WO2013137371A1 - Novel pyrimidine compound and medicine comprising same - Google Patents
Novel pyrimidine compound and medicine comprising same Download PDFInfo
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- WO2013137371A1 WO2013137371A1 PCT/JP2013/057119 JP2013057119W WO2013137371A1 WO 2013137371 A1 WO2013137371 A1 WO 2013137371A1 JP 2013057119 W JP2013057119 W JP 2013057119W WO 2013137371 A1 WO2013137371 A1 WO 2013137371A1
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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 production of 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 an antibody or an antisense oligonucleotide, inhibition of PCSK9 protein function by PCSK9 monoclonal antibody and suppression of PCSK9 protein production by RNA interference have been reported (Non-Patent Documents 5 to 7).
- Non-Patent Document 8 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
- PCSK9 protein function inhibitors or PCSK9 protein production inhibitors of low molecular weight compounds are hardly reported other than 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
- R 1 represents C 1-15 alkyl
- R 2 represents C 1-15 alkyl, cycloalkyl, phenyl, aralkyl, etc.
- R 3 represents C 1-6 alkyl, phenyl, aralkyl, etc.
- R 4 represents C 1-6 alkyl, phenyl, aralkyl and the like
- R 5 represents C 1-6 alkyl, phenyl, aralkyl and the like
- 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 is a hydrogen atom or the following formula (II):
- R 3 represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 3-8 cycloalkyl group
- W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms
- R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 ary
- R 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom)
- R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
- R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbon
- 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 for inhibiting the production of HMG-CoA reductase in a living body of a mammal including a human, wherein the general formula (I And a method comprising administering an effective amount of a compound represented by the above formula, or a salt thereof, or a solvate thereof to a mammal including a human; and HMG-CoA reductase mRNA in a mammal including a human; Diseases caused by the expression (eg inflammation, cancer, Alzheimer's disease, osteoporosis, enlarged prostate, glomerular disease, parasitic infection, viral infection, psoriasis, macular degeneration, etc.)
- R 1 is a hydrogen atom or the following formula (II):
- R 3 represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 3-8 cycloalkyl group
- W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms
- R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group
- R 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom)
- R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
- R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbon
- the compound represented by the general formula (I) of the present invention or a salt thereof, or a solvate thereof exhibits a strong expression inhibitory action on PCSK9 mRNA, as specifically disclosed in Examples described later. Since it shows suppression of PCSK9 protein production, it can be suitably used as an active ingredient of a prophylactic and / or therapeutic agent for diseases based on the production of PCSK9 protein, and is particularly preferably used as an active ingredient of a medicine that lowers blood LDL. be able to.
- C 1-6 alkyl “C 1-4 alkyl”, “halo C 1-6 alkyl”, “C 1-6 alkoxy”, “halo C 1-6 alkoxy”, “C 1 -6 alkylthio ",” C 1-6 alkylsulfinyl “,” C 1-6 alkylsulfonyl “,” C 1-6 alkylsulfonylamino ",” halo C 1-6 alkylsulfonylamino ",” C 1-6 alkyl “Carbonyl”, “C 1-6 alkoxycarbonyl”, “C 3-8 cycloalkyl C 1-6 alkyl”, “C 1-6 alkoxycarbonyl C 1-6 alkyl”, “C 6-10 aryl C 1-6” alkyl ",” C 1-6 alkylthio C 1-6 alkyl “,” C 1-6 alkylsulfinyl C 1-6 alkyl “,” C 1-6 alkylsulfonyl C 1-6 alkyl " "C
- C 1-6 alkyl include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2 -Methylbutyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl and the like.
- C 1-4 alkyl include, for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. And the like.
- C 2-6 alkenyl group refers to a C 2-6 linear or branched alkenyl group having a carbon-carbon double bond at any one or more positions on the alkyl chain.
- Specific examples of the “C 2-6 alkenyl group” include, for example, vinyl, allyl, 1-propenyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, buta -3-en-1-yl, but-1-en-2-yl, but-3-en-2-yl, penta-1-en-1-yl, penta-4-en-1-yl, penta -1-en-2-yl, penta-4-en-2-yl, 3-methyl-but-1-en-1-yl, hexa-1-en-1-yl group, hexa-5-ene- 1-yl and the like can be mentioned.
- examples of the “C 1-6 alkylthio” part in the “C 1-6 alkylthio”, “C 1-6 alkylthio C 1-6 alkyl” group include, for example, methylthio, ethylthio, n-propylthio, isopropylthio , N-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, 2-methylbutylthio, 1-ethylpropylthio, n-hexylthio, isohexylthio, 3- Methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbut
- C 1-6 alkylsulfinyl as the “C 1-6 alkylsulfinyl” section of the "C 1-6 alkylsulfinyl C 1-6 alkyl” group, for example, methylsulfinyl, ethylsulfinyl, n -Propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, 2-methylbutylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl
- C 1-6 alkylsulfonyl examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- haloalkyl includes linear or branched alkyl substituted with a chemically acceptable number of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). Accordingly, examples of “halo C 1-6 alkyl” include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, iodomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.
- halo C 1-6 alkoxy examples include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like. It is done.
- examples of the “C 1-6 alkoxy” moiety in the “C 1-6 alkoxy”, “halo C 1-6 alkoxy”, “C 1-6 alkoxycarbonyl” group include methoxy, ethoxy, n- Propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutyloxy, 1-ethylpropyloxy, n-hexyloxy , Isohexyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,1-dimethylbutyloxy, 1,2 -Dimethylbutyloxy, 1,3-dimethylbutyl Examples include oxy, 2,3-dimethyl
- C 6-10 arylsulfonylamino “C 6-10 aryl”, “C 6-10 aryl C 1-6 alkyl”, “C 6-10 arylthio C 1-6 alkyl”, “ C 6-10 arylsulfinyl C 1-6 alkyl ",” C 6-10 arylsulfonyl C 1-6 alkyl ",” “C 6-10 aryl in C 6-10 aryloxy C 1-6 alkyl” group "portion Examples thereof include phenyl, azulenyl, naphthyl and the like.
- C 3-8 cycloalkyl C 1-6 alkyl as the “C 3-8 cycloalkyl” section of the “C 3-8 cycloalkyl” group, having 3 to 8 carbon atoms, preferably 5 to 7 saturated cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- the “nitrogen-containing saturated heterocycle” is a saturated monocyclic 5- to 7-membered heterocycle containing at least one nitrogen atom.
- pyrrolidine imidazolidine, pyrazolidine, oxazolidine, thiazolidine , Piperidine, piperazine, morpholine, thiomorpholine, 2-oxopyrrolidine, 2-oxopiperidine, 4-oxopiperidine, or 2,6-dioxopiperidine ring.
- the “nitrogen-containing aromatic heterocycle” is an aromatic monocyclic 5- to 6-membered heterocycle containing at least one nitrogen atom, such as pyrrole, imidazole, pyrazole, triazole, Examples include oxazole, isoxazole, oxadiazole, thiazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine ring and the like.
- the C 1-6 alkyl group in R 3 is preferably a C 1-4 alkyl group, and more preferably a methyl group.
- W 1 , W 2 , W 3 , W 4 , W 5 indicate CR 4 , CR 5 , CR 6 , CR 7 , CR 8 respectively, but CR 4 , CR 5 , CR 6 , CR 7 , CR 0 to 2 of 8 may be replaced with nitrogen atoms.
- the C 1-6 alkyl group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 1-4 alkyl group, more preferably a methyl group or an ethyl group.
- the halo C 1-6 alkyl group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a halo C 1-4 alkyl group, more preferably a trifluoromethyl group.
- the C 1-6 alkoxy group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 1-4 alkoxy group, and more preferably a methoxy group.
- the C 6-10 aryl group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a phenyl group.
- R 4, R 5, R 6, R 7, "adjacent to each other in R 8 may have a benzene ring or a substituted group which may have a substituent together
- the nitrogen-containing aromatic heterocycle in the “nitrogen-containing aromatic heterocycle” is preferably a pyrazole ring.
- Examples of the substituent in the “benzene ring which may be adjacent to each other together or a nitrogen-containing aromatic heterocyclic ring which may have a substituent” may be a C 1-6 alkyl group, C 1- A 6 alkoxyl group and a halo C 1-6 alkyl group are preferable, and a methyl group, a methoxy group, and a trifluoromethyl group are more preferable.
- the C 1-6 alkyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 1-4 alkyl group, a methyl group, an ethyl group N-propyl group and n-butyl group are more preferable.
- the C 2-6 alkenyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 2-4 alkenyl group, more preferably an allyl group. .
- N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 , R 8 represents “C 3-8 cycloalkyl C 1-6 which may have a substituent.
- the C 3-8 cycloalkyl C 1-6 alkyl group in the “alkyl group” is preferably a C 3-6 cycloalkyl C 1-4 alkyl group, more preferably a cyclohexylmethyl group, a cyclopentylmethyl group, or a cyclopropylmethyl group.
- the substituent in the “optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group” is preferably a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a benzyloxycarbonylmethyl group, or a carboxymethyl group.
- the C 1-6 alkoxycarbonyl C 1-6 alkyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a methoxycarbonylethyl group.
- the carboxy C 1-6 alkyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a carboxyethyl group.
- the phenyl group is preferred as the C 6-10 aryl group in N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 , R 8 .
- N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 and R 8 may be “C 6-10 aryl C 1-6 optionally having substituent (s)”
- the C 6-10 aryl C 1-6 alkyl group in the “alkyl group” is preferably a phenyl C 1-4 alkyl group, more preferably a benzyl group.
- a methoxy group is preferable.
- the halogen atom in R 2 is preferably a chlorine atom.
- the C 1-6 alkyl group in OR 11 in R 2 is preferably a C 1-4 alkyl group, more preferably a methyl group or an ethyl group.
- the C 1-6 alkylthio C 1-6 alkyl group in OR 11 in R 2 is preferably a C 1-4 alkylthio C 1-4 alkyl group, and more preferably a methylthioethyl group.
- the C 1-6 alkylsulfinyl C 1-6 alkyl group in OR 11 in R 2 preferred is a C 1-4 alkylsulfinyl C 1-4 alkyl group, more preferably a methylsulfinyl ethyl .
- the C 1-6 alkylsulfonyl C 1-6 alkyl group in OR 11 in R 2 preferred is a C 1-4 alkylsulfonyl C 1-4 alkyl group, more preferably a methylsulfonyl ethyl group .
- the C 1-6 alkoxycarbonyl C 1-6 alkyl group in OR 11 in R 2 is preferably a C 1-4 alkoxycarbonyl C 1-4 alkyl group, more preferably an ethoxycarbonylpropyl group. .
- the carboxycarbonyl C 1-6 alkyl group in OR 11 in R 2 is preferably a carboxypropyl group.
- the C 6-10 arylthio C 1-6 alkyl group in OR 11 in R 2 is preferably a phenylthio C 1-6 alkyl group, more preferably a phenylthio C 1-4 alkyl group, An ethyl group is more preferable.
- the C 6-10 arylsulfonyl C 1-6 alkyl group in OR 11 in R 2 is preferably a phenylsulfonyl C 1-6 alkyl group, more preferably a phenylsulfonyl C 1-4 alkyl group.
- a phenylsulfonylethyl group is more preferred.
- the C 6-10 aryloxy C 1-6 alkyl group in OR 11 in R 2 is preferably a phenoxy C 1-6 alkyl group, more preferably a phenoxy C 1-4 alkyl group, An ethyl group is more preferable.
- 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 ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate and acetate.
- 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.
- 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.
- the compound (Ia) in which R 1 is a hydrogen atom and R 2 is OR 11 is described in a known patent document (WO 2008/018529 pamphlet) and the like. It can be manufactured by a method.
- Compound (V) can be produced by reacting 5-bromo-2-chloropyrimidine (III) with amine (IV) in a solvent or without a solvent. At that time, microwave irradiation may be performed.
- the solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination. it can.
- the reaction conditions vary depending on the amine to be used, but are preferably -20 ° C to 180 ° C for 1 minute to 24 hours, more preferably 0 ° C to 150 ° C for 5 minutes to 15 hours.
- Compound (VII) can be produced by reacting compound (V) with alcohol (VI) in a solvent in the presence of a base and a metal catalyst. At that time, microwave irradiation may be performed.
- the solvent is not particularly limited as long as it does not inhibit the reaction.
- tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, etc. may be used alone or in combination. Can do.
- Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metals such as metal lithium, metal sodium, and metal potassium; lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.
- Alkali metal carbonates such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-amyloxy sodium, t-amyloxy potassium, n-butyllithium, s-butyllithium, t-butyllithium and the like can be used.
- the metal catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium.
- palladium complexes such as tetrakis (triphenylphosphine) palladium
- copper reagents such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone.
- a combination of ligands can also be used.
- Examples of the ligand include (2-biphenyl) di-t-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tri (tolyl) phosphine, tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine, triphenylarsine and the like can be used alone or in combination.
- the reaction conditions are preferably 0 ° C. to 180 ° C. for 1 minute to 5 days, more preferably 80 ° C. to 150 ° C. for 1 hour to 24 hours.
- Step 3 is not particularly limited deprotection methods of protecting group R 12 of the resultant compound (VII) in the above methods, the method (Protective Groups in Organic Synthesis Third Edition commonly used as deprotection conditions for the protecting group , John Wiley & Sons, Inc.).
- the compound (Ib) in which R 1 is the formula (II) and R 2 is OR 11 can be found in known patent documents (WO 2008/018529 pamphlet) and the like. It can be produced by the method described.
- Compound (IX) can be produced by reacting 5-bromo-2-chloropyrimidine (III) with amine (VIII) in a solvent or without a solvent. At that time, microwave irradiation may be performed.
- the solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination. it can.
- the reaction conditions vary depending on the amine to be used, but are preferably -20 ° C to 180 ° C for 1 minute to 24 hours, more preferably 0 ° C to 150 ° C for 5 minutes to 15 hours.
- Compound (Ib) can be produced by reacting compound (IX) with alcohol (VI) in a solvent in the presence of a base and a metal catalyst. At that time, microwave irradiation may be performed.
- the solvent is not particularly limited as long as it does not inhibit the reaction.
- tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, etc. may be used alone or in combination. Can do.
- Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metals such as metal lithium, metal sodium, and metal potassium; lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.
- Alkali metal carbonates such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-amyloxy sodium, t-amyloxy potassium, n-butyllithium, s-butyllithium, t-butyllithium and the like can be used.
- the metal catalyst examples include tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium.
- palladium complexes such as tetrakis (triphenylphosphine) palladium
- copper reagents such as cuprous iodide, cuprous bromide and cuprous cyanide may be used alone.
- a combination of ligands can also be used.
- Examples of the ligand include (2-biphenyl) di-t-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tri (tolyl) phosphine, tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine, triphenylarsine and the like can be used alone or in combination.
- the reaction conditions are preferably 0 ° C. to 180 ° C. for 1 minute to 5 days, more preferably 80 ° C. to 150 ° C. for 1 hour to 24 hours.
- the compound (Ib) in which R 1 is the formula (II) can also be produced by the method shown below.
- Step 6 The reaction of compound (Ia) and benzyl halide (X) can be carried out in a solvent in the presence of a base.
- the solvent is not particularly limited.
- the base is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t- Alkoxy alkali metals such as amyloxy sodium and t-amyloxy potassium, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, etc.
- alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t- Alkoxy alkali metals such as amyloxy sodium and t-amyloxy potassium, pyridine, DMAP, collidine, luti
- Heavy metals such as organic bases, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate and potassium bicarbonate Use carbonates, etc. It is possible.
- the reaction conditions vary depending on the starting materials used, but preferably the compound (Ib) is reacted by reacting at 0 ° C. to 180 ° C. for 5 minutes to 2 days, more preferably at 50 ° C. to 120 ° C. for 1 hour to 12 hours. can get.
- the compound (Ib) in which R 1 is the formula (II) and R 2 is OR 11 is obtained by the method described in the patent document (International Publication No. 2008/009435 pamphlet). Can also be manufactured.
- Step 7 The reaction of pyrimidineborane pinacol ester (XI) and benzylamine (VIII) can be carried out in a solvent or without a solvent, in the presence or absence of a base.
- the solvent is not particularly limited.
- N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, Tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol and the like can be used alone or in combination.
- the base is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t- Alkoxy alkali metals such as amyloxy sodium and t-amyloxy potassium, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, etc.
- alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t- Alkoxy alkali metals such as amyloxy sodium and t-amyloxy potassium, pyridine, DMAP, collidine, luti
- Heavy metals such as organic bases, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate and potassium bicarbonate Use carbonates, etc. It is possible.
- Step 8 For the oxidation reaction of the aminopyrimidine derivative (XII), a usual method for converting a boric acid ester residue to a hydroxyl group can be applied. For example, an oxidation reaction with hydrogen peroxide can be used. .
- the solvent is not particularly limited, and for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid, water and the like can be used alone or in combination.
- the alkylation reaction of hydroxypyrimidine compound (XIII) can be carried out in a solvent in the presence of a base.
- the solvent is not particularly limited.
- N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used alone or in combination.
- alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t-amyloxy sodium, t -Alkoxy alkali metals such as amyloxy potassium, organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, Alkali metal hydroxides such as lithium oxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc. Can be used.
- the alkylation reaction of the hydroxypyrimidine compound (XII) can be performed by Mitsunobu reaction of alcohols.
- the Mitsunobu reaction can be carried out in a solvent using a phosphine reagent and an azo reagent or an ethylenedicarboxylic acid reagent, or using a phosphonium ylide reagent.
- the phosphine reagent is not particularly limited, but trialkylphosphine or triarylphosphine, specifically trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, triphenylphosphine. Diphenylphosphinopolystyrene and the like can be used.
- the azo reagent is not particularly limited, but diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1 ′-(azodicarbonyl) piperidine (ADDP), 1,1′-azobis (N, N'-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD) and the like can be used.
- the ethylenedicarboxylic acid reagent is not particularly limited, and dimethyl maleate, diethyl maleate, dimethyl fumarate, diethyl fumarate, and the like can be used.
- the solvent is not particularly limited, but N, N′-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, propionitrile, nitromethane, acetone, ethyl acetate, isopropyl acetate, benzene, toluene, chlorobenzene, chloroform, dichloromethane, 1,2 -Dichloroethane or the like can be used alone or in combination.
- Step 10 The reaction of pyrimidine derivative (Ia) and compound (XIV) can be carried out using a reducing reagent in a solvent in the presence or absence of an acid.
- the dehydration operation may be performed using a Deen-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 .
- Titanium 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, Boron hydride reagents such as lithium triethylborohydride; Aluminum hydride reagents such as lithium aluminum hydride, diisopropylaluminum hydride, sodium bis [2-methoxyethoxy] aluminum hydride; Contact using metal catalyst and hydrogen source Reduction can be used.
- the hydrogen source for catalytic reduction for example, hydrogen, cyclohexadiene, formic acid, ammonium formate, or the like can be used.
- the metal catalyst for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide, platinum black and the like can be used.
- the reaction conditions vary depending on the starting materials used, but preferably the compound (Ic) is reacted by reacting at 0 ° C. to 180 ° C. for 5 minutes to 2 days, more preferably at 0 ° C. to 50 ° C. for 1 hour to 24 hours. can get.
- the compound represented by the general formula (I) in which R 2 is a lower alkylsulfinyl lower alkoxy group or a lower alkylsulfonyl lower alkoxy group can be produced by the following reaction step in addition to the method described above. That is, it can also be obtained by oxidizing the sulfur atom of the compound represented by the general formula (I) in which R 2 is a lower alkylthio-lower alkoxy group.
- oxidation method a usual method for converting a sulfur atom into a sulfinyl group or a sulfonyl group can be applied.
- hydrogen peroxide solution using a catalytic amount of sodium tungstate, molybdenum dichloride dioxide or tantalum pentachloride.
- Oxidation reaction with sodium periodate, potassium periodate, metachloroperbenzoic acid (mCPBA), peracetic acid, PCC, PDC, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N- Iodosuccinimide (NIS), iodine, bromine and the like can be used.
- the solvent is not particularly limited.
- water, methanol, ethanol, isopropanol, acetonitrile, propionitrile, acetone, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, N, N-dimethyl Formamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetic acid, water and the like can be used alone or in combination.
- R 2 is lower alkyl sulfonyl lower alkoxy group
- the compound represented by the general formula (I) also, R 2 obtained by the above method is lower alkylsulfinyl lower alkoxy group, the general formula (I) It can manufacture using the same oxidation reaction conditions from the compound represented by these.
- 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 3 Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of N- (5-hydroxypyrimidin-2-yl) hexanamide 5-Methoxypyrimidin-2-amine (12.3 g, 98.3 mmol) prepared in Example 1 was dissolved in pyridine (123 mL). Hexanoic acid chloride (14.5 g, 108 mmol) was added in an ice bath and stirred at room temperature for 30 minutes. A 1 M aqueous glycine solution (98.3 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred for 1 hour, followed by extraction with chloroform.
- Step 2 Preparation of N- (5-hydroxypyrimidin-2-yl) hexanamide N- (5-methoxypyrimidin-2-yl) hexanamide (17.3 g, 77 mmol) was converted to 1,2-dichloroethane (170 mL). Was added, and boron tribromide (20.5 mL, 216 mmol) was added thereto, followed by heating to reflux for 30 minutes. The reaction solution was quenched with methanol (170 mL) under ice-cooling, and concentrated under reduced pressure, and saturated ammonia methanol (85 mL) was added to the resulting residue under ice-cooling to make it uniform.
- Step 3 Preparation of N- ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ hexanamide N- (5-hydroxypyrimidin-2-yl) hexanamide (8.18 g, 39 mmol) and triphenyl Phosphine (20.5 g, 78 mmol) was mixed, dried under reduced pressure, and then purged with an argon atmosphere. These were dissolved by heating in anhydrous N, N-dimethylformamide (80 mL), cooled to room temperature, and 2-methylthioethanol (5.40 g, 58.6 mmol) was added.
- Step 4 Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine N- ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ hexanamide (6.80 g, 24 mmol) in methanol (68 mL), sodium methoxide (1 M methanol solution, 120 mL, 120 mmol) was added, dissolved in a 60 ° C. oil bath, and stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was extracted from chloroform-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 1 Production of 3-bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine This was produced 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.
- Step 2 Preparation of N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine 3-Bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine (1.50 g, 5.72 mmol), tris (dibenzylideneacetone) (chloroform) dipalladium (0) (592 mg, 0.572 mmol), (2-biphenyl) di-t-butylphosphine (680 mg, 2.28 mmol), sodium t-butoxy (1.65 g, 17.2 mmol) and ethylamine (2.0 M tetrahydrofuran solution, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) were heated to 135 ° C.
- Step 3 Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl ]
- pyridine-3-amine 7.20 g, 31.8 mmol
- cyclopentanecarbaldehyde 3.75 g, 38.2 mmol
- sodium triacetoxyborohydride 8.75 g, 41.3 mmol
- Step 4 Preparation of ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methanol N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy Concentrated hydrochloric acid (20 mL) was added dropwise to a mixed solution of methyl) pyridin-3-amine (8.39 g, 27.2 mmol) in dioxane (400 mL) -water (100 mL), 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.
- Step 5 Preparation of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde ⁇ 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl ⁇ methanol (2.0 g , 7.57 mmol) in chloroform (200 mL) was added manganese dioxide (20 g, 230 mmol), and the mixture was stirred at 55 ° C. for 16 hours. The reaction mixture was filtered through celite, washed with chloroform, and the filtrate was concentrated under reduced pressure.
- Step 6 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) prepared in Example 3 and 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicoline prepared in Step 5
- a solution of aldehyde (1.60 g, 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 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
- the reaction and treatment were conducted in the same manner as in Step 6 of Example 4 using -dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde to obtain the title compound as a pale yellow oil.
- Example 6 Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinolin-2-amine: Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead, 2-chloroquinoline-3-carbaldehyde was used in the same manner as in Step 1 of Example 5 to treat 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde as a yellow oil.
- Step 2 Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinolin-2-amine 3-[( Reaction and treatment in the same manner as in Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde
- the title compound was obtained as a pale yellow oil.
- Example 7 Production of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinolin-2-amine: Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methoxyquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5 Using 2-chloro-6-methoxyquinoline-3-carbaldehyde instead of carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) amino] -6 -Methoxyquinoline-3-carbaldehyde was obtained as a yellow oil.
- Step 2 Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinolin-2-amine
- Example 2 Using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methoxyquinoline-3-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a pale yellow oil.
- Example 8 Of N- (cyclopentylmethyl) -N-ethyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -6- (trifluoromethyl) quinolin-2-amine Manufacturing: Step 1: Preparation of 4-trifluoromethylacetanilide 4-trifluoromethylaniline (3.00 g, 18.6 mmol) was dissolved in pyridine (1.62 g, 20.5 mmol), and acetic anhydride (2.38 g) was stirred in an ice bath. 23.3 mmol) and stirred at room temperature for 30 minutes.
- Step 2 Preparation of 2-chloro-6-trifluoromethylquinoline-3-carbaldehyde While stirring N, N-dimethylformamide (3.38 g, 46.2 mmol) in an ice bath, phosphorus oxychloride (20 g, 130 mmol) and 4-trifluoromethylacetanilide (3.76 g, 18.5 mmol) were sequentially added, and the mixture was stirred at 65 ° C. for 22 hours. The reaction mixture was poured into ice and extracted from ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 3 Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-trifluoromethylquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Using 2-chloro-6-trifluoromethylquinoline-3-carbaldehyde instead of -5-carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) Amino] -6-trifluoromethylquinoline-3-carbaldehyde was obtained as a yellow oil.
- Step 4 N- (Cyclopentylmethyl) -N-ethyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -6- (trifluoromethyl) quinoline-2 -Preparation of amine 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Instead of 2-[(cyclopentylmethyl) (ethyl) amino] -6-trifluoromethylquinoline-3-carbaldehyde Was used and reacted in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
- Example 9 Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinolin-2-amine: Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5 Using 2-chloro-6-methylquinoline-3-carbaldehyde instead of carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) amino] -6 -Methylquinoline-3-carbaldehyde was obtained as a yellow oil.
- Step 2 Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinolin-2-amine
- Example 2 Using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylquinoline-3-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a pale yellow oil.
- Step 2 Preparation of 2-chloro-6-methylnicotinaldehyde To a solution of 2-chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide (1.30 g, 5.83 mmol) in dichloromethane (15 mL) -78 Diisobutylaluminum hydride (0.99 M toluene solution, 12 mL, 11.66 mmol) was added at ° C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 2 M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate.
- dichloromethane 15 mL
- Diisobutylaluminum hydride (0.99 M toluene solution, 12 mL, 11.66 mmol
- Step 3 Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead, 2-chloro-6-methylnicotinaldehyde was reacted and treated in the same manner as in Step 1 of Example 5 to give 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde as a yellow oil Got as.
- Step 4 Preparation of N-( ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 3 Similar to Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde instead of-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment gave the title compound as a pale yellow oil.
- Step 1 Production of 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile 2-Chloro-6-ethylpyridine produced by the method described in WO 1997/19078 -3-carbonitrile (500 mg, 3.00 mmol) and N- (cyclopentylmethyl) -N-ethylamine (1.50 g, 11.8 mmol) prepared by the method described in WO2006 / 07397 pamphlet were mixed, and argon was mixed.
- Step 2 Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile (484 mg, 1.87 mmol) in dichloromethane (5 mL) at ⁇ 78 ° C. was added diisobutylaluminum hydride (0.99 M toluene solution, 1.99 mL, 1.97 mmol) and stirred at the same temperature for 4 hours.
- Step 3 Preparation of N-( ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 3 Similar to Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde instead of-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment gave the title compound as a pale yellow oil.
- Example 12 Production of N-( ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylnicotinaldehyde In place of 2-chloro-6-ethylpyridine-3-carbonitrile, WO 2006/079773 pamphlet Using 2-chloro-5,6-dimethylpyridine-3-carbonitrile prepared by the method described in 1) in the same manner as in Step 1 of Example 11 to give 2-[(cyclopentylmethyl) (ethyl) amino ] -5,6-dimethylnicotinaldehyde was obtained as a pale yellow oil.
- Step 2 N-( ⁇ 2-[(Cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine
- Example 4 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylnicotinaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde
- the reaction and treatment were conducted in a similar manner to 6 to give the title compound as a pale yellow oil.
- Example 13 Production of N-( ⁇ 3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: 3-[(Cyclopentylmethyl) (ethyl) amino] pyrazine produced by the method described in WO 2006/079773 instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 2-carbaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 14 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (3.00 g, 15.6 mmol) in toluene (60 mL ) N- (cyclopentylmethyl) -N-ethylamine (2.70 g, 21.2 mmol) and potassium carbonate (6.50 g, 47.0 mmol) prepared by the method described in WO 2006/079773 pamphlet were added to the solution for 68 hours.
- Step 2 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[( Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (3.34 g, 11.2 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 3 (2.27 g, Acetic acid (317 mg, 5.19 mmol) was added to a toluene (80 mL) solution of 12.3 mmol), and the mixture was heated to reflux for 4 hours using a Dean-Stark apparatus.
- Example 15 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-5-methoxybenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 16 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2,3,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 17 Production of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-5-methylbenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 18 Production of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2,4-difluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 19 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-4-methoxybenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 20 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-4- (trifluoromethyl) benzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil. It was.
- Example 21 Preparation of N- ⁇ 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2-chloro-6-fluoro-3-methylbenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil. It was.
- Example 22 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 23 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2,4,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 24 Production of N- ⁇ 4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 4-chloro-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 25 Production of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 2,5-difluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 26 Production of N- ⁇ 4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 4-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 27 Preparation of N- ⁇ 5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 5-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 28 Preparation of 5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
- Example 29 Preparation of 5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using morpholine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
- Example 30 Preparation of N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using 4-methylpiperidine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
- Example 31 Preparation of N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 14 using cis-2,6-dimethylmorpholine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
- Example 32 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] Preparation of cyclohexyl ⁇ ethyl acetate: Step 1: Preparation of 2- [trans-4-( ⁇ ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate 2-Fluoro-5- (trifluoromethyl) benzaldehyde ( 2.79 g, 14.5 mmol) in a toluene (70 mL) solution prepared by the method described in International Publication No.
- Step 2 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino ) Preparation of methyl] cyclohexyl ⁇ ethyl acetate 2- [trans-4-( ⁇ ethyl [2-formyl-4- (trifluoro) instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Methyl) phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate was used for the reaction and treatment in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
- Example 33 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] Production of cyclohexyl ⁇ acetic acid: 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] Dissolve ethyl cyclohexyl ⁇ acetate (200 mg, 0.35 mmol) in ethanol-tetrahydrofuran (2 mL, 1: 1 mixed solvent) and add 2 M aqueous sodium hydroxide (0.88 mL) while stirring in an ice bath.
- Example 34 Production of N- ⁇ 2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: 2,3,5-trifluorobenzaldehyde is used instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and described in WO 2006/079773 instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in a similar manner to Example 14 using N, N-bis (cyclopropylmethyl) amine produced by the above method to obtain the title compound as a pale yellow oil.
- Example 35 Production of (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of (S) -2-( ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ amino) pyrimidin-5-ol According to the method described in WO2008 / 009435 pamphlet.
- Step 2 Preparation of (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine
- Example 36 Production of (S) —N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine: (S) —N- ⁇ 1- [3,5-Bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 35 (100 mg, 0.24 mmol) in methanol (1 mL) was added tantalum pentachloride (8.4 mg, 0.024 mmol) and 30% aqueous hydrogen peroxide (0.036 mL, 0.32 mmol), and the mixture was stirred at room temperature for 5 hours 30 minutes.
- tantalum pentachloride (4.2 mg, 0.012 mmol) and 30% hydrogen peroxide (0.018 mL, 0.16 mmol) were added, and the mixture was stirred at the same temperature for 1 hour.
- a saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with chloroform.
- the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Example 37 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl Preparation of cyclohexyl ⁇ ethyl acetate: Instead of (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- ⁇ trans-4- With [[ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] cyclohexyl ⁇ ethyl acetate Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as
- Example 38 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl Production of cyclohexyl ⁇ acetic acid: Instead of (S) -N- ⁇ 1- [3,5-bis (trifluoromethyl) phenyl] ethyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- ⁇ trans-4- Performed with [(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] cyclohexyl ⁇ acetic acid Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a pale yellow oil.
- Example 39 Preparation of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (500 mg, 2.60 mmol) in DMSO-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.
- Step 2 Production of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (diallylamino produced in Step 1 ) -5- (trifluoromethyl) benzaldehyde (200 mg, 0.74 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (165 mg, 89 mmol) prepared in Example 3 in toluene (5 Acetic acid (45 mg, 0.75 mmol) was added to the solution, and the mixture was heated to reflux for 5 hours using a Dean-Stark apparatus.
- Example 40 Preparation of N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using 3,5-bis (trifluoromethyl) benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde to give the title compound colorless. Obtained as a solid.
- Example 41 Preparation of 5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to process 2 of example 39 using 3- (trifluoromethyl) benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a colorless solid. It was.
- Example 42 Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide N- (5-hydroxypyrimidin-2-yl) hexanamide (3.00 g) prepared by the method of Step 2 of Example 3 , 14.3 mmol) in DMF (15 mL), potassium carbonate (2.97 g, 21.5 mmol) and 1-bromo-2-chloroethane (4.12 g, 28.7 mmol) were added at room temperature, and the mixture was stirred at 60 ° C. for 20 hours.
- Step 2 Preparation of N- ⁇ 5- [2- (phenylthio) ethoxy] pyrimidin-2-yl ⁇ hexanamide
- DMF dimethyl methoxyethyl
- Sodium hydride 50% in oil: 265 mg, 5.52 mmol
- Step 3 Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine N- ⁇ 5- [2- (phenylthio) ethoxy] pyrimidin-2-yl ⁇ hexanamide (400 mg, prepared 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 is diluted with water and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Example 43 Preparation of 5- (2-phenoxyethoxy) pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 42 using phenol instead of thiophenol, and the title compound was obtained as a colorless solid.
- Example 44 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (phenylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] Preparation of cyclohexyl ⁇ ethyl acetate: 5- [2- (Phenylthio) ethoxy] pyrimidin-2-amine (230 mg, 0.93 mmol) prepared in Example 42 and 2- [trans-4-( ⁇ ethyl [2- Acetic acid (115 mg, 1.92 mmol) was added to a toluene (4 mL) solution of formyl-4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate (414 mg, 1.02 mmol), and the Dean-Stark apparatus was added.
- Example 45 2- [trans-4-( ⁇ ethyl [2-( ⁇ [5- (2-phenoxyethoxy) pyrimidin-2-yl] amino ⁇ methyl) -4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl]
- Ethyl acetate production The title compound was treated in the same manner as in Example 44 using 5- (2-phenoxyethoxy) pyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine. Obtained as a thing.
- Example 46 Preparation of 2- [trans-4-( ⁇ ethyl [2- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate: Using the 5-methoxypyrimidin-2-amine prepared in Example 1 instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment were carried out in the same manner as in Example 44, and the title compound was colorless. Obtained as a solid.
- Example 47 2- [trans-4-( ⁇ [2- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate Manufacturing: Using the 5-ethoxypyrimidin-2-amine prepared in Example 2 instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment were conducted in the same manner as in Example 44, and the title compound was converted to white. Obtained as a solid.
- Example 48 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] Preparation of cyclohexyl ⁇ benzyl acetate: Step 1: Preparation of 2- [trans-4-( ⁇ ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] acetic acid 2- [trans-4- () prepared in Example 32 ⁇ Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] ethyl acetate (9.80 g, 24.5 mmol) was dissolved in ethanol (100 mL) and stirred in an ice bath.
- Step 2 Preparation of 2- [trans-4-( ⁇ ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] acetic acid benzyl 2- [trans-4- ( ⁇ Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] acetic acid (9.11 g, 24.5 mmol) was dissolved in dichloromethane (100 mL), and benzyl alcohol (2.92 g, 27.0 mmol) was dissolved at room temperature. mmol) and N, N-dimethylaminopyridine (4.50 g, 36.8 mmol) were added.
- Step 3 2- ⁇ trans-4-[(ethyl ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino )
- the reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using trifluoromethyl) phenyl] amino ⁇ methyl) cyclohexyl] benzyl acetate to give the title compound as a colorless solid.
- Example 49 Preparation of N- ⁇ 2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 39 using N- (4-methoxybenzyl) ethylamine in place of diallylamine, and the title compound was obtained as a pale-yellow oil.
- Example 51 2- (trans-4- ⁇ [(4-methoxybenzyl) ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ Amino] methyl ⁇ cyclohexyl) ethyl acetate preparation: Step 1: Preparation of ethyl 2- [trans-4- (aminomethyl) cyclohexyl] acetate ⁇ hydrochloride 2- [trans-4- (aminomethyl) cyclohexyl] acetic acid ⁇ hydrochloride (30.0 g, 148 mmol) was added to ethanol ( 150 mL), thionyl chloride (26.7 g, 225 mmol) was added dropwise over 40 minutes while maintaining the temperature at 20 ° C.
- Step 2 Preparation of 2- (trans-4- ⁇ [(4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate
- 2- [trans-4- (aminomethyl) cyclohexyl] ethyl acetate hydrochloride 50 mg, 0.21 mmol
- dichloroethane 0.5 mL
- 4-methoxybenzaldehyde 28.5 mg, 0.21 mmol
- Sodium triacetoxyborohydride 133 mg, 0.63 mmol
- Step 3 2- (trans-4- ⁇ [(4-methoxybenzyl) ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoro Preparation of methyl) phenyl ⁇ amino] methyl ⁇ cyclohexyl) ethyl acetate
- 2- (trans-4- ⁇ [(4-methoxybenzyl) amino] methyl ⁇ cyclohexyl) ethyl acetate instead of diallylamine. Reaction and treatment gave the title compound as a pale yellow oil.
- Example 52 2- ⁇ trans-4-[( ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino) methyl] cyclohexyl ⁇
- Ethyl acetate production N- ⁇ 2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of 2- (trans-4 - ⁇ [(4-methoxybenzyl) ⁇ 2-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ amino] methyl ⁇ cyclohexyl )
- the reaction and treatment were carried out in the same manner as in Example 50 using ethyl acetate to obtain the title compound
- Example 53 2- (trans-4- ⁇ [ ⁇ 2-chloro-6-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -4- (trifluoromethyl) phenyl ⁇ ( Preparation of ethyl) amino] methyl ⁇ cyclohexyl) ethyl acetate: Step 1: Preparation of 2- [trans-4-( ⁇ [2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino ⁇ methyl) cyclohexyl] ethyl acetate 3-Chloro-2-fluoro Trans- ⁇ manufactured by the method described in WO 2004/020393 to a solution of -5- (trifluoromethyl) benzaldehyde (1.00 g, 4.60 mmol) in DMSO-water (4: 1 mixed solution, 6.25 mL).
- 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--diallylamino) -5- (trifluoromethyl) benzaldehyde prepared in Step 1 instead of 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 39 to give the title compound as a pale yellow oil Got as.
- Example 54 Preparation of N- ⁇ 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde To a solution of 2-chloro-6-fluorobenzaldehyde (500 mg, 3.15 mmol) in toluene (10 mL), WO2006 / N- (cyclopentylmethyl) -N-ethylamine (520 mg, 4.09 mmol) and potassium carbonate (1.31 g, 9.48 mmol) produced by the method described in the pamphlet of No.
- Step 2 Preparation of N- ⁇ 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-chloro prepared in Step 1 -6-[(Cyclopentylmethyl) (ethyl) amino] benzaldehyde (830 mg, 3.12 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 3 (560 mg, 3.02 mmol) Acetic acid (105 mg, 1.73 mmol) was added to a toluene (20 mL) solution, and the mixture was heated to reflux for 8 hours using a Dean-Stark apparatus.
- Example 55 Preparation of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 54 using 2-fluoro-6- (trifluoromethyl) benzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 56 Production of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 54 using 2,6-difluorobenzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 57 Production of N- ⁇ 2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to Example 54 using 2,3-difluorobenzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
- Example 58 Preparation of N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in a similar manner to process 2 of example 39 using benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a colorless solid.
- Example 59 Preparation of N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of 5-bromo-N- (4-methoxybenzyl) pyrimidin-2-amine 5-Bromo-2-chloropyrimidine (300 mg, 1.55 mmol) was converted to 4-methoxybenzylamine (2.1 g, 15.4 mmol). The solution was heated and dissolved at 120 ° C. and stirred at the same temperature for 2 hours.
- Step 2 Preparation of N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5-Bromo-N- (4-methoxybenzyl) pyrimidin-2-amine (300 mg, 1.02 mmol) was suspended in toluene (20 mL), cuprous iodide (200 mg, 1.05 mmol), 2-methylthioethanol (1.06 g, 11.5 mmol), N, N′-dimethylethylenediamine (0.83 g, 9.42). mmol) and cesium carbonate (400 mg, 1.22 mmol) were added, and the mixture was stirred at 110 ° C. for 66 hours under an argon atmosphere.
- Example 60 Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinoxalin-2-amine: Step 1: Preparation of ethyl 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carboxylate Ethyl 3-chloroquinoxaline-2-carboxylate (267 mg, 1.13 mmol) and WO 2006/079773 N- (cyclopentylmethyl) -N-ethylamine (1.5 g, 11.8 mmol) produced by the method described in 1) was mixed and stirred at 100 ° C.
- Step 2 Preparation of 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde
- Ethyl 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carboxylate prepared in Step 1 (247 mg , 0.75 mmol) in toluene (3 mL) was added diisobutylaluminum hydride (0.99 mol / L toluene solution, 1.03 mL, 1.02 mmol) at ⁇ 78 ° C., and the mixture was stirred at the same degree for 2 hours.
- Step 3 Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] quinoxalin-2-amine 2- (diallyl
- the reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde in place of amino) -5- (trifluoromethyl) benzaldehyde.
- the compound was obtained as a pale yellow oil.
- Example 61 Production of N- ⁇ [6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: Step 1: Preparation of 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine 3-bromo-6-methoxy-2-[(methoxymethoxy) prepared in Step 1 of Example 4 ) Methyl] pyridine (324.6 mg, 1.24 mmol), Tris (dibenzylideneacetone) (chloroform) dipalladium (0) (32.7 mg, 0.03 mmol), (2-biphenyl) di-t-butylphosphine (18.5 mg, 0.06) mmol), t-butoxy sodium (357 mg, 3.71 mmol) and pyrrolidine (640 mg, 3.74 mmol) in toluene (4.5 mL
- Step 2 Preparation of N- ⁇ [6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl ⁇ -5- [2- (methylthio) ethoxy] pyrimidin-2-amine N- (cyclopentyl 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine instead of methyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine was used in the same manner as in Example 4 to obtain the title compound as a pale yellow oil.
- Example 62 Production of N-( ⁇ 3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl ⁇ methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine: The reaction and treatment were conducted in the same manner as in Example 4 using anisaldehyde in place of cyclopentanecarbaldehyde to obtain the title compound as a pale yellow oil.
- Example 63 N- (cyclopentylmethyl) -N-ethyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production: Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Using pyridine-5-carbaldehyde and using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 6 of Example 4 The title compound was obtained as a pale yellow oil.
- Example 64 N- (cyclopentylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production: Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Using pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 6 of Example 4 The title compound was obtained as a pale yellow oil.
- Example 65 N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -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) obtained in Step 2 of Example 5 Methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine (40.4 mg, 86 ⁇ mol) in acetonitrile (2.0 mL) and molybdenum (VI) dichloride dioxide (1.7 mg, 8.6 ⁇ mol) and 30% Hydrogen peroxide water (9.7 ⁇ L, 86 ⁇ mol) was added and stirred at room temperature for 16 hours
- Example 67 Preparation of 5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: 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 5 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
- Step 2 5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- Step 2 5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- Step 2 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 6 of Example 4, and the title compound Obtained as a yellow oil.
- Example 68 Preparation of N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine: Step 1: Preparation of 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Examples using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in the same manner as in Step 1 of 5 to give 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
- Step 2 Preparation of N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine 3-[( Instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
- Example 69 Preparation of N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine: Step 1: Preparation of 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Example using morpholine instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in the same manner as in Step 1 of 5 to obtain 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
- Step 2 Preparation of N-[(1,3-Dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine 3-[( 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
- Example 70 N, N-bis (cyclopropylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production: Step 1: Preparation of 6- [bis (cyclopropylmethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde N- (cyclopentylmethyl) -N-ethylamine Instead, bis (cyclopropylmethyl) amine was used for the reaction and treatment in the same manner as in Step 1 of Example 5, and 6-bis (cyclopropylmethyl) amine-1,3-dimethyl-1H-pyrazolo [3,4 b] Pyridine-5-carbaldehyde was obtained as a pale yellow oil.
- Step 2 N, N-bis (cyclopropylmethyl) -5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine
- 6-amine 6- [bis (cyclopropylmethyl) amino] -1,3-dimethyl-1H-pyrazolo [3 instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde , 4-b] pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine
- the same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
- Example 71 Preparation of N-benzyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: Step 1: Preparation of 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were carried out using N-benzyl-N-methylamine in the same manner as in Step 1 of Example 5, and 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b Pyridine-5-carbaldehyde was obtained as a pale yellow oil.
- Step 2 N-Benzyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- Step 2 N-Benzyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- Step 2 N-Benzyl-5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- Example 72 Preparation of 5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: Step 1: Preparation of 6- (dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Dimethylamine instead of N- (cyclopentylmethyl) -N-ethylamine Using 6- (dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
- 1 H-NMR (CDCl 3 ) ⁇ : 2.50 (3H, s), 3.15 (6H, s), 3.92 (3H, s), 8.29 (1H, s), 9.99 (1H, s).
- Step 2 Preparation of 5- ⁇ [(5-methoxypyrimidin-2-yl) amino] methyl ⁇ -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine 6- (Dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde
- 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was conducted in the same manner as in Step 6 of Example 4.
- Example 73 N, N-diethyl-1,3-dimethyl-5-[( ⁇ 5- [2- (methylthio) ethoxy] pyrimidin-2-yl ⁇ amino) methyl] -1H-pyrazolo [3,4-b] pyridine- Production of 6-amine: Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. Was used and reacted in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
- Example 76 Preparation of 5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: 6- (Dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 6 of Example 4, and the title compound Obtained as a yellow oil.
- 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
- the same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
- Step 1 Preparation of 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Pyrrolidine instead of N- (cyclopentylmethyl) -N-ethylamine Using 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
- Step 2 N- ⁇ [1,3-Dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine
- 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5 -Carboxaldehyde was used and reacted and treated in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine.
- Example 80 Preparation of 5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine: Step 1: Preparation of 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b A solution of pyridine-5-carbaldehyde (300 mg, 1.43 mmol) and potassium hydroxide (120.4 mg, 2.15 mmol) in methanol (3.0 mL) was heated to reflux for 2 hours and then allowed to cool to room temperature.
- Step 2 Preparation of 5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine 3-[( Instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-methoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
- Example 81 Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate: Step 1: Preparation of ethyl 4-[(2-hexamidopyrimidin-5-yl) oxy] butyrate N- (5-hydroxypyrimidin-2-yl) hexanamide (3.0) prepared by the method of Step 2 of Example 3 g, 14.3 mmol) in N, N-dimethylformamide (15 mL) was added ethyl 4-bromobutyrate (3.35 g, 17.2 mmol) and potassium carbonate (3.0 g, 21.5 mmol), and the mixture was stirred at 60 ° C. for 16 hours.
- Step 1 Preparation of ethyl 4-[(2-hexamidopyrimidin-5-yl) oxy] butyrate N- (5-hydroxypyrimidin-2-yl) hexanamide (3.0) prepared by the method of Step 2 of Example 3 g,
- Step 2 Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate
- sodium ethoxide 421 mg, 6.19 mmol
- concentrated sulfuric acid 835 mg, 8.51 mmol
- Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- Example 82 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino] pyrimidine- Production of 5-yl ⁇ oxy) ethyl butyrate: Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b]
- Example 4 using pyridine-5-carbaldehyde and using ethyl 4-[(2-aminopyrimidin-5-yl) oxy] acetate instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a colorless oil.
- Example 83 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino] pyrimidine- 5-yl ⁇ oxy) butyric acid production: 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino] pyrimidine- 5-yl ⁇ oxy) ethyl butyrate (21 mg, 0.042 mmol) was dissolved in ethanol (1 mL), and 2N aqueous sodium hydroxide solution (0.04 mL) was added with stirring in an ice bath.
- Example 84 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino]
- 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 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 a similar manner to process 1 of example 5 using methyl 3- (methylamino) propionate instead of N-ethylamine, and the title compound 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]
- Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a pale yellow solid.
- Example 85 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino]
- Propionic acid production 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino] pyrimidine- 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] instead of ethyl 5-yl ⁇ oxy) butyrate
- the reaction and treatment were conducted in a similar manner to Example 83 using methyl pyridin-6-yl) (methyl) amino] propionate to give the title compound as a pale yellow oil.
- Example 86 Preparation of ethyl 4-[(2- ⁇ [3,5-bis (trifluoromethyl) benzyl] amino ⁇ pyrimidin-5-yl) oxy] butyrate: It manufactured according to the method as described in a patent document (International Publication No. 2007/088996 pamphlet).
- Example 87 Preparation of 4-[(2- ⁇ [3,5-bis (trifluoromethyl) benzyl] amino ⁇ pyrimidin-5-yl) oxy] butyric acid: 4-( ⁇ 2-[( ⁇ 6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl ⁇ methyl) amino] pyrimidine-
- Example 83 with ethyl 4-[(2- ⁇ [3,5-bis (trifluoromethyl) benzyl] amino ⁇ pyrimidin-5-yl) oxy] butyrate instead of ethyl 5-yl ⁇ oxy) butyrate The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
- Example 88 Production of N- ⁇ [2- (diethylamino) pyridin-3-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine: Step 1: Preparation of 2- (diethylamino) nicotinaldehyde Using 2-chloronicotinaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of-(cyclopentylmethyl) -N-ethylamine, and 2- (diethylamino) nicotinaldehyde was obtained as a pale yellow oil.
- Step 2 Preparation of N- ⁇ [2- (diethylamino) pyridin-3-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Instead of 2- (diethylamino) nicotinaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, as in Step 6 of Example 4 Reaction and treatment gave the title compound as a white solid.
- Example 89 Preparation of N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine: Step 1: Preparation of 2- (diethylamino) benzaldehyde Using 2-chlorobenzaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N- ( The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
- Step 2 Preparation of N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine 3-((cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (diethylamino) Using benzaldehyde, reacting and treating in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, Obtained as a white solid.
- Example 90 Production of N- ⁇ [6- (dimethylamino) pyridin-3-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine: Step 1: Preparation of 6- (diethylamino) nicotinaldehyde Using 6-chloronicotinaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of-(cyclopentylmethyl) -N-ethylamine, and 6- (diethylamino) nicotinaldehyde was obtained as a yellow oil.
- Step 2 Preparation of N- ⁇ [6- (dimethylamino) pyridin-3-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 6- (diethylamino) nicotinaldehyde was used instead of 5- and 5-ethoxypyrimidin-2-amine was used instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, as in Step 6 of Example 4. The title compound was obtained as a white solid.
- Example 91 Preparation of 3- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethylquinolin-2-amine: Step 1: Preparation of 2- (dimethylamino) quinoline-3-carbaldehyde 2-chloroquinoline instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 3-carbaldehyde and using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2- (dimethylamino) quinoline-3-carbohydrate.
- Step 2 Preparation of 3- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethylquinolin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxy Performed using 2- (dimethylamino) quinoline-3-carbaldehyde instead of picolinaldehyde and 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a white solid.
- Example 92 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Production of methyl propionate: Step 1: Preparation of methyl 3- (ethylamino) propionate Reaction was carried out in the same manner as in Step 1 of Example 84 using N-ethylbenzylamine instead of N-methylbenzylamine to give 3- (ethylamino) Methyl propionate was obtained as a colorless oil.
- Step 2 Preparation of methyl 3- [ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] propionate: The reaction and treatment were conducted in a similar manner to process 1 of example 5 using methyl 3- (ethylamino) propionate instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a dark brown oil.
- Step 3 3-[(5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl )
- methyl amino] propionate 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 3- (ethyl [5-formyl-1,3-dimethyl-1H-pyrazolo [3 , 4-b] pyridin-6-yl) amino] propionate and 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 6 of 4 to give the title compound as a tan oil.
- Example 93 Production of N- ⁇ [2- (diethylamino) pyridin-4-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine: Step 1: Production of methyl 2-chloroisonicotinate: Thionyl chloride (769 ⁇ L, 9,5 mmol) was slowly added dropwise to a solution of 2-chloroisonicotinic acid (1.0 g, 6.35 mmol) in methanol (20 mL) at ⁇ 15 ° C. while stirring. After gradually warming up and heating to reflux for 3 hours, the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
- Step 2 Production of methyl 2- (diethylamino) isonicotinate: Methyl 2-chloroisonicotinate (0.7 g, 4.08 mmol), diethylamine (844 ⁇ L, 8.2 mmol), cesium carbonate (2.88 g, 8.2 mmol) and [1,3-bis (2,6-diisopropylphenyl) imidazole-
- a solution of 2-ylidene] (3-chloropyridyl) palladium (II) dichloride 139 mg, 0.2 mmol
- water was added and the mixture was extracted with ethyl acetate.
- Step 3 Preparation of [2- (diethylamino) pyridin-4-yl] methanol
- Lithium aluminum hydride (284 mg, 7.5 mmol) was added to a THF solution of methyl 2- (diethylamino) isonicotinate (626 mg, 3.0 mmol). It added at -78 degreeC under argon atmosphere, and stirred after 2 hours. A 20% aqueous potassium potassium tartrate solution was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 4 Preparation of 4- (bromomethyl) -N, N-diethylpyridin-2-amine [2- (Diethylamino) pyridin-4-yl] methanol (100 mg, 0.55 mmol) and carbon tetrabromide (202 mg, To a dichloromethane solution (2.0 mL) of 0.61 mmol) was added triphenylphosphine (153 mg, 0.58 mmol) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate.
- Step 5 Preparation of N- ⁇ [2- (diethylamino) pyridin-4-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine: 4- (Bromomethyl) -N, N-diethylpyridin-2-amine (153 mg), 2-amino-5-ethoxypyrimidine (35.8 mg, 0.26 mmol) and cesium carbonate (90.7 mg, 0.26 mmol) prepared in Step 4 ) was stirred at room temperature for 48 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Example 94 Preparation of 5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine: Step 1: Preparation of 6- (dipropylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde: The reaction and treatment were conducted in a similar manner to process 1 of example 5 using dipropylamine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a yellow solid.
- Step 2 5- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- the aldehyde was used and reacted and treated in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine.
- Example 95 Preparation of N, N-dibutyl-5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: Step 1: Preparation of 6- (dibutylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde: The reaction and treatment were conducted in a similar manner to process 1 of example 5 using dibutylamine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a yellow solid.
- Step 2 N, N-dibutyl-5- ⁇ [(5-ethoxypyrimidin-2-yl) amino] methyl ⁇ -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine
- Manufacturing instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 6- (dibutylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde
- 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was conducted in the same manner as in Step 6 of Example 4 to give the title compound colorless.
- Step 1 Preparation of 2- (diethylamino) -6-methylquinoline-3-carbaldehyde 2 instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde
- 2-chloro-6-methylquinoline-3-carbaldehyde and using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine the reaction and treatment was conducted in the same manner as in Step 1 of Example 5, and 2- (diethylamino ) -6-methylquinoline-3-carbaldehyde was obtained as a yellow oil.
- Step 2 Preparation of 3- ⁇ [(5-Ethoxypyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-6-methylquinolin-2-amine 3-[(Cyclopentylmethyl) (ethyl) amino] Using 2- (diethylamino) -6-methylquinoline-3-carbaldehyde instead of 6-methoxypicolinaldehyde and 5-ethoxypyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 2-amine, and the title compound was obtained as a white solid.
- Example 97 Preparation of N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine: Step 1: Preparation of 2- (diethylamino) -5- (trifluoromethyl) benzaldehyde Reaction and treatment were conducted in the same manner as in Step 1 of Example 14 using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine. The title compound was obtained as a yellow oil.
- Step 2 Preparation of N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 2- (diethylamino) -5- (trifluoromethyl) benzaldehyde was used instead of 5- and 5-ethoxypyrimidin-2-amine was used instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a yellow solid.
- Step 1 Preparation of 5-bromo-2- (diethylamino) nicotinaldehyde N- against 2- (diethylamino) nicotinaldehyde (300 mg, 1.68 mmol) prepared in Step 1 of Example 88 in acetonitrile (5.0 mL) Bromosuccinimide (315 mg, 1.77 mmol) was added and stirred at room temperature for 1.5 hours.
- reaction mixture was extracted from ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 2 Preparation of 2- (diethylamino) -5-phenylnicotinaldehyde 5-Bromo-2- (diethylamino) nicotinaldehyde (100 mg, 0.39 mmol) and phenylboronic acid (71.1 mg, 0.58 mmol), tetrakis (triphenyl) Phosphine) palladium (0) (22.5 mg, 0.02 mmol) and 2M sodium carbonate solution (487 ⁇ l, 0.98 mmol) were mixed and purged with an argon atmosphere. These were dissolved in a toluene-ethanol solution (4.0 mL-1.0 mL) and stirred at 90 ° C. for 3 hours.
- Step 3 Preparation of N- ⁇ [2- (diethylamino) -5-phenylpyridin-3-yl] methyl ⁇ -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6- Performed using 2- (diethylamino) -5-phenylnicotinaldehyde instead of methoxypicolinaldehyde and 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a colorless oil.
- Example 100 Preparation of N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine: 2-chloro-6- (diethylamino) benzaldehyde (80 mg, 0.38 mmol) and 5-ethoxypyrimidin-2-amine (63.1 mg, 0.45 mmol), acetic acid (23 ⁇ l, 0.38 mmol) in 1,2-dichloroethane (1.8 mL) Sodium triacetoxyborohydride (240 mg, 1.13 mmol) was added to the solution and heated to reflux for 3 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
- Example 101 Preparation of N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine: Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used.
- Example 102 Preparation of 5- ⁇ [(5-chloropyrimidin-2-yl) amino] methyl ⁇ -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine: Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used.
- Test example 1 A test compound was added to HepG2 cells, a human liver cancer 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 2 ⁇ 10 5 cells / well and cultured overnight, and then 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 used 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. By measuring by (ELISA) method, the influence which it has on the amount of PCSK9 production protein of a test compound was confirmed.
- a test compound dissolved in dimethyl sulfoxide (DMSO) or DMSO alone is added to the culture solution at a final concentration of 10 ⁇ M. It added so that it might become.
- the cells were cultured in a CO 2 incubator at 37 ° C. for 48 hours, 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), added 100 ⁇ L to a 96-well plate, and then allowed to stand overnight at room temperature. did. The plate supernatant that had been allowed to stand was rinsed and washed three 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 at a time 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 at a time was added and allowed to stand at 4 ° C. for 18 hours. After washing 3 times with Wash buffer, 100 ⁇ L of Streptavidin-Horseadish peroxide (HRP) diluted 50-fold with Reagent Diluent was added and allowed to stand at room temperature for 20 minutes.
- HRP Streptavidin-Horseadish peroxide
- 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
- a disease involving PCSK9 mRNA expression and PCSK9 protein For example, dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper LDL, hypo HDL, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterol Treatment of blood pressure, cardiovascular disorder, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cancer, obesity, diabetes, Alzheimer's disease or viral infection Or it became clear that it can be used conveniently as an active ingredient of a preventive agent.
- the compound represented by the general formula (I) of the present invention has a PCSK9 mRNA expression inhibitory action, a PCSK9 protein production inhibitory action, and an action of increasing the amount of LDL receptor, and an active pharmaceutical ingredient for reducing LDL.
- 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.
- 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.
- the LDL cholesterol lowering action in the statin drugs can be enhanced, a high LDL cholesterol lowering action can be achieved by combining with the statin drugs.
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Abstract
A medicine which can decrease an LDL level in blood and comprises, as an active ingredient, a compound represented by general formula (I) (wherein R1 represents a hydrogen atom or a group represented by formula (II) (wherein R3 represents a hydrogen atom, a C1-6 alkyl group or the like; and W1 to W5 independently represent any one of CR4 to CR8 (wherein R4 to R8 independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group or the like), wherein zero to two of W1 to W5 may be individually substituted by a nitrogen atom); and R2 represents a C1-6 alkoxy group, a (C1-6 alkylthio)-(C1-6 alkoxy) group, a (C1-6 alkylsulfinyl)-(C1-6 alkoxy) group or the like).
Description
本発明は、プロタンパク質コンバターゼサブチリシン/ケキシン9型(PCSK9:Proprotein convertase subtilisin/kexin 9)mRNAの発現抑制作用などを有するピリミジン化合物を有効成分として含み、血中LDLを低下させることができる医薬に関する。
The present invention includes a pyrimidine compound having a proprotein convertase subtilisin / kexin type 9 (PCSK9: Proprotein convertase subtilisin / kexin 9) mRNA expression inhibitory activity as an active ingredient, and can reduce blood LDL. It relates to medicine.
近年、生活水準の向上に伴う高カロリー、高コレステロール型食への変化、肥満、運動不足、高齢化等により脂質異常症(高脂血症)及びこれに起因する動脈硬化性疾患が急増している。低比重リポタンパク質(LDL)コレステロール値及びトリグリセリド値が心疾患の発症率に正相関することはフラミンガム・スタディの研究を始めとする多くの疫学研究からも明らかにされており、それ故に脂質異常症及び動脈硬化症の薬物治療はLDLを低下させることに重点が置かれている(非特許文献1)。
In recent years, dyslipidemia (hyperlipidemia) and arteriosclerotic diseases resulting from it have increased rapidly due to changes in high calorie, high cholesterol type diet, obesity, lack of exercise, aging, etc. accompanying the improvement of living standards Yes. A number of epidemiological studies, including those in the Framingham study, have shown that low density lipoprotein (LDL) cholesterol and triglyceride levels are positively correlated with the incidence of heart disease. In addition, drug treatment for arteriosclerosis is focused on reducing LDL (Non-patent Document 1).
高LDLコレステロール血症は心血管疾患の強力な危険因子の一つであるが、その治療方法はHMG-CoA還元酵素阻害薬(スタチン)の登場とともに飛躍的に進歩した。しかし、スタチンは強力にLDLコレステロールを低下させるが、心血管疾患による心事故、死亡率の低下は約30%にとどまる。LDLコレステロールをさらに低下させることにより、心血管疾患による死亡リスクをより低減できると考えられるが、スタチンは横紋筋融解症のリスクが高まるため高用量を投与することができないという問題を有している。そこで、スタチンとは作用機序が異なり、かつ、スタチンよりも強力な、またはスタチンと併用することで強力なLDLコレステロール低下作用を有する作用機序の異なる薬剤の開発が求められている。
High LDL cholesterolemia is one of the powerful risk factors for cardiovascular disease, but its treatment method has made great strides with the advent of HMG-CoA reductase inhibitors (statins). However, statins strongly lower LDL cholesterol, but heart accidents due to cardiovascular diseases and the reduction in mortality are only about 30%. It is thought that the risk of death from cardiovascular disease can be further reduced by further reducing LDL cholesterol, but statins have the problem that high doses cannot be administered due to the increased risk of rhabdomyolysis Yes. Therefore, there is a demand for the development of a drug having a mechanism of action different from that of statins and having a stronger action mechanism of LDL cholesterol when used in combination with statins.
一方、プロタンパク質コンバターゼ(PCs)は哺乳類のセリンプロテアーゼファミリーのメンバーであり、細菌におけるサブチリシンや酵母におけるケキシンと相同性が認められている。PCsの一つであるPCSK9(プロタンパク質コンバターゼサブチリシン/ケキシン9型:Proprotein convertase subtilisin/kexin 9)は、主に肝臓で発現して細胞外に分泌され、肝細胞膜表面上でLDL受容体と結合し、LDL受容体の細胞内移行を促進する。細胞内に移行したLDL受容体は細胞内器官で分解を受ける。LDL受容体はコレステロールを含むリポ蛋白を循環血液中から肝臓へと輸送する機能を有しているため、PCSK9タンパクの産生は肝臓へのLDLコレステロールの取り込みを阻害し、結果として、血中LDLコレステロールを上昇させる。実際に、PCSK9遺伝子に機能喪失変異を有するヒトの血中LDLコレステロールレベルは低く維持されている(非特許文献2)。一方、PCSK9遺伝子には機能獲得型変異が報告されており、この変異を有するヒトの血中LDLコレステロールレベルは高く、常染色体優性高コレステロール血症と関連していることが知られている(非特許文献3)。また、動物レベルでは、肝臓のPCSK9を欠損させたマウスのLDLコレステロールは低値であることが示されている(非特許文献4)。
On the other hand, proprotein convertases (PCs) are members of the mammalian serine protease family and have been found to be homologous to subtilisins in bacteria and kexins in yeast. One of the PCs, PCSK9 (Proprotein convertase subtilisin / kexin type 9) is mainly expressed in the liver and secreted outside the cell, and is an LDL receptor on the surface of the liver cell membrane. And promotes the intracellular translocation of the LDL receptor. LDL receptors that have migrated into cells undergo degradation in intracellular organs. Since the LDL receptor has a function of transporting lipoproteins containing cholesterol from the circulating blood to the liver, the production of PCSK9 protein inhibits the uptake of LDL cholesterol into the liver, resulting in blood LDL cholesterol. To raise. Actually, the blood LDL cholesterol level of a human having a loss-of-function mutation in the PCSK9 gene is kept low (Non-patent Document 2). On the other hand, a gain-of-function mutation has been reported for the PCSK9 gene, and the human LDL cholesterol level in humans having this mutation is high, and is known to be associated with autosomal dominant hypercholesterolemia (non-native). Patent Document 3). Moreover, it has been shown that LDL cholesterol in mice lacking PCSK9 in the liver is low at the animal level (Non-patent Document 4).
以上のことより、PCSK9タンパクの産生抑制等によりその量を低減することやPCSK9タンパクの機能を阻害することは、LDL受容体量の増加につながり、ひいては強力なLDLコレステロール低下作用に結びつくものと考えられる。
Based on the above, it is considered that reducing the amount of PCSK9 protein by inhibiting the production thereof or inhibiting the function of PCSK9 protein leads to an increase in the amount of LDL receptor, which in turn leads to a strong LDL cholesterol lowering action. It is done.
このような背景から、最近、PCSK9タンパクの機能阻害や産生抑制に関する研究が活発に行われている。例えば、抗体やアンチセンスオリゴヌクレオチドを用いるものとしては、PCSK9のモノクローナル抗体によるPCSK9タンパクの機能阻害やRNA干渉によるPCSK9タンパクの産生抑制などが報告されている(非特許文献5~7)。また、低分子化合物を用いるものとしては、ベルベリンがHepG2細胞におけるPCSK9のmRNAとタンパクレベルを低下させるという報告(非特許文献8)や、アネキシンA2活性化剤である5-アザシチジンがPCSK9タンパクとアネキシンA2の結合を促進し、LDL受容体の分解を抑制するという報告がある(特許文献1)。しかし、低分子化合物のPCSK9タンパク機能阻害剤又はPCSK9タンパク産生抑制剤は前記したものの他にはほとんど報告がない。
Against this background, research on the inhibition of function and production of PCSK9 protein has been actively conducted recently. For example, as an antibody or an antisense oligonucleotide, inhibition of PCSK9 protein function by PCSK9 monoclonal antibody and suppression of PCSK9 protein production by RNA interference have been reported (Non-Patent Documents 5 to 7). In addition, as a low molecular weight compound, berberine reports that PCSK9 mRNA and protein levels in HepG2 cells are reduced (Non-patent Document 8), and annexin A2 activator 5-azacytidine is a PCSK9 protein and annexin. There is a report that promotes the binding of A2 and suppresses the degradation of the LDL receptor (Patent Document 1). However, PCSK9 protein function inhibitors or PCSK9 protein production inhibitors of low molecular weight compounds are hardly reported other than those described above.
なお、特許文献2~5にはコレステロールエステル転送タンパク(CETP)に対して強い阻害活性を示し、強い血中HDLコレステロール増加作用を有するジベンジルアミン構造を有するピリミジン化合物が開示されており、当該化合物を有効成分として含む医薬が高LDL血症の予防及び/又は治療に有用であることが教示されているが、この教示は、当該医薬がCETPを阻害することによりHDLを上昇させ、LDLに対して相対的にHDLレベルを高めることにより高LDL血症を予防及び/又は治療することができるということにあり、LDLを直接的に低下させる作用を有することを教示しているわけではない。
Patent Documents 2 to 5 disclose pyrimidine compounds having a dibenzylamine structure that exhibit strong inhibitory activity against cholesterol ester transfer protein (CETP) and have a strong blood HDL cholesterol increasing action. It is taught that a drug containing as an active ingredient is useful for the prevention and / or treatment of hyper-LDLemia, but this teaching increases HDL by inhibiting CETP, In other words, hyper-DLLemia can be prevented and / or treated by relatively increasing the HDL level, and does not teach that it has an action of directly reducing LDL.
また、次の一般式(a):
[式中、Yはアルキル基等で置換されてもよいメチレン基等を示し、Aは置換されてもよい複素環等を示し、Bは置換されてもよいフェニル基を示し、R1は水素原子又は置換されてもよいアルキル基を示し、R2は置換されてもよいアルキル基等を示す]で表されるピリミジン誘導体が報告されている(特許文献6)。しかしながら、当該文献に記載された化合物は、CETP阻害活性に基づく動脈硬化性疾患、高脂血症、脂質異常症の予防又は治療薬として有用であることは記載されているものの、PCSK9タンパクの阻害やPCSK9タンパクの発現抑制に関する記載や示唆はない。
Further, the following general formula (a):
[Wherein Y represents a methylene group which may be substituted with an alkyl group, etc., A represents a heterocyclic ring which may be substituted, B represents a phenyl group which may be substituted, and R 1 represents hydrogen. An atom or an alkyl group that may be substituted, and R 2 represents an alkyl group that may be substituted, etc.] has been reported (Patent Document 6). However, although the compounds described in this document are described as being useful as preventive or therapeutic agents for arteriosclerotic diseases, hyperlipidemia, and dyslipidemia based on CETP inhibitory activity, they inhibit PCSK9 protein. There is no description or suggestion regarding the expression suppression of PCSK9 protein.
また、次の一般式(b):
[式中、Xは-N(Ra)-等を示し、RaはC1-C10アルキル等を示し、L1及びL2はC1-C10アルキレンや結合等を示し、L3はC1-C10アリール等を示し、R1、R2及びR3は水素、-ORc等を示し、RcはC1-C10アルキル等を示し、R4は水素等を示し、R5はC3-C10シクロアルキル等を示す。]で表されるピリミジン誘導体が報告されている(特許文献7)。しかしながら、当該文献中に記載された化合物は、CXCR3またはCXCR4等のケモカイン受容体に結合することで、炎症疾患、免疫疾患等の治療に有効であることは記載されているものの、PCSK9タンパクの阻害やPCSK9タンパクの発現抑制に関する記載や示唆はない。
Moreover, the following general formula (b):
[Wherein, X represents —N (R a ) —, R a represents C 1 -C 10 alkyl, etc., L 1 and L 2 represent C 1 -C 10 alkylene, a bond, etc., and L 3 Represents C 1 -C 10 aryl and the like, R 1 , R 2 and R 3 represent hydrogen, —OR c and the like, R c represents C 1 -C 10 alkyl and the like, R 4 represents hydrogen and the like, R 5 represents C 3 -C 10 cycloalkyl or the like. ] Has been reported (Patent Document 7). However, although it is described that the compounds described in the literature are effective for treating inflammatory diseases, immune diseases, etc. by binding to chemokine receptors such as CXCR3 or CXCR4, inhibition of PCSK9 protein There is no description or suggestion regarding the expression suppression of PCSK9 protein.
さらに、次の一般式(c):
[式中、R1はC1-C4アルキルを示し、R2、R3及びR4はアルキルやアルコキシ等を示す。]で表されるピリミジン誘導体が報告されている(特許文献8)。しかしながら、当該文献中に記載された化合物は、インフルエンザの治療に有効であることは記載されているものの、PCSK9タンパクの阻害やPCSK9タンパクの発現抑制に関する記載や示唆はない。
Furthermore, the following general formula (c):
[Wherein R 1 represents C 1 -C 4 alkyl, and R 2 , R 3 and R 4 represent alkyl, alkoxy, or the like. ] Has been reported (Patent Document 8). However, although it is described that the compounds described in the literature are effective in treating influenza, there is no description or suggestion regarding inhibition of PCSK9 protein or suppression of expression of PCSK9 protein.
また、次の一般式(d):
[式中、R1はC1-15アルキル等を示し、R2はC1-15アルキル、シクロアルキル、フェニル、アラルキル等を示し、R3はC1-6アルキル、フェニル、アラルキル等を示し、R4はC1-6アルキル、フェニル、アラルキル等を示し、R5はC1-6アルキル、フェニル、アラルキル等を示す]で表されるピリミジン誘導体が報告されている(特許文献9)。しかしながら、当該文献中に記載された化合物は、ロイコトリエンの合成を阻害することで、肺病、アレルギー、喘息又は炎症疾患等の治療に有効であることは記載されているものの、PCSK9タンパクの阻害やPCSK9タンパクの発現抑制に関する記載や示唆はない。
Further, the following general formula (d):
[Wherein, R 1 represents C 1-15 alkyl, R 2 represents C 1-15 alkyl, cycloalkyl, phenyl, aralkyl, etc., and R 3 represents C 1-6 alkyl, phenyl, aralkyl, etc. , R 4 represents C 1-6 alkyl, phenyl, aralkyl and the like, and R 5 represents C 1-6 alkyl, phenyl, aralkyl and the like] (Patent Document 9). However, although it is described that the compounds described in the literature are effective in treating lung diseases, allergies, asthma, inflammatory diseases and the like by inhibiting the synthesis of leukotrienes, inhibition of PCSK9 protein and PCSK9 There is no description or suggestion regarding protein expression suppression.
PCsは癌細胞の増殖、運動、接着、侵襲に影響を与えることから、癌治療の標的として注目されている(非特許文献9)。その他、PCsは、肥満、糖尿病、動脈硬化症、アルツハイマー病との関連や、後天性免疫不全症候群(AIDS)や重症急性呼吸器症候群(SARS)等のウイルス感染症等の疾患にも関与することが知られている(非特許文献10及び11)。従って、PCSK9タンパク量の低下作用や機能阻害作用を有する化合物は、上記疾患に対する医薬の有効成分としての利用も期待できる。
PCs are attracting attention as targets for cancer treatment because they affect the growth, movement, adhesion, and invasion of cancer cells (Non-patent Document 9). PCs are also involved in obesity, diabetes, arteriosclerosis, Alzheimer's disease, and diseases such as acquired immune deficiency syndrome (AIDS) and severe acute respiratory syndrome (SARS). Is known (Non-Patent Documents 10 and 11). Therefore, a compound having a PCSK9 protein level-reducing action or a function-inhibiting action can be expected to be used as an active ingredient of a medicine for the above diseases.
本発明の課題は、PCSK9mRNAの発現を抑制し、PCSK9タンパク量を低下させ、LDL受容体量を増加させる作用を有する低分子化合物を有効成分として含み、血中LDLを低下させることができる医薬を提供することにある。
An object of the present invention is to provide a medicament capable of reducing blood LDL by containing, as an active ingredient, a low molecular weight compound having an action of suppressing the expression of PCSK9 mRNA, reducing the amount of PCSK9 protein, and increasing the amount of LDL receptor. It is to provide.
本発明者らは、上記目的を達成するため鋭意研究を続けた結果、次の一般式(I):
(式中、R1は、水素原子又は次式(II):
(ここでR3は、水素原子、C1-6アルキル基、ハロC1-6アルキル基、又はC3-8シクロアルキル基を示し、
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示し、ただし、それらのうちの0乃至2個は窒素原子に置き換えてもよく、
R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、C6-10アリール基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいアミノC1-6アルキル基、置換基を有してもよいカルバモイルC1-6アルキル基、C2-6アルケニル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールオキシC1-6アルキル基を示す。)
で表される化合物、若しくはその塩、又はそれらの溶媒和物がPCSK9mRNAに対して優れた発現抑制作用、PCSK9タンパクの産生抑制作用を示すことを見出した。PCSK9mRNA発現抑制作用、PCSK9タンパクの産生抑制作用はLDL受容体の分解を抑制し、ひいては血中LDLを低下させる作用につながるものである。本発明はこの知見を基にして完成された。 As a result of continuing intensive studies to achieve the above object, the present inventors have obtained the following general formula (I):
(In the formula, R 1 is a hydrogen atom or the following formula (II):
(Wherein R 3 represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 3-8 cycloalkyl group,
W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms Well,
R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 An alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) ( or it shows a R 10), or adjacent to each other may form a nitrogen-containing aromatic heterocyclic ring which may have a benzene ring or a substituted group which may have a substituent together
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted amino C 1-6 alkyl group, or an optionally substituted carbamoyl C. 1-6 alkyl group, C 2-6 alkenyl group, optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, carboxy 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 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom),
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group or a C 6-10 aryloxy C 1-6 alkyl group; )
It has been found that the compound represented by the formula (1) or a salt thereof, or a solvate thereof exhibits an excellent expression inhibitory action on PCSK9 mRNA and a PCSK9 protein production inhibitory action. PCSK9 mRNA expression-suppressing action and PCSK9 protein production-suppressing action suppress the degradation of LDL receptor, which leads to the action of lowering blood LDL. The present invention has been completed based on this finding.
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示し、ただし、それらのうちの0乃至2個は窒素原子に置き換えてもよく、
R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、C6-10アリール基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいアミノC1-6アルキル基、置換基を有してもよいカルバモイルC1-6アルキル基、C2-6アルケニル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールオキシC1-6アルキル基を示す。)
で表される化合物、若しくはその塩、又はそれらの溶媒和物がPCSK9mRNAに対して優れた発現抑制作用、PCSK9タンパクの産生抑制作用を示すことを見出した。PCSK9mRNA発現抑制作用、PCSK9タンパクの産生抑制作用はLDL受容体の分解を抑制し、ひいては血中LDLを低下させる作用につながるものである。本発明はこの知見を基にして完成された。 As a result of continuing intensive studies to achieve the above object, the present inventors have obtained the following general formula (I):
W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms Well,
R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 An alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) ( or it shows a R 10), or adjacent to each other may form a nitrogen-containing aromatic heterocyclic ring which may have a benzene ring or a substituted group which may have a substituent together
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted amino C 1-6 alkyl group, or an optionally substituted carbamoyl C. 1-6 alkyl group, C 2-6 alkenyl group, optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, carboxy 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 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom),
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group or a C 6-10 aryloxy C 1-6 alkyl group; )
It has been found that the compound represented by the formula (1) or a salt thereof, or a solvate thereof exhibits an excellent expression inhibitory action on PCSK9 mRNA and a PCSK9 protein production inhibitory action. PCSK9 mRNA expression-suppressing action and PCSK9 protein production-suppressing action suppress the degradation of LDL receptor, which leads to the action of lowering blood LDL. The present invention has been completed based on this finding.
すなわち、本発明により、血中LDLを低下させる医薬であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬が提供される。
That is, according to the present invention, there is provided a medicament for reducing LDL in blood, which comprises the compound represented by the general formula (I), a salt thereof, or a solvate thereof as an active ingredient.
当該医薬及び医薬組成物は、血中LDLコレステロールを低下させることにより、高血中LDLコレステロール状態に起因する疾患(例えば、高LDL血症、脂質異常症(高脂血症)、動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、高コレステロール血症、家族性高コレステロール血症、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧等)の予防及び/又は治療のための医薬として用いることができる。
The medicament and the pharmaceutical composition reduce blood LDL cholesterol, thereby causing diseases caused by high blood LDL cholesterol (for example, hyper LDL dysfunction, dyslipidemia (hyperlipidemia), arteriosclerosis, Atherosclerosis, peripheral vascular disease, hypercholesterolemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic re It can be used as a medicament for the prevention and / or treatment of stenosis, hypertension, etc.
さらに、本発明は、高血中LDLコレステロール状態に起因する疾患の予防及び/又は治療のための医薬を製造するための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用;高血中LDLコレステロール状態に起因する疾患の予防及び/又は治療に用いるための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を提供するものである。
Furthermore, the present invention relates to a compound represented by the above general formula (I) or a salt thereof for producing a medicament for the prevention and / or treatment of a disease caused by a high blood LDL cholesterol state, or a salt thereof, Use of a solvate; providing a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for use in the prevention and / or treatment of a disease caused by high blood LDL cholesterol status To do.
また、本発明により、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むPCSK9mRNA発現抑制剤;前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むPCSK9産生抑制剤が提供される。PCSK9mRNA発現抑制剤の製造のための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用;PCSK9mRNA発現抑制に用いるための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物も本発明により提供される。
In addition, according to the present invention, a compound represented by the general formula (I), a salt thereof, or a PCSK9 mRNA expression inhibitor containing the solvate as an active ingredient; a compound represented by the general formula (I), Alternatively, a PCSK9 production inhibitor containing a salt thereof or a solvate thereof as an active ingredient is provided. Use of the compound represented by the above general formula (I), or a salt thereof, or a solvate thereof for the production of a PCSK9 mRNA expression inhibitor; represented by the above general formula (I) for use in suppressing PCSK9 mRNA expression Or a salt thereof, or a solvate thereof is also provided by the present invention.
さらに、本発明は、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とするPCSK9タンパク量の低下剤;前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とするPCSK9タンパク産生抑制剤;及び前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とするLDL受容体量の増加剤を提供するものである。
Furthermore, the present invention provides a PCSK9 protein amount reducing agent comprising the compound represented by the general formula (I) or a salt thereof, or a solvate thereof as an active ingredient; represented by the general formula (I) PCSK9 protein production inhibitor comprising a compound, or a salt thereof, or a solvate thereof as an active ingredient; and a compound represented by the general formula (I), or a salt thereof, or a solvate thereof as an active ingredient The present invention provides an agent for increasing the amount of LDL receptor.
また、本発明は、PCSK9タンパク量の低下剤、PCSK9タンパク産生抑制剤又はLDL受容体量の増加剤を製造するための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用;及びPCSK9タンパク量の低下、PCSK9タンパク産生抑制又はLDL受容体量の増加に用いるための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を提供するものである。
Further, the present invention provides a compound represented by the above general formula (I) for producing a PCSK9 protein amount reducing agent, a PCSK9 protein production inhibitor or an LDL receptor amount increasing agent, or a salt thereof, or their Use of a solvate; and a compound represented by the above general formula (I) or a salt thereof, or a solvate thereof for use in reducing PCSK9 protein amount, inhibiting PCSK9 protein production, or increasing LDL receptor amount Is to provide.
さらに、本発明は、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分とする、PCsの関与する疾患(癌、肥満、糖尿病、アルツハイマー病、又はウイルス感染症等)の予防及び/又は治療のための医薬を提供するものである。
Furthermore, the present invention relates to a disease associated with PCs (cancer, obesity, diabetes, Alzheimer's disease, or the like, comprising the compound represented by the above general formula (I), a salt thereof, or a solvate thereof as an active ingredient. The present invention provides a medicament for the prevention and / or treatment of viral infections and the like.
さらに、本発明は、PCsの関与する疾患の予防及び/又は治療のための医薬を製造するための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の使用;及びPCsの関与する疾患の予防及び/又は治療に用いるための前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を提供するものである。
Furthermore, the present invention relates to the use of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for the manufacture of a medicament for the prevention and / or treatment of diseases involving PCs. And a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for use in the prevention and / or treatment of diseases involving PCs.
さらに別の観点から、本発明は、前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を有効成分とするHMG-CoA還元酵素mRNA発現抑制剤;前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を有効成分とするHMG-CoA還元酵素産生抑制剤;及び前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を有効成分とするHMG-CoA還元酵素mRNA発現に起因する疾患(例えば、炎症、癌、アルツハイマー病、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染、ウイルス感染、乾癬、黄斑変性など)の予防及び/又は治療のための医薬を提供するものである。
From still another aspect, the present invention provides an HMG-CoA reductase mRNA expression inhibitor comprising as an active ingredient the compound represented by the general formula (I), or a salt thereof, or a solvate thereof; HMG-CoA reductase production inhibitor comprising a compound represented by formula (I), or a salt thereof, or a solvate thereof as an active ingredient; and a compound represented by general formula (I), or a compound thereof Diseases caused by expression of HMG-CoA reductase mRNA containing a salt of glycerin or a solvate thereof as an active ingredient (eg inflammation, cancer, Alzheimer's disease, osteoporosis, prostatic hypertrophy, glomerular disease, parasitic infection, viral infection , Psoriasis, macular degeneration, and the like).
また、本発明は、HMG-CoA還元酵素mRNA発現抑制剤、HMG-CoA還元酵素産生抑制剤、又はHMG-CoA還元酵素mRNA発現に起因する疾患の予防及び/又は治療のための医薬を製造するための前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の使用;及びHMG-CoA還元酵素mRNA発現抑制剤、HMG-CoA還元酵素産生抑制剤、又はHMG-CoA還元酵素mRNA発現に起因する疾患の予防及び/又は治療のための医薬の有効成分として使用するための前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物を提供するものである。
The present invention also provides an HMG-CoA reductase mRNA expression inhibitor, an HMG-CoA reductase production inhibitor, or a medicament for the prevention and / or treatment of diseases caused by HMG-CoA reductase mRNA expression. And the use of a compound represented by the general formula (I), or a salt thereof, or a solvate thereof; and an HMG-CoA reductase mRNA expression inhibitor, an HMG-CoA reductase production inhibitor, or an HMG -A compound represented by the above general formula (I), or a salt thereof, or a solvation thereof for use as an active ingredient of a medicament for the prevention and / or treatment of diseases caused by CoA reductase mRNA expression It provides things.
また、本発明は、ヒトを含む哺乳類動物の生体内においてPCSK9mRNAの発現を抑制する方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法;ヒトを含む哺乳類動物の生体内においてPCSK9タンパク量を低下させる方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法;ヒトを含む哺乳類動物の生体内においてPCSK9タンパクの産生を抑制する方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法;ヒトを含む哺乳類動物の生体内においてLDL受容体量を増加する方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量をヒトを含む哺乳類動物に投与する工程を含む方法;及び、ヒトを含む哺乳類動物の血中LDLを低下させる方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。
The present invention also relates to a method for suppressing the expression of PCSK9 mRNA in vivo in mammals including humans, wherein the compound represented by the general formula (I), a salt thereof, or an effective solvate thereof is used. A method comprising a step of administering an amount to a mammal including a human; a method for reducing the amount of PCSK9 protein in a living body of a mammal including a human, the compound represented by the general formula (I), or a method thereof A method comprising a step of administering an effective amount of a salt or a solvate thereof to a mammal including a human; a method for suppressing the production of PCSK9 protein in a living body of a mammal including a human, wherein the general formula A method comprising administering an effective amount of a compound represented by (I) or a salt thereof, or a solvate thereof to a mammal including a human; A method for increasing the amount of LDL receptor in vivo, wherein an effective amount of the compound represented by the general formula (I), a salt thereof, or a solvate thereof is administered to mammals including humans And a method for lowering blood LDL in mammals including humans, wherein an effective amount of the compound represented by the general formula (I), a salt thereof, or a solvate thereof is obtained. A method comprising the step of administering to a mammal, including a human.
また、本発明は、ヒトを含む哺乳類動物における高血中LDLコレステロール状態に起因する疾患の予防及び/又は治療方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。
The present invention also relates to a method for preventing and / or treating a disease caused by high blood LDL cholesterol status in mammals including humans, the compound represented by the general formula (I), or a salt thereof, or The present invention provides a method comprising the step of administering an effective amount of these solvates to mammals including humans.
さらに、本発明は、ヒトを含む哺乳類動物におけるPCsの関与する疾患(癌、肥満、糖尿病、アルツハイマー病、又はウイルス感染症等)の予防及び/又は治療方法であって、前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。
Furthermore, the present invention is a method for preventing and / or treating diseases (cancer, obesity, diabetes, Alzheimer's disease, viral infection, etc.) involving PCs in mammals including humans, wherein the general formula (I) And a salt thereof, or a solvate thereof, is administered to mammals including humans.
さらに、本発明は、ヒトを含む哺乳類動物の生体内においてHMG-CoA還元酵素mRNAの発現を抑制する方法であって、前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の有効量をヒトを含む哺乳類動物に投与する工程を含む方法;ヒトを含む哺乳類動物の生体内においてHMG-CoA還元酵素の産生を抑制する方法であって、前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法;及び、ヒトを含む哺乳類動物においてHMG-CoA還元酵素mRNA発現に起因する疾患(例えば、炎症、癌、アルツハイマー病、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染、ウイルス感染、乾癬、黄斑変性など)を予防及び/又は治療する方法であって、前記一般式(I)で表される化合物、若しくはそれらの塩、又はそれらの溶媒和物の有効量を、ヒトを含む哺乳類動物に投与する工程を含む方法を提供するものである。
Furthermore, the present invention provides a method for suppressing the expression of HMG-CoA reductase mRNA in the living body of mammals including humans, comprising the compound represented by the general formula (I), or a salt thereof, A method comprising the step of administering an effective amount of a solvate of the above to a mammal including a human; a method for inhibiting the production of HMG-CoA reductase in a living body of a mammal including a human, wherein the general formula (I And a method comprising administering an effective amount of a compound represented by the above formula, or a salt thereof, or a solvate thereof to a mammal including a human; and HMG-CoA reductase mRNA in a mammal including a human; Diseases caused by the expression (eg inflammation, cancer, Alzheimer's disease, osteoporosis, enlarged prostate, glomerular disease, parasitic infection, viral infection, psoriasis, macular degeneration, etc.) A method for preventing and / or treating, comprising a step of administering an effective amount of the compound represented by the general formula (I), or a salt thereof, or a solvate thereof to mammals including humans. A method is provided.
さらに別の観点からは、本発明により、次の一般式(I):
(式中、R1は、水素原子又は次式(II):
(ここでR3は、水素原子、C1-6アルキル基、ハロC1-6アルキル基、又はC3-8シクロアルキル基を示し、
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示し、ただし、それらのうちの0乃至2個は窒素原子に置き換えてもよく、
R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、C6-10アリール基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいアミノC1-6アルキル基、置換基を有してもよいカルバモイルC1-6アルキル基、C2-6アルケニル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールオキシC1-6アルキル基を示し、
但し、R11がC1-4アルキル基であり、W1、W2、W3、W4、W5がCR4、CR5、CR6、CR7、CR8であるとき、R4、R5、R6、R7、R8が、水素原子、C1-4アルキル基、C1-4アルコキシ基、ハロゲン原子、ジエチルアミノ基である化合物を除く。)
で表される化合物、若しくはその塩、又はそれらの溶媒和物が新規物質として提供される。
但し、
5-メトキシピリミジン-2-アミン、
5-エトキシピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、及び
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチルを除く。 From yet another aspect, the present invention provides the following general formula (I):
(In the formula, R 1 is a hydrogen atom or the following formula (II):
(Wherein R 3 represents a hydrogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, or a C 3-8 cycloalkyl group,
W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms Well,
R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 An alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) ( or it shows a R 10), or adjacent to each other may form a nitrogen-containing aromatic heterocyclic ring which may have a benzene ring or a substituted group which may have a substituent together
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted amino C 1-6 alkyl group, or an optionally substituted carbamoyl C. 1-6 alkyl group, C 2-6 alkenyl group, optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, carboxy 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 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom),
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group, or a C 6-10 aryloxy C 1-6 alkyl group,
Provided that when R 11 is a C 1-4 alkyl group and W 1 , W 2 , W 3 , W 4 , W 5 are CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , R 4 , Excludes compounds in which R 5 , R 6 , R 7 , and R 8 are a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogen atom, or a diethylamino group. )
Or a salt thereof, or a solvate thereof is provided as a novel substance.
However,
5-methoxypyrimidin-2-amine,
5-ethoxypyrimidin-2-amine,
5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, and 4-[( Except ethyl 2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyrate.
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示し、ただし、それらのうちの0乃至2個は窒素原子に置き換えてもよく、
R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、C6-10アリール基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいアミノC1-6アルキル基、置換基を有してもよいカルバモイルC1-6アルキル基、C2-6アルケニル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールオキシC1-6アルキル基を示し、
但し、R11がC1-4アルキル基であり、W1、W2、W3、W4、W5がCR4、CR5、CR6、CR7、CR8であるとき、R4、R5、R6、R7、R8が、水素原子、C1-4アルキル基、C1-4アルコキシ基、ハロゲン原子、ジエチルアミノ基である化合物を除く。)
で表される化合物、若しくはその塩、又はそれらの溶媒和物が新規物質として提供される。
但し、
5-メトキシピリミジン-2-アミン、
5-エトキシピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、及び
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチルを除く。 From yet another aspect, the present invention provides the following general formula (I):
W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms Well,
R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 An alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) ( or it shows a R 10), or adjacent to each other may form a nitrogen-containing aromatic heterocyclic ring which may have a benzene ring or a substituted group which may have a substituent together
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted amino C 1-6 alkyl group, or an optionally substituted carbamoyl C. 1-6 alkyl group, C 2-6 alkenyl group, optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, carboxy 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 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom),
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group, or a C 6-10 aryloxy C 1-6 alkyl group,
Provided that when R 11 is a C 1-4 alkyl group and W 1 , W 2 , W 3 , W 4 , W 5 are CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , R 4 , Excludes compounds in which R 5 , R 6 , R 7 , and R 8 are a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogen atom, or a diethylamino group. )
Or a salt thereof, or a solvate thereof is provided as a novel substance.
However,
5-methoxypyrimidin-2-amine,
5-ethoxypyrimidin-2-amine,
5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, and 4-[( Except ethyl 2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyrate.
さらに別の観点からは、本発明により、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチル、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチル、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
並びにそれらの塩、及びそれらの溶媒和物が新規物質として提供される。 From another point of view, according to the present invention,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
Ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Methyl propionate,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-chloropyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
And their salts and their solvates are provided as novel substances.
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチル、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチル、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
並びにそれらの塩、及びそれらの溶媒和物が新規物質として提供される。 From another point of view, according to the present invention,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
Ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Methyl propionate,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-chloropyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
And their salts and their solvates are provided as novel substances.
本発明の前記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物は、後述する実施例に具体的に開示されている通り、PCSK9mRNAに対し強い発現抑制作用を示し、PCSK9タンパクの産生抑制を示すことから、PCSK9タンパクの産生に基づく疾患の予防及び/又は治療剤の有効成分として好適に使用でき、血中LDLを低下させる医薬の有効成分として特に好適に使用することができる。
The compound represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof exhibits a strong expression inhibitory action on PCSK9 mRNA, as specifically disclosed in Examples described later. Since it shows suppression of PCSK9 protein production, it can be suitably used as an active ingredient of a prophylactic and / or therapeutic agent for diseases based on the production of PCSK9 protein, and is particularly preferably used as an active ingredient of a medicine that lowers blood LDL. be able to.
本明細書において、「C1-6アルキル」、「C1-4アルキル」、「ハロC1-6アルキル」、「C1-6アルコキシ」、「ハロC1-6アルコキシ」、「C1-6アルキルチオ」、「C1-6アルキルスルフィニル」、「C1-6アルキルスルホニル」、「C1-6アルキルスルホニルアミノ」、「ハロC1-6アルキルスルホニルアミノ」、「C1-6アルキルカルボニル」、「C1-6アルコキシカルボニル」、「C3-8シクロアルキルC1-6アルキル」、「C1-6アルコキシカルボニルC1-6アルキル」、「C6-10アリールC1-6アルキル」、「C1-6アルキルチオC1-6アルキル」、「C1-6アルキルスルフィニルC1-6アルキル」、「C1-6アルキルスルホニルC1-6アルキル」、「C1-6アルコキシカルボニルアルキル」「カルボキシC1-6アルキル」「C6-10アリールチオC1-6アルキル」、「C6-10アリールスルフィニルC1-6アルキル」、「C6-10アリールスルホニルC1-6アルキル」、「C6-10アリールオキシC1-6アルキル」基における「アルキル」部としては、直鎖、又は分岐鎖のアルキルが挙げられる。「C1-6アルキル」としては、具体的には、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、イソペンチル、ネオペンチル、2-メチルブチル、1-エチルプロピル、n-ヘキシル、イソヘキシル、3-メチルペンチル、2-メチルペンチル、1-メチルペンチル、3,3-ジメチルブチル、2,2-ジメチルブチル、1,1-ジメチルブチル、1,2-ジメチルブチル、1,3-ジメチルブチル、2,3-ジメチルブチル、1-エチルブチル、2-エチルブチル等が挙げられ、「C1-4アルキル」としては、具体的には、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル等が挙げられる。
In the present specification, “C 1-6 alkyl”, “C 1-4 alkyl”, “halo C 1-6 alkyl”, “C 1-6 alkoxy”, “halo C 1-6 alkoxy”, “C 1 -6 alkylthio "," C 1-6 alkylsulfinyl "," C 1-6 alkylsulfonyl "," C 1-6 alkylsulfonylamino "," halo C 1-6 alkylsulfonylamino "," C 1-6 alkyl “Carbonyl”, “C 1-6 alkoxycarbonyl”, “C 3-8 cycloalkyl C 1-6 alkyl”, “C 1-6 alkoxycarbonyl C 1-6 alkyl”, “C 6-10 aryl C 1-6” alkyl "," C 1-6 alkylthio C 1-6 alkyl "," C 1-6 alkylsulfinyl C 1-6 alkyl "," C 1-6 alkylsulfonyl C 1-6 alkyl ""C 1-6 alkoxycarbonylalkyl,""carboxy C 1-6 alkyl", "C 6-10 arylthio C 1-6 alkyl", "C 6-10 arylsulfinyl C 1-6 alkyl", "C 6-10 aryl Examples of the “alkyl” part in the “sulfonyl C 1-6 alkyl” and “C 6-10 aryloxy C 1-6 alkyl” groups include linear or branched alkyl. Specific examples of “C 1-6 alkyl” include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2 -Methylbutyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl and the like. Specific examples of “C 1-4 alkyl” include, for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. And the like.
本明細書において、「C2-6アルケニル基」とは、アルキル鎖上のいずれか1カ所以上に炭素-炭素二重結合を有する炭素数2~6の直鎖、又は分岐鎖のアルケニル基を意味する。「C2-6アルケニル基」としては、具体的には、例えば、ビニル、アリル、1-プロペニル、イソプロペニル、ブタ-1-エン-1-イル、ブタ-2-エン-1-イル、ブタ-3-エン-1-イル、ブタ-1-エン-2-イル、ブタ-3-エン-2-イル、ペンタ-1-エン-1-イル、ペンタ-4-エン-1-イル、ペンタ-1-エン-2-イル、ペンタ-4-エン-2-イル、3-メチル-ブタ-1-エン-1-イル、ヘキサ-1-エン-1-イル基、ヘキサ-5-エン-1-イル等が挙げられる。
In the present specification, the “C 2-6 alkenyl group” refers to a C 2-6 linear or branched alkenyl group having a carbon-carbon double bond at any one or more positions on the alkyl chain. means. Specific examples of the “C 2-6 alkenyl group” include, for example, vinyl, allyl, 1-propenyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, buta -3-en-1-yl, but-1-en-2-yl, but-3-en-2-yl, penta-1-en-1-yl, penta-4-en-1-yl, penta -1-en-2-yl, penta-4-en-2-yl, 3-methyl-but-1-en-1-yl, hexa-1-en-1-yl group, hexa-5-ene- 1-yl and the like can be mentioned.
本明細書において、「C1-6アルキルチオ」、「C1-6アルキルチオC1-6アルキル」基における「C1-6アルキルチオ」部としては、例えば、メチルチオ、エチルチオ、n-プロピルチオ、イソプロピルチオ、n-ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオ、n-ペンチルチオ、イソペンチルチオ、ネオペンチルチオ、2-メチルブチルチオ、1-エチルプロピルチオ、n-ヘキシルチオ、イソヘキシルチオ、3-メチルペンチルチオ、2-メチルペンチルチオ、1-メチルペンチルチオ、3,3-ジメチルブチルチオ、2,2-ジメチルブチルチオ、1,1-ジメチルブチルチオ、1,2-ジメチルブチルチオ、1,3-ジメチルブチルチオ、2,3-ジメチルブチルチオ、1-エチルブチルチオ、2-エチルブチルチオ等が挙げられる。
In the present specification, examples of the “C 1-6 alkylthio” part in the “C 1-6 alkylthio”, “C 1-6 alkylthio C 1-6 alkyl” group include, for example, methylthio, ethylthio, n-propylthio, isopropylthio , N-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, 2-methylbutylthio, 1-ethylpropylthio, n-hexylthio, isohexylthio, 3- Methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1, 3-dimethylbutylthio, 2,3-dimethylbutylthio, 1-ethylbutyl Examples thereof include thio and 2-ethylbutylthio.
本明細書において、「C1-6アルキルスルフィニル」、「C1-6アルキルスルフィニルC1-6アルキル」基における「C1-6アルキルスルフィニル」部としては、例えば、メチルスルフィニル、エチルスルフィニル、n-プロピルスルフィニル、イソプロピルスルフィニル、n-ブチルスルフィニル、イソブチルスルフィニル、sec-ブチルスルフィニル、tert-ブチルスルフィニル、n-ペンチルスルフィニル、イソペンチルスルフィニル、ネオペンチルスルフィニル、2-メチルブチルスルフィニル、1-エチルプロピルスルフィニル、n-ヘキシルスルフィニル、イソヘキシルスルフィニル、3-メチルペンチルスルフィニル、2-メチルペンチルスルフィニル、1-メチルペンチルスルフィニル、3,3-ジメチルブチルスルフィニル、2,2-ジメチルブチルスルフィニル、1,1-ジメチルブチルスルフィニル、1,2-ジメチルブチルスルフィニル、1,3-ジメチルブチルスルフィニル、2,3-ジメチルブチルスルフィニル、1-エチルブチルスルフィニル、2-エチルブチルスルフィニル等が挙げられる。
In the present specification, "C 1-6 alkylsulfinyl", as the "C 1-6 alkylsulfinyl" section of the "C 1-6 alkylsulfinyl C 1-6 alkyl" group, for example, methylsulfinyl, ethylsulfinyl, n -Propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, 2-methylbutylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3,3-dimethyl Butylsulfinyl, 2,2-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2 -Ethylbutylsulfinyl and the like.
本明細書において、「C1-6アルキルスルホニル」、「C1-6アルキルスルホニルアミノ」、「ハロC1-6アルキルスルホニルアミノ」、「C1-6アルキルスルホニルC1-6アルキル」基における「C1-6アルキルスルホニル」部としては、例えば、メチルスルホニル、エチルスルホニル、n-プロピルスルホニル、イソプロピルスルホニル、n-ブチルスルホニル、イソブチルスルホニル、sec-ブチルスルホニル、tert-ブチルスルホニル、n-ペンチルスルホニル、イソペンチルスルホニル、ネオペンチルスルホニル、2-メチルブチルスルホニル、1-エチルプロピルスルホニル、n-ヘキシルスルホニル、イソヘキシルスルホニル、3-メチルペンチルスルホニル、2-メチルペンチルスルホニル、1-メチルペンチルスルホニル、3,3-ジメチルブチルスルホニル、2,2-ジメチルブチルスルホニル、1,1-ジメチルブチルスルホニル、1,2-ジメチルブチルスルホニル、1,3-ジメチルブチルスルホニル、2,3-ジメチルブチルスルホニル、1-エチルブチルスルホニル、2-エチルブチルスルホニル等が挙げられる。
In the present specification, in the “C 1-6 alkylsulfonyl”, “C 1-6 alkylsulfonylamino”, “halo C 1-6 alkylsulfonylamino”, “C 1-6 alkylsulfonyl C 1-6 alkyl” groups Examples of the “C 1-6 alkylsulfonyl” part include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl. , Isopentylsulfonyl, neopentylsulfonyl, 2-methylbutylsulfonyl, 1-ethylpropylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methyl Rupentylsulfonyl, 3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutyl Examples include sulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl and the like.
本明細書において、「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。
In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
本明細書において、「ハロアルキル」とは、化学的に許容される個数のハロゲン原子(フッ素原子、塩素原子、臭素原子、ヨウ素原子等)が置換した直鎖、又は分岐鎖のアルキルが挙げられる。従って、「ハロC1-6アルキル」としては、例えば、フルオロメチル、ジフルオロメチル、トリフルオロメチル、クロロメチル、ブロモメチル、ヨードメチル、2,2,2-トリフルオロエチル、ペンタフルオロエチル等が挙げられる。従って、「ハロC1-6アルコキシ」としては、例えば、フルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、クロロメトキシ、ブロモメトキシ、ヨードメトキシ、2,2,2-トリフルオロエトキシ、ペンタフルオロエトキシ等が挙げられる。
In the present specification, “haloalkyl” includes linear or branched alkyl substituted with a chemically acceptable number of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.). Accordingly, examples of “halo C 1-6 alkyl” include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, iodomethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like. Accordingly, examples of “halo C 1-6 alkoxy” include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like. It is done.
本明細書において、「C1-6アルコキシ」、「ハロC1-6アルコキシ」「C1-6アルコキシカルボニル」基における「C1-6アルコキシ」部としては、例えば、メトキシ、エトキシ、n-プロピルオキシ、イソプロピルオキシ、n-ブチルオキシ、イソブチルオキシ、sec-ブチルオキシ、tert-ブチルオキシ、n-ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、2-メチルブチルオキシ、1-エチルプロピルオキシ、n-ヘキシルオキシ、イソヘキシルオキシ、3-メチルペンチルオキシ、2-メチルペンチルオキシ、1-メチルペンチルオキシ、3,3-ジメチルブチルオキシ、2,2-ジメチルブチルオキシ、1,1-ジメチルブチルオキシ、1,2-ジメチルブチルオキシ、1,3-ジメチルブチルオキシ、2,3-ジメチルブチルオキシ、1-エチルブチルオキシ、2-エチルブチルオキシ等が挙げられる。
In the present specification, examples of the “C 1-6 alkoxy” moiety in the “C 1-6 alkoxy”, “halo C 1-6 alkoxy”, “C 1-6 alkoxycarbonyl” group include methoxy, ethoxy, n- Propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutyloxy, 1-ethylpropyloxy, n-hexyloxy , Isohexyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,1-dimethylbutyloxy, 1,2 -Dimethylbutyloxy, 1,3-dimethylbutyl Examples include oxy, 2,3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy and the like.
本明細書において、「C6-10アリールスルホニルアミノ」、「C6-10アリール」、「C6-10アリールC1-6アルキル」、「C6-10アリールチオC1-6アルキル」、「C6-10アリールスルフィニルC1-6アルキル」、「C6-10アリールスルホニルC1-6アルキル」、「C6-10アリールオキシC1-6アルキル」基における「C6-10アリール」部としては、例えば、フェニル、アズレニル、ナフチル等が挙げられる。
In the present specification, “C 6-10 arylsulfonylamino”, “C 6-10 aryl”, “C 6-10 aryl C 1-6 alkyl”, “C 6-10 arylthio C 1-6 alkyl”, “ C 6-10 arylsulfinyl C 1-6 alkyl "," C 6-10 arylsulfonyl C 1-6 alkyl ",""C 6-10 aryl in C 6-10 aryloxy C 1-6 alkyl" group "portion Examples thereof include phenyl, azulenyl, naphthyl and the like.
本明細書において、「C3-8シクロアルキルC1-6アルキル」、「C3-8シクロアルキル」基における「C3-8シクロアルキル」部としては、炭素数3乃至8個、好ましくは5乃至7個の飽和シクロアルキル基であり、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル及びシクロオクチル等が挙げられる。
In the present specification, "C 3-8 cycloalkyl C 1-6 alkyl", as the "C 3-8 cycloalkyl" section of the "C 3-8 cycloalkyl" group, having 3 to 8 carbon atoms, preferably 5 to 7 saturated cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
本明細書において、「含窒素飽和複素環」としては、少なくとも一つの窒素原子を包含する飽和の単環の5乃至7員の複素環であり、例えば、ピロリジン、イミダゾリジン、ピラゾリジン、オキサゾリジン、チアゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、2-オキソピロリジン、2-オキソピペリジン、4-オキソピペリジン又は2,6-ジオキソピペリジン環等が挙げられる。
In the present specification, the “nitrogen-containing saturated heterocycle” is a saturated monocyclic 5- to 7-membered heterocycle containing at least one nitrogen atom. For example, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, thiazolidine , Piperidine, piperazine, morpholine, thiomorpholine, 2-oxopyrrolidine, 2-oxopiperidine, 4-oxopiperidine, or 2,6-dioxopiperidine ring.
本明細書において、「含窒素芳香族複素環」としては、少なくとも一つの窒素原子を包含する芳香族の単環の5乃至6員の複素環であり、例えば、ピロール、イミダゾール、ピラゾール、トリアゾール、オキサゾール、イソオキサゾール、オキサジアゾール、チアゾール、イソチアゾール、ピリジン、ピラジン、ピリミジン、ピリダジン環等が挙げられる。
In the present specification, the “nitrogen-containing aromatic heterocycle” is an aromatic monocyclic 5- to 6-membered heterocycle containing at least one nitrogen atom, such as pyrrole, imidazole, pyrazole, triazole, Examples include oxazole, isoxazole, oxadiazole, thiazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine ring and the like.
一般式(II)中、R3におけるC1-6アルキル基としては、C1-4アルキル基が好ましく、メチル基がより好ましい。
In general formula (II), the C 1-6 alkyl group in R 3 is preferably a C 1-4 alkyl group, and more preferably a methyl group.
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示すが、ただし、CR4、CR5、CR6、CR7、CR8のうちの0乃至2個は窒素原子に置き換えてもよい。
W 1 , W 2 , W 3 , W 4 , W 5 indicate CR 4 , CR 5 , CR 6 , CR 7 , CR 8 respectively, but CR 4 , CR 5 , CR 6 , CR 7 , CR 0 to 2 of 8 may be replaced with nitrogen atoms.
一般式(II)中、R4、R5、R6、R7、R8におけるC1-6アルキル基としては、C1-4アルキル基が好ましく、メチル基、エチル基がより好ましい。
In the general formula (II), the C 1-6 alkyl group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 1-4 alkyl group, more preferably a methyl group or an ethyl group.
一般式(II)中、R4、R5、R6、R7、R8におけるハロC1-6アルキル基としては、ハロC1-4アルキル基が好ましく、トリフルオロメチル基がより好ましい。
In general formula (II), the halo C 1-6 alkyl group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a halo C 1-4 alkyl group, more preferably a trifluoromethyl group.
一般式(II)中、R4、R5、R6、R7、R8におけるC1-6アルコキシ基としては、C1-4アルコキシ基が好ましく、メトキシ基がより好ましい。
In the general formula (II), the C 1-6 alkoxy group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 1-4 alkoxy group, and more preferably a methoxy group.
一般式(II)中、R4、R5、R6、R7、R8におけるハロゲン原子としては、フッ素、塩素、臭素原子が好ましい。
In general formula (II), as a halogen atom in R < 4 >, R < 5 >, R < 6 >, R < 7 >, R < 8 >, a fluorine, chlorine, bromine atom is preferable.
一般式(II)中、R4、R5、R6、R7、R8におけるC6-10アリール基としては、フェニル基が好ましい。
In general formula (II), the C 6-10 aryl group in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a phenyl group.
一般式(II)中、R4、R5、R6、R7、R8において「隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環」における含窒素芳香族複素環としては、ピラゾール環が好ましい。「隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環」における置換基としてはC1-6アルキル基、C1-6アルコキシル基、ハロC1-6アルキル基が好ましく、メチル基、メトキシ基、トリフルオロメチル基がより好ましい。
In the general formula (II), R 4, R 5, R 6, R 7, "adjacent to each other in R 8 may have a benzene ring or a substituted group which may have a substituent together The nitrogen-containing aromatic heterocycle in the “nitrogen-containing aromatic heterocycle” is preferably a pyrazole ring. Examples of the substituent in the “benzene ring which may be adjacent to each other together or a nitrogen-containing aromatic heterocyclic ring which may have a substituent” may be a C 1-6 alkyl group, C 1- A 6 alkoxyl group and a halo C 1-6 alkyl group are preferable, and a methyl group, a methoxy group, and a trifluoromethyl group are more preferable.
一般式(II)中、R4、R5、R6、R7、R8におけるNR9R10におけるC1-6アルキル基としては、C1-4アルキル基が好ましく、メチル基、エチル基、n-プロピル基、n-ブチル基がより好ましい。
In the general formula (II), the C 1-6 alkyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 1-4 alkyl group, a methyl group, an ethyl group N-propyl group and n-butyl group are more preferable.
一般式(II)中、R4、R5、R6、R7、R8におけるNR9R10におけるC2-6アルケニル基としては、C2-4アルケニル基が好ましく、アリル基がより好ましい。
In the general formula (II), the C 2-6 alkenyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a C 2-4 alkenyl group, more preferably an allyl group. .
一般式(II)中、R4、R5、R6、R7、R8におけるN(R9)(R10)において「置換基を有してよいC3-8シクロアルキルC1-6アルキル基」におけるC3-8シクロアルキルC1-6アルキル基としては、C3-6シクロアルキルC1-4アルキル基が好ましく、シクロヘキシルメチル基、シクロペンチルメチル基、シクロプロピルメチル基がより好ましい。「置換基を有してよいC3-8シクロアルキルC1-6アルキル基」における置換基としては、メトキシカルボニルメチル基、エトキシカルボニルメチル基、ベンジルオキシカルボニルメチル基、カルボキシメチル基が好ましい。
In the general formula (II), N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 , R 8 represents “C 3-8 cycloalkyl C 1-6 which may have a substituent. The C 3-8 cycloalkyl C 1-6 alkyl group in the “alkyl group” is preferably a C 3-6 cycloalkyl C 1-4 alkyl group, more preferably a cyclohexylmethyl group, a cyclopentylmethyl group, or a cyclopropylmethyl group. The substituent in the “optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group” is preferably a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a benzyloxycarbonylmethyl group, or a carboxymethyl group.
一般式(II)中、R4、R5、R6、R7、R8におけるNR9R10におけるC1-6アルコキシカルボニルC1-6アルキル基としては、メトキシカルボニルエチル基が好ましい。
In formula (II), the C 1-6 alkoxycarbonyl C 1-6 alkyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a methoxycarbonylethyl group.
一般式(II)中、R4、R5、R6、R7、R8におけるNR9R10におけるカルボキシC1-6アルキル基としては、カルボキシエチル基が好ましい。
In general formula (II), the carboxy C 1-6 alkyl group in NR 9 R 10 in R 4 , R 5 , R 6 , R 7 , R 8 is preferably a carboxyethyl group.
一般式(II)中、R4、R5、R6、R7、R8におけるN(R9)(R10)においてC6-10アリール基としては、フェニル基が好ましい。
In general formula (II), the phenyl group is preferred as the C 6-10 aryl group in N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 , R 8 .
一般式(II)中、R4、R5、R6、R7、R8におけるN(R9)(R10)において「置換基を有してもよいC6-10アリールC1-6アルキル基」におけるC6-10アリールC1-6アルキル基としては、フェニルC1-4アルキル基が好ましく、ベンジル基がより好ましい。「置換基を有してもよいC6-10アリールC1-6アルキル基」における置換基としては、メトキシ基が好ましい。
In the general formula (II), N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 and R 8 may be “C 6-10 aryl C 1-6 optionally having substituent (s)” The C 6-10 aryl C 1-6 alkyl group in the “alkyl group” is preferably a phenyl C 1-4 alkyl group, more preferably a benzyl group. As the substituent in the “optionally substituted C 6-10 aryl C 1-6 alkyl group”, a methoxy group is preferable.
一般式(II)中、R4、R5、R6、R7、R8におけるN(R9)(R10)において「R9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環」における含窒素飽和複素環としては、モルホリン、ピペリジン、ピロリジンが好ましい。「R9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環」における置換基としては、メチル基が好ましい。
In general formula (II), in N (R 9 ) (R 10 ) in R 4 , R 5 , R 6 , R 7 , R 8 , “R 9 and R 10 together are substituted together with the adjacent nitrogen atom. As the nitrogen-containing saturated heterocyclic ring in the “nitrogen-containing saturated heterocyclic ring optionally having a group”, morpholine, piperidine, and pyrrolidine are preferable. As the substituent in the “nitrogen-containing saturated heterocyclic ring in which R 9 and R 10 may have a substituent together with the adjacent nitrogen atom”, a methyl group is preferable.
一般式(I)中、R2におけるハロゲン原子としては、塩素原子が好ましい。
In general formula (I), the halogen atom in R 2 is preferably a chlorine atom.
一般式(I)中、R2におけるOR11におけるC1-6アルキル基としては、C1-4アルキル基が好ましく、メチル基、エチル基がより好ましい。
In general formula (I), the C 1-6 alkyl group in OR 11 in R 2 is preferably a C 1-4 alkyl group, more preferably a methyl group or an ethyl group.
一般式(I)中、R2におけるOR11におけるC1-6アルキルチオC1-6アルキル基としては、C1-4アルキルチオC1-4アルキル基が好ましく、メチルチオエチル基がより好ましい。
In the general formula (I), the C 1-6 alkylthio C 1-6 alkyl group in OR 11 in R 2 is preferably a C 1-4 alkylthio C 1-4 alkyl group, and more preferably a methylthioethyl group.
一般式(I)中、R2におけるOR11におけるC1-6アルキルスルフィニルC1-6アルキル基としては、C1-4アルキルスルフィニルC1-4アルキル基が好ましく、メチルスルフィニルエチル基がより好ましい。
In the general formula (I), the C 1-6 alkylsulfinyl C 1-6 alkyl group in OR 11 in R 2, preferred is a C 1-4 alkylsulfinyl C 1-4 alkyl group, more preferably a methylsulfinyl ethyl .
一般式(I)中、R2におけるOR11におけるC1-6アルキルスルホニルC1-6アルキル基としては、C1-4アルキルスルホニルC1-4アルキル基が好ましく、メチルスルホニルエチル基がより好ましい。
In the general formula (I), the C 1-6 alkylsulfonyl C 1-6 alkyl group in OR 11 in R 2, preferred is a C 1-4 alkylsulfonyl C 1-4 alkyl group, more preferably a methylsulfonyl ethyl group .
一般式(I)中、R2におけるOR11におけるC1-6アルコキシカルボニルC1-6アルキル基としては、C1-4アルコキシカルボニルC1-4アルキル基が好ましく、エトキシカルボニルプロピル基がより好ましい。
In general formula (I), the C 1-6 alkoxycarbonyl C 1-6 alkyl group in OR 11 in R 2 is preferably a C 1-4 alkoxycarbonyl C 1-4 alkyl group, more preferably an ethoxycarbonylpropyl group. .
一般式(I)中、R2におけるOR11におけるカルボキシカルボニルC1-6アルキル基としては、カルボキシプロピル基が好ましい。
In general formula (I), the carboxycarbonyl C 1-6 alkyl group in OR 11 in R 2 is preferably a carboxypropyl group.
一般式(I)中、R2におけるOR11におけるC6-10アリールチオC1-6アルキル基としては、フェニルチオC1-6アルキル基が好ましく、フェニルチオC1-4アルキル基がより好ましく、フェニルチオエチル基がより好ましい。
In general formula (I), the C 6-10 arylthio C 1-6 alkyl group in OR 11 in R 2 is preferably a phenylthio C 1-6 alkyl group, more preferably a phenylthio C 1-4 alkyl group, An ethyl group is more preferable.
一般式(I)中、R2におけるOR11におけるC6-10アリールスルホニルC1-6アルキル基としては、フェニルスルホニルC1-6アルキル基が好ましく、フェニルスルホニルC1-4アルキル基がより好ましく、フェニルスルホニルエチル基がより好ましい。
In general formula (I), the C 6-10 arylsulfonyl C 1-6 alkyl group in OR 11 in R 2 is preferably a phenylsulfonyl C 1-6 alkyl group, more preferably a phenylsulfonyl C 1-4 alkyl group. A phenylsulfonylethyl group is more preferred.
一般式(I)中、R2におけるOR11におけるC6-10アリールオキシC1-6アルキル基としては、フェノキシC1-6アルキル基が好ましく、フェノキシC1-4アルキル基がより好ましく、フェノキシエチル基がより好ましい。
In general formula (I), the C 6-10 aryloxy C 1-6 alkyl group in OR 11 in R 2 is preferably a phenoxy C 1-6 alkyl group, more preferably a phenoxy C 1-4 alkyl group, An ethyl group is more preferable.
本発明における好ましい化合物、若しくはその塩、又はそれらの溶媒和物としては、
5-メトキシピリミジン-2-アミン、
5-エトキシピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチル、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチル、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチル、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、及び
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
からなる群から選ばれる化合物若しくはその塩、又はそれらの溶媒和物を挙げることができるが、本発明の医薬の有効成分として好適に使用される化合物若しくはその塩、又はそれらの溶媒和物の範囲はこれらに限定されることはない。 As preferred compounds in the present invention, or salts thereof, or solvates thereof,
5-methoxypyrimidin-2-amine,
5-ethoxypyrimidin-2-amine,
5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
Ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] ethyl butyrate,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Methyl propionate,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine, and 5-{[(5-chloro Pyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
The compound or its salt selected from the group which consists of these, or those solvates can be mentioned, However, The compound or its salt suitably used as an active ingredient of the pharmaceutical of this invention, or the range of those solvates Is not limited to these.
5-メトキシピリミジン-2-アミン、
5-エトキシピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチル、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチル、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチル、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、及び
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
からなる群から選ばれる化合物若しくはその塩、又はそれらの溶媒和物を挙げることができるが、本発明の医薬の有効成分として好適に使用される化合物若しくはその塩、又はそれらの溶媒和物の範囲はこれらに限定されることはない。 As preferred compounds in the present invention, or salts thereof, or solvates thereof,
5-methoxypyrimidin-2-amine,
5-ethoxypyrimidin-2-amine,
5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
Ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] ethyl butyrate,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Methyl propionate,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine, and 5-{[(5-chloro Pyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
The compound or its salt selected from the group which consists of these, or those solvates can be mentioned, However, The compound or its salt suitably used as an active ingredient of the pharmaceutical of this invention, or the range of those solvates Is not limited to these.
一般式(I)で表される化合物の塩としては、酸付加塩および塩基付加塩等が挙げられ、医薬として許容される塩であれば特に制限されない。例えば、酸付加塩であれば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩のような鉱酸との酸付加塩;安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、酢酸塩等の有機酸との酸付加塩が挙げられる。また、塩基付加塩であればナトリウム塩、カリウム塩、リチウム塩、カルシウム塩、マグネシウム塩等の金属との塩基付加塩;アンモニア、トリメチルアミン、トリエチルアミン、ピリジン、コリジン、ルチジン等のアミン塩;リシン、アルギニン、ヒスチジン等の有機塩基との塩基付加塩等が挙げられる。
Examples of the salt of the compound represented by the general formula (I) include acid addition salts and base addition salts, and are not particularly limited as long as they are pharmaceutically acceptable salts. For example, in the case of acid addition salts, acid addition salts with mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, methanesulfonate And acid addition salts with organic acids such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate and acetate. In addition, if it is a base addition salt, a base addition salt with a metal such as sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt; amine salt such as ammonia, trimethylamine, triethylamine, pyridine, collidine, lutidine; lysine, arginine And base addition salts with organic bases such as histidine.
一般式(I)で表される化合物、又はその塩の溶媒和物を構成する溶媒としては、例えば、水のほか、生理学的に許容される有機溶媒、例えばエタノール、ヘキサン、酢酸エチルなどを挙げることができるが、これらに限定されることはない。
Examples of the solvent constituting the solvate of the compound represented by the general formula (I) or a salt thereof include, for example, water and physiologically acceptable organic solvents such as ethanol, hexane, and ethyl acetate. However, it is not limited to these.
なお、本発明の上記一般式(I)で表される化合物には、生体内において代謝されて本発明の上記一般式(I)で表される化合物に変換される化合物、いわゆるプロドラッグもすべて包含される。本発明化合物のプロドラッグを形成する基としては、「プログレス・イン・メディシン(Progress in Medicine)」、ライフサイエンス・メディカ社、1985年、5巻、2157-2161ページに記載されている基や、廣川書店1990年刊「医薬品の開発」第7巻 分子設計163-198ページに記載されている基が挙げられる。
The compounds represented by the above general formula (I) of the present invention include all compounds that are metabolized in vivo and converted into the compounds represented by the above general formula (I) of the present invention, so-called prodrugs. Is included. As a group that forms a prodrug of the compound of the present invention, “Progress in Medicine”, Life Science Medica, 1985, Vol. 5, pages 2157-2161, Examples include the groups described in Yodogawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, pp. 163-198.
上記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物は種々の公知の方法で製造することができ、特に制限されるものではなく、例えば、次の反応工程に従い製造することができるが、その製造方法はこれに限定されるものではない。また、下記反応を行う際において、反応部位以外の官能基については必要に応じてあらかじめ保護しておき、適当な段階においてこれを脱保護してもよい。さらに、各工程において、反応は通常行われる方法で行えばよく、単離精製は結晶化、再結晶化、クロマトグラフィー等の慣用される方法を適宜選択し、又は組み合わせて行えばよい。
The compound represented by the above general formula (I), or a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, according to the following reaction step Although it can manufacture, the manufacturing method is not limited to this. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance if necessary, and may be deprotected at an appropriate stage. Further, in each step, the reaction may be carried out by a commonly performed method, and isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, chromatography and the like.
上記一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物は種々の公知の方法で製造することができ、特に制限されるものではなく、例えば、次の反応工程に従い製造することができるが、その製造方法はこれに限定されるものではない。また、下記反応を行う際において、反応部位以外の官能基については必要に応じてあらかじめ保護しておき、適当な段階においてこれを脱保護してもよい。さらに、各工程において、反応は通常行われる方法で行えばよく、単離精製は結晶化、再結晶化、クロマトグラフィー等の慣用される方法を適宜選択し、又は組み合わせて行えばよい。
The compound represented by the above general formula (I), or a salt thereof, or a solvate thereof can be produced by various known methods, and is not particularly limited. For example, according to the following reaction step Although it can manufacture, the manufacturing method is not limited to this. Moreover, when performing the following reaction, functional groups other than the reaction site may be protected in advance if necessary, and may be deprotected at an appropriate stage. Further, in each step, the reaction may be carried out by a commonly performed method, and isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, chromatography and the like.
上記一般式(I)で表される化合物のうちR1が水素原子、R2がOR11である化合物(Ia)は、公知の特許文献(国際公開第2008/018529号パンフレット)等に記載の方法により製造することができる。
Among the compounds represented by the general formula (I), the compound (Ia) in which R 1 is a hydrogen atom and R 2 is OR 11 is described in a known patent document (WO 2008/018529 pamphlet) and the like. It can be manufactured by a method.
[工程1]5-ブロモ-2-クロロピリミジン(III)とアミン(IV)とを、溶媒中又は無溶媒下で反応することにより、化合物(V)を製造することができる。その際、マイクロウエーブ照射を行ってもよい。溶媒としては特に制限はないが、例えば、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、ジメチルスルホキシド、水等を単独又は組み合わせて使用することができる。反応条件は使用するアミンによって異なるが、好ましくは-20℃~180℃にて1分~24時間、さらに好ましくは0℃~150℃にて5分~15時間である。
[Step 1] Compound (V) can be produced by reacting 5-bromo-2-chloropyrimidine (III) with amine (IV) in a solvent or without a solvent. At that time, microwave irradiation may be performed. The solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination. it can. The reaction conditions vary depending on the amine to be used, but are preferably -20 ° C to 180 ° C for 1 minute to 24 hours, more preferably 0 ° C to 150 ° C for 5 minutes to 15 hours.
[工程2]化合物(V)とアルコール(VI)とを、溶媒中、塩基及び金属触媒の存在下に反応することにより化合物(VII)を製造することができる。その際、マイクロウエーブ照射を行ってもよい。溶媒は、反応を阻害しないものであれば特に制限はないが、例えば、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、水等を単独又は組み合わせて使用することができる。塩基としては、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類;金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類;炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、t-ブトキシナトリウム、t-ブトキシカリウム、t-アミルオキシナトリウム、t-アミルオキシカリウム、n-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム等を使用することができる。金属触媒としては、例えば、トリス(ジベンジリデンアセトン)ジパラジウム(0)、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、[1,1’-ビス(ジフェニルフォスフィノ)フェロセン]ジクロロパラジウム(II)、テトラキス(トリフェニルホスフィン)パラジウム等のパラジウム錯体;ヨウ化第一銅、臭化第一銅、青酸第一銅等の銅試薬を単独で用いてもよい。また、配位子を組み合わせて使用することもできる。配位子としては、(2-ビフェニル)ジ-t-ブチルホスフィン、(2-ビフェニル)ジシクロへキシルホスフィン、トリ(トリル)ホスフィン、テトラメチルエチレンジアミン、N,N’-ジメチルエチレンジアミン、グリシン、N,N-ジメチルグリシン、N-メチルグリシン、トリフェニルアルシン等を単独又は組み合わせて使用することができる。反応条件は、好ましくは0℃~180℃にて1分~5日間、さらに好ましくは80℃~150℃にて1時間~24時間である。
[Step 2] Compound (VII) can be produced by reacting compound (V) with alcohol (VI) in a solvent in the presence of a base and a metal catalyst. At that time, microwave irradiation may be performed. The solvent is not particularly limited as long as it does not inhibit the reaction. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, etc. may be used alone or in combination. Can do. Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metals such as metal lithium, metal sodium, and metal potassium; lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Alkali metal carbonates such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-amyloxy sodium, t-amyloxy potassium, n-butyllithium, s-butyllithium, t-butyllithium and the like can be used. Examples of the metal catalyst include tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium. (II), palladium complexes such as tetrakis (triphenylphosphine) palladium; copper reagents such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone. A combination of ligands can also be used. Examples of the ligand include (2-biphenyl) di-t-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tri (tolyl) phosphine, tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine, triphenylarsine and the like can be used alone or in combination. The reaction conditions are preferably 0 ° C. to 180 ° C. for 1 minute to 5 days, more preferably 80 ° C. to 150 ° C. for 1 hour to 24 hours.
[工程3]上記方法で得られた化合物(VII)の保護基R12の脱保護法は特に制限はないが、当該保護基の脱保護条件として一般に用いられる方法(Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.)を参考にして行うことができる。
[Step 3] is not particularly limited deprotection methods of protecting group R 12 of the resultant compound (VII) in the above methods, the method (Protective Groups in Organic Synthesis Third Edition commonly used as deprotection conditions for the protecting group , John Wiley & Sons, Inc.).
上記一般式(I)で表される化合物のうちR1が式(II)、R2がOR11である化合物(Ib)は、公知の特許文献(国際公開第2008/018529号パンフレット)等に記載の方法により製造することができる。
Among the compounds represented by the above general formula (I), the compound (Ib) in which R 1 is the formula (II) and R 2 is OR 11 can be found in known patent documents (WO 2008/018529 pamphlet) and the like. It can be produced by the method described.
[工程4]5-ブロモ-2-クロロピリミジン(III)とアミン(VIII)とを、溶媒中又は無溶媒下で反応することにより、化合物(IX)を製造することができる。その際、マイクロウエーブ照射を行ってもよい。溶媒としては特に制限はないが、例えば、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、ジメチルスルホキシド、水等を単独又は組み合わせて使用することができる。反応条件は使用するアミンによって異なるが、好ましくは-20℃~180℃にて1分~24時間、さらに好ましくは0℃~150℃にて5分~15時間である。
[Step 4] Compound (IX) can be produced by reacting 5-bromo-2-chloropyrimidine (III) with amine (VIII) in a solvent or without a solvent. At that time, microwave irradiation may be performed. The solvent is not particularly limited, and for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water and the like can be used alone or in combination. it can. The reaction conditions vary depending on the amine to be used, but are preferably -20 ° C to 180 ° C for 1 minute to 24 hours, more preferably 0 ° C to 150 ° C for 5 minutes to 15 hours.
[工程5]化合物(IX)とアルコール(VI)とを、溶媒中、塩基及び金属触媒の存在下に反応することにより化合物(Ib)を製造することができる。その際、マイクロウエーブ照射を行ってもよい。溶媒は、反応を阻害しないものであれば特に制限はないが、例えば、テトラヒドロフラン、トルエン、ジオキサン、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、水等を単独又は組み合わせて使用することができる。塩基としては、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類;金属リチウム、金属ナトリウム、金属カリウム等のアルカリ金属類;炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド、t-ブトキシナトリウム、t-ブトキシカリウム、t-アミルオキシナトリウム、t-アミルオキシカリウム、n-ブチルリチウム、s-ブチルリチウム、t-ブチルリチウム等を使用することができる。金属触媒としては、例えば、トリス(ジベンジリデンアセトン)ジパラジウム(0)、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、[1,1’-ビス(ジフェニルフォスフィノ)フェロセン]ジクロロパラジウム(II)、テトラキス(トリフェニルホスフィン)パラジウム等のパラジウム錯体;ヨウ化第一銅、臭化第一銅、青酸第一銅等の銅試薬を単独で用いてもよい。また、配位子を組み合わせて使用することもできる。配位子としては、(2-ビフェニル)ジ-t-ブチルホスフィン、(2-ビフェニル)ジシクロへキシルホスフィン、トリ(トリル)ホスフィン、テトラメチルエチレンジアミン、N,N’-ジメチルエチレンジアミン、グリシン、N,N-ジメチルグリシン、N-メチルグリシン、トリフェニルアルシン等を単独又は組み合わせて使用することができる。反応条件は、好ましくは0℃~180℃にて1分~5日間、さらに好ましくは80℃~150℃にて1時間~24時間である。
[Step 5] Compound (Ib) can be produced by reacting compound (IX) with alcohol (VI) in a solvent in the presence of a base and a metal catalyst. At that time, microwave irradiation may be performed. The solvent is not particularly limited as long as it does not inhibit the reaction. For example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, etc. may be used alone or in combination. Can do. Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; alkali metals such as metal lithium, metal sodium, and metal potassium; lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Alkali metal carbonates such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, t-amyloxy sodium, t-amyloxy potassium, n-butyllithium, s-butyllithium, t-butyllithium and the like can be used. Examples of the metal catalyst include tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium. (II), palladium complexes such as tetrakis (triphenylphosphine) palladium; copper reagents such as cuprous iodide, cuprous bromide and cuprous cyanide may be used alone. A combination of ligands can also be used. Examples of the ligand include (2-biphenyl) di-t-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tri (tolyl) phosphine, tetramethylethylenediamine, N, N′-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine, triphenylarsine and the like can be used alone or in combination. The reaction conditions are preferably 0 ° C. to 180 ° C. for 1 minute to 5 days, more preferably 80 ° C. to 150 ° C. for 1 hour to 24 hours.
上記一般式(I)で表される化合物のうちR1が式(II)である化合物(Ib)は、下記に示す方法によっても製造することができる。
Among the compounds represented by the general formula (I), the compound (Ib) in which R 1 is the formula (II) can also be produced by the method shown below.
[工程6]化合物(Ia)とベンジルハライド(X)との反応は、溶媒中、塩基存在下で行うことができる。溶媒としては特に制限はないが、例えば、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、ジメチルスルホキシド、1,2-ジクロロエタン、クロロホルム、ジクロロメタン、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、テトラヒドロフラン、ジオキサン、アセトニトリル、プロピオニトリル、水等を単独又は組み合わせて使用することができる。塩基としては特に制限はないが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、ナトリウムメトキシド、ナトリウムエトキシド、t-ブトキシナトリウム、t-ブトキシカリウム、t-アミルオキシナトリウム、t-アミルオキシカリウム等のアルコキシアルカリ金属類、ピリジン、DMAP、コリジン、ルチジン、DBU、DBN、DABCO、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N,N-ジイソプロピルペンチルアミン、トリメチルアミン等の有機塩基、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、炭酸水素ナトリウム、炭酸水素カリウム等の重炭酸塩等を使用することができる。反応条件は、使用する原料によって異なるが、好ましくは0℃~180℃にて5分~2日間、さらに好ましくは50℃~120℃にて1時間~12時間反応させることによって化合物(Ib)が得られる。
[Step 6] The reaction of compound (Ia) and benzyl halide (X) can be carried out in a solvent in the presence of a base. The solvent is not particularly limited. For example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene , Benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, water and the like can be used alone or in combination. The base is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t- Alkoxy alkali metals such as amyloxy sodium and t-amyloxy potassium, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, etc. Heavy metals such as organic bases, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate and potassium bicarbonate Use carbonates, etc. It is possible. The reaction conditions vary depending on the starting materials used, but preferably the compound (Ib) is reacted by reacting at 0 ° C. to 180 ° C. for 5 minutes to 2 days, more preferably at 50 ° C. to 120 ° C. for 1 hour to 12 hours. can get.
上記一般式(I)で表される化合物のうちR1が式(II)、R2がOR11である化合物(Ib)は、特許文献(国際公開第2008/009435号パンフレット)記載の方法によっても製造することができる。
Among the compounds represented by the general formula (I), the compound (Ib) in which R 1 is the formula (II) and R 2 is OR 11 is obtained by the method described in the patent document (International Publication No. 2008/009435 pamphlet). Can also be manufactured.
[工程7]ピリミジンボランピナコールエステル(XI)とベンジルアミン(VIII)の反応は、溶媒中又は無溶媒下、塩基の存在下又は非存在下にて行うことができる。溶媒としては特に制限はないが、例えば、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、1,2-ジクロロエタン、クロロホルム、ジクロロメタン、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、テトラヒドロフラン、ジオキサン、アセトニトリル、プロピオニトリル、メタノール、エタノール、イソプロパノール等を単独又は組み合わせて使用することができる。塩基としては特に制限はないが、例えば、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、ナトリウムメトキシド、ナトリウムエトキシド、t-ブトキシナトリウム、t-ブトキシカリウム、t-アミルオキシナトリウム、t-アミルオキシカリウム等のアルコキシアルカリ金属類、ピリジン、DMAP、コリジン、ルチジン、DBU、DBN、DABCO、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N,N-ジイソプロピルペンチルアミン、トリメチルアミン等の有機塩基、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、炭酸水素ナトリウム、炭酸水素カリウム等の重炭酸塩等を使用することができる。
[Step 7] The reaction of pyrimidineborane pinacol ester (XI) and benzylamine (VIII) can be carried out in a solvent or without a solvent, in the presence or absence of a base. The solvent is not particularly limited. For example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, Tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol and the like can be used alone or in combination. The base is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t- Alkoxy alkali metals such as amyloxy sodium and t-amyloxy potassium, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, etc. Heavy metals such as organic bases, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate and potassium bicarbonate Use carbonates, etc. It is possible.
[工程8]アミノピリミジン誘導体(XII)の酸化反応は、ホウ酸エステル残基を水酸基に変換する通常の方法を適用することができ、例えば、過酸化水素水による酸化反応を使用することができる。溶媒としては特に制限はないが、例えば、水、メタノール、エタノール、イソプロパノール、テトラヒドロフラン、N,N-ジメチルホルムアミド、酢酸、水等を単独又は組み合わせて使用することができる。
[Step 8] For the oxidation reaction of the aminopyrimidine derivative (XII), a usual method for converting a boric acid ester residue to a hydroxyl group can be applied. For example, an oxidation reaction with hydrogen peroxide can be used. . The solvent is not particularly limited, and for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, N, N-dimethylformamide, acetic acid, water and the like can be used alone or in combination.
[工程9]ヒドロキシピリミジン化合物(XIII)のアルキル化反応は、溶媒中、塩基の存在下により行うことができる。溶媒としては特に制限はないが、例えば、N,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド、ジオキサン、テトラヒドロフラン、アセトニトリル、プロピオニトリル等を単独又は組み合わせて使用することができ、塩基としては特に制限はないが、水素化リチウム、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類、ナトリウムメトキシド、ナトリウムエトキシド、t-ブトキシナトリウム、t-ブトキシカリウム、t-アミルオキシナトリウム、t-アミルオキシカリウム等のアルコキシアルカリ金属類、ピリジン、DMAP、コリジン、ルチジン、DBU、DBN、DABCO、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N,N-ジイソプロピルペンチルアミン、トリメチルアミン等の有機塩基、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水酸化アルカリ金属類、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属類、炭酸水素ナトリウム、炭酸水素カリウム等の重炭酸塩等を使用することができる。
[Step 9] The alkylation reaction of hydroxypyrimidine compound (XIII) can be carried out in a solvent in the presence of a base. The solvent is not particularly limited. For example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used alone or in combination. Although there is no particular limitation, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, t-butoxy sodium, t-butoxy potassium, t-amyloxy sodium, t -Alkoxy alkali metals such as amyloxy potassium, organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, Alkali metal hydroxides such as lithium oxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc. Can be used.
また、ヒドロキシピリミジン化合物(XII)のアルキル化反応は、アルコール類の光延反応により行うことができる。光延反応は溶媒中、ホスフィン試薬とアゾ試薬又はエチレンジカルボン酸試薬を使用するか、又はホスホニウムイリド試薬を使用し行うことができる。ホスフィン試薬としては特に制限はないが、トリアルキルホスフィン又はトリアリールホスフィン、具体的にはトリメチルホスフィン、トリエチルホスフィン、トリプロピルホスフィン、トリイソプロピルホスフィン、トリブチルホスフィン、トリイソブチルホスフィン、トリシクロヘキシルホスフィン、トリフェニルホスフィン、ジフェニルホスフィノポリスチレン等を使用することができる。アゾ試薬としては特に制限はないが、アゾジカルボン酸ジエチル(DEAD)、アゾジカルボン酸ジイソプロピル(DIAD)、1,1’-(アゾジカルボニル)ピペリジン(ADDP)、1,1’-アゾビス(N,N’-ジイソプロピルホルムアミド)(TIPA)、1,6-ジメチル-1,5,7-ヘキサヒドロ-1,4,6,7-テトラゾシン-2,5-ジオン(DHTD)等を使用することができる。エチレンジカルボン酸試薬としては特に制限はないが、マレイン酸ジメチル、マレイン酸ジエチル、フマル酸ジメチル、フマル酸ジエチル等を使用することができる。溶媒としては特に制限はないが、N,N’-ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、アセトニトリル、プロピオニトリル、ニトロメタン、アセトン、酢酸エチル、酢酸イソプロピル、ベンゼン、トルエン、クロロベンゼン、クロロホルム、ジクロロメタン、1,2-ジクロロエタン等を単独又は組み合わせて使用することができる。
Further, the alkylation reaction of the hydroxypyrimidine compound (XII) can be performed by Mitsunobu reaction of alcohols. The Mitsunobu reaction can be carried out in a solvent using a phosphine reagent and an azo reagent or an ethylenedicarboxylic acid reagent, or using a phosphonium ylide reagent. The phosphine reagent is not particularly limited, but trialkylphosphine or triarylphosphine, specifically trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, triphenylphosphine. Diphenylphosphinopolystyrene and the like can be used. The azo reagent is not particularly limited, but diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1 ′-(azodicarbonyl) piperidine (ADDP), 1,1′-azobis (N, N'-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocine-2,5-dione (DHTD) and the like can be used. The ethylenedicarboxylic acid reagent is not particularly limited, and dimethyl maleate, diethyl maleate, dimethyl fumarate, diethyl fumarate, and the like can be used. The solvent is not particularly limited, but N, N′-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, propionitrile, nitromethane, acetone, ethyl acetate, isopropyl acetate, benzene, toluene, chlorobenzene, chloroform, dichloromethane, 1,2 -Dichloroethane or the like can be used alone or in combination.
上記一般式(I)で表される化合物のうちR1が式(II)、R3が水素原子である化合物(Ic)は、公知の特許文献(国際公開2008/129951号パンフレット)等に記載の方法により製造することができる。
Among the compounds represented by the general formula (I), the compound (Ic) in which R 1 is the formula (II) and R 3 is a hydrogen atom is described in a known patent document (International Publication No. 2008/129951). It can manufacture by the method of.
[工程10]ピリミジン誘導体(Ia)と化合物(XIV)との反応は、溶媒中、酸の存在下又は非存在下にて還元試薬を用いて行うことができる。その際、Deen-Stark装置等を用いて脱水操作を行ってもよい。溶媒としては特に制限はないが、例えば、1,2-ジクロロエタン、クロロホルム、ジクロロメタン、酢酸エチル、酢酸イソプロピル、トルエン、ベンゼン、テトラヒドロフラン、ジオキサン、アセトニトリル、プロピオニトリル、メタノール、エタノール、イソプロパノール等を単独又は組み合わせて使用することができる。酸としては特に制限はないが、例えば酢酸、トリフルオロ酢酸、プロピオン酸、安息香酸等のプロトン酸;四塩化チタン、三フッ化ホウ素、塩化第二スズ等のルイス酸を使用することができる。還元試薬としては特に制限はないが、例えば、トリアセトキシ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素テトラメチルアンモニウム、シアノ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、トリメトキシ水素化ホウ素ナトリウム、トリエチル水素化ホウ素リチウム等の水素化ホウ素系試薬;水素化アルミニウムリチウム、ジイソプロピル水素化アルミニウム、ビス[2-メトキシエトキシ]水素化アルミニウムナトリウム等の水素化アルミニウム試薬;金属触媒及び水素源を用いた接触還元を使用することができる。接触還元の水素源としては、例えば、水素、シクロヘキサジエン、ギ酸、ギ酸アンモニウム等を使用することができる。金属触媒としては、例えば、パラジウム炭素、パラジウム黒、水酸化パラジウム炭素粉末、ラネーニッケル、二酸化白金、白金黒等を使用することができる。反応条件は、使用する原料によって異なるが、好ましくは0℃~180℃にて5分~2日間、さらに好ましくは0℃~50℃にて1時間~24時間反応させることによって化合物(Ic)が得られる。
[Step 10] The reaction of pyrimidine derivative (Ia) and compound (XIV) can be carried out using a reducing reagent in a solvent in the presence or absence of an acid. At this time, the dehydration operation may be performed using a Deen-Stark apparatus or the like. The solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc .; Titanium tetrachloride, boron trifluoride, stannic chloride, etc. can be used. There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Boron hydride reagents such as lithium triethylborohydride; Aluminum hydride reagents such as lithium aluminum hydride, diisopropylaluminum hydride, sodium bis [2-methoxyethoxy] aluminum hydride; Contact using metal catalyst and hydrogen source Reduction can be used. As the hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate, or the like can be used. As the metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide, platinum black and the like can be used. The reaction conditions vary depending on the starting materials used, but preferably the compound (Ic) is reacted by reacting at 0 ° C. to 180 ° C. for 5 minutes to 2 days, more preferably at 0 ° C. to 50 ° C. for 1 hour to 24 hours. can get.
R2が低級アルキルスルフィニル低級アルコキシ基あるいは低級アルキルスルホニル低級アルコキシ基である、一般式(I)で表される化合物は、上述した方法によるほか、次の反応工程によっても製造することができる。すなわち、R2が低級アルキルチオ低級アルコキシ基である一般式(I)で表される化合物の硫黄原子を酸化することによっても得ることができる。
The compound represented by the general formula (I) in which R 2 is a lower alkylsulfinyl lower alkoxy group or a lower alkylsulfonyl lower alkoxy group can be produced by the following reaction step in addition to the method described above. That is, it can also be obtained by oxidizing the sulfur atom of the compound represented by the general formula (I) in which R 2 is a lower alkylthio-lower alkoxy group.
酸化方法としては硫黄原子をスルフィニル基あるいはスルホニル基へと変換する通常の方法を適用することができ、例えば、触媒量のタングステン酸ナトリウム、二塩化二酸化モリブデンあるいは五塩化タンタルを用いた過酸化水素水による酸化反応や、過ヨウ素酸ナトリウム、過ヨウ素酸カリウム、メタクロロ過安息香酸(mCPBA)、過酢酸、PCC、PDC、N-クロロコハク酸イミド(NCS)、N-ブロモコハク酸イミド(NBS)、N-ヨードコハク酸イミド(NIS)、ヨウ素、臭素等を使用することができる。溶媒としては特に制限はないが、例えば、水、メタノール、エタノール、イソプロパノール、アセトニトリル、プロピオニトリル、アセトン、テトラヒドロフラン、ジオキサン、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、四塩化炭素、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドン、酢酸、水等を単独又は組み合わせて使用することができる。
As an oxidation method, a usual method for converting a sulfur atom into a sulfinyl group or a sulfonyl group can be applied. For example, hydrogen peroxide solution using a catalytic amount of sodium tungstate, molybdenum dichloride dioxide or tantalum pentachloride. Oxidation reaction with sodium periodate, potassium periodate, metachloroperbenzoic acid (mCPBA), peracetic acid, PCC, PDC, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N- Iodosuccinimide (NIS), iodine, bromine and the like can be used. The solvent is not particularly limited. For example, water, methanol, ethanol, isopropanol, acetonitrile, propionitrile, acetone, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, N, N-dimethyl Formamide, N, N-dimethylacetamide, N-methylpyrrolidone, acetic acid, water and the like can be used alone or in combination.
また、R2が低級アルキルスルホニル低級アルコキシ基である、一般式(I)で表される化合物も、上記方法にて得られたR2が低級アルキルスルフィニル低級アルコキシ基である、一般式(I)で表される化合物より同様の酸化反応条件を用いて製造することができる。
Further, R 2 is lower alkyl sulfonyl lower alkoxy group, the compound represented by the general formula (I) also, R 2 obtained by the above method is lower alkylsulfinyl lower alkoxy group, the general formula (I) It can manufacture using the same oxidation reaction conditions from the compound represented by these.
前記の各反応で得られた中間体及び目的物は、有機合成化学で常用されている精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して必要に応じて単離、精製することができる。また、中間体においては、特に精製することなく次反応に供することもできる。
Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.
さらに、各種の異性体は異性体間の物理化学的性質の差を利用した常法を適用して単離できる。たとえばラセミ混合物は、例えば酒石酸等の一般的な光学活性酸とのジアステレオマー塩に導き光学分割する方法又は光学活性カラムクロマトグラフィーを用いた方法等の一般的ラセミ分割法により、光学的に純粋な異性体に導くことができる。また、ジアステレオマー混合物は、例えば分別結晶化または各種クロマトグラフィー等により分割できる。また、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。
Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers. For example, a racemic mixture is optically purified by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to various isomers. In addition, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.
本発明の医薬としては上記の有効成分自体を投与してもよいが、好ましくは、当業者に周知の方法によって製造可能な経口用あるいは非経口用の医薬組成物として投与することができる。経口投与に適する医薬用組成物としては、例えば、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、及びシロップ剤等を挙げることができ、非経口投与に適する医薬組成物としては、例えば、静脈内注射剤や筋肉内注射剤などの注射剤、点滴剤、坐剤、吸入剤、点眼剤、点鼻剤、経皮吸収剤、経粘膜吸収剤などを挙げることができるが、これらに限定されることはない。
The active ingredient itself may be administered as the medicament of the present invention, but it can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art. Examples of the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. The pharmaceutical composition suitable for parenteral administration includes Examples include injections such as intravenous injections and intramuscular injections, drops, suppositories, inhalants, eye drops, nasal drops, transdermal absorbents, transmucosal absorbents, etc. It is not limited to.
上記の医薬組成物は、薬理学的、製剤学的に許容しうる添加物を加えて製造することができる。薬理学的、製剤学的に許容しうる添加物の例としては、例えば、賦形剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、保存剤、矯味剤、香料、被膜剤、希釈剤などを挙げることができるが、これらに限定されることはない。
The above pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, binders, extenders, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, Examples include, but are not limited to, flavoring agents, fragrances, coating agents, and diluents.
本発明の医薬の投与量は特に限定されず、疾患の種類、予防又は治療の目的、有効成分の種類などに応じて適宜選択することができ、さらに患者の体重や年齢、症状、投与経路など通常考慮すべき種々の要因に応じて、適宜増減することができる。例えば、経口投与の場合には成人一日あたり有効成分の重量として0.1 ~500mg程度の範囲で用いることができるが、投与量は当業者に適宜選択可能であり、上記の範囲に限定されることはない。
The dosage of the pharmaceutical agent of the present invention is not particularly limited, and can be appropriately selected according to the type of disease, the purpose of prevention or treatment, the type of active ingredient, etc., and the patient's weight and age, symptoms, administration route, etc. It can be increased or decreased as appropriate according to various factors that should be normally considered. For example, in the case of oral administration, the weight of active ingredient per day for an adult can be used in the range of about 0.1 mg to 500 mg, but the dosage can be appropriately selected by those skilled in the art and is limited to the above range. Never happen.
次に、実施例を挙げて本発明をさらに説明するが、本発明はこれら実施例に限定されるものではない。なお、下記実施例中で用いられている略号は下記の意味を示す。
s:シングレット(singlet)
d:ダブレット(doublet)
t:トリプレット(triplet)
q:クアルテット(quartet)
m:マルチプレット(multiplet)
br:ブロード(broad)
J:カップリング定数(coupling constant)
Hz:ヘルツ(Hertz)
CDCl3:重クロロホルム
d6-DMSO:重ジメチルスルホキシド
1H-NMR:プロトン核磁気共鳴
IR:赤外線吸収スペクトル EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl 3 : deuterated chloroform d 6 -DMSO: deuterated dimethyl sulfoxide
1 H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum
s:シングレット(singlet)
d:ダブレット(doublet)
t:トリプレット(triplet)
q:クアルテット(quartet)
m:マルチプレット(multiplet)
br:ブロード(broad)
J:カップリング定数(coupling constant)
Hz:ヘルツ(Hertz)
CDCl3:重クロロホルム
d6-DMSO:重ジメチルスルホキシド
1H-NMR:プロトン核磁気共鳴
IR:赤外線吸収スペクトル EXAMPLES Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these Examples. In addition, the symbol used in the following Example shows the following meaning.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl 3 : deuterated chloroform d 6 -DMSO: deuterated dimethyl sulfoxide
1 H-NMR: proton nuclear magnetic resonance IR: infrared absorption spectrum
実施例1
5-メトキシピリミジン-2-アミンの製造:
特許文献(ドイツ特許公告第1145622号公報)に記載の方法に従い製造した。
1H-NMR (CDCl3) δ: 3.81 (3H, s), 4.88 (2H, br), 8.05 (2H, s). Example 1
Preparation of 5-methoxypyrimidin-2-amine:
It was produced according to the method described in the patent document (German Patent Publication No. 1145622).
1 H-NMR (CDCl 3 ) δ: 3.81 (3H, s), 4.88 (2H, br), 8.05 (2H, s).
5-メトキシピリミジン-2-アミンの製造:
特許文献(ドイツ特許公告第1145622号公報)に記載の方法に従い製造した。
1H-NMR (CDCl3) δ: 3.81 (3H, s), 4.88 (2H, br), 8.05 (2H, s). Example 1
Preparation of 5-methoxypyrimidin-2-amine:
It was produced according to the method described in the patent document (German Patent Publication No. 1145622).
1 H-NMR (CDCl 3 ) δ: 3.81 (3H, s), 4.88 (2H, br), 8.05 (2H, s).
実施例2
5-エトキシピリミジン-2-アミンの製造:
特許文献(ドイツ特許公告第1145622号公報)に記載の方法に従い製造した。
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.2 Hz), 4.01 (2H, q, J = 7.2 Hz), 4.76 (2H, br), 8.04 (2H, s). Example 2
Preparation of 5-ethoxypyrimidin-2-amine:
It was produced according to the method described in the patent document (German Patent Publication No. 1145622).
1 H-NMR (CDCl 3 ) δ: 1.40 (3H, t, J = 7.2 Hz), 4.01 (2H, q, J = 7.2 Hz), 4.76 (2H, br), 8.04 (2H, s).
5-エトキシピリミジン-2-アミンの製造:
特許文献(ドイツ特許公告第1145622号公報)に記載の方法に従い製造した。
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.2 Hz), 4.01 (2H, q, J = 7.2 Hz), 4.76 (2H, br), 8.04 (2H, s). Example 2
Preparation of 5-ethoxypyrimidin-2-amine:
It was produced according to the method described in the patent document (German Patent Publication No. 1145622).
1 H-NMR (CDCl 3 ) δ: 1.40 (3H, t, J = 7.2 Hz), 4.01 (2H, q, J = 7.2 Hz), 4.76 (2H, br), 8.04 (2H, s).
実施例3
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミドの製造
実施例1で製造した5-メトキシピリミジン-2-アミン(12.3 g, 98.3 mmol)をピリジン(123 mL)に溶解し、氷浴中にてヘキサン酸クロリド(14.5 g, 108 mmol)を加え、室温にて30分間攪拌した。反応液に0℃で1 Mグリシン水溶液(98.3 mL)を加え1時間撹拌した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をトルエン共沸した。得られた残渣をクロロホルム-ヘキサンにて再結晶し、N-(5-メトキシピリミジン-2-イル)ヘキサンアミド(18.4 g, 84%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.1 Hz), 1.30-1.40 (4H, m), 1.70-1.78 (2H, m), 2.50-2.70 (2H, m), 3.89 (3H, s), 8.10 (1H, br), 8.28 (2H, s). Example 3
Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of N- (5-hydroxypyrimidin-2-yl) hexanamide 5-Methoxypyrimidin-2-amine (12.3 g, 98.3 mmol) prepared in Example 1 was dissolved in pyridine (123 mL). Hexanoic acid chloride (14.5 g, 108 mmol) was added in an ice bath and stirred at room temperature for 30 minutes. A 1 M aqueous glycine solution (98.3 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred for 1 hour, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was azeotroped with toluene. The obtained residue was recrystallized from chloroform-hexane to give N- (5-methoxypyrimidin-2-yl) hexanamide (18.4 g, 84%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.1 Hz), 1.30-1.40 (4H, m), 1.70-1.78 (2H, m), 2.50-2.70 (2H, m), 3.89 (3H, s), 8.10 (1H, br), 8.28 (2H, s).
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミドの製造
実施例1で製造した5-メトキシピリミジン-2-アミン(12.3 g, 98.3 mmol)をピリジン(123 mL)に溶解し、氷浴中にてヘキサン酸クロリド(14.5 g, 108 mmol)を加え、室温にて30分間攪拌した。反応液に0℃で1 Mグリシン水溶液(98.3 mL)を加え1時間撹拌した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をトルエン共沸した。得られた残渣をクロロホルム-ヘキサンにて再結晶し、N-(5-メトキシピリミジン-2-イル)ヘキサンアミド(18.4 g, 84%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.1 Hz), 1.30-1.40 (4H, m), 1.70-1.78 (2H, m), 2.50-2.70 (2H, m), 3.89 (3H, s), 8.10 (1H, br), 8.28 (2H, s). Example 3
Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of N- (5-hydroxypyrimidin-2-yl) hexanamide 5-Methoxypyrimidin-2-amine (12.3 g, 98.3 mmol) prepared in Example 1 was dissolved in pyridine (123 mL). Hexanoic acid chloride (14.5 g, 108 mmol) was added in an ice bath and stirred at room temperature for 30 minutes. A 1 M aqueous glycine solution (98.3 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred for 1 hour, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was azeotroped with toluene. The obtained residue was recrystallized from chloroform-hexane to give N- (5-methoxypyrimidin-2-yl) hexanamide (18.4 g, 84%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.1 Hz), 1.30-1.40 (4H, m), 1.70-1.78 (2H, m), 2.50-2.70 (2H, m), 3.89 (3H, s), 8.10 (1H, br), 8.28 (2H, s).
工程2:N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミドの製造
N-(5-メトキシピリミジン-2-イル)ヘキサンアミド(17.3 g, 77 mmol)を1,2-ジクロロエタン(170 mL)に懸濁し、三臭化ホウ素(20.5 mL, 216 mmol)を加え、30分間加熱還流した。反応液を氷冷下メタノール(170 mL)で失活し、減圧濃縮して得られた残渣に氷冷下にて飽和アンモニアメタノール(85 mL)を加えて均一とした。減圧濃縮し得られた残渣に水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン = 2:1)にて分離精製し、N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(9.36g, 58%)を淡黄色固体として得た。
1H-NMR (d6-DMSO) δ: 0.86 (3H, t, J = 7.3 Hz), 1.24-1.31 (4H, m), 1.51-1.58 (2H, m), 2.35 (2H, t, J = 7.3 Hz), 8.20 (2H, s), 10.09 (1H, br s), 10.21(1H, s). Step 2: Preparation of N- (5-hydroxypyrimidin-2-yl) hexanamide N- (5-methoxypyrimidin-2-yl) hexanamide (17.3 g, 77 mmol) was converted to 1,2-dichloroethane (170 mL). Was added, and boron tribromide (20.5 mL, 216 mmol) was added thereto, followed by heating to reflux for 30 minutes. The reaction solution was quenched with methanol (170 mL) under ice-cooling, and concentrated under reduced pressure, and saturated ammonia methanol (85 mL) was added to the resulting residue under ice-cooling to make it uniform. Water was added to the residue obtained by concentration under reduced pressure, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (hexane: acetone = 2: 1), and N- (5 -Hydroxypyrimidin-2-yl) hexanamide (9.36 g, 58%) was obtained as a pale yellow solid.
1 H-NMR (d 6 -DMSO) δ: 0.86 (3H, t, J = 7.3 Hz), 1.24-1.31 (4H, m), 1.51-1.58 (2H, m), 2.35 (2H, t, J = 7.3 Hz), 8.20 (2H, s), 10.09 (1H, br s), 10.21 (1H, s).
N-(5-メトキシピリミジン-2-イル)ヘキサンアミド(17.3 g, 77 mmol)を1,2-ジクロロエタン(170 mL)に懸濁し、三臭化ホウ素(20.5 mL, 216 mmol)を加え、30分間加熱還流した。反応液を氷冷下メタノール(170 mL)で失活し、減圧濃縮して得られた残渣に氷冷下にて飽和アンモニアメタノール(85 mL)を加えて均一とした。減圧濃縮し得られた残渣に水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン = 2:1)にて分離精製し、N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(9.36g, 58%)を淡黄色固体として得た。
1H-NMR (d6-DMSO) δ: 0.86 (3H, t, J = 7.3 Hz), 1.24-1.31 (4H, m), 1.51-1.58 (2H, m), 2.35 (2H, t, J = 7.3 Hz), 8.20 (2H, s), 10.09 (1H, br s), 10.21(1H, s). Step 2: Preparation of N- (5-hydroxypyrimidin-2-yl) hexanamide N- (5-methoxypyrimidin-2-yl) hexanamide (17.3 g, 77 mmol) was converted to 1,2-dichloroethane (170 mL). Was added, and boron tribromide (20.5 mL, 216 mmol) was added thereto, followed by heating to reflux for 30 minutes. The reaction solution was quenched with methanol (170 mL) under ice-cooling, and concentrated under reduced pressure, and saturated ammonia methanol (85 mL) was added to the resulting residue under ice-cooling to make it uniform. Water was added to the residue obtained by concentration under reduced pressure, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (hexane: acetone = 2: 1), and N- (5 -Hydroxypyrimidin-2-yl) hexanamide (9.36 g, 58%) was obtained as a pale yellow solid.
1 H-NMR (d 6 -DMSO) δ: 0.86 (3H, t, J = 7.3 Hz), 1.24-1.31 (4H, m), 1.51-1.58 (2H, m), 2.35 (2H, t, J = 7.3 Hz), 8.20 (2H, s), 10.09 (1H, br s), 10.21 (1H, s).
工程3:N-{5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミドの製造
N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(8.18 g, 39 mmol)及びトリフェニルホスフィン(20.5 g, 78 mmol)を混合し、減圧乾燥の後、アルゴン雰囲気置換した。これらを無水N,N-ジメチルホルムアミド(80 mL)に加熱溶解し、室温まで冷却した後、2-メチルチオエタノール(5.40 g, 58.6 mmol)を加えた。氷浴中にてDEAD(2.2 M トルエン溶液, 26.6 mL, 58.6 mmol)を加え、室温にて2時間攪拌した。反応液に水(300 mL)を加えて15分間攪拌の後、クロロホルムにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣を飽和アンモニアメタノール(60 mL)に溶解し、室温にて1時間放置した。反応液を減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 3:1 → ヘキサン:アセトン = 2:1)にて精製し、溶出液を減圧濃縮後、残渣を過熱下にてクロロホルムに溶解した。氷冷して得られた結晶を除去し、ろ液を減圧濃縮した。残渣をクロロホルム-ヘキサンで再結晶しN-{5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(6.80 g, 61%)を淡茶褐色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.1 Hz), 1.26-1.41 (4H, m), 1.70-1.78 (2H, m), 2.22 (3H, s), 2.52-2.68 (2H, m), 2.90 (2H, t, J = 6.6 Hz), 4.22 (2H, t, J = 6.6 Hz), 8.21 (1H, br), 8.30 (2H, s). Step 3: Preparation of N- {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide N- (5-hydroxypyrimidin-2-yl) hexanamide (8.18 g, 39 mmol) and triphenyl Phosphine (20.5 g, 78 mmol) was mixed, dried under reduced pressure, and then purged with an argon atmosphere. These were dissolved by heating in anhydrous N, N-dimethylformamide (80 mL), cooled to room temperature, and 2-methylthioethanol (5.40 g, 58.6 mmol) was added. DEAD (2.2 M toluene solution, 26.6 mL, 58.6 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water (300 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was dissolved in saturated ammonia methanol (60 mL) and allowed to stand at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → hexane: acetone = 2: 1). The eluate was concentrated under reduced pressure, and the residue was then heated. And dissolved in chloroform. Crystals obtained by cooling with ice were removed, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain N- {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide (6.80 g, 61%) as a light brown solid.
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.1 Hz), 1.26-1.41 (4H, m), 1.70-1.78 (2H, m), 2.22 (3H, s), 2.52-2.68 (2H, m), 2.90 (2H, t, J = 6.6 Hz), 4.22 (2H, t, J = 6.6 Hz), 8.21 (1H, br), 8.30 (2H, s).
N-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(8.18 g, 39 mmol)及びトリフェニルホスフィン(20.5 g, 78 mmol)を混合し、減圧乾燥の後、アルゴン雰囲気置換した。これらを無水N,N-ジメチルホルムアミド(80 mL)に加熱溶解し、室温まで冷却した後、2-メチルチオエタノール(5.40 g, 58.6 mmol)を加えた。氷浴中にてDEAD(2.2 M トルエン溶液, 26.6 mL, 58.6 mmol)を加え、室温にて2時間攪拌した。反応液に水(300 mL)を加えて15分間攪拌の後、クロロホルムにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣を飽和アンモニアメタノール(60 mL)に溶解し、室温にて1時間放置した。反応液を減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 3:1 → ヘキサン:アセトン = 2:1)にて精製し、溶出液を減圧濃縮後、残渣を過熱下にてクロロホルムに溶解した。氷冷して得られた結晶を除去し、ろ液を減圧濃縮した。残渣をクロロホルム-ヘキサンで再結晶しN-{5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(6.80 g, 61%)を淡茶褐色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.1 Hz), 1.26-1.41 (4H, m), 1.70-1.78 (2H, m), 2.22 (3H, s), 2.52-2.68 (2H, m), 2.90 (2H, t, J = 6.6 Hz), 4.22 (2H, t, J = 6.6 Hz), 8.21 (1H, br), 8.30 (2H, s). Step 3: Preparation of N- {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide N- (5-hydroxypyrimidin-2-yl) hexanamide (8.18 g, 39 mmol) and triphenyl Phosphine (20.5 g, 78 mmol) was mixed, dried under reduced pressure, and then purged with an argon atmosphere. These were dissolved by heating in anhydrous N, N-dimethylformamide (80 mL), cooled to room temperature, and 2-methylthioethanol (5.40 g, 58.6 mmol) was added. DEAD (2.2 M toluene solution, 26.6 mL, 58.6 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water (300 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was dissolved in saturated ammonia methanol (60 mL) and allowed to stand at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → hexane: acetone = 2: 1). The eluate was concentrated under reduced pressure, and the residue was then heated. And dissolved in chloroform. Crystals obtained by cooling with ice were removed, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain N- {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide (6.80 g, 61%) as a light brown solid.
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.1 Hz), 1.26-1.41 (4H, m), 1.70-1.78 (2H, m), 2.22 (3H, s), 2.52-2.68 (2H, m), 2.90 (2H, t, J = 6.6 Hz), 4.22 (2H, t, J = 6.6 Hz), 8.21 (1H, br), 8.30 (2H, s).
工程4:5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
N-{5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(6.80 g, 24 mmol)をメタノール(68 mL)に懸濁し、ナトリウムメトキシド(1 M メタノール溶液, 120 mL, 120 mmol)を加え、60℃油浴にて溶解し、同温にて2時間攪拌した。反応液を減圧濃縮し得られた残渣をクロロホルム-水より抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をエーテル-ヘキサンにて洗浄ろ取し、表題化合物(2.93 g, 59%)を淡黄色固体として得た。
1H-NMR (CDCl3) δ: 2.21 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.93 (2H, br), 8.06 (2H, s). Step 4: Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine N- {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide (6.80 g, 24 mmol) in methanol (68 mL), sodium methoxide (1 M methanol solution, 120 mL, 120 mmol) was added, dissolved in a 60 ° C. oil bath, and stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was extracted from chloroform-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ether-hexane and collected by filtration to give the title compound (2.93 g, 59%) as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 2.21 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.93 (2H, br), 8.06 ( 2H, s).
N-{5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(6.80 g, 24 mmol)をメタノール(68 mL)に懸濁し、ナトリウムメトキシド(1 M メタノール溶液, 120 mL, 120 mmol)を加え、60℃油浴にて溶解し、同温にて2時間攪拌した。反応液を減圧濃縮し得られた残渣をクロロホルム-水より抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。得られた残渣をエーテル-ヘキサンにて洗浄ろ取し、表題化合物(2.93 g, 59%)を淡黄色固体として得た。
1H-NMR (CDCl3) δ: 2.21 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.93 (2H, br), 8.06 (2H, s). Step 4: Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine N- {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide (6.80 g, 24 mmol) in methanol (68 mL), sodium methoxide (1 M methanol solution, 120 mL, 120 mmol) was added, dissolved in a 60 ° C. oil bath, and stirred at the same temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was extracted from chloroform-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ether-hexane and collected by filtration to give the title compound (2.93 g, 59%) as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 2.21 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.93 (2H, br), 8.06 ( 2H, s).
実施例4
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジンの製造
Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) に記載の方法により製造した(3-ブロモ-6-メトキシピリジン-2-イル)メタノール(10.6 g, 48.6 mmol)のジクロロメタン(150 mL)溶液に氷冷下で、N,N-ジイソプロピルエチルアミン(31.4 g, 243 mmol)及びクロロメチルメチルエーテル(13.3 g, 165 mmol)を順次滴下した。室温に昇温し16時間攪拌後、メタノール(30 mL)を加え30分間攪拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 30:1 → 20:1)を用いて精製し、3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン(12.1 g, 95%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 3.46 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 4.81 (2H, s), 6.59 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.7 Hz). Example 4
Production of N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Production of 3-bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine This was produced by the method described in Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) (3-bromo-6 -Methoxypyridin-2-yl) methanol (10.6 g, 48.6 mmol) in dichloromethane (150 mL) under ice-cooling, N, N-diisopropylethylamine (31.4 g, 243 mmol) and chloromethyl methyl ether (13.3 g) , 165 mmol) was added dropwise. After warming to room temperature and stirring for 16 hours, methanol (30 mL) was added and stirred for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 30: 1 → 20: 1) to give 3-bromo-6-methoxy-2-[(methoxymethoxy ) Methyl] pyridine (12.1 g, 95%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 3.46 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 4.81 (2H, s), 6.59 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.7 Hz).
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジンの製造
Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) に記載の方法により製造した(3-ブロモ-6-メトキシピリジン-2-イル)メタノール(10.6 g, 48.6 mmol)のジクロロメタン(150 mL)溶液に氷冷下で、N,N-ジイソプロピルエチルアミン(31.4 g, 243 mmol)及びクロロメチルメチルエーテル(13.3 g, 165 mmol)を順次滴下した。室温に昇温し16時間攪拌後、メタノール(30 mL)を加え30分間攪拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 30:1 → 20:1)を用いて精製し、3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン(12.1 g, 95%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 3.46 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 4.81 (2H, s), 6.59 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.7 Hz). Example 4
Production of N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Production of 3-bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine This was produced by the method described in Organic & Biomolecular Chemistry 1 (16) 2865-2876 (2003) (3-bromo-6 -Methoxypyridin-2-yl) methanol (10.6 g, 48.6 mmol) in dichloromethane (150 mL) under ice-cooling, N, N-diisopropylethylamine (31.4 g, 243 mmol) and chloromethyl methyl ether (13.3 g) , 165 mmol) was added dropwise. After warming to room temperature and stirring for 16 hours, methanol (30 mL) was added and stirred for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 30: 1 → 20: 1) to give 3-bromo-6-methoxy-2-[(methoxymethoxy ) Methyl] pyridine (12.1 g, 95%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 3.46 (3H, s), 3.93 (3H, s), 4.73 (2H, s), 4.81 (2H, s), 6.59 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.7 Hz).
工程2:N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミンの製造
3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン(1.50 g, 5.72 mmol)、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)(592 mg, 0.572 mmol)、(2-ビフェニル)ジ-t-ブチルホスフィン(680 mg, 2.28 mmol)、t-ブトキシナトリウム(1.65 g, 17.2 mmol)及びエチルアミン(2.0 M テトラヒドロフラン溶液, 15 mL, 30 mmol)のテトラヒドロフラン(15 mL)溶液をマイクロウエーブ照射条件(500 W)にて3分間かけて135℃まで昇温した。反応液を冷却後、セライトろ過し、酢酸エチルで洗浄した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 8:1)を用いて精製し、N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(954 mg, 74%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.27 (3H, t, J = 7.1 Hz), 3.12 (2H, q, J = 7.1 Hz), 3.43 (3H, s), 3.86 (3H, s), 4.23 (1H, br s), 4.68 (2H, s), 4.71 (2H, s), 6.64 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz). Step 2: Preparation of N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine 3-Bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine (1.50 g, 5.72 mmol), tris (dibenzylideneacetone) (chloroform) dipalladium (0) (592 mg, 0.572 mmol), (2-biphenyl) di-t-butylphosphine (680 mg, 2.28 mmol), sodium t-butoxy (1.65 g, 17.2 mmol) and ethylamine (2.0 M tetrahydrofuran solution, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) were heated to 135 ° C. over 3 minutes under microwave irradiation conditions (500 W). The reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridine. -3-Amine (954 mg, 74%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.12 (2H, q, J = 7.1 Hz), 3.43 (3H, s), 3.86 (3H, s), 4.23 ( 1H, br s), 4.68 (2H, s), 4.71 (2H, s), 6.64 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz).
3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン(1.50 g, 5.72 mmol)、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)(592 mg, 0.572 mmol)、(2-ビフェニル)ジ-t-ブチルホスフィン(680 mg, 2.28 mmol)、t-ブトキシナトリウム(1.65 g, 17.2 mmol)及びエチルアミン(2.0 M テトラヒドロフラン溶液, 15 mL, 30 mmol)のテトラヒドロフラン(15 mL)溶液をマイクロウエーブ照射条件(500 W)にて3分間かけて135℃まで昇温した。反応液を冷却後、セライトろ過し、酢酸エチルで洗浄した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 8:1)を用いて精製し、N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(954 mg, 74%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.27 (3H, t, J = 7.1 Hz), 3.12 (2H, q, J = 7.1 Hz), 3.43 (3H, s), 3.86 (3H, s), 4.23 (1H, br s), 4.68 (2H, s), 4.71 (2H, s), 6.64 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz). Step 2: Preparation of N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine 3-Bromo-6-methoxy-2-[(methoxymethoxy) methyl] pyridine (1.50 g, 5.72 mmol), tris (dibenzylideneacetone) (chloroform) dipalladium (0) (592 mg, 0.572 mmol), (2-biphenyl) di-t-butylphosphine (680 mg, 2.28 mmol), sodium t-butoxy (1.65 g, 17.2 mmol) and ethylamine (2.0 M tetrahydrofuran solution, 15 mL, 30 mmol) in tetrahydrofuran (15 mL) were heated to 135 ° C. over 3 minutes under microwave irradiation conditions (500 W). The reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridine. -3-Amine (954 mg, 74%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.12 (2H, q, J = 7.1 Hz), 3.43 (3H, s), 3.86 (3H, s), 4.23 ( 1H, br s), 4.68 (2H, s), 4.71 (2H, s), 6.64 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz).
工程3:N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミンの製造
N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(7.20 g, 31.8 mmol)及びシクロペンタンカルボアルデヒド(3.75 g, 38.2 mmol)の1,2-ジクロロエタン(240 mL)溶液にトリアセトキシ水素化ホウ素ナトリウム(8.75 g, 41.3 mmol)を加え、室温で12時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 8:1)を用いて精製し、N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(8.39 g, 86%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H, d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz). Step 3: Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl ] To a solution of pyridine-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL), sodium triacetoxyborohydride (8.75 g, 41.3 mmol) And stirred at room temperature for 12 hours. Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 8: 1), and N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridine. -3-Amine (8.39 g, 86%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H , d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz).
N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(7.20 g, 31.8 mmol)及びシクロペンタンカルボアルデヒド(3.75 g, 38.2 mmol)の1,2-ジクロロエタン(240 mL)溶液にトリアセトキシ水素化ホウ素ナトリウム(8.75 g, 41.3 mmol)を加え、室温で12時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 8:1)を用いて精製し、N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(8.39 g, 86%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H, d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz). Step 3: Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl ] To a solution of pyridine-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL), sodium triacetoxyborohydride (8.75 g, 41.3 mmol) And stirred at room temperature for 12 hours. Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 8: 1), and N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridine. -3-Amine (8.39 g, 86%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H , d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz).
工程4:{3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メタノールの製造
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(8.39 g, 27.2 mmol)のジオキサン(400 mL)-水(100 mL)混合溶液に濃塩酸(20 mL)を滴下し、50℃で19時間攪拌した。反応液に水酸化ナトリウム水溶液を加え塩基性とし、酢酸エチルで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 15:1)を用いて精製し、{3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メタノール(6.72 g, 94%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.33-1.77 (6H, m), 1.87 (1H, m), 2.77 (2H, d, J = 7.5 Hz), 2.86 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.79 (2H, s), 5.04 (1H, br s), 6.64 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 8.7 Hz). Step 4: Preparation of {3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy Concentrated hydrochloric acid (20 mL) was added dropwise to a mixed solution of methyl) pyridin-3-amine (8.39 g, 27.2 mmol) in dioxane (400 mL) -water (100 mL), and the mixture was stirred at 50 ° C. for 19 hours. The reaction mixture was basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain {3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol ( 6.72 g, 94%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.33-1.77 (6H, m), 1.87 (1H, m), 2.77 (2H , d, J = 7.5 Hz), 2.86 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.79 (2H, s), 5.04 (1H, br s), 6.64 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 8.7 Hz).
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミン(8.39 g, 27.2 mmol)のジオキサン(400 mL)-水(100 mL)混合溶液に濃塩酸(20 mL)を滴下し、50℃で19時間攪拌した。反応液に水酸化ナトリウム水溶液を加え塩基性とし、酢酸エチルで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 15:1)を用いて精製し、{3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メタノール(6.72 g, 94%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.33-1.77 (6H, m), 1.87 (1H, m), 2.77 (2H, d, J = 7.5 Hz), 2.86 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.79 (2H, s), 5.04 (1H, br s), 6.64 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 8.7 Hz). Step 4: Preparation of {3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol N- (cyclopentylmethyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy Concentrated hydrochloric acid (20 mL) was added dropwise to a mixed solution of methyl) pyridin-3-amine (8.39 g, 27.2 mmol) in dioxane (400 mL) -water (100 mL), and the mixture was stirred at 50 ° C. for 19 hours. The reaction mixture was basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain {3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol ( 6.72 g, 94%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.33-1.77 (6H, m), 1.87 (1H, m), 2.77 (2H , d, J = 7.5 Hz), 2.86 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.79 (2H, s), 5.04 (1H, br s), 6.64 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 8.7 Hz).
工程5:3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの製造
{3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メタノール(2.0 g, 7.57 mmol)のクロロホルム(200 mL)溶液に二酸化マンガン(20 g, 230 mmol)を加え、55℃で16時間攪拌した。反応液をセライトろ過し、クロロホルムで洗浄後、ろ液を減圧濃縮した。得られた残渣にクロロホルム(200 mL)及び二酸化マンガン(20 g, 230 mmol)を加え、55℃で6時間攪拌した。反応液をセライトろ過し、クロロホルムで洗浄後、ろ液を減圧濃縮して3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒド(1.68 g, 85%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.36-1.73 (6H, m), 1.95 (1H, m), 2.99 (2H, d, J = 7.6 Hz), 3.13 (2H, q, J = 7.1 Hz), 3.99 (3H, s), 6.93 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 10.4 (1H, s). Step 5: Preparation of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde {3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol (2.0 g , 7.57 mmol) in chloroform (200 mL) was added manganese dioxide (20 g, 230 mmol), and the mixture was stirred at 55 ° C. for 16 hours. The reaction mixture was filtered through celite, washed with chloroform, and the filtrate was concentrated under reduced pressure. Chloroform (200 mL) and manganese dioxide (20 g, 230 mmol) were added to the resulting residue, and the mixture was stirred at 55 ° C. for 6 hours. The reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure to give 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde (1.68 g, 85%) as a pale yellow oil. Obtained.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.36-1.73 (6H, m), 1.95 (1H, m), 2.99 (2H , d, J = 7.6 Hz), 3.13 (2H, q, J = 7.1 Hz), 3.99 (3H, s), 6.93 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz ), 10.4 (1H, s).
{3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メタノール(2.0 g, 7.57 mmol)のクロロホルム(200 mL)溶液に二酸化マンガン(20 g, 230 mmol)を加え、55℃で16時間攪拌した。反応液をセライトろ過し、クロロホルムで洗浄後、ろ液を減圧濃縮した。得られた残渣にクロロホルム(200 mL)及び二酸化マンガン(20 g, 230 mmol)を加え、55℃で6時間攪拌した。反応液をセライトろ過し、クロロホルムで洗浄後、ろ液を減圧濃縮して3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒド(1.68 g, 85%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.36-1.73 (6H, m), 1.95 (1H, m), 2.99 (2H, d, J = 7.6 Hz), 3.13 (2H, q, J = 7.1 Hz), 3.99 (3H, s), 6.93 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz), 10.4 (1H, s). Step 5: Preparation of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde {3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methanol (2.0 g , 7.57 mmol) in chloroform (200 mL) was added manganese dioxide (20 g, 230 mmol), and the mixture was stirred at 55 ° C. for 16 hours. The reaction mixture was filtered through celite, washed with chloroform, and the filtrate was concentrated under reduced pressure. Chloroform (200 mL) and manganese dioxide (20 g, 230 mmol) were added to the resulting residue, and the mixture was stirred at 55 ° C. for 6 hours. The reaction mixture was filtered through celite and washed with chloroform. The filtrate was concentrated under reduced pressure to give 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde (1.68 g, 85%) as a pale yellow oil. Obtained.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.36-1.73 (6H, m), 1.95 (1H, m), 2.99 (2H , d, J = 7.6 Hz), 3.13 (2H, q, J = 7.1 Hz), 3.99 (3H, s), 6.93 (1H, d, J = 9.0 Hz), 7.59 (1H, d, J = 9.0 Hz ), 10.4 (1H, s).
工程6:N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(1.03 g, 5.55 mmol)及び工程5で製造した3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒド(1.60 g, 6.10 mmol)の1,2-ジクロロエタン(60 mL)溶液を室温で10分間攪拌した後、トリアセトキシ水素化ホウ素ナトリウム(1.24 g, 5.83 mmol)を加え、室温で12時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 5:1)を用いて精製し、表題化合物(1.60 g, 67%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.97 (3H, t, J = 7.1 Hz), 1.08-1.25 (2H, m), 1.34-1.70 (6H, m), 1.84 (1H, m), 2.21 (3H, s), 2.81 (2H, d, J = 7.5 Hz), 2.85 (2H, t, J = 6.7 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.12 (2H, t, J = 6.7 Hz), 4.70 (2H, d, J = 4.6 Hz), 6.33 (1H, t, J = 4.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 8.12 (2H, s). Step 6: 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) prepared in Example 3 and 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicoline prepared in Step 5 A solution of aldehyde (1.60 g, 6.10 mmol) in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (1.24 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 12 hours. . Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (1.60 g, 67%) as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.97 (3H, t, J = 7.1 Hz), 1.08-1.25 (2H, m), 1.34-1.70 (6H, m), 1.84 (1H, m), 2.21 (3H , s), 2.81 (2H, d, J = 7.5 Hz), 2.85 (2H, t, J = 6.7 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.12 (2H , t, J = 6.7 Hz), 4.70 (2H, d, J = 4.6 Hz), 6.33 (1H, t, J = 4.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.47 (1H, d , J = 8.6 Hz), 8.12 (2H, s).
実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(1.03 g, 5.55 mmol)及び工程5で製造した3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒド(1.60 g, 6.10 mmol)の1,2-ジクロロエタン(60 mL)溶液を室温で10分間攪拌した後、トリアセトキシ水素化ホウ素ナトリウム(1.24 g, 5.83 mmol)を加え、室温で12時間攪拌した。反応液に水を加えクロロホルムで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 5:1)を用いて精製し、表題化合物(1.60 g, 67%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.97 (3H, t, J = 7.1 Hz), 1.08-1.25 (2H, m), 1.34-1.70 (6H, m), 1.84 (1H, m), 2.21 (3H, s), 2.81 (2H, d, J = 7.5 Hz), 2.85 (2H, t, J = 6.7 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.12 (2H, t, J = 6.7 Hz), 4.70 (2H, d, J = 4.6 Hz), 6.33 (1H, t, J = 4.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 8.6 Hz), 8.12 (2H, s). Step 6: 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) prepared in Example 3 and 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicoline prepared in Step 5 A solution of aldehyde (1.60 g, 6.10 mmol) in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (1.24 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 12 hours. . Water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (1.60 g, 67%) as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.97 (3H, t, J = 7.1 Hz), 1.08-1.25 (2H, m), 1.34-1.70 (6H, m), 1.84 (1H, m), 2.21 (3H , s), 2.81 (2H, d, J = 7.5 Hz), 2.85 (2H, t, J = 6.7 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 4.12 (2H , t, J = 6.7 Hz), 4.70 (2H, d, J = 4.6 Hz), 6.33 (1H, t, J = 4.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 7.47 (1H, d , J = 8.6 Hz), 8.12 (2H, s).
実施例5
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(3.90 g, 18.6 mmol)、及び国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(11.70g, 92.0 mmol)を混合し、アルゴン雰囲気下100℃にて8時間攪拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 10:1 → 5:1)を用いて精製し、6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(9.96g, 99%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.09-1.18 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.46-1.60 (4H, m), 1.61-1.71 (2H, m), 2.30 (1H, m), 2.49 (3H, s), 3.45 (2H, d, J = 7.3 Hz), 3.52 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 8.33 (1H, s), 10.01 (1H, s). Example 5
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] Preparation of pyridine-6-amine:
Step 1: Preparation of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl- 1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N- (cyclopentylmethyl) -N-ethylamine produced by the method described in WO 2006/079773 (11.70 g, 92.0 mmol) were mixed and stirred at 100 ° C. for 8 hours under an argon atmosphere. The residue obtained by concentrating the reaction solution under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5: 1) to give 6-[(cyclopentylmethyl) (ethyl) amino] -1 , 3-Dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (9.96 g, 99%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.09-1.18 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.46-1.60 (4H, m), 1.61-1.71 (2H, m), 2.30 (1H, m), 2.49 (3H, s), 3.45 (2H, d, J = 7.3 Hz), 3.52 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 8.33 (1H, s) , 10.01 (1H, s).
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(3.90 g, 18.6 mmol)、及び国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(11.70g, 92.0 mmol)を混合し、アルゴン雰囲気下100℃にて8時間攪拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 10:1 → 5:1)を用いて精製し、6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(9.96g, 99%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.09-1.18 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.46-1.60 (4H, m), 1.61-1.71 (2H, m), 2.30 (1H, m), 2.49 (3H, s), 3.45 (2H, d, J = 7.3 Hz), 3.52 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 8.33 (1H, s), 10.01 (1H, s). Example 5
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] Preparation of pyridine-6-amine:
Step 1: Preparation of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl- 1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (3.90 g, 18.6 mmol) and N- (cyclopentylmethyl) -N-ethylamine produced by the method described in WO 2006/079773 (11.70 g, 92.0 mmol) were mixed and stirred at 100 ° C. for 8 hours under an argon atmosphere. The residue obtained by concentrating the reaction solution under reduced pressure was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5: 1) to give 6-[(cyclopentylmethyl) (ethyl) amino] -1 , 3-Dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (9.96 g, 99%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.09-1.18 (2H, m), 1.21 (3H, t, J = 7.1 Hz), 1.46-1.60 (4H, m), 1.61-1.71 (2H, m), 2.30 (1H, m), 2.49 (3H, s), 3.45 (2H, d, J = 7.3 Hz), 3.52 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 8.33 (1H, s) , 10.01 (1H, s).
工程2:N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.11-1.22 (5H, m), 1.40-1.75 (6H, m), 2,16 (1H, m), 2.19 (3H, s), 2,45 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.08 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.92 (1H, t, J = 5.6 Hz), 7.85 (1H, s), 8.05 (2H, s). Step 2: N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [ Preparation of 3,4-b] pyridin-6-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3 The reaction and treatment were conducted in the same manner as in Step 6 of Example 4 using -dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.11-1.22 (5H, m), 1.40-1.75 (6H, m), 2,16 (1H, m), 2.19 (3H, s), 2,45 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.08 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.92 (1H, t, J = 5.6 Hz), 7.85 (1H, s), 8.05 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.11-1.22 (5H, m), 1.40-1.75 (6H, m), 2,16 (1H, m), 2.19 (3H, s), 2,45 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.08 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.92 (1H, t, J = 5.6 Hz), 7.85 (1H, s), 8.05 (2H, s). Step 2: N- (Cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [ Preparation of 3,4-b] pyridin-6-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6-[(cyclopentylmethyl) (ethyl) amino] -1,3 The reaction and treatment were conducted in the same manner as in Step 6 of Example 4 using -dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.11-1.22 (5H, m), 1.40-1.75 (6H, m), 2,16 (1H, m), 2.19 (3H, s), 2,45 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 4.08 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.92 (1H, t, J = 5.6 Hz), 7.85 (1H, s), 8.05 (2H, s).
実施例6
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]キノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]キノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.10-1.25 (5H, m), 1.41-1.62 (4H, m), 1.63-1.75 (2H, m), 2.34 (1H, m), 3.48 (2H, d, J = 7.6 Hz), 3.53 (2H, q, J = 7.1 Hz), 7.32 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.65 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.76 (1H, dd, J = 1.2, 8.1 Hz), 7.79 (1H, dd, J = 1.2, 8.1 Hz), 8.45 (1H, s), 10.15 (1H, s). Example 6
Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead, 2-chloroquinoline-3-carbaldehyde was used in the same manner as in Step 1 of Example 5 to treat 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde as a yellow oil. Got as.
1 H-NMR (CDCl 3 ) δ: 1.10-1.25 (5H, m), 1.41-1.62 (4H, m), 1.63-1.75 (2H, m), 2.34 (1H, m), 3.48 (2H, d, J = 7.6 Hz), 3.53 (2H, q, J = 7.1 Hz), 7.32 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.65 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.76 (1H, dd, J = 1.2, 8.1 Hz), 7.79 (1H, dd, J = 1.2, 8.1 Hz), 8.45 (1H, s), 10.15 (1H, s).
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]キノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]キノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.10-1.25 (5H, m), 1.41-1.62 (4H, m), 1.63-1.75 (2H, m), 2.34 (1H, m), 3.48 (2H, d, J = 7.6 Hz), 3.53 (2H, q, J = 7.1 Hz), 7.32 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.65 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.76 (1H, dd, J = 1.2, 8.1 Hz), 7.79 (1H, dd, J = 1.2, 8.1 Hz), 8.45 (1H, s), 10.15 (1H, s). Example 6
Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead, 2-chloroquinoline-3-carbaldehyde was used in the same manner as in Step 1 of Example 5 to treat 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde as a yellow oil. Got as.
1 H-NMR (CDCl 3 ) δ: 1.10-1.25 (5H, m), 1.41-1.62 (4H, m), 1.63-1.75 (2H, m), 2.34 (1H, m), 3.48 (2H, d, J = 7.6 Hz), 3.53 (2H, q, J = 7.1 Hz), 7.32 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.65 (1H, ddd, J = 1.2, 7.1, 8.1 Hz), 7.76 (1H, dd, J = 1.2, 8.1 Hz), 7.79 (1H, dd, J = 1.2, 8.1 Hz), 8.45 (1H, s), 10.15 (1H, s).
工程2:N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]キノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.18 (3H, t, J = 7.1 Hz), 1.40-1.63 (6H, m), 1.65-1.75 (2H, m), 2.20 (3H, s), 2.21 (1H, m), 2.84 (2H, t, J = 6.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 3.34 (2H, d, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 5.2 Hz), 5.60 (1H, t, J = 5.2 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.99 (1H, s), 8.08 (2H, s). Step 2: Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine 3-[( Reaction and treatment in the same manner as in Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.18 (3H, t, J = 7.1 Hz), 1.40-1.63 (6H, m), 1.65-1.75 (2H, m), 2.20 (3H, s), 2.21 (1H , m), 2.84 (2H, t, J = 6.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 3.34 (2H, d, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz) ), 4.73 (2H, d, J = 5.2 Hz), 5.60 (1H, t, J = 5.2 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.99 (1H, s), 8.08 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]キノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.18 (3H, t, J = 7.1 Hz), 1.40-1.63 (6H, m), 1.65-1.75 (2H, m), 2.20 (3H, s), 2.21 (1H, m), 2.84 (2H, t, J = 6.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 3.34 (2H, d, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 5.2 Hz), 5.60 (1H, t, J = 5.2 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.99 (1H, s), 8.08 (2H, s). Step 2: Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine 3-[( Reaction and treatment in the same manner as in Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] quinoline-3-carbaldehyde instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.18 (3H, t, J = 7.1 Hz), 1.40-1.63 (6H, m), 1.65-1.75 (2H, m), 2.20 (3H, s), 2.21 (1H , m), 2.84 (2H, t, J = 6.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 3.34 (2H, d, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz) ), 4.73 (2H, d, J = 5.2 Hz), 5.60 (1H, t, J = 5.2 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.56 (1H, t, J = 7.8 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.99 (1H, s), 8.08 (2H, s).
実施例7
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メトキシキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08-1.20 (5H, m), 1.43-1.72 (6H, m), 2.30 (1H, m), 3.42 (2H, d, J = 7.6 Hz), 3.47 (2H, q, J = 7.0 Hz), 3.89 (3H, s), 7.05 (1H, s), 7.34 (1H, d, J = 9.2 Hz), 7.74 (1H, d, J = 9.2 Hz), 8.38 (1H, s), 10.19 (1H, s). Example 7
Production of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methoxyquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5 Using 2-chloro-6-methoxyquinoline-3-carbaldehyde instead of carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) amino] -6 -Methoxyquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08-1.20 (5H, m), 1.43-1.72 (6H, m), 2.30 (1H, m), 3.42 (2H, d, J = 7.6 Hz), 3.47 (2H , q, J = 7.0 Hz), 3.89 (3H, s), 7.05 (1H, s), 7.34 (1H, d, J = 9.2 Hz), 7.74 (1H, d, J = 9.2 Hz), 8.38 (1H , s), 10.19 (1H, s).
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メトキシキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08-1.20 (5H, m), 1.43-1.72 (6H, m), 2.30 (1H, m), 3.42 (2H, d, J = 7.6 Hz), 3.47 (2H, q, J = 7.0 Hz), 3.89 (3H, s), 7.05 (1H, s), 7.34 (1H, d, J = 9.2 Hz), 7.74 (1H, d, J = 9.2 Hz), 8.38 (1H, s), 10.19 (1H, s). Example 7
Production of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methoxyquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5 Using 2-chloro-6-methoxyquinoline-3-carbaldehyde instead of carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) amino] -6 -Methoxyquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08-1.20 (5H, m), 1.43-1.72 (6H, m), 2.30 (1H, m), 3.42 (2H, d, J = 7.6 Hz), 3.47 (2H , q, J = 7.0 Hz), 3.89 (3H, s), 7.05 (1H, s), 7.34 (1H, d, J = 9.2 Hz), 7.74 (1H, d, J = 9.2 Hz), 8.38 (1H , s), 10.19 (1H, s).
工程2:N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシキノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.15 (3H, t, J = 7.1 Hz), 1.16-1.25 (2H, m), 1.40-1.62 (4H, m), 1.63-1.74 (2H, m), 2.17 (1H, m), 2.18 (3H, s), 2.82 (2H, t, J = 6.6 Hz), 3.25 (2H, q, J = 7.1 Hz), 3.28 (2H, d, J = 7.3 Hz), 3.86 (3H, s), 4.06 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 5.6 Hz), 5.98 (1H, t, J = 5.6 Hz), 6.95 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 2.7, 9.0 Hz), 7.77 (1H, d, J = 9.0 Hz), 7.91 (1H, s), 8.04 (2H, s). Step 2: Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine Example 2 Using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methoxyquinoline-3-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.15 (3H, t, J = 7.1 Hz), 1.16-1.25 (2H, m), 1.40-1.62 (4H, m), 1.63-1.74 (2H, m), 2.17 (1H, m), 2.18 (3H, s), 2.82 (2H, t, J = 6.6 Hz), 3.25 (2H, q, J = 7.1 Hz), 3.28 (2H, d, J = 7.3 Hz), 3.86 (3H, s), 4.06 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 5.6 Hz), 5.98 (1H, t, J = 5.6 Hz), 6.95 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 2.7, 9.0 Hz), 7.77 (1H, d, J = 9.0 Hz), 7.91 (1H, s), 8.04 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシキノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.15 (3H, t, J = 7.1 Hz), 1.16-1.25 (2H, m), 1.40-1.62 (4H, m), 1.63-1.74 (2H, m), 2.17 (1H, m), 2.18 (3H, s), 2.82 (2H, t, J = 6.6 Hz), 3.25 (2H, q, J = 7.1 Hz), 3.28 (2H, d, J = 7.3 Hz), 3.86 (3H, s), 4.06 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 5.6 Hz), 5.98 (1H, t, J = 5.6 Hz), 6.95 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 2.7, 9.0 Hz), 7.77 (1H, d, J = 9.0 Hz), 7.91 (1H, s), 8.04 (2H, s). Step 2: Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine Example 2 Using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methoxyquinoline-3-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.15 (3H, t, J = 7.1 Hz), 1.16-1.25 (2H, m), 1.40-1.62 (4H, m), 1.63-1.74 (2H, m), 2.17 (1H, m), 2.18 (3H, s), 2.82 (2H, t, J = 6.6 Hz), 3.25 (2H, q, J = 7.1 Hz), 3.28 (2H, d, J = 7.3 Hz), 3.86 (3H, s), 4.06 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 5.6 Hz), 5.98 (1H, t, J = 5.6 Hz), 6.95 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 2.7, 9.0 Hz), 7.77 (1H, d, J = 9.0 Hz), 7.91 (1H, s), 8.04 (2H, s).
実施例8
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミンの製造:
工程1:4-トリフルオロメチルアセトアニリドの製造
4-トリフルオロメチルアニリン(3.00 g, 18.6 mmol)をピリジン(1.62 g, 20.5 mmol)に溶解し、氷浴中にて攪拌しつつ無水酢酸(2.38 g, 23.3 mmol)を加え、室温にて30分間攪拌した。反応液を減圧濃縮の後、トルエン共沸して得られた残渣をヘキサンに懸濁し、ろ取した。ヘキサンにて洗浄した後、減圧乾燥し、4-トリフルオロメチルアセトアニリド(3.76 g, 99%)を無色固体として得た。
1H-NMR (CDCl3) δ: 2.09 (3H, s), 7.66 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.6 Hz), 10.30 (1H, br). Example 8
Of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine Manufacturing:
Step 1: Preparation of 4-trifluoromethylacetanilide 4-trifluoromethylaniline (3.00 g, 18.6 mmol) was dissolved in pyridine (1.62 g, 20.5 mmol), and acetic anhydride (2.38 g) was stirred in an ice bath. 23.3 mmol) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue obtained by azeotropic distillation with toluene was suspended in hexane and collected by filtration. After washing with hexane and drying under reduced pressure, 4-trifluoromethylacetanilide (3.76 g, 99%) was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.09 (3H, s), 7.66 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.6 Hz), 10.30 (1H, br).
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミンの製造:
工程1:4-トリフルオロメチルアセトアニリドの製造
4-トリフルオロメチルアニリン(3.00 g, 18.6 mmol)をピリジン(1.62 g, 20.5 mmol)に溶解し、氷浴中にて攪拌しつつ無水酢酸(2.38 g, 23.3 mmol)を加え、室温にて30分間攪拌した。反応液を減圧濃縮の後、トルエン共沸して得られた残渣をヘキサンに懸濁し、ろ取した。ヘキサンにて洗浄した後、減圧乾燥し、4-トリフルオロメチルアセトアニリド(3.76 g, 99%)を無色固体として得た。
1H-NMR (CDCl3) δ: 2.09 (3H, s), 7.66 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.6 Hz), 10.30 (1H, br). Example 8
Of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine Manufacturing:
Step 1: Preparation of 4-trifluoromethylacetanilide 4-trifluoromethylaniline (3.00 g, 18.6 mmol) was dissolved in pyridine (1.62 g, 20.5 mmol), and acetic anhydride (2.38 g) was stirred in an ice bath. 23.3 mmol) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue obtained by azeotropic distillation with toluene was suspended in hexane and collected by filtration. After washing with hexane and drying under reduced pressure, 4-trifluoromethylacetanilide (3.76 g, 99%) was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.09 (3H, s), 7.66 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.6 Hz), 10.30 (1H, br).
工程2:2-クロロ-6-トリフルオロメチルキノリン-3-カルボアルデヒドの製造
N,N-ジメチルホルムアミド(3.38 g, 46.2 mmol)を氷浴中にて攪拌する中にオキシ塩化リン(20 g, 130 mmol)及び4-トリフルオロメチルアセトアニリド(3.76 g, 18.5 mmol)を順次加え、65℃にて22時間攪拌した。反応液を氷中に注ぎ、酢酸エチル-水より抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1)を用いて精製し、2-クロロ-6-トリフルオロメチルキノリン-3-カルボアルデヒド(33 mg, 0.7%)を無色固体として得た。
1H-NMR (CDCl3) δ: 8.05 (1H, d, J = 8.6 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.31 (1H, s), 8.84 (1H, s), 10.58 (1H, s). Step 2: Preparation of 2-chloro-6-trifluoromethylquinoline-3-carbaldehyde While stirring N, N-dimethylformamide (3.38 g, 46.2 mmol) in an ice bath, phosphorus oxychloride (20 g, 130 mmol) and 4-trifluoromethylacetanilide (3.76 g, 18.5 mmol) were sequentially added, and the mixture was stirred at 65 ° C. for 22 hours. The reaction mixture was poured into ice and extracted from ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1), and 2 -Chloro-6-trifluoromethylquinoline-3-carbaldehyde (33 mg, 0.7%) was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 8.05 (1H, d, J = 8.6 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.31 (1H, s), 8.84 (1H, s), 10.58 ( 1H, s).
N,N-ジメチルホルムアミド(3.38 g, 46.2 mmol)を氷浴中にて攪拌する中にオキシ塩化リン(20 g, 130 mmol)及び4-トリフルオロメチルアセトアニリド(3.76 g, 18.5 mmol)を順次加え、65℃にて22時間攪拌した。反応液を氷中に注ぎ、酢酸エチル-水より抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1)を用いて精製し、2-クロロ-6-トリフルオロメチルキノリン-3-カルボアルデヒド(33 mg, 0.7%)を無色固体として得た。
1H-NMR (CDCl3) δ: 8.05 (1H, d, J = 8.6 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.31 (1H, s), 8.84 (1H, s), 10.58 (1H, s). Step 2: Preparation of 2-chloro-6-trifluoromethylquinoline-3-carbaldehyde While stirring N, N-dimethylformamide (3.38 g, 46.2 mmol) in an ice bath, phosphorus oxychloride (20 g, 130 mmol) and 4-trifluoromethylacetanilide (3.76 g, 18.5 mmol) were sequentially added, and the mixture was stirred at 65 ° C. for 22 hours. The reaction mixture was poured into ice and extracted from ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1), and 2 -Chloro-6-trifluoromethylquinoline-3-carbaldehyde (33 mg, 0.7%) was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 8.05 (1H, d, J = 8.6 Hz), 8.21 (1H, d, J = 8.6 Hz), 8.31 (1H, s), 8.84 (1H, s), 10.58 ( 1H, s).
工程3:2-[(シクロペンチルメチル)(エチル)アミノ]-6-トリフルオロメチルキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-トリフルオロメチルキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-トリフルオロメチルキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.14-1.27 (5H, m), 1.50-1.71 (6H, m), 2.35 (1H, m), 3.53 (2H, d, J = 7.3 Hz), 3.59 (2H, q, J = 6.9 Hz), 7.76-7.84 (2H, m), 8.03 (1H, s), 8.46 (1H, s), 10.10 (1H, s). Step 3: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-trifluoromethylquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Using 2-chloro-6-trifluoromethylquinoline-3-carbaldehyde instead of -5-carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) Amino] -6-trifluoromethylquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.14-1.27 (5H, m), 1.50-1.71 (6H, m), 2.35 (1H, m), 3.53 (2H, d, J = 7.3 Hz), 3.59 (2H , q, J = 6.9 Hz), 7.76-7.84 (2H, m), 8.03 (1H, s), 8.46 (1H, s), 10.10 (1H, s).
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-トリフルオロメチルキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-トリフルオロメチルキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.14-1.27 (5H, m), 1.50-1.71 (6H, m), 2.35 (1H, m), 3.53 (2H, d, J = 7.3 Hz), 3.59 (2H, q, J = 6.9 Hz), 7.76-7.84 (2H, m), 8.03 (1H, s), 8.46 (1H, s), 10.10 (1H, s). Step 3: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-trifluoromethylquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Using 2-chloro-6-trifluoromethylquinoline-3-carbaldehyde instead of -5-carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) Amino] -6-trifluoromethylquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.14-1.27 (5H, m), 1.50-1.71 (6H, m), 2.35 (1H, m), 3.53 (2H, d, J = 7.3 Hz), 3.59 (2H , q, J = 6.9 Hz), 7.76-7.84 (2H, m), 8.03 (1H, s), 8.46 (1H, s), 10.10 (1H, s).
工程4:N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-トリフルオロメチルキノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.12-1.25 (5H, m), 1.40-1.77 (6H, m), 2.20 (3H, s), 2.23 (1H, m), 2.85 (2H, t, J = 6.6 Hz), 3.38 (2H, q, J = 7.1 Hz), 3.40 (2H, d, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 5.6 Hz), 5.61 (1H, t, J = 5.6 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.91 (1H, s), 8.03 (1H, s), 8.09 (2H, s). Step 4: N- (Cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinoline-2 -Preparation of amine 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Instead of 2-[(cyclopentylmethyl) (ethyl) amino] -6-trifluoromethylquinoline-3-carbaldehyde Was used and reacted in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.12-1.25 (5H, m), 1.40-1.77 (6H, m), 2.20 (3H, s), 2.23 (1H, m), 2.85 (2H, t, J = 6.6 Hz), 3.38 (2H, q, J = 7.1 Hz), 3.40 (2H, d, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 5.6 Hz) ), 5.61 (1H, t, J = 5.6 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.91 (1H, s), 8.03 (1H, s ), 8.09 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-トリフルオロメチルキノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.12-1.25 (5H, m), 1.40-1.77 (6H, m), 2.20 (3H, s), 2.23 (1H, m), 2.85 (2H, t, J = 6.6 Hz), 3.38 (2H, q, J = 7.1 Hz), 3.40 (2H, d, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 5.6 Hz), 5.61 (1H, t, J = 5.6 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.91 (1H, s), 8.03 (1H, s), 8.09 (2H, s). Step 4: N- (Cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinoline-2 -Preparation of amine 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Instead of 2-[(cyclopentylmethyl) (ethyl) amino] -6-trifluoromethylquinoline-3-carbaldehyde Was used and reacted in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.12-1.25 (5H, m), 1.40-1.77 (6H, m), 2.20 (3H, s), 2.23 (1H, m), 2.85 (2H, t, J = 6.6 Hz), 3.38 (2H, q, J = 7.1 Hz), 3.40 (2H, d, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 5.6 Hz) ), 5.61 (1H, t, J = 5.6 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.90 (1H, d, J = 8.8 Hz), 7.91 (1H, s), 8.03 (1H, s ), 8.09 (2H, s).
実施例9
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メチルキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.10-1.21 (5H, m), 1.41-1.72 (6H, m), 2.32 (1H, m), 2.47 (3H, s), 3.45 (2H, d, J = 7.6 Hz), 3.50 (2H, q, J = 7.0 Hz), 7.48-7.52 (2H, m), 7.71 (1H, d, J = 8.6 Hz), 8.37 (1H, s), 10.15 (1H, s). Example 9
Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5 Using 2-chloro-6-methylquinoline-3-carbaldehyde instead of carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) amino] -6 -Methylquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.10-1.21 (5H, m), 1.41-1.72 (6H, m), 2.32 (1H, m), 2.47 (3H, s), 3.45 (2H, d, J = 7.6 Hz), 3.50 (2H, q, J = 7.0 Hz), 7.48-7.52 (2H, m), 7.71 (1H, d, J = 8.6 Hz), 8.37 (1H, s), 10.15 (1H, s) .
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メチルキノリン-3-カルボアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.10-1.21 (5H, m), 1.41-1.72 (6H, m), 2.32 (1H, m), 2.47 (3H, s), 3.45 (2H, d, J = 7.6 Hz), 3.50 (2H, q, J = 7.0 Hz), 7.48-7.52 (2H, m), 7.71 (1H, d, J = 8.6 Hz), 8.37 (1H, s), 10.15 (1H, s). Example 9
Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylquinoline-3-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5 Using 2-chloro-6-methylquinoline-3-carbaldehyde instead of carbaldehyde, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2-[(cyclopentylmethyl) (ethyl) amino] -6 -Methylquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.10-1.21 (5H, m), 1.41-1.72 (6H, m), 2.32 (1H, m), 2.47 (3H, s), 3.45 (2H, d, J = 7.6 Hz), 3.50 (2H, q, J = 7.0 Hz), 7.48-7.52 (2H, m), 7.71 (1H, d, J = 8.6 Hz), 8.37 (1H, s), 10.15 (1H, s) .
工程2:N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルキノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.07-1.27 (5H, m), 1.40-1.75 (6H, m), 2.03-2.25 (4H, m), 2.44 (3H, s), 2.81 (2H, t, J = 6.6 Hz), 3.21-3.32 (4H, m), 4.02 (2H, t, J = 6.6 Hz), 4.71 (2H, d, J = 5.1 Hz), 6.22 (1H, t, J = 5.1 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.39 (1H, s), 7.75 (1H, d, J = 8.3 Hz), 7.91 (1H, s), 8.01 (2H, s). Step 2: Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine Example 2 Using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylquinoline-3-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.07-1.27 (5H, m), 1.40-1.75 (6H, m), 2.03-2.25 (4H, m), 2.44 (3H, s), 2.81 (2H, t, J = 6.6 Hz), 3.21-3.32 (4H, m), 4.02 (2H, t, J = 6.6 Hz), 4.71 (2H, d, J = 5.1 Hz), 6.22 (1H, t, J = 5.1 Hz) , 7.38 (1H, d, J = 8.3 Hz), 7.39 (1H, s), 7.75 (1H, d, J = 8.3 Hz), 7.91 (1H, s), 8.01 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルキノリン-3-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.07-1.27 (5H, m), 1.40-1.75 (6H, m), 2.03-2.25 (4H, m), 2.44 (3H, s), 2.81 (2H, t, J = 6.6 Hz), 3.21-3.32 (4H, m), 4.02 (2H, t, J = 6.6 Hz), 4.71 (2H, d, J = 5.1 Hz), 6.22 (1H, t, J = 5.1 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.39 (1H, s), 7.75 (1H, d, J = 8.3 Hz), 7.91 (1H, s), 8.01 (2H, s). Step 2: Preparation of N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine Example 2 Using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylquinoline-3-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.07-1.27 (5H, m), 1.40-1.75 (6H, m), 2.03-2.25 (4H, m), 2.44 (3H, s), 2.81 (2H, t, J = 6.6 Hz), 3.21-3.32 (4H, m), 4.02 (2H, t, J = 6.6 Hz), 4.71 (2H, d, J = 5.1 Hz), 6.22 (1H, t, J = 5.1 Hz) , 7.38 (1H, d, J = 8.3 Hz), 7.39 (1H, s), 7.75 (1H, d, J = 8.3 Hz), 7.91 (1H, s), 8.01 (2H, s).
実施例10
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-クロロ-N-メトキシ-N,6-ジメチルピリジン-3-カルボキシアミドの製造
2-クロロ-6-メチルニコチン酸(1.00 g, 5.83 mmol)のテトラヒドロフラン(10 mL)溶液に氷浴中にてN,O-ジメチルヒドロキシアミン塩酸塩(910 mg, 9.33 mmol)、N,N-ジイソプロピルエチルアミン(3.00 g, 23.2 mmol)及びシアノホスホン酸ジエチル(1.43 g, 8.77 mmol)を順次加え、室温にて30分間攪拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 1:1)を用いて精製し、2-クロロ-N-メトキシ-N,6-ジメチルピリジン-3-カルボキシアミドを無色固体として得た。
1H-NMR (CDCl3) δ: 2.58 (3H, s), 3.39 (3H, s), 3.49 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz). Example 10
Production of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide A solution of 2-chloro-6-methylnicotinic acid (1.00 g, 5.83 mmol) in tetrahydrofuran (10 mL) in an ice bath N, O-dimethylhydroxyamine hydrochloride (910 mg, 9.33 mmol), N, N-diisopropylethylamine (3.00 g, 23.2 mmol) and diethyl cyanophosphonate (1.43 g, 8.77 mmol) were sequentially added at room temperature. For 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2- Chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.58 (3H, s), 3.39 (3H, s), 3.49 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz).
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-クロロ-N-メトキシ-N,6-ジメチルピリジン-3-カルボキシアミドの製造
2-クロロ-6-メチルニコチン酸(1.00 g, 5.83 mmol)のテトラヒドロフラン(10 mL)溶液に氷浴中にてN,O-ジメチルヒドロキシアミン塩酸塩(910 mg, 9.33 mmol)、N,N-ジイソプロピルエチルアミン(3.00 g, 23.2 mmol)及びシアノホスホン酸ジエチル(1.43 g, 8.77 mmol)を順次加え、室温にて30分間攪拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 1:1)を用いて精製し、2-クロロ-N-メトキシ-N,6-ジメチルピリジン-3-カルボキシアミドを無色固体として得た。
1H-NMR (CDCl3) δ: 2.58 (3H, s), 3.39 (3H, s), 3.49 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz). Example 10
Production of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide A solution of 2-chloro-6-methylnicotinic acid (1.00 g, 5.83 mmol) in tetrahydrofuran (10 mL) in an ice bath N, O-dimethylhydroxyamine hydrochloride (910 mg, 9.33 mmol), N, N-diisopropylethylamine (3.00 g, 23.2 mmol) and diethyl cyanophosphonate (1.43 g, 8.77 mmol) were sequentially added at room temperature. For 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2- Chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.58 (3H, s), 3.39 (3H, s), 3.49 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz).
工程2:2-クロロ-6-メチルニコチンアルデヒドの製造
2-クロロ-N-メトキシ-N,6-ジメチルピリジン-3-カルボキシアミド(1.30 g, 5.83 mmol)のジクロロメタン(15 mL)溶液に-78℃にてジイソブチル水素化アルミニウム(0.99 M トルエン溶液, 12 mL, 11.66 mmol)を加え、同温にて30分間攪拌した。反応液に2 M水酸化ナトリウム水溶液を加え室温にて30分間攪拌した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 3:1)を用いて精製し、2-クロロ-6-メチルニコチンアルデヒド(828 mg, 91%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.63 (3H, s), 7.25 (1H, d, J = 6.9 Hz), 8.13 (1H, d, J = 6.9 Hz), 10.40 (1H, s). Step 2: Preparation of 2-chloro-6-methylnicotinaldehyde To a solution of 2-chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide (1.30 g, 5.83 mmol) in dichloromethane (15 mL) -78 Diisobutylaluminum hydride (0.99 M toluene solution, 12 mL, 11.66 mmol) was added at ° C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 2 M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1), and 2 -Chloro-6-methylnicotinaldehyde (828 mg, 91%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.63 (3H, s), 7.25 (1H, d, J = 6.9 Hz), 8.13 (1H, d, J = 6.9 Hz), 10.40 (1H, s).
2-クロロ-N-メトキシ-N,6-ジメチルピリジン-3-カルボキシアミド(1.30 g, 5.83 mmol)のジクロロメタン(15 mL)溶液に-78℃にてジイソブチル水素化アルミニウム(0.99 M トルエン溶液, 12 mL, 11.66 mmol)を加え、同温にて30分間攪拌した。反応液に2 M水酸化ナトリウム水溶液を加え室温にて30分間攪拌した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 3:1)を用いて精製し、2-クロロ-6-メチルニコチンアルデヒド(828 mg, 91%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.63 (3H, s), 7.25 (1H, d, J = 6.9 Hz), 8.13 (1H, d, J = 6.9 Hz), 10.40 (1H, s). Step 2: Preparation of 2-chloro-6-methylnicotinaldehyde To a solution of 2-chloro-N-methoxy-N, 6-dimethylpyridine-3-carboxamide (1.30 g, 5.83 mmol) in dichloromethane (15 mL) -78 Diisobutylaluminum hydride (0.99 M toluene solution, 12 mL, 11.66 mmol) was added at ° C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 2 M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1), and 2 -Chloro-6-methylnicotinaldehyde (828 mg, 91%) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.63 (3H, s), 7.25 (1H, d, J = 6.9 Hz), 8.13 (1H, d, J = 6.9 Hz), 10.40 (1H, s).
工程3:2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルニコチンアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メチルニコチンアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルニコチンアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.07-1.21 (5H, m), 1.45-1.85 (6H, m), 2.11 (1H, m), 2.44 (3H, s), 3.44 (2H, d, J = 7.3 Hz), 3.50 (2H, q, J = 7.1 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 9.94 (1H, s). Step 3: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead, 2-chloro-6-methylnicotinaldehyde was reacted and treated in the same manner as in Step 1 of Example 5 to give 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde as a yellow oil Got as.
1 H-NMR (CDCl 3 ) δ: 1.07-1.21 (5H, m), 1.45-1.85 (6H, m), 2.11 (1H, m), 2.44 (3H, s), 3.44 (2H, d, J = 7.3 Hz), 3.50 (2H, q, J = 7.1 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 9.94 (1H, s).
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メチルニコチンアルデヒドを用いて実施例5の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルニコチンアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.07-1.21 (5H, m), 1.45-1.85 (6H, m), 2.11 (1H, m), 2.44 (3H, s), 3.44 (2H, d, J = 7.3 Hz), 3.50 (2H, q, J = 7.1 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 9.94 (1H, s). Step 3: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead, 2-chloro-6-methylnicotinaldehyde was reacted and treated in the same manner as in Step 1 of Example 5 to give 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde as a yellow oil Got as.
1 H-NMR (CDCl 3 ) δ: 1.07-1.21 (5H, m), 1.45-1.85 (6H, m), 2.11 (1H, m), 2.44 (3H, s), 3.44 (2H, d, J = 7.3 Hz), 3.50 (2H, q, J = 7.1 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 9.94 (1H, s).
工程4:N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルニコチンアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 7.1 Hz), 1.10-1.22 (2H, m), 1.42-1.61 (4H, m), 1.63-1.72 (2H, m), 2.07 (1H, m), 2.20 (3H, s), 2.42 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.14 (2H, d, J = 7.3 Hz), 3.15 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.4 Hz), 5.56 (1H, t, J = 5.4 Hz), 6.72 (1H, d, J = 7.6 Hz), 7.45 (1H, d, J = 7.6 Hz), 8.07 (2H, s). Step 4: Preparation of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 3 Similar to Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde instead of-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08 (3H, t, J = 7.1 Hz), 1.10-1.22 (2H, m), 1.42-1.61 (4H, m), 1.63-1.72 (2H, m), 2.07 (1H, m), 2.20 (3H, s), 2.42 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.14 (2H, d, J = 7.3 Hz), 3.15 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.4 Hz), 5.56 (1H, t, J = 5.4 Hz), 6.72 (1H, d, J = 7.6 Hz), 7.45 (1H, d, J = 7.6 Hz), 8.07 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルニコチンアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 7.1 Hz), 1.10-1.22 (2H, m), 1.42-1.61 (4H, m), 1.63-1.72 (2H, m), 2.07 (1H, m), 2.20 (3H, s), 2.42 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.14 (2H, d, J = 7.3 Hz), 3.15 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.4 Hz), 5.56 (1H, t, J = 5.4 Hz), 6.72 (1H, d, J = 7.6 Hz), 7.45 (1H, d, J = 7.6 Hz), 8.07 (2H, s). Step 4: Preparation of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 3 Similar to Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -6-methylnicotinaldehyde instead of-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08 (3H, t, J = 7.1 Hz), 1.10-1.22 (2H, m), 1.42-1.61 (4H, m), 1.63-1.72 (2H, m), 2.07 (1H, m), 2.20 (3H, s), 2.42 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.14 (2H, d, J = 7.3 Hz), 3.15 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.4 Hz), 5.56 (1H, t, J = 5.4 Hz), 6.72 (1H, d, J = 7.6 Hz), 7.45 (1H, d, J = 7.6 Hz), 8.07 (2H, s).
実施例11
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-カルボニトリルの製造
国際公開第1997/19078号パンフレットに記載の方法により製造した2-クロロ-6-エチルピリジン-3-カルボニトリル(500 mg, 3.00 mmol)及び国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(1.50 g, 11.8 mmol)を混合し、アルゴン雰囲気下100℃にて8時間攪拌した。N-(シクロペンチルメチル)-N-エチルアミン(0.19 g, 1.49 mmol)を追加し、100℃にて8時間攪拌した後、反応液をトルエン共沸して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 50:1)を用いて精製し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-カルボニトリル(484 mg, 63%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.22-1.27 (8H, m), 1.49-1.81 (6H, m), 2.33 (1H, m), 2.65 (2H, q, J = 7.6 Hz), 3.64 (2H, d, J = 7.3 Hz), 3.77 (2H, q, J = 7.0 Hz), 6.42 (1H, d, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz). Example 11
Production of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Production of 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile 2-Chloro-6-ethylpyridine produced by the method described in WO 1997/19078 -3-carbonitrile (500 mg, 3.00 mmol) and N- (cyclopentylmethyl) -N-ethylamine (1.50 g, 11.8 mmol) prepared by the method described in WO2006 / 07397 pamphlet were mixed, and argon was mixed. The mixture was stirred at 100 ° C. for 8 hours under an atmosphere. N- (Cyclopentylmethyl) -N-ethylamine (0.19 g, 1.49 mmol) was added, and the mixture was stirred at 100 ° C. for 8 hours. : Ethyl acetate = 50: 1) to give 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile (484 mg, 63%) as a pale yellow oil. It was.
1 H-NMR (CDCl 3 ) δ: 1.22-1.27 (8H, m), 1.49-1.81 (6H, m), 2.33 (1H, m), 2.65 (2H, q, J = 7.6 Hz), 3.64 (2H , d, J = 7.3 Hz), 3.77 (2H, q, J = 7.0 Hz), 6.42 (1H, d, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz).
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-カルボニトリルの製造
国際公開第1997/19078号パンフレットに記載の方法により製造した2-クロロ-6-エチルピリジン-3-カルボニトリル(500 mg, 3.00 mmol)及び国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(1.50 g, 11.8 mmol)を混合し、アルゴン雰囲気下100℃にて8時間攪拌した。N-(シクロペンチルメチル)-N-エチルアミン(0.19 g, 1.49 mmol)を追加し、100℃にて8時間攪拌した後、反応液をトルエン共沸して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 50:1)を用いて精製し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-カルボニトリル(484 mg, 63%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.22-1.27 (8H, m), 1.49-1.81 (6H, m), 2.33 (1H, m), 2.65 (2H, q, J = 7.6 Hz), 3.64 (2H, d, J = 7.3 Hz), 3.77 (2H, q, J = 7.0 Hz), 6.42 (1H, d, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz). Example 11
Production of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Production of 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile 2-Chloro-6-ethylpyridine produced by the method described in WO 1997/19078 -3-carbonitrile (500 mg, 3.00 mmol) and N- (cyclopentylmethyl) -N-ethylamine (1.50 g, 11.8 mmol) prepared by the method described in WO2006 / 07397 pamphlet were mixed, and argon was mixed. The mixture was stirred at 100 ° C. for 8 hours under an atmosphere. N- (Cyclopentylmethyl) -N-ethylamine (0.19 g, 1.49 mmol) was added, and the mixture was stirred at 100 ° C. for 8 hours. : Ethyl acetate = 50: 1) to give 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile (484 mg, 63%) as a pale yellow oil. It was.
1 H-NMR (CDCl 3 ) δ: 1.22-1.27 (8H, m), 1.49-1.81 (6H, m), 2.33 (1H, m), 2.65 (2H, q, J = 7.6 Hz), 3.64 (2H , d, J = 7.3 Hz), 3.77 (2H, q, J = 7.0 Hz), 6.42 (1H, d, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz).
工程2:2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルニコチンアルデヒドの製造
2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-カルボニトリル(484 mg, 1.87 mmol)のジクロロメタン(5 mL)溶液に-78℃にてジイソブチル水素化アルミニウム(0.99 M トルエン溶液, 1.99 mL, 1.97 mmol)を加え、同温にて4時間攪拌した。同温にてジイソブチル水素化アルミニウム(0.99 M トルエン溶液, 0.2 mL, 0.198 mmol)を追加し、同温にて45分間攪拌した後、2 M水酸化ナトリウム水溶液を加え室温にて30分間攪拌し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 50:1)を用いて精製し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルニコチンアルデヒド(233 mg, 48%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.13-1.28 (8H, m), 1.48-1.78 (6H, m), 2.29 (1H, m), 2.71 (2H, q, J = 7.6 Hz), 3.45 (2H, d, J = 7.3 Hz), 3.51 (2H, q, J = 7.0 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 7.8 Hz), 9.94 (1H, s). Step 2: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile (484 mg, 1.87 mmol) in dichloromethane (5 mL) at −78 ° C. was added diisobutylaluminum hydride (0.99 M toluene solution, 1.99 mL, 1.97 mmol) and stirred at the same temperature for 4 hours. Diisobutylaluminum hydride (0.99 M toluene solution, 0.2 mL, 0.198 mmol) was added at the same temperature and stirred for 45 minutes at the same temperature. Then, 2 M aqueous sodium hydroxide solution was added and stirred at room temperature for 30 minutes. Extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 50: 1). -[(Cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde (233 mg, 48%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.13-1.28 (8H, m), 1.48-1.78 (6H, m), 2.29 (1H, m), 2.71 (2H, q, J = 7.6 Hz), 3.45 (2H , d, J = 7.3 Hz), 3.51 (2H, q, J = 7.0 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 7.8 Hz), 9.94 (1H, s ).
2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-カルボニトリル(484 mg, 1.87 mmol)のジクロロメタン(5 mL)溶液に-78℃にてジイソブチル水素化アルミニウム(0.99 M トルエン溶液, 1.99 mL, 1.97 mmol)を加え、同温にて4時間攪拌した。同温にてジイソブチル水素化アルミニウム(0.99 M トルエン溶液, 0.2 mL, 0.198 mmol)を追加し、同温にて45分間攪拌した後、2 M水酸化ナトリウム水溶液を加え室温にて30分間攪拌し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 50:1)を用いて精製し、2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルニコチンアルデヒド(233 mg, 48%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.13-1.28 (8H, m), 1.48-1.78 (6H, m), 2.29 (1H, m), 2.71 (2H, q, J = 7.6 Hz), 3.45 (2H, d, J = 7.3 Hz), 3.51 (2H, q, J = 7.0 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 7.8 Hz), 9.94 (1H, s). Step 2: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridine-3-carbonitrile (484 mg, 1.87 mmol) in dichloromethane (5 mL) at −78 ° C. was added diisobutylaluminum hydride (0.99 M toluene solution, 1.99 mL, 1.97 mmol) and stirred at the same temperature for 4 hours. Diisobutylaluminum hydride (0.99 M toluene solution, 0.2 mL, 0.198 mmol) was added at the same temperature and stirred for 45 minutes at the same temperature. Then, 2 M aqueous sodium hydroxide solution was added and stirred at room temperature for 30 minutes. Extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 50: 1). -[(Cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde (233 mg, 48%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.13-1.28 (8H, m), 1.48-1.78 (6H, m), 2.29 (1H, m), 2.71 (2H, q, J = 7.6 Hz), 3.45 (2H , d, J = 7.3 Hz), 3.51 (2H, q, J = 7.0 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.88 (1H, d, J = 7.8 Hz), 9.94 (1H, s ).
工程3:N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルニコチンアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 7.1 Hz), 1.09-1.25 (2H, m), 1,26 (3H, t, J = 7.6 Hz), 1.40-1.76 (6H, m), 2.11 (1H, m), 2.20 (3H, s), 2.69 (2H, q, J = 7.6 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.08-3.19 (4H, m), 4.11 (2H, t, J = 6.8 Hz), 4.56 (2H, s), 5.94 (1H, br), 6.71 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz), 8.06 (2H, s). Step 3: Preparation of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 3 Similar to Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde instead of-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08 (3H, t, J = 7.1 Hz), 1.09-1.25 (2H, m), 1,26 (3H, t, J = 7.6 Hz), 1.40-1.76 (6H , m), 2.11 (1H, m), 2.20 (3H, s), 2.69 (2H, q, J = 7.6 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.08-3.19 (4H, m) , 4.11 (2H, t, J = 6.8 Hz), 4.56 (2H, s), 5.94 (1H, br), 6.71 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz) , 8.06 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルニコチンアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08 (3H, t, J = 7.1 Hz), 1.09-1.25 (2H, m), 1,26 (3H, t, J = 7.6 Hz), 1.40-1.76 (6H, m), 2.11 (1H, m), 2.20 (3H, s), 2.69 (2H, q, J = 7.6 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.08-3.19 (4H, m), 4.11 (2H, t, J = 6.8 Hz), 4.56 (2H, s), 5.94 (1H, br), 6.71 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz), 8.06 (2H, s). Step 3: Preparation of N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 3 Similar to Step 6 of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylnicotinaldehyde instead of-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Reaction and treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08 (3H, t, J = 7.1 Hz), 1.09-1.25 (2H, m), 1,26 (3H, t, J = 7.6 Hz), 1.40-1.76 (6H , m), 2.11 (1H, m), 2.20 (3H, s), 2.69 (2H, q, J = 7.6 Hz), 2.84 (2H, t, J = 6.8 Hz), 3.08-3.19 (4H, m) , 4.11 (2H, t, J = 6.8 Hz), 4.56 (2H, s), 5.94 (1H, br), 6.71 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 7.6 Hz) , 8.06 (2H, s).
実施例12
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルニコチンアルデヒドの製造
2-クロロ-6-エチルピリジン-3-カルボニトリルの代わりに、国際公開第2006/073973号パンフレットに記載の方法により製造した2-クロロ-5,6-ジメチルピリジン-3-カルボニトリルを用いて実施例11の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルニコチンアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.09-1.29 (5H, m), 1.44-1.75 (6H, m), 2.25 (3H, s), 2.27 (1H, m), 2.41 (3H, s), 3.39 (2H, d, J = 7.6 Hz), 3.44 (2H, q, J = 7.1 Hz), 7.69 (1H, s), 9.99 (1H, s). Example 12
Production of N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylnicotinaldehyde In place of 2-chloro-6-ethylpyridine-3-carbonitrile, WO 2006/079773 pamphlet Using 2-chloro-5,6-dimethylpyridine-3-carbonitrile prepared by the method described in 1) in the same manner as in Step 1 of Example 11 to give 2-[(cyclopentylmethyl) (ethyl) amino ] -5,6-dimethylnicotinaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.09-1.29 (5H, m), 1.44-1.75 (6H, m), 2.25 (3H, s), 2.27 (1H, m), 2.41 (3H, s), 3.39 (2H, d, J = 7.6 Hz), 3.44 (2H, q, J = 7.1 Hz), 7.69 (1H, s), 9.99 (1H, s).
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルニコチンアルデヒドの製造
2-クロロ-6-エチルピリジン-3-カルボニトリルの代わりに、国際公開第2006/073973号パンフレットに記載の方法により製造した2-クロロ-5,6-ジメチルピリジン-3-カルボニトリルを用いて実施例11の工程1と同様に反応・処理し、2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルニコチンアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.09-1.29 (5H, m), 1.44-1.75 (6H, m), 2.25 (3H, s), 2.27 (1H, m), 2.41 (3H, s), 3.39 (2H, d, J = 7.6 Hz), 3.44 (2H, q, J = 7.1 Hz), 7.69 (1H, s), 9.99 (1H, s). Example 12
Production of N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylnicotinaldehyde In place of 2-chloro-6-ethylpyridine-3-carbonitrile, WO 2006/079773 pamphlet Using 2-chloro-5,6-dimethylpyridine-3-carbonitrile prepared by the method described in 1) in the same manner as in Step 1 of Example 11 to give 2-[(cyclopentylmethyl) (ethyl) amino ] -5,6-dimethylnicotinaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.09-1.29 (5H, m), 1.44-1.75 (6H, m), 2.25 (3H, s), 2.27 (1H, m), 2.41 (3H, s), 3.39 (2H, d, J = 7.6 Hz), 3.44 (2H, q, J = 7.1 Hz), 7.69 (1H, s), 9.99 (1H, s).
工程2:N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルニコチンアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.05 (3H, t, J = 7.2 Hz), 1.10-1.23 (2H, m), 1.40-1.75 (6H, m), 2.02 (1H, m), 2.16 (3H, s), 2.20 (3H, s), 2.38 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.09 (2H, d, J = 7.2 Hz), 3.10 (2H, q, J = 7.2 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.6 Hz), 5.68 (1H, t, J = 5.6 Hz), 7.30 (1H, s), 8.07 (2H, s). Step 2: N-({2-[(Cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine Preparation of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylnicotinaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to 6 to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.05 (3H, t, J = 7.2 Hz), 1.10-1.23 (2H, m), 1.40-1.75 (6H, m), 2.02 (1H, m), 2.16 (3H , s), 2.20 (3H, s), 2.38 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.09 (2H, d, J = 7.2 Hz), 3.10 (2H, q, J = 7.2 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.6 Hz), 5.68 (1H, t, J = 5.6 Hz), 7.30 (1H, s), 8.07 (2H , s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルニコチンアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.05 (3H, t, J = 7.2 Hz), 1.10-1.23 (2H, m), 1.40-1.75 (6H, m), 2.02 (1H, m), 2.16 (3H, s), 2.20 (3H, s), 2.38 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.09 (2H, d, J = 7.2 Hz), 3.10 (2H, q, J = 7.2 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.6 Hz), 5.68 (1H, t, J = 5.6 Hz), 7.30 (1H, s), 8.07 (2H, s). Step 2: N-({2-[(Cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine Preparation of Example 4 using 2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylnicotinaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to 6 to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.05 (3H, t, J = 7.2 Hz), 1.10-1.23 (2H, m), 1.40-1.75 (6H, m), 2.02 (1H, m), 2.16 (3H , s), 2.20 (3H, s), 2.38 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.09 (2H, d, J = 7.2 Hz), 3.10 (2H, q, J = 7.2 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.55 (2H, d, J = 5.6 Hz), 5.68 (1H, t, J = 5.6 Hz), 7.30 (1H, s), 8.07 (2H , s).
実施例13
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに国際公開第2006/073973号パンフレットに記載の方法により製造した3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-カルボアルデヒドを用い実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08-1.18 (5H, m), 1.41-1.71 (6H, m), 2.11 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.25 (2H, d, J = 7.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 4.6 Hz), 6.31 (1H, t, J = 4.6 Hz), 8.06 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.11 (2H, s). Example 13
Production of N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
3-[(Cyclopentylmethyl) (ethyl) amino] pyrazine produced by the method described in WO 2006/079773 instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 2-carbaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08-1.18 (5H, m), 1.41-1.71 (6H, m), 2.11 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.25 (2H, d, J = 7.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 4.6 Hz) ), 6.31 (1H, t, J = 4.6 Hz), 8.06 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.11 (2H, s).
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに国際公開第2006/073973号パンフレットに記載の方法により製造した3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-カルボアルデヒドを用い実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.08-1.18 (5H, m), 1.41-1.71 (6H, m), 2.11 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.25 (2H, d, J = 7.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 4.6 Hz), 6.31 (1H, t, J = 4.6 Hz), 8.06 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.11 (2H, s). Example 13
Production of N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
3-[(Cyclopentylmethyl) (ethyl) amino] pyrazine produced by the method described in WO 2006/079773 instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 2-carbaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.08-1.18 (5H, m), 1.41-1.71 (6H, m), 2.11 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.25 (2H, d, J = 7.6 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 4.6 Hz) ), 6.31 (1H, t, J = 4.6 Hz), 8.06 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 2.4 Hz), 8.11 (2H, s).
実施例14
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンズアルデヒドの製造
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(3.00 g, 15.6 mmol)のトルエン(60 mL)溶液に国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(2.70 g, 21.2 mmol)及び炭酸カリウム(6.50 g, 47.0 mmol)を加え、68時間加熱還流を行った。反応液を室温まで放冷後、水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1)を用いて精製し、2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンズアルデヒド(3.34 g, 71%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.09-1.19 (5H, m), 1.43-1.72 (6H, m), 2.15 (1H, m), 3.17 (2H, d, J = 7.6 Hz), 3.33 (2H, q, J = 7.0 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.65 (1H, dd, J = 2.4, 9.0 Hz), 8.03 (1H, d, J = 2.4 Hz), 10.18 (1H, s). Example 14
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (3.00 g, 15.6 mmol) in toluene (60 mL ) N- (cyclopentylmethyl) -N-ethylamine (2.70 g, 21.2 mmol) and potassium carbonate (6.50 g, 47.0 mmol) prepared by the method described in WO 2006/079773 pamphlet were added to the solution for 68 hours. Heating to reflux was performed. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1), 2 -[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (3.34 g, 71%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.09-1.19 (5H, m), 1.43-1.72 (6H, m), 2.15 (1H, m), 3.17 (2H, d, J = 7.6 Hz), 3.33 (2H , q, J = 7.0 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.65 (1H, dd, J = 2.4, 9.0 Hz), 8.03 (1H, d, J = 2.4 Hz), 10.18 (1H , s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンズアルデヒドの製造
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(3.00 g, 15.6 mmol)のトルエン(60 mL)溶液に国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(2.70 g, 21.2 mmol)及び炭酸カリウム(6.50 g, 47.0 mmol)を加え、68時間加熱還流を行った。反応液を室温まで放冷後、水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1)を用いて精製し、2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンズアルデヒド(3.34 g, 71%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.09-1.19 (5H, m), 1.43-1.72 (6H, m), 2.15 (1H, m), 3.17 (2H, d, J = 7.6 Hz), 3.33 (2H, q, J = 7.0 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.65 (1H, dd, J = 2.4, 9.0 Hz), 8.03 (1H, d, J = 2.4 Hz), 10.18 (1H, s). Example 14
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (3.00 g, 15.6 mmol) in toluene (60 mL ) N- (cyclopentylmethyl) -N-ethylamine (2.70 g, 21.2 mmol) and potassium carbonate (6.50 g, 47.0 mmol) prepared by the method described in WO 2006/079773 pamphlet were added to the solution for 68 hours. Heating to reflux was performed. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1), 2 -[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (3.34 g, 71%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.09-1.19 (5H, m), 1.43-1.72 (6H, m), 2.15 (1H, m), 3.17 (2H, d, J = 7.6 Hz), 3.33 (2H , q, J = 7.0 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.65 (1H, dd, J = 2.4, 9.0 Hz), 8.03 (1H, d, J = 2.4 Hz), 10.18 (1H , s).
工程2:N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンズアルデヒド(3.34 g, 11.2 mmol)及び実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(2.27 g, 12.3 mmol)のトルエン(80 mL)溶液に酢酸(317 mg, 5.19 mmol)を加え、Dean-Stark装置を用い4時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム(4.73 g, 22.3 mmol)を加え、室温で60時間攪拌した。反応液に水を加えクロロホルムで抽出した後、有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1 → 10:1 → 4:1)を用いて精製し、表題化合物(4.39 g, 84%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.03 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.43-1.66 (4H, m), 1.67-1.76 (2H, m), 2.00 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.95 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.69 (2H, d, J = 5.6 Hz), 5.54 (1H, t, J = 5.6 Hz), 7.21 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.07 (2H, s). Step 2: Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[( Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (3.34 g, 11.2 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 3 (2.27 g, Acetic acid (317 mg, 5.19 mmol) was added to a toluene (80 mL) solution of 12.3 mmol), and the mixture was heated to reflux for 4 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (4.73 g, 22.3 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 60 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 10: 1 → 4: 1) to obtain the title compound (4.39 g, 84%) as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 1.03 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.43-1.66 (4H, m), 1.67-1.76 (2H, m), 2.00 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.95 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.69 (2H, d, J = 5.6 Hz), 5.54 (1H, t, J = 5.6 Hz), 7.21 (1H, d, J = 8.3 Hz), 7.44 (1H , d, J = 8.3 Hz), 7.62 (1H, s), 8.07 (2H, s).
2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンズアルデヒド(3.34 g, 11.2 mmol)及び実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(2.27 g, 12.3 mmol)のトルエン(80 mL)溶液に酢酸(317 mg, 5.19 mmol)を加え、Dean-Stark装置を用い4時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム(4.73 g, 22.3 mmol)を加え、室温で60時間攪拌した。反応液に水を加えクロロホルムで抽出した後、有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1 → 10:1 → 4:1)を用いて精製し、表題化合物(4.39 g, 84%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.03 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.43-1.66 (4H, m), 1.67-1.76 (2H, m), 2.00 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.95 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.69 (2H, d, J = 5.6 Hz), 5.54 (1H, t, J = 5.6 Hz), 7.21 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.07 (2H, s). Step 2: Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[( Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (3.34 g, 11.2 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 3 (2.27 g, Acetic acid (317 mg, 5.19 mmol) was added to a toluene (80 mL) solution of 12.3 mmol), and the mixture was heated to reflux for 4 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (4.73 g, 22.3 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 60 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 10: 1 → 4: 1) to obtain the title compound (4.39 g, 84%) as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 1.03 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.43-1.66 (4H, m), 1.67-1.76 (2H, m), 2.00 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.95 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.69 (2H, d, J = 5.6 Hz), 5.54 (1H, t, J = 5.6 Hz), 7.21 (1H, d, J = 8.3 Hz), 7.44 (1H , d, J = 8.3 Hz), 7.62 (1H, s), 8.07 (2H, s).
実施例15
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-5-メトキシベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.98 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.63-1.75 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.81 (2H, d, J = 7.3 Hz), 2.84 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 5.8 Hz), 5.71 (1H, t, J = 5.8 Hz), 6.77 (1H, dd, J = 3.2, 8.8 Hz), 6.92 (1H, d, J = 3.2 Hz), 7.13 (1H, d, J = 8.8 Hz), 8.05 (2H, s). Example 15
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-5-methoxybenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.98 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.63-1.75 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.81 (2H, d, J = 7.3 Hz), 2.84 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 5.8 Hz), 5.71 (1H, t, J = 5.8 Hz), 6.77 (1H, dd, J = 3.2, 8.8 Hz), 6.92 (1H, d, J = 3.2 Hz), 7.13 (1H, d, J = 8.8 Hz), 8.05 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-5-メトキシベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.98 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.63-1.75 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.81 (2H, d, J = 7.3 Hz), 2.84 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 5.8 Hz), 5.71 (1H, t, J = 5.8 Hz), 6.77 (1H, dd, J = 3.2, 8.8 Hz), 6.92 (1H, d, J = 3.2 Hz), 7.13 (1H, d, J = 8.8 Hz), 8.05 (2H, s). Example 15
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-5-methoxybenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.98 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.63-1.75 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.81 (2H, d, J = 7.3 Hz), 2.84 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 5.8 Hz), 5.71 (1H, t, J = 5.8 Hz), 6.77 (1H, dd, J = 3.2, 8.8 Hz), 6.92 (1H, d, J = 3.2 Hz), 7.13 (1H, d, J = 8.8 Hz), 8.05 (2H, s).
実施例16
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,3,5-トリフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.10-1.28 (2H, m), 1.43-1.62 (4H, m), 1.65-1.75 (2H, m), 1.95 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.93 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, br s), 5.31 (1H, br), 6.66 (1H, ddd, J = 3.2, 8.5, 11.4 Hz), 6.66 (1H, dd, J = 3.2, 9.3 Hz), 8.07 (2H, s). Example 16
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,3,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.10-1.28 (2H, m), 1.43-1.62 (4H, m), 1.65-1.75 (2H, m), 1.95 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.93 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, br s), 5.31 (1H, br), 6.66 (1H, ddd, J = 3.2, 8.5, 11.4 Hz), 6.66 (1H, dd, J = 3.2, 9.3 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,3,5-トリフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.10-1.28 (2H, m), 1.43-1.62 (4H, m), 1.65-1.75 (2H, m), 1.95 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.93 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, br s), 5.31 (1H, br), 6.66 (1H, ddd, J = 3.2, 8.5, 11.4 Hz), 6.66 (1H, dd, J = 3.2, 9.3 Hz), 8.07 (2H, s). Example 16
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,3,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.10-1.28 (2H, m), 1.43-1.62 (4H, m), 1.65-1.75 (2H, m), 1.95 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.93 (2H, d, J = 7.6 Hz), 3.04 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, br s), 5.31 (1H, br), 6.66 (1H, ddd, J = 3.2, 8.5, 11.4 Hz), 6.66 (1H, dd, J = 3.2, 9.3 Hz), 8.07 (2H, s).
実施例17
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-5-メチルベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.40-1.60 (4H, m), 1.61-1.74 (2H, m), 1.97 (1H, m), 2.05 (3H, s), 2.20 (3H, s), 2.27-2.88 (4H, m), 2.95 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.65 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.0 Hz), 7.09 (1H, d, J = 8.0 Hz), 7.16 (1H, s), 8.08 (2H, s). Example 17
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-5-methylbenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.40-1.60 (4H, m), 1.61-1.74 (2H, m), 1.97 (1H, m), 2.05 (3H, s), 2.20 (3H, s), 2.27-2.88 (4H, m), 2.95 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.65 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.0 Hz), 7.09 (1H, d, J = 8.0 Hz) , 7.16 (1H, s), 8.08 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-5-メチルベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.40-1.60 (4H, m), 1.61-1.74 (2H, m), 1.97 (1H, m), 2.05 (3H, s), 2.20 (3H, s), 2.27-2.88 (4H, m), 2.95 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.65 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.0 Hz), 7.09 (1H, d, J = 8.0 Hz), 7.16 (1H, s), 8.08 (2H, s). Example 17
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-5-methylbenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, t, J = 7.1 Hz), 1.15-1.23 (2H, m), 1.40-1.60 (4H, m), 1.61-1.74 (2H, m), 1.97 (1H, m), 2.05 (3H, s), 2.20 (3H, s), 2.27-2.88 (4H, m), 2.95 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.65 (1H, t, J = 5.6 Hz), 7.03 (1H, d, J = 8.0 Hz), 7.09 (1H, d, J = 8.0 Hz) , 7.16 (1H, s), 8.08 (2H, s).
実施例18
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,4-ジフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.1 Hz), 1.12-1.27 (2H, m), 1.41-1.62 (4H, m), 1.64-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.80-2.88 (4H, m), 2.98 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.51 (1H, t, J = 5.6 Hz), 6.73 (1H, dt, J = 2.9, 8.3 Hz), 6.87 (1H, dd, J = 2.9, 11.0 Hz), 7.31 (1H, t, J = 8.3 Hz), 8.07 (2H, s). Example 18
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,4-difluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.12-1.27 (2H, m), 1.41-1.62 (4H, m), 1.64-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.80-2.88 (4H, m), 2.98 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.51 (1H, t, J = 5.6 Hz), 6.73 (1H, dt, J = 2.9, 8.3 Hz), 6.87 (1H, dd, J = 2.9, 11.0 Hz), 7.31 ( 1H, t, J = 8.3 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,4-ジフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.1 Hz), 1.12-1.27 (2H, m), 1.41-1.62 (4H, m), 1.64-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.80-2.88 (4H, m), 2.98 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.51 (1H, t, J = 5.6 Hz), 6.73 (1H, dt, J = 2.9, 8.3 Hz), 6.87 (1H, dd, J = 2.9, 11.0 Hz), 7.31 (1H, t, J = 8.3 Hz), 8.07 (2H, s). Example 18
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,4-difluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.1 Hz), 1.12-1.27 (2H, m), 1.41-1.62 (4H, m), 1.64-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.80-2.88 (4H, m), 2.98 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.51 (1H, t, J = 5.6 Hz), 6.73 (1H, dt, J = 2.9, 8.3 Hz), 6.87 (1H, dd, J = 2.9, 11.0 Hz), 7.31 ( 1H, t, J = 8.3 Hz), 8.07 (2H, s).
実施例19
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-4-メトキシベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.64-1.73 (2H, m), 2.01 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.98 (2H, q, J = 7.1 Hz), 3.78 (3H, s), 4.11 (2H, t, J = 6.8 Hz), 4.59 (2H, d, J = 4.9 Hz), 5.54 (1H, t, J = 4.9 Hz), 6.60 (1H, dd, J = 2.4, 8.6 Hz), 6.73 (1H, d, J = 2.4 Hz), 7.27 (1H, d, J = 8.6 Hz), 8.07 (2H, s). Example 19
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-4-methoxybenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.64-1.73 (2H, m), 2.01 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.98 (2H, q, J = 7.1 Hz), 3.78 (3H, s), 4.11 (2H, t, J = 6.8 Hz), 4.59 (2H, d, J = 4.9 Hz), 5.54 (1H, t, J = 4.9 Hz), 6.60 (1H, dd, J = 2.4, 8.6 Hz), 6.73 (1H, d, J = 2.4 Hz), 7.27 (1H, d, J = 8.6 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-4-メトキシベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.64-1.73 (2H, m), 2.01 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.98 (2H, q, J = 7.1 Hz), 3.78 (3H, s), 4.11 (2H, t, J = 6.8 Hz), 4.59 (2H, d, J = 4.9 Hz), 5.54 (1H, t, J = 4.9 Hz), 6.60 (1H, dd, J = 2.4, 8.6 Hz), 6.73 (1H, d, J = 2.4 Hz), 7.27 (1H, d, J = 8.6 Hz), 8.07 (2H, s). Example 19
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-4-methoxybenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.15-1.26 (2H, m), 1.40-1.60 (4H, m), 1.64-1.73 (2H, m), 2.01 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.98 (2H, q, J = 7.1 Hz), 3.78 (3H, s), 4.11 (2H, t, J = 6.8 Hz), 4.59 (2H, d, J = 4.9 Hz), 5.54 (1H, t, J = 4.9 Hz), 6.60 (1H, dd, J = 2.4, 8.6 Hz), 6.73 (1H, d, J = 2.4 Hz), 7.27 (1H, d, J = 8.6 Hz), 8.07 (2H, s).
実施例20
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-4-(トリフルオロメチル)ベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.03 (3H, t, J = 7.1 Hz), 1.16-1.28 (2H, m), 1.45-1.63 (4H, m), 1.66-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.92 (2H, d, J = 7.3 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.71 (2H, d, J = 5.4 Hz), 5.51 (1H, t, J = 5.4 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.46 (1H, d, J = 7.8 Hz), 8.07 (2H, s). Example 20
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-4- (trifluoromethyl) benzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil. It was.
1 H-NMR (CDCl 3 ) δ: 1.03 (3H, t, J = 7.1 Hz), 1.16-1.28 (2H, m), 1.45-1.63 (4H, m), 1.66-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.92 (2H, d, J = 7.3 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.71 (2H, d, J = 5.4 Hz), 5.51 (1H, t, J = 5.4 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.37 (1H , s), 7.46 (1H, d, J = 7.8 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-4-(トリフルオロメチル)ベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.03 (3H, t, J = 7.1 Hz), 1.16-1.28 (2H, m), 1.45-1.63 (4H, m), 1.66-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.92 (2H, d, J = 7.3 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.71 (2H, d, J = 5.4 Hz), 5.51 (1H, t, J = 5.4 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.46 (1H, d, J = 7.8 Hz), 8.07 (2H, s). Example 20
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluoro-4- (trifluoromethyl) benzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil. It was.
1 H-NMR (CDCl 3 ) δ: 1.03 (3H, t, J = 7.1 Hz), 1.16-1.28 (2H, m), 1.45-1.63 (4H, m), 1.66-1.75 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.92 (2H, d, J = 7.3 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.71 (2H, d, J = 5.4 Hz), 5.51 (1H, t, J = 5.4 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.37 (1H , s), 7.46 (1H, d, J = 7.8 Hz), 8.07 (2H, s).
実施例21
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-クロロ-6-フルオロ-3-メチルベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.1 Hz), 1.11-1.21 (2H, m), 1.37-1.67 (6H, m), 1.92 (1H, m), 2.21 (3H, s), 2.35 (3H, s), 2.84 (2H, d, J = 7.8 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.96 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.83 (2H, d, J = 4.6 Hz), 5.35 (1H, t, J = 4.6 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.14 (1H, d, J = 8.3 Hz), 8.09 (2H, s). Example 21
Preparation of N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-chloro-6-fluoro-3-methylbenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil. It was.
1 H-NMR (CDCl 3 ) δ: 0.95 (3H, t, J = 7.1 Hz), 1.11-1.21 (2H, m), 1.37-1.67 (6H, m), 1.92 (1H, m), 2.21 (3H , s), 2.35 (3H, s), 2.84 (2H, d, J = 7.8 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.96 (2H, q, J = 7.1 Hz), 4.12 (2H , t, J = 6.8 Hz), 4.83 (2H, d, J = 4.6 Hz), 5.35 (1H, t, J = 4.6 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.14 (1H, d , J = 8.3 Hz), 8.09 (2H, s).
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-クロロ-6-フルオロ-3-メチルベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.95 (3H, t, J = 7.1 Hz), 1.11-1.21 (2H, m), 1.37-1.67 (6H, m), 1.92 (1H, m), 2.21 (3H, s), 2.35 (3H, s), 2.84 (2H, d, J = 7.8 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.96 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.83 (2H, d, J = 4.6 Hz), 5.35 (1H, t, J = 4.6 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.14 (1H, d, J = 8.3 Hz), 8.09 (2H, s). Example 21
Preparation of N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-chloro-6-fluoro-3-methylbenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil. It was.
1 H-NMR (CDCl 3 ) δ: 0.95 (3H, t, J = 7.1 Hz), 1.11-1.21 (2H, m), 1.37-1.67 (6H, m), 1.92 (1H, m), 2.21 (3H , s), 2.35 (3H, s), 2.84 (2H, d, J = 7.8 Hz), 2.86 (2H, t, J = 6.6 Hz), 2.96 (2H, q, J = 7.1 Hz), 4.12 (2H , t, J = 6.8 Hz), 4.83 (2H, d, J = 4.6 Hz), 5.35 (1H, t, J = 4.6 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.14 (1H, d , J = 8.3 Hz), 8.09 (2H, s).
実施例22
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.13-1.28 (2H, m), 1.40-1.61 (4H, m), 1.65-1.74 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.89 (2H, d, J = 7.3 Hz), 2.99 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.6 Hz), 5.63 (1H, t, J = 5.6 Hz), 7.04 (1H, m), 7.16-7.23 (2H, m), 7.35 (1H, d, J = 7.6 Hz), 8.07 (2H, s). Example 22
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.13-1.28 (2H, m), 1.40-1.61 (4H, m), 1.65-1.74 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.89 (2H, d, J = 7.3 Hz), 2.99 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.6 Hz), 5.63 (1H, t, J = 5.6 Hz), 7.04 (1H, m), 7.16-7.23 (2H, m) , 7.35 (1H, d, J = 7.6 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.13-1.28 (2H, m), 1.40-1.61 (4H, m), 1.65-1.74 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.89 (2H, d, J = 7.3 Hz), 2.99 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.6 Hz), 5.63 (1H, t, J = 5.6 Hz), 7.04 (1H, m), 7.16-7.23 (2H, m), 7.35 (1H, d, J = 7.6 Hz), 8.07 (2H, s). Example 22
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.13-1.28 (2H, m), 1.40-1.61 (4H, m), 1.65-1.74 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.89 (2H, d, J = 7.3 Hz), 2.99 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.6 Hz), 5.63 (1H, t, J = 5.6 Hz), 7.04 (1H, m), 7.16-7.23 (2H, m) , 7.35 (1H, d, J = 7.6 Hz), 8.07 (2H, s).
実施例23
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,4,5-トリフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, t, J = 7.1 Hz), 1,12-1 25 (2H, m), 1.43- 1.62 (4H, m), 1.64-1.74 (2H, m), 1.95 (1H, m), 2.20 (3H, s), 2.80 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.42 (1H, t, J = 5.6 Hz), 6.97 (1H, dd, J = 7.6, 12.2 Hz), 7.17 (1H, dd, J = 9.0, 11.5 Hz), 8.07 (2H, s). Example 23
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,4,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, t, J = 7.1 Hz), 1,12-1 25 (2H, m), 1.43- 1.62 (4H, m), 1.64-1.74 (2H, m ), 1.95 (1H, m), 2.20 (3H, s), 2.80 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz) ), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.42 (1H, t, J = 5.6 Hz), 6.97 (1H, dd, J = 7.6, 12.2 Hz) ), 7.17 (1H, dd, J = 9.0, 11.5 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,4,5-トリフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, t, J = 7.1 Hz), 1,12-1 25 (2H, m), 1.43- 1.62 (4H, m), 1.64-1.74 (2H, m), 1.95 (1H, m), 2.20 (3H, s), 2.80 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.42 (1H, t, J = 5.6 Hz), 6.97 (1H, dd, J = 7.6, 12.2 Hz), 7.17 (1H, dd, J = 9.0, 11.5 Hz), 8.07 (2H, s). Example 23
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,4,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, t, J = 7.1 Hz), 1,12-1 25 (2H, m), 1.43- 1.62 (4H, m), 1.64-1.74 (2H, m ), 1.95 (1H, m), 2.20 (3H, s), 2.80 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.91 (2H, q, J = 7.1 Hz) ), 4.11 (2H, t, J = 6.8 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.42 (1H, t, J = 5.6 Hz), 6.97 (1H, dd, J = 7.6, 12.2 Hz) ), 7.17 (1H, dd, J = 9.0, 11.5 Hz), 8.07 (2H, s).
実施例24
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに4-クロロ-2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.3 Hz), 1.17-1.24 (2H, m), 1.42-1.62 (4H, m), 1.63-1.76 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.82-2.88 (4H, m), 2.98 (2H, q, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.00 (1H, dd, J = 2.0, 8.1 Hz), 7.12 (1H, d, J = 2.0 Hz), 7.28 (1H, d, J = 8.1 Hz), 8.06 (2H, s). Example 24
Production of N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 4-chloro-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.3 Hz), 1.17-1.24 (2H, m), 1.42-1.62 (4H, m), 1.63-1.76 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.82-2.88 (4H, m), 2.98 (2H, q, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.00 (1H, dd, J = 2.0, 8.1 Hz), 7.12 (1H, d, J = 2.0 Hz), 7.28 (1H, d, J = 8.1 Hz), 8.06 (2H, s).
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに4-クロロ-2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.02 (3H, t, J = 7.3 Hz), 1.17-1.24 (2H, m), 1.42-1.62 (4H, m), 1.63-1.76 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.82-2.88 (4H, m), 2.98 (2H, q, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.00 (1H, dd, J = 2.0, 8.1 Hz), 7.12 (1H, d, J = 2.0 Hz), 7.28 (1H, d, J = 8.1 Hz), 8.06 (2H, s). Example 24
Production of N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 4-chloro-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.02 (3H, t, J = 7.3 Hz), 1.17-1.24 (2H, m), 1.42-1.62 (4H, m), 1.63-1.76 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.82-2.88 (4H, m), 2.98 (2H, q, J = 7.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.62 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.00 (1H, dd, J = 2.0, 8.1 Hz), 7.12 (1H, d, J = 2.0 Hz), 7.28 (1H, d, J = 8.1 Hz), 8.06 (2H, s).
実施例25
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,5-ジフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.99 (3H, t, J = 7.1 Hz), 1.14-1.27 (2H, m), 1.42-1.62 (4H, m), 1.64-1.73 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.83 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.93 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.51 (1H, t, J = 5.9 Hz), 6.90 (1H, dt, J = 3.2, 8.8 Hz), 7.06 (1H, dd, J = 3.2, 9.8 Hz), 7.14 (1H, dd, J = 5.1, 8.8 Hz), 8.07 (2H, s). Example 25
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,5-difluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.1 Hz), 1.14-1.27 (2H, m), 1.42-1.62 (4H, m), 1.64-1.73 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.83 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.93 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.51 (1H, t, J = 5.9 Hz), 6.90 (1H, dt, J = 3.2, 8.8 Hz), 7.06 (1H, dd, J = 3.2, 9.8 Hz), 7.14 (1H, dd, J = 5.1, 8.8 Hz), 8.07 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,5-ジフルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.99 (3H, t, J = 7.1 Hz), 1.14-1.27 (2H, m), 1.42-1.62 (4H, m), 1.64-1.73 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.83 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.93 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.51 (1H, t, J = 5.9 Hz), 6.90 (1H, dt, J = 3.2, 8.8 Hz), 7.06 (1H, dd, J = 3.2, 9.8 Hz), 7.14 (1H, dd, J = 5.1, 8.8 Hz), 8.07 (2H, s). Example 25
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 2,5-difluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.1 Hz), 1.14-1.27 (2H, m), 1.42-1.62 (4H, m), 1.64-1.73 (2H, m), 1.94 (1H, m), 2.20 (3H, s), 2.83 (2H, d, J = 7.3 Hz), 2.85 (2H, t, J = 6.8 Hz), 2.93 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.51 (1H, t, J = 5.9 Hz), 6.90 (1H, dt, J = 3.2, 8.8 Hz), 7.06 (1H, dd, J = 3.2, 9.8 Hz), 7.14 (1H, dd, J = 5.1, 8.8 Hz), 8.07 (2H, s).
実施例26
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに4-ブロモ-2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.0 Hz), 1.10-1.30 (2H, m), 1.40-1.75 (6H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 8.4 Hz), 2.97 (2H, q, J = 7.0 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.61 (2H, d, J = 4.3 Hz), 5.49 (1H, t, J = 4.3 Hz), 7.15 (1H, dd, J = 2.0, 8.1 Hz), 7.23 (1H, d, J = 8.1 Hz), 7.31 (1H, d, J = 2.0 Hz), 8.06 (2H, s). Example 26
Production of N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 4-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.0 Hz), 1.10-1.30 (2H, m), 1.40-1.75 (6H, m), 1.99 (1H, m), 2.20 (3H , s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 8.4 Hz), 2.97 (2H, q, J = 7.0 Hz), 4.11 (2H, t, J = 6.8 Hz ), 4.61 (2H, d, J = 4.3 Hz), 5.49 (1H, t, J = 4.3 Hz), 7.15 (1H, dd, J = 2.0, 8.1 Hz), 7.23 (1H, d, J = 8.1 Hz) ), 7.31 (1H, d, J = 2.0 Hz), 8.06 (2H, s).
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに4-ブロモ-2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.0 Hz), 1.10-1.30 (2H, m), 1.40-1.75 (6H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 8.4 Hz), 2.97 (2H, q, J = 7.0 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.61 (2H, d, J = 4.3 Hz), 5.49 (1H, t, J = 4.3 Hz), 7.15 (1H, dd, J = 2.0, 8.1 Hz), 7.23 (1H, d, J = 8.1 Hz), 7.31 (1H, d, J = 2.0 Hz), 8.06 (2H, s). Example 26
Production of N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 4-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.0 Hz), 1.10-1.30 (2H, m), 1.40-1.75 (6H, m), 1.99 (1H, m), 2.20 (3H , s), 2.85 (2H, t, J = 6.8 Hz), 2.86 (2H, d, J = 8.4 Hz), 2.97 (2H, q, J = 7.0 Hz), 4.11 (2H, t, J = 6.8 Hz ), 4.61 (2H, d, J = 4.3 Hz), 5.49 (1H, t, J = 4.3 Hz), 7.15 (1H, dd, J = 2.0, 8.1 Hz), 7.23 (1H, d, J = 8.1 Hz) ), 7.31 (1H, d, J = 2.0 Hz), 8.06 (2H, s).
実施例27
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに5-ブロモ-2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, t, J = 7.1 Hz), 1.13-1.24 (2H, m), 1.41-1.61 (4H, m), 1.63-1.73 (2H, m), 1.96 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.94 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.31 (1H, dd, J = 2.4, 8.3 Hz), 7.48 (1H, d, J = 2.4 Hz), 8.07 (2H, s). Example 27
Preparation of N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 5-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, t, J = 7.1 Hz), 1.13-1.24 (2H, m), 1.41-1.61 (4H, m), 1.63-1.73 (2H, m), 1.96 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.94 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.31 (1H , dd, J = 2.4, 8.3 Hz), 7.48 (1H, d, J = 2.4 Hz), 8.07 (2H, s).
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに5-ブロモ-2-フルオロベンズアルデヒドを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, t, J = 7.1 Hz), 1.13-1.24 (2H, m), 1.41-1.61 (4H, m), 1.63-1.73 (2H, m), 1.96 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.94 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.31 (1H, dd, J = 2.4, 8.3 Hz), 7.48 (1H, d, J = 2.4 Hz), 8.07 (2H, s). Example 27
Preparation of N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 5-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, t, J = 7.1 Hz), 1.13-1.24 (2H, m), 1.41-1.61 (4H, m), 1.63-1.73 (2H, m), 1.96 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.86 (2H, d, J = 7.3 Hz), 2.94 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.65 (2H, d, J = 5.6 Hz), 5.49 (1H, t, J = 5.6 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.31 (1H , dd, J = 2.4, 8.3 Hz), 7.48 (1H, d, J = 2.4 Hz), 8.07 (2H, s).
実施例28
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにピペリジンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.53-1.63 (2H, m), 1.70-1.78 (4H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.91 (4H, t, J = 5.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.58 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz), 8.09 (2H, s). Example 28
Preparation of 5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.53-1.63 (2H, m), 1.70-1.78 (4H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.91 (4H , t, J = 5.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.58 (1H, t, J = 5.9 Hz), 7.14 (1H, d , J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz), 8.09 (2H, s).
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにピペリジンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.53-1.63 (2H, m), 1.70-1.78 (4H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.91 (4H, t, J = 5.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.58 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz), 8.09 (2H, s). Example 28
Preparation of 5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.53-1.63 (2H, m), 1.70-1.78 (4H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.91 (4H , t, J = 5.1 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.68 (2H, d, J = 5.9 Hz), 5.58 (1H, t, J = 5.9 Hz), 7.14 (1H, d , J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz), 8.09 (2H, s).
実施例29
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにモルホリンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.99 (4H, t, J = 4.6 Hz), 3.87 (4H, t, J = 4.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.70 (2H, d, J = 5.9 Hz), 5.49 (1H, t, J = 5.9 Hz), 7.17 (1H, d, J = 8.3 Hz), 7.51 (1H, dd, J = 1.7, 8.3 Hz), 7.63 (1H, d, J = 1.7 Hz), 8.08 (2H, s). Example 29
Preparation of 5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using morpholine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.99 (4H, t, J = 4.6 Hz), 3.87 (4H, t, J = 4.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.70 (2H, d, J = 5.9 Hz), 5.49 (1H, t, J = 5.9 Hz), 7.17 (1H, d, J = 8.3 Hz) , 7.51 (1H, dd, J = 1.7, 8.3 Hz), 7.63 (1H, d, J = 1.7 Hz), 8.08 (2H, s).
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにモルホリンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.99 (4H, t, J = 4.6 Hz), 3.87 (4H, t, J = 4.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.70 (2H, d, J = 5.9 Hz), 5.49 (1H, t, J = 5.9 Hz), 7.17 (1H, d, J = 8.3 Hz), 7.51 (1H, dd, J = 1.7, 8.3 Hz), 7.63 (1H, d, J = 1.7 Hz), 8.08 (2H, s). Example 29
Preparation of 5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using morpholine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.99 (4H, t, J = 4.6 Hz), 3.87 (4H, t, J = 4.6 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.70 (2H, d, J = 5.9 Hz), 5.49 (1H, t, J = 5.9 Hz), 7.17 (1H, d, J = 8.3 Hz) , 7.51 (1H, dd, J = 1.7, 8.3 Hz), 7.63 (1H, d, J = 1.7 Hz), 8.08 (2H, s).
実施例30
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりに4-メチルピペリジンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, d, J = 7.3 Hz), 1.45-1.58 (3H, m), 1.71-1.79 (2H, m), 2.21 (3H, s), 2.66-2.76 (2H, m), 2.86 (2H, t, J = 6.6 Hz), 3.10-3.18 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 5.9 Hz), 5.56 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz), 8.09 (2H, s). Example 30
Preparation of N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 4-methylpiperidine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, d, J = 7.3 Hz), 1.45-1.58 (3H, m), 1.71-1.79 (2H, m), 2.21 (3H, s), 2.66-2.76 (2H, m), 2.86 (2H, t, J = 6.6 Hz), 3.10-3.18 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 5.9 Hz) , 5.56 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz) , 8.09 (2H, s).
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりに4-メチルピペリジンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.00 (3H, d, J = 7.3 Hz), 1.45-1.58 (3H, m), 1.71-1.79 (2H, m), 2.21 (3H, s), 2.66-2.76 (2H, m), 2.86 (2H, t, J = 6.6 Hz), 3.10-3.18 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 5.9 Hz), 5.56 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz), 8.09 (2H, s). Example 30
Preparation of N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using 4-methylpiperidine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.00 (3H, d, J = 7.3 Hz), 1.45-1.58 (3H, m), 1.71-1.79 (2H, m), 2.21 (3H, s), 2.66-2.76 (2H, m), 2.86 (2H, t, J = 6.6 Hz), 3.10-3.18 (2H, m), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 5.9 Hz) , 5.56 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.47 (1H, dd, J = 1.7, 8.3 Hz), 7.59 (1H, d, J = 1.7 Hz) , 8.09 (2H, s).
実施例31
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにcis-2,6-ジメチルモルホリンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.21 (6H, d, J = 6.3 Hz), 2.21 (3H, s), 2.52 (2H, t, J = 11.2 Hz), 2.86 (2H, t, J = 6.2 Hz), 3.00 (2H, d, J = 11.2 Hz), 3.82-3.93 (2H, m), 4.13 (2H, t, J = 6.2 Hz), 4.69 (2H, d, J = 5.9 Hz), 5.53 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.08 (2H, s). Example 31
Preparation of N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using cis-2,6-dimethylmorpholine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.21 (6H, d, J = 6.3 Hz), 2.21 (3H, s), 2.52 (2H, t, J = 11.2 Hz), 2.86 (2H, t, J = 6.2 Hz), 3.00 (2H, d, J = 11.2 Hz), 3.82-3.93 (2H, m), 4.13 (2H, t, J = 6.2 Hz), 4.69 (2H, d, J = 5.9 Hz), 5.53 ( 1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.08 (2H, s).
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにcis-2,6-ジメチルモルホリンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.21 (6H, d, J = 6.3 Hz), 2.21 (3H, s), 2.52 (2H, t, J = 11.2 Hz), 2.86 (2H, t, J = 6.2 Hz), 3.00 (2H, d, J = 11.2 Hz), 3.82-3.93 (2H, m), 4.13 (2H, t, J = 6.2 Hz), 4.69 (2H, d, J = 5.9 Hz), 5.53 (1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.08 (2H, s). Example 31
Preparation of N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 14 using cis-2,6-dimethylmorpholine instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.21 (6H, d, J = 6.3 Hz), 2.21 (3H, s), 2.52 (2H, t, J = 11.2 Hz), 2.86 (2H, t, J = 6.2 Hz), 3.00 (2H, d, J = 11.2 Hz), 3.82-3.93 (2H, m), 4.13 (2H, t, J = 6.2 Hz), 4.69 (2H, d, J = 5.9 Hz), 5.53 ( 1H, t, J = 5.9 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.08 (2H, s).
実施例32
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
工程1:2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルの製造
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(2.79 g, 14.5 mmol)のトルエン(70 mL)溶液に国際公開第2004/020393号パンフレットに記載の方法により製造したtrans-{4-[(エチルアミノ)メチル]シクロヘキシル}酢酸エチル(3.50 g, 15.4 mmol)及び炭酸カリウム(6.02 g, 43.6 mmol)を加え、65時間加熱還流を行った。反応液を室温まで放冷後、水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 10:1 → 6:1)を用いて精製し、2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル(5.30 g, 91%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.86-1.01 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.64-1.85 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.64 (1H, dd, J = 2.0, 8.8 Hz), 8.03 (1H, d, J = 2.0 Hz), 10.17 (1H, s). Example 32
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Preparation of cyclohexyl} ethyl acetate:
Step 1: Preparation of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate 2-Fluoro-5- (trifluoromethyl) benzaldehyde ( 2.79 g, 14.5 mmol) in a toluene (70 mL) solution prepared by the method described in International Publication No. 2004/020393, trans- {4-[(ethylamino) methyl] cyclohexyl} ethyl acetate (3.50 g, 15.4 mmol) and potassium carbonate (6.02 g, 43.6 mmol) were added, and the mixture was heated to reflux for 65 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 6: 1). Purification gave ethyl 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetate (5.30 g, 91%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.86-1.01 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.64-1.85 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.64 (1H, dd, J = 2.0, 8.8 Hz), 8.03 (1H, d, J = 2.0 Hz), 10.17 (1H, s ).
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
工程1:2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルの製造
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(2.79 g, 14.5 mmol)のトルエン(70 mL)溶液に国際公開第2004/020393号パンフレットに記載の方法により製造したtrans-{4-[(エチルアミノ)メチル]シクロヘキシル}酢酸エチル(3.50 g, 15.4 mmol)及び炭酸カリウム(6.02 g, 43.6 mmol)を加え、65時間加熱還流を行った。反応液を室温まで放冷後、水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 10:1 → 6:1)を用いて精製し、2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル(5.30 g, 91%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.86-1.01 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.64-1.85 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.64 (1H, dd, J = 2.0, 8.8 Hz), 8.03 (1H, d, J = 2.0 Hz), 10.17 (1H, s). Example 32
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Preparation of cyclohexyl} ethyl acetate:
Step 1: Preparation of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate 2-Fluoro-5- (trifluoromethyl) benzaldehyde ( 2.79 g, 14.5 mmol) in a toluene (70 mL) solution prepared by the method described in International Publication No. 2004/020393, trans- {4-[(ethylamino) methyl] cyclohexyl} ethyl acetate (3.50 g, 15.4 mmol) and potassium carbonate (6.02 g, 43.6 mmol) were added, and the mixture was heated to reflux for 65 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 6: 1). Purification gave ethyl 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetate (5.30 g, 91%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.86-1.01 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.64-1.85 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.64 (1H, dd, J = 2.0, 8.8 Hz), 8.03 (1H, d, J = 2.0 Hz), 10.17 (1H, s ).
工程2:2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.86-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.3 Hz), 1.40 (1H, m), 1.58-1.92 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.20 (3H, s), 2.82-2.88 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.3 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 1.4, 8.3 Hz), 7.62 (1H, d, J = 1.4 Hz), 8.07 (2H, s). Step 2: 2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino ) Preparation of methyl] cyclohexyl} ethyl acetate 2- [trans-4-({ethyl [2-formyl-4- (trifluoro) instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Methyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate was used for the reaction and treatment in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.86-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.3 Hz), 1.40 (1H, m), 1.58-1.92 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.20 (3H, s), 2.82-2.88 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.3 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz), 7.18 (1H , d, J = 8.3 Hz), 7.44 (1H, dd, J = 1.4, 8.3 Hz), 7.62 (1H, d, J = 1.4 Hz), 8.07 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.86-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.3 Hz), 1.40 (1H, m), 1.58-1.92 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.20 (3H, s), 2.82-2.88 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.3 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.44 (1H, dd, J = 1.4, 8.3 Hz), 7.62 (1H, d, J = 1.4 Hz), 8.07 (2H, s). Step 2: 2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino ) Preparation of methyl] cyclohexyl} ethyl acetate 2- [trans-4-({ethyl [2-formyl-4- (trifluoro) instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Methyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate was used for the reaction and treatment in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.86-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.3 Hz), 1.40 (1H, m), 1.58-1.92 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.20 (3H, s), 2.82-2.88 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.3 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz), 7.18 (1H , d, J = 8.3 Hz), 7.44 (1H, dd, J = 1.4, 8.3 Hz), 7.62 (1H, d, J = 1.4 Hz), 8.07 (2H, s).
実施例33
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸の製造:
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル(200 mg, 0.35 mmol)をエタノール-テトラヒドロフラン(2 mL, 1:1混合溶媒)溶媒に溶解し、氷浴中にて撹拌しつつ2 M水酸化ナトリウム水溶液(0.88 mL)を加えた後、50℃まで昇温し、4時間攪拌した。氷浴中にて反応液に2 M塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸マグネシウムにて乾燥後、減圧濃縮し、表題化合物(195 mg, quant.)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.86-1.05 (7H, m), 1.41 (1H, m), 1.63-1.91 (5H, m), 2.16-2.21 (5H, m), 2.81-2.87 (4H, m), 3.00 (2H, q, J = 6.8 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 4.8 Hz), 6.34 (1H, t, J = 4.8 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.43 (1H, dd, J = 2.0, 8.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.06 (2H, s). Example 33
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Production of cyclohexyl} acetic acid:
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Dissolve ethyl cyclohexyl} acetate (200 mg, 0.35 mmol) in ethanol-tetrahydrofuran (2 mL, 1: 1 mixed solvent) and add 2 M aqueous sodium hydroxide (0.88 mL) while stirring in an ice bath. After that, the temperature was raised to 50 ° C. and stirred for 4 hours. The reaction solution was neutralized with 2 M hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (195 mg, quant.) As a colorless amorphous.
1 H-NMR (CDCl 3 ) δ: 0.86-1.05 (7H, m), 1.41 (1H, m), 1.63-1.91 (5H, m), 2.16-2.21 (5H, m), 2.81-2.87 (4H, m), 3.00 (2H, q, J = 6.8 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 4.8 Hz), 6.34 (1H, t, J = 4.8 Hz) , 7.18 (1H, d, J = 8.0 Hz), 7.43 (1H, dd, J = 2.0, 8.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.06 (2H, s).
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸の製造:
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル(200 mg, 0.35 mmol)をエタノール-テトラヒドロフラン(2 mL, 1:1混合溶媒)溶媒に溶解し、氷浴中にて撹拌しつつ2 M水酸化ナトリウム水溶液(0.88 mL)を加えた後、50℃まで昇温し、4時間攪拌した。氷浴中にて反応液に2 M塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸マグネシウムにて乾燥後、減圧濃縮し、表題化合物(195 mg, quant.)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 0.86-1.05 (7H, m), 1.41 (1H, m), 1.63-1.91 (5H, m), 2.16-2.21 (5H, m), 2.81-2.87 (4H, m), 3.00 (2H, q, J = 6.8 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 4.8 Hz), 6.34 (1H, t, J = 4.8 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.43 (1H, dd, J = 2.0, 8.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.06 (2H, s). Example 33
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Production of cyclohexyl} acetic acid:
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Dissolve ethyl cyclohexyl} acetate (200 mg, 0.35 mmol) in ethanol-tetrahydrofuran (2 mL, 1: 1 mixed solvent) and add 2 M aqueous sodium hydroxide (0.88 mL) while stirring in an ice bath. After that, the temperature was raised to 50 ° C. and stirred for 4 hours. The reaction solution was neutralized with 2 M hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (195 mg, quant.) As a colorless amorphous.
1 H-NMR (CDCl 3 ) δ: 0.86-1.05 (7H, m), 1.41 (1H, m), 1.63-1.91 (5H, m), 2.16-2.21 (5H, m), 2.81-2.87 (4H, m), 3.00 (2H, q, J = 6.8 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 4.8 Hz), 6.34 (1H, t, J = 4.8 Hz) , 7.18 (1H, d, J = 8.0 Hz), 7.43 (1H, dd, J = 2.0, 8.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.06 (2H, s).
実施例34
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,3,5-トリフルオロベンズアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりに国際公開第2006/073973号パンフレットに記載の方法により製造したN,N-ビス(シクロプロピルメチル)アミンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: -0.08-0.11 (4H, m), 0.29-0.50 (4H, m), 0.78-0.91 (2H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.88-2.94 (4H, m), 4.11 (2H, t, J = 6.6 Hz), 4.80 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz), 6.66 (1H, ddd, J = 2.9, 8.8, 11.7 Hz), 6.91 (1H, m), 8.06 (2H, s). Example 34
Production of N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
2,3,5-trifluorobenzaldehyde is used instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and described in WO 2006/079773 instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in a similar manner to Example 14 using N, N-bis (cyclopropylmethyl) amine produced by the above method to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: -0.08-0.11 (4H, m), 0.29-0.50 (4H, m), 0.78-0.91 (2H, m), 2.20 (3H, s), 2.85 (2H, t , J = 6.6 Hz), 2.88-2.94 (4H, m), 4.11 (2H, t, J = 6.6 Hz), 4.80 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz ), 6.66 (1H, ddd, J = 2.9, 8.8, 11.7 Hz), 6.91 (1H, m), 8.06 (2H, s).
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに2,3,5-トリフルオロベンズアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりに国際公開第2006/073973号パンフレットに記載の方法により製造したN,N-ビス(シクロプロピルメチル)アミンを用いて実施例14と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: -0.08-0.11 (4H, m), 0.29-0.50 (4H, m), 0.78-0.91 (2H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.88-2.94 (4H, m), 4.11 (2H, t, J = 6.6 Hz), 4.80 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz), 6.66 (1H, ddd, J = 2.9, 8.8, 11.7 Hz), 6.91 (1H, m), 8.06 (2H, s). Example 34
Production of N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
2,3,5-trifluorobenzaldehyde is used instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and described in WO 2006/079773 instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in a similar manner to Example 14 using N, N-bis (cyclopropylmethyl) amine produced by the above method to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: -0.08-0.11 (4H, m), 0.29-0.50 (4H, m), 0.78-0.91 (2H, m), 2.20 (3H, s), 2.85 (2H, t , J = 6.6 Hz), 2.88-2.94 (4H, m), 4.11 (2H, t, J = 6.6 Hz), 4.80 (2H, d, J = 6.1 Hz), 5.48 (1H, t, J = 6.1 Hz ), 6.66 (1H, ddd, J = 2.9, 8.8, 11.7 Hz), 6.91 (1H, m), 8.06 (2H, s).
実施例35
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:(S)-2-({1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミノ)ピリミジン-5-オールの製造
国際公開第2008/009435号パンフレットに記載の方法により製造した(2-クロロピリミジン-5-イル)ボランピナコールエステル(200 mg, 0.83 mmol)及び(S)-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミン(193 mg, 0.75 mmol)をジイソプロピルエチルアミン(0.5 mL)に110℃にて加熱溶解した。混合物を110℃にて1日攪拌した後、室温まで放冷し、酢酸エチル-水より抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をテトラヒドロフラン(3 mL)に溶解した。室温にて30%過酸化水素水(0.93 mL, 9.1 mmol)を加え、同温にて2時間攪拌した。氷浴中にて冷却し、反応液に飽和亜硫酸ナトリウム水溶液を加えて過剰の過酸化水素を分解した後、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン=4:1)を用いて分離し、(S)-2-({1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミノ)ピリミジン-5-オール(279 mg, 粗生成物)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.54 (3H, d, J = 6.8 Hz), 5.09 (1H, m), 5.39 (1H, d, J = 6.6 Hz), 7.71 (1H, s), 7.80 (2H, s), 7.92 (2H, s). Example 35
Production of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of (S) -2-({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-5-ol According to the method described in WO2008 / 009435 pamphlet. The prepared (2-chloropyrimidin-5-yl) borampinacol ester (200 mg, 0.83 mmol) and (S)-{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amine (193 mg, (0.75 mmol) was dissolved in diisopropylethylamine (0.5 mL) by heating at 110 ° C. The mixture was stirred at 110 ° C. for 1 day, allowed to cool to room temperature, and extracted from ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (3 mL). 30% hydrogen peroxide solution (0.93 mL, 9.1 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. After cooling in an ice bath, a saturated aqueous sodium sulfite solution was added to the reaction solution to decompose excess hydrogen peroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane: acetone = 4: 1), (S) -2-({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-5-ol (279 mg, crude product) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.54 (3H, d, J = 6.8 Hz), 5.09 (1H, m), 5.39 (1H, d, J = 6.6 Hz), 7.71 (1H, s), 7.80 ( 2H, s), 7.92 (2H, s).
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:(S)-2-({1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミノ)ピリミジン-5-オールの製造
国際公開第2008/009435号パンフレットに記載の方法により製造した(2-クロロピリミジン-5-イル)ボランピナコールエステル(200 mg, 0.83 mmol)及び(S)-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミン(193 mg, 0.75 mmol)をジイソプロピルエチルアミン(0.5 mL)に110℃にて加熱溶解した。混合物を110℃にて1日攪拌した後、室温まで放冷し、酢酸エチル-水より抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をテトラヒドロフラン(3 mL)に溶解した。室温にて30%過酸化水素水(0.93 mL, 9.1 mmol)を加え、同温にて2時間攪拌した。氷浴中にて冷却し、反応液に飽和亜硫酸ナトリウム水溶液を加えて過剰の過酸化水素を分解した後、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン=4:1)を用いて分離し、(S)-2-({1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミノ)ピリミジン-5-オール(279 mg, 粗生成物)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.54 (3H, d, J = 6.8 Hz), 5.09 (1H, m), 5.39 (1H, d, J = 6.6 Hz), 7.71 (1H, s), 7.80 (2H, s), 7.92 (2H, s). Example 35
Production of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of (S) -2-({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-5-ol According to the method described in WO2008 / 009435 pamphlet. The prepared (2-chloropyrimidin-5-yl) borampinacol ester (200 mg, 0.83 mmol) and (S)-{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amine (193 mg, (0.75 mmol) was dissolved in diisopropylethylamine (0.5 mL) by heating at 110 ° C. The mixture was stirred at 110 ° C. for 1 day, allowed to cool to room temperature, and extracted from ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (3 mL). 30% hydrogen peroxide solution (0.93 mL, 9.1 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. After cooling in an ice bath, a saturated aqueous sodium sulfite solution was added to the reaction solution to decompose excess hydrogen peroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane: acetone = 4: 1), (S) -2-({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-5-ol (279 mg, crude product) was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.54 (3H, d, J = 6.8 Hz), 5.09 (1H, m), 5.39 (1H, d, J = 6.6 Hz), 7.71 (1H, s), 7.80 ( 2H, s), 7.92 (2H, s).
工程2:(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
(S)-2-({1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミノ)ピリミジン-5-オール(279 mg, 上記粗生成物)をイソプロパノール(3 mL)に溶解し、水酸化ナトリウム(35 mg, 0.88 mmol)及び1-クロロ-2-メチルチオエタン(88 mg, 0.80 mmol)を加え、90℃にて2時間30分攪拌した。反応液を酢酸エチル-飽和食塩水より抽出し、有機層を無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン=4:1)を用いて精製し、表題化合物(240 mg, 3段階75%)を淡黄色結晶性粉末として得た。
1H-NMR (CDCl3) δ: 1.58 (3H, d, J = 7.2 Hz), 2.18 (3H, s), 2.83 (2H, t, J = 7.2 Hz), 4.09 (2H, t, J = 7.2 Hz), 5.14 (1H, m), 5.56 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.83 (2H, s), 8.02 (2H, s). Step 2: Preparation of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (S) -2 -({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-5-ol (279 mg, the above crude product) was dissolved in isopropanol (3 mL) and sodium hydroxide ( 35 mg, 0.88 mmol) and 1-chloro-2-methylthioethane (88 mg, 0.80 mmol) were added, and the mixture was stirred at 90 ° C. for 2 hours and 30 minutes. The reaction solution was extracted from ethyl acetate-saturated brine, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: acetone = 4: 1). Purification gave the title compound (240 mg, 3 steps 75%) as a pale yellow crystalline powder.
1 H-NMR (CDCl 3 ) δ: 1.58 (3H, d, J = 7.2 Hz), 2.18 (3H, s), 2.83 (2H, t, J = 7.2 Hz), 4.09 (2H, t, J = 7.2 Hz), 5.14 (1H, m), 5.56 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.83 (2H, s), 8.02 (2H, s).
(S)-2-({1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}アミノ)ピリミジン-5-オール(279 mg, 上記粗生成物)をイソプロパノール(3 mL)に溶解し、水酸化ナトリウム(35 mg, 0.88 mmol)及び1-クロロ-2-メチルチオエタン(88 mg, 0.80 mmol)を加え、90℃にて2時間30分攪拌した。反応液を酢酸エチル-飽和食塩水より抽出し、有機層を無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン=4:1)を用いて精製し、表題化合物(240 mg, 3段階75%)を淡黄色結晶性粉末として得た。
1H-NMR (CDCl3) δ: 1.58 (3H, d, J = 7.2 Hz), 2.18 (3H, s), 2.83 (2H, t, J = 7.2 Hz), 4.09 (2H, t, J = 7.2 Hz), 5.14 (1H, m), 5.56 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.83 (2H, s), 8.02 (2H, s). Step 2: Preparation of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (S) -2 -({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} amino) pyrimidin-5-ol (279 mg, the above crude product) was dissolved in isopropanol (3 mL) and sodium hydroxide ( 35 mg, 0.88 mmol) and 1-chloro-2-methylthioethane (88 mg, 0.80 mmol) were added, and the mixture was stirred at 90 ° C. for 2 hours and 30 minutes. The reaction solution was extracted from ethyl acetate-saturated brine, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: acetone = 4: 1). Purification gave the title compound (240 mg, 3 steps 75%) as a pale yellow crystalline powder.
1 H-NMR (CDCl 3 ) δ: 1.58 (3H, d, J = 7.2 Hz), 2.18 (3H, s), 2.83 (2H, t, J = 7.2 Hz), 4.09 (2H, t, J = 7.2 Hz), 5.14 (1H, m), 5.56 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.83 (2H, s), 8.02 (2H, s).
実施例36
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミンの製造:
実施例35で製造した(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(100 mg, 0.24 mmol)のメタノール(1 mL)溶液に五塩化タンタル(8.4 mg, 0.024 mmol)及び30%過酸化水素水(0.036 mL, 0.32 mmol)を加え、室温にて5時間30分攪拌した。50℃にて1時間攪拌した後、五塩化タンタル(4.2 mg, 0.012 mmol)及び30%過酸化水素水(0.018 mL, 0.16 mmol)を加え、同温にて1時間攪拌した。反応液に飽和亜硫酸ナトリウム水溶液を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン = 4:1→2:1)を用いて精製し、表題化合物(99.5 mg, 93%)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 1.58 (3H, d, J = 7.0 Hz), 5.05 (3H, s), 3.42 (2H, t, J = 5.4 Hz), 4.37 (2H, t, J = 5.4 Hz), 5.12 (1H, m), 5.47 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.82 (2H, s), 8.04 (2H, s). Example 36
Production of (S) —N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
(S) —N- {1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 35 (100 mg, 0.24 mmol) in methanol (1 mL) was added tantalum pentachloride (8.4 mg, 0.024 mmol) and 30% aqueous hydrogen peroxide (0.036 mL, 0.32 mmol), and the mixture was stirred at room temperature for 5 hours 30 minutes. After stirring at 50 ° C. for 1 hour, tantalum pentachloride (4.2 mg, 0.012 mmol) and 30% hydrogen peroxide (0.018 mL, 0.16 mmol) were added, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: acetone = 4: 1 → 2: 1) to obtain the title compound (99.5 mg, 93%) as a colorless amorphous.
1 H-NMR (CDCl 3 ) δ: 1.58 (3H, d, J = 7.0 Hz), 5.05 (3H, s), 3.42 (2H, t, J = 5.4 Hz), 4.37 (2H, t, J = 5.4 Hz), 5.12 (1H, m), 5.47 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.82 (2H, s), 8.04 (2H, s).
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミンの製造:
実施例35で製造した(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(100 mg, 0.24 mmol)のメタノール(1 mL)溶液に五塩化タンタル(8.4 mg, 0.024 mmol)及び30%過酸化水素水(0.036 mL, 0.32 mmol)を加え、室温にて5時間30分攪拌した。50℃にて1時間攪拌した後、五塩化タンタル(4.2 mg, 0.012 mmol)及び30%過酸化水素水(0.018 mL, 0.16 mmol)を加え、同温にて1時間攪拌した。反応液に飽和亜硫酸ナトリウム水溶液を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン = 4:1→2:1)を用いて精製し、表題化合物(99.5 mg, 93%)を無色アモルファスとして得た。
1H-NMR (CDCl3) δ: 1.58 (3H, d, J = 7.0 Hz), 5.05 (3H, s), 3.42 (2H, t, J = 5.4 Hz), 4.37 (2H, t, J = 5.4 Hz), 5.12 (1H, m), 5.47 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.82 (2H, s), 8.04 (2H, s). Example 36
Production of (S) —N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
(S) —N- {1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 35 (100 mg, 0.24 mmol) in methanol (1 mL) was added tantalum pentachloride (8.4 mg, 0.024 mmol) and 30% aqueous hydrogen peroxide (0.036 mL, 0.32 mmol), and the mixture was stirred at room temperature for 5 hours 30 minutes. After stirring at 50 ° C. for 1 hour, tantalum pentachloride (4.2 mg, 0.012 mmol) and 30% hydrogen peroxide (0.018 mL, 0.16 mmol) were added, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: acetone = 4: 1 → 2: 1) to obtain the title compound (99.5 mg, 93%) as a colorless amorphous.
1 H-NMR (CDCl 3 ) δ: 1.58 (3H, d, J = 7.0 Hz), 5.05 (3H, s), 3.42 (2H, t, J = 5.4 Hz), 4.37 (2H, t, J = 5.4 Hz), 5.12 (1H, m), 5.47 (1H, d, J = 6.8 Hz), 7.74 (1H, s), 7.82 (2H, s), 8.04 (2H, s).
実施例37
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルを用いて実施例36と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 7.1 Hz), 3.00 (2H, q, J = 7.1 Hz), 3.07 (3H, s), 3.34 (2H, t, J = 5.4 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.40 (2H, t, J = 5.4 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.54 (1H, t, J = 6.1 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.09 (2H, s). Example 37
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Preparation of cyclohexyl} ethyl acetate:
Instead of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- {trans-4- With [[ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} ethyl acetate Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.88-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 7.1 Hz), 3.00 (2H, q, J = 7.1 Hz), 3.07 (3H, s ), 3.34 (2H, t, J = 5.4 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.40 (2H, t, J = 5.4 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.54 (1H, t, J = 6.1 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.09 (2H, s).
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルを用いて実施例36と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 7.1 Hz), 3.00 (2H, q, J = 7.1 Hz), 3.07 (3H, s), 3.34 (2H, t, J = 5.4 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.40 (2H, t, J = 5.4 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.54 (1H, t, J = 6.1 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.09 (2H, s). Example 37
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Preparation of cyclohexyl} ethyl acetate:
Instead of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- {trans-4- With [[ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} ethyl acetate Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.88-0.98 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 7.1 Hz), 3.00 (2H, q, J = 7.1 Hz), 3.07 (3H, s ), 3.34 (2H, t, J = 5.4 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.40 (2H, t, J = 5.4 Hz), 4.67 (2H, d, J = 6.1 Hz), 5.54 (1H, t, J = 6.1 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.60 (1H, d, J = 2.0 Hz), 8.09 (2H, s).
実施例38
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸の製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸を用いて実施例36と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.87-1.00 (4H, m), 1.01 (3H, t, J = 7.1 Hz), 1.41 (1H, m), 1.65-1.90 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.1 Hz), 2.99 (2H, q, J = 7.1 Hz), 3.07 (3H, s), 3.43 (2H, t, J = 5.1 Hz), 4.39 (2H, t, J = 5.1 Hz), 4.67 (2H, d, J = 5.9 Hz), 6.14 (1H, t, J = 5.9 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.08 (2H, s). Example 38
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Production of cyclohexyl} acetic acid:
Instead of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- {trans-4- Performed with [(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.87-1.00 (4H, m), 1.01 (3H, t, J = 7.1 Hz), 1.41 (1H, m), 1.65-1.90 (5H, m), 2.19 (2H , d, J = 6.8 Hz), 2.85 (2H, d, J = 7.1 Hz), 2.99 (2H, q, J = 7.1 Hz), 3.07 (3H, s), 3.43 (2H, t, J = 5.1 Hz ), 4.39 (2H, t, J = 5.1 Hz), 4.67 (2H, d, J = 5.9 Hz), 6.14 (1H, t, J = 5.9 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.08 (2H, s).
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸の製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸を用いて実施例36と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.87-1.00 (4H, m), 1.01 (3H, t, J = 7.1 Hz), 1.41 (1H, m), 1.65-1.90 (5H, m), 2.19 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.1 Hz), 2.99 (2H, q, J = 7.1 Hz), 3.07 (3H, s), 3.43 (2H, t, J = 5.1 Hz), 4.39 (2H, t, J = 5.1 Hz), 4.67 (2H, d, J = 5.9 Hz), 6.14 (1H, t, J = 5.9 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.08 (2H, s). Example 38
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Production of cyclohexyl} acetic acid:
Instead of (S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, 2- {trans-4- Performed with [(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl} acetic acid Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.87-1.00 (4H, m), 1.01 (3H, t, J = 7.1 Hz), 1.41 (1H, m), 1.65-1.90 (5H, m), 2.19 (2H , d, J = 6.8 Hz), 2.85 (2H, d, J = 7.1 Hz), 2.99 (2H, q, J = 7.1 Hz), 3.07 (3H, s), 3.43 (2H, t, J = 5.1 Hz ), 4.39 (2H, t, J = 5.1 Hz), 4.67 (2H, d, J = 5.9 Hz), 6.14 (1H, t, J = 5.9 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.45 (1H, dd, J = 2.0, 8.3 Hz), 7.59 (1H, d, J = 2.0 Hz), 8.08 (2H, s).
実施例39
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの製造
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(500 mg, 2.60 mmol)のDMSO-水(2:1混合溶液,15 mL)溶液にジアリルアミン(319 mg, 3.28 mmol)及び炭酸ナトリウム(828 mg, 7.81 mmol)を加え、100℃にて2時間攪拌した。ジアリルアミン(158 mg, 1.63 mmol)を追加し、同温にて4時間攪拌した後、反応液を室温まで放冷後、水を加えトルエンで抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 24:1 → 3:2)を用いて精製し、2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒド(567 mg, 81%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 3.91 (4H, d, J = 5.5 Hz), 5.23-5.26 (2H, m), 5.27-5.29 (2H, m), 5.78-5.88 (2H, m), 7.13 (1H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 2.3, 8.7 Hz), 8.04 (1H, d, J = 2.3 Hz), 10.21 (1H, s). Example 39
Preparation of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (500 mg, 2.60 mmol) in DMSO-water (2: 1 mixed solution, 15 mL) solution was added diallylamine (319 mg, 3.28 mmol) and sodium carbonate (828 mg, 7.81 mmol), and the mixture was stirred at 100 ° C. for 2 hours. After diallylamine (158 mg, 1.63 mmol) was added and stirred at the same temperature for 4 hours, the reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: ethyl acetate = 24: 1 → 3: 2). , 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde (567 mg, 81%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 3.91 (4H, d, J = 5.5 Hz), 5.23-5.26 (2H, m), 5.27-5.29 (2H, m), 5.78-5.88 (2H, m), 7.13 (1H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 2.3, 8.7 Hz), 8.04 (1H, d, J = 2.3 Hz), 10.21 (1H, s).
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの製造
2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(500 mg, 2.60 mmol)のDMSO-水(2:1混合溶液,15 mL)溶液にジアリルアミン(319 mg, 3.28 mmol)及び炭酸ナトリウム(828 mg, 7.81 mmol)を加え、100℃にて2時間攪拌した。ジアリルアミン(158 mg, 1.63 mmol)を追加し、同温にて4時間攪拌した後、反応液を室温まで放冷後、水を加えトルエンで抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 24:1 → 3:2)を用いて精製し、2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒド(567 mg, 81%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 3.91 (4H, d, J = 5.5 Hz), 5.23-5.26 (2H, m), 5.27-5.29 (2H, m), 5.78-5.88 (2H, m), 7.13 (1H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 2.3, 8.7 Hz), 8.04 (1H, d, J = 2.3 Hz), 10.21 (1H, s). Example 39
Preparation of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde 2-Fluoro-5- (trifluoromethyl) benzaldehyde (500 mg, 2.60 mmol) in DMSO-water (2: 1 mixed solution, 15 mL) solution was added diallylamine (319 mg, 3.28 mmol) and sodium carbonate (828 mg, 7.81 mmol), and the mixture was stirred at 100 ° C. for 2 hours. After diallylamine (158 mg, 1.63 mmol) was added and stirred at the same temperature for 4 hours, the reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: ethyl acetate = 24: 1 → 3: 2). , 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde (567 mg, 81%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 3.91 (4H, d, J = 5.5 Hz), 5.23-5.26 (2H, m), 5.27-5.29 (2H, m), 5.78-5.88 (2H, m), 7.13 (1H, d, J = 8.7 Hz), 7.63 (1H, dd, J = 2.3, 8.7 Hz), 8.04 (1H, d, J = 2.3 Hz), 10.21 (1H, s).
工程2:N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
工程1で製造した2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒド(200 mg, 0.74 mmol)及び実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(165 mg, 89 mmol)のトルエン(5 mL)溶液に酢酸(45 mg, 0.75 mmol)を加え、Dean-Stark装置を用い5時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム(472 mg, 2.23 mmol)を加え、室温で64時間攪拌した。反応液に飽和重曹水を加え酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 16:1 → 1:1)を用いて精製し、表題化合物(215 mg, 66%)を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.4 Hz), 3.65 (4H, d, J = 6.4 Hz), 4.12 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 6.4 Hz), 5.15 (2H, dd, J = 1.4, 10.1 Hz), 5.20 (2H, dd, J = 1.4, 17.4 Hz), 5.49 (1H, t, J = 6.4 Hz), 5.79 (2H, tdd, J = 6.4, 10.1, 17.4 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.3, 8.7 Hz), 7.63 (1H, d, J = 2.3 Hz), 8.07 (2H, s). Step 2: Production of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (diallylamino produced in Step 1 ) -5- (trifluoromethyl) benzaldehyde (200 mg, 0.74 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (165 mg, 89 mmol) prepared in Example 3 in toluene (5 Acetic acid (45 mg, 0.75 mmol) was added to the solution, and the mixture was heated to reflux for 5 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (472 mg, 2.23 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 64 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 1: 1) to give the title compound (215 mg, 66%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.4 Hz), 3.65 (4H, d, J = 6.4 Hz), 4.12 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 6.4 Hz), 5.15 (2H, dd, J = 1.4, 10.1 Hz), 5.20 (2H, dd, J = 1.4, 17.4 Hz), 5.49 (1H, t, J = 6.4 Hz), 5.79 (2H, tdd, J = 6.4, 10.1, 17.4 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.3, 8.7 Hz), 7.63 (1H , d, J = 2.3 Hz), 8.07 (2H, s).
工程1で製造した2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒド(200 mg, 0.74 mmol)及び実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(165 mg, 89 mmol)のトルエン(5 mL)溶液に酢酸(45 mg, 0.75 mmol)を加え、Dean-Stark装置を用い5時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム(472 mg, 2.23 mmol)を加え、室温で64時間攪拌した。反応液に飽和重曹水を加え酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 16:1 → 1:1)を用いて精製し、表題化合物(215 mg, 66%)を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.4 Hz), 3.65 (4H, d, J = 6.4 Hz), 4.12 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 6.4 Hz), 5.15 (2H, dd, J = 1.4, 10.1 Hz), 5.20 (2H, dd, J = 1.4, 17.4 Hz), 5.49 (1H, t, J = 6.4 Hz), 5.79 (2H, tdd, J = 6.4, 10.1, 17.4 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.3, 8.7 Hz), 7.63 (1H, d, J = 2.3 Hz), 8.07 (2H, s). Step 2: Production of N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (diallylamino produced in Step 1 ) -5- (trifluoromethyl) benzaldehyde (200 mg, 0.74 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (165 mg, 89 mmol) prepared in Example 3 in toluene (5 Acetic acid (45 mg, 0.75 mmol) was added to the solution, and the mixture was heated to reflux for 5 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (472 mg, 2.23 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 64 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 1: 1) to give the title compound (215 mg, 66%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.4 Hz), 3.65 (4H, d, J = 6.4 Hz), 4.12 (2H, t, J = 6.4 Hz), 4.69 (2H, d, J = 6.4 Hz), 5.15 (2H, dd, J = 1.4, 10.1 Hz), 5.20 (2H, dd, J = 1.4, 17.4 Hz), 5.49 (1H, t, J = 6.4 Hz), 5.79 (2H, tdd, J = 6.4, 10.1, 17.4 Hz), 7.13 (1H, d, J = 8.7 Hz), 7.44 (1H, dd, J = 2.3, 8.7 Hz), 7.63 (1H , d, J = 2.3 Hz), 8.07 (2H, s).
実施例40
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに3,5-ビス(トリフルオロメチル)ベンズアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 6.4 Hz), 5.44 (1H, t, J = 6.4 Hz), 7.76 (1H, s), 7.80 (2H, s), 8.08 (2H, s). Example 40
Preparation of N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using 3,5-bis (trifluoromethyl) benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde to give the title compound colorless. Obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 6.4 Hz), 5.44 (1H, t, J = 6.4 Hz), 7.76 (1H, s), 7.80 (2H, s), 8.08 (2H, s).
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに3,5-ビス(トリフルオロメチル)ベンズアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 6.4 Hz), 5.44 (1H, t, J = 6.4 Hz), 7.76 (1H, s), 7.80 (2H, s), 8.08 (2H, s). Example 40
Preparation of N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using 3,5-bis (trifluoromethyl) benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde to give the title compound colorless. Obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 6.4 Hz), 5.44 (1H, t, J = 6.4 Hz), 7.76 (1H, s), 7.80 (2H, s), 8.08 (2H, s).
実施例41
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミンの製造:
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに3-(トリフルオロメチル)ベンズアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.66 (2H, d, J = 6.4 Hz), 5.66 (1H, t, J = 6.4 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 7.8 Hz), 7.61 (1H, s), 8.07 (2H, s). Example 41
Preparation of 5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to process 2 of example 39 using 3- (trifluoromethyl) benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a colorless solid. It was.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.66 (2H, d, J = 6.4 Hz), 5.66 (1H, t, J = 6.4 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 7.8 Hz) , 7.61 (1H, s), 8.07 (2H, s).
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミンの製造:
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに3-(トリフルオロメチル)ベンズアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.66 (2H, d, J = 6.4 Hz), 5.66 (1H, t, J = 6.4 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 7.8 Hz), 7.61 (1H, s), 8.07 (2H, s). Example 41
Preparation of 5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to process 2 of example 39 using 3- (trifluoromethyl) benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a colorless solid. It was.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.66 (2H, d, J = 6.4 Hz), 5.66 (1H, t, J = 6.4 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 7.8 Hz) , 7.61 (1H, s), 8.07 (2H, s).
実施例42
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:N-[5-(クロロエトキシ)ピリミジン-2-イル]ヘキサンアミドの製造
実施例3の工程2の方法により製造したN-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(3.00 g, 14.3 mmol)をDMF(15 mL)に溶解し、室温にて炭酸カリウム(2.97 g, 21.5 mmol)及び1-ブロモ-2-クロロエタン(4.12 g, 28.7 mmol)を加え、60℃にて20時間攪拌した後、反応液を氷水に注ぎ、石油エーテルを加え5分間攪拌した。析出物を濾取し、水及び石油エーテルで洗浄した後、減圧乾燥し、N-[5-(クロロエトキシ)ピリミジン-2-イル]ヘキサンアミド(2.72 g, 70%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.2 Hz), 1.31-1.43 (4H, m), 1.69-1.78 (2H, m), 2.63 (2H, br), 3.83 (2H, t, J = 5.6 Hz), 4.30 (2H, t, J = 5.6 Hz), 8.36 (2H, s), 8.44 (1H, br). Example 42
Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide N- (5-hydroxypyrimidin-2-yl) hexanamide (3.00 g) prepared by the method of Step 2 of Example 3 , 14.3 mmol) in DMF (15 mL), potassium carbonate (2.97 g, 21.5 mmol) and 1-bromo-2-chloroethane (4.12 g, 28.7 mmol) were added at room temperature, and the mixture was stirred at 60 ° C. for 20 hours. After stirring, the reaction solution was poured into ice water, petroleum ether was added, and the mixture was stirred for 5 minutes. The precipitate was collected by filtration, washed with water and petroleum ether, and then dried under reduced pressure to give N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (2.72 g, 70%) as a colorless solid. .
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.31-1.43 (4H, m), 1.69-1.78 (2H, m), 2.63 (2H, br), 3.83 (2H , t, J = 5.6 Hz), 4.30 (2H, t, J = 5.6 Hz), 8.36 (2H, s), 8.44 (1H, br).
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:N-[5-(クロロエトキシ)ピリミジン-2-イル]ヘキサンアミドの製造
実施例3の工程2の方法により製造したN-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(3.00 g, 14.3 mmol)をDMF(15 mL)に溶解し、室温にて炭酸カリウム(2.97 g, 21.5 mmol)及び1-ブロモ-2-クロロエタン(4.12 g, 28.7 mmol)を加え、60℃にて20時間攪拌した後、反応液を氷水に注ぎ、石油エーテルを加え5分間攪拌した。析出物を濾取し、水及び石油エーテルで洗浄した後、減圧乾燥し、N-[5-(クロロエトキシ)ピリミジン-2-イル]ヘキサンアミド(2.72 g, 70%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.2 Hz), 1.31-1.43 (4H, m), 1.69-1.78 (2H, m), 2.63 (2H, br), 3.83 (2H, t, J = 5.6 Hz), 4.30 (2H, t, J = 5.6 Hz), 8.36 (2H, s), 8.44 (1H, br). Example 42
Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide N- (5-hydroxypyrimidin-2-yl) hexanamide (3.00 g) prepared by the method of Step 2 of Example 3 , 14.3 mmol) in DMF (15 mL), potassium carbonate (2.97 g, 21.5 mmol) and 1-bromo-2-chloroethane (4.12 g, 28.7 mmol) were added at room temperature, and the mixture was stirred at 60 ° C. for 20 hours. After stirring, the reaction solution was poured into ice water, petroleum ether was added, and the mixture was stirred for 5 minutes. The precipitate was collected by filtration, washed with water and petroleum ether, and then dried under reduced pressure to give N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (2.72 g, 70%) as a colorless solid. .
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.31-1.43 (4H, m), 1.69-1.78 (2H, m), 2.63 (2H, br), 3.83 (2H , t, J = 5.6 Hz), 4.30 (2H, t, J = 5.6 Hz), 8.36 (2H, s), 8.44 (1H, br).
工程2:N-{5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミドの製造
チオフェノール(486 mg, 4.41 mmol)をDMF(5 mL)に溶解し、氷浴中にて水素化ナトリウム(50% in oil:265 mg, 5.52 mmol)を加え、室温にて15分間攪拌した。反応液に工程1で製造したN-[5-(クロロエトキシ)ピリミジン-2-イル]ヘキサンアミド(1.00 g, 3.68 mmol)のDMF(2 mL)に溶液を氷浴中にて加え、室温にて2時間攪拌した後、氷浴中にて2 M水酸化ナトリウム水溶液を加えた。室温にて5分間攪拌した後、反応液を酢酸エチルより抽出した。有機層を2 M水酸化ナトリウム水溶液及び水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール = 30:1 → 10:1)を用いて精製し、N-{5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(696 mg, 55%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.42 (4H, m), 1.66-1.77 (2H, m), 2.61 (2H, br), 3.29 (2H, t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.25 (1H, tt, J = 2.0, 7.2 Hz), 7.32 (2H, tt, J = 2.0, 7.2 Hz), 7.41 (2H, dt, J = 2.0, 7.2 Hz), 8.22 (2H, s), 8.27 (1H, br). Step 2: Preparation of N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide Thiophenol (486 mg, 4.41 mmol) was dissolved in DMF (5 mL) in an ice bath. Sodium hydride (50% in oil: 265 mg, 5.52 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. A solution of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (1.00 g, 3.68 mmol) prepared in Step 1 in DMF (2 mL) was added to the reaction mixture in an ice bath, and the mixture was brought to room temperature. After stirring for 2 hours, 2 M aqueous sodium hydroxide solution was added in an ice bath. After stirring at room temperature for 5 minutes, the reaction solution was extracted from ethyl acetate. The organic layer was washed with 2 M aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (chloroform → chloroform: methanol = 30: 1 → 10). : 1) to give N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide (696 mg, 55%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.42 (4H, m), 1.66-1.77 (2H, m), 2.61 (2H, br), 3.29 (2H , t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.25 (1H, tt, J = 2.0, 7.2 Hz), 7.32 (2H, tt, J = 2.0, 7.2 Hz), 7.41 (2H, dt, J = 2.0, 7.2 Hz), 8.22 (2H, s), 8.27 (1H, br).
チオフェノール(486 mg, 4.41 mmol)をDMF(5 mL)に溶解し、氷浴中にて水素化ナトリウム(50% in oil:265 mg, 5.52 mmol)を加え、室温にて15分間攪拌した。反応液に工程1で製造したN-[5-(クロロエトキシ)ピリミジン-2-イル]ヘキサンアミド(1.00 g, 3.68 mmol)のDMF(2 mL)に溶液を氷浴中にて加え、室温にて2時間攪拌した後、氷浴中にて2 M水酸化ナトリウム水溶液を加えた。室温にて5分間攪拌した後、反応液を酢酸エチルより抽出した。有機層を2 M水酸化ナトリウム水溶液及び水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール = 30:1 → 10:1)を用いて精製し、N-{5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(696 mg, 55%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.42 (4H, m), 1.66-1.77 (2H, m), 2.61 (2H, br), 3.29 (2H, t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.25 (1H, tt, J = 2.0, 7.2 Hz), 7.32 (2H, tt, J = 2.0, 7.2 Hz), 7.41 (2H, dt, J = 2.0, 7.2 Hz), 8.22 (2H, s), 8.27 (1H, br). Step 2: Preparation of N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide Thiophenol (486 mg, 4.41 mmol) was dissolved in DMF (5 mL) in an ice bath. Sodium hydride (50% in oil: 265 mg, 5.52 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. A solution of N- [5- (chloroethoxy) pyrimidin-2-yl] hexanamide (1.00 g, 3.68 mmol) prepared in Step 1 in DMF (2 mL) was added to the reaction mixture in an ice bath, and the mixture was brought to room temperature. After stirring for 2 hours, 2 M aqueous sodium hydroxide solution was added in an ice bath. After stirring at room temperature for 5 minutes, the reaction solution was extracted from ethyl acetate. The organic layer was washed with 2 M aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (chloroform → chloroform: methanol = 30: 1 → 10). : 1) to give N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide (696 mg, 55%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.30-1.42 (4H, m), 1.66-1.77 (2H, m), 2.61 (2H, br), 3.29 (2H , t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.25 (1H, tt, J = 2.0, 7.2 Hz), 7.32 (2H, tt, J = 2.0, 7.2 Hz), 7.41 (2H, dt, J = 2.0, 7.2 Hz), 8.22 (2H, s), 8.27 (1H, br).
工程3:5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの製造
工程2で製造したN-{5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(400 mg, 1.16 mmol)をメタノール(2.8 mL)に溶解し、ナトリウムメトキシド(25.1 mg, 2.32 mmol)を加え50℃にて2時間攪拌した。反応液を水で希釈した後、クロロホルムで抽出し、有機層を無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール = 100:1 → 10:1)を用いて精製し、表題化合物(282 mg, 99%)を無色固体として得た。
1H-NMR (CDCl3) δ: 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.80 (2H, br), 7.23 (1H, tt, J = 0.8, 7.2 Hz), 7.31 (2H, tt, J = 0.8, 7.2 Hz), 7.40 (2H, dt, J = 0.8, 7.2 Hz), 7.99 (2H, s). Step 3: Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide (400 mg, prepared 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 is diluted with water and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (chloroform → chloroform: methanol = 100: 1 → 10: 1) to give the title compound (282 mg, 99%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.80 (2H, br), 7.23 (1H, tt, J = 0.8 , 7.2 Hz), 7.31 (2H, tt, J = 0.8, 7.2 Hz), 7.40 (2H, dt, J = 0.8, 7.2 Hz), 7.99 (2H, s).
工程2で製造したN-{5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}ヘキサンアミド(400 mg, 1.16 mmol)をメタノール(2.8 mL)に溶解し、ナトリウムメトキシド(25.1 mg, 2.32 mmol)を加え50℃にて2時間攪拌した。反応液を水で希釈した後、クロロホルムで抽出し、有機層を無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール = 100:1 → 10:1)を用いて精製し、表題化合物(282 mg, 99%)を無色固体として得た。
1H-NMR (CDCl3) δ: 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.80 (2H, br), 7.23 (1H, tt, J = 0.8, 7.2 Hz), 7.31 (2H, tt, J = 0.8, 7.2 Hz), 7.40 (2H, dt, J = 0.8, 7.2 Hz), 7.99 (2H, s). Step 3: Preparation of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine N- {5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} hexanamide (400 mg, prepared 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 is diluted with water and extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (chloroform → chloroform: methanol = 100: 1 → 10: 1) to give the title compound (282 mg, 99%) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.80 (2H, br), 7.23 (1H, tt, J = 0.8 , 7.2 Hz), 7.31 (2H, tt, J = 0.8, 7.2 Hz), 7.40 (2H, dt, J = 0.8, 7.2 Hz), 7.99 (2H, s).
実施例43
5-(2-フェノキシエトキシ)ピリミジン-2-アミンの製造:
チオフェノールの代わりにフェノールを用いて実施例42と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 4.27-4.33 (4H, m), 4.82 (2H, br), 6.92-7.01 (3H, m), 7.28-7.33 (2H, m), 8.12 (2H, s). Example 43
Preparation of 5- (2-phenoxyethoxy) pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 42 using phenol instead of thiophenol, and the title compound was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 4.27-4.33 (4H, m), 4.82 (2H, br), 6.92-7.01 (3H, m), 7.28-7.33 (2H, m), 8.12 (2H, s) .
5-(2-フェノキシエトキシ)ピリミジン-2-アミンの製造:
チオフェノールの代わりにフェノールを用いて実施例42と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 4.27-4.33 (4H, m), 4.82 (2H, br), 6.92-7.01 (3H, m), 7.28-7.33 (2H, m), 8.12 (2H, s). Example 43
Preparation of 5- (2-phenoxyethoxy) pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 42 using phenol instead of thiophenol, and the title compound was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 4.27-4.33 (4H, m), 4.82 (2H, br), 6.92-7.01 (3H, m), 7.28-7.33 (2H, m), 8.12 (2H, s) .
実施例44
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
実施例42で製造した5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン(230 mg, 0.93 mmol)及び実施例32の方法に従い製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル(414 mg, 1.02 mmol)のトルエン(4 mL)溶液に酢酸(115 mg, 1.92 mmol)を加え、Dean-Stark装置を用い3.5時間攪拌した。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリフルオロ酢酸(108 mg, 0.95 mmol)及びトリアセトキシ水素化ホウ素ナトリウム(394 mg, 1.86 mmol)を加え、室温で1時間攪拌した。反応液に水を加え酢酸エチルで抽出した後、有機層を飽和重曹水及び飽和食塩水で洗浄し、無水硫酸マグネシウムを用いて乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン = 20:1 → 10:1 → 6:1 → 3:1)を用いて精製し、表題化合物(453 g, 70%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.89-0.97 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.6 Hz), 5.41 (1H, t, J = 5.6 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.22 (1H, tt, J = 1.6, 8.8 Hz), 7.30 (2H, tt, J = 1.6, 8.8 Hz), 7.40 (2H, td, J = 1.6, 8.8 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.01 (2H, s). Example 44
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Preparation of cyclohexyl} ethyl acetate:
5- [2- (Phenylthio) ethoxy] pyrimidin-2-amine (230 mg, 0.93 mmol) prepared in Example 42 and 2- [trans-4-({ethyl [2- Acetic acid (115 mg, 1.92 mmol) was added to a toluene (4 mL) solution of formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate (414 mg, 1.02 mmol), and the Dean-Stark apparatus was added. Stir for 3.5 hours. The reaction solution was allowed to cool to room temperature, and while stirring in an ice bath, trifluoroacetic acid (108 mg, 0.95 mmol) and sodium triacetoxyborohydride (394 mg, 1.86 mmol) were added, and the mixture was stirred at room temperature for 1 hour. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified using silica gel column chromatography (hexane: acetone = 20: 1 → 10: 1 → 6: 1 → 3: 1) to give the title compound (453 g, 70%) Obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.89-0.97 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 3.25 (2H, t , J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.6 Hz), 5.41 (1H, t, J = 5.6 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.22 (1H, tt, J = 1.6, 8.8 Hz), 7.30 (2H, tt, J = 1.6, 8.8 Hz), 7.40 (2H, td , J = 1.6, 8.8 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.01 (2H, s).
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
実施例42で製造した5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン(230 mg, 0.93 mmol)及び実施例32の方法に従い製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル(414 mg, 1.02 mmol)のトルエン(4 mL)溶液に酢酸(115 mg, 1.92 mmol)を加え、Dean-Stark装置を用い3.5時間攪拌した。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリフルオロ酢酸(108 mg, 0.95 mmol)及びトリアセトキシ水素化ホウ素ナトリウム(394 mg, 1.86 mmol)を加え、室温で1時間攪拌した。反応液に水を加え酢酸エチルで抽出した後、有機層を飽和重曹水及び飽和食塩水で洗浄し、無水硫酸マグネシウムを用いて乾燥した。減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:アセトン = 20:1 → 10:1 → 6:1 → 3:1)を用いて精製し、表題化合物(453 g, 70%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.89-0.97 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 3.25 (2H, t, J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.6 Hz), 5.41 (1H, t, J = 5.6 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.22 (1H, tt, J = 1.6, 8.8 Hz), 7.30 (2H, tt, J = 1.6, 8.8 Hz), 7.40 (2H, td, J = 1.6, 8.8 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.01 (2H, s). Example 44
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Preparation of cyclohexyl} ethyl acetate:
5- [2- (Phenylthio) ethoxy] pyrimidin-2-amine (230 mg, 0.93 mmol) prepared in Example 42 and 2- [trans-4-({ethyl [2- Acetic acid (115 mg, 1.92 mmol) was added to a toluene (4 mL) solution of formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate (414 mg, 1.02 mmol), and the Dean-Stark apparatus was added. Stir for 3.5 hours. The reaction solution was allowed to cool to room temperature, and while stirring in an ice bath, trifluoroacetic acid (108 mg, 0.95 mmol) and sodium triacetoxyborohydride (394 mg, 1.86 mmol) were added, and the mixture was stirred at room temperature for 1 hour. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified using silica gel column chromatography (hexane: acetone = 20: 1 → 10: 1 → 6: 1 → 3: 1) to give the title compound (453 g, 70%) Obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.89-0.97 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.14 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 3.25 (2H, t , J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.6 Hz), 5.41 (1H, t, J = 5.6 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.22 (1H, tt, J = 1.6, 8.8 Hz), 7.30 (2H, tt, J = 1.6, 8.8 Hz), 7.40 (2H, td , J = 1.6, 8.8 Hz), 7.43 (1H, dd, J = 2.0, 8.4 Hz), 7.61 (1H, d, J = 2.0 Hz), 8.01 (2H, s).
実施例45
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルの製造:
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-(2-フェノキシエトキシ)ピリミジン-2-アミンを用いて実施例44と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.99 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.63-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.28-4.31 (4H, m), 4.67 (2H, d, J = 6.1 Hz), 5.51 (1H, t, J = 6.1 Hz), 6.92-7.01 (3H, m), 7.18 (1H, d, J = 8.3 Hz), 7.28-7.31 (2H, m,), 7.44 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.11 (2H, s). Example 45
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate production:
The title compound was treated in the same manner as in Example 44 using 5- (2-phenoxyethoxy) pyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine. Obtained as a thing.
1 H-NMR (CDCl 3 ) δ: 0.88-0.99 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.63-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 4.28-4.31 (4H, m), 4.67 (2H, d, J = 6.1 Hz), 5.51 (1H, t, J = 6.1 Hz), 6.92-7.01 (3H, m), 7.18 (1H, d, J = 8.3 Hz), 7.28-7.31 (2H, m,), 7.44 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.11 (2H, s).
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルの製造:
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-(2-フェノキシエトキシ)ピリミジン-2-アミンを用いて実施例44と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.99 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.63-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.28-4.31 (4H, m), 4.67 (2H, d, J = 6.1 Hz), 5.51 (1H, t, J = 6.1 Hz), 6.92-7.01 (3H, m), 7.18 (1H, d, J = 8.3 Hz), 7.28-7.31 (2H, m,), 7.44 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.11 (2H, s). Example 45
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate production:
The title compound was treated in the same manner as in Example 44 using 5- (2-phenoxyethoxy) pyrimidin-2-amine instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine. Obtained as a thing.
1 H-NMR (CDCl 3 ) δ: 0.88-0.99 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.63-1.90 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 4.28-4.31 (4H, m), 4.67 (2H, d, J = 6.1 Hz), 5.51 (1H, t, J = 6.1 Hz), 6.92-7.01 (3H, m), 7.18 (1H, d, J = 8.3 Hz), 7.28-7.31 (2H, m,), 7.44 (1H, d, J = 8.3 Hz), 7.62 (1H, s), 8.11 (2H, s).
実施例46
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルの製造:
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの代わりに実施例1で製造した5-メトキシピリミジン-2-アミンを用いて実施例44と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 0.89-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.2 Hz), 3.01 (2H, q, J = 7.2 Hz), 3.80 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.66 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, s). Example 46
Preparation of 2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate:
Using the 5-methoxypyrimidin-2-amine prepared in Example 1 instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment were carried out in the same manner as in Example 44, and the title compound was colorless. Obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 0.89-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.2 Hz), 3.01 (2H, q, J = 7.2 Hz), 3.80 (3H, s ), 4.11 (2H, q, J = 7.2 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.66 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, s).
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチルの製造:
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの代わりに実施例1で製造した5-メトキシピリミジン-2-アミンを用いて実施例44と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 0.89-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.2 Hz), 3.01 (2H, q, J = 7.2 Hz), 3.80 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.66 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, s). Example 46
Preparation of 2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate:
Using the 5-methoxypyrimidin-2-amine prepared in Example 1 instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment were carried out in the same manner as in Example 44, and the title compound was colorless. Obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 0.89-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 7.2 Hz), 3.01 (2H, q, J = 7.2 Hz), 3.80 (3H, s ), 4.11 (2H, q, J = 7.2 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.66 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.62 (1H, s), 8.05 (2H, s).
実施例47
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチルの製造:
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの代わりに実施例2で製造した5-エトキシピリミジン-2-アミンを用いて実施例44と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 0.88-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.37 (1H, t, J = 6.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.05 (2H, s). Example 47
2- [trans-4-({[2-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate Manufacturing:
Using the 5-ethoxypyrimidin-2-amine prepared in Example 2 instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment were conducted in the same manner as in Example 44, and the title compound was converted to white. Obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 0.88-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q , J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.37 (1H, t, J = 6.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.05 (2H, s).
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチルの製造:
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミンの代わりに実施例2で製造した5-エトキシピリミジン-2-アミンを用いて実施例44と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 0.88-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q, J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.37 (1H, t, J = 6.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.05 (2H, s). Example 47
2- [trans-4-({[2-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate Manufacturing:
Using the 5-ethoxypyrimidin-2-amine prepared in Example 2 instead of 5- [2- (phenylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment were conducted in the same manner as in Example 44, and the title compound was converted to white. Obtained as a solid.
1 H-NMR (CDCl 3 ) δ: 0.88-0.97 (4H, m), 1.02 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 1.40 (1H, m), 1.64-1.88 (5H, m), 2.15 (2H, d, J = 6.8 Hz), 2.85 (2H, d, J = 6.8 Hz), 3.01 (2H, q , J = 7.2 Hz), 4.00 (2H, q, J = 7.2 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.37 (1H, t, J = 6.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.05 (2H, s).
実施例48
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジルの製造:
工程1:2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸の製造
実施例32で製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル(9.80 g, 24.5 mmol)をエタノール(100 mL)に溶解し、氷浴中にて撹拌しつつ2 M水酸化ナトリウム水溶液(36.8 mL, 73.6 mmol)を加えた後、50℃まで昇温し、90分間攪拌した。氷浴中にて反応液に2 M塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を水及び飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮し、2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸(9.11 g, quant.)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-1.02 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.62-1.90 (5H, m), 2.21 (2H, d, J = 7.1 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.64 (1H, dd, J = 2.2, 8.6 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s). Example 48
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Preparation of cyclohexyl} benzyl acetate:
Step 1: Preparation of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid 2- [trans-4- () prepared in Example 32 {Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate (9.80 g, 24.5 mmol) was dissolved in ethanol (100 mL) and stirred in an ice bath. After adding M sodium hydroxide aqueous solution (36.8 mL, 73.6 mmol), it heated up to 50 degreeC and stirred for 90 minutes. The reaction solution was neutralized with 2 M hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid (9.11 g, quant.) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.88-1.02 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.62-1.90 (5H, m), 2.21 (2H , d, J = 7.1 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.64 (1H, dd , J = 2.2, 8.6 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s).
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジルの製造:
工程1:2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸の製造
実施例32で製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル(9.80 g, 24.5 mmol)をエタノール(100 mL)に溶解し、氷浴中にて撹拌しつつ2 M水酸化ナトリウム水溶液(36.8 mL, 73.6 mmol)を加えた後、50℃まで昇温し、90分間攪拌した。氷浴中にて反応液に2 M塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を水及び飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮し、2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸(9.11 g, quant.)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-1.02 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.62-1.90 (5H, m), 2.21 (2H, d, J = 7.1 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.64 (1H, dd, J = 2.2, 8.6 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s). Example 48
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Preparation of cyclohexyl} benzyl acetate:
Step 1: Preparation of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid 2- [trans-4- () prepared in Example 32 {Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate (9.80 g, 24.5 mmol) was dissolved in ethanol (100 mL) and stirred in an ice bath. After adding M sodium hydroxide aqueous solution (36.8 mL, 73.6 mmol), it heated up to 50 degreeC and stirred for 90 minutes. The reaction solution was neutralized with 2 M hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid (9.11 g, quant.) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.88-1.02 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.62-1.90 (5H, m), 2.21 (2H , d, J = 7.1 Hz), 3.09 (2H, d, J = 7.1 Hz), 3.31 (2H, q, J = 7.1 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.64 (1H, dd , J = 2.2, 8.6 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s).
工程2:2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸ベンジルの製造
工程1で製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸(9.11 g, 24.5 mmol)をジクロロメタン(100 mL)に溶解し、室温にてベンジルアルコール(2.92 g, 27.0 mmol)及びN,N-ジメチルアミノピリジン(4.50 g, 36.8 mmol)を加えた。氷浴中にて攪拌しつつ1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(5.17 g, 27.0 mmol)を加えた後、室温に昇温し、24時間攪拌した。反応液を水で希釈した後、クロロホルムにて抽出し、有機層を2 M塩酸、水及び飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 12:1 → 1:1)を用いて精製し、2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸ベンジル(11.60 g, quant.)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.87-1.10 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.67-1.88 (5H, m), 2.22 (2H, d, J = 6.6 Hz), 3.08 (2H, d, J = 6.6 Hz), 3.30 (2H, q, J = 7.1 Hz), 5.09 (2H, s), 7.15 (1H, d, J = 8.0 Hz), 7.72-7.37 (5H, m), 7.64 (1H, dd, J = 2.2, 8.0 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s). Step 2: Preparation of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid benzyl 2- [trans-4- ( {Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid (9.11 g, 24.5 mmol) was dissolved in dichloromethane (100 mL), and benzyl alcohol (2.92 g, 27.0 mmol) was dissolved at room temperature. mmol) and N, N-dimethylaminopyridine (4.50 g, 36.8 mmol) were added. While stirring in an ice bath, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.17 g, 27.0 mmol) was added, and the mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was diluted with water and extracted with chloroform, and the organic layer was washed successively with 2M hydrochloric acid, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 12: 1 → 1: 1) to give 2- [trans-4 -({Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] benzyl acetate (11.60 g, quant.) Was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.87-1.10 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.67-1.88 (5H, m), 2.22 (2H , d, J = 6.6 Hz), 3.08 (2H, d, J = 6.6 Hz), 3.30 (2H, q, J = 7.1 Hz), 5.09 (2H, s), 7.15 (1H, d, J = 8.0 Hz ), 7.72-7.37 (5H, m), 7.64 (1H, dd, J = 2.2, 8.0 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s).
工程1で製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸(9.11 g, 24.5 mmol)をジクロロメタン(100 mL)に溶解し、室温にてベンジルアルコール(2.92 g, 27.0 mmol)及びN,N-ジメチルアミノピリジン(4.50 g, 36.8 mmol)を加えた。氷浴中にて攪拌しつつ1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(5.17 g, 27.0 mmol)を加えた後、室温に昇温し、24時間攪拌した。反応液を水で希釈した後、クロロホルムにて抽出し、有機層を2 M塩酸、水及び飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 12:1 → 1:1)を用いて精製し、2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸ベンジル(11.60 g, quant.)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.87-1.10 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.67-1.88 (5H, m), 2.22 (2H, d, J = 6.6 Hz), 3.08 (2H, d, J = 6.6 Hz), 3.30 (2H, q, J = 7.1 Hz), 5.09 (2H, s), 7.15 (1H, d, J = 8.0 Hz), 7.72-7.37 (5H, m), 7.64 (1H, dd, J = 2.2, 8.0 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s). Step 2: Preparation of 2- [trans-4-({ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid benzyl 2- [trans-4- ( {Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] acetic acid (9.11 g, 24.5 mmol) was dissolved in dichloromethane (100 mL), and benzyl alcohol (2.92 g, 27.0 mmol) was dissolved at room temperature. mmol) and N, N-dimethylaminopyridine (4.50 g, 36.8 mmol) were added. While stirring in an ice bath, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.17 g, 27.0 mmol) was added, and the mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was diluted with water and extracted with chloroform, and the organic layer was washed successively with 2M hydrochloric acid, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate = 12: 1 → 1: 1) to give 2- [trans-4 -({Ethyl [2-formyl-4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] benzyl acetate (11.60 g, quant.) Was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.87-1.10 (4H, m), 1.11 (3H, t, J = 7.1 Hz), 1.54 (1H, m), 1.67-1.88 (5H, m), 2.22 (2H , d, J = 6.6 Hz), 3.08 (2H, d, J = 6.6 Hz), 3.30 (2H, q, J = 7.1 Hz), 5.09 (2H, s), 7.15 (1H, d, J = 8.0 Hz ), 7.72-7.37 (5H, m), 7.64 (1H, dd, J = 2.2, 8.0 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.17 (1H, s).
工程3:2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジルの製造
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに工程2で製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸ベンジルを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 0.86-1.00 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.20 (3H, s), 2.22 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 8.0 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.10 (2H, s), 5.40 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.8 Hz), 7.28-7.38 (5H, m), 7.44 (1H, dd, J = 1.2, 8.8 Hz), 7.62 (1H, d, J = 1.2 Hz), 8.07 (2H, s). Step 3: 2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino ) Preparation of benzyl] methyl] cyclohexyl} 2- [trans-4-({ethyl [2-formyl-4- (ethyl)] prepared in Step 2 instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using trifluoromethyl) phenyl] amino} methyl) cyclohexyl] benzyl acetate to give the title compound as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.86-1.00 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.20 (3H , s), 2.22 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 8.0 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz ), 4.12 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.10 (2H, s), 5.40 (1H, t, J = 6.0 Hz), 7.17 (1H, d , J = 8.8 Hz), 7.28-7.38 (5H, m), 7.44 (1H, dd, J = 1.2, 8.8 Hz), 7.62 (1H, d, J = 1.2 Hz), 8.07 (2H, s).
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに工程2で製造した2-[trans-4-({エチル[2-ホルミル-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸ベンジルを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 0.86-1.00 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.20 (3H, s), 2.22 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 8.0 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.10 (2H, s), 5.40 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 8.8 Hz), 7.28-7.38 (5H, m), 7.44 (1H, dd, J = 1.2, 8.8 Hz), 7.62 (1H, d, J = 1.2 Hz), 8.07 (2H, s). Step 3: 2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino ) Preparation of benzyl] methyl] cyclohexyl} 2- [trans-4-({ethyl [2-formyl-4- (ethyl)] prepared in Step 2 instead of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using trifluoromethyl) phenyl] amino} methyl) cyclohexyl] benzyl acetate to give the title compound as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.86-1.00 (4H, m), 1.01 (3H, t, J = 7.2 Hz), 1.40 (1H, m), 1.66-1.88 (5H, m), 2.20 (3H , s), 2.22 (2H, d, J = 6.8 Hz), 2.84 (2H, d, J = 8.0 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.00 (2H, q, J = 7.2 Hz ), 4.12 (2H, t, J = 6.8 Hz), 4.67 (2H, d, J = 6.0 Hz), 5.10 (2H, s), 5.40 (1H, t, J = 6.0 Hz), 7.17 (1H, d , J = 8.8 Hz), 7.28-7.38 (5H, m), 7.44 (1H, dd, J = 1.2, 8.8 Hz), 7.62 (1H, d, J = 1.2 Hz), 8.07 (2H, s).
実施例49
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
ジアリルアミンの代わりにN-(4-メトキシベンジル)エチルアミンを用いて実施例39と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.02 (2H, q, J = 7.1 Hz), 3.79 (3H, s), 4.10 (2H, s), 4.11 (2H, t, J = 6.6 Hz), 4.74 (2H, d, J = 5.8 Hz), 5.62 (1H, t, J = 5.8 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.63 (1H, s), 8.06 (2H, s). Example 49
Preparation of N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 39 using N- (4-methoxybenzyl) ethylamine in place of diallylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.02 (2H, q, J = 7.1 Hz), 3.79 (3H, s), 4.10 (2H, s), 4.11 (2H, t, J = 6.6 Hz), 4.74 (2H, d, J = 5.8 Hz), 5.62 (1H, t, J = 5.8 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.3 Hz) , 7.63 (1H, s), 8.06 (2H, s).
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
ジアリルアミンの代わりにN-(4-メトキシベンジル)エチルアミンを用いて実施例39と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.02 (2H, q, J = 7.1 Hz), 3.79 (3H, s), 4.10 (2H, s), 4.11 (2H, t, J = 6.6 Hz), 4.74 (2H, d, J = 5.8 Hz), 5.62 (1H, t, J = 5.8 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.63 (1H, s), 8.06 (2H, s). Example 49
Preparation of N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 39 using N- (4-methoxybenzyl) ethylamine in place of diallylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 3.02 (2H, q, J = 7.1 Hz), 3.79 (3H, s), 4.10 (2H, s), 4.11 (2H, t, J = 6.6 Hz), 4.74 (2H, d, J = 5.8 Hz), 5.62 (1H, t, J = 5.8 Hz), 6.82 (2H, d, J = 8.6 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.44 (1H, d, J = 8.3 Hz) , 7.63 (1H, s), 8.06 (2H, s).
実施例50
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(157 mg, 0.31 mmol)をジクロロエタン(3 mL)に溶解し、アニソール(388 mg, 3.12 mmol)を加え氷浴中にて攪拌する中にトリフルオロ酢酸(0.1 mL)を加えた。同温にて90分間攪拌した後、トリフルオロ酢酸(1 mL)を追加し、同温にて1時間攪拌した。同温にて2 M水酸化ナトリウム水溶液を加えて塩基性とした後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した後、減圧濃縮して得られた残渣をクロロホルム-ヘキサンより洗浄濾取し、表題化合物(70.1 mg, 58%)を白色固体として得た。濾液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 10:1 → 6:1 → 1:2)を用いて分離した後、シリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)にて精製し、表題化合物(23.3 mg, 19%)を白色固体として得た(合計93.4 mg, 78%)。
1H-NMR (CDCl3) δ: 1.23 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.16 (2H, q, J = 7.3 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.53 (2H, d, J = 6.6 Hz), 5.17 (1H, t, J = 6.6 Hz), 5.40 (1H, br), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.6 Hz), 8.08 (2H, s). Example 50
Preparation of N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (157 mg, 0.31 mmol) was converted to dichloroethane. (3 mL), anisole (388 mg, 3.12 mmol) was added, and trifluoroacetic acid (0.1 mL) was added while stirring in an ice bath. After stirring at the same temperature for 90 minutes, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The mixture was made basic by adding 2 M aqueous sodium hydroxide solution at the same temperature, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with chloroform-hexane and collected by filtration to give the title compound (70.1 mg, 58%) as a white solid. Got as. The filtrate was separated using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 6: 1 → 1: 2), and then silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1). Purification gave the title compound (23.3 mg, 19%) as a white solid (total 93.4 mg, 78%).
1 H-NMR (CDCl 3 ) δ: 1.23 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.16 (2H, q, J = 7.3 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.53 (2H, d, J = 6.6 Hz), 5.17 (1H, t, J = 6.6 Hz), 5.40 (1H, br), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.6 Hz), 8.08 (2H, s).
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(157 mg, 0.31 mmol)をジクロロエタン(3 mL)に溶解し、アニソール(388 mg, 3.12 mmol)を加え氷浴中にて攪拌する中にトリフルオロ酢酸(0.1 mL)を加えた。同温にて90分間攪拌した後、トリフルオロ酢酸(1 mL)を追加し、同温にて1時間攪拌した。同温にて2 M水酸化ナトリウム水溶液を加えて塩基性とした後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した後、減圧濃縮して得られた残渣をクロロホルム-ヘキサンより洗浄濾取し、表題化合物(70.1 mg, 58%)を白色固体として得た。濾液をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 10:1 → 6:1 → 1:2)を用いて分離した後、シリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)にて精製し、表題化合物(23.3 mg, 19%)を白色固体として得た(合計93.4 mg, 78%)。
1H-NMR (CDCl3) δ: 1.23 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.16 (2H, q, J = 7.3 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.53 (2H, d, J = 6.6 Hz), 5.17 (1H, t, J = 6.6 Hz), 5.40 (1H, br), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.6 Hz), 8.08 (2H, s). Example 50
Preparation of N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (157 mg, 0.31 mmol) was converted to dichloroethane. (3 mL), anisole (388 mg, 3.12 mmol) was added, and trifluoroacetic acid (0.1 mL) was added while stirring in an ice bath. After stirring at the same temperature for 90 minutes, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The mixture was made basic by adding 2 M aqueous sodium hydroxide solution at the same temperature, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with chloroform-hexane and collected by filtration to give the title compound (70.1 mg, 58%) as a white solid. Got as. The filtrate was separated using silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 6: 1 → 1: 2), and then silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1). Purification gave the title compound (23.3 mg, 19%) as a white solid (total 93.4 mg, 78%).
1 H-NMR (CDCl 3 ) δ: 1.23 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.16 (2H, q, J = 7.3 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.53 (2H, d, J = 6.6 Hz), 5.17 (1H, t, J = 6.6 Hz), 5.40 (1H, br), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 2.0 Hz), 7.42 (1H, dd, J = 2.0, 8.6 Hz), 8.08 (2H, s).
実施例51
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチルの製造:
工程1:2-[trans-4-(アミノメチル)シクロヘキシル]酢酸エチル・塩酸塩の製造
2-[trans-4-(アミノメチル)シクロヘキシル]酢酸・塩酸塩(30.0 g, 148 mmol)をエタノール(150 mL)に懸濁し、20℃以下に保ちながら塩化チオニル(26.7 g, 225 mmol)を40分間かけて滴下した後、室温にて19時間攪拌した。反応液を減圧濃縮して得られた残渣にt-ブチルメチルエーテル(150 mL)を加え、30分間攪拌した後、生じた沈殿を濾取し、40℃にて6時間減圧乾燥し、2-[trans-4-(アミノメチル)シクロヘキシル]酢酸エチル・塩酸塩(32.9 g, 94%)を灰白色固体として得た。
1H-NMR (CDCl3) δ: 0.98-1.23 (4H, m), 1.25 (3H, t, J = 7.1 Hz), 1.67-1.97 (6H, m), 2.18 (2H, d, J = 7.1 Hz), 2.84 (2H, br), 4.12 (2H, q, J = 7.1 Hz), 8.31 (3H, br). Example 51
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate preparation:
Step 1: Preparation of ethyl 2- [trans-4- (aminomethyl) cyclohexyl] acetate · hydrochloride 2- [trans-4- (aminomethyl) cyclohexyl] acetic acid · hydrochloride (30.0 g, 148 mmol) was added to ethanol ( 150 mL), thionyl chloride (26.7 g, 225 mmol) was added dropwise over 40 minutes while maintaining the temperature at 20 ° C. or lower, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, t-butyl methyl ether (150 mL) was added to the resulting residue, and the mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration and dried under reduced pressure at 40 ° C. for 6 hours. [Trans-4- (Aminomethyl) cyclohexyl] ethyl acetate hydrochloride (32.9 g, 94%) was obtained as an off-white solid.
1 H-NMR (CDCl 3 ) δ: 0.98-1.23 (4H, m), 1.25 (3H, t, J = 7.1 Hz), 1.67-1.97 (6H, m), 2.18 (2H, d, J = 7.1 Hz ), 2.84 (2H, br), 4.12 (2H, q, J = 7.1 Hz), 8.31 (3H, br).
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチルの製造:
工程1:2-[trans-4-(アミノメチル)シクロヘキシル]酢酸エチル・塩酸塩の製造
2-[trans-4-(アミノメチル)シクロヘキシル]酢酸・塩酸塩(30.0 g, 148 mmol)をエタノール(150 mL)に懸濁し、20℃以下に保ちながら塩化チオニル(26.7 g, 225 mmol)を40分間かけて滴下した後、室温にて19時間攪拌した。反応液を減圧濃縮して得られた残渣にt-ブチルメチルエーテル(150 mL)を加え、30分間攪拌した後、生じた沈殿を濾取し、40℃にて6時間減圧乾燥し、2-[trans-4-(アミノメチル)シクロヘキシル]酢酸エチル・塩酸塩(32.9 g, 94%)を灰白色固体として得た。
1H-NMR (CDCl3) δ: 0.98-1.23 (4H, m), 1.25 (3H, t, J = 7.1 Hz), 1.67-1.97 (6H, m), 2.18 (2H, d, J = 7.1 Hz), 2.84 (2H, br), 4.12 (2H, q, J = 7.1 Hz), 8.31 (3H, br). Example 51
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate preparation:
Step 1: Preparation of ethyl 2- [trans-4- (aminomethyl) cyclohexyl] acetate · hydrochloride 2- [trans-4- (aminomethyl) cyclohexyl] acetic acid · hydrochloride (30.0 g, 148 mmol) was added to ethanol ( 150 mL), thionyl chloride (26.7 g, 225 mmol) was added dropwise over 40 minutes while maintaining the temperature at 20 ° C. or lower, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, t-butyl methyl ether (150 mL) was added to the resulting residue, and the mixture was stirred for 30 minutes. The resulting precipitate was collected by filtration and dried under reduced pressure at 40 ° C. for 6 hours. [Trans-4- (Aminomethyl) cyclohexyl] ethyl acetate hydrochloride (32.9 g, 94%) was obtained as an off-white solid.
1 H-NMR (CDCl 3 ) δ: 0.98-1.23 (4H, m), 1.25 (3H, t, J = 7.1 Hz), 1.67-1.97 (6H, m), 2.18 (2H, d, J = 7.1 Hz ), 2.84 (2H, br), 4.12 (2H, q, J = 7.1 Hz), 8.31 (3H, br).
工程2:2-(trans-4-{[(4-メトキシベンジル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造
2-[trans-4-(アミノメチル)シクロヘキシル]酢酸エチル・塩酸塩(50 mg, 0.21 mmol)をジクロロエタン(0.5 mL)に溶解し、4-メトキシベンズアルデヒド(28.5 mg, 0.21 mmol)を加え、室温にて1時間攪拌した。反応液にトリアセトキシ水素化ホウ素ナトリウム(133 mg, 0.63 mmol)を加え、室温で2時間攪拌した。反応液に水を加えクロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した後、減圧濃縮した。得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)を用いて精製し、2-(trans-4-{[(4-メトキシベンジル)アミノ]メチル}シクロヘキシル)酢酸エチル(45.5 mg, 68%)を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.90-1.26 (4H, m), 1.23 (3H, t, J = 7.3 Hz), 1.60-2.03 (6H, m), 2.15 (2H, d, J = 7.1 Hz), 2.53 (2H, d, J = 6.8 Hz), 3.77 (3H, s), 3.89 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 Hz). Step 2: Preparation of 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate 2- [trans-4- (aminomethyl) cyclohexyl] ethyl acetate hydrochloride (50 mg, 0.21 mmol) was dissolved in dichloroethane (0.5 mL), 4-methoxybenzaldehyde (28.5 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (133 mg, 0.63 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid. Ethyl (45.5 mg, 68%) was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.90-1.26 (4H, m), 1.23 (3H, t, J = 7.3 Hz), 1.60-2.03 (6H, m), 2.15 (2H, d, J = 7.1 Hz ), 2.53 (2H, d, J = 6.8 Hz), 3.77 (3H, s), 3.89 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 6.88 (2H, d, J = 8.8 Hz) ), 7.42 (2H, d, J = 8.8 Hz).
2-[trans-4-(アミノメチル)シクロヘキシル]酢酸エチル・塩酸塩(50 mg, 0.21 mmol)をジクロロエタン(0.5 mL)に溶解し、4-メトキシベンズアルデヒド(28.5 mg, 0.21 mmol)を加え、室温にて1時間攪拌した。反応液にトリアセトキシ水素化ホウ素ナトリウム(133 mg, 0.63 mmol)を加え、室温で2時間攪拌した。反応液に水を加えクロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した後、減圧濃縮した。得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)を用いて精製し、2-(trans-4-{[(4-メトキシベンジル)アミノ]メチル}シクロヘキシル)酢酸エチル(45.5 mg, 68%)を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.90-1.26 (4H, m), 1.23 (3H, t, J = 7.3 Hz), 1.60-2.03 (6H, m), 2.15 (2H, d, J = 7.1 Hz), 2.53 (2H, d, J = 6.8 Hz), 3.77 (3H, s), 3.89 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.8 Hz). Step 2: Preparation of 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate 2- [trans-4- (aminomethyl) cyclohexyl] ethyl acetate hydrochloride (50 mg, 0.21 mmol) was dissolved in dichloroethane (0.5 mL), 4-methoxybenzaldehyde (28.5 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (133 mg, 0.63 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) acetic acid. Ethyl (45.5 mg, 68%) was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.90-1.26 (4H, m), 1.23 (3H, t, J = 7.3 Hz), 1.60-2.03 (6H, m), 2.15 (2H, d, J = 7.1 Hz ), 2.53 (2H, d, J = 6.8 Hz), 3.77 (3H, s), 3.89 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 6.88 (2H, d, J = 8.8 Hz) ), 7.42 (2H, d, J = 8.8 Hz).
工程3:2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチルの製造
ジアリルアミンの代わりに2-(trans-4-{[(4-メトキシベンジル)アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例39と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.82-0.98 (4H, m), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.87 (5H, m), 2.13 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.78 (2H, d, J = 6.8 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.79 (3H, s), 3.03 (2H, s), 4.10 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.77 (2H, d, J = 6.1 Hz), 5.33 (1H, t, J = 6.1 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.64 (1H, s), 8.06 (2H, s). Step 3: 2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoro Preparation of methyl) phenyl} amino] methyl} cyclohexyl) ethyl acetate As in Example 39, using 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of diallylamine. Reaction and treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.82-0.98 (4H, m), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.87 (5H, m), 2.13 (2H , d, J = 6.8 Hz), 2.20 (3H, s), 2.78 (2H, d, J = 6.8 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.79 (3H, s), 3.03 (2H , s), 4.10 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.77 (2H, d, J = 6.1 Hz), 5.33 (1H, t, J = 6.1 Hz) ), 6.81 (2H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.64 (1H, s), 8.06 (2H, s).
ジアリルアミンの代わりに2-(trans-4-{[(4-メトキシベンジル)アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例39と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.82-0.98 (4H, m), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.87 (5H, m), 2.13 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.78 (2H, d, J = 6.8 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.79 (3H, s), 3.03 (2H, s), 4.10 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.77 (2H, d, J = 6.1 Hz), 5.33 (1H, t, J = 6.1 Hz), 6.81 (2H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.64 (1H, s), 8.06 (2H, s). Step 3: 2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoro Preparation of methyl) phenyl} amino] methyl} cyclohexyl) ethyl acetate As in Example 39, using 2- (trans-4-{[(4-methoxybenzyl) amino] methyl} cyclohexyl) ethyl acetate instead of diallylamine. Reaction and treatment gave the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.82-0.98 (4H, m), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.64-1.87 (5H, m), 2.13 (2H , d, J = 6.8 Hz), 2.20 (3H, s), 2.78 (2H, d, J = 6.8 Hz), 2.85 (2H, t, J = 6.8 Hz), 3.79 (3H, s), 3.03 (2H , s), 4.10 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.77 (2H, d, J = 6.1 Hz), 5.33 (1H, t, J = 6.1 Hz) ), 6.81 (2H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 8.3 Hz), 7.64 (1H, s), 8.06 (2H, s).
実施例52
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例50と同様に反応・処理し、表題化合物を淡黄色固体として得た。
1H-NMR (CDCl3) δ: 0.88-1.04 (4H, m), 1.26 (3H, t, J = 7.3 Hz), 1.46 (1H, m), 1.67-1.85 (5H, m), 2.18 (2H, d, J = 6.8 Hz), 2.22 (3H, s), 2.87 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.1 Hz), 4.08-4.18 (4H, m), 4.54 (2H, d, J = 6.1 Hz), 5.21 (1H, t, J = 6.1 Hz), 5.38 (1H, t, J = 6.1 Hz), 6.58 (1H, d, J = 8.3Hz), 7.34 (1H. s), 7.41 (1H, d, J = 8.3 Hz), 8.06 (2H, s). Example 52
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl } Ethyl acetate production:
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of 2- (trans-4 -{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino] methyl} cyclohexyl ) The reaction and treatment were carried out in the same manner as in Example 50 using ethyl acetate to obtain the title compound as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 0.88-1.04 (4H, m), 1.26 (3H, t, J = 7.3 Hz), 1.46 (1H, m), 1.67-1.85 (5H, m), 2.18 (2H , d, J = 6.8 Hz), 2.22 (3H, s), 2.87 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.1 Hz), 4.08-4.18 (4H, m), 4.54 (2H, d, J = 6.1 Hz), 5.21 (1H, t, J = 6.1 Hz), 5.38 (1H, t, J = 6.1 Hz), 6.58 (1H, d, J = 8.3 Hz), 7.34 (1H s), 7.41 (1H, d, J = 8.3 Hz), 8.06 (2H, s).
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの製造:
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例50と同様に反応・処理し、表題化合物を淡黄色固体として得た。
1H-NMR (CDCl3) δ: 0.88-1.04 (4H, m), 1.26 (3H, t, J = 7.3 Hz), 1.46 (1H, m), 1.67-1.85 (5H, m), 2.18 (2H, d, J = 6.8 Hz), 2.22 (3H, s), 2.87 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.1 Hz), 4.08-4.18 (4H, m), 4.54 (2H, d, J = 6.1 Hz), 5.21 (1H, t, J = 6.1 Hz), 5.38 (1H, t, J = 6.1 Hz), 6.58 (1H, d, J = 8.3Hz), 7.34 (1H. s), 7.41 (1H, d, J = 8.3 Hz), 8.06 (2H, s). Example 52
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl } Ethyl acetate production:
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of 2- (trans-4 -{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino] methyl} cyclohexyl ) The reaction and treatment were carried out in the same manner as in Example 50 using ethyl acetate to obtain the title compound as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 0.88-1.04 (4H, m), 1.26 (3H, t, J = 7.3 Hz), 1.46 (1H, m), 1.67-1.85 (5H, m), 2.18 (2H , d, J = 6.8 Hz), 2.22 (3H, s), 2.87 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 6.1 Hz), 4.08-4.18 (4H, m), 4.54 (2H, d, J = 6.1 Hz), 5.21 (1H, t, J = 6.1 Hz), 5.38 (1H, t, J = 6.1 Hz), 6.58 (1H, d, J = 8.3 Hz), 7.34 (1H s), 7.41 (1H, d, J = 8.3 Hz), 8.06 (2H, s).
実施例53
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造:
工程1:2-[trans-4-({[2-クロロ-6-ホルミル-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチルの製造
3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(1.00 g, 4.60 mmol)のDMSO-水(4:1混合溶液,6.25 mL)溶液に国際公開第2004/020393号パンフレットに記載の方法により製造したtrans-{4-[(エチルアミノ)メチル]シクロヘキシル}酢酸エチル(1.334 g, 5.06 mmol)及び炭酸ナトリウム(975 mg, 9.20 mmol)を加え、90℃にて10時間攪拌した。反応液を室温まで放冷後、水を加えトルエンで抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 16:1 → 2:3)を用いて精製し、2-[trans-4-({[2-クロロ-6-ホルミル-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル(1.82 g, 91%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.82-1.02 (4H, m), 1.06 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.45 (1H, m), 1.62-1.82 (5H, m), 2.16 (2H, d, J = 6.8 Hz), 3.14 (2H, d, J = 6.6 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.79 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 2.2 Hz), 10.37 (1H, s). Example 53
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Preparation of ethyl) amino] methyl} cyclohexyl) ethyl acetate:
Step 1: Preparation of 2- [trans-4-({[2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate 3-Chloro-2-fluoro Trans- {manufactured by the method described in WO 2004/020393 to a solution of -5- (trifluoromethyl) benzaldehyde (1.00 g, 4.60 mmol) in DMSO-water (4: 1 mixed solution, 6.25 mL). 4-[(Ethylamino) methyl] cyclohexyl} ethyl acetate (1.334 g, 5.06 mmol) and sodium carbonate (975 mg, 9.20 mmol) were added, and the mixture was stirred at 90 ° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 2: 3). , Ethyl 2- [trans-4-({[2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetate (1.82 g, 91%) Got as.
1 H-NMR (CDCl 3 ) δ: 0.82-1.02 (4H, m), 1.06 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.45 (1H, m), 1.62-1.82 (5H, m), 2.16 (2H, d, J = 6.8 Hz), 3.14 (2H, d, J = 6.6 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 7.79 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 2.2 Hz), 10.37 (1H, s).
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造:
工程1:2-[trans-4-({[2-クロロ-6-ホルミル-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチルの製造
3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(1.00 g, 4.60 mmol)のDMSO-水(4:1混合溶液,6.25 mL)溶液に国際公開第2004/020393号パンフレットに記載の方法により製造したtrans-{4-[(エチルアミノ)メチル]シクロヘキシル}酢酸エチル(1.334 g, 5.06 mmol)及び炭酸ナトリウム(975 mg, 9.20 mmol)を加え、90℃にて10時間攪拌した。反応液を室温まで放冷後、水を加えトルエンで抽出した。有機層を水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 16:1 → 2:3)を用いて精製し、2-[trans-4-({[2-クロロ-6-ホルミル-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル(1.82 g, 91%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.82-1.02 (4H, m), 1.06 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.45 (1H, m), 1.62-1.82 (5H, m), 2.16 (2H, d, J = 6.8 Hz), 3.14 (2H, d, J = 6.6 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.11 (2H, q, J = 7.1 Hz), 7.79 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 2.2 Hz), 10.37 (1H, s). Example 53
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Preparation of ethyl) amino] methyl} cyclohexyl) ethyl acetate:
Step 1: Preparation of 2- [trans-4-({[2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate 3-Chloro-2-fluoro Trans- {manufactured by the method described in WO 2004/020393 to a solution of -5- (trifluoromethyl) benzaldehyde (1.00 g, 4.60 mmol) in DMSO-water (4: 1 mixed solution, 6.25 mL). 4-[(Ethylamino) methyl] cyclohexyl} ethyl acetate (1.334 g, 5.06 mmol) and sodium carbonate (975 mg, 9.20 mmol) were added, and the mixture was stirred at 90 ° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with toluene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel column chromatography (hexane: ethyl acetate = 16: 1 → 2: 3). , Ethyl 2- [trans-4-({[2-chloro-6-formyl-4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] acetate (1.82 g, 91%) Got as.
1 H-NMR (CDCl 3 ) δ: 0.82-1.02 (4H, m), 1.06 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.45 (1H, m), 1.62-1.82 (5H, m), 2.16 (2H, d, J = 6.8 Hz), 3.14 (2H, d, J = 6.6 Hz), 3.37 (2H, q, J = 7.1 Hz), 4.11 (2H, q , J = 7.1 Hz), 7.79 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 2.2 Hz), 10.37 (1H, s).
工程2:2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに工程1で製造した2-[trans-4-({[2-クロロ-6-ホルミル-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチルを用い、実施例39の工程2と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.85-1.01 (4H, m), 1.03 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.42 (1H, m), 1.58-1.82 (3H, m), 1.83-1.95 (2H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.92 (1H, dd, J = 7.3, 13.4 Hz), 3.05 (1H, dd, J = 6.8, 13.4 Hz), 3.15 (1H, qd, J = 7.1, 13.9 Hz), 3.25 (1H, dq, J = 7.1, 13.9 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.68 (1H, dd, J = 5.8, 16.1 Hz), 4.77 (1H, dd, J = 6.1, 16.1 Hz), 5.34 (1H, m), 7.49 (1H, s), 7.54 (1H, s), 8.06 (2H, s). 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--diallylamino) -5- (trifluoromethyl) benzaldehyde prepared in Step 1 instead of 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 39 to give the title compound as a pale yellow oil Got as.
1 H-NMR (CDCl 3 ) δ: 0.85-1.01 (4H, m), 1.03 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.42 (1H, m), 1.58-1.82 (3H, m), 1.83-1.95 (2H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.92 (1H, dd, J = 7.3, 13.4 Hz), 3.05 (1H, dd, J = 6.8, 13.4 Hz), 3.15 (1H, qd, J = 7.1, 13.9 Hz), 3.25 (1H, dq, J = 7.1 , 13.9 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.68 (1H, dd, J = 5.8, 16.1 Hz), 4.77 (1H, dd, J = 6.1, 16.1 Hz), 5.34 (1H, m), 7.49 (1H, s), 7.54 (1H, s), 8.06 (2H, s).
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに工程1で製造した2-[trans-4-({[2-クロロ-6-ホルミル-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチルを用い、実施例39の工程2と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.85-1.01 (4H, m), 1.03 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.42 (1H, m), 1.58-1.82 (3H, m), 1.83-1.95 (2H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.92 (1H, dd, J = 7.3, 13.4 Hz), 3.05 (1H, dd, J = 6.8, 13.4 Hz), 3.15 (1H, qd, J = 7.1, 13.9 Hz), 3.25 (1H, dq, J = 7.1, 13.9 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.68 (1H, dd, J = 5.8, 16.1 Hz), 4.77 (1H, dd, J = 6.1, 16.1 Hz), 5.34 (1H, m), 7.49 (1H, s), 7.54 (1H, s), 8.06 (2H, s). 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--diallylamino) -5- (trifluoromethyl) benzaldehyde prepared in Step 1 instead of 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 39 to give the title compound as a pale yellow oil Got as.
1 H-NMR (CDCl 3 ) δ: 0.85-1.01 (4H, m), 1.03 (3H, t, J = 7.1 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.42 (1H, m), 1.58-1.82 (3H, m), 1.83-1.95 (2H, m), 2.17 (2H, d, J = 6.8 Hz), 2.20 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 2.92 (1H, dd, J = 7.3, 13.4 Hz), 3.05 (1H, dd, J = 6.8, 13.4 Hz), 3.15 (1H, qd, J = 7.1, 13.9 Hz), 3.25 (1H, dq, J = 7.1 , 13.9 Hz), 4.11 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.68 (1H, dd, J = 5.8, 16.1 Hz), 4.77 (1H, dd, J = 6.1, 16.1 Hz), 5.34 (1H, m), 7.49 (1H, s), 7.54 (1H, s), 8.06 (2H, s).
実施例54
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンズアルデヒドの製造
2-クロロ-6-フルオロベンズアルデヒド(500 mg, 3.15 mmol)のトルエン(10 mL)溶液に国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(520 mg, 4.09 mmol)及び炭酸カリウム(1.31 g, 9.48 mmol)を加え、40時間加熱還流を行った。反応液を室温まで放冷後、水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンズアルデヒド(830 mg, 99%)を淡褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.04 (3H, t, J = 7.1 Hz), 1.07-1.17 (2H, m), 1.43-1.61 (4H, m), 1.62-1.71 (2H, m), 2.10 (1H, m), 3.06 (2H, d, J = 7.6 Hz), 3.18 (2H, q, J = 7.1 Hz), 7.03 (1H, d, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 8.1 Hz), 10.21 (1H, s). Example 54
Preparation of N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde To a solution of 2-chloro-6-fluorobenzaldehyde (500 mg, 3.15 mmol) in toluene (10 mL), WO2006 / N- (cyclopentylmethyl) -N-ethylamine (520 mg, 4.09 mmol) and potassium carbonate (1.31 g, 9.48 mmol) produced by the method described in the pamphlet of No. 0703973 were added, and the mixture was heated to reflux for 40 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde (830 mg, 99%) lightly. Obtained as a brown oil.
1 H-NMR (CDCl 3 ) δ: 1.04 (3H, t, J = 7.1 Hz), 1.07-1.17 (2H, m), 1.43-1.61 (4H, m), 1.62-1.71 (2H, m), 2.10 (1H, m), 3.06 (2H, d, J = 7.6 Hz), 3.18 (2H, q, J = 7.1 Hz), 7.03 (1H, d, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 8.1 Hz), 10.21 (1H, s).
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンズアルデヒドの製造
2-クロロ-6-フルオロベンズアルデヒド(500 mg, 3.15 mmol)のトルエン(10 mL)溶液に国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(520 mg, 4.09 mmol)及び炭酸カリウム(1.31 g, 9.48 mmol)を加え、40時間加熱還流を行った。反応液を室温まで放冷後、水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンズアルデヒド(830 mg, 99%)を淡褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.04 (3H, t, J = 7.1 Hz), 1.07-1.17 (2H, m), 1.43-1.61 (4H, m), 1.62-1.71 (2H, m), 2.10 (1H, m), 3.06 (2H, d, J = 7.6 Hz), 3.18 (2H, q, J = 7.1 Hz), 7.03 (1H, d, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 8.1 Hz), 10.21 (1H, s). Example 54
Preparation of N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde To a solution of 2-chloro-6-fluorobenzaldehyde (500 mg, 3.15 mmol) in toluene (10 mL), WO2006 / N- (cyclopentylmethyl) -N-ethylamine (520 mg, 4.09 mmol) and potassium carbonate (1.31 g, 9.48 mmol) produced by the method described in the pamphlet of No. 0703973 were added, and the mixture was heated to reflux for 40 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde (830 mg, 99%) lightly. Obtained as a brown oil.
1 H-NMR (CDCl 3 ) δ: 1.04 (3H, t, J = 7.1 Hz), 1.07-1.17 (2H, m), 1.43-1.61 (4H, m), 1.62-1.71 (2H, m), 2.10 (1H, m), 3.06 (2H, d, J = 7.6 Hz), 3.18 (2H, q, J = 7.1 Hz), 7.03 (1H, d, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.32 (1H, t, J = 8.1 Hz), 10.21 (1H, s).
工程2:N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
工程1で製造した2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンズアルデヒド(830 mg, 3.12 mmol)及び実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(560 mg, 3.02 mmol)のトルエン(20 mL)溶液に酢酸(105 mg, 1.73 mmol)を加え、Dean-Stark装置を用い8時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム(1.33 g, 6.28 mmol)を加え、室温で16時間攪拌した。反応液に水を加えクロロホルムで抽出した後、有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1 → 5:1)を用いて精製し、表題化合物(351 mg, 26%)を淡黄褐色油状物として得た。
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.10-1.21 (2H, m), 1.40-1.57 (4H, m), 1.60-1.69 (2H, m), 1.95 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.87 (2H, d, J = 7.3 Hz), 3.00 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.80 (2H, d, J = 5.1 Hz), 5.39 (1H, t, J = 5.1 Hz), 7.09 (1H, dd, J = 1.7, 7.8 Hz), 7.14 (1H, dd, J = 1.7, 7.8 Hz), 7.16 (1H, t, J = 7.8 Hz), 8.10 (2H, s). Step 2: Preparation of N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-chloro prepared in Step 1 -6-[(Cyclopentylmethyl) (ethyl) amino] benzaldehyde (830 mg, 3.12 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 3 (560 mg, 3.02 mmol) Acetic acid (105 mg, 1.73 mmol) was added to a toluene (20 mL) solution, and the mixture was heated to reflux for 8 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (1.33 g, 6.28 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 5: 1) to give the title compound (351 mg, 26%) as a pale tan oil.
1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.10-1.21 (2H, m), 1.40-1.57 (4H, m), 1.60-1.69 (2H, m), 1.95 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.87 (2H, d, J = 7.3 Hz), 3.00 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.80 (2H, d, J = 5.1 Hz), 5.39 (1H, t, J = 5.1 Hz), 7.09 (1H, dd, J = 1.7, 7.8 Hz), 7.14 (1H, dd, J = 1.7, 7.8 Hz), 7.16 (1H, t, J = 7.8 Hz), 8.10 (2H, s).
工程1で製造した2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンズアルデヒド(830 mg, 3.12 mmol)及び実施例3で製造した5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン(560 mg, 3.02 mmol)のトルエン(20 mL)溶液に酢酸(105 mg, 1.73 mmol)を加え、Dean-Stark装置を用い8時間加熱還流を行った。反応液を室温まで放冷後、氷浴中にて攪拌しつつトリアセトキシ水素化ホウ素ナトリウム(1.33 g, 6.28 mmol)を加え、室温で16時間攪拌した。反応液に水を加えクロロホルムで抽出した後、有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 20:1 → 5:1)を用いて精製し、表題化合物(351 mg, 26%)を淡黄褐色油状物として得た。
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.10-1.21 (2H, m), 1.40-1.57 (4H, m), 1.60-1.69 (2H, m), 1.95 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.87 (2H, d, J = 7.3 Hz), 3.00 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.80 (2H, d, J = 5.1 Hz), 5.39 (1H, t, J = 5.1 Hz), 7.09 (1H, dd, J = 1.7, 7.8 Hz), 7.14 (1H, dd, J = 1.7, 7.8 Hz), 7.16 (1H, t, J = 7.8 Hz), 8.10 (2H, s). Step 2: Preparation of N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-chloro prepared in Step 1 -6-[(Cyclopentylmethyl) (ethyl) amino] benzaldehyde (830 mg, 3.12 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine prepared in Example 3 (560 mg, 3.02 mmol) Acetic acid (105 mg, 1.73 mmol) was added to a toluene (20 mL) solution, and the mixture was heated to reflux for 8 hours using a Dean-Stark apparatus. The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (1.33 g, 6.28 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 5: 1) to give the title compound (351 mg, 26%) as a pale tan oil.
1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.10-1.21 (2H, m), 1.40-1.57 (4H, m), 1.60-1.69 (2H, m), 1.95 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.87 (2H, d, J = 7.3 Hz), 3.00 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.80 (2H, d, J = 5.1 Hz), 5.39 (1H, t, J = 5.1 Hz), 7.09 (1H, dd, J = 1.7, 7.8 Hz), 7.14 (1H, dd, J = 1.7, 7.8 Hz), 7.16 (1H, t, J = 7.8 Hz), 8.10 (2H, s).
実施例55
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-クロロ-6-フルオロベンズアルデヒドの代わりに2-フルオロ-6-(トリフルオロメチル)ベンズアルデヒドを用い、実施例54と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.11-1.20 (2H, m), 1.40-1.70 (6H, m), 1.95 (1H, m), 2.21 (3H, s), 2.83-2.89 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.85 (2H, d, J = 4.4 Hz), 5.44 (1H, t, J = 4.4 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz), 8.07 (2H, s). Example 55
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 54 using 2-fluoro-6- (trifluoromethyl) benzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.11-1.20 (2H, m), 1.40-1.70 (6H, m), 1.95 (1H, m), 2.21 (3H , s), 2.83-2.89 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.85 (2H, d, J = 4.4 Hz), 5.44 (1H, t, J = 4.4 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz), 8.07 (2H , s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-クロロ-6-フルオロベンズアルデヒドの代わりに2-フルオロ-6-(トリフルオロメチル)ベンズアルデヒドを用い、実施例54と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.96 (3H, t, J = 7.1 Hz), 1.11-1.20 (2H, m), 1.40-1.70 (6H, m), 1.95 (1H, m), 2.21 (3H, s), 2.83-2.89 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.85 (2H, d, J = 4.4 Hz), 5.44 (1H, t, J = 4.4 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz), 8.07 (2H, s). Example 55
Preparation of N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 54 using 2-fluoro-6- (trifluoromethyl) benzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.96 (3H, t, J = 7.1 Hz), 1.11-1.20 (2H, m), 1.40-1.70 (6H, m), 1.95 (1H, m), 2.21 (3H , s), 2.83-2.89 (4H, m), 3.01 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.8 Hz), 4.85 (2H, d, J = 4.4 Hz), 5.44 (1H, t, J = 4.4 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz), 8.07 (2H , s).
実施例56
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-クロロ-6-フルオロベンズアルデヒドの代わりに2,6-ジフルオロベンズアルデヒドを用い、実施例54と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.99 (3H, t, J = 7.1 Hz), 1.12-1.23 (2H, m), 1.40-1.61 (4H, m), 1.62-1.72 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.90 (2H, d, J = 7.1 Hz), 3.02 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.72 (2H, d, J = 4.4 Hz), 5.65 (1H, t, J = 4.4 Hz), 6.80 (1H, t, J = 8.3 Hz), 6.95 (1H, d, J = 8.3 Hz), 7.18 (1H, dt, J = 6.6, 8.3 Hz), 8.09 (2H, s). Example 56
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 54 using 2,6-difluorobenzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.1 Hz), 1.12-1.23 (2H, m), 1.40-1.61 (4H, m), 1.62-1.72 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.90 (2H, d, J = 7.1 Hz), 3.02 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.72 (2H, d, J = 4.4 Hz), 5.65 (1H, t, J = 4.4 Hz), 6.80 (1H, t, J = 8.3 Hz), 6.95 (1H , d, J = 8.3 Hz), 7.18 (1H, dt, J = 6.6, 8.3 Hz), 8.09 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-クロロ-6-フルオロベンズアルデヒドの代わりに2,6-ジフルオロベンズアルデヒドを用い、実施例54と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.99 (3H, t, J = 7.1 Hz), 1.12-1.23 (2H, m), 1.40-1.61 (4H, m), 1.62-1.72 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.90 (2H, d, J = 7.1 Hz), 3.02 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.72 (2H, d, J = 4.4 Hz), 5.65 (1H, t, J = 4.4 Hz), 6.80 (1H, t, J = 8.3 Hz), 6.95 (1H, d, J = 8.3 Hz), 7.18 (1H, dt, J = 6.6, 8.3 Hz), 8.09 (2H, s). Example 56
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 54 using 2,6-difluorobenzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.99 (3H, t, J = 7.1 Hz), 1.12-1.23 (2H, m), 1.40-1.61 (4H, m), 1.62-1.72 (2H, m), 1.99 (1H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 2.90 (2H, d, J = 7.1 Hz), 3.02 (2H, q, J = 7.1 Hz), 4.11 (2H, t, J = 6.8 Hz), 4.72 (2H, d, J = 4.4 Hz), 5.65 (1H, t, J = 4.4 Hz), 6.80 (1H, t, J = 8.3 Hz), 6.95 (1H , d, J = 8.3 Hz), 7.18 (1H, dt, J = 6.6, 8.3 Hz), 8.09 (2H, s).
実施例57
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-クロロ-6-フルオロベンズアルデヒドの代わりに2,3-ジフルオロベンズアルデヒドを用い、実施例54と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.12-1.25 (2H, m), 1.41-1.60 (4H, m), 1.62-1.72 (2H, m), 1.97 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.97 (2H, d, J = 7.3 Hz), 3.07 (2H, q, J = 7.1 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 6.0 Hz), 5.46 (1H, t, J = 6.0 Hz), 6.92 (1H, dd, J = 8.1, 12.2 Hz), 7.06 (1H, dt, J = 5.4, 8.1 Hz), 7.14 (1H, d, J = 8.1 Hz), 8.06 (2H, s). Example 57
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 54 using 2,3-difluorobenzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.12-1.25 (2H, m), 1.41-1.60 (4H, m), 1.62-1.72 (2H, m), 1.97 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.97 (2H, d, J = 7.3 Hz), 3.07 (2H, q, J = 7.1 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 6.0 Hz), 5.46 (1H, t, J = 6.0 Hz), 6.92 (1H, dd, J = 8.1, 12.2 Hz), 7.06 (1H, dt, J = 5.4, 8.1 Hz), 7.14 (1H, d, J = 8.1 Hz), 8.06 (2H, s).
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-クロロ-6-フルオロベンズアルデヒドの代わりに2,3-ジフルオロベンズアルデヒドを用い、実施例54と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.01 (3H, t, J = 7.1 Hz), 1.12-1.25 (2H, m), 1.41-1.60 (4H, m), 1.62-1.72 (2H, m), 1.97 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.97 (2H, d, J = 7.3 Hz), 3.07 (2H, q, J = 7.1 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 6.0 Hz), 5.46 (1H, t, J = 6.0 Hz), 6.92 (1H, dd, J = 8.1, 12.2 Hz), 7.06 (1H, dt, J = 5.4, 8.1 Hz), 7.14 (1H, d, J = 8.1 Hz), 8.06 (2H, s). Example 57
Production of N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to Example 54 using 2,3-difluorobenzaldehyde in place of 2-chloro-6-fluorobenzaldehyde, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.12-1.25 (2H, m), 1.41-1.60 (4H, m), 1.62-1.72 (2H, m), 1.97 (1H, m), 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 2.97 (2H, d, J = 7.3 Hz), 3.07 (2H, q, J = 7.1 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.73 (2H, d, J = 6.0 Hz), 5.46 (1H, t, J = 6.0 Hz), 6.92 (1H, dd, J = 8.1, 12.2 Hz), 7.06 (1H, dt, J = 5.4, 8.1 Hz), 7.14 (1H, d, J = 8.1 Hz), 8.06 (2H, s).
実施例58
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりにベンズアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.59 (2H, d, J = 5.8 Hz), 5.48 (1H, t, J = 5.8 Hz), 7.23-7.40 (5H, m), 8.05 (2H, s). Example 58
Preparation of N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to process 2 of example 39 using benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.59 (2H, d, J = 5.8 Hz), 5.48 (1H, t, J = 5.8 Hz), 7.23-7.40 (5H, m), 8.05 (2H, s).
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりにベンズアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を無色固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.59 (2H, d, J = 5.8 Hz), 5.48 (1H, t, J = 5.8 Hz), 7.23-7.40 (5H, m), 8.05 (2H, s). Example 58
Preparation of N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in a similar manner to process 2 of example 39 using benzaldehyde in place of 2- (diallylamino) -5- (trifluoromethyl) benzaldehyde, and the title compound was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.84 (2H, t, J = 6.6 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.59 (2H, d, J = 5.8 Hz), 5.48 (1H, t, J = 5.8 Hz), 7.23-7.40 (5H, m), 8.05 (2H, s).
実施例59
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:5-ブロモ-N-(4-メトキシベンジル)ピリミジン-2-アミンの製造
5-ブロモ-2-クロロピリミジン(300 mg, 1.55 mmol)を4-メトキシベンジルアミン(2.1 g, 15.4 mmol)に120℃にて加熱溶解し、同温にて2時間攪拌した。反応液を直接シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 30:1 → 5:1)にて精製し、5-ブロモ-N-(4-メトキシベンジル)ピリミジン-2-アミン(445.4 mg, 98%)を無色非晶質固体にて得た。
1H-NMR (CDCl3) δ: 3.80 (3H, s), 4.52 (2H, d, J = 5.4 Hz), 5.45 (1H, br), 6.87 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4Hz), 8.28 (2H, s). Example 59
Preparation of N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 5-bromo-N- (4-methoxybenzyl) pyrimidin-2-amine 5-Bromo-2-chloropyrimidine (300 mg, 1.55 mmol) was converted to 4-methoxybenzylamine (2.1 g, 15.4 mmol). The solution was heated and dissolved at 120 ° C. and stirred at the same temperature for 2 hours. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1 → 5: 1) to give 5-bromo-N- (4-methoxybenzyl) pyrimidin-2-amine (445.4 mg, 98% ) Was obtained as a colorless amorphous solid.
1 H-NMR (CDCl 3 ) δ: 3.80 (3H, s), 4.52 (2H, d, J = 5.4 Hz), 5.45 (1H, br), 6.87 (2H, d, J = 8.4 Hz), 7.24 ( 2H, d, J = 8.4Hz), 8.28 (2H, s).
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:5-ブロモ-N-(4-メトキシベンジル)ピリミジン-2-アミンの製造
5-ブロモ-2-クロロピリミジン(300 mg, 1.55 mmol)を4-メトキシベンジルアミン(2.1 g, 15.4 mmol)に120℃にて加熱溶解し、同温にて2時間攪拌した。反応液を直接シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 30:1 → 5:1)にて精製し、5-ブロモ-N-(4-メトキシベンジル)ピリミジン-2-アミン(445.4 mg, 98%)を無色非晶質固体にて得た。
1H-NMR (CDCl3) δ: 3.80 (3H, s), 4.52 (2H, d, J = 5.4 Hz), 5.45 (1H, br), 6.87 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4Hz), 8.28 (2H, s). Example 59
Preparation of N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 5-bromo-N- (4-methoxybenzyl) pyrimidin-2-amine 5-Bromo-2-chloropyrimidine (300 mg, 1.55 mmol) was converted to 4-methoxybenzylamine (2.1 g, 15.4 mmol). The solution was heated and dissolved at 120 ° C. and stirred at the same temperature for 2 hours. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1 → 5: 1) to give 5-bromo-N- (4-methoxybenzyl) pyrimidin-2-amine (445.4 mg, 98% ) Was obtained as a colorless amorphous solid.
1 H-NMR (CDCl 3 ) δ: 3.80 (3H, s), 4.52 (2H, d, J = 5.4 Hz), 5.45 (1H, br), 6.87 (2H, d, J = 8.4 Hz), 7.24 ( 2H, d, J = 8.4Hz), 8.28 (2H, s).
工程2:N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
5-ブロモ-N-(4-メトキシベンジル)ピリミジン-2-アミン(300 mg, 1.02 mmol)をトルエン(20 mL)に懸濁し、ヨウ化第一銅(200 mg, 1.05 mmol)、2-メチルチオエタノール(1.06 g, 11.5 mmol)、N,N’-ジメチルエチレンジアミン(0.83 g, 9.42 mmol)、及び炭酸セシウム(400 mg, 1.22 mmol)を加え、アルゴン雰囲気下110℃にて66時間攪拌した。反応液を直接シリカゲルカラムクロマトグラフィー(酢酸エチル)にて分離した後、シリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 1:1)にて精製し、表題化合物(172 mg)を無色非晶質固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.80 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.51 (2H, d, J = 5.9 Hz), 5.31 (1H, br), 6.86 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 8.05 (2H, s). Step 2: Preparation of N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5-Bromo-N- (4-methoxybenzyl) pyrimidin-2-amine (300 mg, 1.02 mmol) was suspended in toluene (20 mL), cuprous iodide (200 mg, 1.05 mmol), 2-methylthioethanol (1.06 g, 11.5 mmol), N, N′-dimethylethylenediamine (0.83 g, 9.42). mmol) and cesium carbonate (400 mg, 1.22 mmol) were added, and the mixture was stirred at 110 ° C. for 66 hours under an argon atmosphere. The reaction mixture was directly separated by silica gel column chromatography (ethyl acetate) and then purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (172 mg) as a colorless amorphous Obtained as a fine solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.80 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.51 ( 2H, d, J = 5.9 Hz), 5.31 (1H, br), 6.86 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 8.05 (2H, s).
5-ブロモ-N-(4-メトキシベンジル)ピリミジン-2-アミン(300 mg, 1.02 mmol)をトルエン(20 mL)に懸濁し、ヨウ化第一銅(200 mg, 1.05 mmol)、2-メチルチオエタノール(1.06 g, 11.5 mmol)、N,N’-ジメチルエチレンジアミン(0.83 g, 9.42 mmol)、及び炭酸セシウム(400 mg, 1.22 mmol)を加え、アルゴン雰囲気下110℃にて66時間攪拌した。反応液を直接シリカゲルカラムクロマトグラフィー(酢酸エチル)にて分離した後、シリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 1:1)にて精製し、表題化合物(172 mg)を無色非晶質固体として得た。
1H-NMR (CDCl3) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.80 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.51 (2H, d, J = 5.9 Hz), 5.31 (1H, br), 6.86 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 8.05 (2H, s). Step 2: Preparation of N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5-Bromo-N- (4-methoxybenzyl) pyrimidin-2-amine (300 mg, 1.02 mmol) was suspended in toluene (20 mL), cuprous iodide (200 mg, 1.05 mmol), 2-methylthioethanol (1.06 g, 11.5 mmol), N, N′-dimethylethylenediamine (0.83 g, 9.42). mmol) and cesium carbonate (400 mg, 1.22 mmol) were added, and the mixture was stirred at 110 ° C. for 66 hours under an argon atmosphere. The reaction mixture was directly separated by silica gel column chromatography (ethyl acetate) and then purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (172 mg) as a colorless amorphous Obtained as a fine solid.
1 H-NMR (CDCl 3 ) δ: 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.80 (3H, s), 4.10 (2H, t, J = 6.8 Hz), 4.51 ( 2H, d, J = 5.9 Hz), 5.31 (1H, br), 6.86 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 8.05 (2H, s).
実施例60
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミンの製造:
工程1:3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボン酸エチルの製造
3-クロロキノキサリン-2-カルボン酸エチル(267 mg, 1.13 mmol)及び国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(1.5 g, 11.8 mmol)を混合し、100℃にて30分間撹拌した。反応液を減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)にて精製し、3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボン酸エチル(290 mg, 78%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.14-1.24 (5H, m), 1.45 (3H, t, J = 7.3 Hz), 1.47-1.64 (4H, m), 1.67-1.76 (2H, m), 2.35 (1H, m), 3.47 (2H, d, J = 7.3 Hz), 3.56 (2H, q, J = 7.1 Hz), 4.50 (2H, q, J = 7.3 Hz), 7.40 (1H, ddd, J = 1.4, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.70 (1H, dd, J = 1.4, 8.3 Hz), 7.93 (1H, dd, J = 1.4, 8.3 Hz). Example 60
Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine:
Step 1: Preparation of ethyl 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carboxylate Ethyl 3-chloroquinoxaline-2-carboxylate (267 mg, 1.13 mmol) and WO 2006/079773 N- (cyclopentylmethyl) -N-ethylamine (1.5 g, 11.8 mmol) produced by the method described in 1) was mixed and stirred at 100 ° C. for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2- Ethyl carboxylate (290 mg, 78%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.14-1.24 (5H, m), 1.45 (3H, t, J = 7.3 Hz), 1.47-1.64 (4H, m), 1.67-1.76 (2H, m), 2.35 (1H, m), 3.47 (2H, d, J = 7.3 Hz), 3.56 (2H, q, J = 7.1 Hz), 4.50 (2H, q, J = 7.3 Hz), 7.40 (1H, ddd, J = 1.4, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.70 (1H, dd, J = 1.4, 8.3 Hz), 7.93 (1H, dd, J = 1.4, (8.3 Hz).
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミンの製造:
工程1:3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボン酸エチルの製造
3-クロロキノキサリン-2-カルボン酸エチル(267 mg, 1.13 mmol)及び国際公開第2006/073973号パンフレットに記載の方法により製造したN-(シクロペンチルメチル)-N-エチルアミン(1.5 g, 11.8 mmol)を混合し、100℃にて30分間撹拌した。反応液を減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)にて精製し、3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボン酸エチル(290 mg, 78%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.14-1.24 (5H, m), 1.45 (3H, t, J = 7.3 Hz), 1.47-1.64 (4H, m), 1.67-1.76 (2H, m), 2.35 (1H, m), 3.47 (2H, d, J = 7.3 Hz), 3.56 (2H, q, J = 7.1 Hz), 4.50 (2H, q, J = 7.3 Hz), 7.40 (1H, ddd, J = 1.4, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.70 (1H, dd, J = 1.4, 8.3 Hz), 7.93 (1H, dd, J = 1.4, 8.3 Hz). Example 60
Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine:
Step 1: Preparation of ethyl 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carboxylate Ethyl 3-chloroquinoxaline-2-carboxylate (267 mg, 1.13 mmol) and WO 2006/079773 N- (cyclopentylmethyl) -N-ethylamine (1.5 g, 11.8 mmol) produced by the method described in 1) was mixed and stirred at 100 ° C. for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 3: 1) to give 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2- Ethyl carboxylate (290 mg, 78%) was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.14-1.24 (5H, m), 1.45 (3H, t, J = 7.3 Hz), 1.47-1.64 (4H, m), 1.67-1.76 (2H, m), 2.35 (1H, m), 3.47 (2H, d, J = 7.3 Hz), 3.56 (2H, q, J = 7.1 Hz), 4.50 (2H, q, J = 7.3 Hz), 7.40 (1H, ddd, J = 1.4, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.70 (1H, dd, J = 1.4, 8.3 Hz), 7.93 (1H, dd, J = 1.4, (8.3 Hz).
工程2:3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボアルデヒドの製造
工程1で製造した3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボン酸エチル(247 mg, 0.75 mmol)のトルエン(3 mL)溶液に-78℃にて水素化ジイソブチルアルミニウム(0.99 mol/L トルエン溶液, 1.03 mL, 1.02 mmol)を加え、同度にて2時間攪拌した。反応液に同温にてエタノールを加えて過剰の水素化ジイソブチルアルミニウムを失活した後、室温まで上昇し、1 M塩酸を加えた。反応液をクロロホルムで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 4:1)にて精製し、3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボアルデヒド(169 mg, 79%)を黄褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.08-1.19 (2H, m), 1.23 (3H, t, J = 7.1 Hz), 1.44-1.63 (4H, m), 1.64-1.73 (2H, m), 2.32 (1H, m), 3.54 (2H, d, J = 7.6 Hz), 3.59 (2H, q, J = 7.1 Hz), 7.45 (1H, ddd, J = 1.5, 6.8, 8.3 Hz), 7.67 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.73 (1H, dd, J = 1.4, 8.3 Hz), 7.98 (1H, dd, J = 1.4, 8.3 Hz), 10.15 (1H, s). Step 2: Preparation of 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde Ethyl 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carboxylate prepared in Step 1 (247 mg , 0.75 mmol) in toluene (3 mL) was added diisobutylaluminum hydride (0.99 mol / L toluene solution, 1.03 mL, 1.02 mmol) at −78 ° C., and the mixture was stirred at the same degree for 2 hours. Ethanol was added to the reaction solution at the same temperature to deactivate excess diisobutylaluminum hydride, and then the mixture was raised to room temperature and 1 M hydrochloric acid was added. The reaction mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 4: 1) to give 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde (169 mg, 79 %) As a tan oil.
1 H-NMR (CDCl 3 ) δ: 1.08-1.19 (2H, m), 1.23 (3H, t, J = 7.1 Hz), 1.44-1.63 (4H, m), 1.64-1.73 (2H, m), 2.32 (1H, m), 3.54 (2H, d, J = 7.6 Hz), 3.59 (2H, q, J = 7.1 Hz), 7.45 (1H, ddd, J = 1.5, 6.8, 8.3 Hz), 7.67 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.73 (1H, dd, J = 1.4, 8.3 Hz), 7.98 (1H, dd, J = 1.4, 8.3 Hz), 10.15 (1H, s).
工程1で製造した3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボン酸エチル(247 mg, 0.75 mmol)のトルエン(3 mL)溶液に-78℃にて水素化ジイソブチルアルミニウム(0.99 mol/L トルエン溶液, 1.03 mL, 1.02 mmol)を加え、同度にて2時間攪拌した。反応液に同温にてエタノールを加えて過剰の水素化ジイソブチルアルミニウムを失活した後、室温まで上昇し、1 M塩酸を加えた。反応液をクロロホルムで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 4:1)にて精製し、3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボアルデヒド(169 mg, 79%)を黄褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.08-1.19 (2H, m), 1.23 (3H, t, J = 7.1 Hz), 1.44-1.63 (4H, m), 1.64-1.73 (2H, m), 2.32 (1H, m), 3.54 (2H, d, J = 7.6 Hz), 3.59 (2H, q, J = 7.1 Hz), 7.45 (1H, ddd, J = 1.5, 6.8, 8.3 Hz), 7.67 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.73 (1H, dd, J = 1.4, 8.3 Hz), 7.98 (1H, dd, J = 1.4, 8.3 Hz), 10.15 (1H, s). Step 2: Preparation of 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde Ethyl 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carboxylate prepared in Step 1 (247 mg , 0.75 mmol) in toluene (3 mL) was added diisobutylaluminum hydride (0.99 mol / L toluene solution, 1.03 mL, 1.02 mmol) at −78 ° C., and the mixture was stirred at the same degree for 2 hours. Ethanol was added to the reaction solution at the same temperature to deactivate excess diisobutylaluminum hydride, and then the mixture was raised to room temperature and 1 M hydrochloric acid was added. The reaction mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 4: 1) to give 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde (169 mg, 79 %) As a tan oil.
1 H-NMR (CDCl 3 ) δ: 1.08-1.19 (2H, m), 1.23 (3H, t, J = 7.1 Hz), 1.44-1.63 (4H, m), 1.64-1.73 (2H, m), 2.32 (1H, m), 3.54 (2H, d, J = 7.6 Hz), 3.59 (2H, q, J = 7.1 Hz), 7.45 (1H, ddd, J = 1.5, 6.8, 8.3 Hz), 7.67 (1H, ddd, J = 1.4 Hz, 6.8 Hz, 8.3 Hz), 7.73 (1H, dd, J = 1.4, 8.3 Hz), 7.98 (1H, dd, J = 1.4, 8.3 Hz), 10.15 (1H, s).
工程3:N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミンの製造
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.12-1.27 (5H, m), 1.41-1.75 (6H, m), 2.20 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.42 (2H, d, J = 7.3 Hz), 3.44 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.77 (2H, d, J = 4.4 Hz), 6.68 (1H, t, J = 4.4 Hz), 7.51 (1H, ddd, J = 1.2, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.2 Hz, 6.8 Hz, 8.3 Hz), 7.82 (1H, dd, J = 1.2, 8.3 Hz), 7.94 (1H, dd, J = 1.2, 8.3 Hz), 8.14 (2H, s). Step 3: Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine 2- (diallyl The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde in place of amino) -5- (trifluoromethyl) benzaldehyde. The compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.12-1.27 (5H, m), 1.41-1.75 (6H, m), 2.20 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.42 (2H, d, J = 7.3 Hz), 3.44 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.77 (2H, d, J = 4.4 Hz) ), 6.68 (1H, t, J = 4.4 Hz), 7.51 (1H, ddd, J = 1.2, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.2 Hz, 6.8 Hz, 8.3 Hz), 7.82 ( 1H, dd, J = 1.2, 8.3 Hz), 7.94 (1H, dd, J = 1.2, 8.3 Hz), 8.14 (2H, s).
2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの代わりに3-[(シクロペンチルメチル)(エチル)アミノ]キノキサリン-2-カルボアルデヒドを用いて実施例39の工程2と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.12-1.27 (5H, m), 1.41-1.75 (6H, m), 2.20 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.42 (2H, d, J = 7.3 Hz), 3.44 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.77 (2H, d, J = 4.4 Hz), 6.68 (1H, t, J = 4.4 Hz), 7.51 (1H, ddd, J = 1.2, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.2 Hz, 6.8 Hz, 8.3 Hz), 7.82 (1H, dd, J = 1.2, 8.3 Hz), 7.94 (1H, dd, J = 1.2, 8.3 Hz), 8.14 (2H, s). Step 3: Preparation of N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine 2- (diallyl The reaction and treatment were conducted in the same manner as in Step 2 of Example 39 using 3-[(cyclopentylmethyl) (ethyl) amino] quinoxaline-2-carbaldehyde in place of amino) -5- (trifluoromethyl) benzaldehyde. The compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.12-1.27 (5H, m), 1.41-1.75 (6H, m), 2.20 (1H, m), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 3.42 (2H, d, J = 7.3 Hz), 3.44 (2H, q, J = 7.1 Hz), 4.13 (2H, t, J = 6.6 Hz), 4.77 (2H, d, J = 4.4 Hz) ), 6.68 (1H, t, J = 4.4 Hz), 7.51 (1H, ddd, J = 1.2, 6.8, 8.3 Hz), 7.60 (1H, ddd, J = 1.2 Hz, 6.8 Hz, 8.3 Hz), 7.82 ( 1H, dd, J = 1.2, 8.3 Hz), 7.94 (1H, dd, J = 1.2, 8.3 Hz), 8.14 (2H, s).
実施例61
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:6-メトキシ-2-(メトキシメトキシ)メチル-3-(ピロリジン-1-イル)ピリジンの製造
実施例4の工程1で製造した3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン(324.6 mg, 1.24 mmol)、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)(32.7 mg, 0.03 mmol)、(2-ビフェニル)ジ-t-ブチルホスフィン(18.5 mg, 0.06 mmol)、t-ブトキシナトリウム(357 mg, 3.71 mmol)及びピロリジン(640 mg, 3.74 mmol)のトルエン(4.5 mL)溶液を135℃封管にて3時間攪拌した。反応液をクロロホルム-水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)を用いて精製し、6-メトキシ-2-(メトキシメトキシ)メチル-3-(ピロリジン-1-イル)ピリジン(42.7 mg, 14%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.88-1.98 (4H, m), 3.08-3.14 (4H, m), 3.46 (3H, s), 3.90 (3H, s), 4.70 (2H, s), 4.83 (2H, s), 6.63 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz). Example 61
Production of N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine 3-bromo-6-methoxy-2-[(methoxymethoxy) prepared in Step 1 of Example 4 ) Methyl] pyridine (324.6 mg, 1.24 mmol), Tris (dibenzylideneacetone) (chloroform) dipalladium (0) (32.7 mg, 0.03 mmol), (2-biphenyl) di-t-butylphosphine (18.5 mg, 0.06) mmol), t-butoxy sodium (357 mg, 3.71 mmol) and pyrrolidine (640 mg, 3.74 mmol) in toluene (4.5 mL) were stirred in a 135 ° C. sealed tube for 3 hours. The reaction mixture was extracted from chloroform-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (hexane: acetic acid). Purification using ethyl = 3: 1) gave 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine (42.7 mg, 14%) as a yellow oil.
1H-NMR (CDCl3) δ: 1.88-1.98 (4H, m), 3.08-3.14 (4H, m), 3.46 (3H, s), 3.90 (3H, s), 4.70 (2H, s), 4.83 (2H , s), 6.63 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz).
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
工程1:6-メトキシ-2-(メトキシメトキシ)メチル-3-(ピロリジン-1-イル)ピリジンの製造
実施例4の工程1で製造した3-ブロモ-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン(324.6 mg, 1.24 mmol)、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)(32.7 mg, 0.03 mmol)、(2-ビフェニル)ジ-t-ブチルホスフィン(18.5 mg, 0.06 mmol)、t-ブトキシナトリウム(357 mg, 3.71 mmol)及びピロリジン(640 mg, 3.74 mmol)のトルエン(4.5 mL)溶液を135℃封管にて3時間攪拌した。反応液をクロロホルム-水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー(ヘキサン:酢酸エチル = 3:1)を用いて精製し、6-メトキシ-2-(メトキシメトキシ)メチル-3-(ピロリジン-1-イル)ピリジン(42.7 mg, 14%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.88-1.98 (4H, m), 3.08-3.14 (4H, m), 3.46 (3H, s), 3.90 (3H, s), 4.70 (2H, s), 4.83 (2H, s), 6.63 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz). Example 61
Production of N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Preparation of 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine 3-bromo-6-methoxy-2-[(methoxymethoxy) prepared in Step 1 of Example 4 ) Methyl] pyridine (324.6 mg, 1.24 mmol), Tris (dibenzylideneacetone) (chloroform) dipalladium (0) (32.7 mg, 0.03 mmol), (2-biphenyl) di-t-butylphosphine (18.5 mg, 0.06) mmol), t-butoxy sodium (357 mg, 3.71 mmol) and pyrrolidine (640 mg, 3.74 mmol) in toluene (4.5 mL) were stirred in a 135 ° C. sealed tube for 3 hours. The reaction mixture was extracted from chloroform-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (hexane: acetic acid). Purification using ethyl = 3: 1) gave 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine (42.7 mg, 14%) as a yellow oil.
1H-NMR (CDCl3) δ: 1.88-1.98 (4H, m), 3.08-3.14 (4H, m), 3.46 (3H, s), 3.90 (3H, s), 4.70 (2H, s), 4.83 (2H , s), 6.63 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz).
工程2:N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミンの代わりに6-メトキシ-2-(メトキシメトキシ)メチル-3-(ピロリジン-1-イル)ピリジンを用いて、実施例4と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.92-2.01 (4H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.05-3.15 (4H, m), 3.93 (3H, s), 4.12 (2H, t, J = 6.8 Hz), 4.61 (2H, d, J = 3.9 Hz), 6,45 (1H, t, J = 3.9 Hz), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 8.13 (2H, s). Step 2: Preparation of N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine N- (cyclopentyl 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine instead of methyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine Was used in the same manner as in Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.92-2.01 (4H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.05-3.15 (4H, m), 3.93 (3H , s), 4.12 (2H, t, J = 6.8 Hz), 4.61 (2H, d, J = 3.9 Hz), 6,45 (1H, t, J = 3.9 Hz), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 8.13 (2H, s).
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-2-[(メトキシメトキシ)メチル]ピリジン-3-アミンの代わりに6-メトキシ-2-(メトキシメトキシ)メチル-3-(ピロリジン-1-イル)ピリジンを用いて、実施例4と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.92-2.01 (4H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.05-3.15 (4H, m), 3.93 (3H, s), 4.12 (2H, t, J = 6.8 Hz), 4.61 (2H, d, J = 3.9 Hz), 6,45 (1H, t, J = 3.9 Hz), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 8.13 (2H, s). Step 2: Preparation of N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine N- (cyclopentyl 6-methoxy-2- (methoxymethoxy) methyl-3- (pyrrolidin-1-yl) pyridine instead of methyl) -N-ethyl-6-methoxy-2-[(methoxymethoxy) methyl] pyridin-3-amine Was used in the same manner as in Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.92-2.01 (4H, m), 2.20 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.05-3.15 (4H, m), 3.93 (3H , s), 4.12 (2H, t, J = 6.8 Hz), 4.61 (2H, d, J = 3.9 Hz), 6,45 (1H, t, J = 3.9 Hz), 6.60 (1H, d, J = 8.6 Hz), 7.34 (1H, d, J = 8.6 Hz), 8.13 (2H, s).
実施例62
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
シクロペンタンカルボアルデヒドの代わりにアニスアルデヒドを用いて実施例4と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.92 (2H, q, J = 7.1 Hz), 3.77 (3H, s), 3.93 (3H, s), 3.95 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 4.6 Hz), 6.30 (1H, t, J = 4.6 Hz), 6.61 (1H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.39 (1H, d, J = 8.6 Hz), 8.13 (2H, s). Example 62
Production of N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Example 4 using anisaldehyde in place of cyclopentanecarbaldehyde to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.92 (2H, q, J = 7.1 Hz), 3.77 (3H, s), 3.93 (3H, s), 3.95 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 4.6 Hz), 6.30 ( 1H, t, J = 4.6 Hz), 6.61 (1H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.39 (1H, d, J = 8.6 Hz), 8.13 (2H, s).
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの製造:
シクロペンタンカルボアルデヒドの代わりにアニスアルデヒドを用いて実施例4と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.92 (2H, q, J = 7.1 Hz), 3.77 (3H, s), 3.93 (3H, s), 3.95 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 4.6 Hz), 6.30 (1H, t, J = 4.6 Hz), 6.61 (1H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.39 (1H, d, J = 8.6 Hz), 8.13 (2H, s). Example 62
Production of N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Example 4 using anisaldehyde in place of cyclopentanecarbaldehyde to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.1 Hz), 2.21 (3H, s), 2.86 (2H, t, J = 6.6 Hz), 2.92 (2H, q, J = 7.1 Hz), 3.77 (3H, s), 3.93 (3H, s), 3.95 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 4.72 (2H, d, J = 4.6 Hz), 6.30 ( 1H, t, J = 4.6 Hz), 6.61 (1H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.39 (1H, d, J = 8.6 Hz), 8.13 (2H, s).
実施例63
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.12-1.23 (5H, m), 1.40-1.62 (4H, m), 1.64-1.74 (2H, m), 2.16 (1H, m), 2.45 (3H, s), 3.26 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 3.96 (3H, s), 4.65 (2H, s), 5.61 (1H, br), 7.85 (1H, s), 8.05 (2H, s). Example 63
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Using pyridine-5-carbaldehyde and using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 6 of Example 4 The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.12-1.23 (5H, m), 1.40-1.62 (4H, m), 1.64-1.74 (2H, m), 2.16 (1H, m), 2.45 (3H, s) , 3.26 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 3.96 (3H, s), 4.65 (2H, s), 5.61 (1H, br), 7.85 (1H, s), 8.05 (2H, s).
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.12-1.23 (5H, m), 1.40-1.62 (4H, m), 1.64-1.74 (2H, m), 2.16 (1H, m), 2.45 (3H, s), 3.26 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 3.96 (3H, s), 4.65 (2H, s), 5.61 (1H, br), 7.85 (1H, s), 8.05 (2H, s). Example 63
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Using pyridine-5-carbaldehyde and using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 6 of Example 4 The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.12-1.23 (5H, m), 1.40-1.62 (4H, m), 1.64-1.74 (2H, m), 2.16 (1H, m), 2.45 (3H, s) , 3.26 (2H, q, J = 6.8 Hz), 3.27 (2H, d, J = 7.4 Hz), 3.78 (3H, s), 3.96 (3H, s), 4.65 (2H, s), 5.61 (1H, br), 7.85 (1H, s), 8.05 (2H, s).
実施例64
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.11-1.23 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.40-1.76 (6H, m), 2.16 (1H, m), 2.45 (3H, s), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 6.8 Hz), 4.65 (2H, d, J = 5.8 Hz), 5.52 (1H, t, J = 5.8 Hz), 7.85 (1H, s), 8.06 (2H, s). Example 64
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Using pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 6 of Example 4 The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.11-1.23 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.40-1.76 (6H, m), 2.16 (1H, m), 2.45 (3H , s), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 6.8 Hz), 4.65 (2H , d, J = 5.8 Hz), 5.52 (1H, t, J = 5.8 Hz), 7.85 (1H, s), 8.06 (2H, s).
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.11-1.23 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.40-1.76 (6H, m), 2.16 (1H, m), 2.45 (3H, s), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 6.8 Hz), 4.65 (2H, d, J = 5.8 Hz), 5.52 (1H, t, J = 5.8 Hz), 7.85 (1H, s), 8.06 (2H, s). Example 64
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Using pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the same reaction and treatment as in Step 6 of Example 4 The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.11-1.23 (5H, m), 1.39 (3H, t, J = 6.8 Hz), 1.40-1.76 (6H, m), 2.16 (1H, m), 2.45 (3H , s), 3.26 (2H, q, J = 7.1 Hz), 3.27 (2H, d, J = 7.3 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 6.8 Hz), 4.65 (2H , d, J = 5.8 Hz), 5.52 (1H, t, J = 5.8 Hz), 7.85 (1H, s), 8.06 (2H, s).
実施例65
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
実施例5の工程2で得られたN-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン(40.4 mg, 86 μmol)のアセトニトリル溶液(2.0 mL)にモリブデン(VI)ジクロリドジオキシド(1.7 mg, 8.6 μmol)及び30%過酸化水素水(9.7 μL, 86 μmol)を加え室温で16時間攪拌した。反応液に飽和亜硫酸ナトリウム水溶液を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール = 97:3→95:5)を用いて精製し、表題化合物(38.1 mg, 91%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1H-NMR (CDCl3) δ: 1.14-1.26 (5H, m), 1.46-1.71 (6H, m), 2.16 (1H, m), 2.46 (3H, s), 2.70 (3H, s), 2.99-3.04 (1H, m), 3.14-3.19 (1H, m), 3.24-3.29 (4H, m), 4.0 (3H, s), 4.35-4.39 (2H, m), 4.65 (2H, d, J = 5.9 Hz), 5.74 (1H, br), 7.84 (1H, s), 8.08 (2H, s). Example 65
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -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) obtained in Step 2 of Example 5 Methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine (40.4 mg, 86 μmol) in acetonitrile (2.0 mL) and molybdenum (VI) dichloride dioxide (1.7 mg, 8.6 μmol) and 30% Hydrogen peroxide water (9.7 μL, 86 μmol) was added and stirred at room temperature for 16 hours. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3 → 95: 5) to obtain the title compound (38.1 mg, 91%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1 H-NMR (CDCl 3 ) δ: 1.14-1.26 (5H, m), 1.46-1.71 (6H, m), 2.16 (1H, m), 2.46 (3H, s ), 2.70 (3H, s), 2.99-3.04 (1H, m), 3.14-3.19 (1H, m), 3.24-3.29 (4H, m), 4.0 (3H, s), 4.35-4.39 (2H, m ), 4.65 (2H, d, J = 5.9 Hz), 5.74 (1H, br), 7.84 (1H, s), 8.08 (2H, s).
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
実施例5の工程2で得られたN-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン(40.4 mg, 86 μmol)のアセトニトリル溶液(2.0 mL)にモリブデン(VI)ジクロリドジオキシド(1.7 mg, 8.6 μmol)及び30%過酸化水素水(9.7 μL, 86 μmol)を加え室温で16時間攪拌した。反応液に飽和亜硫酸ナトリウム水溶液を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール = 97:3→95:5)を用いて精製し、表題化合物(38.1 mg, 91%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1H-NMR (CDCl3) δ: 1.14-1.26 (5H, m), 1.46-1.71 (6H, m), 2.16 (1H, m), 2.46 (3H, s), 2.70 (3H, s), 2.99-3.04 (1H, m), 3.14-3.19 (1H, m), 3.24-3.29 (4H, m), 4.0 (3H, s), 4.35-4.39 (2H, m), 4.65 (2H, d, J = 5.9 Hz), 5.74 (1H, br), 7.84 (1H, s), 8.08 (2H, s). Example 65
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -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) obtained in Step 2 of Example 5 Methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine (40.4 mg, 86 μmol) in acetonitrile (2.0 mL) and molybdenum (VI) dichloride dioxide (1.7 mg, 8.6 μmol) and 30% Hydrogen peroxide water (9.7 μL, 86 μmol) was added and stirred at room temperature for 16 hours. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3 → 95: 5) to obtain the title compound (38.1 mg, 91%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1 H-NMR (CDCl 3 ) δ: 1.14-1.26 (5H, m), 1.46-1.71 (6H, m), 2.16 (1H, m), 2.46 (3H, s ), 2.70 (3H, s), 2.99-3.04 (1H, m), 3.14-3.19 (1H, m), 3.24-3.29 (4H, m), 4.0 (3H, s), 4.35-4.39 (2H, m ), 4.65 (2H, d, J = 5.9 Hz), 5.74 (1H, br), 7.84 (1H, s), 8.08 (2H, s).
実施例66
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりにN-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンを用いて実施例36と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1H-NMR (CDCl3) δ: 1.14-1.25 (5H, m), 1.47-1.69 (6H, m), 2.13-2.17 (1H, m), 2.46 (3H, s), 3.07 (3H, s), 3.22-3.25 (4H, m), 3.40-3.45 (2H, m), 4.0 (3H, s), 4.36-4.39 (2H, m), 4.65 (2H, d, J = 5.9 Hz), 5.65 (1H, br), 7.83 (1H, s), 8.10 (2H, s). Example 66
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] Preparation of pyridine-6-amine:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -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] pyridine-6- The reaction and treatment were conducted in a similar manner to Example 36 using an amine to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1 H-NMR (CDCl 3 ) δ: 1.14-1.25 (5H, m), 1.47-1.69 (6H, m), 2.13-2.17 (1H, m), 2.46 (3H , s), 3.07 (3H, s), 3.22-3.25 (4H, m), 3.40-3.45 (2H, m), 4.0 (3H, s), 4.36-4.39 (2H, m), 4.65 (2H, d , J = 5.9 Hz), 5.65 (1H, br), 7.83 (1H, s), 8.10 (2H, s).
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりにN-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンを用いて実施例36と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1H-NMR (CDCl3) δ: 1.14-1.25 (5H, m), 1.47-1.69 (6H, m), 2.13-2.17 (1H, m), 2.46 (3H, s), 3.07 (3H, s), 3.22-3.25 (4H, m), 3.40-3.45 (2H, m), 4.0 (3H, s), 4.36-4.39 (2H, m), 4.65 (2H, d, J = 5.9 Hz), 5.65 (1H, br), 7.83 (1H, s), 8.10 (2H, s). Example 66
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] Preparation of pyridine-6-amine:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -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] pyridine-6- The reaction and treatment were conducted in a similar manner to Example 36 using an amine to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1 H-NMR (CDCl 3 ) δ: 1.14-1.25 (5H, m), 1.47-1.69 (6H, m), 2.13-2.17 (1H, m), 2.46 (3H , s), 3.07 (3H, s), 3.22-3.25 (4H, m), 3.40-3.45 (2H, m), 4.0 (3H, s), 4.36-4.39 (2H, m), 4.65 (2H, d , J = 5.9 Hz), 5.65 (1H, br), 7.83 (1H, s), 8.10 (2H, s).
実施例67
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.25 (6H, t, J = 6.8 Hz), 2.49 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.93 (3H, s), 8.34 (1H, s), 10.0 (1H, s). Example 67
Preparation of 5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
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 5 to obtain 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 1.25 (6H, t, J = 6.8 Hz), 2.49 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.93 (3H, s), 8.34 ( 1H, s), 10.0 (1H, s).
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.25 (6H, t, J = 6.8 Hz), 2.49 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.93 (3H, s), 8.34 (1H, s), 10.0 (1H, s). Example 67
Preparation of 5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
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 5 to obtain 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 1.25 (6H, t, J = 6.8 Hz), 2.49 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.93 (3H, s), 8.34 ( 1H, s), 10.0 (1H, s).
工程2:5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 5.4 Hz), 5.55 (1H, br), 7.84 (1H, s), 8.06 (2H, s). Step 2: 5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Preparation 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 6 of Example 4, and the title compound Obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 5.4 Hz), 5.55 (1H, br), 7.84 (1H, s), 8.06 ( 2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 5.4 Hz), 5.55 (1H, br), 7.84 (1H, s), 8.06 (2H, s). Step 2: 5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Preparation 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 6 of Example 4, and the title compound Obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 1.40 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 5.4 Hz), 5.55 (1H, br), 7.84 (1H, s), 8.06 ( 2H, s).
実施例68
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミンの製造:
工程1:1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにピペリジンを用いて実施例5の工程1と同様に反応・処理し、1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.69-1.77 (6H, m), 2.50 (3H, s), 3.42-3.45 (4H, m), 3.94 (3H, s), 8.34 (1H, s), 10.0 (1H, s). Example 68
Preparation of N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Examples using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in the same manner as in Step 1 of 5 to give 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.69-1.77 (6H, m), 2.50 (3H, s), 3.42-3.45 (4H, m), 3.94 (3H, s), 8.34 (1H, s), 10.0 (1H, s).
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミンの製造:
工程1:1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにピペリジンを用いて実施例5の工程1と同様に反応・処理し、1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.69-1.77 (6H, m), 2.50 (3H, s), 3.42-3.45 (4H, m), 3.94 (3H, s), 8.34 (1H, s), 10.0 (1H, s). Example 68
Preparation of N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Examples using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in the same manner as in Step 1 of 5 to give 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.69-1.77 (6H, m), 2.50 (3H, s), 3.42-3.45 (4H, m), 3.94 (3H, s), 8.34 (1H, s), 10.0 (1H, s).
工程2:N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 1.63-1.75 (6H, m), 2.45 (3H, s), 3.18-3.24 (4H, m), 3.97 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.4 Hz), 5.61 (1H, br), 7.84 (1H, s), 8.06 (2H, s). Step 2: Preparation of N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine 3-[( Instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 1.63-1.75 (6H, m), 2.45 (3H, s), 3.18-3.24 (4H, m), 3.97 (3H , s), 4.0 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.4 Hz), 5.61 (1H, br), 7.84 (1H, s), 8.06 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 1.63-1.75 (6H, m), 2.45 (3H, s), 3.18-3.24 (4H, m), 3.97 (3H, s), 4.0 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.4 Hz), 5.61 (1H, br), 7.84 (1H, s), 8.06 (2H, s). Step 2: Preparation of N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine 3-[( Instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 1.63-1.75 (6H, m), 2.45 (3H, s), 3.18-3.24 (4H, m), 3.97 (3H , s), 4.0 (2H, q, J = 7.2 Hz), 4.66 (2H, d, J = 5.4 Hz), 5.61 (1H, br), 7.84 (1H, s), 8.06 (2H, s).
実施例69
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミンの製造:
工程1:1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにモルホリンを用いて実施例5の工程1と同様に反応・処理し、1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.52 (3H, s), 3.44-3.49 (4H, m), 3.89-3.93 (4H, m), 3.96 (3H, s), 8.36 (1H, s), 10.0 (1H, s). Example 69
Preparation of N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Example using morpholine instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in the same manner as in Step 1 of 5 to obtain 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.52 (3H, s), 3.44-3.49 (4H, m), 3.89-3.93 (4H, m), 3.96 (3H, s), 8.36 (1H, s), 10.0 (1H, s).
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミンの製造:
工程1:1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにモルホリンを用いて実施例5の工程1と同様に反応・処理し、1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.52 (3H, s), 3.44-3.49 (4H, m), 3.89-3.93 (4H, m), 3.96 (3H, s), 8.36 (1H, s), 10.0 (1H, s). Example 69
Preparation of N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Example using morpholine instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were conducted in the same manner as in Step 1 of 5 to obtain 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.52 (3H, s), 3.44-3.49 (4H, m), 3.89-3.93 (4H, m), 3.96 (3H, s), 8.36 (1H, s), 10.0 (1H, s).
工程2:N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.24-3.28 (4H, m), 3.84-3.89 (4H, m), 3.98 (3H, s), 4.0 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 5.4 Hz), 5.48 (1H, br), 7.89 (1H, s), 8.07 (2H, s). Step 2: Preparation of N-[(1,3-Dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine 3-[( 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.24-3.28 (4H, m), 3.84-3.89 (4H, m), 3.98 (3H , s), 4.0 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 5.4 Hz), 5.48 (1H, br), 7.89 (1H, s), 8.07 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.24-3.28 (4H, m), 3.84-3.89 (4H, m), 3.98 (3H, s), 4.0 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 5.4 Hz), 5.48 (1H, br), 7.89 (1H, s), 8.07 (2H, s). Step 2: Preparation of N-[(1,3-Dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine 3-[( 1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.24-3.28 (4H, m), 3.84-3.89 (4H, m), 3.98 (3H , s), 4.0 (2H, q, J = 6.8 Hz), 4.67 (2H, d, J = 5.4 Hz), 5.48 (1H, br), 7.89 (1H, s), 8.07 (2H, s).
実施例70
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-[ビス(シクロプロピルメチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにビス(シクロプロピルメチル)アミンを用いて実施例5の工程1と同様に反応・処理し、6-ビス(シクロプロピルメチル)アミン-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.15-0.21 (4H, m), 0.45-0.52 (4H, m), 2.50 (3H, s), 3.42-3.51 (4H, m), 3.94 (3H, s), 8.34 (1H, s), 10.1 (1H, s). Example 70
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
Step 1: Preparation of 6- [bis (cyclopropylmethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde N- (cyclopentylmethyl) -N-ethylamine Instead, bis (cyclopropylmethyl) amine was used for the reaction and treatment in the same manner as in Step 1 of Example 5, and 6-bis (cyclopropylmethyl) amine-1,3-dimethyl-1H-pyrazolo [3,4 b] Pyridine-5-carbaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.15-0.21 (4H, m), 0.45-0.52 (4H, m), 2.50 (3H, s), 3.42-3.51 (4H, m), 3.94 (3H, s) , 8.34 (1H, s), 10.1 (1H, s).
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-[ビス(シクロプロピルメチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにビス(シクロプロピルメチル)アミンを用いて実施例5の工程1と同様に反応・処理し、6-ビス(シクロプロピルメチル)アミン-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.15-0.21 (4H, m), 0.45-0.52 (4H, m), 2.50 (3H, s), 3.42-3.51 (4H, m), 3.94 (3H, s), 8.34 (1H, s), 10.1 (1H, s). Example 70
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amine production:
Step 1: Preparation of 6- [bis (cyclopropylmethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde N- (cyclopentylmethyl) -N-ethylamine Instead, bis (cyclopropylmethyl) amine was used for the reaction and treatment in the same manner as in Step 1 of Example 5, and 6-bis (cyclopropylmethyl) amine-1,3-dimethyl-1H-pyrazolo [3,4 b] Pyridine-5-carbaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.15-0.21 (4H, m), 0.45-0.52 (4H, m), 2.50 (3H, s), 3.42-3.51 (4H, m), 3.94 (3H, s) , 8.34 (1H, s), 10.1 (1H, s).
工程2:N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[ビス(シクロプロピルメチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.11-0.22 (4H, m), 0.41-0.52 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.19-3.24 (4H, m), 3.94-3.99 (5H, m), 4.70 (2H, d, J = 5.4 Hz), 5.80 (1H, br), 7.87 (1H, s), 8.05 (2H, s). Step 2: N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Preparation of 6-amine 6- [bis (cyclopropylmethyl) amino] -1,3-dimethyl-1H-pyrazolo [3 instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde , 4-b] pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.11-0.22 (4H, m), 0.41-0.52 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.19-3.24 (4H, m), 3.94-3.99 (5H, m), 4.70 (2H, d, J = 5.4 Hz), 5.80 (1H, br), 7.87 (1H, s), 8.05 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[ビス(シクロプロピルメチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.11-0.22 (4H, m), 0.41-0.52 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.19-3.24 (4H, m), 3.94-3.99 (5H, m), 4.70 (2H, d, J = 5.4 Hz), 5.80 (1H, br), 7.87 (1H, s), 8.05 (2H, s). Step 2: N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine Preparation of 6-amine 6- [bis (cyclopropylmethyl) amino] -1,3-dimethyl-1H-pyrazolo [3 instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde , 4-b] pyridine-5-carbaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.11-0.22 (4H, m), 0.41-0.52 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 2.47 (3H, s), 3.19-3.24 (4H, m), 3.94-3.99 (5H, m), 4.70 (2H, d, J = 5.4 Hz), 5.80 (1H, br), 7.87 (1H, s), 8.05 (2H, s).
実施例71
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-[ベンジル(メチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにN-ベンジル-N-メチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-[ベンジル(メチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.51 (3H, s), 3.06 (3H, s), 3.91 (3H, s), 4.79 (2H, s), 7.34 (5H, m), 8.35 (1H, s), 10.0 (1H, s). Example 71
Preparation of N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were carried out using N-benzyl-N-methylamine in the same manner as in Step 1 of Example 5, and 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b Pyridine-5-carbaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.51 (3H, s), 3.06 (3H, s), 3.91 (3H, s), 4.79 (2H, s), 7.34 (5H, m), 8.35 (1H, s ), 10.0 (1H, s).
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-[ベンジル(メチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにN-ベンジル-N-メチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-[ベンジル(メチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.51 (3H, s), 3.06 (3H, s), 3.91 (3H, s), 4.79 (2H, s), 7.34 (5H, m), 8.35 (1H, s), 10.0 (1H, s). Example 71
Preparation of N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Instead of N- (cyclopentylmethyl) -N-ethylamine The reaction and treatment were carried out using N-benzyl-N-methylamine in the same manner as in Step 1 of Example 5, and 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b Pyridine-5-carbaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.51 (3H, s), 3.06 (3H, s), 3.91 (3H, s), 4.79 (2H, s), 7.34 (5H, m), 8.35 (1H, s ), 10.0 (1H, s).
工程2:N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[ベンジル(メチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.44 (3H, s), 2.88 (3H, s), 3.72 (3H, s), 3.96 (3H, s), 4.49 (2H, s), 4.70 (2H, d, J = 5.4 Hz), 5.80 (1H, br), 7.23 (1H, dd, J = 7.7 Hz), 7.30 (2H, dd, J = 7.7 Hz), 7.40 (2H, d, J = 7.7 Hz), 7.87 (1H, s), 7.98 (2H, s). Step 2: N-Benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Preparation 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- Using 5-carbaldehyde, reacting and treating in the same manner as in Step 6 of Example 4 using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.44 (3H, s), 2.88 (3H, s), 3.72 (3H, s), 3.96 (3H, s), 4.49 (2H, s), 4.70 (2H, d , J = 5.4 Hz), 5.80 (1H, br), 7.23 (1H, dd, J = 7.7 Hz), 7.30 (2H, dd, J = 7.7 Hz), 7.40 (2H, d, J = 7.7 Hz), 7.87 (1H, s), 7.98 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[ベンジル(メチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.44 (3H, s), 2.88 (3H, s), 3.72 (3H, s), 3.96 (3H, s), 4.49 (2H, s), 4.70 (2H, d, J = 5.4 Hz), 5.80 (1H, br), 7.23 (1H, dd, J = 7.7 Hz), 7.30 (2H, dd, J = 7.7 Hz), 7.40 (2H, d, J = 7.7 Hz), 7.87 (1H, s), 7.98 (2H, s). Step 2: N-Benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Preparation 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 6- [benzyl (methyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine- Using 5-carbaldehyde, reacting and treating in the same manner as in Step 6 of Example 4 using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, The title compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.44 (3H, s), 2.88 (3H, s), 3.72 (3H, s), 3.96 (3H, s), 4.49 (2H, s), 4.70 (2H, d , J = 5.4 Hz), 5.80 (1H, br), 7.23 (1H, dd, J = 7.7 Hz), 7.30 (2H, dd, J = 7.7 Hz), 7.40 (2H, d, J = 7.7 Hz), 7.87 (1H, s), 7.98 (2H, s).
実施例72
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジメチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 3.15 (6H, s), 3.92 (3H, s), 8.29 (1H, s), 9.99 (1H, s). Example 72
Preparation of 5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- (dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Dimethylamine instead of N- (cyclopentylmethyl) -N-ethylamine Using 6- (dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. Got as.
1 H-NMR (CDCl 3 ) δ: 2.50 (3H, s), 3.15 (6H, s), 3.92 (3H, s), 8.29 (1H, s), 9.99 (1H, s).
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジメチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 3.15 (6H, s), 3.92 (3H, s), 8.29 (1H, s), 9.99 (1H, s). Example 72
Preparation of 5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- (dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Dimethylamine instead of N- (cyclopentylmethyl) -N-ethylamine Using 6- (dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. Got as.
1 H-NMR (CDCl 3 ) δ: 2.50 (3H, s), 3.15 (6H, s), 3.92 (3H, s), 8.29 (1H, s), 9.99 (1H, s).
工程2:5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.45 (3H, s), 2.97 (6H, s), 3.81 (3H, s), 3.97 (3H, s), 4.68 (2H, d, J = 5.4 Hz), 5.43 (1H, br), 7.83 (1H, s), 8.08 (2H, s). Step 2: Preparation of 5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine 6- (Dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde And using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was conducted in the same manner as in Step 6 of Example 4. Obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.45 (3H, s), 2.97 (6H, s), 3.81 (3H, s), 3.97 (3H, s), 4.68 (2H, d, J = 5.4 Hz), 5.43 (1H, br), 7.83 (1H, s), 8.08 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.45 (3H, s), 2.97 (6H, s), 3.81 (3H, s), 3.97 (3H, s), 4.68 (2H, d, J = 5.4 Hz), 5.43 (1H, br), 7.83 (1H, s), 8.08 (2H, s). Step 2: Preparation of 5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine 6- (Dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde And using 5-methoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was conducted in the same manner as in Step 6 of Example 4. Obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.45 (3H, s), 2.97 (6H, s), 3.81 (3H, s), 3.97 (3H, s), 4.68 (2H, d, J = 5.4 Hz), 5.43 (1H, br), 7.83 (1H, s), 8.08 (2H, s).
実施例73
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 2.20 (3H, s), 2.46 (3H, s), 2.85 (2H, d, J = 6.6 Hz), 3.31 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.12 (2H, d, J = 6.6 Hz), 4.61-4.65 (2H, m), 5.57 (1H, br), 7.84 (1H, s), 8.09 (2H, s). Example 73
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- Production of 6-amine:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. Was used and reacted in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 2.20 (3H, s), 2.46 (3H, s), 2.85 (2H, d, J = 6.6 Hz), 3.31 ( 4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.12 (2H, d, J = 6.6 Hz), 4.61-4.65 (2H, m), 5.57 (1H, br), 7.84 (1H, s ), 8.09 (2H, s).
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 2.20 (3H, s), 2.46 (3H, s), 2.85 (2H, d, J = 6.6 Hz), 3.31 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.12 (2H, d, J = 6.6 Hz), 4.61-4.65 (2H, m), 5.57 (1H, br), 7.84 (1H, s), 8.09 (2H, s). Example 73
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- Production of 6-amine:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. Was used and reacted in the same manner as in Step 6 of Example 4 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 2.20 (3H, s), 2.46 (3H, s), 2.85 (2H, d, J = 6.6 Hz), 3.31 ( 4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.12 (2H, d, J = 6.6 Hz), 4.61-4.65 (2H, m), 5.57 (1H, br), 7.84 (1H, s ), 8.09 (2H, s).
実施例74
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの代わりにN,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンを用いて実施例65と同様に反応・処理し、表題化合物を各々淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 2.46 (3H, s), 2.69 (3H, s), 3.00-3.05 (1H, m), 3.11-3.15 (1H, m), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.33-4.38 (2H, m), 4.61-4.65 (2H, m), 5.88 (1H, br), 7.84 (1H, s), 8.07 (2H, s). Example 74
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -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, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H instead of pyridine-6-amine -Pyrazolo [3,4-b] pyridin-6-amine was used for the reaction and treatment in the same manner as in Example 65 to obtain the title compounds as pale yellow oils.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 2.46 (3H, s), 2.69 (3H, s), 3.00-3.05 (1H, m), 3.11-3.15 (1H , m), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.33-4.38 (2H, m), 4.61-4.65 (2H, m), 5.88 (1H, br), 7.84 ( 1H, s), 8.07 (2H, s).
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの代わりにN,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンを用いて実施例65と同様に反応・処理し、表題化合物を各々淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 2.46 (3H, s), 2.69 (3H, s), 3.00-3.05 (1H, m), 3.11-3.15 (1H, m), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.33-4.38 (2H, m), 4.61-4.65 (2H, m), 5.88 (1H, br), 7.84 (1H, s), 8.07 (2H, s). Example 74
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -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, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H instead of pyridine-6-amine -Pyrazolo [3,4-b] pyridin-6-amine was used for the reaction and treatment in the same manner as in Example 65 to obtain the title compounds as pale yellow oils.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 2.46 (3H, s), 2.69 (3H, s), 3.00-3.05 (1H, m), 3.11-3.15 (1H , m), 3.32 (4H, q, J = 6.8 Hz), 3.96 (3H, s), 4.33-4.38 (2H, m), 4.61-4.65 (2H, m), 5.88 (1H, br), 7.84 ( 1H, s), 8.07 (2H, s).
実施例75
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりにN,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンを用いて実施例36と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 2.43 (3H, s), 3.06 (3H, s), 3.31 (4H, q, J = 6.8 Hz), 3.39-3.43 (2H, m), 3.96 (3H, s), 4.34-4.39 (2H, m), 4.61-4.66 (2H, m), 5.81 (1H, br), 7.83 (1H, s), 8.08 (2H, s). Example 75
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine Production of -6-amine:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of N, N-diethyl-1 , 3-Dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 2.43 (3H, s), 3.06 (3H, s), 3.31 (4H, q, J = 6.8 Hz), 3.39- 3.43 (2H, m), 3.96 (3H, s), 4.34-4.39 (2H, m), 4.61-4.66 (2H, m), 5.81 (1H, br), 7.83 (1H, s), 8.08 (2H, s).
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりにN,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンを用いて実施例36と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 6.8 Hz), 2.43 (3H, s), 3.06 (3H, s), 3.31 (4H, q, J = 6.8 Hz), 3.39-3.43 (2H, m), 3.96 (3H, s), 4.34-4.39 (2H, m), 4.61-4.66 (2H, m), 5.81 (1H, br), 7.83 (1H, s), 8.08 (2H, s). Example 75
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine Production of -6-amine:
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine instead of N, N-diethyl-1 , 3-Dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine Reaction and treatment were conducted in the same manner as in Example 36 to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 6.8 Hz), 2.43 (3H, s), 3.06 (3H, s), 3.31 (4H, q, J = 6.8 Hz), 3.39- 3.43 (2H, m), 3.96 (3H, s), 4.34-4.39 (2H, m), 4.61-4.66 (2H, m), 5.81 (1H, br), 7.83 (1H, s), 8.08 (2H, s).
実施例76
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.38 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.97 (6H, s), 3.91-3.98 (5H, m), 4.62-4.68 (2H, m), 5.78 (1H, br), 7.83 (1H, s), 8.01 (2H, s). Example 76
Preparation of 5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
6- (Dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 6 of Example 4, and the title compound Obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.38 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.97 (6H, s), 3.91-3.98 (5H, m), 4.62-4.68 (2H m), 5.78 (1H, br), 7.83 (1H, s), 8.01 (2H, s).
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジメチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.38 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.97 (6H, s), 3.91-3.98 (5H, m), 4.62-4.68 (2H, m), 5.78 (1H, br), 7.83 (1H, s), 8.01 (2H, s). Example 76
Preparation of 5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
6- (Dimethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 6 of Example 4, and the title compound Obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.38 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 2.97 (6H, s), 3.91-3.98 (5H, m), 4.62-4.68 (2H m), 5.78 (1H, br), 7.83 (1H, s), 8.01 (2H, s).
実施例77
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造:
工程1:2-(trans-4-{[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりに国際公開第2004/020393号パンフレットに記載の方法により製造したtrans-{4-[(エチルアミノ)メチル]シクロヘキシル}酢酸エチルを用いて実施例5の工程1と同様に反応・処理し、2-(trans-4-{[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]メチル}シクロヘキシル)酢酸エチルを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.96 (4H, m), 1.19-1.26 (6H, m), 1.73-1.79 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.50 (3H, s), 3.36 (2H, q, J = 7.2 Hz), 3.47 (2H, d, J = 6.8 Hz), 3.92 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 8.33 (1H, s), 9.99 (1H, s). Example 77
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] Preparation of Pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
Step 1: Preparation of 2- (trans-4-{[ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl} cyclohexyl) ethyl acetate Example 5 using trans- {4-[(ethylamino) methyl] cyclohexyl} ethyl acetate prepared by the method described in WO 2004/020393 instead of N- (cyclopentylmethyl) -N-ethylamine 2- (trans-4-{[ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl} cyclohexyl) ethyl acetate was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.88-0.96 (4H, m), 1.19-1.26 (6H, m), 1.73-1.79 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.50 (3H, s), 3.36 (2H, q, J = 7.2 Hz), 3.47 (2H, d, J = 6.8 Hz), 3.92 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 8.33 (1H, s), 9.99 (1H, s).
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造:
工程1:2-(trans-4-{[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりに国際公開第2004/020393号パンフレットに記載の方法により製造したtrans-{4-[(エチルアミノ)メチル]シクロヘキシル}酢酸エチルを用いて実施例5の工程1と同様に反応・処理し、2-(trans-4-{[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]メチル}シクロヘキシル)酢酸エチルを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.96 (4H, m), 1.19-1.26 (6H, m), 1.73-1.79 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.50 (3H, s), 3.36 (2H, q, J = 7.2 Hz), 3.47 (2H, d, J = 6.8 Hz), 3.92 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 8.33 (1H, s), 9.99 (1H, s). Example 77
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] Preparation of Pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate:
Step 1: Preparation of 2- (trans-4-{[ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl} cyclohexyl) ethyl acetate Example 5 using trans- {4-[(ethylamino) methyl] cyclohexyl} ethyl acetate prepared by the method described in WO 2004/020393 instead of N- (cyclopentylmethyl) -N-ethylamine 2- (trans-4-{[ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] Methyl} cyclohexyl) ethyl acetate was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.88-0.96 (4H, m), 1.19-1.26 (6H, m), 1.73-1.79 (6H, m), 2.14 (2H, d, J = 6.3 Hz), 2.50 (3H, s), 3.36 (2H, q, J = 7.2 Hz), 3.47 (2H, d, J = 6.8 Hz), 3.92 (3H, s), 4.10 (2H, q, J = 7.2 Hz), 8.33 (1H, s), 9.99 (1H, s).
工程2:2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(trans-4-{[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.95 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.72-1.86 (6H, m), 2.13 (2H, d, J = 6.3 Hz), 2.20 (3H, s), 2.45 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.19-3.23 (4H, m), 3.95 (3H, s), 4.08-4.13 (4H, m), 4.63 (2H, d, J = 5.9 Hz), 5.54 (1H, br), 7.84 (1H, s), 8.07 (2H, s). 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 of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (trans- 4-{[Ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl} cyclohexyl) ethyl acetate using ethyl acetate The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.88-0.95 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.72-1.86 (6H, m ), 2.13 (2H, d, J = 6.3 Hz), 2.20 (3H, s), 2.45 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.19-3.23 (4H, m), 3.95 (3H, s), 4.08-4.13 (4H, m), 4.63 (2H, d, J = 5.9 Hz), 5.54 (1H, br), 7.84 (1H, s), 8.07 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(trans-4-{[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.88-0.95 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.72-1.86 (6H, m), 2.13 (2H, d, J = 6.3 Hz), 2.20 (3H, s), 2.45 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.19-3.23 (4H, m), 3.95 (3H, s), 4.08-4.13 (4H, m), 4.63 (2H, d, J = 5.9 Hz), 5.54 (1H, br), 7.84 (1H, s), 8.07 (2H, s). 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 of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (trans- 4-{[Ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] methyl} cyclohexyl) ethyl acetate using ethyl acetate The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 0.88-0.95 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.72-1.86 (6H, m ), 2.13 (2H, d, J = 6.3 Hz), 2.20 (3H, s), 2.45 (3H, s), 2.85 (2H, t, J = 6.8 Hz), 3.19-3.23 (4H, m), 3.95 (3H, s), 4.08-4.13 (4H, m), 4.63 (2H, d, J = 5.9 Hz), 5.54 (1H, br), 7.84 (1H, s), 8.07 (2H, s).
実施例78
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸の製造:
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの代わりに2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例33と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.93 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.52-1.82 (6H, m), 2.18 (5H, m), 2.44 (3H, s), 2.84 (2H, dd, J = 6.8 Hz), 3.20 (4H, m), 3.94 (3H, s), 4.10 (2H, dd, J = 6.8 Hz), 4.62 (2H, m), 6.23 (1H, br), 7.84 (1H, s), 8.07 (2H, s). Example 78
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] Preparation of Pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] 2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H instead of cyclohexyl} ethyl acetate -Pyrazolo [3,4-b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate was reacted and treated in the same manner as in Example 33 to obtain the title compound as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 0.93 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.52-1.82 (6H, m), 2.18 (5H, m), 2.44 (3H, s ), 2.84 (2H, dd, J = 6.8 Hz), 3.20 (4H, m), 3.94 (3H, s), 4.10 (2H, dd, J = 6.8 Hz), 4.62 (2H, m), 6.23 (1H , br), 7.84 (1H, s), 8.07 (2H, s).
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸の製造:
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチルの代わりに2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチルを用いて実施例33と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 0.93 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.52-1.82 (6H, m), 2.18 (5H, m), 2.44 (3H, s), 2.84 (2H, dd, J = 6.8 Hz), 3.20 (4H, m), 3.94 (3H, s), 4.10 (2H, dd, J = 6.8 Hz), 4.62 (2H, m), 6.23 (1H, br), 7.84 (1H, s), 8.07 (2H, s). Example 78
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] Preparation of Pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) acetic acid:
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] 2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H instead of cyclohexyl} ethyl acetate -Pyrazolo [3,4-b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate was reacted and treated in the same manner as in Example 33 to obtain the title compound as a pale yellow oil. .
1 H-NMR (CDCl 3 ) δ: 0.93 (4H, m), 1.14 (3H, t, J = 7.2 Hz), 1.52-1.82 (6H, m), 2.18 (5H, m), 2.44 (3H, s ), 2.84 (2H, dd, J = 6.8 Hz), 3.20 (4H, m), 3.94 (3H, s), 4.10 (2H, dd, J = 6.8 Hz), 4.62 (2H, m), 6.23 (1H , br), 7.84 (1H, s), 8.07 (2H, s).
実施例79
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:1,3-ジメチル-6-ピロリジン-1-イル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにピロリジンを用いて実施例5の工程1と同様に反応・処理し、1,3-ジメチル-6-ピロリジン-1-イル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.99 (4H, m), 2.49 (3H, s), 3.63 (4H, m), 3.90 (3H, s), 8.25 (1H, s), 10.0 (1H, s). Example 79
Production of N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Pyrrolidine instead of N- (cyclopentylmethyl) -N-ethylamine Using 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. Obtained as a thing.
1 H-NMR (CDCl 3 ) δ: 1.99 (4H, m), 2.49 (3H, s), 3.63 (4H, m), 3.90 (3H, s), 8.25 (1H, s), 10.0 (1H, s ).
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:1,3-ジメチル-6-ピロリジン-1-イル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにピロリジンを用いて実施例5の工程1と同様に反応・処理し、1,3-ジメチル-6-ピロリジン-1-イル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.99 (4H, m), 2.49 (3H, s), 3.63 (4H, m), 3.90 (3H, s), 8.25 (1H, s), 10.0 (1H, s). Example 79
Production of N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Pyrrolidine instead of N- (cyclopentylmethyl) -N-ethylamine Using 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde as a pale yellow oil. Obtained as a thing.
1 H-NMR (CDCl 3 ) δ: 1.99 (4H, m), 2.49 (3H, s), 3.63 (4H, m), 3.90 (3H, s), 8.25 (1H, s), 10.0 (1H, s ).
工程2:N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに1,3-ジメチル-6-ピロリジン-1-イル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 6.8 Hz), 1.94 (4H, m), 2.43 (3H, s), 3.66 (4H, m), 3.90 (3H, s), 3.98 (2H, q, J = 6.8 Hz), 4.64 (2H, m), 5.29 (1H, br), 7.72 (1H, s), 8.02 (2H, s). Step 2: N-{[1,3-Dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine Preparation of 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5 -Carboxaldehyde was used and reacted and treated in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine. The compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 6.8 Hz), 1.94 (4H, m), 2.43 (3H, s), 3.66 (4H, m), 3.90 (3H, s), 3.98 (2H, q, J = 6.8 Hz), 4.64 (2H, m), 5.29 (1H, br), 7.72 (1H, s), 8.02 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに1,3-ジメチル-6-ピロリジン-1-イル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 6.8 Hz), 1.94 (4H, m), 2.43 (3H, s), 3.66 (4H, m), 3.90 (3H, s), 3.98 (2H, q, J = 6.8 Hz), 4.64 (2H, m), 5.29 (1H, br), 7.72 (1H, s), 8.02 (2H, s). Step 2: N-{[1,3-Dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine Preparation of 3-[(Cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 1,3-dimethyl-6-pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-5 -Carboxaldehyde was used and reacted and treated in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine. The compound was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 6.8 Hz), 1.94 (4H, m), 2.43 (3H, s), 3.66 (4H, m), 3.90 (3H, s), 3.98 (2H, q, J = 6.8 Hz), 4.64 (2H, m), 5.29 (1H, br), 7.72 (1H, s), 8.02 (2H, s).
実施例80
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミンの製造:
工程1:6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(300 mg, 1.43 mmol)及び水酸化カリウム(120.4 mg, 2.15 mmol)のメタノール(3.0 mL)溶液を2時間加熱還流した後、室温まで放冷した。水(20 mL)を加えて析出した固体を濾取し、水で洗浄して6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(263.8 mg, 90%)を白色固体として得た。
1H-NMR (CDCl3) δ: 2.52 (3H, s), 3.98 (3H, s), 4.14 (3H, s), 8.46 (1H, s), 10.4 (1H, s). Example 80
Preparation of 5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine:
Step 1: Preparation of 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b A solution of pyridine-5-carbaldehyde (300 mg, 1.43 mmol) and potassium hydroxide (120.4 mg, 2.15 mmol) in methanol (3.0 mL) was heated to reflux for 2 hours and then allowed to cool to room temperature. Water (20 mL) was added and the precipitated solid was collected by filtration, washed with water and washed with 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (263.8 mg). , 90%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 2.52 (3H, s), 3.98 (3H, s), 4.14 (3H, s), 8.46 (1H, s), 10.4 (1H, s).
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミンの製造:
工程1:6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(300 mg, 1.43 mmol)及び水酸化カリウム(120.4 mg, 2.15 mmol)のメタノール(3.0 mL)溶液を2時間加熱還流した後、室温まで放冷した。水(20 mL)を加えて析出した固体を濾取し、水で洗浄して6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒド(263.8 mg, 90%)を白色固体として得た。
1H-NMR (CDCl3) δ: 2.52 (3H, s), 3.98 (3H, s), 4.14 (3H, s), 8.46 (1H, s), 10.4 (1H, s). Example 80
Preparation of 5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine:
Step 1: Preparation of 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde 6-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b A solution of pyridine-5-carbaldehyde (300 mg, 1.43 mmol) and potassium hydroxide (120.4 mg, 2.15 mmol) in methanol (3.0 mL) was heated to reflux for 2 hours and then allowed to cool to room temperature. Water (20 mL) was added and the precipitated solid was collected by filtration, washed with water and washed with 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde (263.8 mg). , 90%) as a white solid.
1 H-NMR (CDCl 3 ) δ: 2.52 (3H, s), 3.98 (3H, s), 4.14 (3H, s), 8.46 (1H, s), 10.4 (1H, s).
工程2:5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.46 (3H, s), 3.79 (3H, s), 3.95 (3H, s), 4.07 (3H, s), 4.58 (2H, m), 5.42 (1H, br), 7.81 (1H, s), 8.06 (2H, s).
実施例81
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチルの製造:
工程1:4-[(2-ヘキサアミドピリミジン-5-イル)オキシ]酪酸エチルの製造
実施例3の工程2の方法により製造したN-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(3.0 g,14.3 mmol)のN,N-ジメチルホルムアミド(15 mL)溶液に4-ブロモ酪酸エチル(3.35 g,17.2 mmol)、炭酸カリウム(3.0 g,21.5 mmol)加え、60℃で16時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し、4-[(2-ヘキサンアミドピリミジン-5-イル)オキシ]酪酸エチル(5.06 g,粗生成物)を得た。
1H-NMR (CDCl3) δ: 0.91 (3H, br), 1.25-1.37 (7H, m), 1.73 (2H, br), 2.14-2.15 (2H, m), 2.50-2.62 (4H, m), 4.09-4.17 (4H, m), 8.28-8.36 (3H, m). Step 2: Preparation of 5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine 3-[( Instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-methoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.46 (3H, s), 3.79 (3H, s), 3.95 (3H, s), 4.07 (3H, s), 4.58 (2H, m), 5.42 (1H, br ), 7.81 (1H, s), 8.06 (2H, s).
Example 81
Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate:
Step 1: Preparation of ethyl 4-[(2-hexamidopyrimidin-5-yl) oxy] butyrate N- (5-hydroxypyrimidin-2-yl) hexanamide (3.0) prepared by the method of Step 2 of Example 3 g, 14.3 mmol) in N, N-dimethylformamide (15 mL) was added ethyl 4-bromobutyrate (3.35 g, 17.2 mmol) and potassium carbonate (3.0 g, 21.5 mmol), and the mixture was stirred at 60 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-[(2-hexaneamidopyrimidin-5-yl) oxy. ] Ethyl butyrate (5.06 g, crude product) was obtained.
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, br), 1.25-1.37 (7H, m), 1.73 (2H, br), 2.14-2.15 (2H, m), 2.50-2.62 (4H, m) , 4.09-4.17 (4H, m), 8.28-8.36 (3H, m).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-メトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.46 (3H, s), 3.79 (3H, s), 3.95 (3H, s), 4.07 (3H, s), 4.58 (2H, m), 5.42 (1H, br), 7.81 (1H, s), 8.06 (2H, s).
実施例81
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチルの製造:
工程1:4-[(2-ヘキサアミドピリミジン-5-イル)オキシ]酪酸エチルの製造
実施例3の工程2の方法により製造したN-(5-ヒドロキシピリミジン-2-イル)ヘキサンアミド(3.0 g,14.3 mmol)のN,N-ジメチルホルムアミド(15 mL)溶液に4-ブロモ酪酸エチル(3.35 g,17.2 mmol)、炭酸カリウム(3.0 g,21.5 mmol)加え、60℃で16時間攪拌した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し、4-[(2-ヘキサンアミドピリミジン-5-イル)オキシ]酪酸エチル(5.06 g,粗生成物)を得た。
1H-NMR (CDCl3) δ: 0.91 (3H, br), 1.25-1.37 (7H, m), 1.73 (2H, br), 2.14-2.15 (2H, m), 2.50-2.62 (4H, m), 4.09-4.17 (4H, m), 8.28-8.36 (3H, m). Step 2: Preparation of 5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine 3-[( Instead of cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde was used, and 5- [2 The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-methoxypyrimidin-2-amine in place of-(methylthio) ethoxy] pyrimidin-2-amine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.46 (3H, s), 3.79 (3H, s), 3.95 (3H, s), 4.07 (3H, s), 4.58 (2H, m), 5.42 (1H, br ), 7.81 (1H, s), 8.06 (2H, s).
Example 81
Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate:
Step 1: Preparation of ethyl 4-[(2-hexamidopyrimidin-5-yl) oxy] butyrate N- (5-hydroxypyrimidin-2-yl) hexanamide (3.0) prepared by the method of Step 2 of Example 3 g, 14.3 mmol) in N, N-dimethylformamide (15 mL) was added ethyl 4-bromobutyrate (3.35 g, 17.2 mmol) and potassium carbonate (3.0 g, 21.5 mmol), and the mixture was stirred at 60 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-[(2-hexaneamidopyrimidin-5-yl) oxy. ] Ethyl butyrate (5.06 g, crude product) was obtained.
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, br), 1.25-1.37 (7H, m), 1.73 (2H, br), 2.14-2.15 (2H, m), 2.50-2.62 (4H, m) , 4.09-4.17 (4H, m), 8.28-8.36 (3H, m).
工程2:4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチルの製造
工程1で得た4-[(2-ヘキサンアミドピリミジン-5-イル)オキシ]酪酸エチル(1 g,上記粗生成物)のエタノール(4 mL)溶液にナトリウムエトキシド(421 mg,6.19 mmol)加え、5時間加熱還流した。放冷後、濃硫酸(835 mg,8.51 mmol)加え、16時間加熱還流した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル = 1:2)を用いて精製し、表題化合物(862 mg, 二段階100%)を黄色固形物として得た。
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.1 Hz), 2.09 (2H, tt, J = 6.6 Hz), 2.50 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.80 (2H, br), 8.03 (2H, s). Step 2: Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate Ethyl 4-[(2-hexaneamidopyrimidin-5-yl) oxy] butyrate obtained in Step 1 (1 g, above) To a solution of the crude product) in ethanol (4 mL) was added sodium ethoxide (421 mg, 6.19 mmol), and the mixture was heated to reflux for 5 hours. After allowing to cool, concentrated sulfuric acid (835 mg, 8.51 mmol) was added, and the mixture was heated to reflux for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 1: 2) was used to obtain the title compound (862 mg, two-step 100%) as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.1 Hz), 2.09 (2H, tt, J = 6.6 Hz), 2.50 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.80 (2H, br), 8.03 (2H, s).
工程1で得た4-[(2-ヘキサンアミドピリミジン-5-イル)オキシ]酪酸エチル(1 g,上記粗生成物)のエタノール(4 mL)溶液にナトリウムエトキシド(421 mg,6.19 mmol)加え、5時間加熱還流した。放冷後、濃硫酸(835 mg,8.51 mmol)加え、16時間加熱還流した。反応液に水を加え酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をカラムクロマトグラフィー(ヘキサン:酢酸エチル = 1:2)を用いて精製し、表題化合物(862 mg, 二段階100%)を黄色固形物として得た。
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.1 Hz), 2.09 (2H, tt, J = 6.6 Hz), 2.50 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.80 (2H, br), 8.03 (2H, s). Step 2: Preparation of ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate Ethyl 4-[(2-hexaneamidopyrimidin-5-yl) oxy] butyrate obtained in Step 1 (1 g, above) To a solution of the crude product) in ethanol (4 mL) was added sodium ethoxide (421 mg, 6.19 mmol), and the mixture was heated to reflux for 5 hours. After allowing to cool, concentrated sulfuric acid (835 mg, 8.51 mmol) was added, and the mixture was heated to reflux for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 1: 2) was used to obtain the title compound (862 mg, two-step 100%) as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.1 Hz), 2.09 (2H, tt, J = 6.6 Hz), 2.50 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 4.15 (2H, q, J = 7.1 Hz), 4.80 (2H, br), 8.03 (2H, s).
実施例82
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチルの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに4-[(2-アミノピリミジン-5-イル)オキシ]酢酸エチルを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.13-1.17 (5H, m), 1.26 (3H, t, J = 7.1 Hz), 1.47-1.68 (6H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 6.3 Hz), 3.24-3.28 (4H, m), 3.94-3.98 (5H, m), 4.14 (2H, q, J = 7.1 Hz), 4.64 (2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.9 Hz), 7.84 (1H, s), 8.04 (2H, s). Example 82
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- Production of 5-yl} oxy) ethyl butyrate:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Example 4 using pyridine-5-carbaldehyde and using ethyl 4-[(2-aminopyrimidin-5-yl) oxy] acetate instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.13-1.17 (5H, m), 1.26 (3H, t, J = 7.1 Hz), 1.47-1.68 (6H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 6.3 Hz), 3.24-3.28 (4H, m), 3.94-3.98 (5H, m), 4.14 (2H, q, J = 7.1 Hz), 4.64 ( 2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.9 Hz), 7.84 (1H, s), 8.04 (2H, s).
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチルの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに4-[(2-アミノピリミジン-5-イル)オキシ]酢酸エチルを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.13-1.17 (5H, m), 1.26 (3H, t, J = 7.1 Hz), 1.47-1.68 (6H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 6.3 Hz), 3.24-3.28 (4H, m), 3.94-3.98 (5H, m), 4.14 (2H, q, J = 7.1 Hz), 4.64 (2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.9 Hz), 7.84 (1H, s), 8.04 (2H, s). Example 82
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- Production of 5-yl} oxy) ethyl butyrate:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6-[(cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] Example 4 using pyridine-5-carbaldehyde and using ethyl 4-[(2-aminopyrimidin-5-yl) oxy] acetate instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 to obtain the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.13-1.17 (5H, m), 1.26 (3H, t, J = 7.1 Hz), 1.47-1.68 (6H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 6.3 Hz), 3.24-3.28 (4H, m), 3.94-3.98 (5H, m), 4.14 (2H, q, J = 7.1 Hz), 4.64 ( 2H, d, J = 5.9 Hz), 5.63 (1H, t, J = 5.9 Hz), 7.84 (1H, s), 8.04 (2H, s).
実施例83
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸の製造:
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル(21 mg, 0.042 mmol)をエタノール(1 mL)に溶解し、氷浴中にて撹拌しつつ2 N水酸化ナトリウム水溶液(0.04 mL)を加えた後、50℃まで昇温し、2時間攪拌した。氷浴中にて反応液に2 N塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー(クロロホルム:メタノール = 20:1)を用いて精製し、表題化合物(9.1 mg, 50%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.15 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 6.8 Hz), 1.47-1.68 (4H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 7.2 Hz), 3.26 (4H, m), 3.96 (5H, m), 4.14 (2H, q, J = 7.2 Hz), 4.64 (2H, m), 5.63 (1H, br), 7.84 (1H, s), 8.04 (2H, s). Example 83
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid production:
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate (21 mg, 0.042 mmol) was dissolved in ethanol (1 mL), and 2N aqueous sodium hydroxide solution (0.04 mL) was added with stirring in an ice bath. The temperature was raised to and stirred for 2 hours. The reaction mixture was neutralized with 2N hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified using silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to give the title compound (9.1 mg, 50% ) Was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 6.8 Hz), 1.47-1.68 (4H, m), 2.06-2.17 (3H, m ), 2.45 (3H, s), 2.50 (2H, t, J = 7.2 Hz), 3.26 (4H, m), 3.96 (5H, m), 4.14 (2H, q, J = 7.2 Hz), 4.64 (2H m), 5.63 (1H, br), 7.84 (1H, s), 8.04 (2H, s).
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸の製造:
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル(21 mg, 0.042 mmol)をエタノール(1 mL)に溶解し、氷浴中にて撹拌しつつ2 N水酸化ナトリウム水溶液(0.04 mL)を加えた後、50℃まで昇温し、2時間攪拌した。氷浴中にて反応液に2 N塩酸を加えて中和した後、酢酸エチルで抽出し、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲル分取薄層クロマトグラフィー(クロロホルム:メタノール = 20:1)を用いて精製し、表題化合物(9.1 mg, 50%)を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.15 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 6.8 Hz), 1.47-1.68 (4H, m), 2.06-2.17 (3H, m), 2.45 (3H, s), 2.50 (2H, t, J = 7.2 Hz), 3.26 (4H, m), 3.96 (5H, m), 4.14 (2H, q, J = 7.2 Hz), 4.64 (2H, m), 5.63 (1H, br), 7.84 (1H, s), 8.04 (2H, s). Example 83
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid production:
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate (21 mg, 0.042 mmol) was dissolved in ethanol (1 mL), and 2N aqueous sodium hydroxide solution (0.04 mL) was added with stirring in an ice bath. The temperature was raised to and stirred for 2 hours. The reaction mixture was neutralized with 2N hydrochloric acid in an ice bath, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified using silica gel preparative thin layer chromatography (chloroform: methanol = 20: 1) to give the title compound (9.1 mg, 50% ) Was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 6.8 Hz), 1.47-1.68 (4H, m), 2.06-2.17 (3H, m ), 2.45 (3H, s), 2.50 (2H, t, J = 7.2 Hz), 3.26 (4H, m), 3.96 (5H, m), 4.14 (2H, q, J = 7.2 Hz), 4.64 (2H m), 5.63 (1H, br), 7.84 (1H, s), 8.04 (2H, s).
実施例84
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルの製造:
工程1:3-(メチルアミノ)プロピオン酸メチルの製造
アクリル酸メチル(10 mL, 0.12 mmol)のメタノール溶液(50 mL)にN-メチルベンジルアミン(17.1 mL, 0.13 mmol)を加え室温下、15時間攪拌した。続いて反応液に10 % パラジウム炭素(6.43 g)及びギ酸アンモニウム(10.0 g, 0.16 mmol)加え一時間加熱還流した。放冷後、セライト及びシリカゲルでろ過し、減圧濃縮して3-(メチルアミノ)プロピオン酸メチル(6.7 g, 47%)を無色油状物として得た。
1H-NMR (CDCl3) δ: 2.44 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 2.86 (2H, t, J = 6.3 Hz), 3.69 (3H, s). Example 84
3-[(5-{[(5-Ethoxypyrimidin-2-yl) 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 hours. Subsequently, 10% palladium carbon (6.43 g) and ammonium formate (10.0 g, 0.16 mmol) were added to the reaction solution, and the mixture was heated to reflux for 1 hour. After allowing to cool, the mixture was filtered through celite and silica gel, and concentrated under reduced pressure to give methyl 3- (methylamino) propionate (6.7 g, 47%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 2.44 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 2.86 (2H, t, J = 6.3 Hz), 3.69 (3H, s).
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルの製造:
工程1:3-(メチルアミノ)プロピオン酸メチルの製造
アクリル酸メチル(10 mL, 0.12 mmol)のメタノール溶液(50 mL)にN-メチルベンジルアミン(17.1 mL, 0.13 mmol)を加え室温下、15時間攪拌した。続いて反応液に10 % パラジウム炭素(6.43 g)及びギ酸アンモニウム(10.0 g, 0.16 mmol)加え一時間加熱還流した。放冷後、セライト及びシリカゲルでろ過し、減圧濃縮して3-(メチルアミノ)プロピオン酸メチル(6.7 g, 47%)を無色油状物として得た。
1H-NMR (CDCl3) δ: 2.44 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 2.86 (2H, t, J = 6.3 Hz), 3.69 (3H, s). Example 84
3-[(5-{[(5-Ethoxypyrimidin-2-yl) 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 hours. Subsequently, 10% palladium carbon (6.43 g) and ammonium formate (10.0 g, 0.16 mmol) were added to the reaction solution, and the mixture was heated to reflux for 1 hour. After allowing to cool, the mixture was filtered through celite and silica gel, and concentrated under reduced pressure to give methyl 3- (methylamino) propionate (6.7 g, 47%) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 2.44 (3H, s), 2.52 (2H, t, J = 6.3 Hz), 2.86 (2H, t, J = 6.3 Hz), 3.69 (3H, s).
工程2:3-[(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりに3-(メチルアミノ)プロピオン酸メチルを用いて実施例5の工程1と同様に反応・処理し、表題化合物を茶色油状物として得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.12 (3H, s), 3.87 (2H, t, J = 6.3 Hz), 3.92 (3H, s), 8.31 (1H, s), 9.97 (1H, s). Step 2: Preparation of methyl 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate N- (cyclopentylmethyl)- The reaction and treatment were conducted in a similar manner to process 1 of example 5 using methyl 3- (methylamino) propionate instead of N-ethylamine, and the title compound was obtained as a brown oil.
1 H-NMR (CDCl 3 ) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.12 (3H, s), 3.87 (2H, t, J = 6.3 Hz), 3.92 ( 3H, s), 8.31 (1H, s), 9.97 (1H, s).
N-(シクロペンチルメチル)-N-エチルアミンの代わりに3-(メチルアミノ)プロピオン酸メチルを用いて実施例5の工程1と同様に反応・処理し、表題化合物を茶色油状物として得た。
1H-NMR (CDCl3) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.12 (3H, s), 3.87 (2H, t, J = 6.3 Hz), 3.92 (3H, s), 8.31 (1H, s), 9.97 (1H, s). Step 2: Preparation of methyl 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] propionate N- (cyclopentylmethyl)- The reaction and treatment were conducted in a similar manner to process 1 of example 5 using methyl 3- (methylamino) propionate instead of N-ethylamine, and the title compound was obtained as a brown oil.
1 H-NMR (CDCl 3 ) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.12 (3H, s), 3.87 (2H, t, J = 6.3 Hz), 3.92 ( 3H, s), 8.31 (1H, s), 9.97 (1H, s).
工程3:3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに3-[(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を黄白色固体として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.67 (2H, t, J = 6.3 Hz), 2.95 (3H, s), 3.66 (5H, m), 3.98 (5H, m), 4.64 (2H, m), 5.46 (1H, br), 7.87 (1H, s), 8.04 (2H, s). Step 3: 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Preparation of methyl amino] propionate 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4] instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde -B] Performed with methyl pyridin-6-yl) (methyl) amino] propionate using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.67 (2H, t, J = 6.3 Hz), 2.95 (3H, s), 3.66 ( 5H, m), 3.98 (5H, m), 4.64 (2H, m), 5.46 (1H, br), 7.87 (1H, s), 8.04 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに3-[(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を黄白色固体として得た。
1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.67 (2H, t, J = 6.3 Hz), 2.95 (3H, s), 3.66 (5H, m), 3.98 (5H, m), 4.64 (2H, m), 5.46 (1H, br), 7.87 (1H, s), 8.04 (2H, s). Step 3: 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl ) Preparation of methyl amino] propionate 3-[(5-formyl-1,3-dimethyl-1H-pyrazolo [3,4] instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde -B] Performed with methyl pyridin-6-yl) (methyl) amino] propionate using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a pale yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.67 (2H, t, J = 6.3 Hz), 2.95 (3H, s), 3.66 ( 5H, m), 3.98 (5H, m), 4.64 (2H, m), 5.46 (1H, br), 7.87 (1H, s), 8.04 (2H, s).
実施例85
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸の製造:
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチルの代わりに3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルを用いて実施例83と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.35 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.68 (2H, t, J = 6.3 Hz), 2.93 (3H, s), 3.68 (2H, t, J = 6.3 Hz), 3.94 (5H, m), 4.64 (2H, m), 5.30 (1H, br), 7.86 (1H, s), 8.00 (2H, s). Example 85
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid production:
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] instead of ethyl 5-yl} oxy) butyrate The reaction and treatment were conducted in a similar manner to Example 83 using methyl pyridin-6-yl) (methyl) amino] propionate to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.35 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.68 (2H, t, J = 6.3 Hz), 2.93 (3H, s), 3.68 ( 2H, t, J = 6.3 Hz), 3.94 (5H, m), 4.64 (2H, m), 5.30 (1H, br), 7.86 (1H, s), 8.00 (2H, s).
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸の製造:
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチルの代わりに3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチルを用いて実施例83と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.35 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.68 (2H, t, J = 6.3 Hz), 2.93 (3H, s), 3.68 (2H, t, J = 6.3 Hz), 3.94 (5H, m), 4.64 (2H, m), 5.30 (1H, br), 7.86 (1H, s), 8.00 (2H, s). Example 85
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid production:
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] instead of ethyl 5-yl} oxy) butyrate The reaction and treatment were conducted in a similar manner to Example 83 using methyl pyridin-6-yl) (methyl) amino] propionate to give the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.35 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.68 (2H, t, J = 6.3 Hz), 2.93 (3H, s), 3.68 ( 2H, t, J = 6.3 Hz), 3.94 (5H, m), 4.64 (2H, m), 5.30 (1H, br), 7.86 (1H, s), 8.00 (2H, s).
実施例86
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチルの製造:
特許文献(国際公開第2007/088996号パンフレット)に記載の方法に従い製造した。
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.2 Hz), 2.02-2.09 (2H, m), 2.50 (2H, t, J = 7.2 Hz), 3.98 (2H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.69-4.71 (2H, m), 5.42 (1H, br), 7.76 (1H, s), 7.81 (2H, s), 8.05 (2H, s). Example 86
Preparation of ethyl 4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyrate:
It manufactured according to the method as described in a patent document (International Publication No. 2007/088996 pamphlet).
1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.2 Hz), 2.02-2.09 (2H, m), 2.50 (2H, t, J = 7.2 Hz), 3.98 (2H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.69-4.71 (2H, m), 5.42 (1H, br), 7.76 (1H, s), 7.81 (2H, s), 8.05 (2H , s).
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチルの製造:
特許文献(国際公開第2007/088996号パンフレット)に記載の方法に従い製造した。
1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.2 Hz), 2.02-2.09 (2H, m), 2.50 (2H, t, J = 7.2 Hz), 3.98 (2H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.69-4.71 (2H, m), 5.42 (1H, br), 7.76 (1H, s), 7.81 (2H, s), 8.05 (2H, s). Example 86
Preparation of ethyl 4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyrate:
It manufactured according to the method as described in a patent document (International Publication No. 2007/088996 pamphlet).
1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.2 Hz), 2.02-2.09 (2H, m), 2.50 (2H, t, J = 7.2 Hz), 3.98 (2H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.69-4.71 (2H, m), 5.42 (1H, br), 7.76 (1H, s), 7.81 (2H, s), 8.05 (2H , s).
実施例87
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸の製造:
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチルの代わりに4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチルを用いて実施例83と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.08-2.13 (2H, m), 2.55 (2H, t, J = 7.2 Hz), 3.09-3.11 (1H, m), 4.06 (2H, t, J = 7.2 Hz), 4.70-4.72 (2H, m), 6.49 (1H, br), 7.75 (1H, s), 7.81 (2H, s), 8.10 (2H, s). Example 87
Preparation of 4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid:
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- Example 83 with ethyl 4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyrate instead of ethyl 5-yl} oxy) butyrate The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.08-2.13 (2H, m), 2.55 (2H, t, J = 7.2 Hz), 3.09-3.11 (1H, m), 4.06 (2H, t, J = 7.2 Hz ), 4.70-4.72 (2H, m), 6.49 (1H, br), 7.75 (1H, s), 7.81 (2H, s), 8.10 (2H, s).
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸の製造:
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチルの代わりに4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチルを用いて実施例83と同様に反応・処理し、表題化合物を淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 2.08-2.13 (2H, m), 2.55 (2H, t, J = 7.2 Hz), 3.09-3.11 (1H, m), 4.06 (2H, t, J = 7.2 Hz), 4.70-4.72 (2H, m), 6.49 (1H, br), 7.75 (1H, s), 7.81 (2H, s), 8.10 (2H, s). Example 87
Preparation of 4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid:
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- Example 83 with ethyl 4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyrate instead of ethyl 5-yl} oxy) butyrate The same reaction and treatment were performed to obtain the title compound as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 2.08-2.13 (2H, m), 2.55 (2H, t, J = 7.2 Hz), 3.09-3.11 (1H, m), 4.06 (2H, t, J = 7.2 Hz ), 4.70-4.72 (2H, m), 6.49 (1H, br), 7.75 (1H, s), 7.81 (2H, s), 8.10 (2H, s).
実施例88
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:2-(ジエチルアミノ)ニコチンアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロニコチンアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、2-(ジエチルアミノ)ニコチンアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 3.51 (4H, q, J = 7.2 Hz), 6.68-9.73 (1H, m), 7.91-7.99 (1H, m), 8.29-8.36 (1H, m), 9.98 (1H, s). Example 88
Production of N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 2- (diethylamino) nicotinaldehyde Using 2-chloronicotinaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of-(cyclopentylmethyl) -N-ethylamine, and 2- (diethylamino) nicotinaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 3.51 (4H, q, J = 7.2 Hz), 6.68-9.73 (1H, m), 7.91-7.99 (1H, m ), 8.29-8.36 (1H, m), 9.98 (1H, s).
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:2-(ジエチルアミノ)ニコチンアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロニコチンアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、2-(ジエチルアミノ)ニコチンアルデヒドを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 3.51 (4H, q, J = 7.2 Hz), 6.68-9.73 (1H, m), 7.91-7.99 (1H, m), 8.29-8.36 (1H, m), 9.98 (1H, s). Example 88
Production of N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 2- (diethylamino) nicotinaldehyde Using 2-chloronicotinaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of-(cyclopentylmethyl) -N-ethylamine, and 2- (diethylamino) nicotinaldehyde was obtained as a pale yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 3.51 (4H, q, J = 7.2 Hz), 6.68-9.73 (1H, m), 7.91-7.99 (1H, m ), 8.29-8.36 (1H, m), 9.98 (1H, s).
工程2:N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)ニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.09 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 3.22 (4H, q, J = 7.2 Hz), 4.0 (2H, q, J = 7.2 Hz), 4.60 (2H, d, J = 5.4 Hz), 5.58 (1H, br), 6.82-6.93 (1H, m), 7.54-7.67 (1H, m), 8.06 (2H, s), 8.19-8.24 (1H, m). Step 2: Preparation of N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Instead of 2- (diethylamino) nicotinaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, as in Step 6 of Example 4 Reaction and treatment gave the title compound as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.09 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 3.22 (4H, q, J = 7.2 Hz), 4.0 (2H, q, J = 7.2 Hz), 4.60 (2H, d, J = 5.4 Hz), 5.58 (1H, br), 6.82-6.93 (1H, m), 7.54-7.67 (1H, m), 8.06 (2H, s ), 8.19-8.24 (1H, m).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)ニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.09 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 3.22 (4H, q, J = 7.2 Hz), 4.0 (2H, q, J = 7.2 Hz), 4.60 (2H, d, J = 5.4 Hz), 5.58 (1H, br), 6.82-6.93 (1H, m), 7.54-7.67 (1H, m), 8.06 (2H, s), 8.19-8.24 (1H, m). Step 2: Preparation of N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde Instead of 2- (diethylamino) nicotinaldehyde and using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, as in Step 6 of Example 4 Reaction and treatment gave the title compound as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.09 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 3.22 (4H, q, J = 7.2 Hz), 4.0 (2H, q, J = 7.2 Hz), 4.60 (2H, d, J = 5.4 Hz), 5.58 (1H, br), 6.82-6.93 (1H, m), 7.54-7.67 (1H, m), 8.06 (2H, s ), 8.19-8.24 (1H, m).
実施例89
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミンの製造:
工程1:2-(ジエチルアミノ)ベンズアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロベンズアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、表題化合物をを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 7.2 Hz), 3.20 (4H, q, J = 7.2 Hz), 7.02-7.11 (1H, m), 7.13-7.21 (1H, m), 7.45-7.53 (1H, m), 7.72-7.82 (1H, m), 10.4 (1H, s). Example 89
Preparation of N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 2- (diethylamino) benzaldehyde Using 2-chlorobenzaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N- ( The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 7.2 Hz), 3.20 (4H, q, J = 7.2 Hz), 7.02-7.11 (1H, m), 7.13-7.21 (1H, m ), 7.45-7.53 (1H, m), 7.72-7.82 (1H, m), 10.4 (1H, s).
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミンの製造:
工程1:2-(ジエチルアミノ)ベンズアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロベンズアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、表題化合物をを淡黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.07 (6H, t, J = 7.2 Hz), 3.20 (4H, q, J = 7.2 Hz), 7.02-7.11 (1H, m), 7.13-7.21 (1H, m), 7.45-7.53 (1H, m), 7.72-7.82 (1H, m), 10.4 (1H, s). Example 89
Preparation of N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 2- (diethylamino) benzaldehyde Using 2-chlorobenzaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N- ( The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a pale-yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.07 (6H, t, J = 7.2 Hz), 3.20 (4H, q, J = 7.2 Hz), 7.02-7.11 (1H, m), 7.13-7.21 (1H, m ), 7.45-7.53 (1H, m), 7.72-7.82 (1H, m), 10.4 (1H, s).
工程2:N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)ベンズアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.01-1.12 (6H, m), 1.38 (3H, t, J = 7.2 Hz), 3.01-3.13 (4H, m), 4.0 (2H, q, J = 7.2 Hz), 4.65 (2H, m), 4.83 (1H, br), 7.05-7.36 (4H, m), 8.06 (1H, s). Step 2: Preparation of N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine 3-((cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (diethylamino) Using benzaldehyde, reacting and treating in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, Obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.01-1.12 (6H, m), 1.38 (3H, t, J = 7.2 Hz), 3.01-3.13 (4H, m), 4.0 (2H, q, J = 7.2 Hz ), 4.65 (2H, m), 4.83 (1H, br), 7.05-7.36 (4H, m), 8.06 (1H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)ベンズアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.01-1.12 (6H, m), 1.38 (3H, t, J = 7.2 Hz), 3.01-3.13 (4H, m), 4.0 (2H, q, J = 7.2 Hz), 4.65 (2H, m), 4.83 (1H, br), 7.05-7.36 (4H, m), 8.06 (1H, s). Step 2: Preparation of N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine 3-((cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 2- (diethylamino) Using benzaldehyde, reacting and treating in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, Obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.01-1.12 (6H, m), 1.38 (3H, t, J = 7.2 Hz), 3.01-3.13 (4H, m), 4.0 (2H, q, J = 7.2 Hz ), 4.65 (2H, m), 4.83 (1H, br), 7.05-7.36 (4H, m), 8.06 (1H, s).
実施例90
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:6-(ジエチルアミノ)ニコチンアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに6-クロロニコチンアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-(ジエチルアミノ)ニコチンアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 3.60 (4H, q, J = 7.2 Hz), 6.51 (1H, d, J = 9.3 Hz), 7.88 (1H, d, J = 9.3 Hz), 8.53 (1H, s), 9.74 (1H, s). Example 90
Production of N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 6- (diethylamino) nicotinaldehyde Using 6-chloronicotinaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of-(cyclopentylmethyl) -N-ethylamine, and 6- (diethylamino) nicotinaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 3.60 (4H, q, J = 7.2 Hz), 6.51 (1H, d, J = 9.3 Hz), 7.88 (1H, d, J = 9.3 Hz), 8.53 (1H, s), 9.74 (1H, s).
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:6-(ジエチルアミノ)ニコチンアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに6-クロロニコチンアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、6-(ジエチルアミノ)ニコチンアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 3.60 (4H, q, J = 7.2 Hz), 6.51 (1H, d, J = 9.3 Hz), 7.88 (1H, d, J = 9.3 Hz), 8.53 (1H, s), 9.74 (1H, s). Example 90
Production of N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 6- (diethylamino) nicotinaldehyde Using 6-chloronicotinaldehyde instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde, N The reaction and treatment were conducted in a similar manner to process 1 of example 5 using diethylamine instead of-(cyclopentylmethyl) -N-ethylamine, and 6- (diethylamino) nicotinaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 3.60 (4H, q, J = 7.2 Hz), 6.51 (1H, d, J = 9.3 Hz), 7.88 (1H, d, J = 9.3 Hz), 8.53 (1H, s), 9.74 (1H, s).
工程2:N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)ニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 4.48 (2H, s), 6.44 (1H, d, J = 9.3 Hz), 7.44 (1H, d, J = 9.3 Hz), 8.02 (1H, s), 8.15 (2H, s). Step 2: Preparation of N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 6- (diethylamino) nicotinaldehyde was used instead of 5- and 5-ethoxypyrimidin-2-amine was used instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, as in Step 6 of Example 4. The title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 4.48 (2H, s), 6.44 (1H, d, J = 9.3 Hz), 7.44 (1H, d, J = 9.3 Hz), 8.02 (1H, s), 8.15 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)ニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 4.48 (2H, s), 6.44 (1H, d, J = 9.3 Hz), 7.44 (1H, d, J = 9.3 Hz), 8.02 (1H, s), 8.15 (2H, s). Step 2: Preparation of N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 6- (diethylamino) nicotinaldehyde was used instead of 5- and 5-ethoxypyrimidin-2-amine was used instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, as in Step 6 of Example 4. The title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 4.48 (2H, s), 6.44 (1H, d, J = 9.3 Hz), 7.44 (1H, d, J = 9.3 Hz), 8.02 (1H, s), 8.15 (2H, s).
実施例91
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミンの製造:
工程1:2-(ジメチルアミノ)キノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロキノリン-3-カルボアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、2-(ジメチルアミノ)キノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.24 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.32-7.34 (1H, m), 7.66-7.68 (1H, m), 7.75-7.79 (2H, m), 8.45 (1H, s), 10.1 (1H, s). Example 91
Preparation of 3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine:
Step 1: Preparation of 2- (dimethylamino) quinoline-3-carbaldehyde 2-chloroquinoline instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 3-carbaldehyde and using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2- (dimethylamino) quinoline-3-carbohydrate. The aldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.24 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.32-7.34 (1H, m), 7.66-7.68 (1H, m ), 7.75-7.79 (2H, m), 8.45 (1H, s), 10.1 (1H, s).
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミンの製造:
工程1:2-(ジメチルアミノ)キノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロキノリン-3-カルボアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、2-(ジメチルアミノ)キノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.24 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.32-7.34 (1H, m), 7.66-7.68 (1H, m), 7.75-7.79 (2H, m), 8.45 (1H, s), 10.1 (1H, s). Example 91
Preparation of 3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine:
Step 1: Preparation of 2- (dimethylamino) quinoline-3-carbaldehyde 2-chloroquinoline instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 3-carbaldehyde and using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine, the same reaction and treatment as in Step 1 of Example 5 was carried out to give 2- (dimethylamino) quinoline-3-carbohydrate. The aldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.24 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.32-7.34 (1H, m), 7.66-7.68 (1H, m ), 7.75-7.79 (2H, m), 8.45 (1H, s), 10.1 (1H, s).
工程2:3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジメチルアミノ)キノリン-3-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.18 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz), 3.37 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 4.72-7.73 (2H, m), 5.64 (1H, br), 7.30-7.34 (1H, m), 7.54-7.56 (1H, m), 7.63-7.65 (1H, m), 7.84-7.85 (1H, m), 8.00 (1H, s), 8.06 (2H, s). Step 2: Preparation of 3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxy Performed using 2- (dimethylamino) quinoline-3-carbaldehyde instead of picolinaldehyde and 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.18 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz), 3.37 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 4.72-7.73 (2H, m), 5.64 (1H, br), 7.30-7.34 (1H, m), 7.54-7.56 (1H, m), 7.63-7.65 (1H, m) , 7.84-7.85 (1H, m), 8.00 (1H, s), 8.06 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジメチルアミノ)キノリン-3-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.18 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz), 3.37 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 4.72-7.73 (2H, m), 5.64 (1H, br), 7.30-7.34 (1H, m), 7.54-7.56 (1H, m), 7.63-7.65 (1H, m), 7.84-7.85 (1H, m), 8.00 (1H, s), 8.06 (2H, s). Step 2: Preparation of 3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxy Performed using 2- (dimethylamino) quinoline-3-carbaldehyde instead of picolinaldehyde and 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.18 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 7.2 Hz), 3.37 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 7.2 Hz), 4.72-7.73 (2H, m), 5.64 (1H, br), 7.30-7.34 (1H, m), 7.54-7.56 (1H, m), 7.63-7.65 (1H, m) , 7.84-7.85 (1H, m), 8.00 (1H, s), 8.06 (2H, s).
実施例92
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチルの製造:
工程1:3-(エチルアミノ)プロピオン酸メチルの製造
N-メチルベンジルアミンの代わりにN-エチルベンジルアミンを用いて実施例84の工程1と同様に反応・処理し、3-(エチルアミノ)プロピオン酸メチルを無色油状物として得た。
1H-NMR (CDCl3) δ: 1.11 (3H, t, J = 7.1 Hz), 2.54 (2H, t, J = 6.6 Hz), 2.66 (2H, q, J = 7.1 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.69 (3H, s). Example 92
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Production of methyl propionate:
Step 1: Preparation of methyl 3- (ethylamino) propionate Reaction was carried out in the same manner as in Step 1 of Example 84 using N-ethylbenzylamine instead of N-methylbenzylamine to give 3- (ethylamino) Methyl propionate was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.11 (3H, t, J = 7.1 Hz), 2.54 (2H, t, J = 6.6 Hz), 2.66 (2H, q, J = 7.1 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.69 (3H, s).
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチルの製造:
工程1:3-(エチルアミノ)プロピオン酸メチルの製造
N-メチルベンジルアミンの代わりにN-エチルベンジルアミンを用いて実施例84の工程1と同様に反応・処理し、3-(エチルアミノ)プロピオン酸メチルを無色油状物として得た。
1H-NMR (CDCl3) δ: 1.11 (3H, t, J = 7.1 Hz), 2.54 (2H, t, J = 6.6 Hz), 2.66 (2H, q, J = 7.1 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.69 (3H, s). Example 92
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Production of methyl propionate:
Step 1: Preparation of methyl 3- (ethylamino) propionate Reaction was carried out in the same manner as in Step 1 of Example 84 using N-ethylbenzylamine instead of N-methylbenzylamine to give 3- (ethylamino) Methyl propionate was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.11 (3H, t, J = 7.1 Hz), 2.54 (2H, t, J = 6.6 Hz), 2.66 (2H, q, J = 7.1 Hz), 2.89 (2H, t, J = 6.6 Hz), 3.69 (3H, s).
工程2:3-[エチル(5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]プロピオン酸メチルの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりに3-(エチルアミノ)プロピオン酸メチルを用いて実施例5の工程1と同様に反応・処理し、表題化合物を暗褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.24 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 2.73 (2H, t, J = 7.2 Hz), 3.45 (2H, q, J = 7.2 Hz), 3.66 (3H, s), 3.81 (2H, t, J = 7.2 Hz), 3.94 (3H, s), 8.36 (1H, s), 9.99 (1H, s).
工程3:3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸酸メチルの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに3-(エチル[5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]プロピオン酸メチルを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を黄褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.18 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 3.23 (2H, q, J = 7.2 Hz), 3.64 (3H, s), 3.69 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 7.2 Hz), 4.61-4.62 (2H, m), 5.23 (1H, br), 7.88 (1H, s), 8.06 (2H, s). Step 2: Preparation of methyl 3- [ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] propionate:
The reaction and treatment were conducted in a similar manner to process 1 of example 5 using methyl 3- (ethylamino) propionate instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a dark brown oil.
1 H-NMR (CDCl 3 ) δ: 1.24 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 2.73 (2H, t, J = 7.2 Hz), 3.45 (2H, q, J = 7.2 Hz), 3.66 (3H, s), 3.81 (2H, t, J = 7.2 Hz), 3.94 (3H, s), 8.36 (1H, s), 9.99 (1H, s).
Step 3: 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl ) Preparation of methyl amino] propionate 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 3- (ethyl [5-formyl-1,3-dimethyl-1H-pyrazolo [3 , 4-b] pyridin-6-yl) amino] propionate and 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 6 of 4 to give the title compound as a tan oil.
1 H-NMR (CDCl 3 ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 3.23 (2H, q, J = 7.2 Hz), 3.64 (3H, s), 3.69 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 7.2 Hz), 4.61-4.62 (2H, m), 5.23 (1H, br), 7.88 (1H, s), 8.06 (2H, s).
N-(シクロペンチルメチル)-N-エチルアミンの代わりに3-(エチルアミノ)プロピオン酸メチルを用いて実施例5の工程1と同様に反応・処理し、表題化合物を暗褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.24 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 2.73 (2H, t, J = 7.2 Hz), 3.45 (2H, q, J = 7.2 Hz), 3.66 (3H, s), 3.81 (2H, t, J = 7.2 Hz), 3.94 (3H, s), 8.36 (1H, s), 9.99 (1H, s).
工程3:3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸酸メチルの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに3-(エチル[5-ホルミル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)アミノ]プロピオン酸メチルを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を黄褐色油状物として得た。
1H-NMR (CDCl3) δ: 1.18 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 3.23 (2H, q, J = 7.2 Hz), 3.64 (3H, s), 3.69 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 7.2 Hz), 4.61-4.62 (2H, m), 5.23 (1H, br), 7.88 (1H, s), 8.06 (2H, s). Step 2: Preparation of methyl 3- [ethyl (5-formyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) amino] propionate:
The reaction and treatment were conducted in a similar manner to process 1 of example 5 using methyl 3- (ethylamino) propionate instead of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a dark brown oil.
1 H-NMR (CDCl 3 ) δ: 1.24 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 2.73 (2H, t, J = 7.2 Hz), 3.45 (2H, q, J = 7.2 Hz), 3.66 (3H, s), 3.81 (2H, t, J = 7.2 Hz), 3.94 (3H, s), 8.36 (1H, s), 9.99 (1H, s).
Step 3: 3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl ) Preparation of methyl amino] propionate 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde instead of 3- (ethyl [5-formyl-1,3-dimethyl-1H-pyrazolo [3 , 4-b] pyridin-6-yl) amino] propionate and 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 6 of 4 to give the title compound as a tan oil.
1 H-NMR (CDCl 3 ) δ: 1.18 (3H, t, J = 7.2 Hz), 1.39 (3H, t, J = 7.2 Hz), 2.46 (3H, s), 2.59 (2H, t, J = 7.2 Hz), 3.23 (2H, q, J = 7.2 Hz), 3.64 (3H, s), 3.69 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 3.99 (2H, q, J = 7.2 Hz), 4.61-4.62 (2H, m), 5.23 (1H, br), 7.88 (1H, s), 8.06 (2H, s).
実施例93
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:2-クロロイソニコチン酸メチルの製造:
2-クロロイソニコチン酸(1.0 g, 6.35 mmol)のメタノール(20 mL)溶液に塩化チオニル(769 μL, 9,5 mmol)を-15℃にて攪拌しつつ、ゆっくり滴下した。徐々に昇温し3時間加熱還流した後、反応液を減圧濃縮し、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して2-クロロイソニコチン酸メチル(1.05 g, 96%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 3.98 (3H, s), 7.78 (1H, d, J = 5.0 Hz), 7.90 (1H, s), 8.55 (1H, d, J = 5.0 Hz). Example 93
Production of N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Production of methyl 2-chloroisonicotinate:
Thionyl chloride (769 μL, 9,5 mmol) was slowly added dropwise to a solution of 2-chloroisonicotinic acid (1.0 g, 6.35 mmol) in methanol (20 mL) at −15 ° C. while stirring. After gradually warming up and heating to reflux for 3 hours, the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-chloroisonicotinate (1.05 g, 96%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 3.98 (3H, s), 7.78 (1H, d, J = 5.0 Hz), 7.90 (1H, s), 8.55 (1H, d, J = 5.0 Hz).
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:2-クロロイソニコチン酸メチルの製造:
2-クロロイソニコチン酸(1.0 g, 6.35 mmol)のメタノール(20 mL)溶液に塩化チオニル(769 μL, 9,5 mmol)を-15℃にて攪拌しつつ、ゆっくり滴下した。徐々に昇温し3時間加熱還流した後、反応液を減圧濃縮し、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して2-クロロイソニコチン酸メチル(1.05 g, 96%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 3.98 (3H, s), 7.78 (1H, d, J = 5.0 Hz), 7.90 (1H, s), 8.55 (1H, d, J = 5.0 Hz). Example 93
Production of N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Production of methyl 2-chloroisonicotinate:
Thionyl chloride (769 μL, 9,5 mmol) was slowly added dropwise to a solution of 2-chloroisonicotinic acid (1.0 g, 6.35 mmol) in methanol (20 mL) at −15 ° C. while stirring. After gradually warming up and heating to reflux for 3 hours, the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-chloroisonicotinate (1.05 g, 96%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 3.98 (3H, s), 7.78 (1H, d, J = 5.0 Hz), 7.90 (1H, s), 8.55 (1H, d, J = 5.0 Hz).
工程2:2-(ジエチルアミノ)イソニコチン酸メチルの製造:
2-クロロイソニコチン酸メチル(0.7 g, 4.08 mmol)、ジエチルアミン(844 μL, 8.2 mmol)、炭酸セシウム(2.88 g, 8.2 mmol)及び[1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾール-2-イリデン](3-クロロピリジル)パラジウム(II)ジクロリド(139 mg, 0.2 mmol)のDMF溶液をアルゴン雰囲気下、100℃で7時間攪拌した。放冷後、水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して2-(ジエチルアミノ)イソニコチン酸メチル(626 mg, 74%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.20 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 3.92 (3H, s), 6.98 (1H, d, J = 5.1 Hz), 7.04 (1H, s), 8.23 (1H, d, J = 5.1 Hz). Step 2: Production of methyl 2- (diethylamino) isonicotinate:
Methyl 2-chloroisonicotinate (0.7 g, 4.08 mmol), diethylamine (844 μL, 8.2 mmol), cesium carbonate (2.88 g, 8.2 mmol) and [1,3-bis (2,6-diisopropylphenyl) imidazole- A solution of 2-ylidene] (3-chloropyridyl) palladium (II) dichloride (139 mg, 0.2 mmol) in DMF was stirred at 100 ° C. for 7 hours under an argon atmosphere. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2- (diethylamino) isonicotinate (626 mg, 74 %) As a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.20 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 3.92 (3H, s), 6.98 (1H, d, J = 5.1 Hz), 7.04 (1H, s), 8.23 (1H, d, J = 5.1 Hz).
2-クロロイソニコチン酸メチル(0.7 g, 4.08 mmol)、ジエチルアミン(844 μL, 8.2 mmol)、炭酸セシウム(2.88 g, 8.2 mmol)及び[1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾール-2-イリデン](3-クロロピリジル)パラジウム(II)ジクロリド(139 mg, 0.2 mmol)のDMF溶液をアルゴン雰囲気下、100℃で7時間攪拌した。放冷後、水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して2-(ジエチルアミノ)イソニコチン酸メチル(626 mg, 74%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.20 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 3.92 (3H, s), 6.98 (1H, d, J = 5.1 Hz), 7.04 (1H, s), 8.23 (1H, d, J = 5.1 Hz). Step 2: Production of methyl 2- (diethylamino) isonicotinate:
Methyl 2-chloroisonicotinate (0.7 g, 4.08 mmol), diethylamine (844 μL, 8.2 mmol), cesium carbonate (2.88 g, 8.2 mmol) and [1,3-bis (2,6-diisopropylphenyl) imidazole- A solution of 2-ylidene] (3-chloropyridyl) palladium (II) dichloride (139 mg, 0.2 mmol) in DMF was stirred at 100 ° C. for 7 hours under an argon atmosphere. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2- (diethylamino) isonicotinate (626 mg, 74 %) As a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.20 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 3.92 (3H, s), 6.98 (1H, d, J = 5.1 Hz), 7.04 (1H, s), 8.23 (1H, d, J = 5.1 Hz).
工程3:[2-(ジエチルアミノ)ピリジン-4-イル]メタノールの製造
2-(ジエチルアミノ)イソニコチン酸メチル(626 mg, 3.0 mmol)のTHF溶液に水素化アルミニウムリチウム(284 mg, 7.5 mmol)をアルゴン雰囲気下-78℃にて加え、2時間後攪拌した。20%酒石酸ナトリウムカリウム水溶液を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 3:2→2:3)を用いて精製し、[2-(ジエチルアミノ)ピリジン-4-イル]メタノール(315 mg, 58%)を黄色固体として得た。
1H-NMR (CDCl3) δ: 1.18 (6H, t, J = 7.1 Hz), 3.52 (4H, q, J = 7.2 Hz), 4.62 (3H, s), 6.45 (1H, d, J = 5.1 Hz), 6.48 (1H, s), 8.09 (1H, d, J = 5.1 Hz). Step 3: Preparation of [2- (diethylamino) pyridin-4-yl] methanol Lithium aluminum hydride (284 mg, 7.5 mmol) was added to a THF solution of methyl 2- (diethylamino) isonicotinate (626 mg, 3.0 mmol). It added at -78 degreeC under argon atmosphere, and stirred after 2 hours. A 20% aqueous potassium potassium tartrate solution was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel chromatography (hexane: ethyl acetate = 3: 2 → 2: 3). , [2- (diethylamino) pyridin-4-yl] methanol (315 mg, 58%) was obtained as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.18 (6H, t, J = 7.1 Hz), 3.52 (4H, q, J = 7.2 Hz), 4.62 (3H, s), 6.45 (1H, d, J = 5.1 Hz), 6.48 (1H, s), 8.09 (1H, d, J = 5.1 Hz).
2-(ジエチルアミノ)イソニコチン酸メチル(626 mg, 3.0 mmol)のTHF溶液に水素化アルミニウムリチウム(284 mg, 7.5 mmol)をアルゴン雰囲気下-78℃にて加え、2時間後攪拌した。20%酒石酸ナトリウムカリウム水溶液を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 3:2→2:3)を用いて精製し、[2-(ジエチルアミノ)ピリジン-4-イル]メタノール(315 mg, 58%)を黄色固体として得た。
1H-NMR (CDCl3) δ: 1.18 (6H, t, J = 7.1 Hz), 3.52 (4H, q, J = 7.2 Hz), 4.62 (3H, s), 6.45 (1H, d, J = 5.1 Hz), 6.48 (1H, s), 8.09 (1H, d, J = 5.1 Hz). Step 3: Preparation of [2- (diethylamino) pyridin-4-yl] methanol Lithium aluminum hydride (284 mg, 7.5 mmol) was added to a THF solution of methyl 2- (diethylamino) isonicotinate (626 mg, 3.0 mmol). It added at -78 degreeC under argon atmosphere, and stirred after 2 hours. A 20% aqueous potassium potassium tartrate solution was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel chromatography (hexane: ethyl acetate = 3: 2 → 2: 3). , [2- (diethylamino) pyridin-4-yl] methanol (315 mg, 58%) was obtained as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.18 (6H, t, J = 7.1 Hz), 3.52 (4H, q, J = 7.2 Hz), 4.62 (3H, s), 6.45 (1H, d, J = 5.1 Hz), 6.48 (1H, s), 8.09 (1H, d, J = 5.1 Hz).
工程4:4-(ブロモメチル)-N, N-ジエチルピリジン-2-アミンの製造
[2-(ジエチルアミノ)ピリジン-4-イル]メタノール(100 mg, 0.55 mmol)及び四臭化炭素(202 mg, 0.61 mmol)のジクロロメタン溶液(2.0 mL)にトリフェニルホスフィン(153 mg, 0.58 mmol)を0℃にて加え、室温にて30分攪拌後、水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して4-(ブロモメチル)-N, N-ジエチルピリジン-2-アミン(327 mg)の粗生成物を得た。
1H-NMR (CDCl3) δ: 1.18 (6H, t, J = 7.1 Hz), 3.50 (4H, q, J = 7.2 Hz), 4.30 (2H, s), 6.43 (1H, s), 6.48 (1H, d, J = 5.1 Hz), 8.10 (1H, d, J = 5.1 Hz). Step 4: Preparation of 4- (bromomethyl) -N, N-diethylpyridin-2-amine [2- (Diethylamino) pyridin-4-yl] methanol (100 mg, 0.55 mmol) and carbon tetrabromide (202 mg, To a dichloromethane solution (2.0 mL) of 0.61 mmol) was added triphenylphosphine (153 mg, 0.58 mmol) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 4- (bromomethyl) -N, N-diethylpyridin-2-amine (327 mg). .
1 H-NMR (CDCl 3 ) δ: 1.18 (6H, t, J = 7.1 Hz), 3.50 (4H, q, J = 7.2 Hz), 4.30 (2H, s), 6.43 (1H, s), 6.48 ( 1H, d, J = 5.1 Hz), 8.10 (1H, d, J = 5.1 Hz).
[2-(ジエチルアミノ)ピリジン-4-イル]メタノール(100 mg, 0.55 mmol)及び四臭化炭素(202 mg, 0.61 mmol)のジクロロメタン溶液(2.0 mL)にトリフェニルホスフィン(153 mg, 0.58 mmol)を0℃にて加え、室温にて30分攪拌後、水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して4-(ブロモメチル)-N, N-ジエチルピリジン-2-アミン(327 mg)の粗生成物を得た。
1H-NMR (CDCl3) δ: 1.18 (6H, t, J = 7.1 Hz), 3.50 (4H, q, J = 7.2 Hz), 4.30 (2H, s), 6.43 (1H, s), 6.48 (1H, d, J = 5.1 Hz), 8.10 (1H, d, J = 5.1 Hz). Step 4: Preparation of 4- (bromomethyl) -N, N-diethylpyridin-2-amine [2- (Diethylamino) pyridin-4-yl] methanol (100 mg, 0.55 mmol) and carbon tetrabromide (202 mg, To a dichloromethane solution (2.0 mL) of 0.61 mmol) was added triphenylphosphine (153 mg, 0.58 mmol) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 4- (bromomethyl) -N, N-diethylpyridin-2-amine (327 mg). .
1 H-NMR (CDCl 3 ) δ: 1.18 (6H, t, J = 7.1 Hz), 3.50 (4H, q, J = 7.2 Hz), 4.30 (2H, s), 6.43 (1H, s), 6.48 ( 1H, d, J = 5.1 Hz), 8.10 (1H, d, J = 5.1 Hz).
工程5:N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程4で製造した4-(ブロモメチル)-N, N-ジエチルピリジン-2-アミン(153 mg)、2-アミノ-5-エトキシピリミジン(35.8 mg, 0.26 mmol)及び炭酸セシウム(90.7 mg, 0.26 mmol)のDMF溶液(2.6 mL)を室温にて48時間攪拌した後、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 3:2→1:1)を用いて精製し、表題化合物(2.9 mg, 二段階4%)を黄色油状物として得た。
NMR (CDCl3) δ: 1.14 (6H, t, J = 7.1 Hz), 1.39 (3H, t, J = 7.0 Hz), 3.48 (4H, q, J = 7.1 Hz), 4.00 (2H, q, J = 7.0 Hz), 4.49-4.51 (2H, m), 5.34 (1H, br), 6.42 (1H, s), 6.46 (1H, d, J = 5.1 Hz), 8.06-8.08 (3H, m). Step 5: Preparation of N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine:
4- (Bromomethyl) -N, N-diethylpyridin-2-amine (153 mg), 2-amino-5-ethoxypyrimidine (35.8 mg, 0.26 mmol) and cesium carbonate (90.7 mg, 0.26 mmol) prepared in Step 4 ) Was stirred at room temperature for 48 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel chromatography (hexane: ethyl acetate = 3: 2 → 1: 1). To give the title compound (2.9 mg, 2% 4%) as a yellow oil.
NMR (CDCl 3 ) δ: 1.14 (6H, t, J = 7.1 Hz), 1.39 (3H, t, J = 7.0 Hz), 3.48 (4H, q, J = 7.1 Hz), 4.00 (2H, q, J = 7.0 Hz), 4.49-4.51 (2H, m), 5.34 (1H, br), 6.42 (1H, s), 6.46 (1H, d, J = 5.1 Hz), 8.06-8.08 (3H, m).
工程4で製造した4-(ブロモメチル)-N, N-ジエチルピリジン-2-アミン(153 mg)、2-アミノ-5-エトキシピリミジン(35.8 mg, 0.26 mmol)及び炭酸セシウム(90.7 mg, 0.26 mmol)のDMF溶液(2.6 mL)を室温にて48時間攪拌した後、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 3:2→1:1)を用いて精製し、表題化合物(2.9 mg, 二段階4%)を黄色油状物として得た。
NMR (CDCl3) δ: 1.14 (6H, t, J = 7.1 Hz), 1.39 (3H, t, J = 7.0 Hz), 3.48 (4H, q, J = 7.1 Hz), 4.00 (2H, q, J = 7.0 Hz), 4.49-4.51 (2H, m), 5.34 (1H, br), 6.42 (1H, s), 6.46 (1H, d, J = 5.1 Hz), 8.06-8.08 (3H, m). Step 5: Preparation of N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine:
4- (Bromomethyl) -N, N-diethylpyridin-2-amine (153 mg), 2-amino-5-ethoxypyrimidine (35.8 mg, 0.26 mmol) and cesium carbonate (90.7 mg, 0.26 mmol) prepared in Step 4 ) Was stirred at room temperature for 48 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified using silica gel chromatography (hexane: ethyl acetate = 3: 2 → 1: 1). To give the title compound (2.9 mg, 2% 4%) as a yellow oil.
NMR (CDCl 3 ) δ: 1.14 (6H, t, J = 7.1 Hz), 1.39 (3H, t, J = 7.0 Hz), 3.48 (4H, q, J = 7.1 Hz), 4.00 (2H, q, J = 7.0 Hz), 4.49-4.51 (2H, m), 5.34 (1H, br), 6.42 (1H, s), 6.46 (1H, d, J = 5.1 Hz), 8.06-8.08 (3H, m).
実施例94
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジプロピルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジプロピルアミンを用いて実施例5の工程1と同様に反応・処理し、表題化合物を黄色固体として得た。
1H-NMR (CDCl3) δ: 0.89 (6H, t, J = 7.2 Hz), 1.68 (4H, m), 2.49 (3H, s), 3.44 (4H, t, J = 7.2 Hz), 3.91 (3H, s), 8.33 (1H, s), 9.99 (1H, s). Example 94
Preparation of 5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- (dipropylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde:
The reaction and treatment were conducted in a similar manner to process 1 of example 5 using dipropylamine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 0.89 (6H, t, J = 7.2 Hz), 1.68 (4H, m), 2.49 (3H, s), 3.44 (4H, t, J = 7.2 Hz), 3.91 ( 3H, s), 8.33 (1H, s), 9.99 (1H, s).
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジプロピルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジプロピルアミンを用いて実施例5の工程1と同様に反応・処理し、表題化合物を黄色固体として得た。
1H-NMR (CDCl3) δ: 0.89 (6H, t, J = 7.2 Hz), 1.68 (4H, m), 2.49 (3H, s), 3.44 (4H, t, J = 7.2 Hz), 3.91 (3H, s), 8.33 (1H, s), 9.99 (1H, s). Example 94
Preparation of 5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- (dipropylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde:
The reaction and treatment were conducted in a similar manner to process 1 of example 5 using dipropylamine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 0.89 (6H, t, J = 7.2 Hz), 1.68 (4H, m), 2.49 (3H, s), 3.44 (4H, t, J = 7.2 Hz), 3.91 ( 3H, s), 8.33 (1H, s), 9.99 (1H, s).
工程2:5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジプロピルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.87 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 1.60 (4H, m), 2.45 (3H, s), 3.24 (4H, t, J = 7.2 Hz), 3.95-4.00 (5H, m), 4.63 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H, s). Step 2: 5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine Manufacturing:
6- (Dipropylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbohydrate instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The aldehyde was used and reacted and treated in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine. Obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.87 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 1.60 (4H, m), 2.45 (3H, s), 3.24 ( 4H, t, J = 7.2 Hz), 3.95-4.00 (5H, m), 4.63 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジプロピルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.87 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 1.60 (4H, m), 2.45 (3H, s), 3.24 (4H, t, J = 7.2 Hz), 3.95-4.00 (5H, m), 4.63 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H, s). Step 2: 5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine Manufacturing:
6- (Dipropylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbohydrate instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The aldehyde was used and reacted and treated in the same manner as in Step 6 of Example 4 using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine. Obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 0.87 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 1.60 (4H, m), 2.45 (3H, s), 3.24 ( 4H, t, J = 7.2 Hz), 3.95-4.00 (5H, m), 4.63 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H, s).
実施例95
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジブチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジブチルアミンを用いて実施例5の工程1と同様に反応・処理し、表題化合物を黄色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (6H, t, J = 7.2 Hz), 1.30 (4H, m), 1.63 (4H, m), 2.49 (3H, s), 3.47 (4H, t, J = 7.2 Hz), 3.91 (3H, s), 8.32 (1H, s), 9.98 (1H, s). Example 95
Preparation of N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- (dibutylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde:
The reaction and treatment were conducted in a similar manner to process 1 of example 5 using dibutylamine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 0.91 (6H, t, J = 7.2 Hz), 1.30 (4H, m), 1.63 (4H, m), 2.49 (3H, s), 3.47 (4H, t, J = 7.2 Hz), 3.91 (3H, s), 8.32 (1H, s), 9.98 (1H, s).
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
工程1:6-(ジブチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの製造:
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジブチルアミンを用いて実施例5の工程1と同様に反応・処理し、表題化合物を黄色固体として得た。
1H-NMR (CDCl3) δ: 0.91 (6H, t, J = 7.2 Hz), 1.30 (4H, m), 1.63 (4H, m), 2.49 (3H, s), 3.47 (4H, t, J = 7.2 Hz), 3.91 (3H, s), 8.32 (1H, s), 9.98 (1H, s). Example 95
Preparation of N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Step 1: Preparation of 6- (dibutylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde:
The reaction and treatment were conducted in a similar manner to process 1 of example 5 using dibutylamine in place of N- (cyclopentylmethyl) -N-ethylamine, and the title compound was obtained as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 0.91 (6H, t, J = 7.2 Hz), 1.30 (4H, m), 1.63 (4H, m), 2.49 (3H, s), 3.47 (4H, t, J = 7.2 Hz), 3.91 (3H, s), 8.32 (1H, s), 9.98 (1H, s).
工程2:N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジブチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.89 (6H, t, J = 7.2 Hz), 1.29 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 1.56 (4H, m), 2.45 (3H, s), 3.27 (4H, t, J = 7.2 Hz), 3.94-4.00 (5H, m), 4.62 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H, s). Step 2: N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Manufacturing:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 6- (dibutylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde And using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was conducted in the same manner as in Step 6 of Example 4 to give the title compound colorless. Obtained as an oil.
1 H-NMR (CDCl 3 ) δ: 0.89 (6H, t, J = 7.2 Hz), 1.29 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 1.56 (4H, m), 2.45 ( 3H, s), 3.27 (4H, t, J = 7.2 Hz), 3.94-4.00 (5H, m), 4.62 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H , s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジブチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 0.89 (6H, t, J = 7.2 Hz), 1.29 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 1.56 (4H, m), 2.45 (3H, s), 3.27 (4H, t, J = 7.2 Hz), 3.94-4.00 (5H, m), 4.62 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H, s). Step 2: N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine Manufacturing:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 6- (dibutylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde And using 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was conducted in the same manner as in Step 6 of Example 4 to give the title compound colorless. Obtained as an oil.
1 H-NMR (CDCl 3 ) δ: 0.89 (6H, t, J = 7.2 Hz), 1.29 (4H, m), 1.38 (3H, t, J = 6.8 Hz), 1.56 (4H, m), 2.45 ( 3H, s), 3.27 (4H, t, J = 7.2 Hz), 3.94-4.00 (5H, m), 4.62 (2H, s), 5.60 (1H, br), 7.84 (1H, s), 8.03 (2H , s).
実施例96
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミンの製造:
工程1:2-(ジエチルアミノ)-6-メチルキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メチルキノリン-3-カルボアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、2-(ジエチルアミノ)-6-メチルキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 2.47 (3H, s), 3.51 (4H, q, J = 7.2 Hz), 7.49-7.52 (2H, m), 7.70 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 10.1 (1H, s). Example 96
Production of 3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine:
Step 1: Preparation of 2- (diethylamino) -6-methylquinoline-3-carbaldehyde 2 instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 2-chloro-6-methylquinoline-3-carbaldehyde and using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine, the reaction and treatment was conducted in the same manner as in Step 1 of Example 5, and 2- (diethylamino ) -6-methylquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 2.47 (3H, s), 3.51 (4H, q, J = 7.2 Hz), 7.49-7.52 (2H, m), 7.70 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 10.1 (1H, s).
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミンの製造:
工程1:2-(ジエチルアミノ)-6-メチルキノリン-3-カルボアルデヒドの製造
6-クロロ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドの代わりに2-クロロ-6-メチルキノリン-3-カルボアルデヒドを用い、N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例5の工程1と同様に反応・処理し、2-(ジエチルアミノ)-6-メチルキノリン-3-カルボアルデヒドを黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 2.47 (3H, s), 3.51 (4H, q, J = 7.2 Hz), 7.49-7.52 (2H, m), 7.70 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 10.1 (1H, s). Example 96
Production of 3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine:
Step 1: Preparation of 2- (diethylamino) -6-methylquinoline-3-carbaldehyde 2 instead of 6-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde Using 2-chloro-6-methylquinoline-3-carbaldehyde and using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine, the reaction and treatment was conducted in the same manner as in Step 1 of Example 5, and 2- (diethylamino ) -6-methylquinoline-3-carbaldehyde was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 2.47 (3H, s), 3.51 (4H, q, J = 7.2 Hz), 7.49-7.52 (2H, m), 7.70 (1H, d, J = 8.6 Hz), 8.38 (1H, s), 10.1 (1H, s).
工程2:3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)-6-メチルキノリン-3-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 2.45 (3H, s), 3.34 (4H, q, J = 7.2 Hz), 3.93 (2H, q, J = 6.8 Hz), 4.71 (2H, s), 5.81 (1H, br), 7.38-7.40 (2H, m), 7.74 (1H, d, J = 8.6 Hz), 7.92 (1H, s), 8.02 (2H, s). Step 2: Preparation of 3-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine 3-[(Cyclopentylmethyl) (ethyl) amino] Using 2- (diethylamino) -6-methylquinoline-3-carbaldehyde instead of 6-methoxypicolinaldehyde and 5-ethoxypyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 2-amine, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 2.45 (3H, s), 3.34 (4H, q, J = 7.2 Hz), 3.93 (2H, q, J = 6.8 Hz), 4.71 (2H, s), 5.81 (1H, br), 7.38-7.40 (2H, m), 7.74 (1H, d, J = 8.6 Hz), 7.92 (1H, s), 8.02 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)-6-メチルキノリン-3-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 2.45 (3H, s), 3.34 (4H, q, J = 7.2 Hz), 3.93 (2H, q, J = 6.8 Hz), 4.71 (2H, s), 5.81 (1H, br), 7.38-7.40 (2H, m), 7.74 (1H, d, J = 8.6 Hz), 7.92 (1H, s), 8.02 (2H, s). Step 2: Preparation of 3-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine 3-[(Cyclopentylmethyl) (ethyl) amino] Using 2- (diethylamino) -6-methylquinoline-3-carbaldehyde instead of 6-methoxypicolinaldehyde and 5-ethoxypyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 2-amine, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 2.45 (3H, s), 3.34 (4H, q, J = 7.2 Hz), 3.93 (2H, q, J = 6.8 Hz), 4.71 (2H, s), 5.81 (1H, br), 7.38-7.40 (2H, m), 7.74 (1H, d, J = 8.6 Hz), 7.92 (1H, s), 8.02 (2H, s).
実施例97
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミンの製造:
工程1:2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例14の工程1と同様に反応・処理し、表題化合物を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.14 (6H, t, J = 7.2 Hz), 3.31 (4H, q, J = 7.2 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.66 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, s), 10.2 (1H, s). Example 97
Preparation of N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 2- (diethylamino) -5- (trifluoromethyl) benzaldehyde Reaction and treatment were conducted in the same manner as in Step 1 of Example 14 using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine. The title compound was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.14 (6H, t, J = 7.2 Hz), 3.31 (4H, q, J = 7.2 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.66 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, s), 10.2 (1H, s).
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミンの製造:
工程1:2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドの製造
N-(シクロペンチルメチル)-N-エチルアミンの代わりにジエチルアミンを用いて実施例14の工程1と同様に反応・処理し、表題化合物を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.14 (6H, t, J = 7.2 Hz), 3.31 (4H, q, J = 7.2 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.66 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, s), 10.2 (1H, s). Example 97
Preparation of N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 2- (diethylamino) -5- (trifluoromethyl) benzaldehyde Reaction and treatment were conducted in the same manner as in Step 1 of Example 14 using diethylamine instead of N- (cyclopentylmethyl) -N-ethylamine. The title compound was obtained as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.14 (6H, t, J = 7.2 Hz), 3.31 (4H, q, J = 7.2 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.66 (1H, dd, J = 2.7, 8.6 Hz), 8.04 (1H, s), 10.2 (1H, s).
工程2:N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を黄色固体として得た。
1H-NMR (CDCl3) δ: 1.04 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.06 (4H, q, J = 7.2 Hz), 4.00(2H, q, J = 6.8 Hz), 4.67 (2H, s), 5.62 (1H, br), 7.18 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 8.05 (2H, s). Step 2: Preparation of N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 2- (diethylamino) -5- (trifluoromethyl) benzaldehyde was used instead of 5- and 5-ethoxypyrimidin-2-amine was used instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.04 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.06 (4H, q, J = 7.2 Hz), 4.00 (2H, q, J = 6.8 Hz), 4.67 (2H, s), 5.62 (1H, br), 7.18 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 8.05 (2H, s).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンズアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を黄色固体として得た。
1H-NMR (CDCl3) δ: 1.04 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.06 (4H, q, J = 7.2 Hz), 4.00(2H, q, J = 6.8 Hz), 4.67 (2H, s), 5.62 (1H, br), 7.18 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 8.05 (2H, s). Step 2: Preparation of N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde 2- (diethylamino) -5- (trifluoromethyl) benzaldehyde was used instead of 5- and 5-ethoxypyrimidin-2-amine was used instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a yellow solid.
1 H-NMR (CDCl 3 ) δ: 1.04 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.06 (4H, q, J = 7.2 Hz), 4.00 (2H, q, J = 6.8 Hz), 4.67 (2H, s), 5.62 (1H, br), 7.18 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 8.05 (2H, s).
実施例98
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒドの製造
実施例88の工程1で製造した2-(ジエチルアミノ)ニコチンアルデヒド(300 mg, 1.68 mmol)のアセトニトリル溶液(5.0 mL)に対しN-ブロモコハク酸イミド(315 mg, 1.77 mmol)を加え、室温で1.5時間攪拌した。反応液を酢酸エチル-水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 10:1)を用いて精製し、5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒド(288 mg, 67%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 8.04 (1H, d, J = 2.7 Hz), 8.32 (1H, d, J = 2.7 Hz), 9.90 (1H, s). Example 98
Production of N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 5-bromo-2- (diethylamino) nicotinaldehyde N- against 2- (diethylamino) nicotinaldehyde (300 mg, 1.68 mmol) prepared in Step 1 of Example 88 in acetonitrile (5.0 mL) Bromosuccinimide (315 mg, 1.77 mmol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was extracted from ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10 1) to give 5-bromo-2- (diethylamino) nicotinaldehyde (288 mg, 67%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 8.04 (1H, d, J = 2.7 Hz), 8.32 (1H, d, J = 2.7 Hz), 9.90 (1H, s).
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
工程1:5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒドの製造
実施例88の工程1で製造した2-(ジエチルアミノ)ニコチンアルデヒド(300 mg, 1.68 mmol)のアセトニトリル溶液(5.0 mL)に対しN-ブロモコハク酸イミド(315 mg, 1.77 mmol)を加え、室温で1.5時間攪拌した。反応液を酢酸エチル-水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 10:1)を用いて精製し、5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒド(288 mg, 67%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 8.04 (1H, d, J = 2.7 Hz), 8.32 (1H, d, J = 2.7 Hz), 9.90 (1H, s). Example 98
Production of N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
Step 1: Preparation of 5-bromo-2- (diethylamino) nicotinaldehyde N- against 2- (diethylamino) nicotinaldehyde (300 mg, 1.68 mmol) prepared in Step 1 of Example 88 in acetonitrile (5.0 mL) Bromosuccinimide (315 mg, 1.77 mmol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was extracted from ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10 1) to give 5-bromo-2- (diethylamino) nicotinaldehyde (288 mg, 67%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.2 Hz), 3.49 (4H, q, J = 7.2 Hz), 8.04 (1H, d, J = 2.7 Hz), 8.32 (1H, d, J = 2.7 Hz), 9.90 (1H, s).
工程2:2-(ジエチルアミノ)-5-フェニルニコチンアルデヒドの製造
5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒド(100 mg, 0.39 mmol)及びフェニルボロン酸(71.1 mg, 0.58 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(22.5 mg, 0.02 mmol)、2M 炭酸ナトリウム溶液(487 μl, 0.98 mmol)を混合し、アルゴン雰囲気置換した。これらをトルエン-エタノール溶液(4.0 mL-1.0 mL)に溶解し、90℃で3時間攪拌した。反応液を酢酸エチル-水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 10:1→5:1)を用いて精製し、2-(ジエチルアミノ)-5-フェニルニコチンアルデヒド(95.3 mg, 96%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.28 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.44 (2H, dd, J = 7.7, 7.7 Hz), 7.55 (2H, d, J = 7.7 Hz), 8.20 (1H, d, J = 2.7 Hz), 8.60 (1H, d, J = 2.7 Hz), 10.1 (1H, s). Step 2: Preparation of 2- (diethylamino) -5-phenylnicotinaldehyde 5-Bromo-2- (diethylamino) nicotinaldehyde (100 mg, 0.39 mmol) and phenylboronic acid (71.1 mg, 0.58 mmol), tetrakis (triphenyl) Phosphine) palladium (0) (22.5 mg, 0.02 mmol) and 2M sodium carbonate solution (487 μl, 0.98 mmol) were mixed and purged with an argon atmosphere. These were dissolved in a toluene-ethanol solution (4.0 mL-1.0 mL) and stirred at 90 ° C. for 3 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 10 To 5: 1) to give 2- (diethylamino) -5-phenylnicotinaldehyde (95.3 mg, 96%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.28 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.44 ( 2H, dd, J = 7.7, 7.7 Hz), 7.55 (2H, d, J = 7.7 Hz), 8.20 (1H, d, J = 2.7 Hz), 8.60 (1H, d, J = 2.7 Hz), 10.1 ( 1H, s).
5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒド(100 mg, 0.39 mmol)及びフェニルボロン酸(71.1 mg, 0.58 mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(22.5 mg, 0.02 mmol)、2M 炭酸ナトリウム溶液(487 μl, 0.98 mmol)を混合し、アルゴン雰囲気置換した。これらをトルエン-エタノール溶液(4.0 mL-1.0 mL)に溶解し、90℃で3時間攪拌した。反応液を酢酸エチル-水より抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮して得られた残渣をシリカゲルクロマトグラフィー(ヘキサン:酢酸エチル = 10:1→5:1)を用いて精製し、2-(ジエチルアミノ)-5-フェニルニコチンアルデヒド(95.3 mg, 96%)を黄色油状物として得た。
1H-NMR (CDCl3) δ: 1.28 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.44 (2H, dd, J = 7.7, 7.7 Hz), 7.55 (2H, d, J = 7.7 Hz), 8.20 (1H, d, J = 2.7 Hz), 8.60 (1H, d, J = 2.7 Hz), 10.1 (1H, s). Step 2: Preparation of 2- (diethylamino) -5-phenylnicotinaldehyde 5-Bromo-2- (diethylamino) nicotinaldehyde (100 mg, 0.39 mmol) and phenylboronic acid (71.1 mg, 0.58 mmol), tetrakis (triphenyl) Phosphine) palladium (0) (22.5 mg, 0.02 mmol) and 2M sodium carbonate solution (487 μl, 0.98 mmol) were mixed and purged with an argon atmosphere. These were dissolved in a toluene-ethanol solution (4.0 mL-1.0 mL) and stirred at 90 ° C. for 3 hours. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 10 To 5: 1) to give 2- (diethylamino) -5-phenylnicotinaldehyde (95.3 mg, 96%) as a yellow oil.
1 H-NMR (CDCl 3 ) δ: 1.28 (6H, t, J = 7.2 Hz), 3.55 (4H, q, J = 7.2 Hz), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.44 ( 2H, dd, J = 7.7, 7.7 Hz), 7.55 (2H, d, J = 7.7 Hz), 8.20 (1H, d, J = 2.7 Hz), 8.60 (1H, d, J = 2.7 Hz), 10.1 ( 1H, s).
工程3:N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)-5-フェニルニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.13 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 3.27 (4H, q, J = 7.2 Hz), 3.96 (2H, q, J = 6.8 Hz), 4.65 (2H, s), 5.87 (1H, br), 7.31 (1H, dd, J = 7.7, 7.7 Hz), 7.40 (2H, dd, J = 7.7, 7.7 Hz), 7.50 (2H, d, J = 7.7 Hz), 7.83 (1H, d, J = 2.7 Hz), 8.02 (2H, s), 8.47 (1H, d, J = 2.7 Hz). Step 3: Preparation of N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6- Performed using 2- (diethylamino) -5-phenylnicotinaldehyde instead of methoxypicolinaldehyde and 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.13 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 3.27 (4H, q, J = 7.2 Hz), 3.96 (2H, q, J = 6.8 Hz), 4.65 (2H, s), 5.87 (1H, br), 7.31 (1H, dd, J = 7.7, 7.7 Hz), 7.40 (2H, dd, J = 7.7, 7.7 Hz), 7.50 (2H, d, J = 7.7 Hz), 7.83 (1H, d, J = 2.7 Hz), 8.02 (2H, s), 8.47 (1H, d, J = 2.7 Hz).
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに2-(ジエチルアミノ)-5-フェニルニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.13 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 3.27 (4H, q, J = 7.2 Hz), 3.96 (2H, q, J = 6.8 Hz), 4.65 (2H, s), 5.87 (1H, br), 7.31 (1H, dd, J = 7.7, 7.7 Hz), 7.40 (2H, dd, J = 7.7, 7.7 Hz), 7.50 (2H, d, J = 7.7 Hz), 7.83 (1H, d, J = 2.7 Hz), 8.02 (2H, s), 8.47 (1H, d, J = 2.7 Hz). Step 3: Preparation of N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine 3-[(cyclopentylmethyl) (ethyl) amino] -6- Performed using 2- (diethylamino) -5-phenylnicotinaldehyde instead of methoxypicolinaldehyde and 5-ethoxypyrimidin-2-amine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Reaction and treatment were conducted in the same manner as in Step 6 of Example 4 to give the title compound as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.13 (6H, t, J = 7.2 Hz), 1.36 (3H, t, J = 6.8 Hz), 3.27 (4H, q, J = 7.2 Hz), 3.96 (2H, q, J = 6.8 Hz), 4.65 (2H, s), 5.87 (1H, br), 7.31 (1H, dd, J = 7.7, 7.7 Hz), 7.40 (2H, dd, J = 7.7, 7.7 Hz), 7.50 (2H, d, J = 7.7 Hz), 7.83 (1H, d, J = 2.7 Hz), 8.02 (2H, s), 8.47 (1H, d, J = 2.7 Hz).
実施例99
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.20 (4H, q, J = 7.2 Hz), 4.00 (2H, q, J = 6.8 Hz), 4.56 (2H, s), 5.67 (1H, br), 7.71 (1H, d, J = 2.7 Hz), 8.03 (2H, s), 8.24 (1H, d, J = 2.7 Hz). Example 99
Production of N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
5- [2- (Methylthio) ethoxy] pyrimidin-2-amine using 5-bromo-2- (diethylamino) nicotinaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.08 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.20 (4H, q, J = 7.2 Hz), 4.00 (2H, q, J = 6.8 Hz), 4.56 (2H, s), 5.67 (1H, br), 7.71 (1H, d, J = 2.7 Hz), 8.03 (2H, s), 8.24 (1H, d, J = 2.7 Hz).
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに5-ブロモ-2-(ジエチルアミノ)ニコチンアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに5-エトキシピリミジン-2-アミンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.08 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.20 (4H, q, J = 7.2 Hz), 4.00 (2H, q, J = 6.8 Hz), 4.56 (2H, s), 5.67 (1H, br), 7.71 (1H, d, J = 2.7 Hz), 8.03 (2H, s), 8.24 (1H, d, J = 2.7 Hz). Example 99
Production of N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine:
5- [2- (Methylthio) ethoxy] pyrimidin-2-amine using 5-bromo-2- (diethylamino) nicotinaldehyde instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde The reaction and treatment were conducted in a similar manner to process 6 of example 4 using 5-ethoxypyrimidin-2-amine in place of, and the title compound was obtained as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.08 (6H, t, J = 7.2 Hz), 1.39 (3H, t, J = 6.8 Hz), 3.20 (4H, q, J = 7.2 Hz), 4.00 (2H, q, J = 6.8 Hz), 4.56 (2H, s), 5.67 (1H, br), 7.71 (1H, d, J = 2.7 Hz), 8.03 (2H, s), 8.24 (1H, d, J = 2.7 Hz).
実施例100
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミンの製造:
2-クロロ-6-(ジエチルアミノ)ベンズアルデヒド(80 mg, 0.38 mmol)及び5-エトキシピリミジン-2-アミン(63.1 mg, 0.45 mmol)、酢酸(23 μl, 0.38 mmol)の1,2-ジクロロエタン(1.8 mL)溶液にトリアセトキシ水素化ホウ素ナトリウム(240 mg, 1.13 mmol)を加え、3時間過熱還流した。反応液に飽和炭酸水素ナトリウム溶液を加え酢酸エチルで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 7:1→3:1)を用いて精製し、N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン(53.2 mg, 42%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.98 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 3.02 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 6.8 Hz), 4.80 (2H, s), 5.71 (1H, br), 7.13-7.20 (3H, m), 8.03 (2H, s). Example 100
Preparation of N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine:
2-chloro-6- (diethylamino) benzaldehyde (80 mg, 0.38 mmol) and 5-ethoxypyrimidin-2-amine (63.1 mg, 0.45 mmol), acetic acid (23 μl, 0.38 mmol) in 1,2-dichloroethane (1.8 mL) Sodium triacetoxyborohydride (240 mg, 1.13 mmol) was added to the solution and heated to reflux for 3 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 3: 1) to give N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidine-2. -Amine (53.2 mg, 42%) was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.98 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 3.02 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 6.8 Hz), 4.80 (2H, s), 5.71 (1H, br), 7.13-7.20 (3H, m), 8.03 (2H, s).
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミンの製造:
2-クロロ-6-(ジエチルアミノ)ベンズアルデヒド(80 mg, 0.38 mmol)及び5-エトキシピリミジン-2-アミン(63.1 mg, 0.45 mmol)、酢酸(23 μl, 0.38 mmol)の1,2-ジクロロエタン(1.8 mL)溶液にトリアセトキシ水素化ホウ素ナトリウム(240 mg, 1.13 mmol)を加え、3時間過熱還流した。反応液に飽和炭酸水素ナトリウム溶液を加え酢酸エチルで抽出した。有機層を併せ、水及び飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル = 7:1→3:1)を用いて精製し、N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン(53.2 mg, 42%)を無色固体として得た。
1H-NMR (CDCl3) δ: 0.98 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 3.02 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 6.8 Hz), 4.80 (2H, s), 5.71 (1H, br), 7.13-7.20 (3H, m), 8.03 (2H, s). Example 100
Preparation of N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine:
2-chloro-6- (diethylamino) benzaldehyde (80 mg, 0.38 mmol) and 5-ethoxypyrimidin-2-amine (63.1 mg, 0.45 mmol), acetic acid (23 μl, 0.38 mmol) in 1,2-dichloroethane (1.8 mL) Sodium triacetoxyborohydride (240 mg, 1.13 mmol) was added to the solution and heated to reflux for 3 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 3: 1) to give N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidine-2. -Amine (53.2 mg, 42%) was obtained as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 0.98 (6H, t, J = 7.2 Hz), 1.38 (3H, t, J = 6.8 Hz), 3.02 (4H, q, J = 7.2 Hz), 3.98 (2H, q, J = 6.8 Hz), 4.80 (2H, s), 5.71 (1H, br), 7.13-7.20 (3H, m), 8.03 (2H, s).
実施例101
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-アミノピリミジンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.23 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.70 (2H, s), 5.93 (1H, br), 6.55 (1H, dd, J = 4.5, 4.5 Hz), 7.85 (1H, s), 8.29 (2H, d, J = 4.5 Hz). Example 101
Preparation of N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. And the same reaction and treatment as in Step 6 of Example 4 was carried out using 2-aminopyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine to obtain the title compound as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.23 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.70 ( 2H, s), 5.93 (1H, br), 6.55 (1H, dd, J = 4.5, 4.5 Hz), 7.85 (1H, s), 8.29 (2H, d, J = 4.5 Hz).
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-アミノピリミジンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を白色固体として得た。
1H-NMR (CDCl3) δ: 1.16 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.23 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.70 (2H, s), 5.93 (1H, br), 6.55 (1H, dd, J = 4.5, 4.5 Hz), 7.85 (1H, s), 8.29 (2H, d, J = 4.5 Hz). Example 101
Preparation of N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. And the same reaction and treatment as in Step 6 of Example 4 was carried out using 2-aminopyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine to obtain the title compound as a white solid.
1 H-NMR (CDCl 3 ) δ: 1.16 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.23 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.70 ( 2H, s), 5.93 (1H, br), 6.55 (1H, dd, J = 4.5, 4.5 Hz), 7.85 (1H, s), 8.29 (2H, d, J = 4.5 Hz).
実施例102
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-アミノ-5-クロロピリミジンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.15 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.30 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.66 (2H, s), 5.95 (1H, br), 7.81 (1H, s), 8.21 (2H, s). Example 102
Preparation of 5-{[(5-chloropyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. And using 2-amino-5-chloropyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was carried out in the same manner as in Step 6 of Example 4 to give the title compound as a colorless oil Obtained as a thing.
1 H-NMR (CDCl 3 ) δ: 1.15 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.30 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.66 ( 2H, s), 5.95 (1H, br), 7.81 (1H, s), 8.21 (2H, s).
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミンの製造:
3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピコリンアルデヒドの代わりに6-(ジエチルアミノ)-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-カルボアルデヒドを用い、5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミンの代わりに2-アミノ-5-クロロピリミジンを用いて実施例4の工程6と同様に反応・処理し、表題化合物を無色油状物として得た。
1H-NMR (CDCl3) δ: 1.15 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.30 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.66 (2H, s), 5.95 (1H, br), 7.81 (1H, s), 8.21 (2H, s). Example 102
Preparation of 5-{[(5-chloropyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine:
Instead of 3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypicolinaldehyde, 6- (diethylamino) -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-carbaldehyde is used. And using 2-amino-5-chloropyrimidine instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine, the reaction and treatment was carried out in the same manner as in Step 6 of Example 4 to give the title compound as a colorless oil Obtained as a thing.
1 H-NMR (CDCl 3 ) δ: 1.15 (6H, t, J = 7.2 Hz), 2.46 (3H, s), 3.30 (4H, t, J = 7.2 Hz), 3.96 (3H, s), 4.66 ( 2H, s), 5.95 (1H, br), 7.81 (1H, s), 8.21 (2H, s).
上記実施例によって得られた化合物を表1に示す。
The compounds obtained in the above examples are shown in Table 1.
試験例1
ヒト肝癌細胞株であるHepG2細胞に被検化合物を添加し、24時間培養後のPCSK9mRNA発現量を定量リアルタイムPCRで測定した。すなわち、HepG2細胞を24穴プレートに2 x 105cells/wellの濃度で播種し一晩培養した後、ジメチルスルホキシド(DMSO)に溶解した被検化合物を培養液に対して1000分の1倍量加えた。CO2 インキュベーターにて37℃で24時間培養後、ISOGEN(ニッポンジーン社、カタログ番号31-02501)を500 μL加えてtotal RNAの抽出を行った。抽出したtotal RNAからHigh Capacity cDNA Reverse Transcription kit(アプライドバイオシステムズ社、カタログ番号4368813)を用いてcDNAを合成した。ヒトPCSK9mRNA発現量はヒトPCSK9に特異的なプライマー(Kourimate S. et.al., J Biol Chem. Vol.283, p9666)及びFast SYBR Green master mix (アプライドバイオシステムズ社、カタログ番号4385614)を用いて測定した。測定機器は7900HT Fast Realtime PCR systemを用いた。 Test example 1
A test compound was added to HepG2 cells, a human liver cancer 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 2 × 10 5 cells / well and cultured overnight, and then the test compound dissolved in dimethyl sulfoxide (DMSO) is 1/1000 times the volume of the culture solution. added. After culturing at 37 ° C. for 24 hours in a CO 2 incubator, 500 μL of ISOGEN (Nippon Gene, catalog number 31-02501) was added, and total RNA was extracted. CDNA was synthesized from the extracted total RNA using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, catalog number 4368813). The expression level of human PCSK9 mRNA was determined using primers specific to human PCSK9 (Kourimate S. et.al., J Biol Chem. Vol.283, p9666) and Fast SYBR Green master mix (Applied Biosystems, catalog number 4385614). It was measured. The measuring instrument used was a 7900HT Fast Realtime PCR system.
ヒト肝癌細胞株であるHepG2細胞に被検化合物を添加し、24時間培養後のPCSK9mRNA発現量を定量リアルタイムPCRで測定した。すなわち、HepG2細胞を24穴プレートに2 x 105cells/wellの濃度で播種し一晩培養した後、ジメチルスルホキシド(DMSO)に溶解した被検化合物を培養液に対して1000分の1倍量加えた。CO2 インキュベーターにて37℃で24時間培養後、ISOGEN(ニッポンジーン社、カタログ番号31-02501)を500 μL加えてtotal RNAの抽出を行った。抽出したtotal RNAからHigh Capacity cDNA Reverse Transcription kit(アプライドバイオシステムズ社、カタログ番号4368813)を用いてcDNAを合成した。ヒトPCSK9mRNA発現量はヒトPCSK9に特異的なプライマー(Kourimate S. et.al., J Biol Chem. Vol.283, p9666)及びFast SYBR Green master mix (アプライドバイオシステムズ社、カタログ番号4385614)を用いて測定した。測定機器は7900HT Fast Realtime PCR systemを用いた。 Test example 1
A test compound was added to HepG2 cells, a human liver cancer 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 2 × 10 5 cells / well and cultured overnight, and then the test compound dissolved in dimethyl sulfoxide (DMSO) is 1/1000 times the volume of the culture solution. added. After culturing at 37 ° C. for 24 hours in a CO 2 incubator, 500 μL of ISOGEN (Nippon Gene, catalog number 31-02501) was added, and total RNA was extracted. CDNA was synthesized from the extracted total RNA using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, catalog number 4368813). The expression level of human PCSK9 mRNA was determined using primers specific to human PCSK9 (Kourimate S. et.al., J Biol Chem. Vol.283, p9666) and Fast SYBR Green master mix (Applied Biosystems, catalog number 4385614). It was measured. The measuring instrument used was a 7900HT Fast Realtime PCR system.
測定値はβ-Actin mRNAの発現量で補正し、DMSOのみ添加した細胞のPCSK9mRNA発現量を1とし、被検化合物を添加した細胞のPCSK9mRNA発現量を相対値で算出した。結果を表2に示す。表2からわかるように、本発明の化合物はPCSK9mRNA発現量を抑制することが確認された。
The measured value was corrected by the expression level of β-Actin-mRNA, and the PCSK9 mRNA expression level of the cells to which DMSO alone was added was 1, and the PCSK9 mRNA expression level of the cells to which the test compound was added was calculated as a relative value. The results are shown in Table 2. As can be seen from Table 2, the compound of the present invention was confirmed to suppress the expression level of PCSK9 mRNA.
試験例2:化合物のHepG2細胞に及ぼすPCSK9タンパク産生量の測定
ヒト肝癌細胞株であるHepG2細胞に被験化合物を添加し、48時間培養後の培養上清中のPCSK9タンパク量をEnzyme-Linked ImmunoSorbent Assay(ELISA)法にて測定することにより、被験化合物のPCSK9産生タンパク量に及ぼす影響を確認した。 Test Example 2: Measurement of PCSK9 Protein Production Amount of Compound on HepG2 Cells A test compound was added to HepG2 cells, a human hepatoma cell line, and the amount of PCSK9 protein in the culture supernatant after 48 hours of culture was measured using Enzyme-Linked Immunosorbent Assay. By measuring by (ELISA) method, the influence which it has on the amount of PCSK9 production protein of a test compound was confirmed.
ヒト肝癌細胞株であるHepG2細胞に被験化合物を添加し、48時間培養後の培養上清中のPCSK9タンパク量をEnzyme-Linked ImmunoSorbent Assay(ELISA)法にて測定することにより、被験化合物のPCSK9産生タンパク量に及ぼす影響を確認した。 Test Example 2: Measurement of PCSK9 Protein Production Amount of Compound on HepG2 Cells A test compound was added to HepG2 cells, a human hepatoma cell line, and the amount of PCSK9 protein in the culture supernatant after 48 hours of culture was measured using Enzyme-Linked Immunosorbent Assay. By measuring by (ELISA) method, the influence which it has on the amount of PCSK9 production protein of a test compound was confirmed.
すなわち、HepG2細胞を6穴プレートに7×105cells/wellの濃度で播種し三晩培養した後、ジメチルスルホキシド(DMSO)に溶解した被験化合物、又はDMSOのみを培養液に対して終濃度10μMとなるように添加した。細胞をCO2 インキュベーターにて37℃で48時間培養した後、細胞培養上清を回収した。回収した細胞培養上清を3000×gにて遠心後、上清を回収し、これを細胞培養上清サンプルとして使用した。
That is, after seeding HepG2 cells in a 6-well plate at a concentration of 7 × 10 5 cells / well and culturing for three nights, a test compound dissolved in dimethyl sulfoxide (DMSO) or DMSO alone is added to the culture solution at a final concentration of 10 μM. It added so that it might become. The cells were cultured in a CO 2 incubator at 37 ° C. for 48 hours, and then the cell culture supernatant was collected. The collected cell culture supernatant was centrifuged at 3000 × g, and the supernatant was collected and used as a cell culture supernatant sample.
Human PCSK9 ELISA kit(R&D:DY3888)よりCapture Antibodyを2.0μg/mLとなるようにPhosphate Buffered Saline(PBS)にて溶解し、96穴プレートに100μLずつ添加した後、室温にて一晩静置した。静置したPlateの上清をすて、Wash buffer(0.05% Tween20 in PBS, pH 7.2-7.4)400μLにて3回洗浄した。Reagent Diluent Buffer(1% Bovine serum albumin(BSA) in PBS, pH 7.2-7.4, 0.2μm filtered)300μLを添加し、1時間室温にて静置した後、Wash bufferにて3回洗浄した。作成した細胞培養上清サンプルをReagent Diluent Bufferにて50倍~100倍希釈し、100μLずつ96穴プレートに添加後、室温にて2時間静置した。Wash bufferにて3回洗浄した後、100μLずつReagent Diluentにて希釈したDetection antibodyを添加し、18時間4℃静置した。Wash bufferにて3回洗浄した後、Reagent Diluentにて50倍希釈したStreptavidin-Horseradish peroxidase(HRP)を100μLずつ添加し、20分室温静置した。Wash bufferにて3回洗浄した後、Substrate Solutionを100μLずつ添加し、20分遮光室温静置した。次にStop solution(2N H2SO4)を50μLずつ添加し、プレートを軽く撹拌させ、450nmの光学密度を測定した。なお、補正値として570nmの光学密度を測定した。産生されたPCSK9タンパク量は、Kitに付属している精製PCSK9タンパクを用いた検量線から算出した。また、データはコントロール(DMSOのみを培養液に加えた培養上清サンプル)を1としたときの相対値を表示した。結果を表3に示す。表3からわかるように、本発明の化合物はPCSK9タンパク産生量を抑制することが確認された。
From the Human PCSK9 ELISA kit (R & D: DY3888), Capture Antibody was dissolved at 2.0 μg / mL in Phosphate Buffered Saline (PBS), added 100 μL to a 96-well plate, and then allowed to stand overnight at room temperature. did. The plate supernatant that had been allowed to stand was rinsed and washed three times with 400 μL of wash buffer (0.05% Tween 20 in PBS, pH 7.2-7.4). Add 300 μL of Reagent Diluent Buffer (1% Bovine serum albumin (BSA) in PBS, pH 7.2-7.4, 0.2 μm filtered) and let stand at room temperature for 1 hour, then 3 times with Wash buffer Washed. The prepared cell culture supernatant sample was diluted 50- to 100-fold with Reagent Diluent Buffer, added 100 μL at a time to a 96-well plate, and allowed to stand at room temperature for 2 hours. After washing with Wash buffer three times, Detection antibody diluted with Reagent Diluent 100 μL at a time was added and allowed to stand at 4 ° C. for 18 hours. After washing 3 times with Wash buffer, 100 μL of Streptavidin-Horseadish peroxide (HRP) diluted 50-fold with Reagent Diluent was added and allowed to stand at room temperature for 20 minutes. After washing three times with a wash buffer, 100 μL of Substrate Solution was added, and the mixture was allowed to stand at room temperature for 20 minutes in the dark. Next, Stop solution (2N H 2 SO 4 ) was added in 50 μL aliquots, the plate was gently stirred, and the optical density at 450 nm was measured. In addition, the optical density of 570 nm was measured as a correction value. The amount of PCSK9 protein produced was calculated from a calibration curve using purified PCSK9 protein attached to Kit. In addition, the data represent relative values when the control (culture supernatant sample in which only DMSO was added to the culture solution) was set to 1. The results are shown in Table 3. As can be seen from Table 3, it was confirmed that the compound of the present invention suppresses PCSK9 protein production.
以上の薬理試験結果より、本発明の化合物、若しくはその塩、又はそれらの溶媒和物は、強力なPCSK9mRNA発現抑制作用及びPCSK9タンパク産生抑制作用を有し、PCSK9mRNA発現、PCSK9タンパクが関与する疾患(例えば、脂質異常症(高脂血症)、動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、高LDL血症、低HDL血症、高コレステロール血症、高トリグリセリド血症、家族性高コレステロール血症、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧、癌、肥満、糖尿病、アルツハイマー病又はウイルス感染症等の治療又は予防剤の有効成分として好適に使用できることが明らかとなった。
From the above pharmacological test results, the compound of the present invention, or a salt thereof, or a solvate thereof has a strong PCSK9 mRNA expression inhibitory action and PCSK9 protein production inhibitory action, and a disease involving PCSK9 mRNA expression and PCSK9 protein ( For example, dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper LDL, hypo HDL, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterol Treatment of blood pressure, cardiovascular disorder, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cancer, obesity, diabetes, Alzheimer's disease or viral infection Or it became clear that it can be used conveniently as an active ingredient of a preventive agent.
本発明の一般式(I)で表される化合物は、PCSK9mRNA発現抑制作用及びPCSK9タンパク産生抑制作用及びLDL受容体量を増加する作用を有しており、LDLを低下させるための医薬の有効成分として使用できるほか、PCSK9mRNA発現抑制剤、PCSK9タンパク産生抑制剤、LDL受容体量を増加する薬剤などの有効成分として好適に使用することができる。さらにはスタチン系薬剤におけるLDLコレステロール低下作用を増強することができるので、スタチン系薬剤との組み合わせにより高いLDLコレステロール低下作用を達成することができる。
The compound represented by the general formula (I) of the present invention has a PCSK9 mRNA expression inhibitory action, a PCSK9 protein production inhibitory action, and an action of increasing the amount of LDL receptor, and an active pharmaceutical ingredient for reducing LDL. In addition, it can be suitably used as an active ingredient such as a PCSK9 mRNA expression inhibitor, a PCSK9 protein production inhibitor, and a drug that increases the amount of LDL receptor. Furthermore, since the LDL cholesterol lowering action in the statin drugs can be enhanced, a high LDL cholesterol lowering action can be achieved by combining with the statin drugs.
Claims (14)
- 次の一般式(I):
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示し、ただし、それらのうちの0乃至2個は窒素原子に置き換えてもよく、
R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、C6-10アリール基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいアミノC1-6アルキル基、置換基を有してもよいカルバモイルC1-6アルキル基、C2-6アルケニル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールオキシC1-6アルキル基を示す)
で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。 The following general formula (I):
W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms Well,
R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 An alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) ( or it shows a R 10), or adjacent to each other may form a nitrogen-containing aromatic heterocyclic ring which may have a benzene ring or a substituted group which may have a substituent together
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted amino C 1-6 alkyl group, or an optionally substituted carbamoyl C. 1-6 alkyl group, C 2-6 alkenyl group, optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, carboxy 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 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom),
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group or a C 6-10 aryloxy C 1-6 alkyl group)
Or a salt thereof, or a solvate thereof as an active ingredient. - 一般式(I)で表される化合物が、
5-メトキシピリミジン-2-アミン、
5-エトキシピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチル、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチル、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチル、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-クロロ-6-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
である請求項1に記載の医薬。 The compound represented by the general formula (I) is
5-methoxypyrimidin-2-amine,
5-ethoxypyrimidin-2-amine,
5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
Ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] ethyl butyrate,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Methyl propionate,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2-chloro-6- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-chloropyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
The medicament according to claim 1, wherein - 請求項1又は2に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むPCSK9mRNA発現抑制剤。 A PCSK9 mRNA expression inhibitor comprising the compound represented by the general formula (I) according to claim 1 or 2 or a salt thereof, or a solvate thereof as an active ingredient.
- 請求項1又は2に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むPCSK9タンパク産生抑制剤。 A PCSK9 protein production inhibitor comprising the compound represented by formula (I) according to claim 1 or 2, or a salt thereof, or a solvate thereof as an active ingredient.
- 請求項1又は2に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含むLDL受容体量の増加剤。 An agent for increasing the amount of LDL receptor comprising, as an active ingredient, the compound represented by formula (I) according to claim 1 or 2, or a salt thereof, or a solvate thereof.
- 高LDL血症の予防及び/又は治療に用いる請求項1又は2に記載の医薬。 The medicament according to claim 1 or 2, which is used for prevention and / or treatment of hyper-LDLemia.
- スタチン系薬剤によるLDLコレステロール低下作用を増強するための医薬であって、請求項1又は2に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。 A medicament for enhancing the LDL cholesterol lowering action by a statin drug, comprising the compound represented by the general formula (I) according to claim 1 or 2, a salt thereof, or a solvate thereof as an active ingredient Containing as a medicine.
- 動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧、癌、肥満、糖尿病、アルツハイマー病、ウイルス感染症、炎症、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染症、乾癬又は黄斑変性の予防及び/又は治療のための医薬であって、請求項1又は2に記載の一般式(I)で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含む医薬。 Arteriosclerosis, atherosclerosis, peripheral vascular disease, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cancer, obesity, A medicament for the prevention and / or treatment of diabetes, Alzheimer's disease, viral infection, inflammation, osteoporosis, prostatic hypertrophy, glomerular disease, parasitic infection, psoriasis or macular degeneration, according to claim 1 or 2. Or a salt thereof or a solvate thereof as an active ingredient.
- 次の一般式(I):
W1、W2、W3、W4、W5は、それぞれCR4、CR5、CR6、CR7、CR8を示し、ただし、それらのうちの0乃至2個は窒素原子に置き換えてもよく、
R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、C6-10アリール基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいアミノC1-6アルキル基、置換基を有してもよいカルバモイルC1-6アルキル基、C2-6アルケニル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールC1-6アルキル基を示し、、
但し、R11がC1-4アルキル基であり、W1、W2、W3、W4、W5がCR4、CR5、CR6、CR7、CR8であるとき、R4、R5、R6、R7、R8が、水素原子、C1-4アルキル基、C1-4アルコキシ基、ハロゲン原子、ジエチルアミノ基である化合物を除き、
さらに、5-メトキシピリミジン-2-アミン、
5-エトキシピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]-6-メトキシピリジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル
N-(4-メトキシベンジル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{[6-メトキシ-3-(ピロリジン-1-イル)ピリジン-2-イル]メチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[エチル(4-メトキシベンジル)アミノ]-6-メトキシピリミジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、及び
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸エチル
を除く)
で表される化合物、若しくはその塩、又はそれらの溶媒和物。 The following general formula (I):
W 1 , W 2 , W 3 , W 4 , W 5 represent CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , respectively, provided that 0 to 2 of them are replaced with nitrogen atoms Well,
R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, Halo C 1-6 alkoxy group, hydroxyl group, C 6-10 aryl group, cyano group, nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 An alkylsulfonylamino group, a halo C 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) ( or it shows a R 10), or adjacent to each other may form a nitrogen-containing aromatic heterocyclic ring which may have a benzene ring or a substituted group which may have a substituent together
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted amino C 1-6 alkyl group, or an optionally substituted carbamoyl C. 1-6 alkyl group, C 2-6 alkenyl group, optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, C 1-6 alkoxycarbonyl C 1-6 alkyl group, carboxy 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 9 and R 10 may be taken together to form a nitrogen-containing saturated heterocyclic ring which may have a substituent with an adjacent nitrogen atom),
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group,
Provided that when R 11 is a C 1-4 alkyl group and W 1 , W 2 , W 3 , W 4 , W 5 are CR 4 , CR 5 , CR 6 , CR 7 , CR 8 , R 4 , Except for compounds in which R 5 , R 6 , R 7 , R 8 are a hydrogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, a halogen atom, or a diethylamino group,
In addition, 5-methoxypyrimidin-2-amine,
5-ethoxypyrimidin-2-amine,
5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] -6-methoxypyridin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-{[6-methoxy-3- (pyrrolidin-1-yl) pyridin-2-yl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3- [ethyl (4-methoxybenzyl) amino] -6-methoxypyrimidin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine, and 4-[( 2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] ethyl butyrate)
Or a salt thereof, or a solvate thereof. - R4、R5、R6、R7、R8は、それぞれ同一又は異なって、水素原子、ハロゲン原子、C1-6アルキル基、ハロC1-6アルキル基、C1-6アルコキシ基、ハロC1-6アルコキシ基、水酸基、シアノ基、ニトロ基、C1-6アルキルチオ基、C1-6アルキルスルフィニル基、C1-6アルキルスルホニル基、C1-6アルキルスルホニルアミノ基、ハロC1-6アルキルスルホニルアミノ基、C6-10アリールスルホニルアミノ基、カルボキシル基、C1-6アルキルカルボニル基、C1-6アルコキシカルボニル基、又はN(R9)(R10)を示すか、又は隣接する同士が一緒になって置換基を有してもよいベンゼン環又は置換基を有してもよい含窒素芳香族複素環を形成してもよく、
R9、及びR10は、それぞれ同一又は異なって、水素原子、C1-6アルキル基、置換基を有してもよいC3-8シクロアルキルC1-6アルキル基、C6-10アリール基、置換基を有してもよいC6-10アリールC1-6アルキル基、若しくはC3-8シクロアルキル基を示すか、又はR9、及びR10が一緒になって隣接する窒素原子とともに置換基を有してもよい含窒素飽和複素環を形成してもよい)を示し、
R2は水素原子、ハロゲン原子、又はOR11を示し、
R11はC1-6アルキル基、C1-6アルキルチオC1-6アルキル基、C1-6アルキルスルフィニルC1-6アルキル基、C1-6アルキルスルホニルC1-6アルキル基、C1-6アルコキシカルボニルC1-6アルキル基、カルボキシC1-6アルキル基、C6-10アリールチオC1-6アルキル基、C6-10アリールスルフィニルC1-6アルキル基、C6-10アリールスルホニルC1-6アルキル基、又はC6-10アリールオキシC1-6アルキル基を示す、
で表される請求項9に記載の化合物、若しくはその塩、又はそれらの溶媒和物。 R 4 , R 5 , R 6 , R 7 , R 8 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, halo C 1-6 alkoxy group, a hydroxyl group, a cyano group, a nitro group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 1-6 alkylsulfonylamino group, halo C A 1-6 alkylsulfonylamino group, a C 6-10 arylsulfonylamino group, a carboxyl group, a C 1-6 alkylcarbonyl group, a C 1-6 alkoxycarbonyl group, or N (R 9 ) (R 10 ), Or adjacent to each other may form a benzene ring which may have a substituent or a nitrogen-containing aromatic heterocyclic ring which may have a substituent,
R 9 and R 10 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl C 1-6 alkyl group, or 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 9 and R 10 taken together are adjacent nitrogen atoms And a nitrogen-containing saturated heterocyclic ring which may have a substituent may be formed)
R 2 represents a hydrogen atom, a halogen atom, or OR 11 ;
R 11 represents a C 1-6 alkyl group, a C 1-6 alkylthio C 1-6 alkyl group, a C 1-6 alkylsulfinyl C 1-6 alkyl group, a C 1-6 alkylsulfonyl C 1-6 alkyl group, C 1 -6 alkoxycarbonyl C 1-6 alkyl group, carboxy C 1-6 alkyl group, C 6-10 arylthio C 1-6 alkyl group, C 6-10 arylsulfinyl C 1-6 alkyl group, C 6-10 arylsulfonyl A C 1-6 alkyl group or a C 6-10 aryloxy C 1-6 alkyl group,
The compound of Claim 9 represented by these, its salt, or those solvates. - 一般式(I)で表される化合物が、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
である請求項10に記載の化合物、若しくはその塩、又はそれらの溶媒和物。 The compound represented by the general formula (I) is
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
The compound according to claim 10, or a salt thereof, or a solvate thereof. - 一般式(I)で表される化合物が、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メトキシ-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-6-(トリフルオロメチル)キノリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-6-メチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノリン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-メチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-6-エチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({2-[(シクロペンチルメチル)(エチル)アミノ]-5,6-ジメチルピリジン-3-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-({3-[(シクロペンチルメチル)(エチル)アミノ]ピラジン-2-イル}メチル)-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-メトキシベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]-3-メチルベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-4,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-クロロ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-5-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{4-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{5-ブロモ-2-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-ピペリジノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[2-モルホリノ-5-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
N-[2-(4-メチルピペリジノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(cis-2,6-ジメチルモルホリノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-{2-[ビス(シクロプロピルメチル)アミノ]-3,5-ジフルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
(S)-N-{1-[3,5-ビス(トリフルオロメチル)フェニル]エチル}-5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸、
N-[2-(ジアリルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[3,5-ビス(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
5-[2-(メチルチオ)エトキシ]-N-[3-(トリフルオロメチル)ベンジル]ピリミジン-2-アミン、
5-[2-(フェニルチオ)エトキシ]ピリミジン-2-アミン、
5-(2-フェノキシエトキシ)ピリミジン-2-アミン、
2-{trans-4-[(エチル{2-[({5-[2-(フェニルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-[trans-4-({エチル[2-({[5-(2-フェノキシエトキシ)ピリミジン-2-イル]アミノ}メチル)-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({エチル[2-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル]アミノ}メチル)シクロヘキシル]酢酸エチル、
2-[trans-4-({[2-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-4-(トリフルオロメチル)フェニル](エチル)アミノ}メチル)シクロヘキシル]酢酸エチル、
2-{trans-4-[(エチル{2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸ベンジル、
N-{2-[エチル(4-メトキシベンジル)アミノ]-5-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-[2-(エチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
2-(trans-4-{[(4-メトキシベンジル){2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ]メチル}シクロヘキシル)酢酸エチル、
2-{trans-4-[({2-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}アミノ)メチル]シクロヘキシル}酢酸エチル、
2-(trans-4-{[{2-クロロ-6-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-4-(トリフルオロメチル)フェニル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
N-{2-クロロ-6-[(シクロペンチルメチル)(エチル)アミノ]ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-(トリフルオロメチル)ベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-6-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-{2-[(シクロペンチルメチル)(エチル)アミノ]-3-フルオロベンジル}-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-ベンジル-5-[2-(メチルチオ)エトキシ]ピリミジン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-3-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]キノキサリン-2-アミン、
N-(シクロペンチルメチル)-N-エチル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N-エチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-(シクロペンチルメチル)-N-エチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-[(1,3-ジメチル-6-ピペリジノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N-[(1,3-ジメチル-6-モルホリノ-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]-5-エトキシピリミジン-2-アミン、
N,N-ビス(シクロプロピルメチル)-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N-ベンジル-5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,1,3-トリメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-メトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルフィニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジエチル-1,3-ジメチル-5-[({5-[2-(メチルスルホニル)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N,1,3-テトラメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸エチル、
2-(trans-4-{[{1,3-ジメチル-5-[({5-[2-(メチルチオ)エトキシ]ピリミジン-2-イル}アミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-イル}(エチル)アミノ]メチル}シクロヘキシル)酢酸、
N-{[1,3-ジメチル-6-(ピロリジン-1-イル)-1H-ピラゾロ[3,4-b]ピリジン-5-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-メトキシ-N-[(6-メトキシ-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル)メチル]ピリミジン-2-アミン、
4-[(2-アミノピリミジン-5-イル)オキシ]酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸エチル、
4-({2-[({6-[(シクロペンチルメチル)(エチル)アミノ]-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-5-イル}メチル)アミノ]ピリミジン-5-イル}オキシ)酪酸、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸メチル、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(メチル)アミノ]プロピオン酸、
4-[(2-{[3,5-ビス(トリフルオロメチル)ベンジル]アミノ}ピリミジン-5-イル)オキシ]酪酸、
N-{[2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-[2-(ジエチルアミノ)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[6-(ジメチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルキノリン-2-アミン、
3-[(5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-イル)(エチル)アミノ]プロピオン酸メチル、
N-{[2-(ジエチルアミノ)ピリジン-4-イル]メチル}-5-エトキシピリミジン-2-アミン、
5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-N,N-ジプロピル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
N,N-ジブチル-5-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
3-{[(5-エトキシピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-6-メチルキノリン-2-アミン、
N-[2-(ジエチルアミノ)-5-(トリフルオロメチル)ベンジル]-5-エトキシピリミジン-2-アミン、
N-{[2-(ジエチルアミノ)-5-フェニルピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N-{[5-ブロモ-2-(ジエチルアミノ)ピリジン-3-イル]メチル}-5-エトキシピリミジン-2-アミン、
N,N-ジエチル-1,3-ジメチル-5-[(ピリミジン-2-イルアミノ)メチル]-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
5-{[(5-クロロピリミジン-2-イル)アミノ]メチル}-N,N-ジエチル-1,3-ジメチル-1H-ピラゾロ[3,4-b]ピリジン-6-アミン、
である請求項9に記載の化合物、若しくはその塩、又はそれらの溶媒和物。 The compound represented by the general formula (I) is
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 -B] pyridine-6-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methoxy-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -6- (trifluoromethyl) quinolin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-6-methyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinolin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-methylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -6-ethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2-[(cyclopentylmethyl) (ethyl) amino] -5,6-dimethylpyridin-3-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({3-[(cyclopentylmethyl) (ethyl) amino] pyrazin-2-yl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-piperidino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [2-morpholino-5- (trifluoromethyl) benzyl] pyrimidin-2-amine,
N- [2- (4-methylpiperidino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} acetic acid,
N- {2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
(S) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl ] Cyclohexyl} ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl Cyclohexyl} acetic acid,
N- [2- (diallylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [3,5-bis (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
5- [2- (methylthio) ethoxy] -N- [3- (trifluoromethyl) benzyl] pyrimidin-2-amine,
5- [2- (phenylthio) ethoxy] pyrimidin-2-amine,
5- (2-phenoxyethoxy) pyrimidin-2-amine,
2- {trans-4-[(ethyl {2-[({5- [2- (phenylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} ethyl acetate,
2- [trans-4-({ethyl [2-({[5- (2-phenoxyethoxy) pyrimidin-2-yl] amino} methyl) -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] Ethyl acetate,
2- [trans-4-({ethyl [2-{[(5-methoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] amino} methyl) cyclohexyl] ethyl acetate,
2- [trans-4-({[2-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate,
2- {trans-4-[(ethyl {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] Cyclohexyl} benzyl acetate,
N- {2- [ethyl (4-methoxybenzyl) amino] -5- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- [2- (ethylamino) -5- (trifluoromethyl) benzyl] -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
2- (trans-4-{[(4-methoxybenzyl) {2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl } Amino] methyl} cyclohexyl) ethyl acetate,
2- {trans-4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} amino) methyl] cyclohexyl }Ethyl acetate,
2- (trans-4-{[{2-chloro-6-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} ( Ethyl) amino] methyl} cyclohexyl) ethyl acetate,
N- {2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6- (trifluoromethyl) benzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -6-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {2-[(cyclopentylmethyl) (ethyl) amino] -3-fluorobenzyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N-benzyl-5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-3-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] quinoxalin-2-amine,
N- (cyclopentylmethyl) -N-ethyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N-ethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
N- (cyclopentylmethyl) -N-ethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3 4-b] pyridin-6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N-[(1,3-dimethyl-6-piperidino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N-[(1,3-dimethyl-6-morpholino-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] -5-ethoxypyrimidin-2-amine,
N, N-bis (cyclopropylmethyl) -5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-6- Amines,
N-benzyl-5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, 1,3-trimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-methoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine- 6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
N, N-diethyl-1,3-dimethyl-5-[({5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4-b] pyridine -6-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N, 1,3-tetramethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
2- (trans-4-{[{1,3-dimethyl-5-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -1H-pyrazolo [3,4 b] pyridin-6-yl} (ethyl) amino] methyl} cyclohexyl) ethyl acetate,
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) acetic acid,
N-{[1,3-dimethyl-6- (pyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-5-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-methoxy-N-[(6-methoxy-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) methyl] pyrimidin-2-amine,
Ethyl 4-[(2-aminopyrimidin-5-yl) oxy] butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) ethyl butyrate,
4-({2-[({6-[(Cyclopentylmethyl) (ethyl) amino] -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl} methyl) amino] pyrimidine- 5-yl} oxy) butyric acid,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Methyl propionate,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (methyl) amino] Propionic acid,
4-[(2-{[3,5-bis (trifluoromethyl) benzyl] amino} pyrimidin-5-yl) oxy] butyric acid,
N-{[2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N- [2- (diethylamino) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[6- (dimethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethylquinolin-2-amine,
3-[(5-{[(5-Ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-yl) (ethyl) amino] Methyl propionate,
N-{[2- (diethylamino) pyridin-4-yl] methyl} -5-ethoxypyrimidin-2-amine,
5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-N, N-dipropyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
N, N-dibutyl-5-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
3-{[(5-ethoxypyrimidin-2-yl) amino] methyl} -N, N-diethyl-6-methylquinolin-2-amine,
N- [2- (diethylamino) -5- (trifluoromethyl) benzyl] -5-ethoxypyrimidin-2-amine,
N-{[2- (diethylamino) -5-phenylpyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N-{[5-bromo-2- (diethylamino) pyridin-3-yl] methyl} -5-ethoxypyrimidin-2-amine,
N, N-diethyl-1,3-dimethyl-5-[(pyrimidin-2-ylamino) methyl] -1H-pyrazolo [3,4-b] pyridin-6-amine,
5-{[(5-chloropyrimidin-2-yl) amino] methyl} -N, N-diethyl-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-6-amine,
The compound according to claim 9, or a salt thereof, or a solvate thereof. - 請求項9~12のいずれか1項記載の化合物、若しくはその塩、又はそれらの溶媒和物、及び医薬として許容される担体を含む医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 9 to 12, or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
- 請求項9~12のいずれか1項記載の化合物、若しくはその塩、又はそれらの溶媒和物の、有効量をヒトを含む哺乳類動物に投与することを特徴とする動脈硬化症、アテローム性動脈硬化症、末梢血管疾患、心臓血管障害、狭心症、虚血、心虚血、血栓症、心筋梗塞、再灌流障害、血管形成性再狭窄、高血圧、癌、肥満、糖尿病、アルツハイマー病、ウイルス感染症、炎症、骨粗鬆症、前立腺肥大、糸球体疾患、寄生虫感染症、乾癬又は黄斑変性から選ばれる疾患を予防及び/又は治療する方法。
An arteriosclerosis or atherosclerosis characterized by administering an effective amount of the compound according to any one of claims 9 to 12 or a salt thereof, or a solvate thereof to a mammal including a human. Disease, peripheral vascular disease, cardiovascular disorder, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, cancer, obesity, diabetes, Alzheimer's disease, viral infection A method for preventing and / or treating a disease selected from inflammation, osteoporosis, prostatic hypertrophy, glomerular disease, parasitic infection, psoriasis or macular degeneration.
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