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WO2014017569A1 - Produit pharmaceutique destiné à faire baisser le taux de cholestérol ldl sanguin - Google Patents

Produit pharmaceutique destiné à faire baisser le taux de cholestérol ldl sanguin 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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Prior art keywords
amino
methyl
ethyl
trifluoromethyl
ethoxy
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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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Kowa Co Ltd
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Kowa Co Ltd
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    • 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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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • 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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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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

La présente invention concerne un produit pharmaceutique destiné à faire baisser le taux de cholestérol LDL sanguin. Ledit produit pharmaceutique contient un composé représenté par la formule (I) en tant que principe actif, ledit composé ayant pour effet d'inhiber l'expression de l'ARNm de PCSK9, de faire baisser le taux de protéine PCSK9 et d'augmenter la quantité de récepteurs des LDL. (Dans la formule (I), R1 représente un atome d'hydrogène, un groupe hydroxyle, un groupe alcoxyle en C1 à C6 ou équivalent ; R représente un groupe alkyle en C1 à C6 ou équivalent ; la structure cyclique Q représente un groupe phényle ou un noyau hétérocyclique monocyclique ou bicyclique ; et chacun des R2 et R3 représente un atome d'hydrogène, un groupe alkyle en C1 à C6, un groupe alcényle en C2 à C6, un groupe cycloalkyle en C3 à C8 alkyle en C1 à C6 ou équivalent.)
PCT/JP2013/070128 2012-07-26 2013-07-25 Produit pharmaceutique destiné à faire baisser le taux de cholestérol ldl sanguin Ceased WO2014017569A1 (fr)

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EP3225240A4 (fr) * 2014-11-28 2018-06-06 Kowa Company, Ltd. Médicament
WO2018189705A1 (fr) 2017-04-13 2018-10-18 Cadila Healthcare Limited Vaccin pcsk9 à base de nouveaux peptides

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Publication number Priority date Publication date Assignee Title
TW201823222A (zh) * 2016-12-23 2018-07-01 財團法人生物技術開發中心 化合物、醫藥組成物及其用途

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WO2013008164A2 (fr) * 2011-07-08 2013-01-17 Novartis Ag Méthode de traitement de l'athérosclérose chez des patients présentant un taux élevé de triglycérides
WO2013024358A2 (fr) * 2011-08-18 2013-02-21 Dr. Reddy's Laboratories Ltd. Composés amines hétérocycliques substitués comme inhibiteurs de la protéine de transfert d'ester cholesterylique (cetp)
WO2013046045A1 (fr) * 2011-09-27 2013-04-04 Dr. Reddy's Laboratories, Ltd. Dérivés de 5 - benzylaminométhyl - 6 - aminopyrazolo [3, 4 -b] pyridine utiles comme inhibiteurs de la cholestéryl ester -transfer protéine (cetp) dans le traitement de l'athérosclérose

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3225240A4 (fr) * 2014-11-28 2018-06-06 Kowa Company, Ltd. Médicament
WO2018189705A1 (fr) 2017-04-13 2018-10-18 Cadila Healthcare Limited Vaccin pcsk9 à base de nouveaux peptides

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