JP5319457B2 - Pyrimidine compounds having a novel dibenzylamine structure and pharmaceuticals containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a substance exhibiting strong inhibiting activity against a cholesterol ester transfer protein (CETP). <P>SOLUTION: The compound is expressed by general formula (I) (R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>and R<SP>5</SP>are each a hydrogen atom, a halo-lower alkyl, a cyano group or the like; R<SP>6</SP>is an alkyl group, cycloalkyl group or the like; R<SP>7</SP>, R<SP>8</SP>, R<SP>9</SP>and R<SP>10</SP>are each hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group or the like; R<SP>11</SP>and R<SP>12</SP>are each a hydrogen atom, a lower alkyl group, a lower cycloalkyl-lower alkyl group or the like; and R<SP>13</SP>is a hydrogen atom, a halogen atom or the like). <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a pyrimidine compound having a novel dibenzylamine structure having a cholesterol ester transfer protein (CETP) inhibitory activity and a medicament containing the same.

  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. Since low-density lipoprotein (LDL) cholesterol and triglyceride levels are positively correlated with the incidence of heart disease, conventional drug treatments for dyslipidemia and arteriosclerosis focus on lowering blood lipids. It has been. On the other hand, many studies have shown that high-density lipoprotein (HDL) cholesterol levels in plasma and the occurrence of ischemic heart disease are inversely related. HypoHDLemia is a risk of arteriosclerosis. It is considered as one of the factors. However, there are no drugs that selectively and significantly increase HDL levels at present, and their development is expected.

  Cholesterol ester transfer protein (CETP) is a very hydrophobic protein that transfers cholesterol ester from HDL cholesterol to LDL cholesterol, very low density lipoprotein (VLDL) cholesterol, etc., and inhibits transfer by CETP. Can be increased.

  Niacin also significantly increases HDL cholesterol, but has serious tolerance problems such as hot flashes, dizziness, palpitation and reduced compliance. Fibrates and HMG-CoA reductase inhibitors only slightly increase HDL cholesterol levels (10-12%), but adequately address the medical need to significantly increase plasma HDL cholesterol levels and slow the progression of atherosclerosis It has not been. On the other hand, the increase in HDL cholesterol level by CETP inhibitors is strong, and regression of arteriosclerotic lesions that cannot be surpassed by fibrates and HMG-CoA reductase inhibitors can be expected, preventing unprecedented arteriosclerosis or dyslipidemia Alternatively, it may be possible to supply a therapeutic agent. In addition, CETP inhibitors cause an increase in HDL cholesterol and a decrease in LDL cholesterol and VLDL cholesterol by a mechanism different from that of HMG-CoA reductase inhibitors, so it is possible to use CETP inhibitors in combination with HMG-CoA reductase inhibitors. A synergistic effect is also expected.

  CETP is mainly produced in the liver and small intestine in humans, and it is considered that CETP expressed in the small intestine is involved in lipid absorption. There has also been a report for the purpose of suppressing lipid absorption by inhibiting CETP in the small intestine (Patent Document 1).

  So far, there have been several reports of compounds aimed at inhibiting CETP activity. For example, a thiol derivative that forms a disulfide bond by reaction with a cysteine residue of CETP and inhibits CETP activity has been reported (Patent Document 2, Non-Patent Document 1). However, thiol derivatives need to be administered in large quantities for expression of action, and there are concerns about side effects due to disulfide bond formation with other proteins. Moreover, there is no description which suggests the compound of this invention.

  Tetrahydroquinoline derivatives have been disclosed as CETP inhibitors that have a different mechanism of action from thiol derivatives (Patent Documents 3 to 5). However, these are highly fat-soluble compounds, and due to their low oral absorbability due to their low water solubility, pharmaceutical preparations are required to obtain a sufficient blood concentration for the expression of their efficacy (Patent Document 6). . Moreover, there is no description which suggests the compound of this invention.

  In addition, tetrahydronaphthyridine derivatives, benzyl (heterocyclic methyl) amine derivatives and the like are also disclosed as compounds showing CETP inhibitory activity (Patent Documents 7 to 12). However, like the tetrahydroquinoline derivative, it is a very high fat-soluble compound. Moreover, there is no description which suggests the compound of this invention.

  Furthermore, a compound having a dibenzylamine structure is also disclosed (Patent Document 13). However, unlike the pyrimidine compound having a dibenzylamine structure of the present invention, it does not have a substituent such as a lower alkyl group at the benzylic carbon atom, and there is no description suggesting the compound of the present invention. Furthermore, sufficient CETP inhibitory activity was not obtained.

In addition, a tri-substituted amine derivative having CETP inhibitory activity has been reported (Patent Document 14). However, this publication does not specifically disclose a compound having a substituent (such as R ^{6 in the following} general formula) such as an alkyl group on the carbon atom at the benzyl position, which is a feature of the compound of the present invention. the IC ₅₀ values are 50μM or less for only is described that it is (JP 14,89 pp) compounds with potent CETP inhibitory activity to the extent that the present invention compound has (IC ₅₀ values less than the 1 [mu] M) There is no specific description or description that suggests its existence.

International Publication No. 2006/098394 Pamphlet JP 11-49743 A International Publication No. 2000/17164 Pamphlet International Publication No. 2000/17165 Pamphlet International Publication No. 2000/17166 Pamphlet International Publication No. 2003/63868 Pamphlet International Publication No. 2005/095395 Pamphlet International Publication No. 2006/056854 Pamphlet International Publication No. 2006/073973 Pamphlet International Publication No. 2007/073934 Pamphlet International Publication No. 2007/128568 Pamphlet International Publication No. 2007/088999 Pamphlet International Publication No. 2004/020393 Pamphlet International Publication No. 2007/088996 Pamphlet

Circulation 105 (18), 2159-2165 (2002)

  An object of the present invention is to provide a novel compound exhibiting strong inhibitory activity against CETP.

As a result of continuing intensive studies to achieve the above object, the present inventors have found that the compound represented by the general formula (I)
(Where
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, halogen atom, lower alkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, hydroxyl group, cyano Group, nitro group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, halolower alkylsulfonylamino group, arylsulfonylamino group, amino group which may have a substituent, carboxyl group , Lower alkylcarbonyl group, or lower alkoxycarbonyl group,
R ⁶ represents a lower alkyl group, a halo lower alkyl group, a lower cycloalkyl group, or a lower cycloalkyl lower alkyl group,
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl group, a lower cycloalkyl lower alkyl group, a halo lower alkyl group or a lower alkoxy group. Halo lower alkoxy group, lower alkoxy lower alkoxy group, hydroxyl group, cyano group, nitro group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylsulfonylamino group, halolower alkylsulfonylamino group, arylsulfonylamino A group, an amino group which may have a substituent, a carboxyl group, a lower alkylcarbonyl group, or a lower alkoxycarbonyl group;
R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted lower cycloalkyl lower alkyl group, an aryl group, or an optionally substituted aryl lower alkyl. A group, or a lower cycloalkyl group, or R ¹¹ and R ¹² together may form a nitrogen-containing saturated heterocyclic ring which may have a substituent with the adjacent nitrogen atom,
R ¹³ represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkylthio lower alkoxy group, a lower alkylsulfinyl lower alkoxy group, a lower alkylsulfonyl lower alkoxy group, an aryl lower alkoxy group which may have a substituent, a hydroxyl group, a lower Alkylamino group, lower dialkylamino group, lower alkylthio lower alkylamino group, lower alkylsulfinyl lower alkylamino group, lower alkylsulfonyl lower alkylamino group, arylamino group, cyclic amino optionally having hetero atom Group, lower alkoxy lower alkoxy group, lower alkoxy lower alkylamino group, hydroxy lower alkoxy group, hydroxy lower alkylamino group, acylamino group, lower alkylsulfonylamino group, lower alkoxycarbonyl lower group A alkoxy group, a hydroxycarbonyl lower alkoxy group, an amino lower alkoxy group, a lower alkylamino lower alkoxy group, or a lower dialkylamino lower alkoxy group;
Furthermore, general formula (I) represents both the individual enantiomers and mixtures thereof. )
The present invention was completed by discovering that the compound represented by the above formula, or a salt thereof, or a solvate thereof has excellent CETP inhibitory activity.

The pyrimidine compound having a dibenzylamine structure of the present invention is a novel compound, and in particular, a compound having a known CETP inhibitory activity in that it has a substituent (R ⁶ in the above general formula) at the benzylic carbon atom. The structure is completely different.

That is, this invention provides the compound represented by the said general formula (I), its salt, or those solvates.
The present invention also provides a pharmaceutical comprising the compound represented by formula (I) or a salt thereof, or a solvate thereof as an active ingredient, preferably dyslipidemia (hyperlipidemia), arteriosclerosis , Atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, The present invention provides a medicament for the treatment or prevention of diseases such as cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension.

Furthermore, the present invention provides a CETP inhibitor and an HDL elevating agent containing the compound represented by the general formula (I) or a salt thereof, or a solvate thereof as an active ingredient.
Furthermore, the present invention provides a pharmaceutical composition comprising the compound represented by the general formula (I), or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

  Furthermore, the present invention relates to dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, It is a method for treating or preventing diseases such as familial hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension. Thus, the present invention provides a method comprising the step of administering an effective amount of the compound represented by the above general formula (I), a salt thereof, or a solvate thereof to mammals including humans.

The present invention also relates to a method for inhibiting CETP in vivo 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.
The present invention also relates to a method for increasing the blood HDL cholesterol level in the living body of mammals including humans, the compound represented by the general formula (I), a salt thereof, or a solvate thereof. A method comprising the step of administering an effective amount of to a mammal, including a human.

  Furthermore, the present invention relates to dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, For the treatment or prevention of diseases such as familial hypercholesterolemia, cardiovascular disorders, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension The present invention provides use of the compound represented by the above general formula (I), a salt thereof, or a solvate thereof for producing a preparation.

In addition, the present invention provides a compound represented by the above general formula (I), a salt thereof, or a solvate thereof for producing a preparation for inhibiting CETP in vivo in mammals including humans. Is intended to provide the use of
The present invention also provides a compound represented by the above general formula (I) or a salt thereof, or a salt thereof, for producing a preparation for increasing blood HDL cholesterol level in the living body of mammals including humans The use of a solvate of

  Furthermore, the present invention provides a pharmaceutical comprising a combination of (a) the compound represented by the general formula (I), or a salt thereof, or a solvate thereof, and (b) an HMG-CoA reductase inhibitor. Preferably, dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, familial A medicine for the treatment or prevention of diseases such as hypercholesterolemia, cardiovascular disorder, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension It is to provide.

  Furthermore, the present invention provides a combined pharmaceutical composition comprising (a) a compound represented by the above general formula (I), or a salt thereof, or a solvate thereof, and (b) an HMG-CoA reductase inhibitor. Is to provide.

  The compound represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof shows a strong inhibitory activity against CETP, as specifically disclosed in Test Examples described later. Since it has a strong blood HDL cholesterol increasing action, it can be suitably used as an active ingredient of a CETP inhibitor and further as an active ingredient of an HDL raising agent.

  In addition, the compound represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof is preferably used as an active ingredient of a medicine due to CETP inhibitory activity and blood HDL cholesterol increasing action. Dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia Suitable as an active ingredient of a medicament for the treatment or prevention of diseases such as cardiovascular disorders, angina pectoris, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension Can be used for Furthermore, it can be suitably used as an active ingredient of the above-mentioned pharmaceutical having a low CYP inhibitory action.

FIG. 1 shows N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl } Methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 3) at 10 mg / kg, 30 mg / kg and 100 mg / kg doses for 7 days repeated in hamsters It is a figure which shows the HDL cholesterol density | concentration in plasma.

In the present invention, the lower alkyl group, halo lower alkyl group, lower cycloalkyl lower alkyl group, aryl lower alkyl group, hydroxycarbonyl lower alkyl group, lower alkoxycarbonyl lower alkyl group, and the lower alkyl group in the lower alkoxycarbonyl lower alkyl group are linear or branched. One having 1 to 6 carbon atoms (denoted as C ₁ -C ₆ alkyl), for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n- A pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group and the like can be mentioned.

In the present invention, lower alkoxy group, halo lower alkoxy group, lower alkylthio lower alkoxy group, lower alkylsulfinyl lower alkoxy group, lower alkylsulfonyl lower alkoxy group, aryl lower alkoxy group, lower alkoxy lower alkoxy group, lower alkoxy lower alkylamino group, The lower alkoxy group in the hydroxy lower alkoxy group, the hydroxycarbonyl lower alkoxy group, the amino lower alkoxy group, the lower alkylamino lower alkoxy group, and the lower dialkylamino lower alkoxy group is linear or branched having 1 to 6 carbon atoms. (referred to as C ₁ -C ₆ alkoxy), for example, a methoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, t-butoxy group, n- pentyloxy , 2-methylbutoxy group, 2,2-dimethyl-propoxy group and the like.

Lower alkylthio group in the present invention, a lower alkylthio-lower alkoxy group, the lower alkylthio group in the lower alkylthio-lower alkyl amino group, denoted linear or branched chain ones having 1 to 6 carbon atoms and (C ₁ -C ₆ alkylthio ), For example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, n-pentylthio group, 2-methylbutylthio group, 2,2-dimethyl And a propylthio group.

In the present invention, the lower alkylsulfinyl group in the lower alkylsulfinyl group, lower alkylsulfinyl lower alkoxy group, lower alkylsulfinyl lower alkylamino group is a linear or branched one having 1 to 6 carbon atoms (C ₁ -C ₆ alkylsulfinyl), for example, methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, t-butylsulfinyl group, n-pentylsulfinyl group, Examples include 2-methylbutylsulfinyl group and 2,2-dimethylpropylsulfinyl group.

In the present invention, the lower alkylsulfonyl group in the lower alkylsulfonyl group, lower alkylsulfonyl lower alkoxy group, lower alkylsulfonyl lower alkylamino group is a linear or branched one having 1 to 6 carbon atoms (C ₁ -C ₆ alkylsulfonyl), for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, Examples include 2-methylbutylsulfonyl group and 2,2-dimethylpropylsulfonyl group.

In the present invention, the lower alkyl group, a linear or branched chain ones having 2 to 6 carbon atoms (referred to as C ₂ -C ₆ alkylcarbonyl), for example, methylcarbonyl group, ethylcarbonyl group, n- propyl Examples include carbonyl group, isopropylcarbonyl group, n-butylcarbonyl group, isobutylcarbonyl group, t-butylcarbonyl group, n-pentylcarbonyl group, 2-methylbutylcarbonyl group, 2,2-dimethylpropylcarbonyl group and the like.

In the present invention, the lower alkoxycarbonyl group in the lower alkoxycarbonyl group and the lower alkoxycarbonyl lower alkyl group is a linear or branched one having 2 to 6 carbon atoms (denoted as C ₂ -C ₆ alkoxycarbonyl), for example, , Methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group, 2-methylbutoxycarbonyl group 2,2-dimethylpropoxycarbonyl group and the like.

In the present invention, the acylamino group, (referred to as C ₂ -C ₆ acylamino) straight or branched chain ones having 2 to 6 carbon atoms, e.g., acetylamino group, n- propionylamino group, isopropionyl amino group , Butyrylamino group, isobutyrylamino group, t-butyrylamino group, n-pentanoylamino group, 2-methylbutyrylamino group, 2,2-dimethylpropionylamino group, and the like.

In the present invention, lower alkylamino group, lower alkylthio lower alkylamino group, lower alkylsulfinyl lower alkylamino group, lower alkylsulfonyl lower alkylamino group, lower alkoxy lower alkylamino group, hydroxy lower alkylamino group, lower alkylamino lower alkoxy the lower alkylamino group in group (referred to as C ₁ -C ₆ alkylamino) straight or branched chain ones having 1 to 6 carbon atoms, for example, methylamino group, ethylamino group, n- propylamino group Isopropylamino group, n-butylamino group, isobutylamino group, t-butylamino group, n-pentylamino group, 2-methylbutylamino group, 2,2-dimethylpropylamino group and the like.

In the present invention, the lower dialkylamino group and the lower dialkylamino group in the lower dialkylamino lower alkoxy group are each an amino group (di- or di-) substituted with two identical or different linear or branched alkyl groups having 1 to 6 carbon atoms. referred to as C ₁ -C ₆ alkylamino), for example, (ethyl) (methyl) amino group, (isopropyl) (n-propyl) amino group, (n- butyl) (isobutyl) amino group, (t-butyl) (N-pentyl) amino group, (2,2-dimethylpropyl) (2-methylbutyl) amino group and the like can be mentioned.

In the present invention, a lower alkylsulfonylamino group, a lower alkylsulfonylamino group in halo-lower alkylsulfonylamino group, referred to as linear or branched chain ones having 1 to 6 carbon atoms (C ₁ -C ₆ alkylsulfonylamino ), For example, methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, isopropylsulfonylamino group, n-butylsulfonylamino group, isobutylsulfonylamino group, t-butylsulfonylamino group, n-pentylsulfonylamino Group, 2-methylbutylsulfonylamino group, 2,2-dimethylpropylsulfonylamino group and the like.

As the lower cycloalkyl group in the present invention, the lower cycloalkyl group in the lower cycloalkyl lower alkyl group is a cyclic one having 3 to 8 carbon atoms (denoted as C ₃ -C ₈ cycloalkyl), such as a cyclopropyl group, A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. are mentioned.

In the present invention, the aryl group in the aryl group, aryl lower alkyl group, aryl lower alkoxy group, arylamino group, arylsulfonylamino group has 6 to 10 carbon atoms (denoted as C ₆ -C ₁₀ aryl), for example, , Phenyl group, naphthyl group and the like.

  Examples of the halogen atom in the halogen atom, halo lower alkyl group, and halo lower alkoxy group in the present invention include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the general formula (I), examples of the halo-lower alkyl group in R ¹ , R ² , R ³ , R ⁴ , and R ⁵ include, for example, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, and pentafluoro The lower alkyl group which 1-5 halogen atoms, such as an ethyl group, substituted is mentioned, A trifluoromethyl group is preferable. Examples of the halo lower alkoxy group include a lower alkoxy group substituted with 1 to 5 halogen atoms such as a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, and a pentafluoroethoxy group.

In the general formula (I), in R ¹ , R ² , R ³ , R ⁴ , and R ⁵ , examples of the substituent in the amino group that may have a substituent include a lower alkyl group and a halo-lower alkyl group. And aryl groups. One or two of these substituents may be substituted.

In the general formula (I), R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or a halo C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, halo C ₁ -C ₆ alkoxy group, or preferably a cyano group, a hydrogen atom, and more that a halo C ₁ -C ₆ alkyl group, or a cyano group Preferably, R ¹ , R ³ , and R ⁵ are hydrogen atoms, and R ² and R ⁴ are the same or different, and are particularly preferably a halo C ₁ -C ₆ alkyl group or a cyano group.

In the general formula (I), examples of the lower alkyl group for R ⁶ include a methyl group and an ethyl group. The lower alkyl group for R ⁶ is more preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

In general formula (I), examples of the halo-lower alkyl group for R ⁶ include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, and a pentafluoroethyl group. And a lower alkyl group substituted with 1 to 5 halogen atoms.

In the general formula (I), examples of the lower cycloalkyl group represented by R ⁶ include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group.

In the general formula (I), examples of the lower cycloalkyl lower alkyl group represented by R ⁶ include C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl groups such as cyclopropylmethyl group and cyclopentylmethyl group.

In general formula (I), R ⁶ is a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, or a C ₃ -C ₈ cycloalkyl C ₁ -C. _It is preferably a ₆ alkyl group, more preferably a C ₁ -C ₆ alkyl group, still more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

In the general formula (I), examples of the halogen atom in R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ include a fluorine atom, a chlorine atom, and a bromine atom.

In the general formula (I), examples of the lower alkyl group for R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ include a methyl group. The lower alkyl group for R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is more preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, and a methyl group being Particularly preferred.

In the general formula (I), examples of the halo-lower alkyl group for R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ include a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, and the like. A lower alkyl group substituted with 1 to 5 halogen atoms, and a trifluoromethyl group is preferred.

In the general formula (I), examples of the lower alkoxy group in R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ include a methoxy group. As the lower alkoxy group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , a linear or branched alkoxy group having 1 to 4 carbon atoms is more preferable, a methoxy group or an ethoxy group is more preferable, and a methoxy group is more preferable. Particularly preferred.

In general formula (I), in R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ , examples of the substituent in the amino group that may have a substituent include a lower alkyl group, a halo lower alkyl group, and an aryl group. Etc.

In the general formula (I), R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, Or a C ₁ -C ₆ alkoxy group, wherein R ⁷ , R ⁹ and R ¹⁰ are hydrogen atoms, R ⁸ is a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group group, or more preferably from C ₁ -C ₆ alkoxy group.

In one preferred embodiment of R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ , at least one of R ⁸ , R ⁹ , and R ¹⁰ is a halogen atom, and R ⁷ , R ⁸ , R ⁹ , And the remainder in R ¹⁰ is preferably a hydrogen atom, more preferably R ⁷ , R ⁹ and R ¹⁰ are hydrogen atoms, and R ⁸ is a halogen atom, more preferably a bromine atom.

In another preferred embodiment of R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ , R ⁸ is a C ₁ -C ₆ alkyl group, and R ⁷ , R ⁹ , and R ¹⁰ are the same or Differently, it is preferably a hydrogen atom or a halogen atom, more preferably, R ⁸ is a C ₁ -C ₆ alkyl group, and R ⁷ , R ⁹ , and R ¹⁰ are hydrogen atoms.

In another preferred embodiment of R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ , at least one of R ⁸ and R ⁹ is a halo C ₁ -C ₆ alkyl group, and R ⁷ , The remainder in R ⁸ , R ⁹ , and R ¹⁰ is preferably a hydrogen atom, R ⁸ is a halo C ₁ -C ₆ alkyl group, and R ⁷ , R ⁹ , and R ¹⁰ are each a hydrogen atom. preferable.

In another preferred embodiment of R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ , at least one of R ⁸ and R ⁹ is a C ₁ -C ₆ alkoxy group, and R ⁷ , R 9 Preferably, the remainder in ⁸ , R ⁹ and R ¹⁰ is a hydrogen atom, more preferably R ⁸ is a C ₁ -C ₆ alkoxy group and R ⁷ , R ⁹ and R ¹⁰ are hydrogen atoms. .

In the general formula (I), examples of the lower alkyl group in R ¹¹ and R ¹² include a methyl group, an ethyl group, and an n-propyl group. As the lower alkyl group for R ¹¹ and R ¹² , a linear or branched alkyl group having 1 to 4 carbon atoms is more preferable, a methyl group or an ethyl group is further preferable, and an ethyl group is particularly preferable.

In the general formula (I), examples of the lower cycloalkyl lower alkyl group in R ¹¹ and R ¹² include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cyclopropylethyl group, a cyclopropyl group, and the like. C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl groups such as butylethyl group, cyclopentylethyl group, cyclohexylethyl group and the like can be mentioned. The lower cycloalkyl lower alkyl group for R ¹¹ and R ¹² is preferably a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group, more preferably a cyclopropylmethyl group, a cyclopentylmethyl group, or a cyclohexylmethyl group, A cyclopropylmethyl group and a cyclopentylmethyl group are particularly preferred.

In general formula (I), as the substituent in the lower cycloalkyl lower alkyl group which may have a substituent in R ¹¹ and R ¹² , for example, a lower alkyl group, a halo lower alkyl group, a hydroxycarbonyl group, A lower alkoxycarbonyl group, a hydroxycarbonyl lower alkyl group, a lower alkoxycarbonyl lower alkyl group and the like can be mentioned, and a hydroxycarbonyl C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group is preferred. Moreover, although the substitution position of these substituents is not particularly limited, in the present invention, substitution on a lower cycloalkyl group is preferred. Further, the number of such substituents is preferably 1 to 3. Examples of the lower cycloalkyl lower alkyl group having such a substituent include {4-[(hydroxycarbonyl) methyl] cyclohexyl} methyl group, {4-[(ethoxycarbonyl) methyl] cyclohexyl} -methyl group, etc. hydroxycarbonyl C ₁ -C ₆ alkyl group as a substituent on the cycloalkyl group, or C ₂ -C ₆ alkoxycarbonyl C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl that one have a carbonyl C ₁ -C ₆ alkyl group Groups.

In the general formula (I), examples of the nitrogen-containing saturated heterocyclic ring formed by R ¹¹ and R ¹² together with the adjacent nitrogen atom include R, such as pyrrolidino group, piperidino group, homopiperidino group, morpholino group, etc. ¹¹ and R ¹² may have 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in addition to the adjacent nitrogen atom. An 8-membered nitrogen-containing saturated heterocyclic ring is mentioned. The nitrogen-containing saturated heterocyclic ring formed by R ¹¹ and R ¹² together with the adjacent nitrogen atom may have a substituent, and examples of the substituent include a lower alkyl group, a halo lower alkyl group, And lower cycloalkyl group. In addition, the number of such substituents is preferably 1 to 2. Examples of the nitrogen-containing saturated heterocyclic ring formed by R ¹¹ and R ¹² together with the adjacent nitrogen atom having such a substituent include 4-methylpiperidino group and cis-2,6-dimethylmorpholino group C ₁ -C ₆ alkyl group 1 to 2 having a piperidino group, or a morpholino group and the like as a group.

In general formula (I), in R ¹¹ and R ¹² , the substituent in the aryl lower alkyl group which may have a substituent is, for example, a halogen atom, a lower alkyl group, a halo lower alkyl group, or a lower alkoxy group. , A halo lower alkoxy group, or a cyano group. Further, the number of such substituents is preferably 1 to 3. Further, the substitution position of these substituents is not particularly limited, but in the present invention, substitution on the aryl ring of the aryl lower alkyl group is preferred. Examples of such a group, C ₁ -C ₆ phenyl C ₁ may have an alkoxy group -C ₆ alkyl group as a substituent on the phenyl group, e.g., 4-methoxybenzyl group and the like.

In general formula (I), R ¹¹ and R ¹² are the same or different and each represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group may have its hydroxycarbonyl as a substituent on the cycloalkyl group C ₁ -C ₆ alkyl or C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group Or a C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl group optionally having a C ₁ -C ₆ alkoxy group as a substituent on the aryl ring, or R ¹¹ and R ¹² together it is and nitrogen-containing saturated heterocyclic ring (the heterocyclic ring C ₁ -C ₆ alkyl group may 5-8 membered have as substituent together with the adjacent nitrogen atom, the nitrogen atom to which R ¹¹ and R ¹² are adjacent In addition, from the group consisting of nitrogen atom, oxygen atom, and sulfur atom It is preferably forms a barrel (1) or more heteroatoms which may have 1 or 2), C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl C ₁ -C _6, An alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group has a hydroxycarbonyl C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkoxycarbonyl C ₁ -C as a substituent on the cycloalkyl group; ₆ may have one alkyl group), or R ¹¹ and R ¹² together with the adjacent nitrogen atom together with the morpholino group or piperidino group (the morpholino group or piperidino group is substituted C more preferably those which form ₁ -C ₆ alkyl groups may be the have one or two) as the base, an ethyl group, cyclopentylmethyl group, ethoxycarbonylmethyl cyclo Cyclohexylmethyl group, or hydroxycarbonyl or a methyl cyclohexyl methyl group, or R ^11, and a morpholino group with the nitrogen atom to which R ¹² is adjacent together, piperidino group, methylpiperidino group, especially preferable to form the dimethyl morpholino group .

In the general formula (I), examples of the lower alkoxy group for R ¹³ include C ₁ -C ₆ alkoxy groups such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group, and a methoxy group is preferable.

In general formula (I), examples of the lower alkylthio-lower alkoxy group for R ¹³ include C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy groups such as methylthiomethoxy group, 2-methylthioethoxy group, and 3-methylthiopropoxy group. And 2-methylthioethoxy group is preferred.

In the general formula (I), as the lower alkylsulfinyl lower alkoxy group in R ¹³ , C ₁ -C ₆ alkylsulfinyl C ₁ -C such as methylsulfinylmethoxy group, 2-methylsulfinylethoxy group, 3-methylsulfinylpropoxy group, etc. ₆ alkoxy group is mentioned, 2-methylsulfinylethoxy group is preferable.

In the general formula (I), examples of the lower alkylsulfonyl-lower alkoxy group in R ^13, methylsulfonyl methoxy, 2-methylsulfonylethoxy group, C ₁ -C ₆ alkylsulfonyl C ₁ -C, and 3-methylsulfonyl propoxy group ₆ alkoxy group is mentioned, 2-methylsulfonyl ethoxy group is preferable.

In the general formula (I), the lower alkoxycarbonyl lower alkoxy group in R ¹³ includes methoxycarbonylmethoxy group, ethoxycarbonylmethoxy group, methoxycarbonylethoxy group, ethoxycarbonylethoxy group, methoxycarbonylpropoxy group, ethoxycarbonylpropoxy group, methoxy carbonyl-butoxy group, and C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group such as ethoxycarbonyl butoxy group, ethoxycarbonyl propoxycarbonyl group is preferable.

In the general formula (I), examples of the hydroxycarbonyl lower alkoxy group for R ¹³ include hydroxycarbonyl C ₁ -C ₆ alkoxy groups such as hydroxycarbonylmethoxy group, hydroxycarbonylethoxy group, hydroxycarbonylpropoxy group, hydroxycarbonylbutoxy group and the like. And a hydroxycarbonylpropoxy group is preferred.

In general formula (I), examples of the cyclic amino group that may have a hetero atom as a constituent atom in R ¹³ include a pyrrolidinyl group, a morpholinyl group, and a piperidinyl group, and a morpholino group and a piperidino group are preferable.

In the general formula (I), examples of the substituent in the aryl lower alkoxy group which may have a substituent in R ¹³ include a halogen atom, a lower alkyl group, a halo lower alkyl group, and a cyano group. Further, the substitution position of these substituents is not particularly limited, but in the present invention, substitution on the aryl ring of the aryl lower alkoxy group is preferred. Further, the number of such substituents is preferably 1 to 3. As such a group, a phenyl C ₁ -C ₆ alkoxy group which may have 1 to 3 halogen atoms, halo C ₁ -C ₆ alkyl groups, or cyano groups as substituents on the phenyl group, for example, 3,5-bis (trifluoromethyl) benzyl group, 3-cyano-5-trifluoromethylbenzyloxy group, 2,3-difluorobenzyloxy group and the like can be mentioned.

In the general formula (I), R ^13, halogen atom, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfonyl C ₁ -C ₆ alkoxy group, hydroxyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, hydroxycarbonyl C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkoxy group (the C ₆ -C ₁₀ aryl C ₁ -C ₆ alkoxy group has a halogen atom, a halo C ₁ -C ₆ alkyl group, or a cyano group as a substituent on the aryl ring. may be), morpholinyl group, or preferably a piperidinyl group, C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, C ₁ C ₆ alkylsulfonyl C ₁ -C ₆ alkoxy group, hydroxyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, or particularly preferably a hydroxycarbonyl C ₁ -C ₆ alkoxy group.

In the above general formula (I), as a preferable combination of substituents, in the above general formula (I),
R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C _{A 6} alkoxy group, a halo C ₁ -C ₆ alkoxy group, or a cyano group,
R ⁶ is a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl group, or a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group,
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group. Group,
R ¹¹ and R ¹² are the same or different and each represents a C ₁ -C ₆ alkyl group, a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C _6). alkyl group may have its hydroxycarbonyl as a substituent on the cycloalkyl group C ₁ -C ₆ alkyl or C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group), or on the aryl ring A C ₆ -C ₁₀ aryl C ₁ -C ₆ alkyl group which may have a C ₁ -C ₆ alkoxy group as a substituent, or R ¹¹ and R ¹² together with an adjacent nitrogen atom A 5- to 8-membered nitrogen-containing saturated heterocyclic ring which may have a C ₁ -C ₆ alkyl group as a substituent (in addition to the nitrogen atom adjacent to R ¹¹ and R ¹² , the heterocyclic ring includes a nitrogen atom, oxygen One or more selected from the group consisting of atoms and sulfur atoms Is intended to form the B atoms may be a have 1-2),
R ¹³ is a halogen atom, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl Sulfonyl C ₁ -C ₆ alkoxy group, hydroxyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, hydroxycarbonyl C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl C ₁ -C ₆ alkoxy group ( The C ₆ -C ₁₀ aryl C ₁ -C ₆ alkoxy group may have a halogen atom, a halo C ₁ -C ₆ alkyl group, or a cyano group as a substituent on the aryl ring), a morpholinyl group, Or a piperidinyl group is preferred,
R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and each is a hydrogen atom, a halo C ₁ -C ₆ alkyl group, or a cyano group,
R ⁶ is a C ₁ -C ₆ alkyl group,
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group. Group,
R ¹¹ and R ¹² are the same or different and each represents a C ₁ -C ₆ alkyl group or a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C ₆ The alkyl group may have _one hydroxycarbonyl C ₁ -C ₆ alkyl group or C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group as a substituent on the cycloalkyl group), or Or R ¹¹ and R ¹² together with the adjacent nitrogen atom together with a morpholino group or piperidino group (the morpholino group or piperidino group has ₁ to 2 C ₁ -C ₆ alkyl groups as substituents; Is also good)
R ¹³ is a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl C ₁ -C ₆ alkoxy group, hydroxyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, or hydroxy carbonyl C ₁ -C ₆ alkoxy group,
More preferably,
R ¹ , R ³ , and R ⁵ are hydrogen atoms,
R ² and R ⁴ are the same or different and each is a halo C ₁ -C ₆ alkyl group or a cyano group,
R ⁶ is a C ₁ -C ₆ alkyl group,
R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are any of the following i) to iv):
i) At least one of R ⁸ , R ⁹ , and R ¹⁰ is a halogen atom, preferably a bromine atom, and the remainder in R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is a hydrogen atom.
ii) R ⁸ is a C ₁ -C ₆ alkyl group, and R ⁷ , R ⁹ and R ¹⁰ are the same or different and each is a hydrogen atom or a halogen atom.
iii) At least one of R ⁸ and R ⁹ is a halo C ₁ -C ₆ alkyl group, and the remainder in R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is a hydrogen atom.
iv) At least one of R ⁸ and R ⁹ is a C ₁ -C ₆ alkoxy group, and the remainder in R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is a hydrogen atom.
R ¹¹ and R ¹² are the same or different and each represents a C ₁ -C ₆ alkyl group or a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C ₆ The alkyl group may have a hydroxycarbonyl C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group as a substituent on the cycloalkyl group), or R ¹¹ and R ¹² together with the adjacent nitrogen atom, a morpholino group or piperidino group (the morpholino group or piperidino group may have one or two C ₁ -C ₆ alkyl groups as substituents. )
R ¹³ is a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylsulfonyl C ₁ -C ₆ alkoxy group, hydroxyl group, C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, or hydroxy carbonyl C ₁ -C ₆ alkoxy group,
Is particularly preferred.

As preferred compounds in the present invention, or salts thereof, or solvates thereof,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 1),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine (Example 2),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 3),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 4),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 5),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 6),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 7),

N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 8),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 9),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 10),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 11),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 12),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 13),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 14),

N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine (Example 15),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 16),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 17),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 18),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine (Example 19),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine (Example 20),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 21),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 22),

N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 23),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 24),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 25),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 26),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 27),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 28),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine (Example 29),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 30),

3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl } -5- (trifluoromethyl) benzonitrile (Example 31),
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Ethyl} -5- (trifluoromethyl) benzonitrile (Example 32),
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 33),
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 34),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine (Example 35),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine (Example 36),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine (Example 37),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine (Example 38),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine (Example 39),

N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 40),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (Example 41),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 42),
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate (Example 43),
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (Example 44),
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate (Example 45),

trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4- ( Trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (Example 46),
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (Example 47),
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine (Example 48),
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 49),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5-methoxypyrimidin-2-amine (Example 50),
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5-hydroxypyrimidin-2-amine (Example 51),
4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) )] Amino} pyrimidin-5-yl) ethyl butyrate (Example 52) or 4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[( Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)] amino} pyrimidin-5-yl) butyric acid (Example 53),
Or its salt or those solvates are mentioned.

The general formula (I) represents both individual enantiomers and mixtures thereof. That is, in the compound represented by the general formula (I) of the present invention, the carbon atom to which R ⁶ is bonded is an asymmetric carbon, but the present invention is an isomer having any configuration based on the asymmetric carbon. Including, for example, racemates and any one of the enantiomers. In addition, the invention includes all other stereoisomers that may occur.

Examples of the salt of the compound represented by the general formula (I) include a hydrochloric acid addition salt, and the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; benzoate, methanesulfonate, ethanesulfonate, benzene Examples include, but are not limited to, acid addition salts of organic acids such as sulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, and acetate.
Examples of the solvate of the compound represented by the general formula (I) or a salt thereof include, but are not limited to, hydrates and the like.

  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, “Drug Development”, Volume 7, Molecular Design, pages 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. 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.

Method for producing compound represented by general formula (I), salt thereof, or solvate thereof
I. Production method of compound represented by general formula (I), or a salt thereof, or a solvate thereof The compound represented by general formula (I) of the present invention can be produced by the following method. That is, as shown in the following reaction path diagram 1, the aldehyde derivative represented by the general formula (II) is reacted with the pyrimidine-2-amine derivative represented by the general formula (IV) using a reductive amination technique. Or when the compound having the leaving group W ¹ represented by the general formula (III) is reacted with the pyrimidine-2-amine derivative represented by the general formula (IV) with a base, the compound represented by the general formula (V) is represented. The resulting amine compound is obtained. When the amine compound represented by the general formula (V) is reacted with the compound having the leaving group W ² represented by the general formula (VI) with a base, the compound represented by the general formula (I) of the present invention is converted to the compound represented by the general formula (I). Can be manufactured.
This reaction path is represented by the chemical reaction formula as follows.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ are represented by the general formula ( I is the same as in I), and W ¹ and W ² represent a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an arylsulfonyloxy group.

  The reaction of the aldehyde derivative (II) and the pyrimidine-2-amine derivative (IV) can be performed using a reducing reagent in a solvent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like. The solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. . There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Catalytic reduction using a borohydride reagent such as lithium triethylborohydride, an aluminum hydride reagent such as lithium aluminum hydride, diisopropylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, a metal catalyst and a hydrogen source Can be used. As a hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.

The reaction of the compound (III) having a leaving group W ¹ and the pyrimidine-2-amine derivative (IV) can be performed 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, for example, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, alkali metals such as metal lithium, metal sodium, metal potassium, lithium hydroxide, sodium hydroxide, water Alkali metal hydroxides such as potassium oxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide Sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, may be used t-butyl lithium and the like.

The reaction of the amine compound (V) obtained by the above method and the compound (VI) having a leaving group W ² can be performed 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, Is not particularly limited, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide It can be used sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, t-butyl lithium and the like.

In addition to the method described above, the compound represented by the general formula (I) of the present invention can also be produced by the following method. That is, as shown in the following reaction route diagram 2, a compound having a leaving group W ² represented by general formula (VI) is reacted with a base with a pyrimidine-2-amine derivative represented by general formula (IV). Or by reacting the pyrimidine-2-amine derivative represented by the general formula (IV) with the ketone derivative represented by the general formula (VII) using a reductive amination technique, The amine compound represented is obtained. When the amine compound represented by the general formula (VIII) is reacted with the compound having the leaving group W ¹ represented by the general formula (III) with a base, the compound represented by the general formula (I) of the present invention is converted to the compound represented by the general formula (I). Can be manufactured.
This reaction path is represented by the chemical reaction formula as follows.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ are represented by the general formula ( I is the same as in I), and W ¹ and W ² represent a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an arylsulfonyloxy group.

The reaction of the pyrimidine-2-amine derivative (IV) and the compound (VI) having a leaving group W ² can be performed in a solvent in the presence of a base. The solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited. Are, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali carbonate metals, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexameth Rujishirajido, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, may be used t-butyl lithium and the like.

  The reaction of the pyrimidine-2-amine derivative (IV) and the ketone derivative (VII) can be performed using a reducing reagent in a solvent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like. The solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. . There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Contact using borohydride reagents such as lithium triethylborohydride, lithium aluminum hydride, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used. As a hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.

The reaction of the compound (III) having the leaving group W ¹ and the amine compound (VIII) can be performed in a solvent in the presence of a base. The solvent is not particularly limited, but for example, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile and the like can be used, and the base is not particularly limited. Are, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. Alkali metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali carbonate metals, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexameth Rujishirajido, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, may be used t-butyl lithium and the like.

Next, the aldehyde derivative (II) used in the above reaction, the compound (III) having a leaving group W ¹ , the pyrimidine-2-amine derivative (IV), and the method for producing the compound (VI) having a leaving group W ² An example is shown.

1 Method for producing aldehyde derivative represented by general formula (II) and compound having leaving group W ¹ represented by formula (III) The aldehyde derivative (II) and the compound having leaving group W ¹ ( III) can be used as it is or can be appropriately produced by a known method. For example, it can be produced by the following method, but is not limited thereto.

As shown in FIG. 3 below, when an o-fluoroaldehyde derivative represented by the general formula (IX) and an amine represented by the general formula (X) are reacted, the aldehyde represented by the general formula (II) A derivative is obtained.
This reaction path is represented by the chemical reaction formula as follows.

(In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are the same as those in the general formula (I).)

  The reaction of o-fluoroaldehyde derivative (IX) and amines (X) can be carried out in a solvent in the presence of a base. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, N, N- dimethylformamide, N-methylpyrrolidone, water etc. can be used individually or in combination. Although there is no restriction | limiting in particular as a base, For example, alkali metal hydrides, such as lithium hydride, sodium hydride, potassium hydride, alkali metals, such as lithium metal, sodium metal, and potassium metal, lithium hydroxide, hydroxylation Alkali metal hydroxides such as sodium and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, 1,4-diazabicyclo [2.2.2] octene (DABCO), lithium diisopropyl Amide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n-butyllithium, s-butyllithium , T-Buchi It is possible to use the lithium or the like. The reaction conditions vary depending on the raw materials used, but the desired product is generally obtained by reacting at 0 to 180 ° C., preferably 50 to 160 ° C. for 5 minutes to 2 weeks, preferably 3 hours to 1 week.

The aldehyde derivative (II) and the compound (III) having a leaving group W ¹ can also be produced by the following method. That is, as shown in FIG. 4 below, the hydroxyl group of the alcohol derivative represented by the general formula (XI) is protected with the protecting group R ¹⁴ to obtain an ether derivative represented by the general formula (XII). The protecting group R ¹⁴ in the general formula (XII) is a protecting group generally used as a protecting group for a hydroxyl group, and is not particularly limited, but is a methoxymethyl group, a benzyloxymethyl group, a 4-methoxybenzyloxymethyl group, a methoxy group. Ethoxymethyl group, ethoxyethyl group, t-butyldimethylsilyl group, triethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, triphenylsilyl group, 4-methoxybenzyl group, benzyl group, 3,4-dimethoxy A benzyl group, 2,4,6-trimethylbenzyl group, trityl group and the like are preferable. When an ether derivative represented by the general formula (XII) is reacted with an amine represented by the general formula (XIII), an amine derivative represented by the general formula (XIV) is obtained. The obtained amine derivative represented by the general formula (XIV) is reacted with a compound having a leaving group W ⁴ represented by the general formula (XV) or an aldehyde derivative represented by the general formula (XVI). When the method of reductive amination in which the imine obtained by the reaction with is subjected to a reduction reaction, an amine derivative represented by the general formula (XVII) is obtained. The protecting group R ¹⁴ of the amine derivative represented by the general formula (XVII) thus obtained is deprotected to obtain an alcohol compound represented by the general formula (XVIII), and then the resulting hydroxyl group is oxidized to give the general formula (II Is obtained. The compound having a leaving group W ¹ represented by the general formula alcohol moiety of the general formula (XVIII) alcohol compound represented by the converted into leaving group W ¹ (III) is obtained.
This reaction path is represented by the chemical reaction formula as follows.

(In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² are as defined in the general formula (I), and W ³ and W ⁴ are a halogen atom and an alkylsulfonyloxy group. , A haloalkylsulfonyloxy group or an arylsulfonyloxy group, R ¹⁴ represents a protecting group, R ′ ¹² is a lower alkyl group or lower cycloalkylalkyl having one fewer carbon atoms at the bonding position to the nitrogen atom than R ^12. Group or lower cycloalkyl group.)

The introduction of the protective group R ¹⁴ into the alcohol derivative (XI) is not particularly limited, but reference is made to a method generally used as a protective condition for the protective group (Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc.). Can be done.

  The reaction of the obtained ether derivative (XII) and amines (XIII) may be carried out in the presence of a base or in the presence of a metal catalyst in a solvent, in the presence of a metal catalyst. it can. At that time, microwave irradiation may be performed. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, N, N- dimethylformamide, N-methylpyrrolidone, water etc. can be used individually or in combination. The base is not particularly limited, but examples thereof 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 hydroxide and sodium hydroxide. Alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium Hexamethyl disilazide, potassium hexamethyl disilazide, t-butoxy sodium, t-butoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium 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), tetrakis (triphenylphosphine) palladium or the like may be used alone, but a combination of ligands such as (2-biphenyl) di-t-butylphosphine and (2-biphenyl) dicyclohexylphosphine is used. You can also While the reaction conditions vary depending on the raw materials used, the desired product is generally obtained by reacting at 0 to 180 ° C., preferably 80 to 160 ° C. for 5 minutes to 72 hours, preferably 10 minutes to 24 hours. In the case of irradiation with microwaves, the reaction is started at room temperature under microwave irradiation, preferably from room temperature to 80 to 150 ° C., and preferably from 1 minute to 20 hours including the temperature rising time. Can be obtained by reacting for 1 minute to 3 hours.

The reaction of the amine derivative (XIV) obtained by the above reaction and the compound (XV) having a leaving group W ⁴ can be performed 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, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, lithium hydroxide, sodium hydroxide, water Alkali metal hydroxides such as potassium oxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide Sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, may be used t-butyl lithium and the like.

  The reaction of the amine derivative (XIV) and the aldehyde derivative (XVI) can be performed using a reducing reagent in a solvent in the presence or absence of an acid. At that time, the dehydration operation may be performed using a Dean-Stark apparatus or the like. The solvent is not particularly limited, but for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol or the like alone or Can be used in combination. Although there is no restriction | limiting in particular as an acid, For example, Lewis acids, such as acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, etc., proton tetrachloride, boron trifluoride, stannic chloride, etc. can be used. . There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, Catalytic reduction using a borohydride reagent such as lithium triethylborohydride, an aluminum hydride reagent such as lithium aluminum hydride, diisopropylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, a metal catalyst and a hydrogen source Can be used. As a hydrogen source for catalytic reduction, for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide carbon powder, Raney nickel, platinum dioxide. Platinum black or the like can be used.

The deprotection of the protecting group R ¹⁴ of the amine derivative (XVII) obtained by the above method is not particularly limited, but a method generally used as deprotection conditions for the protecting group (Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc.).

For the oxidation reaction from the alcohol compound (XVIII) to the aldehyde derivative (II), a usual method for oxidizing a hydroxyl group to an aldehyde can be applied. For example, oxidation conditions such as Swern oxidation, Moffatt oxidation, Dess-Martin oxidation, etc. , Pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), manganese dioxide, tetrapropylammonium perruthenate (TPAP) and the like can be used. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, a dichloromethane, chloroform, 1, 2- dichloroethane, N, N- dimethylformamide etc. can be used individually or in combination.
On the other hand, the reaction for synthesizing the compound (III) having the leaving group W ¹ from the alcohol compound (XVIII) can be selected according to the kind of the leaving group as follows.

W ¹ is an alkylsulfonyloxy group of a compound having a leaving group W ¹ (III), when the halo alkylsulfonyloxy group or an arylsulfonyloxy group, the compound (III) in a solvent in the presence or absence of a base, an alcohol It can be obtained by reacting compound (XVIII) with an alkylsulfonic acid esterifying agent, a haloalkylsulfonic acid esterifying agent or an arylsulfonic acid esterifying agent. The alkylsulfonic acid esterifying agent is not particularly limited, and for example, methanesulfonyl chloride, methanesulfonic anhydride, ethanesulfonyl chloride, benzylsulfonyl chloride, allylsulfonyl chloride and the like can be used. Although there is no restriction | limiting in particular as a haloalkylsulfonic acid esterifying agent, For example, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, chloromethanesulfonyl chloride, etc. can be used. The arylsulfonic acid esterifying agent is not particularly limited, and for example, benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride and the like can be used. The solvent is not particularly limited. For example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, N, N-dimethylformamide, etc. Or they can be used in combination. The base is not particularly limited. For example, pyridine, 4-dimethylaminopyridine (DMAP), collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5 -Diazabicyclo [4.3.0] non-5-ene (DBN), DABCO, triethylamine, 2,6-di-t-butylpyridine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine, etc. Organic bases, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate , Alkali metal carbonates such as cesium carbonate, and bicarbonate metals such as sodium bicarbonate and potassium bicarbonate. Can be used.

When W ¹ of the compound having a leaving group W ¹ (II) is a halogen atom, the compound (II) is a solvent or without a solvent in the presence or absence of a base, an alcohol compound (XVIII) with a halogenating agent It can obtain by reaction with. The halogenating agent is not particularly limited, but phosphorus oxychloride, phosphorus pentachloride, triphenylphosphine dichloride, triphenylphosphine dibromide, triphenylphosphite dichloride, triphenylphosphite dibromide, tribromide Phosphorus, thionyl chloride, triphenylphosphine and carbon tetrachloride, triphenylphosphine and carbon tetrabromide, triphenylphosphine and iodine and imidazole, triphenylphosphine and N-iodosuccinimide (NIS), methanesulfonyl chloride and DMAP, etc. A chlorinating agent, a brominating agent or an iodinating agent may be mentioned. For example, 1,2-dichloroethane, chloroform, dichloromethane, diethyl ether, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile and the like can be used alone or in combination. The base is not particularly limited. For example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, 2,6-di-t-butylpyridine, N, N-diisopropylethylamine, N, N-diisopropyl Organic bases such as pentylamine and trimethylamine, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and the like can be used.

2 Method for Producing Pyrimidin-2-amine Derivative (IV) The above pyrimidine-2-amine derivative (IV) can be used as it is, or can be suitably produced by a known method. For example, pyrimidine-2 -Depending on the type of R ¹³ substituted at the 5-position of the amine derivative (IV), it can be produced by the following method, but is not limited thereto.

2-1 R ¹³ is a lower dialkylamino group, or a method for producing a pyrimidine-2-amine derivative (IV ′) which is a cyclic amino group that may have a hetero atom in the ring constituent atom. As described above, the reaction of 5-bromopyrimidin-2-amine (XIX) with a lower dialkylamine represented by the general formula (XX) or a cyclic amine which may have a hetero atom in the ring atom, yields a general formula (IV ′ And a pyrimidin-2-amine derivative in which R ¹³ is a lower dialkylamino group or a cyclic amino group that may have a hetero atom in the ring constituent atom.
This reaction path is represented by the chemical reaction formula as follows.

(In the formula, R ¹⁵ and R ¹⁶ are the same or different and each is a lower alkyl group, or R ¹⁵ and R ¹⁶ together have a hetero atom in the ring member atom together with the adjacent nitrogen atom. To form a cyclic amine which may be

  The reaction of 5-bromopyrimidin-2-amine (XIX) and the lower dialkylamine represented by the general formula (XX) or a cyclic amine which may have a hetero atom in the ring atom is carried out in a solvent or without solvent. The reaction method of aryl halides and amines performed in the presence or absence of a base and in the presence of a metal catalyst can be applied. This reaction can be performed, for example, by reacting both compounds in a solvent in the presence of a metal catalyst. At that time, microwave irradiation may be performed. Examples of the metal catalyst include tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium. (II), a palladium complex such as tetrakis (triphenylphosphine) palladium, or a monovalent copper reagent such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone. Combination of ligands such as -biphenyl) di-t-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tetramethylethylenediamine, N, N'-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine Can also be used. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, N, N- dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water etc. can be used individually or in combination. The base is not particularly limited, but examples thereof 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 hydroxide and sodium hydroxide. Alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium Hexamethyl disilazide, potassium hexamethyl disilazide, t-butoxy sodium, t-butoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium and the like can be used. The desired product is obtained by reacting at 0 to 180 ° C., preferably 80 to 150 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days.

2-2 Method for producing 2-aminopyrimidine derivative (IV ″) in which R ¹³ is a lower alkoxy group, a lower alkylthio lower alkoxy group, a lower alkoxy lower alkoxy group, or a lower dialkylamino lower alkoxy group-1
As shown in FIG. 6 below, the reaction is performed by reacting 5-bromo-2-chloropyrimidine (XXI) with an amine represented by the general formula (XXII) substituted with a deprotectable functional group R ^17. A pyrimidine-2-amine derivative represented by (XXIII) is obtained. The obtained pyrimidine-2-amine derivative represented by the general formula (XXIII) and the lower alkyl alcohol, lower alkylthio lower alkyl alcohol, lower alkoxy lower alkyl alcohol, or lower dialkylamino lower represented by the general formula (XXIV) The ether compound represented by the general formula (XXV) is obtained by the reaction of the alkyl alcohol, R ¹⁷ of the ether compound represented by the general formula (XXV) is deprotected, and represented by the general formula (IV ″) , R ¹³ is a lower alkoxythio group, a lower alkylthio lower alkoxy group, a lower alkoxy lower alkoxy group, or a lower dialkylamino lower alkoxy group.
This reaction path is represented by the chemical reaction formula as follows.

(In the formula, R ¹⁷ represents a protecting group, and R ¹⁸ represents a lower alkyl group, a lower alkylthio-lower alkyl group, a lower alkoxy lower alkyl group, or a lower dialkylamino lower alkyl group.)

  The target product is obtained by reacting 5-bromo-2-chloropyrimidine (XXI) with amine (XXII) in a solvent or without solvent. At that time, microwave irradiation may be performed. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, N, N- dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water etc. can be used individually or in combination. The reaction conditions vary depending on the type of amine represented by the general formula (XXII) to be used, but are generally -20 to 180 ° C, preferably 0 to 150 ° C for 1 minute to 24 hours, preferably 5 minutes to 10 hours. The target product is obtained by the reaction.

  The reaction of the obtained pyrimidine-2-amine derivative (XXIII) and alcohol (XXIV) is carried out in a solvent or without solvent in the presence or absence of a base and in the presence of a metal catalyst. Similar reaction techniques can be applied. In this reaction, for example, by reacting both compounds in a solvent in the presence of a metal catalyst, the target ether compound (XXV) is obtained. At that time, microwave irradiation may be performed. Examples of the metal catalyst include tris (dibenzylideneacetone) dipalladium (0), tris (dibenzylideneacetone) (chloroform) dipalladium (0), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium. (II), a palladium complex such as tetrakis (triphenylphosphine) palladium, or a monovalent copper reagent such as cuprous iodide, cuprous bromide, cuprous cyanide may be used alone. Combination of ligands such as -biphenyl) di-t-butylphosphine, (2-biphenyl) dicyclohexylphosphine, tetramethylethylenediamine, N, N'-dimethylethylenediamine, glycine, N, N-dimethylglycine, N-methylglycine Can also be used. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, N, N- dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water etc. can be used individually or in combination. The base is not particularly limited, but examples thereof 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 hydroxide and sodium hydroxide. Alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium Hexamethyl disilazide, potassium hexamethyl disilazide, t-butoxy sodium, t-butoxy potassium, n-butyl lithium, s-butyl lithium, t-butyl lithium and the like can be used. The desired product is obtained by reacting at 0 to 180 ° C., preferably 80 to 150 ° C. for 1 minute to 5 days, preferably 1 hour to 3 days.

Deprotection of the protecting group R ¹⁷ of the ether compound (XXV) obtained by the above method is not particularly limited, but a method generally used as deprotection conditions for the protecting group (Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc.).

2-3 Method for producing 2-aminopyrimidine compound (IV ″) in which R ¹³ is a lower alkoxy group, a lower alkylthio lower alkoxy group, a lower alkoxy lower alkoxy group, or a lower dialkylamino lower alkoxy group-2
As shown in FIG. 7 below, the acetal derivative represented by the general formula (XXVI) is subjected to the Vilsmeier reaction to obtain the aminoacrolein derivative represented by the general formula (XXVII). R ¹⁹ and R ²⁰ in the general formula (XXVI) are a lower alkyl group or a protecting group generally used as a protecting group for a hydroxyl group, and are not particularly limited. A benzyl group, a p-methoxybenzyl group, a 2,4,6-trimethylbenzyl group and the like are preferable. R ²¹ and R ^{22 in} general formula (XXVII) are the same or different and each represents a lower alkyl group or an arylalkyl group which may have a substituent, or together, together with an adjacent nitrogen atom A nitrogen-saturated heterocyclic ring may be formed, and there is no particular limitation, but the same or different, such as methyl group, ethyl group, propyl group, benzyl group, p-methoxybenzyl group, 2,4,6-trimethylbenzyl group Preferably, the nitrogen-containing saturated heterocyclic ring formed together with the adjacent nitrogen atom is preferably piperidine, pyrrolidine or morpholine.

The aminopyrimidine derivative represented by the general formula (XXIX) is obtained by the reaction of the aminoacrolein derivative represented by the general formula (XXVII) and the guanidine salt (XXVIII). HA in the general formula (XXVIII) represents an acid that forms a salt with guanidine. The acid forming the guanidine salt used here is not particularly limited, but hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, acetic acid, hydrobromic acid, hydroiodic acid and the like are preferable. The amino group of the aminopyrimidine derivative (XXIX) is protected with a protecting group R ²³ to obtain a compound represented by the general formula (XXX). The protecting group R ²³ in the general formula (XXX) is a protecting group generally used as an amino protecting group, and is not particularly limited, but is a formyl group, acetyl group, propionyl group, butyryl group, hexanoyl group, trifluoro Acetyl group, benzoyl group, cyclohexylcarbonyl group, benzyloxycarbonyl group, 2,2,2-trichloroethylcarbonyl group, t-butoxycarbonyl group, 4-methoxybenzyl group, benzyl group, 3,4-dimethoxybenzyl group, 2 , 4,6-trimethylbenzyl group, trifluoromethanesulfonyl group and the like are preferable. Deprotection of R ¹⁹ of the compound represented by the general formula (XXX) thus obtained yields a hydroxypyrimidine derivative represented by the general formula (XXXI). Mitsunobu reaction of this hydroxypyrimidine derivative (XXXI) with lower alkyl alcohol, lower alkylthio lower alkyl alcohol, lower alkoxy lower alkyl alcohol, or lower dialkylamino lower alkyl alcohol represented by general formula (XXIV), or leaving group W ^The ether compound represented by the general formula (XXXIII) is obtained by the reaction with the compound (XXXII) having ⁵ and R ²³ of the ether compound represented by the general formula (XXXIII) is deprotected to obtain the general formula (IV ′ A 2-aminopyrimidine derivative represented by ') wherein R ¹³ is a lower alkoxy group, a lower alkylthio lower alkoxy group, a lower alkoxy lower alkoxy group, or a lower dialkylamino lower alkoxy group is obtained.
This reaction path is represented by the chemical reaction formula as follows.

(Wherein R ¹⁸ represents a lower alkyl group, a lower alkylthio lower alkyl group, a lower alkoxy lower alkyl group, or a lower dialkylamino lower alkyl group, R ¹⁹ and R ²⁰ represent a lower alkyl group or a protecting group, R ²¹ And R ²² are the same or different and each represents a lower alkyl group or an aryl lower alkyl group which may have a substituent, or a nitrogen-containing saturated heterocyclic ring formed together with an adjacent nitrogen atom. R ²³ represents a protecting group, W ⁵ represents a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group or an arylsulfonyloxy group, and HA represents an acid which forms a salt with guanidine.

  In the Vilsmeier reaction of the acetal derivative (XXVI), the target product is obtained by reacting with a Vilsmeier reagent in a solvent or without a solvent. Although there is no restriction | limiting in particular as a Vilsmeier reagent, As a formamide to be used, for example, N, N- dimethylformamide, N, N-diethylformamide, N-formylpiperidine, N-formylpyrrolidine, N-formylmorpholine etc. should be used. As the phosphorus reagent to be used, for example, phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide, or phosphorus halides such as phosphorus pentachloride and phosphorus pentabromide can be used. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, benzene, a dioxane, chloroform, a dichloromethane, 1, 2- dichloroethane etc. can be used individually or in combination. The reaction conditions vary depending on the acetal derivative represented by the general formula (XXVI) to be used, but are generally -20 to 150 ° C, preferably 0 to 100 ° C for 5 minutes to 1 week, preferably 30 minutes to 100 hours. To obtain the target product.

  The reaction of the obtained aminoacrolein derivative (XXVII) and guanidine salt (XXVIII) is carried out in a solvent in the presence of a base to obtain the target aminopyrimidine derivative (XXIX). The base is not particularly limited, but alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexa Methyl disilazide, potassium hexamethyldisilazide, methoxy sodium, methoxy potassium, ethoxy sodium, ethoxy potassium, t-butoxy sodium, t-butoxy potassium, n-butyl lithium, s-butyl lithium, t-Butyllithium or the like can be used. The solvent is not particularly limited, but methanol, ethanol, isopropanol, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, benzene, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, acetonitrile, Nitromethane, water and the like can be used alone or in combination. The reaction conditions vary depending on the aminoacrolein derivative (XXVII) to be used, but in general, it is reacted at −20 to 150 ° C., preferably 0 to 100 ° C. for 30 minutes to 1 week, preferably 30 minutes to 5 days. Is obtained.

For the introduction of the protective group R ²³ into the amino group of the aminopyrimidine derivative (XXIX), refer to a method generally used as a protective condition of the protective group (Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc.). Can be done.

The deprotection of R ¹⁹ of the compound represented by the general formula (XXX) is not particularly limited, but can be performed using a Lewis acid or a proton acid in a solvent. The Lewis acid is not particularly limited, and boron tribromide, boron trichloride, aluminum chloride, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate, ethyl aluminum dichloride, diethyl aluminum chloride and the like can be used. Although there is no restriction | limiting in particular as a proton acid, Hydrobromic acid, hydroiodic acid, etc. can be used. Although there is no restriction | limiting in particular as a solvent, Toluene, benzene, chloroform, a dichloromethane, 1, 2- dichloroethane, chlorobenzene, nitrobenzene, acetonitrile, nitromethane, an acetic acid etc. can be used individually or in combination. The reaction conditions vary depending on the compound represented by the general formula (XXX) to be used, but in general, the reaction is carried out at −20 to 150 ° C., preferably 0 to 120 ° C. for 10 minutes to 3 days, preferably 10 minutes to 30 hours. The desired product is obtained. When R ¹⁹ is an arylmethyl group such as a benzyl group, a p-methoxybenzyl group, or a 2,4,6-trimethylbenzyl group, deprotection can be performed by a hydrogenation technique other than the above. Although there is no restriction | limiting in particular as a hydrogen source of hydrogenation, Hydrogen, formic acid, ammonium formate, a cyclohexadiene, etc. can be used. Although there is no restriction | limiting in particular as a hydrogenation catalyst, Palladium carbon, palladium black, platinum black, platinum dioxide, Raney nickel, palladium hydroxide carbon powder, etc. can be used. Although there is no restriction | limiting in particular as a solvent, Methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, N, N- dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, acetic acid, water, etc. can be used individually or in combination. The reaction conditions vary depending on the compound represented by the general formula (XXX) to be used, but the reaction is generally carried out at 0 to 150 ° C., preferably 0 to 100 ° C. for 30 minutes to 3 days, preferably 30 minutes to 50 hours. The desired product is obtained.

The ether compound (XXXIII) is obtained by the Mitsunobu reaction between the hydroxypyrimidine derivative (XXXI) and the alcohol (XXIV) or the compound (XXXII) having a leaving group W ⁵ . The Mitsunobu reaction between the hydroxypyrimidine derivative (XXXI) and the alcohol compound (XXIV) 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, 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 etc. can be used individually or in combination. The reaction conditions vary depending on the hydroxypyrimidine derivative (XXXI) to be used. In general, the target product is reacted by reacting at 0 to 120 ° C., preferably 0 to 100 ° C. for 30 minutes to 3 days, preferably 30 minutes to 50 hours. can get.

The reaction of the hydroxypyrimidine derivative (XXXI) and the compound (XXXII) having a leaving group W ⁵ can be performed 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, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium metal, lithium hydroxide, sodium hydroxide and hydroxide Alkali metal hydroxides such as potassium, lithium carbonate, sodium carbonate, potassium carbonate, alkali carbonates such as cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Thorium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, may be used t-butyl lithium and the like.

Although deprotection is not particularly limited protecting group R ²³ of the ether compound obtained by the above method (XXXIII), a method generally used as deprotection conditions for the protecting group (Protective Groups in Organic Synthesis Fourth Edition , John Wiley & Sons, Inc.).

The hydroxypyrimidine derivative (XXXI) used in the above production method can be produced by the following method in addition to the above method. That is, as shown in the following reaction scheme 8, 5-hydroxy-2-amine amino group and a hydroxyl group of (XXXIV) is protected with a protecting group R ^23, to give the compound represented by the general formula (XXXV), the protecting group R ²³ of the oxygen functional group selectively deprotected can be produced. The protecting group R ²³ in the general formula (XXXV) is generally a protecting group that can be introduced into both a hydroxyl group and an amino group, and there is no particular limitation, but a formyl group, an acetyl group, a propionyl group, a butyryl group, a hexanoyl group, Trimethylacetyl group, trifluoroacetyl group, benzoyl group, cyclohexylcarbonyl group, benzyloxycarbonyl group, 2,2,2-trichloroethylcarbonyl group, t-butoxycarbonyl group, 4-methoxybenzyl group, benzyl group, 3,4 -Dimethoxybenzyl group, 2,4,6-trimethylbenzyl group, trifluoromethanesulfonyl group and the like are preferable.
This reaction path is represented by the chemical reaction formula as follows.

(In the formula, R ²³ represents a protecting group.)

Not particularly limited for introducing the protective group R ²³ into the amino group and hydroxyl group of 5-hydroxy-2-amine (XXXIV), the methods (Protective Groups in Organic Synthesis Fourth Edition commonly used as a protective condition of the protecting group , John Wiley & Sons, Inc.).

The deprotection of the protective group R ²³ introduced into the oxygen functional group of the compound (XXXV) obtained by the above method is not particularly limited, but a method generally used as deprotection conditions for the protective group (Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc.).

3 compound having a leaving group W ² compound having the manufacturing method described above the leaving group W ² of (VI) (VI) may either accept those available, or can be suitably prepared by a known method, for example, Although it is possible to manufacture by the following methods, it is not limited to this.

As shown in the following reaction route diagram 9, a ketone derivative represented by the general formula (VII) is reduced to obtain an alcohol derivative represented by the general formula (XXXVIII). Moreover, when the alkyl metal reagent represented by general formula (XXXVII) is made to react with the aldehyde derivative represented by general formula (XXXVI), the alcohol derivative represented by general formula (XXXVIII) will be obtained. The metal M in the general formula (XXXVII) is preferably an alkali metal such as lithium, sodium or potassium, or a magnesium halide forming a Grignard reagent such as magnesium chloride, magnesium bromide or magnesium iodide. The alcohol moiety of the alcohol derivative represented by the general formula (XXXVIII) is converted into leaving group W ^2, the compound having a leaving group W ² can be obtained of the general formula (VI).
This reaction path is represented by the chemical reaction formula as follows.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ have the same meanings as in the general formula (I), and W ² is a halogen atom, an alkylsulfonyloxy group, a haloalkylsulfonyl. Represents an oxy group or an arylsulfonyloxy group.)

  The reduction reaction of the ketone derivative (VII) can be performed using a reducing reagent in a solvent. 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, acetic acid, triethyl Fluoroacetic acid or the like can be used alone or in combination. There is no particular limitation as a reducing reagent, for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride, A borohydride reagent such as lithium triethylborohydride, an aluminum hydride reagent such as lithium aluminum hydride, diisopropylaluminum hydride, and sodium bis (2-methoxyethoxy) aluminum hydride can be used.

The reaction between the aldehyde derivative (XXXVI) and the alkyl metal reagent represented by the general formula (XXXVII) can be carried out by reacting both compounds in an anhydrous solvent. Although there is no restriction | limiting in particular as a solvent, For example, tetrahydrofuran, toluene, a dioxane, hexane etc. can be used individually or in combination. The reaction conditions vary depending on the raw materials used, but in general, the reaction is carried out at −100 to 100 ° C., preferably −78 to 50 ° C. for 5 minutes to 72 hours, preferably 10 minutes to 24 hours. XXXVIII) is obtained.
The reaction for synthesizing the compound (VI) having a leaving group W ² from the alcohol compound (XXXVIII) can be selected according to the type of the leaving group W ² as follows.

When W ² of the compound having a leaving group W ² (VI) is a sulfonyloxy group, the compound (VI) in a solvent in the presence or absence of a base, and a sulfonic acid esterifying agent alcohol compound (XXXVIII) It can obtain by reaction of. The sulfonic acid esterifying agent is not particularly limited. Chloromethanesulfonyl, benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride can be used. The solvent is not particularly limited, and for example, 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile, N, N-dimethylformamide, etc. alone Or they can be used in combination. The base is not particularly limited. For example, pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, trimethylamine and other organic bases, hydrogenated Alkali metal hydrides such as lithium, sodium hydride and potassium hydride; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate Bicarbonates such as alkali metals, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be used.

When W ² of the compound having a leaving group W ² (VI) is a halogen atom, the compound (VI) is a solvent or without a solvent in the presence or absence of a base, an alcohol compound (XXXVIII) with a halogenating agent It can obtain by reaction with. The halogenating agent is not particularly limited, but phosphorus oxychloride, phosphorus pentachloride, triphenylphosphine dichloride, triphenylphosphine dibromide, triphenylphosphite dichloride, triphenylphosphite dibromide, tribromide Chlorinating and brominating agents such as phosphorus, thionyl chloride, triphenylphosphine and carbon tetrachloride, triphenylphosphine and carbon tetrabromide, triphenylphosphine and iodine and imidazole, triphenylphosphine and NIS, methanesulfonyl chloride and DMAP Or an iodinating agent. For example, 1,2-dichloroethane, chloroform, dichloromethane, diethyl ether, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, dioxane, acetonitrile, propionitrile and the like can be used alone or in combination. The base is not particularly limited. For example, organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, N, N-diisopropylethylamine, N, N-diisopropylpentylamine, and trimethylamine, lithium carbonate Further, alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and the like can be used.

A method for producing a compound represented by the general formula (I), a salt thereof, or a solvate thereof, wherein R ¹³ is a lower alkylsulfinyl lower alkoxy group or a lower alkylsulfonyl lower alkoxy group
The compound represented by the general formula (I) in which R ¹³ 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, were prepared using pyrimidin-2-amine derivative R ¹³ is a lower alkylthio-lower alkoxy group (IV ''), R ¹³ is a lower alkylthio-lower alkoxy group, the compound represented by the general formula (I) It can also be obtained by oxidizing the sulfur atom.

  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), PCC, PDC, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), NIS, iodine, bromine Etc. can be used. The solvent is not particularly limited. For example, water, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, N, N-dimethylformamide, acetic acid, etc. Or they can be used in combination.

Further, R ¹³ is lower alkyl sulfonyl lower alkoxy group, the compound represented by the general formula (I), R ¹³ obtained by the above method is lower alkylsulfinyl lower alkoxy group, the general formula (I) It can also manufacture using the oxidation reaction conditions similar from the compound represented by these.

Among the compounds represented by the general formula (I), a method for producing a compound represented by the structural formula (I ″) in which R ¹³ is a hydroxyl group, or a salt thereof, or a solvate thereof. Among the compounds represented by formula (I), the compound represented by the structural formula (I ″) in which R ¹³ is a hydroxyl group can be produced by the following reaction step in addition to appropriately applying the above-described method. That is, among the compounds represented by the general formula (I), the aminopyrimidine derivative (XXIX) is used as the pyrimidine-2-amine derivative (IV) and represented by the structural formula (I ′) produced according to the reaction path diagram 1 or 2. By deprotecting a portion corresponding to R ¹⁹ of the compound, a compound represented by the general formula (I ″) in which R ¹³ is a hydroxyl group can be produced.
This reaction path is represented by the chemical reaction formula as follows.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are those in the general formula (I) R ¹⁹ represents a lower alkyl group or a protecting group.

The deprotection of R ¹⁹ of compound (I ″) is not particularly limited, but can be performed using a Lewis acid or a protonic acid in a solvent. The Lewis acid is not particularly limited, and boron tribromide, boron trichloride, aluminum chloride, trimethylsilyl iodide, trimethylsilyl trifluoromethanesulfonate, ethyl aluminum dichloride, diethyl aluminum chloride and the like can be used. Although there is no restriction | limiting in particular as a proton acid, Hydrobromic acid, hydroiodic acid, etc. can be used. Although there is no restriction | limiting in particular as a solvent, Toluene, benzene, chloroform, a dichloromethane, 1, 2- dichloroethane, chlorobenzene, nitrobenzene, acetonitrile, nitromethane, an acetic acid etc. can be used individually or in combination. The reaction conditions vary depending on the compound represented by the general formula (I ″) to be used, but are generally −20 to 150 ° C., preferably 0 to 120 ° C., 10 minutes to 3 days, preferably 10 minutes to 30 hours. The target product is obtained by the reaction.

When R ¹⁹ is an arylmethyl group such as a benzyl group, a p-methoxybenzyl group, or a 2,4,6-trimethylbenzyl group, deprotection can be performed by a hydrogenation technique other than the above. Although there is no restriction | limiting in particular as a hydrogen source of hydrogenation, Hydrogen, formic acid, ammonium formate, a cyclohexadiene, etc. can be used. Although there is no restriction | limiting in particular as a hydrogenation catalyst, Palladium carbon, palladium black, platinum black, platinum dioxide, Raney nickel, palladium hydroxide carbon powder, etc. can be used. Although there is no restriction | limiting in particular as a solvent, Methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, N, N- dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, acetic acid, water, etc. can be used individually or in combination. The reaction conditions vary depending on the compound represented by the general formula (I ″) to be used, but the reaction is generally carried out at 0 to 150 ° C., preferably 0 to 100 ° C. for 30 minutes to 3 days, preferably 30 minutes to 50 hours. To obtain the target product. Moreover, it can also carry out with reference to the method (Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, Inc.) generally used as deprotection conditions for the protecting group.

The compound represented by the structural formula (I ″) in which R ¹³ is a hydroxyl group is a compound represented by the general formula (I) in which R ¹³ is a lower alkylsulfinyl lower alkoxy group or a lower alkylsulfonyl lower alkoxy group. It can also be produced by deprotecting a lower alkylsulfinyl lower alkyl group or a lower alkylsulfonyl lower alkyl group.

  The deprotection reaction of the lower alkylsulfinyl lower alkyl group or the lower alkylsulfonyl lower alkyl group can be carried out by reacting with a base in a solvent. The solvent is not particularly limited, but for example, methanol, ethanol, isopropanol, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, propionitrile, water, etc. are used alone or in combination. The base is not particularly limited. For example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as metal lithium, metal sodium and metal potassium, hydroxide Alkali metal hydroxides such as lithium, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium diisopropylamide, sodium diisopropylamide and potassium diisopropyl Use pyramide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxysodium, t-butoxypotassium, n-butyllithium, s-butyllithium, t-butyllithium, etc. can do.

The compound represented by the general formula (I) in which R ¹³ is a lower alkoxy group which may have a substituent is represented by the general formula (I ″) in which R ¹³ obtained by the above method is a hydroxyl group. It can also be produced by an etherification reaction of the compound represented.

  For the etherification reaction, a Mitsunobu reaction or a usual method using an alkyl halide can be applied. 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. Although there is no restriction | limiting in particular as an azo reagent, DEAD, diisopropyl azodicarboxylate, ADDP, TIPA, DHTD, etc. 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 etc. can be used individually or in combination.

  The reaction using an alkyl halide 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, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as lithium metal, sodium metal and potassium metal, lithium hydroxide, sodium hydroxide and hydroxide Alkali metal hydroxides such as potassium, lithium carbonate, sodium carbonate, potassium carbonate, alkali carbonates such as cesium carbonate, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, Thorium hexamethyldisilazide, potassium hexamethyldisilazide, t-butoxy sodium, t-butoxy potassium, n- butyl lithium, s- butyl lithium, may be used t-butyl lithium and the like.

  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.

Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. For example, a racemic mixture can be optically purified by a general racemic resolution method such as a method of optical resolution leading to 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.
The obtained compound (I) can be converted to an acid addition salt by a conventional method. Moreover, it can also be set as the solvate and hydrate of solvents, such as a reaction solvent and a recrystallization solvent.

  Examples of the administration form of a pharmaceutical comprising the compound of the present invention, or a salt thereof, or a solvate thereof as an active ingredient include, for example, oral administration or intravenous injection by tablets, capsules, granules, powders, syrups, etc. Parenteral administration by intramuscular injection, suppository, inhalation, transdermal absorption agent, eye drop, nasal drop and the like. In order to prepare pharmaceutical preparations of such various dosage forms, this active ingredient can be used alone or in other pharmaceutically acceptable carriers, that is, excipients, binders, extenders, disintegrants, Surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, diluents and the like can be appropriately combined to prepare a pharmaceutical composition.

  The HMG-CoA reductase inhibitor used in the pharmaceutical combination composition of the present invention inhibits the biological conversion of hydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by HMG-CoA reductase. Compounds such as lovastatin, simvastatin, fluvastatin, pravastatin, pitavastatin, atorvastatin, rosuvastatin and the like.

  The dose of the medicament of the present invention varies depending on the patient's weight, age, sex, symptoms, etc., but in the case of a normal adult, the compound represented by the general formula (I) is usually 0.1 to 500 mg per day, particularly 1 to 300 mg. mg can be administered orally or parenterally in one or several divided doses.

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

Example 1
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Step 1: Production of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5- [2- (methylthio) ethoxy] pyrimidin-2-amine was produced by the method described in a) below. It was also produced separately by the method described in b) below. At this time, for N- (5-hydroxypyrimidin-2-yl) hexaneamide, which is a production intermediate in the method described in b) below, in addition to the method described in b), the method described in c) and d) separately below Also manufactured.

a) Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine-1
5-Bromo-2-chloropyrimidine (300 mg, 1.55 mmol) was dissolved in 4-methoxybenzylamine (2.10 g, 15.4 mmol) by heating 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 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).

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-methylthio Ethanol (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 solution was directly attached to silica gel column chromatography (ethyl acetate) and separated, and then purified by silica gel preparative thin layer chromatography (hexane: ethyl acetate = 1: 1), and N- (4-methoxybenzyl) -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine (172 mg) was obtained as a colorless amorphous 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).

N- (4-methoxybenzyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (172 mg) was dissolved in trifluoroacetic acid (3 mL) at room temperature and stirred at 60 ° C. for 2.5 hours. did. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 15: 1) to give 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (34 mg, 2 steps 18%) as a colorless amorphous 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).

b) Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine-2
5-Methoxypyrimidin-2-amine (12.3 g, 98.3 mmol) was dissolved in pyridine (123 mL), hexanoic acid chloride (14.5 g, 108 mmol) was added in an ice bath, and the mixture was 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).

N- (5-methoxypyrimidin-2-yl) hexanamide (17.3 g, 77 mmol) was suspended in 1,2-dichloroethane (170 mL), boron tribromide (20.5 mL, 216 mmol) was added, and 30 Heated to reflux for minutes. The reaction mixture was quenched with methanol (170 mL) under ice-cooling, and concentrated under reduced pressure, and saturated ammonia methanol (85 mL) was added 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-hydroxypyrimidin-2-yl) hexanamide (8.18 g, 39 mmol) and triphenylphosphine (20.5 g, 78 mmol) were mixed, dried under reduced pressure, and then purged with an argon atmosphere. These were heated and dissolved 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- [2- (methylthio) ethoxy] pyrimidin-2-yl} hexanamide (6.80 g, 24 mmol) was suspended in methanol (68 mL), and sodium methoxide (1 M methanol solution, 120 mL, 120 mmol) was added, dissolved in an oil bath at 60 ° C., and stirred at the same temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure 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 obtained residue was washed with ether-hexane and collected by filtration to give 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (2.93 g, 59%) as a pale yellow solid.

c) Production of N- (5-hydroxypyrimidin-2-yl) hexanamide-2
5-Hydroxypyrimidin-2-amine (40.0 g, 360 mmol) was dissolved in pyridine (200 mL), hexanoic acid chloride (121 g, 899 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr. Methanol (100 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue 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 dissolved in methanol (200 mL), and stirred with ice-cooling, a saturated ammonia-methanol solution (250 mL) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: acetone = 2: 1) to give N- (5-hydroxypyrimidin-2-yl) hexanamide (39.5 g, 52%). Obtained as a colorless solid.

d) Production of N- (5-hydroxypyrimidin-2-yl) hexanamide-3
While [(2,2-diethoxyethoxy) methyl] benzene (8.30 g, 37.0 mmol) was stirred with ice cooling, phosphorus pentachloride (8.09 g, 38.8 mmol) was added over 15 minutes. After stirring for 15 minutes at the same temperature, the mixture was heated and stirred in a 75 ° C. oil bath for 75 minutes. After stirring at room temperature for 20 minutes and cooling, anhydrous N, N-dimethylformamide (8.6 mL, 111 mmol) was added at the same temperature, and the mixture was stirred at room temperature for 3 days. After adding an 8 M aqueous sodium hydroxide solution in an ice bath until the pH reached 8 or more, the mixture was diluted with water and extracted with ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: acetone = 4: 1 → 2: 1). Then, 2- (benzyloxy) -3- (dimethylamino) acrylaldehyde (4.05 g, 53%) was obtained as a brown oil.
¹ H-NMR (CDCl ₃ ) δ: 3.04 (6H, s), 4.96 (2H, s), 6.17 (1H, s), 7.28-7.43 (5H, m), 8.64 (1H, s).

2- (Benzyloxy) -3- (dimethylamino) acrylaldehyde (10.9 g, 53 mmol) was dissolved in N-methylpyrrolidone (85 mL) and guanidine hydrochloride (15.3 g, 160 mmol) was added. Sodium hydride (50% in oil, 15.3 g, 320 mmol) was added while stirring in an ice bath, and the mixture was stirred in an oil bath at 80 ° C. for 1 hour. Water was added in an ice bath to decompose excess sodium hydride, followed by extraction from ether-water. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (hexane: acetone = 10: 1 → 4: 1 → 2: 1 → 1: 1), the eluate was concentrated under reduced pressure, and the residue was washed with ether-hexane. Washing and filtration were performed to obtain 5- (benzyloxy) pyrimidin-2-amine (6.99 g, 65%) as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 4.76 (2H, br s), 5.03 (2H, s), 7.28-7.43 (5H, m), 8.08 (2H, s).

Pyridine (30 mL, 0.37 mmol) is added to a solution of 5- (benzyloxy) pyrimidin-2-amine (60.0 g, 0.30 mmol) in dichloromethane (400 mL), and hexanoic acid chloride (46.0 g) is stirred in an ice bath. , 0.34 mmol) in dichloromethane (100 mL) was added dropwise and stirred at the same temperature for 1 hour. 1 M Hydrochloric acid (500 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from chloroform-hexane to give N- [5- (benzyloxy) pyrimidin-2-yl] hexanamide (87.1 g, 98%) as colorless needle crystals.
¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 6.9 Hz), 1.34-1.39 (4H, m), 1.69-1.75 (2H, m), 2.55-2.61 (2H, m), 5.12 (2H, s), 7.34-7.44 (5H, m), 7.96 (1H, br), 8.32 (2H, s).

  N- [5- (benzyloxy) pyrimidin-2-yl] hexanamide (87.1 g, 0.29 mmol) is dissolved in methanol (2.4 L), 10% palladium on carbon (20 g) is added, and hydrogen atmosphere is used at room temperature. Stir for 3 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and N- (5-hydroxypyrimidin-2-yl) hexanamide. (28.0 g, 46%) was obtained as a pale yellow solid.

Step 2: Preparation of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane 3,5-bis (trifluoromethyl) acetophenone (2.00 g, 7.81 mmol) in methanol (20 mL) To the mixture was added sodium borohydride (591 mg, 15.6 mmol) with stirring in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction solution was added 1 M hydrochloric acid in an ice bath until the pH was 7 or less, and then the reaction solution was concentrated under reduced pressure. Water (20 mL) was added to the resulting residue, 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 1- [3,5-bis (trifluoromethyl) phenyl] ethanol (2.00 g, 99%) as a colorless solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.55 (3H, d, J = 6.6 Hz), 2.00 (1H, br s), 5.05 (1H, q, J = 6.6 Hz), 7.79 (1H, s), 7.85 (2H, s).

To a solution of 1- [3,5-bis (trifluoromethyl) phenyl] ethanol (500 mg, 1.94 mmol) in toluene (5 mL) was added phosphorus tribromide (550 mg, 2.03 mmol), and overnight at room temperature. Stir. 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 by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (258 mg, 41%) was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 2.08 (3H, d, J = 7.1 Hz), 5.21 (1H, q, J = 7.1 Hz), 7.81 (1H, s), 7.87 (2H, s).

Step 3: 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) synthesized by the method described in International Publication No. 2006/073973 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).

Step 4: N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} Preparation of methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (3.34 g) obtained in Step 3 , 11.2 mmol) and 5- [2- (methylthio) ethoxy] pyrimidin-2-amine (2.27 g, 12.3 mmol) obtained in Step 1 in toluene (80 mL) solution with acetic acid (317 mg, 5.19 mmol). In addition, 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), and N-({2-[(cyclopentylmethyl) (ethyl) amino]- 5- (Trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (4.39 g, 84%) was obtained 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).

  N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (4.39 g, 9.37 mmol ) In tetrahydrofuran (40 mL) was stirred under ice-cooling, sodium hydride (50% in oil, 1.80 g, 37.5 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction solution was cooled to −78 ° C., and 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (6.02 g, 18.7 mmol) obtained in Step 2 in N, N-dimethylformamide ( 40 mL) solution was added and stirred for 2.5 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 20). : 1), and the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (Trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (6.03 g, 91%) was obtained as a pale yellow oil.

Example 2 and Example 3
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine and N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) ( Preparation of ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoro) obtained in Example 1 Methyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine (348 mg, 0.49 mmol) in acetonitrile (7 mL) and molybdenum dichloride dioxide (14.6 mg, 0.073 mmol) and 30 % Aqueous hydrogen peroxide (220 mg, 1.94 mmol) was added, and the mixture was stirred at room temperature for 23 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 using silica gel preparative thin layer chromatography (hexane: acetone = 2: 1), and N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N- ({2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine (Compound of Example 2: 32.8 mg, 9%) as a yellow oil, N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5 -(Trifluoromethyl) phenyl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine (Compound of Example 3: 295 mg, 81%) was obtained as a pale yellow oil.

Example 4
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
Using 2-fluoro-5-methoxybenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, and 2-[(cyclopentylmethyl) (ethyl) Amino] -5-methoxybenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.1 Hz), 1.09-1.24 (2H, m), 1.38-1.70 (6H, m), 1.94 (1H, m), 2.94 (2H , d, J = 7.6 Hz), 3.06 (2H, q, J = 7.1 Hz), 3.83 (3H, s), 7.12 (1H, dd, J = 3.2, 8.8 Hz), 7.23 (1H, d, J = 8.8 Hz), 7.31 (1H, d, J = 3.2 Hz), 10.49 (1H, s).

  Step 4 of Example 1 using 2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxybenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino]- 5-Methoxyphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 5
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 4 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(Cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, Target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) Was obtained 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 6
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 Preparation of [2- (methylthio) ethoxy] pyrimidin-2-amine:
Using 2,3,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were conducted in the same manner as in Step 3 of Example 1, and 2-[(cyclopentylmethyl) (ethyl ) Amino] -3,5-difluorobenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 6.6 Hz), 1.07-1.20 (2H, m), 1.41-1.70 (6H, m), 1.89 (1H, m), 3.03 (2H , d, J = 7.6 Hz), 3.13 (2H, q, J = 6.6 Hz), 7.04 (1H, m), 7.34 (1H, m), 10.50 (1H, d, J = 3.4 Hz).

  Using 2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorobenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The reaction and treatment were conducted in the same manner as in Step 4, and the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino ] -3,5-difluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 7
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 Preparation of [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 6 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(Cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was used in the same reaction and treatment as in Example 3. The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluoropheny The} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 8
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
Using 2-fluoro-5-methylbenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, and 2-[(cyclopentylmethyl) (ethyl) Amino] -5-methylbenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.1 Hz), 1.14-1.19 (2H, m), 1.43-1.67 (6H, m), 2.01 (1H, m), 2.33 (3H , s), 2.99 (2H, d, J = 7.6 Hz), 3.12 (2H, q, J = 7.1 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.32 (1H, dd, J = 2.2, 8.3 Hz), 7.62 (1H, d, J = 2.2 Hz), 10.39 (1H, s).

  Step 4 of Example 1 using 2-[(cyclopentylmethyl) (ethyl) amino] -5-methylbenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino]- 5-Methylphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 9
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 8 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl)- 5 To obtain [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 10
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Step 3 of Example 1 using 2,4-difluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and 2-[(cyclopentylmethyl) (ethyl) amino] -4-Fluorobenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.1 Hz), 1.10-1.21 (2H, m), 1.42-1.73 (6H, m), 2.11 (1H, m), 3.06 (2H , d, J = 7.6 Hz), 3.23 (2H, q, J = 7.1 Hz), 6.75 (1H, m), 6.82 (1H, dd, J = 2.4, 8.8 Hz), 7.81 (1H, dd, J = 7.1, 8.8 Hz), 10.18 (1H, s).

  Step 4 of Example 1 using 2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorobenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino]- 4-Fluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 11
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 10 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl which is the target compound The 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 12
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
Using 2-fluoro-4-methoxybenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, and 2-[(cyclopentylmethyl) (ethyl) Amino] -4-methoxybenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.1 Hz), 1.14-1.19 (2H, m), 1.46-1.68 (6H, m), 2.10 (1H, m), 3.03 (2H , d, J = 7.6 Hz), 3.20 (2H, q, J = 7.1 Hz), 3.89 (3H, s), 6.60-6.64 (2H, m), 7.80 (1H, d, J = 9.5 Hz), 10.18 (1H, s).

  Step 4 of Example 1 using 2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxybenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino]- 4-Methoxyphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 13
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 12 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl which is the target compound The 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 14
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Using 2-fluoro-4- (trifluoromethyl) benzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were conducted in the same manner as in Step 3 of Example 1, and 2-[(cyclopentylmethyl ) (Ethyl) amino] -4- (trifluoromethyl) benzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.05-1.19 (5H, m), 1.50-1.71 (6H, m), 2.08 (1H, m), 3.12 (2H, d, J = 7.8 Hz), 3.26 (2H , q, J = 7.1 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.87 (1H, d, J = 7.8 Hz), 10.28 (1H, s).

  Example using 2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde In the same manner as in Step 4 of 1, the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl ) Amino] -4- (trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 15 and Example 16
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine and N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) ( Preparation of ethyl) amino] -4- (trifluoromethyl) phenyl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 14 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Example 2 and Example 3 using 2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine The reaction and treatment were carried out in the same manner as above, and N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (tri Fluoro (Til) phenyl} methyl) -5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine (Compound of Example 15) as a pale yellow oil, N- {1- [3,5-bis (trifluoro) Methyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidine-2 -Amine (Compound of Example 16) was obtained as a pale yellow oil.

Example 17
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Using 2-chloro-6-fluoro-3-methylbenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, and 2-chloro-6--6 [(Cyclopentylmethyl) (ethyl) amino] -3-methylbenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 6.8 Hz), 1.08-1.20 (2H, m), 1.43-1.73 (6H, m), 2.05 (1H, m), 2.36 (3H , s), 3.00 (2H, d, J = 7.6 Hz), 3.11 (2H, q, J = 6.8 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz) ), 10.25 (1H, s).
Example using 2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylbenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde In the same manner as in Step 4 of 1, the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentyl) Methyl) (ethyl) amino] -3-methylphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 18
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 17 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-Chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was used in the same manner as in Example 3. Treatment, target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino]- 3-me The butylphenyl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 19
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) Preparation of ethoxy] pyrimidin-2-amine:
Using 2-fluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1 to obtain 2-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde. Obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.1 Hz), 1.11-1.21 (2H, m), 1.42-1.72 (6H, m), 2.07 (1H, m), 3.06 (2H , d, J = 7.6 Hz), 3.19 (2H, q, J = 7.1 Hz), 7.08 (1H, t, J = 8.1 Hz), 7.19 (1H, d, J = 8.1 Hz), 7.49 (1H, dt , J = 1.6, 8.1 Hz), 7.80 (1H, dd, J = 1.6, 8.1 Hz), 10.35 (1H, s).

  Reaction similar to step 4 of Example 1 using 2-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde Processed and target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl)- 5- [2- (Methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 20
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylsulfonyl) ) Preparation of ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 19 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(Cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3 to obtain the title compound as a pale compound. Obtained as a yellow oil.

Example 21
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 Preparation of [2- (methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Step 3 of Example 1 using 2,4,5-trifluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and 2-[(cyclopentylmethyl) (ethyl ) Amino] -4,5-difluorobenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.1 Hz), 1.09-1.23 (2H, m), 1.43-1.71 (6H, m), 2.02 (1H, m), 2.99 (2H , d, J = 7.6 Hz), 3.15 (2H, q, J = 7.1 Hz), 7.00 (1H, dd, J = 6.6, 12.0 Hz), 7.61 (1H, dd, J = 9.3, 10.2 Hz), 10.26 (1H, d, J = 2.9 Hz).

  Using 2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorobenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The reaction and treatment were conducted in the same manner as in Step 4, and the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino ] -4,5-difluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 22
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 Preparation of [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 21 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(Cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was used in the same reaction and treatment as in Example 3. The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorofe Was obtained Le} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale brown oil.

Example 23
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
Using 4-chloro-2-fluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were conducted in the same manner as in Step 3 of Example 1, and 4-chloro-2-[(cyclopentylmethyl) was obtained. ) (Ethyl) amino] benzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.1 Hz), 1.09-1.20 (2H, m), 1.43-1.73 (6H, m), 2.10 (1H, m), 3.06 (2H , d, J = 7.6 Hz), 3.22 (2H, q, J = 7.1 Hz), 7.03 (1H, dd, J = 2.0, 8.3 Hz), 7.12 (1H, d, J = 2.0 Hz), 7.73 (1H , d, J = 8.3 Hz), 10.22 (1H, s).

  Step 4 of Example 1 using 4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde And the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl ) Amino] phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 24
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 23 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl)- - to obtain [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale brown oil.

Example 25
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
The reaction and treatment were conducted in the same manner as in Step 3 of Example 1 using 2,5-difluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, and 2-[(cyclopentylmethyl) (ethyl) amino] -5-Fluorobenzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.1 Hz), 1.11-1 21 (2H, m), 1.42-1.69 (6H, m), 1.98 (1H, m), 2.99 ( 2H, d, J = 7.3 Hz), 3.11 (2H, q, J = 7.1 Hz), 7.21-7.25 (2H, m), 7.48 (1H, m), 10.40 (1H, d, J = 3.2 Hz).

  Step 4 of Example 1 using 2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorobenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino]- 5-Fluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a light brown oil.

Example 26
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 25 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, The title compound was obtained as a pale yellow oil.

Example 27
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
Using 4-bromo-2-fluorobenzaldehyde instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were conducted in the same manner as in Step 3 of Example 1, and 4-bromo-2-[(cyclopentylmethyl) was obtained. ) (Ethyl) amino] benzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.04-1.19 (5H, m), 1.49-1.69 (6H, m), 2.10 (1H, m), 3.05 (2H, d, J = 7.6 Hz), 3.21 (2H , q, J = 7.1 Hz), 7.21 (1H, d, J = 8.4 Hz), 7.28 (1H, s), 7.64 (1H, d, J = 8.4 Hz), 10.22 (1H, s).

  Step 4 of Example 1 using 4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl ) Amino] phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 28
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 27 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(Cyclopentylmethyl) (ethyl) amino] -4-bromophenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl)- - to obtain [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 29
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 Preparation of-(methylthio) ethoxy] pyrimidin-2-amine:
Using 5-bromo-2-fluorobenzaldehyde in place of 2-fluoro-5- (trifluoromethyl) benzaldehyde, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, to obtain 5-bromo-2-[(cyclopentylmethyl). ) (Ethyl) amino] benzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.04-1.19 (5H, m), 1.49-1.69 (6H, m), 2.04 (1H, m), 3.03 (2H, d, J = 7.6 Hz), 3.19 (2H , q, J = 7.1 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.89 (1H, s), 10.23 (1H, s).

  Step 4 of Example 1 using 5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde And the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl ) Amino] phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 30
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 Preparation of-(methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({obtained in Example 29 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3, The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl)- - to obtain [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 31
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl } -5- (Trifluoromethyl) benzonitrile production:
3- (hydroxymethyl) -5- (trifluoromethyl) benzonitrile (2.70 g, 13.4 mmol) synthesized by the method described in JP-A-2003-221376 is dissolved in acetone (30 mL), and 2 M- Jones reagent (26.8 mL, 53.6 mmol) was added and stirred for 12 hours. The reaction mixture was diluted with water (15 mL), and extracted with ether. The organic layers were combined, back-extracted with a 2 M aqueous sodium hydroxide solution, neutralized by adding 1 M hydrochloric acid to the aqueous layer, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-cyano-5- (trifluoromethyl) benzoic acid (2.44 g, 85%) as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 8.18 (1H, s), 8.60 (2H, s).

While stirring a solution of 3-cyano-5- (trifluoromethyl) benzoic acid (200 mg, 0.93 mmol) in tetrahydrofuran (2 mL) in an ice bath, N, O-dimethylhydroxyamine hydrochloride (145 mg, 1.49) mmol) and N, N-diisopropylethylamine (470 mg, 3.64 mmol) and diethyl cyanophosphate (DEPC) (227 mg, 1.39 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 1 M hydrochloric acid (0.5 mL) was added to the resulting residue, 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 purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 3-cyano- N-methoxy-N-methyl-5- (trifluoromethyl) benzamide (196 mg, 82%) was obtained as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 3.42 (3H, s), 3.56 (3H, s), 8.00 (1H, s), 8.22 (2H, s).

While stirring a solution of 3-cyano-N-methoxy-N-methyl-5- (trifluoromethyl) benzamide (196 mg, 0.76 mmol) in anhydrous tetrahydrofuran (2 mL) in an ice bath, methylmagnesium bromide (0.96 M ether solution, 0.95 mL, 0.91 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-acetyl-5- (trifluoromethyl) benzonitrile (162 mg, 100%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 8.10 (1H, s), 8.41 (2H, s).

Using 3-acetyl-5- (trifluoromethyl) benzonitrile instead of 3,5-bis (trifluoromethyl) acetophenone, the reaction and treatment were carried out in the same manner as in Step 2 of Example 1, to obtain 3- (1-bromoethyl). ) -5- (trifluoromethyl) benzonitrile was obtained as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 2.07 (3H, d, J = 7.1 Hz), 5.57 (1H, m), 7.90 (1H, s), 7.92 (2H, s).

  Using 4- (1-bromoethyl) -5- (trifluoromethyl) benzonitrile in place of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane, step 4 of Example 1 and The reaction and treatment were carried out in the same manner, and the target compound 3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylthio) Ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile was obtained as a pale yellow oil.

Example 32
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Preparation of ethyl} -5- (trifluoromethyl) benzonitrile:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoro obtained in Example 31 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine Methylphenyl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile was reacted and treated in the same manner as in Example 3, The target compound 3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylsulfonyl) Ethoxy] pyrimidin-2-yl} amino] ethyl} -5- (trifluoromethyl) benzonitrile as a pale yellow oil.

Example 33
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Ethylmagnesium bromide (1.00 M anhydrous tetrahydrofuran solution, 1.86 mL, 1.86) was stirred in a solution of 3,5-bis (trifluoromethyl) benzaldehyde (300 mg, 1.24 mmol) in anhydrous tetrahydrofuran (3 mL) in an ice bath. mmol) and stirred at the same temperature for 30 minutes. 1 M hydrochloric acid was added to the reaction solution in an ice bath until the pH became 7 or less, and the reaction solution 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 purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 1- [ 3,5-bis (trifluoromethyl) phenyl] -1-propanol (165 mg, 49%) was obtained as a colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.4 Hz), 1.77-1.84 (2H, m), 2.01 (1H, d, J = 3.6 Hz), 4.79 (1H, m), 7.79 (1H, s), 7.82 (2H, s).

Similar to step 2 of Example 1 using 1- [3,5-bis (trifluoromethyl) phenyl] -1-propanol instead of 1- [3,5-bis (trifluoromethyl) phenyl] ethanol Reaction and treatment gave 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] propane as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7.3 Hz), 2.14-2.34 (2H, m), 4.90 (1H, m), 7.80 (1H, s), 7.83 (2H, s ).

  Example 1 using 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] propane instead of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane The reaction and treatment were conducted in the same manner as in Step 4, and the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino ] -5- (trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 34
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({obtained in Example 33 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was used in the same manner as in Example 3.・ N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (tri The Ruoromechiru) phenyl} methyl) -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 35
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
Using piperidine instead of N- (cyclopentylmethyl) -N-ethylamine, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, to give 2- (piperidino) -5- (trifluoromethyl) benzaldehyde as a yellow oil. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.57-1.69 (2H, m), 1.70-1.82 (4H, m), 3.08-3.18 (4H, m), 7.14 (1H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 2.3, 8.5 Hz), 8.03 (1H, d, J = 2.3 Hz), 10.20 (1H, s).

  Similar to Step 4 of Example 1, substituting 2- (piperidino) -5- (trifluoromethyl) benzaldehyde for 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl is reacted and treated. } -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine was obtained as a yellow oil.

Example 36
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[obtained in Example 35 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (Piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3 to obtain the target compound. N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- ( Methylsulfonyl Ethoxy] pyrimidin-2-amine as a colorless amorphous.

Example 37
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Preparation of ethoxy] pyrimidin-2-amine:
Using morpholine in place of N- (cyclopentylmethyl) -N-ethylamine, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, to give 2- (morpholino) -5- (trifluoromethyl) benzaldehyde as a yellow oil. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 3.12-3.20 (4H, m), 3.87-3.95 (4H, m), 7.17 (1H, d, J = 8.6 Hz), 7.75 (1H, dd, J = 2.0, 8.6 Hz), 8.06 (1H, d, J = 2.0 Hz), 10.25 (1H, s).

  Similar to Step 4 of Example 1, substituting 2- (morpholino) -5- (trifluoromethyl) benzaldehyde for 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl is reacted and treated. } -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine was obtained as a brown oil.

Example 38
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Preparation of sulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[obtained in Example 37 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3 to obtain the target compound. N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- ( Methylsulfonyl Ethoxy] pyrimidin-2-amine as a pale yellow crystalline powder.

Example 39
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- Preparation of (methylthio) ethoxy] pyrimidin-2-amine:
Using 4-methylpiperidine in place of N- (cyclopentylmethyl) -N-ethylamine, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1 to obtain 2- (4-methylpiperidino) -5- (trifluoromethyl) benzaldehyde. Was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, d, J = 6.3 Hz), 1.36-1.51 (2H, m), 1.59 (1H, m), 1.70-1.84 (2H, m), 2.88-3.02 (2H, m), 3.28-3.42 (2H, m), 7.14 (1H, d, J = 8.5 Hz), 7.68 (1H, dd, J = 2.2, 8.5 Hz), 8.03 (1H, d, J = 2.2 Hz), 10.18 (1H, s).

  Step 4 of Example 1 using 2- (4-methylpiperidino) -5- (trifluoromethyl) benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde In the same manner, the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) ) Phenyl] methyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine was obtained as a yellow oil.

Example 40
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- Preparation of (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[obtained in Example 39 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (4-Methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3 for the purpose The compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5 [2 (Methylsulfonyl) ethoxy] pyrimidin-2-amine as a colorless amorphous.

Example 41
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- Preparation of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine:
Using cis-2,6-dimethylmorpholine instead of N- (cyclopentylmethyl) -N-ethylamine, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1 to obtain 2- (cis-2,6-dimethylmorpholino). -5- (Trifluoromethyl) benzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.4 Hz), 2.66-2.77 (2H, m), 3.08-3.20 (2H, m), 3.84-3.98 (2H, m), 7.14 (1H, d, J = 8.5 Hz), 7.73 (1H, dd, J = 1.7, 8.5 Hz), 8.05 (1H, d, J = 1.7 Hz), 10.22 (1H, s).

  Example using 2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) benzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde In the same manner as in Step 4 of 1, the target compound N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6- Dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a yellow oil.

Example 42
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- Preparation of 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[obtained in Example 41 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine 2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was used in the same manner as in Example 3.・ N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (tri Fluoromethyl) phenyl Methyl} -5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a colorless amorphous.

Example 43 and Example 44
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate and trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ] Preparation of ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid:
Example 1 using trans- {4-[(ethylamino) methyl] cyclohexyl} ethyl acetate synthesized by the method described in WO 2004/020393 instead of N- (cyclopentylmethyl) -N-ethylamine In the same manner as in Step 3, the trans- [4-({[2- (formyl) -4- (trifluoromethyl) phenyl] (ethyl) amino} methyl) cyclohexyl] ethyl acetate was treated as a yellow oil. Obtained.
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 ).

Trans- [4-({[2- (formyl) -4- (trifluoromethyl) phenyl] (ethyl) instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde Amino} methyl) cyclohexyl] ethyl acetate is used to react and treat with 5- [2- (methylthio) ethoxy] pyrimidin-2-amine in the same manner as in Step 4 of Example 1, and trans- {4-[({2 -[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate as a pale yellow oil Got as.
¹ H-NMR (CDCl ₃ ) δ: 0.88-0.96 (4H, m), 1.02 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.60-1.85 (5H, m), 2.15 (2H, d, J = 6.6 Hz), 2.20 (3H, s), 2.84-2.87 (4H, m), 3.00 (2H, q, J = 7.1Hz), 4.11 (2H, q, J = 7.1 Hz), 4.12 (2H, t, J = 6.7 Hz), 4.67 (2H, d, J = 5.9 Hz), 5.48 (1H, t, J = 5.9 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).

  trans- {4-[({2-[({5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] Sodium hydride (50% in oil, 3.4 mg, 0.072 mmol) was added to a solution of ethyl cyclohexyl} acetate (10.2 mg, 0.018 mmol) in tetrahydrofuran (0.3 mL) under ice-cooling and stirred at room temperature for 30 minutes. did. The reaction solution was cooled to −78 ° C., and a solution of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (6.9 mg, 0.021 mmol) in N, N-dimethylformamide (0.3 mL) was added. The mixture was stirred for 14 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1 → chloroform: methanol = 20: 1). Trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine-2- Yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate (Example 43 compound: 1.8 mg, 12%) as a pale yellow oil, trans- {4 -[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- ( Trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (Example 44 compound: 3.2 mg, 23%) was obtained as a pale yellow oil.

Example 45
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Preparation of methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate:
Trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidine- obtained in Example 43 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate (284 mg, 0.351 mmol) in methanol (4 mL) in 30% aqueous hydrogen peroxide (0.2 mL, 1.76 mmol) and tantalum pentachloride (12.6 mg, 0.035 mmol) were added, and the mixture was stirred at room temperature for 2 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 preparative thin layer chromatography (hexane: acetone = 3: 2), and trans- {4-[({2-[({1- [3,5-bis (trifluoro Methyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate ( 277 mg, 94%) was obtained as a white amorphous.

Example 46
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4- ( Preparation of (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid:
Trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidine obtained in Example 45 2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate (100 mg, 0.119 mmol) in ethanol (1 mL) and 2M aqueous sodium hydroxide solution And stirred at 50 ° C. for 2 hours. The reaction mixture was acidified with 1M hydrochloric acid and 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 preparative thin layer chromatography on silica gel (hexane: ethyl acetate = 1: 1, 2% acetic acid) and trans- {4-[({2-[({1- [3 5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid (57.6 mg, 68%) was obtained as a yellow oil.

Example 47
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- Trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) obtained in Example 44 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine ) Phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid The reaction and treatment were conducted in the same manner as in Example 3, and the target compound trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (Methylsulfonyl Ethoxy] was obtained as a pyrimidin-2-yl} amino) methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} a pale yellow oil acetate.

Example 48
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ Preparation of 2- (methylthio) ethoxy] pyrimidin-2-amine:
2,3,5-trifluorobenzaldehyde is used instead of 2-fluoro-5- (trifluoromethyl) benzaldehyde and described in WO 2006/073973 pamphlet instead of N- (cyclopentylmethyl) -N-ethylamine Using the N, N-bis (cyclopropylmethyl) amine synthesized by the above method, the reaction and treatment were carried out in the same manner as in Step 3 of Example 1, to obtain 2- [bis (cyclopropylmethyl) amino] -3,5-difluoro. Benzaldehyde was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ: -0.08-0.07 (4H, m), 0.31-0.39 (4H, m), 0.68-0.80 (2H, m), 2.97 (2H, d, J = 6.8 Hz), 2.98 (2H, d, J = 7.1 Hz), 7.04 (1H, ddd, J = 2.9, 8.0, 11.5 Hz), 7.35 (1H, ddd, J = 1.5, 2.9, 8.0 Hz), 10.69 (1H, d, J = 3.4 Hz).

  Step of Example 1 using 2- [bis (cyclopropylmethyl) amino] -3,5-difluorobenzaldehyde instead of 2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde The reaction and treatment were conducted in the same manner as in No. 4, and the target compound N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (Trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was obtained as a pale yellow oil.

Example 49
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ Preparation of 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) obtained in Example 46 instead of 5- [2- (methylthio) ethoxy] pyrimidin-2-amine -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [2- (methylthio) ethoxy] pyrimidin-2-amine was reacted and treated in the same manner as in Example 3. N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl which is the target compound The 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine as a pale yellow oil.

Example 50
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- Production of 5-methoxypyrimidin-2-amine:
2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) benzaldehyde (320 mg, 1.069 mmol) and 2-amino-5-methoxypyrimidine (147 mg, 1.176 mmol) in toluene (8 mL) Acetic acid (64 mg, 1.069 mmol) was added to the solution, and the mixture was heated to reflux for 4 hours using a Dean-Stark apparatus. The reaction solution was allowed to cool to room temperature, sodium triacetoxyborohydride (453 mg, 2.138 mmol) was added while stirring in an ice bath, and the mixture was stirred at room temperature for 28 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1), and N-[{2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} Methyl) -5-methoxypyrimidin-2-amine was obtained as a pale yellow oil (388 mg, 87%).
¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.2 Hz), 1.15-1.26 (2H, m), 1.43-1.58 (4H, m), 1.66-1.73 (2H, m), 1.96 -2.05 (1H, m), 2.95 (2H, d, J = 7.2 Hz), 3.04 (2H, q, J = 7.2 Hz), 3.81 (1H, s), 4.69 (2H, d, J = 6.0 Hz) , 5.44 (1H, br t, J = 6.0 Hz), 7.20 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 8.2 Hz), 7.62 (1H, s), 8.07 (2 H, s).

  N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5-methoxypyrimidin-2-amine (378 mg, 0.925 mmol) in tetrahydrofuran (4 mL) While the solution was stirred under ice-cooling, sodium hydride (50% in oil, 178 mg, 3.70 mmol) was added, followed by stirring at 50 ° C. for 1 hour. The reaction solution was cooled to −78 ° C. and a solution of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (594 mg, 1.85 mmol) in anhydrous N, N-dimethylformamide (4 mL). Was added dropwise, followed by stirring for 3 hours under ice cooling. Water was added to the reaction solution, and the mixture was extracted 3 times with hexane: ethyl acetate = 2: 1. 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 chromatography (hexane: ethyl acetate = 20: 1), and N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2 -[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5-methoxypyrimidin-2-amine was obtained as a pale orange oil (477 mg, 80%).

Example 51
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- Production of 5-hydroxypyrimidin-2-amine:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoro) obtained in Example 50 Methyl) phenyl} methyl) -5-methoxypyrimidin-2-amine (200 mg, 0.31 mmol) in 1,2-dichloroethane (4 mL) was added to boron tribromide (1.0 M in dichloromethane, 1.54 mL, 1.54 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, methanol (4 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel chromatography (hexane: chloroform: methanol = 10: 10: 1) to give N- {1- [3,5-bis (trifluoromethyl). Phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) -5-hydroxypyrimidin-2-amine (182 mg, 93%) Obtained as pale orange crystals.

Example 52
4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) )] Amino} pyrimidin-5-yl) Preparation of ethyl butyrate:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoro) obtained in Example 51 Methyl) phenyl} methyl) -5-hydroxypyrimidin-2-amine (156 mg, 0.25 mmol) in N, N-dimethylformamide (4 mL) in ethyl 4-bromobutyrate (58 mg, 0.30 mmol) and potassium carbonate (102 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. 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 chromatography (hexane: ethyl acetate = 10: 1) to give 4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ( {2-[(Cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)] amino} pyrimidin-5-yl) ethyl butyrate (155 mg, 84%) was obtained as a pale yellow oil. It was.

Example 53
4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) )] Amino} pyrimidin-5-yl) butyric acid:
4- (2-{[{1- [3,5-Bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- () obtained in Example 52. To a solution of trifluoromethyl) phenyl} methyl)] amino} pyrimidin-5-yl) butyrate in ethanol (4 mL) was added 2M aqueous sodium hydroxide solution (0.34 mL, 0.69 mmol), and the mixture was stirred at room temperature for 9 hours. The reaction solution was neutralized by adding 2M hydrochloric acid under ice-cooling, and concentrated under reduced pressure. The residue obtained was purified by silica gel preparative thin layer chromatography (chloroform: methanol = 10: 1), and 4- ( 2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)] amino } Pyrimidin-5-yl) butyric acid (156 mg, 94%) was obtained as a colorless foam.

The compounds obtained by the above examples are shown in Table 1.

Test example 1
Measurement of CETP inhibitory action in human plasma A compound solution prepared by dissolving the compound of Example in Polyethyleneglycol / N-methyl-2-pyrrolidone (vol / vol = 1/1) is added to human plasma and incubated in a 37 ° C constant temperature bath for 4 hours. did. CETP activity in this plasma was measured with a Cholesteryl Ester Transfer Protein Activity kit (Roar Biomedical, catalog number: RB-CETP). That is, add 95 μL of buffer solution (10 mM tris, 150 mM NaCl, 2 mM EDTA, pH 7.4), Donor particle 2 μL and Acceptor particle 2 μL to 96-well plate, add 1 μL of human plasma after incubation, Incubated for 2 hours in a 37 ° C constant temperature bath. After the incubation, fluorescence intensity (Fluorescence intensity; FLU) was measured with a fluorescence plate reader (excitation wavelength: 465 nm, fluorescence wavelength: 535 nm). From the following formula 1, CETP activity (% of control) at a plurality of concentrations was determined for each of the compounds of Examples.
CETP activity (% of control) = (Sample FLU−Blank FLU) × 100 / (Control FLU−Blank FLU) (Formula 1)
Where
BlankFLU: Fluorescence intensity of plasma-free sample
ControlFLU: Fluorescence intensity of plasma without compound solution
SampleFLU: Fluorescence intensity of compound solution-added plasma is shown.

The value obtained by subtracting the value of CETP activity from 100 is defined as the CETP inhibition rate of the example compound. For each example compound, the concentration (IC ₅₀ ) that inhibits CETP activity by 50% from the value of the CETP inhibition rate at multiple concentrations. Calculated. The results are shown in Table 2.

Test example 2
Measurement of blood HDL cholesterol increasing action in normal hamsters.
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine (Example 3), or 4 (S)-[(3,5-bis-trines disclosed in WO2000 / 17164 Fluoromethyl-benzyl) -methoxycarbonyl-amino] -2 (R) -ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Torcetrapib) in 5% Tween 80 solution ( After suspending in a control vehicle, it was orally administered once a day for 7 days to a normal hamster (male Syrian Hamster) using a metal sonde. Blood was collected 2 hours after administration on day 7 of administration to obtain plasma. Analysis of lipoproteins in plasma was carried out by automatic measurement by an HPLC system using a post-label method according to the method described in J. Lipid. Res., 43, p805-814. That is, 15 μL of plasma sample was diluted 10-fold with PBS containing 1 mM EDTA, and then connected to an HPLC system (liquid feeding unit: Shimadzu LC-20A system, manufactured by Shimadzu Corporation), a gel filtration column (Superose 6 column (column size: 10 ×)) 300 μm), 80 μL was injected into GE Healthcare Bioscience. PBS containing 1 mM EDTA was used as a running buffer, and separation was performed at a flow rate of 0.5 mL / min and a column temperature of 40 ° C. Cholesterol measurement reagent (Cholesterol E Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.) is mixed with the eluate from the column at a flow rate of 0.25 mL / min, and the solution is sent to 40 ° C. in a reaction coil (0.5 mm × 15 m). And reacted. Cholesterol in the eluate from the reaction coil was detected at a wavelength of 600 nm. The area ratio of the HDL fraction in the total peak area of the obtained cholesterol was determined, and the amount of HDL cholesterol was calculated by multiplying the total cholesterol quantity measured in advance using Cholesterol E Test Wako by the area ratio of the HDL fraction.

Each of the control group (control vehicle administration group) and each compound administration group (10 mg / kg, 30 mg / kg, 100 mg / kg administration group for Example Compound 3, 10 mg / kg, 100 mg / kg administration group for Torcetrapib) Five normal hamsters grouped in advance using plasma total cholesterol as an index were used.
The plasma HDL cholesterol concentration (HDL-C, mg / dl) in each group is shown in FIG. In addition, the * mark and *** mark in FIG. 1 and Table 3 are the results of a multigroup comparison test (Dunnett's multiple comparison test) performed between the control group and each compound administration group, respectively, and the risk rate is 5%. It indicates that there is a significant difference below (p <0.05) and a risk rate of 0.1% or less (p <0.001).
Moreover, the increase rate of the amount of HDL cholesterol with respect to a control group in each compound administration group was calculated by the following formula 2 as an increase rate of HDL cholesterol, and was shown by%. The results are shown in Table 3.
HDL cholesterol increase rate (%) = [(average HDL cholesterol level of each compound administration group−average HDL cholesterol level of control group) / average HDL cholesterol level of control group] × 100 (Formula 2)

  From the above pharmacological test results, the compound of the present invention, or a salt thereof, or a solvate thereof has potent CETP inhibitory activity and blood HDL cholesterol increasing action. It became clear that it can be used suitably as an active ingredient. Furthermore, due to CETP inhibitory activity and blood HDL cholesterol increasing action, more specifically as active pharmaceutical ingredients, more specifically dyslipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, low HDL , Hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis or It was revealed that it can be suitably used as an active ingredient of a medicament for the treatment or prevention of diseases such as hypertension.

  As specifically disclosed in the test examples, the compound of the present invention, or a salt thereof, or a solvate thereof exhibits a strong inhibitory activity against CETP, and further has a strong blood HDL cholesterol increasing action. Therefore, it can be suitably used as an active ingredient of a CETP inhibitor and further as an active ingredient of an HDL elevating agent. Furthermore, due to CETP inhibitory activity and blood HDL cholesterol increasing action, more specifically as active pharmaceutical ingredients, more specifically dyslipidemia (hyperlipidemia), arteriosclerosis, atherosclerosis, peripheral vascular disease, high LDLemia, hypoHDLemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, It can be suitably used as an active ingredient of a medicament for the treatment or prevention of diseases such as angiogenic restenosis or hypertension. Furthermore, it can also be suitably used as an active ingredient of the above-mentioned medicament with little CYP inhibitory action.

Claims (6)

A medicine,
The following general formula (I)
(Where
R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and each represents a hydrogen atom, a halo C ₁ -C ₆ alkyl group, or a cyano group,
R ⁶ represents a C ₁ -C ₆ alkyl group,
R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group. Group,
R ¹¹ and R ¹² are the same or different and each represents a C ₁ -C ₆ alkyl group or a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C _{The 6} alkyl group may have _one hydroxycarbonyl C ₁ -C ₆ alkyl group or C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group as a substituent on the cycloalkyl group) Or R ¹¹ and R ¹² together with the adjacent nitrogen atom together with a morpholino group or piperidino group (the morpholino group or piperidino group has ₁ to 2 C ₁ -C ₆ alkyl groups as substituents. May be), and
R ¹³ represents C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfonyl C ₁ A —C ₆ alkoxy group, a hydroxyl group, a C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, or a hydroxycarbonyl C ₁ -C ₆ alkoxy group;
Furthermore, general formula (I) represents both the individual enantiomers and mixtures thereof. )
Or a salt thereof or a solvate thereof as an active ingredient. The compound represented by the general formula (I) is:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl } -5- (trifluoromethyl) benzonitrile,
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Ethyl} -5- (trifluoromethyl) benzonitrile,
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4- ( Trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid,
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5-methoxypyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5-hydroxypyrimidin-2-amine,
4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) )] Amino} pyrimidin-5-yl) butyrate or 4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) ) Amino] -5- (trifluoromethyl) phenyl} methyl)] amino} pyrimidin-5-yl) butyric acid,
The medicament according to claim 1, wherein Dyslipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, narrow The medicament according to claim 1 or 2, which is a therapeutic or prophylactic agent for diseases of heart disease, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension. A pharmaceutical composition comprising:
The following general formula (I)
(Where
R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and each represents a hydrogen atom, a halo C ₁ -C ₆ alkyl group, or a cyano group,
R ⁶ represents a C ₁ -C ₆ alkyl group,
R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are the same or different and each represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halo C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group. Group,
R ¹¹ and R ¹² are the same or different and each represents a C ₁ -C ₆ alkyl group or a C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl group (the C ₃ -C ₈ cycloalkyl C ₁ -C _{The 6} alkyl group may have _one hydroxycarbonyl C ₁ -C ₆ alkyl group or C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group as a substituent on the cycloalkyl group) Or R ¹¹ and R ¹² together with the adjacent nitrogen atom together with a morpholino group or piperidino group (the morpholino group or piperidino group has ₁ to 2 C ₁ -C ₆ alkyl groups as substituents. May be), and
R ¹³ represents C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfinyl C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylsulfonyl C ₁ A —C ₆ alkoxy group, a hydroxyl group, a C ₂ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkoxy group, or a hydroxycarbonyl C ₁ -C ₆ alkoxy group;
Furthermore, general formula (I) represents both the individual enantiomers and mixtures thereof. )
Or a salt thereof, or a solvate thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier. The compound represented by the general formula (I) is:
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methoxyphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -3,5-difluorophenyl} methyl) -5 [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-methylphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-fluorophenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4-methoxyphenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfinyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-chloro-6-[(cyclopentylmethyl) (ethyl) amino] -3-methylphenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylthio) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2- (methylsulfonyl) ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -4,5-difluorophenyl} methyl) -5 [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-chloro-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5-fluorophenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({4-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({5-bromo-2-[(cyclopentylmethyl) (ethyl) amino] phenyl} methyl) -5- [2 -(Methylsulfonyl) ethoxy] pyrimidin-2-amine,
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino] ethyl } -5- (trifluoromethyl) benzonitrile,
3- {1-[({2-[(cyclopentylmethyl) (ethyl) amino] -5-trifluoromethylphenyl} methyl) {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino] Ethyl} -5- (trifluoromethyl) benzonitrile,
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] propyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (piperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methylthio ) Ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (morpholino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (methyl Sulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (Methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (4-methylpiperidino) -5- (trifluoromethyl) phenyl] methyl} -5- [2- (Methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- 5- [2- (methylthio) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-{[2- (cis-2,6-dimethylmorpholino) -5- (trifluoromethyl) phenyl] methyl}- 5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylthio) ethoxy] pyrimidin-2-yl} amino) methyl ] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} ethyl acetate,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} [5- (hydroxy) pyrimidin-2-yl] amino) methyl] -4- ( Trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid,
trans- {4-[({2-[({1- [3,5-bis (trifluoromethyl) phenyl] ethyl} {5- [2- (methylsulfonyl) ethoxy] pyrimidin-2-yl} amino) Methyl] -4- (trifluoromethyl) phenyl} (ethyl) amino) methyl] cyclohexyl} acetic acid,
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ 2- (methylthio) ethoxy] pyrimidin-2-amine,
N-({2- [bis (cyclopropylmethyl) amino] -3,5-difluorophenyl} methyl) -N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -5- [ 2- (methylsulfonyl) ethoxy] pyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5-methoxypyrimidin-2-amine,
N- {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} -N-({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl)- 5-hydroxypyrimidin-2-amine,
4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) amino] -5- (trifluoromethyl) phenyl} methyl) )] Amino} pyrimidin-5-yl) butyrate or 4- (2-{[{1- [3,5-bis (trifluoromethyl) phenyl] ethyl} ({2-[(cyclopentylmethyl) (ethyl) ) Amino] -5- (trifluoromethyl) phenyl} methyl)] amino} pyrimidin-5-yl) butyric acid,
The pharmaceutical composition according to claim 4. Dyslipidemia, arteriosclerosis, atherosclerosis, peripheral vascular disease, hyper-LDL, hypo-HDL, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, narrow The pharmaceutical composition according to claim 4 or 5, which is used for treatment or prevention of diseases of heart disease, ischemia, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, or hypertension. .