JPWO2006043515A1 - Pyrimidine-5-carboxylic acid derivatives - Google Patents

Abstract

A novel pyrimidine-5-carboxylic acid derivative having PPARγ modulator activity or a pharmacologically acceptable salt thereof is provided. A pyrimidine-5-carboxylic acid derivative represented by the general formula (1) or a salt thereof [specific example: 4-anilino-6- (benzylthio) -2- (methylthio) pyrimidine-5 carboxylic acid]. [Selection figure] None

Description

  The present invention relates to a novel pyrimidine-5-carboxylic acid derivative having PPARγ modulator activity or a pharmacologically acceptable salt thereof and a pharmaceutical use thereof.

  Peroxisome proliferator activated receptor (PPAR) is a member of the nuclear receptor family.

  In general, it is known that there are partial agonists or partial antagonists (these are collectively referred to as “modulators”) in addition to agonists and antagonists in the nuclear receptor group. Examples of other nuclear receptor family modulators include raloxifene and tamoxifen, which are partial agonists or partial antagonists for the estrogen receptor. Partial agonists have the property of having a lower transcriptional activity than agonists. In addition, when a partial antagonist is simultaneously present when an agonist is present, transcription activation by the agonist is suppressed, but the degree of suppression is smaller than that of the antagonist. In general, partial agonists often exhibit the properties of partial antagonists.

  These partial agonists and partial antagonists are often created with the intention of suppressing the tissue-specific undesirable effects exhibited by agonists and antagonists and eliciting tissue-specific desirable effects.

By the way, various thiazolidinedione derivatives are non-insulin-dependent diabetes (NIDDM).
mellitus) model animals exhibit hypoglycemic action and are expected as a new NIDDM having an insulin resistance releasing action. Recent studies have revealed that these thiazolidinedione derivatives also act as PPARγ modulators and specifically activate PPARγ (Non-patent Document 1). Since there is a strong correlation between the PPARγ activation ability of such thiazolidinedione derivatives and the blood glucose lowering effect in hereditary obese mice, it is considered that PPARγ may be a target molecule for the pharmacological action of thiazolidinedione derivatives (non- Patent Document 2).

  PPARγ is considered to be a factor deeply involved in adipocyte differentiation (Non-patent Documents 3 and 4).

Furthermore, PPARγ regulates cell differentiation and lipid metabolism at the transcriptional level (Non-patent Documents 5 and 6), and PPRE (Peroxisomal).
Proliferator-activated receptor responsive element (DNA sequence recognized by PPAR) is apolipoprotein A-1 (Non-patent document 7) gene, lipoprotein lipase (Non-patent document 8, Non-patent document 9), etc., and affects serum lipid profile It is a gene promoter related to lipid metabolism.

  From these findings, PPARγ is deeply involved in pathological conditions such as diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, and regression osteoporosis. It is thought that there is. Therefore, development of novel compounds having excellent properties as pharmaceuticals, such as having excellent PPARγ modulator activity and few side effects, is desired as preventive and therapeutic agents for various pathological conditions as described above.

Currently, the following compounds and the like are disclosed as compounds having PPARγ modulator activity.
(1) The specification of Patent Document 1 includes a formula:

Wherein R ¹ and R ² are independently H, halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl and C ₁ -C ₁₀ alkoxy; Ar ¹ and Ar ² are aryl and heteroaryl; X , W ¹ and W ² are single bonds, Y or Y (CH ₂ ) _n Y ¹ ; Y and Y ¹ are single bonds, O, S, SO, SO ₂ and NR; R is H, C ₁ -C ₃ alkyl And C ₂ -C ₃ alkenyl.) And the like.
(2) The specification of Patent Document 2 includes the formula:

(In the formula, B represents a substituted aryl group, B represents a substituted aryl group, a substituted cycloalkyl group or a substituted heterocyclic group, R ^a represents H or an alkyl group, X represents a bond, O, S; , CH ₂ , CO, NH, SO ₂ NH, NHSO ₂ , CONH, NHCO, or OCH ₂ group, and n represents 0 or 1).
(3) The specification of Patent Document 3 includes the formula:

(In the formula, R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X and Y are the same or different and represent a bond, etc .; Q is a carbon number of 2 to 20 Ring A represents a nitrogen-containing 5-membered heterocyclic ring which may further have 1 to 3 substituents; W represents a divalent hydrocarbon residue having 1 to 20 carbon atoms; V represents a bond, R ² represents an optionally substituted heterocyclic group, etc.), and the like.
(4) The specification of Patent Document 4 includes a formula:

(Wherein X is O or S; R ¹ , R ² and R ³ are hydrogen atoms, carboxyl groups, etc .; Ar is an aromatic ring or heterocycle; R ⁴ is H etc .; R ⁵ is H etc .; R ⁶ is H etc; R ⁷ is H or the like; Y is an oxygen atom or a nitrogen atom;. n is such compound represented by indicating from 1 to 4) is disclosed.

  However, none of the above publications disclose specific disclosure regarding pyrimidine-5-carboxylic acid derivatives.

  On the other hand, in the specification of Patent Document 5, a compound having an endothelin antagonistic activity is represented by the formula:

(Wherein, X and Y are O, S or NH; Ar ¹ , Ar ² and Ar ³ represent a 5-6 membered aryl group and a heteroaryl group having 1 to 2 heteroatoms). And the like are disclosed. In this publication, the following compounds are used as pyrimidine-5-carboxylic acid derivatives:

However, there is no description or suggestion of PPARγ modulator action. In addition, it cannot be overemphasized that such a compound is not contained in a claim of this application.
WO01 / 30343 pamphlet WO03 / 035602 pamphlet WO03 / 000685 pamphlet WO99 / 08501 pamphlet WO97 / 25321 pamphlet Lehmann et al., Journal of Biological Chemistry, 1995, 270, p. 12953-12956. Willson et al., Journal of Medicinal Chemistry, 1996, 39, p. 665-668. Tontonoz et al., Genes and Development, 1994, Volume 8, p. 1224-1234. Tontonoz et al., Cell, 1994, 79, p. 1147-1156. Spiegelman, Eur. J. Med. Res., 1997, Volume 2, p. 457-464. Tontonoz & Nagy, Curr. Opin. Lipidol, 1999, Vol. 10, p.485-490. Steal, Atherosclerosis, 1998, 137 (suppulo), S19-S23. Schhnjans, EMBO J., 1996, 15 (suppulo), p.5536-5548. Lefebvre, Arterio Thrombo Vasc. Biol., 1997, Vol. 17, p. 1756-1764.

  Currently, it has excellent PPARγ modulator action as a prophylactic and therapeutic agent for various pathological conditions such as the above-described preventive or therapeutic drugs for various pathological conditions, and is a sufficiently satisfactory pharmaceutical from the viewpoint of few side effects. No resulting compound has been found.

  The object of the present invention is to find a novel compound having a PPARγ modulator action, and various pathological conditions involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, high fat It is to provide a prophylactic or therapeutic agent for blood pressure, arteriosclerosis, regressive osteoporosis and the like.

  As a result of intensive studies, the present inventors have found that pyrimidine-5-carboxylic acid derivatives have a PPARγ modulator action, and various pathological conditions involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, It was found useful for the treatment, prevention or suppression of hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, degenerative osteoporosis, etc., and the present invention was completed.

That is, the present invention
1) The following general formula (1)

Wherein X represents S, SO, SO ₂ or NH;
Y represents O, S, SO, SO ₂ or NH;
Q ¹ and Q ² are the same or different and each represents a single bond, C ₁ -C ₆ alkylene which may have a substituent or — (CH ₂ ) _n W—, and W represents O, S or NR ² . R ² represents a hydrogen atom or a C _{1 to} C ₆ alkyl group, n represents 2 to 6;
A and B are the same or different and are an aryl group, a cycloalkyl group or a heterocyclic group (the A and B are the same or different, a halogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, An aryl group, a nitro group, an aminosulfonyl group optionally substituted with one or two identical or different C ₁ -C ₆ alkyl groups, an amino group, a mono- or di-substituted C ₁ -C ₆ alkylamino group, ₁ to 3 substituents each independently selected from an oxo group, a hydroxyl group, and a C _{1 to} C ₆ alkoxy group optionally substituted with a halogen atom (two adjacent substituents are bonded to each other) Which may form a ring) and may have)
R ¹ represents ZR ³ (Z represents O, S, SO or SO ₂ , R ³ represents a hydrogen atom, a C _{1 to} C ₁₀ alkyl group, an aryl group or an aralkyl group) or NR ⁴ R ⁵ (R ⁴ and R ⁵ are bonded to each other to form a ring, or the same or different, and a hydrogen atom, a C ₁ -C ₇ alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a C ₁ -C ₆ alkylcarbonyl group , C ₁ -C ₆ alkylsulfonyl group or represents a.) of an aryl sulfonyl group, the R ^3, R ⁴ and R ⁵ are the same or different, a halogen atom, C ₁ ~ optionally substituted by a halogen atom C ₆ alkoxy group, a hydroxyl group, a amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkoxycarbonyl group, a 1 to 3 substituents selected from among carboxyl group It may be. )
A pyrimidine-5-carboxylic acid derivative represented by the formula:

2) The following general formula (1a)

(Wherein Y represents O, S or NH, and Q ¹ , Q ² , W, R ² , n, A, B and R ¹ are the same as above.) -5-carboxylic acid derivatives or salts thereof,

3) The following general formula (1b)

(Wherein Y represents O, S or NH, and Q ¹ , Q ² , W, R ² , n, A, B and R ¹ are the same as above.) -5-carboxylic acid derivatives or salts thereof,

4) The pyrimidine-5-carboxylic acid derivative or the salt thereof according to 1) above, wherein, in the general formula (1), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene.

5) The pyrimidine-5-carboxylic acid derivative or the salt thereof according to 2) above, wherein in the general formula (1a), Q ¹ and Q ² are each represented by C ₁ -C ₆ alkylene which may have a substituent. ,

6) The pyrimidine-5-carboxylic acid derivative or the salt thereof according to 3), wherein in the general formula (1b), Q ¹ and Q ² are each optionally represented by C ₁ -C ₆ alkylene. ,

7) In the above general formula (1a), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene, and R ¹ is a C ₁ -C ₁₀ alkylthio group. ) Pyrimidine-5-carboxylic acid derivatives or salts thereof,

8) In the above general formula (1b), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene, and R ¹ is a C ₁ -C ₁₀ alkylthio group. ) Pyrimidine-5-carboxylic acid derivatives or salts thereof,

9) In the general formula (1a), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene, and R ¹ is a mono- or di-substituted C ₁ -C ₇ alkylamino group, The pyrimidine-5-carboxylic acid derivative or the salt thereof according to 2) above, which is represented by a cyclic amino group optionally containing 1 to 3 heteroatoms,

10) In the general formula (1b), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene, and R ¹ is a mono- or di-substituted C ₁ -C ₇ alkylamino group, The pyrimidine-5-carboxylic acid derivative or the salt thereof according to 3) above, which is represented by a cyclic amino group which may contain 1 to 3 heteroatoms,

11) A therapeutic, preventive or suppressive agent for non-insulin-dependent diabetes mellitus, comprising the pyrimidine-5-carboxylic acid derivative or the salt thereof according to any one of 1) to 10) as an active ingredient,

12) A therapeutic, prophylactic or inhibitory agent for obesity comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of 1) to 10) as an active ingredient,

13) A therapeutic, prophylactic or inhibitory agent for hyperglycemia, comprising as an active ingredient the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of 1) to 10),

14) A therapeutic, prophylactic or inhibitory agent for hyperlipidemia, comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of 1) to 10) as an active ingredient,

15) The treatment, prevention, or suppression of hypercholesterolemia characterized by containing the pyrimidine-5-carboxylic acid derivative or salt thereof according to any one of 1) to 10) as an active ingredient,

16) A therapeutic, preventive or suppressive agent for hypertriglyceridemia comprising the pyrimidine-5-carboxylic acid derivative or the salt thereof according to any one of 1) to 10) as an active ingredient,

17) A therapeutic, preventive or inhibitory agent for insulin resistance comprising the pyrimidine-5-carboxylic acid derivative or salt thereof according to any one of 1) to 10) as an active ingredient,

18) A therapeutic, prophylactic or inhibitory agent for hyperinsulinemia comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of 1) to 10) as an active ingredient,

19) A therapeutic, prophylactic or inhibitory agent for arteriosclerosis comprising the pyrimidine-5-carboxylic acid derivative or the salt thereof according to any one of 1) to 10) as an active ingredient,

20) The present invention relates to a therapeutic, preventive or inhibitory agent for degenerative osteoporosis characterized by containing the pyrimidine-5-carboxylic acid derivative or salt thereof according to any one of 1) to 10) as an active ingredient.

  The present invention has been found that a novel pyrimidine-5-carboxylic acid derivative or a salt thereof has an excellent PPARγ modulator action.

  Furthermore, the compounds of the present invention and their salts are safe with low toxicity. Therefore, the compounds of the present invention and salts thereof are used in various pathologies involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, regression, Stage osteoporosis and the like) has high utility for treatment, prevention or suppression.

The present invention is described in detail below.
For X and Y, X represents S, SO, SO ₂ or NH, and Y represents O, S, SO, SO ₂ or NH.

  Preferable X includes S or NH.

  Preferred examples of Y include O, S, and NH.

  A preferable combination of X and Y includes a case where X is S, a case where Y is O, S or NH.

Q ¹ and Q ² for Q ¹ and Q ² are the same or different, a single bond, which may have a substituent C ₁ -C ₆ alkylene or - (CH ₂₎ shows the _n W-, W is O , S or NR ² , R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and n represents 2-6.

Examples of the “C ₁ -C ₆ alkylene” include methylene, ethylene, propylene, butylene, and the substituents that these may have include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group. And alkyl groups such as a group, butyl group, isobutyl group, cyclobutyl group, sec-butyl group, tert-butyl group, cyclopentyl group, and cyclopentyl group.

Examples of the “ring formed by combining R ³ and R ⁴ with each other” include a cyclopropane ring, a cyclobutane ring, a cycloheptane ring, a cyclohexane ring, and the like.

Examples of the “C ₁ -C ₆ alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like.

W represents O, S or NR ² . R ² represents a hydrogen atom or a C ₁ -C ₆ alkyl group.

Examples of the “C ₁ -C ₆ alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, cyclobutyl group, sec-butyl group, tert-butyl group, cyclopentyl group Etc.

  n is preferably 1 to 3.

  More preferably, the case where n is 1 is mentioned.

About A and B In the general formula (1), A and B are the same or different and each represents an aryl group, a cycloalkyl group or a heterocyclic group. A and B may be the same or different and may have a substituent. The substituent may be substituted at any substitutable position in the ring, and the number thereof may be about 1 to 3. Two adjacent substituents may be bonded to each other to form a ring. Examples of the substituent for A and B include, for example, a halogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, an aryl group, a nitro group, one or two identical or different C _1- C ₆ alkyl group optionally substituted aminosulfonyl group, an amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, an oxo group, a hydroxyl group, and a good C ₁ -C be substituted with a halogen atom ₆ alkoxy group and the like.

  Here, examples of the “aryl group” include an aromatic hydrocarbon group having 5 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, and an anthracenyl group.

  Examples of the “cycloalkyl group” include 3 to 10-membered saturated hydrocarbon group which may be condensed such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, norbornyl group and adamantyl group. be able to.

  The “heterocyclic group” is a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. For example, a furyl group, a thienyl group, a pyrrolyl group , Azepinyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-oxadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl And aromatic heterocyclic groups such as groups, pyrazinyl groups, and groups such as morpholyl groups, thiomorpholinyl groups, pyrrolidinyl groups, pyrrolinyl groups, imidazolidinyl groups, imidazolinyl groups, pyrazolidinyl groups, pyrazolinyl groups, piperidyl groups, piperazinyl groups, etc. Can do. The “heterocyclic group” may be condensed with another cyclic group, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzoisothiazo group. Ryl, chromenyl, chromanonyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolidinyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl Quinoxalinyl group, quinazolinyl group, carbazolyl group, carbolinyl group, acridinyl group, isoindolinyl group and the like.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

Examples of the “C ₁ -C ₆ alkyl group optionally substituted with a halogen atom” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. , Fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, 1-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group, 2,2,2- A trifluoroethyl group etc. are mentioned.

Examples of the “aminosulfonyl group optionally substituted by one or two identical or different C ₁ -C ₆ alkyl groups” include an aminosulfonyl group, a methylaminosulfonyl group, an ethylaminosulfonyl group, and a dimethylaminosulfonyl group. Etc.

Examples of the “mono- or di-substituted C ₁ -C ₆ alkylamino group” include methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, dimethylamino group, diethylamino group, dipropyl Amino group, dibutylamino group, dipentylamino group, dihexylamino group, diisopropylamino group, ethylmethylamino group, methylpropylamino group, methylbutylamino group, methylpentylamino group, methylhexylamino group, 2-hydroxyethylamino group 3-hydroxypropylamino group, 4-hydroxybutylamino group, 2-methoxyethylamino group, 3-methoxypropylamino group, 4-methoxybutylamino group, 2-aminoethylamino group, 3-aminopropylamino group, 4-aminobutylamino group Methoxycarbonylmethyl group, carboxymethyl methylamino group.

Examples of the “C ₁ -C ₆ alkoxy group optionally substituted with a halogen atom” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, Fluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, 1-fluoroethoxy group, 1-chloroethoxy group, 2-chloroethoxy group, difluoromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2 , 2-trifluoroethoxy group and the like.

  As the “ring which two adjacent substituents may combine to form each other”, when the two substituents forming the ring are both present on the same carbon, for example,

And when two substituents forming a ring are adjacent to each other, for example,

Etc.

  Preferred examples of A include a phenyl group, a pyridyl group, a furyl group, a thienyl group, and a cyclohexyl group.

  More preferable A includes a phenyl group and the like.

  Preferred examples of B include a phenyl group, a pyridyl group, a furyl group, a thienyl group, and a cyclohexyl group.

  More preferable B is a phenyl group.

For R ¹ , R ¹ represents ZR ³ (Z represents O, S, SO or SO ₂ , R ³ represents a hydrogen atom, a C _{1 to} C ₁₀ alkyl group, an aryl group or an aralkyl group) or NR ⁴ R ⁵ (or R ⁴ and R ⁵ are bonded to each other to form a ring, the same or different, a hydrogen atom, C ₁ -C ₇ alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, C ₁ -C ₆ alkylcarbonyl group, C ₁ -C ₆ alkylsulfonyl group or arylsulfonyl group. here, R ^3, R ⁴ and R ⁵ are the same or different, may have a substituent group. substituents, It may be substituted at any substitutable position, and the number thereof may be about 1 to 3. Further, two adjacent substituents may be bonded to each other to form a ring. .R ^3, Examples of the substituent of R ⁴ and R ^5, for example, halogen Child, optionally substituted by a halogen atom C ₁ -C ₆ alkoxy group, a hydroxyl group, an amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkoxycarbonyl group, a carboxyl group and Can be mentioned.

Here, “aryl group”, “cycloalkyl group”, “halogen atom”, “C ₁ -C ₆ alkoxy group optionally substituted with halogen atom” and “mono- or di-substituted C ₁ -C ₆ alkylamino” The “group” is the same as described above.

Examples of the “C ₁ -C ₁₀ alkyl group” include a heptyl group, an octyl group, a nonyl group, a decyl group and the like in addition to the “C ₁ -C ₆ alkyl group”.

  Examples of the “aralkyl group” include benzyl group, phenethyl group, 3-phenylpropyl group, α-methylbenzyl group and the like.

Examples of the “C ₁ -C ₇ alkyl group” include a heptyl group and the like in addition to the “C ₁ -C ₆ alkyl group”.

Examples of the “C ₁ -C ₆ alkylcarbonyl group” include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, a butylcarbonyl group, a tert-butylcarbonyl group, and the like.

Examples of the “C ₁ -C ₆ alkylsulfonyl group” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, a trifluoromethylsulfonyl group, and the like.

  Examples of the “arylsulfonyl group” include a phenylsulfonyl group and a toluenesulfonyl group.

Examples of the “C ₁ -C ₆ alkoxycarbonyl group” include methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, butyloxycarbonyl group, tert-butyloxycarbonyl group and the like.

  Examples of the “3- to 7-membered cyclic amino group optionally containing 1 to 3 heteroatoms” include an azetidino group, a pyrrolidino group, a piperidino group, a morpholino group, a thiomorpholino group, a piperazino group, a 4-methylpiperazino group, Homopiperazino group, 2-oxopyrrolidino group, 3-oxomorpholino group, 2-oxomorpholino group and the like can be mentioned.

Examples of the “C ₁ -C ₁₀ alkylthio group” include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group, a heptylthio group, an octylthio group, a nonylthio group, and a decylthio group.

Preferable R ₁ includes methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group, hexylthio group, heptylthio group, octylthio group, dimethylamino group, pyrrolidino group, piperidino group, morpholino group and the like.

Preferred compounds of the present invention include, for example, 4-anilino-2- (methylthio) -6- (benzylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6- (phenethylamino) -pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[[4- (dimethylamino) benzyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[[4- (aminosulfonyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[[3,5-bis (trifluoromethyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(2-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] thio] pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylmethylamino) -6- (cyclopentylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) methylbenzyl] thio] pyrimidine-5-carboxylic acid,
4-[(2-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(2-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(α-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-chlorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-methoxybenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-fluorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-anilino-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-chloroanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-methoxyanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-fluoroanilino) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4-anilino-6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6- (phenethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(2-fluorobenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(3-fluorobenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(4-fluorobenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(2-methoxybenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(3-methoxybenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(4-methoxybenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(2-methylbenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(3-methylbenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(4-methylbenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (cyclohexylmethylamino) -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[[4- (dimethylamino) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6- (furfurylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[[3,5-bis (trifluoromethyl) benzyl] amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (dimethylamino) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2-piperidinopyrimidine-5-carboxylic acid benzylthio) -2-morpholinopyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (n-butylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2,6-bis (benzylamino) pyrimidine-5-carboxylic acid,
4- (benzyloxy) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (cyclopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid,
6- (4-chloroanilino) -4- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (furfurylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[[2- (1-methylpyrrolidin-2-yl) ethyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[3- (2-oxopyrrolidin-1-yl) propyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[(tetrahydrofuran-2-yl) methyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(2-morpholinoethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(2-piperidinoethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[2- (1-pyrrolidinyl) ethyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[[2- (1,3-dioxolan-2-yl) ethyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[2- (cyclohexen-1-yl) ethyl] amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[[2-[(5-nitropyridin-2-yl) amino] ethyl] amino] pyrimidine-5-carboxylic acid,
4-[(2-anilinoethyl) amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -2- (methylthio) -6-[(2-phenoxyethyl) amino] pyrimidine-5-carboxylic acid,
4- (benzylthio) -6-[[3- (1-imidazolyl) propyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid,
4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid,
4-anilino-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6- (4-methylanilino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -6- (4-methoxyanilino) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (cyclohexylthio) -2- (methylthio) -6- [4- (trifluoromethyl) anilino] pyrimidine-5-carboxylic acid,
4, 6- (dibenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4,6- (dibenzylthio) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid,
4, 6- (dibenzylthio) -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4- (benzylamino) -2- (N-butylmethylamino) -6-chloropyrimidine-5-carboxylic acid,
4- (benzylamino) -6-chloro-2- (dibutylamino) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6-chloro-2- (heptylamino) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6-chloro-2- (cyclopropylamino) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-fluorobenzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-chlorobenzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4,6-bis (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-methoxybenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-chlorobenzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4,6-bis (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-chlorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4,6-bis (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (4-fluorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (butylthio) pyrimidine-5-carboxylic acid,
4,6-bis (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4,6-bis (benzyloxy) -2- (dimethylamino) pyrimidine-5-carboxylic acid,
4,6-bis (benzyloxy) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid,
4,6-bis (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzyloxy) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid,
4- (benzylamino) -6- (benzylthio) -2- (octylthio) pyrimidine-5-carboxylic acid,
4,6-bis (benzylthio) -2- (butylthio) pyrimidine-5-carboxylic acid,
4,6-bis (benzylthio) -2- (octylthio) pyrimidine-5-carboxylic acid,
4,6-bis (benzylthio) -2- (morpholino) pyrimidine-5-carboxylic acid,
Etc. can be exemplified.

When the compound of the present invention forms a salt, it means a salt with a pharmaceutically acceptable non-toxic base or acid (for example, an inorganic or organic base and an inorganic or organic acid). Salts derived from pharmaceutically acceptable non-toxic bases include inorganic bases such as aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium. Salts (particularly preferably ammonium, calcium, manganese, potassium and sodium salts) or primary, secondary, tertiary amines, substituted amines (eg naturally occurring substituted amines), cyclic amines and bases Organic bases such as ionic ion exchange resins (eg, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl) Morpholine, N-ethylpiperidine, gluca And a salt with mine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, tripropylamine, tripropylamine, tromethamine, and the like. Examples of salts derived from non-toxic acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, Examples thereof include pharmaceutically acceptable salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.

  Furthermore, this invention compound or its salt may exist as a hydrate or a solvate. All of the hydrates and solvates formed by the pyrimidine-5-carboxylic acid derivative represented by the general formula (1) or a salt thereof including the preferred compounds specifically described above are all It is included in the scope of the invention. Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, diisopropyl ether and the like.

  The compound of the present invention or a salt thereof includes an optically active substance, a stereoisomer or a rotational isomer in addition to a racemate.

  The compound of the present invention can be produced by various synthetic methods. Next, typical production methods of the compound of the present invention and salts thereof will be described.

(Method A)

(First step)
In this step, compound (a) (R ¹ is the above in the same) to the introduction of hydroxycarbonyl group compound (b) (R ¹ is the same. To above) is a step for preparing a. In this step, compound (b) can be produced by reacting compound (a) with a base and then reacting the compound to be a carbonyl source. Examples of the base used in this step include lithium diisopropylamide and butyl lithium. The reaction can be carried out at -100 ° C to 0 ° C, preferably at -100 ° C to -50 ° C. Carbon dioxide etc. can be illustrated as a carbonyl source used at this process. The completion of the reaction can be carried out by treatment with water and a suitable acid (hydrochloric acid or the like).

(Second step)
This step is a step of producing compound (c) (R ⁶ represents an alkyl group or an aryl group) from compound (b) by an esterification reaction.
This reaction is a method for forming an ester bond well known in organic synthetic chemistry, and is suitably performed in the presence of a normal solvent.

This reaction can be performed by reacting with an alkyl halide or the like under basic conditions. When a base is used in this reaction, an alkali carbonate such as sodium bicarbonate or potassium carbonate can be exemplified. Examples of the alkyl halide used in this reaction include methyl iodide, ethyl iodide, benzyl bromide, benzyl chloride and the like. Examples of the solvent used in this reaction include inert solvents not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate and the like. Used. This condensation reaction can be carried out by treating at -20 ° C to 100 ° C for 30 minutes to 48 hours.
This reaction can also be achieved by using sulfuric acid as a catalyst using an alcohol solvent such as methanol or ethanol.
Furthermore, this reaction can also be achieved by reacting a corresponding acyl halide such as carboxylic acid chloride with methanol, ethanol or the like.

(Third process)
This step is a step for producing the compound (e) by substituting the compound (d) for the chloro atom of the compound (c) (R ¹ and R ⁶ are the same as above). This step is carried out in the presence or absence of an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, DBU or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate, N, N- Performed by treatment at -20 to 50 ° C. for 30 minutes to 48 hours in a solvent such as dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, pyridine, quinoline, dichloromethane can do.

(Fourth process)
This step is a step for producing a compound (g) by substituting the compound (f) for the chloro atom of the compound (e) (R ¹ and R ⁶ are the same as above).
This step can be performed according to the third step.

(Fifth process)
This step is a step of producing compound (h) by hydrolyzing the ester group of compound (g) (R ¹ and R ⁶ are the same as described above).

  This step is performed in the presence of a base in a solvent that does not affect the reaction according to a conventional method.

  Examples of the base include alkali metal salts such as potassium hydroxide and sodium hydroxide.

  Examples of the solvent that does not affect the reaction include tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, water, and the like.

  The reaction temperature is usually about 0 to about 150 ° C.

The reaction time is usually about 0.5 to about 48 hours.
(Method B)

(First step)
In this step, compound (a) (R ¹ is the same. Above) by introducing a hydroxy group in compound (b) (R ¹ is the same. To above) is a step for preparing a.
This step can be carried out according to the first method A.

(Second step)
This step is a step for producing the compound (i) by substituting the compound (f) for the chloro atom of the compound (b) (R ¹ is the same as above).
This step can be performed in accordance with the third step of Method A.

(Third process)
This step is a step of producing compound (h) by substituting the chloro atom of compound (i) (R ¹ is the same as above) with compound (d).
This step can be performed in accordance with the third step of Method A.

(Method C)

(First step)
This step is a step for producing a compound (b-1) by introducing a hydroxycarbonyl group into the compound (a-1).
This step can be carried out according to the first method A.

(Second step)
This step is a step of producing compound (c-1) (R ⁶ represents an alkyl group or an aryl group) from compound (b-1) by an esterification reaction.
This step can be performed according to the second method A.

(Third process)
This step is a step for producing a compound (j) by substituting the compound (f) for the chloro atom of the compound (c-1) (R ⁶ is the same as above).
This step can be performed in accordance with the third step of Method A.

(Fourth process)
This step is a step for producing the compound (k) by oxidizing the methylthio group of the compound (j) (R ⁶ is the same as described above).
This step is performed in the presence of various oxidizing agents in a solvent that does not affect the reaction.

  Examples of the oxidizing agent used in this step include organic oxides such as m-chloroperbenzoic acid, peracetic acid and magnesium monoperphthalate, and inorganic peroxides such as hydrogen peroxide and potassium permanganate. It is done. This reaction is carried out at about −20 to about 80 ° C., preferably about 0 to about 30 ° C., for 0.5 to 72 hours using 2 to 10 equivalents, preferably 2 to 3 equivalents, of the oxidizing agent. It can be implemented by processing.

  Examples of the solvent used in this reaction include dichloromethane, toluene, ethyl acetate, dimethoxyethane, ethyl ether, dioxane, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like.

(Fifth process)
This step is a step of producing compound (n) by reacting compound (k) (R ⁶ is the same as above) and compound (m).

  In this reaction, 1 to 20 equivalents of compound (m) is used with respect to compound (k) in the presence or absence of a base at about −50 to about 100 ° C., preferably about −20 to about 30 ° C. For 0.5 to 24 hours. When a base is used, suitable bases include, for example, organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, N, N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate, Examples thereof include inorganic bases such as calcium carbonate, cesium carbonate, and tripotassium phosphate. When a solvent is used, an inert solvent not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, xylene, toluene, ethanol or water is used. It is done.

(Sixth process)
This step is a step for producing the compound (g-1) by substituting the compound (d) for the chloro atom of the compound (n) (R ⁶ is the same as above).
This step can be performed in accordance with the third step of Method A.

(Seventh step)
This step is a step of producing compound (h-1) by hydrolyzing the ester group of compound (g-1) (R ⁶ is the same as described above).
This step can be performed according to the fifth method A.

  The compound (1) of the present invention can be isolated and purified by ordinary separation means (for example, extraction, recrystallization, distillation, chromatography, etc.). Moreover, when the obtained compound forms a salt, various salts can be produced by a usual method or a method equivalent thereto (for example, neutralization).

  The compound (1) of the present invention or a salt thereof alone or mixed with an appropriate pharmacologically acceptable excipient or diluent, such as tablets, capsules, granules, powders or syrups It can be administered as a pharmaceutical composition orally or parenterally as a preparation such as an injection or suppository.

  These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

  The excipient may be an organic excipient or an inorganic excipient. The organic economy is, for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α starch, dextrin; cellulose derivatives such as crystalline cellulose; Dextran; or pullulan and the like. Inorganic excipients include, for example, light inorganic silicic acid, synthetic aluminum silicate, calcium silicate, magnesium silicate derivatives such as magnesium aluminate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; Alternatively, it may be a sulfate such as calcium sulfate.

  Lubricants include, for example, stearic acid, calcium stearate, metal stearate such as magnesium stearate; talc; colloidal silica; waxes such as bee gum; adipic acid; sulfate such as sodium sulfate; glycol; It can be an acid; sodium benzoate; DL-leucine; fatty acid sodium; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid and silicic acid hydrate; or the starch derivative.

  The binder can be, for example, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the excipients described above.

  Disintegrants are, for example, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; or chemically modified such as carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone. Starches and celluloses.

  Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenethyl alcohol; benzalkonium chloride; cresols such as phenol and cresol; thimerosal; Can be dehydroacetic acid; or sorbic acid.

  The flavoring agent can be, for example, commonly used sweeteners, acidulants, and fragrances.

  The dose varies depending on the type of the compound (1) or salt thereof, the route of administration, the age of the patient, symptoms, etc., but for example, 0.001 as the compound (1) or salt thereof for mammals including humans. ~ 500 mg / kg / day. Administration is, for example, once a day or divided into several times.

Examples Hereinafter, the present invention will be described in more detail based on test examples, examples and reference examples. Moreover, since the novel compound is contained also in the raw material compound used for manufacture of this invention compound (1), the manufacture example of a raw material compound is demonstrated as a reference example. The compounds of the present invention are not limited to the compounds described in the following examples, and may be changed without departing from the scope of the present invention.

<Reference Example 1>

To a solution of methyl 4-anilino-6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 153; 100 mg, 0.323 mmol) in tetrahydrofuran (0.5 mL) was added triethylamine (0.05 mL, 0 .359 mmol) and phenylmethanethiol (45.0 mg, 0.362 mmol) were added with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4-anilino-6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxyl. Methyl acid was obtained (35.6 mg, 28%).
MS (FAB ⁺ ) m / z: 398 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 20 N 3 O 2 S 2 Calculated: 398.0997
Actual value: 398.1002.

<Reference Example 2>

To a solution of methyl 4- (benzylamino) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 152; 100 mg, 0.309 mmol) in N, N-dimethylformamide (1 mL) was added carbonic acid. Potassium (85.5 mg, 0.619 mmol) and phenylmethanethiol (42.5 mg, 0.342 mmol) were added with ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4- (benzylamino) -6- (benzylthio) -2- (methylthio) pyrimidine- Methyl 5-carboxylate was obtained (126 mg, 99%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Actual value: 412.1112.

<Reference Example 3>

In the same manner as in Reference Example 1, methyl 4-chloro-2- (methylthio) -6- (phenethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 154; 57.4 mg, 0.170 mmol) and phenylmethane Thiol (23.2 mg, 0.187 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6- (phenethylamino) -pyrimidine-5-carboxylate (38.7 mg, 53%) .
MS (FAB ⁺ ) m / z: 426 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 2 S 2 Calculated: 426.1310
Actual value: 426.1327.

<Reference Example 4>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 102 mg, 0.299 mmol) and 2-chlorobenzylamine (44.2 mg, 0.314 mmol) gave methyl 4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (93.9 mg, 70%).
MS (FAB ⁺ ) m / z: 446 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 ClN 3 O 2 S 2 Calculated: 446.0764
Actual value: 446.0758.

<Reference Example 5>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 102 mg, 0.299 mmol) and 3-chlorobenzylamine (44.2 mg, 0.314 mmol) gave methyl 4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (113 mg, 85% ).
MS (FAB ⁺ ) m / z: 446 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 ClN 3 O 2 S 2 Calculated: 446.0764
Actual value: 446.0741.

<Reference Example 6>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 3.00 g, 8.80 mmol) and 4-chloro Benzylamine (1.50 g, 10.6 mmol) gave methyl 4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (3. 59 g, 91%).
MS (FAB ⁺ ) m / z: 446 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 ClN 3 O 2 S 2 Calculated: 446.0764
Actual value: 446.0741.

<Reference Example 7>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 96.5 mg, 0.283 mmol) and 2-fluoro Benzylamine (35 μL, 0.306 mmol) gave methyl 4- (benzylthio) -6-[(2-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (66.2 mg, 54%).
MS (EI) m / z: 429 (M ⁺ ).
_{HRMS (EI): C 21 H} 20 FN 3 O 2 S 2 Calculated: 429.0981
Actual value: 429.0992.

<Reference Example 8>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 101 mg, 0.296 mmol) and 3-fluorobenzylamine (35 μL, 0.307 mmol) gave methyl 4- (benzylthio) -6-[(3-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (57.3 mg, 45% ).
MS (FAB ⁺ ) m / z: 430 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₁ FN ₃ O ₂ S ₂ : 430.1059
Actual value: 430.1023.

<Reference Example 9>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 117 mg, 0.343 mmol) and 4-fluorobenzylamine (40 μL, 0.352 mmol) gave methyl 4- (benzylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (109 mg, 74%).
MS (EI) m / z: 429 (M ⁺ ).
_{HRMS (EI): C 21 H} 20 FN 3 O 2 S 2 Calculated: 429.0981
Actual value: 429.1010.

<Reference Example 10>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 200 mg, 0.587 mmol) and 2-methoxybenzylamine (80.2 mg, 0.582 mmol) gave methyl 4- (benzylthio) -6-[(2-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (211 mg, 81% ).
MS (EI) m / z: 441 (M ⁺ ).
_{HRMS (EI): C 22 H} 23 N 3 O 3 S 2 Calculated: 441.1181
Found: 441.1194.

<Reference Example 11>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 202 mg, 0.593 mmol) and 3-methoxybenzylamine (90 μL, 0.703 mmol) gave methyl 4- (benzylthio) -6-[(3-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (235 mg, 90%).
MS (EI) m / z: 441 (M ⁺ ).
_{HRMS (EI): C 22 H} 23 N 3 O 3 S 2 Calculated: 441.1181
Found: 441.1183.

<Reference Example 12>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 205 mg, 0.601 mmol) and 4-methoxybenzylamine (95 μL, 0.724 mmol) gave methyl 4- (benzylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (233 mg, 88%).
MS (EI) m / z: 441 (M ⁺ ).
_{HRMS (EI): C 22 H} 23 N 3 O 3 S 2 Calculated: 441.1181
Found: 441.1197.

<Reference Example 13>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 112 mg, 0.329 mmol) and 2-methylbenzylamine (40 μL, 0.323 mmol) gave methyl 4- (benzylthio) -6-[(2-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (70.1 mg, 50% ).
MS (FAB ⁺ ) m / z: 426 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 2 S 2 Calculated: 426.1310
Found: 426.1313.

<Reference Example 14>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 109 mg, 0.320 mmol) and 3-methylbenzylamine (45 μL, 0.359 mmol) gave methyl 4- (benzylthio) -6-[(3-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (60.0 mg, 44% ).
MS (FAB ⁺ ) m / z: 426 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 2 S 2 Calculated: 426.1310
Actual value: 426.1317.

<Reference Example 15>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 100 mg, 0.293 mmol) and 4-methylbenzylamine (45 μL, 0.353 mmol) gave methyl 4- (benzylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (57.4 mg, 46% ).
MS (EI) m / z: 425 (M ⁺ ).
_{HRMS (EI): C 22 H} 23 N 3 O 2 S 2 Calculated: 425.1232
Found: 425.1261.

<Reference Example 16>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 105 mg, 0.308 mmol) and 2- (trifluoro Methyl) benzylamine (50 μL, 0.356 mmol) gives methyl 4- (benzylthio) -2- (methylthio) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (76.6 mg, 52%).
MS (EI) m / z: 479 (M ⁺ ).
_{HRMS (EI): C 22 H} 20 F 3 N 3 O 2 S 2 Calculated: 479.0949
Actual value: 479.0963.

<Reference Example 17>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 186 mg, 0.546 mmol) and 3- (trifluoro Methyl) benzylamine (90 μL, 0.628 mmol) gives methyl 4- (benzylthio) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (185 mg, 71%).
MS (EI) m / z: 479 (M ⁺ ).
_{HRMS (EI): C 22 H} 20 F 3 N 3 O 2 S 2 Calculated: 479.0949
Actual value: 479.0963.

<Reference Example 18>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 191 mg, 0.560 mmol) and 4- (trifluoro Methyl) benzylamine (95 μL, 0.673 mmol) gives methyl 4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (167 mg, 62%).
MS (EI) m / z: 479 (M ⁺ ).
_{HRMS (EI): C 22 H} 20 F 3 N 3 O 2 S 2 Calculated: 479.0949
Actual value: 479.0973.

<Reference Example 19>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 208 mg, 0.610 mmol) and cyclohexylmethylamine (80 μL) 0.615 mmol) gave methyl 4- (benzylthio) -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (110 mg, 43%).
MS (EI) m / z: 417 (M ⁺ ).
_{HRMS (EI): C 21 H} 27 N 3 O 2 S 2 Calculated: 417.1545
Actual value: 417.1592.

<Reference Example 20>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 100 mg, 0.293 mmol) and 4- (trifluoro Methoxy) benzylamine (45 μL, 0.295 mmol) gives methyl 4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylate (136 mg, 94%).
MS (FAB ⁺ ) m / z: 496 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 21 F 3 N 3 O 3 S 2 Calculated: 496.0976
Actual value: 496.0985.

<Reference Example 21>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 97.4 mg, 0.286 mmol) and 4-phenyl Benzylamine (60.2 mg, 0.329 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylate (105 mg, 75%).
MS (FAB ⁺ ) m / z: 488 (M + H ⁺ ).
_{^{HRMS (FAB +): C 27}} H 26 N 3 O 2 S 2 Calculated: 488.1466
Actual value: 488.1477.

<Reference Example 22>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 97.1 mg, 0.285 mmol) and 4-tert -Butylbenzylamine (60 μL, 0.342 mmol) gave methyl 4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 72.0 mg, 54%).
MS (FAB ⁺ ) m / z: 468 (M + H ⁺ ).
_{^{HRMS (FAB +): C 25}} H 30 N 3 O 2 S 2 Calculated: 468.1779
Actual value: 468.1795.

<Reference Example 23>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 85.3 mg, 0.250 mmol) and 4- ( From dimethylamino) benzylamine (62.0 mg, 0.278 mmol), methyl 4- (benzylthio) -6-[[4- (dimethylamino) benzyl] amino] -2- (methylthio) pyrimidine-5-carboxylate Obtained (94.3 mg, 83%).
MS (FAB ⁺ ) m / z: 455 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 27 N 4 O 2 S 2 Calculated: 455.1575
Actual value: 455.1565.

<Reference Example 24>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 85.3 mg, 0.250 mmol) and 4- ( Aminosulfonyl) benzylamine (61.8 mg, 0.278 mmol) yields methyl 4-[[4- (aminosulfonyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate. Obtained (106 mg, 86%).
MS (FAB ⁺ ) m / z: 491 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₃ N ₄ O ₄ S ₃ : 491.0881
Actual value: 491.0854.

<Reference Example 25>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 85.3 mg, 0.250 mmol) and (2- Pyridyl) methylamine (30.0 mg, 0.277 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylate ( 87.5 mg, 85%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 21 N 4 O 2 S 2 Calculated: 413.1106
Found: 413.1129.

<Reference Example 26>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 102 mg, 0.299 mmol) and (3-pyridyl) Methylamine (34.0 mg, 0.314 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylate (91. 0 mg, 74%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 21 N 4 O 2 S 2 Calculated: 413.1106
Actual value: 413.1149.

<Reference Example 27>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 85.3 mg, 0.250 mmol) and (4- Pyridyl) methylamine (30.0 mg, 0.277 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylate ( 81.3 mg, 79%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 21 N 4 O 2 S 2 Calculated: 413.1106
Actual value: 413.1131.

<Reference Example 28>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 98.2 mg, 0.250 mmol) and 2,4 -Dichlorobenzylamine (31.1 mg, 0.250 mmol) gives methyl 4- (benzylthio) -6-[(2,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (82.7 mg, 69%). MS (FAB ⁺ ) m / z: 480 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 Cl 2 N 3 O 2 S 2 Calculated: 480.0374
Actual value: 480.0405.

<Reference Example 29>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 91.2 mg, 0.268 mmol) and 3,4 -Dichlorobenzylamine (40 μL, 0.300 mmol) gave methyl 4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 85.9 mg, 67%).
MS (FAB ⁺ ) m / z: 480 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 Cl 2 N 3 O 2 S 2 Calculated: 480.0374
Actual value: 480.0360.

<Reference Example 30>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 99.4 mg, 0.292 mmol) and 2,4 -Difluorobenzylamine (40 μL, 0.336 mmol) gave methyl 4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 102 mg, 78%).
MS (FAB ⁺ ) m / z: 448 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 F 2 N 3 O 2 S 2 Calculated: 448.0965
Actual value: 448.0945.

<Reference Example 31>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 93.4 mg, 0.274 mmol) and 3,4 -Difluorobenzylamine (40 μL, 0.338 mmol) gave methyl 4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 75.2 mg, 61%). MS (FAB ⁺ ) m / z: 448 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 F 2 N 3 O 2 S 2 Calculated: 448.0965
Actual value: 448.0978.

<Reference Example 32>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 94.0 mg, 0.276 mmol) and 3,5 From bis (trifluoromethyl) benzylamine (86.7 mg, 0.357 mmol) to 4-[[3,5-bis (trifluoromethyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) Methyl pyrimidine-5-carboxylate was obtained (122 mg, 80%).
MS (FAB ⁺ ) m / z: 548 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 20 F 6 N 3 O 2 S 2 Calculated: 548.0901
Actual value: 548.0883.

<Reference Example 33>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 97.0 mg, 0.285 mmol) and 3-fluoro From 5- (trifluoromethyl) benzylamine (50 μL, 0.341 mmol) to 4- (benzylthio) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] -2- (methylthio) Methyl pyrimidine-5-carboxylate was obtained (76.2 mg, 54%).
MS (FAB ⁺ ) m / z: 498 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 20 F 4 N 3 O 2 S 2 Calculated: 498.0933
Actual value: 498.0932.

<Reference Example 34>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 98.8 mg, 0.290 mmol) and 2,4 -Dimethoxybenzylamine (45 μL, 0.300 mmol) gave methyl 4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 118 mg, 86%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 26 N 3 O 4 S 2 Calculated: 472.1365
Actual value: 472.1349.

<Reference Example 35>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 92.1 mg, 0.270 mmol) and 3,4 -Dimethoxybenzylamine (50 μL, 0.332 mmol) gave methyl 4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 116 mg, 91%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 26 N 3 O 4 S 2 Calculated: 472.1365
Actual value: 472.1349.

<Reference Example 36>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 4-methoxyphenyl) methanethiol (55.5 mg, 0.360 mmol) from methyl 4- (cyclohexylmethylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate Was obtained (109 mg, 81%).
MS (FAB ⁺ ) m / z: 448 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 30 N 3 O 3 S 2 Calculated: 448.1729
Actual value: 448.1689.

<Reference Example 37>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 4-Fluorophenyl) methanethiol (51.2 mg, 0.360 mmol) from methyl 4- (cyclohexylmethylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate Was obtained (130 mg, 99%).
MS (FAB ⁺ ) m / z: 436 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₇ FN ₃ O ₂ S ₂ : 436.1529
Actual value: 436.1552.

<Reference Example 38>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( From 4-chlorophenyl) methanethiol (57.1 mg, 0.360 mmol), methyl 4-[(4-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate was obtained. Obtained (133 mg, 98%).
MS (FAB ⁺ ) m / z: 452 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 27 ClN 3 O 2 S 2 Calculated: 452.1233
Actual value: 452.1209.

<Reference Example 39>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 4-methylphenyl) methanethiol (50.0 mg, 0.362 mmol) from methyl 4- (cyclohexylmethylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate Was obtained (110 mg, 85%).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 30 N 3 O 2 S 2 Calculated: 432.1779
Actual value: 432.1781.

<Reference Example 40>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 3-methylphenyl) methanethiol (50.0 mg, 0.362 mmol) to methyl 4- (cyclohexylmethylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate Was obtained (125 mg, 97%).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 30 N 3 O 2 S 2 Calculated: 432.1779
Actual value: 432.1745.

<Reference Example 41>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 2-methylphenyl) methanethiol (50.0 mg, 0.362 mmol) from methyl 4- (cyclohexylmethylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate Was obtained (125 mg, 97%).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 30 N 3 O 2 S 2 Calculated: 432.1779
Actual value: 432.1798.

<Reference Example 42>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 2-Chlorophenyl) methanethiol (57.1 mg, 0.360 mmol) yields methyl 4-[(2-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate. Obtained (130 mg, 96%).
MS (FAB ⁺ ) m / z: 452 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 27 ClN 3 O 2 S 2 Calculated: 452.1233
Actual value: 452.1216.

<Reference Example 43>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( 2,4-Dichlorophenyl) methanethiol (69.5 mg, 0.360 mmol) from 4- (cyclohexylmethylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5 Methyl carboxylate was obtained (140 mg, 96%).
MS (FAB ⁺ ) m / z: 486 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 26 Cl 2 N 3 O 2 S 2 Calculated: 486.0844
Actual value: 486.0858.

<Reference Example 44>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and ( From 3,4-dichlorophenyl) methanethiol (69.5 mg, 0.360 mmol), 4- (cyclohexylmethylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5 Methyl carboxylate was obtained (138 mg, 95%).
MS (FAB ⁺ ) m / z: 486 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 26 Cl 2 N 3 O 2 S 2 Calculated: 486.0844
Actual value: 486.0847.

<Reference Example 45>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and [ From 3- (trifluoromethyl) phenyl] methanethiol (69.2 mg, 0.360 mmol), 4- (cyclohexylmethylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] thio Methyl pyrimidine-5-carboxylate was obtained (140 mg, 96%).
MS (FAB ⁺ ) m / z: 486 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 27 F 3 N 3 O 2 S 2 Calculated: 486.1497
Found: 486.1501.

<Reference Example 46>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and cyclohexyl Mercaptan (41.9 mg, 0.360 mmol) gave methyl 4- (cyclohexylmethylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (110 mg, 90%).
MS (FAB ⁺ ) m / z: 410 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 32 N 3 O 2 S 2 Calculated: 410.1936
Found: 410.1981.

<Reference Example 47>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 163; 99.0 mg, 0.300 mmol) and cyclopentyl Mercaptan (36.8 mg, 0.360 mmol) gave methyl 4- (cyclohexylmethylamino) -6- (cyclopentylthio) -2- (methylthio) pyrimidine-5-carboxylate (115 mg, 97%).
MS (FAB ⁺ ) m / z: 396 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 30 N 3 O 2 S 2 Calculated: 396.1779
Actual value: 396.1791.

<Reference Example 48>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (4 -Methoxyphenyl) methanethiol (55.5 mg, 0.360 mmol) gives methyl 4- (cyclohexylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (108 mg, 83%).
MS (FAB ⁺ ) m / z: 434 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 3 S 2 Calculated: 434.1572
Found: 434.1586.

<Reference Example 49>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (4 -Fluorophenyl) methanethiol (51.2 mg, 0.360 mmol) gives methyl 4- (cyclohexylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (122 mg, 96%).
MS (FAB ⁺ ) m / z: 422 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₂₅ FN ₃ O ₂ S ₂ : 422.1372
Actual value: 422.1420.

<Reference Example 50>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (4 -Chlorophenyl) methanethiol (57.1 mg, 0.360 mmol) gives methyl 4-[(4-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (131 mg, 99%).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 25 ClN 3 O 2 S 2 Calculated: 438.1077
Actual value: 438.1069.

<Reference Example 51>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (4 -Methylphenyl) methanethiol (50.0 mg, 0.362 mmol) gives methyl 4- (cyclohexylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (113 mg, 90%).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Found: 418.1661.

<Reference Example 52>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (3 -Methylphenyl) methanethiol (50.0 mg, 0.362 mmol) gives methyl 4- (cyclohexylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (119 mg, 95%).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Found: 418.1607.

<Reference Example 53>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (2 -Methylphenyl) methanethiol (50.0 mg, 0.362 mmol) gives methyl 4- (cyclohexylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (125 mg, 99%).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Found: 418.1667.

<Reference Example 54>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 162; 94.8 mg, 0.300 mmol) and [3 From-(trifluoromethyl) phenyl] methanethiol (69.2 mg, 0.360 mmol) to 4- (cyclohexylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] thio] pyrimidine Methyl -5-carboxylate was obtained (131 mg, 93%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 25 F 3 N 3 O 2 S 2 Calculated: 472.1340
Actual value: 472.1378.

<Reference Example 55>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (2 -Chlorophenyl) methanethiol (57.1 mg, 0.360 mmol) gives methyl 4-[(2-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (130 mg, 99%).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 25 ClN 3 O 2 S 2 Calculated: 438.1077
Actual value: 438.1031.

<Reference Example 56>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (2 , 4-Dichlorophenyl) methanethiol (69.5 mg, 0.360 mmol) from 4- (cyclohexylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid Methyl was obtained (141 mg, 99%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 Cl 2 N 3 O 2 S 2 Calculated: 472.0687
Found: 472.0707.

<Reference Example 57>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 162; 94.8 mg, 0.300 mmol) and (3 , 4-Dichlorophenyl) methanethiol (69.5 mg, 0.360 mmol) from 4- (cyclohexylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid Methyl was obtained (140 mg, 99%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 Cl 2 N 3 O 2 S 2 Calculated: 472.0687
Actual value: 472.0690.

<Reference Example 58>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 99.9 mg, 0.300 mmol) and (4 -Fluorophenyl) methanethiol (51.2 mg, 0.360 mmol) gives methyl 4- (cyclohexylthio) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (81.5 mg, 62%).
MS (FAB ⁺ ) m / z: 439 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₂₄ FN ₂ O ₂ S ₃ : 439.0984
Actual value: 439.0937.

<Reference Example 59>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 99.9 mg, 0.300 mmol) and (4 -Chlorophenyl) methanethiol (51.7 mg, 0.360 mmol) gives methyl 4-[(4-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (120 mg, 88%).
MS (FAB ⁺ ) m / z: 455 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 ClN 2 O 2 S 3 Calculated: 455.0688
Actual value: 455.0660.

<Reference Example 60>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 99.9 mg, 0.300 mmol) and (4 -Methylphenyl) methanethiol (50.0 mg, 0.362 mmol) gives methyl 4- (cyclohexylthio) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (90.0 mg, 69%).
MS (FAB ⁺ ) m / z: 435 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 27 N 2 O 2 S 3 Calculated: 435.1235
Actual value: 435.1241.

<Reference Example 61>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 99.9 mg, 0.300 mmol) and (2 -Methylphenyl) methanethiol (50.0 mg, 0.362 mmol) gives methyl 4- (cyclohexylthio) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (89.5 mg, 69%).
MS (FAB ⁺ ) m / z: 435 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 27 N 2 O 2 S 3 Calculated: 435.1235
Actual value: 435.1263.

<Reference Example 62>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 99.9 mg, 0.300 mmol) and (2 -Chlorophenyl) methanethiol (57.1 mg, 0.360 mmol) gives methyl 4-[(2-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (84.0 mg, 62%).
MS (FAB ⁺ ) m / z: 455 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 ClN 2 O 2 S 3 Calculated: 455.0688
Actual value: 455.0711.

<Reference Example 63>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 99.9 mg, 0.300 mmol) and (4 -Methoxyphenyl) methanethiol (55.5 mg, 0.360 mmol) gives methyl 4- (cyclohexylthio) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (87.7 mg, 65%).
MS (FAB ⁺ ) m / z: 451 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 27 N 2 O 3 S 3 Calculated: 451.1184
Actual value: 451.1230.

<Reference Example 64>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 85.3 mg, 0.250 mmol) and α-methyl Benzylamine (36.4 mg, 0.300 mmol) gave methyl 4- (benzylthio) -6-[(α-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (101 mg, 95%).
MS (FAB ⁺ ) m / z: 426 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 2 S 2 Calculated: 426.1310
Actual value: 426.1341.

<Reference Example 65>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And benzylamine (38.2 mg, 0.360 mmol) gave methyl 4- (benzylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate ( 122 mg, 92%).
MS (FAB ⁺ ) m / z: 442 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 3 S 2 Calculated: 442.1259
Found: 442.1248.

<Reference Example 66>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And 4-chlorobenzylamine (50.6 mg, 0.360 mmol) from 4-[(4-chlorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5 Methyl carboxylate was obtained (131 mg, 92%).
MS (FAB ⁺ ) m / z: 476 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 ClN 3 O 3 S 2 Calculated: 476.0869
Actual value: 476.0893.

<Reference Example 67>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And 4-methylbenzylamine (49.4 mg, 0.360 mmol) from 4-[(4-methoxybenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5 Methyl carboxylate was obtained (127 mg, 90%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 26 N 3 O 4 S 2 Calculated: 472.1365
Actual value: 472.1347.

<Reference Example 68>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And 4-fluorobenzylamine (45.1 mg, 0.360 mmol) from 4-[(4-fluorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5 Methyl carboxylate was obtained (114 mg, 83%).
MS (FAB ⁺ ) m / z: 460 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₃ FlN ₃ O ₃ S ₂ : 460.1165
Actual value: 460.1183.

<Reference Example 69>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And aniline (33.6 mg, 0.361 mmol) gave methyl 4-anilino-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (73.8 mg, 58%).
MS (FAB ⁺ ) m / z: 428 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 3 S 2 Calculated: 428.1103
Actual value: 428.1122.

<Reference Example 70>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And 4-chloroaniline (40.9 mg, 0.360 mmol) gave methyl 4- (4-chloroanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate. (43.6 mg, 32%).
MS (FAB ⁺ ) m / z: 462 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 ClN 3 O 3 S 2 Calculated: 462.0713
Actual value: 462.0745.

<Reference Example 71>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And 4-methoxyaniline (44.4 mg, 0.361 mmol) from methyl 4- (4-methoxyanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate Was obtained (34.0 mg, 25%).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 4 S 2 Calculated: 458.1208
Actual value: 458.1236.

<Reference Example 72>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 111 mg, 0.299 mmol) And 4-fluoroaniline (40.0 mg, 0.360 mmol) gave methyl 4- (4-fluoroanilino) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate. (68.0 mg, 51%).
MS (FAB ⁺ ) m / z: 446 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 FN 3 O 3 S 2 Calculated: 446.1008
Actual value: 446.1019.

<Reference Example 73>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and aniline ( 28.0 mg, 0.301 mmol) gave methyl 4-anilino-6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylate (70.0 mg, 71%).
MS (FAB ⁺ ) m / z: 395 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₃ N ₄ O ₂ S: 395.1542
Actual value: 395.1533.

<Reference Example 74>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and benzylamine (33.0 mg, 0.308 mmol) gave methyl 4- (benzylamino) -6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylate (80.0 mg, 78%).
MS (FAB ⁺ ) m / z: 409 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S Calculated: 409.1698
Actual value: 409.1651.

<Reference Example 75>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and phenethylamine ( 33.0 mg, 0.272 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6- (phenethylamino) pyrimidine-5-carboxylate (83.0 mg, 79%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₂ S: 423.1855
Actual value: 423.1834.

<Reference Example 76>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2- Chlorobenzylamine (39.0 mg, 0.275 mmol) gave methyl 4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate ( 85.0 mg, 77%).
MS (FAB ⁺ ) m / z: 443 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 ClN 4 O 2 S Calculated: 443.1309
Found: 443.1307.

<Reference Example 77>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3- Chlorobenzylamine (39.0 mg, 0.275 mmol) gave methyl 4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate ( 84.5 mg, 76%).
MS (FAB ⁺ ) m / z: 443 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 ClN 4 O 2 S Calculated: 443.1309
Found: 443.1307.

<Reference Example 78>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- Chlorobenzylamine (39.0 mg, 0.275 mmol) gave methyl 4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate ( 83.5 mg, 75%).
MS (FAB ⁺ ) m / z: 443 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 ClN 4 O 2 S Calculated: 443.1309
Found: 443.1293.

<Reference Example 79>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2- Fluorobenzylamine (34.7 mg, 0.277 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-fluorobenzyl) amino] pyrimidine-5-carboxylate ( 62.2 mg, 58%). MS (FAB ⁺ ) m / z: 427 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₄ FN ₄ O ₂ S: 427.1604
Found: 427.1605.

<Reference Example 80>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3- Fluorobenzylamine (34.7 mg, 0.277 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-fluorobenzyl) amino] pyrimidine-5-carboxylate ( 48.5 mg, 45%). MS (FAB ⁺ ) m / z: 427 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₄ FN ₄ O ₂ S: 427.1604
Found: 427.1600.

<Reference Example 81>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- Fluorobenzylamine (34.7 mg, 0.277 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-fluorobenzyl) amino] pyrimidine-5-carboxylate ( 97.0 mg, 91%). MS (FAB ⁺ ) m / z: 427 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₄ FN ₄ O ₂ S: 427.1604
Found: 427.1605.

<Reference Example 82>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2- Methoxybenzylamine (37.8 mg, 0.276 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-methoxybenzyl) amino] pyrimidine-5-carboxylate ( 79.9 mg, 73%). MS (FAB ⁺ ) m / z: 439 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₃ S: 439.1804
Actual value: 439.1764.

<Reference Example 83>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3- Methoxybenzylamine (37.8 mg, 0.276 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-methoxybenzyl) amino] pyrimidine-5-carboxylate ( 70.8 mg, 65%). MS (FAB ⁺ ) m / z: 439 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₃ S: 439.1804
Actual value: 439.1764.

<Reference Example 84>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- Methoxybenzylamine (37.8 mg, 0.276 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-methoxybenzyl) amino] pyrimidine-5-carboxylate ( 96.8 mg, 88%). MS (FAB ⁺ ) m / z: 439 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₃ S: 439.1804
Found: 439.1786.

<Reference Example 85>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2- Methylbenzylamine (33.6 mg, 0.277 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-methylbenzyl) amino] pyrimidine-5-carboxylate ( 69.8 mg, 66%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₂ S: 423.1855
Actual value: 423.1885.

<Reference Example 86>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3- Methylbenzylamine (33.6 mg, 0.278 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-methylbenzyl) amino] pyrimidine-5-carboxylate ( 102 mg, 97%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₂ S: 423.1855
Found: 423.1823.

<Reference Example 87>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- Methylbenzylamine (33.5 mg, 0.276 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-methylbenzyl) amino] pyrimidine-5-carboxylate ( 82.2 mg, 95%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₂ S: 423.1855
Found: 423.1886.

<Reference Example 88>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2- From (trifluoro) methylbenzylamine (48.5 mg, 0.277 mmol), 4- (benzylthio) -2- (dimethylamino) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5 Methyl carboxylate was obtained (59.5 mg, 50%).
MS (FAB ⁺ ) m / z: 477 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₄ F ₃ N ₄ O ₂ S: 477.1572
Actual value: 477.1585.

<Reference Example 89>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3- From (trifluoro) methylbenzylamine (48.5 mg, 0.277 mmol), 4- (benzylthio) -2- (dimethylamino) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5 Methyl carboxylate was obtained (77.4 mg, 65%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₄ F ₃ N ₄ O ₂ S: 477.1572
Found: 477.1524.

<Reference Example 90>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- From (trifluoro) methylbenzylamine (48.5 mg, 0.277 mmol), 4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5 Methyl carboxylate was obtained (105 mg, 88%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₄ F ₃ N ₄ O ₂ S: 477.1572
Found: 477.1616.

<Reference Example 91>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (Compound of Reference Example 158; 84.5 mg, 0.250 mmol) and cyclohexylmethyl Amine (31.2 mg, 0.276 mmol) gave methyl 4- (benzylthio) -6- (cyclohexylmethylamino) -2- (dimethylamino) pyrimidine-5-carboxylate (83.5 mg, 81% ).
MS (FAB ⁺ ) m / z: 415 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₃₁ N ₄ O ₂ S: 415.2168
Actual value: 415.2177.

<Reference Example 92>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- From (trifluoromethoxy) benzylamine (53.0 mg, 0.277 mmol), 4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5 Methyl carboxylate was obtained (69.4 mg, 56%).
MS (FAB ⁺ ) m / z: 493 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₄ F ₃ N ₄ O ₃ S: 493.1521
Actual value: 493.1514.

<Reference Example 93>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- Phenylbenzylamine (50.9 mg, 0.278 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylate ( 92.0 mg, 76%).
MS (FAB ⁺ ) m / z: 485 (M + H ⁺ ).
_{^{HRMS (FAB +): C 28}} H 29 N 4 O 2 S Calculated: 485.2011
Actual value: 485.2021.

<Reference Example 94>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- From tert-butylbenzylamine (45.0 mg, 0.276 mmol), methyl 4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate was obtained. Obtained (95.7 mg, 82%).
MS (FAB ⁺ ) m / z: 465 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₆ H ₃₃ N ₄ O ₂ S: 465.2324
Actual value: 465.2325.

<Reference Example 95>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 4- From (dimethylamino) benzylamine dihydrochloride (62.0 mg, 0.278 mmol) to 4- (benzylthio) -2- (dimethylamino) -6-[[4- (dimethylamino) benzyl] amino] pyrimidine-5 -Methyl carboxylate was obtained (73.1 mg, 65%).
MS (FAB ⁺ ) m / z: 451 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₉ N ₅ O ₂ S: 451.22042
Actual value: 451.20603.

<Reference Example 96>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and (2 -Pyridyl) methylamine (30.0 mg, 0.277 mmol) gives methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylate (77.5 mg, 76%). MS (FAB ⁺ ) m / z: 410 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1651
Actual value: 510.1643.

<Reference Example 97>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and (3 -Pyridyl) methylamine (30.0 mg, 0.277 mmol) gives methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylate (79.9 mg, 78%).
MS (FAB ⁺ ) m / z: 410 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1651
Actual value: 510.1636.

<Reference Example 98>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and (4 -Pyridyl) methylamine (30.0 mg, 0.277 mmol) gives methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylate (66.0 mg, 64%).
MS (FAB ⁺ ) m / z: 410 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₄ N ₅ O ₂ S: 410.1651
Actual value: 510.1627.

<Reference Example 99>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (Compound of Reference Example 158; 84.5 mg, 0.250 mmol) and furfuryl Methylamine (27.0 mg, 0.278 mmol) gave methyl 4- (benzylthio) -2- (dimethylamino) -6- (furfurylamino) pyrimidine-5-carboxylate (70.0 mg, 70 %).
MS (FAB ⁺ ) m / z: 399 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₂₃ N ₄ O ₃ S: 399.1491
Actual value: 399.1519.

<Reference Example 100>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3, From 4-dichlorobenzylamine (48.5 mg, 0.275 mmol), methyl 4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate Obtained (63.7 mg, 53%).
MS (FAB ⁺ ) m / z: 477 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 Cl 2 N 4 O 2 S Calculated: 477.0919
Actual value: 477.0930.

<Reference Example 101>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2, From 4-difluorobenzylamine (39.7 mg, 0.277 mmol), methyl 4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate Obtained (68.5 mg, 62%).
MS (FAB ⁺ ) m / z: 445 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₃ F ₂ N ₄ O ₂ S: 445.1510
Found: 445.1487.

<Reference Example 102>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3, From 4-difluorobenzylamine (39.7 mg, 0.277 mmol), methyl 4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate Obtained (98.4 mg, 89%).
MS (FAB ⁺ ) m / z: 445 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₃ F ₂ N ₄ O ₂ S: 445.1510
Found: 445.1472.

<Reference Example 103>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3, From 5-bis (trifluoromethyl) benzylamine (66.9 mg, 0.275 mmol), 4- (benzylthio) -6-[[3,5-bis (trifluoromethyl) benzyl] amino] -2- (dimethyl). Amino) methyl methyl pyrimidine-5-carboxylate was obtained (99.6 mg, 73%).
MS (FAB ⁺ ) m / z: 545 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₃ F ₆ N ₄ O ₂ S: 545.1446
Found: 545.1446.

<Reference Example 104>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3- From fluoro-5- (trifluoromethyl) benzylamine (53.2 mg, 0.275 mmol), 4- (benzylthio) -2- (dimethylamino) -6-[[3-fluoro-5- (trifluoromethyl) Methyl [benzyl] amino] pyrimidine-5-carboxylate was obtained (77.3 mg, 63%).
MS (FAB ⁺ ) m / z: 495 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₃ F ₄ N ₄ O ₂ S: 495.1478
Actual value: 495.1465.

<Reference Example 105>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 2, From 4-dimethoxybenzylamine (46.0 mg, 0.275 mmol), methyl 4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate was obtained. Obtained (74.5 mg, 64%).
MS (FAB ⁺ ) m / z: 469 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₉ N ₄ O ₄ S: 469.1910
Found: 469.1865.

<Reference Example 106>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 158; 84.5 mg, 0.250 mmol) and 3, 4-Dimethoxybenzylamine (46.0 mg, 0.275 mmol) yields methyl 4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate. Obtained (66.8 mg, 57%).
MS (FAB ⁺ ) m / z: 469 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₉ N ₄ O ₄ S: 469.1910
Actual value: 469.1941.

<Reference Example 107>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (the compound of Reference Example 159; 89.0 mg, 0.245 mmol) and benzyl Amine (27.5 mg, 0.257 mmol) gave methyl 4- (benzylamino) -6- (benzylthio) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (80.8 mg, 76% ).
MS (FAB ⁺ ) m / z: 435 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₇ N ₄ O ₂ S: 435.1855
Actual value: 435.1881.

<Reference Example 108>

In the same manner as in Reference Example 1, methyl 4- (benzylamino) -6-chloro-2-piperidinopyrimidine-5-carboxylate (Compound of Reference Example 142; 69.0 mg, 0.191 mmol) and phenylmethane The methyl 4- (benzylamino) -6- (benzylthio) -2-piperidinopyrimidine-5-carboxylate was obtained from thiol (28.5 mg, 0.229 mmol) (71.5 mg, 83%).
¹ H-NMR (400 Mz, CDCl ₃ ) ppm: 1.46-1.54 (4H, m), 1.59-1.67 (2H,
m), 3.70-3.84 (4H, m), 3.80 (3H, s), 4.31 (2H, s), 4.66 (2H, d, J = 5.5Hz),
7.20-7.41 (10H, m), 8.78-8.85 (1H, br).

<Reference Example 109>

In the same manner as in Reference Example 1, methyl 4- (benzylamino) -6-chloro-2-morpholinopyrimidine-5-carboxylate (compound of Reference Example 143; 41.5 mg, 0.114 mmol) and phenylmethanethiol ( 17.0 mg, 0.137 mmol) gave methyl 4- (benzylamino) -6- (benzylthio) -2-morpholinopyrimidine-5-carboxylate (34.6 mg, 67%).
¹ H-NMR (400 Mz, CDCl ₃ ) ppm: 3.60-3.68 (4H, m), 3.73-3.84 (4H,
m), 3.81 (3H, s), 4.30 (2H, s), 4.66 (2H, d, J = 5.5Hz), 7.20-7.40 (10H, m), 8.84-8.90 (1H,
br).

<Reference Example 110>

In the same manner as in Reference Example 1, methyl 4- (benzylamino) -6-chloro-2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylate (the compound of Reference Example 144; 60.0 mg, 0.160 mmol) and phenylmethanethiol (30.0 mg, 0.242 mmol) from 4- (benzylamino) -6- (benzylthio) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid Methyl was obtained (34.4 mg, 46%).
MS (FAB ⁺ ) m / z: 464 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₅ H ₃₀ N ₅ O ₂ S: 464.2120
Actual value: 464.22093.

<Reference Example 111>

In the same manner as in Reference Example 1, methyl 4- (benzylamino) -6-chloro-2- (butylamino) pyrimidine-5-carboxylate (the compound of Reference Example 145; 50.0 mg, 0.143 mmol) and phenyl Methanethiol (21.5 mg, 0.173 mmol) gave methyl 4- (benzylamino) -6- (benzylthio) -2- (n-butylamino) pyrimidine-5-carboxylate (58.6 mg, 94%).
¹ H-NMR (400Mz, CDCl ₃ ) ppm: 0.90 (3H, t, J = 7.3Hz),
1.28-1.40 (2H, m), 1.46-1.58 (2H, m), 3.31-3.47 (2H, m), 3.80 (3H, s),
4.24-4.42 (2H, br), 4.61-4.75 (2H, br), 5.02-5.13 (1H, br), 7.20-7.42 (10H, m),
8.73-8.98 (1H, br).

<Reference Example 112>

In the same manner as in Reference Example 1, methyl 4-chloro-2,6-bis (benzylamino) pyrimidine-5-carboxylate (compound of Reference Example 150; 90.0 mg, 0.235 mmol) and phenylmethanethiol (43 .8 mg, 0.353 mmol) gave methyl 4- (benzylthio) -2,6-bis (benzylamino) pyrimidine-5-carboxylate (64.8 mg, 59%).
MS (FAB ⁺ ) m / z: 471 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₇ H ₂₇ N ₄ O ₂ S: 471.1855
Actual value: 471.1896.

<Reference Example 113>

In the same manner as in Reference Example 2, methyl 4-chloro-6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 155; 100 mg, 0.279 mmol) And benzyl alcohol (60.5 mg, 0.559 mmol) gave benzyl 4- (benzyloxy) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate ( 124 mg, 88%).
MS (FAB ⁺ ) m / z: 506 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₇ H ₂₅ ClN ₃ O ₃ S: 506.1305
Actual value: 506.1294.

<Reference Example 114>

In the same manner as in Reference Example 1, methyl 6- (benzylamino) -4-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 152; 150 mg, 0.463 mmol) and benzyl alcohol (100 mg) 0.925 mmol) gave methyl 4- (benzylamino) -6- (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylate (165 mg, 90%).
MS (EI) m / z: 395 (M ⁺ ).
HRMS (EI): Calculated as C ₂₁ H ₂₁ N ₃ O ₃ S: 395.1304
Actual value: 395.1306.

<Reference Example 115>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 102 mg, 0.299 mmol) and cyclopropylamine (19 0.0 mg, 0.333 mmol) gave methyl 4- (benzylthio) -6- (cyclopropylamino) -2- (methylthio) pyrimidine-5-carboxylate (64.8 mg, 60%).
MS (EI) m / z: 361 (M ⁺ ).
_{HRMS (EI): C 17 H} 19 N 3 O 2 S 2 Calculated: 361.0919
Actual value: 361.0879.

<Reference Example 116>

In the same manner as in Reference Example 1, methyl 4-chloro-6- (4-chloroanilino) -2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 156; 86.1 mg, 0.250 mmol) and phenyl Methanethiol (34.5 mg, 0.278 mmol) gave methyl 6- (4-chloroanilino) -4- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (36.5 mg, 34% ).
MS (EI) m / z: 431 (M ^<+> ).
_{HRMS (EI): C 20 H} 18 ClN 3 O 2 S 2 Calculated: 431.0529
Actual value: 431.0530.

<Reference Example 117>

In the same manner as in Reference Example 2, methyl 4- (benzylamino) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 152; 97.2 mg, 0.300 mmol) and furfuryl Methyl mercaptan (34.5 mg, 0.302 mmol) gave methyl 4- (benzylamino) -6- (furfurylthio) -2- (methylthio) pyrimidine-5-carboxylate (65.0 mg, 54%) .
MS (FAB ⁺ ) m / z: 402 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 20 N 3 O 3 S 2 Calculated: 402.0946
Actual value: 402.0989.

<Reference Example 118>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 2- (2- From aminoethyl) -1-methylpyrrolidine (113 mg, 0.881 mmol) to 4- (benzylthio) -6-[[2- (1-methylpyrrolidin-2-yl) ethyl] amino] -2- (methylthio) pyrimidine Methyl-5-carboxylate was obtained (139 mg, 55%).
MS (FAB ⁺ ) m / z: 433 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 29 N 4 O 2 S 2 Calculated: 433.1732
Actual value: 433.1742.

<Reference Example 119>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 1- (3- Aminopropyl) -2-pyrrolidinone (125 mg, 0.879 mmol) to 4- (benzylthio) -2- (methylthio) -6-[[3- (2-oxopyrrolidin-1-yl) propyl] amino] pyrimidine- Methyl 5-carboxylate was obtained (184 mg, 50%).
MS (EI) m / z: 446 (M ⁺ ).
_{HRMS (EI): C 21 H} 26 N 4 O 3 S 2 Calculated: 446.1446
Actual value: 446.1459.

<Reference Example 120>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and tetrahydrofurfurylamine (89 0.0 mg, 0.880 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[[(tetrahydrofuran-2-yl) methyl] amino] pyrimidine-5-carboxylate (195 mg, 82%).
MS (FAB ⁺ ) m / z: 406 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 24 N 3 O 3 S 2 Calculated: 406.1259
Actual value: 406.1276.

<Reference Example 121>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 4- (2- Aminoethyl) morpholine (115 mg, 0.883 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(2-morpholinoethyl) amino] pyrimidine-5-carboxylate (130 mg, 51%).
MS (FAB ⁺ ) m / z: 435 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 27 N 4 O 3 S 2 Calculated: 435.1525
Actual value: 435.1529.

<Reference Example 122>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 1- (2- Aminoethyl) piperidine (113 mg, 0.881 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(2-piperidinoethyl) amino] pyrimidine-5-carboxylate (175 mg, 69 %).
MS (FAB ⁺ ) m / z: 433 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 29 N 4 O 2 S 2 Calculated: 433.1732
Actual value: 433.1759.

<Reference Example 123>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 1- (2- Aminoethyl) pyrrolidine (100 mg, 0.876 mmol) gives methyl 4- (benzylthio) -2- (methylthio) -6-[[2- (1-pyrrolidinyl) ethyl] amino] pyrimidine-5-carboxylate (132 mg, 54%).
MS (FAB ⁺ ) m / z: 419 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 27 N 4 O 2 S 2 Calculated: 419.1575
Found: 419.1596.

<Reference Example 124>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 2- (2- From aminoethyl) -1,3-dioxolane (103 mg, 0.879 mmol) to 4- (benzylthio) -6-[[2- (1,3-dioxolan-2-yl) ethyl] amino] -2- (methylthio ) Methyl pyrimidine-5-carboxylate was obtained (50 mg, 20%).
MS (EI) m / z: 421 (M ⁺ ).
_{HRMS (EI): C 19 H} 23 N 3 O 4 S 2 Calculated: 421.1130
Found: 421.1143.

<Reference Example 125>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 1- (2- Aminoethyl) -cyclohexene (110 mg, 0.879 mmol) to methyl 4- (benzylthio) -2- (methylthio) -6-[[2- (cyclohexen-1-yl) ethyl] amino] pyrimidine-5-carboxylate Was obtained (117 mg, 47%).
MS (EI) m / z: 429 (M ⁺ ).
_{HRMS (EI): C 22 H} 27 N 3 O 2 S 2 Calculated: 429.1545
Found: 429.1526.

<Reference Example 126>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 200 mg, 0.587 mmol) and 2-[(2 -Aminoethyl) amino] -5-nitro-pyridine (160 mg, 0.878 mmol) to 4- (benzylthio) -2- (methylthio) -6-[[2-[(5-nitropyridin-2-yl) Methyl amino] ethyl] amino] pyrimidine-5-carboxylate was obtained (148 mg, 52%).
MS (EI) m / z: 486 (M ⁺ ).
_{HRMS (EI): C 21 H} 22 N 6 O 4 S 2 Calculated: 486.1144
Actual value: 486.1152.

<Reference Example 127>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and N-phenylethylenediamine ( 120 mg, 0.881 mmol) gave methyl 4-[(2-anilinoethyl) amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (268 mg, 99%).
MS (FAB ⁺ ) m / z: 441 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S 2 Calculated: 441.1419
Found: 441.1417.

<Reference Example 128>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 157; 200 mg, 0.587 mmol) and phenoxyethanolamine (121 mg, 0.882 mmol) gave methyl 4- (benzylthio) -2- (methylthio) -6-[(2-phenoxyethyl) amino] pyrimidine-5-carboxylate (216 mg, 83%).
MS (FAB ⁺ ) m / z: 442 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 3 S 2 Calculated: 442.1259
Found: 442.1268.

<Reference Example 129>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 200 mg, 0.587 mmol) and 1- (3- Aminopropyl) imidazole (110 mg, 0.879 mmol) gives methyl 4- (benzylthio) -6-[[3- (1-imidazolyl) propyl] amino] -2- (methylthio) pyrimidine-5-carboxylate (214 mg, 85%).
MS (FAB ⁺ ) m / z: 430 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 N 5 O 2 S 2 Calculated: 430.1371
Actual value: 430.1372.

<Reference Example 130>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 200 mg, 0.601 mmol) and benzylamine (96 .6 mg, 0.902 mmol) gave methyl 4- (benzylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (187 mg, 77%).
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1484.

<Reference Example 131>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 200 mg, 0.601 mmol) and 4-chlorobenzyl Amine (128 mg, 0.904 mmol) gave methyl 4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (192 mg, 73% ).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 25 ClN 3 O 2 S 2 Calculated: 438.1077
Actual value: 438.1058.

<Reference Example 132>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 200 mg, 0.601 mmol) and 4-methoxybenzyl The amine (124 mg, 0.904 mmol) gave methyl 4- (cyclohexylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (178 mg, 68% ).
MS (FAB ⁺ ) m / z: 434 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 3 S 2 Calculated: 434.1572
Actual value: 434.1571.

<Reference Example 133>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4-fluorobenzyl The amine (84.9 mg, 0.678 mmol) gave methyl 4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (144 mg, 76%). MS (FAB ⁺ ) m / z: 422 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₂₅ FN ₃ O ₂ S ₂ : 422.1372
Found: 422.1329.

<Reference Example 134>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4-methylbenzyl The amine (82.2 mg, 0.678 mmol) gave methyl 4- (cyclohexylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (90. 0 mg, 48%).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Found: 418.1654.

<Reference Example 135>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4- (tri From fluoromethyl) benzylamine (119 mg, 0.679 mmol), methyl 4- (cyclohexylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate Obtained (138 mg, 65%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 25 F 3 N 3 O 2 S 2 Calculated: 472.1340
Actual value: 472.1380.

<Reference Example 136>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4-chlorobenzyl The amine (86.2 mg, 0.676 mmol) gave methyl 4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (135 mg, 71%).
MS (FAB ⁺ ) m / z: 424 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 ClN 3 O 2 S 2 Calculated: 424.0920
Actual value: 424.0912.

<Reference Example 137>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4-fluorobenzyl Amine (75.1 mg, 0.676 mmol) gave methyl 4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (147 mg, 80%).
MS (FAB ⁺ ) m / z: 408 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 FN 3 O 2 S 2 Calculated: 408.1216
Actual value: 408.1239.

<Reference Example 138>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and aniline (63. 0 mg, 0.676 mmol) gave methyl 4-anilino-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (70.3 mg, 40%).
MS (FAB ⁺ ) m / z: 390 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 24 N 3 O 2 S 2 Calculated: 390.1310
Actual value: 390.1324.

<Reference Example 139>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4-methylaniline (72.4 mg, 0.676 mmol) gave methyl 4- (cyclohexylthio) -6- (4-methylanilino) -2- (methylthio) pyrimidine-5-carboxylate (82.7 mg, 46%) .
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1505.

<Reference Example 140>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 150 mg, 0.451 mmol) and 4-methoxyaniline (83.2 mg, 0.676 mmol) gave methyl 4- (cyclohexylthio) -6- (4-methoxyanilino) -2- (methylthio) pyrimidine-5-carboxylate (92.9 mg, 49 %).
MS (FAB ⁺ ) m / z: 420 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 3 S 2 Calculated: 420.1416
Actual value: 420.1459.

<Reference Example 141>

In the same manner as in Reference Example 2, methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 161; 200 mg, 0.603 mmol) and 4- (tri Fluoromethyl) aniline (145 mg, 0.9001 mmol) gave methyl 4- (cyclohexylthio) -2- (methylthio) -6- [4- (trifluoromethyl) anilino] pyrimidine-5-carboxylate ( 98.1 mg, 36%).
MS (EI) m / z: 457 (M ⁺ ).
_{HRMS (EI): C 20 H} 22 F 3 N 3 O 2 S 2 Calculated: 457.1106
Actual value: 457.1131.

<Reference Example 142>

4- (Benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (compound of Reference Example 151; 130 mg, 0.365 mmol) was dissolved in tetrahydrofuran (1 mL) and triethylamine (0. (06 mL, 0.430 mmol) and piperazine (31.1 mg, 0.365 mmol) were added with ice cooling, followed by further stirring for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4- (benzylamino) -6-chloro-2-piperidinopyrimidine-5- Methyl carboxylate was obtained (75.0 mg, 57%).
MS (EI) m / z: 360 (M ⁺ ).
_{RMS (EI): C 18 H} 21 ClN 4 O 2 Calculated: 360.1353
Actual value: 360.1374.

<Reference Example 143>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and morpholine (31 0.9 mg, 0.366 mmol) gave methyl 4- (benzylamino) -6-chloro-2-morpholinopyrimidine-5-carboxylate (45.4 mg, 34%).
MS (EI) m / z: 362 (M ⁺ ).
_{HRMS (EI): C 17 H} 19 ClN 4 O 3 Calculated: 362.1146
Actual value: 362.1138.

<Reference Example 144>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and 1-methyl Piperazine (32.0 mg, 0.367 mmol) gave methyl 4- (benzylamino) -6-chloro-2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylate (66.0 mg). 48%).
MS (EI) m / z: 375 (M ⁺ ).
_{HRMS (EI): C 18 H} 22 ClN 5 O 2 Calculated: 375.1462
Actual value: 375.1480.

<Reference Example 145>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and butylamine (26 0.7 mg, 0.365 mmol) gave methyl 4- (benzylamino) -6-chloro-2- (butylamino) pyrimidine-5-carboxylate (56.3 mg, 44%).
MS (EI) m / z: 348 (M ⁺ ).
_{HRMS (EI): C 17 H} 21 ClN 4 O 2 Calculated: 348.1353
Actual value: 348.1345.

<Reference Example 146>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and N-butyl Methylamine (31.9 mg, 0.366 mmol) gave methyl 4- (benzylamino) -2- (N-butylmethylamino) -6-chloropyrimidine-5-carboxylate (39.0 mg, 29 %).
MS (EI) m / z: 362 (M ⁺ ).
_{HRMS (EI): C 18 H} 23 ClN 4 O 2 Calculated: 362.1510
Actual value: 362.1512.

<Reference Example 147>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and dibutylamine ( 47.2 mg, 0.365 mmol) gave methyl 4- (benzylamino) -6-chloro-2- (dibutylamino) pyrimidine-5-carboxylate (29.0 mg, 20%).
MS (EI) m / z: 404 (M ⁺ ).
_{HRMS (EI): C 21 H} 29 ClN 4 O 2 Calculated: 404.1979
Actual value: 404.1986.

<Reference Example 148>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and heptylamine ( 42.1 mg, 0.365 mmol) gave methyl 4- (benzylamino) -6-chloro-2- (heptylamino) pyrimidine-5-carboxylate (74.1 mg, 52%).
MS (EI) m / z: 390 (M ⁺ ).
_{HRMS (EI): C 20 H} 27 ClN 4 O 2 Calculated: 390.1823.
Actual value: 390.1816.

<Reference Example 149>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (Compound of Reference Example 151; 130 mg, 0.365 mmol) and cyclopropylamine (20.9 mg, 0.366 mmol) gave methyl 4- (benzylamino) -6-chloro-2- (cyclopropylamino) pyrimidine-5-carboxylate (54.2 mg, 45%).
MS (EI) m / z: 332 (M ⁺ ).
_{HRMS (EI): C 16 H} 17 ClN 4 O 2 Calculated: 332.1040
Actual value: 332.11052.

<Reference Example 150>

In the same manner as in Reference Example 142, methyl 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5-carboxylate (the compound of Reference Example 151; 130 mg, 0.365 mmol) and benzylamine ( 40.0 mg, 0.373 mmol) gave methyl 2,6-bis (benzylamino) -4-chloropyrimidine-5-carboxylate (100 mg, 72%).
MS (EI) m / z: 382 (M ⁺ ).
_{HRMS (EI): C 20 H} 19 ClN 4 O 2 Calculated: 382.1197
Actual value: 382.1218.

<Reference Example 151>

4- (Benzylamino) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 152; 4.17 g, 12.9 mmol) was dissolved in tetrahydrofuran (120 mL), and m-chloro After adding perbenzoic acid (5.00 g, 29.0 mmol) with ice cooling, the mixture was further stirred for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 4- (benzylamino) -6-chloro-2- (methylsulfonyl) pyrimidine-5. -Methyl carboxylate was obtained (4.12 g, 90%).
MS (EI) m / z: 355 (M ⁺ ).
_{HRMS (EI): C 14 H} 14 ClN 3 O 4 S Calculated: 355.0394
Actual value: 355.0352.

<Reference Example 152>

Methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 164; 900 mg, 3.56 mmol) was dissolved in tetrahydrofuran (10 mL) and triethylamine (0.60 mL, 4.30 mmol). And benzylamine (381 mg, 3.56 mmol) were added with ice cooling, followed by further stirring for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4- (benzylamino) -6-chloro-2- (methylthio) pyrimidine-5- Methyl carboxylate was obtained (1.10 g, 95%).
MS (EI) m / z: 323 (M ⁺ ).
_{HRMS (EI): C 14 H} 14 ClN 3 O 2 S Calculated: 323.0495
Actual value: 323.0500.

<Reference Example 153>

In the same manner as in Reference Example 152, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 1.02 g, 4.03 mmol) and aniline (375 mg, 4.03 mmol) ) Gave methyl 4-anilino-6-chloro-2- (methylthio) pyrimidine-5-carboxylate (1.09 g, 88%).
MS (FAB ⁺ ) m / z: 310 (M + H ⁺ ).
_{^{HRMS (FAB +): C 13}} H 13 ClN 3 O 2 S Calculated: 310.0417
Actual value: 310.0403.

<Reference Example 154>

In the same manner as in Reference Example 152, from methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 254 mg, 1.00 mmol) and phenethylamine (121 mg, 0.999 mmol) , Methyl 4-chloro-2- (methylthio) -6- (phenethylamino) pyrimidine-5-carboxylate was obtained (324 mg, 96%).
MS (FAB ⁺ ) m / z: 338 (M + H ⁺ ).
_{^{HRMS (FAB +): C 15}} H 17 ClN 3 O 2 S Calculated: 338.0730
Found: 338.0747.

<Reference Example 155>

In the same manner as in Reference Example 152, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 507 mg, 2.00 mmol) and 4-chlorobenzylamine (290 mg, 2 .05 mmol) gave methyl 4-chloro-6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (586 mg, 82%).
MS (FAB ⁺ ) m / z: 358 (M + H ⁺ ).
_{^{HRMS (FAB +): C 14}} H 14 Cl 2 N 3 O 2 S Calculated: 358.0184
Actual value: 358.0163.

<Reference Example 156>

In the same manner as in Reference Example 152, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 507 mg, 2.00 mmol) and 4-chloroaniline (262 mg, 2. 05 mmol) gave methyl 4-chloro-6-[(4-chloroanilino) amino] -2- (methylthio) pyrimidine-5-carboxylate (636 mg, 92%).
MS (EI) m / z: 343 (M ⁺ ).
_{HRMS (EI): C 13 H} 11 Cl 2 N 3 O 2 S Calculated: 342.9949
Actual value: 342.99961.

<Reference Example 157>

To a solution of methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 164; 17.6 g, 69.5 mmol) in N, N-dimethylformamide (100 mL) was added potassium carbonate (9 .70 g, 70.2 mmol) and phenylmethanethiol (8.68 mg, 69.9 mmol) were added with ice cooling, followed by stirring for 1 hour under ice cooling and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxyl. Methyl acid was obtained (22.9 g, 97%).
MS (EI) m / z: 340 (M ⁺ ).
_{HRMS (EI): C 14 H} 13 ClN 2 O 2 S 2 Calculated: 340.0107
Actual value: 340.0117.

<Reference Example 158>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (dimethylamino) pyrimidine-5-carboxylate (Compound of Reference Example 165; 3.00 g, 12.0 mmol) and phenylmethanethiol (1. 49 g, 12.0 mmol) gave methyl 4- (benzylthio) -6-chloro-2- (dimethylamino) pyrimidine-5-carboxylate (3.64 g, 90%).
MS (EI) m / z: 337 (M ⁺ ).
HRMS (EI): Calculated as C ₁₅ H ₁₆ ClN ₃ O ₂ S: 337.0652
Actual value: 337.0653.

<Reference Example 159>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2-pyrrolidinopyrimidine-5-carboxylate (compound of Reference Example 166; 100 mg, 0.362 mmol) and phenylmethanethiol (45.0 mg,. 362 mmol) gave methyl 4- (benzylthio) -6-chloro-2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (97.8 g, 74%).
MS (EI) m / z: 363 (M ⁺ ).
HRMS (EI): Calculated as C ₁₇ H ₁₈ ClN ₃ O ₂ S: 363.0808
Actual value: 363.0855.

<Reference Example 160>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 7.36 g, 29.1 mmol) and (4-methoxyphenyl) methane Thiol (4.49 g, 29.1 mmol) gave methyl 4-chloro-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (6.45 g, 60 %).
MS (EI) m / z: 370 (M ⁺ ).
_{HRMS (EI): C 15 H} 15 ClN 2 O 3 S 2 Calculated: 370.0213
Actual value: 370.0247.

<Reference Example 161>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 4.00 g, 15.8 mmol) and cyclohexyl mercaptan (1.85 g, 15.9 mmol) gave methyl 4-chloro-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (3.93 g, 75%).
MS (FAB ⁺ ) m / z: 333 (M + H ⁺ ).
_{^{HRMS (FAB +): C 13}} H 18 ClN 2 O 2 S 2 Calculated: 333.0498
Actual value: 333.0504.

<Reference Example 162>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 1.27 g, 5.02 mmol) and cyclohexylamine (498 mg, 5. 02 mmol) gave methyl 4-chloro-6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (1.48 g, 93%).
MS (FAB ⁺ ) m / z: 316 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₁₃ H ₁₉ ClN ₃ O ₂ S: 316.0887
Actual value: 316.0919.

<Reference Example 163>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 164; 4.00 g, 15.8 mmol) and cyclohexylmethylamine (1.80 g) 15.9 mmol) gave methyl 4-chloro-6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (5.18 g, 99%).
MS (EI) m / z: 329 (M ⁺ ).
_{HRMS (EI): C 14 H} 20 ClN 3 O 2 S Calculated: 329.0965
Actual value: 329.0971.

<Reference Example 164>

To a solution of 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylic acid (the compound of Reference Example 167; 16.7 g, 69.9 mmol) in N, N-dimethylformamide (150 mL) was added potassium carbonate (11. 6 g, 83.9 mmol) and methyl iodide (5.50 mL, 88.3 mmol) were added with ice cooling, followed by stirring under ice cooling for 0.5 hour and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate. (17.6 g, 99%).
MS (EI) m / z: 252 (M ⁺ ).
HRMS (EI): Calculated as C ₇ H ₆ Cl ₂ N ₂ O ₂ S: 251.9527
Actual value: 251.9538.

<Reference Example 165>

In the same manner as in Reference Example 164, 4,6-dichloro-2- (dimethylamino) pyrimidine-5-carboxylic acid (Compound of Reference Example 168; 4.24 g, 18.0 mmol) and methyl iodide (1.20 mL) , 19.3 mmol) gave methyl 4,6-dichloro-2- (dimethylamino) pyrimidine-5-carboxylate (4.50 g, 99%).
MS (EI) m / z: 249 (M ^<+> ).
_{HRMS (EI): C 8 H} 9 Cl 2 N 3 O 2 Calculated: 249.0072
Actual value: 249.0049.

<Reference Example 166>

In the same manner as in Reference Example 164, 4,6-dichloro-2-pyrrolodinopyrimidine-5-carboxylic acid (Compound of Reference Example 169; 1.05 g, 4.01 mmol) and methyl iodide (0.30 mL, 4 .82 mmol) gave methyl 4,6-dichloro-2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (1.06 g, 96%).
MS (EI) m / z: 275 (M ⁺ ).
_{HRMS (EI): C 10 H} 11 Cl 2 N 3 O 2 Calculated: 275.0228
Actual value: 275.0240.

<Reference Example 167>

Lithium diisopropylamide in tetrahydrofuran (diisopropylamine (3.0 mL, 21.4 mmol) diluted with tetrahydrofuran (25 mL) and diluted at −20 ° C. with n-butyllithium (13.6 mL, 20.7 mol, 1.52 mol / L). Hexane solution) was added, and the mixture was stirred for 1 hour at −20 ° C.), and a solution of 4,6-dichloro-2- (methylthio) pyrimidine (2.70 g, 13.8 mmol) in tetrahydrofuran (5 mL) was added. Was added at −78 ° C. and stirred for 3 hours. Carbon dioxide was bubbled into the reaction solution for 10 minutes, water was added, and the temperature was raised to room temperature. 2 mol / L hydrochloric acid (25 mL) was added to adjust to pH = 1, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was washed with toluene to obtain 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylic acid (1.93 g, 58%).
MS (EI) m / z: 238 (M ⁺ ).
HRMS (EI): Calculated as C ₆ H ₄ Cl ₂ N ₂ O ₂ S: 237.9371
Actual value: 237.9383.

<Reference Example 168>

In the same manner as in Reference Example 167, 4,6-dichloro-2- (dimethylamino) pyrimidine (the compound of Reference Example 171; 28.3 g, 0.147 mmol) was converted into 4,6-dichloro-2- (dimethylamino). ) Pyrimidine-5-carboxylic acid (23.1 g, 67%) was obtained.
MS (EI) m / z: 235 (M ⁺ ).
_{HRMS (EI): C 7 H} 7 Cl 2 N 3 O 2 Calculated: 234.9915
Actual value: 234.9927.

<Reference Example 169>

In the same manner as in Reference Example 167, 4,6-dichloro-2- (1-pyrrolidinyl) was converted from 4,6-dichloro-2-pyrrolidinopyrimidine (the compound of Reference Example 170; 36.0 g, 0.165 mmol). Pyrimidine-5-carboxylic acid (27.4 g, 63%) was obtained.
MS (EI) m / z: 261 (M ⁺ ).
_{HRMS (EI): C 9 H} 9 Cl 2 N 3 O 2 Calculated: 261.0072
Actual value: 261.0029.

<Reference Example 170>

Pyrrolidine (21.5 g, 0.302 mol) was dissolved in methanol (100 mL), 10% hydrogen chloride-methanol (500 mL) was added, and the mixture was stirred at 0 ° C. for 0.5 hr and then at room temperature for 1 hr. The solvent was distilled off. Cyanamide (15.2 g, 0.362 mol) and butanol (20 mL) were added to the resulting residue, and the mixture was heated to reflux for 10 hours. The residue obtained by distilling off the solvent was dissolved in ethanol (300 mL), and tert-butoxypotassium (67.8 g, 0.604 mol) and diethyl malonate (58.0 g, 0.362 mol) were added. Heated to reflux for hours. After cooling the reaction solution, water (300 mL) was added, acetic acid was added to adjust the pH to 4, and the precipitated crystals were collected by filtration. Phosphorus oxychloride (400 mL, 4.29 mol) was added to the obtained crystals and heated to reflux for 10 hours. Water was added to the residue obtained by distilling off the solvent and sodium carbonate was added to adjust to pH = 11, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4,6-dichloro-2- (1-pyrrolidinyl) pyrimidine (36.0 g, 55 %)was gotten.
MS (EI) m / z: 217 (M ⁺ ).
HRMS (EI): Calculated _{C 8 H 9 Cl 2 N 3} : 217.0174
Actual value: 217.0181.

<Reference Example 171>

To a solution of potassium tert-butoxy (20.0 g, 0.178 mmol) in ethanol (250 mL) was added N, N-dimethylguanidine sulfate (12.0 g, 44.1 mmol) and diethyl malonate (15.0 g, 93.7 mmol). ) And heated to reflux for 5 hours. 10% Hydrogen chloride-methanol (200 mL) was added to the residue obtained by distilling off the solvent, followed by stirring at room temperature for 1 hour, and then the solvent was distilled off. Phosphorous oxychloride (160 mL, 1.72 mol) was added to the obtained residue, and the mixture was heated to reflux for 2 hours. Water and sodium carbonate were added to the residue obtained by distilling off the solvent to adjust the pH to 11, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4,6-dichloro-2- (dimethylamino) pyrimidine (9.14 g, 54%). )was gotten.
MS (EI) m / z: 191 (M ⁺ ).
_{HRMS (EI): C 6 H} 7 Cl Calculated ₂ N _3: 191.0017
Actual value: 190.9992.

<Reference Example 172>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 100 mg, 0.293 mmol) and (4-fluorophenyl) ) Methanethiol (45.8 mg, 0.322 mmol) gave methyl 4- (benzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (60.7 mg) 46%).
MS (FAB ⁺ ) m / z: 447 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₀ FN ₂ O ₂ S ₃ : 447.0671
Actual value: 447.0690.

<Reference Example 173>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 100 mg, 0.293 mmol) and (4-chlorophenyl) Methanethiol (51.1 mg, 0.322 mmol) gave methyl 4- (benzylthio) -6- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (127 mg, 94% ).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 ClN 2 O 2 S 3 Calculated: 463.0375

Actual value: 463.0361.

<Reference Example 174>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 100 mg, 0.293 mmol) and (4-methoxyphenyl) ) Methanethiol (49.7 mg, 0.322 mmol) gave methyl 4- (benzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (68.7 mg). 51%).
MS (FAB ⁺ ) m / z: 459 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 N 2 O 3 S 3 Calculated: 459.0871

Actual value: 459.0880.

<Reference Example 175>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 157; 100 mg, 0.293 mmol) and (4-methylphenyl) ) Methanethiol (44.5 mg, 0.322 mmol) gave methyl 4- (benzylthio) -6- (4-methylbenzylamino) -2- (methylthio) pyrimidine-5-carboxylate (110 mg, 82 %).
MS (FAB ⁺ ) m / z: 443 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 N 2 O 2 S 3 Calculated: 443.0992

Actual value: 443.0928.

<Reference Example 176>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 100 mg, 0.270 mmol) and ( 4-Fluorophenyl) methanethiol (46.0 mg, 0.323 mmol) gives methyl 4- (4-fluorobenzylthio) -6- (methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate. (81.8 mg, 64%).
MS (FAB ⁺ ) m / z: 477 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₂ FN ₂ O ₃ S ₃ : 477.0777

Actual value: 477.0733.

<Reference Example 177>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 100 mg, 0.270 mmol) and ( 4-Chlorophenyl) methanethiol (51.3 mg, 0.323 mmol) gives methyl 4- (4-chlorobenzylthio) -6- (methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (99.0 mg, 74%).
MS (FAB ⁺ ) m / z: 493 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 22 ClN Calculated ₂ O ₃ S _3: 493.0481

Actual value: 493.0517.

<Reference Example 178>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 100 mg, 0.270 mmol) and ( 4-Methoxyphenyl) methanethiol (49.9 mg, 0.324 mmol) gave methyl 4,6-bis (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (80. 6 mg, 61%).
MS (FAB ⁺ ) m / z: 489 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 25 N 2 O 4 S 3 Calculated: 489.0976

Actual value: 489.0986.

<Reference Example 179>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 160; 100 mg, 0.270 mmol) and ( 4-methylphenyl) methanethiol (44.7 mg, 0.323 mmol) to methyl 4- (4-methoxybenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate Was obtained (67.0 mg, 53%).
MS (FAB ⁺ ) m / z: 473 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 25 N 2 O 3 S 3 Calculated: 473.1027

Actual value: 473.1053.

<Reference Example 180>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 192; 100 mg, 0.266 mmol) and ( 4-Fluorophenyl) methanethiol (45.4 mg, 0.319 mmol) gives methyl 4- (4-chlorobenzylthio) -6- (fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate. (100 mg, 78%).
MS (FAB ⁺ ) m / z: 481 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 19 ClFN 2 O 2 S 3 Calculated: 481.0281

Actual value: 481.0315.

<Reference Example 181>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 192; 100 mg, 0.266 mmol) and ( 4-Chlorophenyl) methanethiol (50.6 mg, 0.319 mmol) gave methyl 4,6-bis (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (102 mg, 77 %).
MS (FAB ⁺ ) m / z: 497 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 19 Cl 2 N 2 O 2 S 3 Calculated: 496.9986

Actual value: 496.9940.

<Reference Example 182>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 192; 100 mg, 0.266 mmol) and ( 4-methylphenyl) methanethiol (44.1 mg, 0.319 mmol) to methyl 4- (4-chlorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate Was obtained (89.0 mg, 70%).
MS (FAB ⁺ ) m / z: 477 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 22 ClN 2 O 2 S 3 Calculated: 477.0532

Actual value: 477.0538.

<Reference Example 183>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 193; 100 mg, 0.279 mmol) and ( 4-Fluorophenyl) methanethiol (47.6 mg, 0.335 mmol) gave methyl 4,6-bis (fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (108 mg, 83% ).
MS (FAB ⁺ ) m / z: 465 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 19 F 2 N 2 O 2 S 3 Calculated: 465.0577

Actual value: 465.0536.

<Reference Example 184>

In the same manner as in Reference Example 1, methyl 6-chloro-4- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 193; 100 mg, 0.279 mmol) and ( 4-methylphenyl) methanethiol (46.2 mg, 0.334 mmol) to methyl 4- (4-fluorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate Was obtained (89.7 mg, 70%).
MS (FAB ⁺ ) m / z: 461 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₂ FN ₂ O ₂ S ₃ : 461.0827

Actual value: 461.0871.

<Reference Example 185>

In the same manner as in Reference Example 2, methyl 4- (benzylthio) -2- (butylthio) -6-chloropyrimidine-5-carboxylate (Compound of Reference Example 194; 82.0 mg, 0.214 mmol) and benzylamine ( 27.5 mg, 0.257 mmol) gave methyl 4- (benzylamino) -6- (benzylthio) -2- (butylthio) pyrimidine-5-carboxylate (95.0 mg, 98%).
MS (EI) m / z: 453 (M ⁺ ).
HRMS (EI): Calculated as C ₂₄ H ₂₇ N ₃ O ₂ S ₂ : 453.1545

Actual value: 453.1573.

<Reference Example 186>

In the same manner as in Reference Example 2, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 164; 70.0 mg, 0.277 mmol) and (4-methylphenyl) methane From thiol (91.8 mg, 0.664 mmol), methyl 4,6-bis (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate was obtained (111 mg, 88%).
MS (FAB ⁺ ) m / z: 457 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 25 N 2 O 2 S 3 Calculated: 457.1078

Actual value: 457.1063.

<Reference Example 187>

To a solution of methyl 4,6-dichloro-2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 165; 100 mg, 0.400 mmol) in N, N-dimethylformamide (1 mL), cesium carbonate (261 mg, 0.801 mmol) and benzyl alcohol (130 mg, 1.20 mmol) were added and stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4,6-bis (benzyloxy) -2- (dimethylamino) pyrimidine-5- Methyl carboxylate was obtained (107 mg, 68%).
MS (FAB ⁺ ) m / z: 394 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 4 Calculated: 394.1767

Actual value: 394.1786.

<Reference Example 188>

In the same manner as in Reference Example 187, methyl 4,6-dichloro-2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (Compound of Reference Example 166; 111 mg, 0.402 mmol) and benzyl alcohol (130 mg, 1. 20 mmol) gave methyl 4,6-bis (benzyloxy) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (64.1 mg, 38%).
MS (FAB ⁺ ) m / z: 420 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₆ N ₃ O ₄ : 420.1923

Actual value: 420.1959.

<Reference Example 189>

In the same manner as in Reference Example 187, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 2.54 g, 10.0 mmol) and benzyl alcohol (3.25 mg, 30.1 mmol) gave methyl 4,6-bis (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylate (1.65 g, 42%).
MS (FAB ⁺ ) m / z: 397 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₁ N ₂ O ₄ S: 397.1222

Actual value: 397.1226.

<Reference Example 190>

In the same manner as in Reference Example 187, methyl 4- (benzylthio) -6-chloro-2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 157; 171 mg, 0.502 mmol) and benzyl alcohol (60. 0 mg, 0.555 mmol) gave methyl 4- (benzyloxy) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (50.0 mg, 24%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 N 2 O 3 S 2 Calculated: 413.0994

Actual value: 413.1030.

<Reference Example 191>

In the same manner as in Reference Example 1, methyl 4- (benzylthio) -6-chloro-2- (octylthio) pyrimidine-5-carboxylate (the compound of Reference Example 195; 110 mg, 0.251 mmol) and benzylamine (32. 0 mg, 0.299 mmol) gave methyl 4- (benzylamino) -6- (benzylthio) -2- (octylthio) pyrimidine-5-carboxylate (112 mg, 88%).
MS (EI) m / z: 509 (M ⁺ ).
_{HRMS (EI): C 28 H} 35 N 3 O 2 S 2 Calculated: 509.2171

Actual value: 509.2138.

<Reference Example 192>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 1.00 g, 3.95 mmol) and (4-chlorophenyl) methanethiol (640 mg, 4.03 mmol) gave methyl 4-chloro-6- (chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (1.39 g, 94%).
MS (FAB ⁺ ) m / z: 375 (M + H ⁺ ).
_{^{HRMS (FAB +): C 14}} H 13 Cl 2 N 2 O 2 S 2 Calculated: 374.9796

Actual value: 374.9798.

<Reference Example 193>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylate (Compound of Reference Example 164; 1.00 g, 3.95 mmol) and (4-fluorophenyl) methane The methyl thiol (573 mg, 4.03 mmol) gave methyl 4-chloro-6- (fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (1.39 g, 98%).
MS (FAB ⁺ ) m / z: 359 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₁₄ H ₁₃ ClFN ₂ O ₂ S ₂ : 359.0091

Actual value: 359.0052.

<Reference Example 194>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (butylthio) pyrimidine-5-carboxylate (Compound of Reference Example 196; 96.0 mg, 0.325 mmol) and phenylmethanethiol (41.0 mg) 0.330 mmol) gave methyl 4- (benzylthio) -2- (butylthio) -6-chloropyrimidine-5-carboxylate (107 mg, 86%).
MS (FAB ⁺ ) m / z: 383 (M + H ⁺ ).
_{^{HRMS (FAB +): C 17}} H 20 ClN 2 O 2 S 2 Calculated: 383.0655

Actual value: 383.0696.

<Reference Example 195>

In the same manner as in Reference Example 157, methyl 4,6-dichloro-2- (octylthio) pyrimidine-5-carboxylate (Compound of Reference Example 197; 126 mg, 0.359 mmol) and phenylmethanethiol (45.0 mg, 0 .362 mmol) gave methyl 4- (benzylthio) -6-chloro-2- (octylthio) pyrimidine-5-carboxylate (110 mg, 70%).
MS (EI) m / z: 438 (M ⁺ ).
_{HRMS (EI): C 21 H} 27 ClN 2 O 2 S 2 Calculated: 438.1202

Actual value: 438.1167.

<Reference Example 196>

In the same manner as in Reference Example 164, 4,6-dichloro-2- (butylthio) pyrimidine-5-carboxylic acid (Compound of Reference Example 198; 1.21 g, 4.30 mmol) and methyl iodide (0.3 mL, 4.82 mmol) gave methyl 4,6-dichloro-2- (butylthio) pyrimidine-5-carboxylate (1.00 g, 66%).
MS (EI) m / z: 294 (M ⁺ ).
_{HRMS (EI): C 10 H} 12 Cl 2 N 2 O 2 S Calculated: 293.9997

Actual value: 293.99977.

<Reference Example 197>

In the same manner as in Reference Example 164, 4,6-dichloro-2- (octylthio) pyrimidine-5-carboxylic acid (Compound of Reference Example 199; 445 mg, 1.32 mmol) and methyl iodide (0.1 mL, 1.. 61 mmol) gave methyl 4,6-dichloro-2- (octylthio) pyrimidine-5-carboxylate (400 mg, 86%).
MS (EI) m / z: 350 (M ⁺ ).
_{HRMS (EI): C 14 H} 20 Cl 2 N 2 O 2 S Calculated: 350.0623

Actual value: 350.0657.

<Reference Example 198>

In the same manner as in Reference Example 167, 4,6-dichloro-2- (butylthio) pyrimidine was obtained from 4,6-dichloro-2- (butylthio) pyrimidine (the compound of Reference Example 200; 1.59 g, 6.70 mmol). -5-carboxylic acid was obtained (1.40 g, 74%).
MS (EI) m / z: 280 (M ⁺ ).
HRMS (EI): Calculated as C ₉ H ₁₀ Cl ₂ N ₂ O ₂ S: 279.9840

Actual value: 279.9844.

<Reference Example 199>

In the same manner as in Reference Example 167, 4,6-dichloro-2- (octylthio) pyrimidine-5 was converted from 4,6-dichloro-2- (octylthio) pyrimidine (the compound of Reference Example 201; 680 mg, 2.32 mmol). -Carboxylic acid was obtained (420 mg, 54%).
MS (EI) m / z: 336 (M ⁺ ).
HRMS (EI): Calculated as C ₁₃ H ₁₈ Cl ₂ N ₂ O ₂ S: 336.0466

Actual value: 336.0446.

<Reference Example 200>

Ethanol (50 mL) and 3 mol / L NaOH aqueous solution (12 mL) were added to thiobarbituric acid (5.22 g, 36.2 mmol), heated under reflux for 1 hour, and then butyl iodide (4.20 mL, 36.9 mmol) was added. And refluxed for 2 hours. After cooling the reaction solution, the crystals were collected by filtration. Phosphorus oxychloride (15.0 mL, 0.161 mol) and N, N-dimethylaniline (5.2 mL, 41.0 mmol) were added to the obtained crystals, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled, added to ice water, stirred for 3 hours, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to give 2- (butylthio) -4,6-dichloropyrimidine (1.61 g, 19%). was gotten.
MS (FAB ⁺ ) m / z: 237 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₈ H ₁₁ Cl ₂ N ₂ S: 237.0020

Actual value: 236.9995.

<Reference Example 201>

In the same manner as in Reference Example 200, 4,6-dichloro-2- (octylthio) pyrimidine was prepared from thiobarbituric acid (5.22 g, 36.2 mmol) and 1-bromooctane (6.30 mL, 36.2 mmol). Was obtained (696 mg, 7%).
MS (FAB ⁺ ) m / z: 293 (M + H ⁺ ).
_{^{HRMS (FAB +): C 12}} H 19 Cl 2 N 2 S Calculated: 293.0646

Actual value: 293.0623.

<Reference Example 202>

After morpholine (26.3 mL, 0.302 mol) is dissolved in methanol (100 mL), 10% hydrogen chloride-methanol (500 mL) is added, and the mixture is stirred at 0 ° C. for 0.5 hour and then at room temperature for 1 hour. The solvent was distilled off. Cyanamide (15.2 g, 0.362 mol) and butanol (20 mL) were added to the resulting residue, and the mixture was heated to reflux for 10 hours. The residue obtained by distilling off the solvent was dissolved in ethanol (300 mL), and tert-butoxypotassium (67.8 g, 0.604 mol) and diethyl malonate (58.0 g, 0.362 mol) were added. Heated to reflux for hours. After cooling the reaction solution, water (300 mL) was added, acetic acid was added to adjust the pH to 4, and the precipitated crystals were collected by filtration. Phosphorus oxychloride (158 mL, 1.70 mol) was added to the obtained crystals and heated to reflux for 10 hours. Water was added to the residue obtained by distilling off the solvent and sodium carbonate was added to adjust to pH = 11, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain 4,6-dichloro-2-morpholinopyrimidine (7.58 g). Next, a solution of lithium diisopropylamide in tetrahydrofuran (diisopropylamine (6.30 mL, 45.1 mmol) was diluted with tetrahydrofuran (64.8 mL), and n-butyllithium (17.3 mL, 44.7 mol, 2.59 mol / L hexane solution) was added, and the mixture was stirred at -20 ° C. for 1 hour for adjustment.) To 4,6-dichloro-2- (methylthio) pyrimidine (7.58 g) in tetrahydrofuran (10 mL) The solution was added at −78 ° C. and stirred for 3 hours. Carbon dioxide was bubbled into the reaction solution for 10 minutes, water was added, and the temperature was raised to room temperature. 2 mol / L hydrochloric acid was added to adjust to pH = 1, followed by extraction with ethyl acetate and drying over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was washed with toluene to obtain 4,6-dichloro-2-morpholinopyrimidine-5-carboxylic acid (7.30 g, 9%).
MS (EI) m / z: 277 (M ⁺ ).
_{HRMS (EI): C 9 H} 9 Cl 2 N 3 O 3 Calculated: 277.0021

Actual value: 276.9995.

4-anilino-6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (compound of Reference Example 1; 30.0 mg, 75.5 μmol), tetrahydrofuran (0.5 mL), and methanol (0. 5 mol) was added with a 3 mol / L aqueous potassium hydroxide solution (0.2 mL), and the mixture was heated to reflux for 4 hours. Water and 2N hydrochloric acid (0.4 mL) were added to the reaction mixture to adjust to pH = 1, and the precipitated crystals were collected by filtration to give 4-anilino-6- (benzylthio) -2- (methylthio) pyrimidine-5- Carboxylic acid was obtained (26.5 mg, 92%).
MS (FAB ⁺ ) m / z: 384 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 18 N 3 O 2 S 2 Calculated: 384.0840
Actual value: 384.0851.

In the same manner as in Example 1, from methyl 4- (benzylamino) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 2; 108 mg, 0.262 mmol), 4 -(Benzylamino) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (80.0 mg, 77%).
MS (EI) m / z: 397 (M ⁺ ).
_{HRMS (EI): C 20 H} 19 N 3 O 2 S 2 Calculated: 397.0919
Actual value: 397.0944.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6- (phenethylamino) -pyrimidine-5-carboxylate (the compound of Reference Example 3; 33.0 mg, 77.5 μmol) Gave 4- (benzylthio) -2- (methylthio) -6- (phenethylamino) -pyrimidine-5-carboxylic acid (29.7 mg, 93%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Actual value: 412.1176.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 4; 80.0 mg, 0.195 mmol) gave 4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (73.0 mg, 87%).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 19 ClN 3 O 2 S 2 Calculated: 432.0607
Found: 432.0638.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 5; 100 mg, 0. 244 mmol) gave 4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (94.5 mg, 90%).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 19 ClN 3 O 2 S 2 Calculated: 432.0607
Actual value: 432.0621.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 6; 3.29 g, 7.38 mmol) gave 4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (3.14 g, 98%).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 19 ClN 3 O 2 S 2 Calculated: 432.0607
Found: 432.0613.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 7; 54.3 mg, 0.126 mmol) gave 4- (benzylthio) -6-[(2-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (48.7 mg, 93%).
MS (FAB ⁺ ) m / z: 416 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₁₉ FN ₃ O ₂ S ₂ : 416.0903
Actual value: 416.0904.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 8; 44.5 mg, 0.104 mmol) gave 4- (benzylthio) -6-[(3-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (39.1 mg, 90%).
MS (FAB ⁺ ) m / z: 416 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₁₉ FN ₃ O ₂ S ₂ : 416.0903
Actual value: 416.0889.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 9; 83.5 mg, 0.194 mmol) gave 4- (benzylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (76.5 mg, 95%).
MS (FAB ⁺ ) m / z: 416 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₁₉ FN ₃ O ₂ S ₂ : 416.0903
Actual value: 416.0901.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 10; 118 mg, 0. 268 mmol) gave 4- (benzylthio) -6-[(2-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (96.8 mg, 84%).
MS (FAB ⁺ ) m / z: 428 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 3 S 2 Calculated: 428.1103
Actual value: 428.1096.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 11; 89.3 mg, 0.202 mmol) gave 4- (benzylthio) -6-[(3-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (81.6 mg, 94%).
MS (FAB ⁺ ) m / z: 428 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 3 S 2 Calculated: 428.1103
Found: 428.1109.

4444

4444

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 12; 131 mg, 0. 297 mmol) gave 4- (benzylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (118 mg, 93%).
MS (FAB ⁺ ) m / z: 428 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 3 S 2 Calculated: 428.1103
Actual value: 428.1096.
¹ H-NMR (400Mz, DMSO-d ₆ ) ppm: 2.48 (3H, s), 3.80 (3H, s),
3.83 (3H, s), 4.37 (2H, s), 4.66 (2H, d, J = 5.5 Hz), 6.86 (2H, d, J = 8.6 Hz),
7.24 (4H, m), 7.31 (2H, t, J = 7.3 Hz), 7.39 (2H, d, J = 7.3 Hz), 8.82 (1H, br).

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 13; 55.0 mg, 0.129 mmol) gave 4- (benzylthio) -6-[(2-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (49.6 mg, 93%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Found: 412.1174.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 14; 45.4 mg, 0.107 mmol) gave 4- (benzylthio) -6-[(3-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (39.3 mg, 89%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Found: 412.1169.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 15; 48.4 mg, 0.114 mmol) gave 4- (benzylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (44.0 mg, 94%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Actual value: 412.1144.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 16; 56.2 mg, 0.117 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid (48. 4 mg, 89%).
MS (FAB ⁺ ) m / z: 466 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₁₉ F ₃ N ₃ O ₂ S ₂ : 466.0871
Actual value: 466.0858.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 17; 63.7 mg, 0.133 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid (47. 9 mg, 77%).
MS (FAB ⁺ ) m / z: 466 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₁₉ F ₃ N ₃ O ₂ S ₂ : 466.0871
Actual value: 466.0914.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 18; 105 mg, 0.219 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid (88.2 mg, 87%).
MS (FAB ⁺ ) m / z: 466 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₁₉ F ₃ N ₃ O ₂ S ₂ : 466.0871
Actual value: 466.0888.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 19; 89.3 mg, 0.214 mmol) Gave 4- (benzylthio) -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (80.1 mg, 93%).
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1484.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 20; 48.2 mg, 97.3 μmol) gave 4- (benzylthio) -2- (methylthio) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylic acid (41. 4 mg, 88%).
MS (FAB ⁺ ) m / z: 482 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 19 F 3 N 3 O 3 S 2 Calculated: 482.0820
Actual value: 482.0851.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 21; 52.4 mg, 0.107 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylic acid (48.4 mg, 96%).
MS (FAB ⁺ ) m / z: 474 (M + H ⁺ ).
_{^{HRMS (FAB +): C 26}} H 24 N 3 O 2 S 2 Calculated: 474.1310
Actual value: 474.1313.

実施例１と同様の方法により、４−（ベンジルチオ）−６−［（４−ｔｅｒｔ−ブチルベンジル）アミノ］−２−（メチルチオ）ピリミジン−５−カルボン酸メチル（参考例２２の化合物；５０．０ｍｇ、０．１０７ｍｍｏｌ）から、４−（ベンジルチオ）−６−［（４−ｔｅｒｔ−ブチルベンジル）アミノ］−２−（メチルチオ）ピリミジン−５−カルボン酸が得られた（１９．２ｍｇ、４０％）。
MS(FAB⁺)m/z:454(M+H⁺)．
HRMS(FAB⁺):C₂₄H₂₈N₃O₂S₂として計算値:454.1623
実測値:454.1603．

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 22; 50. 0 mg, 0.107 mmol) gave 4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (19.2 mg, 40% ).
MS (FAB ⁺ ) m / z: 454 (M + H ⁺ ).
_{^{HRMS (FAB +): C 24}} H 28 N 3 O 2 S 2 Calculated: 454.1623
Actual value: 454.1603.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[[4- (dimethylamino) benzyl] amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 23; 83 4.0 mg, 0.183 mmol) gave 4- (benzylthio) -6-[[4- (dimethylamino) benzyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid (47.0 mg, 58%).
MS (FAB ⁺ ) m / z: 441 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S 2 Calculated: 441.1419
Found: 441.1422.

In the same manner as in Example 1, methyl 4-[[4- (aminosulfonyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 24; 88 0.0 mg, 0.179 mmol) gave 4-[[4- (aminosulfonyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (79.0 mg, 93%).
MS (FAB ⁺ ) m / z: 477 (M + H ⁺ ).
HRMS (FAB ^+): Calculated _{C 20 H 21 N 4 O 4} S 3: 477.0725
Actual value: 477.0727.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 25; 76.0 mg, 0.184 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylic acid (60.0 mg, 82%).
MS (FAB ⁺ ) m / z: 399 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 19 N 4 O 2 S 2 Calculated: 399.0949
Actual value: 399.0952.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 26; 73.0 mg, 0.177 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylic acid (25.0 mg, 35%).
MS (EI) m / z: 398 (M ⁺ ).
_{HRMS (EI): C 19 H} 18 N 4 O 2 S 2 Calculated: 398.0871
Actual value: 398.0841.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 27; 70.0 mg, 0.170 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylic acid (62.5 mg, 92%).
MS (FAB ⁺ ) m / z: 399 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 19 N 4 O 2 S 2 Calculated: 399.0949
Actual value: 399.0941.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 28; 72. 7 mg, 0.151 mmol) gave 4- (benzylthio) -6-[(2,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (67.5 mg, 96% ).
MS (FAB ⁺ ) m / z: 466 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 18 Cl 2 N 3 O 2 S 2 Calculated: 466.0218
Actual value: 466.0220.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 29; 58. 2 mg, 0.121 mmol) gave 4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (52.6 mg, 93% ).
MS (FAB ⁺ ) m / z: 466 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 18 Cl 2 N 3 O 2 S 2 Calculated: 466.0218
Actual value: 466.0227.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 30; 50. 9 mg, 0.117 mmol) gave 4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (45.4 mg, 90% ).
MS (FAB ⁺ ) m / z: 434 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 18 F 2 N 3 O 2 S 2 Calculated: 434.0809
Actual value: 434.0836.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 31; 58. 7 mg, 0.131 mmol) gave 4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (51.3 mg, 90% ).
MS (FAB ⁺ ) m / z: 434 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 18 F 2 N 3 O 2 S 2 Calculated: 434.0809
Actual value: 434.0818.

In the same manner as in Example 1, methyl 4-[[3,5-bis (trifluoromethyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (Reference Example 32) From 73.7 mg, 0.135 mmol) from 4-[[3,5-bis (trifluoromethyl) benzyl] amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid. Obtained (58.3 mg, 81%).
MS (FAB ⁺ ) m / z: 534 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 18 F 6 N 3 O 2 S 2 Calculated: 534.0745
Actual value: 534.0752.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] -2- (methylthio) pyrimidine-5-carboxylate (Reference Example) 33 compound; 54.2 mg, 0.109 mmol) from 4- (benzylthio) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] -2- (methylthio) pyrimidine-5-carvone The acid was obtained (46.6 mg, 88%).
MS (FAB ⁺ ) m / z: 484 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 18 F 4 N 3 O 2 S 2 Calculated: 484.0777
Actual value: 484.00781.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 34; 58. 5 mg, 0.124 mmol) gave 4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (50.0 mg, 88% ).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 4 S 2 Calculated: 458.1208
Actual value: 458.1192.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 35; 47. 7 mg, 0.101 mmol) gave 4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (45.1 mg, 98% ).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 4 S 2 Calculated: 458.1208
Actual value: 458.1189.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 36; 89. 6 mg, 0.200 mmol) gave 4- (cyclohexylmethylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (70.0 mg, 81% ).
MS (FAB ⁺ ) m / z: 434 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 3 S 2 Calculated: 434.1572
Found: 434.1576.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 37; 100 mg, 0.230 mmol) gave 4- (cyclohexylmethylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (70.0 mg, 72%).
MS (FAB ⁺ ) m / z: 422 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₂₅ FN ₃ O ₂ S ₂ : 422.1372
Actual value: 422.1404.

In the same manner as in Example 1, methyl 4-[(4-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 38; 100 mg, 0.221 mmol) gave 4-[(4-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (75.6 mg, 78%).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 25 ClN 3 O 2 S 2 Calculated: 438.1077
Actual value: 438.1069.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 39; 82. 0 mg, 0.190 mmol) gave 4- (cyclohexylmethylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (52.1 mg, 66% ).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Actual value: 418.1609.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 40; 97. 8 mg, 0.227 mmol) gave 4- (cyclohexylmethylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (42.8 mg, 45% ).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Found: 418.1641.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 41; 93. 0 mg, 0.215 mmol) gave 4- (cyclohexylmethylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (61.0 mg, 68% ).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 28 N 3 O 2 S 2 Calculated: 418.1623
Found: 418.1619.

In the same manner as in Example 1, methyl 4-[(2-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 42; 94. 0 mg, 0.208 mmol) gave 4-[(2-chlorobenzyl) thio] -6- (cyclohexylmethylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (62.0 mg, 68% ).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 25 ClN 3 O 2 S 2 Calculated: 438.1077
Actual value: 438.1071.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 43; 114 mg, 0.234 mmol) gave 4- (cyclohexylmethylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (75.0 mg, 68%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 Cl 2 N 3 O 2 S 2 Calculated: 472.0687
Actual value: 472.0698.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 44; 102 mg, 0.210 mmol) gave 4- (cyclohexylmethylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (68.0 mg, 69%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 24 Cl 2 N 3 O 2 S 2 Calculated: 472.0687
Actual value: 472.0735.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] thio] pyrimidine-5-carboxylate (of Reference Example 45 Compound; 94.0 mg, 0.194 mmol) gives 4- (cyclohexylmethylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) benzyl] thio] pyrimidine-5-carboxylic acid. (50.8 mg, 56%).
MS (FAB ⁺ ) m / z: 472 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 25 F 3 N 3 O 2 S 2 Calculated: 472.1340
Actual value: 472.1357.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 46; 75.0 mg, 0.183 mmol) ) Gave 4- (cyclohexylmethylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (38.6 mg, 53%).
MS (FAB ⁺ ) m / z: 396 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 30 N 3 O 2 S 2 Calculated: 396.1779
Actual value: 396.1796.

In the same manner as in Example 1, methyl 4- (cyclohexylmethylamino) -6- (cyclopentylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 47; 94.5 mg, 0.239 mmol) ) Gave 4- (cyclohexylmethylamino) -6- (cyclopentylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (50.5 mg, 55%).
MS (FAB ⁺ ) m / z: 382 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 28 N 3 O 2 S 2 Calculated: 382.1623
Actual value: 382.1664.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 48; 82.0 mg) 0.189 mmol) gave 4- (cyclohexylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (62.0 mg, 78%).
MS (FAB ⁺ ) m / z: 420 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 3 S 2 Calculated: 420.1416
Found: 420.1429.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 49; 111 mg, 0 .263 mmol) gave 4- (cyclohexylamino) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (81.0 mg, 76%).
MS (FAB ⁺ ) m / z: 408 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 FN 3 O 2 S 2 Calculated: 408.1216
Actual value: 408.1235.

In the same manner as in Example 1, methyl 4-[(4-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 50; 115 mg, 0 .263 mmol) gave 4-[(4-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (87.3 mg, 78%).
MS (FAB ⁺ ) m / z: 424 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 ClN 3 O 2 S 2 Calculated: 424.0920
Found: 424.0896.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 51; 90.0 mg) 0.216 mmol) gave 4- (cyclohexylamino) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (64.5 mg, 74%).
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1487.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 52; 97.0 mg 0.232 mmol) gave 4- (cyclohexylamino) -6-[(3-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (62.1 mg, 66%).
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1450.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 53; 94.0 mg 0.225 mmol) gave 4- (cyclohexylamino) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (70.2 mg, 77%).
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1487.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) methylbenzyl] thio] pyrimidine-5-carboxylate (of Reference Example 54 Compound; 96.0 mg, 0.204 mmol) gives 4- (cyclohexylamino) -2- (methylthio) -6-[[3- (trifluoromethyl) methylbenzyl] thio] pyrimidine-5-carboxylic acid (66.0 mg, 71%).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 23 F 3 N 3 O 2 S 2 Calculated: 458.1184
Actual value: 458.1205.

In the same manner as in Example 1, methyl 4-[(2-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 55; 100 mg, 0 .228 mmol) gave 4-[(2-chlorobenzyl) thio] -6- (cyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (61.3 mg, 63%).
MS (FAB ⁺ ) m / z: 424 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 ClN 3 O 2 S 2 Calculated: 424.0920
Found: 424.0926.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 56; 118 mg) , 0.250 mmol) afforded 4- (cyclohexylamino) -6-[(2,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (88.5 mg, 77% ).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 22 Cl 2 N 3 O 2 S 2 Calculated: 458.0531
Actual value: 458.0496.

In the same manner as in Example 1, methyl 4- (cyclohexylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 57; 107 mg) 0.226 mmol) gave 4- (cyclohexylamino) -6-[(3,4-dichlorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (89.0 mg, 86% ).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 22 Cl 2 N 3 O 2 S 2 Calculated: 458.0531
Actual value: 458.0496.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 58; 62.0 mg 0.141 mmol) gave 4- (cyclohexylthio) -6-[(4-fluorobenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (18.9 mg, 32%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₁₉ H ₂₂ FN ₂ O ₂ S ₃ : 425.0827
Actual value: 425.0857.

In the same manner as in Example 1, methyl 4-[(4-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 59; 88.0 mg) 0.193 mmol) gave 4-[(4-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (27.4 mg, 35%).
MS (FAB ⁺ ) m / z: 441 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₁₉ H ₂₂ ClN ₂ O ₂ S ₃ : 441.0532
Found: 441.0522.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 60; 72.0 mg 0.166 mmol) gave 4- (cyclohexylthio) -6-[(4-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (47.5 mg, 68%).
MS (FAB ⁺ ) m / z: 421 (M + H ⁺ ).
HRMS (FAB ^+): Calculated _{C 20 H 25 N 2 O 2} S 3: 421.1078
Found: 421.1110.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 61; 68.5 mg 0.157 mmol) gave 4- (cyclohexylthio) -6-[(2-methylbenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (28.3 mg, 43%).
MS (FAB ⁺ ) m / z: 421 (M + H ⁺ ).
HRMS (FAB ^+): Calculated _{C 20 H 25 N 2 O 2} S 3: 421.1078
Actual value: 421.1078.

In the same manner as in Example 1, methyl 4-[(2-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 62; 64.0 mg 0.141 mmol) gave 4-[(2-chlorobenzyl) thio] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (44.5 mg, 72%).
MS (FAB ⁺ ) m / z: 441 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₁₉ H ₂₂ ClN ₂ O ₂ S ₃ : 441.0532
Found: 441.0554.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 63; 66.5 mg) 0.148 mmol) gave 4- (cyclohexylthio) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (45.0 mg, 70%).
MS (FAB ⁺ ) m / z: 437 (M + H ⁺ ).
HRMS (FAB ^+): Calculated _{C 20 H 25 N 2 O 3} S 3: 437.1027
Actual value: 437.1051.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(α-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 64; 94.0 mg, 0.221 mmol) gave 4- (benzylthio) -6-[(α-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (70.0 mg, 77%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Found: 412.1134.

In the same manner as in Example 1, methyl 4- (benzylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 65; 93.6 mg) 0.212 mmol) gave 4- (benzylamino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (85.0 mg, 94%).
MS (FAB ⁺ ) m / z: 428 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 3 S 2 Calculated: 428.1103
Actual value: 428.1125.

In the same manner as in Example 1, methyl 4-[(4-chlorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (of Reference Example 66 Compound; 93.0 mg, 0.195 mmol) gives 4-[(4-chlorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (89.0 mg, 99%).
MS (FAB ⁺ ) m / z: 462 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 ClN 3 O 3 S 2 Calculated: 462.0713
Actual value: 462.0741.

In the same manner as in Example 1, methyl 4-[(4-methoxybenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (of Reference Example 67 Compound; 92.0 mg, 0.195 mmol) gives 4-[(4-methoxybenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (82.7 mg, 93%).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 24 N 3 O 4 S 2 Calculated: 458.1208
Actual value: 458.1231.

In the same manner as in Example 1, methyl 4-[(4-fluorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (of Reference Example 68) Compound; 87.0 mg, 0.189 mmol) gives 4-[(4-fluorobenzyl) amino] -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (78.2 mg, 93%).
MS (FAB ⁺ ) m / z: 446 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 FN 3 O 3 S 2 Calculated: 446.1008
Found: 446.0978.

In the same manner as in Example 1, methyl 4-anilino-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 69; 53.0 mg, 0. 124 mmol) gave 4-anilino-6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (47.9 mg, 93%).
MS (FAB ⁺ ) m / z: 414 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 20 N 3 O 3 S 2 Calculated: 414.0946
Found: 414.0907.

In the same manner as in Example 1, methyl 4- (4-chloroanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 70; 37. 0 mg, 80.1 μmol) gave 4- (4-chloroanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (33.7 mg, 94% ).
MS (FAB ⁺ ) m / z: 448 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 19 ClN 3 O 3 S 2 Calculated: 448.0556
Actual value: 448.0543.

In the same manner as in Example 1, methyl 4- (4-methoxyanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 71; 28.0 mg, 61.2 μmol) gave 4- (4-methoxyanilino) -6-[(4-methoxybenzyl) thio] -2- (methylthio) pyrimidine-5-carboxylic acid (23. 8 mg, 88%).
MS (FAB ⁺ ) m / z: 444 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 4 S 2 Calculated: 444.1052
Actual value: 444.1068.

In the same manner as in Example 1, methyl 4- (4-fluoroanilino) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 72; 51. 0 mg, 0.114 mmol) gave 4- (4-fluoroanilino) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (46.0 mg, 94% ).
MS (FAB ⁺ ) m / z: 432 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₁₉ FN ₃ O ₃ S ₂ : 432.0852
Actual value: 432.0883.

In the same manner as in Example 1, from methyl 4-anilino-6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 73; 60.0 mg, 0.152 mmol), 4 -Anilino-6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylic acid was obtained (56.2 mg, 97%).
MS (FAB ⁺ ) m / z: 381 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₂₁ N ₄ O ₂ S: 381.1385
Actual value: 381.1425.

In the same manner as in Example 1, methyl 4- (benzylamino) -6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 74; 70.0 mg, 0.171 mmol) Gave 4- (benzylamino) -6- (benzylthio) -2- (dimethylamino) pyrimidine-5-carboxylic acid (60.0 mg, 89%).
MS (FAB ⁺ ) m / z: 395 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₃ N ₄ O ₂ S: 395.1542
Actual value: 395.1589.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6- (phenethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 75; 71.0 mg, 0.168 mmol) Gave 4- (benzylthio) -2- (dimethylamino) -6- (phenethylamino) pyrimidine-5-carboxylic acid (68.6 mg, 99%).
MS (FAB ⁺ ) m / z: 409 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S Calculated: 409.1698
Actual value: 409.1727.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 76; 72.0 mg) 0.163 mmol) gave 4- (benzylthio) -6-[(2-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (61.1 mg, 87%).
MS (FAB ⁺ ) m / z: 429 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₂ ClN ₄ O ₂ S: 429.1152
Found: 429.1130.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 77; 73.0 mg) 0.165 mmol) gave 4- (benzylthio) -6-[(3-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (66.1 mg, 93%).
MS (FAB ⁺ ) m / z: 429 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₂ ClN ₄ O ₂ S: 429.1152
Found: 429.1169.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 78; 72.0 mg 0.163 mmol) gave 4- (benzylthio) -6-[(4-chlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (65.7 mg, 94%).
MS (FAB ⁺ ) m / z: 429 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₂ ClN ₄ O ₂ S: 429.1152
Found: 429.1138.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-fluorobenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 79; 53.0 mg) 0.124 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(2-fluorobenzyl) amino] pyrimidine-5-carboxylic acid (48.5 mg, 95%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₂ FN ₄ O ₂ S: 413.1448
Actual value: 413.1487.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-fluorobenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 80; 41.5 mg) 97.3 μmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(3-fluorobenzyl) amino] pyrimidine-5-carboxylic acid (36.4 mg, 91%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₂ FN ₄ O ₂ S: 413.1448
Found: 413.1428.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-fluorobenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 81; 80.0 mg) 0.188 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(4-fluorobenzyl) amino] pyrimidine-5-carboxylic acid (67.6 mg, 87%).
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₂ FN ₄ O ₂ S: 413.1448
Actual value: 413.11461.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-methoxybenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 82; 69.0 mg) 0.157 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(2-methoxybenzyl) amino] pyrimidine-5-carboxylic acid (64.2 mg, 96%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₅ N ₄ O ₃ S: 425.1647
Found: 425.1624.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-methoxybenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 83; 61.0 mg) 0.139 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(3-methoxybenzyl) amino] pyrimidine-5-carboxylic acid (59.0 mg, 99%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₅ N ₄ O ₃ S: 425.1647
Found: 425.1664.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-methoxybenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 84; 70.0 mg) 0.160 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(4-methoxybenzyl) amino] pyrimidine-5-carboxylic acid (53.6 mg, 79%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₅ N ₄ O ₃ S: 425.1647
Actual value: 425.1643.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-methylbenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 85; 59.5 mg) 0.141 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(2-methylbenzyl) amino] pyrimidine-5-carboxylic acid (54.1 mg, 94%).
MS (FAB ⁺ ) m / z: 409 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S Calculated: 409.1698
Actual value: 409.1682.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-methylbenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 86; 87.0 mg) 0.206 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(3-methylbenzyl) amino] pyrimidine-5-carboxylic acid (80.0 mg, 95%).
MS (FAB ⁺ ) m / z: 409 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S Calculated: 409.1698
Actual value: 409.1709.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-methylbenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 87; 71.0 mg) 0.168 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(4-methylbenzyl) amino] pyrimidine-5-carboxylic acid (63.4 mg, 92%).
MS (FAB ⁺ ) m / z: 409 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 25 N 4 O 2 S Calculated: 409.1698
Actual value: 409.1718.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 88) 50.0 mg, 0.105 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[[2- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid ( 48.6 mg, 99%).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₂ F ₃ N ₄ O ₂ S: 463.1416
Actual value: 463.1406.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 89) 66.0 mg, 0.139 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[[3- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid ( 57.5 mg, 89%).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₂ F ₃ N ₄ O ₂ S: 463.1416
Actual value: 463.1443.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 90) 81.0 mg, 0.170 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid ( 72.7 mg, 92%).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₂ F ₃ N ₄ O ₂ S: 463.1416
Actual value: 463.1438.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (cyclohexylmethylamino) -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 91; 70.0 mg, 0.169 mmol) ) Gave 4- (benzylthio) -6- (cyclohexylmethylamino) -2- (dimethylamino) pyrimidine-5-carboxylic acid (63.7 mg, 94%).
MS (FAB ⁺ ) m / z: 401 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₉ N ₄ O ₂ S: 401.2011
Actual value: 401.2025.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 92 60.8 mg, 0.123 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[[4- (trifluoromethoxy) benzyl] amino] pyrimidine-5-carboxylic acid ( 53.9 mg, 92%).
MS (FAB ⁺ ) m / z: 479 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₂ F ₃ N ₄ O ₃ S: 479.1365
Found: 479.1354.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 93; 80.0 mg) 0.165 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(4-phenylbenzyl) amino] pyrimidine-5-carboxylic acid (73.9 mg, 95%).
MS (FAB ⁺ ) m / z: 471 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₇ H ₂₇ N ₄ O ₂ S: 471.1855
Found: 471.11851.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 94; 76 0.5 mg, 0.165 mmol) gave 4- (benzylthio) -6-[(4-tert-butylbenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (64.6 mg, 87%).
MS (FAB ⁺ ) m / z: 451 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₅ H ₃₁ N ₄ O ₂ S: 451.2168
Actual value: 451.2126.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[[4- (dimethylamino) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 95; 60.5 mg, 0.134 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[[4- (dimethylamino) benzyl] amino] pyrimidine-5-carboxylic acid (44. 0 mg, 75%).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₈ N ₅ O ₂ S: 438.1964
Found: 438.1984.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 96; 1.25 g) , 3.05 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(2-pyridylmethyl) amino] pyrimidine-5-carboxylic acid (1.20 g, 99%).
MS (FAB ⁺ ) m / z: 396 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 22 N 5 O 2 S Calculated: 396.1494
Actual value: 396.1498.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 97; 1.20 g 2.93 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(3-pyridylmethyl) amino] pyrimidine-5-carboxylic acid (1.16 g, 99%).
MS (FAB ⁺ ) m / z: 396 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 22 N 5 O 2 S Calculated: 396.1494
Actual value: 396.1521.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 98; 56.0 mg) 0.137 mmol) gave 4- (benzylthio) -2- (dimethylamino) -6-[(4-pyridylmethyl) amino] pyrimidine-5-carboxylic acid (49.0 mg, 90%).
MS (FAB ⁺ ) m / z: 396 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 22 N 5 O 2 S Calculated: 396.1494
Actual value: 396.1506.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6- (furfurylamino) pyrimidine-5-carboxylate (the compound of Reference Example 99; 58.3 mg, 0.146 mmol) ) Gave 4- (benzylthio) -2- (dimethylamino) -6- (furfurylamino) pyrimidine-5-carboxylic acid (50.4 mg, 90%).
MS (FAB ⁺ ) m / z: 385 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₁₉ H ₂₁ N ₄ O ₃ S: 385.1334
Actual value: 385.1315.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 100; 52 0.1 mg, 0.109 mmol) gave 4- (benzylthio) -6-[(3,4-dichlorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (48.3 mg, 96%).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₁ Cl ₂ N ₄ O ₂ S: 463.0762
Actual value: 463.0722.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 101; 58 0.0 mg, 0.130 mmol) gave 4- (benzylthio) -6-[(2,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (53.4 mg, 95%).
MS (FAB ⁺ ) m / z: 431 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₁ F ₂ N ₄ O ₂ S: 431.1353
Actual value: 431.1386.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 102; 82 0.0 mg, 0.184 mmol) gave 4- (benzylthio) -6-[(3,4-difluorobenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (78.8 mg, 99%).
MS (FAB ⁺ ) m / z: 431 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₁ F ₂ N ₄ O ₂ S: 431.1353
Actual value: 431.1350.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[[3,5-bis (trifluoromethyl) benzyl] amino] -2- (dimethylamino) pyrimidine-5-carboxylate (Reference Example) 103 compound; 84.7 mg, 0.156 mmol) from 4- (benzylthio) -6-[[3,5-bis (trifluoromethyl) benzyl] amino] -2- (dimethylamino) pyrimidine-5-carboxyl The acid was obtained (76.4 mg, 92%). MS (FAB ⁺ ) m / z: 531 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₁ F ₆ N ₄ O ₂ S: 531.1289
Actual value: 531.1315.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (dimethylamino) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (reference Compound of Example 104; 62.0 mg, 0.125 mmol) from 4- (benzylthio) -2- (dimethylamino) -6-[[3-fluoro-5- (trifluoromethyl) benzyl] amino] pyrimidine-5 -Carboxylic acid was obtained (54.2 mg, 90%).
MS (FAB ⁺ ) m / z: 481 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₁ F ₄ N ₄ O ₂ S: 481.1321
Found: 481.1354.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 105; 64 4.0 mg, 0.137 mmol) gave 4- (benzylthio) -6-[(2,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (58.0 mg, 93%).
MS (FAB ⁺ ) m / z: 455 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₄ S: 455.1753
Actual value: 455.1779.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 106; 55 .8 mg, 0.119 mmol) gave 4- (benzylthio) -6-[(3,4-dimethoxybenzyl) amino] -2- (dimethylamino) pyrimidine-5-carboxylic acid (46.0 mg, 85%).
MS (FAB ⁺ ) m / z: 455 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₄ S: 455.1753
Actual value: 455.1770.

In the same manner as in Example 1, methyl 4- (benzylamino) -6- (benzylthio) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (the compound of Reference Example 107; 1.20 g, 2.76 mmol) ) Gave 4- (benzylamino) -6- (benzylthio) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid (1.15 g, 99%).
MS (FAB ⁺ ) m / z: 421 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₅ N ₄ O ₂ S: 421.1698
Found: 421.1694.

In the same manner as in Example 1, from methyl 4- (benzylamino) -6- (benzylthio) -2-piperidinopyrimidine-5-carboxylate (the compound of Reference Example 108; 63.0 mg, 0.140 mmol) 4- (benzylamino) -6- (benzylthio) -2-piperidinopyrimidine-5-carboxylic acid was obtained (59.0 mg, 97%).
MS (FAB ⁺ ) m / z: 435 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₇ N ₄ O ₂ S: 435.1855
Found: 435.1899.

In the same manner as in Example 1, methyl 4- (benzylamino) -6- (benzylthio) -2-morpholinopyrimidine-5-carboxylate (the compound of Reference Example 109; 27.7 mg, 61.5 μmol) to 4 -(Benzylamino) -6- (benzylthio) -2-morpholinopyrimidine-5-carboxylic acid was obtained (24.0 mg, 89%).
MS (FAB ⁺ ) m / z: 437 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₅ N ₄ O ₃ S: 437.1647
Actual value: 437.1626.

26. In the same manner as in Example 1, methyl 4- (benzylamino) -6- (benzylthio) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylate (the compound of Reference Example 110; 27. 5 mg, 59.3 μmol) gave 4- (benzylamino) -6- (benzylthio) -2- (4-methylpiperazin-1-yl) pyrimidine-5-carboxylic acid (14.7 mg, 55% ).
MS (FAB ⁺ ) m / z: 450 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₈ N ₅ O ₂ S: 450.1964
Actual value: 450.1973.

In the same manner as in Example 1, methyl 4- (benzylamino) -6- (benzylthio) -2- (n-butylamino) pyrimidine-5-carboxylate (the compound of Reference Example 111; 47.6 mg, 0. 109 mmol) gave 4- (benzylamino) -6- (benzylthio) -2- (n-butylamino) pyrimidine-5-carboxylic acid (38.0 mg, 83%).
MS (FAB ⁺ ) m / z: 423 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₃ H ₂₇ N ₄ O ₂ S: 423.1855
Found: 423.1880.

In the same manner as in Example 1, from methyl 4- (benzylthio) -2,6-bis (benzylamino) pyrimidine-5-carboxylate (the compound of Reference Example 112; 52.0 mg, 0.110 mmol), 4- (Benzylthio) -2,6-bis (benzylamino) pyrimidine-5-carboxylic acid was obtained (40.7 mg, 81%).
MS (FAB ⁺ ) m / z: 457 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₆ H ₂₅ N ₄ O ₂ S: 457.1698
Actual value: 457.1672.

In the same manner as in Example 1, benzyl 4- (benzyloxy) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 113; 124 mg, 0 245 mmol) gave 4- (benzyloxy) -6-[(4-chlorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (50.3 mg, 49%).
MS (FAB ⁺ ) m / z: 416 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₁₉ ClN ₃ O ₃ S: 416.0836
Actual value: 416.0853.

In the same manner as in Example 1, methyl 4- (benzylamino) -6- (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 114; 80.0 mg, 0.202 mmol) Gave 4- (benzylamino) -6- (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylic acid (61.8 mg, 80%). MS (FAB ⁺ ) m / z: 382 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 20 N 3 O 3 S Calculated: 382.1225
Actual value: 382.1191.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (cyclopropylamino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 115; 57.0 mg, 0.158 mmol) Gave 4- (benzylthio) -6- (cyclopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (52.0 mg, 95%).
MS (FAB ⁺ ) m / z: 348 (M + H ⁺ ).
_{^{HRMS (FAB +): C 16}} H 18 N 3 O 2 S 2 Calculated: 348.0840
Actual value: 348.0850.

In the same manner as in Example 1, methyl 6- (4-chloroanilino) -4- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 116; 30.0 mg, 69.5 μmol) From 6- (4-chloroanilino) -4- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (15.0 mg, 52%).
MS (FAB ⁺ ) m / z: 418 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 17 ClN 3 O 2 S 2 Calculated: 418.0451
Found: 418.0432.

In the same manner as in Example 1, from methyl 4- (benzylamino) -6- (furfurylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 117; 50.0 mg, 0.125 mmol) 4- (benzylamino) -6- (furfurylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (48.5 mg, 99%). MS (FAB ⁺ ) m / z: 388 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 18 N 3 O 3 S 2 Calculated: 388.0790
Actual value: 388.0782.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[[2- (1-methylpyrrolidin-2-yl) ethyl] amino] -2- (methylthio) pyrimidine-5-carboxylate (reference From the compound of Example 118; 128 mg, 0.296 mmol), 4- (benzylthio) -6-[[2- (1-methylpyrrolidin-2-yl) ethyl] amino] -2- (methylthio) pyrimidine-5-carboxylic The acid was obtained (96.4 mg, 78%).
MS (FAB ⁺ ) m / z: 419 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 27 N 4 O 2 S 2 Calculated: 419.1575
Actual value: 419.1591.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[3- (2-oxopyrrolidin-1-yl) propyl] amino] pyrimidine-5-carboxylate (reference From the compound of Example 119; 174 mg, 0.390 mmol), 4- (benzylthio) -2- (methylthio) -6-[[3- (2-oxopyrrolidin-1-yl) propyl] amino] pyrimidine-5-carvone The acid was obtained (167 mg, 99%).
MS (FAB ⁺ ) m / z: 433 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 25 N 4 O 3 S 2 Calculated: 433.1368
Found: 433.1354.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[(tetrahydrofuran-2-yl) methyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 120; 195 mg, 0.481 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[[(tetrahydrofuran-2-yl) methyl] amino] pyrimidine-5-carboxylic acid (123 mg, 65% ).
MS (FAB ⁺ ) m / z: 392 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 22 N 3 O 3 S 2 Calculated: 392.1103
Actual value: 392.1105.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(2-morpholinoethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 121; 130 mg,. 300 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[(2-morpholinoethyl) amino] pyrimidine-5-carboxylic acid (77.0 mg, 61%).
MS (FAB ⁺ ) m / z: 421 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 25 N 4 O 3 S 2 Calculated: 421.1368
Found: 421.1353.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(2-piperidinoethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 122; 175 mg, 0.405 mmol ) Gave 4- (benzylthio) -2- (methylthio) -6-[(2-piperidinoethyl) amino] pyrimidine-5-carboxylic acid (150 mg, 88%).
MS (FAB ⁺ ) m / z: 419 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 27 N 4 O 2 S 2 Calculated: 419.1575
Found: 419.1570.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[2- (1-pyrrolidinyl) ethyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 123; 132 mg, 0.315 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[[2- (1-pyrrolidinyl) ethyl] amino] pyrimidine-5-carboxylic acid (105 mg, 82% ).
MS (FAB ⁺ ) m / z: 405 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 25 N 4 O 2 S 2 Calculated: 405.1419
Actual value: 405.1445.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[[2- (1,3-dioxolan-2-yl) ethyl] amino] -2- (methylthio) pyrimidine-5-carboxylate ( From the compound of Reference Example 124; 50.0 mg, 0.119 mmol), 4- (benzylthio) -6-[[2- (1,3-dioxolan-2-yl) ethyl] amino] -2- (methylthio) pyrimidine -5-carboxylic acid was obtained (40.0 mg, 83%).
MS (FAB ⁺ ) m / z: 408 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 22 N 3 O 4 S 2 Calculated: 408.1052
Actual value: 408.1004.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[[2- (cyclohexen-1-yl) ethyl] amino] pyrimidine-5-carboxylate (of Reference Example 125 Compound (115 mg, 0.268 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[[2- (cyclohexen-1-yl) ethyl] amino] pyrimidine-5-carboxylic acid ( 84.5 mg, 76%).
MS (FAB ⁺ ) m / z: 416 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 26 N 3 O 2 S 2 Calculated: 416.1466
Actual value: 416.1473.

In a manner similar to Example 1, 4- (benzylthio) -2- (methylthio) -6-[[2-[(5-nitropyridin-2-yl) amino] ethyl] amino] pyrimidine-5-carboxylic acid From methyl (compound of reference example 126; 148 mg, 0.304 mmol) to 4- (benzylthio) -2- (methylthio) -6-[[2-[(5-nitropyridin-2-yl) amino] ethyl] amino Pyrimidine-5-carboxylic acid was obtained (137 mg, 95%).
MS (FAB ⁺ ) m / z: 473 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 21 N 6 O 4 S 2 Calculated: 473.1066
Actual value: 473.1088.

In the same manner as in Example 1, methyl 4-[(2-anilinoethyl) amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 127; 268 mg, 0.609 mmol) ) Gave 4-[(2-anilinoethyl) amino] -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (140 mg, 54%).
MS (FAB ⁺ ) m / z: 427 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 23 N 4 O 2 S 2 Calculated: 427.1262

Found: 427.1278.

In the same manner as in Example 1, methyl 4- (benzylthio) -2- (methylthio) -6-[(2-phenoxyethyl) amino] pyrimidine-5-carboxylate (the compound of Reference Example 128; 216 mg, 0. 490 mmol) gave 4- (benzylthio) -2- (methylthio) -6-[(2-phenoxyethyl) amino] pyrimidine-5-carboxylic acid (203 mg, 97%).
MS (FAB ⁺ ) m / z: 428 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 3 S 2 Calculated: 428.1103
Actual value: 428.1104.

In the same manner as in Example 1, methyl 4- (benzylthio) -6-[[3- (1-imidazolyl) propyl] amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 129; 208 mg, 0.484 mmol) gave 4- (benzylthio) -6-[[3- (1-imidazolyl) propyl] amino] -2- (methylthio) pyrimidine-5-carboxylic acid (171 mg, 85% ).
MS (FAB ⁺ ) m / z: 416 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 22 N 5 O 2 S 2 Calculated: 416.1215
Actual value: 416.1211.

In the same manner as in Example 1, from methyl 4- (benzylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 130; 178 mg, 0.442 mmol), 4- (Benzylamino) -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (139 mg, 81%).
MS (FAB ⁺ ) m / z: 390 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 24 N 3 O 2 S 2 Calculated: 390.1310
Actual value: 390.1264.

In the same manner as in Example 1, methyl 4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 131; 180 mg, 0 .414 mmol) gave 4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (156 mg, 89%).
MS (FAB ⁺ ) m / z: 424 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 ClN 3 O 2 S 2 Calculated: 424.0920
Actual value: 424.0912.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 132; 166 mg, 0 .384 mmol) gave 4- (cyclohexylthio) -6-[(4-methoxybenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (136 mg, 84%).
MS (FAB ⁺ ) m / z: 420 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 3 S 2 Calculated: 420.1416
Actual value: 420.1371.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 133; 140 mg, 0 .332 mmol) gave 4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (125 mg, 92%).
MS (FAB ⁺ ) m / z: 408 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 23 FN 3 O 2 S 2 Calculated: 408.1216
Actual value: 408.1247.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 134; 82.0 mg) 0.196 mmol) gave 4- (cyclohexylthio) -6-[(4-methylbenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (55.7 mg, 70%).
MS (FAB ⁺ ) m / z: 404 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 26 N 3 O 2 S 2 Calculated: 404.1466
Actual value: 404.1488.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylate (the compound of Reference Example 135) 130 mg, 0.276 mmol) gave 4- (cyclohexylthio) -2- (methylthio) -6-[[4- (trifluoromethyl) benzyl] amino] pyrimidine-5-carboxylic acid (118 mg, 94%).
MS (FAB ⁺ ) m / z: 458 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 23 F 3 N 3 O 2 S 2 Calculated: 458.1184
Actual value: 458.1183.

In the same manner as in Example 1, methyl 4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 136; 115 mg, 0 271 mmol) gave 4-[(4-chlorobenzyl) amino] -6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (67.8 mg, 61%).
MS (FAB ⁺ ) m / z: 410 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 21 ClN 3 O 2 S 2 Calculated: 410.0764
Found: 410.0769.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 137; 123 mg, 0 .301 mmol) gave 4- (cyclohexylthio) -6-[(4-fluorobenzyl) amino] -2- (methylthio) pyrimidine-5-carboxylic acid (84.8 mg, 72%).
MS (FAB ⁺ ) m / z: 394 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 21 FN 3 O 2 S 2 Calculated: 394.1059
Actual value: 394.1089.

In the same manner as in Example 1, from methyl 4-anilino-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 138; 65.0 mg, 0.167 mmol), 4 -Anilino-6- (cyclohexylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (44.0 mg, 70%).
MS (FAB ⁺ ) m / z: 376 (M + H ⁺ ).
_{^{HRMS (FAB +): C 18}} H 22 N 3 O 2 S 2 Calculated: 376.1153

Actual value: 376.1145.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6- (4-methylanilino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 139; 75.0 mg, 0.186 mmol) ) Gave 4- (cyclohexylthio) -6- (4-methylanilino) -2- (methylthio) pyrimidine-5-carboxylic acid (57.9 mg, 80%).
MS (FAB ⁺ ) m / z: 390 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 24 N 3 O 2 S 2 Calculated: 390.1310
Actual value: 390.1282.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -6- (4-methoxyanilino) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 140; 85.0 mg, 0 .203 mmol) gave 4- (cyclohexylthio) -6- (4-methoxyanilino) -2- (methylthio) pyrimidine-5-carboxylic acid (77.7 mg, 94%).
MS (FAB ⁺ ) m / z: 406 (M + H ⁺ ).
_{^{HRMS (FAB +): C 19}} H 24 N 3 O 3 S 2 Calculated: 406.1259
Actual value: 406.1246.

In the same manner as in Example 1, methyl 4- (cyclohexylthio) -2- (methylthio) -6- [4- (trifluoromethyl) anilino] pyrimidine-5-carboxylate (the compound of Reference Example 141; 98. 0 mg, 0.214 mmol) gave 4- (cyclohexylthio) -2- (methylthio) -6- [4- (trifluoromethyl) anilino] pyrimidine-5-carboxylic acid (59.6 mg, 63% ).
MS (EI) m / z: 443 (M ⁺ ).
_{HRMS (EI): C 19 H} 20 F 3 N 3 O 2 S 2 Calculated: 443.0949
Actual value: 443.0923.

To a solution of 4,6-dichloro-2- (methylthio) pyrimidine-5-carboxylic acid (the compound of Reference Example 167; 120 mg, 0.502 mmol) in N, N-dimethylformamide (1 mL) was added potassium carbonate (138 mg,. 999 mmol) and phenylmethanethiol (124 mg, 1.00 mmol) were added with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled with ice and 2N hydrochloric acid was added to adjust to pH = 1, and the precipitated crystals were collected by filtration and washed successively with water and ethanol to give 4,6- (dibenzylthio) -2- (methylthio) pyrimidine. -5-carboxylic acid was obtained (180 mg, 86%).
MS (FAB ⁺ ) m / z: 415 (M + H ⁺ ).
HRMS (FAB ^+): Calculated _{C 20 H 19 N 2 O 2} S 3: 415.0609
Found: 415.0578.
¹ H-NMR (400Mz, DMSO-d6) ppm: 2.55 (3H, s), 4.38 (4H, s), 7.22-7.42 (10H,
m), 14.1 (1H, br)

In a manner similar to Example 142, 4,6-dichloro-2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid (compound of Reference Example 166; 900 mg, 3.43 mmol) and phenylmethanethiol (938 mg, 7. 55 mmol) gave 4,6- (dibenzylthio) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid (1.44 g, 96%).
MS (FAB ⁺ ) m / z: 438 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 24 N 3 O 2 S 2 Calculated: 438.1310
Actual value: 438.1317.

In the same manner as in Example 142, 4,6-dichloro-2- (dimethylamino) pyrimidine-5-carboxylic acid (the compound of Reference Example 168; 900 mg, 3.81 mmol) and phenylmethanethiol (1.05 g, 8 .45 mmol) gave 4,6- (dibenzylthio) -2- (dimethylamino) pyrimidine-5-carboxylic acid (1.49 g, 95%).
MS (FAB ⁺ ) m / z: 412 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 2 S 2 Calculated: 412.1153
Actual value: 412.1179.

4- (Benziamino) -2- (N-butylmethylamino) -6-chloropyrimidine-5-carboxylate (Compound of Reference Example 146; 40.4 mg, 0.111 mmol) of N, N-dimethylformamide (0 0.5 mL) solution was added with potassium carbonate (46.0 mg, 0.333 mmol) and phenylmethanethiol (28.0 mg, 0.225 mmol) and stirred at 80 ° C. for 3 hours. Since the reaction solution was cooled with ice and 2N hydrochloric acid was added to adjust to pH = 1, precipitation occurred, so that 4- (benzylamino) -2- (N-butylmethylamino) -6-chloropyrimidine-5-carboxylic acid was obtained. Obtained (19.0 mg, 39%).
MS (FAB ⁺ ) m / z: 437 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₉ N ₄ O ₂ S: 437.2011
Found: 437.1968.

In the same manner as in Example 145, methyl 4- (benzylamino) -6-chloro-2- (dibutylamino) pyrimidine-5-carboxylate (the compound of Reference Example 147; 22.4 mg, 54.3 μmol) and phenylmethane The thiol (13.5 mg, 0.109 mmol) gave 4- (benzylamino) -6-chloro-2- (dibutylamino) pyrimidine-5-carboxylic acid (18.0 mg, 69%).
MS (FAB ⁺ ) m / z: 479 (M + H ⁺ ).
_{^{HRMS (FAB +): C 27}} H 35 N 4 O 2 S Calculated: 479.2481
Actual value: 479.2491.

In a manner similar to Example 145, methyl 4- (benzamino) -6-chloro-2- (heptylamino) pyrimidine-5-carboxylate (Compound of Reference Example 148; 68.0 mg, 0.174 mmol) and phenylmethane From thiol (43.5 mg, 0.350 mmol), 4- (benzamino) -6-chloro-2- (heptylamino) pyrimidine-5-carboxylic acid was obtained (48.7 mg, 60%).
MS (FAB ⁺ ) m / z: 465 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₆ H ₃₃ N ₄ O ₂ S: 465.2324
Actual value: 465.2351.

In a manner similar to that in Example 145, methyl 4- (benzylamino) -6-chloro-2- (cyclopropylamino) pyrimidine-5-carboxylate (compound of reference example 149; 47.6 mg, 0.143 mmol) and phenyl From methanethiol (35.5 mg, 0.286 mmol), 4- (benzamino) -6-chloro-2- (cyclopropylamino) pyrimidine-5-carboxylic acid was obtained (52.0 mg, 89%).
MS (FAB ⁺ ) m / z: 407 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₂ H ₂₃ N ₄ O ₂ S: 407.1542.

Actual value: 407.1522.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 172; 50.0 mg, 0. 112 mmol) gave 4- (benzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (39.2 mg, 81%).
MS (FAB ⁺ ) m / z: 433 (M + H ⁺ ).
HRMS (FAB ^+): Calculated _{C 20 H 18 FN 2 O 2} S 3: 433.0514

Actual value: 433.0536.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 173; 99.0 mg, 0. 214 mmol) gave 4- (benzylthio) -6- (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (78.1 mg, 81%).
MS (FAB ⁺ ) m / z: 449 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 18 ClN 2 O 2 S 3 Calculated: 449.0219

Actual value: 449.0208.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 174; 57.2 mg, 0. 125 mmol) gave 4- (benzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (44.0 mg, 79%).
MS (FAB ⁺ ) m / z: 445 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 N 2 O 3 S 3 Calculated: 445.0714

Actual value: 445.0729.

In the same manner as in Example 1, methyl 4- (benzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 175; 90.0 mg; 197 mmol) gave 4- (benzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (39.6 mg, 47%).
MS (FAB ⁺ ) m / z: 429 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 21 N 2 O 2 S 3 Calculated: 429.0765

Actual value: 429.0796.

In the same manner as in Example 1, methyl 4- (4-fluorobenzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 176; 76. 8 mg, 0.161 mmol) gave 4- (4-fluorobenzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (61.1 mg, 82% ).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 FN 2 O 3 S 3 Calculated: 463.0620
Actual value: 463.0638.

In the same manner as in Example 1, methyl 4- (4-chlorobenzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 177; 85. 0 mg, 0.172 mmol) gave 4- (4-chlorobenzylthio) -6- (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (72.5 mg, 88% ).
MS (FAB ⁺ ) m / z: 479 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 ClN Calculated ₂ O ₃ S _3: 479.0325

Actual value: 479.0368.

In the same manner as in Example 1, from methyl 4,6-bis (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 178; 70.0 mg, 0.143 mmol) 4,6-bis (4-methoxybenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (60.7 mg, 89%).
MS (FAB ⁺ ) m / z: 475 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 N 2 O 4 S 3 Calculated: 475.0820

Actual value: 475.0830.

In the same manner as in Example 1, methyl 4- (4-methoxybenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 179; 57. 0 mg, 0.121 mmol) gave 4- (4-methoxybenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (39.0 mg, 70% ).
MS (FAB ⁺ ) m / z: 459 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 N 2 O 3 S 3 Calculated: 459.0871

Actual value: 459.0836.

実施例１と同様の方法により、４−（４−クロロベンジルチオ）−６−（４−フルオロベンジルチオ）−２−（メチルチオ）ピリミジン−５−カルボン酸メチル（参考例１８０の化合物；８４．０ｍｇ、０．１７５ｍｍｏｌ）から、４−（４−クロロベンジルチオ）−６−（４−フルオロベンジルチオ）−２−（メチルチオ）ピリミジン−５−カルボン酸が得られた（４７．６ｍｇ、５８％）。
MS(FAB⁺)m/z:467(M+H⁺).
HRMS(FAB⁺):C₂₀H₁₇ClFN₂O₂S₃として計算値:467.0125

実測値:467.0083.

In the same manner as in Example 1, methyl 4- (4-chlorobenzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 180; 84. 0 mg, 0.175 mmol) gave 4- (4-chlorobenzylthio) -6- (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (47.6 mg, 58% ).
MS (FAB ⁺ ) m / z: 467 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 17 ClFN 2 O 2 S 3 Calculated: 467.0125

Actual value: 467.0083.

In the same manner as in Example 1, from methyl 4,6-bis (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 181; 85.0 mg, 0.171 mmol) 4,6-bis (4-chlorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (58.5 mg, 71%).
MS (FAB ⁺ ) m / z: 483 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 17 Cl 2 N 2 O 2 S 3 Calculated: 482.9829
Actual value: 482.9862.

In the same manner as in Example 1, methyl 4- (4-chlorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 182; 74. 0 mg, 0.155 mmol) gave 4- (4-chlorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (57.3 mg, 80% ).
MS (FAB ⁺ ) m / z: 463 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 20 ClN 2 O 2 S 3 Calculated: 463.0375

Actual value: 463.0361.

In the same manner as in Example 1, from methyl 4,6-bis (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 183; 86.8 mg, 0.187 mmol) 4,6-bis (4-fluorobenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (42.5 mg, 50%).
MS (FAB ⁺ ) m / z: 451 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 17 F 2 N 2 O 2 S 3 Calculated: 451.0420
Actual value: 451.0402.

In the same manner as in Example 1, methyl 4- (4-fluorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 184; 75. 7 mg, 0.164 mmol) gave 4- (4-fluorobenzylthio) -6- (4-methylbenzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid (55.6 mg, 76% ).
MS (FAB ⁺ ) m / z: 447 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₂₀ FN ₂ O ₂ S ₃ : 447.0671

Actual value: 447.0700.

In the same manner as in Example 1, from methyl 4- (benzylamino) -6- (benzylthio) -2- (butylthio) pyrimidine-5-carboxylate (the compound of Reference Example 185; 77.0 mg, 0.170 mmol) 4- (benzylamino) -6- (benzylthio) -2- (butylthio) pyrimidine-5-carboxylic acid was obtained (55.0 mg, 74%).
MS (FAB ⁺ ) m / z: 440 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 26 N 3 O 2 S 2 Calculated: 440.1466

Actual value: 440.1483.

In the same manner as in Example 1, from methyl 4,6-bis (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 186; 91.3 mg, 0.200 mmol), 4,6 -Bis (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (58.2 mg, 66%).
MS (FAB ⁺ ) m / z: 443 (M + H ⁺ ).
_{^{HRMS (FAB +): C 22}} H 23 N 2 O 2 S 3 Calculated: 443.0922

Actual value: 443.0955.

In the same manner as in Example 1, from methyl 4,6-bis (benzyloxy) -2- (dimethylamino) pyrimidine-5-carboxylate (the compound of Reference Example 187; 74.0 mg, 0.188 mmol), 4 , 6-Bis (benzyloxy) -2- (dimethylamino) pyrimidine-5-carboxylic acid was obtained (42.0 mg, 59%).
MS (FAB ⁺ ) m / z: 380 (M + H ⁺ ).
_{^{HRMS (FAB +): C 21}} H 22 N 3 O 4 Calculated: 380.1610

Actual value: 380.1651.

In the same manner as in Example 1, from methyl 4,6-bis (benzyloxy) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylate (the compound of Reference Example 188; 54.6 mg, 0.130 mmol), 4,6-bis (benzyloxy) -2- (1-pyrrolidinyl) pyrimidine-5-carboxylic acid was obtained (42.5 mg, 81%).
MS (FAB ⁺ ) m / z: 406 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 24 N 3 O 4 Calculated: 406.1767

Actual value: 406.1766.

In the same manner as in Example 1, from methyl 4,6-bis (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 189; 62.4 mg, 0.157 mmol), 6-bis (benzyloxy) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (17.0 mg, 28%).
MS (FAB ⁺ ) m / z: 383 (M + H ⁺ ).
HRMS (FAB ⁺ ): Calculated as C ₂₀ H ₁₉ N ₂ O ₄ S: 383.1066

Actual value: 383.1111.

In the same manner as in Example 1, from methyl 4- (benzyloxy) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylate (the compound of Reference Example 190; 45.0 mg, 0.109 mmol) 4- (benzyloxy) -6- (benzylthio) -2- (methylthio) pyrimidine-5-carboxylic acid was obtained (40.0 mg, 92%).
MS (FAB ⁺ ) m / z: 399 (M + H ⁺ ).
_{^{HRMS (FAB +): C 20}} H 19 N 2 O 3 S 2 Calculated: 399.0837

Actual value: 399.0872.

In the same manner as in Example 1, from methyl 4- (benzylamino) -6- (benzylthio) -2- (octylthio) pyrimidine-5-carboxylate (the compound of Reference Example 191; 93.0 mg, 0.182 mmol) 4- (benzylamino) -6- (benzylthio) -2- (octylthio) pyrimidine-5-carboxylic acid was obtained (85.3 mg, 95%). MS (FAB ⁺ ) m / z: 496 (M + H ⁺ ).
_{^{HRMS (FAB +): C 27}} H 34 N 3 O 2 S 2 Calculated: 496.2092

Actual value: 496.2107.

In the same manner as in Example 145, methyl 4,6-dichloro-2- (butylthio) pyrimidine-5-carboxylate (the compound of Reference Example 198; 84.4 mg, 0.300 mmol) and phenylmethanethiol (95.0 mg) 0.765 mmol) provided 4,6-bis (benzylthio) -2- (butylthio) pyrimidine-5-carboxylic acid (120 mg, 88%).
MS (FAB ⁺ ) m / z: 457 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 25 N 2 O 2 S 3 Calculated: 457.1078

Actual value: 457.1093.

In the same manner as in Example 145, methyl 4,6-dichloro-2- (octylthio) pyrimidine-5-carboxylate (compound of Reference Example 199; 50.6 mg, 0.150 mmol) and phenylmethanethiol (47.0 mg) 0.378 mmol) gave 4,6-bis (benzylthio) -2- (octylthio) pyrimidine-5-carboxylic acid (56.0 mg, 73%).
MS (FAB ⁺ ) m / z: 513 (M + H ⁺ ).
_{^{HRMS (FAB +): C 27}} H 33 N 2 O 2 S 3 Calculated: 513.1704

Actual value: 513.1674.

In a manner similar to Example 145, methyl 4,6-dichloro-2- (morpholino) pyrimidine-5-carboxylate (compound of Reference Example 202; 111 mg, 0.399 mmol) and phenylmethanethiol (110 mg, 0.886 mmol) ) Gave 4,6-bis (benzylthio) -2- (morpholino) pyrimidine-5-carboxylic acid (168 mg, 93%).
MS (FAB ⁺ ) m / z: 454 (M + H ⁺ ).
_{^{HRMS (FAB +): C 23}} H 24 N 3 O 3 S 2 Calculated: 454.1259

Actual value: 454.1271.

  Next, with respect to the compounds of the present invention, the results supporting the usefulness are shown by test examples.

<Test Example 1>
Evaluation of PPARγ modulator activity
Transcriptional activation test for human peroxisome proliferator activated receptor (PPAR) γ
CHO-K1 cells cultured in Ham's F12 medium containing 10% fetal bovine serum were subjected to yeast binding factor GAL4 DNA binding region and human PPARγ ligand binding region (Biochemistry,
1993, 32, 5598) and a receptor plasmid (pM-hPPARγLBD) and its reporter plasmid (STRATAGENE, firefly luciferase reporter plasmid), and a Renilla luciferase plasmid (Promega) for internal standard, Co-transfected with Lipofectamine (Invitrogen) at 37 ° C. for 2 hours in a serum-free state. Then Ham's containing 10% defatted cow serum
After adding the test compound in F12 medium and culturing at 37 ° C. for 20 hours, both luciferase activities were measured, and a dose-dependent curve was drawn using the values corrected by the internal standard. The EC ₅₀ value and ME value of the test compound are defined as follows. When the PPARγ transcription activity value of the positive control group (addition concentration 1 μmol / L rosiglitazone alone treatment) is 100% and the PPARγ transcription activity value of the control group is 0%, the maximum PPARγ transcription activity value of the test compound alone Is ME (%). At this time, the concentration of the test compound showing the value of ME / 2 is calculated as the EC ₅₀ value. The results of EC ₅₀ value and ME value calculated in this way were used for evaluation of PPARγ modulator activity. The measurement results are shown in Table 1.

  From Table 1, it can be seen that the compound (1) of the present invention or a salt thereof exhibits excellent PPARγ modulator activity.

  The present invention has been found that a novel pyrimidine-5-carboxylic acid derivative or a salt thereof has an excellent PPARγ modulator action.

  Furthermore, the compounds of the present invention and their salts are safe with low toxicity. Therefore, the compounds of the present invention and salts thereof are used in various pathological states involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, regression, etc. It is intended to provide a highly useful drug effective for treatment, prevention or suppression of stage osteoporosis and the like.

Claims (20)

The following general formula (1)

Wherein X represents S, SO, SO ₂ or NH;
Y represents O, S, SO, SO ₂ or NH;
Q ¹ and Q ² are the same or different and each represents a single bond, C ₁ -C ₆ alkylene which may have a substituent or — (CH ₂ ) _n W—, and W represents O, S or NR ² . R ² represents a hydrogen atom or a C _{1 to} C ₆ alkyl group, n represents 2 to 6;
A and B are the same or different and are an aryl group, a cycloalkyl group or a heterocyclic group (the A and B are the same or different, a halogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a halogen atom, An aryl group, a nitro group, an aminosulfonyl group optionally substituted with one or two identical or different C ₁ -C ₆ alkyl groups, an amino group, a mono- or di-substituted C ₁ -C ₆ alkylamino group, ₁ to 3 substituents each independently selected from an oxo group, a hydroxyl group, and a C _{1 to} C ₆ alkoxy group optionally substituted with a halogen atom (two adjacent substituents are bonded to each other) Which may form a ring) and may have)
R ¹ represents ZR ³ (Z represents O, S, SO or SO ₂ , R ³ represents a hydrogen atom, a C _{1 to} C ₁₀ alkyl group, an aryl group or an aralkyl group) or NR ⁴ R ⁵ (R ⁴ and R ⁵ are bonded to each other to form a ring, or the same or different, and a hydrogen atom, a C ₁ -C ₇ alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a C ₁ -C ₆ alkylcarbonyl group , C ₁ -C ₆ alkylsulfonyl group or represents a.) of an aryl sulfonyl group, the R ^3, R ⁴ and R ⁵ are the same or different, a halogen atom, C ₁ ~ optionally substituted by a halogen atom C ₆ alkoxy group, a hydroxyl group, a amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkoxycarbonyl group, a 1 to 3 substituents selected from among carboxyl group It may be. ) Or a salt thereof. The following general formula (1a)

(Wherein Y represents O, S or NH, and Q ¹ , Q ² , W, R ² , n, A, B and R ¹ are the same as above). Pyrimidine-5-carboxylic acid derivatives or salts thereof. The following general formula (1b)

(Wherein Y represents O, S or NH, and Q ¹ , Q ² , W, R ² , n, A, B and R ¹ are the same as above). Pyrimidine-5-carboxylic acid derivatives or salts thereof. ^2. The pyrimidine-5-carboxylic acid derivative or a salt thereof according to claim 1, wherein in the general formula (1), Q ¹ and Q ² are C ₁ -C ₆ alkylene which may have a substituent. The pyrimidine-5-carboxylic acid derivative or a salt thereof according to claim 2, wherein in the general formula (1a), Q ¹ and Q ² are C ₁ -C ₆ alkylene which may have a substituent. The pyrimidine-5-carboxylic acid derivative or a salt thereof according to claim 3, wherein, in the general formula (1b), Q ¹ and Q ² are C ₁ -C ₆ alkylene which may have a substituent. In Formula (1a), a good C ₁ -C ₁₀ alkylene optionally Q ¹ and Q ² is substituted, as defined in claim 2 R ¹ is a C ₁ -C ₆ alkylthio group Pyrimidine-5-carboxylic acid derivatives or salts thereof. In formula (1b), and Q ¹ and Q ² is substituted is also good C ₁ -C ₆ alkylene, according to claim 3 R ¹ is C ₁ -C ₁₀ alkylthio group Pyrimidine-5-carboxylic acid derivatives or salts thereof. In the general formula (1a), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene, R ¹ is a mono- or di-substituted C ₁ -C ₇ alkylamino group, 1 to The pyrimidine-5-carboxylic acid derivative or a salt thereof according to claim 2, which is a cyclic amino group which may contain three heteroatoms. In the general formula (1b), Q ¹ and Q ² are optionally substituted C ₁ -C ₆ alkylene, R ¹ is a mono- or di-substituted C ₁ -C ₇ alkylamino group, 1 to The pyrimidine-5-carboxylic acid derivative or a salt thereof according to claim 3, which is a cyclic amino group which may contain 3 heteroatoms. A therapeutic, preventive, or suppressive agent for non-insulin-dependent diabetes mellitus, comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient. The treatment, prevention, or suppression agent of obesity characterized by including the pyrimidine-5-carboxylic acid derivative or its salt of any one of Claims 1-10 as an active ingredient. A therapeutic, prophylactic or inhibitory agent for hyperglycemia, comprising as an active ingredient the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10. A therapeutic, prophylactic or inhibitory agent for hyperlipidemia, comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient. A therapeutic, preventive or suppressive agent for hypercholesterolemia comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient. A therapeutic, prophylactic or inhibitory agent for hypertriglyceridemia, comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient. A therapeutic, prophylactic or inhibitory agent for insulin resistance comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient. A therapeutic, preventive, or suppressive agent for hyperinsulinemia, comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient. A therapeutic, prophylactic or inhibitory agent for arteriosclerosis comprising the pyrimidine-5-carboxylic acid derivative or salt thereof according to any one of claims 1 to 10 as an active ingredient. A therapeutic, preventive or suppressive agent for degenerative osteoporosis, comprising the pyrimidine-5-carboxylic acid derivative or a salt thereof according to any one of claims 1 to 10 as an active ingredient.