）で表されるアミン化合物に一般式（IV）で表される脱離基Ｗ１を有する化合物を塩基で反応させることにより製造することができる。 Of the compounds represented by the general formula (I), R is
Figure JPOXMLDOC01-appb-C000045
 R 9 represents a hydrogen atom, and
Figure JPOXMLDOC01-appb-C000046
 But,
Figure JPOXMLDOC01-appb-C000047
 Compound (Ia) is a leaving group W represented by general formula (IV) to an amine compound represented by general formula (III), which can be produced by the method described in the pamphlet of International Publication No. 2008/129951. It can be produced by reacting a compound having 1 with a base.
　この反応経路を化学反応式で示すと次の通りである。
Figure JPOXMLDOC01-appb-C000048
 （式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ１０、Ｒ１１、Ｒ１２、及びＲ１３は、前記の一般式（I）におけるものと同義であり、Ｗ１はハロゲン原子、アルキルスルホニルオキシ基、ハロアルキルスルホニルオキシ基又はアリールスルホニルオキシ基を示す。） This reaction path is represented by the chemical reaction formula as follows.
Figure JPOXMLDOC01-appb-C000048
 (Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 are the same as those in the general formula (I). And W 1 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an arylsulfonyloxy group.)
　一般式（III）で表されるアミン化合物と脱離基Ｗ１を有する化合物（IV）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては、特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を単独又は組み合わせて使用することができ、塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔ－ブトキシナトリウム、ｔ－ブトキシカリウム、ｔ－ペントキシナトリウム、ｔ－ペントキシカリウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等を使用することができる。 The reaction of the amine compound represented by the general formula (III) and the compound (IV) having a leaving group W 1 can be performed in a solvent in the presence of a base. The solvent is not particularly limited, and for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used alone or in combination as a base. Is not particularly limited, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisi Zido, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t- Butyl lithium or the like can be used.
　また、上記一般式（I）で表される化合物のうち、Ｒが
Figure JPOXMLDOC01-appb-C000049
 を示し、Ｒ９が水素原子を示す化合物（Ib）は、公知の特許文献（国際公開第２００８／１１１６０４号パンフレット、国際公開第２００８／１２９９５１号パンフレット）等に記載の方法により製造することができる一般式（V）で示される脱離基Ｗ２を有す化合物に一般式（VI）で示されるベンジルアミノピリミジン誘導体を塩基で反応させることにより製造することができる。 Of the compounds represented by the general formula (I), R is
Figure JPOXMLDOC01-appb-C000049
 Compound (Ib) in which R 9 represents a hydrogen atom can be produced by a method described in known patent documents (International Publication No. 2008/111604, International Publication No. 2008/129951) and the like. It can be produced by reacting a compound having the leaving group W 2 represented by the general formula (V) with a benzylaminopyrimidine derivative represented by the general formula (VI) with a base.
　この反応経路を化学反応式で示すと次の通りである。
Figure JPOXMLDOC01-appb-C000050
 （式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、及び
Figure JPOXMLDOC01-appb-C000051
 は、前記の一般式（I）におけるものと同義であり、Ｗ２はハロゲン原子、アルキルスルホニルオキシ基、ハロアルキルスルホニルオキシ基又はアリールスルホニルオキシ基を示す。） This reaction path is represented by the chemical reaction formula as follows.
Figure JPOXMLDOC01-appb-C000050
 (Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and
Figure JPOXMLDOC01-appb-C000051
 Is synonymous with that in the general formula (I), and W 2 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, or an arylsulfonyloxy group. )
　脱離基Ｗ２を有す化合物（V）とベンジルアミノピリミジン誘導体（VI）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を使用することができ、塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔ－ブトキシナトリウム、ｔ－ブトキシカリウム、ｔ－ペントキシナトリウム、ｔ－ペントキシカリウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等を使用することができる。 The reaction of the compound (V) having a leaving group W 2 and the benzylaminopyrimidine derivative (VI) can be performed in a solvent in the presence of a base. The solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited. Are, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
　上記ベンジルアミノピリミジン誘導体（VI）は、一般式（VII）で示されるピリミジン－２－アミン誘導体に一般式（IV）で示される脱離基Ｗ１を有す化合物を塩基で反応させることにより製造することができる。また、ベンジルアミノピリミジン誘導体（VI）は一般式（VII）で示されるピリミジン－２－アミン誘導体に一般式（VIII）で示されるアルデヒド誘導体を還元的アミノ化の手法を用いて反応させることにより製造することができる。 The benzylaminopyrimidine derivative (VI) is produced by reacting a pyrimidine-2-amine derivative represented by the general formula (VII) with a compound having a leaving group W 1 represented by the general formula (IV) with a base. can do. The benzylaminopyrimidine derivative (VI) is produced by reacting the pyrimidine-2-amine derivative represented by the general formula (VII) with the aldehyde derivative represented by the general formula (VIII) using a reductive amination method. can do.
　この反応経路を化学反応式で示すと次の通りである。
Figure JPOXMLDOC01-appb-C000052
 （式中、Ｒ１、Ｒ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８は、前記の一般式（I）におけるものと同義であり、Ｗ１はハロゲン原子、アルキルスルホニルオキシ基、ハロアルキルスルホニルオキシ基又はアリールスルホニルオキシ基を示す。） This reaction path is represented by the chemical reaction formula as follows.
Figure JPOXMLDOC01-appb-C000052
 (Wherein R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 have the same meanings as those in the general formula (I), and W 1 represents a halogen atom, an alkylsulfonyloxy group, a haloalkyl. Represents a sulfonyloxy group or an arylsulfonyloxy group.)
　ピリミジン－２－アミン（VII）誘導体と脱離基Ｗ１を有す化合物（IV）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を使用することができ、塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔ－ブトキシナトリウム、ｔ－ブトキシカリウム、ｔ－ペントキシナトリウム、ｔ－ペントキシカリウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等を使用することができる。 The reaction of the pyrimidine-2-amine (VII) derivative and the compound (IV) having a leaving group W 1 can be performed in a solvent in the presence of a base. The solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited. Are, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
　ピリミジン－２－アミン（VII）誘導体とアルデヒド誘導体（VIII）の反応は、溶媒中、酸の存在下又は非存在下にて還元試薬を用いて行うことができる。その際、Dean-Stark装置等を用いて脱水操作を行ってもよい。溶媒としては特に制限はないが、例えば、１，２－ジクロロエタン、クロロホルム、ジクロロメタン、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、テトラヒドロフラン、ジオキサン、アセトニトリル、プロピオニトリル、メタノール、エタノール、イソプロパノール等を単独又は組み合わせて使用することができる。酸としては特に制限はないが、例えば、酢酸、トリフルオロ酢酸、プロピオン酸、安息香酸等のプロトン酸、四塩化チタン、三フッ化ホウ素、塩化第二スズ等のルイス酸を使用することができる。還元試薬としては特に制限はないが、例えば、トリアセトキシ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素テトラメチルアンモニウム、シアノ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、トリメトキシ水素化ホウ素ナトリウム、トリエチル水素化ホウ素リチウム等の水素化ホウ素系試薬、水素化アルミニウムリチウム、ジイソプロピル水素化アルミニウム、ビス（２－メトキシエトキシ）水素化アルミニウムナトリウム等の水素化アルミニウム試薬、金属触媒及び水素源を用いた接触還元を使用することができる。接触還元の水素源としては、例えば、水素、シクロヘキサジエン、ギ酸、ギ酸アンモニウム等を使用することができ、金属触媒としては、例えば、パラジウム炭素、パラジウム黒、水酸化パラジウム炭素粉末、ラネーニッケル、二酸化白金、白金黒等を使用することができる。 The reaction of the pyrimidine-2-amine (VII) derivative and the aldehyde derivative (VIII) can be carried out in a solvent using a reducing reagent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like. The solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. . There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Contact using borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used. As a hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.
　上記一般式（I）で表される化合物のうち、ＲがＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を示す化合物（Ic）は、公知の特許文献（国際公開第２００８／１１１６０４号パンフレット、国際公開第２００８／１２９９５１号パンフレット）等に記載の方法により製造することができる一般式（IX）で示されるアミン化合物に一般式（X）で表される脱離基Ｗ３を有する化合物を塩基で反応させることにより製造することができる。 Among the compounds represented by the above general formula (I), R has a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, and a substituent. Compound (Ic) which may be an amino C 1-6 alkyl group, a carbamoyl C 1-6 alkyl group which may have a substituent, or a C 3-8 cycloalkyl C 1-6 alkyl group is disclosed in known patents. An amine compound represented by the general formula (IX) that can be produced by a method described in literatures (International Publication No. 2008/111604, Pamphlet of International Publication No. 2008/129951) is represented by General Formula (X). It can be produced by reacting a compound having a leaving group W 3 with a base.
　この反応経路を化学反応式で示すと次の通りである。
Figure JPOXMLDOC01-appb-C000053
 （式中、Ｒ１、Ｒ２、Ｒ３、及び
Figure JPOXMLDOC01-appb-C000054
 は、前記の一般式（I）におけるものと同義であり、Ｗ３はハロゲン原子、アルキルスルホニルオキシ基、ハロアルキルスルホニルオキシ基又はＣ６－１０アリールスルホニルオキシ基を、Ｒ１６はＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を示す。） This reaction path is represented by the chemical reaction formula as follows.
Figure JPOXMLDOC01-appb-C000053
 (Wherein R 1 , R 2 , R 3 , and
Figure JPOXMLDOC01-appb-C000054
 Is as defined in the general formula (I), W 3 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or a C 6-10 arylsulfonyloxy group, and R 16 represents a C 1-6 alkyl. Group, carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, amino C 1-6 alkyl group optionally having substituent, carbamoyl C 1 optionally having substituent A -6 alkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group; )
　一般式（IX）で表されるアミン化合物と脱離基Ｗ３を有する化合物（X）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては、特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を単独又は組み合わせて使用することができ、塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔ－ブトキシナトリウム、ｔ－ブトキシカリウム、ｔ－ペントキシナトリウム、ｔ－ペントキシカリウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等を使用することができる。 The reaction of the amine compound represented by the general formula (IX) and the compound (X) having a leaving group W 3 can be performed in a solvent in the presence of a base. The solvent is not particularly limited, and for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used alone or in combination as a base. Is not particularly limited, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisi Zido, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t- Butyl lithium or the like can be used.
　また、上記一般式（I）で表される化合物のうち、ＲがＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を示す化合物（Ic）は、公知の特許文献（国際公開第２００８／１１１６０４号パンフレット、国際公開第２００８／１２９９５１号パンフレット）等に記載の方法により製造することができる一般式（V）で示される脱離基を有す化合物に一般式（XI）で示されるアルキルアミノピリミジン誘導体を塩基で反応させることにより製造することができる。 Among the compounds represented by the general formula (I), R has a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, and a substituent. Compound (Ic) showing an optionally amino C 1-6 alkyl group, an optionally substituted carbamoyl C 1-6 alkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group is known. In general, compounds having a leaving group represented by the general formula (V) that can be produced by the method described in the patent documents (Patent Documents WO 2008/111604, WO 2008/129951) It can be produced by reacting an alkylaminopyrimidine derivative represented by the formula (XI) with a base.
　この反応経路を化学反応式で示すと次の通りである。
Figure JPOXMLDOC01-appb-C000055
 （式中、Ｒ１、Ｒ２、Ｒ３、及び
Figure JPOXMLDOC01-appb-C000056
 は、前記の一般式（I）におけるものと同義であり、Ｗ２はハロゲン原子、アルキルスルホニルオキシ基、ハロアルキルスルホニルオキシ基又はアリールスルホニルオキシ基を、Ｒ１６はＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を示す。） This reaction path is represented by the chemical reaction formula as follows.
Figure JPOXMLDOC01-appb-C000055
 (Wherein R 1 , R 2 , R 3 , and
Figure JPOXMLDOC01-appb-C000056
 Is as defined in the general formula (I), W 2 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an arylsulfonyloxy group, R 16 represents a C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, optionally substituted amino C 1-6 alkyl group, optionally substituted carbamoyl C 1-6 alkyl group Or a C 3-8 cycloalkyl C 1-6 alkyl group. )
　脱離基を有す化合物（V）とアルキルアミノピリミジン誘導体（XI）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を使用することができ、塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔ－ブトキシナトリウム、ｔ－ブトキシカリウム、ｔ－ペントキシナトリウム、ｔ－ペントキシカリウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等を使用することができる。 The reaction of the compound (V) having a leaving group and the alkylaminopyrimidine derivative (XI) can be performed in a solvent in the presence of a base. The solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited. Are, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
　上記アルキルアミノピリミジン誘導体（XI）は、一般式（VII）で示されるピリミジン－２－アミン誘導体に一般式（X）で示される脱離基Ｗ３を有す化合物を塩基で反応させることにより製造することができる。また、アルキルアミノピリミジン誘導体（XI）は一般式（VII）で示されるピリミジン－２－アミン誘導体に一般式（XII）で示されるアルデヒド誘導体、または一般式（XIII）で示されるケトン誘導体を還元的アミノ化の手法を用いて反応させることにより製造することができる。 The alkylaminopyrimidine derivative (XI) is produced by reacting a pyrimidine-2-amine derivative represented by the general formula (VII) with a compound having a leaving group W 3 represented by the general formula (X) with a base. can do. The alkylaminopyrimidine derivative (XI) is a reductive reaction of the pyrimidine-2-amine derivative represented by the general formula (VII) to the aldehyde derivative represented by the general formula (XII) or the ketone derivative represented by the general formula (XIII). It can manufacture by making it react using the method of amination.
　この反応経路を化学反応式で示すと次の通りである。
Figure JPOXMLDOC01-appb-C000057
 （式中、Ｒ１は、前記の一般式（I）におけるものと同義であり、Ｗ３はハロゲン原子、アルキルスルホニルオキシ基、ハロアルキルスルホニルオキシ基又はＣ６－１０アリールスルホニルオキシ基を、Ｒ１６はＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を、Ｒ１７はＲ１７－ＣＨ２－がＲ１６を示す原子団を、Ｒ１８及びＲ１９は（Ｒ１８）（Ｒ１９）ＣＨ－がＲ１６を示す原子団を示す。） This reaction path is represented by the chemical reaction formula as follows.
Figure JPOXMLDOC01-appb-C000057
 (In the formula, R 1 have the same meanings as those explained for the general formula (I), W 3 represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or a C 6-10 arylsulfonyloxy group, R 16 Has a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, an amino C 1-6 alkyl group which may have a substituent, and a substituent An optionally substituted carbamoyl C 1-6 alkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group, R 17 represents an atomic group in which R 17 —CH 2 — represents R 16 , and R 18 and R 19 represent (R 18 ) (R 19 ) CH— represents an atomic group in which R 16 is represented.
　ピリミジン－２－アミン（VII）誘導体と脱離基を有す化合物（X）の反応は溶媒中、塩基の存在下により行うことができる。溶媒としては特に制限は無いが、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を使用することができ、塩基としては特に制限は無いが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムジイソプロピルアミド、ナトリウムジイソプロピルアミド、カリウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、ｔ－ブトキシナトリウム、ｔ－ブトキシカリウム、ｔ－ペントキシナトリウム、ｔ－ペントキシカリウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等を使用することができる。 The reaction of the pyrimidine-2-amine (VII) derivative and the compound (X) having a leaving group can be performed in a solvent in the presence of a base. The solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited. Are, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hex Use methyl disilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-pentoxy sodium, t-pentoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium, etc. Can do.
　ピリミジン－２－アミン（VII）誘導体とアルデヒド誘導体（XII）又はケトン誘導体（XIII）の反応は、溶媒中、酸の存在下又は非存在下にて還元試薬を用いて行うことができる。その際、Dean-Stark装置等を用いて脱水操作を行ってもよい。溶媒としては特に制限はないが、例えば、１，２－ジクロロエタン、クロロホルム、ジクロロメタン、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、テトラヒドロフラン、ジオキサン、アセトニトリル、プロピオニトリル、メタノール、エタノール、イソプロパノール等を単独又は組み合わせて使用することができる。酸としては特に制限はないが、例えば、酢酸、トリフルオロ酢酸、プロピオン酸、安息香酸等のプロトン酸、四塩化チタン、三フッ化ホウ素、塩化第二スズ等のルイス酸を使用することができる。還元試薬としては特に制限はないが、例えば、トリアセトキシ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素テトラメチルアンモニウム、シアノ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、トリメトキシ水素化ホウ素ナトリウム、トリエチル水素化ホウ素リチウム等の水素化ホウ素系試薬、水素化アルミニウムリチウム、ジイソプロピル水素化アルミニウム、ビス（２－メトキシエトキシ）水素化アルミニウムナトリウム等の水素化アルミニウム試薬、金属触媒及び水素源を用いた接触還元を使用することができる。接触還元の水素源としては、例えば、水素、シクロヘキサジエン、ギ酸、ギ酸アンモニウム等を使用することができ、金属触媒としては、例えば、パラジウム炭素、パラジウム黒、水酸化パラジウム炭素粉末、ラネーニッケル、二酸化白金、白金黒等を使用することができる。 The reaction between the pyrimidine-2-amine (VII) derivative and the aldehyde derivative (XII) or ketone derivative (XIII) can be carried out in a solvent using a reducing reagent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like. The solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. . There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Contact using borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used. As a hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.
　前記の各反応で得られた中間体及び目的物は、有機合成化学で常用されている精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して必要に応じて単離、精製することができる。また、中間体においては、特に精製することなく次反応に供することもできる。 Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.
　さらに、各種の異性体は異性体間の物理化学的性質の差を利用した常法を適用して単離できる。たとえばラセミ混合物は、例えば酒石酸等の一般的な光学活性酸とのジアステレオマー塩に導き光学分割する方法又は光学活性カラムクロマトグラフィーを用いた方法等の一般的ラセミ分割法により、光学的に純粋な異性体に導くことができる。また、ジアステレオマー混合物は、例えば分別結晶化または各種クロマトグラフィー等により分割できる。また、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers. For example, a racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to various isomers. In addition, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.
　本発明の医薬としては上記の有効成分自体を投与してもよいが、好ましくは、当業者に周知の方法によって製造可能な経口用あるいは非経口用の医薬組成物として投与することができる。経口投与に適する医薬用組成物としては、例えば、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、及びシロップ剤等を挙げることができ、非経口投与に適する医薬組成物としては、例えば、静脈内注射剤や筋肉内注射剤などの注射剤、点滴剤、坐剤、吸入剤、点眼剤、点鼻剤、経皮吸収剤、経粘膜吸収剤などを挙げることができるが、これらに限定されることはない。 The active ingredient itself may be administered as the medicament of the present invention, but it can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art. Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes Examples include injections such as intravenous injections and intramuscular injections, drops, suppositories, inhalants, eye drops, nasal drops, transdermal absorbents, transmucosal absorbents, etc. It is not limited to.
　上記の医薬組成物は、薬理学的、製剤学的に許容しうる添加物を加えて製造することができる。薬理学的、製剤学的に許容しうる添加物の例としては、例えば、賦形剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、保存剤、矯味剤、香料、被膜剤、希釈剤などを挙げることができるが、これらに限定されることはない。 The above pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, Examples include, but are not limited to, flavoring agents, fragrances, coating agents, and diluents.
　本発明の医薬の投与量は特に限定されず、疾患の種類、予防又は治療の目的、有効成分の種類などに応じて適宜選択することができ、さらに患者の体重や年齢、症状、投与経路など通常考慮すべき種々の要因に応じて、適宜増減することができる。例えば、経口投与の場合には成人一日あたり有効成分の重量として０．１ ～５００ｍｇ程度の範囲で用いることができるが、投与量は当業者に適宜選択可能であり、上記の範囲に限定されることはない。 The dosage of the pharmaceutical agent of the present invention is not particularly limited, and can be appropriately selected according to the type of disease, the purpose of prevention or treatment, the type of active ingredient, etc., and the patient's weight and age, symptoms, administration route, etc. It can be increased or decreased as appropriate according to various factors that should be normally considered. For example, in the case of oral administration, the weight of active ingredient per day for an adult can be used in the range of about 0.1 mg to 500 mg, but the dosage can be appropriately selected by those skilled in the art and is limited to the above range. Never happen.
　次に、実施例を挙げて本発明をさらに説明するが、本発明はこれら実施例に限定されるものではない。なお、下記実施例中で用いられている略号は下記の意味を示す。
ｓ：シングレット（ｓｉｎｇｌｅｔ）
ｄ：ダブレット（ｄｏｕｂｌｅｔ）
ｔ：トリプレット（ｔｒｉｐｌｅｔ）
ｑ：クアルテット（ｑｕａｒｔｅｔ）
ｍ：マルチプレット（ｍｕｌｔｉｐｌｅｔ）
ｂｒ：ブロード（ｂｒｏａｄ）
Ｊ：カップリング定数（ｃｏｕｐｌｉｎｇ ｃｏｎｓｔａｎｔ）
Ｈｚ：ヘルツ（Ｈｅｒｔｚ）
ＣＤＣｌ３：重クロロホルム
ｄ６－ＤＭＳＯ：重ジメチルスルホキシド
１Ｈ-ＮＭＲ：プロトン核磁気共鳴
ＩＲ：赤外線吸収スペクトル
ＭＴＢＥ：メチルｔ－ブチルエーテル EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl 3 : deuterated chloroform d 6 -DMSO: deuterated dimethyl sulfoxide
1 H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum MTBE: methyl t-butyl ether
実施例１
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 1
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 2
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylsulfinyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 3
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メトキシベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 4
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例５
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メトキシベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 5
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例６
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－３，５－ジフルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 6
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例７
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－３，５－ジフルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 7
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例８
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メチルベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 8
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例９
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メチルベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 9
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１０
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－フルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 10
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１１
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－フルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 11
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１２
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－メトキシベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 12
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１３
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－メトキシベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 13
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１４
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 14
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１５
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 15
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylsulfinyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１６
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 16
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１７
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－クロロ－６－［（シクロペンチルメチル）（エチル）アミノ］－３－メチルベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 17
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [ Preparation of 2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１８
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－クロロ－６－［（シクロペンチルメチル）（エチル）アミノ］－３－メチルベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 18
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例１９
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 19
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidine -2- Production of amines:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２０
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 20
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylsulfonyl) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２１
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４，５－ジフルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 21
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２２
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４，５－ジフルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 22
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２３
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－クロロ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 23
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２４
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－クロロ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 24
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２５
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－フルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 25
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ) Ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２６
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－フルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 26
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２７
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 27
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２８
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 28
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例２９
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛５－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 29
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３０
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛５－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 30
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３１
３－［１－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）エチル］－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 31
3- [1-({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) ethyl] Production of -5- (trifluoromethyl) benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３２
３－［１－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）エチル］－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 32
3- [1-({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) ethyl ] -5- (Trifluoromethyl) benzonitrile production:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３３
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 33
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３４
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 34
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３５
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］－Ｎ－［２－ピペリジノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 35
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine- 2-Amine production:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３６
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［２－ピペリジノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 36
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine -2- Production of amines:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３７
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］－Ｎ－［２－モルホリノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 37
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine- 2-Amine production:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３８
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［２－モルホリノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 38
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine -2- Production of amines:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例３９
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（４－メチルピペリジノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 39
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) Preparation of [Ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４０
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（４－メチルピペリジノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 40
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylsulfonyl) ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４１
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（cis－２，６－ジメチルモルホリノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 41
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ Preparation of 2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４２
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（cis－２，６－ジメチルモルホリノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 42
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４３
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 43
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Preparation of methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４４
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 44
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Preparation of methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４５
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　国際公報第２０１３／０８１０８７号パンフレット記載の方法により得られる２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸　塩酸塩（100 mg, 0.1224 mmol）をイソプロパノール（1 mL）に懸濁させ、氷浴中にて攪拌しつつ30%過酸化水素水（13.9 μL, 0.1346 mmol）及び五塩化タンタル（4.8 mg, 0.0122 mmol）を加え、室温で14時間攪拌した。氷浴中にて反応液に飽和亜硫酸ナトリウム水溶液を加え、クロロホルムで抽出した後、有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール = 10：1）を用いて精製し、標題化合物を無色油状物として得た。 Example 45
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfinyl) ethoxy] pyrimidine- 2-Il} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} obtained by the method described in the pamphlet of International Publication No. 2013/081087] {5- [2- (Methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid hydrochloride (100 mg, 0.1224 mmol) Was suspended in isopropanol (1 mL), and 30% hydrogen peroxide (13.9 μL, 0.1346 mmol) and tantalum pentachloride (4.8 mg, 0.0122 mmol) were added with stirring in an ice bath. Stir. A saturated aqueous sodium sulfite solution was added to the reaction mixture in an ice bath, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound as a colorless oil.
1H-NMR (CDCl3) δ: 0.83-1.01 (7H, m), 1.36 (1H, m), 1.54 (2H, d, J = 7.2 Hz), 1.60-1/82 (5H, m), 2.13-2.24 (2H, m), 2.73 (3H, s), 2.77-2.87 (4H, m), 3.08, 3.10 (mixed 1H, each dd, J = 4.0, 13.2 and 4.8, 13.2 Hz), 3.18, 3.20 (mixed 1H, dd, J = each 4.8, 13.2 Hz), 4.55, 4.56 (mixed 1H, each d, J = each 17.2 Hz), 6.27 (1H, q, J = 7.2 Hz), 7.15 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.37 (1H, d, J = 8.0 Hz), 7.72 (1H, s), 7.76 (2H, s), 8.14 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.83-1.01 (7H, m), 1.36 (1H, m), 1.54 (2H, d, J = 7.2 Hz), 1.60-1 / 82 (5H, m), 2.13 -2.24 (2H, m), 2.73 (3H, s), 2.77-2.87 (4H, m), 3.08, 3.10 (mixed 1H, each dd, J = 4.0, 13.2 and 4.8, 13.2 Hz), 3.18, 3.20 ( mixed 1H, dd, J = each 4.8, 13.2 Hz), 4.55, 4.56 (mixed 1H, each d, J = each 17.2 Hz), 6.27 (1H, q, J = 7.2 Hz), 7.15 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.37 (1H, d, J = 8.0 Hz), 7.72 (1H, s), 7.76 (2H, s), 8.14 (2H, s).
実施例４６
Ｎ－｛２－［ビス（シクロプロピルメチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 46
N- {2- [bis (cyclopropylmethyl) amino] -5- (trifluoromethyl) benzyl} -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４７
Ｎ－｛２－［ビス（シクロプロピルメチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１２９９５１号パンフレット）に記載の方法に従い製造した。 Example 47
N- {2- [bis (cyclopropylmethyl) amino] -5- (trifluoromethyl) benzyl} -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/129951 pamphlet).
実施例４８
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造：
　特許文献（日本国公開特許公報２０１０－０７７１１６）に記載の方法に従い製造した。 Example 48
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} Preparation of amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
実施例４９
２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（ヒドロキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　特許文献（日本国公開特許公報２０１０－０７７１１６）に記載の方法に従い製造した。 Example 49
2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4 Preparation of-(trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
実施例５０
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造： Example 50
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
工程１：２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンズアルデヒドの製造
　２－フルオロ－５－（トリフルオロメチル）ベンズアルデヒド（500 mg, 2.60 mmol）のジメチルスルホキシド－水（2：1混同溶液，15 mL）溶液にジアリルアミン（319 mg, 3.28 mmol）及び炭酸ナトリウム（828 mg, 7.81 mmol）を加え、100℃にて2時間攪拌した。ジアリルアミン（158 mg, 1.63 mmol）を追加し、同温にて4時間攪拌した後、反応液を室温まで放冷後、水を加えトルエンで抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して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 = 24：1 → 3：2）を用いて精製し、２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンズアルデヒド（567 mg, 81%）を黄色油状物として得た。 Step 1: Preparation of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (500 mg, 2.60 mmol) in dimethyl sulfoxide-water (2: 1 mixed solution) , 15 mL) solution was added diallylamine (319 mg, 3.28 mmol) and sodium carbonate (828 mg, 7.81 mmol), and the mixture was stirred at 100 ° C. for 2 hours. After diallylamine (158 mg, 1.63 mmol) was added and stirred at the same temperature for 4 hours, the reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: ethyl acetate = 24: 1 → 3: 2). , 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde (567 mg, 81%) was obtained as a yellow oil.
1H-NMR (CDCl3) δ: 3.91 (4H, d, J = 5.5 Hz), 5.23-5.26 (4H, m), 5.27-5.29 (2H, m), 5.78-5.88 (2H, m), 7.13 (1H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 2.3, 8.7 Hz), 8.04 (1H, d, J = 2.3 Hz), 10.21 (1H, s). 1 H-NMR (CDCl 3 ) δ: 3.91 (4H, d, J = 5.5 Hz), 5.23-5.26 (4H, m), 5.27-5.29 (2H, m), 5.78-5.88 (2H, m), 7.13 (1H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 2.3, 8.7 Hz), 8.04 (1H, d, J = 2.3 Hz), 10.21 (1H, s).
工程２：Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造
　工程１で得られた２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンズアルデヒド（200 mg, 0.74 mmol）及び特許文献（国際公開第２００８／１２９９５１号パンフレット）記載の実施例１の方法により合成した５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（165 mg, 89 mmol）のトルエン（5 mL）溶液に酢酸（45 mg, 0.75 mmol）を加え、Dean－Stark装置を用い5時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム（472 mg, 2.23 mmol）を加え、室温で64時間攪拌した。反応液に飽和重曹水を加え酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル = 16：1 → 1：1）を用いて精製し、Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（215 mg, 66%）を無色固体として得た。 Step 2: Preparation of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (diallyl obtained in Step 1 Amino) -5- (trifluoromethyl) benzaldehyde (200 mg, 0.74 mmol) and 5- [2- (methylthio) ethoxy synthesized by the method of Example 1 described in the patent literature (WO 2008/129951 pamphlet) Acetic acid (45 mg, 0.75 mmol) was added to a solution of pyrimidine-2-amine (165 mg, 89 mmol) in toluene (5 mL), and the mixture was heated to reflux for 5 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (472 mg, 2.23 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 64 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 1: 1) to give N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5. -[2- (Methylthio) ethoxy] pyrimidin-2-amine (215 mg, 66%) was obtained as a colorless solid.
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.4 Hz), 3.65 (4H, d, J = 6.4 Hz), 4.12 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 6.4 Hz), 5.15 (2H, dd, J = 1.4, 10.1 Hz), 5.20 (2H, dd, J = 1.4, 17.4 Hz), 5.79 (2H, tdd, J = 6.4, 10.1, 17.4 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.3, 8.7 Hz), 7.63 (1H, d, J = 2.3 Hz), 8.07 (2H, s). 1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.4 Hz), 3.65 (4H, d, J = 6.4 Hz), 4.12 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 6.4 Hz), 5.15 (2H, dd, J = 1.4, 10.1 Hz), 5.20 (2H, dd, J = 1.4, 17.4 Hz), 5.79 (2H, tdd, J = 6.4, 10.1, 17.4 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.3, 8.7 Hz), 7.63 (1H, d, J = 2.3 Hz), 8.07 (2H , s).
工程３：（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（138 mg, 0.31 mmol）をＮ，Ｎ－ジメチルホルムアミド（4 mL）に溶解し、－20℃にて水素化ナトリウム（50% in oil：45 mg, 0.94 mmol）を加え、同温にて1時間攪拌した。－30℃に冷却し、（Ｒ）－１－（１－ブロモエチル）－３，５－ビス（トリフルオロメチル）ベンゼン（202 mg, 0.63 mmol）を加え、同温にて18時間攪拌した。氷浴中にて反応液に10%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、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル = 24：1 → 2：1）を用いて精製し、標題化合物（197 mg, 92%）を無色油状物として得た。 Step 3: (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5 Preparation of [2- (methylthio) ethoxy] pyrimidin-2-amine:
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (138 mg, 0.31 mmol) was converted to N, N-dimethylformamide ( 4 mL), sodium hydride (50% in oil: 45 mg, 0.94 mmol) was added at −20 ° C., and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to −30 ° C., (R) -1- (1-bromoethyl) -3,5-bis (trifluoromethyl) benzene (202 mg, 0.63 mmol) was added, and the mixture was stirred at the same temperature for 18 hours. A 10% aqueous ammonium chloride solution was added to the reaction mixture in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 24: 1 → 2: 1) to give the title compound (197 mg, 92%) as a colorless oil.
1H-NMR (CDCl3) δ: 1.46 (3H, d, J = 7.1 Hz), 2.22 (3H, s), 2.88 (2H, t, J = 6.6 Hz), 3.54 (4H, d, J = 5.6 Hz), 4.17 (2H, t, J = 6.6 Hz), 4.68 (1H, d, J = 17.1 Hz), 4.82 (1H, d, J = 17.1 Hz), 5.12 (2H, dd, J = 1.5, 10.2 Hz), 5.16 (2H, dd, J = 1.5, 18.8 Hz), 5.66 (2H, tdd, J = 5.6, 10.2, 18,8 Hz), 6.21 (1H, q, J = 7.1 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.28 (1H, s), 7.35 (1H, d, J = 8.3 Hz), 7.68 (1H, s), 7.73 (2H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.46 (3H, d, J = 7.1 Hz), 2.22 (3H, s), 2.88 (2H, t, J = 6.6 Hz), 3.54 (4H, d, J = 5.6 Hz), 4.17 (2H, t, J = 6.6 Hz), 4.68 (1H, d, J = 17.1 Hz), 4.82 (1H, d, J = 17.1 Hz), 5.12 (2H, dd, J = 1.5, 10.2 Hz), 5.16 (2H, dd, J = 1.5, 18.8 Hz), 5.66 (2H, tdd, J = 5.6, 10.2, 18,8 Hz), 6.21 (1H, q, J = 7.1 Hz), 7.03 (1H , d, J = 8.3 Hz), 7.28 (1H, s), 7.35 (1H, d, J = 8.3 Hz), 7.68 (1H, s), 7.73 (2H, s), 8.16 (2H, s).
実施例５１
（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（183 mg, 0.27 mmol）をジクロロメタン（2.5 mL）に溶解し、アルゴン雰囲気下にて１，３－ジメチルバルビタール酸（253 mg, 1.62 mmol）及びテトラキス（トリフェニルホスフィン）パラジウム（6.2 mg, 0.0054 mmol）を加え、35℃にて2時間30分間攪拌した。反応液を減圧濃縮して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 = 16：1 → 3：2）を用いて精製し、標題化合物（108 mg, 67%）を白色油状物として得た。 Example 51
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Preparation of [Ethoxy] pyrimidin-2-amine:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine (183 mg, 0.27 mmol) was dissolved in dichloromethane (2.5 mL), and 1,3-dimethylbarbital acid (253 mg, 1.62 mmol) and tetrakis (tri Phenylphosphine) palladium (6.2 mg, 0.0054 mmol) was added, and the mixture was stirred at 35 ° C. for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 3: 2) to give the title compound (108 mg, 67%) as a white oil. Obtained.
1H-NMR (CDCl3) δ: 1.75 (2H, d, J = 7.1 Hz), 2.20 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 4.13 (2H, t, J = 6.8 Hz), 4.73 (1H, d, J = 15.4 Hz), 4.84 (2H, br), 4.85 (1H, d, J = 15.4 Hz), 5.66 (1H, q, J = 7.1 Hz), 6.54 (1H, d, J = 8.6 Hz), 7.01 (1H, d, J = 1.4 Hz), 7.20 (1H, d, J = 1.4, 8.6 Hz), 7.57 (2H, s), 7.58 (1H, s), 8.10 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.75 (2H, d, J = 7.1 Hz), 2.20 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 4.13 (2H, t, J = 6.8 Hz), 4.73 (1H, d, J = 15.4 Hz), 4.84 (2H, br), 4.85 (1H, d, J = 15.4 Hz), 5.66 (1H, q, J = 7.1 Hz), 6.54 (1H, d, J = 8.6 Hz), 7.01 (1H, d, J = 1.4 Hz), 7.20 (1H, d, J = 1.4, 8.6 Hz), 7.57 (2H, s), 7.58 (1H, s), 8.10 ( 2H, s).
実施例５２
（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（98 mg, 0.16 mmol）をイソプロパノール（0.6 mL）に溶解し、タングステン酸ナトリウム・２水和物（16 mg, 0.049 mmol）及び30%過酸化水素水（56 mg, 1.6 mmol）を室温にて順次加え、同温にて15時間攪拌した。反応液に水を加え、クロロホルムにて抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール = 300：1 → 15：1）を用いて分離した後、シリカゲル分取薄層クロマトグラフィー（クロロホルム：メタノール ＝ 25：1）にて精製し、標題化合物（103 mg, quant.）を無色油状物として得た。 Example 52
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ) Preparation of ethoxy] pyrimidin-2-amine:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine (98 mg, 0.16 mmol) is dissolved in isopropanol (0.6 mL), sodium tungstate dihydrate (16 mg, 0.049 mmol) and 30% aqueous hydrogen peroxide (56 mg, 1.6 mmol) was sequentially added at room temperature, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (chloroform: methanol = 300: 1 → 15: 1) and then purified by silica gel preparative thin layer chromatography (chloroform: methanol = 25: 1) The title compound (103 mg, quant.) Was obtained as a colorless oil.
1H-NMR (CDCl3) δ: 1.76 (2H, d, J = 7.1 Hz), 3.07 (3H, s), 3.44 (2H, t, J = 5.2 Hz), 4.42 (2H, t, J = 5.2 Hz), 4.71 (1H, d, J = 15.4 Hz), 4.79 (2H, br), 4.89 (1H, d, J = 15.4 Hz), 5.63 (1H, q, J = 7.1 Hz), 6.57 (1H, d, J = 8.3 Hz), 7.03 (1H, s), 7.22 (1H, d, J = 8.3 Hz), 7.56 (2H, s), 7.59 (1H, s), 8.12 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.76 (2H, d, J = 7.1 Hz), 3.07 (3H, s), 3.44 (2H, t, J = 5.2 Hz), 4.42 (2H, t, J = 5.2 Hz), 4.71 (1H, d, J = 15.4 Hz), 4.79 (2H, br), 4.89 (1H, d, J = 15.4 Hz), 5.63 (1H, q, J = 7.1 Hz), 6.57 (1H, d, J = 8.3 Hz), 7.03 (1H, s), 7.22 (1H, d, J = 8.3 Hz), 7.56 (2H, s), 7.59 (1H, s), 8.12 (2H, s).
実施例５３
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　ジアリルアミンの代わりにＮ－（４－メトキシベンジル）エチルアミンを用いて実施例５０と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 53
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} Preparation of -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 50 using N- (4-methoxybenzyl) ethylamine in place of diallylamine, and the title compound was obtained as a pale-yellow oil.
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.1 Hz), 1.43 (3H, d, J = 7.1 Hz), 2.21 (3H, s), 2.87 (2H, t, J = 6.6 Hz), 2.87 (2H, t, J = 6.6 Hz), 2.80-2.92 (2H, m), 3.77 (3H, s), 3.97 (2H, s), 4.15 (2H, t, J = 6.6 Hz), 4.72 (1H, d, J = 17.1 Hz), 4.92 (1H, d, J = 17.1 Hz), 6.16 (1H, q, J = 7.1 Hz), 6.77 (2H, td, J = 2.0, 8.8 Hz), 7.07 (2H, td, J = 2.0, 8.8 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.26 (1H, d, J = 2.0 Hz, overlapped with CHCl3), 7.38 (1H, d, J = 2.0, 8.3 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.14 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.1 Hz), 1.43 (3H, d, J = 7.1 Hz), 2.21 (3H, s), 2.87 (2H, t, J = 6.6 Hz), 2.87 (2H, t, J = 6.6 Hz), 2.80-2.92 (2H, m), 3.77 (3H, s), 3.97 (2H, s), 4.15 (2H, t, J = 6.6 Hz), 4.72 (1H, d, J = 17.1 Hz), 4.92 (1H, d, J = 17.1 Hz), 6.16 (1H, q, J = 7.1 Hz), 6.77 (2H, td, J = 2.0, 8.8 Hz), 7.07 (2H, td, J = 2.0, 8.8 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.26 (1H, d, J = 2.0 Hz, overlapped with CHCl 3 ), 7.38 (1H, d, J = 2.0, 8.3 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.14 (2H, s).
実施例５４
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（6.47 mg, 8.66 mmol）を１，２－ジクロロエタン（6.3 mL）に溶解し、アニソール（9.31 g, 86.1 mmol）を加え氷浴中にて攪拌する中にトリフルオロ酢酸（9.89 g, 86.7 mmo;）を加え、室温にて7時間攪拌した。氷浴中にて2M水酸化ナトリウム水溶液を加えて塩基性とした後、１，２－ジクロロエタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した後、減圧濃縮して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：クロロホルム = 3：1 → 1：3）を用いて精製した。得られた淡黄色油状物をヘキサン－MTBE（10：1）混合溶媒にて45分間攪拌後、生じた析出物を濾取し、ヘキサンにて洗浄した。減圧乾燥し、標題化合物（2.90 g, 53%）を無色固体として得た。 Example 54
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine (6.47 mg, 8.66 mmol) is dissolved in 1,2-dichloroethane (6.3 mL), and anisole (9.31 g, 86.1 mmol) is added to the solution in an ice bath. To the mixture, trifluoroacetic acid (9.89 g, 86.7 mmo;) was added and stirred at room temperature for 7 hours. The mixture was made basic by adding 2M aqueous sodium hydroxide solution in an ice bath, and then extracted with 1,2-dichloroethane. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: chloroform = 3: 1 → 1: 3). did. The resulting pale yellow oil was stirred with a mixed solvent of hexane-MTBE (10: 1) for 45 minutes, and the resulting precipitate was collected by filtration and washed with hexane. Drying under reduced pressure gave the title compound (2.90 g, 53%) as a colorless solid.
1H-NMR (CDCl3) δ: 1.13 (3H, t, J = 7.1 Hz), 1.78 (3H, d, J = 7.1 Hz), 2.20 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.05-3.14 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 4.68 (1H, d, J = 15.4 Hz), 4.98 (1H, d, J = 15.4 Hz), 5.45 (1H, q, J = 7.1 Hz), 5.81 (1H, br), 6.48 (1H, d, J = 8.5 Hz), 7.07 (1H, d, J = 1.7 Hz), 7.31 (1H, dd, J = 1.7, 8.5 Hz), 7.49 (2H, s), 7.55 (1H, s), 8.08 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.13 (3H, t, J = 7.1 Hz), 1.78 (3H, d, J = 7.1 Hz), 2.20 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.05-3.14 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 4.68 (1H, d, J = 15.4 Hz), 4.98 (1H, d, J = 15.4 Hz), 5.45 ( 1H, q, J = 7.1 Hz), 5.81 (1H, br), 6.48 (1H, d, J = 8.5 Hz), 7.07 (1H, d, J = 1.7 Hz), 7.31 (1H, dd, J = 1.7 , 8.5 Hz), 7.49 (2H, s), 7.55 (1H, s), 8.08 (2H, s).
実施例５５
（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンを用いて実施例５２と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 55
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoro) instead of ethoxy] pyrimidin-2-amine Methyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 52 to obtain the title compound as a colorless amorphous.
1H-NMR (CDCl3) δ: 1.14 (3H, t, J = 7.1 Hz), 1.78 (3H, d, J = 6.8 Hz), 3.07 (3H, s), 3.08-3.13 (2H, m), 3.44 (2H, t, J = 5.4 Hz), 4.41 (2H, t, J = 5.4 Hz), 4.65 (1H, d, J = 15.4 Hz), 5.01 (1H, d, J = 15.4 Hz), 5.42 (1H, q, J = 7.1 Hz), 5.69 (1H, br), 6.50 (1H, d, J = 8.6 Hz), 7.09 (1H, s), 7.33 (1H, d, J = 8.6 Hz), 7.48 (2H, s), 7.56 (1H, s), 8.10 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.14 (3H, t, J = 7.1 Hz), 1.78 (3H, d, J = 6.8 Hz), 3.07 (3H, s), 3.08-3.13 (2H, m), 3.44 (2H, t, J = 5.4 Hz), 4.41 (2H, t, J = 5.4 Hz), 4.65 (1H, d, J = 15.4 Hz), 5.01 (1H, d, J = 15.4 Hz), 5.42 ( 1H, q, J = 7.1 Hz), 5.69 (1H, br), 6.50 (1H, d, J = 8.6 Hz), 7.09 (1H, s), 7.33 (1H, d, J = 8.6 Hz), 7.48 ( 2H, s), 7.56 (1H, s), 8.10 (2H, s).
実施例５６
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造：
　ジアリルアミンの代わりに２－（ｔｒａｎｓ－４－｛［（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例５０と同様に反応・処理し、標題化合物を黄褐色油状物として得た。 Example 56
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate:
The reaction and treatment were conducted in a similar manner to Example 50 using 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate in place of diallylamine, and the title compound was obtained as a tan oil. It was.
1H-NMR (CDCl3) δ: 0.78-0.94 (4H, m), 1.24 (3H, t, J = 7.2 Hz), 1.38 (1H, m), 1.43 (3H, d, J = 7.2 Hz), 1.58-1.73 (4H, m), 1.81 (1H, m), 2.12 (2H, d, J = 6.0 Hz), 2.20 (3H, s), 2.66 (1H, dd, J = 8.0, 13.2 Hz), 2.79 (1H, dd, J = 6.0, 13.2 Hz), 2.86 (2H, t, J = 6.8 Hz), 3.76 (3H, s), 3.83 (1H, d, J = 14.4 Hz), 3.94 (1H, d, J = 14.4 Hz), 4.07-4.17 (4H, m), 4.74 (1H, d, J = 17.2 Hz), 4.98 (1H, d, J = 17.2 Hz), 6.20 (1H, q, J = 7.2 Hz), 6.74 (2H, dd, J = 2.4, 8.8 Hz), 7.01 (2H, dd, J = 2.4, 8.8 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.39 (1H, dd, J = 2.0, 8.4 Hz), 7.74 (3H, s), 8.11 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.78-0.94 (4H, m), 1.24 (3H, t, J = 7.2 Hz), 1.38 (1H, m), 1.43 (3H, d, J = 7.2 Hz), 1.58-1.73 (4H, m), 1.81 (1H, m), 2.12 (2H, d, J = 6.0 Hz), 2.20 (3H, s), 2.66 (1H, dd, J = 8.0, 13.2 Hz), 2.79 (1H, dd, J = 6.0, 13.2 Hz), 2.86 (2H, t, J = 6.8 Hz), 3.76 (3H, s), 3.83 (1H, d, J = 14.4 Hz), 3.94 (1H, d, J = 14.4 Hz), 4.07-4.17 (4H, m), 4.74 (1H, d, J = 17.2 Hz), 4.98 (1H, d, J = 17.2 Hz), 6.20 (1H, q, J = 7.2 Hz) , 6.74 (2H, dd, J = 2.4, 8.8 Hz), 7.01 (2H, dd, J = 2.4, 8.8 Hz), 7.13 (1H, d, J = 8.4 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.39 (1H, dd, J = 2.0, 8.4 Hz), 7.74 (3H, s), 8.11 (2H, s).
実施例５７
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチル（42 mg, 0.047 mmol）をエタノール（1 mL）に溶解し、氷浴中にて撹拌しつつ2M 水酸化ナトリウム水溶液（0.1 mL）を加えた後、50℃まで昇温し、2時間攪拌した。氷浴中にて反応液に2M 塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：1）を用いて精製し、標題化合物（31 mg, 77%）を淡黄色油状物として得た。 Example 57
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Il} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate (42 mg, 0.047 mmol) was dissolved in ethanol (1 mL) and ice bathed. 2M Aqueous sodium hydroxide solution (0.1 mL) was added while stirring in, and then the mixture was warmed to 50 ° C. and stirred for 2 hours. The reaction mixture was neutralized by adding 2M hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (31 mg, 77 %) As a pale yellow oil.
1H-NMR (CDCl3) δ: 0.78-0.96 (4H, m), 1.39 (1H, m), 1.44 (3H, d, J = 7.1 Hz), 1.60-1.83 (5H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.65 (1H, dd, J = 8.0, 12.9 Hz), 2.78 (1H, dd, J = 5.6, 12.9 Hz), 2.86 (2H, t, J = 6.0 Hz), 3.76 (3H, s), 3.83 (1H, d, J = 12.4 Hz), 3.93 (1H, d, J = 12.4 Hz), 4.14 (2H, t, J = 6.0 Hz), 4.68 (1H, d, J = 17.3 Hz), 4.98 (1H, d, J = 17.3 Hz), 6.21 (1H, q, J = 6.8 Hz), 6.74 (2H, d, J = 8.5 Hz), 7.01 (2H, d, J = 8.5 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.23 (1H, s), 7.39 (1H, d, J = 8.3 Hz), 7.73 (2H, s), 7.74 (1H, s), 8.11 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.78-0.96 (4H, m), 1.39 (1H, m), 1.44 (3H, d, J = 7.1 Hz), 1.60-1.83 (5H, m), 2.17 (2H , d, J = 6.8 Hz), 2.20 (3H, s), 2.65 (1H, dd, J = 8.0, 12.9 Hz), 2.78 (1H, dd, J = 5.6, 12.9 Hz), 2.86 (2H, t, J = 6.0 Hz), 3.76 (3H, s), 3.83 (1H, d, J = 12.4 Hz), 3.93 (1H, d, J = 12.4 Hz), 4.14 (2H, t, J = 6.0 Hz), 4.68 (1H, d, J = 17.3 Hz), 4.98 (1H, d, J = 17.3 Hz), 6.21 (1H, q, J = 6.8 Hz), 6.74 (2H, d, J = 8.5 Hz), 7.01 (2H , d, J = 8.5 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.23 (1H, s), 7.39 (1H, d, J = 8.3 Hz), 7.73 (2H, s), 7.74 (1H , s), 8.11 (2H, s).
実施例５８
２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸の製造：
　（Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸を用いて実施例５４と同様に反応・処理し、標題化合物を淡黄色アモルファスとして得た。 Example 58
2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} Instead of -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) ) Phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid Was used and reacted in the same manner as in Example 54 to obtain the title compound as a pale yellow amorphous.
1H-NMR (CDCl3) δ: 0.84-0.99 (4H, m), 1.35 (1H, br), 1.54-1.80 (8H, m), 2.21 (3H, s), 2.22 (2H, d, J = 6.4 Hz), 2.84-2.91 (4H, m), 4.12 (2H, t, J = 6.4 Hz), 4.71 (1H, d, J = 15.6 Hz), 4.98 (1H, d, J = 15.6 Hz), 5.44 (1H, q, J = 6.8 Hz), 5.75 (1H br), 6.46 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 1.6 Hz), 7.30 (1H, dd, J = 1.6, 8.4 Hz), 7.47 (2H, s), 7.54 (1H, s), 8.07 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.84-0.99 (4H, m), 1.35 (1H, br), 1.54-1.80 (8H, m), 2.21 (3H, s), 2.22 (2H, d, J = 6.4 Hz), 2.84-2.91 (4H, m), 4.12 (2H, t, J = 6.4 Hz), 4.71 (1H, d, J = 15.6 Hz), 4.98 (1H, d, J = 15.6 Hz), 5.44 (1H, q, J = 6.8 Hz), 5.75 (1H br), 6.46 (1H, d, J = 8.4 Hz), 7.06 (1H, d, J = 1.6 Hz), 7.30 (1H, dd, J = 1.6 , 8.4 Hz), 7.47 (2H, s), 7.54 (1H, s), 8.07 (2H, s).
実施例５９
２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸の製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸を用いて実施例５２と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 59
2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- Preparation of 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Instead of ethoxy] pyrimidin-2-amine, 2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [ 2- (Methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid was used in the same manner as in Example 52 to give the title compound. Was obtained as a colorless amorphous.
1H-NMR (CDCl3) δ: 0.84-1.02 (4H, m), 1.34 (1H, br), 1.46-1.80 (8H, m), 2.23 (2H, d, J = 6.4 Hz), 2.89 (2H, d, J = 6.4 Hz), 3.08 (3H, s), 3.45 (2H, t, J = 5.6 Hz), 4.40 (2H, t, J = 5.6 Hz), 4.70 (1H, d, J = 15.6 Hz), 5.04 (1H, d, J = 15.6 Hz), 5.40 (1H, q, J = 6.8 Hz), 5.59 (1H br), 6.48 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.32 (1H, dd, J = 2.0, 8.8 Hz), 7.46 (2H, s), 7.55 (1H, s), 8.10 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.84-1.02 (4H, m), 1.34 (1H, br), 1.46-1.80 (8H, m), 2.23 (2H, d, J = 6.4 Hz), 2.89 (2H , d, J = 6.4 Hz), 3.08 (3H, s), 3.45 (2H, t, J = 5.6 Hz), 4.40 (2H, t, J = 5.6 Hz), 4.70 (1H, d, J = 15.6 Hz) ), 5.04 (1H, d, J = 15.6 Hz), 5.40 (1H, q, J = 6.8 Hz), 5.59 (1H br), 6.48 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.32 (1H, dd, J = 2.0, 8.8 Hz), 7.46 (2H, s), 7.55 (1H, s), 8.10 (2H, s).
実施例６０
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造： Example 60
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 Preparation of -yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
工程１：Ｎ－［５－（クロロエトキシ）ピリミジン－２－イル］ヘキサンアミドの製造
　特許文献（国際公開第２００８／１２９９５１号パンフレット）記載の実施例１の方法により合成したＮ－（５－ヒドロキシピリミジン－２－イル）ヘキサンアミド（3.00 g, 14.3 mmol）をＮ，Ｎ－ジメチルホルムアミド（15 mL）に溶解し、室温にて炭酸カリウム（2.97 g, 21.5 mmol）及び１－ブロモ－２－クロロエタン（4.12 g, 28.7 mmol）を加え、60℃にて20時間攪拌した後、反応液を氷水に注ぎ、石油エーテルを加え5分間攪拌した。析出物を濾取し、水及び石油エーテルで洗浄した後、減圧乾燥し、Ｎ－［５－（クロロエトキシ）ピリミジン－２－イル］ヘキサンアミド（2.72 g, 70%）を無色固体として得た。 Step 1: Production of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide N- (5-hydroxy) synthesized by the method of Example 1 described in the patent document (WO 2008/129951 pamphlet) Pyrimidin-2-yl) hexanamide (3.00 g, 14.3 mmol) was dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (2.97 g, 21.5 mmol) and 1-bromo-2-chloroethane were dissolved at room temperature. (4.12 g, 28.7 mmol) was added, and the mixture was stirred at 60 ° C. for 20 hours. The reaction mixture was poured into ice water, petroleum ether was added, and the mixture was stirred for 5 minutes. The precipitate was collected by filtration, washed with water and petroleum ether, and then dried under reduced pressure to give N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (2.72 g, 70%) as a colorless solid. .
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.2 Hz), 1.31-1.43 (4H, m), 1.69-1.78 (2H, m), 2.63 (2H, br), 3.83 (2H, t, J = 5.6 Hz), 4.30 (2H, t, J = 5.6 Hz), 8.36 (2H, s), 8.44 (1H, br). 1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.31-1.43 (4H, m), 1.69-1.78 (2H, m), 2.63 (2H, br), 3.83 (2H , t, J = 5.6 Hz), 4.30 (2H, t, J = 5.6 Hz), 8.36 (2H, s), 8.44 (1H, br).
工程２：Ｎ－｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝ヘキサンアミドの製造
　チオフェノール（486 mg, 4.41 mmol）をＮ，Ｎ－ジメチルホルムアミド（5 mL）に溶解し、氷浴中にて水素化ナトリウム（50% in oil：265 mg, 5.52 mmol）を加え、室温にて15分間攪拌した。反応液に工程１で得られたＮ－［５－（クロロエトキシ）ピリミジン－２－イル］ヘキサンアミド（1.00 g, 3.68 mmol）のＮ，Ｎ－ジメチルホルムアミド（2 mL）に溶液を氷浴中にて加え、室温にて2時間攪拌した後、氷浴中にて2M水酸化ナトリウム水溶液を加えた。室温にて5分間攪拌した後、反応液を酢酸エチルより抽出し、有機層を2M水酸化ナトリウム水溶液及び水で洗浄した。無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム→クロロホルム：メタノール = 30：1 → 10：1）を用いて精製し、Ｎ－｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝ヘキサンアミド（696 mg, 55%）を無色固体として得た。 Step 2: Preparation of N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide Thiophenol (486 mg, 4.41 mmol) was dissolved in N, N-dimethylformamide (5 mL). Sodium hydride (50% in oil: 265 mg, 5.52 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 15 minutes. In the reaction solution, N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (1.00 g, 3.68 mmol) obtained in Step 1 was added to N, N-dimethylformamide (2 mL) in an ice bath. After stirring at room temperature for 2 hours, 2M aqueous sodium hydroxide solution was added in an ice bath. After stirring at room temperature for 5 minutes, the reaction solution was extracted from ethyl acetate, and the organic layer was washed with 2M aqueous sodium hydroxide solution and water. The residue obtained by drying over anhydrous sodium sulfate and concentration under reduced pressure was purified using silica gel column chromatography (chloroform → chloroform: methanol = 30: 1 → 10: 1), and N- {5- [2 -(Phenylthio) ethoxy] pyrimidin-2-yl} hexanamide (696 mg, 55%) was obtained as a colorless solid.
1H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.42 (4H, m), 1.66-1.77 (2H, m), 2.61 (2H, br), 3.29 (2H, t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.25 (1H, tt, J = 2.0, 7.2 Hz), 7.32 (2H, tt, J = 2.0, 7.2 Hz), 7.41 (2H, dt, J = 2.0, 7.2 Hz), 8.22 (2H, s), 8.27 (1H, br). 1 H-NMR (CDCl 3 ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.42 (4H, m), 1.66-1.77 (2H, m), 2.61 (2H, br), 3.29 (2H , t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.25 (1H, tt, J = 2.0, 7.2 Hz), 7.32 (2H, tt, J = 2.0, 7.2 Hz), 7.41 (2H, dt, J = 2.0, 7.2 Hz), 8.22 (2H, s), 8.27 (1H, br).
工程３：５－［２－（フェニルチオ）エトキシ］ピリミジン－２－アミンの製造
　工程２で得られたＮ－｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝ヘキサンアミド（400 mg, 1.16 mmol）をメタノール（2.8 mL）に溶解し、ナトリウムメトキシド（25.1 mg, 2.32 mmol）を加え50℃にて2時間攪拌した。反応液を水で希釈した後、クロロホルムで抽出し、有機層を無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム→クロロホルム：メタノール = 100：1 → 10：1）を用いて精製し、５－［２－（フェニルチオ）エトキシ］ピリミジン－２－アミン（282 mg, 99%）を無色固体として得た。 Step 3: Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide (400 mg) obtained in Step 2 , 1.16 mmol) was dissolved in methanol (2.8 mL), sodium methoxide (25.1 mg, 2.32 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (chloroform → chloroform: methanol = 100: 1 → 10: 1) to give 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine (282 mg, 99%) as a colorless solid.
1H-NMR (CDCl3) δ: 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.80 (2H, br), 7.23 (1H, tt, J = 0.8, 7.2 Hz), 7.31 (2H, tt, J = 0.8, 7.2 Hz), 7.40 (2H, dt, J = 0.8, 7.2 Hz), 7.99 (2H, s). 1 H-NMR (CDCl 3 ) δ: 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.80 (2H, br), 7.23 (1H, tt, J = 0.8 , 7.2 Hz), 7.31 (2H, tt, J = 0.8, 7.2 Hz), 7.40 (2H, dt, J = 0.8, 7.2 Hz), 7.99 (2H, s).
工程４：２－｛ｔｒａｎｓ－４－［（エチル｛２－［（｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチルの製造
　工程３で得られた５－［２－（フェニルチオ）エトキシ］ピリミジン－２－アミン（230 mg, 0.93 mmol）及び特許文献（国際公開第２００８／１２９９５１号パンフレット）記載の実施例４３の方法に従い製造した２－［ｔｒａｎｓ－４－（｛エチル［２－ホルミル－４－（トリフルオロメチル）フェニル］アミノ｝メチル）シクロヘキシル］酢酸エチル（414 mg, 1.02 mmol）のトルエン（4 mL）溶液に酢酸（115 mg, 1.92 mmol）を加え、Dean-Stark装置を用い3.5時間攪拌した。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリフルオロ酢酸（108 mg, 0.95 mmol）及びトリアセトキシ水素化ホウ素ナトリウム（394 mg, 1.86 mmol）を加え、室温で1時間攪拌した。反応液に水を加え酢酸エチルで抽出した後、有機層を飽和重曹水及び飽和食塩水で洗浄し、無水硫酸マグネシウムを用いて乾燥した。減圧濃縮して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：アセトン = 20：1 → 10：1 → 6：1 → 3：1）を用いて精製し、２－｛ｔｒａｎｓ－４－［（エチル｛２－［（｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチル（453 g, 70%）を淡黄色油状物として得た。 Step 4: 2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino ) Preparation of methyl] cyclohexyl} ethyl acetate 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine (230 mg, 0.93 mmol) obtained in Step 3 and a patent document (WO 2008/129951) Of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate (414 mg, 1.02 mmol) prepared according to the method of Example 43 described. Acetic acid (115 mg, 1.92 mmol) was added to a toluene (4 mL) solution, and the mixture was stirred for 3.5 hours using a Dean-Stark apparatus. The reaction solution was allowed to cool to room temperature, and while stirring in an ice bath, trifluoroacetic acid (108 mg, 0.95 mmol) and sodium triacetoxyborohydride (394 mg, 1.86 mmol) were added, and the mixture was stirred at room temperature for 1 hour. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified using silica gel column chromatography (hexane: acetone = 20: 1 → 10: 1 → 6: 1 → 3: 1) to give 2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} ethyl acetate (453 g, 70% ) Was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.89-0.97 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.6 Hz), 5.41 (1H, t, J = 5.6 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.22 (1H, tt, J = 1.6, 8.8 Hz), 7.30 (2H, tt, J = 1.6, 8.8 Hz), 7.40 (2H, td, J = 1.6, 8.8 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.01 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.89-0.97 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 3.25 (2H, t , J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.6 Hz), 5.41 (1H, t, J = 5.6 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.22 (1H, tt, J = 1.6, 8.8 Hz), 7.30 (2H, tt, J = 1.6, 8.8 Hz), 7.40 (2H, td , J = 1.6, 8.8 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.01 (2H, s).
工程５：２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造
　Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－｛ｔｒａｎｓ－４－［（エチル｛２－［（｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチルを用いて実施例５０の工程３と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Step 5: 2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] Preparation of pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate N- [2- (diallylamino) -5- (trifluoromethyl) 2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidine-2 instead of benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine -Il} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} ethyl acetate was reacted and treated in the same manner as in Step 3 of Example 50 to obtain a standard. The title compound was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.80-0.97 (7H, m), 1.24 (3H, t, J = 7.2 Hz), 1.37 (1H, m), 1.44 (3H, d, J = 7.6 Hz), 1.62-1.85 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.6, 13.2 Hz), 2.83 (1H, dd, J = 6.4, 13.2 Hz), 2.88 (2H, q, J = 7.2 Hz), 3.28 (2H, t, J = 6.8 Hz), 4,10 (2H, t, J = 6.8 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.62 (1H, d, J = 17.2 Hz), 4.85 (1H, d, J = 17.2 Hz), 6.19 (1H, q, J = 6.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.21 (1H, s), 7.22 (1H, t, J = 7.6 Hz), 7.30 (2H, t, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.41 (2H, d, J = 7.6 Hz), 7.70 (1H, s), 7.72 (2H, s), 8.08 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.80-0.97 (7H, m), 1.24 (3H, t, J = 7.2 Hz), 1.37 (1H, m), 1.44 (3H, d, J = 7.6 Hz), 1.62-1.85 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.6, 13.2 Hz), 2.83 (1H, dd, J = 6.4, 13.2 Hz), 2.88 (2H, q, J = 7.2 Hz), 3.28 (2H, t, J = 6.8 Hz), 4,10 (2H, t, J = 6.8 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.62 (1H, d, J = 17.2 Hz), 4.85 (1H, d, J = 17.2 Hz), 6.19 (1H, q, J = 6.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.21 (1H , s), 7.22 (1H, t, J = 7.6 Hz), 7.30 (2H, t, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.41 (2H, d, J = 7.6 Hz) ), 7.70 (1H, s), 7.72 (2H, s), 8.08 (2H, s).
実施例６１
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 61
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 Preparation of —yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 2- (trans-4-{[{2-[({( S) -1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } (Ethyl) amino] methyl} cyclohexyl) ethyl acetate was used for the reaction and treatment in the same manner as in Example 57 to obtain the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.79-0.97 (7H, m), 1.38 (1H, m), 1.43 (3H, d, J = 6.8 Hz), 1.62-1.82 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.6, 13.2 Hz), 2.83 (1H, dd, J = 6.4, 13.2 Hz), 2.87 (2H, q, J = 7.2 Hz), 3.28 (2H, t, J = 6.8 Hz), 4,14 (2H, t, J = 6.8 Hz), 4.61 (1H, d, J = 17.2 Hz), 4.85 (1H, d, J = 17.2 Hz), 6.20 (1H, q, J = 6.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.21 (1H, s), 7.22 (1H, t, J = 7.6 Hz), 7.30 (2H, t, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.41 (2H, d, J = 7.6 Hz), 7.70 (1H, s), 7.72 (2H, s), 8.08 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.79-0.97 (7H, m), 1.38 (1H, m), 1.43 (3H, d, J = 6.8 Hz), 1.62-1.82 (5H, m), 2.19 (2H , d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.6, 13.2 Hz), 2.83 (1H, dd, J = 6.4, 13.2 Hz), 2.87 (2H, q, J = 7.2 Hz), 3.28 (2H, t, J = 6.8 Hz), 4,14 (2H, t, J = 6.8 Hz), 4.61 (1H, d, J = 17.2 Hz), 4.85 (1H, d, J = 17.2 Hz), 6.20 (1H, q, J = 6.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.21 (1H, s), 7.22 (1H, t, J = 7.6 Hz), 7.30 (2H, t, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.41 (2H, d, J = 7.6 Hz), 7.70 (1H, s), 7.72 (2H, s), 8.08 (2H, s).
実施例６２
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸を用いて実施例５２と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 62
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfonyl) ethoxy] pyrimidine- 2-Il} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Instead of ethoxy] pyrimidin-2-amine, 2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [ 2- (Phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid was used for the same reaction and treatment as in Example 52. The title compound was obtained as a colorless amorphous.
1H-NMR (CDCl3) δ: 0.82-0.96 (7H, m), 1.38 (1H, m), 1.44 (3H, d, J = 6.8 Hz), 1.64-1.82 (5H, m), 2.20 (2H, d, J = 6.8 Hz), 2.70 (1H, dd, J = 8.0, 12.8 Hz), 2.83 (1H, dd, J = 6.0, 12.8 Hz), 2.88 (2H, q, J = 7.2 Hz), 3.60 (2H, d, J = 6.0 Hz), 4,35 (2H, t, J = 6.0 Hz), 4.60 (1H, d, J = 17.2 Hz), 4.82 (1H, d, J = 17.2 Hz), 6.17 (1H, q, J = 6.8 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.17 (1H, s), 7.38 (1H, d, J = 8.4 Hz), 7.57 (2H, t, J = 7.6 Hz), 7.66 (1H, t, J = 7.6 Hz), 7.71 (3H, s), 7.88 (2H, s), 7.94 (2H, d, J = 7.6 Hz). 1 H-NMR (CDCl 3 ) δ: 0.82-0.96 (7H, m), 1.38 (1H, m), 1.44 (3H, d, J = 6.8 Hz), 1.64-1.82 (5H, m), 2.20 (2H , d, J = 6.8 Hz), 2.70 (1H, dd, J = 8.0, 12.8 Hz), 2.83 (1H, dd, J = 6.0, 12.8 Hz), 2.88 (2H, q, J = 7.2 Hz), 3.60 (2H, d, J = 6.0 Hz), 4,35 (2H, t, J = 6.0 Hz), 4.60 (1H, d, J = 17.2 Hz), 4.82 (1H, d, J = 17.2 Hz), 6.17 (1H, q, J = 6.8 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.17 (1H, s), 7.38 (1H, d, J = 8.4 Hz), 7.57 (2H, t, J = 7.6 Hz), 7.66 (1H, t, J = 7.6 Hz), 7.71 (3H, s), 7.88 (2H, s), 7.94 (2H, d, J = 7.6 Hz).
実施例６３
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造：
　チオフェノールの代わりにフェノールを用いて実施例６０と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 63
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate preparation:
The reaction and treatment were conducted in a similar manner to Example 60 using phenol instead of thiophenol, and the title compound was obtained as a pale-yellow oil.
1H-NMR (CDCl3) δ: 0.80-0.97 (7H, m), 1.24 (3H, t, J = 7.1 Hz), 1.38 (1H, m), 1.44 (3H, d, J = 7.1 Hz), 1.63-1.85 (5H, m), 2.14 (2H, d, J = 6.6 Hz), 2.69 (1H, dd, J = 7.8, 13.0 Hz), 2.84 (1H, dd, J = 6.1, 13.0 Hz), 2.89 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.29-4.37 (4H, m), 4.63 (1H, d, J = 17.1 Hz), 4.86 (1H, d, J = 17.1 Hz), 6.22 (1H, q, J = 7.1 Hz), 6.92-7.01 (3H, m), 7.12 (1H, d, J = 8.3 Hz), 7.24 (1H, s), 7.28-7.33 (2H, m), 7.38 (1H, d, J = 7.8 Hz), 7.71 (1H, s), 7.74 (2H, s), 8.20 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.80-0.97 (7H, m), 1.24 (3H, t, J = 7.1 Hz), 1.38 (1H, m), 1.44 (3H, d, J = 7.1 Hz), 1.63-1.85 (5H, m), 2.14 (2H, d, J = 6.6 Hz), 2.69 (1H, dd, J = 7.8, 13.0 Hz), 2.84 (1H, dd, J = 6.1, 13.0 Hz), 2.89 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.29-4.37 (4H, m), 4.63 (1H, d, J = 17.1 Hz), 4.86 (1H, d, J = 17.1 Hz), 6.22 (1H, q, J = 7.1 Hz), 6.92-7.01 (3H, m), 7.12 (1H, d, J = 8.3 Hz), 7.24 (1H, s), 7.28-7.33 ( 2H, m), 7.38 (1H, d, J = 7.8 Hz), 7.71 (1H, s), 7.74 (2H, s), 8.20 (2H, s).
実施例６４
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 64
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) Preparation of amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 2- (trans-4-{[{2-[({( S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl] amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate was used for the reaction and treatment in the same manner as in Example 57 to obtain the title compound as a colorless amorphous.
1H-NMR (CDCl3) δ: 0.82-0.97 (7H, m), 1.38 (1H, m), 1.44 (3H, d, J = 6.8 Hz), 1.63-1.85 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.8, 13.7 Hz), 2.84 (1H, dd, J = 6.0, 13.7 Hz), 2.89 (2H, q, J = 6.9 Hz), 4.29-4.37 (4H, m), 4.62 (1H, d, J = 17.4 Hz), 4.86 (1H, d, J = 17.4 Hz), 6.23 (1H, q, J = 6.8 Hz), 6.85-7.00 (3H, m), 7.12 (1H, d, J = 8.3 Hz), 7.24 (1H, s), 7.28-7.33 (2H, m), 7.38 (1H, d, J = 7.8 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.20 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.82-0.97 (7H, m), 1.38 (1H, m), 1.44 (3H, d, J = 6.8 Hz), 1.63-1.85 (5H, m), 2.19 (2H , d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.8, 13.7 Hz), 2.84 (1H, dd, J = 6.0, 13.7 Hz), 2.89 (2H, q, J = 6.9 Hz), 4.29 -4.37 (4H, m), 4.62 (1H, d, J = 17.4 Hz), 4.86 (1H, d, J = 17.4 Hz), 6.23 (1H, q, J = 6.8 Hz), 6.85-7.00 (3H, m), 7.12 (1H, d, J = 8.3 Hz), 7.24 (1H, s), 7.28-7.33 (2H, m), 7.38 (1H, d, J = 7.8 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.20 (2H, s).
実施例６５
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造： Example 65
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} Preparation of -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate:
工程１：２－［ｔｒａｎｓ－４－（｛エチル［２－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］アミノ｝メチル）シクロヘキシル］酢酸エチルの製造
　５－［２－（フェニルチオ）エトキシ］ピリミジン－２－アミンの代わりに５－メトキシピリミジン－２－アミンを用いて実施例６０の工程４と同様に反応・処理し、２－［ｔｒａｎｓ－４－（｛エチル［２－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］アミノ｝メチル）シクロヘキシル］酢酸エチル標題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 0.89-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.2 Hz), 3.01 (2H, q, J = 7.2 Hz), 3.80 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.66 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, s). Step 1: 2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate The reaction and treatment were carried out in the same manner as in Step 4 of Example 60 using 5-methoxypyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, and 2- [trans- 4-({Ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid ethyl ester The title compound was obtained as a colorless solid. .
1 H-NMR (CDCl 3 ) δ: 0.89-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.2 Hz), 3.01 (2H, q, J = 7.2 Hz), 3.80 (3H, s ), 4.11 (2H, q, J = 7.2 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.66 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, s).
工程２：２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造
　Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－［ｔｒａｎｓ－４－（｛エチル［２－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］アミノ｝メチル）シクロヘキシル］酢酸エチルを用いて実施例５０の工程３と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Step 2: 2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino ] Preparation of methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2 2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) instead of-(methylthio) ethoxy] pyrimidin-2-amine ) Phenyl] amino} methyl) cyclohexyl] ethyl acetate was used in the same manner as in Step 3 of Example 50 to give the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.80-0.96 (7H, m), 1.25 (3H, t, J = 7.2 Hz), 1.38 (1H, m), 1.44 (3H, d, J = 7.2 Hz), 1.62-1.80 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.6, 13.4 Hz), 2.84 (1H, dd, J = 6.4, 13.4 Hz), 2.89 (2H, q, J = 7.2 Hz), 3.84 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.62 (1H, d, J = 16.8 Hz), 4.86 (1H, d, J = 16.8 Hz), 6.21 (1H, q, J = 7.2 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.24 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 2.0, 8.0 Hz), 7.70 (1H, s), 7.74 (2H, s), 8.13 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.80-0.96 (7H, m), 1.25 (3H, t, J = 7.2 Hz), 1.38 (1H, m), 1.44 (3H, d, J = 7.2 Hz), 1.62-1.80 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 7.6, 13.4 Hz), 2.84 (1H, dd, J = 6.4, 13.4 Hz), 2.89 (2H, q, J = 7.2 Hz), 3.84 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.62 (1H, d, J = 16.8 Hz), 4.86 (1H, d, J = 16.8 Hz), 6.21 (1H, q, J = 7.2 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.24 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 2.0, 8.0 Hz), 7.70 (1H, s), 7.74 (2H, s), 8.13 (2H, s).
実施例６６
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 66
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} Preparation of -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -[Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) 2- [trans-4-({[2-{[{( S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl ) Cyclohexyl] Using ethyl acetate, the reaction and treatment were carried out in the same manner as in Example 57 to obtain the title compound as a colorless amorphous.
1H-NMR (CDCl3) δ: 0.80-0.96 (7H, m), 1.38 (1H, m), 1.44 (3H, d, J = 7.2 Hz), 1.63-1.80 (5H, m), 2.19 (2H, d, J = 6.4 Hz), 2.69 (1H, dd, J = 8.0, 12.8 Hz), 2.83 (1H, dd, J = 6.0, 12.8 Hz), 2.89 (2H, q, J = 7.2 Hz), 3.84 (3H, s), 4.62 (1H, d, J = 14.8 Hz), 4.86 (1H, d, J = 14.8 Hz), 6.21 (1H, q, J = 7.2 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.24 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 2.0, 8.0 Hz), 7.70 (1H, s), 7.73 (2H, s), 8.13 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.80-0.96 (7H, m), 1.38 (1H, m), 1.44 (3H, d, J = 7.2 Hz), 1.63-1.80 (5H, m), 2.19 (2H , d, J = 6.4 Hz), 2.69 (1H, dd, J = 8.0, 12.8 Hz), 2.83 (1H, dd, J = 6.0, 12.8 Hz), 2.89 (2H, q, J = 7.2 Hz), 3.84 (3H, s), 4.62 (1H, d, J = 14.8 Hz), 4.86 (1H, d, J = 14.8 Hz), 6.21 (1H, q, J = 7.2 Hz), 7.11 (1H, d, J = 8.0 Hz), 7.24 (1H, d, J = 2.0 Hz), 7.37 (1H, dd, J = 2.0, 8.0 Hz), 7.70 (1H, s), 7.73 (2H, s), 8.13 (2H, s) .
実施例６７
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造： Example 67
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Preparation of -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate:
工程１：２－［ｔｒａｎｓ－４－（｛［２－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造
　５－［２－（フェニルチオ）エトキシ］ピリミジン－２－アミンの代わりに５－エトキシピリミジン－２－アミンを用いて実施例６０の工程４と同様に反応・処理し、２－［ｔｒａｎｓ－４－（｛［２－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルを白色固体として得た。
1H-NMR (CDCl3) δ: 0.88-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 4.11 (2H, q, J = 6.8 Hz),  4.67 (2H, d, J = 6.0 Hz), 5.37 (1H, t, J = 6.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.05 (2H, s). Step 1: 2- [trans-4-({[2-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] Preparation of ethyl acetate Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 4 of Example 60 was carried out. trans-4-({[2-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate as a white solid Obtained.
1 H-NMR (CDCl 3 ) δ: 0.88-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q , J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.37 (1H, t, J = 6.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.05 (2H, s).
工程２：２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造
Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－［ｔｒａｎｓ－４－（｛［２－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルを用いて実施例５０の工程３と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Step 2: 2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino ] Preparation of ethyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2 2- (trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) instead of-(methylthio) ethoxy] pyrimidin-2-amine Phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate was used for the reaction and treatment in the same manner as in Step 3 of Example 50 to obtain the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.80-0.96 (7H, m), 1.24 (3H, t, J = 6.8 Hz), 1.39 (1H, m), 1.41 (3H, t, J = 7.2 Hz), 1.44 (3H, d, J = 7.2 Hz), 1.62-1.80 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 8.0, 12.8 Hz), 2.84 (1H, dd, J = 6.0, 12.8 Hz), 2.89 (2H, q, J = 6.8 Hz), 4.04 (2H, q, J = 6.8 Hz), 4.08-4.16 (2H, m), 4.62 (1H, d, J = 12.8 Hz), 4.85 (1H, d, J = 12.8 Hz), 6.21 (1H, q, J = 7.2 Hz), 7.11 (1H, d, J = 8.8 Hz), 7.24 (1H, s), 7.37 (1H, d, J = 8.8 Hz), 7.70 (1H, s), 7.74 (2H, s), 8.12 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.80-0.96 (7H, m), 1.24 (3H, t, J = 6.8 Hz), 1.39 (1H, m), 1.41 (3H, t, J = 7.2 Hz), 1.44 (3H, d, J = 7.2 Hz), 1.62-1.80 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 8.0, 12.8 Hz), 2.84 (1H , dd, J = 6.0, 12.8 Hz), 2.89 (2H, q, J = 6.8 Hz), 4.04 (2H, q, J = 6.8 Hz), 4.08-4.16 (2H, m), 4.62 (1H, d, J = 12.8 Hz), 4.85 (1H, d, J = 12.8 Hz), 6.21 (1H, q, J = 7.2 Hz), 7.11 (1H, d, J = 8.8 Hz), 7.24 (1H, s), 7.37 (1H, d, J = 8.8 Hz), 7.70 (1H, s), 7.74 (2H, s), 8.12 (2H, s).
実施例６８
２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 68
2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Preparation of -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -[Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) 2- [trans-4-({[2-{[{( S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl ) Cyclohexyl] Using ethyl acetate, the reaction and treatment were carried out in the same manner as in Example 57 to obtain the title compound as a colorless amorphous.
1H-NMR (CDCl3)δ: 0.82-0.96 (7H, m), 1.39 (1H, m), 1.40 (3H, t, J = 7.2 Hz), 1.44 (3H, d, J = 6.8 Hz), 1.62-1.80 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 8.0, 13.2 Hz), 2.83 (1H, dd, J = 6.4, 13.2 Hz), 2.89 (2H, q, J = 7.2 Hz), 4.04 (2H, q, J = 7.2 Hz), 4.61 (1H, d, J = 16.8 Hz), 4.85 (1H, d, J = 16.8 Hz), 6.21 (1H, q, J = 6.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.24 (1H, s), 7.37 (1H, d, J = 8.4 Hz), 7.70 (1H, s), 7.73 (2H, s), 8.12 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.82-0.96 (7H, m), 1.39 (1H, m), 1.40 (3H, t, J = 7.2 Hz), 1.44 (3H, d, J = 6.8 Hz), 1.62-1.80 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.69 (1H, dd, J = 8.0, 13.2 Hz), 2.83 (1H, dd, J = 6.4, 13.2 Hz), 2.89 (2H, q, J = 7.2 Hz), 4.04 (2H, q, J = 7.2 Hz), 4.61 (1H, d, J = 16.8 Hz), 4.85 (1H, d, J = 16.8 Hz), 6.21 (1H , q, J = 6.8 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.24 (1H, s), 7.37 (1H, d, J = 8.4 Hz), 7.70 (1H, s), 7.73 (2H , s), 8.12 (2H, s).
実施例６９
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造： Example 69
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
工程１：２－［ｔｒａｎｓ－４－（｛［２－クロロ－６－ホルミル－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造
　２－フルオロ－５－（トリフルオロメチル）ベンズアルデヒド（1.00 g, 4.60 mmol）のジメチルスルホキシド－水（4：1混合溶液，6.25 mL）溶液に国際公開第２００４／０２０３９３号パンフレットに記載の方法により合成したtrans－｛４－［（エチルアミノ）メチル］シクロヘキシル｝酢酸エチル（1.334 g, 5.06 mmol）及び炭酸ナトリウム（975 mg, 9.20 mmol）を加え、90℃にて10時間攪拌した。反応液を室温まで放冷後、水を加えトルエンで抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して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 = 16：1 → 2：3）を用いて精製し、２－［ｔｒａｎｓ－４－（｛［２－クロロ－６－ホルミル－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル（1.82 g, 91%）を黄色油状物として得た。 Step 1: Preparation of 2- [trans-4-({[2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate 2-Fluoro-5- ( Trans- {4- [trifluoromethyl) benzaldehyde (1.00 g, 4.60 mmol) synthesized in a dimethyl sulfoxide-water (4: 1 mixed solution, 6.25 mL) solution by the method described in WO 2004/020393 pamphlet. (Ethylamino) methyl] cyclohexyl} ethyl acetate (1.334 g, 5.06 mmol) and sodium carbonate (975 mg, 9.20 mmol) were added, and the mixture was stirred at 90 ° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 2: 3). , Ethyl 2- [trans-4-({[2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetate (1.82 g, 91%) Got as.
1H-NMR (CDCl3)δ : 0.82-1.02 (4H, m), 1.06 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.45 (1H, m), 1.62-1.82 (5H, m), 2.16 (2H, d, J = 6.8 Hz), 3.14 (1H, d, J = 6.6 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.79 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 2.2 Hz). 1 H-NMR (CDCl 3 ) δ: 0.82-1.02 (4H, m), 1.06 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.45 (1H, m), 1.62-1.82 (5H, m), 2.16 (2H, d, J = 6.8 Hz), 3.14 (1H, d, J = 6.6 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 7.79 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 2.2 Hz).
工程２：２－（ｔｒａｎｓ－４－｛［｛２－クロロ－６－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造
　２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンズアルデヒドの代わりに工程１で得られた２－［ｔｒａｎｓ－４－（｛［２－クロロ－６－ホルミル－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルを用い、実施例５０の工程２と同様に反応・処理し、２－（ｔｒａｎｓ－４－｛［｛２－クロロ－６－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを淡黄色油状物として得た。 Step 2: 2- (trans-4-{[{2-Chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) Preparation of ethyl phenyl} (ethyl) amino] methyl} cyclohexyl) acetate 2- [trans-4-({[2]) obtained in Step 1 instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde -Chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate was reacted and treated in the same manner as in Step 2 of Example 50 to give 2- (trans-4 — {[{2-Chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } (Ethyl) amino] methyl} cyclohexyl) ethyl acetate was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.85-1.01 (4H, m), 1.03 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.42 (1H, m), 1.58-1.82 (3H, m), 1.83-1.95 (2H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.92 (1H, dd, J = 7.3, 13.4 Hz), 3.05 (1H, dd, J = 6.8, 13.4 Hz), 3.15 (1H, qd, J = 7.1, 13.9 Hz), 3.25 (1H, dq, J = 7.1, 13.9 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.68 (1H, dd, J = 5.8, 16.1 Hz), 4.77 (1H, dd, J = 6.1, 16.1 Hz), 5.34 (1H, m), 7.49 (1H, s), 7.54 (1H, s), 8.06 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.85-1.01 (4H, m), 1.03 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.42 (1H, m), 1.58-1.82 (3H, m), 1.83-1.95 (2H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.92 (1H, dd, J = 7.3, 13.4 Hz), 3.05 (1H, dd, J = 6.8, 13.4 Hz), 3.15 (1H, qd, J = 7.1, 13.9 Hz), 3.25 (1H, dq, J = 7.1 , 13.9 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.68 (1H, dd, J = 5.8, 16.1 Hz), 4.77 (1H, dd, J = 6.1, 16.1 Hz), 5.34 (1H, m), 7.49 (1H, s), 7.54 (1H, s), 8.06 (2H, s).
工程３：２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造
　Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに工程２で得られた２－（ｔｒａｎｓ－４－｛［｛２－クロロ－６－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例５０の工程３と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Step 3: 2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] Preparation of pyrimidin-2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate N- [2- (diallylamino) -5- ( 2- (trans-4-{[{2-Chloro-6-[({{chloromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine obtained in Step 2 5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate The reaction and treatment were conducted in a similar manner to process 3 of example 50, and the title compound was obtained as a pale-yellow oil.
1H-NMR (CDCl3) δ: 0.61-1.00 (7H, m), 1.25 (3H, t, J = 7.1 Hz), 1.31, 1.41 (mixed 1H, each m), 1.50-1.85 (8H, m), 2.11, 2.16 (mixed 2H, each d, J = each 6.6 Hz), 2.21 (3H, s), 2.73, 2.78 (mixed 1H, each dd, J = 6.4, 14.2 and 7.3, 13.4 Hz), 2.87 (2H, t, J = 6.6 Hz), 2.96-3.13, 3.16-3.25 (mixed 3H, each m), 4.07-4.18 (4H, m), 4.61 (1H, d, J = 16.6 Hz), 4.84, 4.65 (mixed 1H, each d, J = each 16.6 Hz), 6.29, 6.31 (mixed 1H, each q, J = 6.6 and 6.8 Hz), 7.06, 7.09 (mixed 1H, each s), 7.42, 6.43 (mixed 1H, each s), 7.72 (2H, s), 7.74, 7.75 (mixed 1H, each s), 8.11 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.61-1.00 (7H, m), 1.25 (3H, t, J = 7.1 Hz), 1.31, 1.41 (mixed 1H, each m), 1.50-1.85 (8H, m) , 2.11, 2.16 (mixed 2H, each d, J = each 6.6 Hz), 2.21 (3H, s), 2.73, 2.78 (mixed 1H, each dd, J = 6.4, 14.2 and 7.3, 13.4 Hz), 2.87 (2H , t, J = 6.6 Hz), 2.96-3.13, 3.16-3.25 (mixed 3H, each m), 4.07-4.18 (4H, m), 4.61 (1H, d, J = 16.6 Hz), 4.84, 4.65 (mixed 1H, each d, J = each 16.6 Hz), 6.29, 6.31 (mixed 1H, each q, J = 6.6 and 6.8 Hz), 7.06, 7.09 (mixed 1H, each s), 7.42, 6.43 (mixed 1H, each s ), 7.72 (2H, s), 7.74, 7.75 (mixed 1H, each s), 8.11 (2H, s).
実施例７０
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 70
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 Preparation of -yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 2- (trans-4-{[{2-[({( S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6-chloro-4- (tri Fluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate was reacted and treated in the same manner as in Example 57 to obtain the title compound as a colorless amorphous.
1H-NMR (CDCl3) δ: 0.58-0.72, 0.75-1.02 (mixed 7H, each m), 1.32, 1.42 (mixed 1H, each m), 1.50-1.85 (8H, m), 2.17, 2.21 (mixed 2H, each d, J = 6.8 and 7.1 Hz), 2.20 (3H, s), 2.72, 2.76 (mixed 1H, each dd, J = 7.8, 14.2 and 7.6, 13.6 Hz), 2.87 (2H, t, J = 6.8 Hz), 2.97-3.26 (3H, m), 4.15 (2H, t, J = 6.8 Hz), 4.59 (1H, d, J = 18.1 Hz), 4.84 (1H, d, J = 18.1 Hz), 6.30, 6.32 (mixed 1H, each q, J = 6.1 and 6.3 Hz), 7.07, 7.09 (mixed 1H, each s), 7.42, 7.43 (mixed 1H, each s), 7.72 (2H, s), 7.74, 7.75 (mixed 1H, each s), 8.11 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.58-0.72, 0.75-1.02 (mixed 7H, each m), 1.32, 1.42 (mixed 1H, each m), 1.50-1.85 (8H, m), 2.17, 2.21 (mixed 2H, each d, J = 6.8 and 7.1 Hz), 2.20 (3H, s), 2.72, 2.76 (mixed 1H, each dd, J = 7.8, 14.2 and 7.6, 13.6 Hz), 2.87 (2H, t, J = 6.8 Hz), 2.97-3.26 (3H, m), 4.15 (2H, t, J = 6.8 Hz), 4.59 (1H, d, J = 18.1 Hz), 4.84 (1H, d, J = 18.1 Hz), 6.30 , 6.32 (mixed 1H, each q, J = 6.1 and 6.3 Hz), 7.07, 7.09 (mixed 1H, each s), 7.42, 7.43 (mixed 1H, each s), 7.72 (2H, s), 7.74, 7.75 ( mixed 1H, each s), 8.11 (2H, s).
実施例７１
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸を用いて実施例５２と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 71
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Instead of ethoxy] pyrimidin-2-amine, 2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [ 2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid as in Example 52 Reaction and treatment gave the title compound as a colorless amorphous.
1H-NMR (CDCl3) δ: 0.60-1.05 (7H, m), 1.33, 1.41 (mixed 1H, each m), 1.50-1.90 (8H, m), 2.18, 2.22 (mixed 2H, each d, J = each 6.6 Hz), 2.81 (1H, dd, J = 7.6, 13.6 Hz), 2.95-3.23 (6H, m), 3.45 (2H, t, J = 5.2 Hz), 4.43 (2H, t, J = 5.2 Hz), 4.57, 4.62 (mixed 1H, each d, J = each 17.3 Hz), 4.82, 4.90 (mixed 1H, each d, J = each 17.3 Hz), 6.30, 6.32 (mixed 1H, each q, J = each 6.8 Hz), 7.04, 7.06 (mixed 1H, each s), 7.42, 7.44 (mixed 1H, each s), 7.73 (2H, s), 7.76 (1H, s), 8.13 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.60-1.05 (7H, m), 1.33, 1.41 (mixed 1H, each m), 1.50-1.90 (8H, m), 2.18, 2.22 (mixed 2H, each d, J = each 6.6 Hz), 2.81 (1H, dd, J = 7.6, 13.6 Hz), 2.95-3.23 (6H, m), 3.45 (2H, t, J = 5.2 Hz), 4.43 (2H, t, J = 5.2 Hz), 4.57, 4.62 (mixed 1H, each d, J = each 17.3 Hz), 4.82, 4.90 (mixed 1H, each d, J = each 17.3 Hz), 6.30, 6.32 (mixed 1H, each q, J = each 6.8 Hz), 7.04, 7.06 (mixed 1H, each s), 7.42, 7.44 (mixed 1H, each s), 7.73 (2H, s), 7.76 (1H, s), 8.13 (2H, s).
実施例７２
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－メトキシピリミジン－２－アミンの製造：
　特許文献（日本国公開特許公報２０１０－０７７１１６）に記載の方法に従い製造した。 Example 72
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5-methoxy Preparation of pyrimidine-2-amine:
It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
実施例７３
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－ヒドロキシピリミジン－２－アミンの製造：
　特許文献（日本国公開特許公報２０１０－０７７１１６）に記載の方法に従い製造した。 Example 73
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5-hydroxy Preparation of pyrimidine-2-amine:
It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
実施例７４
４－（｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝）アミノ］ピリミジン－５－イル｝オキシ）酪酸エチルの製造：
　特許文献（日本国公開特許公報２０１０－０７７１１６）に記載の方法に従い製造した。 Example 74
4-({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl}) Production of ethyl amino] pyrimidin-5-yl} oxy) butyrate:
It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
実施例７５
４－（｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝）アミノ］ピリミジン－５－イル｝オキシ）酪酸の製造：
　特許文献（日本国公開特許公報２０１０－０７７１１６）に記載の方法に従い製造した。 Example 75
4-({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl}) Amino] pyrimidin-5-yl} oxy) butyric acid:
It was produced according to the method described in Patent Literature (Japanese Published Patent Application 2010-077116).
実施例７６
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造： Example 76
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
工程１：３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒドの製造
　Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) に記載の方法により合成した（３－ブロモ－６－メトキシピリジン－２－イル）メタノール（10.6 g, 48.6 mmol）のジクロロメタン（150 mL）溶液に氷冷下で、Ｎ，Ｎ－ジイソプロピルエチルアミン（31.4 g, 243 mmol）及びクロロメチルメチルエーテル（13.3 g, 165 mmol）を順次滴下した。室温に昇温し16時間攪拌後、メタノール（30 mL）を加え30分間攪拌した。反応液を減圧濃縮して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 = 30：1 → 20：1）を用いて精製し、３－ブロモ－６－メトキシ－２－［（メトキシメトキシ）メチル］ピリジン（12.1g, 95%）を淡黄色油状物として得た。 Step 1: Production of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Synthesized by the method described in Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) (3-bromo-6 -Methoxypyridin-2-yl) methanol (10.6 g, 48.6 mmol) in dichloromethane (150 mL) under ice-cooling, N, N-diisopropylethylamine (31.4 g, 243 mmol) and chloromethyl methyl ether (13.3 g) , 165 mmol) was added dropwise. After warming to room temperature and stirring for 16 hours, methanol (30 mL) was added and stirred for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 30: 1 → 20: 1) to give 3-bromo-6-methoxy-2-[(methoxymethoxy ) Methyl] pyridine (12.1 g, 95%) was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 3.46 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 4.81 (2H, s), 6.59 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.7 Hz). 1 H-NMR (CDCl 3 ) δ: 3.46 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 4.81 (2H, s), 6.59 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.7 Hz).
　３－ブロモ－６－メトキシ－２－［（メトキシメトキシ）メチル］ピリジン（1.50 g, 5.72 mmol）、トリス（ジベンジリデンアセトン）（クロロホルム）ジパラジウム（０）（592 mg, 0.572 mmol）、（２－ビフェニル）ジ－t－ブチルホスフィン（680 mg, 2.28 mmol）、t－ブトキシナトリウム（1.65 g, 17.2 mmol）及びエチルアミン（2.0M テトラヒドロフラン溶液, 15 mL, 30 mmol）のテトラヒドロフラン（15 mL）溶液をマイクロウェーブ照射条件（500W）にて３分間かけて135℃まで昇温した。反応液を冷却後、セライトろ過し、酢酸エチルで洗浄した。反応液を減圧濃縮して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 = 8：1）を用いて精製し、Ｎ－エチル－６－メトキシ－２－［（メトキシメトキシ）メチル］ピリジン－３－アミン（954 mg, 74%）を黄色油状物として得た。 3-bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine (1.50 g, 5.72 mmol), tris (dibenzylideneacetone) (chloroform) dipalladium (0) (592 mg, 0.572 mmol), (2 -Biphenyl) di-t-butylphosphine (680 mg, 2.28 mmol), t-butoxy sodium (1.65 g, 17.2 mmol) and ethylamine (2.0M tetrahydrofuran solution, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) The temperature was raised to 135 ° C. over 3 minutes under microwave irradiation conditions (500 W). The reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridine. -3-Amine (954 mg, 74%) was obtained as a yellow oil.
1H-NMR (CDCl3) δ: 1.27 (3H, t, J = 7.1 Hz), 3.12 (2H, q, J = 7.1 Hz), 3.43 (3H, s), 3.86 (3H, s), 4.23 (1H br s), 4.68 (2H, s), 4.71 (2H, s), 6.64 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz). 1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.12 (2H, q, J = 7.1 Hz), 3.43 (3H, s), 3.86 (3H, s), 4.23 ( 1H br s), 4.68 (2H, s), 4.71 (2H, s), 6.64 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz).
　Ｎ－エチル－６－メトキシ－２－［（メトキシメトキシ）メチル］ピリジン－３－アミン（7.20 g, 31.8 mmol）及びシクロペンタンカルボアルデヒド（3.75 g, 38.2 mmol）の１，２－ジクロロエタン（240 mL）溶液にトリアセトキシ水素化ホウ素ナトリウム（8.75 g, 41.3 mmol）を加え、室温で12時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル = 8：1）を用いて精製し、Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシ－２－［（メトキシメトキシ）メチル］ピリジン－３－アミン（8.39 g, 86%）を淡黄色油状物として得た。 1,2-dichloroethane (240－２mL) of N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) ) Sodium triacetoxyborohydride (8.75 g, 41.3 mmol) was added to the solution and stirred at room temperature for 12 hours. Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 8: 1), and N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridine. -3-Amine (8.39 g, 86%) was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H, d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz). 1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H , d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz).
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシ－２－［（メトキシメトキシ）メチル］ピリジン－３－アミン（8.39 g, 27.2 mmol）のジオキサン（400 mL）－水（100 mL）混合溶液に濃塩酸（20 mL）を滴下し、50℃で19時間攪拌した。反応液に水酸化ナトリウム水溶液を加え塩基性とし、酢酸エチルで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル = 15：1）を用いて精製し、｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メタノール（6.72 g, 94%）を淡黄色油状物として得た。 N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine (8.39 g, 27.2 mmol) in dioxane (400 mL) -water (100 mL) Concentrated hydrochloric acid (20 mL) was added dropwise thereto, and the mixture was stirred at 50 ° C. for 19 hours. The reaction mixture was basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give {3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol ( 6.72 g,） 94%) was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.33-1.77 (6H, m), 1.87 (1H, m), 2.77 (2H, d, J = 7.5 Hz), 2.86 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.79 (2H, s), 5.04 (1H, br s), 6.64 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 8.7 Hz). 1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.33-1.77 (6H, m), 1.87 (1H, m), 2.77 (2H , d, J = 7.5 Hz), 2.86 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.79 (2H, s), 5.04 (1H, br s), 6.64 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 8.7 Hz).
　｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メタノール（2.0 g, 7.57 mmol）のクロロホルム（200 mL）溶液に二酸化マンガン（20 g, 230 mmol）を加え、55℃で16時間攪拌した。反応液をセライトろ過し、クロロホルムで洗浄後、ろ液を減圧濃縮した。得られた残渣にクロロホルム（200 mL）及び二酸化マンガン（20 g, 230 mmol）を加え、55℃で6時間攪拌した。反応液をセライトろ過し、クロロホルムで洗浄後、ろ液を減圧濃縮して３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒド（1.68 g, 85%）を淡黄色油状物として得た。 To a solution of {3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol (2.0 g, 7.57 mmol) in chloroform (200 mL) was added manganese dioxide (20 g, 230 mmol). And stirred at 55 ° C. for 16 hours. The reaction mixture was filtered through celite, washed with chloroform, and the filtrate was concentrated under reduced pressure. Chloroform (200 mL) and manganese dioxide (20 g, 230 mmol) were added to the obtained residue, and the mixture was stirred at 55 ° C for 6 hours. The reaction mixture was filtered through Celite, washed with chloroform, and the filtrate was concentrated under reduced pressure to give 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde (1.68 g, 85%) as a pale yellow oil. Obtained.
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.36-1.73 (6H, m), 1.95 (1H, m), 2.99 (2H, d, J = 7.6 Hz), 3.13 (2H, q, J = 7.1 Hz), 3.99 (3H, s), 6.93 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 10.4 (1H, s). 1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.36-1.73 (6H, m), 1.95 (1H, m), 2.99 (2H , d, J = 7.6 Hz), 3.13 (2H, q, J = 7.1 Hz), 3.99 (3H, s), 6.93 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz ), 10.4 (1H, s).
工程２：Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造
　５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（1.03 g, 5.55 mmol）及び工程１で得られた３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒド（1.60 g, 6.10 mmol）の１，２－ジクロロエタン（60 mL）溶液を室温で10分間攪拌した後、トリアセトキシ水素化ホウ素ナトリウム（1.24 g, 5.83 mmol）を加え、室温で12時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル = 5：1）を用いて精製し、Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（1.60 g, 67%）を淡黄色油状物として得た。 Step 2: Preparation of N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5 -[2- (methylthio) ethoxy] pyrimidin-2-amine (1.03 g, 5.55 mmol) and 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde (1.60 g, A solution of 6.10 mmol) in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (1.24 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl. } Methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (1.60 g, 67%) was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.97 (3H, t, J = 7.1 Hz), 1.08-1.25 (2H, m), 1.34-1.70 (6H, m), 1.84 (1H, m), 2.21 (3H, s), 2.81 (2H, d, J = 7.5 Hz), 2.85 (2H, t, J = 6.7 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.12 (2H, t, J = 6.7 Hz), 4.70 (2H, d, J = 4.6 Hz), 6.33 (1H, t, J = 4.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 8.12 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.97 (3H, t, J = 7.1 Hz), 1.08-1.25 (2H, m), 1.34-1.70 (6H, m), 1.84 (1H, m), 2.21 (3H , s), 2.81 (2H, d, J = 7.5 Hz), 2.85 (2H, t, J = 6.7 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.12 (2H , t, J = 6.7 Hz), 4.70 (2H, d, J = 4.6 Hz), 6.33 (1H, t, J = 4.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.47 (1H, d , J = 8.6 Hz), 8.12 (2H, s).
工程３：Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造
　Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（168 mg, 0.39 mmol）のＮ，Ｎ－ジメチルホルムアミド（1 mL）溶液を氷冷下攪拌する中に水素化ナトリウム（50％ in oil, 24 mg, 1.4 mmol）を加え、50℃にて30分間攪拌した。反応液を－78℃に冷却し、国際公開第２００８／０１８５２９号パンフレットに記載の方法に従い製造した１－ブロモ－１－［３，５－ビス（トリフルオロメチル）フェニル］エタン（250 mg, 0.78 mmol）のＮ，Ｎ－ジメチルホルムアミド（0.5 mL）溶液を加え室温まで昇温しつつ12時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 3：1）を用いて精製し、目的化合物であるＮ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン（88.1 mg, 34%）を淡黄色油状物として得た。 Step 3: N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} Preparation of methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5 While stirring a solution of-[2- (methylthio) ethoxy] pyrimidin-2-amine (168 mg, 0.39 mmol) in N, N-dimethylformamide (1 mL) under ice-cooling, sodium hydride (50% in oil, 24 mg, 1.4 mmol) was added, and the mixture was stirred at 50 ° C. for 30 minutes. The reaction solution was cooled to −78 ° C., and 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (250 mg, 0.78) produced according to the method described in WO2008 / 018529 pamphlet. mmol) in N, N-dimethylformamide (0.5 mL) was added, and the mixture was stirred for 12 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3 1), and the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-Methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (88.1 mg, 34%) was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.89 (3H, t, J = 7.1 Hz), 1.04-1.18 (2H, m), 1.36-1.69 (9H, m), 1.86 (1H, m), 2.19 (3H, s), 2.66-2.86 (6H, m), 3.43 (3H, s), 4.10 (2H, t, J = 6.6 Hz), 4.66 (1H, d, J = 17.6 Hz), 5.10 (1H, d, J = 17.6 Hz), 6.17 (1H, q, J = 7.1 Hz), 6.49 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.74 (1H, s), 7.80 (2H, s), 8.08 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.89 (3H, t, J = 7.1 Hz), 1.04-1.18 (2H, m), 1.36-1.69 (9H, m), 1.86 (1H, m), 2.19 (3H , s), 2.66-2.86 (6H, m), 3.43 (3H, s), 4.10 (2H, t, J = 6.6 Hz), 4.66 (1H, d, J = 17.6 Hz), 5.10 (1H, d, J = 17.6 Hz), 6.17 (1H, q, J = 7.1 Hz), 6.49 (1H, d, J = 8.8 Hz), 7.33 (1H, d, J = 8.8 Hz), 7.74 (1H, s), 7.80 (2H, s), 8.08 (2H, s).
実施例７７
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 77
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- Preparation of 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例７８
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 78
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例７９
５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造： Example 79
5-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) Preparation of —N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
工程１：６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドの製造
　６－クロロ－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒド（3.90 g, 18.6 mmol）、及び国際公開第２００６／０７３９７３号パンフレットに記載の方法により製造したＮ－（シクロペンチルメチル）－Ｎ－エチルアミン（11.70g, 92.0 mmol）を混合し、アルゴン雰囲気下100℃にて8時間攪拌した。反応液を減圧濃縮して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 ＝ 10：1 → 5：1）を用いて精製し、６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒド（9.96g, 99%）を黄色油状物として得た。 Step 1: Preparation of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl- 1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N- (cyclopentylmethyl) -N-ethylamine produced by the method described in WO 2006/079773 (11.70 g, 92.0 mmol) were mixed and stirred at 100 ° C. for 8 hours under an argon atmosphere. The residue obtained by concentrating the reaction solution under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5: 1) to give 6-[(cyclopentylmethyl) (ethyl) amino] -1 , 3-Dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (9.96 g, 99%) was obtained as a yellow oil.
1H-NMR (CDCl3) δ: 1.09-1.18 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.46-1.60 (4H, m), 1.61-1.71 (2H, m), 2.30 (1H, m), 2.49 (3H, s), 3.45 (2H, d, J = 7.3 Hz), 3.52 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 8.33 (1H, s), 10.01 (1H, s). 1 H-NMR (CDCl 3 ) δ: 1.09-1.18 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.46-1.60 (4H, m), 1.61-1.71 (2H, m), 2.30 (1H, m), 2.49 (3H, s), 3.45 (2H, d, J = 7.3 Hz), 3.52 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 8.33 (1H, s) , 10.01 (1H, s).
工程２：Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒドの代わりに６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドを用いて実施例７６の工程２と同様に反応・処理し、Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを淡黄色油状物として得た。 Step 2: N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [ Preparation of 3,4-b] pyridin-6-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3 -Dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was reacted and treated in the same manner as in Step 2 of Example 76 to obtain N- (cyclopentylmethyl) -N-ethyl-1,3. -Dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine Obtained as a yellow oil.
1H-NMR (CDCl3) δ: 1.11-1.22 (5H, m), 1.40-1.75 (6H, m), 2,16 (1H, m), 2.19 (3H, s), 2,45 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.08 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.92 (1H, t, J = 5.6 Hz), 7.85 (1H, s), 8.05 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.11-1.22 (5H, m), 1.40-1.75 (6H, m), 2,16 (1H, m), 2.19 (3H, s), 2,45 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.08 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.92 (1H, t, J = 5.6 Hz), 7.85 (1H, s), 8.05 (2H, s).
工程３：５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりにＮ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを用いて実施例７６の工程３と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Step 3: 5-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- ( Preparation of cyclopentylmethyl) -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine N-({3-[(cyclopentylmethyl) (ethyl) amino] -6- Methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({ 5- [2- (Methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine is used in the same manner as in Step 3 of Example 76. place The title compound was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.07 (3H, t, J = 7.1 Hz), 1.14-1.18 (2H, m), 1.41 (3H, d, J = 7.3 Hz), 1.45-1.73 (6H, m), 2.11 (1H, m), 2.22 (3H, s), 2.37 (3H, s), 2.89 (2H, t, J = 6.6 Hz), 2.95 (1H, m), 3.05-3.17 (2H, m), 3.40 (1H, m), 3.95 (3H, s), 4.18 (2H, t, J = 6.6 Hz), 4.55 (1H, d, J = 16.4 Hz), 4.87 (1H, d, J = 16.4 Hz), 6.20 (1H, q, J = 7.1 Hz), 7.50 (1H, s), 7.69 (1H, s), 7.77 (2H, s), 8.19 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.07 (3H, t, J = 7.1 Hz), 1.14-1.18 (2H, m), 1.41 (3H, d, J = 7.3 Hz), 1.45-1.73 (6H, m ), 2.11 (1H, m), 2.22 (3H, s), 2.37 (3H, s), 2.89 (2H, t, J = 6.6 Hz), 2.95 (1H, m), 3.05-3.17 (2H, m) , 3.40 (1H, m), 3.95 (3H, s), 4.18 (2H, t, J = 6.6 Hz), 4.55 (1H, d, J = 16.4 Hz), 4.87 (1H, d, J = 16.4 Hz) , 6.20 (1H, q, J = 7.1 Hz), 7.50 (1H, s), 7.69 (1H, s), 7.77 (2H, s), 8.19 (2H, s).
実施例８０
５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 80
5-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) Preparation of —N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８１
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 81
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) Production of —N-ethylquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８２
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 82
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) Preparation of —N-ethylquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８３
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 83
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) Preparation of —N-ethyl-6-methoxyquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８４
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 84
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) Preparation of —N-ethyl-6-methoxyquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８５
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－（トリフルオロメチル）キノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 85
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) Preparation of —N-ethyl-6- (trifluoromethyl) quinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８６
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－（トリフルオロメチル）キノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 86
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl Preparation of —N-ethyl-6- (trifluoromethyl) quinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８７
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メチルキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 87
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) Preparation of —N-ethyl-6-methylquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８８
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メチルキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 88
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) Preparation of —N-ethyl-6-methylquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例８９
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－メチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 89
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９０
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－メチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 90
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl)- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９１
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－エチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 91
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９２
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－エチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 92
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl)- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９３
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５，６－ジメチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 93
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl ) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９４
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５，６－ジメチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 94
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl ) -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９５
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 95
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) Production of —N-ethylquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９６
３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 96
3-[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) Preparation of —N-ethylquinolin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９７
３－｛１－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］エチル｝－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 97
3- {1-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) {5- [2 Preparation of-(Methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９８
３－｛１－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］エチル｝－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 98
3- {1-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) {5- [2 Preparation of-(Methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例９９
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］ピラジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 99
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例１００
Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］ピラジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／１１１６０４号パンフレット）に記載の方法に従い製造した。 Example 100
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/111604 pamphlet).
実施例１０１
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 101
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) Preparation of [benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０２
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 102
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [3- (trifluoromethyl ) Preparation of benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０３
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 103
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [3- (trifluoromethyl ) Preparation of benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０４
Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 104
Preparation of N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine :
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０５
Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 105
N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine Manufacturing:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０６
Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 106
Of N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine Manufacturing:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０７
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 107
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } -5- (Trifluoromethyl) benzonitrile production:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０８
３－［（｛２－［［３－シアノ－５－（トリフルオロメチル）ベンジル］（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）アミノ］ピリミジン－５－イル｝オキシ）メチル］－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 108
3-[({2-[[3-Cyano-5- (trifluoromethyl) benzyl] ({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) amino] Preparation of Pyrimidin-5-yl} oxy) methyl] -5- (trifluoromethyl) benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１０９
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 109
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Production of methyl} -5- (trifluoromethyl) benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１０
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 110
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Production of methyl} -5- (trifluoromethyl) benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１１
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 111
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１２
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 112
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- Preparation of (methylsulfinyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１３
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 113
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１４
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 114
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Production of benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１５
３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 115
3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Production of methyl} benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１６
Ｎ－［２，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 116
N- [2,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１７
Ｎ－［２，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 117
N- [2,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- Preparation of (methylsulfinyl) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１８
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 118
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１１９
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 119
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２０
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 120
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfonyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２１
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジクロロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 121
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２２
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジクロロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 122
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２３
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 123
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２４
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 124
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２５
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 125
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfonyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２６
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 126
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethoxy) Preparation of [benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２７
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 127
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [3- (trifluoromethoxy ) Preparation of benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２８
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 128
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [3- (trifluoromethoxy ) Preparation of benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１２９
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメチルベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 129
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３０
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメチルベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 130
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３１
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，４－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 131
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３２
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，４－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 132
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３３
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，５－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 133
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,5-difluorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３４
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，５－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 134
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,5-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３５
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，６－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 135
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３６
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，６－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 136
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３７
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 137
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylthio) ethoxy] Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３８
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［（２，３－ジフルオロベンジル）オキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 138
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5-[(2,3-difluorobenzyl ) Preparation of oxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１３９
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 139
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy Production of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４０
５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 140
5-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Production of isophthalonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４１
５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 141
5-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Production of methyl} isophthalonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４２
５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 142
5-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Production of methyl} isophthalonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４３
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 143
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [4- (trifluoromethyl) Preparation of [benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４４
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 144
N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [4- (trifluoromethyl ) Preparation of benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４５
Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 145
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [4- (trifluoromethyl ) Preparation of benzyl] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４６
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－５－ブロモ－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 146
N- [3,5-bis (trifluoromethyl) benzyl] -5-bromo-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) pyrimidine- 2-Amine production:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４７
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－モルホリノピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 147
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5-morpholinopyrimidine- 2-Amine production:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４８
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－ピペリジノピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 148
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5-piperidino Preparation of pyrimidine-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１４９
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 149
N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) Preparation of [Ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５０
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 150
N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylsulfinyl) ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５１
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 151
N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylsulfonyl) ) Preparation of ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５２
６－［（［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－５－［（シクロペンチルメチル）（エチル）アミノ］ピリジン－２－オールの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 152
6-[([3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -5-[(cyclopentylmethyl) (ethyl) Production of amino] pyridin-2-ol:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５３
４－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 153
4-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Production of benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５４
４－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリルの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 154
4-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Production of methyl} benzonitrile:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５５
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［エチル（４－メトキシベンジル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　特許文献（国際公開第２００８／０１８５２９号パンフレット）に記載の方法に従い製造した。 Example 155
N- [3,5-bis (trifluoromethyl) benzyl] -N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
It manufactured according to the method as described in a patent document (International publication 2008/018529 pamphlet).
実施例１５６
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの製造：
　Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに国際公開第２００８／１２９９５１号パンフレットに記載の方法に従い製造したＮ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンを用い、（Ｒ）－１－（１－ブロモエチル）－３，５－ビス（トリフルオロメチル）ベンゼンの代わりに３，５－ビス（トリフルオロメチル）ベンジルブロミドを用いて実施例５０の工程３と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 156
N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) Preparation of [Ethoxy] pyrimidin-2-amine:
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of WO 2008/129951 N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared according to (R) Reaction and treatment in the same manner as in Step 3 of Example 50 using 3,5-bis (trifluoromethyl) benzyl bromide instead of -1- (1-bromoethyl) -3,5-bis (trifluoromethyl) benzene The title compound was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 0.99-1.10 (2H, m), 1.35-1.65 (6H, m), 1.96 (1H, m), 2.22 (3H, s), 2.88 (2H, d, J = 7.6 Hz), 2.89 (2H, t, J = 6.6 Hz), 2.95 (2H, q, J = 7.1 Hz), 4.17 (2H, t, J = 6.6 Hz), 4.81 (2H, s), 4.99 (2H, s), 7.18 (1H, d, J = 8.3 Hz), 7.27 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.3 Hz), 7.64 (2H, s), 7.72 (1H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 0.99-1.10 (2H, m), 1.35-1.65 (6H, m), 1.96 (1H, m), 2.22 (3H , s), 2.88 (2H, d, J = 7.6 Hz), 2.89 (2H, t, J = 6.6 Hz), 2.95 (2H, q, J = 7.1 Hz), 4.17 (2H, t, J = 6.6 Hz) ), 4.81 (2H, s), 4.99 (2H, s), 7.18 (1H, d, J = 8.3 Hz), 7.27 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.3 Hz), 7.64 (2H, s), 7.72 (1H, s), 8.16 (2H, s).
実施例１５７
Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミンの製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりにＮ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンを用いて実施例５２と同様に反応・処理し、標題化合物を淡黄色アモルファスとして得た。 Example 157
N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylsulfonyl) ) Preparation of ethoxy] pyrimidin-2-amine:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl instead of ethoxy] pyrimidin-2-amine } -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 52 to obtain the title compound as a pale yellow amorphous.
1H-NMR (CDCl3) δ: 0.97 (3H, t, J = 7.1 Hz), 0.99-1.10 (2H, m), 1.35-1.65 (6H, m), 1.96 (1H, m), 2.89 (2H, d, J = 7.6 Hz), 2.95 (2H, q, J = 7.1 Hz), 3.10 (3H, s), 3.46 (2H, t, J = 5.4 Hz), 4.46 (2H, t, J = 5.4 Hz), 4.82 (2H, s), 5.00 (2H, s), 7.19 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 2.0, 8.6 Hz), 7.64 (2H, s), 7.73 (1H, s), 8.18 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.97 (3H, t, J = 7.1 Hz), 0.99-1.10 (2H, m), 1.35-1.65 (6H, m), 1.96 (1H, m), 2.89 (2H , d, J = 7.6 Hz), 2.95 (2H, q, J = 7.1 Hz), 3.10 (3H, s), 3.46 (2H, t, J = 5.4 Hz), 4.46 (2H, t, J = 5.4 Hz ), 4.82 (2H, s), 5.00 (2H, s), 7.19 (1H, d, J = 8.6 Hz), 7.25 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 2.0, 8.6 Hz), 7.64 (2H, s), 7.73 (1H, s), 8.18 (2H, s).
実施例１５８
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルの製造：
　Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに国際公開第２００８／１２９９５１号パンフレットに記載の方法に従い製造した２－｛ｔｒａｎｓ－４－［（エチル｛２－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチルを用い、（Ｒ）－１－（１－ブロモエチル）－３，５－ビス（トリフルオロメチル）ベンゼンの代わりに３，５－ビス（トリフルオロメチル）ベンジルブロミドを用いて実施例５０の工程３と同様に反応・処理し、標題化合物を淡褐色油状物として得た。 Example 158
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 Preparation of-(trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate:
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of WO 2008/129951 2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino prepared according to ) Methyl] cyclohexyl} ethyl acetate, and 3,5-bis (trifluoromethyl) benzyl bromide instead of (R) -1- (1-bromoethyl) -3,5-bis (trifluoromethyl) benzene In the same manner as in Step 3 of Example 50, the title compound was obtained as a light brown oil.
1H-NMR (CDCl3) δ: 0.76-0.91 (4H, m), 0.95 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.35 (1H, m), 1.55-1.73 (4H, m), 2.11 (2H, d, J = 6.8 Hz), 2.22 (3H, s), 2.79 (2H, d, J = 6.8 Hz), 2.89 (2H, t, J = 6.6 Hz), 2.92 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.17 (2H, t, J = 6.6 Hz), 4.80 (2H, s), 5.00 (2H, s), 7.16 (1H, d, J = 8.3 Hz), 7.25 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 2.0, 8.3 Hz), 7.62 (2H, s), 7.72 (1H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.76-0.91 (4H, m), 0.95 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.35 (1H, m), 1.55-1.73 (4H, m), 2.11 (2H, d, J = 6.8 Hz), 2.22 (3H, s), 2.79 (2H, d, J = 6.8 Hz), 2.89 (2H, t, J = 6.6 Hz ), 2.92 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.17 (2H, t, J = 6.6 Hz), 4.80 (2H, s), 5.00 (2H, s ), 7.16 (1H, d, J = 8.3 Hz), 7.25 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 2.0, 8.3 Hz), 7.62 (2H, s), 7.72 (1H , s), 8.16 (2H, s).
実施例１５９
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 159
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 Preparation of — (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -[Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 2- [trans-4-({[2-({[3 , 5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl The reaction and treatment were conducted in the same manner as in Example 57 using ethyl acetate to give the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.74-0.90 (4H, m), 0.95 (3H, t, J = 7.1 Hz), 1.35 (1H, m), 1.57-1.75 (4H, m), 2.16 (2H, d, J = 6.6 Hz), 2.22 (3H, s), 2.79 (2H, d, J = 7.1 Hz), 2.89 (2H, t, J = 6.6 Hz), 2.91 (2H, q, J = 7.1 Hz), 4.17 (2H, t, J = 6.6 Hz), 4.80 (2H, s), 5.00 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.6 Hz), 7.61 (2H, s), 7.72 (1H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.74-0.90 (4H, m), 0.95 (3H, t, J = 7.1 Hz), 1.35 (1H, m), 1.57-1.75 (4H, m), 2.16 (2H , d, J = 6.6 Hz), 2.22 (3H, s), 2.79 (2H, d, J = 7.1 Hz), 2.89 (2H, t, J = 6.6 Hz), 2.91 (2H, q, J = 7.1 Hz ), 4.17 (2H, t, J = 6.6 Hz), 4.80 (2H, s), 5.00 (2H, s), 7.16 (1H, d, J = 8.6 Hz), 7.26 (1H, d, J = 2.0 Hz) ), 7.42 (1H, dd, J = 2.0, 8.6 Hz), 7.61 (2H, s), 7.72 (1H, s), 8.16 (2H, s).
実施例１６０
２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸の製造：
　（Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸を用いて実施例５２と同様に反応・処理し、標題化合物を無色アモルファスとして得た。 Example 160
2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino} methyl)- Preparation of 4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid:
(S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) 2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidine- instead of ethoxy] pyrimidin-2-amine 2-yl} amino} methyl) -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid was used in the same manner as in Example 52 to obtain the title compound as a colorless amorphous. .
1H-NMR (CDCl3) δ: 0.75-0.90 (4H, m), 0.95 (3H, t, J = 7.1 Hz), 1.36 (1H, m), 1.58-1.77 (4H, m), 2.17 (2H, d, J = 6.8 Hz), 2.79 (2H, d, J = 7.1 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.10 (3H, s), 3.46 (2H, t, J = 5.2 Hz), 4.45 (2H, t, J = 5.2 Hz), 4.82 (2H, s), 5.00 (2H, s), 7.17 (1H, d, J = 8.5 Hz), 7.23 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 2.0, 8.5 Hz), 7.61 (2H, s), 7.73 (1H, s), 8.17 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.75-0.90 (4H, m), 0.95 (3H, t, J = 7.1 Hz), 1.36 (1H, m), 1.58-1.77 (4H, m), 2.17 (2H , d, J = 6.8 Hz), 2.79 (2H, d, J = 7.1 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.10 (3H, s), 3.46 (2H, t, J = 5.2 Hz ), 4.45 (2H, t, J = 5.2 Hz), 4.82 (2H, s), 5.00 (2H, s), 7.17 (1H, d, J = 8.5 Hz), 7.23 (1H, d, J = 2.0 Hz) ), 7.43 (1H, dd, J = 2.0, 8.5 Hz), 7.61 (2H, s), 7.73 (1H, s), 8.17 (2H, s).
実施例１６１
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造： Example 161
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] Preparation of pyridine-6-amine:
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン（25.4 mg, 0.054 mmol）のＮ，Ｎ－ジメチルホルムアミド（0.5 mL）溶液を-15℃にて攪拌する中に水素化ナトリウム（60％ in oil, 5.2 mg, 0.13 mmol）を加え、室温にて30分間攪拌した。反応液を－15℃に冷却し、ヨウ化メチル（23 mg, 0.16 mmol）を加え室温まで昇温しつつ4時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣を分取薄層クロマトグラフィー（ヘキサン：アセトン ＝ 1：1）を用いて精製し、標題化合物（10.0 mg, 38%）を淡黄色油状物として得た。 N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] Sodium hydride (60% in oil, 5.2 mg, 0.13) while stirring a solution of N, N-dimethylformamide (0.5 mL) in pyridine-6-amine (25.4 mg, 0.054 mmol) at -15 ° C mmol) and stirred at room temperature for 30 minutes. The reaction solution was cooled to −15 ° C., methyl iodide (23 mg, 0.16 mmol) was added, and the mixture was stirred for 4 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to preparative thin layer chromatography (hexane: acetone = 1: 1) to give the title compound (10.0 mg, 38%) as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.11-1.27 (5H, m), 1.40-1.67 (6H, m), 2.18 (1H, m), 2.21 (3H, s), 2.41 (3H, s), 2.87 (2H, t, J = 6.9 Hz), 3.01 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.26 (2H, d, J = 7.8 Hz), 3.96 (3H, s), 4.15 (2H, t, J = 6.9 Hz), 4.89 (2H, s), 7.52 (1H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.11-1.27 (5H, m), 1.40-1.67 (6H, m), 2.18 (1H, m), 2.21 (3H, s), 2.41 (3H, s), 2.87 (2H, t, J = 6.9 Hz), 3.01 (3H, s), 3.18 (2H, q, J = 7.3 Hz), 3.26 (2H, d, J = 7.8 Hz), 3.96 (3H, s), 4.15 (2H, t, J = 6.9 Hz), 4.89 (2H, s), 7.52 (1H, s), 8.16 (2H, s).
実施例１６２
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造： Example 162
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Production of -6-amine:
工程１：Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンズアルデヒドの代わりに６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドを用い、５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに５－メトキシピリミジン－２－アミンを用いて実施例５０の工程２と同様に反応・処理し、Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを淡黄色油状物として得た。 Step 1: N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Preparation of 6-amine 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4] instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde -B] Similar to Step 2 of Example 50 using pyridine-5-carbaldehyde and using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine. N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1 after reaction and treatment H-pyrazolo [3,4-b] pyridin-6-amine was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.12-1.23 (5H, m), 1.40-1.62 (4H, m), 1.64-1.74 (2H, m), 2.16 (1H, m), 2.45 (3H, s), 3.26 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 3.96 (3H, s), 4.65 (2H, s), 5.61 (1H, br), 7.85 (1H, s), 8.05 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.12-1.23 (5H, m), 1.40-1.62 (4H, m), 1.64-1.74 (2H, m), 2.16 (1H, m), 2.45 (3H, s) , 3.26 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 3.96 (3H, s), 4.65 (2H, s), 5.61 (1H, br), 7.85 (1H, s), 8.05 (2H, s).
工程２：Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりにＮ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを用いて実施例１６１と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Step 2: N- (Cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4 b] Preparation of Pyridin-6-amine N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl}- The reaction and treatment were conducted in a similar manner to Example 161 using 1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6-amine, and the title compound was obtained as a pale-yellow oil.
1H-NMR (CDCl3) δ: 1.13-1.27 (5H, m), 1.40-1.77 (46, m), 2.18 (1H, m), 2.41 (3H, s), 3.01 (3H, s), 3.19 (2H, q, J = 6.9 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.83 (3H, s), 3.97 (3H, s), 4.90 (2H, s), 7.53 (1H, s), 8.15 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.13-1.27 (5H, m), 1.40-1.77 (46, m), 2.18 (1H, m), 2.41 (3H, s), 3.01 (3H, s), 3.19 (2H, q, J = 6.9 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.83 (3H, s), 3.97 (3H, s), 4.90 (2H, s), 7.53 (1H, s) , 8.15 (2H, s).
実施例１６３
Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造： Example 163
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Production of -6-amine:
工程１：Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンズアルデヒドの代わりに６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドを用い、５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに５－エトキシピリミジン－２－アミンを用いて実施例５０の工程２と同様に反応・処理し、Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを淡黄色油状物として得た。 Step 1: N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Preparation of 6-amine 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4] instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde -B] Similar to Step 2 of Example 50 using pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine. N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1 after reaction and treatment H-pyrazolo [3,4-b] pyridin-6-amine was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.11-1.23 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.40-1.76 (6H, m), 2.16 (1H, m), 2.45 (3H, s), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 6.8 Hz), 4.65 (2H, d, J = 5.8 Hz), 5.52 (1H, t, J = 5.8 Hz), 7.85 (1H, s), 8.06 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.11-1.23 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.40-1.76 (6H, m), 2.16 (1H, m), 2.45 (3H , s), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 6.8 Hz), 4.65 (2H , d, J = 5.8 Hz), 5.52 (1H, t, J = 5.8 Hz), 7.85 (1H, s), 8.06 (2H, s).
工程２：Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりにＮ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを用いて実施例１６１と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Step 2: N- (Cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4 b] Preparation of Pyridin-6-amine N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl- The reaction and treatment were conducted in a similar manner to Example 161 using 1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6-amine, and the title compound was obtained as a pale-yellow oil.
1H-NMR (CDCl3) δ: 1.13-1.30 (5H, m), 1.41 (3H, t, J = 6.8 Hz), 1.42-1.76 (6H, m), 2.18 (1H, m), 2.40 (3H, s), 3.01 (3H, s), 3.18 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.03 (2H, q, J = 6.8 Hz), 4.90 (2H, s), 7.53 (1H, s), 8.14 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.13-1.30 (5H, m), 1.41 (3H, t, J = 6.8 Hz), 1.42-1.76 (6H, m), 2.18 (1H, m), 2.40 (3H , s), 3.01 (3H, s), 3.18 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.03 (2H, q, J = 6.8 Hz), 4.90 (2H, s), 7.53 (1H, s), 8.14 (2H, s).
実施例１６４
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン（26.3 mg, 0.056 mmol）のＮ，Ｎ－ジメチルホルムアミド（0.5 mL）溶液を-15℃にて攪拌する中に水素化ナトリウム（60％ in oil, 5.4 mg, 0.14 mmol）を加え、室温にて30分間攪拌した。反応液を－15℃に冷却し、ヨウ化エチル（26.2 mg, 0.17 mmol）を加え室温まで昇温しつつ4時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣を分取薄層クロマトグラフィー（ヘキサン：アセトン ＝ 1：1）を用いて精製し、標題化合物（11.1 mg, 40%）を淡黄色油状物として得た。 Example 164
N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 4-b] Preparation of pyridine-6-amine:
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] While stirring a solution of pyridine-6-amine (26.3 mg, 0.056 mmol) in N, N-dimethylformamide (0.5 mL) at -15 ° C, sodium hydride (60% in oil, 5.4 mg, 0.14 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was cooled to −15 ° C., ethyl iodide (26.2 mg, 0.17 mmol) was added, and the mixture was stirred for 4 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using 1: 1) to give the title compound (11.1 mg, 40%) as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.12 (3H, t, J = 7.1 Hz), 1.13-1.28 (5H, m), 1.42-1.76 (6H, m), 2.18 (1H, m), 2.21 (3H, s), 2.40 (3H, s), 2.87 (2H, t, J = 6.8 Hz), 3.19 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.6 Hz), 3.48 (2H, q, J = 7.1 Hz), 3.96 (3H, s), 4.15 (2H, t, J = 6.8 Hz), 4.86 (2H, s), 7.57 (1H, s), 8.15 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.12 (3H, t, J = 7.1 Hz), 1.13-1.28 (5H, m), 1.42-1.76 (6H, m), 2.18 (1H, m), 2.21 (3H , s), 2.40 (3H, s), 2.87 (2H, t, J = 6.8 Hz), 3.19 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.6 Hz), 3.48 (2H , q, J = 7.1 Hz), 3.96 (3H, s), 4.15 (2H, t, J = 6.8 Hz), 4.86 (2H, s), 7.57 (1H, s), 8.15 (2H, s).
実施例１６５
Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［エチル（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりにＮ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを用いて実施例１６４と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Example 165
N- (cyclopentylmethyl) -N-ethyl-5-{[ethyl (5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo instead of pyridine-6-amine The reaction and treatment were conducted in the same manner as in Example 164 using [3,4-b] pyridin-6-amine to give the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.12 (3H, t, J = 6.9 Hz), 1.13-1.27 (8H, m), 1.40-1.77 (46, m), 2.18 (1H, m), 2.40 (3H, s), 3.01 (3H, s), 3.19 (2H, q, J = 6.9 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.48 (2H, q, J = 6.9 Hz), 3.82 (3H, s), 3.96 (3H, s), 4.86 (2H, s), 7.58 (1H, s), 8.14 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.12 (3H, t, J = 6.9 Hz), 1.13-1.27 (8H, m), 1.40-1.77 (46, m), 2.18 (1H, m), 2.40 (3H , s), 3.01 (3H, s), 3.19 (2H, q, J = 6.9 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.48 (2H, q, J = 6.9 Hz), 3.82 (3H , s), 3.96 (3H, s), 4.86 (2H, s), 7.58 (1H, s), 8.14 (2H, s).
実施例１６６
Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（エチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりにＮ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを用いて実施例１６４と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Example 166
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (ethyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Production of -6-amine:
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo instead of pyridine-6-amine The reaction and treatment were conducted in the same manner as in Example 164 using [3,4-b] pyridin-6-amine to give the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.12 (3H, t, J = 6.9 Hz), 1.13-1.27 (5H, m), 1.41 (3H, t, J = 6.9 Hz), 1.42-1.77 (6H, m), 2.18 (1H, m), 2.40 (3H, s), 3.19 (2H, q. J = 6.9 Hz), 3.27 (2H, d, J = 7.8 Hz), 3.47 (2H, q, J = 6.9 Hz), 3.96 (3H, s), 4.02 (2H, q, J = 6.9 Hz), 4.86 (2H, s), 7.58 (1H, s), 8.13 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.12 (3H, t, J = 6.9 Hz), 1.13-1.27 (5H, m), 1.41 (3H, t, J = 6.9 Hz), 1.42-1.77 (6H, m ), 2.18 (1H, m), 2.40 (3H, s), 3.19 (2H, q. J = 6.9 Hz), 3.27 (2H, d, J = 7.8 Hz), 3.47 (2H, q, J = 6.9 Hz) ), 3.96 (3H, s), 4.02 (2H, q, J = 6.9 Hz), 4.86 (2H, s), 7.58 (1H, s), 8.13 (2H, s).
実施例１６７
２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造：
工程１：２－（ｔｒａｎｓ－４－｛［エチル（５－ホルミル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチルアミンの代わりに国際公開第２００４／０２０３９３号パンフレットに記載の方法により製造したｔｒａｎｓ－｛４－［（エチルアミノ）メチル］シクロヘキシル｝酢酸エチルを用いて実施例７９の工程１と同様に反応・処理し、２－（ｔｒａｎｓ－４－｛［エチル（５－ホルミル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］メチル｝シクロヘキシル）酢酸エチルを淡黄色油状物として得た。 Example 167
2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] Preparation of pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
Step 1: Preparation of 2- (trans-4-{[ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl} cyclohexyl) ethyl acetate Example 79 using trans- {4-[(ethylamino) methyl] cyclohexyl} ethyl acetate prepared by the method described in WO 2004/020393 instead of N- (cyclopentylmethyl) -N-ethylamine 2- (trans-4-{[Ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl} cyclohexyl) ethyl acetate was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.88-0.96 (4H, m), 1.19-1.26 (6H, m), 1.73-1.79 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.50 (3H, s), 3.36 (2H, q, J = 7.2 Hz), 3.47 (2H, d, J = 6.8 Hz), 3.92 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 8.33 (1H, s), 9.99 (1H, s). 1 H-NMR (CDCl 3 ) δ: 0.88-0.96 (4H, m), 1.19-1.26 (6H, m), 1.73-1.79 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.50 (3H, s), 3.36 (2H, q, J = 7.2 Hz), 3.47 (2H, d, J = 6.8 Hz), 3.92 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 8.33 (1H, s), 9.99 (1H, s).
工程２：２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造
３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒドの代わりに２－（ｔｒａｎｓ－４－｛［エチル（５－ホルミル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例７６の工程２と同様に反応・処理し、２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを淡黄色油状物として得た。 Step 2: 2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 , 4-b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate preparation 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (trans- Step 2 of Example 76 with ethyl 4-{[ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl} cyclohexyl) acetate The reaction and treatment were conducted in the same manner to give 2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] Was obtained as 1H- pyrazolo [3,4-b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetate as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.88-0.95 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.72-1.86 (6H, m), 2.13 (2H, d, J = 6.3 Hz), 2.20 (3H, s), 2.45 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.19-3.23 (4H, m), 3.95 (3H, s), 4.08-4.13 (4H, m), 4.63 (2H, d, J = 5.9 Hz), 5.54 (1H, br), 7.84 (1H, s), 8.07 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.88-0.95 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.72-1.86 (6H, m ), 2.13 (2H, d, J = 6.3 Hz), 2.20 (3H, s), 2.45 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.19-3.23 (4H, m), 3.95 (3H, s), 4.08-4.13 (4H, m), 4.63 (2H, d, J = 5.9 Hz), 5.54 (1H, br), 7.84 (1H, s), 8.07 (2H, s).
工程３：２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりに２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例１６１と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Step 3: 2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [ Preparation of 3,4-b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [ Instead of 2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine, 2- (trans-4-{[{1,3- Dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-yl} (ethyl) amino] methyl } Cyclohex Sil) Ethyl acetate was used for the reaction and treatment in the same manner as in Example 161 to obtain the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.87-1.01 (4H, m), 1.15 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.66-1.84 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.21 (3H, s), 2.41 (3H, s), 2.87 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 3.14 (2H, q, J = 7.2 Hz), 3.20 (2H, d, J = 6.8 Hz), 3.95 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 4.15 (2H, t, J = 6.3 Hz), 4.88 (2H, s), 7.53 (1H, s), 8.15 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.87-1.01 (4H, m), 1.15 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.66-1.84 (6H, m ), 2.14 (2H, d, J = 6.3 Hz), 2.21 (3H, s), 2.41 (3H, s), 2.87 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 3.14 (2H , q, J = 7.2 Hz), 3.20 (2H, d, J = 6.8 Hz), 3.95 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 4.15 (2H, t, J = 6.3 Hz ), 4.88 (2H, s), 7.53 (1H, s), 8.15 (2H, s).
実施例１６８
２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 168
2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] Preparation of pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 2- (trans-4-{[{1,3-dimethyl- 5-[(Methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-yl} (ethyl) amino] methyl} Cyclohexyl) ethyl acetate was used for the reaction and treatment in the same manner as in Example 57 to obtain the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.88-0.98 (4H, m), 1.15 (3H, t, J = 7.2 Hz), 1.72-1.84 (6H, m), 2.18 (2H, d, J = 6.3 Hz), 2.21 (3H, s), 2.41 (3H, s), 2.87 (2H, t, J = 6.3 Hz), 3.00 (3H, s), 3.14 (2H, q, J = 7.2 Hz), 3.20 (2H, d, J = 6.8 Hz), 3.96 (3H, s), 4.14 (2H, t, J = 6.3 Hz), 4.87 (2H, s), 7.52 (1H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.88-0.98 (4H, m), 1.15 (3H, t, J = 7.2 Hz), 1.72-1.84 (6H, m), 2.18 (2H, d, J = 6.3 Hz ), 2.21 (3H, s), 2.41 (3H, s), 2.87 (2H, t, J = 6.3 Hz), 3.00 (3H, s), 3.14 (2H, q, J = 7.2 Hz), 3.20 (2H , d, J = 6.8 Hz), 3.96 (3H, s), 4.14 (2H, t, J = 6.3 Hz), 4.87 (2H, s), 7.52 (1H, s), 8.16 (2H, s).
実施例１６９
４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチルの製造： Example 169
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Preparation of ethyl pyrimidin-5-yl} oxy) butanoate:
工程１：４－［（２－ヘキサンアミドピリミジン－５－イル）オキシ］ブタン酸エチルの製造
Ｎ－（５－ヒドロキシピリミジン－２－イル）ヘキサン酸アミド（3.0 g，14.3 mmol）のＮ，Ｎ－ジメチルホルムアミド（15 mL）溶液に４－ブロモブタン酸エチル（3.35 g，17.2 mmol）、炭酸カリウム（3.0 g，21.5 mmol）加え、60℃で16時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し、４－［（２－ヘキサンアミドピリミジン－５－イル）オキシ］ブタン酸エチルの残渣（粗体：5.06 g）を得た。 Step 1: Preparation of ethyl 4-[(2-hexaneamidopyrimidin-5-yl) oxy] butanoate N- (5-hydroxypyrimidin-2-yl) hexanoic acid amide (3.0 g, 14.3 mmol) N, N -Ethyl 4-bromobutanoate (3.35 g, 17.2 mmol) and potassium carbonate (3.0 g, 21.5 mmol) were added to a dimethylformamide (15 mL) solution, and the mixture was stirred at 60 ° C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-[(2-hexaneamidopyrimidin-5-yl) oxy. A residue of ethyl butanoate (crude: 5.06 g) was obtained.
1H-NMR (CDCl3) δ: 0.91 (3H, br), 1.25-1.37 (7H, m), 1.73 (2H, br), 2.14-2.15 (2H, m), 2.50-2.62 (4H, m), 4.09-4.17 (4H, m), 8.28-8.36 (3H, m). 1 H-NMR (CDCl 3 ) δ: 0.91 (3H, br), 1.25-1.37 (7H, m), 1.73 (2H, br), 2.14-2.15 (2H, m), 2.50-2.62 (4H, m) , 4.09-4.17 (4H, m), 8.28-8.36 (3H, m).
工程２：４－［（２－アミノピリミジン－５－イル）オキシ］ブタン酸エチルの製造
　４－［（２－ヘキサンアミドピリミジン－５－イル）オキシ］ブタン酸エチル（粗体：1 g）のエタノール（4 mL）溶液にナトリウムエトキシド（421 mg，6.19 mmol）加え、5時間加熱還流した。放冷後、濃硫酸（835 mg，8.51 mmol）加え、16時間加熱還流した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：2）を用いて精製し、４－［（２－アミノピリミジン－５－イル）オキシ］ブタン酸エチル（862 mg, 二段階100％）を黄色固形物として得た。 Step 2: Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butanoate Ethyl 4-[(2-hexaneamidopyrimidin-5-yl) oxy] butanoate (crude: 1 g) Sodium ethoxide (421 mg, 6.19 mmol) was added to an ethanol (4 mL) solution, and the mixture was heated to reflux for 5 hours. After allowing to cool, concentrated sulfuric acid (835 mg, 8.51 mmol) was added, and the mixture was heated to reflux for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 1: 2) to give ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butanoate (862 mg, 100% two steps) as a yellow solid.
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.1 Hz), 2.09 (2H, tt, J = 6.6 Hz), 2.50 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.80 (2H, br), 8.03 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.1 Hz), 2.09 (2H, tt, J = 6.6 Hz), 2.50 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.80 (2H, br), 8.03 (2H, s).
工程３：４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチルの製造
　３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒドの代わりに６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドを用い、５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに４－［（２－アミノピリジン－５－イル）オキシ］ブタン酸エチルを用いて実施例７６の工程２と同様に反応・処理し、４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチルを淡黄色油状物として得た。 Step 3: 4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino ] Preparation of ethyl pyrimidin-5-yl} oxy) butanoate 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6-[(cyclopentylmethyl) (ethyl) amino] -1, Using 3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 4-[(2-aminopyridine- 5- (yl) oxy] butanoic acid ethyl was used for the reaction and treatment in the same manner as in Step 2 of Example 76 to give 4-({2-[({6-[(cyclopentylmethyl) (ethyl) a]. Mino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidin-5-yl} oxy) butanoic acid ethyl ester was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.13-1.17 (5H, m), 1.26 (3H, t, J = 7.1 Hz), 1.47-1.68 (6H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 6.3 Hz), 3.24-3.28 (4H, m), 3.94-3.98 (5H, m), 4.14 (2H, q, J = 7.1 Hz), 4.64 (2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.9 Hz), 7.84 (1H, s), 8.04 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.13-1.17 (5H, m), 1.26 (3H, t, J = 7.1 Hz), 1.47-1.68 (6H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 6.3 Hz), 3.24-3.28 (4H, m), 3.94-3.98 (5H, m), 4.14 (2H, q, J = 7.1 Hz), 4.64 ( 2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.9 Hz), 7.84 (1H, s), 8.04 (2H, s).
工程４：４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチルの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりに４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチルを用いて実施例１６１と同様に反応・処理し、表題化合物を淡黄色油状物として得た。 Step 4: 4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) ( Preparation of methyl) amino] pyrimidin-5-yl} oxy) butanoate N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidine -2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of 4-({2-[({6-[(cyclopentylmethyl) (ethyl) amino]- 1,3-Dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidin-5-yl} oxy) reacted and treated in the same manner as in Example 161. , Title compound Was obtained as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.14-1.23 (5H, m), 1.28 (3H, t, J = 7.1 Hz), 1.48-1.67 (6H, m), 2.07-2.22 (3H, m), 2.41 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 3.18 (2H, q, J = 7.1 Hz), 3.26 (2H, d, J = 7.6 Hz), 3.97 (3H, s), 4.01 (2H, t, J = 6.3 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.89 (2H, s), 7.53 (1H, s), 8.13 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.14-1.23 (5H, m), 1.28 (3H, t, J = 7.1 Hz), 1.48-1.67 (6H, m), 2.07-2.22 (3H, m), 2.41 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 3.18 (2H, q, J = 7.1 Hz), 3.26 (2H, d, J = 7.6 Hz), 3.97 (3H, s), 4.01 (2H, t, J = 6.3 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.89 (2H, s), 7.53 (1H, s), 8.13 (2H, s) .
実施例１７０
４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチルを用いて実施例５７と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 170
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) butanoic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 4-({2-[({6-[(cyclopentylmethyl) (Ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino] pyrimidin-5-yl} oxy) conducted with ethyl butanoate Reaction and treatment were conducted in the same manner as in Example 57 to obtain the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 0.88-0.96 (4H, m), 1.15 (3H, t, J = 6.8 Hz), 1.72-1.84 (5H, m), 2.17-2.21 (2H, m), 2.41 (3H, s), 2.87 (2H, t, J = 6.8 Hz), 3.00 (3H, s), 3.16 (2H, q, J = 6.8 Hz), 3.20 (2H, d, J = 6.8 Hz), 3.96 (3H, s), 4.14 (2H, t, J = 6.8 Hz), 4.87 (2H, s), 7.52 (1H, s), 8.16 (2H, s). 1 H-NMR (CDCl 3 ) δ: 0.88-0.96 (4H, m), 1.15 (3H, t, J = 6.8 Hz), 1.72-1.84 (5H, m), 2.17-2.21 (2H, m), 2.41 (3H, s), 2.87 (2H, t, J = 6.8 Hz), 3.00 (3H, s), 3.16 (2H, q, J = 6.8 Hz), 3.20 (2H, d, J = 6.8 Hz), 3.96 (3H, s), 4.14 (2H, t, J = 6.8 Hz), 4.87 (2H, s), 7.52 (1H, s), 8.16 (2H, s).
実施例１７１
２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチルの製造： Example 171
2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Il} amino) Production of methyl acetate:
工程１：２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝アミノ）酢酸メチルの製造
　６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４，－ｂ］ピリジン－５－カルボアルデヒド（200 mg, 0.81 mmol）のメタノール（3.2 mL）溶液を0℃にて攪拌する中にグリシンメチルエステル塩酸塩（153 mg，1.22 mmol）、トリエチルアミン（123 mg，1.22 mmol）を加え、室温にて16時間攪拌した。反応液を0℃に冷却し、水素化ホウ素ナトリウム（61.4 mg, 1.62 mmol）を加え室温まで昇温しつつ4時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：1）を用いて精製し、２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝アミノ）酢酸メチル（139 mg, 53%）を黄色油状物として得た。 Step 1: Preparation of methyl 2-({[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} amino) amino acetate 6- (diethylamino)- While stirring a solution of 1,3-dimethyl-1H-pyrazolo [3,4, -b] pyridine-5-carbaldehyde (200 mg, 0.81 mmol) in methanol (3.2 mL) at 0 ° C., glycine methyl ester hydrochloride Salt (153 mg, 1.22 mmol) and triethylamine (123 mg, 1.22 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ° C., sodium borohydride (61.4 mg, 1.62 mmol) was added, and the mixture was stirred for 4 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 1: 1) and methyl 2-({[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} amino) acetate (139 mg , 53%) as a yellow oil.
1H-NMR (CDCl3) δ: 1.13 (6H, t, J = 6.9 Hz), 2.49 (3H, s), 3.29 (4H, q, J = 6.9 Hz), 3.38 (2H, s), 3.72 (3H, s), 3.85 (2H, s), 3.96 (3H, s), 7.86 (1H, s). 1 H-NMR (CDCl 3 ) δ: 1.13 (6H, t, J = 6.9 Hz), 2.49 (3H, s), 3.29 (4H, q, J = 6.9 Hz), 3.38 (2H, s), 3.72 ( 3H, s), 3.85 (2H, s), 3.96 (3H, s), 7.86 (1H, s).
工程２：２－［（５－ブロモピリミジン－２－イル）｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝アミノ］酢酸メチルの製造
　２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝アミノ）酢酸メチル（130 mg，0.41 mmol）のトルエン溶液に５－ブロモ－２－クロロピリミジン(94.5 mg，0.49 mmol)、ジイソプロピルエチルアミン（63 mg，0.49 mmol）を加え、110℃にて16時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：1）を用いて精製し、２－［（５－ブロモピリミジン－２－イル）｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝アミノ］酢酸メチル（158 mg, 82%）を無色油状物として得た。 Step 2: 2-[(5-Bromopyrimidin-2-yl) {[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} amino] Preparation of methyl acetate 2-({[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} amino) methyl acetate (130 mg, 0.41 mmol) To a toluene solution of 5-bromo-2-chloropyrimidine (94.5 mg, 0.49 mmol) and diisopropylethylamine (63 mg, 0.49 mmol) were added and stirred at 110 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to give 2-[(5-bromopyrimidin-2-yl) {[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl. ] Methyl} amino] methyl acetate (158 mg, 82%) was obtained as a colorless oil.
1H-NMR (CDCl3) δ: 1.13 (6H, t, J = 7.2 Hz), 2.44 (3H, s), 3.26 (4H, q. J = 7.2 Hz), 3.07 (3H, s), 3.97 (3H, s), 4.11 (2H, s), 4.97 (2H, s), 7.72 (1H, s), 8.36 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.13 (6H, t, J = 7.2 Hz), 2.44 (3H, s), 3.26 (4H, q. J = 7.2 Hz), 3.07 (3H, s), 3.97 ( 3H, s), 4.11 (2H, s), 4.97 (2H, s), 7.72 (1H, s), 8.36 (2H, s).
工程３：２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチルの製造
　２－［（５－ブロモピリミジン－２－イル）｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝アミノ］酢酸メチル（158 mg, 82%）（150 mg, 0.32 mmol）のジオキサン溶液にヨウ化銅（6.0 mg，0.03 mmol）、Ｎ,Ｎ－ジメチルエチレンジアミン（6.8 μL，0.06 mmol）、ヨウ化ナトリウム（94.4 mg，0.63 mmol）を加え、16時間過熱還流した。放冷後、反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥後、減圧濃縮し、２－［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－ヨードピリミジン－２－イル）アミノ］酢酸メチルの残渣を得た。
1H-NMR (CDCl3) δ: 1.13 (6H, t, J = 7.2 Hz), 2.44 (3H, s), 3.26 (4H, q. J = 7.2 Hz), 3.07 (3H, s), 3.97 (3H, s), 4.10 (2H, s), 4.97 (2H, s), 7.72 (1H, s), 8.46 (2H, s). Step 3: 2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine -2-yl} amino) Production of methyl acetate 2-[(5-bromopyrimidin-2-yl) {[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- To a solution of methyl 5-yl] methyl} amino] acetate (158 mg, 82%) (150 mg, 0.32 mmol) in dioxane, copper iodide (6.0 mg, 0.03 mmol), N, N-dimethylethylenediamine (6.8 μL, 0.06 mmol) and sodium iodide (94.4 mg, 0.63 mmol) were added, and the mixture was heated to reflux for 16 hours. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, 2-[{[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5- A residue of methyl iodopyrimidin-2-yl) amino] acetate was obtained.
1 H-NMR (CDCl 3 ) δ: 1.13 (6H, t, J = 7.2 Hz), 2.44 (3H, s), 3.26 (4H, q. J = 7.2 Hz), 3.07 (3H, s), 3.97 ( 3H, s), 4.10 (2H, s), 4.97 (2H, s), 7.72 (1H, s), 8.46 (2H, s).
　上述の粗生成物のトルエン溶液に２－（メチルチオ）エタノール（146 μL，1.56 mmol）、ヨウ化銅（24 mg，0.13 mmol）、1,10-フェナントロリン（45.4 mg，0.25 mmol）、炭酸セシウム（167 mg，0.47 mmol）を加え、110℃にて20時間攪拌した。反応液をろ過後、減圧濃縮し得られた残渣を分取薄層クロマトグラフィー（ヘキサン：アセトン ＝ 3：2）を用いて精製し、表題化合物（12.9 mg, 8% (2 steps））を無色油状物として得た。 To the toluene solution of the above crude product, 2- (methylthio) ethanol (146 μL, 1.56 mmol), copper iodide (24 mg, 0.13 mmol), 1,10-phenanthroline (45.4 mg, 0.25 mmol), cesium carbonate ( 167 mg, 0.47 mmol) was added, and the mixture was stirred at 110 ° C. for 20 hours. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was purified using preparative thin layer chromatography (hexane: acetone = 3: 2) to give the title compound (12.9 mg, 8% (2 steps)) colorless. Obtained as an oil.
1H-NMR (CDCl3) δ: 1.13 (6H, t, J = 6.9 Hz), 2.11 (3H, s), 2.21 (3H, s), 2.43 (3H, s), 2.67 (2H, t, J = 6.9 Hz), 2.87 (2H, t, J = 6.9 Hz), 3.27 (4H, q, J = 6.9 Hz), 3.96 (3H, s), 4.12 (2H, s), 4.14 (2H, t, J = 6.9 Hz), 4.27 (2H, t, J = 6.9 Hz), 4.97 (2H, s), 7.76 (1H, s), 8.15 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.13 (6H, t, J = 6.9 Hz), 2.11 (3H, s), 2.21 (3H, s), 2.43 (3H, s), 2.67 (2H, t, J = 6.9 Hz), 2.87 (2H, t, J = 6.9 Hz), 3.27 (4H, q, J = 6.9 Hz), 3.96 (3H, s), 4.12 (2H, s), 4.14 (2H, t, J = 6.9 Hz), 4.27 (2H, t, J = 6.9 Hz), 4.97 (2H, s), 7.76 (1H, s), 8.15 (2H, s).
実施例１７２
２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチルを用いて実施例５７と同様に反応・処理し、標題化合物を淡黄色油状物として得た。 Example 172
2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Il} amino) acetic acid production:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 2-({[6- (diethylamino) -1,3-dimethyl -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) reacted in the same manner as in Example 57 using methyl acetate. Treatment gave the title compound as a pale yellow oil.
1H-NMR (CDCl3) δ: 1.12 (6H, t, J = 7.1 Hz), 2.21 (3H, s), 2.42 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 3.28 (4H, q, J = 7.1 Hz), 3.96 (3H, s), 4.12-4.14 (4H, m), 4.96 (2H, s), 7.75 (1H, s), 8.15 (2H, s). 1 H-NMR (CDCl 3 ) δ: 1.12 (6H, t, J = 7.1 Hz), 2.21 (3H, s), 2.42 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 3.28 ( 4H, q, J = 7.1 Hz), 3.96 (3H, s), 4.12-4.14 (4H, m), 4.96 (2H, s), 7.75 (1H, s), 8.15 (2H, s).
実施例１７３
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルの製造：
工程１：３－（メチルアミノ）プロピオン酸メチルの製造
アクリル酸メチル（10 mL, 0.12 mmol）のメタノール溶液（50 mL）にＮ－メチルベンジルアミン（17.1 mL, 0.13 mmol）を加え、室温下、15時間攪拌した。続いて反応液に10% パラジウム炭素（6.43 g）及びギ酸アンモニウム（10.0 g, 0.16 mmol）加え一時間加熱還流した。放冷後、セライト及びシリカゲルでろ過し、減圧濃縮して３－（メチルアミノ）プロピオン酸メチル（6.7 g, 47%）を無色油状物として得た。
1H-NMR (CDCl3) δ: 2.44 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 2.86 (2H, t, J = 6.3 Hz), 3.69 (3H, s). Example 173
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] Production of methyl propionate:
Step 1: Preparation of methyl 3- (methylamino) propionate N-methylbenzylamine (17.1 mL, 0.13 mmol) was added to a methanol solution (50 mL) of methyl acrylate (10 mL, 0.12 mmol) at room temperature. Stir for 15 hours. Subsequently, 10% palladium carbon (6.43 g) and ammonium formate (10.0 g, 0.16 mmol) were added to the reaction solution, and the mixture was heated to reflux for 1 hour. After allowing to cool, the mixture was filtered through celite and silica gel, and concentrated under reduced pressure to give methyl 3- (methylamino) propionate (6.7 g, 47%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 2.44 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 2.86 (2H, t, J = 6.3 Hz), 3.69 (3H, s).
工程２：３－［（５－ホルミル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ]プロピオン酸メチルの製造
Ｎ－（シクロペンチルメチル）－Ｎ－エチルアミンの代わりに３－（メチルアミノ）プロピオン酸メチルを用いて実施例７９の工程１と同様に反応・処理し、３－［（５－ホルミル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ]プロピオン酸メチルを茶色油状物として得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.12 (3H, s), 3.87 (2H, t, J = 6.3 Hz), 3.92 (3H, s), 8.31 (1H, s), 9.97 (1H, s). Step 2: Preparation of methyl 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate N- (cyclopentylmethyl)- The reaction and treatment were conducted in the same manner as in Step 1 of Example 79 using methyl 3- (methylamino) propionate instead of N-ethylamine to give 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [ Methyl 3,4-b] pyridin-6-yl) (methyl) amino] propionate was obtained as a brown oil.
1 H-NMR (CDCl 3 ) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.12 (3H, s), 3.87 (2H, t, J = 6.3 Hz), 3.92 ( 3H, s), 8.31 (1H, s), 9.97 (1H, s).
工程３：３－［（５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルの製造
３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒドの代わりに３－［（５－ホルミル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルを用い、５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに５－エトキシピリミジン－２－アミンを用いて実施例７６の工程２と同様に反応・処理し、３－［（５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルを黄白色固体として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.67 (2H, t, J = 6.3 Hz), 2.95 (3H, s), 3.66 (5H, m), 3.98 (5H, m), 4.64 (2H, m), 5.46 (1H, br), 7.87 (1H, s), 8.04 (2H, s). Step 3: 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Preparation of methyl] amino] propionate 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4] instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde -B] Performed using methyl pyridin-6-yl) (methyl) amino] propionate using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine The reaction and treatment were conducted in the same manner as in Step 2 of Example 76 to give 3-[(5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4 b] pyridin-6-yl) (methyl) amino] propionate as a yellowish white solid.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.67 (2H, t, J = 6.3 Hz), 2.95 (3H, s), 3.66 ( 5H, m), 3.98 (5H, m), 4.64 (2H, m), 5.46 (1H, br), 7.87 (1H, s), 8.04 (2H, s).
工程４：３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりに３－［（５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルを用いて実施例１６１と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 2.63-2.75 (2H, m), 2.94 (6H, s), 3.59 (3H, s), 3.72-3.87 (2H, m), 3.97 (3H, s), 4.01 (2H, q, J = 7.2 Hz), 4.86-4.95 (2H, m), 7.51 (1H. s), 8.13 (2H, s). Step 4: 3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl ) Preparation of methyl (methyl) amino] propionate N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine instead of 3-[(5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl The reaction and treatment were conducted in a similar manner to Example 161 using -1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate, to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 2.63-2.75 (2H, m), 2.94 (6H, s), 3.59 (3H, s ), 3.72-3.87 (2H, m), 3.97 (3H, s), 4.01 (2H, q, J = 7.2 Hz), 4.86-4.95 (2H, m), 7.51 (1H.s), 8.13 (2H, s).
実施例１７４
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチルを用いて実施例５７と同様に反応・処理し、標題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 2.62-2.75 (2H, m), 2.92 (6H, s), 3.72 (3H, s), 3.94 (3H, s), 3.97-4.04 (2H, m), 4.86-4.92 (2H, m), 7.50 (1H. s), 8.14 (2H, s). Example 174
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Production of amino] propionic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 3-[(5-{[(5-ethoxypyrimidine-2- Yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate methyl as in Example 57 Treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 2.38 (3H, s), 2.62-2.75 (2H, m), 2.92 (6H, s), 3.72 (3H, s ), 3.94 (3H, s), 3.97-4.04 (2H, m), 4.86-4.92 (2H, m), 7.50 (1H.s), 8.14 (2H, s).
実施例１７５
３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸メチルの製造：
　３－［（５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチル（156 mg, 0.38 mmol）のDMF（1.5 mL）溶液を-60℃に冷却し、水素化ナトリウム（30.4 mg, 0.76 mmol）を加え、15分間攪拌した後、テトラブチルアンモニウムヨージド（140 mg, 0.38 mmol）及び３，５－ビス（トリフルオロメチル）ベンジルブロミド（174 μL, 0.95 mmol）を加え0℃まで徐々に昇温しつつ3時間攪拌した。反応液を酢酸エチル－水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー（ヘキサン：酢酸エチル = １：２）を用いて精製し、表題化合物（183.8 mg, 76%）を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.43 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 2.85 (3H, s), 3.54-3.61 (5H, m), 3.96 (3H, s), 4.06 (2H, q, J = 7.2 Hz), 4.79 (3H, s), 4.95 (3H, s), 7.55 (1H, s), 7.66 (2H, s), 7.68 (1H, s), 8.17 (2H, s).  Example 175
3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- Preparation of methyl 6-yl] (methyl) amino} propionate:
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] A solution of methyl propionate (156 mg, 0.38 mmol) in DMF (1.5 mL) was cooled to −60 ° C., sodium hydride (30.4 mg, 0.76 mmol) was added, and the mixture was stirred for 15 minutes, followed by tetrabutylammonium iodide ( 140 mg, 0.38 mmol) and 3,5-bis (trifluoromethyl) benzyl bromide (174 μL, 0.95 mmol) were added, and the mixture was stirred for 3 hours while gradually warming to 0 ° C. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel preparative thin layer chromatography (hexane: Purification using ethyl acetate = 1: 2) gave the title compound (183.8 mg, 76%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.43 (3H, t, J = 7.2 Hz), 2.37 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 2.85 (3H, s), 3.54- 3.61 (5H, m), 3.96 (3H, s), 4.06 (2H, q, J = 7.2 Hz), 4.79 (3H, s), 4.95 (3H, s), 7.55 (1H, s), 7.66 (2H , s), 7.68 (1H, s), 8.17 (2H, s).
実施例１７６
３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸メチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.42 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 2.62 (2H, t, J = 7.2 Hz), 2.86 (3H, s), 3.58 (2H, t, J = 7.2 Hz), 3.94 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.78 (3H, s), 4.94 (3H, s), 7.53 (1H, s), 7.62 (2H, s), 7.66 (1H, s), 8.15 (2H, s).  Example 176
3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- Preparation of 6-yl] (methyl) amino} propionic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 3-{[5-({[bis (trifluoromethyl) benzyl] ] (5-Ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl] (methyl) amino} propionate methyl Reaction and treatment were conducted in the same manner as in Example 57 to obtain the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.42 (3H, t, J = 7.2 Hz), 2.35 (3H, s), 2.62 (2H, t, J = 7.2 Hz), 2.86 (3H, s), 3.58 ( 2H, t, J = 7.2 Hz), 3.94 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.78 (3H, s), 4.94 (3H, s), 7.53 (1H, s), 7.62 (2H, s), 7.66 (1H, s), 8.15 (2H, s).
実施例１７７
３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］プロピオン酸メチルの製造：
　３－［（５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチル（157 mg, 0.38 mmol）をDMF（2 mL）及びトルエン（1 mL）の混合溶媒に溶解し、-40℃にてナトリウム t－ペントキシド（83.4 mg, 0.76 mmol）を加え3時間攪拌した。反応液を酢酸エチル－水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー（ヘキサン：酢酸エチル = １：２）を用いて精製し、表題化合物（34.7 mg, 22%）を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.42 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 2.95 (3H, d, J = 4.6 Hz), 3.63 (3H, s), 3.72 (2H, t, J = 7.2 Hz), 3.91 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 6.82 (1H, s), 7.54 (1H, s), 8.13 (2H, s).  Example 177
3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Production of methyl propionate:
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Dissolve methyl propionate (157 mg, 0.38 mmol) in a mixed solvent of DMF (2 mL) and toluene (1 mL), add sodium t-pentoxide (83.4 mg, 0.76 mmol) at -40 ° C, and stir for 3 hours. did. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel preparative thin layer chromatography (hexane: Purification using ethyl acetate = 1: 2) gave the title compound (34.7 mg, 22%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.42 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 2.95 (3H, d, J = 4.6 Hz), 3.63 (3H, s), 3.72 (2H, t, J = 7.2 Hz), 3.91 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 6.82 ( 1H, s), 7.54 (1H, s), 8.13 (2H, s).
実施例１７８
５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
工程１：６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドの製造
　Ｎ－（シクロペンチルメチル）－Ｎ－エチルアミンの代わりにジエチルアミンを用いて実施例７９の工程１と同様に反応・処理し、６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.25 (6H, t, J = 6.8 Hz), 2.49 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.93 (3H, s), 8.34 (1H, s), 10.0 (1H, s). Example 178
5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Manufacturing:
Step 1: Preparation of 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine Reaction and treatment were conducted in the same manner as in Step 1 of Example 79 to obtain 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 1.25 (6H, t, J = 6.8 Hz), 2.49 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.93 (3H, s), 8.34 ( 1H, s), 10.0 (1H, s).
工程２：５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピコリンアルデヒドの代わりに６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－カルボアルデヒドを用い、５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミンの代わりに５－エトキシピリミジン－２－アミンを用いて実施例７６の工程２と同様に反応・処理し、５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 5.4 Hz), 5.55 (1H, br), 7.84 (1H, s), 8.06 (2H, s). Step 2: 5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Preparation 6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde And using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, reaction and treatment in the same manner as in Step 2 of Example 76, and 5-{[ (5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine as a pale yellow oil Got as.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 5.4 Hz), 5.55 (1H, br), 7.84 (1H, s), 8.06 ( 2H, s).
工程３：５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造
　５－｛［（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン（30 mg, 0.08 mmol）のDMF（1.5 mL）溶液を-15℃に冷却し、水素化ナトリウム（6.5 mg, 0.16 mmol）を加え、30分間攪拌した後、ヨウ化メチル（15.2 μL, 0.24 mmol）を加え室温まで徐々に昇温しつつ24時間攪拌した。反応液を酢酸エチル－水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル = ２：１）を用いて精製し、表題化合物（30.1 mg, 97%）を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.02 (3H, s), 3.28 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.89 (2H, s), 7.55 (1H, s), 8.15 (2H, s). Step 3: 5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 Preparation of amine 5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine (30 mg, 0.08 mmol) in DMF (1.5 mL) was cooled to −15 ° C., sodium hydride (6.5 mg, 0.16 mmol) was added, and the mixture was stirred for 30 min, then methyl iodide (15.2 μL, 0.24 mmol) ) And stirred for 24 hours while gradually warming to room temperature. The reaction mixture was extracted from ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate = 2). 1) to give the title compound (30.1 mg, 97%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.02 (3H, s), 3.28 ( 4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.89 (2H, s), 7.55 (1H, s), 8.15 (2H, s).
実施例１７９
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチルの製造：
　ヨウ化メチルの代わりに３－（ブロモメチル）安息香酸メチルを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.06 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.87 (3H, s), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.74 (2H, s), 4.86 (2H, s), 7.32 (1H, dd, J = 7.6 Hz), 7.41 (1H, d, J = 7.6 Hz), 7.58 (1H, s), 7.86 (1H, s), 7.88 (1H, d, J = 7.6 Hz), 8.16 (2H, s).  Example 179
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of methyl benzoate:
The reaction and treatment were conducted in a similar manner to Example 178 using methyl 3- (bromomethyl) benzoate instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.06 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.87 (3H, s), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.74 (2H, s), 4.86 (2H, s), 7.32 (1H, dd, J = 7.6 Hz), 7.41 (1H, d, J = 7.6 Hz), 7.58 (1H, s), 7.86 (1H, s), 7.88 (1H, d, J = 7.6 Hz), 8.16 (2H, s).
実施例１８０
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチルの製造：
　ヨウ化メチルの代わりに４－（ブロモメチル）安息香酸メチルを用いて実施例１７８と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.05 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.20 (4H, q, J = 6.8 Hz), 3.90 (3H, s), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.74 (2H, s), 4.86 (2H, s), 7.25 (2H, d, J = 8.2 Hz), 7.59 (1H, s), 7.92 (2H, d, J = 8.2 Hz), 8.16 (2H, s).  Example 180
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of methyl benzoate:
The reaction and treatment were conducted in a similar manner to Example 178 using methyl 4- (bromomethyl) benzoate instead of methyl iodide, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.05 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.20 (4H, q, J = 6.8 Hz), 3.90 (3H, s), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.74 (2H, s), 4.86 (2H, s), 7.25 (2H, d, J = 8.2 Hz), 7.59 (1H, s), 7.92 (2H, d, J = 8.2 Hz), 8.16 (2H, s).
実施例１８１
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.06 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.75 (2H, s), 4.87 (2H, s), 7.33 (1H, dd, J = 7.7 Hz), 7.43 (1H, d, J = 7.7 Hz), 7.60 (1H, s), 7.89 (1H, s), 7.93 (1H, d, J = 7.7 Hz), 8.18 (2H, s). Example 181
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of benzoic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) 3-{[{[6- (diethylamino) -1,3- Dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} methyl benzoate was reacted and treated in the same manner as in Example 57. The title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.06 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.75 (2H, s), 4.87 (2H, s), 7.33 (1H, dd, J = 7.7 Hz), 7.43 ( 1H, d, J = 7.7 Hz), 7.60 (1H, s), 7.89 (1H, s), 7.93 (1H, d, J = 7.7 Hz), 8.18 (2H, s).
実施例１８２
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸の製造：
　２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチルの代わりに４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチルを用いて実施例５７と同様に反応・処理し、標題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.06 (6H, t, J = 6.8 Hz), 1.43 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.98 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.76 (2H, s), 4.87 (2H, s), 7.25 (2H, d, J = 8.2 Hz), 7.56 (1H, s), 7.96 (2H, d, J = 8.2 Hz), 8.17 (2H, s).  Example 182
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of benzoic acid:
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of 4-{[{[6- (diethylamino) -1,3- Dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} methyl benzoate was reacted and treated in the same manner as in Example 57. The title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.06 (6H, t, J = 6.8 Hz), 1.43 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.98 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.76 (2H, s), 4.87 (2H, s), 7.25 (2H, d, J = 8.2 Hz), 7.56 ( 1H, s), 7.96 (2H, d, J = 8.2 Hz), 8.17 (2H, s).
実施例１８３
５－｛［ベンジル（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりにベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.06 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 4.84 (2H, s), 7.21-7.26 (5H, m), 7.58 (1H, s), 8.15 (2H, s).  Example 183
Preparation of 5-{[benzyl (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
The reaction and treatment were conducted in a similar manner to Example 178 using benzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.06 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 4.84 (2H, s), 7.21-7.26 (5H, m), 7.58 (1H, s ), 8.15 (2H, s).
実施例１８４
５－｛［（５－エトキシピリミジン－２－イル）（４－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに４－フルオロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.65 (2H, s), 4.82 (2H, s), 6.94 (2H, dd, J = 8.6, 8.6 Hz), 7.18 (2H, dd, J = 8.6, 8.6 Hz), 7.58 (1H, s), 8.16 (2H, s).  Example 184
5-{[(5-Ethoxypyrimidin-2-yl) (4-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 4-fluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.65 (2H, s), 4.82 (2H, s), 6.94 (2H, dd, J = 8.6, 8.6 Hz), 7.18 (2H, dd, J = 8.6, 8.6 Hz), 7.58 (1H, s), 8.16 (2H, s).
実施例１８５
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸イソプロピルの製造：
　アルゴン雰囲気下、特許文献（国際公開第２０１１／１５２５０８号パンフレット）記載の方法により合成した２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸（500 mg，0.62 mmol）の２－プロパノール（5 mL）溶液に、濃硫酸（20 μL）を加え、23時間加熱還流した。反応液を冷却した後、飽和炭酸水素ナトリウム水溶液（5 mL）で中和し、酢酸エチルにより抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル ＝ 10：1 → 1：2）を用いて精製し、表題化合物（202 mg，３８％）を白色アモルファスとして得た。
1H-NMR (CDCl3) : 0.87-0.96 (7H, m), 1.21 (6H, d, J = 6.3 Hz), 1.38 (1H, m), 1.45 (3H, d, J = 7.1 Hz), 1.67-1.80 (5H, m), 2.11 (2H, d, J = 6.6 Hz), 2.72 (1H, m), 2.87 (1H, m), 2.89 (2H, q, J= 7.1 Hz), 3.09 (3H, s), 3.45 (2H, t, J= 5.2 Hz), 4.45 (2H, t, J = 5.4 Hz), 4.65 (1H, d, J = 16.6 Hz), 4.87 (1H, d, J = 17.1 Hz), 4.99 (1H, quintet, J = 6.3 Hz), 6.19 (1H, q, J = 7.1 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.19 (1H, s), 7.38 (1H, d, J = 8.1 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.16 (2H, s). Example 185
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) isopropyl acetate:
2- (trans-4-{[{2-[({(S) -1- [3,5-Bis () synthesized by the method described in Patent Document (International Publication No. 2011/152508 pamphlet) under an argon atmosphere] Trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid Concentrated sulfuric acid (20 μL) was added to a solution of (500 mg, 0.62 mmol) in 2-propanol (5 mL), and the mixture was heated to reflux for 23 hours. The reaction mixture was cooled, neutralized with saturated aqueous sodium hydrogen carbonate solution (5 mL), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 1: 2) to give the title compound (202 mg, 38%) as a white amorphous.
1 H-NMR (CDCl 3 ): 0.87-0.96 (7H, m), 1.21 (6H, d, J = 6.3 Hz), 1.38 (1H, m), 1.45 (3H, d, J = 7.1 Hz), 1.67 -1.80 (5H, m), 2.11 (2H, d, J = 6.6 Hz), 2.72 (1H, m), 2.87 (1H, m), 2.89 (2H, q, J = 7.1 Hz), 3.09 (3H, s), 3.45 (2H, t, J = 5.2 Hz), 4.45 (2H, t, J = 5.4 Hz), 4.65 (1H, d, J = 16.6 Hz), 4.87 (1H, d, J = 17.1 Hz) , 4.99 (1H, quintet, J = 6.3 Hz), 6.19 (1H, q, J = 7.1 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.19 (1H, s), 7.38 (1H, d, J = 8.1 Hz), 7.71 (1H, s), 7.73 (2H, s), 8.16 (2H, s).
実施例１８６
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸メチルの製造：
　２-プロパノールの代わりにメタノールを用い、実施例１８５と同様に反応処理し、表題化合物を白色アモルファスとして得た。
1H-NMR (CDCl3) : 0.84-0.96 (7H, m), 1.38 (1H. m), 1.45 (3H, d, J = 7.3 Hz), 1.67-1.80 (5H, m), 2.16 (2H, d, J = 6.6 Hz), 2.72 (1H, m), 2.86 (1H, m), 2.89 (2H, q, J = 7.1 Hz), 3.09 (3H, s), 3.45 (2H, t, J= 5.2 Hz), 3.65 (3H, s), 4.45 (2H, t, J = 5.4 Hz), 4.64 (1H, d, J = 17.3 Hz), 4.87 (1H, d, J = 17.1 Hz), 6.20 (1H, q, J = 7.1 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.19 (1H, s), 7.38 (1H, d, J = 8.3 Hz), 7.72 (3H, s), 8.16 (2H, s). Example 186
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- Preparation of methyl 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetate:
The reaction was conducted in the same manner as in Example 185 using methanol instead of 2-propanol to obtain the title compound as a white amorphous.
1 H-NMR (CDCl 3 ): 0.84-0.96 (7H, m), 1.38 (1H.m), 1.45 (3H, d, J = 7.3 Hz), 1.67-1.80 (5H, m), 2.16 (2H, d, J = 6.6 Hz), 2.72 (1H, m), 2.86 (1H, m), 2.89 (2H, q, J = 7.1 Hz), 3.09 (3H, s), 3.45 (2H, t, J = 5.2 Hz), 3.65 (3H, s), 4.45 (2H, t, J = 5.4 Hz), 4.64 (1H, d, J = 17.3 Hz), 4.87 (1H, d, J = 17.1 Hz), 6.20 (1H, q, J = 7.1 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.19 (1H, s), 7.38 (1H, d, J = 8.3 Hz), 7.72 (3H, s), 8.16 (2H, s).
実施例１８７
２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸の製造：
　アルゴン雰囲気下、２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸（200 mg，0.237 mmol）の２－プロパノール（2 mL）溶液に、タングステン酸ナトリウム二水和物（7.8 mg，0.0237 mmol）および30%過酸化水素水（0.074 mL，0.74 mmol）を加え、室温にて１０．５時間撹拌した。過剰の過酸化水素を10%亜硫酸水素ナトリウム水溶液（１mL）で失活した後、反応液をクロロホルムで抽出し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲル分取薄層クロマトグラフィー（ヘキサン：酢酸エチル ＝ 1：1）で精製し、表題化合物（123 mg，61%）を白色アモルファスとして得た。
1H-NMR (CDCl3): 0.82-1.05 (7H, m), 1.37 (1H. brs), 1.53 (3H, d, J = 5.6 Hz), 1.65-1.84 (6H, m), 2.10-2.30 (2H, m), 2.70-2.95 (4H, m), 3.12-3.28 (2H, m), 4.15-4.30 (1H, m), 4.45-4.52 (1H, m), 4.53-4.66 (1H, m), 4.75-4.88 (1H, m), 6.22-6.32 (1H, m), 7.15 (1H, d, J = 8.4 Hz), 7.21 (1H, s), 7.38 (1H, d, J = 8.4 Hz), 7.48-7.60 (3H, m), 7.62-7.73 (3H, m), 7.76 (2H, s), 8.08 (1H, s), 8.09 (1H, s). Example 187
2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfinyl) ethoxy] pyrimidine- 2-Il} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
Under an argon atmosphere, 2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] ] Pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid (200 mg, 0.237 mmol) in 2-propanol (2 mL) Sodium acid dihydrate (7.8 mg, 0.0237 mmol) and 30% aqueous hydrogen peroxide (0.074 mL, 0.74 mmol) were added, and the mixture was stirred at room temperature for 10.5 hours. Excess hydrogen peroxide was quenched with 10% aqueous sodium bisulfite solution (1 mL), and then the reaction solution was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (123 mg, 61%) as a white amorphous.
1 H-NMR (CDCl 3 ): 0.82-1.05 (7H, m), 1.37 (1H.brs), 1.53 (3H, d, J = 5.6 Hz), 1.65-1.84 (6H, m), 2.10-2.30 ( 2H, m), 2.70-2.95 (4H, m), 3.12-3.28 (2H, m), 4.15-4.30 (1H, m), 4.45-4.52 (1H, m), 4.53-4.66 (1H, m), 4.75-4.88 (1H, m), 6.22-6.32 (1H, m), 7.15 (1H, d, J = 8.4 Hz), 7.21 (1H, s), 7.38 (1H, d, J = 8.4 Hz), 7.48 -7.60 (3H, m), 7.62-7.73 (3H, m), 7.76 (2H, s), 8.08 (1H, s), 8.09 (1H, s).
実施例１８８
５－｛［（３，５－ジフルオロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに３，５－ジフルオロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 6.8 Hz), 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 4.87 (2H, s), 6.63-6.73 (3H, m), 7.58 (1H, s), 8.16 (2H, s).  Example 188
5-{[(3,5-difluorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Production of -6-amine:
The reaction and treatment were conducted in a similar manner to Example 178 using 3,5-difluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.08 (6H, t, J = 6.8 Hz), 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 4.87 (2H, s), 6.63-6.73 (3H, m), 7.58 (1H, s ), 8.16 (2H, s).
実施例１８９
５－｛［（５－エトキシピリミジン－２－イル）（２－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに２－フルオロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.39 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.95 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.81 (2H, s), 4.88 (2H, s), 6.91-7.23 (4H, m), 7.55 (1H, s), 8.15 (2H, s).  Example 189
5-{[(5-Ethoxypyrimidin-2-yl) (2-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 2-fluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.39 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.95 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.81 (2H, s), 4.88 (2H, s), 6.91-7.23 (4H, m), 7.55 (1H, s ), 8.15 (2H, s).
実施例１９０
５－｛［（５－エトキシピリミジン－２－イル）（３－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに３－フルオロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.68 (2H, s), 4.85 (2H, s), 6.89-6.96 (3H, m), 7.17-7.21 (1H, m), 7.58 (1H, s), 8.16 (2H, s).  Example 190
5-{[(5-Ethoxypyrimidin-2-yl) (3-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 3-fluorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.68 (2H, s), 4.85 (2H, s), 6.89-6.96 (3H, m), 7.17-7.21 (1H m), 7.58 (1H, s), 8.16 (2H, s).
実施例１９１
５－｛［（２－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに２－クロロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.05 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.20 (4H, q, J = 6.8 Hz), 3.95 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.83 (2H, s), 4.88 (2H, s), 7.12-7.16 (3H, m), 7.28-7.30 (1H, m), 7.60 (1H, s), 8.14 (2H, s).  Example 191
5-{[(2-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 2-chlorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.05 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.20 (4H, q, J = 6.8 Hz), 3.95 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.83 (2H, s), 4.88 (2H, s), 7.12-7.16 (3H, m), 7.28-7.30 (1H m), 7.60 (1H, s), 8.14 (2H, s).
実施例１９２
５－｛［（３－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに３－クロロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.65 (2H, s), 4.85 (2H, s), 7.06-7.08 (1H, m), 7.16-7.18 (3H, m), 7.57 (1H, s), 8.16 (2H, s).  Example 192
5-{[(3-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 3-chlorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.05 (2H, q, J = 7.2 Hz), 4.65 (2H, s), 4.85 (2H, s), 7.06-7.08 (1H, m), 7.16-7.18 (3H m), 7.57 (1H, s), 8.16 (2H, s).
実施例１９３
５－｛［（４－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに４－クロロベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 4.83 (2H, s), 7.12 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.57 (1H, s), 8.15 (2H, s).  Example 193
5-{[(4-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 4-chlorobenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 4.83 (2H, s), 7.12 (2H, d, J = 8.6 Hz), 7.21 ( 2H, d, J = 8.6 Hz), 7.57 (1H, s), 8.15 (2H, s).
実施例１９４
５－｛［（５－エトキシピリミジン－２－イル）（２－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに２－メチルベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.03 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.17 (3H, s), 2.41 (3H, s), 3.19 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.72 (2H, s), 4.83 (2H, s), 7.02-7.11 (4H, m), 7.56 (1H, s), 8.14 (2H, s). Example 194
5-{[(5-Ethoxypyrimidin-2-yl) (2-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 2-methylbenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.03 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.17 (3H, s), 2.41 (3H, s), 3.19 ( 4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.72 (2H, s), 4.83 (2H, s), 7.02-7.11 (4H, m ), 7.56 (1H, s), 8.14 (2H, s).
実施例１９５
５－｛［（５－エトキシピリミジン－２－イル）（４－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに４－メチルベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.06 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.66 (2H, s), 4.84 (2H, s), 7.04-7.11 (4H, m), 7.56 (1H, s), 8.14 (2H, s). Example 195
5-{[(5-Ethoxypyrimidin-2-yl) (4-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 4-methylbenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.06 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.30 (3H, s), 2.40 (3H, s), 3.22 ( 4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.66 (2H, s), 4.84 (2H, s), 7.04-7.11 (4H, m ), 7.56 (1H, s), 8.14 (2H, s).
実施例１９６
５－｛［（５－エトキシピリミジン－２－イル）（３－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに３－メチルベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.26 (3H, s), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.67 (2H, s), 4.84 (2H, s), 6.80-7.16 (4H, m), 7.56 (1H, s), 8.15 (2H, s). Example 196
5-{[(5-Ethoxypyrimidin-2-yl) (3-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 3-methylbenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.26 (3H, s), 2.40 (3H, s), 3.22 ( 4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.67 (2H, s), 4.84 (2H, s), 6.80-7.16 (4H, m ), 7.56 (1H, s), 8.15 (2H, s).
実施例１９７
５－｛［（５－エトキシピリミジン－２－イル）（４－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに４－メトキシベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.76 (3H, s), 3.97 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 4.82 (2H, s), 6.78 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.56 (1H, s), 8.15 (2H, s). Example 197
5-{[(5-Ethoxypyrimidin-2-yl) (4-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 4-methoxybenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.08 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.76 (3H, s), 3.97 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 4.82 (2H, s), 6.78 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6 Hz), 7.56 (1H, s), 8.15 (2H, s).
実施例１９８
４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリルの製造：
　ヨウ化メチルの代わりに４－シアノベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.05 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.20 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 4.86 (2H, s), 7.28 (2H, d, J = 8.2 Hz), 7.54 (2H, d, J = 8.2 Hz), 7.60 (1H, s), 8.15 (2H, s). Example 198
4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of benzonitrile:
The reaction and treatment were conducted in a similar manner to Example 178 using 4-cyanobenzyl bromide instead of methyl iodide, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.05 (6H, t, J = 6.8 Hz), 1.42 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.20 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.04 (2H, q, J = 7.2 Hz), 4.71 (2H, s), 4.86 (2H, s), 7.28 (2H, d, J = 8.2 Hz), 7.54 ( 2H, d, J = 8.2 Hz), 7.60 (1H, s), 8.15 (2H, s).
実施例１９９
５－｛［（シクロプロピルメチル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに（ブロモメチル）シクロプロパンを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.11 (2H, m), 0.38 (2H, m), 0.99 (1H, m), 1.17 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.39 (3H, s), 3.27-3.34 (6H, m), 3.96 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.99 (2H, s), 7.57 (1H, s), 8.14 (2H, s). Example 199
5-{[(Cyclopropylmethyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
The reaction and treatment were conducted in a similar manner to Example 178 using (bromomethyl) cyclopropane in place of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.11 (2H, m), 0.38 (2H, m), 0.99 (1H, m), 1.17 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.39 (3H, s), 3.27-3.34 (6H, m), 3.96 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.99 (2H, s), 7.57 (1H , s), 8.14 (2H, s).
実施例２００
２－｛ｔｒａｎｓ－４－［（エチル｛２－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチルの製造：
　Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの代わりに国際公開第２００８／１２９９５１号パンフレットに記載の方法に従い製造した２－｛ｔｒａｎｓ－４－［（エチル｛２－［（｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチルを用いて実施例１６４と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) : 0.96-0.98 (4H, m), 1.02 (3H, t, J = 7.0 Hz), 1.11 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.70-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.21 (3H, t), 2.85-2.89 (4H, m), 2.97 (2H, q, J= 7.1 Hz), 3.47 (2H, q, J= 7.0 Hz), 4.09-4.15 (4H, m), 4.90 (2H, s), 7.16 (1H, d, J = 8.3 Hz), 7.34 (1H, s), 7.40 (1H, d, J = 8.6 Hz), 8.12 (2H, s). Example 200
2- {trans-4-[(ethyl {2-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Preparation of cyclohexyl} ethyl acetate:
N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 Instead of 4-b] pyridin-6-amine, 2- {trans-4-[(ethyl {2-[({5- [2- (methylthiol)]] was prepared according to the method described in WO2008 / 129951. )] Ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} ethyl acetate was used in the same manner as in Example 164, and the title compound was pale yellow. Obtained as an oil.
1 H-NMR (CDCl 3 ): 0.96-0.98 (4H, m), 1.02 (3H, t, J = 7.0 Hz), 1.11 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.70-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.21 (3H, t), 2.85-2.89 (4H, m), 2.97 ( 2H, q, J = 7.1 Hz), 3.47 (2H, q, J = 7.0 Hz), 4.09-4.15 (4H, m), 4.90 (2H, s), 7.16 (1H, d, J = 8.3 Hz), 7.34 (1H, s), 7.40 (1H, d, J = 8.6 Hz), 8.12 (2H, s).
実施例２０１
５－｛［（５－エトキシピリミジン－２－イル）（３－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミンの製造：
　ヨウ化メチルの代わりに３－メトキシベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.73 (3H, s), 3.96 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.68 (2H, s), 4.85 (2H, s), 6.77 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.57 (1H, s), 8.15 (2H, s). Example 201
5-{[(5-Ethoxypyrimidin-2-yl) (3-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Production of amines:
The reaction and treatment were conducted in a similar manner to Example 178 using 3-methoxybenzyl bromide instead of methyl iodide, and the title compound was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.73 (3H, s), 3.96 (3H, s), 4.02 (2H, q, J = 7.2 Hz), 4.68 (2H, s), 4.85 (2H, s), 6.77 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.57 (1H, s), 8.15 (2H, s).
実施例２０２
２－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリルの製造：
　ヨウ化メチルの代わりに２－シアノベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.06 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.95 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.92 (2H, s), 4.96 (2H, s), 7.27-7.29 (2H, m), 7.44 (1H, dd, J = 7.7, 7.7 Hz), 7.56 (1H, d, J = 7.7 Hz), 7.59 (1H, s), 8.14 (2H, s). Example 202
2-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of benzonitrile:
The reaction and treatment were conducted in a similar manner to Example 178 using 2-cyanobenzyl bromide instead of methyl iodide, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.06 (6H, t, J = 6.8 Hz), 1.41 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 3.21 (4H, q, J = 6.8 Hz), 3.95 (3H, s), 4.03 (2H, q, J = 7.2 Hz), 4.92 (2H, s), 4.96 (2H, s), 7.27-7.29 (2H, m), 7.44 (1H, dd , J = 7.7, 7.7 Hz), 7.56 (1H, d, J = 7.7 Hz), 7.59 (1H, s), 8.14 (2H, s).
実施例２０３
３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリルの製造：
　ヨウ化メチルの代わりに３－シアノベンジルブロミドを用いて実施例１７８と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 6.8 Hz), 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.06 (2H, q, J = 7.2 Hz), 4.68 (2H, s), 4.86 (2H, s), 7.33 (1H, dd, J = 7.7, 7.7 Hz), 7.41 (1H, d, J = 7.7 Hz), 7.47-7.49 (2H, m), 7.57 (1H, s), 8.16 (2H, s). Example 203
3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Production of benzonitrile:
The reaction and treatment were conducted in a similar manner to Example 178 using 3-cyanobenzyl bromide instead of methyl iodide, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.08 (6H, t, J = 6.8 Hz), 1.43 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.22 (4H, q, J = 6.8 Hz), 3.97 (3H, s), 4.06 (2H, q, J = 7.2 Hz), 4.68 (2H, s), 4.86 (2H, s), 7.33 (1H, dd, J = 7.7, 7.7 Hz), 7.41 (1H, d, J = 7.7 Hz), 7.47-7.49 (2H, m), 7.57 (1H, s), 8.16 (2H, s).
　上記実施例によって得られた化合物を表１に示す。これらのうち、実施例４５、５０－７１、及び１５６－２０３の化合物は新規化合物である。従って、本発明により、実施例４５、５０－７１、及び１５６－２０３の化合物からなる群から選ばれる化合物、若しくはその塩、又はそれらの溶媒和物が提供される。 The compounds obtained in the above examples are shown in Table 1. Of these, the compounds of Examples 45, 50-71, and 156-203 are novel compounds. Accordingly, the present invention provides a compound selected from the group consisting of the compounds of Examples 45, 50-71, and 156-203, or a salt thereof, or a solvate thereof.
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
試験例１
　ヒト肝癌細胞株であるＨｅｐＧ２細胞に被検化合物を添加し、24時間培養後のＰＣＳＫ９ｍＲＮＡ発現量を定量リアルタイムPCRで測定した。すなわち、ＨｅｐＧ２細胞を24穴プレートに3×105cells/wellの濃度で播種し、3晩培養後、ジメチルスルホキシド(DMSO)に溶解した被検化合物を培養液に対して1000分の1倍量加えた。CO2 インキュベーターにて37℃で24時間培養後、ISOGEN（ニッポンジーン社、カタログ番号31-02501）を500 μL加えてtotal RNAの抽出を行った。抽出したtotal RNAからHigh Capacity cDNA Reverse Transcription kit（アプライドバイオシステムズ社、カタログ番号4368813）を用いてcDNAを合成した。ヒトＰＣＳＫ９ｍＲＮＡ発現量はヒトＰＣＳＫ９に特異的なプライマー（Kourimate S. et.al., J Biol Chem. Vol.283, p9666）及びFast SYBR Green master mix （アプライドバイオシステムズ社、カタログ番号4385614）を用いて測定した。測定機器は7900HT Fast Realtime PCR systemを用いた。 Test example 1
A test compound was added to HepG2 cells, a human hepatoma cell line, and the expression level of PCSK9 mRNA after 24 hours of culture was measured by quantitative real-time PCR. That is, HepG2 cells are seeded in a 24-well plate at a concentration of 3 × 10 5 cells / well, cultured for 3 nights, and the test compound dissolved in dimethyl sulfoxide (DMSO) is 1/1000 times the volume of the culture solution. added. After culturing at 37 ° C. for 24 hours in a CO 2 incubator, 500 μL of ISOGEN (Nippon Gene, catalog number 31-02501) was added, and total RNA was extracted. CDNA was synthesized from the extracted total RNA using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, catalog number 4368813). The expression level of human PCSK9 mRNA was determined using primers specific to human PCSK9 (Kourimate S. et.al., J Biol Chem. Vol.283, p9666) and Fast SYBR Green master mix (Applied Biosystems, catalog number 4385614). It was measured. The measuring instrument was a 7900HT Fast Realtime PCR system.
　測定値はβ-Actin mRNAの発現量で補正し、DMSOのみ添加した細胞のＰＣＳＫ９ｍＲＮＡ発現量を1とし、被検化合物を添加した細胞のＰＣＳＫ９ｍＲＮＡ発現量を相対値で算出した。結果を表２に示す。表２からわかるように、本発明の化合物はＰＣＳＫ９ｍＲＮＡ発現量を抑制することが確認された。 The measured value was corrected by the expression level of β-Actin-mRNA, and the PCSK9 mRNA expression level of the cells to which DMSO alone was added was 1, and the PCSK9 mRNA expression level of the cells to which the test compound was added was calculated as a relative value. The results are shown in Table 2. As can be seen from Table 2, the compound of the present invention was confirmed to suppress the expression level of PCSK9 mRNA.
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
試験例２：化合物のＨｅｐＧ２細胞に及ぼすＰＣＳＫ９タンパク産生量の測定
　ヒト肝癌細胞株であるＨｅｐＧ２細胞に被験化合物を添加し、４８時間培養後の培養上清中のＰＣＳＫ９タンパク量をＥｎｚｙｍｅ－Ｌｉｎｋｅｄ　ＩｍｍｕｎｏＳｏｒｂｅｎｔ　Ａｓｓａｙ（ＥＬＩＳＡ）法にて測定することにより、被験化合物のＰＣＳＫ９産生タンパク量に及ぼす影響を確認した。
　すなわち、ＨｅｐＧ２細胞を６穴プレートに７×１０５ｃｅｌｌｓ／ｗｅｌｌの濃度で播種し三晩培養した後、ジメチルスルホキシド（ＤＭＳＯ）に溶解した被験化合物、又はＤＭＳＯのみを培養液に対して終濃度１０μＭとなるように添加した。細胞をＣＯ２ インキュベーターにて３７℃で４８時間培養した後、細胞培養上清を回収した。回収した細胞培養上清を３０００×ｇにて遠心後、上清を回収し、これを細胞培養上清サンプルとして使用した。 Test Example 2: Measurement of PCSK9 Protein Production Amount of Compound on HepG2 Cells A test compound was added to HepG2 cells, a human hepatoma cell line, and the amount of PCSK9 protein in the culture supernatant after 48 hours of culture was measured using Enzyme-Linked Immunosorbent Assay. By measuring by (ELISA) method, the influence which it has on the PCSK9 production protein amount of a test compound was confirmed.
That is, after seeding HepG2 cells in a 6-well plate at a concentration of 7 × 10 5 cells / well and culturing for three nights, a test compound dissolved in dimethyl sulfoxide (DMSO) or DMSO alone is added to the culture solution at a final concentration of 10 μM. It added so that it might become. The cells were cultured for 48 hours at 37 ° C. in a CO 2 incubator, and then the cell culture supernatant was collected. The collected cell culture supernatant was centrifuged at 3000 × g, and the supernatant was collected and used as a cell culture supernatant sample.
　Ｈｕｍａｎ　ＰＣＳＫ９　ＥＬＩＳＡ　ｋｉｔ（Ｒ＆Ｄ：ＤＹ３８８８）よりＣａｐｔｕｒｅ　Ａｎｔｉｂｏｄｙを２．０μｇ／ｍＬとなるようにＰｈｏｓｐｈａｔｅ　Ｂｕｆｆｅｒｅｄ　Ｓａｌｉｎｅ（ＰＢＳ）にて溶解し、９６穴プレートに１００μＬずつ添加した後、室温にて一晩静置した。静置したＰｌａｔｅの上清をすて、Ｗａｓｈ　ｂｕｆｆｅｒ（０．０５％　Ｔｗｅｅｎ２０　ｉｎ　ＰＢＳ，　ｐＨ　７．２－７．４）４００μＬにて３回洗浄した。Ｒｅａｇｅｎｔ　Ｄｉｌｕｅｎｔ　Ｂｕｆｆｅｒ（１％　Ｂｏｖｉｎｅ　ｓｅｒｕｍ　ａｌｂｕｍｉｎ（ＢＳＡ）　ｉｎ　ＰＢＳ，　ｐＨ　７．２－７．４，　０．２μｍ　ｆｉｌｔｅｒｅｄ）３００μＬを添加し、１時間室温にて静置した後、Ｗａｓｈ　ｂｕｆｆｅｒにて３回洗浄した。作成した細胞培養上清サンプルをＲｅａｇｅｎｔ　Ｄｉｌｕｅｎｔ　Ｂｕｆｆｅｒにて５０倍～１００倍希釈し、１００μＬずつ９６穴プレートに添加後、室温にて２時間静置した。Ｗａｓｈ　ｂｕｆｆｅｒにて３回洗浄した後、１００μＬずつＲｅａｇｅｎｔ　Ｄｉｌｕｅｎｔにて希釈したＤｅｔｅｃｔｉｏｎ　ａｎｔｉｂｏｄｙを添加し、１８時間４℃静置した。Ｗａｓｈ　ｂｕｆｆｅｒにて３回洗浄した後、Ｒｅａｇｅｎｔ　Ｄｉｌｕｅｎｔにて５０倍希釈したＳｔｒｅｐｔａｖｉｄｉｎ－Ｈｏｒｓｅｒａｄｉｓｈ　ｐｅｒｏｘｉｄａｓｅ（ＨＲＰ）を１００μＬずつ添加し、２０分室温静置した。Ｗａｓｈ　ｂｕｆｆｅｒにて３回洗浄した後、Ｓｕｂｓｔｒａｔｅ　Ｓｏｌｕｔｉｏｎを１００μＬずつ添加し、２０分遮光室温静置した。次にＳｔｏｐ　ｓｏｌｕｔｉｏｎ（２Ｎ　Ｈ２ＳＯ４）を５０μＬずつ添加し、プレートを軽く撹拌させ、４５０ｎｍの光学密度を測定した。なお、補正値として５７０ｎｍの光学密度を測定した。産生されたＰＣＳＫ９タンパク量は、Ｋｉｔに付属している精製ＰＣＳＫ９タンパクを用いた検量線から算出した。また、データはコントロール（ＤＭＳＯのみを培養液に加えた培養上清サンプル）を１としたときの相対値を表示した。
Figure JPOXMLDOC01-appb-T000125
 From the Human PCSK9 ELISA kit (R & D: DY3888), Capture Antibody was dissolved at 2.0 μg / mL in Phosphate Buffered Saline (PBS), and 100 μL each was added to a 96-well plate and allowed to stand overnight at room temperature. did. The plate plate supernatant was washed and washed 3 times with 400 μL of wash buffer (0.05% Tween 20 in PBS, pH 7.2-7.4). Add 300 μL of Reagent Diluent Buffer (1% Bovine serum albumin (BSA) in PBS, pH 7.2-7.4, 0.2 μm filtered) and let stand at room temperature for 1 hour, then 3 times with Wash buffer Washed. The prepared cell culture supernatant sample was diluted 50- to 100-fold with Reagent Diluent Buffer, added 100 μL to a 96-well plate, and allowed to stand at room temperature for 2 hours. After washing with Wash buffer three times, detection antibody diluted with Reagent Diluent 100 μL each was added, and allowed to stand at 4 ° C. for 18 hours. After washing with Wash buffer three times, 100 μL of Streptavidin-Horseadish peroxidase (HRP) diluted 50-fold with Reagent Diluent was added and allowed to stand at room temperature for 20 minutes. After washing three times with a wash buffer, 100 μL of Substrate Solution was added, and the mixture was allowed to stand at room temperature for 20 minutes in the dark. Next, Stop solution (2N H 2 SO 4 ) was added in 50 μL aliquots, the plate was gently stirred, and the optical density at 450 nm was measured. In addition, the optical density of 570 nm was measured as a correction value. The amount of PCSK9 protein produced was calculated from a calibration curve using purified PCSK9 protein attached to Kit. In addition, the data represent relative values when the control (culture supernatant sample in which only DMSO was added to the culture solution) was set to 1.
Figure JPOXMLDOC01-appb-T000125
　以上の薬理試験結果より、本発明の化合物、若しくはその塩、又はそれらの溶媒和物は、強力なＰＣＳＫ９ｍＲＮＡ発現抑制作用、及びＰＣＳＫ９タンパク産生抑制作用を有し、ＰＣＳＫ９ｍＲＮＡ発現、ＰＣＳＫ９タンパクが関与する疾患（例えば、脂質異常症（高脂血症）、動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、高ＬＤＬ血症、低ＨＤＬ血症、高コレステロール血症、高トリグリセリド血症、家族性高コレステロール血症、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧、癌、肥満、糖尿病、アルツハイマー病又はウイルス感染症等の治療又は予防剤の有効成分として好適に使用できることが明らかとなった。 From the above pharmacological test results, the compound of the present invention, or a salt thereof, or a solvate thereof has a strong PCSK9 mRNA expression inhibitory action and PCSK9 protein production inhibitory action, and a disease involving PCSK9 mRNA expression and PCSK9 protein. (For example, dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hyper-triglyceridemia, familial high Cholesterolemia, cardiovascular disorder, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cancer, obesity, diabetes, Alzheimer's disease or viral infection, etc. It became clear that it can be used suitably as an active ingredient of a therapeutic or prophylactic agent.
　本発明の一般式（I）で表される化合物は、ＰＣＳＫ９ｍＲＮＡ発現抑制作用、及びＰＣＳＫ９タンパク産生抑制作用及びＬＤＬ受容体量を増加する作用を有しており、ＬＤＬを低下させるための医薬の有効成分として使用できるほか、ＰＣＳＫ９ｍＲＮＡ発現抑制剤、ＰＣＳＫ９タンパク産生抑制剤、ＬＤＬ受容体量を増加する薬剤などの有効成分として好適に使用することができる。さらにはスタチン系薬剤におけるＬＤＬコレステロール低下作用を増強することができるので、スタチン系薬剤との組み合わせにより高いＬＤＬコレステロール低下作用を達成することができる。
  The compound represented by the general formula (I) of the present invention has a PCSK9 mRNA expression-inhibiting action, a PCSK9 protein production-inhibiting action, and an action to increase the amount of LDL receptor, and an effective pharmaceutical for reducing LDL Besides being usable as a component, it can be suitably used as an active ingredient such as a PCSK9 mRNA expression inhibitor, a PCSK9 protein production inhibitor, and a drug that increases the amount of LDL receptor. Furthermore, since the LDL cholesterol lowering action in the statin drugs can be enhanced, a high LDL cholesterol lowering action can be achieved by combining with the statin drugs.

Claims (9)

  1. 血中ＬＤＬを低下させるための医薬であって、次の一般式（I）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｒ１は、水素原子、ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルキルチオＣ１－６アルコキシ基、Ｃ１－６アルキルスルフィニルＣ１－６アルコキシ基、Ｃ１－６アルキルスルホニルＣ１－６アルコキシ基、置換基を有してもよいＣ６－１０アリールＣ１－６アルコキシ基、水酸基、Ｃ１－６アルキルアミノ基、ジＣ１－６アルキルアミノ基、Ｃ１－６アルキルチオＣ１－６アルキルアミノ基、Ｃ１－６アルキルスルフィニルＣ１－６アルキルアミノ基、Ｃ１－６アルキルスルホニルＣ１－６アルキルアミノ基、Ｃ６－１０アリールアミノ基、環構成原子にヘテロ原子を有してもよい環状アミノ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルキルアミノ基、ヒドロキシＣ１－６アルコキシ基、ヒドロキシＣ１－６アルキルアミノ基、Ｃ１－６アシルアミノ基、Ｃ１－６アルキルスルホニルアミノ基、Ｃ１－６アルコキシカルボニルＣ１－６アルコキシ基、カルボキシＣ１－６アルコキシ基、アミノＣ１－６アルコキシ基、Ｃ１－６アルキルアミノＣ１－６アルコキシ基、ジＣ１－６アルキルアミノＣ１－６アルコキシ基、フェニルチオＣ１－６アルコキシ基、フェニルスルフィニルＣ１－６アルコキシ基、フェニルスルホニルＣ１－６アルコキシ基、及びフェノキシＣ１－６アルコキシ基を示し、
    Ｒ２、及びＲ３は、それぞれ同一又は異なって、水素原子、Ｃ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、Ｃ２－６アルケニル基、置換基を有してもよいＣ３－８シクロアルキルＣ１－６アルキル基、Ｃ６－１０アリール基、置換基を有してもよいＣ６－１０アリールＣ１－６アルキル基、若しくはＣ３－８シクロアルキル基を示すか、又はＲ２、及びＲ３が一緒になって隣接する窒素原子とともに置換基を有してもよく環構成原子にヘテロ原子を有してもよい環状アミノ基を形成してもよく、
    ＲはＣ１－６アルキル基、カルボキシＣ１－６アルキル基、Ｃ１－６アルコキシカルボニルＣ１－６アルキル基、置換基を有してもよいアミノＣ１－６アルキル基、置換基を有してもよいカルバモイルＣ１－６アルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基または次式（i）：
    Figure JPOXMLDOC01-appb-C000002
     （ここでＲ４、Ｒ５、Ｒ６、Ｒ７、及びＲ８は、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、水酸基、シアノ基、ニトロ基、Ｃ１－６アルキルチオ基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、ハロＣ１－６アルキルスルホニルアミノ基、Ｃ６－１０アリールスルホニルアミノ基、置換基を有してもよいアミノ基、カルボキシル基、Ｃ１－６アルキルカルボニル基、又はＣ１－６アルコキシカルボニル基を示し、
    Ｒ９は、水素原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ３－８シクロアルキル基、又はＣ３－８シクロアルキルＣ１－６アルキル基を示す）を示し、
    式（I）中、
    Figure JPOXMLDOC01-appb-C000003
     は、次式（ii）：
    Figure JPOXMLDOC01-appb-C000004
     （ここでＲ１０、Ｒ１１、Ｒ１２、及びＲ１３は、それぞれ同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、水酸基、シアノ基、ニトロ基、Ｃ１－６アルキルチオ基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ１－６アルキルスルホニルアミノ基、ハロＣ１－６アルキルスルホニルアミノ基、Ｃ６－１０アリールスルホニルアミノ基、置換基を有してもよいアミノ基、カルボキシル基、Ｃ１－６アルキルカルボニル基、又はＣ１－６アルコキシカルボニル基を示す）
    または次式（iii）：
    Figure JPOXMLDOC01-appb-C000005
     （ここでＲ１４及びＲ１５は、同一又は異なって、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－６アルコキシ基、水酸基、シアノ基、ニトロ基、Ｃ１－６アルキルチオ基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、スルホンアミド基、置換基を有してもよいアミノ基、カルボキシル基、Ｃ１－６アルキルカルボニル基、又はＣ１－６アルコキシカルボニル基を示し、
    Figure JPOXMLDOC01-appb-C000006
     は、環構成原子が６～１０個であり、環構成原子の少なくとも一つが窒素原子である単環性又は二環性の複素環を示す）を示し、さらに一般式（I）は個々の鏡像異性体、及びその混合物の両方を示す。ただし、２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸（II）
    Figure JPOXMLDOC01-appb-C000007
     の個々の鏡像異性体、及びその混合物を除く。）
    で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。     A medicament for lowering blood LDL, which has the following general formula (I):
    Figure JPOXMLDOC01-appb-C000001
     Wherein R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkylthio C 1-6 alkoxy group, a C 1-6 alkylsulfinyl C 1-6 alkoxy group, a C 1-6 An alkylsulfonyl C 1-6 alkoxy group, an optionally substituted C 6-10 aryl C 1-6 alkoxy group, a hydroxyl group, a C 1-6 alkylamino group, a di C 1-6 alkylamino group, C 1 -6 alkylthio C 1-6 alkylamino group, C 1-6 alkylsulfinyl C 1-6 alkylamino group, C 1-6 alkylsulfonyl C 1-6 alkylamino group, C 6-10 arylamino group, ring atom the cyclic amino group which may have a hetero atom, C 1-6 alkoxy C 1-6 alkoxy group, C 1-6 alkoxy-C 1-6 alkylamino group, hydroxy C -6 alkoxy, hydroxy-C 1-6 alkylamino group, C 1-6 acylamino group, C 1-6 alkylsulfonylamino group, C 1-6 alkoxycarbonyl C 1-6 alkoxy group, a carboxy C 1-6 alkoxy group Amino C 1-6 alkoxy group, C 1-6 alkylamino C 1-6 alkoxy group, diC 1-6 alkylamino C 1-6 alkoxy group, phenylthio C 1-6 alkoxy group, phenylsulfinyl C 1-6 An alkoxy group, a phenylsulfonyl C 1-6 alkoxy group, and a phenoxy C 1-6 alkoxy group;
    R 2 and R 3 are the same or different and each has a hydrogen atom, a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, or a substituent. An optionally substituted amino C 1-6 alkyl group, an optionally substituted carbamoyl C 1-6 alkyl group, a C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl C 1 Represents a -6 alkyl group, a C 6-10 aryl group, an optionally substituted C 6-10 aryl C 1-6 alkyl group, or a C 3-8 cycloalkyl group, or R 2 and R 3 may form a cyclic amino group which may have a substituent together with the adjacent nitrogen atom or may have a hetero atom in the ring constituent atom,
    R is a C 1-6 alkyl group, a carboxy C 1-6 alkyl group, a C 1-6 alkoxycarbonyl C 1-6 alkyl group, an amino C 1-6 alkyl group which may have a substituent, or a substituent. An optionally substituted carbamoyl C 1-6 alkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group or the following formula (i):
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R 4 , R 5 , R 6 , R 7 , and R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1- 6 alkoxy, halo C 1-6 alkoxy group, a hydroxyl group, a cyano group, a nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino Group, halo C 1-6 alkylsulfonylamino group, C 6-10 arylsulfonylamino group, optionally substituted amino group, carboxyl group, C 1-6 alkylcarbonyl group, or C 1-6 alkoxycarbonyl Group,
    R 9 represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl C 1-6 alkyl group).
    In formula (I),
    Figure JPOXMLDOC01-appb-C000003
     Is the following formula (ii):
    Figure JPOXMLDOC01-appb-C000004
     (Wherein R 10 , R 11 , R 12 and R 13 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl group. C 1-6 alkyl group, halo C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group, hydroxyl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, C 6-10 arylsulfonylamino group And an optionally substituted amino group, carboxyl group, C 1-6 alkylcarbonyl group, or C 1-6 alkoxycarbonyl group)
    Or the following formula (iii):
    Figure JPOXMLDOC01-appb-C000005
     Wherein R 14 and R 15 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group, a halo C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkoxy group, hydroxyl group, cyano group, nitro group, C 1-6 alkylthio group, C A 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, a sulfonamide group, an optionally substituted amino group, a carboxyl group, a C 1-6 alkylcarbonyl group, or a C 1-6 alkoxycarbonyl group Show
    Figure JPOXMLDOC01-appb-C000006
     Represents a monocyclic or bicyclic heterocyclic ring having 6 to 10 ring atoms and at least one of the ring atoms is a nitrogen atom), and the general formula (I) is an individual mirror image. Both isomers and mixtures thereof are shown. However, 2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine-2- Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid (II)
    Figure JPOXMLDOC01-appb-C000007
     Individual enantiomers, and mixtures thereof. )
    Or a salt thereof, or a solvate thereof as an active ingredient.
  2. 一般式（I）で表される化合物が、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メトキシベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メトキシベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－３，５－ジフルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－３，５－ジフルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メチルベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－メチルベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－フルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－フルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－メトキシベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－メトキシベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－クロロ－６－［（シクロペンチルメチル）（エチル）アミノ］－３－メチルベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－クロロ－６－［（シクロペンチルメチル）（エチル）アミノ］－３－メチルベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４，５－ジフルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－４，５－ジフルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－クロロ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－クロロ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－フルオロベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－フルオロベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛４－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛５－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛５－ブロモ－２－［（シクロペンチルメチル）（エチル）アミノ］ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ３－［１－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）エチル］－５－（トリフルオロメチル）ベンゾニトリル、
    ３－［１－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）エチル］－５－（トリフルオロメチル）ベンゾニトリル、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］－Ｎ－［２－ピペリジノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［２－ピペリジノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］－Ｎ－［２－モルホリノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［２－モルホリノ－５－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（４－メチルピペリジノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（４－メチルピペリジノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（cis－２，６－ジメチルモルホリノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（cis－２，６－ジメチルモルホリノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    Ｎ－｛２－［ビス（シクロプロピルメチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛２－［ビス（シクロプロピルメチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（ヒドロキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
    ２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－メトキシピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－ヒドロキシピリミジン－２－アミン、
    ４－（｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝）アミノ］ピリミジン－５－イル｝オキシ）酪酸エチル、
    ４－（｛２－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝）アミノ］ピリミジン－５－イル｝オキシ）酪酸、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシキノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メトキシキノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－（トリフルオロメチル）キノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－（トリフルオロメチル）キノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メチルキノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチル－６－メチルキノリン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－メチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－メチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－エチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－６－エチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５，６－ジメチルピリジン－３－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛２－［（シクロペンチルメチル）（エチル）アミノ］－５，６－ジメチルピリジン－３－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
    ３－［（｛１－［３，５－ビス（トリフルオロメチル）フェニル］プロピル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－Ｎ－（シクロペンチルメチル）－Ｎ－エチルキノリン－２－アミン、
    ３－｛１－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］エチル｝－５－（トリフルオロメチル）ベンゾニトリル、
    ３－｛１－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］エチル｝－５－（トリフルオロメチル）ベンゾニトリル、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］ピラジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］ピラジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［３－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－ベンジル－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリル、
    ３－［（｛２－［［３－シアノ－５－（トリフルオロメチル）ベンジル］（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）アミノ］ピリミジン－５－イル｝オキシ）メチル］－５－（トリフルオロメチル）ベンゾニトリル、
    ３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリル、
    ３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝－５－（トリフルオロメチル）ベンゾニトリル、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
    ３－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
    Ｎ－［２，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－［２，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジフルオロベンジル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジクロロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジクロロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメトキシベンジル）－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［３－（トリフルオロメトキシ）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメチルベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，５－ジメチルベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，４－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（３，４－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，５－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，５－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，６－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，６－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［（２，３－ジフルオロベンジル）オキシ］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－Ｎ－（２，３－ジフルオロベンジル）－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    ５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリル、
    ５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリル、
    ５－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝イソフタロニトリル、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルフィニル）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルスルホニル）エトキシ］－Ｎ－［４－（トリフルオロメチル）ベンジル］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－５－ブロモ－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－モルホリノピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－ピペリジノピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛［６－メトキシ－３－（ピロリジン－１－イル）ピリジン－２－イル］メチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ６－［（［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－５－［（シクロペンチルメチル）（エチル）アミノ］ピリジン－２－オール、
    ４－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
    ４－｛［（｛３－［（シクロペンチルメチル）（エチル）アミノ］－６－メトキシピリジン－２－イル｝メチル）｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ］メチル｝ベンゾニトリル、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－（｛３－［エチル（４－メトキシベンジル）アミノ］－６－メトキシピリジン－２－イル｝メチル）－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
    ２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    ２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［エチル（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（エチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチル、
    ４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸、
    ２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチル、
    ２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸、
    ３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチル、
    ３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸、
    ３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸メチル、
    ３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸、
    ３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］プロピオン酸メチル、
    ５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
    ４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
    ３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
    ４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
    ５－｛［ベンジル（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（４－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸イソプロピル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸メチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ５－｛［（３，５－ジフルオロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（２－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（３－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（２－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（３－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（４－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（２－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（４－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（３－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（４－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
    ５－｛［（シクロプロピルメチル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－｛ｔｒａｎｓ－４－［（エチル｛２－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチル、
    ５－｛［（５－エトキシピリミジン－２－イル）（３－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、又は
    ３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
    である請求項１に記載の医薬。     The compound represented by the general formula (I) is
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidine -2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylsulfonyl) ethoxy] Pyrimidine-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
    3- [1-({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) ethyl] -5- (trifluoromethyl) benzonitrile,
    3- [1-({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) ethyl ] -5- (trifluoromethyl) benzonitrile,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine- 2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidine -2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine- 2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidine -2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino ) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    N- {2- [bis (cyclopropylmethyl) amino] -5- (trifluoromethyl) benzyl} -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
    N- {2- [bis (cyclopropylmethyl) amino] -5- (trifluoromethyl) benzyl} -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4 -(Trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    (S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
    (S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid,
    2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
    2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5-methoxy Pyrimidine-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5-hydroxy Pyrimidine-2-amine,
    4-({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl}) Amino] pyrimidin-5-yl} oxy) ethyl butyrate,
    4-({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl}) Amino] pyrimidin-5-yl} oxy) butyric acid,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    5-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
    5-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethylquinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethylquinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-6-methoxyquinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-6-methoxyquinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-6- (trifluoromethyl) quinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-6- (trifluoromethyl) quinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethyl-6-methylquinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethyl-6-methylquinolin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl ) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl ) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl) -N-ethylquinolin-2-amine,
    3-[({1- [3,5-Bis (trifluoromethyl) phenyl] propyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -N- (cyclopentylmethyl ) -N-ethylquinolin-2-amine,
    3- {1-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) {5- [2 -(Methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile,
    3- {1-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) {5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
    N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) Benzyl] pyrimidin-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [3- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [3- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
    N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
    N-benzyl-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
    3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } -5- (trifluoromethyl) benzonitrile,
    3-[({2-[[3-Cyano-5- (trifluoromethyl) benzyl] ({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) amino] Pyrimidin-5-yl} oxy) methyl] -5- (trifluoromethyl) benzonitrile,
    3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} -5- (trifluoromethyl) benzonitrile,
    3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Methyl} -5- (trifluoromethyl) benzonitrile,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylsulfinyl) ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Benzonitrile,
    3-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} benzonitrile,
    N- [2,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    N- [2,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylsulfinyl) ethoxy] pyrimidin-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-difluorobenzyl) -5- [2- (methylsulfonyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dichlorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethoxybenzyl) -5- [2- (methylsulfonyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethoxy) Benzyl] pyrimidin-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [3- (trifluoromethoxy ) Benzyl] pyrimidin-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [3- (trifluoromethoxy ) Benzyl] pyrimidin-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,5-dimethylbenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (3,4-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,5-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,5-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,6-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylthio) ethoxy] Pyrimidine-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5-[(2,3-difluorobenzyl ) Oxy] pyrimidin-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -N- (2,3-difluorobenzyl) -5- [2- (methylsulfinyl) ethoxy ] Pyrimidine-2-amine,
    5-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Isophthalonitrile,
    5-{[({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} isophthalonitrile,
    5-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Methyl} isophthalonitrile,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] -N- [4- (trifluoromethyl) Benzyl] pyrimidin-2-amine,
    N-({3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfinyl) ethoxy] -N- [4- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
    N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylsulfonyl) ethoxy] -N- [4- (trifluoromethyl ) Benzyl] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -5-bromo-N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) pyrimidine- 2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5-morpholinopyrimidine- 2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5-piperidino Pyrimidine-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylsulfinyl) ) Ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
    6-[([3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -5-[(cyclopentylmethyl) (ethyl) Amino] pyridin-2-ol,
    4-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] methyl } Benzonitrile,
    4-{[({{3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) {5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino] Methyl} benzonitrile,
    N- [3,5-bis (trifluoromethyl) benzyl] -N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
    2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
    2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino} methyl)- 4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
    N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 4-b] pyridin-6-amine,
    N- (cyclopentylmethyl) -N-ethyl-5-{[ethyl (5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (ethyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) ethyl butanoate,
    4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) butanoic acid,
    2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Yl} amino) methyl acetate,
    2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Il} amino) acetic acid,
    3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] methyl propionate,
    3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] propionic acid,
    3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} methyl propionate,
    3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} propionic acid,
    3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl propionate,
    5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
    3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
    4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
    3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
    4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
    5-{[benzyl (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
    5-{[(5-Ethoxypyrimidin-2-yl) (4-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) isopropyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) methyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    5-{[(3,5-difluorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    5-{[(5-Ethoxypyrimidin-2-yl) (2-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (3-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(2-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(3-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(4-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (2-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (4-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (3-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (4-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile,
    5-{[(Cyclopropylmethyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
    2- {trans-4-[(ethyl {2-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
    5-{[(5-Ethoxypyrimidin-2-yl) (3-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    2-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile or 3-{[{[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) Amino] methyl} benzonitrile,
    The medicament according to claim 1, wherein
  3. 請求項１又は２に記載の一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むＰＣＳＫ９ｍＲＮＡ発現抑制剤。 A PCSK9 mRNA expression inhibitor comprising the compound represented by the general formula (I) according to claim 1 or 2 or a salt thereof, or a solvate thereof as an active ingredient.
  4. 請求項１又は２に記載の一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むＰＣＳＫ９タンパク産生抑制剤。 A PCSK9 protein production inhibitor comprising the compound represented by formula (I) according to claim 1 or 2, or a salt thereof, or a solvate thereof as an active ingredient.
  5. 請求項１又は２に記載の一般式（I）で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むＬＤＬ受容体量の増加剤。 An agent for increasing the amount of LDL receptor comprising, as an active ingredient, the compound represented by formula (I) according to claim 1 or 2, or a salt thereof, or a solvate thereof.
  6. 高ＬＤＬ血症の予防及び／又は治療に用いる請求項１又は２に記載の医薬。 The medicament according to claim 1 or 2, which is used for prevention and / or treatment of hyper-LDLemia.
  7. スタチン系薬剤によるＬＤＬコレステロール低下作用を増強するための医薬であって、請求項１又は２に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。 A medicament for enhancing LDL cholesterol lowering action by a statin drug, comprising the compound represented by the general formula (I) according to claim 1 or 2, or a salt thereof, or a solvate thereof as an active ingredient Containing as a medicine.
  8. 動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧、癌、肥満、糖尿病、アルツハイマー病、ウイルス感染症、炎症、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染症、乾癬又は黄斑変性の予防及び／又は治療のための医薬であって、請求項１又は２に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。 Arteriosclerosis, atherosclerosis, peripheral vascular disease, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cancer, obesity, A medicament for the prevention and / or treatment of diabetes, Alzheimer's disease, viral infection, inflammation, osteoporosis, prostatic hypertrophy, glomerular disease, parasitic infection, psoriasis or macular degeneration, according to claim 1 or 2. Or a salt thereof or a solvate thereof as an active ingredient.
  9. ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（ジアリルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－［２－アミノ－５－（トリフルオロメチル）ベンジル］－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－｛２－［エチル（４－メトキシベンジル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    （Ｓ）－Ｎ－｛１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝－Ｎ－［２－（エチルアミノ）－５－（トリフルオロメチル）ベンジル］－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（４－メトキシベンジル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
    ２－｛ｔｒａｎｓ－４－［（｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝［５－（２－フェノキシエトキシ）ピリミジン－２－イル］アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－メトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
    ２－［ｔｒａｎｓ－４－（｛［２－｛［｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－６－クロロ－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルチオ）エトキシ］ピリミジン－２－アミン、
    Ｎ－［３，５－ビス（トリフルオロメチル）ベンジル］－Ｎ－｛２－［（シクロペンチルメチル）（エチル）アミノ］－５－（トリフルオロメチル）ベンジル｝－５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－アミン、
    ２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸エチル、
    ２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    ２－［ｔｒａｎｓ－４－（｛［２－（｛［３，５－ビス（トリフルオロメチル）ベンジル］｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ｝メチル）－４－（トリフルオロメチル）フェニル］（エチル）アミノ｝メチル）シクロヘキシル］酢酸、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［（５－メトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－Ｎ－エチル－５－｛［エチル（５－メトキシピリミジン－２－イル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    Ｎ－（シクロペンチルメチル）－５－｛［（５－エトキシピリミジン－２－イル）（エチル）アミノ］メチル｝－Ｎ－エチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸エチル、
    ２－（ｔｒａｎｓ－４－｛［｛１，３－ジメチル－５－［（メチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸エチル、
    ４－（｛２－［（｛６－［（シクロペンチルメチル）（エチル）アミノ］－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル｝メチル）（メチル）アミノ］ピリミジン－５－イル｝オキシ）ブタン酸、
    ２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸メチル、
    ２－（｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）酢酸、
    ３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸メチル、
    ３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）（メチル）アミノ］プロピオン酸、
    ３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸メチル、
    ３－｛［５－（｛［ビス（トリフルオロメチル）ベンジル］（５－エトキシピリミジン－２－イル）アミノ｝メチル）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル］（メチル）アミノ｝プロピオン酸、
    ３－［（５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－イル）アミノ］プロピオン酸メチル、
    ５－｛［（５－エトキシピリミジン－２－イル）（メチル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
    ４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸メチル、
    ３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
    ４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝安息香酸、
    ５－｛[ベンジル（５－エトキシピリミジン－２－イル）アミノ]メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛[（５－エトキシピリミジン－２－イル）（４－フルオロベンジル）アミノ]メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸イソプロピル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（メチルスルホニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸メチル、
    ２－（ｔｒａｎｓ－４－｛［｛２－［（｛（Ｓ）－１－［３，５－ビス（トリフルオロメチル）フェニル］エチル｝｛５－［２－（フェニルスルフィニル）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝（エチル）アミノ］メチル｝シクロヘキシル）酢酸、
    ５－｛［（３，５－ジフルオロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（２－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（３－フルオロベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（２－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（３－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（４－クロロベンジル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（２－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（４－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（３－メチルベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ５－｛［（５－エトキシピリミジン－２－イル）（４－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ４－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
    ５－｛［（シクロプロピルメチル）（５－エトキシピリミジン－２－イル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－｛ｔｒａｎｓ－４－［（エチル｛２－［（エチル｛５－［２－（メチルチオ）エトキシ］ピリミジン－２－イル｝アミノ）メチル］－４－（トリフルオロメチル）フェニル｝アミノ）メチル］シクロヘキシル｝酢酸エチル、
    ５－｛［（５－エトキシピリミジン－２－イル）（３－メトキシベンジル）アミノ］メチル｝－Ｎ，Ｎ－ジエチル－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－６－アミン、
    ２－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、及び
    ３－｛［｛［６－（ジエチルアミノ）－１，３－ジメチル－１Ｈ－ピラゾロ［３，４－ｂ］ピリジン－５－イル］メチル｝（５－エトキシピリミジン－２－イル）アミノ］メチル｝ベンゾニトリル、
    からなる群から選ばれる化合物、若しくはその塩、又はそれらの溶媒和物。     2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    (S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
    (S) -N- [2-amino-5- (trifluoromethyl) benzyl] -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
    (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid,
    2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
    2- {trans-4-[({2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (2-phenoxyethoxy) pyrimidin-2-yl) ] Amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
    2- [trans-4-({[2-{[{(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} (5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2 -Yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -6-chloro-4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
    N- [3,5-bis (trifluoromethyl) benzyl] -N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
    2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
    2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino} methyl) -4 -(Trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    2- [trans-4-({[2-({[3,5-bis (trifluoromethyl) benzyl] {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino} methyl)- 4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetic acid,
    N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
    N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    N- (cyclopentylmethyl) -N-ethyl-5-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1,3-dimethyl-1H-pyrazolo [3 4-b] pyridin-6-amine,
    N- (cyclopentylmethyl) -N-ethyl-5-{[ethyl (5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) (ethyl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
    2- (trans-4-{[{1,3-dimethyl-5-[(methyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) ethyl butanoate,
    4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) (methyl) amino ] Pyrimidin-5-yl} oxy) butanoic acid,
    2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Yl} amino) methyl acetate,
    2-({[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Il} amino) acetic acid,
    3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] methyl propionate,
    3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Amino] propionic acid,
    3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} methyl propionate,
    3-{[5-({[Bis (trifluoromethyl) benzyl] (5-ethoxypyrimidin-2-yl) amino} methyl) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- 6-yl] (methyl) amino} propionic acid,
    3-[(5-{[(5-Ethoxypyrimidin-2-yl) (methyl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl propionate,
    5-{[(5-ethoxypyrimidin-2-yl) (methyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
    3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
    4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Methyl benzoate,
    3-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
    4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} benzoic acid,
    5-{[benzyl (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
    5-{[(5-Ethoxypyrimidin-2-yl) (4-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) isopropyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) methyl acetate,
    2- (trans-4-{[{2-[({(S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (phenylsulfinyl) ethoxy] pyrimidine- 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino] methyl} cyclohexyl) acetic acid,
    5-{[(3,5-difluorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine -6-amine,
    5-{[(5-Ethoxypyrimidin-2-yl) (2-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (3-fluorobenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(2-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(3-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(4-Chlorobenzyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (2-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (4-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (3-methylbenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    5-{[(5-Ethoxypyrimidin-2-yl) (4-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    4-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile,
    5-{[(Cyclopropylmethyl) (5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
    2- {trans-4-[(ethyl {2-[(ethyl {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
    5-{[(5-Ethoxypyrimidin-2-yl) (3-methoxybenzyl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6 -Amines,
    2-{[{[6- (Diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) amino] methyl} Benzonitrile and 3-{[{[6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} (5-ethoxypyrimidin-2-yl) Amino] methyl} benzonitrile,
    A compound selected from the group consisting of: or a salt thereof, or a solvate thereof.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3225240A4 (en) * 2014-11-28 2018-06-06 Kowa Company, Ltd. Medicine
WO2018189705A1 (en) 2017-04-13 2018-10-18 Cadila Healthcare Limited Novel peptide based pcsk9 vaccine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201823222A (en) * 2016-12-23 2018-07-01 財團法人生物技術開發中心 Compound, pharmaceutical composition and use thereof

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004323504A (en) * 2002-08-30 2004-11-18 Japan Tobacco Inc Dibenzylamine compound and its pharmaceutical use
WO2006098394A1 (en) * 2005-03-14 2006-09-21 Japan Tobacco Inc. Method for inhibiting lipid absorption and lipid absorption inhibitor
JP2007506646A (en) * 2003-09-26 2007-03-22 日本たばこ産業株式会社 Method for inhibiting remnant lipoprotein production
WO2007088996A1 (en) * 2006-01-31 2007-08-09 Mitsubishi Tanabe Pharma Corporation Trisubstituted amine compounds as inhibitors of -cholesteryl ester transfer protein cetp
WO2007088999A1 (en) * 2006-01-31 2007-08-09 Mitsubishi Tanabe Pharma Corporation Trisubstituted amine compound
WO2008018529A1 (en) * 2006-08-11 2008-02-14 Kowa Company, Ltd. Novel pyrimidine compound having benzyl(pyridylmethyl)amine structure and pharmaceutical comprising the compound
JP2008528447A (en) * 2004-12-31 2008-07-31 レディ ユーエス セラピューティックス， インコーポレイテッド Novel benzylamine derivatives as CETP inhibitors
WO2008111604A1 (en) * 2007-03-13 2008-09-18 Kowa Company, Ltd. Novel pyrimidine compound having benzyl(heterocyclicmethyl)amine structure and pharmaceutical product containing the same
WO2008129951A1 (en) * 2007-04-13 2008-10-30 Kowa Company, Ltd. Novel pyrimidine compound having dibenzylamine structure, and medicine comprising the compound
JP2009051827A (en) * 2007-07-30 2009-03-12 Mitsubishi Tanabe Pharma Corp Pharmaceutical composition
JP2009051828A (en) * 2007-07-30 2009-03-12 Mitsubishi Tanabe Pharma Corp Pharmaceutical composition
JP2009522224A (en) * 2005-12-29 2009-06-11 ノバルティス アクチエンゲゼルシャフト Pyridinylamine derivatives as inhibitors of cholesteryl ester transfer protein (CETP)
JP2009536172A (en) * 2006-05-10 2009-10-08 ノバルティス アクチエンゲゼルシャフト Bicyclic derivatives as CETP inhibitors
JP2010077116A (en) * 2008-08-25 2010-04-08 Kowa Co New pyrimidine compound having dibenzylamine structure and medicine containing the same
WO2012046681A1 (en) * 2010-10-04 2012-04-12 興和株式会社 Agent for inhibiting expression of lipid metabolism related mrna
WO2013008164A2 (en) * 2011-07-08 2013-01-17 Novartis Ag Method of treating atherosclerosis in high triglyceride subjects
WO2013024358A2 (en) * 2011-08-18 2013-02-21 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (cetp) inhibitors
WO2013046045A1 (en) * 2011-09-27 2013-04-04 Dr. Reddy's Laboratories, Ltd. 5 - benzylaminomethyl - 6 - aminopyrazolo [3, 4 -b] pyridine derivatives as cholesteryl ester -transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004323504A (en) * 2002-08-30 2004-11-18 Japan Tobacco Inc Dibenzylamine compound and its pharmaceutical use
JP2007506646A (en) * 2003-09-26 2007-03-22 日本たばこ産業株式会社 Method for inhibiting remnant lipoprotein production
JP2008528447A (en) * 2004-12-31 2008-07-31 レディ ユーエス セラピューティックス， インコーポレイテッド Novel benzylamine derivatives as CETP inhibitors
WO2006098394A1 (en) * 2005-03-14 2006-09-21 Japan Tobacco Inc. Method for inhibiting lipid absorption and lipid absorption inhibitor
JP2009522224A (en) * 2005-12-29 2009-06-11 ノバルティス アクチエンゲゼルシャフト Pyridinylamine derivatives as inhibitors of cholesteryl ester transfer protein (CETP)
WO2007088996A1 (en) * 2006-01-31 2007-08-09 Mitsubishi Tanabe Pharma Corporation Trisubstituted amine compounds as inhibitors of -cholesteryl ester transfer protein cetp
WO2007088999A1 (en) * 2006-01-31 2007-08-09 Mitsubishi Tanabe Pharma Corporation Trisubstituted amine compound
JP2009524577A (en) * 2006-01-31 2009-07-02 田辺三菱製薬株式会社 Trisubstituted amine compounds as cholesteryl ester transport protein inhibitors
JP2009524579A (en) * 2006-01-31 2009-07-02 田辺三菱製薬株式会社 Trisubstituted amine compounds
JP2009536172A (en) * 2006-05-10 2009-10-08 ノバルティス アクチエンゲゼルシャフト Bicyclic derivatives as CETP inhibitors
WO2008018529A1 (en) * 2006-08-11 2008-02-14 Kowa Company, Ltd. Novel pyrimidine compound having benzyl(pyridylmethyl)amine structure and pharmaceutical comprising the compound
WO2008111604A1 (en) * 2007-03-13 2008-09-18 Kowa Company, Ltd. Novel pyrimidine compound having benzyl(heterocyclicmethyl)amine structure and pharmaceutical product containing the same
WO2008129951A1 (en) * 2007-04-13 2008-10-30 Kowa Company, Ltd. Novel pyrimidine compound having dibenzylamine structure, and medicine comprising the compound
JP2009051828A (en) * 2007-07-30 2009-03-12 Mitsubishi Tanabe Pharma Corp Pharmaceutical composition
JP2009051827A (en) * 2007-07-30 2009-03-12 Mitsubishi Tanabe Pharma Corp Pharmaceutical composition
JP2010077116A (en) * 2008-08-25 2010-04-08 Kowa Co New pyrimidine compound having dibenzylamine structure and medicine containing the same
WO2012046681A1 (en) * 2010-10-04 2012-04-12 興和株式会社 Agent for inhibiting expression of lipid metabolism related mrna
WO2013008164A2 (en) * 2011-07-08 2013-01-17 Novartis Ag Method of treating atherosclerosis in high triglyceride subjects
WO2013024358A2 (en) * 2011-08-18 2013-02-21 Dr. Reddy's Laboratories Ltd. Substituted heterocyclic amine compounds as cholestryl ester-transfer protein (cetp) inhibitors
WO2013046045A1 (en) * 2011-09-27 2013-04-04 Dr. Reddy's Laboratories, Ltd. 5 - benzylaminomethyl - 6 - aminopyrazolo [3, 4 -b] pyridine derivatives as cholesteryl ester -transfer protein (cetp) inhibitors useful for the treatment of atherosclerosis

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3225240A4 (en) * 2014-11-28 2018-06-06 Kowa Company, Ltd. Medicine
WO2018189705A1 (en) 2017-04-13 2018-10-18 Cadila Healthcare Limited Novel peptide based pcsk9 vaccine

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