WO2005085212A1 - Substituted pyrimidine derivative - Google Patents

Abstract

A novel pyrimidine derivative characterized by having a saturated 6-membered heterocyclic group (for example, substituted piperidino) at the 2-position, a substituted amino group at the 4-position and a cyclic group at one of the 5- and 6-positions, or its salt. Because of having an effect of controlling the function of CC chemokine receptor 4 (CCR4) and showing an excellent antiinflammatory effect, the above compound is useful as a preventive or a remedy for inflammatory diseases, allergic diseases, autoimmune diseases and so on in which, in particular, CCR4 or TARC and/or MDC participate.

Description

 Substituted pyrimidine derivatives

 Technical field

 The present invention relates to a novel substituted pyrimidine derivative, and a medicament containing the same as an active ingredient, particularly a therapeutic agent for an inflammatory disease.

 Background art

 [0002] Chemokines, which are cell chemotactic factors, are broadly classified into two types, CXCZ chemokines and CCZ iS chemokines, depending on their structural characteristics. In addition, these chemokine receptors belong to the family of seven transmembrane G-protein coupled receptors, and are composed of CXC chemokine receptor and CC chemokine receptor (Pharmacological Reviews, 52, 145, 2000).

 CC chemokine receptor 4 (CCR4) is clawed from T lymphocytes and thymus (Biochemical and Biophysical Research communications, 218, 337, 1996, European Journal of Immunology, 26, 3021, 1996), and is initially referred to as a Th2 type T cell. It was mainly reported to be expressed (Journal of Experimental Medicine, 187, 875, 1998). And subsequent detailed analysis indicated that CCR4 was widely present in ThE and Th2 efecta 'memory T cells (Journal of Immunology, 166, 103, 2001; The Journal of Clinical Investigation, 108 , 1331, 2001). More recent studies have also shown that CCR4 is present on almost all skin-directed T cells (Nature, 400, 776, 1999) and monocyte 'macrophages, dendritic cells, and NK cells ( Arthritis &

 Rheumatism, 44, 1022, 2001).

Thymus and activation-regulated chemoine (I'ARC) and macrophage-derived chemokine (MDC) are specific ligands for CCR4 (CCJ chemokines) (Journal of Biological Chemistry, 272, 1503ο, 1997, Journal of Biological chemistry, 273, 1764, 1998). TARC was found as a T cell chemotactic factor (Journal of Biological Chemistry, 271, 21514, 1996), and MDC was discovered as a chemotactic factor for monocytes' macrophages and ΝΚ cells (Journal of Experimental Medicine, 185, 1595, 1997). Chemokines are also known to have the characteristics of both inflammatory chemokines and homeostatic chemokines. Today, 20, 254, 1999).

 Numerous reports have suggested that CCR4 and its ligands, TARC and MDC, are involved in various diseases such as inflammatory diseases, allergic diseases, and autoimmune diseases. For example, asthma (The Journal of Clinical Investigation, 107, 1357, 2001), atopic dermatitis (Journal of Investigative Dermatology, 115, 640, 2000), psoriasis (Laboratory

Investigation, 81, 335, 2001), rheumatoid arthritis (Arthritis & Rheumatism, 44, 2750, 2001), and inflammatory bowel disease (Clinical & Experimental Immunology, 132, 332, 2003). Therefore, CCR4 function modulators are expected as agents for preventing or treating these diseases and the like. Various drugs such as steroids are used as prophylactic or therapeutic agents for the above-mentioned inflammatory diseases, allergic diseases, autoimmune diseases, etc. There is a strong need for the development of drugs based on this.

 A gazette published after the application on which the priority of the present application is based describes that a pyrimidine derivative represented by the following general formula has an anti-inflammatory effect based on the regulation of functions of TARC and the like (Patent Document 1).

[Chemical 1]

(In the above formula (I), Ar is a substituted or unsubstituted aryl, R ¹ is NR ³ (R ² is a hydrogen atom or a substituted or unsubstituted lower alkyl, and R ³ is a substituted or unsubstituted A represents lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aromatic heterocyclic aralkyl, etc., and A represents formula (III), etc. [m ¹ is an integer of 0 to 2, n is 0 to An integer of 4, a ¹ represents a number capable of substituting 0 force], Q represents -NR ⁷ [R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a substituted or unsubstituted lower alkyl, etc. ] Or a substituted or unsubstituted alicyclic heterocyclic group.

The application does not include compounds having aryl or heteroalkyl as R ² or R ³ . It has been reported that a 5-cyanopyrimidine derivative represented by the following general formula has an anti-inflammatory effect based on the regulation of functions such as TARC (Patent Document 2).

 [Formula 2]

(In the above formula (I), R ¹ and R ³ are the same or different and each represent a hydrogen atom, -NR ⁴ R ⁵ [R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom, a substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, etc.], and R ² represents the above formula (II), etc., where Q is a nitrogen atom or CH, and A is a short bond , Carbonyl, R, etc., R is a substituted or unsubstituted alicyclic heterocyclic group, etc., ma is an integer of 0-2, ya is 0-replaceable integer, na is an integer of 0-4. For details, refer to the gazette.)

 [0005] It has been reported that a compound represented by the following general formula has a function of regulating the function of TARC or the like (Patent Document 3).

[Formula 3]

(Where m and η are the same or different and are an integer of 13 [provided that m + n is 4 or less], R ¹ is -NR ⁴ R ⁵ [where R ⁴ and R ⁵ are H, Represents an aralkyl etc.], r is an integer of 0-4, s is 0-substitutable number, G is a nitrogen atom, CH, etc., q is an integer of 0-2, E is A single bond, -C (C = 0)-, etc., R ^1Q represents an optionally substituted alicyclic heterocyclic group, etc., A represents a single bond, -0-, etc., R ³ represents H, substituted Represents an alkyl or the like, which may be referred to for details.

[0006] Further, it is described that a compound represented by the following general formula is useful as a therapeutic drug for central diseases based on GPR88 inhibition (Patent Document 4).

(Where A is a substituted or unsubstituted aryl, cycloalkyl, etc., R ¹ is a hydrogen atom, etc., R ² is a hydrogen atom, etc., -NR ⁴ [wherein, R ³ and R ⁴ are hydrogen atoms, etc. Or R ³ and R ⁴ together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group], and X is 1,2,3,4-tetrazole-5-yl and the like. , Y represents a hydrogen atom or the like, and r represents an integer of 0 to 4. For details, refer to the gazette.

This publication does not specifically disclose compounds having a cyclic amino group as R ^{2 and} a cyclic group as X. In addition, there is no disclosure of a function regulating effect and an anti-inflammatory effect of CCR4.

 [0007] Patent Document 1: International Publication No. 04Z074260 pamphlet

 Patent Document 2: International Publication No. 03Z082855 pamphlet

 Patent Document 3: International Publication No. 03Z104230 pamphlet

 Patent Document 4: WO 04Z054617 pamphlet

 Disclosure of the invention

 Problems to be solved by the invention

[0008] An object of the present invention is to provide a safe and powerful preventive / therapeutic agent for inflammatory diseases, allergic diseases, autoimmune diseases and the like, which has a function of regulating CCR4 function and replaces conventional steroids. .

 Means for solving the problem

[0009] The present inventors have diligently studied compounds having a CCR4 function regulating action. As a result, a pyrimidine derivative CCR4 having a saturated 6-membered heterocyclic group such as substituted piperidino at the 2-position, a substituted amino group at the 4-position, and a ring group at one of the 5- or 6-position. The present inventors have found that they are useful as function regulators, and have completed the present invention. The compound of the present invention is different from the compound described in Patent Document 1 in that a ring group is directly bonded to the 4-position of the pyrimidine ring via a nitrogen atom. Further, the compound of the present invention is a 5- or 6-position of the pyrimidine skeleton. And has a basic structure different from the compounds described in Patent Documents 2 and 3.

 That is, the present invention relates to the following compounds.

 [1] A substituted pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

 [Formula 5]

(The symbols in the formula have the following meanings.

 A: substituted !, may! /, Aryl or substituted !, may! /, Cycloalkyl,

B: A substituted or unsubstituted monocyclic or bicyclic hydrocarbon ring group, or a substituted or unsubstituted monocyclic or bicyclic heterocyclic group,

R ¹ : -R °, halogen, -OH, -OR °, halogeno lower alkyl,

X: CR ³ X «N,

R ³ : — H, — R. Or— CN,

 L: bond, -CO-, lower alkylene, -CO- (lower alkylene)-or-(lower alkylene) -CO-,

[Formula 6]

D: monocyclic heterocycloalkyl or cycloalkyl,

Provided that when X is N and L is a bond, W is a group (i), and the group is bonded to X at a carbon atom. R ² : same or different, -R °, halogen, -OH, -0R °, halogeno lower alkyl, -R °° -0H, -CON (R ⁸ ) (R ⁹ ), -R ⁰⁰ -OR ° ,-R ^QQ -N (R ⁸ ) (R ⁹ ),-R ^QQ -CN,-R ^QQ -N (R ⁸ )-CO- R °,

R ⁰⁰ -N (R ⁸ ) -SO-R °, -R °°-0-CO-R °, -R °° -CO-R. Or ^{- R °° - CON (R 8} ) (R 9),

 twenty two

R ⁸ and R ⁹ : same or different, -H or -R °,

R ¹¹ and R ^12: same or different from each other, - 0H, -0R °, ^{halogen, - N (R 8) (} R 9), - CN, - N (R 8) - CO- R °, - N ( R ⁸ ) -SO-R °, -0-CO-R °, -CO-R. Or a group consisting of -CON (R ⁸ ) (R ⁹ )

 twenty two

Optionally substituted with a group selected from the group consisting of lower alkyl,

 R °: lower alkyl,

R ^QQ : lower alkylene,

 m: 0, 1, 2, 3 or 4. )

 A preferred embodiment of the present invention is a derivative shown below.

[2] A substituted pyrimidine derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.

[Formula 7]

 (The symbols in the formula have the following meanings.

 A: substituted !, may! /, Aryl or substituted !, may! /, Cycloalkyl,

B: a substituted or unsubstituted monocyclic or bicyclic hydrocarbon ring group, or a substituted or unsubstituted monocyclic or bicyclic heterocyclic group,

R ¹ : -R °, halogen, -OH, -OR °, halogeno lower alkyl,

X: CR ³ X «N,

Y: CR ⁴ or N, where X force CR ³ indicates Y, and X indicates N, Y indicates CR ⁴ .

Z: CR ⁵ R ⁶ , NR ⁷ or 0, R ² : same or different, -R °, halogen, -OH, -0R °, halogeno lower alkyl, -R °° -0H, -CON (R ⁸ ) (R ⁹ ), -R ⁰⁰ -OR ° ,-R ^QQ -N (R ⁸ ) (R ⁹ ),-R ^QQ -CN,-R ^QQ -N (R ⁸ )-CO- R °, -R ⁰⁰ -N (R ⁸ ) -SO-R ° , -R °°-0-CO-R °, -R °° -CO-R. Or ^{- R °° - CON (R 8} ) (R 9),

 twenty two

R ⁸ and R ⁹ : same or different, -H or -R °,

R ⁵ and R ⁶ : the same or different, the groups described in H or R ² or R ⁵ and R ⁶ are

R ⁷ :-H ゝ-R °,-R °°-OH ゝ-CON (R ⁸ ) (R ⁹ ),-R °°-0- R °,-R °°-N (R ⁸ ) (R ^9), - R °° - CNゝ^{-R °° - N (R 8)} - CO- R. , -R. . ^{- N (R 8) - SO} - R. , -R. . -0-CO-R. , -R. . -CO-R. Or -R. . -C0N (R ⁸

 twenty two

XR ⁹ ),

 R °: lower alkyl,

R ^QQ : lower alkylene,

 m: 0, 1, 2, 3, or 4,

 k: 0, 1 or 2. )

 Among the derivatives according to the above [2], more preferred embodiments are the derivatives according to the following [3]-[9] and salts thereof:

 [3] The derivative according to the above [2], wherein X is CH and Y is N.

 [4] More preferably, the derivative according to the above [3], wherein A is substituted or may be phenyl.

[5] The derivative of the above-mentioned [4], wherein B is preferably an optionally substituted monocyclic heteroaryl or an optionally substituted V, or a phenyl.

 [6] More preferably, B is substituted, may be, pyridyl, substituted !, may be, chel, substituted, may be, furyl or substituted, may be, The derivative according to the above [5], which is a phenol.

 [7] More preferably, the derivative according to the above [6], wherein Z is CH.

 2

[8] More preferably, R ² is halogeno lower alkyl, -R °° -OH, -R °° -OR. Or -CON (R ⁸

) (R ⁹ ).

 [9] The derivative according to [8], wherein k is 1.

(10) Particularly preferably, the derivative or the derivative thereof according to (1), wherein Pharmaceutically acceptable salts: {1 '-[4-[(4-chlorophenol) amino] -5- (4-fluorophenyl) pyrimidine-2-yl] -1,4' -Bipiperidin-3-yl} methanol, {1- [4-[(4-chlorophenyl) amino] -5- (4-fluorophenyl) -6-methylpyrimidine-2-yl] -1,4 ^ Bipiperidin-3-yl} methanol, {1 '-[4-[(4-chloro-2-fluorophenyl) amino] -5- (4-fluorophenyl) pyrimidine-2 -Yl] -1,4, -bipiperidin-3-yl} methanol, (1,-{4-[(4-chlorophenol) amino] -5-phenylpyrimidine-2-yl} -1,4'-Bipiperidin-3-yl) methanol, (1,-{4-[(4-chlorophenol) amino] -6-isopropyl-5-phenylpyrimidin-2-yl} -1,4, -Bipiberidin-3-yl) methanol, {1 [4-[(4-chlorophenol) amino] -5- (2,4-difluorophenyl) pyrimidine-2 -Yl] -1,4'-Bipiperidine-3- } Methanol, {1- [4-[(4-chlorophenol) amino] -5- (2-chyl) pyrimidine-2-yl] -1,4-bipiperidine-3-yl } Methanol and {1 '-[4-[(4-chloro-2-fluorophenyl) amino] -6- (4-fluorophenyl) pyrimidine-2-yl] -1,4-bipiperidine-3 -Ill} Methanol.

[0013] The present invention also relates to a pharmaceutical composition comprising the substituted pyrimidine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition is a CCR4 or a modulator of TARC and Z or MDC function, more preferably an inflammatory disease, an allergic disease or an autoimmune disease, particularly preferably asthma or atopic dermatitis Alternatively, the above-mentioned pharmaceutical composition which is a prophylactic or therapeutic agent for rheumatoid arthritis.

 In another embodiment, a substituted pyrimidine derivative represented by the general formula (I) according to [1]-[10] for the manufacture of a prophylactic or therapeutic agent for an inflammatory disease, an allergic disease or an autoimmune disease. Or a pharmaceutically acceptable salt thereof, wherein the substituted pyrimidine derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to (1)-(10) is used in an effective amount, It is a method for preventing or treating an inflammatory disease, an allergic disease or an autoimmune disease, which is administered to a mammal.

 The invention's effect

[0014] The substituted pyrimidine derivative of the present invention has a function of regulating the function of CCR4 or TARC and Z or MDC, and has an advantage that it has a strong effect in a model of an inflammatory disease, an allergic disease or an autoimmune disease. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

 In the present specification, “alkyl” and “alkylene” mean a straight or branched hydrocarbon chain. "Lower alkyl" is preferably an alkyl group having 116 carbon atoms, more preferably an alkyl group having 114 carbon atoms, and still more preferably methyl and ethyl. "Lower alkylene" means a divalent group formed by removing one arbitrary hydrogen atom from the above "lower alkyl", preferably alkylene having 114 carbon atoms, more preferably methylene, ethylene and It is propylene.

 “Halogen” refers to F, Cl, Br and I. "Halogeno lower alkyl" means preferably alkyl having 1 to 6 carbon atoms substituted with one or more halogen, more preferably C alkyl substituted with one or more F, Preferably, fluoromethyl, diflu

 1-6

 Orthomethyl, trifluoromethyl and trifluoroethyl.

 [0016] "Cycloalkyl" is preferably cycloalkyl having 3 to 10 carbon atoms, and may be crosslinked. More preferred are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. “Aryl” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and includes a phenyl group fused with “cycloalkyl”. Preferably, they are phenyl and naphthyl, and more preferably, phenyl. The “monocyclic or bicyclic hydrocarbon ring group” includes both monocyclic or bicyclic “cycloalkyl” and monocyclic or bicyclic “aryl”.

[0017] The term "monocyclic heterocyclic group" refers to a monocyclic 3- to 8-membered, preferably 5- to 7-membered cyclic group containing 1 to 4 hetero atoms selected from 0, S and N forces. And includes a monocyclic heteroaryl which is an unsaturated ring, a monocyclic heterocycloalkyl which is a saturated ring, and a ring group in which the monocyclic heteroaryl is partially hydrogenated. As the monocyclic heteroaryl, preferably, pyridyl, pyrazul, pyrimidyl, pyridazyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxaziazolyl and the like. No. As a monocyclic heterocycloalkyl or a ring group in which a heteroaryl group is partially hydrogenated, preferably, piberidyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, Trahydroviral, morpholinyl and the like.

 The “bicyclic heterocyclic group” is a ring group in which the above-mentioned monocyclic heterocycles are fused together or a benzene ring and a monocyclic heterocycle are condensed. Preferably, indolyl, benzofuryl, benzoche , Indazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, dihydrobenzofuranyl, tetrahydroquinolyl, and indolinyl.

 In the “monocyclic heterocyclic group” and “bicyclic heterocyclic group”, the ring atom S or N may be oxidized to form an oxoxide-dioxide. Further, in the heterocycloalkyl and the ring group in which the heteroaryl is partially hydrogenated, an arbitrary carbon atom may be substituted with an oxo group.

“May be substituted” means “unsubstituted” or “having 115 identical or different substituents”.

 The substituent in "substituted or may be aryl" and "substituted or may be cycloalkyl" is preferably halogen, lower alkyl, -OH, -0-lower alkyl, -CN , -S-lower alkyl, NO, more preferably halogen, lower alkyl, -OH

 2,

-0-lower alkyl, -CN, even more preferably halogen, -CN.

 Substituents in the “optionally substituted monocyclic or bicyclic hydrocarbon ring group” and the “optionally substituted monocyclic or bicyclic heterocyclic group” are preferably halogen, lower Alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, -CN, NO,

 2, NH, and preferably 2 is halogen, lower alkyl, or halogeno lower alkyl.

 [0019] The compound of the present invention represented by the formula (I) (hereinafter abbreviated as compound (I)) may have a geometric isomer or a tautomer depending on the type of a substituent. Or a mixture of the isomers.

 Further, the compound (I) may have an asymmetric carbon atom, and an (R) -form or (S) -form optical isomer based on this may exist. The present invention includes all of the optical isomers as a mixture or an isolated one.

Further, the compound (I) also includes a pharmacologically acceptable prodrug. A pharmacologically acceptable prodrug is defined as the NH4 of the present invention by solvolysis or under physiological conditions. It is a compound having a group that can be converted to OH, COH, and the like. As a base to form a prodrug

2

 For example, the groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198.

 Compound (I) may form an acid addition salt or a salt with a base depending on the type of substituent. The strong salt is a pharmaceutically acceptable salt, specifically, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propion. Acid addition salts with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid, sodium And inorganic bases such as potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortin; and ammonium salts.

 Furthermore, the present invention also encompasses pharmaceutical compositions containing various hydrates and solvates of compound (I) and salts thereof and polymorphic substances.

 [0021] (Manufacturing method)

 Compound (I), which is an active ingredient of the present invention, and pharmaceutically acceptable salts thereof are produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the type of substituent. can do. At that time, depending on the type of the functional group, it is effective in production technology to protect the functional group with an appropriate protecting group at the stage of the raw material or intermediate or to replace it with a group that can be easily converted to the functional group. May be important. Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like, and their protecting groups are described, for example, in Protective Groups in Organic Synthesis (Third Edition) by Green (TW Greene) and Utz (PGM Wuts). , 1999) ", which may be appropriately selected and used according to the reaction conditions. In such a method, a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group or converting it to a desired group as necessary.

Further, the prodrug of the compound (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate or by carrying out a reaction using the obtained compound (I) as in the case of the above-mentioned protective group. The reaction is carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc. Can be performed.

 [0022] First manufacturing method

 [Formula 8]

(In the formula, L represents a leaving group. The same applies hereinafter.)

 1

 This production method is a method for producing a compound (I) of the present invention by subjecting a pyrimidine derivative (1) having a leaving group at the 2-position to a cyclic amine diversion compound (2) by ibuso substitution.

 Examples of the leaving group represented by L include a halogen, an alkylsulfiel group, an alkylsulfol

1

 And the like. The reaction is carried out by subjecting compound (1) to a solvent inert to the reaction, in the presence or absence of a base or acid (preferably hydrogen chloride), using an equivalent or excess amount of (2) under cooling and heating under reflux. It usually takes place for one hour and five days. The solvent is not particularly limited as long as it is inert to the reaction, but, for example, aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy Ethers such as ethane (DME) and 1,2-dietoxetane (DEE); halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, methanol, ethanol, 2-propanol, butanol, etc. Alcohols, Ν, Ν-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like. Bases include organic bases such as triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo- [5.4.0] -7-indene (DBU), 2,6-lutidine, sodium carbonate, and carbonate. Inorganic bases such as potassium, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be mentioned.

[0023] Second manufacturing method

本製法はピペラジノ基を有するピリミジン誘導体 (3)とカルボン酸ィ匕合物 (4)をアミ ドィ匕反応に付し、本発明化合物 (la)を製造する方法である。 [Formula 9]

This production method is a method for producing a compound (la) of the present invention by subjecting a pyrimidine derivative (3) having a piperazino group (3) and a carboxylic acid conjugate (4) to an amidoni reaction.

 The reaction is carried out by using the compound (3) and the compound (4) in an equal amount or one of them in excess, and using a condensing agent (eg, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), -Ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1-carbylbis-1H-imidazole (CDI), etc., and in some cases, further additives (eg, N-hydroxysuccinimide ( (HONSu), 1-hydroxybenzotriazole (HOBt), etc.) with stirring under cooling and heating, preferably at room temperature, usually for 1 hour to 1 day. Further, instead of these reagents, it is also possible to use a solid phase reagent having a functional group having the same action (for example, PS-carpoimide (Argonaut Technologies, USA)). Alternatively, the active ester form of the compound (4) and the above additive may be isolated and then reacted with the compound (3). The solvent is not particularly limited as long as it is inert to the reaction.For example, aromatic hydrocarbons, ethers, halogenated hydrocarbons, Ν, Ν-dimethylformamide (DMF), N-methylpyrrolidone (NMP) , Dimethyl sulfoxide (DMSO) and the like. These solvents are used alone or in combination of two or more. In some cases, it is advantageous to carry out the reaction in the presence of a base such as triethylamine, DIPEA, pyridine or the like in order to make the reaction proceed smoothly.

Third manufacturing method

General formula (I) in ring A or B, or a compound having various substituents on the group R ^2, the invention compound (I) as a raw material, it is apparent reaction, or these variations to those skilled in the art Can be easily synthesized. For example, the following reaction can be applied

(1) Amidation and esterification By using the compound of the present invention having a hydroxyl group or an amino group as a raw material and using a carboxylic acid or a reactive derivative thereof, various amido- or esteri-conjugated compounds can be produced. The reaction can be carried out, for example, by referring to the method described in “Experimental Chemistry Course (4th edition)”, edited by The Chemical Society of Japan, Vol. 22 (1992) (Maruzen).

(2) Reduction

 The compound of the present invention having an NH group can be produced by a reduction reaction of a compound having a nitro group.

2

Wear. For example, the method can be carried out according to the method described in “Experimental Chemistry Lecture (4th edition)”, edited by The Chemical Society of Japan, Vol.

Raw material synthesis

[Formula 10]

Wherein L is -C1 or -Br, U is -Br, -Cl, -I or -O-SO-CF, Q is -B (OH), -B (0-

2 2 3 2 lower alkyl) or -SnBu. The same applies hereinafter. )

 twenty three

The starting compound (1) can be produced by subjecting a pyrimidine derivative (5) to an ipamine substitution reaction with an amine compound (6), and then performing a coupling reaction using the adduct (7) and the compound (8). You. The same conditions as in the first production method can be applied to the ipso substitution reaction. The coupling reaction can be performed, for example, by the method described in “Chemical Experiment Course (4th edition)”, edited by The Chemical Society of Japan, Vol. 25 (1992) (Maruzen). [Formula 11]

(In the formula, R ^1Q represents a lower alkyl group. The same applies hereinafter.)

In the formula (1), the compound (la) wherein L ¹ is a methylsulfinyl group can be produced according to the above reaction route. Here, methyl and ethyl are preferable as the lower alkyl of R ^{1Q. In} the above reaction route, the coupling reaction is described in the above-mentioned Nippon Dani Gakkai, “Experimental Chemistry Course (4th edition)”, Vol. 25 (1992) (Maruzen) It can be carried out by the method described. The alkylation is carried out using an alkylating agent such as methyl iodide or dimethyl sulfate in a solvent such as aromatic hydrocarbons, ethers, or halogenated hydrocarbons, or a mixed solvent thereof. Halogenide uses a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, or salty chloride, or a brominating agent such as phosphorus oxybromide in an equimolar excess to obtain an aromatic hydrocarbon or halogenated hydrocarbon. The reaction is carried out in a solvent inert to the reaction or the like or without a solvent. The same conditions as in the first production method can be applied to the ipso substitution reaction. Oxidation can be carried out by using an ordinary method of oxidation reaction of the sulfur group. For example, the method described in The Chemical Society of Japan, “Experimental Chemistry Course (4th edition)”, Vol. 23 (1992) (Maruzen) can be mentioned. . [Formula 12]

 The starting compound (3) can be produced by subjecting the pyrimidine derivative (1) to a piperazine (14) by an ipso substitution reaction. The same conditions as in the first production method can be applied to the ipso substitution reaction.

[Formula 13]

(In the formula, P represents a protecting group for an amino group. The same applies hereinafter.)

The cyclic amine conjugates (2a) and (2b) can be produced by the method shown in the above formula. For the protecting group P and the deprotection reaction, the method described in the above-mentioned “Protective Groups in Organic Synthesis (3rd edition)” for the amino group deprotection reaction and the like can be applied. For the reductive alkylation, a conventional method of reductive alkylation can be used. For example, it is described in “Experimental Chemistry Lecture (4th edition)” edited by The Chemical Society of Japan, Vol. 20 (1992) (Maruzen). Method.

[0028]

環状アミンィ匕合物（2c)及び（2d)は、上記式に示す方法により製造できる。 その他、種々の環状アミン化合物（2)は、例えば、水酸基を有する化合物より、アル キル化剤（アルキルハライドゃスルホン酸アルキルエステル等）によるアルキル化又 は光延反応によりアルキルエーテル基、フッ素化剤（三フッ化ジェチルァミノ硫黄や 三フッ化モルホリノ硫黄等）によりフルォロ基、フタルイミドとの光延反応によりフタルイ ミド基を有する化合物へと、それぞれ変換できる。

The cyclic amine conjugates (2c) and (2d) can be produced by the method shown in the above formula. In addition, various cyclic amine compounds (2) can be prepared by, for example, alkylating a compound having a hydroxyl group with an alkylating agent (eg, alkyl halide ゃ sulfonic acid alkyl ester) or an alkyl ether group by a Mitsunobu reaction to form a fluorinating agent. The compound can be converted to a compound having a phthalimido group by a Mitsunobu reaction with a fluorimido group and phthalimide, respectively.

[0029] The reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. The salt can be produced by subjecting it to a usual salt-forming treatment.

 Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

 Various isomers can be isolated by a conventional method utilizing physical differences between the isomers. For example, the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. Further, the optical isomer is produced from an appropriate optically active starting compound.

 [0030] The pharmacological activity of the compound of the present invention was confirmed by the following test.

1. Effects on [ ³⁵ S] GTP y S binding test via CCR4

 (1) Acquisition of human CCR4-expressing cell line

A vector (including the neomycin resistance gene) with the human CCR4 gene inserted downstream of the EF-1a promoter was prepared and transferred to the mouse pre B cell line B300-19 cells by the electoporation method. Transformation These cells were cultured in a medium supplemented with G418, and a single cell line that constantly and stably expresses human CCR4 was obtained by the limiting dilution method.

 (2) Preparation of membrane fraction of human CCR4-expressing cell line

Human CCR4 expressing cells were collected, washed with PBS, and suspended in Lysis Buffer (10 mM Hepes pH 7.5, 2 mM EDTA, protainase inhibitor). After placing the suspension on ice for 15 minutes, the cells were disrupted with a homogenizer and centrifuged (20000 rpm, 10 min, 4 ° C). _{0 The} supernatant was ultracentrifuged (22K, 30 min, 4 ° C). Thereafter, the pellet suspended in PBS was used as a membrane fraction in subsequent experiments.

 (3) GTP y S binding test

 Test compounds were prepared at 20 mM Hepes pH 7.05, 100 mM NaCl, 5 mM MgCl,

 2

GDP 2 μ Human, Human MDC ゝ [ ³⁵ S] GTPyS 150 pM, Wheatgerm agglutinin SPA beads 1 mg and Human CCR4 expressing cell line membrane fraction 1 μg 1 hour 30 minutes at room temperature in a reaction mixture And the radioactivity was measured.

 3 shows the inhibitory activity values (IC [nM]) of the main examples.

 50

 Example 1: 82

 Example 2: 110

 Example 3: 25

 Example 6: 72

 Example 10: 46

 Example 16: 28

 Example 19: 52

 Example 20: 85

 Example 24: 86

 From these results, it was confirmed that the compound of the present invention has a strong CCR4 function regulating action.

 Comparative compound: 4-[(2,6-difluorobenzyl) amino] -2-[(3R, 5S) -3,5-dimethyl

-1,4, -Bipiperidine-1, -yl] pyrimidine-5-carbo-tolyl (compound 4 of Patent Document 2 described above)

44) showed 25% inhibitory activity at a concentration of 100 nM.

2. Cell migration activity test by Boyden Chamber method The test compound was suspended in the above-mentioned human CCR4-expressing cells at a concentration of 10 ⁶ cells / well / 0.2 mL, and incubated at room temperature for 5 minutes. The lower well was added with human MDC (3nM @ProproTech), a dedicated filter was placed, and the cell suspension treated with the test compound was added to the upper well to initiate the reaction. 3 hours at 37 ° C in a CO incubator

 2

After incubation, the number of cells in the lower well was quantified using ATPLite-M (PerkinElmer).

 The compounds of Examples 2, 3, 6, 10, 16, 19, 20, 22, and 24 showed an inhibitory activity of 50% or more at 1 M concentration. In particular, the compound of Example 3 had an IC of 120 nM.

 50

 Comparative compound: 4-[(2,6-difluorobenzyl) amino] -2-[(3R, 5S) -3,5-dimethyl-1,4, -bipiperidine-1, -yl] pyrimidine -5-carbo-tolyl (compound 444 of Patent Document 2) showed an inhibitory activity of 22% at a concentration of 1 μΜ.

3.Effects on mouthoxazolone-induced contact dermatitis

 The abdomen of Balb / c mice (6-10 weeks old, female, Nippon Chillers' Riva) was sensitized by applying 150 L of 3% oxazolone / ethanol solution (Sigma-Aldrich Japan). Six days after sensitization, 10 L of a 1% oxazolone / ethanol solution was applied to both sides of the right ear. The test drug was administered 12 hours after application of the oxazolone solution (test drug administration group), and the control group received only the solvent used to dissolve the test drug. The thickness of the right pinna was measured using a thickness gauge (Mitsutoyo) before and 20 hours after application, and the swelling (thickness increase = measured value 20 hours later, measured value before application) was calculated. The inhibition rate was calculated by the following formula using the group to which the oxazolone solution was applied without sensitization as the normal group. The above test was performed on 5 animals per group.

Inhibition rate = (swelling of control group swelling of test drug administration group) xl00 / (swelling of control group-swelling of normal group)

 The compounds of Examples 2, 6, 10, 19 and 20 showed significant inhibitory activity at 30 mg / kg oral administration.

 From these results, excellent anti-inflammatory action of the compound of the present invention was confirmed.

4.Effects on mouse collagen-induced arthritis

Effects on mouse collagen-induced arthritis It is evaluated using the method described in Pharmacology, 88, 332 (2002).

 In addition to the above test examples, for example, Immunology, 98, 345 (1999) mouse asthma modenole described, Journal of Investigative Dermatorogy, 111, 86 (1998) described oxazolone-induced chronic contact dermatitis model (atopic The pharmacological action of the compound of the present invention can be confirmed by various evaluation models generally used for evaluating an anti-inflammatory action, such as a dermatitis model).

 From the above test, the compound of the present invention has a strong CCR4 function regulating action, and a favorable pharmacological action was confirmed in models of inflammatory diseases and the like.

[0032] A preparation containing one or more of compound (I) or a salt thereof as an active ingredient is prepared using a carrier, an excipient, and other additives that are usually used for formulation.

 For oral administration, tablets, pills, capsules, granules, powders, liquids, etc., or parenteral injections, such as intravenous injections, intramuscular injections, suppositories, transdermals, nasal formulations, inhalants, etc. Any of the forms may be used. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration subject.However, for oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per day for an adult. This should be given once or in 2-4 doses. In the case of intravenous administration depending on the symptoms, the dose is usually in the range of 0.0001 mg / kg to 10 mg / kg per adult once or more times a day. In the case of inhalation, the dose is usually in the range of 0.0001 mg / kg to 1 mg / kg for an adult once or more times a day.

 Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, one or more active substance (s) at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, or a solubilizer according to a conventional method. Tablets or pills may be coated with sugar coating or a gastric or enteric coating agent, if necessary.

[0033] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups. Agents, elixirs, etc., and generally used inert solvents such as purified water and ethanol. The composition may contain, in addition to the inert solvent, auxiliaries such as solubilizers, wetting agents and suspending agents, sweeteners, flavoring agents, fragrances and preservatives.

 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizing agent, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these are prepared by preparing a sterile solid composition, dissolving and suspending it in sterile water or a sterile injection solvent before use.

[0034] Transmucosal agents such as inhalants and transnasal agents are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods. For example, an excipient and as Ratatosu Ya starch, furthermore, _P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate. For administration, an appropriate inhalation or insufflation device can be used. Solutions or suspensions of the compounds, alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier, using known devices or nebulizers, such as metered dose inhalers. Can be administered as A dry powder inhaler or the like can utilize a dry powder or a powder-containing capsule that can be used for single or multiple doses. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or diacid carbon, etc. .

External preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments and the like. It contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like. For example, ointment or lotion bases include polyethylene glycol, carboxybutyl polymer, white petrolatum, beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl Anore konore, cetyl alcohol, lauromacrogol, sonolebitan sesquioleate and the like. Example

 Hereinafter, the production method of the compound (I) of the present invention will be described in more detail with reference to Examples. The compounds of the present invention are not limited to the compounds described in the following Examples. The production methods of the starting compounds are shown in Reference Examples.

 The following abbreviations are used in Reference Examples and Tables below. The number before the substituent indicates the substitution position.

 Ex: Example number, REx: Reference example number, Dat: Physicochemical data (F: FAB-MS (M + H) +, FN: FAB-MS (M-H)-, ES: ESI-MS (M + H) +, ESN: ESI-MS (M-H)-, EI: m-MS (M +), AP: APCI- MS (M + H) +, APN: APCI- MS (M-H)-, NMR1: Features in NMR in CDC1

 Three

 Δ (ppm) of typical peak, NMR2: δ of characteristic peak in NMR in DMSO-d

 6

 (ppm), EA: Elemental analysis value (%) (Cal: Calculated value; Fnd: Actual measurement value)), Sal: Salt and contained solvent (HC1: Hydrochloride, No description: Free form, number before component is for example 2HC1 represents dihydrochloride), Str: Structural formula, Syn: Production method (Numbers represent the example numbers produced in the same manner), Config: Stereochemistry (Indicates the absolute configuration of carbon marked with *), Me : Methyl, Ph: Fer, Ac: Acetyl, Boc: tert-Butoxycanoleboninole.

[0037] Reference Example 1

 Heat 5-bromo-2,4-dichloropyrimidine and 4-chloroaline in acetonitrile in the presence of DIPEA under reflux for 3 days to give 5-bromo-2-chloro-N- (4-chloro-methyl) Pyrimidin-4-amine was obtained. ES: 318, 320.

 Reference example 2

 An aqueous solution of sodium carbonate and tetrakis (triphenylphosphine) palladium were added successively to an acetonitrile solution of 5-bromo-2-chloro-N- (4-chlorophenol) pyrimidine-4-amine and 4-fluorophenylboronic acid. And heated at 85 ° C. to give 2-chloro-N- (4-chlorophenol) -5- (4-fluorophenol) pyrimidin-4-amine. ES: 334.

 Reference example 3

₄ _ black port - ₅ _ Yodo _ ₆ _ methyl - ₂ _ (Mechirusurufue - Le) pyrimidine Reference Example 2 using the same Thus, 4-chloro-5- (4-fluorophenyl) -6-methyl-2- (methylsulfur) pyrimidine was obtained. F: 269.

Reference example 4

 A 1M aqueous hydrochloric acid solution was added to a 2-propanol solution of 4-chloro-5- (4-fluorophenyl) -6-methyl-2- (methylsulferyl) pyrimidine and 4-cyclolorine, and 3 The mixture was heated under reflux for an hour to obtain N- (4-chlorophenol) -5- (4-fluorophenyl) -6-methyl-2- (methylsulfur) pyrimidin-4-amine. ES: 360.

Reference Example 5

 N- (4-chlorophenol) -5- (4-fluorophenyl) -6-methyl-2- (methylsulfuryl) pyrimidin-4-amine was added to dichloromethane in dichloromethane under ice-cooling. Treatment with oral benzoic acid gave N- (4-chlorophenyl) -5- (4-fluorophenyl) -6-methyl-2- (methylsulfuryl) pyrimidin-4-amine. ES: 376.

Reference example 6

 N- (4-chlorophenol) -2- (methylsulfur) -6-phenylpyrimidin-4-amine is treated with m-chlorobenzoic acid in dichloromethane at room temperature to give N There was obtained-(4-chlorophenol) -2- (methylsulfol) -6-phenylpyrimidin-4-amine. F: 360.

Reference Example 7

 Methyl (4-fluorophenyl) acetate and methyl formate were added dropwise to a mixture of sodium hydride and DMF under ice-cooling, and the mixture was stirred at room temperature for 17 hours, then methyl iodide was added, and the mixture was further stirred at room temperature for 5 hours. This gave methyl 2- (4-fluorophenyl) -3-methoxyacrylate. This compound was reacted with thiourea in ethanol in the presence of sodium methoxide to give 5- (4-fluorophenyl) -2-thioxo-2,3-dihydropyrimidin-4 (1H) -one. F: 223.

Reference Example 8

 5- (4-Fluorophenyl) -2-thioxo-2,3-dihydropyrimidin-4 (1H) -one is reacted with methyl iodide in DMF to give 5- (4-fluorophenyl) -2 -(Methylsulfur) pyrimidin-4 (3H) -one was obtained. ES: 237.

Reference Example 9

5- (4-fluorophenyl) -2- (methylsulfur) pyrimidin-4 (3H) -one The reaction was carried out at 100 ° C for 2 hours with Rindo phosphorus to obtain 4-chloro-5- (4-fluorophenyl) -2- (methylsulfeninole) pyrimidine. ES: 255.

 Reference example 10

 A mixture of tert-butyl 4-oxopiperidine-1-carboxylate, 3-piperidinemethanol, 10% noradium carbon and methanol was stirred under a hydrogen atmosphere to give tert-butyl 3- (hydroxymethyl) -1, 4'-Bipiperidine-1'-carboxylate. ES: 299.

[0039] Reference Example 11

 tert-Butyl 3- (hydroxymethyl) -1,4'-bipiperidine-1'-carboxylate is treated with 4M hydrochloric acid-ethyl acetate solution in methanol to give 1,4'-bipiperidine-3-methanol 2HCl Salt was obtained. ES: 199.

 Reference Example 12

 tert-butyl 4-oxopiperidine-1-carboxylate and (3S) -ethyl ethyl pecotate in the same manner as in Reference Example 10 to obtain tert-butyl (3S) -3- (ethoxycarbol) -1, 4′-Bipiperidine-1′-carboxylate (ES: 341) was obtained. The THF solution was added to a suspension of lithium hydroxide boron in THF, and the mixture was stirred under reflux with heating to give tert-butyl (3S) -3- (hydroxymethyl) -1,4′-bipiperidine-1 ′. -A carboxylate was obtained. ES: 299.

 The compound of Reference Examples 13-24 was prepared in the same manner as in Reference Example 2, the compound of Reference Examples 25-29 was prepared in the same manner as in Reference Example 3, and the compound of Reference Example 30- was prepared in the same manner as in Reference Example 4. Using the compound of Reference Example 38 and the compound of Reference Example 38 in the same manner as in Reference Example 11, the compound of Reference Example 40 was obtained by using the corresponding raw materials. Manufactured. Table 14 shows the structure and physical data of the compound of Reference Example (13-40).

 [0040] Reference Example 41

A mixed solution of ethyl 2-pyridine-2-yl acetate, acetic anhydride and ethyl ethyl formate was heated under reflux in the presence of zinc chloride for 12 hours to obtain ethyl 3-ethoxy-2-pyridine-2-yl acrylate. This compound was reacted with thiourea in ethanol in the presence of sodium methoxide to obtain the sodium salt of 5-pyridin-2-yl-2-thioxo-2,3-dihydropyrimidin-4 (1H) -one. Was. ES: 206. Reference Example 42

5-Pyridin-2-yl-2-thioxo-2,3-dihydropyrimidin-4 (1H) -one 2- (methylsulfuryl) -5-pyridine in the same manner as in Reference Example 8 using the sodium salt -2-ylpyrimidin-4 (3H) _one was obtained. Dichloroethane solution of the compound under ice-cooling Toriechiruamin, stirring the main Shirukurorido mosquito卩Ete 1 hour, ₂ - pyridine-2-Irupirimiji down 4 I le methanesulfonate - (Mechirusurufa - Le) - ₅ Obtained. A solution of this compound and 4-chloroaline in ethanol is heated under reflux for 4 hours in the presence of mesylic acid, and N- (4-chlorophenol) -2- (methylsulfanyl) -5-pyridine-2- The ylpyrimidin-4-amine was obtained. ES: 329.

Reference Example 43

 6-Isopropyl-2-mercaptopyrimidin-4-ol is reacted with methane in ethanol in the presence of an aqueous sodium hydroxide solution at room temperature for 2 hours to give 6-isopropyl-2- (methylsulfuryl) pyrimidine-4- (3H )-Got on. EI: 184.

Reference example 44

 6-Isopropyl-2- (methylthio) pyrimidin-4- (3H) -one is reacted with N-odosuccinimide at 70 ° C for 2 hours in chloroform to give 5-Iodo-6-isopropyl-2- (Methylthio) pyrimidin-4- (3H) -one was obtained. F: 311.

Reference Example 45

 5-cyanouracil was reacted with a 50% aqueous solution of hydroxylamine in methanol at 70 ° C for 2.5 hours to give Ν'-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxyimidine. Damide was obtained. This compound was reacted with acetic anhydride in a mixed solvent of THF and DMF at 100 ° C for 1.5 days to give 5- (5-methyl-1,2,4-oxaziazol-3-yl) pyrimidine-2,4 (1H , 3H) -Zion was obtained. The compound was reacted with phosphorus oxychloride and getylurin at 100 ° C for 3 hours to give 2,4-dichloro-5- (5-methyl-1,2,4-oxaziazol-3-yl). L) Pyrimidine was obtained. NMR1: 9.15 (1H, s), 2.73 (3H, s).

Reference Example 46

Acetic acid, an aqueous formaldehyde solution and sodium triacetoxyborohydride were added to a solution of tert-butyl 4-[(3-hydroxypropyl) amino] piperidine-1-carboxylate in dichloroethane, and the mixture was added at room temperature for 19 hours. React with tert-butyl 4-[(3-hydroxypropyl) (methyl Ru) amino] piperidine-1-carboxylate was obtained. F: 273 ₀

 Reference Example 47

 tert-Butyl 4-[(3-hydroxypropyl) amino] piperidine-1-carboxylate is reacted with iodide tyl in DMF in the presence of sodium carbonate at room temperature for 18 hours to give tert-butyl 4- [ethyl ( 3-Hydroxypropyl) amino] piperidine-1-carboxylate was obtained. F: 287. Reference Example 48

 The same operation as in Reference Example 10 was performed using tert-butyl 4-oxopiperidine-1-carboxylate and 4-aminobutan-1-ol to obtain tert-butyl 4-[(4-hydroxybutyl) amino] piperidine. -1-carboxylate was obtained. The same operation as in Reference Example 46 was performed using this compound to obtain tert-butyl 4-[(4-hydroxybutyl) (methyl) amino] piperidine-1-carboxylate. The same operation as in Reference Example 11 was performed using this compound to obtain 4- [methyl (piperidin-4-yl) amino] butanol. NMR2: 2.65 (3H, d, J = 5.2 Hz), 1.89-2.05 (2H, m), 1.38-1.53 (2H, m).

 [0042] Reference Example 49-76

 In the same manner as in the method of Reference Example 1, the compound of Reference Example 49-54 (the solvent was THF) and the compound of Reference Example 69 (the solvent was DEE) were used in the same manner as in the method of Reference Example 2. The compound of Reference Example 61 was treated in the same manner as in Reference Example 9 using the compound of 55-60 and the compound of 63-66 (the solvent was DME), and the compound of Reference Example 62 was treated in the same manner as in Reference Example 44. The compound of Reference Example 67 (the solvent is trifluoromethanesulfonic acid) and the compound of Reference Example 67 and the compound of Reference Example 68 in the same manner as in the method of Reference Example 4 (4 M hydrogen chloride-ethyl acetate solution instead of 1 M hydrochloric acid) The compound of Reference Example 70 was treated in the same manner as in Reference Example 5, and the compounds of Reference Examples 71 and 72 were treated in the same manner as in Reference Example 10. Example 73- The compound of Reference Example 76 was used in the same manner as in the method of Reference Example 48, and the compound of Reference Example 76 was used. Manufactured using The structures and physical data of the compounds of Reference Examples 49-76 are shown in Tables 5-8, respectively.

 Reference Example 77

The 2-chloro-N- (4-chloropyrrole) -5-phenylpyrimidin-4-amine was reacted with piperazine in DEE at 130 ° C for 18 hours to give N- (4- Black mouth ferrule) -5-Feel-2-Pyrazine-1-y Lupyrimidin-4-amine was obtained. F: 366.

Reference 78

 N- (4-chlorophenol) -5-phenyl-2-pyrazine-1-ylpyrimidine-4-amine and (2R) -l- (t-butoxycarbol) piperidine- 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole were added to a THF solution of 2-carboxylic acid and reacted at room temperature for 17 hours to give tert-butyl (2R)- 2-[(4- {4-[(4-chlorophenyl) amino] -5-phenylpyrimidine-2-yl} piperazine-1-yl) carbol] piperidine-1-carboxylate Obtained. ES: 577.

Example 1

 2—Black mouth—N— (4-Black mouth phenol) —5— (4—Black mouth phenol) pyrimidine—4-Amine 179 mg of 1,4-dioxane in 20 ml of DBU 233 mg, 1 , 4'-Biridine-3-ylmethanol dihydrochloride (139 mg) was added, and the mixture was heated at 100 ° C for 13 hours. The reaction solution was brought to room temperature, silica gel was added to the reaction solution, and the solvent was distilled off.The residue was purified by silica gel column chromatography (chloroform-methanol-28% aqueous ammonia solution). 4-chloro mouth phenol) -5- (4-chloro mouth pyrimidine-2-yl] -1,4 shibipiperidin-3-yl} methanol 200 mg in pale yellow amorphous crystals As obtained. This compound was dissolved in methanol, and 0.29 ml of a 4 M hydrochloric acid / ethyl acetate solution was added. The crystal was recrystallized from isopropanol-ethyl acetate-methanol to give {1 ′ — [4 — [(4-chlorophenol— Lu) amino] -5- (4-chlorophenol) pyrimidine-2-yl] -1,4'-bipiperidin-3-yl} methanol dihydrochloride (92 mg) was obtained as white crystals.

Example 2

 Using 236 mg of 2-chloro-N- (4-chlorophenol) -5- (4-fluorophenol) pyrimidine-4-amine (except that DMF is used as the solvent) Then, the reaction was carried out at 80 ° C for 4 days using DIPEA as a base) to give {1 ′-[4-[(4-chlorophenyl) amino] -5- (4-fluorophenyl) pyrimidine-2 -Yl] -1,4'-Bipiperidin-3-yl} methanol dihydrochloride 39 mg was obtained as white crystals.

Example 3

N- (4-chloro-2-fluorophenyl) -5- (4-fluorophenyl) -2- (methylsulfiel) pyrimidine-4-amine (450 mg) in the same manner as in Example 1 (However, DEE is used as a solvent. The reaction was carried out at 130 ° C for 21 hours using (3S) -1,4'-viridin-3-ylmethanol dihydrochloride instead of 1,4'-viridin-3-ylmethanol dihydrochloride. Let me do)

 {(3S) -1,-[4-[(4-chloro-2-fluorophenyl) amino] -5- (4-fluorophenyl) pyrimidine-2-yl] -1,4'-bipiperidine -217 mg of methanol 2-hydrochloride were obtained as light brown crystals.

Example 4

 Using 506 mg of N- (4-chlorophenol) -2- (methylsulfol) -6-phenylpyrimidine-4-amine in the same manner as in Example 1, except that the solvent The reaction was carried out with ethoxyethanol at 130 ° C for 2.5 days using diisopropylethylamine as a base) (1,-{4-[(4-chlorophenol) amino] -6 -Fervirimidine-2-yl} -1,4, -bipiperidin-3-yl) methanol dihydrochloride (87 mg) was obtained as pale yellow crystals.

 Example 5

 The same operation as in Reference Example 5 described above was performed using 413 mg of N-4-chloromouth-6- (3-fluorophenyl) -2- (methylsulfur) pyrimidine-4-amine to obtain N-4- Black mouth-6- (3-fluorophenyl) -2- (methylsulfiel) pyrimidin-4-amine was obtained. Using this compound and in the same manner as in Example 1, {1 '-[4-[(4-chlorophenol) amino] -6- (3-fluorophenyl) pyrimidine-2-yl]- 170 mg of 1,4-bipiperidin-3-yl} methanol dihydrochloride was obtained as pale yellow crystals

Example 6

A saturated aqueous solution of sodium bicarbonate was added to 853 mg of N- (4-chlorophenol) -2- (methylsulfur) -5-phenylpyrimidine-4-amine hydrochloride and extracted with chloroform. did. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off, and N- (4-chlorophenyl) -2- (methylsulfur) -5-phenylpyrimidine-4 was removed. 770 mg of -amine was obtained as a pale yellow oil. Using this compound, the same operation as in Reference Example 5 described above was performed to obtain N- (4-chlorophenol) -2- (methylsulfuryl) -5-phenylpyrimidine-4-amine 960 mg. Obtained. Using this compound in the same manner as in Example 1 (but using DEE as a solvent and reacting at 130 ° C. for 19 hours) to give (1,-{4-[(4-chlorophenyl) amino]] -5-Phenylpyrimidine-2-yl} -1,4, -bipiperidin-3-yl) methanol dihydrochloride (524 mg) as orange crystals It was.

Example 7

 The same operation as in Reference Example 4 described above was performed using 277 mg of 4-chloro-6- (3-methoxyphenyl) -2- (methylsulfur) pyrimidine !, N- (4-chlorophenol) 251 mg of 6- (3-methoxyphenyl) -2- (methylsulfur) pyrimidine-4-amine were obtained as colorless crystals. The same operation as in Reference Example 5 described above was performed using this compound, and N- (4-chlorophenol) -6- (3-methoxyphenyl) -2- (methylsulfiel) was obtained. Pyrimidin-4-amine was obtained. [1] [4-[(4-chlorophenol) amino] -6- (3-methoxyphenyl) pyrimidin-2-yl]- 198 mg of 1,4'-bipiperidin-3-yl} methanol dihydrochloride was obtained as white crystals.

Example 8-22

 Example compounds shown in Tables 9 to 10 below were produced in the same manner as in Example 17 using the corresponding starting materials.

Example 23

 Using the same method as in Example 1 except that 250 mg of 2-chloro-N-cycloheptyl-5-phenylpyrimidine-4-amine was used (however, the reaction was carried out at 120 ° C. for 2 days using DEE as a solvent). ) Then, add 178 mg of (1 '-[4- (cycloheptylamino) -5-phenylpyrimidine-2-yl] -1,4, -bipiperidin-3-yl) methanol dihydrochloride to pale yellow Obtained as crystals.

Example 24

To a solution of 201 mg of N- (4-chloro-2-fluorophenyl) -6-isopropyl-2- (methylthio) -5-phenylpyrimidin-4-amine in 15 ml of chloroform in ice-cold form (15 ml) was added ice-cooled. 143 mg of m-chloroperbenzoic acid (> 65%) was added thereto, and the mixture was stirred at room temperature for 2 hours at 0 ° C. An aqueous solution of sodium thiosulfate and an aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain N_ (4-chlorophenol) _6_isopropyl-2- (methylsulfuryl) -5-phenylpyrimidine-4-amine Got. To a mixture of this compound and 140 mg of 1.4, -bipiperidin-3-ylmethanol dihydrochloride, 7 ml of DEE and 0.28 ml of DBU were successively added and stirred at 120 ° C for 2 days. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and dissolved. The medium was distilled off. The obtained residue was purified by silica gel column chromatography (form-form-methanol-28% aqueous ammonia) to give (1,-{4-[(4-form-methyl) amino] -6-isopropyl -5-Phenylpyrimidine-2-yl} -1,4'-bipiperidin-3-yl) methanol (125 mg) was obtained. This compound was dissolved in 5 ml of methanol, and 0.2 ml of a 4 M hydrogen chloride-dioxane solution was heated to form a hydrochloride, and then the solvent was distilled off. The obtained product was washed with getyl ether to give (1,-{4-[(4-chlorophenol) amino] -6-isopropyl-5-phenylpyrimidine-2-yl}- 75 mg of 1,4, -bipiperidin-3-yl) methanol dihydrochloride was obtained as beige crystals. Example 25

 tert-Butyl (2R)-2-[(4- {4-[(4-chlorophenol) amino] -5-phenylpyrimidine-2-yl} piperazine-1-yl) carbonyl] pi To a solution of 291 mg of lysine-1-carboxylate in 6 ml of methanol was added 3 ml of a 4M solution of hydrogen chloride-ethyl acetate, and the mixture was stirred at room temperature for 16 hours. Reaction liquid power The solvent obtained by distilling off the solvent was crystallized by adding a mixed solvent of isopropanol and diisopropyl ether to crystallize, and N- (4-chlorophenyl) -5-phenyl was added.

242 mg of 2- {4-[(2R) -piperidin-2-ylcarbol] piperazine-1-yl} pyrimidine-4-amine 2 hydrochloride was obtained as colorless crystals.

Example 26—39

 The compounds of Examples 26 to 39 shown in Tables 11 to 12 described below were produced in the same manner as in the method of Example 125 using the corresponding raw materials.

Example 40

 215 mg of N- (4-chlorophenol) -5-phenyl-2-pyrazine-1-ylpyrimidine-4-amine and ((2S) -1- (tert-butoxycarbol) pyrrolidine Tert-butyl (2S) -2- [2- (4- {4-[(4-chlorophenol) using 135 mg of -2-yl] acetic acid in the same manner as in Reference Example 78. ) Amino] -5-phenylpyrimidine-2-yl} piperazine-1-yl) -2-oxoethyl] pyrrolidine-1-force ropoxylate. In the same manner as in Example 25 using this compound, N- (4-chlorophenol) -5-phenyl-2- {4-[(2S) -pyrrolidine-2-ylacetyl] pidazine 213 mg of 1-yl} pyrimidine-4-amine dihydrochloride was obtained as a colorless amorphous solid.

The structure and physical properties of the compound of Example 140 are shown in Table 9-112. Tables 13 to 15 show the structures of other compounds of the present invention. These are based on the above-mentioned manufacturing methods and examples. The compounds can be easily synthesized by using the methods described and those obvious to those skilled in the art, or variations thereof.

 [table 1]

[0049]

[0050] [Table 3]

[Table 4]

[Table 5]

n [oo]

SCSC00 / S00Zdf / X3d εε [8 挲] [eeoo]

SCSC00 / S00Zdf / X3d [6 挲] [9S00]

SCSC00 / S00idf / X3d 9ε

Ex Syn Dat 1 Sal

 F: 512; NMR 2: 7.83 (IH, s), 7.43 (IH, d, J = 8.8

1 1

Hz), 1.10-1.19 (1H, m ); Sal: 2HC1.0.5H 2 O: 496; NMR2: 8.18 (IH, s), 7.36 (2H, t, J = 8.8

2

Hz), 1.14-1.19 (IH, m ); Sal:. 2HC1 H 2 0

 IH, s), 7.09 (IH, d, J = 7.2

8 1 or F: 508; NMR2: 7.72 (

Hz), 1.04-1.19 (IH, m); Sal: 2HC1.3H ₂₀

9 1 _F x ^F F: 514; NMR 2: 7.95 (IH, s), 7.36-7.40 (5H, m),

1.10-1.19 (1H, m); Sal: 2HC1.3H ₂₀

 F: 514; NMR2: 7.91 (IH, s), 7.23- 7.27 (IH, m),

10 1

2.60-2.68 (IH, m); Sal : 2HC1.1.5H 2 0

 F: 514; NMR 2: 8.18 (IH, s), 7.34 (IH, br s),

11 1

1.10-1.19 (IH, m): Sal: 2HC1.0.5H ₂ O

 F: 546; NMR2: 7.92 (1H, s), 7.72-7.83 (4H, m),

12 1

1.14-1.19 (IH, m); Sal :. 2HC1 H 2 0

 F: 503; NMR2: 7.98 (2H, d, 1 = 1.2 Hz), 7.90 (1H,

^{13 1 NC Xk s), 1.04-1.16} (IH, m); Sal: 2HC1.1.5H 2 0

 ES: 479; NMR2: 8.04 (IH, s), 7.96 (] H, br s),

14 1

1.10-1.19 (IH, m); Sal: 3HC1.4H ₂₀

 F: 484; NMR2: 7.91 (IH, s), 7.79 (IH, s),

15 1

1.10-1.19 (IH, m); Sal: 2HC1.4H ₂₀

 F: 484; NMR2: 8.19 (IH. S), 7.32 (1H, s),

16 1

1.05-1.19 (IH, m); Sal: 2HC1.2H _: 0

 ES: 468: NMR2: 8.05 (1H, s), 7.93 (IH. S),

17 1

1.04-1.19 (IH, m): Sal: 2HCI.4H _: 0

 F: 538; NMR2: 7.80 (1 H, s), 7.05 (1 H, s),

18 2

4.50-4.63 (2H, m); Sal : 2HC1.3H 2 0 10]

Ex S n R ¹ X 'Config Dat / Sal

: 514; EA: Cal (. C: 7 H 30 ClF 2 N 5 O.2HC1 H 2 0) C, 53.61; H, 5.66; N, 11.58; CI, 17.58; F,

3 3 -H -F S

. 6.28 Fnd:. C, 53.78 ; H, 5.62; N, 11.76; CI, 17.84; F, 6.42 .; Sal: 2HC1 H 2 0

 F: 478; NMR2: 7.74 (2H, d, J = 8.8 Hz),

4 4 6-Ph -H -H S 6.67 (1H, s), 2.94-3.12 (2H, m); Sal: 2HC1.

2H ₂ 0

 F: 496; NMR2: 7.56-7.61 (IH, m), 7.41 (2H,

5 5 -H -H RS d, J = 8.8 Hz), 1.05-1.18 (lH, m); Sal: 2HC1.

2.5H ₂ 0

 F: 478; NMR 2: 7.76 (1H, m), 4.51-4.66 (2H,

6 6 5-Ph -H -H RS

 m), 1.06-1.24 (1H, m): Sal: 2HC1.0.5H O

F: 508; NMR2: 7.74 (2H, d, J = 8.8 Hz), 3.85

7 7 -H -H RS

(3H, s), 1.13-1.19 ( lH, m); Sal: 2HC1.2H 2 0

F: 496; NMR2: 7.73 (2H, dd, J = 8.8, 5.2 Hz),

18] -H -H RS 6.63 (1H, s), 1.10-1.19 (IH, m); Sal: 2HC1.

 2.5H 0

 F: 510; NMR2: 4.58-4.78 (2H, m), 2.15 (3H,

19 3 6-Me -H RS

s), 1.05-1.23 (IH, m); Sal: 2HC1.2H ₂₀

F: 514; NMR2: 7.52 (2H, d, J = 9.6 Hz),

20 5 -II -F RS 6.72 (111, s), 1.12-1.18 (IH, m): Sal: 2HC1.

2.5H _: 0

 F: 484; NMR2: 7.95 (1 H, s), 7.38 (2H, d,

21 5 ⁶ -H -H RS J = 8.8 Hz), 1.10-1.1 (1H, m); Sal: 2HC1.

3H ₂ 0

 F: 502: N R2: 8.04 (1H, t, J = 8.8 Hz) .6.64

22 5 -H -F RS

(lH, s), 2.63-2.65 (IH. m); Sal: 2HCI. 1.5H _: 0 11]

L— W

L—W

13]

13]

[0062] [表 15] [Table 14]

[Table 15]

 Industrial applicability

[0063] The substituted pyrimidine derivative of the present invention has a function of modulating the function of CCR4 or TARC and / or MDC, and therefore has various inflammatory diseases, allergic diseases, autoimmune diseases and the like (eg, asthma, allergic rhinitis). , Allergic conjunctivitis, hay fever, dermatitis (atopic dermatitis, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis Disease, insulin-dependent diabetes mellitus (IDDM), organ transplant rejection, cancer, inflammatory bowel disease (ulcerative colitis, Crohn's disease), interstitial cystitis, sepsis, pain) It is for. In particular, it is useful as a prophylactic / therapeutic agent for asthma, atopic dermatitis or rheumatoid arthritis.

Claims

The scope of the claims A substituted pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. [Formula 15]

(The symbols in the formula have the following meanings.  A: substituted !, may! /, Aryl or substituted !, may! /, Cycloalkyl,  B: A substituted or unsubstituted monocyclic or bicyclic hydrocarbon ring group, or a substituted or unsubstituted monocyclic or bicyclic heterocyclic group, R ¹ : -R °, halogen, -OH, -OR °, halogeno lower alkyl, X: CR ³ X «N, R ³ : — H, — R. Or— CN,  L: bond, -CO-, lower alkylene, -CO- (lower alkylene)-or-(lower alkylene) -CO-, [Formula 16]

 D: monocyclic heterocycloalkyl or cycloalkyl,  However, when X is N and L is a bond, W is a group (i), and the group is bonded to X at a carbon atom. R ² : same or different, -R °, halogen, -OH, -OR °, halogeno lower alkyl, -R °° -OH, -CON (R ⁸ ) (R ⁹ ), -R ⁰⁰ -OR ° ,-R ^QQ -N (R ⁸ ) (R ⁹ ), -R ^QQ -CN, -R ^QQ -N (R ⁸ ) -CO-R °, -R ⁰ . ^{- N (R 8) - SO} - R °, - R °° - O- CO- R °, - R °° - CO - R. Or ^{- R °° - CON (R 8} ) (R 9), twenty two R ⁸ and R ⁹ : same or different, -H or -R °, R ¹¹ and R ^12: same or different from each other, - 0H, -0R °, ^{halogen, - N (R 8) (} R 9), - CN, - N (R 8) - CO- R °, - N ( R ⁸ ) -SO-R °, -0-CO-R °, -CO-R. Or a group consisting of -CON (R ⁸ ) (R ⁹ )  twenty two Optionally substituted with a group selected from the group consisting of lower alkyl,  R °: lower alkyl,  Lower alkylene,  m: 0, 1, 2, 3 or 4. ) A substituted pyrimidine derivative represented by the following general formula (Π) or a pharmaceutically acceptable salt thereof. [Formula 17]

 (The symbols in the formula have the following meanings.  A: substituted !, may! /, Aryl or substituted !, may! /, Cycloalkyl, B: A substituted or unsubstituted monocyclic or bicyclic hydrocarbon ring group, or a substituted or unsubstituted monocyclic or bicyclic heterocyclic group, R ¹ : -R °, halogen, -OH, -OR °, halogeno lower alkyl, X: CR ³ X «N, Y: CR ⁴ or N, where X force CR ³ indicates Y, and X indicates N, Y indicates CR ⁴ . Z: CR ⁵ R ⁶ , NR ⁷ or 0, R ² : same or different, -R °, halogen, -0H, -0R °, halogeno lower alkyl, -R °° -0H, -CON (R ⁸ ) (R ⁹ ), -R ⁰⁰ -OR ° ,-R ^QQ -N (R ⁸ ) (R ⁹ ), -R ^QQ -CN, -R ^QQ -N (R ⁸ ) -CO-R °, -R ⁰ . ^{- N (R 8) - SO} - R °, - R °° - 0- CO- R °, - R °° - CO - R. Or ^{- R °° - CON (R 8} ) (R 9),  twenty two R ³ , R ⁸ and R ⁹ : the same or different, -H or -R °, R ⁵ and R ⁶ are the same or different from each other, and the group described in H or R ² or R ⁵ and R ⁶ Become a Kiso, ^{R 7: - H, - R} °, - R °° - OH, - CON (R 8) (R 9), - R °° - O- R °, - R °° - N (R 8) (R ^{9), - R °° - CN} , -R °° - N (R 8) - CO- R °, - R °° - N (R 8) - SO - R °, - R °° - O- CO -R °, -R °° -CO-R. Or -R °° -CON (R ⁸  twenty two XR ⁹ ),  R °: lower alkyl, R ^QQ : lower alkylene,  m: 0, 1, 2, 3, or 4,  k: 0, 1 or 2. )  [3] The compound according to claim 2, wherein X is CH and Y is.  [4] The compound according to claim 3, wherein A is substituted or may be a phenyl.  [5] The compound according to claim 4, wherein B is substituted !, may! /, Monocyclic heteroaryl or substituted, may be, or may be phenyl. [6] The compound according to claim 5, wherein Z is CH.  2  [7] {1 '-[4-[(4-chlorophenol) amino] -5- (4-fluorophenyl) pyrimidine-2-yl] -1,4'-bipiperidine- 3-yl} methanol, {1- [4-[(4-chlorophenyl) amino] -5- (4-fluorophenyl) -6-methylpyrimidine-2-yl] -1,4 Bipiperidin-3-yl} methanol, {1 [4-[(4-chloro-2-fluorophenyl) amino] -5- (4-fluorophenyl) pyrimidine-2-yl] -1 , 4'-Bipiperidin-3-yl} methanol, (1,-{4-[(4-chlorophenol) amino] -5-phenylpyrimidine-2-yl} -1,4 '-Bipiperidin-3-yl) methanol, (1,-{4-[(4-chlorophenyl) amino] -6-isopropyl-5-phenylpyrimidine-2-yl} -1,4 '-Bipiperidin-3-yl) methanol, {1'-[4-[(4-chlorophenol) amino] -5- (2,4-difluorophenyl) pyrimidine-2-yl] -1,4'-Bipiperidin-3-yl} methanol, {1 and [4-[(4- 2- (2-phenyl) pyrimidine-2-yl] -1,4, -bipiperidin-3-yl} methanol and {1- [4-[(4-chloro Mouth-2-fluorophenyl) amino] -6- (4-fluorophenyl) pyrimidine-2-yl] -1,4-bipiperidin-3-yl} methanol. The derivative according to claim 1, which is selected, or a pharmaceutically acceptable salt thereof. [8] A pharmaceutical composition comprising the derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [9] A derivative according to claim 1, or a pharmaceutically acceptable salt thereof, and a CCR4 or TARC and Z or MDC function regulator, which is capable of acting as a pharmaceutically acceptable carrier. [10] The pharmaceutical composition according to claim 8, which is an agent for preventing or treating an inflammatory disease, an allergic disease or an autoimmune disease. [11] The pharmaceutical composition according to claim 8, which is a prophylactic or therapeutic agent for asthma. 12. The pharmaceutical composition according to claim 8, which is a prophylactic or therapeutic agent for atopic dermatitis. 13. The pharmaceutical composition according to claim 8, which is a prophylactic or therapeutic agent for rheumatoid arthritis. [14] The derivative or the pharmaceutical thereof according to claim 1, for the manufacture of a CCR4 or TARC and Z or MDC function modulator, or a prophylactic or therapeutic agent for an inflammatory disease or a self-immune disease. Use of a chemically acceptable salt. [15] A method for preventing or treating an inflammatory disease, an allergic disease or an autoimmune disease, comprising administering to a patient a therapeutically effective amount of the substituted pyrimidine derivative or a salt thereof according to claim 1.