PYRIMIDINE DERIVATIVE

Abstract

Cystic fibrosis is developed through mutation of Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is one type of chloride channel. An object of the present invention is to provide compounds effective in the treatment of cystic fibrosis that open a chloride channel different from CFTR, which is the cause of the disease, and do not depend on CFTR.

Compounds of the present invention are compounds or pharmaceutically acceptable salts thereof that open calcium dependent chloride channels (CaCCs) via G-protein coupled receptor 39 (GPR39) agonism to have strong chloride ion-secretory action, and are represented by the following general formula (I):

General formula (I):

##STR00001##

wherein, X represents a carboxyl group or a tetrazolyl group; Q represents a C.sub.1-C.sub.3 alkylene group, an oxygen atom, a sulfur atom, etc.; G represents a phenyl group where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.2 represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B: Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; Group B: OH, O-M, SH, S-M, NH.sub.2, NH-M, and N-M.sub.2, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C; Group C: a halogen atom, a cyano group, a phenyl group, a pyridyl group, etc., wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and Group D: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.

Claims

1. A compound represented by general formula (I): ##STR00126## wherein, X represents a carboxyl group or a tetrazolyl group; Q represents a C.sub.1-C.sub.3 alkylene group, an oxygen atom, a sulfur atom, or R.sup.aN, where R.sup.a represents a hydrogen atom or a C.sub.1-C.sub.3 alkyl group; G represents a phenyl group, where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.3 alkoxy group, and a trihalo C.sub.1-C.sub.6 alkyl group; R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.3 alkoxy C.sub.1-C.sub.6 alkyl group, or a C.sub.3-C.sub.6 cycloalkyl group; and R.sup.2 represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B, or a pharmaceutically acceptable salt thereof: Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; Group B: OH, O-M, SH, S-M, NH.sub.2, NH-M, and N-M.sub.2, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C; Group C: a halogen atom, a hydroxy group, a cyano group, a carbamoyl group, a carboxyl group, a C.sub.1-C.sub.6 alkoxycarbonyl group, a C.sub.1-C.sub.3 alkoxy group, a phenyl group, and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and Group D: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, and a trihalo C.sub.1-C.sub.6 alkyl group.

2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, in formula (I), X represents a carboxyl group.

3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, in formula (I), Q represents a methylene group, an oxygen atom, or a sulfur atom.

4. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, in formula (I), G is a phenyl group having 1 to 3 substituents independently selected from the group consisting of a chlorine atom, a fluorine atom, a cyano group, a C.sub.1-C.sub.3 alkyl group, a C.sub.1-C.sub.3 alkoxy group and a trihalomethyl group, or an unsubstituted phenyl group.

5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, in formula (I), G is a phenyl group having 1 to 2 substituents independently selected from the group consisting of a chlorine atom and a fluorine atom.

6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein, in formula (I), R.sup.1 represents a C.sub.1-C.sub.6 alkyl group.

7. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein, in formula (I), R.sup.2 is a C.sub.1-C.sub.6 alkyl group that may be substituted with one pyridyl group, or O-M, S-M, NH-M, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1, or a C.sub.3-C.sub.6 cycloalkyl group that may have one substituent independently selected from the following group C.sup.1: Group C.sup.1: a halogen atom, a cyano group, a phenyl group, and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D.sup.1; and Group D.sup.1: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group.

8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, in formula (I), Q represents a methylene group, an oxygen atom, or a sulfur atom; G is a phenyl group having 1 to 2 substituents independently selected from the group consisting of a chlorine atom and a fluorine atom; R.sup.1 is a C.sub.1-C.sub.3 alkyl group; and R.sup.2 is a C.sub.1-C.sub.6 alkyl group that may be substituted with one pyridyl group, or O-M, S-M, NH-M, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1, or a C.sub.3-C.sub.6 cycloalkyl group that may have one substituent independently selected from the following group C.sup.1: Group C.sup.1: a halogen atom, a cyano group, a phenyl group, and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D.sup.1; and Group D.sup.1: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group.

9. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one selected from the following group: 5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid; 5-((2-chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid; 5-(2-chloro-3-fluorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-ethyl-6-(3-fluoropropoxy)pyrimidine-2-carboxylic acid; 5-(2,4-dichlorobenzyl)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid; 4-(benzyloxy)-5-(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-methyl-6-(pyridin-4-ylmethoxy)pyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylic acid; 5-(2,4-dichlorophenoxy)-4-methyl-6-(methylamino)pyrimidine-2-carboxylic acid; 5-(2,4-dichlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid; 5-(2,3-dichlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-ethoxy-6-methylpyrimidine-2-carboxylic acid; 5-(2-chloro-3-fluorobenzyl)-4-ethoxy-6-ethylpyrimidine-2-carboxylic acid; 5-(2,3-dichlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-(cis-3-cyanocyclobutoxy)-6-methylpyrimidine-2-carboxylic acid; 5-(2,4-dichlorobenzyl)-4,6-dimethylpyrimidine-2-carboxylic acid; and 5-(2,4-dichlorobenzyl)-N,6-dimethyl-2-(1H-tetrazol-5-yl)pyrimidine-4-amine.

10. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is any one selected from the following group: 5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid; 5-((2-chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid; 5-(2-chloro-3-fluorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-ethyl-6-(3-fluoropropoxy)pyrimidine-2-carboxylic acid; 5-(2,4-dichlorobenzyl)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid; 4-(benzyloxy)-5-(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid; 5-(2-chlorobenzyl)-4-methyl-6-(pyridin-4-ylmethoxy)pyrimidine-2-carboxylic acid; and 5-(2-chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylic acid.

11. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid.

12. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 5-(2-chlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid.

13. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein the pharmaceutically acceptable salt is a hydrochloride salt, a trifluoroacetate salt, a magnesium salt, a calcium salt, a zinc salt, a sodium salt, a tert-butylamine salt, or a diisopropylamine salt.

14. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is 5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid, or a magnesium salt, a calcium salt, a zinc salt, a sodium salt, a tert-butylamine salt, or a diisopropylamine salt thereof.

15. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid]magnesium salt having a crystal form having main peaks at diffraction angles 2=11.82, 13.74, 14.26, 15.38, 21.56, 23.42, 24.14, 27.82, 28.72, and 31.06 in a powder X-ray diffraction pattern obtained by irradiation with copper K radiation (wavelength =1.54 angstroms).

16. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid]magnesium salt having a crystal form having main peaks at diffraction angles 2=5.18, 10.44, 18.98, 19.68, 22.36, 23.76, 26.34, and 27.96 in a powder X-ray diffraction pattern obtained by irradiation with copper K radiation (wavelength =1.54 angstroms).

17. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is 5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid having a crystal form having main peaks at diffraction angles 2=6.68, 10.54, 16.16, 20.16, 21.22, 21.58, 24.20, 25.16, and 33.92 in a powder X-ray diffraction pattern obtained by irradiation with copper K radiation (wavelength =1.54 angstroms).

18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

19. A pharmaceutical composition according to claim 18 for use in the treatment of cystic fibrosis.

20. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 for use in the treatment of cystic fibrosis.

21. A method for treating cystic fibrosis comprising administering a pharmacologically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 to a warm-blooded animal.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0150] FIG. 1 is a graph showing change in expression level of human GPR39 in CuFi-1 cells through siRNA treatment (mRNA expression analysis). The vertical axis is expressed as a relative expression level towards the control siRNA treated group. The graph is shown with the mean value (N=3) and the standard deviation.

[0151] FIG. 2 is a graph showing effects on the chloride secretory activity of each compound in CuFi-1 cells through siRNA treatment. The vertical axis is expressed as an increase in the rate of the average value of fluorescence values at five points between 110 and 120 seconds, relative to the average value of fluorescence values at 17 points between 1 and 34 seconds within the measurement time of 120 seconds. The graph is shown with the mean value (N=8) and the standard deviation.

[0152] FIG. 3 is a graph showing the moisture transporting action of each compound in MucilAir-CF cells (lot # MD048502), which have a F508 homozygous mutation in the class II mutation of CFTR. The vertical axis is expressed as a percentage of remaining moisture. The mean value and the standard deviation are shown. Dunnett's multiple comparison test with the group without addition of Example 38 or the control groups is performed, and groups with a p-value of no more than 0.01 are shown with **. By using #, it is shown that the p-value via Student's t test is 0.032 between the group without addition of Example 38 and the group to which a combination of VX-809 (30 M) and VX-770 (1 M) is added.

[0153] FIG. 4 is a graph showing the moisture transporting action of each compound in MucilAir-CF cells (lot # MD020802), which have a 2184A+W1282X mutation in the class I mutation of CFTR. The vertical axis is expressed as a percentage of remaining moisture. The mean value and the standard deviation are shown. Dunnett's multiple comparison test with the group without addition of Example 38 or the control groups was performed, and groups with a p-value of no more than 0.01 are shown with **.

[0154] FIG. 5 is a graph showing the moisture transporting action of each compound in MucilAir-CF cells (lot # MD062201), which have a N1303K heterozygous mutation in the class II mutation of CFTR. The vertical axis is expressed as a percentage of remaining moisture. The mean value and the standard deviation are shown. Dunnett's multiple comparison test with the group without addition of Example 38 or the control groups was performed, and groups with a p-value of no more than 0.01 are shown with **.

[0155] FIG. 6 shows a powder X-ray diffraction pattern of the crystal obtained in Example 107.

[0156] FIG. 7 shows a powder X-ray diffraction pattern of the crystal obtained in Example 108.

[0157] FIG. 8 shows a powder X-ray diffraction pattern of the crystal obtained in Example 109.

[0158] FIG. 9 shows a powder X-ray diffraction pattern of the crystal obtained in Example 110.

[0159] FIG. 10 shows a powder X-ray diffraction pattern of the crystal obtained in Example 111.

[0160] FIG. 11 shows a powder X-ray diffraction pattern of the crystal obtained in Example 112.

[0161] FIG. 12 shows a powder X-ray diffraction pattern of the crystal obtained in Example 113.

[0162] FIG. 13 shows a powder X-ray diffraction pattern of the crystal obtained in Example 114.

DESCRIPTION OF EMBODIMENTS

[0163] Next, typical production processes for compounds represented by general formula (I) will be described. Compounds of the present invention can be produced by various production processes. The production processes shown below are given merely for illustrative purposes and the present invention should not be construed to be limited thereby. A compound represented by general formula (I) and production intermediates thereof may be produced utilizing various known reactions mentioned below. Upon production, functional groups may be protected with appropriate protecting groups at the stage of the raw material or an intermediate. Examples of such functional groups may include a hydroxy group, a carboxyl group, an amino group, etc. For types of protecting groups, as well as conditions for introducing and removing these protecting groups, reference may be made to those described in, for example, Protective Groups in Organic Synthesis, Third Edition (T. W. Green and P. G. M. Wuts, John Wiley & Sons, Inc., New York).

[Production Process 1]

[0164] Among compounds represented by formula (I), compound 1a shown below may be produced, for example, via the following reaction formula:

wherein, G and R.sup.1 have the same meanings as described above; Q.sup.1 represents a C.sub.1-C.sub.3 alkylene group, and P.sup.a, P.sup.b, and P.sup.c represent protecting groups; and
R.sup.2a represents a group selected from the following group B.sup.1a.
Group B.sup.1a: O-M.sup.1a, S-M.sup.1a, NH-M.sup.1a, and N-(M.sup.1a).sub.2,
wherein M.sup.1a is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1a, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1a;
Group C.sup.1a: a fluorine atom, a hydroxy group, a cyano group, a carbamoyl group, a carboxyl group, a C.sub.1-C.sub.6 alkoxycarbonyl group, a C.sub.1-C.sub.6 alkoxy group, a phenyl group, and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D.sup.1a; and
Group D.sup.1a: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, and a trihalo C.sub.1-C.sub.6 alkyl group.

##STR00004## ##STR00005##

(1) Conversion of Compound 2a to Compound 3a

[0165] The conversion of compound 2a to compound 3a may be performed by having the ester compound 2a react with a corresponding alkyl halide in an appropriate solvent that does not exert adverse effects on the reaction (for example, benzene, toluene, diethyl ether, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or the like, or a mixed solvent thereof) in the presence of an appropriate base (for example, sodium hydride, sodium methoxide, potassium tert-butoxide, etc., or a mixture thereof) at a temperature from 30 C. to the boiling point of the solvent used for the reaction, preferably from 0 C. to 100 C. The reaction time is preferably from 10 minutes to 72 hours, and more preferably from 8 hours to 24 hours.

[0166] As for compound 2a, the raw material for production, it may be commercially obtained or synthesized in accordance with known methods.

(2) Conversion of Compound 3a to Compound 5a

[0167] The conversion of compound 3a to compound 5a may be performed by having compound 4 react in an appropriate solvent that does not exert adverse effects on the reaction (for example, N,N-dimethylformamide, acetone, etc., or a mixed solvent thereof) in the presence of an appropriate base (for example, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, N-methylmorpholine, pyridine, 2,6-lutidine, diazabicyclo[5.4.0]undec-7-ene, etc., or a mixture thereof) at a temperature from room temperature to the boiling point of the solvent used for the reaction, preferably from 50 C. to 100 C. As for the amount of the base, an excess amount may be used. The reaction time is preferably from 1 hour to 72 hours, and more preferably from 8 hours to 24 hours.

[0168] Compound 4, the raw material for production, may be synthesized in accordance with a method described in a reference example.

(3) Conversion of Compound 5a to Compound 6a

[0169] The conversion of compound 5a to compound 6a may be performed by having a chlorination agent, such as carbon tetrachloride, trichloroacetonitrile, N-chlorosuccinimide, react in an appropriate solvent that does not exert adverse effects on the reaction (for example, toluene, 1,4-dioxane, 1,2-dichloroethane, tetrahydrofuran, etc., or a mixed solvent thereof) in the presence of triphenylphosphine at a temperature from 30 C. to the boiling point of the solvent used for the reaction, preferably from room temperature to 120 C. The reaction time is preferably from 10 minutes to 12 hours, and more preferably from 30 minutes to 2 hours. Moreover, when P.sup.b is a methyl group, the conversion may be performed by treating with an appropriate chlorination agent (for example, oxalyl chloride, thionyl chloride, phosphorous oxychloride, etc.) in an appropriate solvent that does not exert adverse effects on the reaction (for example, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, etc., or a mixed solvent thereof) at a temperature from 30 C. to 100 C. or the boiling point of the solvent used for the reaction, preferably from room temperature to 100 C. The reaction time is preferably from 10 minutes to 24 hours, and more preferably from 30 minutes to 12 hours. Bases, such as triethylamine, N,N-dimethylaniline, and N,N-diethylaniline may also be added, as necessary. Furthermore, it is possible to add N,N-dimethylformamide and the like as a reaction accelerator.

(4) Conversion of Compound 6a to Compound 7a

[0170] In the conversion of compound 6a to compound 7a, the reaction conditions of deprotection are different depending on the type of P.sup.b. When P.sup.b is a methyl group, the conversion may be performed by treating with a deprotecting agent, such as boron tribromide, in an appropriate solvent that does not exert adverse effects on the reaction (for example, dichloromethane, chloroform, etc., or a mixed solvent thereof) at a temperature from 78 C. to the boiling point of the solvent used for the reaction, preferably from 40 C. to room temperature. The reaction time is preferably from 1 hour to 72 hours, and more preferably from 2 hours to 24 hours. When P.sup.b is a tert-butyl group, the conversion may be performed by treating with trifluoroacetic acid, hydrochloric acid, formic acid, or the like at a temperature from 30 C. to the boiling point of the solvent used for the reaction, preferably from 20 C. to room temperature. The reaction time is preferably from 10 minutes to 72 hours, and more preferably from 30 minutes to 24 hours.

(5) Conversion of Compound 7a to Compound 8a

[0171] The conversion of compound 7a to compound 8a may be performed through a general oxidation reaction of converting a primary alcohol to a carboxylic acid. Representative examples of oxidizing agents may include potassium permanganate, chromium trioxide and dilute sulfuric acid (Jones oxidation), or (2,2,6,6-tetramethyl-1-piperidinyl)oxyl (TEMPO) and a cooxidizing agent (such as hypochlorite salts, bromite salts, N-chlorosuccinimide). Examples of solvents used for the reaction include acetone, acetonitrile, water, etc., or a mixed solvent thereof, and the conversion may be performed at a reaction temperature of from 78 C. to 100 C. or the boiling point of the solvent, preferably from room temperature to 80 C., and in a reaction time from 1 hour to 48 hours, preferably 1 hour to 24 hours.

[0172] It is also possible to oxidize an aldehyde again, which is obtained by oxidizing compound 7a, to obtain compound 8a. As an oxidation reaction to obtain an aldehyde, reactions using chromic acid [pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), etc.], dimethyl sulfoxide and oxalyl chloride (Swern oxidation), dimethyl sulfoxide and acetic anhydride, dimethyl sulfoxide and pyridine sulfur trioxide complex, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin reagent), etc. are known. As an oxidation reaction to obtain a carboxylic acid from an aldehyde, Pinnick oxidation, which uses sodium chlorite in the coexistence of 2-methyl-2-butene, is known.

(6) Conversion of Compound 8a to Compound 9a

[0173] The conversion of compound 8a to compound 9a may be performed through a general protection reaction of the carboxyl group. For example, the conversion may be performed by treating with an appropriate acid catalyst (for example, hydrogen chloride, sulfuric acid, thionyl chloride, or the like) in a lower alcohol corresponding to P.sup.c, such as methanol or ethanol, at a temperature from room temperature to the boiling point of the solvent used for the reaction, preferably from room temperature to 100 C. The reaction time is preferably from 10 minutes to 72 hours, and more preferably from 30 minutes to 24 hours.

[0174] Moreover, a tert-butyl ester may be obtained by treating with an appropriate esterification agent (for example, N,N-dimethylformamide di-tert-butyl acetal, 0-tert-butyl-N,N-diisopropylisourea, etc.) in an appropriate solvent that does not exert adverse effects on the reaction (toluene, dichloromethane, etc., or a mixed solvent thereof) at a temperature from room temperature to the boiling point of the solvent used for the reaction, preferably from room temperature to 100 C. The reaction time is preferably from 10 minutes to 72 hours, and more preferably from 30 minutes to 24 hours.

(7) Conversion of Compound 9a to Compound 10a

[0175] The conversion of compound 9a to compound 10a is performed through a nucleophilic substitution reaction between compound 9a and an alcohol, amine, or thiol. For example, when an alcohol is used to perform the substitution reaction described above, the reaction may be performed by treating with an appropriate base (for example, sodium hydride, potassium carbonate, cesium carbonate, etc.) in an appropriate solvent that does not exert adverse effects on the reaction (tetrahydrofuran, acetone, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, etc., or a mixed solvent thereof) at a temperature from room temperature to the boiling point of the solvent used for the reaction, preferably from room temperature to 100 C. The reaction time is preferably from 6 hours to 72 hours, and more preferably from 12 hours to 24 hours. As for the amount of the base used, one to excess molar equivalents relative to compound 9a may be used, and more preferably, 1 to 5 molar equivalents are used. As for the amount of the alcohol used, one to excess molar equivalents relative to compound 10a may be used, and it is also possible to perform the reaction using the alcohol as the solvent. It is also possible to perform the reaction using metal alkoxides. Furthermore, a catalytic amount of a crown ether may be added.

[0176] For example, when an amine is used to perform the reaction described above, the reaction may be performed by treating with an appropriate base (for example, inorganic bases, such as potassium carbonate and cesium carbonate, organic bases, such as triethylamine and N,N-diisopropylethylamine), or by using an excess amount of the amine without using the base in an appropriate solvent that does not exert adverse effects on the reaction (tetrahydrofuran, 1,4-dioxane, etc., or a mixed solvent thereof) at a temperature from room temperature to the boiling point of the solvent used for the reaction, preferably from room temperature to 100 C. The reaction time is preferably from 6 hours to 72 hours, and more preferably from 12 hours to 24 hours. As for the amount of the base used, one to excess molar equivalents relative to compound 9a may be used, and more preferably, 1 to 2 molar equivalents are used. As for the amount of the amine used, 1 to 2 molar equivalents will do when the base is used, and a range of 2 to 30 molar equivalents relative to compound 9a is preferred when the base is not used. The reaction described above may also be conducted by treating in a sealed tube or under microwave irradiation.

[0177] Moreover, when a thiol is used to perform the substitution reaction described above, the reaction may be performed by conducting a basically similar method as for the case when an alcohol is used.

(8) Conversion of Compound 10a to Compound 1a

[0178] In the conversion of compound 10a to compound 1a, the reaction conditions of deprotection are different depending on the type of P.sup.c. When P.sup.c is a methyl group, the conversion may be performed by treating with an appropriate base (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, or the like) in an appropriate solvent that does not exert adverse effects on the reaction (for example, mention may be made of methanol, ethanol, water, tetrahydrofuran, 1,4-dioxane, etc., or a mixed solvent thereof, but an organic solvent that is miscible with water at any ratio is preferable) at a temperature from 30 C. to the boiling point of the solvent used for the reaction, preferably from room temperature to 100 C. The reaction time is preferably from 10 minutes to 72 hours, and more preferably from 30 minutes to 24 hours. When P.sup.c is a tert-butyl group, the conversion may be performed by, in addition to the above described deprotection reaction, treating with trifluoroacetic acid, hydrochloric acid, formic acid, or the like at a temperature from 30 C. to the boiling point of the solvent used for the reaction, preferably from 20 C. to room temperature. The reaction time is preferably from 10 minutes to 72 hours, and more preferably from 30 minutes to 24 hours.

[Production Process 2]

[0179] Compound 1a may also be obtained by performing the substitution reaction described in step (7) of the above [production process 1] to compound 8a of the [production process 1].

##STR00006##

(1) Conversion of Compound 8a to Compound 1a

[0180] The conversion of compound 8a to compound 1a may be conducted by a similar substitution reaction as for the method described in step (7) of the above [production process 1].

[Production Process 3]

[0181] Among compounds represented by formula (I), compound 1b shown below may be produced, for example, via the following reaction formula:

wherein, G, R.sup.1, P.sup.a, P.sup.b, and R.sup.2a have the same meanings as described above.

##STR00007##

(1) Conversion of Compound 2b to Compound 3b

[0182] The conversion of compound 2b to compound 3b may be performed by having a corresponding phenol derivative react in an appropriate solvent that does not exert adverse effects on the reaction (for example, N,N-dimethylformamide, acetone, etc., or a mixed solvent thereof) in the presence of an appropriate base (for example, potassium carbonate, cesium carbonate, etc.) at a temperature from room temperature to the boiling point of the solvent used for the reaction, preferably from 50 C. to 100 C. As for the amount of the base, an excess amount may be used. The reaction time is preferably from 1 hour to 72 hours, and more preferably from 8 hours to 24 hours.

(2) Conversion of Compound 3b to Compound 5b

[0183] The conversion of compound 3b to compound 5b may be conducted by a similar, general cyclization reaction as for the method described in step (2) of the above [production process 1].

(3) Conversion of Compound 5b to Compound 6b

[0184] The conversion of compound 5b to compound 6b may be conducted by a similar, general chlorination reaction as for the method described in step (3) of the above [production process 1].

(4) Conversion of Compound 6b to Compound 7b

[0185] The conversion of compound 6b to compound 7b may be conducted by a similar, general deprotection reaction as for the method described in step (4) of the above [production process 1].

(5) Conversion of Compound 7b to Compound 8b

[0186] The conversion of compound 7b to compound 8b may be conducted by a similar, general oxidation reaction as for the method described in step (5) of the above [production process 1].

(6) Conversion of Compound 8b to Compound 1b

[0187] The conversion of compound 8b to compound 1b may be conducted by a similar, general substitution reaction as for the method described in step (7) of the above [production process 1].

[Production Process 4]

[0188] Among compounds represented by formula (I), compound 1c shown below may be produced from a starting raw material of 6c, which may be produced through the above [production process 1] or the above [production process 3], for example, via the following reaction formula:

wherein, G, R.sup.1, and P.sup.b have the same meanings as described above, but P.sup.b is desirably a tert-butyl group; Q.sup.2 represents a C.sub.1-C.sub.3 alkylene group or an oxygen atom; and M.sup.b represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1b, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1b.
Group C.sup.1b: a cyano group, a C.sub.1-C.sub.6 alkoxy group, a phenyl group, and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D.sup.1b; and
Group D.sup.1c: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, and a trihalo C.sub.1-C.sub.6 alkyl group.

##STR00008##

(1) Conversion of Compound 6c to Compound 11c

[0189] The conversion of compound 6c to compound 11c may be conducted by a similar substitution reaction as for the case when an alcohol is used, described in step (7) of the above [production process 1].

(2) Conversion of Compound 11c to Compound 12c

[0190] The conversion of compound 11c to compound 12c may be conducted by a similar, general deprotection reaction as for the method described in step (4) of the above [production process 1].

(3) Conversion of Compound 12c to Compound 1c

[0191] The conversion of compound 12c to compound 1c may be conducted by a similar, general oxidation reaction as for the method described in step (5) of the above [production process 1].

[Production Process 5]

[0192] Among compounds represented by formula (I), compound 1d shown below may be produced, for example, via the following reaction formula:

wherein, G, R.sup.1, P.sup.a, and P.sup.b have the same meanings as described above, but P.sup.b is desirably a tert-butyl group; and M.sup.1d represents a hydrogen atom, a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C.sup.1d, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C.
Group C.sup.1d: a cyano group, a C.sub.1-C.sub.6 alkoxy group, a phenyl group, and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D.sup.1d; and
Group D.sup.1d: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, and a trihalo C.sub.1-C.sub.6 alkyl group.

##STR00009## ##STR00010##

(1) Conversion of Compound 3d to Compound 5d

[0193] The conversion of compound 3d to compound 5d may be conducted by a similar, general cyclization reaction as for the method described in step (2) of the above [production process 1], and compound 3d, the raw material for production, may be synthesized in accordance with known methods.

(2) Conversion of Compound 5d to Compound 6d

[0194] The conversion of compound 5d to compound 6d may be conducted by a similar, general chlorination reaction as for the method described in step (3) of the above [production process 1].

(3) Conversion of Compound 6d to Compound 13d

[0195] The conversion of compound 6d to compound 13d may be conducted by a similar substitution reaction as for the method described in step (1) of the above [production process 4].

(4) Conversion of Compound 13d to Compound 14d

[0196] The conversion of compound 13d to compound 14d may be performed by using a reducing agent, such as lithium aluminum hydride and diisobutylaluminum hydride, in an appropriate solvent that does not exert adverse effects on the reaction (for example, diethyl ether, tetrahydrofuran, 1,4-dioxane, etc., or a mixed solvent thereof) at a temperature no more than room temperature, preferably from 78 C. to 0 C. The conversion may also be performed by using sodium borohydride or the like with a protic solvent, such as methanol, ethanol and water, or a mixed solvent thereof with the above described nonprotic solvent at a temperature no more than room temperature, preferably from 20 C. to around room temperature.

(5) Conversion of Compound 14d to Compound 15d

[0197] The conversion of compound 14d to compound 15d may be performed by having carbon tetrabromide react in an appropriate solvent that does not exert adverse effects on the reaction (for example, dichloromethane, 1,4-dioxane, 1,2-dichloroethane, tetrahydrofuran, etc., or a mixed solvent thereof) in the presence of triphenylphosphine at a temperature from 30 C. to the boiling point of the solvent used for the reaction, preferably from room temperature to 60 C. The reaction time is preferably from 30 minutes to 72 hours, and more preferably from 1 hour to 24 hours.

(6) Conversion of Compound 15d to Compound 11d

[0198] The conversion of compound 15d to compound 11d may be performed by conducting a coupling reaction with the use of known techniques in organic chemistry. Thus, the conversion is conducted in an appropriate solvent that does not exert adverse effects on the reaction (for example, N,N-dimethylformamide, tetrahydrofuran, dimethyl ethylene glycol, 1,4-dioxane, water or the like, or a mixed solvent thereof) in the presence of an appropriate organoboronic acid, organotin, organozinc, or organomagnesium derivative, etc., and an appropriate transition metal catalyst (as for the metal catalyst, palladium catalysts are preferable, and examples thereof include [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex, or dichlorobis(triphenylphosphine)palladium(II) and tetrakis(triphenylphosphine)palladium(0), etc.), as necessary with the addition of an organic or inorganic base (for example, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, N,N-diisopropylethylamine, etc.), a ligand (for example, triphenylphosphine, etc.), and a known reaction accelerating additive (for example, lithium chloride, copper iodide, or the like). In the above coupling reaction, the reaction temperature is preferably from 0 C. to 300 C., and more preferably from room temperature to 200 C. The reaction described above may also be conducted by treating in a sealed tube or under microwave irradiation. It is preferred that both of the organoboronic acid or the like and the base are used in an amount of one to excess molar equivalents relative to compound 15d, and it is more preferred that 1 to 1.5 molar equivalents for the organoboronic acid or the like and 1 to 5 molar equivalents for the base are used. The reaction time is preferably from 10 minutes to 60 hours, and more preferably from 30 minutes to 24 hours.

(7) Conversion of Compound 11d to Compound 12d

[0199] The conversion of compound 11d to compound 12d may be conducted by a similar, general deprotection reaction as for the method described in step (4) of the above [production process 1].

(8) Conversion of Compound 12d to Compound 1d

[0200] The conversion of compound 12d to compound 1d may be conducted by a similar, general oxidation reaction as for the method described in step (5) of the above [production process 1].

[Production Process 6]

[0201] Among compounds represented by formula (I), compound 1e shown below may be produced from a starting raw material of 9e, which may be produced through the above [production process 1] or the above [production process 3], for example, via the following reaction formula:

wherein, G, R.sup.1, P.sup.c, and Q.sup.2 have the same meanings as described above; and R.sup.2e represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 phenyl groups and pyridyl groups.

[0202] Here, the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D.sup.1e:

Group D.sup.1e: a cyano group, a C.sub.1-C.sub.6 alkyl group, a C.sub.1-C.sub.6 alkoxy group, and a trihalo C.sub.1-C.sub.6 alkyl group.

##STR00011##

(1) Conversion of Compound 9e to Compound 10e

[0203] The conversion of compound 9e to compound 10e may be performed by conducting a similar, general coupling reaction as for the method described in step (6) of the above [production process 5].

[0204] Compound 10e may also be obtained by performing, to compound 9e, a coupling reaction using an alkyne compound (Sonogashira reaction) or a coupling reaction using an alkene compound (Mizoroki-Heck reaction) to obtain a corresponding alkyne compound or alkene compound, followed by performing a hydrogenation reaction.

(2) Conversion of Compound 10e to Compound 1e

[0205] The conversion of compound 10e to compound 1e may be performed by a similar, general deprotection reaction as for the method described in step (8) of the above [production process 1].

[0206] A compound of the present invention represented by general formula (I) can be formed into a pharmaceutically acceptable salt, if desired. A compound of the present invention represented by general formula (I) can be formed into a salt by having the compound react with an acid when it has a basic group, or by having the compound react with a base when it has an acidic group. Exemplary pharmaceutically acceptable salts (salts based on a basic group and salts based on an acidic group) are as described above.

[0207] In the present invention, the compound represented by general formula (I) encompasses compounds labeled with an atomic isotope or a radioisotope. Such labeled compounds can be produced by, for example, using a raw material labeled with an isotope instead of the raw material in the production method of the present invention.

[0208] A compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof encompasses those in the form of a hydrate. Such hydrates may be produced by leaving the compound in the atmosphere or by having it recrystallized to absorb water molecules.

[0209] A compound of the present invention represented by general formula (I) or a salt thereof encompasses those in the form of a solvate. Such solvates may be produced by leaving the compound in a solvent or by having it recrystallized in a solvent to absorb a certain kind of solvent.

[0210] A compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the dosage form may include oral administration with tablets, capsules, granules, emulsions, pills, powders, syrups (solutions) and the like, and parenteral administration with injections (intravenous, intramuscular, subcutaneous, or intraperitoneal administration), drip infusions, suppositories (rectal administration) and the like. Such various formulations can be prepared according to usual methods using a base component, as well as adjuvants that may normally be used in the field of preparing medicaments, such as excipients, binders, disintegrators, lubricants, correctives, solubilizers, suspending agents, and coating agents.

[0211] In the case of a tablet, examples of carriers that can be used include: excipients, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders, such as water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; disintegrators, such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; integration inhibitors, such as sucrose, stearin, cocoa butter and hydrogenated oil; absorption promoters, such as quaternary ammonium salts and sodium lauryl sulfate; moisturizing agents, such as glycerine and starch; adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid; lubricants, such as purified talc, stearate salts, borax powder and polyethylene glycol; and others. Furthermore, tablets may be formed into those coated in usual manners, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double-layer tablets, and multilayered tablets, as necessary.

[0212] In the case of a pill, examples of carriers that can be used include: excipients, such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin and talc; binders, such as powdered gum arabic, powdered tragacanth, gelatin and ethanol; disintegrators, such as laminaran and agar; and others.

[0213] In the case of a suppository, a wide range of carriers conventionally known in this field can be used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semisynthetic glycerides, and the like.

[0214] In the case of an injection, the formulation may be prepared as a solution, an emulsion, or a suspension. Preferably, such solutions, emulsions, and suspensions are sterilized and are isotonic with blood. Solvents used for producing these solutions, emulsions, and suspensions are not particularly limited as long as they can be used as diluents for medical use, and examples thereof may include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of sodium chloride, glucose, or glycerine for preparation of an isotonic solution may be included in the formulation, and usual solubilizers, buffering agents, soothing agents, and the like may also be included.

[0215] Furthermore, coloring agents, preservatives, flavors, flavoring agents, sweetening agents, and the like can be included in the above described formulation, as necessary. Moreover, other medical products may also be included.

[0216] The amount of an active component compound contained in the above described formulations is not particularly limited and appropriately selected within a wide range, but is usually 0.5 to 70% by weight in the total composition, preferably 1 to 30% by weight.

[0217] The dose varies depending on symptoms, age and the like of the patient (a warm-blooded animal, in particular, a human). However, it is desirable that, in the case of oral administration, a single dose from 0.01 mg/kg of body weight as the lower limit (preferably 0.1 mg/kg of body weight) to 500 mg/kg of body weight as the upper limit (preferably 100 mg/kg of body weight), and in the case of intravenous administration, a single dose from 0.001 mg/kg of body weight as the lower limit (preferably 0.01 mg/kg of body weight) to 50 mg/kg of body weight as the upper limit (preferably 10 mg/kg of body weight) is administered one to several times per day depending on symptoms.

[0218] Hereinafter, the present invention will be explained in more detail with reference to the Reference Examples, Examples, and Test Examples. However, the scope of the present invention shall not be limited to these examples.

[0219] Elution in column chromatography in the Reference Examples and Examples was performed under observation by thin layer chromatography (TLC). In the TLC observation, silica gel 60 F254 manufactured by Merck KGaA was used as a TLC plate; a solvent used as an eluting solvent in column chromatography was used as a developing solvent; and a UV detector was adopted in a detection method. In the column chromatography, an automatic purification apparatus from Yamazen Corp. or an automatic purification apparatus from Shokosha Co., Ltd. was appropriately used. The eluting solvent used was a solvent specified on the basis of a Reference Example or Example. The abbreviations used in the Reference Examples and Examples are as defined below.

[0220] mg: milligram, g: gram, l: microliter, ml: milliliter, L: liter, M: molar concentration, and MHz: megahertz.

[0221] In the Examples below, nuclear magnetic resonance (hereinafter, referred to as .sup.1H-NMR: 400 MHz) spectra were indicated by chemical shift values (ppm) determined with tetramethylsilane as a standard. Splitting patterns were indicated by s=singlet, d=doublet, t=triplet, q=quartet, sept=septet, m=multiplet, and br=broad.

[0222] Powder X-ray diffractometry was performed with a wavelength of CuK at =1.54 angstroms using a reflection-type powder X-ray diffractometer (RINT-TTR III) manufactured by Rigaku Corp. Samples were measured using a non-reflecting sample holder (tube voltage: 50 kV, tube current: 300 mA, scanning range: 2 to 40, scan rate: 20/min, sampling width: 0.02, rotational speed: 120 rpm).

[0223] In moisture measurement, a Karl Fischer moisture titrator (coulometric titration system MKC-610) manufactured by Kyoto Electronics Manufacturing Co., Ltd. was used (anolyte: HYDRANAL-Coulomat AG (Sigma-Aldrich Co. LLC), catholyte: HYDRANAL-Coulomat CG (Sigma-Aldrich Co. LLC)).

[0224] In thermal analysis (thermogravimetry differential thermal analysis: TG-DTA), TG/DTA6200 manufactured by Hitachi High-Tech Science Corp. was used (rate of temperature increase: 10 C./min, atmosphere gas: nitrogen, nitrogen gas flow rate: 200 mL/min).

Example 1

5-(2,4-Dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0225] ##STR00012## ##STR00013##

[Step 1]

Methyl 2-(2,4-dichlorobenzyl)-3-oxobutanoate

[0226] To a solution of sodium methoxide (7.35 g) in tetrahydrofuran (188 ml), methyl 3-oxobutanoate (11.36 ml) was added under ice cooling under a nitrogen atmosphere, and the mixture was stirred at the same temperature as above for 30 minutes. 2,4-Dichlorobenzyl chloride (13 ml) was added dropwise to the reaction solution, and the mixture was heated to reflux for 18 hours. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with diethyl ether. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (12.8 g).

[0227] .sup.1H-NMR (CDCl.sub.3) : 2.23 (3H, s), 3.23 (2H, s), 3.70 (3H, s), 3.91 (1H, dd, J=8.3, 6.7 Hz), 7.12-7.21 (2H, m), 7.37 (1H, d, J=2.0 Hz).

[Step 2]

5-(2,4-Dichlorobenzyl)-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one

[0228] To a solution of the compound (3.96 g) obtained in step 1 above in N,N-dimethylformamide (8 ml), the compound (4.4 g) obtained in step 1 of Reference Example 1 and 1,8-diazabicyclo[5.4.0]undec-7-ene (9 ml) were added, and the mixture was stirred at 70 C. for 7 hours under microwave irradiation. After cooling, the reaction solution was diluted with ice water. Ammonium chloride (7 g) was added to the aqueous solution, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (4.53 g).

[0229] .sup.1H-NMR (CDCl.sub.3) : 2.21 (3H, s), 3.52 (3H, s), 3.95 (2H, s), 4.38 (2H, s), 6.96 (1H, d, J=8.3 Hz), 7.11 (1H, dd, J=8.3, 2.1 Hz), 7.38 (1H, d, J=2.1 Hz), 9.75 (1H, br s).

[0230] MS (m/z): 313 (M+H).sup.+.

[Step 3]

4-Chloro-5-(2,4-dichlorobenzyl)-2-(methoxymethyl)-6-methylpyrimidine

[0231] A solution of N-chlorosuccinimide (2.1 g) and triphenylphosphine (4.2 g) in 1,4-dioxane (160 ml) was stirred at room temperature for 30 minutes under a nitrogen atmosphere. A solution of the compound (1.07 g) obtained in step 2 above in 1,4-dioxane (160 ml) was added to the reaction solution, and the mixture was heated to reflux for 30 minutes. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with chloroform, washed with a saturated aqueous solution of sodium bicarbonate and water in this order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (928 mg).

[0232] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 3.57 (3H, s), 4.21 (2H, s), 4.65 (2H, s), 6.58 (1H, d, J=8.4 Hz), 7.11 (1H, dd, J=8.4, 2.1 Hz), 7.46 (1H, d, J=2.1 Hz).

[0233] MS (m/z): 331 (M+H).sup.+.

[Step 4]

(4-Chloro-5-(2,4-dichlorobenzyl)-6-methylpyrimidin-2-yl)methanol

[0234] To a solution of the compound (927 mg) obtained in step 3 above in dichloromethane (5.6 ml), boron tribromide (1.0 M solution in dichloromethane, 2.8 ml) was added at 78 C. under an argon atmosphere, and the mixture was stirred for 4 hours under ice cooling. Methanol (113 l) was added to the reaction solution, and then, the mixture was diluted with water, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was dissolved in ethyl acetate. Then, n-hexane was added to the solution, and the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate). The compound obtained and the precipitate described above were combined to obtain the title compound (708 mg).

[0235] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 3.34-3.50 (1H, m), 4.21 (2H, br m), 4.80 (1H, br m), 6.59 (1H, d, J=8.4 Hz), 7.13 (1H, dd, J=8.4, 2.3 Hz), 7.47 (1H, d, J=2.3 Hz).

[0236] MS (m/z): 317 (M+H).sup.+.

[Step 5]

4-Chloro-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylic acid

[0237] To a solution of the compound (700 mg) obtained in step 4 above in acetonitrile (11 ml), a sodium phosphate buffer solution (0.67 M, pH 6.7, 8.2 ml) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (25 mg) were added, and the mixture was warmed to 35 C. Then, an aqueous sodium chlorite solution (2.0 M, 2.2 ml) and an aqueous sodium hypochlorite solution (0.26%, 1.3 ml) were added dropwise thereto over 3 hours. The mixture was stirred at 35 C. for 16 hours, then diluted with water under ice cooling, and rendered basic by the addition of a 2 M aqueous sodium hydroxide solution. Tert-butyl methyl ether was added to the mixed solution obtained to separate two layers. The aqueous layer was rendered acidic by the addition of 2 M hydrochloric acid under ice cooling, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (693 mg).

[0238] .sup.1H-NMR (DMSO-d.sub.6) : 2.48 (3H, s), 4.24 (2H, s), 6.80 (1H, dd, J=8.4, 1.4 Hz), 7.29 (2H, dd, J=8.4, 2.2 Hz), 7.68-7.73 (1H, m).

[0239] MS (m/z): 331 (M+H).sup.+.

[Step 6]

Tert-butyl 4-chloro-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylate

[0240] To a solution of the compound (500 mg) obtained in step 5 above in pyridine (3 ml), benzenesulfonyl chloride (233 l) was added under a nitrogen atmosphere, and the mixed solution was stirred at room temperature for 1 hour. Tert-butyl alcohol (173 l) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Benzenesulfonyl chloride (233 l) was added again to the reaction solution, and the mixture was stirred for 1 hour. Then, tert-butyl alcohol (173 l) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the mixture was stirred for 10 minutes, followed by extraction with diethyl ether. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (431 mg).

[0241] .sup.1H-NMR (CDCl.sub.3) : 1.67 (9H, s), 2.53 (3H, s), 4.26 (2H, s), 6.53 (1H, d, J=8.3 Hz), 7.11 (1H, dd, J=8.3, 2.1 Hz), 7.47 (1H, d, J=2.1 Hz).

[Step 7]

Tert-butyl 5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylate

[0242] To a solution of the compound (30 mg) obtained in step 6 above in 2-propanol (0.8 ml), an aqueous ethylamine solution (33%, 115 l) was added, and the mixture was stirred at 95 C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (22.7 mg).

[0243] .sup.1H-NMR (CDCl.sub.3) : 1.14 (3H, t, J=7.2 Hz), 1.65 (9H, s), 2.46 (3H, s), 3.48-3.57 (2H, m), 3.87 (2H, s), 4.33-4.56 (1H, br m), 6.68 (1H, d, J=8.4 Hz), 7.11 (1H, dd, J=8.4, 2.1 Hz), 7.46 (1H, d, J=2.1 Hz).

[0244] MS (m/z): 396 (M+H).sup.+.

[Step 8]

5-(2,4-Dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0245] To the compound (22.7 mg) obtained in step 7 above, a 4 M solution of hydrochloric acid in 1,4-dioxane (0.3 ml) was added, and the mixture was stirred at 50 C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in methanol. Diethyl ether was added to the solution, and the resulting precipitate was collected by filtration to obtain the title compound (13.7 mg).

[0246] .sup.1H-NMR (DMSO-d.sub.6) : 1.10 (3H, t, J=7.2 Hz), 2.20 (3H, s), 3.41-3.51 (2H, m), 3.93 (2H, s), 6.74 (1H, d, J=8.3 Hz), 7.30 (1H, dd, J=8.3, 2.3 Hz), 7.69 (1H, d, J=2.3 Hz).

[0247] MS (m/z): 340 (M+H).sup.+.

[0248] The following compounds were obtained by the same method as Example 1.

TABLE-US-00001 TABLE 1 Example Name and structure Instrumental data 2 5-(2,4-Dichlorobenzyl)-4-methyl-6- .sup.1H-NMR (DMSO-d.sub.6) : 0.81 (3H, (n-propylamino)pyrimidine-2- t, J = 7.4 Hz), 1.48-1.60 (2H, m) carboxylic acid hydrochloride 2.26 (3H, s) 3.40-3.48 (2H, m) 3.96 [00014] (2H, s) 6.81 (1H, d, J = 8.3 Hz) 7.30 (1H, dd, J = 8.3, 2.2 Hz) 7.70 (1H, d, J = 2.2 Hz) 8.28 (1H, br s). MS (m/z): 354 (M + H).sup.+. 3 5-(2,4-Dichlorobenzyl)-4- .sup.1H-NMR (DMSO-d.sub.6) : 1.13 (7 H, (diethylamino)-6-methylpyrimidine-2- t, J = 6.8 Hz), 2.29 (3H, s), 3.37 (4 carboxylic acid hydrochloride H, q, J = 6.8 Hz), 3.98 (2H, s), 7.06 [00015] (1H, d, J = 8.4 Hz), 7.39 (1H, dd, J = 8.4, 2.2 Hz), 7.74 (1H, d, J = 2.2 Hz). MS (m/z): 368 (M + H).sup.+. 4 (S)-4-((1-Amino-1-oxopropan-2- .sup.1H-NMR (DMSO-d.sub.6) : 1.32 (3H, yl)amino)-5-(2,4-dichlorobenzyl)-6- d, J = 7.3 Hz), 2.28 (3H, s), 4.06 methylpyrimidine-2-carboxylic acid (2H, s), 4.76-4.87 (1H, m), 6.90 hydrochloride (1H, d, J = 8.4 Hz), 7.10 (1H, s), [00016] (1H, s), 7.69 (1H, d, J = 2.1 Hz), 7.98 (1H, br s). MS (m/z): 383 (M + H).sup.+.

Example 5

5-(2,4-Dichlorobenzyl)-4-((3-isopropoxypropyl)amino)-6-methylpyrimidine-2-carboxylic acid

[0249] ##STR00017##

[Step 1]

(5-(2,4-Dichlorobenzyl)-4-((3-isopropoxypropyl)amino)-6-methylpyrimidin-2-yl)methanol

[0250] To a solution of the compound (23 mg) obtained in step 4 of Example 1 in ethanol (1 ml), 3-isopropoxypropan-1-amine (51 l) and N,N-diisopropylethylamine (126 l) were added, and the mixture was stirred at 90 C. for 22 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (25 mg), which was used in the next reaction as it was.

[Step 2]

5-(2,4-Dichlorobenzyl)-4-((3-isopropoxypropyl)amino)-6-methylpyrimidine-2-carboxylic acid

[0251] To a solution of the compound (25 mg) obtained in step 1 above in 2-propanol (63 l), chromium(VI) oxide (2.5 M solution in sulfuric acid, 25 l) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Acetone (628 l) was added to the reaction solution, and the mixture was further stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and then, the residue obtained was diluted with water, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (6.6 mg).

[0252] .sup.1H-NMR (CDCl.sub.3) : 0.98 (6H, d, J=6.1 Hz), 1.67-1.86 (2H, m), 2.40 (3H, s), 3.36-3.52 (3H, m), 3.58-3.75 (2H, m), 3.85 (2H, s), 6.00 (1H, br s), 6.64 (1H, d, J=7.9 Hz), 7.13 (1H, d, J=7.9 Hz), 7.45 (1H, s).

[0253] MS (m/z): 412 (M+H).sup.+.

Example 6

5-(2,4-Dichlorobenzyl)-4-((2-hydroxy-2-methylpropyl)amino)-6-methylpyrimidine-2-carboxylic acid

[0254] ##STR00018##

[Step 1]

5-(2,4-Dichlorobenzyl)-4-((2-hydroxy-2-methylpropyl)amino)-6-methylpyrimidine-2-carboxylic acid

[0255] To a solution of the compound (28.6 mg) obtained in step 5 of Example 1 and 1-amino-2-methylpropan-2-ol (35 mg) in tetrahydrofuran (1 ml), N,N-diisopropylethylamine (0.15 ml) was added, and the mixture was stirred at 70 C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in chloroform. Acetic acid (0.15 ml) was added to the solution, followed by extraction with water. The extract was washed with ethyl acetate and then concentrated under reduced pressure. The residue obtained was purified by column chromatography (chloroform/methanol) using diol-modified silica gel to obtain the title compound (5.1 mg).

[0256] .sup.1H-NMR (CDCl.sub.3) : 1.06 (6H, s), 2.38 (3H, s), 3.31-3.51 (2H, br m), 3.86 (2H, s), 4.92 (1H, br s), 6.73 (1H, d, J=8.3 Hz), 7.06-7.15 (1H, m), 7.43 (1H, d, J=1.8 Hz).

[0257] MS (m/z): 384 (M+H).sup.+.

Example 7

4-Amino-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylic acid trifluoroacetate

[0258] ##STR00019##

[Step 1]

tert-Butyl 5-(2,4-dichlorobenzyl)-4-((2,4-dimethoxybenzyl)amino)-6-methylpyrimidine-2-carboxylate

[0259] To a solution of the compound (100 mg) obtained in step 6 of Example 1 in 2-propanol (1.3 ml), 2,4-dimethoxybenzylamine (78 l) and triethylamine (0.18 ml) were added, and the mixture was stirred at 120 C. for 1 hour under microwave irradiation. After cooling, the reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (125 mg).

[0260] .sup.1H-NMR (CDCl.sub.3) : 1.68 (9H, s), 2.40 (3H, s), 3.57 (3H, s), 3.78 (3H, s), 3.83 (2H, s), 4.55 (2H, d, J=5.9 Hz), 5.11 (1H, t, J=5.9 Hz), 6.32-6.39 (2H, m), 6.52 (1H, d, J=8.4 Hz), 6.98 (1H, dd, J=8.3, 2.1 Hz), 7.28 (1H, d, J=8.3 Hz), 7.44 (1H, d, J=2.1 Hz).

[0261] MS (m/z): 518 (M+H).sup.+.

[Step 2]

4-Amino-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylic acid trifluoroacetate

[0262] To a solution of the compound (125 mg) obtained in step 1 above in 1,4-dioxane (1.2 ml), a 4 M solution of hydrochloric acid in 1,4-dioxane (1.2 ml) was added, and the mixed solution was stirred at 50 C. for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in dichloromethane (1.2 ml). Trifluoroacetic acid (1.2 ml) was added to the solution, and the mixture was stirred at room temperature for 40 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue obtained. The precipitate was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain the title compound (40.2 mg).

[0263] .sup.1H-NMR (DMSO-d.sub.6) : 2.21 (3H, s), 3.92 (2H, s), 6.02 (1H, s), 6.55 (1H, s), 6.79 (1H, d, J=8.3 Hz), 7.31 (1H, dd, J=8.3, 2.2 Hz), 7.67 (1H, d, J=2.2 Hz).

[0264] MS (m/z): 314 (M+H).sup.+.

Example 8

4-((Carboxymethyl)amino)-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0265] ##STR00020##

[Step 1]

tert-Butyl 4-((2-(tert-butoxy)-2-oxoethyl)amino)-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylate

[0266] To a solution of the compound (47 mg) obtained in step 6 of Example 1 and glycine tert-butyl ester hydrochloride (102 mg) in 2-propanol (0.6 ml), triethylamine (0.17 ml) was added, and the mixture was stirred at 100 C. for 3 hours under microwave irradiation. After cooling, the reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (42.1 mg).

[0267] .sup.1H-NMR (CDCl.sub.3) : 1.44 (9H, s), 1.64 (9H, s), 2.43 (3H, s), 3.94 (2H, s), 4.14 (2H, d, J=4.9 Hz), 5.09 (1H, t, J=4.9 Hz), 6.69 (1H, d, J=8.4 Hz), 7.10 (1H, dd, J=8.4, 2.1 Hz), 7.46 (1H, d, J=2.1 Hz).

[0268] MS (m/z): 482 (M+H).sup.+.

[Step 2]

4-((Carboxymethyl)amino)-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0269] To the compound (42 mg) obtained in step 1 above, a 4 M solution of hydrochloric acid in 1,4-dioxane (0.9 ml) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in methanol. Diethyl ether was added to the solution, and the resulting precipitate was collected by filtration to obtain the title compound (24.3 mg).

[0270] .sup.1H-NMR (DMSO-d.sub.6) : 2.27 (3H, s), 3.99 (2H, s), 4.13 (2H, d, J=5.8 Hz), 6.84 (1H, d, J=8.4 Hz), 7.28 (1H, dd, J=8.4, 2.1 Hz), 7.69 (1H, d, J=2.1 Hz), 8.34 (1H, br s).

[0271] MS (m/z): 370 (M+H).sup.+.

Example 9

5-(2,4-Dichlorobenzyl)-4-(ethylamino)-6-isopropylpyrimidine-2-carboxylic acid

[0272] ##STR00021## ##STR00022##

[Step 1]

Methyl 2-(2,4-dichlorobenzyl)-4-methyl-3-oxopentanoate

[0273] To a suspension of potassium tert-butoxide (867 mg) in tetrahydrofuran (20 ml), methyl 4-methyl-3-oxopentanoate (1.00 ml) and tert-butyl alcohol (67 l) were added under ice cooling, and the mixture was stirred for 20 minutes under ice cooling. 2,4-Dichlorobenzyl chloride (0.97 ml) was added to the reaction solution, and then, the mixture was stirred at 70 C. for 3.5 hours. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (941 mg).

[0274] .sup.1H-NMR (CDCl.sub.3) : 0.91 (3H, d, J=7.0 Hz), 1.07 (3H, d, J=6.8 Hz), 2.70 (1H, spt, J=6.9 Hz), 3.17-3.28 (2H, m), 3.69 (3H, s), 4.12 (1H, t, J=7.5 Hz), 7.11-7.19 (2H, m), 7.36 (1H, d, J=1.9 Hz).

[Step 2]

5-(2,4-Dichlorobenzyl)-6-isopropyl-2-(methoxymethyl)pyrimidin-4(3H)-one

[0275] A solution of the compound (938 mg) obtained in step 1 above, the compound (578 mg) obtained in step 1 of Reference Example 1, and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.40 ml) in N,N-dimethylformamide (8 ml) were stirred at 120 C. for 1 hour under microwave irradiation. After cooling, the reaction solution was stirred again at 120 C. for 1 hour under microwave irradiation. After cooling, water and a saturated aqueous solution of ammonium chloride were added to the reaction solution, followed by extraction with chloroform. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (637 mg). 1H-NMR (CDCl3) : 1.06 (6H, d, J=6.7 Hz), 2.90 (1H, spt, J=6.7 Hz), 3.52 (3H, s), 3.96 (2H, s), 4.41 (2H, s), 6.89 (1H, d, J=8.3 Hz), 7.09 (1H, dd, J=8.4, 2.1 Hz), 7.38 (1H, d, J=2.1 Hz), 9.80 (1H, br s).

[0276] MS (m/z): 341 (M+H).sup.+.

[Step 3]

4-Chloro-5-(2,4-dichlorobenzyl)-6-isopropyl-2-(methoxymethyl)pyrimidine

[0277] To a solution of the compound (625 mg) obtained in step 2 above in chloroform (10 ml), phosphoryl chloride (0.85 ml) was added, and the mixture was heated to reflux for 4 hours. After cooling, the reaction solution was poured into ice, and the mixture was rendered alkaline by the addition of a 2 M aqueous sodium hydroxide solution, followed by extraction with chloroform. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (443 mg).

[0278] .sup.1H-NMR (CDCl.sub.3) : 1.18 (6H, d, J=6.8 Hz), 3.02 (1H, spt, J=6.7 Hz), 3.58 (3H, s), 4.21 (2H, s), 4.66 (2H, s), 6.54 (1H, d, J=8.4 Hz), 7.11 (1H, dd, J=8.3, 2.2 Hz), 7.46 (1H, d, J=2.1 Hz).

[0279] MS (m/z): 359, 361 (M+H).sup.+.

[Step 4]

(4-Chloro-5-(2,4-dichlorobenzyl)-6-isopropylpyrimidin-2-yl)methanol

[0280] The title compound (392 mg) was obtained by the same method as step 4 of Example 1 using the compound (438 mg) obtained in step 3 above.

[0281] .sup.1H-NMR (CDCl.sub.3) : 1.19 (6H, d, J=6.7 Hz), 3.06 (1H, spt, J=6.7 Hz), 3.55 (1H, t, J=5.0 Hz), 4.23 (2H, s), 4.81 (2H, d, J=5.0 Hz), 6.55 (1H, d, J=8.3 Hz), 7.12 (1H, dd, J=8.4, 2.1 Hz), 7.47 (1H, d, J=2.1 Hz).

[0282] MS (m/z): 345, 347 (M+H).sup.+.

[Step 5]

4-Chloro-5-(2,4-dichlorobenzyl)-6-isopropylpyrimidine-2-carboxylic acid

[0283] To a solution of the compound (380 mg) obtained in step 4 above in acetonitrile (5 ml), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (12 mg) and a sodium phosphate buffer solution (0.67 M, pH 6.7, 4 ml) were added, and the mixture was warmed to 35 C. Then, an aqueous sodium chlorite solution (2.0 M, 1.10 ml) and an aqueous sodium hypochlorite solution (0.26%, 1.26 ml) were added dropwise thereto over 30 minutes. The mixture was stirred at 35 C. for 17 hours and then diluted with water under ice cooling, and a 2 M aqueous sodium hydroxide solution was added to the aqueous solution. The mixed solution obtained was rendered acidic by the addition of a 2 M aqueous hydrochloric acid solution, and the precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (382 mg).

[0284] .sup.1H-NMR (CDCl.sub.3) : 1.24 (6H, d, J=6.7 Hz), 3.16 (1H, spt, J=6.7 Hz), 4.32 (2H, s), 6.50 (1H, d, J=8.3 Hz), 7.13 (1H, dd, J=8.3, 2.1 Hz), 7.49 (1H, d, J=2.1 Hz).

[0285] MS (m/z): 359, 361 (M+H).sup.+.

[Step 6]

tert-Butyl 4-chloro-5-(2,4-dichlorobenzyl)-6-isopropylpyrimidine-2-carboxylate

[0286] To the compound (376 mg) obtained in step 5 above, a solution of 2-tert-butyl-1,3-diisopropylisourea (419 mg) in dichloromethane (5 ml) was added, and the mixture was stirred at room temperature for 45 minutes. 2-Tert-butyl-1,3-diisopropylisourea (209 mg) was further added to the reaction solution, and the mixture was stirred at room temperature for 18.5 hours. Insoluble matter precipitated in the reaction solution was removed by filtration. Then, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (347 mg).

[0287] .sup.1H-NMR (CDCl.sub.3) : 1.22 (6H, d, J=6.7 Hz), 1.66 (9H, s), 3.07 (1H, spt, J=6.7 Hz), 4.26 (2H, s), 6.50 (1H, d, J=8.4 Hz), 7.10 (1H, dd, J=8.3, 2.2 Hz), 7.47 (1H, d, J=2.1 Hz).

[Step 7]

Tert-butyl 5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-isopropylpyrimidine-2-carboxylate

[0288] To a solution of the compound (339 mg) obtained in step 6 above in 2-propanol (8 ml), an aqueous ethylamine solution (33%, 1.22 ml) was added, and the mixture was stirred at 90 C. for 7.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel chromatography (n-hexane/ethyl acetate) to obtain the title compound (290 mg).

[0289] .sup.1H-NMR (CDCl.sub.3) : 1.12 (3H, t, J=7.2 Hz), 1.23 (6H, d, J=6.8 Hz), 1.63 (9H, s), 3.05 (1H, spt, J=6.7 Hz), 3.50 (2H, qd, J=7.2, 5.4 Hz), 3.88 (2H, s), 4.34 (1H, t, J=5.0 Hz), 6.66 (1H, d, J=8.4 Hz), 7.10 (1H, dd, J=8.4, 2.1 Hz), 7.46 (1H, d, J=2.1 Hz) MS (m/z): 424 (M+H).sup.+.

[Step 8]

5-(2,4-Dichlorobenzyl)-4-(ethylamino)-6-isopropylpyrimidine-2-carboxylic acid

[0290] To the compound (284 mg) obtained in step 7 above, a 4 M solution of hydrochloric acid in 1,4-dioxane (4 ml) was added, and the mixture was stirred at 50 C. for 2 hours. After cooling, the solvent in the reaction solution was distilled off under reduced pressure, and the residue obtained was diluted with chloroform (3 ml). Triethylamine (0.14 ml) was added to the solution, followed by purification by silica gel chromatography (chloroform/methanol) to obtain the title compound (189 mg).

[0291] .sup.1H-NMR (CDCl.sub.3) : 1.14 (3H, t, J=7.2 Hz), 1.24 (6H, d, J=6.8 Hz), 3.13 (1H, spt, J=6.7 Hz), 3.57 (2H, qd, J=7.2, 5.5 Hz), 3.93 (2H, s), 4.66 (1H, br s), 6.65 (1H, d, J=8.4 Hz), 7.15 (1H, dd, J=8.4, 2.1 Hz), 7.49 (1H, d, J=2.1 Hz).

[0292] MS (m/z): 368 (M+H).sup.+.

[0293] The following compounds were obtained by the same method as Example 9.

TABLE-US-00002 TABLE 2 Example Name and structure Instrumental data 10 4-Cyclopropyl-5-(2,4-dichlorobenzyl)-6- .sup.1H-NMR (CDCl.sub.3) : 0.98-1.07 (2H, (ethylamino)pyrimidine-2-carboxylic acid m), 1.16 (3H, t, J = 7.2 Hz), 1.19-1.24 [00023] (2H, m), 1.93-2.03 (1H, m), 3.55 (2H, qd, J = 6.7 Hz), 4.04 (2H, s), 4.69 (1H, br s), 6.80 (1H, d, J = 8.3 Hz), 7.12- 7.20 (1H, m), 7.48 (1H, d, J = 1.5 Hz). MS (m/z): 366 (M + H).sup.+. 11 5-(2-Chlorobenzyl)-4-ethyl-6- .sup.1H-NMR (CDCl.sub.3) : 1.26 (3H, t, J = (methylamino)pyrimidine-2-carboxylic 7.5 Hz), 2.77 (2H, q, J = 7.6 Hz), 3.05 acid (3H, d, J = 4.9 Hz), 3.98 (2H, s), 4.83 [00024] (1H, br s), 6.69-6.75 (1H, m), 7.16 (1H, td, J = 7.6, 1.3 Hz), 7.21-7.27 (1H, m), 7.47 (1H, dd, J = 8.0, 1.3 Hz). MS (m/z): 306 (M + H).sup.+. 12 5-(2-Chlorobenzyl)-4-ethyl-6- .sup.1H-NMR (CDCl.sub.3) : 1.12 (3H, t, J = (ethylamino)pyrimidine-2-carboxylic acid 7.2 Hz), 1.26 (3H, t, J = 7.6 Hz), 2.79 [00025] (2H, q, J = 7.5 Hz), 3.53 (2H, qd, J = 7.2, 5.4 Hz), 3.99 (2H, s), 4.73 (1H, br s), 6.74-6.79 (1H, m), 7.16 (1H, td, J = 7.5, 1.3 Hz), 7.20-7.30 (1H, m), 7.46 (1H, dd, J = 7.9, 1.3 Hz). MS (m/z): 320 (M + H).sup.+. 13 5-(2-Chlorobenzyl)-4-isopropyl-6- .sup.1H-NMR (CDCl.sub.3) : 1.25 (6H, d, J = (methylamino)pyrimidine-2-carboxylic 6.7 Hz), 3.06 (3H, d, J = 4.8 Hz), 3.16 acid (1H, spt, J = 6.7 Hz), 3.98 (2H, s), 4.78 [00026] (1H, br s), 6.66-6.73 (1H, m), 7.16 (1H, td, J = 7.6, 1.3 Hz), 7.20-7.30 (1H, m), 7.47 (1H, dd, J = 7.9, 1.3 Hz). MS (m/z): 320 (M + H).sup.+. 14 5-(2-Chlorobenzyl)-4-(ethylamino)-6- .sup.1H-NMR (CDCl.sub.3) : 1.12 (3H, t, J = isopropylpyrimidine-2-carboxylic acid 7.2 Hz), 1.26 (6H, d, J = 6.8 Hz), 3.19 [00027] (1H, spt, J = 6.7 Hz), 3.56 (2H, qd, J = 7.2, 5.4 Hz), 3.99 (2H, s), 4.71 (1H, br s), 6.69-6.77 (1H, m), 7.16 (1H, td, J = 7.6, 1.3 Hz), 7.21-7.28 (1H, m), 7.47 (1H, dd, J = 8.0, 1.3 Hz). MS (m/z): 334 (M + H).sup.+.

Example 15

5-(2,4-Dichlorobenzyl)-4-ethyl-6-(ethylamino)pyrimidine-2-carboxylic acid

[0294] ##STR00028##

[Step 1]

5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid

[0295] To a solution of 4-chloro-5-(2,4-dichlorobenzyl)-6-ethylpyrimidine-2-carboxylic acid (0.22 g) obtained by the same method as steps 1 to 5 of Example 9 in 2-propanol (6 ml), an aqueous ethylamine solution (6.7 M, 1 ml) was added, and the mixture was stirred at 90 C. for 24 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol). The eluted fraction was concentrated under reduced pressure, and water and a 1 M aqueous sodium hydroxide solution were added to the crude product obtained, followed by washing with diethyl ether. The aqueous layer was neutralized with 1 M hydrochloric acid, followed by extraction with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue obtained, and the resulting solid was collected by filtration to obtain the title compound (76 mg).

[0296] .sup.1H-NMR (CD.sub.3OD) : 1.12 (3H, t, J=7.6 Hz), 1.18 (3H, t, J=7.2 Hz), 2.70 (2H, q, J=7.6 Hz), 3.72 (2H, q, J=7.2 Hz), 4.02 (2H, s), 6.83 (1H, d, J=8.3 Hz), 7.24 (1H, dd, J=8.4, 2.1 Hz), 7.56 (1H, d, J=2.1 Hz).

[0297] MS (m/z): 354 (M+H).sup.+.

Example 16

5-(2,4-Dichlorobenzyl)-4-(ethylamino)-6-(methoxymethyl)pyrimidine-2-carboxylic acid

[0298] ##STR00029##

[Step 1]

5-(2,4-Dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid

[0299] To tert-butyl 5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-(methoxymethyl)pyrimidine-2-carboxylate (363 mg) obtained by the same method as steps 1 to 7 of Example 1, a 4 M solution of hydrochloric acid in 1,4-dioxane (6 ml) was added, and the mixture was stirred overnight at room temperature. A 4 M solution of hydrochloric acid in 1,4-dioxane (2 ml) was further added to the reaction solution, and the mixture was stirred at 40 C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water. The pH of the aqueous solution was adjusted to approximately 5 by the gradual addition of a 1 M aqueous sodium hydroxide solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by column chromatography (chloroform/methanol) using diol-modified silica gel to obtain the title compound (278 mg).

[0300] .sup.1H-NMR (CDCl.sub.3) : 1.14 (3H, t, J=7.4 Hz), 3.39 (3H, s), 3.49-3.56 (2H, m), 4.05 (2H, s), 4.56 (2H, s), 4.81 (1H, br s), 6.83 (1H, d, J=8.0 Hz), 7.15 (1H, d, J=8.0 Hz), 7.48 (1H, s).

[0301] MS (m/z): 373 (M+H).sup.+.

Example 17

5-(2,4-Dichlorophenoxy)-4-methyl-6-(methylamino)pyrimidine-2-carboxylic acid

[0302] ##STR00030## ##STR00031##

[Step 1]

Methyl 2-(2,4-dichlorophenoxy)-3-oxobutanoate, and methyl 2-(2,4-dichlorophenoxy)-3-hydroxy-2-butenoate

[0303] To a suspension of 2,4-dichlorophenol (3.0 g) and cesium carbonate (6.0 g) in acetone (20 ml), methyl 2-chloro-3-oxobutanoate (2.2 ml) was added, and the mixture was heated to reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water. The aqueous solution was rendered acidic with 6 M hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/chloroform) to obtain the title compounds (4.54 g) as a tautomeric mixture.

[0304] .sup.1H-NMR (CDCl.sub.3) : 1.99 (3H, s), 2.47 (1.5H, s), 3.74 (3H, s), 3.83 (1.5H, s), 5.02 (0.5H, s), 6.70 (1H, d, J=8.8 Hz), 6.78 (0.5H, d, J=8.9 Hz), 7.13 (1H, dd, J=8.8, 2.4 Hz), 7.15-7.20 (0.5H, m), 7.41 (1H, d, J=2.4 Hz), 7.43 (0.5H, d, J=2.5 Hz), 11.29 (1H, s).

[Step 2]

5-(2,4-Dichlorophenoxy)-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one

[0305] To a solution of the compound (1.66 g) obtained in step 1 above and the compound (0.746 g) obtained in step 1 of Reference Example 1 in N,N-dimethylformamide (3 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 ml) was added, and the mixture was stirred at 70 C. for 16 hours. After cooling, the reaction solution was diluted with water, and 2 M hydrochloric acid (3.3 ml) was added to the aqueous solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (1.69 g).

[0306] .sup.1H-NMR (CDCl.sub.3) : 2.28 (3H, s), 3.52 (3H, s), 4.40 (2H, s), 6.62 (1H, d, J=8.8 Hz), 7.09 (1H, dd, J=8.8, 2.5 Hz), 7.43 (1H, d, J=2.5 Hz), 10.03 (1H, br s).

[0307] MS (m/z): 315 (M+H).sup.+.

[Step 3]

4-Chloro-5-(2,4-dichlorophenoxy)-2-(methoxymethyl)-6-methylpyrimidine

[0308] To a suspension of the compound (1.69 g) obtained in step 2 above in chloroform (12 ml), phosphoryl chloride (2.5 ml) was added, and the mixture was stirred at 100 C. for 30 minutes under microwave irradiation. After cooling, the reaction solution was poured into ice water, and the mixture was rendered basic by the addition of a 2 M aqueous sodium hydroxide solution, followed by extraction with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.08 g).

[0309] .sup.1H-NMR (CDCl.sub.3) : 2.48 (3H, s), 3.57 (3H, s), 4.66 (2H, s), 6.37 (1H, d, J=8.8 Hz), 7.12 (1H, dd, J=8.8, 2.5 Hz), 7.50 (1H, d, J=2.5 Hz).

[0310] MS (m/z): 333 (M+H).sup.+.

[Step 4]

(4-Chloro-5-(2,4-dichlorophenoxy)-6-methylpyrimidin-2-yl)methanol

[0311] To a solution of the compound (1.08 g) obtained in step 3 above in dichloromethane (16 ml), boron tribromide (1.0 M solution in dichloromethane, 3.24 ml) was added at 78 C. under a nitrogen atmosphere, and the mixed solution was stirred at 0 C. for 4 hours. Methanol (1.3 ml) was added to the reaction solution, and then, the mixture was diluted with water, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (927 mg).

[0312] .sup.1H-NMR (CDCl.sub.3) : 2.47 (3H, s), 3.27 (1H, t, J=5.3 Hz), 4.81 (2H, d, J=5.3 Hz), 6.38 (1H, d, J=8.8 Hz), 7.13 (1H, dd, J=8.8, 2.5 Hz), 7.51 (1H, d, J=2.5 Hz).

[0313] MS (m/z): 319 (M+H).sup.+.

[Step 5]

4-Chloro-5-(2,4-dichlorophenoxy)-6-methylpyrimidine-2-carboxylic acid

[0314] The title compound (918 mg) was obtained by the same method as step 5 of Example 1 using the compound (926 mg) obtained in step 4 above.

[0315] .sup.1H-NMR (CDCl.sub.3) : 2.60 (3H, s), 6.43 (1H, d, J=8.8 Hz), 7.17 (1H, dd, J=8.8, 2.5 Hz), 7.54 (1H, d, J=2.5 Hz).

[0316] MS (m/z): 333 (M+H).sup.+.

[Step 6]

5-(2,4-Dichlorophenoxy)-4-methyl-6-(methylamino)pyrimidine-2-carboxylic acid

[0317] To a solution of the compound (20 mg) obtained in step 5 above in 2-propanol (0.6 ml), an aqueous methylamine solution (12 M, 50 l) was added, and the mixture was stirred at 70 C. for 4 hours in a sealed container. The reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water. The pH of the aqueous solution was adjusted to approximately 4 by the addition of 1 M hydrochloric acid, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was dissolved in ethyl acetate. n-Hexane was added to the solution. The resulting precipitate was collected by filtration, then washed with n-hexane, and dried under reduced pressure to obtain the title compound (14.1 mg).

[0318] .sup.1H-NMR (CDCl.sub.3) : 2.26 (3H, s), 3.12 (3H, d, J=5.0 Hz), 5.30-5.43 (1H, br m), 6.46 (1H, d, J=8.8 Hz), 7.14 (1H, dd, J=8.8, 2.5 Hz), 7.51 (1H, d, J=2.5 Hz).

[0319] MS (m/z): 328 (M+H).sup.+.

Example 18

5-((2-Chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid

[0320] ##STR00032##

[Step 1]

2-(Methoxymethyl)-6-methylpyrimidin-4(3H)-one

[0321] To a suspension of sodium ethoxide (11.3 g) in ethanol (25.0 ml), methyl 3-oxobutanoate (7.41 ml) and the compound (8.58 g) obtained in step 1 of Reference Example 1 were added at room temperature, and the mixture was heated to reflux for 3 days. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in water. The pH of the aqueous solution was adjusted to 5.5 by the addition of 6 M hydrochloric acid, followed by extraction with dichloromethane and ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (7.38 g).

[0322] .sup.1H-NMR (CDCl.sub.3) : 2.28 (3H, s), 3.51 (3H, s), 4.38 (2H, s), 6.17 (1H, s).

[0323] MS (m/z): 155 (M+H).sup.+.

[Step 2]

5-Iodo-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one

[0324] To the compound (5.33 g) obtained in step 1 above in a 1 M aqueous sodium hydroxide solution (57 ml), iodine (9.04 g) was added at room temperature, and the mixture was heated to reflux for 18 hours. The reaction solution was left standing at 0 C. for 1 hour, and then, water was added thereto, followed by extraction with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (5.14 g).

[0325] .sup.1H-NMR (CDCl.sub.3) : 2.57 (3H, s), 3.52 (3H, s), 4.36 (2H, s), 9.75 (1H, br s).

[0326] MS (m/z): 281 (M+H).sup.+.

[Step 3]

5-((2-Chlorophenyl)thio)-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one

[0327] To a solution of the compound (1.00 g) obtained in step 2 above in toluene (17.9 ml), 2-chlorothiophenol (608 l), copper iodide (136 mg), Neocuproine (149 mg), and potassium carbonate (1.48 g) were added at room temperature, and the mixture was stirred overnight at 80 C. After cooling, water was added to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (971 mg).

[0328] .sup.1H-NMR (CDCl.sub.3) : 2.52 (3H, s), 3.53 (3H, s), 4.42 (2H, s), 6.88 (1H, ddd, J=7.7, 1.9, 1.0 Hz), 7.04-7.13 (2H, m), 7.35 (1H, ddd, J=7.7, 3.0, 1.8 Hz), 9.93 (1H, br s).

[0329] MS (m/z): 297 (M+H).sup.+.

[Step 4]

4-Chloro-5-((2-chlorophenyl)thio)-2-(methoxymethyl)-6-methylpyrimidine

[0330] The title compound (1.72 g) was obtained by the same method as step 3 of Example 17 using the compound (2.01 g) obtained in step 3 above.

[0331] .sup.1H-NMR (CDCl.sub.3) : 2.72 (3H, s), 3.61 (3H, s), 4.70 (2H, s), 6.68 (1H, dd, J=7.7, 1.7 Hz), 7.11-7.21 (2H, m), 7.43 (1H, dd, J=7.8, 1.6 Hz).

[0332] MS (m/z): 315 (M+H).sup.+.

[Step 5]

(4-Chloro-5-((2-chlorophenyl)thio)-6-methylpyrimidin-2-yl)methanol

[0333] The title compound (2.12 g) was obtained by the same method as step 4 of Example 17 using the compound (2.57 g) obtained in step 4 above.

[0334] .sup.1H-NMR (CDCl.sub.3) : 2.72 (3H, s), 3.38 (1H, t, J=5.2 Hz), 4.85 (2H, d, J=5.4 Hz), 6.69 (1H, ddd, J=7.5, 2.3, 1.6 Hz), 7.13-7.23 (2H, m), 7.44 (1H, ddd, J=7.2, 2.0, 1.0 Hz).

[0335] MS (m/z): 301 (M+H).sup.+.

[Step 6]

4-Chloro-5-((2-chlorophenyl)thio)-6-methylpyrimidine-2-carboxylic acid

[0336] The title compound (1.72 g) was obtained by the same method as step 5 of Example 1 using the compound (2.12 g) obtained in step 5 above.

[0337] .sup.1H-NMR (CD.sub.3OD) : 2.78 (3H, s), 6.94 (1H, dd, J=7.8, 1.6 Hz), 7.18-7.30 (2H, m), 7.47 (1H, dd, J=7.8, 1.4 Hz).

[0338] MS (m/z): 315 (M+H).sup.+.

[Step 7]

5-((2-Chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid

[0339] To a suspension of the compound (2.5 g) obtained in step 6 above in 2-propanol (80 ml), an aqueous ethylamine solution (33%, 5.8 ml) was added, and the mixture was stirred at 95 C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and water and a saturated aqueous solution of potassium bisulfate were added to the residue obtained, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate/n-hexane was added to the residue obtained. The precipitate was collected by filtration to obtain the title compound (0.97 g).

[0340] .sup.1H-NMR (CDCl.sub.3) : 1.19 (3H, t, J=7.3 Hz), 2.59 (3H, s), 3.54-3.61 (2H, m), 6.22 (1H, br s), 6.59 (1H, dd, J=7.5, 2.3 Hz), 7.09-7.19 (2H, m), 7.42 (1H, dd, J=7.5, 1.5 Hz).

[0341] MS (m/z): 324 (M+H).sup.+.

[0342] The following compounds were obtained by the same method as Example 18.

TABLE-US-00003 TABLE 3 Example Name and Structure Instrumental data 19 [00033] .sup.1H-NMR (CD.sub.3OD) : 1.09 (3H, t, J = 7.2 Hz), 1.15 (6H, d, J = 6.8 Hz), 3.51 (2H, q, J = 7.2 Hz), 3.62 (1H, spt, J = 6.8 Hz), 6.58-6.66 (1H, m), 7.07-7.17 (2H, m), 7.36-7.44 (1H, m). MS (m/z): 352 (M + H).sup.+. 20 [00034] .sup.1H-NMR (CD.sub.3OD) : 1.14 (3H, t, J = 7.2 Hz), 1.18 (3H, t, J = 6.8 Hz), 2.96 (2H, q, J = 7.5 Hz), 3.67 (2H, q, J = 7.1 Hz), 6.73-6.80 (1H, m), 7.17-7.24 (2H, m), 7.43-7.49 (1H, m). MS (m/z): 338 (M + H).sup.+. 21 [00035] .sup.1H-NMR (CD.sub.3OD) : 1.09 (6H, t, J = 6.4 Hz), 2.92 (2H, br s), 3.48- 3.71 (2H, m), 6.58 (1H, d, J = 6.7 Hz), 7.15 (1H, d, J = 5.7 Hz), 7.50 (1H, s). MS (m/z): 372 (M + H).sup.+.

Example 22

5-((2-Chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0343] ##STR00036##

[Step 1]

tert-Butyl 4-chloro-5-((2-chlorophenyl)thio)-6-methylpyrimidine-2-carboxylate

[0344] To a solution of the compound (200 mg) obtained in step 6 of Example 18 in N,N-dimethylacetamide (2.0 ml), tert-butyl alcohol (300 l) and N-methylimidazole (250 l) were added at room temperature, and the mixture was stirred at 40 C. p-Toluenesulfonyl chloride (242 mg) was added to the reaction solution, and the mixture was stirred at 40 C. for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (156 mg).

[0345] .sup.1H-NMR (CDCl.sub.3) : 1.66 (9H, s), 2.72 (3H, s), 6.75 (1H, dd, J=7.8, 1.7 Hz), 7.09-7.22 (2H, m), 7.42 (1H, dd, J=7.8, 1.4 Hz).

[Step 2]

tert-Butyl 5-((2-chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylate

[0346] To a solution of the compound (1.63 g) obtained in step 1 above in 2-propanol (53.0 ml), an aqueous ethylamine solution (33%, 3.66 ml) was added at room temperature, and the mixture was stirred at 95 C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water. 2 M hydrochloric acid was added to the aqueous solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.84 g).

[0347] .sup.1H-NMR (CDCl.sub.3) : 1.16 (3H, t, J=7.3 Hz), 1.65 (9H, s), 2.56 (3H, s), 3.55 (2H, qd, J=7.7, 5.7 Hz), 5.99 (1H, t, J=4.9 Hz), 6.58 (1H, dd, J=7.7, 1.7 Hz), 7.03-7.15 (2H, m), 7.39 (1H, dd, J=7.7, 1.6 Hz).

[0348] MS (m/z): 380 (M+H).sup.+.

[Step 3]

5-((2-Chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0349] To the compound (1.83 g) obtained in step 2 above, a 4 M solution of hydrochloric acid in 1,4-dioxane (24.1 ml) was added at room temperature, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in methanol. Diethyl ether was added to the solution, and the resulting precipitate was collected by filtration to obtain the title compound (1.53 g).

[0350] .sup.1H-NMR (CD.sub.3OD) : 1.19 (3H, t, J=7.2 Hz), 2.63 (3H, s), 3.71 (2H, q, J=7.2 Hz), 6.86-6.92 (1H, m), 7.20-7.29 (2H, m), 7.50 (1H, ddd, J=7.9, 2.3, 1.4 Hz).

[0351] MS (m/z): 324 (M+H).sup.+.

[0352] The following compounds were obtained by the same method as Example 22.

TABLE-US-00004 TABLE 4 Example Name and Structure Instrumental data 23 [00037] .sup.1H-NMR (CD.sub.3OD) : 2.67 (3H, s), 3.17 (3H, s), 7.20-7.29 (3H, m), 7.30-7.37 (2H, m). MS (m/z): 276 (M + H).sup.+. 24 [00038] .sup.1H-NMR (CD.sub.3OD) : 1.24 (3H, t, J = 7.2 Hz), 2.59 (3H, s), 3.75 (2H, q, J = 7.2 Hz), 7.07 (1H, d, J = 7.9 Hz), 7.39-7.47 (1H, m), 7.47-7.55 (1H, m), 7.75-7.85 (1H, m). MS (m/z): 358 (M + H).sup.+. 25 [00039] .sup.1H-NMR (CD.sub.3OD) : 1.15 (3H, t, J = 7.2 Hz), 2.58 (3, s), 3.68 (2H, q, J = 7.0 Hz), 6.99-7.22 (3H, m), 7.22-7.34 (1H, m). MS (m/z): 308 (M + H).sup.+. 26 [00040] .sup.1H-NMR (CD.sub.3OD) : 1.34 (6H, d, J = 6.8 Hz), 2.56 (3H, s), 3.19 (3H, s), 3.47 (1H, spt, J = 6.7 Hz), 6.75 (1H, dd, J = 7.7, 1.5 Hz), 7.08 (1H, ddd, J = 7.7, 7.7, 1.5 Hz), 7.23 (1H, ddd, J = 7.0, 7.0, 1.0 Hz), 7.39 (1H, dd, J = 7.9, 1.0 Hz). MS (m/z): 318 (M + H).sup.+. 27 [00041] .sup.1H-NMR (CD.sub.3OD) : 2.46 (3H, s), 2.59 (3H, s), 3.17 (3H, s), 6.75 (1H, dd, J = 7.7, 1.3 Hz), 7.06- 7.18 (2H, m), 7.26 (1H, d, J = 7.2 Hz). MS (m/z): 290 (M + H).sup.+. 28 [00042] .sup.1H-NMR (CD.sub.3OD) : 2.64 (3H, s), 3.14 (3H, s), 6.78 (1H, d, J = 6.7 Hz), 7.16-7.22 (1H, m), 7.42 (1H, d, J = 8.2 Hz). MS (m/z): 344 (M + H).sup.+. 29 [00043] .sup.1H-NMR (CD.sub.3OD) : 2.62 (3H, s), 3.17 (3H, s), 6.88-6.97 (1H, m), 7.00-7.07 (1H, m), 7.35-7.41 (1H, m). MS (m/z): 328 (M + H).sup.+. 30 [00044] .sup.1H-NMR (CD.sub.3OD) : 1.23 (6H, d, J = 6.5 Hz), 2.63 (3H, s), 4.74 (1H, spt, J = 6.6 Hz), 6.94 (1H, ddd, J = 7.0, 3.4, 1.8 Hz), 7.21-7.30 (2H, m), 7.50 (1H, ddd, J = 7.5, 2.3, 1.5 Hz). MS (m/z): 338 (M + H).sup.+. 31 [00045] .sup.1H-NMR (DMSO-d.sub.6) : 1.10 (3H, t, J = 7.2 Hz), 2.04 (3H, s), 3.37- 3.47 (2H, m), 6.67 (1H, d, J = 8.9 Hz), 7.30 (1H, dd, J = 8.9, 2.5 Hz), 7.70-7.79 (2H, m). MS (m/z): 342 (M + H).sup.+.

Example 32

5-(2,4-Dichlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid

[0353] ##STR00046##

[Step 1]

5-(2,4-Dichlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid

[0354] A suspension of the compound (21 mg) obtained in step 5 of Example 1 and cesium carbonate (42 mg) in methanol (0.6 ml) was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water and then rendered acidic with 2 M hydrochloric acid. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (18.4 mg).

[0355] .sup.1H-NMR (CDCl.sub.3) : 2.47 (3H, s), 4.07-4.12 (5H, m), 6.62 (1H, d, J=8.3 Hz), 7.11 (1H, dd, J=8.3, 2.3 Hz), 7.44 (1H, d, J=2.3 Hz).

[0356] MS (m/z): 327 (M+H).sup.+.

[0357] The following compounds were obtained by the same method as Example 32.

TABLE-US-00005 TABLE 5 Example Name and Structure Instrumental data 33 [00047] .sup.1H-NMR (CDCl.sub.3) : 1.34 (3H, t, J = 7.1 Hz), 2.48 (3H, s), 4.08 (2H, s), 4.54 (2H, q, J = 7.1 Hz), 6.68 (1H, d, J = 8.4 Hz), 7.11 (1H, dd, J = 8.4, 2.1 Hz), 7.43 (1H, d, J = 2.1 Hz). MS (m/z): 341 (M + H).sup.+. 34 [00048] .sup.1H-NMR (CDCl.sub.3) : 2.51 (3H, s), 4.06 (3H, s), 6.44 (1H, d, J = 8.8 Hz), 7.12 (1H, dd, J = 8.8, 2.5 Hz), 7.48 (1H, d, J = 2.5 Hz). MS (m/z): 329 (M + H).sup.+. 35 [00049] .sup.1H-NMR (DMSO-d.sub.6) : 1.14 (3H, t, J = 7.0 Hz), 2.36 (3H, s), 4.39 (2H, d, J = 7.0 Hz), 6.86 (1H, d, J = 8.8 Hz), 7.28 (1H, dd, J = 8.8, 2.5 Hz), 7.75 (1H, d, J = 2.5 Hz). MS (m/z): 343 (M + H).sup.+. 36 [00050] .sup.1H-NMR (CD.sub.3OD) : 2.66 (3H, s), 4.00 (3H, s), 6.84 (1H, d, J = 8.7 Hz), 7.20 (1H, dd, J = 8.5, 2.3 Hz), 7.51 (1H, d, J = 2.3 Hz). MS (m/z): 345 (M + H).sup.+. 37 [00051] .sup.1H-NMR (CD.sub.3OD) : 1.21 (3H, t, J = 7.2 Hz), 2.99 (2H, q, J = 7.2 Hz), 3.98 (3H, s), 6.68 (1H, d, J = 8.5 Hz), 7.16 (1H, dd, J = 8.6, 2.2 Hz), 7.47 (1H, d, J = 2.3 Hz). MS (m/z): 359 (M + H).sup.+.

Example 38

5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid

[0358] ##STR00052##

[Step 1]

Methyl 2-(2-chlorobenzyl)-3-oxobutanoate

[0359] To a suspension of sodium hydride (60% oil, 0.68 g) in tetrahydrofuran (25 ml), a solution of methyl 3-oxobutanoate (3.0 g) in tetrahydrofuran (5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of 2-chlorobenzyl bromide (5.3 g) in tetrahydrofuran (5 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 2 days. Ice water and 1 M hydrochloric acid were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (5.6 g).

[0360] .sup.1H-NMR (CDCl.sub.3) : 2.22 (3H, s), 3.24 (1H, dd, J=14.1, 8.0 Hz), 3.30 (1H, dd, J=14.1, 6.8 Hz), 3.69 (3H, s), 3.97 (1H, dd, J=8.2, 6.7 Hz), 7.14-7.19 (2H, m), 7.22-7.25 (1H, m), 7.33-7.36 (1H, m).

[Step 2]

2-(tert-Butoxymethyl)-5-(2-chlorobenzyl)-6-methylpyrimidin-4(3H)-one

[0361] To a solution of the compound (5.6 g) obtained in step 1 above in N,N-dimethylformamide (30 ml), the compound (5.8 g) obtained in step 1 of Reference Example 2 above and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.5 ml) were added, and the mixture was stirred at 75 C. for 26 hours. After cooling, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue obtained, and the resulting precipitate was collected by filtration to obtain the title compound (2.8 g).

[0362] .sup.1H-NMR (CDCl.sub.3) : 1.29 (9H, s), 2.20 (3H, s), 4.01 (2H, s), 4.40 (2H, s), 6.98-7.02 (1H, m), 7.09-7.14 (2H, m), 7.34-7.38 (1H, m).

[Step 3]

2-(tert-Butoxymethyl)-4-chloro-5-(2-chlorobenzyl)-6-methylpyrimidine

[0363] To a suspension of the compound (2.8 g) obtained in step 2 above in toluene (10 ml), triphenylphosphine (6.9 g) and trichloroacetonitrile (0.88 ml) were added, and the mixture was stirred at 120 C. for 1 hour. After cooling, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with chloroform. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (2.7 g).

[0364] .sup.1H-NMR (CDCl.sub.3) : 1.33 (9H, s), 2.44 (3H, s), 4.24 (2H, s), 4.63 (2H, s), 6.65 (1H, dd, J=7.5, 1.8 Hz), 7.12 (1H, td, J=7.5, 1.4 Hz), 7.19 (1H, td, J=7.7, 1.7 Hz), 7.43 (1H, dd, J=7.9, 1.4 Hz).

[Step 4]

2-(tert-Butoxymethyl)-5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine

[0365] To a solution of the compound (1.5 g) obtained in step 3 above in methanol (4 ml), cesium carbonate (1.44 g) was added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (1.15 g).

[0366] .sup.1H-NMR (CDCl.sub.3) : 1.33 (9H, s), 2.34 (3H, s), 3.95 (3H, s), 4.03 (2H, s), 4.55 (2H, s), 6.68-6.71 (1H, m), 7.07 (1H, td, J=7.5, 1.4 Hz), 7.14 (1H, td, J=7.7, 1.8 Hz), 7.38 (1H, dd, J=7.9, 1.4 Hz).

[Step 5]

(5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidin-2-yl)methanol

[0367] To the compound (1.15 g) obtained in step 4 above, trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 24.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.81 g).

[0368] .sup.1H-NMR (CDCl.sub.3) : 2.36 (3H, s), 3.76 (1H, t, J=4.9 Hz), 3.95 (3H, s), 4.05 (2H, s), 4.69 (2H, d, J=4.8 Hz), 6.70 (1H, dd, J=7.3, 1.5 Hz), 7.10 (1H, td, J=7.5, 1.4 Hz), 7.15 (1H, td, J=7.5, 1.8 Hz), 7.40 (1H, dd, J=7.8, 1.5 Hz).

[Step 6]

5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid

[0369] To a solution of the compound (0.8 g) obtained in step 5 above in acetonitrile (6 ml), a sodium phosphate buffer solution (0.67 M, pH 6.7, 4 ml) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (31 mg) were added, and the mixture was stirred at 35 C. An aqueous sodium chlorite solution (2.0 M, 3.3 ml) and an aqueous sodium hypochlorite solution (0.26%, 2.9 ml) were added dropwise at the same time to the mixture, and the resulting mixture was stirred at 35 C. for 23.5 hours. After cooling, the reaction solution was diluted with a 2 M aqueous sodium hydroxide solution (4 ml). A 10% aqueous sodium thiosulfate solution (6 ml) was added to the solution under ice cooling, and the mixture was stirred at the same temperature as above for 30 minutes. Ethyl acetate was added to the reaction solution to separate two layers. Then, 2 M hydrochloric acid (10 ml) was added to the aqueous layer, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. n-Hexane/ethyl acetate was added to the residue obtained, and the resulting precipitate was collected by filtration to obtain the title compound (0.71 g).

[0370] .sup.1H-NMR (CDCl.sub.3) : 2.45 (3H, s), 4.08 (3H, s), 4.13 (2H, s), 6.67 (1H, dd, J=7.3, 2.0 Hz), 7.11 (1H, td, J=7.5, 1.3 Hz), 7.18 (1H, td, J=7.7, 1.7 Hz), 7.41 (1H, dd, J=7.9, 1.4 Hz).

[0371] MS (m/z): 293 (M+H).sup.+.

[0372] The following compounds were obtained by the same method as Example 38.

TABLE-US-00006 TABLE 6 Example Name and Structure Instrumental data 39 [00053] .sup.1H-NMR (CDCl.sub.3) : 1.21 (3H, t, J = 7.5 Hz), 2.74 (2H, q, J = 7.5 Hz), 4.09 (3H, s), 4.15 (2H, s), 6.65 (1H, dd, J = 7.6, 1.5 Hz), 7.11 (1H, td, J = 7.6, 1.3 Hz), 7.18 (1H, td, J = 7.7, 1.8 Hz), 7.42 (1H, dd, J = 8.0, 1.3 Hz). MS (m/z): 307 (M + H).sup.+. 40 [00054] .sup.1H-NMR (CDCl.sub.3) : 1.22 (3H, t, J = 7.5 Hz), 2.75 (2H, q, J = 7.5 Hz), 4.09 (5H, s), 6.63 (1H, dd, J = 8.8, 6.0 Hz), 6.84 (1H, td, J = 8.3, 2.8 Hz), 7.18 (1H, dd, J = 8.4, 2.6 Hz). MS (m/z): 325 (M + H).sup.+. 41 [00055] .sup.1H-NMR (CDCl.sub.3) : 1.23 (3H, t, J = 7.5 Hz), 2.73 (2H, q, J = 7.5 Hz), 4.09 (3H, s), 4.17 (2H, s), 6.52 (1H, dd, J = 7.8, 1.3 Hz), 7.05 (1H, t, J = 7.9 Hz), 7.36 (1H, dd, J = 7.9, 1.3 Hz). MS (m/z): 341 (M + H).sup.+. 42 [00056] .sup.1H-NMR (CDCl.sub.3) : 1.24 (3H, t, J = 7.5 Hz), 2.82 (2H, q, J = 7.5 Hz), 4.02 (2H, s), 4.11 (3H, s), 6.83 (1H, t, J = 8.2 Hz), 7.02 (1H, dd, J = 8.3, 2.5 Hz), 7.09 (1H, dd, J = 9.8, 2.0 Hz). MS (m/z): 325 (M + H).sup.+. 43 [00057] .sup.1H-NMR (CDCl.sub.3) : 1.23 (3H, t, J = 7.5 Hz), 2.82 (2H, q, J = 7.5 Hz), 4.07 (2H, s), 4.11 (3H, s), 6.87 (1H, td, J = 7.7, 1.8 Hz), 6.98-7.08 (2H, m), 7.17-7.24 (1H, m). MS (m/z): 291 (M + H).sup.+. 44 [00058] .sup.1H-NMR (CDCl.sub.3) : 1.23 (3H, t, J = 7.5 Hz), 2.74 (2H, q, J = 7.5 Hz), 4.09 (3H, s), 4.16 (2H, s), 6.42-6.45 (1H, m), 7.02-7.12 (2H, m). MS (m/z): 325 (M + H).sup.+.

Example 45

5-(2-Dichlorobenzyl)-4-methoxy-6-(n-propyl)pyrimidine-2-carboxylic acid hydrochloride

[0373] ##STR00059##

[Step 1]

5-(2-Dichlorobenzyl)-4-methoxy-6-(n-propyl)pyrimidine-2-carboxylic acid hydrochloride

[0374] To a solution of (5-(2-chlorobenzyl)-4-methoxy-6-(n-propyl)pyrimidin-2-yl)methanol (0.32 g) obtained by the same method as steps 1 to 5 of Example 38 in acetonitrile (3 ml), a sodium phosphate buffer solution (0.67 M, pH 6.7, 2 ml) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (11 mg) were added, and the mixture was stirred at 35 C. An aqueous sodium chlorite solution (2.0 M, 1.20 ml) and an aqueous sodium hypochlorite solution (0.26%, 1.04 ml) were added dropwise at the same time to the mixture, and the resulting mixture was stirred at 35 C. for 4.5 hours. After cooling, the reaction solution was diluted with a 2 M aqueous sodium hydroxide solution (2 ml). A 10% aqueous sodium thiosulfate solution (3 ml) was added to the solution under ice cooling, and the mixture was stirred at the same temperature as above for 30 minutes. Ethyl acetate was added to the reaction solution to separate two layers. Then, 2 M hydrochloric acid (5 ml) was added to the aqueous layer, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. A 4 M solution of hydrochloric acid in ethyl acetate (2 ml) was added to the residue obtained, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue obtained, and the resulting precipitate was collected by filtration to obtain the title compound (295 mg).

[0375] .sup.1H-NMR (DMSO-d.sub.6) : 0.82 (3H, t, J=7.3 Hz), 1.50-1.59 (2H, m), 2.59-2.64 (2H, m), 3.93 (3H, s), 4.07 (2H, s), 6.76 (1H, dd, J=7.7, 1.6 Hz), 7.20 (1H, td, J=7.3, 1.8 Hz), 7.26 (1H, td, J=7.5, 1.8 Hz), 7.49 (1H, dd, J=7.8, 1.3 Hz).

[0376] MS (m/z): 321 (M+H).sup.+.

[0377] The following compounds were obtained by the same method as Example 45.

TABLE-US-00007 TABLE 7 Example Name and Structure Instrumental data 46 [00060] .sup.1H-NMR (DMSO-d.sub.6) : 0.83 (3H, t, J = 7.4 Hz), 1.50- 1.61 (2H, m), 2.59-2.65 (2H, m), 3.92 (3H, s), 4.03 (2H, s), 6.83 (1H, dd, J = 8.7, 6.1 Hz), 7.08 (1H, td, J = 8.5, 2.8 Hz), 7.48 (1H, dd, J = 8.8, 2.8 Hz). MS (m/z): 339 (M + H).sup.+. 47 [00061] .sup.1H-NMR (DMSO-d.sub.6) : 0.85 (3H, t, J = 7.3 Hz), 1.52-1.62 (2H, m), 2.66-2.72 (2H, m), 3.93 (3H, s), 3.99 (2H, s), 6.98 (1H, t, J = 8.4 Hz), 7.17 (1H, dd, J = 8.2, 2.1 Hz), 7.41 (1H, dd, J = 10.0, 2.3 Hz). MS (m/z): 339 (M + H).sup.+.

Example 48

5-(2,3-Dichlorobenzyl)-4-ethoxy-6-ethylpyrimidine-2-carboxylic acid

[0378] ##STR00062##

[Step 1]

2-(tert-Butoxymethyl)-5-(2,3-dichlorobenzyl)-4-ethoxy-6-ethylpyrimidine

[0379] To a solution of 2-(tert-butoxymethyl)-4-chloro-5-(2,3-dichlorobenzyl)-6-ethylpyrimidine (0.5 g) obtained by the same method as steps 1 to 3 of Example 38 in ethanol (2 ml), cesium carbonate (0.42 g) was added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (0.51 g).

[0380] .sup.1H-NMR (CDCl.sub.3) : 1.15 (3H, t, J=7.5 Hz), 1.26 (3H, t, J=7.0 Hz), 1.31 (9H, s), 2.62 (2H, q, J=7.5 Hz), 4.05 (2H, s), 4.41 (2H, q, J=7.1 Hz), 4.54 (2H, s), 6.61 (1H, dd, J=7.8, 1.5 Hz), 7.01 (1H, t, J=8.0 Hz), 7.31 (1H, dd, J=8.0, 1.5 Hz).

[Step 2]

(5-(2,3-Dichlorobenzyl)-4-ethoxy-6-ethylpyrimidin-2-yl)methanol

[0381] The title compound (0.43 g) was obtained by the same method as step 5 of Example 38 using the compound (0.51 g) obtained in step 1 above.

[0382] .sup.1H-NMR (CDCl.sub.3) : 1.18 (3H, t, J=7.8 Hz), 1.27 (3H, t, J=7.5 Hz), 2.64 (2H, q, J=7.5 Hz), 3.86 (1H, t, J=4.6 Hz), 4.08 (2H, s), 4.39 (2H, q, J=7.3 Hz), 4.68 (2H, d, J=4.5 Hz), 6.61 (1H, dd, J=7.8, 2.0 Hz), 7.03 (1H, t, J=7.9 Hz), 7.33 (1H, dd, J=8.0, 1.8 Hz).

[Step 3]

5-(2,3-Dichlorobenzyl)-4-ethoxy-6-ethylpyrimidine-2-carboxylic acid

[0383] The title compound (74 mg) was obtained by the same method as step 6 of Example 38 using the compound (0.43 g) obtained in step 2 above.

[0384] .sup.1H-NMR (CDCl.sub.3) : 1.23 (3H, t, J=7.5 Hz), 1.32 (3H, t, J=7.0 Hz), 2.75 (2H, q, J=7.5 Hz), 4.17 (2H, s), 4.55 (2H, q, J=7.1 Hz), 6.56-6.59 (1H, m), 7.05 (1H, t, J=7.9 Hz), 7.36 (1H, dd, J=8.0, 1.5 Hz).

[0385] MS (m/z): 355 (M+H).sup.+.

[0386] The following compounds were obtained by the same method as Example 48.

TABLE-US-00008 TABLE 8 Example Name and Structure Instrumental data 49 [00063] .sup.1H-NMR (CDCl.sub.3) : 1.34 (3H, t, J = 7.5 Hz), 2.49 (3H, s), 4.08 (2H, s), 4.54 (2H, q, J = 7.1 Hz), 6.73 (1H, dd, J = 8.7, 5.9 Hz), 6.86 (1H, td, J = 8.2, 2.7 Hz), 7.17 (1H, dd, J = 8.4, 2.6 Hz). MS (m/z): 325 (M + H).sup.+. 50 [00064] .sup.1H-NMR (CDCl.sub.3) : 1.33 (3H, t, J = 7.0 Hz), 2.48 (3H, s), 4.16 (2H, s), 4.54 (2H, q, J = 7.1 Hz), 6.62 (1H, dd, J = 7.8, 1.5 Hz), 7.06 (1H, t, J = 7.9 Hz), 7.37 (1H, dd, J = 8.0, 1.5 Hz). MS (m/z): 341 (M + H).sup.+. 51 [00065] .sup.1H-NMR (CDCl.sub.3) : 1.25 (3H, t, J = 7.5 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.84 (2H, q, J = 7.5 Hz), 4.01 (2H, s), 4.55 (2H, q, J = 7.1 Hz), 6.88 (1H, t, J = 8.3 Hz), 7.02 (1H, dd, J = 8.3, 1.8 Hz), 7.09 (1H, dd, J = 9.8, 2.0 Hz). MS (m/z): 339 (M + H).sup.+.

Example 52

5-(2-Chlorobenzyl)-4-ethoxy-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0387] ##STR00066##

[Step 1]

5-(2-Chlorobenzyl)-4-ethoxy-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0388] The title compound (315 mg) was obtained by the same method as step 1 of Example 45 using (5-(2-chlorobenzyl)-4-ethoxy-6-methylpyrimidin-2-yl)methanol (0.27 g) obtained by the same method as steps 1 and 2 of Example 48.

[0389] .sup.1H-NMR (DMSO-d.sub.6) : 1.20 (3H, t, J=7.3 Hz), 2.39 (3H, s), 4.06 (2H, s), 4.38 (2H, q, J=7.0 Hz), 6.84 (1H, dd, J=7.3, 1.8 Hz), 7.21 (1H, td, J=7.3, 1.5 Hz), 7.26 (1H, td, J=7.5, 1.8 Hz), 7.47 (1H, dd, J=7.7, 1.4 Hz).

[0390] MS (m/z): 307 (M+H).sup.+.

[0391] The following compounds were obtained by the same method as Example 52.

TABLE-US-00009 TABLE 9 Example Name and Structure Instrumental data 53 [00067] .sup.1H-NMR (DMSO-d.sub.6) : 0.77 (3H, t, J = 7.4 Hz), 1.55-1.65 (2H, m), 2.41 (3H, s), 4.07 (2H, s), 4.27 (2H, t, J = 6.4 Hz), 6.83 (1H, dd, J = 7.7, 1.6 Hz), 7.20 (1H, td, J = 7.3, 1.5 Hz), 7.25 (1H, td, J = 7.5, 2.0 Hz), 7.47 (1H, dd, J = 7.8, 1.5 Hz). MS (m/z): 321 (M + H).sup.+. 54 [00068] .sup.1H-NMR (DMSO-d.sub.6) : 1.10 (3H, t, J = 7.3 Hz), 1.16 (6H, d, J = 6.3 Hz), 2.70 (2H, q, J = 8.0 Hz), 4.05 (2H, s), 5.30-5.37 (1H, m), 6.83 (1H, dd, J = 7.4, 1.9 Hz), 7.18-7.27 (2H, m), 7.47 (1H, dd, J = 7.7, 1.6 Hz). MS (m/z): 336 (M + H).sup.+. 55 [00069] .sup.1H-NMR (DMSO-d.sub.6) : 1.10 (3H, t, J = 7.5 Hz), 1.20 (3H, t, J = 7.0 Hz), 2.70 (2H, q, J = 8.3 Hz), 4.03 (2H, s), 4.38 (2H, q, J = 7.0 Hz), 6.87 (1H, dd, J = 8.8, 6.3 Hz), 7.09 (1H, td, J = 8.5, 2.7 Hz), 7.46 (1H, dd, J = 8.8, 2.8 Hz). MS (m/z): 339 (M + H).sup.+. 56 [00070] .sup.1H-NMR (DMSO-d.sub.6) : 1.24 (3H, t, J = 7.0 Hz), 2.46 (3H, s), 3.96 (2H, s), 4.38 (2H, q, J = 7.0 Hz), 7.08 (1H, t, J = 8.3 Hz), 7.18 (1H, dd, J = 8.3, 2.0 Hz), 7.40 (1H, dd, J = 10.2, 2.1 Hz). MS (m/z): 325 (M + H).sup.+. 57 [00071] .sup.1H-NMR (DMSO-d.sub.6) : 1.23 (3H, t, J = 7.0 Hz), 2.38 (3H, s), 3.74 (3H, s), 3.97 (2H, s), 4.39 (2H, q, J = 7.0 Hz), 6.76 (1H, d, J = 8.5 Hz), 6.80 (1H, dd, J = 8.8, 2.5 Hz), 7.06 (1H, d, J = 2.3 Hz). MS (m/z): 337 (M + H).sup.+. 58 [00072] .sup.1H-NMR (DMSO-d.sub.6) : 0.87 (3H, t, J = 7.4 Hz), 1.23 (3H, t, J = 7.0 Hz), 1.53-1.63 (2H, m), 2.69-2.74 (2H, m), 3.98 (2H, s), 4.38 (2H, q, J = 7.0 Hz), 7.04 (1H, t, J = 8.4 Hz), 7.18 (1H, dd, J = 8.3, 2.0 Hz), 7.40 (1H, dd, J = 10.2, 2.1 Hz). MS (m/z) : 353 (M + H).sup.+. 59 [00073] .sup.1H-NMR (DMSO-d.sub.6) : 1.11 (3H, t, J = 7.5 Hz), 1.23 (3H, t, J = 7.3 Hz), 2.76 (2H, q, J = 7.5 Hz), 4.01 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 7.00 (1H, td, J = 7.8, 1.8 Hz), 7.09 (1H, td, J = 7.4, 1.3 Hz), 7.14-7.20 (1H, m), 7.23-7.30 (1H, m). MS (m/z): 305 (M + H).sup.+. 60 [00074] .sup.1H-NMR (DMSO-d.sub.6) : 1.13 (3H, t, J = 7.5 Hz), 1.21 (3H, t, J = 7.0 Hz), 2.78 (2H, q, J = 7.5 Hz), 4.04 (2H, s), 4.37 (2H, q, J = 7.0 Hz), 6.98 (1H, td, J = 7.5, 1.8 Hz), 7.11 (1H, td, J = 7.8, 1.0 Hz), 7.44 (1H, td, J = 7.8, 1.5 Hz). MS (m/z): 339 (M + H).sup.+. 61 [00075] .sup.1H-NMR (DMSO-d.sub.6) : 1.11 (3H, t, J = 7.5 Hz), 1.19 (3H, t, J = 7.0 Hz), 2.70 (2H, q, J = 7.5 Hz), 4.10 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 6.67 (1H, d, J = 7.3 Hz), 7.22-7.31 (2H, m). MS (m/z): 339 (M + H).sup.+. 62 [00076] .sup.1H-NMR (DMSO-d.sub.6) : 1.09 (3H, t, J = 7.5 Hz), 1.20 (3H, t, J = 7.3 Hz), 2.68 (2H, q, J = 7.5 Hz), 4.07 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 6.81 (1H, dd, J = 7.5, 1.8 Hz), 7.21 (1H, td, J = 7.3, 1.8 Hz), 7.25 (1H, td, J = 7.5, 2.0 Hz), 7.48 (1H, dd, J = 7.8, 1.5 Hz). MS (m/z): 321 (M + H).sup.+. 63 [00077] .sup.1H-NMR (DMSO-d.sub.6) : 1.11 (3H, t, J = 7.5 Hz), 1.90-2.05 (2H, m), 2.72 (2H, q, J = 7.5 Hz), 4.09 (2H, s), 4.33 (2H, dt, J = 46.9, 6.3 Hz), 4.41 (2H, t, J = 6.8 Hz), 6.81 (1H, dd, J = 7.5, 1.8 Hz), 7.21 (1H, td, J = 7.5, 1.5 Hz), 7.26 (1H, td, J = 7.5, 1.8 Hz), 7.48 (1H, dd, J = 7.8, 1.5 Hz). MS (m/z): 353 (M + H).sup.+. 64 [00078] .sup.1H-NMR (DMSO-d.sub.6) : 0.76 (3H, t, J = 7.4 Hz), 1.11 (3H, t, J = 7.5 Hz), 1.55-1.64 (2H, m), 2.71 (2H, q, J = 7.5 Hz), 4.08 (2H, s), 4.28 (2H, t, J = 6.3 Hz), 6.79 (1H, dd, J = 7.5, 1.8 Hz), 7.20 (1H, td, J = 7.5, 1.5 Hz), 7.25 (1H, td, J = 7.5, 1.8 Hz), 7.48 (1H, dd, J = 7.9, 1.4 Hz). MS (m/z) : 335 (M + H).sup.+.

Example 65

5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid

[0392] ##STR00079## ##STR00080##

[Step 1]

Methyl 2-(tert-butoxymethyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate

[0393] To a solution of dimethyl 2-(1-methoxyethylidene)malonate (Angew. Chem. Int. Ed., 2013, 52, 8736-8741) (1.57 g) in acetonitrile (40 ml), the compound (1.53 g) obtained in step 1 of Reference Example 2 and triethylamine (5.81 ml) were added, and the mixture was stirred at room temperature for 20 minutes and then stirred at 60 C. for 3.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate/methanol and n-hexane/ethyl acetate) to obtain the title compound (1.04 g).

[0394] .sup.1H-NMR (CDCl.sub.3) : 1.28 (9H, s), 2.38 (3H, s), 3.92 (3H, s), 4.39 (2H, s), 9.80 (1H, br s).

[0395] MS (m/z): 255 (M+H).sup.+.

[Step 2]

Methyl 2-(tert-butoxymethyl)-4-chloro-6-methylpyrimidine-5-carboxylate

[0396] The title compound (727 mg) was obtained by the same method as step 3 of Example 38 using the compound (1.02 g) obtained in step 1 above.

[0397] .sup.1H-NMR (CDCl.sub.3) : 1.30 (9H, s), 2.56 (3H, s), 3.98 (3H, s), 4.63 (2H, s).

[0398] MS (m/z): 273 (M+H).sup.+.

[Step 3]

Methyl 2-(tert-butoxymethyl)-4-methoxy-6-methylpyrimidine-5-carboxylate

[0399] The title compound (292 mg) was obtained by the same method as step 4 of Example 38 using the compound (406 mg) obtained in step 2 above.

[0400] .sup.1H-NMR (CDCl.sub.3) : 1.30 (9H, s), 2.49 (3H, s), 3.91 (3H, s), 4.02 (3H, s), 4.54 (2H, s).

[0401] MS (m/z): 269 (M+H).sup.+.

[Step 4]

(2-(tert-Butoxymethyl)-4-methoxy-6-methylpyrimidin-5-yl)methanol

[0402] To a solution of the compound (284 mg) obtained in step 3 above in tetrahydrofuran (10 ml), diisobutyl aluminum hydride (1.5 M solution in toluene, 2.12 ml) was added dropwise at 78 C. over 5 minutes, and the mixture was stirred for 2 hours under ice cooling. 1 M hydrochloric acid, water, and a saturated aqueous solution of Rochelle salt were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (249 mg).

[0403] .sup.1H-NMR (CDCl.sub.3) : 1.30 (9H, s), 2.01 (1H, t, J=6.5 Hz), 2.53 (3H, s), 4.03 (3H, s), 4.52 (2H, s), 4.69 (2H, d, J=6.5 Hz).

[0404] MS (m/z): 241 (M+H).sup.+.

[Step 5]

5-(Bromomethyl)-2-(tert-butoxymethyl)-4-methoxy-6-methylpyrimidine

[0405] To a solution of the compound (202 mg) obtained in step 4 above in dichloromethane (4 ml), triphenylphosphine (242 mg) was added under ice cooling, and then, a solution of carbon tetrabromide (306 mg) in dichloromethane (1 ml) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for 20 hours. Then, triphenylphosphine (110 mg) and carbon tetrabromide (139 mg) were further added thereto, and the mixture was further stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (175 mg).

[0406] .sup.1H-NMR (CDCl.sub.3) : 1.30 (9H, s), 2.52 (3H, s), 4.05 (3H, s), 4.49 (2H, s), 4.51 (2H, s).

[0407] MS (m/z): 303, 305 (M+H).sup.+.

[Step 6]

2-(tert-Butoxymethyl)-5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine

[0408] To a solution of the compound (50 mg) obtained in step 5 above in dimethyl ethylene glycol (1 ml), 2-chlorophenylboronic acid (28.4 mg), cesium carbonate (107 mg), tetrakis(triphenylphosphine)palladium(0) (9.5 mg), and water (0.5 ml) were added, and the mixture was stirred at 80 C. for 45 minutes under microwave irradiation. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (48.3 mg).

[0409] .sup.1H-NMR (CDCl.sub.3) : 1.33 (9H, s), 2.34 (3H, s), 3.95 (3H, s), 4.03 (2H, s), 4.55 (2H, s), 6.67-6.72 (1H, m), 7.04-7.10 (1H, m), 7.10-7.16 (1H, m), 7.38 (1H, dd, J=7.8, 1.4 Hz).

[0410] MS (m/z): 335 (M+H).sup.+.

[Step 7]

(5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidin-2-yl)methanol

[0411] To the compound (44.7 mg) obtained in step 6 above, trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue obtained. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (24.8 mg).

[0412] .sup.1H-NMR (CDCl.sub.3) : 2.36 (3H, s), 3.76 (1H, br. t, J=4.8 Hz), 3.95 (3H, s), 4.05 (2H, s), 4.69 (2H, d, J=4.6 Hz), 6.68-6.72 (1H, m), 7.07-7.12 (1H, m), 7.12-7.18 (1H, m), 7.40 (1H, dd, J=7.8, 1.4 Hz).

[0413] MS (m/z): 279 (M+H).sup.+.

[Step 8]

5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid

[0414] To a solution of the compound (21.8 mg) obtained in step 7 above in acetonitrile (0.6 ml), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (0.9 mg) and a sodium phosphate buffer solution (0.67 M, pH 6.7, 0.45 ml) were added at room temperature. The mixture was warmed to 35 C. Then, an aqueous sodium chlorite solution (2.0 M, 78 l) and an aqueous sodium hypochlorite solution (0.26%, 90 l) were added dropwise thereto at the same time, and the mixture was stirred at 35 C. for 17 hours. After cooling, water and a 2 M aqueous sodium hydroxide solution were added to the reaction solution, and then, an aqueous sodium thiosulfate solution (0.4 M) and diethyl ether were added under ice cooling to separate two layers. The aqueous layer was neutralized with 2 M hydrochloric acid, followed by extraction with chloroform. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue obtained, and the resulting precipitate was collected by filtration and dried to obtain the title compound (19.3 mg).

[0415] The instrumental data was consistent with the instrumental data of the compound obtained in step 6 of Example 38.

[0416] The following compounds were obtained by the same method as Example 65.

TABLE-US-00010 TABLE 10 Example Name and Structure Instrumental data 66 [00081] .sup.1H-NMR (CDCl.sub.3) : 2.47 (3H, s), 4.09 (3H, s), 4.16 (2H, s), 6.55 (1H, dd, J = 7.8, 1.5 Hz), 7.06 (1H, t, J = 7.9 Hz), 7.37 (1H, dd, J = 7.9, 1.5 Hz). MS (m/z): 327 (M + H).sup.+. 67 [00082] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 3.77 (3H, s), 4.06 (2H, s), 4.09 (3H, s), 6.56-6.62 (1H, m), 6.64-6.70 (1H, m), 6.97 (1H, d, J = 2.5 Hz). MS (m/z): 323 (M + H).sup.+. 68 [00083] .sup.1H-NMR (CDCl.sub.3) : 2.48 (3H, s), 4.09 (3H, s), 4.17 (2H, s), 6.81 (1H, d, J = 8.2 Hz), 7.35-7.42 (1H, m), 7.67-7.72 (1H, m). MS (m/z): 361 (M + H).sup.+. 69 [00084] .sup.1H-NMR (CDCl.sub.3) : 2.47 (3H, s), 4.09 (3H, s), 4.09 (2H, s), 6.66 (1H, dd, J = 8.7, 6.0 Hz), 6.85 (1H, td, J = 8.3, 2.6 Hz), 7.18 (1H, dd, J = 8.3, 2.7 Hz). MS (m/z): 311 (M + H).sup.+. 70 [00085] .sup.1H-NMR (CDCl.sub.3) : 1.18 (6H, d, J = 6.7 Hz), 3.16 (1H, spt, J = 6.7 Hz), 4.09 (3H, s), 4.16 (2H, s), 6.58-6.65 (1H, m), 7.11 (1H, td, J = 7.5, 1.3 Hz), 7.14-7.21 (1H, m), 7.42 (1H, dd, J = 7.9, 1.3 Hz). MS (m/z): 321 (M + H).sup.+. 71 [00086] .sup.1H-NMR (CDCl.sub.3) : 1.20 (6H, d, J = 6.7 Hz), 3.14 (1H, spt, J = 6.7 Hz), 4.09 (3H, s), 4.10 (2H, s), 6.56 (1H, d, J = 8.4 Hz), 7.10 (1H, dd, J = 8.3, 2.1 Hz), 7.44 (1H, d, J = 2.1 Hz). MS (m/z): 355 (M + H).sup.+. 72 [00087] .sup.1H-NMR (CDCl.sub.3) : 1.21 (6H, d, J = 6.8 Hz), 3.13 (1H, spt, J = 6.7 Hz), 4.09 (3H, s), 4.19 (2H, s), 6.75 (1H, d, J = 8.3 Hz), 7.34-7.40 (1H, m), 7.70 (1H, d, J = 1.1 Hz). MS (m/z): 389 (M + H).sup.+. 73 [00088] .sup.1H-NMR (CDCl.sub.3) : 1.31 (6H, d, J = 6.8 Hz), 2.45 (3H, s), 3.30 (1H, spt, J = 6.9 Hz), 4.06 (3H, s), 4.08 (2H, s), 6.45-6.52 (1H, m), 7.01 (1H, td, J = 7.5, 1.3 Hz), 7.18-7.24 (1H, m), 7.33 (1H, dd, J = 7.8, 1.1 Hz). MS (m/z): 301 (M + H).sup.+.

Example 74

5-(2-Chlorobenzyl)-4-isopropoxy-6-methylpyrimidine-2-carboxylic acid

[0417] ##STR00089##

[Step 1]

(4-Chloro-5-(2-chlorobenzyl)-6-methylpyrimidin-2-yl)methanol

[0418] The compound (47.49 g) obtained in step 3 of Example 38 was dissolved in trifluoroacetic acid (100 ml), and the mixture was stirred overnight at room temperature. The reaction solution was washed with n-hexane, and toluene (280 ml) was added thereto. A saturated aqueous solution of sodium carbonate (100 ml) was added dropwise to the solution obtained, and the mixture was stirred to separate two layers. The organic layer was washed with a saturated aqueous solution of sodium carbonate and water in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Ethyl acetate (50 ml) was added to the residue obtained, and the mixture was stirred at 60 C. until dissolution. The solution obtained was cooled to room temperature. Then, n-hexane (200 ml) was added dropwise thereto with stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was further stirred for 1.5 hours under ice cooling, and then, the precipitate was collected by filtration, washed with a n-hexane/ethyl acetate mixed solvent (6:1), and then dried under reduced pressure to obtain the title compound (17.81 g). Also, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) and then recrystallized with ethyl acetate/n-hexane to further obtain the title compound (4.31 g).

[0419] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 3.45 (1H, br s), 4.27 (2H, s), 4.80 (2H, s), 6.62-6.68 (1H, m), 7.09-7.17 (1H, m), 7.17-7.24 (1H, m), 7.44 (1H, dd, J=7.9, 1.4 Hz).

[0420] MS (m/z): 283 (M+H).sup.+.

[Step 2]

4-Chloro-5-(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid

[0421] The compound (22.05 g) obtained in step 1 above was suspended in acetonitrile (400 ml), and a sodium phosphate buffer solution (0.67 M, pH 6.7, 300 ml) was added to the suspension. (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (853 mg) was added to the obtained mixed solution, and the mixture was warmed to 35 C. Then, an aqueous sodium chlorite solution (2.0 M, 80 ml) and an aqueous sodium hypochlorite solution (0.26%, 20 ml) were added dropwise thereto over 30 minutes. After stirring at 35 C. for 1 hour, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (853 mg) was further added thereto, and the mixture was stirred for 1 hour. (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (853 mg) was further added thereto, and the mixture was stirred for 1 hour. After cooling to room temperature, ice (390 g) was added to the reaction solution, a 2 M aqueous sodium hydroxide solution (176 ml) was gradually added, then sodium thiosulfate (30.0 g) was added, and the mixture was stirred and then concentrated under reduced pressure. Toluene (200 ml) was added to the residue, and the mixture was stirred. After separation of two layers, the aqueous layer was filtered through celite. The aqueous solution obtained was rendered acidic (pH 3) by the dropwise addition of 6 M hydrochloric acid at room temperature, and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (21.24 g).

[0422] .sup.1H-NMR (CDCl.sub.3) : 4.28 (2H, s), 6.78 (1H, dd, J=7.7, 1.4 Hz), 7.17-7.27 (1H, m), 7.27-7.35 (1H, m), 7.54 (1H, dd, J=7.9, 1.3 Hz), 13.89 (1H, br s).

[0423] MS (m/z): 297 (M+H).sup.+.

[Step 3]

tert-Butyl 4-chloro-5-(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylate

[0424] To a solution of the compound (18.24 g) obtained in step 2 above in N,N-dimethylacetamide (155 ml), N-methylimidazole (24.5 ml) and tert-butyl alcohol (29.3 ml) were added, and the mixture was warmed to 40 C. p-Toluenesulfonyl chloride (23.4 g) was added in small portions to the reaction solution, and the mixture was stirred at 40 C. for 30 minutes. After cooling, ethyl acetate, n-hexane, and water were added to the reaction solution, and the mixture was stirred to separate two layers. The organic layer was washed with water and a saturated aqueous solution of sodium bicarbonate in this order and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (15.95 g).

[0425] .sup.1H-NMR (CDCl.sub.3) : 1.67 (9H, s), 2.53 (3H, s), 4.31 (2H, s), 6.56-6.63 (1H, m), 7.07-7.15 (1H, m), 7.17-7.24 (1H, m), 7.44 (1H, dd, J=8.0, 1.3 Hz).

[0426] MS (m/z): 353 (M+H).sup.+.

[Step 4]

5-(2-Chlorobenzyl)-4-isopropoxy-6-methylpyrimidine-2-carboxylic acid

[0427] A suspension of the compound (70 mg) obtained in step 3 above and cesium carbonate (194 mg) in 2-propanol (2 ml) was heated to reflux for 16 hours. After cooling, the reaction solution was diluted with water, and the pH of the aqueous solution was adjusted to approximately 4 by the addition of 1 M hydrochloric acid. A saturated amount of common salt was added to the mixed solution obtained, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (53.4 mg).

[0428] .sup.1H-NMR (DMSO-d.sub.6) : 1.16 (6H, d, J=6.1 Hz), 2.38 (3H, s), 4.00 (2H, s), 5.21-5.49 (1H, br m), 6.48-6.93 (1H, br m), 6.96-7.33 (2H, br m), 7.35-7.52 (1H, m).

[0429] MS (m/z): 321 (M+H).sup.+.

Example 75

5-(2,4-Dichlorobenzyl)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid

[0430] ##STR00090##

[Step 1]

5-(2,4-Dichlorobenzyl)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid

[0431] A solution of the compound (25 mg) obtained in step 5 of Example 1 and sodium methanethiolate (50% by weight, 32 mg) in N,N-dimethylformamide (0.4 ml) was stirred at room temperature for 17 hours. The reaction solution was diluted with water and then neutralized with 1 M hydrochloric acid, and the precipitate was collected by filtration and washed with water. The crude product obtained was purified by silica gel column chromatography (chloroform/methanol). The eluted fraction was concentrated under reduced pressure, and the residue obtained was suspended in ethanol. The suspension was diluted with water and cooled under ice cooling, and then, the resulting precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (8.6 mg).

[0432] .sup.1H-NMR (CDCl.sub.3) : 1.16 (6H, d, J=6.1 Hz), 2.38 (3H, s), 4.00 (2H, s), 5.19-5.53 (1H, br m), 6.52-6.96 (1H, br m), 6.99-7.30 (2H, m), 7.34-7.56 (1H, m).

[0433] MS (m/z): 343 (M+H).sup.+.

[0434] The following compounds were obtained by the same method as Example 75.

TABLE-US-00011 TABLE 11 Example Name and Structure Instrumental data 76 [00091] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 2.65 (3H, s), 4.21 (2H, s), 6.57-6.64 (1H, m), 7.11 (1H, td, J = 7.5, 1.3 Hz), 7.17-7.24 (1H, m), 7.45 (1H, dd, J = 8.0, 1.2 Hz). MS (m/z): 309 (M + H).sup.+. 77 [00092] .sup.1H-NMR (CD.sub.3OD) : 1.17 (3H, t, J = 7.0 Hz), 2.54 (3H, s), 3.60 (2H, q, J = 7.0 Hz), 6.57 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 8.5, 2.1 Hz), 7.50 (1H, d, J = 2.1 Hz). MS (m/z): 375 (M + H).sup.+. 78 [00093] .sup.1H-NMR (CDCl.sub.3) : 1.23 (3H, t, J = 7.5 Hz), 2.65 (3H, s), 2.73 (2H, q, J = 7.5 Hz), 4.22 (2H, s), 6.57-6.63 (1H, m), 7.11 (1H, td, J = 7.5, 1.3 Hz), 7.17-7.24 (1H, m), 7.45 (1H, dd, J = 8.0, 1.2 Hz). MS (m/z): 323 (M + H).sup.+.

Example 79

5-(2,4-Dichlorobenzyl)-4-(ethylthio)-6-methylpyrimidine-2-carboxylic acid

[0435] ##STR00094##

[Step 1]

5-(2,4-Dichlorobenzyl)-4-(ethylthio)-6-methylpyrimidine-2-carboxylic acid

[0436] To a solution of the compound (20 mg) obtained in step 5 of Example 1 in N,N-dimethylformamide (0.3 ml), ethanethiol (22 l) and cesium carbonate (40 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and then neutralized with 1 M hydrochloric acid, and the resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (16.4 mg).

[0437] .sup.1H-NMR (CDCl.sub.3) : 1.40 (3H, t, J=7.4 Hz), 2.45 (3H, s), 3.30 (2H, q, J=7.4 Hz), 4.13 (2H, s), 6.54 (1H, d, J=8.3 Hz), 7.10 (1H, dd, J=8.3, 2.3 Hz), 7.47 (1H, d, J=2.3 Hz).

[0438] MS (m/z): 357 (M+H).sup.+.

[0439] The following compounds were obtained by the same method as Example 79.

TABLE-US-00012 TABLE 12 Example Name and Structure Instrumental data 80 [00095] .sup.1H-NMR (CDCl.sub.3) : 1.39 (3H, t, J = 7.3 Hz), 2.40 (3H, s), 3.27 (2H, q, J = 7.3 Hz), 6.38 (1H, d, J = 8.8 Hz), 7.07-7.16 (1H, m), 7.52 (1H, d, J = 2.4 Hz). MS (m/z): 359 (M + H).sup.+. 81 [00096] .sup.1H-NMR (CD.sub.3OD) : 1.34 (3H, t, J = 7.3 Hz), 2.42 (3H, br s), 3.26- 3.34 (2H, m), 4.27 (2H, br s), 6.87 (1H, d, J = 8.0 Hz), 7.54 (1H, d, J = 8.0, 1.4 Hz), 7.90 (1H, d, J = 1.5 Hz). MS (m/z): 348 (M + H).sup.+. 82 [00097] .sup.1H-NMR (CD.sub.3OD) : 2.55 (3H, br s), 3.39 (2H, t, J = 6.0 Hz), 3.72 (2H, t, J = 6.5 Hz), 4.55 (1H, s), 6.61 (1H, d, J = 8.5 Hz), 7.17 (1H, dd, J = 8.6, 2.2 Hz), 7.51 (1H, d, J = 2.3 Hz). MS (m/z): 391 (M + H).sup.+.

Example 83

5-((2-Chlorophenyl)thio)-4-(isopropylthio)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0440] ##STR00098##

[Step 1]

tert-Butyl 5-((2-chlorophenyl)thio)-4-(isopropylthio)-6-methylpyrimidine-2-carboxylate

[0441] To a solution of the compound (600 mg) obtained in step 1 of Example 22 in tetrahydrofuran (12.0 ml), sodium 2-propanethiolate (349 mg) was added at 0 C., and the mixture was stirred at the same temperature as above for 2 hours. Water and 1 M hydrochloric acid were added in this order to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate and n-hexane/acetone) to obtain the title compound (302 mg).

[0442] .sup.1H-NMR (CDCl.sub.3) : 1.41 (6H, d, J=6.9 Hz), 1.65 (9H, s), 2.58 (3H, s), 4.02 (1H, spt, J=6.9 Hz), 6.53 (1H, dd, J=7.9, 2.3 Hz), 7.02-7.14 (2H, m), 7.39 (1H, dd, J=8.0, 3.4 Hz).

[0443] MS (m/z): 411 (M+H).sup.+.

[Step 2]

5-((2-Chlorophenyl)thio)-4-(isopropylthio)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0444] To the compound (195.8 mg) obtained in step 1 above, a 4 M solution of hydrochloric acid in 1,4-dioxane (2.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in methanol. n-Hexane was added to the solution, and the resulting precipitate was collected by filtration to obtain the title compound (115 mg).

[0445] .sup.1H-NMR (CD.sub.3OD) : 1.37 (6H, d, J=6.9 Hz), 2.55 (3H, s), 4.13 (1H, spt, J=6.8 Hz), 6.64 (1H, dd, J=7.5, 2.1 Hz), 7.12-7.23 (2H, m), 7.44 (1H, dd, J=7.3, 1.7 Hz).

[0446] MS (m/z): 355 (M+H).sup.+.

[0447] The following compound was obtained by the same method as Example 83.

TABLE-US-00013 TABLE 13 Example Name and Structure Instrumental data 84 [00099] .sup.1H-NMR (CD.sub.3OD) : 1.39 (6H, d, J = 6.9 Hz), 2.39 (3H, s), 4.18 (2H, s), 4.21-4.31 (1H, m), 6.61-6.68 (1H, m), 7.11-7.19 (1H, m), 7.19- 7.27 (1H, m), 7.46 (1H, dd, J = 7.9, 1.3 Hz). MS (m/z): 337 (M + H).sup.+.

Example 85

5-((2-Chlorophenyl)amino)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid hydrochloride

[0448] ##STR00100##

[Step 1]

4-Chloro-5-iodo-2-(methoxymethyl)-6-methylpyrimidine

[0449] To a solution of the compound (533 mg) obtained in step 2 of Example 18 in chloroform (11.0 ml), phosphoryl chloride (532 l) was added at room temperature, and the mixture was stirred at 100 C. for 80 minutes under microwave irradiation. After cooling, the reaction solution was poured into ice water, and the mixture was vigorously stirred. The pH of the reaction solution was adjusted to 10 by the addition of a 2 M aqueous sodium hydroxide solution, followed by separation of two layers. The organic layer was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (189 mg).

[0450] .sup.1H-NMR (CDCl.sub.3) : 2.81 (3H, s), 3.53 (3H, s), 4.58 (2H, s).

[0451] MS (m/z): 299 (M+H).sup.+.

[Step 2]

(4-Chloro-5-iodo-6-methylpyrimidin-2-yl)methanol

[0452] The title compound (492 mg) was obtained by the same method as step 4 of Example 17 using the compound (601 mg) obtained in step 1 above.

[0453] .sup.1H-NMR (CDCl.sub.3) : 2.83 (3H, s), 3.28 (1H, t, J=5.3 Hz), 4.76 (2H, d, J=5.3 Hz).

[0454] MS (m/z): 284 (M+H).sup.+.

[Step 3]

4-Chloro-5-iodo-6-methylpyrimidine-2-carboxylic acid

[0455] The title compound (433 mg) was obtained by the same method as step 5 of Example 1 using the compound (492 mg) obtained in step 2 above.

[0456] .sup.1H-NMR (CDCl.sub.3) : 2.93 (3H, s).

[0457] MS (m/z): 433 (M+H).sup.+.

[Step 4]

tert-Butyl 4-chloro-5-iodo-6-methylpyrimidine-2-carboxylate

[0458] The title compound (2.39 g) was obtained by the same method as step 1 of Example 22 using the compound (2.36 g) obtained in step 3 above.

[0459] .sup.1H-NMR (CDCl.sub.3) : 1.64 (9H, s), 2.87 (3H, s).

[Step 5]

tert-Butyl 5-iodo-4-methyl-6-(methylthio)pyrimidine-2-carboxylate

[0460] To a solution of the compound (93.4 mg) obtained in step 4 above in tetrahydrofuran (2.90 ml), sodium thiomethoxide (40.6 mg) was added at 0 C., and the mixture was stirred at the same temperature as above for 2 hours. Water and 1 M hydrochloric acid were added in this order to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (67.5 mg).

[0461] .sup.1H-NMR (CDCl.sub.3) : 1.63 (9H, s), 2.60 (3H, s), 2.74 (3H, s).

[Step 6]

tert-Butyl 5-((2-chlorophenyl)amino)-4-methyl-6-(methylthio)pyrimidine-2-carboxylate

[0462] To a solution of the compound (28.2 mg) obtained in step 5 above in 1,4-dioxane (540 l), 2-chloroaniline (8.1 l), tris(dibenzylideneacetone)dipalladium(0) (7.1 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13.4 mg), and cesium carbonate (75.0 mg) were added at room temperature, and the mixture was stirred at 95 C. for 7 hours. Water was added to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (22.6 mg).

[0463] .sup.1H-NMR (CDCl.sub.3) : 1.59 (9H, s), 2.33 (3H, s), 2.52 (3H, s), 5.59 (1H, s), 6.13 (1H, dd, J=8.4, 1.4 Hz), 6.74 (1H, ddd, J=7.7, 7.7, 1.5 Hz), 6.95-7.01 (1H, m), 7.31 (1H, dd, J=8.0, 1.4 Hz).

[0464] MS (m/z): 366 (M+H).sup.+.

[Step 7]

5-((2-Chlorophenyl)amino)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid hydrochloride

[0465] The title compound (11.5 mg) was obtained by the same method as step 3 of Example 22 using the compound (22.6 mg) obtained in step 6 above.

[0466] .sup.1H-NMR (CD.sub.3OD) : 2.35 (3H, s), 2.57 (3H, s), 6.20 (1H, dd, J=8.2, 1.4 Hz), 6.78 (1H, t, J=7.7 Hz), 6.93 (1H, s), 7.02-7.08 (1H, m), 7.35 (1H, dd, J=8.0, 1.4 Hz).

[0467] MS (m/z): 310 (M+H).sup.+.

Example 86

5-((2-Chlorophenyl)amino)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0468] ##STR00101##

[Step 1]

tert-Butyl 5-((tert-butoxycarbonyl)(2-chlorophenyl)amino)-4-methyl-6-(methylthio)pyrimidine-2-carboxylate

[0469] To a solution of the compound (171 mg) obtained in step 6 of Example 85 in acetonitrile (2.50 ml), di-tert-butyl dicarbonate (306 mg) was added at room temperature, and the mixture was heated to reflux for 27 hours. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (150 mg).

[0470] .sup.1H-NMR (CDCl.sub.3) : 1.46 (9H, br s), 1.64 (9H, s), 2.45 (3H, s), 2.63 (3H, s), 6.98-7.22 (3H, m), 7.45 (1H, dd, J=7.5, 1.6 Hz).

[0471] MS (m/z): 466 (M+H).sup.+.

[Step 2]

tert-Butyl 5-((tert-butoxycarbonyl)(2-chlorophenyl)amino)-4-methyl-6-(methylsulfonyl)pyrimidine-2-carboxylate

[0472] To a solution of the compound (150 mg) obtained in step 1 above in 2-dichloromethane (8.00 ml), m-chloroperbenzoic acid (75%, 296 mg) was added at 0 C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (172 mg).

[0473] .sup.1H-NMR (CDCl.sub.3) : 1.49 (9H, s), 1.64 (9H, s), 2.46 (3H, s), 3.36 (3H, s), 7.12-7.17 (1H, m), 7.19-7.24 (2H, m), 7.44-7.50 (1H, m).

[Step 3]

tert-Butyl 5-((tert-butoxycarbonyl)(2-chlorophenyl)amino)-4-(ethylamino)-6-methylpyrimidine-2-carboxylate

[0474] To a solution of the compound (160 mg) obtained in step 2 above in 2-propanol (5.0 ml), an aqueous ethylamine solution (33%, 480 l) was added at room temperature, and the mixture was stirred at 95 C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (123 mg).

[0475] .sup.1H-NMR (CDCl.sub.3) : 1.15 (3H, t, J=7.2 Hz), 1.44 (9H, s), 1.62 (9H, s), 2.52 (3H, s), 3.41-3.56 (2H, m), 6.98-7.04 (1H, m), 7.16-7.24 (2H, m), 7.44-7.49 (1H, m).

[Step 4]

5-((2-Chlorophenyl)amino)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride

[0476] The title compound (7.5 mg) was obtained by the same method as step 3 of Example 22 using the compound (33.4 mg) obtained in step 3 above.

[0477] .sup.1H-NMR (CD.sub.3OD) : 1.21 (3H, t, J=7.2 Hz), 2.28 (3H, s), 3.71 (2H, q, J=7.2 Hz), 6.40 (1H, dd, J=8.2, 1.1 Hz), 6.81 (1H, t, J=7.7 Hz), 6.93 (1H, s), 7.07-7.14 (1H, m), 7.38 (1H, dd, J=8.0, 1.4 Hz).

[0478] MS (m/z): 307 (M+H).sup.+.

Example 87

5-(2-Chlorobenzyl)-4-methyl-6-(methylamino)pyrimidine-2-carboxylic acid

[0479] ##STR00102##

[Step 1]

5-(2-Chlorobenzyl)-4-methyl-6-(methylamino)pyrimidine-2-carboxylic acid

[0480] To a solution of the compound (50 mg) obtained in step 2 of Example 74 in 2-propanol (1.7 ml), an aqueous methylamine solution (12 M, 0.07 ml) was added, and the mixture was stirred at 90 C. for 3 hours under microwave irradiation. After cooling, an aqueous methylamine solution (12 M, 0.07 ml) was further added thereto, and the mixture was further stirred at 90 C. for 1 hour under microwave irradiation. The reaction solution was diluted with water under ice cooling and then rendered acidic with 2 M hydrochloric acid, followed by extraction with ethyl acetate. The aqueous layer was saturated with common salt and neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (25.6 mg).

[0481] .sup.1H-NMR (CD.sub.3OD) : 2.34 (3H, s), 3.14 (3H, s), 4.05 (2H, s), 6.83 (1H, d, J=7.5 Hz), 7.11-7.24 (1H, m), 7.24-7.33 (1H, m), 7.48 (1H, dd, J=7.8, 1.4 Hz).

[0482] MS (m/z): 292 (M+H).sup.+.

Example 88

4,5-Bis(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid

[0483] ##STR00103##

[Step 1]

tert-Butyl 4,5-bis(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylate

[0484] To a suspension of the compound (50 mg) obtained in step 3 of Example 74 and tetrakis(triphenylphosphine)palladium(0) (3.4 mg) in tetrahydrofuran (0.5 ml), 2-chlorobenzylzinc chloride (0.5 M solution in tetrahydrofuran, 0.31 ml) was added under an argon atmosphere, and the mixture was stirred at 50 C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/ethyl acetate) and amine-coated silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (12.7 mg).

[0485] .sup.1H-NMR (CDCl.sub.3) : 1.65 (9H, s), 2.47 (3H, s), 4.11 (2H, s), 4.26 (2H, s), 6.36 (1H, d, J=7.8 Hz), 6.93-7.02 (1H, m), 7.02-7.18 (4H, m), 7.22-7.29 (1H, m), 7.38 (1H, dd, J=8.0, 1.2 Hz).

[0486] MS (m/z): 443 (M+H).sup.+.

[Step 2]

4,5-Bis(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid

[0487] To a solution of the compound (12.7 mg) obtained in step 1 above in 1,4-dioxane (0.3 ml), a 4 M aqueous lithium hydroxide solution (36 l) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water, and 2 M hydrochloric acid (73 l) was added to the aqueous solution. The precipitate was collected by filtration, washed with water, and then dried in air. The solid obtained was dissolved in chloroform. n-Hexane was added to the solution, and the resulting precipitate was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain the title compound (7.6 mg).

[0488] .sup.1H-NMR (CDCl.sub.3) : 2.58 (3H, s), 4.22-4.29 (4H, m), 6.44 (1H, d, J=8.0 Hz), 7.03-7.11 (2H, m), 7.12-7.24 (3H, m), 7.30-7.36 (1H, m), 7.44 (1H, dd, J=8.0, 1.2 Hz).

[0489] MS (m/z): 387 (M+H).sup.+.

Example 89

5-(2-Chlorobenzyl)-4-((3-cyanobenzyl)oxy)-6-methylpyrimidine-2-carboxylic acid

[0490] ##STR00104##

[Step 1]

tert-Butyl 5-(2-chlorobenzyl)-4-((3-cyanobenzyl)oxy)-6-methylpyrimidine-2-carboxylate

[0491] A suspension of the compound (120 mg) obtained in step 3 of Example 74, 18-crown-6 ether (18 mg), potassium carbonate (95 mg) and 3-cyanobenzyl alcohol (80 l) in dimethyl sulfoxide (1.1 ml) was stirred at 80 C. for 17 hours. After cooling, the reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (92.8 mg).

[0492] .sup.1H-NMR (CDCl.sub.3) : 1.67 (9H, s), 2.51 (3H, s), 4.13 (2H, s), 5.46 (2H, s), 6.62 (1H, dd, J=7.7, 1.3 Hz), 7.03-7.10 (1H, m), 7.16-7.23 (1H, m), 7.35-7.41 (1H, m), 7.42 (1H, dd, J=8.0, 1.3 Hz), 7.48-7.59 (3H, m).

[0493] MS (m/z): 450 (M+H).sup.+.

[Step 2]

5-(2-Chlorobenzyl)-4-((3-cyanobenzyl)oxy)-6-methylpyrimidine-2-carboxylic acid

[0494] To a solution of the compound (92.8 mg) obtained in step 1 above in 1,4-dioxane (2 ml), a 4 M aqueous lithium hydroxide solution (258 l) was added, and the mixture was stirred at 40 C. for 2 hours. The reaction solution was diluted with water, and 2 M hydrochloric acid (526 l) was added to the aqueous solution. The mixture was stirred for 30 minutes, and then, the precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (67 mg).

[0495] .sup.1H-NMR (CD.sub.3OD) : 2.53 (3H, s), 4.19 (2H, s), 5.53 (2H, s), 6.79 (1H, dd, J=7.7, 1.4 Hz), 7.10-7.16 (1H, m), 7.18-7.26 (1H, m), 7.39-7.49 (2H, m), 7.50-7.54 (1H, m), 7.55-7.65 (2H, m).

[0496] MS (m/z): 394 (M+H).sup.+.

[0497] The following compounds were obtained by the same method as Example 89.

TABLE-US-00014 TABLE 14 Ex- am- ple Name and Structure Instrumental data 90 [00105] .sup.1H-NMR (CD.sub.3OD) : 2.47 (3H, s), 4.17 (2H, s), 5.51 (2H, s), 6.76 (1H, dd, J = 7.7, 1.4 Hz), 7.06-7.13 (1H, m), 7.15-7.23 (1H, m), 7.24-7.32 (5H, m), 7.40 (1H, dd, J = 8.0, 1.3 Hz). MS (m/z): 369 (M + H).sup.+. 91 [00106] .sup.1H-NMR (CD.sub.3OD) : 2.23-2.36 (2H, m), 2.49 (3H, s), 2.86-3.03 (3H, m), 4.18 (2H, s), 5.35 (1H, s), 6.90 (1H, dd, J = 7.4, 1.8 Hz), 7.15-7.28 (2H, m), 7.44 (1H, dd, J = 7.7, 1.6 Hz). MS (m/z): 358 (M + H).sup.+. 92 [00107] .sup.1H-NMR (CD.sub.3OD) : 2.40-2.49 (2H, m), 2.53 (3H, s), 2.82-2.96 (2H, m), 3.01-3.11 (1H, m), 4.14 (2H, s), 5.60- 5.69 (1H, m), 6.73 (1H, dd, J = 7.6, 1.4 Hz), 7.10-7.17 (1H, m), 7.17-7.24 (1H, m), 7.43 (1H, dd, J = 7.9, 1.4 Hz). MS (m/z): 358 (M + H).sup.+. 93 [00108] .sup.1H-NMR (CDCl.sub.3) : 2.50 (3H, s), 4.18 (2H, s), 5.56 (2H, s), 6.77 (1H, dd, J = 7.6, 1.3 Hz), 7.06-7.14 (1H, m), 7.16-7.24 (1H, m), 7.35-7.43 (2H, m), 7.75-7.82 (1H, m), 8.53 (1H, s). MS (m/z): 370 (M + H).sup.+ 94 [00109] .sup.1H-NMR (CD.sub.3OD) : 2.52 (3H, s), 4.24 (2H, s), 5.60 (2H, s), 6.84 (1H, dd, J = 7.7, 1.4 Hz), 7.12-7.19 (1H, m), 7.20-7.26 (1H, m), 7.27-7.32 (2H, m), 7.44 (1H, dd, J = 7.9, 1.3 Hz), 8.41- 8.46 (2H, m). MS (m/z): 370 (M + H).sup.+. 95 [00110] .sup.1H-NMR (CD.sub.3OD) : 2.49 (3H, s), 4.22 (2H, s), 5.61 (2H, s), 6.82 (1H, dd, J = 7.7, 1.4 Hz), 7.08-7.15 (1H, m), 7.17-7.23 (1H, m), 7.29-7.37 (2H, m), 7.40 (1H, dd, J = 7.9, 1.3 Hz), 7.72-7.80 (1H, m), 8.45-8.52 (1H, m). MS (m/z): 370 (M + H).sup.+. 96 [00111] .sup.1H-NMR (CD.sub.3OD) : 2.48 (3H, s), 2.53 (3H, s), 4.16 (2H, s), 5.53 (2H, s), 6.75 (1H, dd, J = 7.7, 1.3 Hz), 7.06-7.14 (1H, m), 7.16-7.23 (1H, m), 7.29 (1H, d, J = 8.0 Hz), 7.39 (1H, dd, J = 8.0, 1.3 Hz), 7.72 (1H, dd, J = 8.0, 2.3 Hz), 8.45 (1H, d, J = 2.3 Hz). MS (m/z): 384 (M + H).sup.+. 97 [00112] .sup.1H-NMR (CD.sub.3OD) : 2.47 (3H, s), 4.15 (2H, s), 5.48 (2H, s), 6.75 (1H, dd, J = 7.6, 1.4 Hz), 6.95-7.03 (2H, m), 7.07-7.14 (1H, m), 7.16-7.23 (1H, m), 7.27-7.35 (2H, m), 7.39 (1H, dd, J = 8.0, 1.3 Hz). MS (m/z): 387 (M + H).sup.+. 98 [00113] .sup.1H-NMR (CD.sub.3OD) : 2.50 (3H, s), 4.18 (2H, s), 5.50 (2H, s), 6.78 (1H, dd, J = 7.8, 1.4 Hz), 6.93-7.03 (2H, m), 7.06-7.15 (2H, m), 7.17-7.23 (1H, m), 7.24-7.33 (1H, m), 7.41 (1H, dd, J = 8.0, 1.3 Hz). MS (m/z): 387 (M + H).sup.+. 99 [00114] .sup.1H-NMR (CD.sub.3OD) : 2.47 (3H, s), 4.14 (2H, s), 5.57 (2H, s), 6.77 (1H, dd, J = 7.8, 1.4 Hz), 7.02-7.12 (3H, m), 7.13-7.20 (1H, m), 7.28-7.40 (3H, m), MS (m/z): 387 (M + H).sup.+. 100 [00115] .sup.1H-NMR (CD.sub.3OD) : 2.48 (3H, s), 4.13 (2H, s), 5.53 (2H, s), 6.76 (1H, dd, J = 7.7, 1.4 Hz), 6.83-6.96 (2H, m), 7.04-7.11 (1H, m), 7.13-7.21 (1H, m), 7.36 (1H, dd, J = 8.0, 1.3 Hz), 7.38-7.46 (1H, m). MS (m/z): 405 (M + H).sup.+.

Example 101

5-(2-Chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylic acid

[0498] ##STR00116##

[Step 1]

tert-Butyl 5-(2-chlorobenzyl)-4-methyl-6-(pyridin-4-ylethynyl)pyrimidine-2-carboxylate

[0499] A suspension of the compound (150 mg) obtained in step 3 of Example 74, bis(triphenylphosphine)palladium(II) chloride (30 mg), copper(I) iodide (5 mg), 4-ethynylpyridine (88 mg), and triethylamine (0.6 ml) in toluene (2 ml) was stirred at 100 C. for 2 hours under an argon atmosphere. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (93.2 mg).

[0500] .sup.1H-NMR (CDCl.sub.3) : 1.69 (9H, s), 2.55 (3H, s), 4.42 (2H, s), 6.66 (1H, dd, J=7.8, 1.4 Hz), 7.08-7.15 (1H, m), 7.17-7.23 (1H, m), 7.28-7.33 (2H, m), 7.45 (1H, dd, J=7.9, 1.3 Hz), 8.60-8.64 (2H, m).

[0501] MS (m/z): 420 (M+H).sup.+.

[Step 2]

tert-Butyl 5-(2-chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylate

[0502] To a solution of the compound (93.2 mg) obtained in step 1 above in ethanol (2.2 ml), 5% palladium carbon (56% aqueous, 42.4 mg) was added, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (87.7 mg).

[0503] .sup.1H-NMR (CDCl.sub.3) : 1.66-1.72 (9H, m), 2.50 (3H, s), 3.00-3.13 (4H, m), 4.09 (2H, s), 6.34 (1H, dd, J=7.5, 1.0 Hz), 7.00-7.07 (1H, m), 7.11 (2H, d, J=5.8 Hz), 7.16-7.23 (1H, m), 7.44 (1H, dd, J=8.0, 1.2 Hz), 8.43 (2H, d, J=5.8 Hz).

[0504] MS (m/z): 424 (M+H).sup.+.

[Step 3]

5-(2-Chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylic acid

[0505] To a solution of the compound (87.7 mg) obtained in step 2 above in 1,4-dioxane (2 ml), a 4 M aqueous lithium hydroxide solution (259 l) was added, and the mixture was stirred at 40 C. for 2.5 hours. The reaction solution was diluted with water, and 2 M hydrochloric acid (528 l) was added to the aqueous solution. Then, the mixture was saturated with common salt, followed by extraction with chloroform three times. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was dissolved in ethanol (2 ml). Diethyl ether (4 ml) and n-hexane (20 ml) were added to the solution, and the mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with n-hexane, and then dried under reduced pressure to obtain the title compound (64 mg).

[0506] .sup.1H-NMR (DMSO-d.sub.6) : 2.40 (3H, s), 2.97-3.07 (4H, m), 4.16 (2H, s), 6.57 (1H, dd, J=7.8, 1.4 Hz), 7.12-7.19 (1H, m), 7.25-7.30 (3H, m), 7.52 (1H, dd, J=8.0, 1.2 Hz), 8.45 (2H, d, J=5.9 Hz).

[0507] MS (m/z): 368 (M+H).sup.+.

[0508] The following compound was obtained by the same method as Example 101.

TABLE-US-00015 TABLE 15 Example Name and Structure Instrumental data 102 [00117] .sup.1H-NMR (CD.sub.3OD) : 2.49 (3H, s), 3.01-3.12 (4H, m), 4.20 (2H, s), 6.52 (1H, d, J = 7.8 Hz), 7.07-7.17 (1H, m), 7.19-7.30 (1H, m), 7.36 (1H, dd, J = 7.6, 5.1 Hz), 7.48 (1H, dd, J = 8.0, 1.1 Hz), 7.67-7.75 (1H, m), 8.30-8.40 (2H, m). MS (m/z): 368 (M + H).sup.+.

Example 103

5-(2-Chlorobenzyl)-4,6-dimethylpyrimidine-2-carboxylic acid

[0509] ##STR00118##

[Step 1]

3-(2-Chlorobenzyl)pentane-2,4-dione

[0510] To a solution of pentane-2,4-dione (4.62 g) in ethanol (20 ml), sodium ethoxide (5.23 g) was added, and the mixture was stirred at room temperature for 1 hour. 2-Chlorobenzyl bromide (3.16 g) was added to the reaction solution, and the mixture was stirred at 80 C. for 2 hours. Water and dichloromethane were added to the reaction solution to separate two layers. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (2.77 g).

[0511] .sup.1H-NMR (CDCl.sub.3) : 2.03 (3H, s), 2.16 (3H, s), 3.25 (2H, d, J=7.3 Hz), 4.14 (1H, t, J=7.3 Hz), 7.04-7.24 (3H, m), 7.33-7.41 (1H, m).

[Step 2]

Ethyl 5-(2-chlorobenzyl)-4,6-dimethylpyrimidine-2-carboxylate

[0512] To a solution of the compound (500 mg) obtained in step 1 above in methanol (2.5 ml), ammonium acetate (172 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. Then, ethyl cyanoformate (218 l) and a 4 M solution of hydrochloric acid in 1,4-dioxane (2.5 ml) were added to the residue obtained, and the mixture was stirred at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and water, a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the residue obtained to separate two layers. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (109 mg).

[0513] .sup.1H-NMR (CDCl.sub.3) : 1.47 (3H, t, J=7.2 Hz), 2.52 (6H, s), 4.18 (2H, s), 4.55 (2H, q, J=7.2 Hz), 6.48-6.53 (1H, m), 7.05-7.24 (2H, m), 7.43-7.48 (1H, m).

[Step 3]

5-(2-Chlorobenzyl)-4,6-dimethylpyrimidine-2-carboxylic acid

[0514] To a solution of the compound (109 mg) obtained in step 2 above in methanol (2 ml), a 1 M aqueous sodium hydroxide solution (0.537 ml) was added, and the mixture was stirred at room temperature for 1 hour. 1 M hydrochloric acid (5 ml) and chloroform were added to the reaction solution to separate two layers. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (44.5 mg).

[0515] .sup.1H-NMR (CDCl.sub.3) : 2.55 (6H, s), 4.21 (2H, s), 6.50 (1H, d, J=8.0 Hz), 7.13 (1H, dd, J=8.0, 8.0 Hz), 7.23 (1H, dd, J=8.0, 8.0 Hz), 7.47 (1H, d, J=8.0 Hz).

[0516] MS (m/z): 277 (M+H).sup.+.

[0517] The following compound was obtained by the same method as Example 103.

TABLE-US-00016 TABLE 16 Example Name and Structure Instrumental data 104 [00119] .sup.1H-NMR (CDCl.sub.3) : 2.55 (6H, s), 4.16 (2H, s), 6.43 (1H, d, J = 8.3 Hz), 7.12 (1H, dd, J = 8.3, 2.3 Hz), 7.50 (1H, d, J = 2.3 Hz). MS (m/z): 311 (M + H).sup.+.

Example 105

5-(2,4-Dichlorobenzyl)-N,6-dimethyl-2-(1H-tetrazol-5-yl)pyrimidin-4-amine

[0518] ##STR00120##

[Step 1]

4-Chloro-5-(2,4-dichlorobenzyl)-6-methylpyrimidine-2-carboxamide

[0519] To a suspension of the compound (1 g) obtained in step 5 of Example 1 in chloroform (10 ml), thionyl chloride (0.88 ml) was added, and the mixture was stirred at 80 C. for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in tetrahydrofuran (15 ml). This solution was cooled to 78 C. An aqueous ammonia solution (28%, 1.5 ml) was added thereto, and the mixture was stirred at the same temperature as above for 30 minutes. The temperature of the reaction solution was raised to 0 C., and 2 M hydrochloric acid (13 ml) was added thereto, followed by extraction with chloroform. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (930 mg).

[0520] MS (m/z): 330 (M+H).sup.+.

[Step 2]

5-(2,4-Dichlorobenzyl)-4-methyl-6-(methylamino)pyrimidine-2-carboxamide

[0521] To a solution of the compound (110 mg) obtained in step 1 above in ethanol (2.5 ml), an aqueous methylamine solution (40%, 0.23 ml) was added, and the mixture was stirred at 115 C. for 45 minutes under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (81 mg).

[0522] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 3.02 (3H, d, J=4.8 Hz), 3.90 (2H, s), 4.58 (1H, br s), 5.65 (1H, br s), 6.66 (1H, d, J=8.0 Hz), 7.13 (1H, dd, J=8.0, 2.1 Hz), 7.47 (1H, d, J=2.1 Hz), 7.80 (1H, br s).

[0523] MS (m/z): 325 (M+H).sup.+.

[Step 3]

5-(2,4-Dichlorobenzyl)-N,6-dimethyl-2-(1H-tetrazol-5-yl)pyrimidin-4-amine

[0524] To a solution of the compound (80 mg) obtained in step 2 above in acetonitrile (6 ml), sodium azide (160 mg) and tetrachlorosilane (0.14 ml) were added, and the mixture was stirred at 90 C. for 6 hours. After cooling, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by column chromatography (chloroform/methanol) using diol-modified silica gel to obtain the title compound (24 mg).

[0525] .sup.1H-NMR (CD.sub.3OD) : 2.35 (3H, s), 3.13 (3H, s), 4.01 (2H, s), 6.84 (1H, d, J=8.0 Hz), 7.23 (1H, dd, J=8.0, 2.1 Hz), 7.55 (1H, d, J=2.1 Hz).

[0526] MS (m/z): 350 (M+H).sup.+.

[0527] The following compound was obtained by the same method as Example 105.

TABLE-US-00017 TABLE 17 Example Name and Structure Instrumental data 106 [00121] .sup.1H-NMR (CD.sub.3OD) : 1.99-2.46 (3H, m), 2.91-3.09 (3H, m), 6.66 (1H, d, J = 8.8 Hz), 7.22 (1H, br s), 7.46 (1H, d, J = 1.8 Hz). MS (m/z): 368 (M + H).sup.+.

Example 107

5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid 3/2-hydrate

[0528] ##STR00122##

[Step 1]

5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid 3/2-hydrate

[0529] To the compound (200 mg) obtained in step 6 of Example 38, 2-propanol (1.8 ml) and water (0.2 ml) were added, and the mixture was stirred at 95 C. for 15 minutes. After cooling to room temperature, the mixture was stirred overnight at room temperature. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (188 mg).

[0530] .sup.1H-NMR (CDCl.sub.3) : 2.46 (3H, s), 4.09 (3H, s), 4.14 (2H, s), 6.66-6.69 (1H, m), 7.12 (1H, td, J=7.5, 1.5 Hz), 7.19 (1H, td, J=7.7, 1.8 Hz), 7.42 (1H, dd, J=7.9, 1.4 Hz).

[0531] Anal. Calcd for C.sub.14H.sub.13C.sub.1N.sub.2O.sub.3.3/2H.sub.2O: C, 52.59; H, 5.04; Cl, 11.09; N, 8.76.

[0532] Found: C, 52.40; H, 5.07; Cl, 11.17; N, 8.70.

[0533] FIG. 6 shows the diffraction pattern of a compound obtained in the same way as above in powder X-ray diffraction (CuK, =1.54 angstroms, scan rate=2/min). Main peaks with high relative intensity in FIG. 6 are shown in Table 18.

TABLE-US-00018 TABLE 18 Peak Relative No. 2 d value intensity 1 6.68 13.22 10 2 10.54 8.39 100 3 16.16 5.48 23 4 20.16 4.40 12 5 21.22 4.18 60 6 21.58 4.11 17 7 24.20 3.67 16 8 25.16 3.54 17 9 33.92 2.64 9

Reference Example 1

2-Methoxyacetimidamide hydrochloride

[0534] ##STR00123##

[Step 1]

2-Methoxyacetimidamide hydrochloride

[0535] To a solution of 2-methoxyacetonitrile (47.9 g) in methanol (240 ml), sodium methoxide (3.64 g) was added, and the mixture was stirred at room temperature for 3 hours. Ammonium chloride (36.1 g) was added to the reaction solution, and the mixture was stirred overnight at 40 C. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in 2-propanol (50 ml). Acetone (200 ml) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (73.35 g).

[0536] .sup.1H-NMR (DMSO-d.sub.6) : 3.35 (3H, s), 4.25 (2H, s), 9.06 (4H, br s).

Reference Example 2

2-(tert-Butoxy)acetimidamide hydrochloride

[0537] ##STR00124##

[Step 1]

2-(tert-Butoxy)acetimidamide hydrochloride

[0538] To a solution of 2-(tert-butoxy)acetonitrile (Nature Chemistry, 2010, 937-943) (69.89 g) in methanol (400 ml), sodium methoxide (3.08 g) was added, and the mixture was stirred at room temperature for 8 hours. Ammonium chloride (34.69 g) was added to the reaction solution, and the mixture was stirred overnight at 40 C. and then stirred overnight at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethanol (400 ml) was added to the residue obtained, and the mixture was stirred at 80 C. for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (300 ml) was added to the residue obtained, then n-hexane (300 ml) was added dropwise with stirring at 40 C., and the mixture was stirred overnight at room temperature. The suspension was filtered to obtain the title compound (68.57 g).

[0539] .sup.1H-NMR (DMSO-d.sub.6) : 1.19 (9H, s), 4.21 (2H, s), 8.61 (4H, br s).

Reference Example 3

trans-3-Hydroxycyclobutanecarbonitrile

[0540] ##STR00125##

[Step 1]

trans-3-Cyanocyclobutyl 4-nitrobenzoate

[0541] To a solution of cis-3-hydroxycyclobutanecarbonitrile (WO2013/30138) (247 mg), 4-nitrobenzoic acid (850 mg) and triphenylphosphine (1.34 g) in tetrahydrofuran (13 ml), diisopropyl azodicarboxylate (0.52 ml) was added under an argon atmosphere, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/ethyl acetate) and recrystallized with ethyl acetate/n-hexane to obtain the title compound (169 mg).

[0542] .sup.1H-NMR (CDCl.sub.3) : 2.62-2.75 (2H, m), 2.88-3.01 (2H, m), 3.22-3.32 (1H, m), 5.49-5.59 (1H, m), 8.18-8.22 (2H, m), 8.28-8.32 (2H, m).

[Step 2]

trans-3-Hydroxycyclobutanecarbonitrile

[0543] To a solution of the compound (169 mg) obtained in step 1 above in tetrahydrofuran (6.8 ml), a 2 M aqueous sodium hydroxide solution (1.7 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (60.7 mg).

[0544] .sup.1H-NMR (CDCl.sub.3) : 1.97 (1H, d, J=4.8 Hz), 2.28-2.42 (2H, m), 2.60-2.74 (2H, m), 3.01-3.12 (1H, m), 4.63-4.71 (1H, m).

Example 108

Magnesium bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate]

[0545] To a compound (301.89 mg) obtained in the same way as in Example 107, 2-propanol (1208 l) and water (3302 l) were added. To this solution, a 1.0 mol/l aqueous potassium hydroxide solution (989 l) was added, and then, a 1.0 mol/l aqueous magnesium chloride solution (539 l) was added. This mixed solution was stirred at 40 C. for approximately 24 hours and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration and dried overnight at room temperature. Then, water (6.0 ml) was added thereto, and the mixture was stirred at room temperature for approximately 2 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (274.93 mg, recovery rate: 88%).

[0546] Elemental analysis values as C.sub.28H.sub.24Cl.sub.2MgN.sub.4O.sub.6.3.0H.sub.2O

[0547] Calcd: C, 50.82; H, 4.57; N, 8.47; Cl, 10.71; Mg, 3.67.

[0548] Found: C, 50.63; H, 4.69; N, 8.41; Cl, 10.88; Mg, 3.63.

[0549] From the results mentioned above, the compound obtained was presumed to be magnesium bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate] hydrate.

[0550] FIG. 7 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 7 are shown in Table 19.

TABLE-US-00019 TABLE 19 Peak Relative No. 2 d value intensity 1 5.18 17.05 100 2 10.44 8.47 19 3 18.98 4.67 17 4 19.68 4.51 10 5 22.36 3.97 12 6 23.76 3.74 21 7 26.34 3.38 28 8 27.96 3.19 19

Example 109

[0551] Magnesium bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate]

[0552] To a compound (1501 mg) obtained in the same way as in Example 107, 2-propanol (6005 l) and water (16.42 ml) were added. To this solution, a 1.0 mol/l aqueous potassium hydroxide solution (4920 l) was added, and then, a 1.0 mol/l aqueous magnesium chloride solution (2679 l) was added. This mixed solution was stirred at 40 C. for approximately 2 days. Then, a small amount of seed crystals obtained in the same way as the method given below was added thereto, and the mixture was further stirred at 40 C. for approximately 1 day and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration. Water (30.0 ml) was added thereto, and the mixture was stirred at room temperature for approximately 2 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (1416 mg, recovery rate: 93%).

[0553] Method for Obtaining Seed Crystals

[0554] A compound (701.13 mg) obtained in the same way as in Example 108 was dissolved by the addition of a 1,4-dioxane/dimethyl sulfoxide (1/1) solution (30 ml). 428 l of this solution was dispensed, and the solvent was distilled off by freeze drying. 20% aqueous 2-propanol (100 l) was added to the freeze-dried product obtained, and the mixture was stirred at 40 C. for approximately 24 hours. Then, the solid was collected by filtration and dried overnight at room temperature to obtain seed crystals.

[0555] Elemental analysis values as C.sub.28H.sub.24Cl.sub.2MgN.sub.4O.sub.6.2H.sub.2O

[0556] Calcd: C, 52.24; H, 4.38; N, 8.70; Cl, 11.01; Mg, 3.78.

[0557] Found: C, 51.82; H, 4.52; N, 8.64; Cl, 10.90; Mg, 3.70.

[0558] Moisture content values (Karl Fischer method) as C.sub.28H.sub.24Cl.sub.2MgN.sub.4O.sub.6.2H.sub.2O

[0559] Calcd: 5.58%.

[0560] Found: 6.10%.

[0561] Rate of decrease in mass (thermal analysis TG-DTA) as C.sub.28H.sub.24Cl.sub.2MgN.sub.4O.sub.6.2H.sub.2O

[0562] Calcd: 5.58%.

[0563] Found: 5.61%.

[0564] From the measurement results mentioned above, the compound obtained was presumed to be monomagnesium bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate] dihydrate.

[0565] FIG. 8 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 8 are shown in Table 20.

TABLE-US-00020 TABLE 20 Peak Relative No. 2 d value intensity 1 11.82 7.48 52 2 13.74 6.44 51 3 14.26 6.21 75 4 15.38 5.76 59 5 21.56 4.12 37 6 23.42 3.80 100 7 24.14 3.68 92 8 27.82 3.20 33 9 28.72 3.11 34 10 31.06 2.88 31

Example 110

Calcium bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate]

[0566] To a compound (300.93 mg) obtained in the same way as in Example 107, 2-propanol (1202 l) and water (3284 l) were added. To this solution, a 1.0 mol/l aqueous potassium hydroxide solution (985 l) was added, and then, a 1.0 mol/l aqueous calcium chloride solution (538 l) was added. This mixed solution was stirred at 40 C. for approximately 24 hours and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration and dried overnight at room temperature. Then, water (6.0 ml) was added thereto, and the mixture was stirred at room temperature for approximately 2 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (301.22 mg, recovery rate: 92%).

[0567] Elemental analysis values as C.sub.28H.sub.24Cl.sub.2CaN.sub.4O.sub.6.4.0H.sub.2O

[0568] Calcd: C, 48.35; H, 4.64; N, 8.05; Cl, 10.19; Ca, 5.76.

[0569] Found: C, 48.10; H, 4.74; N, 7.98; Cl, 10.26; Ca, 4.28.

[0570] From the results mentioned above, the compound obtained was presumed to be calcium bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate] hydrate.

[0571] FIG. 9 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 9 are shown in Table 21.

TABLE-US-00021 TABLE 21 Peak Relative No. 2 d value intensity 1 5.94 14.87 100 2 7.40 11.94 30 3 11.62 7.61 13 4 11.96 7.39 14 5 13.98 6.33 60 6 14.88 5.95 31 7 19.52 4.54 13 8 22.32 3.98 12 9 23.76 3.74 13 10 24.80 3.59 18

Example 111

Zinc bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate]

[0572] To a compound (300.10 mg) obtained in the same way as in Example 107, 2-propanol (1200 l) and water (3280 l) were added. To this solution, a 1.0 mol/l aqueous potassium hydroxide solution (984 l) was added, and then, a 1.0 mol/l aqueous zinc bromide solution (538 l) was added. This mixed solution was stirred at 40 C. for approximately 24 hours and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration and dried overnight at room temperature. Then, water (6.0 ml) was added thereto, and the mixture was stirred at room temperature for approximately 2 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (293.65 mg, recovery rate: 92%).

[0573] Elemental analysis values as C.sub.28H.sub.24Cl.sub.2ZnN.sub.4O.sub.6.1.5H.sub.2O

[0574] Calcd: C, 49.76; H, 4.03; N, 8.29; Cl, 10.49.

[0575] Found: C, 49.94; H, 4.12; N, 8.28; Cl, 10.61.

[0576] From the results mentioned above, the compound obtained was presumed to be zinc bis[5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate] hydrate.

[0577] FIG. 10 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 10 are shown in Table 22.

TABLE-US-00022 TABLE 22 Peak Relative No. 2 d value intensity 1 6.10 14.48 97 2 12.28 7.20 100 3 13.44 6.58 13 4 14.08 6.28 25 5 15.34 5.77 35 6 19.16 4.63 24 7 21.78 4.08 30 8 23.60 3.77 21 9 24.70 3.60 22 10 31.76 2.82 17

Example 112

Sodium 5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate

[0578] To a compound (301.24 mg) obtained in the same way as in Example 107, ethanol (5042 l) was added, and a 1.0 mol/l solution of sodium hydroxide in ethanol (982 l) was added. This mixed solution was stirred at 40 C. for approximately 24 hours and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (289.98 mg, recovery rate: 97%).

[0579] FIG. 11 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 11 are shown in Table 23.

TABLE-US-00023 TABLE 23 Peak Relative No. 2 d value intensity 1 5.64 15.66 51 2 6.00 14.72 100 3 9.68 9.13 44 4 16.40 5.40 21 5 18.16 4.88 29 6 24.30 3.66 66 7 25.54 3.48 17

Example 113

Tert-butylammonium 5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate

[0580] To a compound (300.90 mg) obtained in the same way as in Example 107, acetone (5913 l) was added, and tert-butylamine (105 l) was added. This mixed solution was stirred at 40 C. for approximately 24 hours and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (332.74 mg, recovery rate: 97%).

[0581] Elemental analysis values as C.sub.14H.sub.13C.sub.1N.sub.2O.sub.3.1.0C.sub.4H.sub.11N

[0582] Calcd: C, 59.09; H, 6.61; N, 11.49; Cl, 9.69.

[0583] Found: C, 58.69; H, 6.53; N, 11.34; Cl, 9.74.

[0584] FIG. 12 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 12 are shown in Table 24.

TABLE-US-00024 TABLE 24 Peak Relative No. 2 d value intensity 1 6.84 12.91 77 2 9.34 9.46 69 3 13.66 6.48 100 4 15.38 5.76 38 5 17.92 4.95 29 6 18.36 4.83 42 7 22.04 4.03 54 8 22.52 3.94 30 9 23.12 3.84 72 10 30.24 2.95 32

Example 114

Diisopropylamine 5-(2-Chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylate

[0585] To a compound (300.05 mg) obtained in the same way as in Example 107, acetone (5863 l) was added, and diisopropylamine (138 l) was added. This mixed solution was stirred at 40 C. for approximately 24 hours and subsequently left at room temperature for approximately 0.5 hours. The solid was collected by filtration and dried overnight at room temperature to obtain the title compound (353.95 mg, recovery rate: 96%).

[0586] Elemental analysis values as C.sub.14H.sub.13C.sub.1N.sub.2O.sub.3.1.0C.sub.6H.sub.15N

[0587] Calcd: C, 60.98; H, 7.16; N, 10.67; Cl, 9.00.

[0588] Found: C, 60.89; H, 7.17; N, 10.65; Cl, 9.05.

[0589] FIG. 13 shows the powder X-ray diffraction pattern (CuK, =1.54 angstroms, scan rate=20/min). Main peaks with high relative intensity in FIG. 13 are shown in Table 25.

TABLE-US-00025 TABLE 25 Peak Relative No. 2 d value intensity 1 13.00 6.80 80 2 13.34 6.63 42 3 14.06 6.29 100 4 17.58 5.04 90 5 20.44 4.34 33 6 20.98 4.23 44 7 22.80 3.90 41 8 23.38 3.80 79 9 25.60 3.48 50 10 26.96 3.30 72

Formulation Example

[0590] After mixing 5 g of a compound obtained in the Examples, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate with a blender, tablets are then produced with a tabletting machine.

Test Example 1

[0591] Examination of Secretory Activity for Chloride Ions of Test Compounds

[0592] Measurement of the secretory activity for chloride ions was performed in accordance with a previous report (West and Molloy, 1996). CuFi-1 cells were plated on a 96 well plate in 310.sup.4 cells/well and incubated for two nights. After removing the culture medium, 100 L/well of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) (diluted with culture medium and the concentration adjusted to 5 mM) was added. After the addition of MQAE, the cells were incubated for one night so that the indicator was passively loaded. After the loading, the cells were washed two times with Assay buffer, and 100 L/well of Assay buffer was added. The secretory capacity for chloride ions was measured using FlexStation 1 (fluorescence wavelength of Ex: 355 nm/Em: 460 nm). In order to measure the basic value, nothing was added for 34 seconds immediately after the start of the measurement. Then, at this point, 100 L/well of the test compound and zinc (final concentration: 10 M) diluted with Assay buffer, which is free of chloride ions, was added, and the measurement was continued for 86 seconds (total measurement time: 120 seconds). The secretory capacity for chloride ions was calculated by dividing the average of RFU values in 10 seconds between 110 seconds and 120 seconds after the start of the measurement with the average between 0 second and 34 seconds (the basic value). The secretory activity for chloride ions of the test compound (EC.sub.50 value) was calculated by obtaining the secretory capacity for chloride ions at each concentration of the serially diluted test compound, and determining a concentration of the test compound that provides a secretory capacity of 50% from two secretory capacities and concentrations sandwiching 50% of the maximum response of each compound.

[0593] The results are described in Table 26.

TABLE-US-00026 TABLE 26 Example EC.sub.50 No. (nM) 1 9.4 2 24.2 3 53.0 4 19.6 5 30.3 6 50.3 7 41.7 8 50.6 9 5.5 10 7.3 11 11.1 12 6.7 13 5.6 14 5.0 15 10.8 16 52.7 17 15.7 18 4.6 19 13.1 20 5.9 21 18.6 22 7.1 23 86.0 24 12.9 25 14.6 26 14.4 27 14.0 28 2.8 29 6.9 30 9.5 31 34.9 32 17.1 33 18.4 34 80.1 35 29.3 36 80.6 37 30.3 38 10.0 39 5.5 40 8.1 41 16.3 42 7.6 43 66.7 44 9.4 45 14.7 46 15.9 47 8.6 48 9.4 49 24.8 50 10.2 51 8.2 52 15.8 53 15.8 54 15.4 55 7.6 56 16.0 57 20.8 58 13.0 59 24.6 60 12.0 61 11.4 62 4.9 63 4.8 64 14.9 65 66 17.4 67 15.9 68 4.0 69 26.7 70 59.9 71 30.2 72 2.6 73 35.2 74 33.4 75 3.7 76 15.2 77 14.6 78 4.6 79 6.6 80 49.4 81 5.5 82 30.8 83 50.7 84 10.4 85 30.2 86 13.1 87 8.2 88 7.1 89 5.1 90 6.4 91 13.2 92 5.1 93 2.2 94 2.2 95 3.3 96 2.4 97 5.7 98 13.5 99 5.1 100 11.1 101 8.9 102 5.2 103 20.8 104 9.9 105 2.1 106 2.9

[0594] It is to be noted that the compounds of Example 38 and Examples 107 to 114 are an anhydride, hydrates, or different types of salts or hydrates thereof, derived from the same compound. In Test Examples 1 to 3, a compound from any of these Examples was used as a test compound.

Test Example 2

[0595] Effects of GPR39 Knockdown on Chloride Secretion by Test Compounds

[0596] In order to confirm that chloride ion secretion by the test compound observed in Test. Example 1 was induced via GPR39, GPR39 knockdown was conducted. CuFi-1 cells cultured in Pneumacult-EX (STEMCELL Technologies Inc.) were plated on a 96 well plate in 310.sup.4 cells/100 L/well. Then, human GPR39 siRNA (MISSION siRNA SASI_Hs02_00332000, SASI_Hs02_00332001, Sigma-Aldrich Co. LLC) or control siRNA (Ambion Silencer Select, Thermo Fisher Scientific Inc.) was added in 1 pmol/10 L/well using Lipofectamine RNAiMAX (Thermo Fisher Scientific Inc.), and the cells were incubated for two nights. In order for the final concentration to be 5 mM, 10 L/well of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) diluted with culture medium was added. After the addition of MQAE, the cells were incubated for one night so that the indicator was passively loaded. Hereafter, washing and measurement of the secretory capacity for chloride ions were conducted in the same way as Test Example 1. In addition, analysis on gene expression of GPR39 was performed using RNA extracted from wells to which the same method was carried out. Total RNA was extracted from cells using RNAiso Plus (Takara Bio Inc.), and purified using RNeasy Micro Kit (Qiagen). Then, cDNA was synthesized using High Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific Inc.), and quantitative PCR was conducted using TaqMan Gene Expression Assays (human GPR39: Hs00230762_m1, human GAPDH: Hs02758991_g1, Thermo Fisher Scientific Inc.) and THUNDERBIRD Probe qPCR Mix (TOYOBO CO., LTD.). Through the calibration curve method, a relative expression level of GPR39 compensated with GAPDH was calculated. The results are shown in FIG. 1 and FIG. 2.

[0597] With the siRNA treatment, GPR39 knockdown was confirmed (See FIG. 1. siGPR39-1: 17%, siGPR39-2: 15% versus control siRNA). In GPR39 knockdown conditions, the chloride ion secretion by the test compound (the compound of Example 107) in CuFi-1 cells was remarkably suppressed, compared to the control siRNA treated group (See FIG. 2. siGPR39-1: 17%, siGPR39-2: 37% versus control siRNA). The chloride ion secretion by UTP was not affected by the GPR39 knockdown (See FIG. 2. siGPR39-1: 111%, siGPR39-2: 89% versus control siRNA). As such, it was shown that the chloride secretion by the test compound in CuFi-1 cells was induced via GPR39.

Test Example 3

[0598] Effects of Test Compound in ALI Assay Using Fluid Transfer as an Indicator

[0599] MucilAir-CF cells were commercially obtained from Epithelix Sarl. The cells are obtained by ALI (Air-Liquid Interface) culturing primary bronchial epithelial cells from patients with cystic fibrosis having F508 homozygous mutation (class II mutation), 2184A+W1282X (class I mutation), and N1303K heterozygous mutation (class II mutation). After the acquisition, the resistance value, mucin production, and ciliary movement were confirmed, followed by addition of 200 L of HBSS (+) into the upper layer and washing of mucin. Into the upper layer, a volume of 100 L/well of culture medium was added, and into the lower layer, a volume of 500 L/well of culture medium, in which the test compound and zinc (final concentration: 10 M) were dissolved, was added. The weight of the culture medium in the upper layer was measured 72 hours after the addition of the test compound, and the fluid transfer activity of the test compound was determined. As control drugs, effects of single VX-809 (lumacaftor) (Selleck Chemicals), and a combination of VX-809 (lumacaftor) and VX-770 (ivacaftor) (Selleck Chemicals) were also examined. As the test compound, the compound of Example 38 was used. The results are shown in FIGS. 3, 4 and 5.

[0600] In the ALI culture with F508 homozygous mutation, the compound of Example 38 induced the fluid transfer in a concentration-dependent manner. Its effects were on the same level as the single VX-809 and the combination of VX-809 and VX-770. Furthermore, in mutations other than the F508 homozygous mutation (2184A+W1282X (class I mutation) and N1303K heterozygous mutation), the compound of Example 38 also showed activities equivalent to that in the F508 homozygous mutation, showing a possibility of being effective independent of CFTR mutation. However, the combination of VX-809 and VX-770 had weak effects in 2184A+W1282X (class I mutation), and it is believed that the effects were dependent on CFTR mutation. In particular, the effects of the compound of Example 38 in 2184A+W1282X (class I mutation) were significant relative to the combination of VX-809 and VX-770.

INDUSTRIAL APPLICABILITY

[0601] A compound of the present invention represented by general formula (I) or a pharmaceutically acceptable salt thereof has strong chloride ion-secretory action via GPR39 agonism and moves moisture. Therefore, a compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent for cystic fibrosis, non-CF bronchiectasis, primary ciliary dyskinesia, dry eye, constipation, adiposity, diabetes mellitus, ulcerative colitis, Crohn's disease, depression, COPD, and the like.