WO2006123639A1 - Pyrimidine derivative - Google Patents

Abstract

A compound represented by the general formula (1) which has an inhibitory effect on PDE4 activity and produces little adverse side effects: wherein Ar1 represents a furyl, thienyl, triazolyl, thiazolyl, oxazolyl or benzothiazolyl group; Ar2 represents -E-AR21-G-Q (where Ar21 represents a benzene or naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group or an alkenylene group; and Q represents a carboxyl group, -CON(R41)(R42) or -COOR43), -E-Ar21-G2-G-Q (where E, Ar21, G and Q are as defined above; and G2 represents -O-, -S-, -SO-, -SO2- or -NRG21-) or a monocyclic aromatic heterocyclic ring other than a pyrazolyl group; R1 and R2 are the same as or different from each other and independently represent a hydrogen atom, an alkyl group which may be substituted or the like; and R3 represents a hydrogen atom or an alkyl group which may be substituted.

Description

 Specification

 Pyrimidine derivatives

 Technical field

 [0001] The present invention relates to a novel pyrimidine derivative having an anti-inflammatory action and useful as an active ingredient of a medicine.

 Background art

 [0002] Stimulation from the outside, such as neurotransmitters and hormones, is transmitted into cells via receptors on the cell membrane. This biological signal is generated by enzymes such as adenylate cyclase or dallate cyclase, and the intracellular second messengers cyclic adenosine 3 ', 5,-phosphate (cAMP) and cyclic guanosine. 3 ,, 5,-It is known that its action is manifested by increasing the concentration of phosphoric acid (cGMP). It is nucleotide phosphodiesterase (PDE) that degrades cAMP and cGMP and regulates their concentrations! At least 11 types of PDEs are currently classified based on differences in gene sequences and pharmacological properties (Non-patent Documents 1 and 2). Among them, type 4PDE (PDE4) selectively degrades cAMP and decreases intracellular cAMP concentration. PDE4 has been found in many tissues and cells including blood vessels, heart, intestine, brain, spleen, bronchial smooth muscle, leukocytes, and lymphocytes. It is known that cAMP increased by inhibiting PDE4 at these sites exerts an effect of preventing or ameliorating many diseases.

PDE4 inhibitor suppresses inflammatory cell activity, suppresses tumor necrosis factor a (TNF-α) release, suppresses degranulation, suppresses release of inflammatory site force-in, It has effects such as suppression (Non-Patent Documents 3 to 5) and is considered to be effective for many inflammatory, allergic, and immune related diseases. For example, in respiratory diseases, it is effective for asthma, chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, inflammatory airway disease, emphysema, adult respiratory distress syndrome (ARDS), etc. In particular, the effectiveness of lofuromilast and cilomilast, which are PDE4 inhibitors, has been confirmed in clinical trials for COPD and asthmatic patients (Non-patent Document 6). Joint-related diseases are related to skin diseases such as rheumatism, osteoarthritis, acute arthritis, and chronic arthritis. Diseases related to the gastrointestinal tract such as atopic dermatitis, psoriasis, seborrheic eczema, allergic contact eczema, etc. Allergic rhinitis, chronic rhinitis, allergic conjunctivitis etc. are reported as diseases, and immune system related diseases are reported to be effective for transplant rejection, multiple sclerosis, AIDS, etc. (Non-patent Document 7) ~ 12). In addition, it is known that PDE4 inhibition in bronchial smooth muscle relaxes smooth muscle, and this is also considered to be effective for respiratory diseases such as asthma and COPD.

On the other hand, PDE4 inhibitors may cause side effects such as vomiting as an undesirable effect. Side effects such as nausea and nausea have been reported in clinical trials such as rolipram and silomilast. One of the causes of these side effects is the selectivity between PDE4 isoforms. Four isoforms (A, B, C, D) have been reported in PDE4, and lysoform B is involved in pharmacological actions such as anti-inflammatory effects, while lyoform D is associated with side effects such as vomiting and nausea. (Non-patent Document 13).

To date, PDE4 inhibitors have been reported because they are expected to be effective against many diseases (Patent Documents 1 to 3), but currently reported PDE4 inhibitors are effective and have side effects. Satisfied in terms, not a spider! /.

Patent Document 1: W098Z45268 Publication

Patent Document 2: WO95Z01338

Patent Document 3: W099Z55696

Non-Patent Literature l: Soderling, S. H. and Beavo, J. A., Curr. Opin. Cell. Biol, 12, pl74— 1 79, 2000

Non-Patent Document 2: Hetman, J. M., et al, Proc. Natl. Acad. Sci. U S A., 97, pl2891- 128 95, 2000

Non-patent document 3: Teixeira, MM, et al., Trends Pharmacol. Sci., 18, pl64-170, 1997 Non-patent document 4: Beavo, JA, et al., Trends Pharmacol. Sci., 11, pl50-155 , 1990 Non-patent literature 5: Nicholson, C. D "et al" Trends Pharmacol. Sci., 12, pl9-27, 1991 Non-patent literature 6: Lipworth, BJ, Lancet, 365, pl67-175, 2005

Non-Patent Document 7: Dyke, HJ and Montana, JG, Expert Opin.Investig. Drugs, 11, pi -13, 2002

 Non-patent literature 8: Burnouf, C, et al., Curr. Pharm. Des., 8, pl255-1296, 2002 Non-patent literature 9: Banner, K. H. and Trevethick, M. A., Trends Pharmacol. Sci., 25, p4

30-436, 2004

 Non-Patent Document 10: Rickards, K. J., et al "Vet. Immunol. ImmunopathoL, 98, pl53-165, 2004

 Non-patent literature ll: Sun, Y., et al "J. Immunol, 165, pl755-1761, 2000

 Non-Patent Document 12: Dousa, M. K., et al., Clin. Nephrol, 47, pl87-189, 1997

 Non-Patent Document 13: Lipworth, B. J., Lancet, 365, pl67-175, 2005

 Disclosure of the invention

 Problems to be solved by the invention

[0003] An object of the present invention is to provide a novel substance having a PDE4 activity inhibitory action. More specifically, it is an object of the present invention to provide a novel substance having excellent PDE4 activity inhibitory action and few side effects.

 Means for solving the problem

[0004] As a result of intensive studies to solve the above problems, the present inventor has found that a novel compound represented by the following general formula (1) has an excellent anti-inflammatory action. The present invention has been completed based on the above findings.

[0005] That is, according to the present invention,

 [A1] The following general formula (1)

 [Chemical 1]

[In the general formula (1), Ar ¹ is a furyl group, Choi - group, Toriazoriru group, a thiazolyl group, Okisazo Lil group, or base indicates Nzochiazoriru group; Ar ¹ may be substituted; Ar ² is - E—Ar GQ (Ar represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group or an alkylene group; Q represents a carboxy group, —CON (R ⁴¹ ) (R ⁴² ) (R ⁴¹ and R ⁴² may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aryl group. Or R ⁴¹ and R ⁴² together form a 3- to 7-membered ring to represent a cyclic amine as N (R ⁴¹ ) (R ⁴² ), provided that when R ⁴¹ is a hydroxyl group, R ⁴² is A group other than a hydroxyl group), or —COOR ⁴³ (R ⁴³ represents an optionally substituted alkyl group or an optionally substituted aryl group)), E—Ar ²¹ —G ² — GQ (E, Ar ²¹ , G, Q are as defined above; G ² is one O, one S, one SO, one SO—, or one NR ^G21

 2

1 (R ^G21 represents a hydrogen atom, an ^optionally substituted alkyl group, an optionally substituted acyl group, or an optionally substituted sulfonyl group). Or Ar ² may be substituted; R ¹ and R ² may be the same or different and each independently , A hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted group A good alkylthio group, substituted, may be an alkylsulfier group, or substituted !, may! / Represents an alkylsulfonyl group, and R ³ may be a hydrogen atom or substituted An alkyl group is shown. Or a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

[A2] Ar ¹ may be substituted, but the compound described in [A1] above, which is a [furyl group or a chael group], possible stereoisomers or racemates thereof, or pharmacological thereof Acceptable salts, hydrates, solvates, or prodrugs thereof;

[A3] Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, and a substituted In addition, the compound according to the above [A1] or [A2], which may be substituted by one or a plurality of groups each independently selected from the group consisting of an acyl group] force, possible stereoisomers thereof, or Racemates, or pharmaceutically acceptable salts, hydrates, solvates thereof, or prodrugs thereof; [A ^ Ar ¹ is independently selected from the group consisting of [halogen atom, optionally substituted alkyl group, optionally substituted V, alkoxy group, and optionally substituted, amino group]. The compound described in the above [A1] or [A2], its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof, water, Solvates, solvates, or prodrugs thereof;

[ASjAr ¹ is [halogen atom, lower alkyl group, trifluoromethyl group, hydroxymethyl group, hydroxyethyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, —NH group, lower alkylamino group] Group, lower dialkylamino group, acylamino group,

 2

The compound according to [A1] or [A2], which may be substituted with one or more groups each independently selected from the group consisting of a lower alkylsulfonylamino group], possible stereoisomers or racemates thereof Or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

[A6] Ar ¹ may be substituted with one or more halogen atoms, but the compound according to the above [A1] or [A2], its possible stereoisomer or racemate, or its pharmacology Acceptable salts, hydrates, solvates, or prodrugs thereof;

[A7] Ar ¹ is substituted by one or more halogen atoms, the compound according to the above [A1] or [A2], its possible stereoisomer or racemate, or pharmacologically acceptable Salts, hydrates, solvates, or prodrugs thereof;

[88] The compound according to [81] or [82], wherein 8: ¹ is unsubstituted, its possible stereoisomer or racemate, or a pharmaceutically acceptable salt thereof. , Hydrates, solvates, or prodrugs thereof;

[The compound according to any one of the above [A1] to [A8], wherein AR ¹ is a lower alkyl group, a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt or hydrate thereof , Solvates, or prodrugs thereof;

[AIO] The compound according to any one of the above [A1] to [A9], wherein R ² is a lower alkyl group or a lower alkenyl group, a possible stereoisomer or racemate thereof, or a pharmacologically acceptable salt thereof. Salts, hydrates, solvates, or prodrugs thereof;

[A11] The compound according to any one of the above [A1] to [A9], wherein R ² is a lower alkyl group, Its possible stereoisomers or racemates, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

[A12] The compound according to any one of the above [A1] to [A11], wherein R ³ is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmacologically acceptable salt thereof, hydration Products, solvates, or prodrugs thereof;

[A13] The compound according to any one of [A1] to [A12], which is Ar S—E—Ar ²¹ —G—Q (E, Ar ²¹ , G, Q are as defined above), Possible stereoisomers or racemates, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

[A14] The compound according to any one of the above [A1] to [A13], wherein Ar ²¹ is a benzene ring, possible stereoisomers or racemates thereof, or pharmaceutically acceptable salts, hydrates thereof Products, solvates, or prodrugs thereof;

 [A15] The compound according to any one of the above [A1] to [A14], wherein E is a single bond and [G is a single bond or a lower alkylene group], possible stereoisomers or racemates thereof, Or a pharmacologically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

 [A16] The compound according to any one of the above [A1] to [A14], wherein E is a single bond and G is a lower alkylene group, its possible stereoisomer or racemate, or its pharmacological Acceptable salts, hydrates, solvates, or prodrugs thereof;

[A17] The compound according to any one of the above [A1] to [A16], wherein Q is a carboxy group, its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof, hydration Products, solvates, or prodrugs thereof;

[A18] Ar ² is substituted with one or more groups each independently selected from the group consisting of [hydroxyl group, halogen atom, optionally substituted alkyl group, and optionally substituted alkoxy group]. However, the compounds described in any one of the above [A1] to [A17], possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates thereof, Solvates, or prodrugs thereof;

[A19] Ar ² is [hydroxyl group, halogen atom, lower alkyl group, trifluoromethyl group, lower group The compound according to any one of [A1] to [A17] above, which is substituted with one or more groups each independently selected from the group consisting of an alkoxy group and a trifluoromethoxy group] , Possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

[8-20] The compound in any one of the above [81] to [A17], possible stereoisomers thereof, or 8: 1: ² substituted with one or more halogen atoms Racemates, or pharmacologically acceptable salts, hydrates, solvates, or prodrugs thereof;

[A21] The compound according to any one of [A1] to [A17], wherein Ar ² is substituted by one or more halogen atoms, possible stereoisomers or racemates thereof, or a pharmacological thereof A salt, hydrate, solvate or prodrug thereof; [A22] The compound according to any one of [A1] to [A17] above, wherein Ar ² is unsubstituted, Stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

[ASSjAr ¹ is a chael group, Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, I also, Amino groups and substituted, by also, Yogu Ar ² optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar ² GQ, Ar ²¹ is a benzene ring or a benzene ring substituted with one or more halogen atoms, E is a single bond, G force methylene group, Q is a carboxy group, on Ar ² The compound according to [A1], further having no substituent, wherein R ¹ is a methyl group or an ethyl group, R ² is an aryl group, an ethyl group, or a hydroxymethyl group, and R ³ is a hydrogen atom. , Its possible stereoisomers or racemates, or its drugs Histological acceptable Ru salts, hydrates, solvates or prodrugs thereof;

[AS ^ Ar ¹ is a chael group, Ar ¹ is [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted alkylthio group, substituted Ar ² which may be substituted by one or a plurality of groups each independently selected from the group consisting of an amino group and a substituted acyl group]. Ar ² GQ, Ar ²¹ is a benzene ring, E is a single bond, G is a methylene group, Q is a carboxy group, Ar ² has no further substituents, and R ¹ is a methyl group Or a ethyl group, R ² is an aryl group, an ethyl group, or a hydroxymethyl group, and R ³ is a hydrogen atom, the possible stereoisomer or racemate thereof, or A pharmacologically acceptable salt, hydrate, solvate, or prodrug thereof; [ASSjAr ¹ is a chael group, Ar ¹ is a [halogen atom, optionally substituted alkyl, Group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted, optionally, amino group, and a substituted, optionally substituted, acyl group] each independently from the group May be substituted by one or more groups selected by Ar ² is —E—Ar ² GQ, Ar ²¹ is a benzene ring, E is a single bond, G is a methylene group, Q is a carboxy group, and Ar ² is further substituted. not perforated, R ¹ is methyl group or Echiru group, R ² is Ariru group, compounds described in the [A1] R ³ is a hydrogen atom, possible stereoisomers or racemates of that, Or a pharmacologically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

[ASejAr ¹ is a chael group, Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, I also, Amino groups and substituted, by also, Yogu Ar ² optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar ² GQ, Ar ²¹ is a benzene ring, E is a single bond, G is a methylene group, Q is a carboxy group, Ar ² has no further substituents, and R ¹ is a methyl group Or an ethyl group, R ² is an ethyl group, and R ³ is a hydrogen atom, the compound according to [A1], its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof. Salts, hydrates, solvates, or prodrugs thereof;

[ASYjAr ¹ is a chael group, Ar ¹ is [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted alkylthio group, substituted, I also, Amino groups and substituted, by also, Yogu Ar ² optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar ² GQ, Ar ²¹ substituted with a benzene ring or one or more halogen atoms A benzene ring, E is a single bond, G force methylene group, Q is a carboxy group, no further substituent on Ar ² , R ¹ is a methyl group or an ethyl group, R A compound of the above-mentioned [A1], which is a ^2- force S-hydroxymethyl group, and R ³ is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt, hydrate thereof, Solvates, or prodrugs thereof;

[ASSjAr ¹ is a chael group, Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, I also, Amino groups and substituted, by also, Yogu Ar ² optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar ² GQ, Ar ²¹ is a benzene ring, E is a single bond, G is a methylene group, Q is a carboxy group, Ar ² has no further substituents, and R ¹ is a methyl group Or an ethyl group, R ² is a hydroxymethyl group, and R ³ is a hydrogen atom, the compound according to [A1], a possible stereoisomer or racemate thereof, or a pharmacologically acceptable salt thereof. A salt, hydrate, solvate, or prodrug thereof;

[AS Ar ¹ is a chael group, Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, , I even, Amino groups and substituted, by also, Yogu Ar ² optionally substituted by one or more groups chosen independently represent from Ashiru radical forces also the group is - E-Ar ² GQ, Ar ²¹ is a benzene ring substituted with one or more halogen atoms, E is a single bond, G is a methylene group, Q is a carboxy group, and is further placed on Ar ² The compound according to [A1], which has no substituent, R ¹ is a methyl group or an ethyl group, R ² is a hydroxymethyl group, and R ³ is a hydrogen atom, its possible stereoisomer or Racemate, or pharmacologically acceptable salt, hydrate, solvate thereof These prodrugs;

[ASC ^ Ar ¹ is independently selected from the group consisting of [halogen atom, optionally substituted alkyl group, optionally substituted V, alkoxy group, and optionally substituted, amino group]. The compounds described in any one of the above [A1] to [A29], possible stereoisomers or racemates thereof, or pharmacologically thereof may be substituted with one or more groups selected from Acceptable salts, hydrates, solvates, or prodrugs thereof;

[A3 Ar ¹ is [halogen atom, lower alkyl group, trifluoromethyl group, hydroxymethyl group, hydroxyethyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, —NH group, lower An alkylamino group, a lower dialkylamino group, an acylamino group,

 2

The compound according to any one of the above [A1] to [A29], which is substituted with one or more groups each independently selected from the group consisting of a lower alkylsulfonylamino group], Stereoisomers or racemates, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof;

[ASSjAr ¹ is [halogen atom, lower alkyl group, trifluoromethyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, NH group, lower alkylamino group]

 2

Group, lower dialkylamino group, or acylamino group], each of which is substituted by one or more groups independently selected from the group consisting of [A1] to [A29]. A compound, possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

 [Eight eight is! Or may be substituted by a plurality of halogen atoms ^ :!] to [A29], its possible stereoisomer or racemate, or its pharmacological Acceptable salts, hydrates, solvates, or prodrugs thereof;

(A34) The compound according to any one of (A1) to (A7) or (A9) to (A29), wherein Ar ¹ is substituted with one or more halogen atoms, and possible stereoisomers thereof! / Is a racemate, or a pharmacologically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

[A35] The compound according to any ^one of the above [A1] to [A29], wherein Ar ¹ is unsubstituted, its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof, water Hydrates, solvent solvates, or prodrugs thereof;

[A36] The compound according to any one of [A1] to [A35], a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof Or a medicament containing these prodrugs as active ingredients; [A37] The medicament according to [A36], which is a preventive and Z or therapeutic agent for inflammation;

 [A38] The medicament according to [A36], which is a preventive and Z or therapeutic agent for chronic obstructive pulmonary disease;

[A39] The medicament according to [A36] to [A38], which is a PDE4 activity inhibitor;

 [A40] The compound according to any one of the above [A1] to [A35], a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof Or PDE4 activity inhibitors containing these prodrugs as active ingredients;

 [A41] The above [A1] for producing the pharmaceutical according to any one of [A36] to [A39] above

To [A35], possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or use of these prodrugs ;

 [A42] A method for the prevention and Z or treatment of inflammation, the compound according to any one of the above [A1] to [A35], a possible stereoisomer or racemate thereof, or a pharmacologically acceptable method thereof. Administering a prophylactic and Z or therapeutically effective amount of a salt, hydrate, solvate, or prodrug thereof to a mammal, including a human;

[A43] A method for inhibiting PDE4 activity in vivo in mammals including humans, comprising the compound according to any one of the above [A1] to [A35], its possible stereoisomer or racemate Administering an effective amount of the body, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof to a mammal, including a human;

[B1] General formula (1)

[In the general formula (1), Ar ¹ is a furyl group, Choi - group, Toriazoriru group, a thiazolyl group, Okisazo Lil group, or base indicates Nzochiazoriru group; Ar ¹ may be substituted; Ar ² is - E—Ar GQ (Ar ²¹ represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group, or an alkylene group; Q represents a carboxy group; , -CON (R ⁴¹ ) (R ⁴² ) (R ⁴¹ and R ⁴² may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or a substituted group. May represent a aryl group, or R ⁴¹ and R ⁴² together form a 3- to 7-membered ring to represent a cyclic amine as N (R ⁴¹ ) (R ⁴² ), provided that R ⁴¹ And R ⁴² is a group other than a hydroxyl group), or —COOR ⁴³ (R ⁴³ represents an optionally substituted alkyl group or an optionally substituted aryl group). Or Ar ² may be substituted; R ¹ and R ² may be the same or different and each independently represents hydrogen; An atom, an optionally substituted alkyl group, an optionally substituted alkyl group, or an optionally substituted alkyl group, R ³ represents a hydrogen atom or an optionally substituted alkyl group; Indicates. Or a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

[B2] Ar ¹ may be substituted, and the compound according to [B1] above, which is a [furyl group or a phenyl group], a possible stereoisomer or racemate thereof, or a pharmacologically acceptable salt thereof. Salts, hydrates, solvates, or prodrugs thereof;

 [83] The group wherein 8 is [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted alkylthio group, and optionally substituted acyl group]. The compound according to the above [B1] or [B2], its possible stereoisomer or racemate, or its pharmacologically acceptable group, which may be substituted by one or more groups each independently selected from Salts, hydrates, solvates, or prodrugs thereof;

 [Β4] The compound according to any one of [Β1] to [Β3], wherein Ι ^ is a lower alkyl group, its possible stereoisomer or racemate, or a pharmaceutically acceptable salt thereof, Hydrates, solvates, or prodrugs thereof;

[B5] The compound according to any one of [Β1] to [Β4], wherein R ² is a lower alkyl group or a lower alkyl group, possible stereoisomers or racemates thereof, or pharmacologically thereof. Acceptable salts, hydrates, solvates, or prodrugs thereof;

[B6] wherein R ² is a lower alkyl group [B1] - [B5], the compound according to any displacement, its Possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

[B7] The compound according to any one of the above [B1] to [B5], wherein R ² is a lower alkenyl group, possible stereoisomers or racemates thereof, pharmacologically acceptable salts thereof, water Solvates, solvates, or prodrugs thereof;

[B8] The compound according to any one of the above [B1] to [B7], wherein R ³ is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmacologically acceptable salt thereof, hydration Products, solvates, or prodrugs thereof;

[B9] The compound according to any one of the above [B1] to [B8], wherein Ar ^{2 is} —E—Ar ²¹ —G—Q, its possible stereoisomer or racemate, or pharmacologically thereof Acceptable salts, hydrates, solvates, or prodrugs thereof;

[B10] The compound according to any one of [B1] to [B9], wherein Ar ²¹ is a benzene ring, a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, Hydrates, solvates, or prodrugs thereof;

 [B11] The compound according to any one of [B1] to [B10] above, wherein E is a single bond, and [G is a single bond or a lower alkylene group], possible stereoisomers or racemates thereof Or a pharmacologically acceptable salt, hydrate, solvate thereof, or a prodrug thereof;

 [B12] The compound according to any one of [B1] to [B11], wherein E is a single bond, and G is a lower alkylene group, a possible stereoisomer or racemate thereof, or a pharmacological thereof Acceptable salts, hydrates, solvates, or prodrugs thereof;

[B13] The compound according to any one of the above [B1] to [B12], wherein Q is a carboxy group, its possible stereoisomer or racemate, or a pharmacologically acceptable salt thereof, hydration Products, solvates, or prodrugs thereof;

[B14] Ar ² is substituted with one or more groups each independently selected from the group consisting of [hydroxyl group, halogen atom, optionally substituted alkyl group, and optionally substituted alkoxy group]. However, the compounds according to any one of the above [B1] to [B13], possible stereoisomers or racemates thereof, or pharmacologically acceptable salts thereof, hydration Products, solvates, or prodrugs thereof;

[BlSjAr ¹ is a chael group, Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, and a substituted Ar ² is —E—Ar ²¹ —G—Q, and Ar ²¹ is a ben, which may be substituted by one or more groups each independently selected from the group that also has an acyl group] force. Zen ring, E is a single bond, G is a methylene group, Q is a carboxy group, no further substituent on Ar ² , R ¹ is a methyl group or an ethyl group, R The compound according to [B1], wherein ² is an aryl group or an ethyl group, and R ³ is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt or hydrate thereof , Solvates, or prodrugs thereof;

 [B16] The compound according to any one of the above [B1] to [B15], its possible stereoisomer or racemate, or a pharmaceutically acceptable salt, hydrate, solvate thereof Or a medicament containing these prodrugs as active ingredients;

 [B17] The medicament according to [B16], which is a preventive and Z or therapeutic agent for inflammation;

 [B18] The medicament according to [B16] or [B17], which is a PDE4 activity inhibitor;

 [B19] The compound according to any one of [B1] to [B15], a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof Or PDE4 activity inhibitors containing these prodrugs as active ingredients;

 [B20] [B16]-[B18] !, [B1]-

Use of the compound according to any of [B15], possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof;

 [B21] A method for the prevention and Z or treatment of inflammation, the compound according to any one of the above [B1] to [B15], its possible stereoisomer or racemate, or a pharmacologically acceptable method thereof Administering a prophylactic and Z or therapeutically effective amount of a salt, hydrate, solvate, or prodrug thereof to a mammal, including a human;

[B22] A method for inhibiting PDE4 activity in vivo in mammals including humans, comprising the compound according to any one of the above [B1] to [B15], its possible stereoisomer or Administering a racemate, or a pharmacologically acceptable salt, hydrate, solvate thereof, or an effective amount of a prodrug thereof to a mammal including a human;

[C1] General formula (1)

[In the general formula (1), Ar ¹ represents a furyl group, a chael group, a triazolyl group, a thiazolyl group, an oxazolyl group, or a benzothiazolyl group; Ar ¹ may be substituted; Ar ² represents a carboxy group; Represents a thiophene group, a carboxyalkylphenol group, a carboxynaphthyl group, a carboxyalkylnaphthyl group, or a monocyclic aromatic heterocycle other than a virazolyl group; Ar ² may be substituted; R ¹ R ² may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or a substituted group. Represents an alkyl group, and R ³ represents a hydrogen atom or an alkyl group. Or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; [C2] Ar ² is carboxyalkylnaphthyl A compound, a possible stereoisomer or racemate thereof, or a group, a carboxyphenol group, a carboxyalkyl group, or a [monocyclic aromatic heterocycle other than a virazolyl group], Pharmacologically acceptable salts, hydrates, solvates, or prodrugs thereof;

[C3] The compound according to [C1] above, wherein Ar ² is a carboxyphenol group, a carboxyalkylphenol group, or a [monocyclic aromatic heterocycle other than a virazolyl group], possible stereoisomers thereof, or Racemate, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or prodrug thereof;

[C4] Ar ¹ is substituted !, may be! /, Substituted with an alkoxy group !, the compounds according to the above [C1] to [C3], possible stereoisomers or racemates thereof, or Pharmacologically acceptable salts, hydrates, solvates, or prodrugs thereof; 5] The compound according to any one of the above [C1] to [C4], wherein 1 ^ is lower alkyl, its possible stereoisomer or racemate, or a pharmacologically acceptable salt or hydrate thereof Solvates, or prodrugs thereof;

 Or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to any one of the above [C1] to [C4], its possible stereoisomer or racemate, Or prodrugs thereof;

[C7] The R ² is a lower alkyl group [C1] - [C6], compounds according to any displacement, possible stereoisomers or racemates of that or a pharmaceutically acceptable salt thereof, Hydrates, solvates, or prodrugs thereof;

[C8] The compound according to any one of the above [C1] to [C6], wherein R ² is a lower alkyl group, a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof Hydrates, solvates, or prodrugs thereof;

[C9] The compound according to any one of the above [C1] to [C8], wherein R ³ is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmacologically acceptable salt thereof, water Hydrates, solvent solvates, or prodrugs thereof;

 [C10] The compound according to any one of the above [C1] to [C9], its possible stereoisomer or racemate, or a pharmaceutically acceptable salt, hydrate, solvate thereof Or pharmaceuticals containing these prodrugs as active ingredients;

 [C11] The medicament according to [C10], which is a preventive and Z or therapeutic agent for inflammation;

 [C12] The medicament according to [C10] or [C11], which is a PDE4 activity inhibitor;

 [C13] The compound according to any one of the above [C1] to [C9], its possible stereoisomer or racemate, or a pharmacologically acceptable salt, hydrate or solvate thereof Or a PDE4 activity inhibitor containing these prodrugs as active ingredients;

 [C14] The above-mentioned [C10] to [C12] !, the compound according to any one of the above [C1] to [C9] for producing the pharmaceutical according to any one, its possible stereoisomer or racemate Or the use of a pharmacologically acceptable salt, hydrate, solvate or prodrug thereof;

[C15] A method for preventing and / or treating inflammation, comprising the above [C1] to [C9] A prophylactic and Z or therapeutically effective amount of the described compound, possible stereoisomers or racemates thereof, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof; Comprising the step of administering to a mammal comprising: and

 [C16] A method for inhibiting PDE4 activity in vivo in mammals including humans, the compound according to any one of the above [C1] to [C9], possible stereoisomers or racemates thereof, or A method comprising administering an effective amount of a pharmacologically acceptable salt, hydrate, solvate, or prodrug thereof to a mammal, including a human.

 Is provided.

 The invention's effect

 [0006] The compound of the present invention or a salt thereof exhibits a strong PDE4 inhibitory action in the living body of mammals including humans, and thus, for example, a medicament for prevention and Z or treatment of various diseases caused by inflammation. It is useful as an active ingredient. In addition, the compound of the present invention or a salt thereof can be used as an active ingredient of a safe pharmaceutical with extremely low toxicity.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0007] The present invention will be specifically described below.

 In the present specification, unless otherwise specified, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 In the present specification, the “lower” substituent means a substituent having up to 10 carbon atoms constituting the substituent, for example, a substituent having 1 to 6 carbon atoms. Preferred examples include substituents having 1 to 3 numbers.

 [0009] Examples of the alkyl group include a saturated hydrocarbon group which is linear, branched, cyclic, or a combination thereof, and a lower alkyl group is preferable. The lower alkyl group refers to an alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably an alkyl group having 1 to 3 carbon atoms. The same applies to the alkyl moiety of other substituents having an alkyl moiety (for example, an alkoxy group).

[0010] Preferred examples of the alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group, and further includes 4 to 6 carbon atoms. As the alkyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, Cyclobutyl, cyclopropylmethyl, n-pentyl, cyclopentyl, cyclopropylethyl, cyclobutylmethyl, n-hexyl, cyclohexyl, cyclopropylpropyl, cyclobutylethyl, or cyclopentylmethyl Groups and the like can be mentioned as suitable examples. As the alkyl group, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group is particularly preferable. Most preferably, the alkyl group includes a methyl group. There is also another embodiment in which an ethyl group is mentioned as the most preferred alkyl group.

 [0011] Examples of the alkenyl group include a lower alkenyl group containing one or more double bonds, and a lower alkenyl group containing one double bond is preferable. The lower alkenyl group refers to an alkenyl group having 2 to 10 carbon atoms, and an alkenyl group having 2 to 4 carbon atoms is preferable, and an alkenyl group having 2 to 4 carbon atoms is particularly preferable. . Examples of the alkenyl group having 2 to 4 carbon atoms include a bur group, a allyl group, a propenyl group, a butylidene group, a but-1-enyl group, a but-2-enyl group, and a but-3-yl group. Preferred examples of the alkyl group include pentylidene group, bent-1-ethyl group, pent-2-ethyl group, bent-3- Preferred examples include an enyl group or a bent-4-enyl group. The alkenyl group is particularly preferably a vinyl group, more preferably a buyl group, a allyl group, or a probe group, or a allyl group, more preferably a allyl group.

 [0012] Examples of the alkynyl group include a lower alkynyl group containing one or more triple bonds, and a lower alkyn group containing one triple bond is preferable. The lower alkynyl group is preferably an alkynyl group having 2 to 5 carbon atoms. Specifically, ethynyl group, prop-1-yl group, prop-2-yl group, but-1-yl group, but-2-ynyl group, but-3-yl group Vent-1-yl group, bent-2-yl group, bent-3-yl group, or bent-4-yl group are preferable examples. A -2-ynyl group or a -2-ynyl group is more preferred, and a propyl-2-ynyl group is more preferred, which is more preferably a prop-2-ynyl group.

[0013] The alkylene group can be exemplified by a divalent residue obtained by removing any one hydrogen atom from the alkyl group described above, and is linear, branched, cyclic, or those And a saturated hydrocarbon divalent group, and a lower alkylene group is preferred. A lower alkylene group is an alkylene group having 1 to 10 carbon atoms, An alkylene group having 1 to 6 carbon atoms is preferred, and an alkylene group having 1 to 3 carbon atoms is more preferred, and an alkylene group having 1 carbon atom is more preferred. Examples of the alkylene group having 1 carbon atom include a methylene group, and preferable examples of the alkylene group having 2 to 3 carbon atoms include an ethylene group, an n-propylene group, an isopropylene group, and a cyclopropylene group. As examples of suitable alkylene groups having 4 to 6 carbon atoms, any one hydrogen atom may be removed from the groups listed in the above examples of suitable alkyl groups having 4 to 6 carbon atoms. Bivalent residues that can be produced. As the alkylene group, a methylene group, an ethylene group, an n-propylene group, or an isopropylene group is particularly preferable. The most preferred alkylene group is a methylene group. There is another embodiment in which an ethylene group is mentioned as the most preferable alkylene group.

 [0014] Examples of the alkellene group include divalent residues formed by removing any one hydrogen atom from the alkenyl group described above, and include one or two or more double groups. And a lower alkylene group containing a bond, and a lower alkylene group containing one double bond is preferred. The lower alkylene group refers to an alkylene group having 2 to 10 carbon atoms, and an alkylene group having 2 to 4 carbon atoms is preferable to an alkylene group having 2 to 5 carbon atoms. Is particularly preferred. Examples of the alkylene group having 2 to 4 carbon atoms include a beylene group, a pavemental group, a but-1-erene group, a but-2-erene group, and a but-3-ene group. -Len group and the like are listed as preferred examples. Furthermore, as the alkylene group having 5 carbon atoms, any one hydrogen atom from the groups listed in the examples of the preferred alkenyl groups having 5 carbon atoms is used. Examples of divalent residues that can be formed by removing. The alkylene group is particularly preferably a vinylene group or a vinylene group, more preferably a propylene group.

[0015] Examples of the alkoxy group include a saturated alkyl ether group which is linear, branched, cyclic, or a combination thereof, and a lower alkoxy group is preferable. As the lower alkoxy group, an alkoxy group having 1 to 6 carbon atoms is exemplified. An alkoxy group having 1 to 4 carbon atoms is preferable. Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, n_propoxy group, isopropoxy group, cyclopropoxy group, n-butoxy group, isobutoxy group, _s -butoxy group, and _t -butoxy group. , Cyclobutoxy group, cyclopropyl methoxy group and the like are preferable examples. Further, as the alkoxy group having 5 or 6 carbon atoms, n- Pentyloxy, cyclopentyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, n-hexyloxy, cyclohexyloxy, cyclopropylpropyloxy, cyclobutylethyloxy, or cyclopentylmethyl A suitable example is a silicon group.

 [0016] The alkylthio group includes a saturated alkylthioether group which is linear, branched, cyclic, or a combination thereof, and a lower alkylthio group is preferred. As the lower alkylthio group, an alkylthio group having 1 to 4 carbon atoms is preferable. Specifically, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, isobutylthio group, s-butylthio group, t-butylthio group, cycloptylthio group, or A suitable example is a cyclopropylmethylthio group.

 [0017] Examples of the alkoxycarbo yl group include groups having a carbonyl group at the end of the above alkoxy group, and a lower alkoxy carbo yl group is preferable. The lower alkoxy carbo group includes a group having a carbo group attached to the end of an alkoxy group having 1 to 6 carbon atoms. A carbo yl group is attached to the end of an alkoxy group having 1 to 4 carbon atoms. The group attached is preferred. Specific examples include a methoxycarbon group, an ethoxycarbon group, an n-propoxy carbonyl carbonyl group, an isopropoxy carbonyl carbonyl group, a cyclopropoxy carbonyl group, an n-butoxy carbonyl group, and an isobutoxy carbonyl group. Preferred examples include a s-butoxycarbonyl group, a t-butoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopropylmethoxycarbonyl group, and the like.

 Examples of the alkoxy group include an alkenyl ether group having an oxygen atom at the end of the alkenyl group, and a lower alkenyl oxy group containing one or more double bonds is preferred. A lower alkenyloxy group containing one double bond is more preferred. As the lower alkoxy group, an alkoxy group having 2 to 4 carbon atoms is preferred. Specifically, a vinyloxy group, an aryloxy group, or a propenyloxy group is preferable, and an aryloxy group is particularly preferable.

[0019] Examples of the alkarylthio group include an alkenyl thioether group having a sulfur atom attached to the terminal of the alkenyl group, and the like, and a lower alkenyl group containing one or more double bonds. A dialkylthio group is preferred A lower alkylthio group containing one double bond is more preferred. The lower alkthio group is preferably an alkthio group having 2 to 4 carbon atoms. Specifically, a arylthio group, in which a berylthio group, a arylthio group, or a propenylthio group is preferable, is particularly preferable.

[0020] The acyl group is preferably, for example, an alkanoyl group or an aryl carbonate group, and is exemplified as an example. A lower alkanoyl group in which an alkanoyl group is preferred is more preferred. The alkanol group includes a saturated alkylcarbonyl group that is linear, branched, cyclic, or a combination thereof. The alkyl moiety may contain one or more unsaturated bonds. Good. As the lower alkanoyl group, an acyl group having 2 to 5 carbon atoms is preferred. Specifically, acetyl group, propanol group, butanol group, 2_methyl propanol group, cyclopropyl carbonyl group, pentanoyl group, 3-methyl butanol group, 2,2-dimethyl propanol group, or cyclobutyl carbonyl group, etc. Is a suitable example.

 [0021] As the acyloxy group, for example, an alkanoyloxy group (alkylcarboxyloxy group) or an allylcarbonyloxy group can be mentioned as a preferred example, and a lower alkanoyloxy group preferred by an alkanoyloxy group is further exemplified. preferable. The alkyl part of the alkanoyloxy group may contain one or more unsaturated bonds. As the lower alkyl oxy group, an acyloxy group having 2 to 5 carbon atoms is preferable. Specifically, acetooxy group, propanoyloxy group, butanoyloxy group, 2-methylpropanoyloxy group, cyclopropylcarboxoxy group, pentanooxy group, 3_methylbutanoyloxy group, 2,2-dimethyl group A suitable example is a propanoyloxy group or a cyclobutylcarboxoxy group.

[0022] Preferred examples of the alkyl sulfier group include lower alkyl sulfier groups. As the lower alkylsulfur group, an alkylsulfur group having 1 to 4 carbon atoms is preferable. Specifically, methylsulfyl group, ethylsulfuryl group, n-propylsulfuryl group, isopropylsulfuryl group, cyclopropylsulfuryl group, n-butylsulfuryl group, isobutylsulfuryl group, s-butyl Sulfiel group, t-butylsulfier group, cycloptylsulfier group, or cyclopropylmethyls A suitable example is a luffyl group.

 [0023] Preferred examples of the alkylsulfol group include lower alkylsulfol groups. As the lower alkyl sulfo group, an alkyl sulfo group having 1 to 4 carbon atoms is preferable. Specifically, methylsulfol group, ethylsulfol group, n-propylsulfol group, isopropylsulfol group, cyclopropylsulfol group, n-butylsulfonyl group, isobutylsulfol group, s Preferred examples include a -butylsulfol group, a t-butylsulfonyl group, a cycloptylsulfol group, or a cyclopropylmethylsulfol group.

 [0024] Preferred examples of the alkyl-strength rubamoyl group include lower alkyl-strength rubamoyl groups. As the lower alkyl strength rubamoyl group, an alkyl strength rubamoyl group having 1 to 4 carbon atoms is preferable. Specifically, methyl carbamoyl group, ethyl carbamoyl group, n-propyl strength rubamoyl group, isopropyl strength rubamoyl group, cyclopropyl carbamoyl group, n-butyl carbamoyl group, isobutyl carbamoyl group, s-butyl carbamoyl group, t-butyl A suitable example is a rucarbamoyl group, a cycloptylcarbamoyl group, or a cyclopropylmethylcarbamoyl group.

 [0025] Examples of amino groups include NH groups.

 2

 [0026] Examples of aryl rings include monocyclic aromatic rings and condensed polycyclic aromatic rings. The aryl ring may be a hydrocarbon ring, but as a ring constituent atom other than a carbon atom, for example, a nitrogen atom, a sulfur atom, and one or more heteroatoms selected from the group power of oxygen nuclear power are selected. One or more, for example, 1 to 3 may be included.

[0027] Examples of the monocyclic aromatic ring include a monocyclic aromatic hydrocarbon or a monocyclic aromatic heterocycle containing one or more heteroatoms. A monocyclic aromatic hydrocarbon includes a benzene ring. Monocyclic aromatic heterocycles include 5- or 6-membered aromatic heterocycles containing one or more heteroatoms. Specific examples of the 5- or 6-membered aromatic heterocycle include thiophene, pyridine, furan, thiazole, oxazole, azole, pyrazine, pyrimidine, pyrrole, imidazole, pyridazine, isothiazole, isoxazole, 1, Suitable examples include 2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and furazane. [0028] Examples of the condensed polycyclic aromatic ring include condensed polycyclic aromatic hydrocarbons, condensed polycyclic aromatic heterocycles containing one or more heteroatoms, and the like. Examples of the condensed polycyclic aromatic hydrocarbon include, for example, a condensed polycyclic having 9 to 14 carbon atoms, that is, a bicyclic or tricyclic aromatic hydrocarbon. Specific examples include naphthalene, indene, Fluorene, anthracene or the like is a suitable example. The condensed polycyclic aromatic heterocycle includes, for example, a 9 to 14-membered, preferably 9- or 10-membered condensed polycyclic aromatic heterocycle containing 1 or more heteroatoms, for example 1 to 4 heteroatoms. Specific examples include benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazonole, benzisothiazole, naphtho [2,3-b] thiophene, quinoline, isoquinoline, indole, quinoxaline, phenanthridine Preferable examples include phenothiazine, phenoxazine, phthalazine, naphthyridine, quinazoline, cinnoline, carbazole, 13 carboline, atalidine, phenazine, phthalimide, and thixanthene.

 [0029] The aryl group includes, for example, a monocyclic aromatic group or a condensed polycyclic aromatic group, and is a monovalent aromatic group formed by removing any one hydrogen atom from the aryl ring described above. Residues can be exemplified.

 [0030] Examples of the monocyclic aromatic group include monovalent residues formed by removing any one hydrogen atom from a monocyclic aromatic ring. Specific examples of the monocyclic aromatic group include a phenyl group, a phenyl group (2- or 3-phenyl group), a pyridyl group (2-, 3- or 4-pyridyl group), and a furyl group (2- or 3-furyl group), thiazolyl group (2-, 4- or 5-thiazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group), pyrazolyl group (1-, 3- or 4-pyrazolyl group) 2-birazinyl group, pyrimidyl group (2-, 4- or 5-pyrimidyl group), pyrrolyl group (1-, 2- or 3-pyrrolyl group), imidazolyl group (1-, 2- or 4) -Imidazolyl group), pyridazil group (3- or 4-pyridazyl group), 3-isothiazolyl group, 3-isoxazolyl group, 1,2,4-oxadiazole-5-yl group, or 1,2 A suitable example is a 1,4-oxadiazol-3-yl group.

 [0031] The condensed polycyclic aromatic group is a monovalent group formed by removing any one hydrogen atom from a condensed polycyclic aromatic ring having 2 to 4, preferably 2 or 3 ring forces. Of the residues

[0032] Specific examples of the condensed polycyclic aromatic group include 1-naphthyl group, 2-naphthyl group, 2-indene Group, 2-anthryl group, quinolyl group (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-, 4-, 5 -, 6-, 7- or 8-isoquinolyl group), indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group), isoindolyl group (1-, 2-, 4- or 5-isoindolyl group), phthaladyl group (1-, 5- or 6-phthaladyl group), quinoxalinyl group (2-, 3- or 5-quinoxalyl group), benzofuryl group (2-, 3-, 4-, 5- or 6-benzofulleryl group), benzothiazolyl group (2-, 4-, 5- or 6-benzothiazolyl group), benzimidazolyl group (1-, 2-, 4-, 5 -Or 6-benzimidazolyl group), a fluoro group (1-, 2-, 3- or 4-fluoro group), a thixanthur group, and the like are preferable examples.

[0033] Substituted! As the substituent in the alkyl group, examples of the substituent include a hydroxyl group, a cyano group, a halogen atom, an alkoxy group, an alkylthio group, and an alkoxy group optionally substituted with one or more halogen atoms. , Alkyloxy groups, alkyloxy groups, acyl groups, acyloxy groups, alkylsulfuryl groups, alkylsulfol groups, alkyl strength rubamoyl groups, alkylamino groups, dialkylamino groups, and any one or more halogen atoms An alkylamino group, an acylamino group, an acyl (alkyl) amino group, an alkylsulfoamino group, an alkylsulfo (alkyl) amino group, or an alkylsulfonyl optionally substituted with one or more halogen atoms An amino group, an alkylsulfo (alkyl) amino group optionally substituted with one or more halogen atoms, or However, an aryl group or the like may be mentioned as a preferred example, a hydroxyl group, a halogen atom or an alkoxy group may be mentioned as a more preferred example, an alkoxy group or a fluorine atom may be mentioned as a more preferred example, and an alkoxy group. Groups are particularly preferred examples. There is also another embodiment in which a fluorine atom is particularly preferred.

 In the present specification, the number of substituents in an optionally substituted group (that is, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, etc.) is not particularly limited, but is usually 1 to several. 1 is preferable. In another embodiment, when the substituent in the optionally substituted group is a halogen atom, the number of the substituent is preferably 1 to 3.

[0034] As the alkyl group which may be substituted, preferred examples of the alkyl group described above are preferable. In another embodiment, the optionally substituted alkyl group includes the above-mentioned substituents. Preferred is an alkyl group substituted by a suitable substituent in the alkyl group. Examples of the alkyl group which may be substituted include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, and cyclobutyl. Group, cyclopropylmethyl group, n-pentyl group, cyclopentyl group, cyclopropylethyl group, cyclobutylmethyl group, n-hexyl group, cyclohexyl group, cyclopropylpropyl group, cyclobutylethyl group, Preferred examples include cyclopentylmethyl group, trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group, methoxymethyl group, or 2-methoxyethyl group, and more preferable examples include methyl group and ethyl group. N-propyl group, isopropyl group, trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group, methoxymethyl Group, or a 2-Metokishechiru group, and a methyl group, Echiru group, hydroxymethyl group, 2-hydroxy E chill group, and a methoxymethyl group as a particularly preferred example.

[0035] Substituted in the alkenyl group, substituted !, or the substituent in the alkyl group may be substituted as described above! /, Same as the substituent in the alkyl group.

 Although the alkenyl group may be substituted, the preferred examples of the alkenyl group described above are preferably substituted. The alkynyl group which may be substituted is preferably the above-described alkenyl group. A preferred example is preferred.

[0036] The substituent in the alkoxy group may be the same as the substituent in the alkyl group, which may be substituted. The alkoxy group may be substituted, but preferred examples of the alkoxy group described above are preferred. In another embodiment, the substituted! /, May! /, And the alkoxy group is preferably a suitable alkoxy group substituted by a suitable substituent in the alkoxy group as described above. Better ,. Specifically, methoxy group, ethoxy group, n_propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, trifluoromethoxy group, or 2-methoxyethoxy group Group is mentioned as a preferred example, more preferred examples include methoxy group, ethoxy group, trifluoromethoxy group, or 2-methoxyethoxy group, and particularly preferred examples include methoxy group or ethoxy group, A most preferred example is a methoxy group. [0037] The substituent in the optionally substituted alkylthio group is the same as the above-described substituent in the substituted V or alkyl group. The alkylthio group is preferably the above-mentioned preferred example of the alkylthio group. Specifically, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, isobutylthio group, s-butylthio group, t-butylthio group, cycloptylthio group, cyclopropyl A methylthio group, a 2-methoxyethylthio group or the like is a preferred example, and a more preferred example is a methylthio group, an ethylthio group, or a 2-methoxyethylthio group, and a particularly preferred example is methylthio group. Group, or an ethylthio group.

 [0038] Substituted! As the alkoxy carbo group, the above-described substituted V may be one having a carbonyl group attached to the terminal of the alkoxy group. It is done. Specifically, methoxycarbon group, ethoxycarbon group, n-propoxycarbol group, isopropoxycanenoboninole group, cyclopropoxynoleboninore group, n-butoxycanonolonol group, iso A butoxycarbol group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopropylmethoxycarbonyl group, and the like are given as preferred examples. Group, an ethoxycarbo ol group, or a t-butoxy carbo ol group, and particularly preferred examples include a methoxy carbo ol group or an ethoxy carbo ol group.

[0039] The amino group which may be substituted includes NH group, alkylamino group, dialkyla

 2

Mino group, acylamino group, acyl (alkyl) amino group, alkylsulfolumino group, alkylsulfo (alkyl) amino group, alkylamino group optionally substituted with one or more halogen atoms, one or more halogens Examples thereof include an alkylsulfoamino group optionally substituted with an atom, or an alkylsulfoamino group optionally substituted with one or more halogen atoms. Further, the optionally substituted amino group includes 1 or 2 substituted !, may! /, An amino group substituted with an alkyl group, 1 or 2 substituted, Alternatively, an amino group substituted with an aryl group, substituted !, or an aryl group and substituted, or an amino group substituted with an alkyl group, substituted! , An amino group substituted with an acyl group, substituted !, or an alkyl group substituted with an acyl group Amino group substituted with an optionally substituted alkylsulfol group, substituted! The alkylamino group substituted with an alkylsulfol group, substituted !, or the alkyl strength ruberamoylamino group, substituted !, or the alkylthio strength ruberamolyamino group, substituted. May be substituted arylmolybamino group, may be substituted Varylthiolamino group, substituted !, may be alkyloxycarbolamino group, or may be substituted A xylcarbolumino group may also be mentioned.

[0040] The alkylamino group is preferably a lower alkylamino group, and examples thereof include. The lower alkylamino group is preferably an alkylamino group having 1 to 4 carbon atoms. Specifically, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, _n -butylamino group, isobutylamino group, s-butylamino group, t-butylamino group, cyclobutylamino group Group, cyclopropylmethylamino group and the like are preferable examples, and more preferable examples include methylamino group, ethylamino group, and isopropylamino group, and particularly preferable examples include methylamino group and ethylamino group. It is done.

 [0041] Examples of the dialkylamino group include an amino group substituted with the same or different alkyl group, and a lower dialkylamino group is usually preferred. As the lower dialkylamino group, an amino group substituted with an alkyl having 1 to 4 carbon atoms is preferable. Specifically, dimethylamino group, ethyl (methyl) amino group, jetylamino group, methyl (n-propyl) amino group, isopropyl (methyl) amino group, cyclopropyl (methyl) amino group, n-butyl (methyl) Preferred examples include amino group, isobutyl (methyl) amino group, s-butyl (methyl) amino group, t-butyl (methyl) amino group, cyclobutyl (methyl) amino group, and cyclopropylmethyl (methyl) amino group. More preferred examples include a dimethylamino group, a dimethylamino group, or an ethyl (methyl) amino group, and particularly preferred examples include a dimethylamino group or a jetylamino group.

[0042] Examples of the isylamino group include an amino group substituted with the above-mentioned acyl group, and preferred examples of the acyl group are the same as those described above. Specific examples include an acetylamino group, a propanoylamino group, a butanoylamino group, a 2-methylpropanoylamino group, a cyclopropylcarbono group. Preferred examples include a boramino group, a pentanolumino group, a 3-methylbutanoylamino group, a 2,2-dimethylpropanolumino group, and a cyclobutylcarbolamino group. , An acetylamino group, a propanoylamino group, or a 2,2-dimethylpropanoylamino group, and particularly preferred examples include an acetylamino group or a propanoylamino group.

 [0043] Examples of the acyl (alkyl) amino group include one asil group and an amino group substituted with one alkyl group at the same time. Preferred examples of the acyl group and the alkyl group include: It is the same. Specifically, a acetyl (methyl) amino group, a methyl (propanoyl) amino group, a butanol (methyl) amino group, a methyl (2-methylpropanoyl) amino group, a cyclopentacarbonyl (methyl) amino group, Preferred examples include methyl (pentanoyl) amino group, methyl (3-methylbutanol) amino group, 2,2-dimethylpropanol (methyl) amino group, and cycloptylcarbonyl (methyl) amino group, and more preferred. Examples include a acetyl (methyl) amino group or a methyl (propanol) amino group, and particularly preferably a acetyl (methyl) amino group.

 [0044] Examples of the alkylsulfoamino group include an amino group substituted with the alkylsulfo group. Preferred examples of the alkylsulfo group are the same as those described above. Specifically, methyl sulfo-lamino group, ethyl sulfo-lamino group, n-propyl sulforamino group, isopropyl sulfo-lamino group, cyclopropyl sulfo-lamino group, n-butyl sulfo-lamino group, isobutyl sulfo-lamino group, Suitable examples include s-butylsulfo-amino group, t-butylsulfo-lumino group, cyclobutylsulfo-lumino group, and cyclopropylmethylsulfo-lumino group, and more preferably methylsulfo-lumino group, ethylsulfo group. -Luamino group or n-propylsulfo-lumino group is mentioned, and methylsulfol group or ethylsulfo group is particularly preferred.

[0045] The alkylsulfo (alkyl) amino group includes one alkylsulfo group and an amino group substituted simultaneously with one alkyl group. Preferred examples are the same as described above. Specifically, methyl (methylsulfol) amino group, ethylsulfol (methyl) amino group, methyl (n-propylsulfurate) Hol) amino group, isopropylsulfol (methyl) amino group, cyclopropylsulfol

(Methyl) amino group, n-butylsulfol (methyl) amino group, isobutylsulfol (methyl) amino group, s-butylsulfol (methyl) amino group, t-butylsulfol (methyl) amino group , Cycloptylsulfo (methyl) amino group, or cyclopropylmethylsulfo (methyl) amino group, and more preferably, methyl (methylsulfo) amino group or ethylsulfonyl ( A methyl) amino group, particularly preferably a methyl (methylsulfonyl) amino group.

[0046] Examples of the alkylamino group optionally substituted with one or more halogen atoms include alkylamino groups in which one or more hydrogen atoms of the above alkylamino groups are substituted with any kind of halogen atoms. An alkylamino group having 1 to 4 carbon atoms optionally substituted with one or more halogen atoms is preferred. In the case of being substituted with two or more halogen atoms, the halogen atoms may be the same or different. Specific examples include a chloromethylamino group, a dichloromethylamino group, a trichloromethylamino group, a fluoromethylamino group, a difluoromethylamino group, a trifluoromethylamino group, and a fluorethylamino group. Or a 2,2,2-trifluoroethylamino group and the like are preferable examples, more preferably a trifluoromethylamino group, or a 2,2,2-trifluoroethylamino group, Particularly preferred is a trifluoromethylamino group.

 [0047] The alkylsulfo-lumino group optionally substituted with one or more halogen atoms includes an alkylsulfonyl in which one or more hydrogen atoms of the alkylsulfo-lumino group are substituted with any kind of halogen atom Examples of the amino group include an alkylsulfonylamino group having 1 to 4 carbon atoms optionally substituted with one or more halogen atoms. When substituted with two or more halogen atoms, the halogen atoms may be the same or different. Specific examples include a trifluoromethylsulfo-lumino group.

[0048] As the alkylsulfol (alkyl) amino group optionally substituted with one or more halogen atoms, one or more hydrogen atoms of the aforementioned alkylsulfol (alkyl) amino group may be of any kind. Illustrative are alkylsulfol (alkyl) amino groups substituted with halogen atoms, usually an alkyl of 1 to 4 carbon atoms optionally substituted with one or more halogen atoms. Killsulfol (alkyl) amino groups are preferred. When substituted with two or more halogen atoms, the halogen atoms may be the same or different. Specific examples include a methyl (trifluoromethylsulfo) amino group.

1 or 2 substituted or may be substituted in an amino group substituted with an alkyl group, or the alkyl group may be substituted as described above or may be used as an alkyl group. A preferred example is preferred. As the amino group substituted with 1 or 2 substituted !, may! /, Or alkyl groups, preferred examples of the alkylamino group and dialkylamino group described above are preferable. In another embodiment, the amino group substituted with one or two optionally substituted alkyl groups may be substituted as described above, or may be substituted with a suitable substituent in the alkyl group. Or, an amino group substituted with two alkyl groups is preferred. In another embodiment, the amino group substituted with one or two optionally substituted alkyl groups may be substituted with a suitable substituent in the alkyl group as described above. Preferred is an amino group substituted with one alkyl group. In still another embodiment, the amino group substituted with one or two optionally substituted alkyl groups may be substituted as described above, or may be substituted with a suitable substituent in the alkyl group. U, preferably an amino group substituted with one alkyl group and one lower alkyl group. Specifically, a dimethylamino group, a jetylamino group, an ethylmethylamino group, a methoxyethylamino group, a methyl (methoxyethyl) amino group, a hydroxyethylamino group, or a hydroxyethyl (methyl) amino group is preferred. Particularly preferred examples include dimethylamino group, methoxyethylamino group, and hydroxyethylamino group.

1 or 2 substituted, may be substituted in an amino group substituted with an aryl group !, or may be an aryl group, which will be described later, may be substituted as an aryl group. Preferred examples are preferred. In addition, as the amino group substituted with one or two optionally substituted aryl groups, an amino group substituted with one preferred example of the aforementioned aryl group is preferred! /. Especially preferred! As an example, mention may be made of a phenylamino group.

Substituted, aryl, and substituted !, may! /, Amino groups substituted with alkyl groups, substituted, and preferred aryl groups, for example Similarly, the substituent in the alkyl group which may be substituted is the above-described substituted group. ! However, preferred examples of alkyl groups are preferred. Substituted !, may, or aryl groups and may be substituted, alkylamino groups substituted with alkyl groups include substituted! Alkylamino groups substituted with aryl groups. Is preferred. Particular preference is given to the methyl (phenyl) amino group as an example.

As the substituent of the asil group in the alkylamino group which may be substituted or may be substituted with an acyl group and the alkylamino group which may be substituted and may be substituted with an acyl group, However, preferred examples of substituents on the acyl group are preferred. Replaced

However, particularly preferred examples of the amino group substituted with an acyl group include an acetylylamino group, a propanoylamino group, a butanoylamino group, and a phenylacetylamino group.

Substituted, may be an amino group substituted with an alkylsulfol group, and substituted

The substituent of the alkyl sulfo group in the alkyl amino group substituted with the alkyl sulfo group may be substituted as described later !, may! /, The substitution in the alkyl sulfo group. Preferred examples of groups are preferred. Particularly preferable examples of the amino group substituted and substituted with an alkylsulfol group include a methanesulfonylamino group, a trifluoromethanesulfo-lumino group, a methyl (methanesulfol) amino group, or Mention may be made of methyl (trifluoromethanesulfol) amino group.

The substituent in the alkyl strength ruberamoylamino group may be substituted when the substitution position of the substituent is on the alkyl group, the substituent may be substituted as described above. Preferred examples of the substituent are preferred, or when the substitution position of the substituent is on the nitrogen atom of the alkyl strength ruberamoylamino group, the substituent is a preferred example of the alkyl group which may be substituted as described above. Or a hydrogen atom is preferred. Replaced! However, there may be one or more substituents in the alkyl strength ruberamoylamino group, and each may be independently the same or different. As the optionally substituted alkylcarbamoylamino group, a group in which one substituent exists and the substitution position is on the alkyl group is preferable. Particularly preferred examples include ethylcarbamoylamino group and methylcarbamoylamino group.

Substituted, but the alkylthio group may be a ruberamoylamino group! It is the same as the respective cases corresponding to the examples of the alkyl power ruberamoylamino group. Particularly preferred examples include an ethylthio-powered ruberamoylamino group or a methylthio-powered ruberamoylamino group.

 Even if substituted, the alkyloxycarbolamino group is preferably preferred! /, And examples thereof are the same as in the respective cases corresponding to the examples of the alkyl power ruberamoylamino group. Particularly preferred examples include an ethoxycarbo-amino group or a methoxycarbo-amino group.

 Even if it is substituted, as a substituent in the aryl group ruberamoylamino group, when the substitution position of the substituent is on the aryl group, a preferred example of the aryl group may be substituted as described later. When the substitution position of the substituent is on the nitrogen of the aryl group ruberamoylamino group, the substituent may be substituted as described above, but a preferred example of an alkyl group or a hydrogen atom is preferred. There may be one or more substituents in the aryl group ruberamoylamino group which may be substituted, and each may be independently the same or different. The optionally substituted allyl force ruberamoylamino group is preferably a group that is present as a substituent on the allyl force ruberamoylamino group and the substitution position is on the allyl group. . A particularly preferred example is an optionally substituted phenylcarbamoylamino group.

 Even if it is substituted, it is preferable to use the arylo-powered ruberamoylamino group, and examples thereof are the same as those in the respective examples corresponding to the above-mentioned examples of the arylo-powered ruberamoylamino group. Although preferred, the aryloxycarbo-lamino groups are preferred! /, And examples thereof are the same as those in the respective cases corresponding to the above-described examples of the aryl force ruberamoylamino groups. Particular preference is given to mention, as an example, a substituted thiol-molybamoylamino group.

 [0049] The substituent in the acyl group may be the same force as the substituent in the alkyl group that may be substituted, in particular, one or more halogen atoms are preferred. Yes.

[0050] The optionally substituted acyl group is preferably an acyl group optionally substituted with one or more halogen atoms. From 2 carbon atoms optionally substituted with one or more halogen atoms. An acyl group of 5 is preferred. When substituted with two or more halogen atoms, the halogen atoms may be the same or different. A suitable example is a trifluoroacetyl group.

 [0051] In addition, there may be substituted !, but the acyl group includes an acetyl group, a propanol group, a butanol group, a 2-methyl propanol group, a cyclopropyl carbonyl group, a pentanoyl group, and a 3-methyl butanol group. Group, 2,2-dimethylpropanol group, cyclobutylcarbol group, etc. are preferred, more preferably acetyl group, propanol group, or 2,2-dimethylpropanol group, particularly preferably acetyl group. Group or a propanol group.

 [0052] As the acyloxy group, the above-mentioned substituted! Is preferably one having an oxygen atom attached to the terminal of the acyl group. A suitable example is a trifluoroacetoxy group.

 [0053] In addition, substituted! May be used. Examples of the acyloxy group include acetoxy group, propanoyloxy group, butanoyloxy group, 2-methylpropanoyloxy group, cyclopropyl group sulfonyloxy group, and pentanoyloxy group. , 3-methylbutanoyloxy group, 2,2-dimethylpropanoyloxy group, cyclobutylcarboxoxy group, etc. are more preferable, acetooxy group, propanoloxy group, or 2 1,2-dimethylpropanoyloxy group, particularly preferably acetooxy group or propanoyloxy group.

 [0054] The substituent in the optionally substituted alkylsulfier group is the same force as the substituent in the above optionally substituted alkyl group, and particularly preferably one or more halogen atoms.

 [0055] The optionally substituted alkylsulfiel group is preferably an alkylsulfinyl group optionally substituted with one or more halogen atoms. The number of carbon atoms arbitrarily substituted with one or more halogen atoms is preferred. 1 to 4 alkylsulfier groups are preferred! When substituted with two or more halogen atoms, the halogen atoms may be the same or different. A preferred example is a trifluoromethanesulfinyl group.

[0056] Besides, substituted! May be used. Examples of the alkylsulfur group include methylsulfyl group, ethylsulfuryl group, n-propylsulfuryl group, isopropylsulfuryl group. Group, cyclopropylsulfuryl group, n-butylsulfuryl group, isobutylsulfuryl group, s-butylsulfuryl group, t-butylsulfuryl group, cycloptylsulfuryl group, or cyclopropylmethylsulfuryl group More preferred examples of which are preferred include methylsulfyl group or ethylsulfuryl group, and particularly preferred is methylsulfuryl group.

 [0057] The substituent in the optionally substituted alkylsulfonyl group is the same force as the substituent in the above optionally substituted alkyl group, and particularly preferably one or more halogen atoms.

 [0058] The substituted alkylsulfonyl group is preferably an alkylsulfonyl group optionally substituted with one or more halogen atoms. The number of carbon atoms optionally substituted with one or more halogen atoms is 1-4. The alkylsulfol group is preferred! When two or more halogen atoms are substituted, the halogen atoms may be the same or different. A suitable example is a trifluoromethanesulfonyl group.

 [0059] In addition, the alkylsulfol group may be substituted !, methylsulfol group, ethylsulfol group, n-propylsulfol group, isopropylsulfol group, cyclopropyl group. A sulfo group, an n-butyl sulfo group, an isobutyl sulfo group, an s-butyl sulfonyl group, a t-butyl sulfo group, a cyclobutyl sulfo group, or a cyclopropyl methyl sulfonyl group is preferred. More preferable examples include a methylsulfol group or an ethylsulfol group, and a methylsulfol group is particularly preferable.

 [0060] Substituted in the aryl ring, may be substituted, and the substituent in the aryl group may be a hydroxyl group, an alkyl group optionally substituted with one or more hydroxyl groups, Halogen atom, alkyl group optionally substituted with one or more halogen atoms, alkoxy group, alkylthio group, alkoxy group optionally substituted with one or more halogen atoms

, Alkyloxy group, alkylthio group, acyl group, acyloxy group, alkylsulfuryl group, alkylsulfol group, alkyl strength rubamoyl group, alkylamino group, dialkylamino group, any one or more halogen atoms Substituted alkylamino groups, acylamino groups, acyl (alkyl) amino groups, alkylsulfo-amino groups, alkyls Preferred are a sulfonyl (alkyl) amino group, an alkyl sulfo-lamino group optionally substituted with one or more halogen atoms, or an alkyl sulfonyl (alkyl) amino group optionally substituted with one or more halogen atoms. Take as an example.

 [0061] Substituted !, may be an aryl ring, may be substituted !, or an aryl group may be the aforementioned aryl group or aryl group having the above-mentioned substituents. Preferred examples include a reel ring and an aryl group.

In the general formula (1), Ar ¹ represents a furyl group, a phenyl group, a triazolyl group, a thiazolyl group, an oxazolyl group, or a benzothiazolyl group, and Ar ¹ may be substituted. Ar ¹ is substituted, even I, being a tooth replacement, Nakutemoyo, but, Ar ¹ is substituted!, Rukoto is good Masui. There is also another embodiment in which it is preferably not substituted. Ar ¹ is particularly preferably a furyl group, a chenyl group, or a thiazolyl group, more preferably a furyl group or a chenyl group, and even more preferably a chenyl group. There is also another embodiment in which a furyl group is particularly preferred. In the general formula (1), preferred examples showing the position at which Ar ¹ is bonded to the pyrimidine ring and the position and number of the substituent when Ar ¹ is present are shown below. However, in the following structure, V represents the position bonded to the 2-position of the pyrimidine ring in the general formula (1),

W ² represents the position to which the substituent is bonded.

When Ar ¹ is a furyl group,

[0063] [Chemical 2]

A -1 ΑΠ-2 Ar1-3 A -4 Ar1-5 AM -6 A-Ar1-8

 Ar1 -9 A -10 Ar1 -11 Ar1 -12 A -13 A -14 is preferred

[0064] [Chemical 3]

-w ¹

AM-4 A -5 Ar1 -6 A-Ar1 -8 Power

[0065] [Chemical 4]

 Ar1-4 Ar1-5 Ar1-8 is particularly preferred.

When Ar ¹ is a chaer group,

[0066] [Chemical 5]

A -15 Ar1-16 A -17 AM- 18 A -19 Ar1-21 A -22

 Ar1-23 Ar1-24 AM -25 A -26 Ar1-27 A -28 is preferred,

[0067] [Chemical 6]

 A -17 Ar1-18 Ar1-19 A -20 A -21 Ar1-22

[0068] [Chemical 7] v -s

w ¹ -w

w ¹

 ArM8 AM -19 Ar1-22 force S More preferable,

[0069] [Chemical 8] No w.

Arl-19 Is particularly preferred.

When Ar ¹ is a triazolyl group,

[Chemical 9]

 AM -29 AM -30 Ar1-31 A -32

Tl

A -36

 Prefer

[0071] [Chemical 10]

Ar1-31 Ar 32 Ar1-38 Ar1-39 Ar 40 ^A `` 1 is more preferred

[0072] [Chemical 11]

 A -33 Ar1-38 Ar -40

 Is particularly preferred.

When Ar ¹ is a thiazolyl group,

 [0073] [Chemical 12]

Prefer

[0074] [Chemical 13]

AM-47 power is preferred

[0075] [Chemical 14]

 AM-47 Ar1-48 Ar1, 49 A -51 are particularly preferred.

When Ar ¹ is an oxazolyl group,

 [0076] [Chemical 15] /

W ¹

ΑΠ-62

Prefer

[0077] [Chemical 16] w ¹丫.

 0 w

N w ¹

w ¹ '/,

W ¹ w ¹ VV

 Ar1'59 Ad -60 A -61 A -62 AM -63 A -64

[0078] [Chemical 17] w ¹ ,

 N

ΐ ^v V

A -59 A -60 Ar 61 A -63 Is particularly preferred.

When Ar ¹ is a benzothiazolyl group,

[0079] [Chemical 18]

Prefer

[0080] [Chemical 19]

 Ar1-68 A -69 Ar1-70 AM -71 Ar Jin 72 Power

[0081] [Chemical 20]

 Ar 68 A -70 AM -71 is particularly preferred.

[0082] When Ar ¹ is substituted, the substituent is preferably a halogen atom, a hydroxyl group, Group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group. An optionally substituted alkylthio group, an optionally substituted amino group, an optionally substituted alkoxycarbonyl group, an optionally substituted acyl group, an optionally substituted alkylsulfier group, a substituted An optionally substituted alkylsulfol group, an optionally substituted aryl group, —CON (RU) (R ¹² ) (R ¹¹ and R ¹² may be the same or different, and each independently. , A hydrogen atom, an optionally substituted alkyl group, or a substituted, may represent an aryl group, or R ¹¹ and R ¹² together form a 3- to 7-membered ring to form an NR ¹¹ ) (R ¹² ) represents a cyclic amine. ), And -SO N (R ¹³ ) (R ¹⁴ ) (R ¹³

 2

And R ¹⁴ may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, or R ¹³ and R ¹⁴ Together form a 3- to 7-membered ring, and N (R ¹³ ) (R ¹⁴ ) represents a cyclic amine. ) Is any one or more groups selected from the group consisting of 1) or 2 groups, more preferably 1 group. In another embodiment, two groups are more preferable. When Ar ¹ is substituted, the substituent is more preferably a halogen atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkoxy group, or optionally substituted. An alkylthio group, an optionally substituted amino group, an optionally substituted alkoxycarbonyl group, an optionally substituted acyl group, an optionally substituted alkylsulfonyl group, a substituted An aryl group, —CON (R ¹¹ ) (R ¹² ) (R ¹¹ and R ¹² are as defined above), and —SO N (R ¹³ ) (R ¹⁴ ) (R ¹³ and R ¹⁴

 2

Is an arbitrary group selected from the group consisting of the above and more preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group. An optionally substituted amino group, an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, and —CON (R ¹¹ ) (R ¹² ) (R ¹¹ and R ¹² are as defined above) Any group selected from the group of forces. When Ar ¹ is substituted, the substituent includes: a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted Preferred is an amino group which may be substituted, and any group selected from the group which may be substituted or may also be an acyl group. There are also embodiments. In the case where Ar ¹ is substituted, the substituent is a group consisting of [halogen atom, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted amino group]. There is another embodiment in which any group selected is more preferable. Further, when Ar ¹ is substituted, as the substituent, [halogen atom, optionally substituted alkyl group, substituted or optionally alkoxy group] any group selected from the group consisting of There are other preferred embodiments. When Ar ¹ is substituted, the substituent is particularly preferably an optionally substituted alkoxy group. When Ar ¹ is substituted, there is another embodiment in which an amino group which may be substituted is particularly preferable as the substituent. In the case where the substituent in Ar ¹ is substituted or an amino group, it is not particularly limited as long as it is an amino group as described above, but it is not particularly limited, but —NH group, alkylamino group, dialkylamino group

 2

Group, an acylamino group, an acyl (alkyl) amino group, an alkylsulfolumino group, an alkylsulfo (alkyl) amino group, an alkylamino group optionally substituted with one or more halogen atoms, and one or more halogens An alkylsulfo-amino group optionally substituted with an atom or an alkylsulfo (alkyl) amino group optionally substituted with one or more halogen atoms is preferred and Ar ¹ is substituted In this case, there is another embodiment in which CON (R ¹¹ ) (R ¹² ) (R ¹¹ and R ¹² are as defined above) is particularly preferable as the substituent. Furthermore, when Ar ¹ is substituted, there is another embodiment in which a halogen atom is particularly preferable as the substituent. The halogen atom is particularly preferably bromine, preferably fluorine, chlorine or bromine. There is another embodiment in which chlorine or fluorine is preferred as the halogen atom. Further, there is another embodiment in which chlorine is preferred as the halogen atom, and there is another embodiment in which fluorine is further preferred. When Ar ¹ is substituted with a plurality of substituents, the substituents may be the same or different.

A particularly preferred combination of the above is a case where Ar ¹ is a chaer group and is substituted with one halogen atom, and has the above-mentioned Arl-19 bonding mode.

Ar ² represents E—Ar ²¹ —GQ (Ar ²¹ represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group, or an alkene group; and Q represents a carboxy group. Group, CON (R ⁴¹ ) (R ⁴² ) (R ⁴¹ and R ⁴² may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or a substituted group; However, it may be an aryl group, or R ⁴¹ and R ⁴² together form a 3- to 7-membered ring to represent a cyclic amine as N (R ⁴¹ ) (R ⁴² ). However, when R ⁴¹ is a hydroxyl group, R ⁴² is a group other than a hydroxyl group. ), Or —COOR ⁴³ (R ⁴³ represents an optionally substituted alkyl group or an optionally substituted aryl group). ), -E-Ar ²¹ -G ² -G- Q (E, Ar ²¹ , G, Q are as defined above, G ² is —O, S—, SO—, —SO—,

2 or NR ²¹ — (R ²¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted acyl group, or an optionally substituted sulfol group). ), Or [monocyclic aromatic heterocycle other than virazolyl group], Ar ² may be substituted.

Ar ² one as E-Ar ²¹ - GQ, one ^{E-Ar 21 - G 2 -GQ} , or [monocyclic aromatic heterocyclic ring other than Birazorinore radical can be mentioned, E- Ar ²¹ - GQ or one E —Ar ²¹ —G ² —G —Q is preferred, and E—Ar ²¹ —GQ is more preferred. Further, E—Ar ²¹ —G ² -G—Q is more preferred, and there is another embodiment.

Ar ² is substituted !, may! /, And is substituted !, and may not be !, but Ar ² is preferably substituted! There is also another embodiment in which substitution is preferred.

When Ar ² is substituted, the substituent is preferably a halogen atom, a hydroxyl group, a cyan group, a nitro group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, An optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, and an optionally substituted alkoxy carbo group. An optionally substituted acyl group, a substituted, may be an alkylsulfier group, a substituted !, may! /, An alkylsulfonyl group, an optionally substituted aryl group, CON (RU) (R ¹² ) (R ¹¹ and R ¹² may be the same or different, and each independently represents a hydrogen atom, an optionally substituted alkyl group, or a substituted, Yo R ¹¹ and R ¹² together form a 3- to 7-membered ring and represent a cyclic amine as NR ¹¹ ) (R ¹² ). ) And — SO N (R ¹³ ) (R

 2

¹⁴ ) (R ¹³ and R ¹⁴ may be the same or different, and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group. Or R ¹³ and R ¹⁴ together form a 3- to 7-membered ring, and N (R ¹³ ) (R ¹⁴ ) represents a cyclic amine.) Any one or more selected from the group consisting of Group, more preferably halogen An atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, an optionally substituted Alkoxycarbonyl group, optionally substituted acyl group, optionally substituted alkylsulfonyl group, optionally substituted aryl group, —CO

NR ¹¹ ) (R ¹² ) (R ¹¹ and R ¹² are as defined above), and SO N (R ¹³ ) (R ¹⁴ ) (R ¹³ and

 2

And R ¹⁴ is as defined above), more preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group. The amino group may be any one or more groups selected from the group consisting of When Ar ² is substituted, the substituent is particularly preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group. . In addition, Ar ² is one or more groups selected from the group consisting of [hydroxyl group, halogen atom, substituted, alkyl group, and substituted !, may! /, Alkoxy group]. There is another embodiment in which it is particularly preferably substituted by. When Ar ² is substituted with a halogen atom, the halogen atom is particularly preferably bromine, preferably fluorine, chlorine or bromine. There is another embodiment in which chlorine or fluorine is preferred as the halogen atom. Further, there is another embodiment in which chlorine is preferable as the halogen atom, and there is another embodiment in which fluorine is more preferable. When Ar ² is substituted with a plurality of substituents, the substituents may be the same or different. Also, when Ar ² is substituted, it is preferred that it is substituted with one or two groups. It is more preferred that it is substituted with one group. There is also another embodiment in which substitution with two groups is more preferred. Replacement which may also be a substituent on Ar ² is to connexion bond such together with a portion of another Ar ² on optionally substituted substituent or Ar ^2,, or connexion same such together It may be combined with an oxygen atom, sulfur atom, or nitrogen atom to form a ring. Substituents on Ar ² is connexion bond such together with a portion of the Ar ^2, or together such connexion same oxygen atom, a sulfur atom, or as an example of joined to form a ring with nitrogen atom is A case where Ar ² is a phthalimido-5-yl group or a 1,4-dioxo 1,2,3,4-tetrahydrophthalazine-6-yl group can be exemplified. In particular, when Ar ² is substituted with two alkyl groups, the alkyl groups may be joined together to form a ring. When Ar ² is substituted, examples of the substitution position of the substituent include substitutable positions on Ar ² . When Ar ² is one E—Ar ²¹ —G—Q and Ar ² is substituted, the substitution position of the substituent is preferably E, Ar ²¹ , or G. Ar ²¹ Or, it is more preferable to be on Ar ²¹ which is more preferable on G. When Ar ^{2 is} —E—Ar ²¹ —G—Q, Ar ² is substituted, the substitution position of the substituent is on G, and G is an alkylene group, A preferred example is the same force as that exemplified in the substituent of Ar ² above. Further, two bonds formed by removing two hydrogen atoms on the same carbon on the alkylene group are joined together. An example in which they are bonded to the same oxygen atom and substituted as an oxo isomer can also be mentioned as a preferred example.

Specific examples of Ar ²¹ include a benzene ring or a naphthalene ring, and a benzene ring is preferred.

 Specific examples of E include a single bond or a lower alkylene group, and a single bond, a methylene group, a single bond in which an ethylene group is preferable, or a single bond in which an ethylene group is more preferable is more preferable.

 Specific examples of G include a single bond, a lower alkylene group, and a lower alkylene group, and a single bond, a methylene group, an ethylene group, or a beylene group are preferred, a single bond, a methylene group, Or, a single bond in which a beylene group is more preferable or a methylene group in which a methylene group is more preferable is particularly preferable. There is another embodiment in which G is more preferably a lower alkylene group, preferably a single bond or a lower alkylene group. As a combination of E and G, it is preferable that E is a single bond and [G is a single bond or a lower alkylene group]. E is a single bond and G is a lower alkylene group. It is more preferable that

Specific examples of the substitution position of E and G for Ar ^21, E-Ar ²¹ - as G,

[Chemical 21]

 Ar21-1 Ar21 -2 Ar21-3

ΑΓ21-12 Ar21-15 ^Ar21 " ¹⁶ ΑΓ21-17

 ΑΓ21-13 Ar21-14

 Are mentioned,

[0084] [Chemical 22]

Ar21 -15 Ατ21-1β Ar21-17

 ΑΓ21-13 is preferred,

[0085] [Chemical 23]

ΑΓ21-2 ΑΓ21-Β Ar21-15 Ar21-16

 ΑΓ21-7 AT21-1 Power is preferred

[0086] [Chemical 24]

 AT21-1 ΑΓ21-15 is even more preferred

[Chemical 25]

Ar21-1 Is particularly preferred.

Specific examples of Q include a carboxy group, CON (R ⁴¹ ) (R ⁴² ), or —COOR ⁴³ , and a carboxy group or a carboxy group that is preferred to —CON (R ⁴¹ ) (R ⁴² ) is more preferred. I like it.

R ⁴¹ and R ⁴² may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, a substituted, an alkyl group, or a substituted !, may! /, Aryl R ⁴¹ and R ⁴² together form a 3- to 7-membered ring, and N (R ⁴¹ ) (R ⁴² ) represents a cyclic amine. However, when R ⁴¹ is a hydroxyl group, R ⁴² is a group other than a hydroxyl group. R ⁴¹ is most preferably a hydrogen atom, preferably a hydrogen atom or an optionally substituted alkyl group, or a hydrogen atom more preferably a methyl group. R ⁴² is a hydrogen atom, hydroxyl group or substituted! However, an aryl group that may be substituted with an aryl group, or an alkyl group or an alkoxy group, is preferably a hydrogen atom, a hydroxyl group, or an alkyl group. More preferred are an atom, a hydroxyl group, or a methyl group.

As R ⁴³ , substituted !, may be an alkyl group, or may be substituted, an aryl group may be mentioned as a specific example, and an optionally substituted alkyl group is preferred. A methyl group or an ethyl group, in which an alkyl group is more preferable, is particularly preferable.

When Ar ² is one E— Ar ²¹ — G ² — G— Q, G ² is one O, one S, one SO—, one SO—, or NR ^G21 — (R ^G21 is a hydrogen atom, substituted Optionally substituted alkyl group, substituted

2

And an optionally substituted acyl group or an optionally substituted sulfol group. ), There is no particular limitation, but O—, —S—, or —NH is particularly preferred. Further, R ^G21 in —NR ^G21 — is more preferably a hydrogen atom. Preferred examples of E, Ar ²¹ , G, and Q when Ar ² is one E—Ar ²¹ —G ² —GQ are the same as described above.

Further, as Ar ² , the following examples are also preferable. Ar ² represents a carboxyphenyl group, a carboxyalkyl phenyl group, a carboxy naphthyl group, a carboxyalkyl naphthyl group, or [monocyclic aromatic heterocycle other than virazolyl group], Ar ² is substituted, Moyo ヽ. Ar ² is preferably a carboxyphenyl group, a carboxyalkylphenyl group, or a carboxycinnaftyl group. Ar ² may be a carboxyphenol group or a carboxyalkyl group. There is also another embodiment in which a phenyl group or [monocyclic aromatic heterocycle other than virazolyl group] is preferred. A carboxyphenol group is particularly preferred. In addition, there is another embodiment in which a carboxyalkylphenyl group is particularly preferable as Ar ² . Furthermore, a carboxynaphthyl group is particularly preferred as Ar ² , and there is another embodiment.

When Ar ² is a carboxyalkyl furol group or a carboxyalkyl naphthyl group, the “alkyl” in these groups preferably has 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. More preferably, one or two is even more preferable, and one is particularly preferable.

In the general formula (1) shows the position in which Ar ² is bound to Amino group, and preferred examples showing the location and number of the substituent, if the substituent is present on Ar ² below. However, in the following structure, X represents the position bonded to the amino group in the general formula (1),

Upsilon ² indicates the position of attachment of substituents, Zeta is an alkylene group respectively.

When Ar ² is a carboxyphenyl group,

[0088] [Chemical 26]

Prefer

[0089] [Chemical 27]

Power

[0090] [Chemical 28]

 -1 Ar2-2 Ar2-4 Ar2-5 is more preferred

[Chemical 29]

 Ai2-1 Ar2-4 Ar2-l is particularly preferred

 [Chemical 30]

"COOH

 Ar2-1

 Is most preferred.

When Ar ² is a carboxyalkyl phenyl group,

[0093] [Chemical 31]

 Ar2-23 Ar2-24 Ar2-25 Ar2-26 is preferred

[0094] [Chemical 32]

Power

[0095] [Chemical 33]

 Ar2-14 Ar2-17 Ar2-18 Force S

 [0096] [Chemical 34]

, COOH

 Ar2-14

Is particularly preferred When Ar ² is a carboxynaphthyl group,

 [0097] [Chemical 35]

 H

Ar2-27 Ar2-28 _{Ar9. 9} is preferred tool

[0098] [Chemical 36]

 Ar2-27 Ar2-28

 Is more preferred

[Chemical 37]

 Ar2-27

 Is particularly preferred.

When Ar ² is a carboxyalkylnaphthyl group [0100] [Chemical 38]

Is preferred

[0101] [Chemical 39]

 Ar2-30 Ar2-31 Power

[0102] [Chemical 40]

 Ar2-30 is particularly preferred.

When Ar ² is substituted, the substituent is preferably a halogen atom, a hydroxyl group, a cyan group, a carboxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, or a substituted group. An optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted amino group, an optionally substituted alkoxy carbo group, a substituted An optionally substituted acyl group, an optionally substituted alkylsulfier group, an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, —CON (RU) (R ¹² ) (R ¹¹ and R ¹² may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or a substituted or unsubstituted aryl group, Alternatively R ¹¹ and R ¹² Forming a connexion 3-7 membered ring such the cord shows a cyclic amine as NR ¹¹⁾ (R ^12). ), And -SO N (R ¹³ ) (R ¹⁴ ) (R ¹³

 2

And R ¹⁴ may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aryl group, or R ¹³ and R ¹⁴ Together form a 3- to 7-membered ring, and N (R ¹³ ) (R ¹⁴ ) represents a cyclic amine. Any one or more groups selected from the group consisting of: a halogen atom, a hydroxyl group, a cyano group, an optionally substituted alkyl group, an optionally substituted alkoxy group, and a substituted group. An optionally substituted alkylthio group, an optionally substituted amino group, an optionally substituted alkoxycarbonyl group, an optionally substituted acyl group, an optionally substituted alkylsulfonyl group, An optionally substituted aryl group, —CON (RU

) (R ¹² ) (R ¹¹ and R ¹² are as defined above), and —SO N (R ¹³ ) (R ¹⁴ ) (R ¹³ and R ¹⁴ are

 2

An arbitrary group selected from the group consisting of the same as defined above, more preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, a substituted However, it is an arbitrary group selected from the group consisting of amino groups. When Ar ² is substituted, the substituent is particularly preferably a halogen atom, an optionally substituted alkyl group, or an optionally substituted alkoxy group. Ar ² with multiple substituents When substituted, the substituents may be the same or different.

As the above-mentioned particularly preferred U, the combination is that Ar ² is a carboxyalkyl phenyl group and is an alkyl group-powered methylene group, and is substituted with one halogen atom on the phenyl group. An example having 18 bonding modes, or an example in which Ar ² is a carboxyalkylphenol group and the alkyl group is a alkylene group, and has the above Ar2-14 bonding mode.

In the general formula (1), R ¹ and R ² may be the same or different and each independently represents a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted alkenyl. A group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted, optionally, alkylsulfier group, or a substituted !, may! /, Alkylsulfol Indicates a group. R ¹ and R ² are preferably an alkyl group which may be substituted, or V which is substituted, or a alkenyl group! R ¹ is substituted !, may! /, An alkyl group is more preferred, a lower alkyl group having 1 to 3 carbon atoms is more preferred, and a methyl group or an ethyl group is particularly preferred, and an ethyl group is most preferred. preferable. In addition, there is another embodiment in which methyl group is most preferable as R ¹ . R ² is an optionally substituted alkyl group, or an optionally substituted alkyl group, more preferably a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group having 2 to 4 carbon atoms. An alkenyl group is more preferably a methyl group, an ethyl group, a propyl group, or an aryl group, and an ethyl group or an aryl group is particularly preferable. In another embodiment, the aryl group is most preferred. There is also another embodiment in which an ethyl group is most preferred. There is also another embodiment in which a methyl group substituted with a hydroxyl group is most preferred.

R ³ is a hydrogen atom or a substituted or unsubstituted alkyl group. R ³ is particularly preferably a hydrogen atom or a hydrogen atom, preferably a lower alkyl group, or more preferably a methyl group.

 The combination of each substituent in the compound represented by the general formula (1) is not particularly limited.

<1 8 !: compounds in which ¹ is a furyl group;

<2> a compound in which Ar ¹ is a chael group;

<3 8 !: compounds in which ¹ is a triazolyl group; Kuhachi !: A compound in which ¹ is a thiazolyl group;

<5 8 !: compounds in which ¹ is an oxazolyl group;

<6 8 !: compounds in which ¹ is a benzothiazolyl group;

<7 8 !: ¹ substituted !, may! /, Substituted with an alkoxy group!

<8 8 !: Compound in which ¹ is substituted, but is substituted with an amino group;

9> Ar ¹ is substituted with —CON (RU) (R ¹² ) (R ¹¹ and R ¹² are as defined above);

<10> a compound in which Ar ² is a carboxyphenol group;

<11> a compound in which Ar ² is a carboxyalkylphenol group;

<12> a compound in which Ar ² is a carboxynaphthyl group;

<13> a compound in which Ar ² is a carboxyalkylnaphthyl group;

<14> a compound in which Ar ² is a monocyclic aromatic heterocycle other than a pyrazolyl group;

<15> Ar ² is substituted !, na! /, Compound;

<16> Ar ² is substituted with a norogen atom!

<17> Compounds in which Ar ² is substituted !, may! /, Substituted with alkyl groups!

<18> Ar ² is substituted !, may! /, An alkoxy group is substituted!

<19> 1 ^ is a lower alkyl group having 1 to 3 carbon atoms;

<20> a compound in which R ² is a lower alkyl group having 1 to 4 carbon atoms;

<21> a compound in which R ² is a lower alkenyl group having 2 to 4 carbon atoms;

<22> a compound in which R ³ is a hydrogen atom;

 <23> a compound which is <1> and <7> above;

 <24> a compound which is <1> and <8> above;

 <25> a compound which is <1> and <9> above;

 <26> a compound which is <1> above 10>;

<27> a compound which is <1> above 11>

 <28> a compound which is <1> the above 12>

 <29> a compound which is <1> above-mentioned 13>

<30> a compound which is <1> above 14>; <31> a compound which is <1> above 15>;

 <32> a compound which is <2> and <7> above;

 <33> a compound which is <2> and <8> above;

 <34> a compound which is <2> and <9> above;

<35> a compound that is 2> hot 10>;

 <36> Compound which is <2> above 11>

<37> Compound which is <2> above-mentioned 12>

 <38> a compound which is the above <2> hot 13>;

 <39> the compound which is <14> the above 14 <2>;

 <40> a compound that is <2> above 15>;

<41> a compound which is <4> and <7> above;

<42> the compound which is <4> powerful <8> above;

 <43> a compound which is <4> and <9> above;

<44> Compound <4> Powerful 10> above;

 <45> a compound that is <4> above 11>

<46> a compound which is <4> the above 12>

 <47> a compound that is <4> above-mentioned 13>

<48> Compound <14> Powerful 14> above;

 <49> A compound that is <4> Fat 15> above;

<50> Above 23> to <49> !, in any case, a compound which is <19>; <51> Above <23> to <50> !, < <52> a compound of <23> above <50>, in any case, a compound of <21>; <53> any of <23> above <52> A compound that is 22>;

<54 Eight !: Compounds in which ¹ is substituted with a neurogen atom!

<55 8 !: ¹ substituted !, may! /, Substituted with alkyl groups !, compounds;

<56 Eight !: ¹ substituted !, may! /, Substituted with an alkylthio group!

<57 Eight !: ¹ substituted !, may! /, Substituted with an acyl group!

<58 Eight !: Compound in which ¹ is substituted with an alkyl group! <59 Eight !: Compound in which ¹ is substituted with an alkylthio group!

<60 Eight !: Compound in which ¹ is substituted with an acyl group!

<61 Eight !: Compounds in which ¹ is substituted with an alkoxy group!

62> Ar ² is a compound that is —E—Ar ²¹ —G—Q;

<63> The above compound 62> and a compound wherein Ar ²¹ is a benzene ring;

64> Above 62> and Ar ²¹ is a naphthalene ring;

 <65> the above <62>, wherein E is a single bond;

 <66> the above <62> and a compound wherein G is a single bond or a lower alkylene group; <67> the above <62> and a compound wherein G is a lower alkylene group;

 <68> The above compound 62, and G is a lower alkylene group having 1 and 3 carbon atoms;

<69> Compounds as described above 62 and G force S methylene group;

<70> The above compound 62 and a compound wherein Q is a carboxy group;

71> Ar ² is substituted with a hydroxyl group;

<72> a compound in which Ar ² is substituted with an alkyl group!

<73> a compound in which Ar ² is substituted with an alkoxy group!

 <74> 1 ^ is a lower alkyl group;

<75> a compound wherein R ² is a lower alkyl group;

<76> compounds wherein R ² is a lower alkenyl group;

<77> The above compound <8>, <9>, and <54> to <61>, wherein the compound is 7>

 <78> A compound according to any one of <9> and <54> to <61>, and <8>;

<79> Compounds <54> to <61> above and <9>;<80><55> to <61> above! <81> A compound of <56> to <61> above, <55> a compound of <55> to <61><82> Compounds <58> to <61> above <58> Compounds <58> to <61><83><59><61> a compound that is 58> <84> The above 60> to <61> !, the compound which is all over 59, <85> the above 61> all over 60>;

<86> Above compound 17>, <18>, and <71>, a compound that is 16>

 <87> A compound which is a 17> in any one of the above 18 and 71> to <73>;

<88> Above 71> ~ <73> !, compound that has a bite 18>; 89> Above 72>-<73> !, anyway, A compound that is 71>

<90> a compound which is <72> hot 73> above;

 <91> The above 63> and 64> !, a compound which is in the range 65>; <92> The above 66> to <69>! 91 is a compound;

<93> a compound which is <70> above-mentioned 92>

 <94> Any of the above <1> and <2> and the above 7> to <9>, <54> to <61>, and <77> to <85>! ;

<95> A compound that is <94> in any one of <15> to <18>, <71> to <73>, and <86> to <90>;

<96> Above 10> to <14>, <62> to <70>, and <91> to <93>

 <97> Above 19> and 74> !, and in any case, <96> compounds; <98> Above <20>, <21>, <75>, and <76>! A compound that is <97> to the shear force!

 <99> a compound that is <22> above 98>;

<100> a compound in which R ² is a methyl group substituted by a lower alkoxy group;

<101> R ² is a compound which is a hydroxymethyl group or an ethoxymethyl group;

<102> a compound in which R ² is a hydroxymethyl group;

103> Compounds in which R ² is a methyl group substituted with a lower alkylthio group;

<104> a compound in which R ² is a methyl group substituted with a lower alkylsulfier group;

<105> a compound in which R ² is a methyl group substituted by a lower alkylsulfol group; <106> a compound in which R ² is an ethyl group;

 <107> A compound which is <96> in any of the above <100> to <106>; <108> A compound which is <97> in any of the above <100> to <106>; <109> In any of <107> and <108>, a compound wherein <22>.

[0105] In addition, a salt of the compound represented by the above formula 1) or a compound represented by formula <1>, wherein the combination of each substituent in the compound represented by the formula (1) is limited;

 A pharmacologically acceptable salt of the compound represented by the general formula (1) or the compound represented by the above <1> to <109>, wherein the combination of each substituent in the compound represented by the general formula (1) is limited;

 A prodrug of the compound represented by the general formula (1) or a compound represented by the general formula (1), wherein the combination of the substituents in the compound represented by the general formula (1) is limited; Or a prodrug of a salt of the compound of <1> to <109>, wherein the combination of each substituent in the compound represented by the general formula (1) is limited; the compound represented by the general formula (1), or the general Preferred is a prodrug of a pharmacologically acceptable salt of the compound of the above <1> to <109>, wherein the combination of each substituent in the compound represented by the formula (1) is limited.

 [0106] Specifically, preferred examples of the compound of the present invention represented by the general formula (1) include the following compounds:

[0107] [Chemical 41]

Cl.60f / 900Zdf / 13d 1-9 6ε9εΖΐ / 900ί OAV

meomoozdf / ud 6 € 9 € ίΙ / 9 ε OAV

ClZ, 60f / 900ZdT / X3d 98 6C9Cil / 900Z OJS \

U60 £ / 90QZd £ / 13d 68 6C9CZl / 900Z OAV

ει.6οε / 9θοζ <ΐΓ / χ3 <ι 96

£ U60 £ / 900Zd £ / L3d 16 6 £ 9ε / 900Ζ OAV

The scope of the present invention is not limited to these preferred examples

[0108] In addition, possible stereoisomers or racemates of these compounds, or pharmacologically acceptable salts, hydrates, solvates thereof, or prodrugs thereof are also within the scope of the present invention.

 [0109] The compound of the present invention is a novel compound not described in the literature. The compound of the present invention represented by the general formula (1) can be produced, for example, by the following method, but the production method of the compound of the present invention is not particularly limited.

 [0110] In each reaction, the reaction time is not particularly limited. However, since the progress of the reaction can be easily traced by a known analysis means, it may be terminated when the yield of the target product is maximized.

 [0111] The compound of the present invention represented by the general formula (1) can be produced, for example, according to the reverse synthesis route of the following reaction route.

[0112] [Chemical 42]

For example, in the compound represented by the general formula (1), the general formula (2) [—in the general formula (2), R ³ is as defined above, and Ar ^la , Ar ^2a , R ^la , and R ^2a are Each of them is synonymous with Ar ¹ Ar ² , R ¹ , and R ² , or one or more groups thereof may be protected. The compound represented by the general formula (1) can be produced by simultaneously or sequentially deprotecting all protecting groups. The deprotection reaction may be carried out according to a known method such as the method described in Protective Groups organic synthesis, John Wiley and ¾ons fll (1999).

In the compound represented by the general formula (2), the general formula (3) [in the general formula (3), Ar ^la , R ^la , and R ^2a are as defined above. And a compound represented by the general formula (4): [In the general formula (4), Ar ² and R ³ are as defined above. Can be produced by reacting in the presence of an acid. In the reaction of the compound represented by the general formula (3) and the compound represented by the general formula (4), the amount of the compound represented by the general formula (4) is used in the compound represented by the general formula (3). The power of 1Z10 to 10 equivalents, preferably 1Z5 equivalents to 5 equivalents, more preferably 1 equivalents to 3 equivalents. Purity, yield, purification efficiency, etc. of the compound represented by the general formula (2) May be designed as appropriate. As the compound represented by the general formula (4) to be used, an acid addition salt such as hydrochloric acid can be used. Examples of the acid include mineral acids such as hydrochloric acid, nitric acid, and sulfuric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and P-toluenesulfonic acid. Acetic acid or trifluoroacetic acid is a preferred example. It is done. The acid dose is preferably an equivalent amount or an excess amount relative to the compound represented by the general formula (3), for example, 1 to 10 equivalents, more preferably 1 to 20 equivalents. Preferably as an excess, for example a solvent Can be used in quantities. Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butyl acetate, and acetonitrile. Preferred examples include black mouth form, toluene, and tetrahydrofuran.

. Also, a mixture of two or more of these solvents can be used. Alternatively, it is also preferable to use the acid used in the above reaction as a solvent. Preferred reaction conditions include conditions where acetic acid is used in a solvent amount. The reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 1 to 96 hours, preferably 3 to 60 hours, and examples thereof.

Among the compounds represented by the general formula (2), particularly for compounds having a carboxylic acid ester moiety in the structure of the compound, as in the method for producing the compound represented by the general formula (2), Force that can be produced by reacting Hydrochloric acid is preferable as an acid to be used, and an example is mentioned. Alcohol is preferable as a solvent used in the reaction. Specific examples are methanol, ethanol, and 1 propanol. Or 2-propanol, with methanol or ethanol being more preferred! /.

Among the compounds represented by the general formula (2), when E in Ar ² in the general formula (1) corresponding to the Ar ^2a moiety in the general formula (2) represents an alkylene group, in the general formula (2) The compound shown can be produced by reacting the compound represented by the general formula (3) and the compound represented by the general formula (4) in the presence of a base. In the reaction of the compound represented by the general formula (3) and the compound represented by the general formula (4), the amount of the compound represented by the general formula (4) is used with respect to the compound represented by the general formula (3). 10 to 10 equivalents of 1Z can be used, preferably 1 to 5 equivalents of 1Z, more preferably 1 to 3 equivalents The purity, yield, purification efficiency, etc. of the compound represented by the general formula (2) What is necessary is just to design suitably in consideration. Bases include triethylamine, diisopropylethylamine, or 1,8 diazabicyclo [5.4.0.

] Organic bases such as Undekar 7 are listed, and 1,8 diazabicyclo [5. 4. 0] Unde force 7-Yen is preferred U, for example. The dose of the base is preferably equivalent or excessive to the compound represented by the general formula (3), for example, 1 to 10 equivalents, more preferably 1 to 20 equivalents. As a solvent used in the reaction, for example, Dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, propanol, butanol, ethyl acetate, butyl acetate, or acetonitrile. Butanol is a preferred example. Also, a mixture of two or more of these solvents can be used. The reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 0.1 to 96 hours, preferably 1 to 60 hours, and is exemplified.

Among the compounds represented by the general formula (2), Q [Q in Ar ² in the general formula (1) corresponding to Ar ^2a portion of the general formula (2) are as defined above. ] Represents —CON (R ⁴¹ ) (R ⁴² ) [R ⁴¹ and R ⁴² are as defined above]. ], The compound corresponds to the Ar ^2a moiety in the general formula (2), Q in Ar ² in the general formula (1) [Q is as defined above]. ] By reacting a compound having a carboxy group with ammonia, primary amine, secondary amine, or hydroxyamine in the presence of a condensing agent, if necessary, in the presence of a base. Can be manufactured. The amount of ammonia, primary amine, secondary amine, or hydroxyamine used is as follows. Q in Ar ² in general formula (1) corresponding to the Ar ^2a moiety in general formula (2) It is synonymous. ] Represents —CON (R ⁴¹ ) (R ⁴² ) [R ⁴¹ and R ⁴² are as defined above]. ], The compound is represented by Q in Ar ² in the general formula (1) corresponding to the Ar ^2a moiety in the general formula (2) [Q is as defined above]. ] Can be used in an amount of 10 to 100 equivalents, preferably 1 to 10 equivalents, relative to the compound having a carboxyl group. As the condensing agent, dicyclohexylcarbodiimide (DCC), O— (7-azabenzotriazole-1-yl) N, N, Ν ′, Ν, —tetramethyl carboxy-phosphate hexaphosphate ( HATU), or 1-ethyl-3- [3-dimethylaminopropyl] carpositimide (EDC) hydrochloride. As the amount of the condensing agent used, Q [Q in Ar ² in the general formula (1) corresponding to the Ar ^2a moiety in the general formula (2) is as defined above. ] Represents —CON (R ⁴¹ ) (R ⁴² ) [R ⁴¹ and R ⁴² are as defined above]. ], The compound has the same meaning as defined above for Q [Q in Ar ² in general formula (1) corresponding to the Ar ^2a moiety in general formula (2). ] Can be used in an equivalent amount to an excess amount relative to the compound showing a carboxy group, and examples thereof include 1 to 10 equivalents, preferably 1 to 5 equivalents. It is also desirable to add an auxiliary agent to the condensation reaction. Hydroxybenzotriazole (HO BT). Examples of the base include trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. Preferred is triethylamine, diisopropylethylamine, N-methylmorpholine, or pyridine. Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, pyridine, and dimethylformamide. It is also suitable to use a mixture of two or more of these solvents. Preferred is dimethylformamide or tetrahydrofuran. The reaction temperature is usually from −80 ° C to 100 ° C. Although reaction time is not specifically limited, Usually, 1 to 96 hours are illustrated, and 2 to 48 hours are preferable examples. Ammonia, primary amine, secondary amine, or hydroxyamine in the reaction may be protected. For example, protected hydroxylated amine may be O- (2-methoxypropane-2-yl. ) Hydroxyamine, and the protecting group can be deprotected according to a known method (Mori, K., Tetrahedron, 44, 6013 (1988)).

Among the compounds represented by the general formula (2), Ar ¹ in the formula (1) corresponding to Ar ^la moiety in the general formula (2) is, be also good Ariru or substituted optionally be substituted In the case of a compound substituted with a good alkenyl group, Ar ¹ in general formula (1) corresponding to the Ar ^la moiety in general formula (2) is substituted with bromine or iodine. It can also be produced from a compound. The production can be carried out under the known Suzuki reaction conditions or under the Heck reaction conditions. The reaction conditions are described in known literature (RFHeck, Organic Reactions, 27, 345 (1 982)., RFHeck, Palladium Reagents in urganic Synthesis). , Academic Press, 1985., N. Miyaura et.al, J. Am. Chem. Soc., 107, 972 (1985)., N. Miyaya, A. Suzuki, Chem. R ev. 95, 2457 (1995) ) Etc.

Among the compounds represented by the general formula (2), a compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an optionally substituted alkyl group In this case, in the compound, Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) may be substituted, an alkenyl group or a substituted group. Substituted by an alkyl group! It can also be produced from these compounds. Examples of the production method include a method using catalytic hydrogen reduction. In addition, the catalytic hydrogen reduction can be carried out using a catalyst in a solvent under a hydrogen atmosphere. Examples of the catalyst include palladium-carbon, acid platinum, platinum-carbon, palladium hydroxide and the like. Examples of the solvent used for the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, and ethanol. Tetrahydrofuran or methanol is preferred. It is also preferable to use a mixture of two or more of these solvents. The reaction temperature is usually from –80 ° C to 100 ° C. The temperature is preferably 0 ° C to 50 ° C. Although the reaction time is not particularly limited, it is usually 1 to 96 hours, preferably 3 hours and 48 hours, and examples are given.

Among the compounds represented by the general formula (2), a compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an optionally substituted amino group In this case, the compound can also be produced from the compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with bromine or iodine. The production can be carried out via a known Buchwald-Hart wig reaction, and the reaction conditions are known (AR Mud, S 丄. Buchwald, Top. Curr. Chem., 219, 131 (2002). JF Hartwig, Angew. Chem., Int. Ed., 37, 2046 (1998)., D. Baranano, G. Mann, Hartwig, JF Curr. Org. Chem. 1, 28 7 (1997)., CGFrost, P. Mendonca, J. Chem. Soc. Perkin Trans. 1, 1998, 2615.). Depending on the reaction conditions, the product may be obtained in a state where the amino group is protected. In such a case, a derivative having an amino group can be produced by appropriately performing a deprotection reaction.

Among the general formula (2) compound represented by, Ar ¹ in the formula (1) corresponding to Ar ^la portion of the general formula (2), [optionally substituted Ashiru group, substituted Alkyl sulfonyl group, optionally substituted alkyl rubamoyl group, optionally substituted alkylthio rubamoyl group, optionally substituted allyl force rubamoyl group, substituted, or It is substituted with an aryloxy carbamoyl group, substituted !, or an alkyloxycarbonyl group, or may be substituted with an amino group substituted with an aryloxycarbol group]. A compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an electrophile is reacted with an electrophile. It can also be manufactured. Examples of electrophiles include acyl chloride, acyl bromide, acid anhydride, alkylsulfonyl chloride, alkyl sulfonic acid anhydride, aryl chloride sulfone, aryl sulfonic acid anhydride, isocyanate, isothiocyanate, and power rubamoyl chloride. Or black formate. The electrophile is used in an equivalent or excess amount relative to the compound in which Ar ¹ in general formula (1) corresponding to the Ar ^la moiety in general formula (2) is substituted with an amino group. For example, 1 to 10 equivalents are preferred, and preferably 1 to 3 equivalents. If necessary for the reaction, a base can be used, and the base may be either an organic or inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, Examples thereof include trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. As the dose of the base, it is preferable that Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is an equivalent amount or an excess amount relative to the compound substituted with the amino group. More preferably, 1 to 100 equivalents, particularly preferably 1 to 10 equivalents are exemplified. An inert solvent can be used as a solvent used in the reaction. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, and butyl acetate. Preferred is dichloromethane, jetyl ether, or tetrahydrofuran. It is also suitable to use a mixture of two or more of these solvents. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably from −10 ° C. to 50 ° C. Although the reaction time is not particularly limited, it is usually exemplified by 0.2 to 24 hours, and preferably 1 to 5 hours.

Among the compounds represented by the general formula (2), the general formula (2) General formula corresponding to Ar ^2a moiety in (1) of Ar ² guard E-Ar ²¹ - G- is Q, and G is A compound which is an alkylene group and has two bonds formed by removing two hydrogen atoms on the same carbon on the alkylene group, bonded together to the same oxygen atom and substituted as an oxo isomer for, among the compounds represented by the general formula (2), the general formula (2) Ar ² in the general formula (1) corresponds to Ar ^2a moiety in guard E-Ar ²¹ - G- is Q, And G is an alkylene group, and is produced by subjecting a compound substituted on the alkylene group by a hydroxyl group to an oxidation reaction. Can do. Examples of the oxidation reaction include a method using a Dess-Martin reagent, a Swern acid method, or an acid method using chromic acid. These acid methods can be easily carried out by those skilled in the art.

Among the compounds represented by the general formula (2), Ar ¹ in the formula (1) corresponding to Ar ^la moiety in the general formula (2) is a compound substituted by an alkyl group substituted by a hydroxyl group In this case, among the compounds represented by the general formula (2), a compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an acyl group is subjected to a reduction reaction. It can be manufactured by providing. Examples of the reducing conditions include hydride reduction. Examples of the hydride reduction condition include a condition in which a metal hydride is reacted in the presence of an acid if necessary. Examples of the metal hydride include hydrosilane such as triethylsilane, sodium borohydride, sodium tellurium hydride and the like. As for the amount of metal hydride used, Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) among the compounds represented by the general formula (2) is substituted with an acyl group. The compound can be used in an equivalent amount to an excess amount with respect to the compound, and examples thereof include 1 equivalent to 20 equivalents, preferably 1 equivalent to 10 equivalents. If necessary, the reaction can be carried out in the presence of an acid, which may be either an organic or inorganic acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid, Or, boron trifluoride 'diethyl ether complex may be mentioned, and trifluoroacetic acid is preferred. The amount of acid, among the compounds represented by the general formula (2), Ar ¹ in the formula (1) that corresponds to Ar ^la moiety in the general formula (2) is substituted by Ashiru group It can be used in an equivalent amount to an excess amount with respect to the compound, and is preferably 1 equivalent to 20 equivalents, more preferably 1 equivalent to 10 equivalents. It is also preferable to use an excess amount of acid as a solvent. Examples of the solvent used for the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxetane, methanol, and ethanol. Tetrahydrofuran or dichloromethane is preferred. It is also suitable to use a mixture of two or more of these solvents. The reaction temperature is usually from −80 ° C to 100 ° C. Preferably, it is 0 ° C to 50 ° C. The reaction time is not particularly limited, but usually 1 to 48 hours is exemplified, and 3 hours A preferred example is 24 hours in between.

Further, among the compounds represented by the general formula (2), Ar ¹ in the formula (1) corresponding to Ar ^la portion of the general formula (2) in is replaced by an alkyl group substituted by a hydroxyl group In the compound represented by the general formula (2), Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an alkenyl group. It can be produced by subjecting the compound to a hydroxylation reaction by a hydroboration reaction. The hydroxylation reaction by hydroboration reaction can be easily performed by those skilled in the art.

Among the general formula (2) compound represented by Amino groups Ar ¹ in the general formula (1) corresponding to Ar ^la portion of the general formula (2), it is substituted with alkyl group which may be substituted for compounds that have been substituted in, the compounds of the general formula (2) a r ¹ of the general formula (1) corresponding to Ar ^la moiety is substituted with Amino group Ru compound in an alkylating agent If necessary, it can be produced by reacting in the presence of a base. As the alkylating agent, for example, a corresponding alkyl halide can be used, and examples thereof include alkyl iodide, alkyl bromide, alkyl chloride, 2-bromoethyl methyl ether and the like. As the amount of the alkylating agent used, Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) in the compound represented by the general formula (2) is substituted with an amino group. It is preferable to use an equivalent amount or an excess amount with respect to the compound in question, for example, 1 equivalent to 10 equivalents, preferably 1 equivalent to 3 equivalents. If necessary in the reaction, a base can be used, and the base may be either an organic or inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, Examples thereof include trimethylamine, triethylamine, disopropylethylamine, N-methylmorpholine, pyridine, and 2,6-lutidine. As the dose of the base, it is preferable that Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is an equivalent amount or an excess amount relative to the compound substituted with an amino group. More preferably, it is 1 equivalent to 100 equivalents. More preferably, it is 1 equivalent to 10 equivalents. An inert solvent can be used as a solvent used in the reaction. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, and butyl acetate. Preferably dichloromethane, Jetille One ter or tetrahydrofuran. It is also suitable to use a mixture of two or more of these solvents. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably from −10 ° C. to 50 ° C. Although the reaction time is not particularly limited, it is usually from 0.2 hours to 24 hours, and preferably from 1 hour to 5 hours. In addition, a compound in which Ar ¹ in general formula (1) corresponding to the Ar ^la moiety in general formula (2) is substituted with an amino group substituted with an optionally substituted alkyl group is generally A compound in which Ar ¹ in formula (1) corresponding to the Ar ^la moiety in formula (2) is substituted with an amino group is added to a solvent in the presence of an aldehyde or ketone, and optionally in the presence of an acid. It can also be produced by reductive amination reaction conditions in which a reducing agent acts. Examples of the solvent used in the reaction include jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, and acetonitrile. Methanol or acetonitrile is preferred. It is also suitable to use a mixture of two or more of these solvents. Examples of the aldehyde or ketone include formaldehyde, acetoaldehyde, and acetone. Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an amino group. It is preferable to use an equivalent amount or an excess amount with respect to the compound, more preferably 1 equivalent to 10 equivalents. Acetic acid or an acidic buffer solution is preferred as the acid to be used as necessary. Sodium cyanobium hydride is preferred as a reducing agent. Equivalent or excessive to the compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with an amino group. The amount used is preferably 1 equivalent to 10 equivalents. The reaction temperature is usually from -20 ° C to 100 ° C, preferably from -10 ° C to 50 ° C. Although reaction time is not specifically limited, Usually, 0.2 to 36 hours are illustrated, and 1 to 24 hours are preferable examples. Among the compounds represented by the general formula (2), when Ar ¹ in the general formula (2) General formula corresponding to Ar ^la moiety in (1) is a compound which is substituted with iodine, the compounds have the general formula (2) Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in (2) is reacted with a bromine substituted compound and an iodinating agent in the presence of a copper salt and an amine if necessary. Can be manufactured. Examples of the iodine glaze include iodide salts such as sodium iodide and potassium iodide, and the amount used is preferably equivalent or excessive. As a copper salt, for example, Yowi copper (I) can be mentioned as a preferred example, and a catalytic amount is preferably used. Ammin and Examples thereof include N, N, monodimethyl-1,2-diaminocyclohexane and the like, and a catalytic amount is preferably used. An inert solvent such as dioxane or tetrahydrofuran can be used as the solvent. The reaction temperature is preferably from room temperature to 150 ° C. The reaction time is exemplified by 1 to 50 hours, preferably 3 to 30 hours.

Among the compounds represented by the general formula (2), when Ar ¹ in the general formula (1) corresponding to Ar ^la moiety in the general formula (2) is a compound which is substituted by chlorine, the compounds have the general formula It can be produced by reacting a compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la part in (2) is substituted with bromine and copper chloride. An example of a preferable copper salt is copper (I) chloride, and it is preferable to use an equivalent amount or an excess amount. As the solvent, an inert solvent such as N, N-dimethylformamide, dioxane or tetrahydrofuran can be used. The reaction temperature is preferably from room temperature to 150 ° C. The reaction time is exemplified from 1 to 50 hours, preferably 3 to 30 hours U.

Among the compounds represented by the general formula (2), Ar ¹ in the general formula (2) General formula corresponding to Ar ^la moiety in (1) is optionally substituted alkyl - substituted with Le group In the case of a compound, the compound can also be produced from the compound in which Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) is substituted with bromine or iodine. . The production can be carried out under the known Sonogashira reaction conditions. For the reaction conditions, the known literature (K. Sonogashira, et al. Tetrahedron lett., 50, 4467 (1975)., J. Organomet Chem., 653, 46 (2002).).

Among the compounds represented by the general formula (2), Ar ¹ in the formula (1) corresponding to Ar ^la moiety in the general formula (2) is optionally substituted alkylsulfonyl - is substituted by Le group In the compound, Ar ¹ in the general formula (1) corresponding to the Ar ^la moiety in the general formula (2) may be substituted or substituted with an alkylthio group. It can also be produced by reacting a compound with an oxidizing agent in a solvent. Examples of the solvent used in the reaction include dichloromethane, chloroform, tetrasalt-carbon, and the like. Preferred is dichloromethane. It is also suitable to use a mixture of two or more of these solvents. The reaction temperature is usually from −80 ° C. to 100 ° C. The temperature is preferably 0 ° C to 50 ° C. The reaction time is not particularly limited, but usually 0.1 hour force is also exemplified by 48 hours, and 0.3 to 24 hours is preferable. A good example.

In the compound represented by the general formula (3), the general formula (5) [In the general formula (5), Ar ^la , R ^la , and R ^2a are as defined above. Can be produced by reacting in the presence of a cross-linking agent. As the cross-linking agent, there may be mentioned acid salts such as phosphorus oxychloride, sodium chloride, or oxalyl chloride. The acid salt is preferably phosphorus oxychloride. The amount of the cross-linking agent used can be 1 to 10 equivalents, preferably 1 to 5 equivalents, more preferably 1 to 3 equivalents, relative to the compound represented by the general formula (5). is there. In another embodiment, it is preferable to use an excess amount of the cross-linking agent relative to the compound represented by the general formula (5), for example, more preferably as a solvent. The reaction is also preferably carried out in the presence of an amine such as triethylamine or Ν, Ν-dimethylamine, and the equivalent of amine at this time is preferably, for example, 0.5 to 10 equivalents. More preferably, it is 1 to 3 equivalents. Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butylacetate, and acetonitrile. In another embodiment, it is also preferable to use the cross-linking agent as a solvent. The reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 0.1 hours to 100 hours, and preferred examples are 0.5 hours to 10 hours.

Among the compounds represented by the general formula (3) in the case of Ar ^1, corresponding to Ar ^la portion of the general formula (3) is, is substitution, even by, substituted by an alkoxy group, Ru compound, The compound can be produced from a compound in which Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) is substituted with a hydroxyl group. The production can be carried out under known Mitsunobu reaction conditions, and the reaction conditions are known (Mitsunobu, 0., Synthesis, 1981, 1 "Hughes, DL, Org. React., 42, 335 (1992). ) Etc.

Among the compounds represented by the general formula (3), when Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) is substituted with a hydroxyl group, the compound is represented by the general formula (3). It can be produced from a compound in which Ar ¹ corresponding to the Ar ^la moiety of is substituted with a methoxy group. The production method is a demethylation reaction as a deprotection method. For example, Protective Groups in Or ganic Synthesis, John Wiley and Sons flj (1999).

Among the compounds represented by the general formula (3), Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) may be substituted with an alkyl group, or may be substituted with an aminomethyl group In this case, the compound is a compound in which Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) is substituted with a chloromethyl group, in the presence of a base in a solvent, if necessary, in the presence of primary or 2 It can be produced by reacting a grade amine. Examples of the base used as necessary include triethylamine. The primary or secondary amine can be used in an amount equivalent to 1 equivalent or excess of the compound in which Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) is substituted with a chloromethyl group. , Preferably 1 to 10 equivalents. Examples of primary amines that can be used in the reaction include methylamine. Examples of secondary amines that can be used in the reaction include dimethylamine. Examples of the solvent used for the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butyl acetate, and acetonitrile. The reaction temperature can usually be 0 ° C to 200 ° C, preferably 20 ° C to 100 ° C. The reaction time is not particularly limited, but usually 0.1 to 100 hours is exemplified, and 1 to 30 hours are preferred examples.

Among the compounds represented by the general formula (3), when Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) is substituted with a chloromethyl group, the compound is represented by the general formula (3). It can be produced by reacting a compound obtained by substituting Ar ¹ corresponding to the Ar ^la moiety with a hydroxymethyl group in the presence of a cross-linking agent. Examples of the cross-linking agent include acid salts such as phosphorus oxychloride, thionyl chloride, and salt oxalyl. The acid chloride is preferably phosphorus oxychloride. The amount of the cross-linking agent used can be from 1Z10 to 10 equivalents, preferably 1Z5 based on the compound in which Ar ¹ corresponding to the Ar ^la part in the general formula (3) is substituted with a hydroxymethyl group Equivalent to 5 equivalents, more preferably 1 equivalent to 3 equivalents. In another embodiment, the amount of the cross-linking agent used is excessive with respect to the compound in which Ar ¹ corresponding to the Ar ^la moiety in the general formula (3) is substituted with a hydroxymethyl group. It is also preferable to use an amount, for example, as a solvent. The reaction is also preferably carried out in the presence of an amine such as triethylamine or Ν, Ν-dimethylamine, and the equivalent of the amine at this time is preferably, for example, 0.5 to 10 equivalents. More preferably, it is ˜3 equivalents. Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, butyl acetate, and acetonitrile. Moreover, it is also preferable to use the said cross-cloning agent as a solvent as another aspect. The reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. The reaction time is not particularly limited, but usually 0.1 to 100 hours is exemplified, and 0.5 hour force is also a preferred example of 10 hours.

The compound represented by the general formula (3) can be used with a protective group introduced or deprotected as necessary. The introduction of the protecting group and the deprotection reaction may be carried out according to a known method, for example, the method described in Protective Groups Organic Synthesis ^ John Wiley anaions (1999).

 Examples of the compound represented by the general formula (4) include commercially available 4-aminobenzoic acid (manufactured by Aldrich), 6 amino-2-naphthalene carboxylic acid (manufactured by Oakwood), 4 aminophenylacetic acid (manufactured by Aldrich), 4- Amino-1-methoxybenzoic acid (manufactured by Aldrich) and the like can be used.

The compound represented by the general formula (4) can also be produced by subjecting the corresponding nitro compound to a reduction reaction. Examples of the reduction reaction include a method using catalytic hydrogen reduction or a method using a metal-hydrogen complex compound. The catalytic hydrogen reduction can be carried out using a catalyst in a solvent in a hydrogen atmosphere. Examples of the catalyst include palladium-carbon, acid platinum, platinum carbon, palladium hydroxide and the like. Examples of the solvent used in the reaction include dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, jetinoreethenole, tetrahydrofuran, dixanthane, dimethoxyethane, methanol, and ethanol. . Tetrahydrofuran or methanol is preferred. It is also suitable to use a mixture of two or more of these solvents. The reaction temperature is usually from 80 ° C to 100 ° C, preferably 0 ° C to 50 ° C. Reaction time is Although not particularly limited, usually 1 to 96 hours are exemplified, and 3 to 48 hours are preferable examples. The reduction reaction with the metal hydride complex can be carried out in a solvent by adding additives as necessary. Preferred examples of the metal hydride complex include sodium borohydride. The metal hydride complex can be used in an equivalent amount or an excess amount relative to the nitro compound, preferably 1 to 10 equivalents. Examples of the solvent used in the reaction include jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, or ethanol. Tetrahydrofuran or methanol is preferred. It is also suitable to use a mixture of two or more of these solvents. It is preferable to use Lewis acid or metal salt as an additive, and preferable examples include nickel salt. The additive may be used in an excess amount of a catalytic amount relative to the -tro compound, and is preferably 0.01 to 1 equivalent. The reaction temperature is usually from −80 ° C. to 100 ° C., preferably from −20 ° C. to 50 ° C. The reaction time is not particularly limited, but is usually 0.1 to 96 hours, and preferred examples are 0.5 to 24 hours. Examples of the -tro compound in the reaction include commercially available compounds such as Ethyl 4-nitrophenyl glyoxylate (Lancaster). Corresponding -tro compounds can also be prepared by the -troation reaction of aromatic compounds. The nitration reaction can be carried out by reacting nitric acid or nitrate in sulfuric acid, and can be carried out based on known reaction conditions. Moreover, the intermediate body which has a carboxymethyl group among this nitro compound can be manufactured with the following method. First, for the corresponding bromo compound, trimethylsilylacetonitrile, metal complexes such as Pd (dba), complex such as Xantphos, etc.

 twenty three

A cyanomethyl compound is produced by using a body ligand and a metal salt such as zinc fluoride. The production can be carried out by a known method (Wu, Shi et al., J. Am. Chem. Soc, 127, 15824- (2005).). Subsequently, a carboxymethyl compound can be produced by carrying out a hydrolysis reaction on the cyanomethyl compound. The hydrolysis reaction can be carried out by allowing water and an acid to act in a solvent. As the amount of water, it is more preferable to use an excess amount as a preferred solvent or solvent. As the solvent to be used, water, THF, 1,4 dioxane, methanol, ethanol and the like are preferable. As the acid to be used, hydrochloric acid, sulfuric acid and the like are preferable, and sulfuric acid is more preferable. The amount of acid used is the cyanome It is preferable to use an excess amount relative to the chill form. Specifically, a method in which an aqueous solution obtained by diluting concentrated sulfuric acid with water twice is used as a solvent. The reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 0.1 to 96 hours, and preferred examples are 1 to 10 hours.

Furthermore, the compound represented by the general formula (4) can also be produced by a commercially available halogen compound via the known Buchwald Hartwig reaction, and the reaction conditions are known (AR Muci, S 丄. Buchwald, Top. Curr. Chem., 219, 131 (2002)., JFHartwig, Angew. Chem., Int. Ed., 37, 2046 (1998)., D. Baranano, G. Mann, Hartwig, JF Curr. Org. Chem. 1, 287 (1997)., CGFrost, P. Mendonca, J. Chem. Soc. Perkin Trans. 1, 1998, 2615.) and the like. Depending on the reaction conditions, the product may be obtained in a state where the amino group is protected. In that case, a derivative having an amino group can be produced by appropriately performing a deprotection reaction. Examples of commercially available halogenated compounds include Methyl 2- (4-bromophenyl) -2,2-dimethylacetate (Tronto). The compound represented by the general formula (4) can be used after introducing a protecting group if necessary, and certain! / ヽ can be deprotected. The introduction of the protecting group and the deprotection reaction may be carried out in accordance with a known method, for example, the method described in Protective Groups Organic Synthesis ^ John Wiley anaions (1999).

In the compound represented by the general formula (5), R ^la and R ^2a are as defined above, and R ⁴ represents a lower alkyl group. And a compound represented by the general formula (7) [-In the general formula (7), Ar ^la has the same meaning as described above. Can be produced by reacting in the presence of a base. In the reaction of the compound represented by the general formula (6) and the compound represented by the general formula (7), the amount of the compound represented by the general formula (7) is used with respect to the compound represented by the general formula (6). 10 to 10 equivalents can be used, preferably from 1 to 5 equivalents, more preferably from 0.5 to 2 equivalents, but the purity, yield and purification of the compound represented by the general formula (5) What is necessary is just to design suitably considering efficiency etc. In addition, as the compound represented by the general formula (7) to be used, it is preferable to use an acid addition salt such as hydrochloric acid. The base used in the reaction is sodium methoxide or sodium ethoxide. Examples thereof include metal alkoxides, carbonates such as sodium carbonate, potassium carbonate, or cesium carbonate, metal hydrides such as sodium hydride, sodium hydroxide, potassium hydroxide, and the like. Sodium ethoxide, sodium methoxide, or sodium hydride is preferred. Examples of the dose of the base to be used include 1Z5 equivalents to 10 equivalents, preferably 1Z2 equivalents to 3 equivalents, relative to the compound represented by the formula (7). In the case where the compound represented by the general formula (7) is used as an acid addition salt, it is also preferable to use an excess of 1 equivalent of a base in order to neutralize the acid addition salt. Solvents used in the reaction include, for example, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol nomonomethylenoateol, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene. , Jetyl ether, Tetrahydrofuran, Dioxane, Dimethoxyethane, Diethylene glycol dimethyl ether, Ethyl acetate, Butyl acetate or Acetonitrile, etc., Ethanol, methanol, Propanol, Isopropanol, Ethylene glycol, Propylene glycol, or Jet render alcohol monomethyl ether Is mentioned as a preferred example, more preferably ethanol or ethylene glycol. Two or more of these solvents can be used in combination. The reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is typically 1 to 96 hours, preferably 3 to 36 hours, and is exemplified.

Among the compounds represented by the general formula (5), R ² corresponding to R ^2a moiety in the general formula (5) [§ alkoxy group, Ashiruokishi group or have the Amin may be substituted with an alkyl group, In the case of a compound that is a methyl group substituted with a shear force], the compound is obtained by adding an alcohol, a carboxylic acid, or an amine to a compound in which R ^2a in general formula (5) is substituted with a bromomethyl group. It can manufacture by making it act as. Examples of the alcohol include methanol and ethanol, examples of the carboxylic acid include acetic acid, and examples of the amine include dimethylamine. As a solvent used for the production, when the nucleophile is an alcohol or a carboxylic acid, it is preferable to use the alcohol or the carboxylic acid as a solvent. When an amine is used as the nucleophile, an alcohol such as methanol or ethanol is used. It is preferable to use an organic solvent Good. When the nucleophile used is an alcohol or carboxylic acid, it is desirable to add an acid such as hydrochloric acid as necessary. The equivalent of the nucleophile used is equivalent or excess, preferably 1 to 100 equivalents. The reaction temperature is usually 0 ° C to 200 ° C, preferably 10 ° C to 50 ° C. The reaction time is not particularly limited, but is usually 0.1 to 96 hours, and preferred examples are 0.5 to 36 hours. In addition, the compound in which R ^2a in the general formula (5) is substituted with a bromomethyl group is different from the compound having the R ^2a force S methyl group in the general formula (5) in the presence of a radical initiator in a solvent. It can be produced by reacting N-prosuccinimide (NBS). Examples of the solvent include dichloromethane, black mouth form, carbon tetrachloride, benzene, toluene, xylene, and the like. As the radical initiator, it is preferable to use a catalytic amount with respect to the compound in which R ^2a in the general formula (5) in which 2-2′-azobis (isoptyl-tolyl) is preferred is a methyl group. NBS can be used in an excess amount of 1 equivalent, and preferably 1 equivalent to 10 equivalents. The reaction temperature can usually be carried out at 0 ° C to 200 ° C, preferably 50 ° C to 150 ° C. Although the reaction time is not particularly limited, it is usually 0.1 to 96 hours, and preferred examples are 0.5 to 36 hours.

 [0117] The compound represented by the general formula (5) can be used after introducing or deprotecting a protecting group, if necessary. The introduction of the protecting group and the deprotection reaction may be carried out according to a known method, for example, the method described in Protective Groups in Organic Synthesis ^ John Wiley and Sons (1999).

[0118] The compound represented by the general formula (6) includes, for example, commercially available acetyl acetoacetate (manufactured by Aldrich), benzoyl cetyl acetate (manufactured by Aldrich), 2-benzylacetoacetate ethyl (manufactured by Aldrich), 4,4, 4-Ethylfluoroacetoacetate (Aldrich), Propioleethyl acetate (Aldric h), 2-Cyanacetoacetate (Alfa Aesar), 2-Ethylacetoacetate (Aldrich), etc. And 2-allylacetoacetate acetate obtained by a known method (J. Org. Chem, 60, 856-862, 1995, etc.) or a known method (J. Org. Chem, 42, 459-, 19 77). 2) Ethyl 2-ethyl-3-oxopentanoate obtained by (2) or methyl 2-methoxyacetoacetate obtained by a known method (Tet rahedron, 44, 1603-, 1988). [0119] The compound represented by the general formula (7) is, for example, commercially available 2-thiophene carboxymidamide hydrochloride (Maybridge), 3-thiophene carboxymidamide hydrochloride (Maybridge), 3- Furancarboxymidamide hydrochloride (manufactured by Maybridge) can be used, and a commercially available aromatic derivative can be amidinized by a known method (4th edition, Experimental Chemistry Course, 20th and 21st, Maruzen). May be used. By this method, for example, 5-methoxythiophene-2-carboxymidamide hydrochloride can be produced from 2-methoxythiophene (Aldrich).

[0120] More specifically, first, a commercially available aromatic derivative is subjected to a formylation reaction to produce an aromatic aldehyde intermediate. The formylation reaction can be carried out under known Vilsmeier reaction conditions. Next, an aromatic-tolyl intermediate is produced by oximation of the aromatic aldehyde intermediate followed by a dehydration reaction. The oximation and dehydration reaction can be produced by reacting hydroxylamine or a salt thereof with an aromatic aldehyde intermediate. A base such as sodium acetate or triethylamine may be used as a reaction accelerator. It is also preferable to use a dehydrating agent depending on the completion of oximation. Examples of the dehydrating agent include anhydrous phthalic acid silk silk lide. Subsequently, the compound represented by the general formula (7) can be produced by subjecting the obtained aromatic-tolyl intermediate to an amidinolysis reaction. As the amidination reaction, a method in which lithium bis (trimethylsilyl) amide is used, a method in which an aluminum amide compound is allowed to act, or a method in which a metal alkoxide is first acted and then a salt or ammonium is allowed to act. Etc. can be mentioned. Among the aromatic aldehyde intermediates in the production method, in the case where the corresponding Ar ¹ is substituted with a bromine atom, the compound is produced by carrying out a bromination reaction on the corresponding aromatic aldehyde compound. can do. The bromination reaction can be carried out by using a brominating agent in a solvent. A preferred example of the brominating agent is bromine. It is preferable to use an acidic solvent as the solvent. Specifically, acetic acid can be mentioned as a more preferable example. The reaction temperature is usually from 20 ° C to 100 ° C, preferably 0 ° C to 30 ° C. The reaction time is not particularly limited, but is usually 0.1 to 96 hours, and preferred examples are 0.5 to 36 hours. In addition, among the aromatic-tolyl intermediates in the production method, the 2-alkylthiothiazole derivative has an alkylthiolate metal salt in the solvent acting on the corresponding 2 bromothiazole derivative. Can be manufactured. Examples of the alkyl thiolate metal salt include sodium methanolate. The dose of the alkylthiolate metal salt is 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to the 2-bromothiazole derivative. Examples of the solvent used in the reaction include ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, diethylene glycol monomethyl ether, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, Examples include jetyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, ethyl acetate, butyl acetate, acetonitrile, N, N-dimethylformamide, or dimethyl sulfoxide, and ethanol, methanol, or N, N— Dimethylformamide is a preferred example. In addition, two or more of these solvents can be mixed and used. The reaction temperature is usually from −50 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C. Reaction time is not particularly limited. Generally, 0.1 to 96 hours are exemplified, and 1 to 36 hours are preferable examples.

 The compound represented by the general formula (6) and the compound represented by the general formula (7) can be used after introducing or deprotecting a protecting group, if necessary. The introduction of the protecting group and the deprotection reaction may be carried out according to a publicly known force method, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1999).

 [0121] The compound of the present invention and the respective starting materials, compounds, and intermediates thus obtained can be isolated and purified according to conventional methods such as extraction, distillation, and chromatography.

[0122] A salt thereof can be produced from the compound represented by the general formula (1). The method for producing the salt is not particularly limited, and as a method for producing the acid addition salt, for example, the compound of the general formula (1) is dissolved in alcohols such as methanol and ethanol, and an equivalent or several times the amount of the acid component is obtained. These acid addition salts can be obtained by adding. The acid component used may be any acid component corresponding to the acid addition salt described below. Hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen sulfate, dihydrogen phosphate, citrate, maleic acid, tartaric acid, fumaric acid Suitable examples include pharmacologically acceptable mineral acids or organic acids such as darconic acid or methanesulfonic acid. In addition, as a method for producing a base addition salt, the acid addition salt In the same manner as in the method for producing the compound, it can be carried out using a base component instead of the acid component. Examples of the base component used include sodium hydroxide, potassium hydroxide, N-methyl-D-glucamine, N, N, -dibenzylethylenediamine as long as the base component corresponds to the base addition salt described below. Preferable examples include pharmacologically acceptable bases such as min, 2-aminoethanol, tris (hydroxymethyl) aminomethane, arginine, or lysine.

 [0123] The type of the salt of the compound of the general formula (1) in the present invention is not particularly limited, and may be any of an acid addition salt or a base addition salt, and takes the form of an intramolecular counter ion. Anyway. Examples of the acid addition salt include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, kenate, maleate, tartrate, fumarate, dulconate, or Methane sulfonates or addition salts with optically active acids such as camphor sulfonic acid, mandelic acid, or substituted mandelic acids are included. Examples of the base addition salt include metal salts such as sodium salt and potassium salt, N-methyl-D-dalkamine, N, N, -dibenzylethylenediamine, 2-aminoethanol, tris (hydroxymethyl) aminomethane, Examples thereof include addition salts with organic bases such as arginine or lysine. However, it goes without saying that the types of salts are not limited to these and can be selected as appropriate by those skilled in the art. Of these, pharmacologically acceptable salts are preferred. Note that the compound of the present invention may exist as a hydrate or a solvate, and these substances are also included in the scope of the present invention.

 When the compound force represented by the general formula (1) is also used as the prodrug, for example, by using a prodrug reagent such as a corresponding halogen compound, the hydroxyl group and the compound in the compound represented by the general formula (1) Amino group strength It can be produced by appropriately introducing a group constituting a prodrug into one or more selected groups according to a conventional method and then isolating and purifying it according to a conventional method as needed. In addition, a group constituting a prodrug can be appropriately introduced into the carboxyl group in the compound represented by the general formula (1) using a prodrug reagent such as a corresponding alcohol or amine according to a conventional method. In order to obtain the prodrug, it may be produced using a protecting group present in the compound represented by the general formula (2).

[0124] The prodrug of the compound of the general formula (1) in the present invention is not particularly limited, Examples thereof include compounds in which a group constituting a prodrug is introduced into one or more arbitrary groups selected from a hydroxyl group, an amino group, and a carboxyl group of the compound represented by the general formula (1). Examples of the group constituting a prodrug with respect to a hydroxyl group and an amino group include an acyl group and an alkoxycarbonyl group. Preferable examples include a acetyl group, a pionyl group, a methoxycarbonyl group, or an ethoxycarbonyl group, and an ethoxycarbonyl group is particularly preferable. In some embodiments, a acetyl group is preferred, in some embodiments a propiol group is preferred, and in other embodiments a methoxycarbonyl group is preferred. Examples of groups constituting prodrugs with respect to force lpoxyl groups include, for example, methyl group, ethyl group, n_propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, amino group. Examples are a group, a methylamino group, an ethylamino group, a dimethylamino group, or a jetylamino group. Preferable examples include ethyl group, n-propyl group, isopropyl group and the like, and ethyl group is particularly preferable. There is also another embodiment in which an n-propyl group is particularly preferred. There is also another embodiment in which an isopropyl group is preferred.

 [0125] The compound represented by the general formula (1) may have an asymmetric carbon. The stereochemistry of these asymmetric carbons is not particularly limited, and may be either S configuration or R configuration, or a mixture of both! /. Stereoisomers such as optically active forms or diastereoisomers in pure form based on these asymmetric carbons, any mixture of stereoisomers, racemates, etc. are all included in the scope of the present invention.

[0126] The compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof has a strong PDE4 activity inhibitory action as shown in Test Example 1 described later, and has a high activity. Because it has metabolic stability, it is useful as an active ingredient in medicine. Inhibition of PDE4 activity is known to elevate intracellular cAMP concentration and to elicit effects that prevent, treat and Z or ameliorate many diseases. For example, it suppresses the activity of inflammatory cells (eosinophils, neutrophils, monocytes, macrophages, mast cells, CD4 + T lymphocytes, CD8 + T lymphocytes). It also suppresses the production and release of inflammatory site force-in (IL1, IL6, IL8, etc.) typified by tumor necrosis factor a (TNF-a). Based on these facts, the compound of the present invention is considered to be effective for the prevention and alleviation of many inflammatory, allergic or immune system related diseases. In particular, TNF-a is known as a causative agent for many inflammatory diseases. By observing the inhibitory effect of TNF-a production in whole blood or cells of animals stimulated with polysaccharide (LPS), the anti-inflammatory action of the compound of the present invention can be indirectly proved. As shown in Test Example 2 and Test Example 4 described later, this compound is expected to exert a strong anti-inflammatory action because it exhibits a potent TNF-α production inhibitory action in both in vitro and in vivo tests. The

Specific uses of the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof include asthma, chronic obstructive disease (COPD), pneumoconiosis as a respiratory related disease. Examples include prevention and Z or treatment of bronchial asthma, acute bronchitis, chronic bronchitis, inflammatory airway disease, emphysema, eosinophilic granulomas, adult respiratory distress syndrome (ARDS), pulmonary fibrosis, etc. The Examples of joint-related diseases include rheumatism, osteoarthritis, acute arthritis, chronic arthritic gouty arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, spondyloarthritis and the like. Examples of diseases related to skin diseases include atopic dermatitis, psoriasis, seborrheic eczema, allergic contact eczema, and all types of urticaria. Examples of diseases related to the gastrointestinal region include irritable colitis, ulcerative colitis, Crohn's disease, collagenous colitis, polypic colitis and the like. Examples of diseases related to the eye-nose region include allergic rhinitis, chronic rhinitis, allergic conjunctivitis, irradiation conjunctivitis, catarrhal conjunctivitis, infectious conjunctivitis, and allergic pharyngitis. Examples of diseases related to the immune system include transplant rejection, multiple sclerosis, AIDS and the like. Inflammation in each tissue is accompanied by pain, which is considered to be effective in relieving pain associated with inflammation. Symptoms of the above diseases include pain, fever and gout. PDE4 inhibitors have been shown to be effective in animal models of depression (such as forced swimming tests) or animal models of memory (maze tests) (Saccomano, NA, et al., J. Med. Chem., 34 , p291-298, 1991; O 'Donnell, JM and Zhang, HT, Trends Pharmacol.Sci., 25, pl58-163, 2004; Zhang, HT and O' Donnell, JM, Psychopharmacology. 150, p311-316, 2000 o Since these improvements are thought to be caused by central nervous system activity caused by an increase in intracellular cAMP, the compound of the present invention, its salt, or its prodrug is affected by central nervous system activity. It is expected to be effective for diseases that can be improved. For example, learning 'memory loss, Alzheimer's disease, arteriosclerotic dementia, depression, par Examples include Kinson's disease, Huntington's disease, and delayed movement disorder.

 The compounds of the present invention, salts thereof, or prodrugs are expected to be effective against infectious diseases. In particular, viral infections whose symptoms worsen by increasing or decreasing the production of TNF-a in the host body, such as HIV, cytomegalovirus (CMV), influenza virus, herpes virus (such as herpes zoster virus or simple herpes virus) Etc. are exemplified. Inhibition of PDE4 activity can prevent proliferative cell chemotaxis or invasion, and therefore the compounds of the present invention, their salts, or prodrugs can be used to prevent tumor growth and entry into normal tissues. can do.

[0127] Also in the circulatory region, experimental animals and clinical studies have shown that inflammatory site force-in generation and cardiac and neutrophil infiltration during cardiac and cerebral ischemia or atherosclerotic layers of blood vessels Has been shown to do. Therefore, the compound of the present invention, a salt thereof, or a prodrug thereof is also applied to diseases in the cardiovascular region. For example, cardiac ischemia, cerebral ischemia, heart failure

, Arteriosclerosis, in-stent restenosis and the like.

[0128] PDE4 inhibitory power Since it has been shown to be effective in osteoporosis models such as ovariectomized mice, the use of the compound of the present invention, a salt thereof, or a prodrug thereof for bone diseases represented by osteoporosis (Waki, Y., et al, Jpn. J. Pharmacol, 79, p477-483, 1999; Miyamoto, K., et al., Biochem. Pharmacol, 54, p613-617, 1997)

[0129] Since it has been shown that a PDE4 inhibitor is effective in a mouse diabetes model (NOD mouse) !, the compound of the present invention, a salt thereof, or a prodrug thereof can be used for diabetes. Can be used (Pyne, NJ and Furman, BL, Diabetologia, 46, pl l79-1189, 2003) o

[0130] The compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for the prevention and Z or treatment of asthma, for example, bronchial asthma For example, suppression of contraction of isolated bronchi, asthma model of bronchial asthma, inhibition of migration of human peripheral blood leukocytes (Kunihiko Iizuka: Allergy, 47, p.943, 1998, Kunihiko Iizuka, Akihiro Yoshii: Japanese Journal of Respirology, 37: pl96 , 1999). Administration of the compound of the present invention, a salt thereof, or a prodrug thereof at 0.1 to 1000 mgZkg, preferably 0.1 to 100 mgZkg As a therapeutic agent for bronchial asthma by measuring the increase in bronchial resistance due to acetylcholine inhalation and histological analysis by oral administration, intravenous administration, or intraperitoneal administration to model animals. Usefulness can be confirmed.

 [0131] The compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicine for prevention, Z or treatment of chronic obstructive pulmonary disease (COPD). For example, suppression of contraction of isolated bronchi, asthma model animal of bronchial asthma, exposure model of tobacco smoke exposure in guinea pigs (Keiichi Sugami et al., 73rd Annual Meeting of the Pharmacological Society of Japan, 2000), inhibition of migration of human peripheral blood leukocytes, etc. Can be confirmed. A compound of the present invention, a salt thereof, or a prodrug thereof is administered orally, intravenously, or intraperitoneally to a guinea pig exposed to tobacco smoke at a dose of 0.1-lOOOOmgZkg, preferably 0.1-lOOmgZkg. The usefulness of COPD as a therapeutic drug can be confirmed by measuring the number of migrating leukocytes in bronchoalveolar lavage fluid and histological analysis.

[0132] The compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for the prevention and Z or treatment of pulmonary fibrosis. , Bleomycin-induced pulmonary fibrosis animal model, etc., for example, according to the method described in Am. J. Respir. Crit. Care Med., 163, p210-217, 2001. The compound of the present invention, a salt thereof, or a prodrug thereof is orally administered intravenously to a pulmonary fibrosis mouse model at a dose of 0.1 to 1000 mg / kg, preferably 0.1 to 100 mg Zkg. Or by intraperitoneal injection and measuring respiratory function and the amount of hydroxyproline in lung tissue, its usefulness as a therapeutic agent for pulmonary fibrosis can be confirmed.

[0133] The compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for the prevention and Z or treatment of rheumatoid arthritis. Or confirmed using a mouse collagen-induced arthritis model (Griffith, MM, et al, Arthritis Rheumatism, 24, p781, 1981; Wooley, PH, et al, J. Exp. Med., 154, p688, 1981.) it can. The compound of the present invention, a salt thereof, or a prodrug thereof is administered orally, intravenously to a model mouse or model rat at a dose of 0.1-100 mg / kg, preferably 0.1-100 mg / kg, or Intraperitoneally administered, measuring footpad volume, and measuring bone destruction progress, confirmed its usefulness as a therapeutic agent for rheumatoid arthritis. It can be recognized.

It is a stress load model that the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicament for prevention and Z or treatment of irritable bowel syndrome. This can be confirmed by administration to animals. Examples of stress model animals include restraint stress model rats (Miyata, K., et al, J. Pharmacol. Exp. Ther., 259, p8 15-819, 1991) and CRH-administered rat models (Miyata, K., et al. al, Am. J. Physiol., 274 (1998) G827-831) and the like. The compound of the present invention, a salt thereof, or a prodrug thereof is administered orally, intravenously or intraperitoneally to a stress model animal at a dose of 0.1-1000 mg / kg, preferably 0.1-lOOmgZkg. Measure the number of defecations. The usefulness as a remedy for irritable bowel syndrome can be confirmed by the effect of reducing the number of defecations.

The fact that the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof is useful as an active ingredient of a medicine for prevention and Z or treatment of allergy is atopic skin It can be confirmed according to the method described in, for example, an allergic mouse model, for example, Allergy 50 (12) 1152-1116 (2001). When inducing skin eruptions using an antelope mite antigen on NC / Nga mice pretreated with a surfactant or an organic solvent, the compound of the present invention, a salt thereof, or a prodrug thereof is 0.1-lOOOOmgZkg, preferably 0 1—lOOmgZkg can be administered orally, intravenously or intraperitoneally, and its usefulness as an allergy drug can be confirmed by measuring plasma IgE level and eosinophil count.

 The usefulness of the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof as an active ingredient of a medicine for prevention and Z or treatment of bone disease is, for example, removal of the ovary (Golub, LM, et al, Ann. NY Acad. Sci "878, p290-310, 1999) The compound of the present invention and its salt , Or a prodrug thereof is administered orally, intravenously, or intraperitoneally to OVX mice at a dose of 0.1-lOOOmgZkg, preferably 0.1-lOOmgZkg, and the root loss and skeletal bone weight are measured. It can be confirmed to be useful as a remedy for dysplasia and osteoporosis due to the inhibitory effect on root loss and the decrease in skeletal bone weight.

About the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof It is preferable that the side effect of vomiting as a side effect is small! /, For example, can be confirmed by experiments using ferrets (Robichaud, A "et al, Neuropharmacology, 38, p289-297, 1999; Endo, T. , et al "Biogenic. Amines., 9, pl63-175, 1992). The compound should be administered orally, intravenously, or intraperitoneally to the ferret at a dose of 0.1-lOOOmg Zkg, preferably 0.1-lOOmgZkg, and then observe the frequency of vomiting and vomiting behavior. This makes it possible to confirm the presence or absence of side effects.

 [0135] Furthermore, the fact that the action of vomiting is small can also be confirmed by using, for example, a gastric emptying test using mice (Haga, K., et al., Arch. Int Pharmacodyn., 328, p344-355, 1994; Sato, Y., et al., Biol. Pharm. Bull, 20, p752-755, 1997). This test is a method for quantifying the transfer rate for delivering the stomach contents to the small intestine. Drugs with emetic action have the effect of slowing this transfer rate. A test meal containing 0.1 to 1000 mg / kg of a compound, preferably 0.1 to lOOmgZkg, administered orally, intravenously or intraperitoneally to mice, and then containing a dye such as phenol red Is taken orally, the stomach is taken out after a certain period of time, and the amount of test meal remaining in the stomach is quantified to confirm the presence or absence of undesirable side effects.

[0136] The compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof has a less adverse effect on gastrointestinal disorders, which is an undesirable side effect. It can be confirmed by measuring gastric acid secretion enhancing activity (BergLindh et.al, Act a Physiol.Scand, 97: 401-414,1976 and Sack et.al, Am J.Physiol.243: G313-G319,198 2) . In particular, by comparing TNF-α production inhibitory activity using mouse mononuclear cells, which is an index of drug efficacy as an anti-inflammatory treatment, and gastric acid secretion enhancing activity using the above rabbit gastric gland cells, drug efficacy and undesirable side effects It can indicate a deviation from a certain digestive tract disorder. By examining the selectivity of PDE4 isoforms Β and D for the compound of the present invention represented by the above general formula (1), a salt thereof, or a prodrug thereof, the efficacy and undesirable side effects such as vomiting and nausea Can be shown. Selectivity for each PDE4 isoform can be demonstrated by its inhibitory activity in normal enzyme assays. For example, in vitro inhibitory activity of PDE4B and 4D may be measured as a method for examining the selectivity of PDE4B and 4D. That is, the test compound was added to 40 mM Tris—HCl (pH 7 4), 5 mM MgCl, 4 mM 2-Mercaptoethanol, 3 M cAMP, 0.83 μ Ci [

2

H] —Add to the reaction mixture (100 1) containing the catalytic site of cAMP and human-type PDE4B and incubate at room temperature for 10 minutes. After stopping the enzymatic reaction by adding 25 1 of trichloroacetic acid to the reaction mixture, 0.1M 2 — [[Tris (hydroxylmethyl) methyl] amino] — 1 ethanesulfonic acid (TES) buffer (pH 8.0) Mix with neutral alumina equilibrated with). The supernatant is removed and neutral alumina is washed with a sufficient amount of 0.1M TES buffer and then eluted with 2N NaO 2 H. [ ³ H] —Evaluate the in vitro inhibitory activity of the test compound against PDE4B by placing 500 1 of the eluate containing 5 'AMP product into a scintillation vial containing 3 ml of a scintillation cocktail and measuring the radioactivity. (Catherine Bar delle et.al, Analytical Biochemistry, 275, 148-155, 1999). The inhibitory activity of PDE4D can be measured in the same manner.

It is also possible to examine the selectivity of PDE4B and 4D by using crude enzymes PDE4B and 4D obtained by culturing and purifying cells derived from a specific cancer cell line or tissue under certain conditions. It seems possible (International Immunopharmacology, 2, 1647-1656, 200 2). In other words, use HL60 cell line in RPMI1640 medium containing 10% non-immobilized fetal bovine serum and 1.3% DMSO for 10 days at 37 ° C, 95% air / 5% CO.

 2

 . After culturing for 10 days, collect the HL60 cell line, wash it, and make a lysate. Fractionation of lysates by anion exchange chromatography, selective hydrolysis of cAMP, and use of a specific fraction that is strongly inhibited by rolipram, a PDE4 selective inhibitor, as a partially purified PDE4B product By doing so, in vitro inhibitory activity against PDE4B can be measured. Similarly to the above, the PDE4D enzyme can be measured for in vitro inhibitory activity against PDE4D by using a partially purified PDE4D preparation obtained from U937 cultured in the usual manner (C. Shepherd et al. al., British Journal Of Pharmacology, 142, 339-351, 200 4).

 In addition, the usefulness of the compound of the present invention represented by the general formula (1), a salt thereof, or a prodrug thereof is also confirmed by the value of the PDE4B inhibitory activity, which is an index of drug efficacy as an anti-inflammatory treatment. It seems possible to do.

The medicament of the present invention includes a compound represented by the general formula (1) or a salt thereof as an active ingredient. For example, a compound or a salt thereof administered as a prodrug is metabolized in vivo to give a compound represented by the general formula (1) or a pharmacologically acceptable product thereof. In the scope of the pharmaceutical of the present invention.

 [0138] As the medicament of the present invention, one or a mixture of two or more of the compound represented by the general formula (1) or a pharmacologically acceptable salt thereof may be used as it is. A pharmaceutical composition is prepared by adding one or more pharmacologically acceptable carriers to one or a mixture of two or more of the compounds represented by 1) or a pharmacologically acceptable salt thereof. It is preferable to prepare and administer. Although the kind of carrier accept | permitted pharmacologically is not specifically limited, For example, an excipient | filler, a binder, a disintegrating agent, a lubricant, or an additive etc. are illustrated. Examples of the excipient include D-mannthol. Examples of the binder include carboxymethyl cellulose. Examples of the disintegrant include corn starch. Examples of the lubricant include glycerin. Examples of the additive include paraoxybenzoic acid esters. Further, examples of additives include surfactants such as polyoxyethylenesorbitan monooleate (tween 80) and HC60.

 [0139] When the medicament of the present invention is administered to humans, it can be orally administered in the form of tablets, powders, granules, capsules, dragees, liquids, syrups, etc., or injections, drops, suppositories. It can also be administered parenterally in the form of transdermal or absorbent. Inhalation in the form of sprays such as aerosols and dry powders is also preferred and can be mentioned as dosage forms.

[0140] The administration period of the medicament of the present invention is not particularly limited, but when it is administered for therapeutic purposes, the period during which clinical symptoms of each disease are determined to be expressed is selected as the administration period in principle. Can do. In general, administration is usually continued for several weeks to 1 year, but it can be further continued depending on the disease state, or it can be continued after recovery from clinical symptoms. . Furthermore, even if clinical symptoms do not appear, it can be administered prophylactically at the discretion of the clinician. The dosage of the medicament of the present invention is not particularly limited. 1S For example, generally 0.01 to 2000 mg of an active ingredient per day for an adult can be divided into several doses. The frequency of dosing can be administered once a month, daily, preferably once to Z weeks to 3 times Z weeks, or 5 times Z weeks, or daily. Daily dose, The administration period and administration frequency may be increased or decreased as appropriate depending on the patient's age, weight, physical health, disease to be treated and its severity.

 Furthermore, for the purpose of enhancing the therapeutic effect, the drug of the present invention and a drug that does not adversely affect the action of the drug of the present invention can be used in combination. Examples of such drugs for combined use include the combination of the medicament of the present invention and the following A) -TT).

 A) Iprato mouth bromide anticholinergic agents: tioto mouth bromide, oxytropium bromide, etc.

B) β 1 or 13 2 -adrenergic receptor agonist: metaproterenol, isoproterenol nore, isoprenaline, anolebutero monore, sanorebutanore, fonoremoterenore, sanolemeterol, terbutaline, orciprenaline, vitorterol, Pirbuterol and so on.

 C) Theofylin and aminophylline

 D) Leukotriene biosynthesis inhibitor (5-lipoxygenase inhibitor)

 Ii) Leukotrien (LTB4, LTC4, LTD4 and LTE4) receptor antagonists: Plan norecast, Zafinole norecast, Montenorecast, etc.

 F) Thromboxane A2 synthase inhibitor: Ozadarel hydrochloride and the like.

 G) Chemical mediator release inhibitor: sodium cromoglycate, tralast, amlexanox, levirinast, ibudilast, tazanolast, pemirolast, etc.

 H) Histamine HI receptor antagonists: ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, terfenadine, emedastine fumarate, epinastine hydrochloride, istemizole, ebastine, fuexofenadine hydrochloride, olopatadine hydrochloride, bepotastiti besylate And cetirizine hydrochloride.

 I) Th2 site force-in inhibitor: suplatast tosylate and the like.

J) Histamine H2 receptor antagonist

 K) Muscarinic receptors (Ml, M2, M3) Antagost

L) Matrix 'meta-oral protease (MMP) inhibitor

 M) Darcocorticoids: full-solid, triamcinolone acetonide, solid dipropionate methasone, budesodium, flutizone propionate, mometasone furoate, etc.

N) COX-1 inhibitor (NSAID)

0) COX-2 inhibitor P) Antibody against tumor necrosis factor (TNF-a); Remicade

Q) Antibodies against interleukin 6 receptor (MRA)

R) Antibodies against endogenous inflammatory substances

S) DMARD: leflunomide and the like.

 T) Immunosuppressive drugs: cyclosporine, mizoribine, methotrexate, etc.

U) Anti-gout agents: Cortisine etc.

 V) Xanthine oxidase inhibitor: alopurinol and the like.

 W) Uric acid excretion promoters: pluvenecid, sulfinvirazone, benzbromaon, etc. X) Transforming growth factor (TGF β) receptor antagonist

Υ) Transforming growth factor (TGF β) receptor kinase inhibitor

Ii) antidepressants

 Ii) Anti-Alzheimer drugs

 ΒΒ) Capsaicin

 CC) Tryptase inhibitor

 DD) Platelet activating factor (PAF) antagonist

 EE) Interleukin converting enzyme (ICE) inhibitor

 FF) Adhesion molecule inhibitors: VLA-4 antagonists etc.

 GG) IMPDH inhibitor

 HH) serotonin 3 (5-HT3) receptor and serotonin 4 (5-HT4) receptor antagonist

 II) Bradykinin I B1—Receptor Antagonist, Bradykinin I B2—Receptor Antagonist

 JJ) Cathebcin

 KK) MAP kinase inhibitor

 LL) glucose monophosphate dehydrogenase inhibitor

 MM) Antitumor agent

 NN) Insulin-like growth factor type 1 (IGF— 1) Mimetic

OO) Platelet-derived growth factor (PDGF) PP) Fibroblast growth factor: bFGF etc.

 QQ) Granulocyte-macrophage mouth-priming factor (GM-CSF)

 RR) Elastase inhibitor

 SS) Adenosine A2a receptor antagonist

 TT) Various diabetes drugs

 The administration time of the aforementioned concomitant drug is not limited, and the drug of the present invention and the concomitant drug may be administered to the administration subject at the same time or with a time difference. The dose of the concomitant drug may be appropriately selected according to the administration subject, administration route, disease, combination of the drug of the present invention and the concomitant drug, etc., according to the clinically used dose. it can.

 [0142] The administration mode of the concomitant drug is not particularly limited, as long as the drug of the present invention and the concomitant drug are combined in administration. Examples of such dosage forms include: 1) A single preparation obtained by simultaneously formulating the compound of the present invention, its salt, or its prodrug, which is an active ingredient of the medicament of the present invention, and a concomitant drug. 2) Simultaneous administration of two types of preparations obtained by separately formulating the medicament of the present invention and the concomitant drug by the same route, 3) Formulating the medicament of the present invention and the concomitant drug separately Administration of the two preparations obtained at the same time by the same administration route, and 4) simultaneous preparation of the two preparations obtained by separately formulating the pharmaceutical of the present invention and the concomitant drug in different administration routes. 5) Administration of the two preparations obtained by separately formulating the medicament of the present invention and the concomitant drug at different time intervals in different administration routes (for example, for the concomitant use of the medicament of the present invention next Administration in the order of drugs, or administration in the reverse order).

 [0143] The mixing ratio of the medicament of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.

[0144] The usefulness of the medicament of the present invention is that mammals including humans (for example, mice, rats, hamsters, frets, inu, monkeys, etc.) and cells of mammals including humans (immune cells, inflammation, etc.) (E.g., cells, cancer progenitor cells, primary cells, living cells, etc.), effects on the compound of the present invention, salts thereof, or prodrugs thereof, and changes in Z or blood concentration (e.g., maximum blood concentration). Effective blood concentration duration, blood half-life, AUC, etc.) Further, by examining the low toxicity of the compound of the present invention, a salt thereof, or a prodrug thereof, it can be confirmed that the usefulness as a medicament is higher. Furthermore, the usefulness can be confirmed by the blood concentration transition in humans or animals, enzyme induction, enzyme inhibition, and stability to microsomes.

 Example

 [0145] Hereinafter, the present invention will be described more specifically with reference to examples and test examples. However, the scope of the present invention is not limited to the following examples.

 [0146] In the following Examples, various analyzes were performed as follows unless otherwise specified. For thin layer chromatography (TLC), Precoated silicagel 60 F254 (Merck) was used, and spots were confirmed by UV (254 nm) irradiation. As a filler for the silica gel column, Kogel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) was used. In the operations in the examples, “concentration” means evaporation of the solvent or excess reagent under reduced pressure using an evaporator (manufactured by Tokyo Science Instruments Co., Ltd.).

 [0147] LC-MS HPLC was performed using a column (Develosil C30-UG-54.6X50mm) manufactured by Japan Nomura Chemical Co., using water-acetonitrile (containing 0.1% (ν / ν) acetic acid) gradient elution. The target product was eluted by. The detailed elution conditions are shown below.

 Flow rate: 2ml, mm

 Solvent: Eight liquids = water, 0.1% (ν / ν) acetic acid contained, liquid = acetonitrile, 0.1% (ν / ν) acetic acid contained 0 min to 5 min: [A solution 95% + B solution 5% (v / v)) to (A solution 2% + B solution 98% (v / v))

 From 5 minutes to 6 minutes: [A liquid 2% + B liquid 98% (v / v)]

 From 6 minutes to 7.5 minutes: [A liquid 95% + B liquid 5% (v / v)]

 Examples and reference examples that are specifically described for LC conditions indicate that they are measured under the following solvent conditions.

 LC condition 1

Solvent: Eight liquids = water, 0.1% (ν / ν) acetic acid contained, liquid = acetonitrile, 0.1% (ν / ν) acetic acid contained 0 min to 5 min: [A solution 95% + B solution 5% (v / v)) to (A solution 2% + B solution 98% (v / v)) From 5 minutes to 6 minutes: [A liquid 2% + B liquid 98% (v / v)]

From 6 minutes to 7.5 minutes: [A liquid 95% + B liquid 5% (v / v)]

LC condition 2

Solvent: Eight liquids = water, 0.1% (ν / ν) acetic acid contained, liquid = acetonitrile, 0.1% (ν / ν) acetic acid contained 0 min to 5 min: [A solution 95% + B solution 5% (v / v)) to (A solution 0% + B solution 100% (v / v))

 From 5 minutes to 9 minutes: Hold at [A solution 0% + B solution 100% (v / v)]

From 9 minutes to 10 minutes: Hold at [A liquid 95% + B liquid 5% (v / v)]

LC condition 3

Solvent: Eight liquids = water, 0.1% (ν / ν) acetic acid, liquid = acetonitrile, 0.1% (ν / ν) acetic acid 0 min to 5 min: [A solution 70% + B solution 30% (v / v)) to (A solution 2% + B solution 98% (v / v))

 From 5 minutes to 6 minutes: [A liquid 2% + B liquid 98% (v / v)]

From 6 minutes to 7.5 minutes: [Retained at 70% solution A + 30% solution B (v / v)

LC condition 4

Solvent: Eight liquids = water, 0.1% (ν / ν) acetic acid, liquid = acetonitrile, 0.1% (ν / ν) acetic acid 0 min to 5 min: [A solution 50% + B solution 50% (v / v)) to (A solution 2% + B solution 98% (v / v))

 From 5 minutes to 6 minutes: [A liquid 2% + B liquid 98% (v / v)]

 From 6 minutes to 7.5 minutes: Hold at [A solution 50% + B solution 50% (v / v)]

<Reference Example 1> 5-Aryl-6-methyl-2- (thiophen-2-yl) pyrimidin-4 (3H) -one Known literature (J. Org. Chem. 1995, 60, 856-862.) 2-ethyl allylacetoacetate (255 mg) and thiophene-2-carboximidamide hydrochloride (244 mg, manufactured by Maybridge) obtained by the method described in 1) were dissolved in ethylene glycol (7.5 mL), and sodium ethoxide (206 mg , Manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at 120 ° C for 15 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, 2M hydrochloric acid (1.0 mL) and water (50 mL) were added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated. A silica gel column (hexane / ethyl acetate = 3/1) was applied to obtain 135 mg of the title compound. Reference Example 2 5-Ethyl-6-methyl-2- (thiophen-2-yl) pyrimidin-4 (3H) -one

2 Ethylacetoacetate acetate (1.90 g, manufactured by Wako Pure Chemical Industries, Ltd.) and thiophene-2-carboxyimidoamide hydrochloride (1.63 g, manufactured by Maybridge) are dissolved in methanol (80 mL), and hydrogenated sodium (mineral oil 40% Added, 3.21 g, manufactured by Wako Pure Chemical Industries, Ltd.), and stirred at 55 ° C for 24 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and neutralized with 2M hydrochloric acid. Furthermore, water (200 mL) was added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated. The resulting residue was washed with jetyl ether to give 979 mg of the title compound.

<Reference Example 3> 5-Aryl-4-chloro-6-methyl-2- (thiophen-2-yl) pyrimidine The compound of Reference Example 1 (130 mg) was dissolved in phosphorus oxychloride (8 mL) and a nitrogen atmosphere. The mixture was stirred at 100 ° C for 2 hours. Concentrate the reaction mixture, add saturated aqueous sodium bicarbonate (7 mL) and water (30 mL) to the resulting residue, extract with ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and concentrate to give 132 mg of the title compound. Obtained.

Reference Example 4 5-Methoxythiophene-2-carbaldehyde

 2-Methoxythiophene (4.41 mL, manufactured by Aldrich) was dissolved in Ν, Ν-dimethylformamide (45 mL), and phosphorus oxychloride (6.12 mL) was added dropwise under ice cooling, followed by stirring for 1 hour. Then 2M sodium hydroxide (35mL) was added and stirred at 90 ° C for 10 minutes. Water (150 mL) was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated. The resulting residue was subjected to column chromatography (hexane / ethyl acetate = 5/1). As a result, 5.86 g of the title compound was obtained.

 <Reference Example 5> 5-Methoxythiophene-2-carbo-tolyl

 The compound of Reference Example 4 (3.20 g), hydroxylamine hydrochloride (6.27 g, manufactured by Wako Pure Chemical Industries, Ltd.), and sodium acetate (7.37 g, manufactured by Wako Pure Chemical Industries, Ltd.) are dissolved in acetic acid (150 mL), and 100 ° The mixture was stirred at C for 11 hours. The reaction mixture was filtered, the filtrate was concentrated, water (250 mL) was added to the resulting residue, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The resulting residue was subjected to column chromatography (hexane / ethyl acetate = 3/1) to obtain 2.20 g of the title compound.

Reference Example 6 5-Methoxythiophene-2-carboxamidine Dissolve the compound of Reference Example 5 (281 mg) in jetyl ether (12 mL), add lithium bis (trimethylsilyl) amide in 2M hexane (4 mL) at 0 ° C under a nitrogen atmosphere, and stir at room temperature for 1 hour. did. After that, 2M hydrochloric acid (6mL) and water (10mL) were added at 0 ° C, and 2M sodium hydroxide aqueous solution (9mL) was added to the separated aqueous layer, extracted with chloroform, and the organic layer was extracted with magnesium sulfate. Concentration was performed after drying with a solution to obtain 267 mg of the title compound.

 <Example 1> 4- (5-Allyl-6-methyl-2- (thiophen-2-yl) pyrimidine-4-ylamino) Benzoic acid

 The compound of Reference Example 3 (37 mg) and 4-aminobenzoic acid (40.9 mg, manufactured by Nacalai Testa) were dissolved in acetic acid (2 mL) and stirred at 100 ° C. for 43 hours. Concentrate the reaction mixture, add saturated aqueous sodium hydrogen carbonate solution (lmL) and water (25mL) to the residue, extract with ethyl acetate, wash with saturated Japanese salt water, dry over magnesium sulfate, and concentrate. The residue was subjected to preparative thin layer chromatography (black mouth form / methanol = 15/1) to give 27 mg of the title compound. L ji-\ «: 1" ^ 1 ^: Retention time 3.98 minutes, m / z 352 (M + H).

<Examples 2 to 27>

 The compounds of Examples 2 to 27 were synthesized according to the method of Example 1. Details of Examples 2 to 27 are shown in Table 1. The meanings of the symbols in Table 1 are as shown below. “Exp.”: Example number, “Str.”; Example compound, “RT”: LCMS retention time (minutes), “MS”; LCMS mass spectral data, “Ref.” Correspondence A method for producing an intermediate. The symbols in the Ref. Column indicate the method for producing the intermediate as follows. “A”: production method shown in Reference Example 1, “B”: production method shown in Reference Example 2, “C”: production method shown in Reference Example 3, “D”: production shown in Reference Example 4 “E”: production method shown in Reference Example 5, “F”: production method shown in Reference Example 6.

[table 1]

<Reference Example 7> Methyl 5-formylthiophene-2-carboxylate

5-formylthiophene-2-carboxylic acid (3.13 g, manufactured by Tokyo Chemical Industry Co., Ltd.) is dissolved in Ν, Ν-dimethylformamide (lOOmL), sodium carbonate (8.64 g, manufactured by Wako Pure Chemical Industries, Ltd.), and odomethane (2.49 mL) , Manufactured by Tokyo Chemical Industry Co., Ltd.) at room temperature and stirred for 11 hours. Not from reaction mixture The solute was filtered off, water (200 mL) was extracted with sodium ketyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated to give 3.26 g of the title compound.

<Reference Example 8> Methyl 5-cyanothiophene-2-carboxylate

 Hydroxylamine hydrochloride (1.44 g, Wako Pure Chemical Industries, Ltd.) was suspended in acetonitrile (80 mL), triethylamine (2.88 mL, Wako Pure Chemical Industries, Ltd.), acetonitrile (100 mL) of the compound of Reference Example 7 (2.93 g), ) Solution and phthalic anhydride (2.82 g, manufactured by Aldrich) were sequentially added at room temperature and stirred at 90 ° C. for 48 hours in a nitrogen atmosphere. After concentrating the reaction solution, ethyl acetate was added to the resulting residue, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 6/1) to obtain 2.48 g of the title compound.

 <Reference Example 9> Ethyl 2-isobutyrylpenta-4-enoate

 Isobutyryl acetate ethyl (3.16 g, manufactured by Wako Pure Chemical Industries, Ltd.), allyltrimethylsilane (4.15 mL, manufactured by A1 drich) are dissolved in methanol (400 mL), and diammonium cerium nitrate (23.06 g, manufactured by Kanto Chemical Co., Inc.) ) Was added at room temperature and stirred as such for 1 hour. After the reaction solution was concentrated, water (250 mL) was extracted with vigorous jetyl ether, dried over magnesium sulfate and concentrated to the resulting residue. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 10/1) to obtain 2.03 g of the title compound.

 Reference Example 10 4-Methoxythiophene-3-carboxamidine

 Under nitrogen atmosphere, add anhydrous toluene (8 ml, manufactured by Kanto Chemical Co., Ltd.) to a salt solution (157 mg, manufactured by Aldrich Co., Ltd.) and stir it under ice cooling with a toluene solution of trimethylaluminum (2.0 M, 1.47 ml, manufactured by Kanto Daigaku Co., Ltd.) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Thereafter, 4-methoxythiophene-3-carbo-tolyl (272 mg) dissolved in toluene (2 ml, manufactured by Kanto Chemical Co., Inc.) was added dropwise to the reaction mixture at room temperature, and then stirred at 80 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, then transferred to a mixture of silica gel 60 (14 g, Merck) and black mouth form (20 ml, Wako Pure Chemical Industries), stirred for 5 minutes, and filtered through a glass filter. The filtrate was concentrated and dried to obtain 458 mg of the title compound.

Reference Example 11 5-Bromothiophene-2-carboxamidine

5-bromothiophene-2-carbo-tolyl (333 μ1, Aldrich) was added to anhydrous methanol (7 ml, dissolved in Wako Pure Chemical Industries, Ltd.), sodium methoxide (28% methanol solution, 288 1) was added dropwise at room temperature and stirred for 1 hour. Thereafter, sodium chloride sodium (321 mg, manufactured by Aldrich) and anhydrous ethanol (7 ml, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was stirred at 90 ° C. for 14 hours. The residue obtained by concentrating the filtrate was washed several times with jetyl ether and filtered to obtain 660 mg of the title compound.

 Reference Example 12 Ethyl 2-ethyl-3-oxohexanoate

 Butyryl acetate (8.20 mL, manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in acetone (50 mL), and bromoethane (4.85 mL, manufactured by Aldrich) and potassium carbonate (13.82 g, manufactured by Wako Pure Chemical Industries, Ltd.) were sequentially added. The mixture was heated to reflux. Insoluble material was filtered off from the reaction mixture and concentrated. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 10/1) to give 5.75 g of the title compound. <Reference Example 13> 4-Bromo-2- (diethoxymethyl) thiophene

 4-Bromothiophene-2-carbaldehyde (2.3 g, Aldrich) is dissolved in ethanol (30 ml), salt ammonium (706 mg, Aldrich), triethoxymethane (2.2 ml, Wako Pure Chemical Industries, Ltd.) After stirring, the mixture was stirred at 60 ° C for 1 hour in a nitrogen atmosphere. The reaction mixture was then allowed to cool to room temperature and filtered through filter paper, and the mother liquor was concentrated to dryness to give 2.6 g of the title compound.

<Reference Example 14> 2- (Diethoxymethyl) -4-methoxythiophene

 Compound of Reference Example 13 (0.65 g), sodium methoxide (1.76 ml, 28% methanol solution, manufactured by Wako Pure Chemical Industries, Ltd.), copper oxide (236 mg, manufactured by Wako Pure Chemical Industries, Ltd.) and potassium iodide (498 mg, Wako Pure Chemical Industries, Ltd.) Was dissolved in methanol (2 ml) and stirred at 120 ° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through celite, washed several times with methanol, and the mother liquor was concentrated to give 670 mg of the title compound.

 <Reference Example 15> 4-Methoxythiophene-2-carbaldehyde

The compound of Reference Example 14 (2.63 g) was dissolved in methanol (30 ml), 5N aqueous hydrochloric acid solution (5 ml, manufactured by Wako Pure Chemical Industries, Ltd.) was slowly added dropwise, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was neutralized by adding 5N aqueous sodium hydroxide solution (2 ml, manufactured by Wako Pure Chemical Industries, Ltd.), concentrated, and the resulting residue was added with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After washing with an aqueous solution, the organic layer is dried over magnesium sulfate and concentrated. Totography (hexane / ethyl acetate = 20/1) gave 842 mg of the title compound.

<Reference Example 16> 5-Bromothiophene-3-carbaldehyde

 Thiophene-3-carbaldehyde (3.65 ml, manufactured by Aldrich) is dissolved in dichloromethane (100 ml), and bromine (1.13 ml, manufactured by Wako Pure Chemical Industries, Ltd.) and anhydrous sodium chloride aluminum (8.78 g, manufactured by Aldrich) are added. After that, the mixture was stirred at 45 ° C for 2 hours. The reaction mixture was stirred under ice-cooling, water and saturated ammonium chloride were slowly added, extracted with dichloromethane, and washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated to obtain 5.94 g of the title compound as a mixture (1: 1) with thiophene-3-force rubaldehyde.

<Reference Example 17> 2- (4-Aminophenyl) -2-hydroxyacetate

 Nitrogen atmosphere 2- (4-Nitrofuryl) -2-oxoacetate (0.99 g) was dissolved in methanol (40 ml), and 10% Pd / C (0.48 g) was added. The nitrogen atmosphere was replaced with a hydrogen atmosphere under reduced pressure, and the mixture was stirred at room temperature for 3 hours. The mixture obtained by filtering the reaction solution was concentrated and then applied to a silica gel column (hexane / ethyl acetate = 1/1) to obtain 837.2 mg of the title compound.

<Reference Example 18> 5- (4-Methoxyphenoxy) thiophene-2-carbo-tolyl

 4-Methoxyphenol (149 mg, manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in DMF (3 ml), and sodium hydride (48 mg, manufactured by Kanto Yigaku Co., Ltd.) was added with stirring under ice cooling, followed by stirring for 45 minutes. To the reaction mixture, 5-bromothiophene-2-carbo-tolyl (111 μ1, Aldrich) was further stirred for 22 hours at 120 ° C, allowed to cool to room temperature, the solvent was distilled off, and water was added. And extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 20/1) to give 68.5 mg of the title compound. <Reference Example 19> Methyl 2- (4- (benzyloxycarbolumino) phenol) -2-methylpropanoate

2- (4-Bromophenol) -methyl 2-methylpropanoate (203.5 mg, manufactured by Tronto) is dissolved in 1,4-dioxane (5 ml), cesium carbonate (311.3 mg), tris (benzylideneacetone) ) Diparadium (0) (69.9 mg), xanthophos (180.3 mg, manufactured by Strem), and benzyl strength rubamate (145.9 mg) were added. The mixture was stirred at 100 ° C for 15.5 hours under a nitrogen atmosphere. A large excess of methylene chloride was added, followed by filtration. The reaction mixture was concentrated and then applied to a silica gel column (hexane / ethyl acetate = 4/1) to obtain 138.8 mg of the title compound. Reference Example 20 Methyl 2- (4-aminophenol) -2-methylpropanoate In a nitrogen atmosphere, the compound of Reference Example 19 (116.4 mg) was dissolved in methanol (5 ml), and 10% Pd / C (38.6 mg) was added. The nitrogen atmosphere was replaced with a hydrogen atmosphere under reduced pressure, and the mixture was stirred at room temperature for 3 hours. The mixture obtained by passing the reaction solution was concentrated to obtain 64.7 mg of the title compound.

<Reference Example 21> 5- (4-Chromium-5-Ethyl-6-methylpyrimidine-2-yl) thiophene-3-ol

 4-Black mouth-5-ethyl-2- (4-methoxythiophen-2-yl) -6-methylpyrimidine (860 mg) was dissolved in black mouth form (45 mL), and the temperature was 0 ° C under nitrogen atmosphere. After dropwise addition of 1.0M boron tribromide Z dichloromethane solution (15 mL, manufactured by aldrich), the mixture was stirred at 0 ° C for 30 minutes, and further stirred at room temperature for 1 hour. After the reaction mixture was diluted with black mouth form (45 mL), 5% aqueous sodium hydrogen carbonate solution (100 ml) was stirred at room temperature for 30 minutes, extracted with black mouth form, washed with saturated brine, The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 800 mg of the title compound.

<Reference Example 22> 4 -Black mouth-5-ethyl-2- (5-hydroxymethylthiophen-2-yl) -6-methylpyrimidine

 The compound of Reference Example 23 (90 mg) was dissolved in tetrahydrofuran (10 mL), sodium borohydride (53 mg, manufactured by Wako Pure Chemical Industries, Ltd.) was added at room temperature, and the mixture was stirred as it was for 4 hours. Water (30 mL) was extracted from the reaction mixture with sodium ketyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated to obtain 83 mg of the title compound.

 <Reference Example 23> 4-Black mouth-5-ethyl-2- (5-formylthiophene-2-yl) -6-methylpyrimidine

 2- (5- (Diethoxymethyl) thiophen-2-yl) -5-ethyl-6-methylpyrimidin-4 (3H) -one (201 mg) is dissolved in phosphorus oxychloride (10 mL) and added under nitrogen atmosphere. The mixture was stirred at 100 ° C for 2.5 hours. Concentrate the reaction mixture, add saturated aqueous sodium hydrogen carbonate solution (15 mL) and water (25 mL) to the residue, extract with ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and concentrate to give the title compound. 165 mg was obtained.

 Reference Example 24 2- (5- (dimethoxymethyl) thiophen-2-yl) -5-ethyl-6-methylpyrimidin-4 (3H) -one

2- (5- (Diethoxymethyl) thiophen-2-yl) -5-ethyl-6-methylpyrimidine-4 (3H)- On (150 mg) was dissolved in methanol (8 mL) and tetrahydrofuran (4 mL), 5M hydrochloric acid (1.5 mL) was added at room temperature, and the mixture was stirred as such for 1.5 hours. After neutralization with 5M sodium hydroxide aqueous solution (1.5mL), water (25mL) was further extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated to give 122mg of the title compound. Got.

 <Reference Example 25> 5-Ethyl-2- (5-ethoxymethylthiophen-2-yl) -6-methylpyrimidine-4C3I "0-year-old

 2- (5- (diethoxymethyl) thiophen-2-yl) -5-ethyl-6-methylpyrimidin-4 (3H) -one (52 mg) was dissolved in dichloromethane (5 mL) and triethylsilane (124 L, Manufactured by Tokyo Chemical Industry Co., Ltd.) and boron trifluoride jetyl ether complex (98 L, manufactured by Tokyo Chemical Industry Co., Ltd.) were sequentially prepared at room temperature and stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution (2 mL) was added to the reaction mixture, and water (25 mL) was further extracted with cake form, washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained residue was subjected to preparative thin-layer chromatography (black mouth form / methanol = 20/1) to obtain 23 mg of the title compound.

 <Example 28> 5- (4- (4-carboxyphenylamino) -5-ethyl-6-methylpyrimidine-2-yl) thiophene-2-carboxylic acid

 Dissolve methyl 5- (4- (4-carboxyphenylamino) -5-ethyl-6-methylpyrimidine-2-yl) thiophene-2-carboxylate (lOmg) in methanol (4 mL) and add 2M water. An aqueous sodium oxide solution (389 mL) was added and stirred at 60 ° C. for 11 hours. The reaction mixture was ice-cooled, 2M hydrochloric acid (389 mL) and water (25 mL) were added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated to give the title compound lOmg. LC-MS: HPLC retention time 4.20 min, m / z 384 (M + H). <Example 29> 2- (4- (2- (5-Bromothiophen-2-yl) -5-ethyl-6- Methylpyrimidine-4-ylamino) phenol) ethyl acetate

2- (5-bromothiophene-2-yl) -4-chloro-5-ethyl-6-methylpyrimidine (2 g) was dissolved in ethanol (20 ml) and 4-aminophenyl acetate (2.27 g) was dissolved. And 35 to 37% aqueous hydrochloric acid (0.9 ml, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was stirred at 55 ° C for 23 hours. The reaction mixture was concentrated, ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was stirred for 15 minutes, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and the resulting residue was subjected to column chromatography (hexane / ethyl acetate = 5/1 to 2/1) to give the title 2.29 g of compound was obtained. LC-MS: HPLC retention time 5.88 min (LC condition 1), m / z 460 (M + H). <Example 30> 2- (4- (5-ethyl-2- (5- (4-ethylpropyl) ) Thiophene-2-yl) -6-methylrubiridine-4-ylamino) phenol) methyl acetate

 The compound of Example 29 (60.3 mg) was dissolved in toluene (0.338 ml) and methanol (0.135 ml), and 2M aqueous sodium carbonate solution (122 μ1), tetrakistriphenylphosphine palladium (15.6 mg, manufactured by Aldrich) ) And 4-ethylphenylboronic acid (30.5 mg, manufactured by Aldrich) were added and stirred at 85 ° C. for 13 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, washed several times with methanol, and the mother liquor was concentrated. Water was added to the resulting residue, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated. The resulting residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give the title compound. 15.4 mg was obtained. LC-MS: HPL C retention time 6.3 minutes (LC condition 1), m / z 472 (M + H).

 <Example 31> 2- (4- (5- (4-Ethylphenol) thiophen-2-yl) -6-methylpyrimidine-4-ylamino) fur) acetic acid

 The compound of Example 30 (15.4 mg) was dissolved in methanol (0.4 ml), 1N aqueous sodium hydroxide solution (0.1 ml, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 16 hours. A 1N aqueous hydrochloric acid solution (0.1 ml, Wako Pure Chemical Industries, Ltd.) was added to the reaction mixture, the solvent was distilled off, water was added, and the mixture was extracted with chloroform.The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography (black mouth form / methanol = 15/1) to obtain 10.9 mg of the title compound. LC-MS: HPLC retention time 5.18 min (LC condition 1), m / z 458 (M + H).

 <Example 32> 4- (2- (5-Ethyl-6-methyl-2- (thiophen-2-yl) pyrimidine-4-ylamino) ethyl) benzoic acid

2- (thiophen-2-yl) -4-chloro-5-ethyl-6-methylpyrimidine (20.5 mg) was dissolved in 1-butanol (1.5 ml) to give triethylamine (116.9 1), 4- (2-Aminoethyl) benzoic acid (85.0 mg, manufactured by Aldrich) was added, and the mixture was stirred at 120 ° C for 17 hours. The reaction mixture was allowed to cool to room temperature, 1,8-diazabicyclo [5.4.0] unde-7-en (500 μ1, made by Aldrich) was added, and the mixture was stirred at 120 ° C. for 3 hr. The reaction mixture was allowed to cool to room temperature and neutralized with 2M hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The obtained residue was applied to a silica gel column (black / form / methanol = 95/5) to obtain 7.8 mg of the title compound. LC-MS: HPLC retention time 3.42 minutes (LC condition 1), m / z 368 (M + H).

 <Example 33> 2- (4- (5-Ethyl-6-methyl-2- (thiophen-2-yl) pyrimidine-4-ylamino) phenol) acetamide

 2- (4- (5-Ethyl-6-methyl-2- (thiophen-2-yl) pyrimidine-4-ylamino) phenol) Acetic acid (10.7 mg) was dissolved in tetrahydrofuran (lml) and diisopropyl Tyramine (6.35 μ 1), 0- (7-azabenzotriazol-1-yl) Ν, Ν, Ν ', Ν, -Tetramethylol-umhexafluorophosphate (13.7mg, (Applied Biosystems) was added and stirred at room temperature for 10 minutes. Then, 28% aqueous ammonia (1001) was added, and the mixture was further stirred at room temperature for 23.5 hours. The reaction mixture was applied to a silica gel column (black mouth form / methanol = 95/5) to obtain 2.2 mg of the title compound. LC-MS: HPLC retention time 3.34 minutes (LC condition 1), m / z 353 (M + H).

<Example 34> 2- (4- (5-Ethyl-6-methyl-2- (5-propylthiophen-2-yl) pyrimidin-4-ylamino) phenol) ethyl acetate

 (Z) -2- (4- (5-Ethyl-6-methyl-2- (5- (prop-1-yl) thiophen-2-yl) pyrimidine-4-ylamino) phenol) acetic acid Ethyl (22 mg) was dissolved in tetrahydrofuran (0.5 ml), methanol (0.5 ml) and dichloromethane (0.1 ml), and after 10% Pd-C (5 mg, manufactured by MERCK) was prepared, the mixture was stirred under a hydrogen atmosphere for 2 hours. . The reaction mixture was filtered through celite, washed successively with ethyl acetate, chloroform, and methanol, and concentrated to obtain 20.5 mg of the title compound. LC-MS: HPLC retention time 1.96 minutes (LC condition 4), m / z 424 (M + H).

 <Example 35> 2- (4- (2- (5-aminothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) fur) ethyl) ethyl acetate

2- (4- (2- (5-Bromothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) ethyl acetate (30 mg), benzophenone imine (22 Tokyo) Kasei), 9,9, -dimethyl-4,5-bis (diphenylphosphino) xanthene (15.1 mg, manufactured by STREM), cesium carbonate (42.6 mg, manufactured by Wako Pure Chemical Industries) and palladium acetate ( 2.9 mg (manufactured by Aldrich) was dissolved in 1,4-dioxane (654 L) and stirred at 90 ° C. for 16 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through celite, concentrated, and the resulting residue was dissolved in methanol (654 L). Sodium acetate (21.5 mg, manufactured by Wako Pure Chemical Industries, Ltd.) and hydroxylamine hydrochloride (13.6 mg And manufactured by Wako Pure Chemical Industries, Ltd.) and stirred at room temperature for 3 hours. The reaction mixture was filtered through celite and concentrated. It was subjected to ram chromatography (black mouth form / methanol = 90/1) to obtain 21.2 mg of the title compound. LC-MS: HPLC retention time 3.55 min (LC condition 1), m / z 397 (M + H).

<Example 36> 2- (4- (2- (5-acetamidothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) ethyl acetate

 The compound of Example 35 (10 mg) was dissolved in dichloromethane (500 L), triethylamine (4.23 μL, manufactured by TCI) was added, and acetic anhydride (2.87 L, manufactured by Wako Pure Chemical Industries) was added at 0 ° C. The solution was added dropwise and stirred at room temperature for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, extracted with dichloromethane, the organic layer was dried over anhydrous magnesium sulfate and concentrated.The resulting residue was subjected to column chromatography (black mouth form / methanol = 90/1), The title compound lO.Omg was obtained. L C-MS: HPLC retention time 3.58 min (LC condition 1), m / z 439 (M + H).

 <Example 37> 2- (4- (5-Ethyl-6-methyl-2- (thiophen-2-yl) pyrimidine-4-ylamino) phenol) -2-ethyl acetate

 2- (4- (5-Ethyl-6-methyl-2- (thiophen-2-yl) pyrimidine-4-ylamino) phenyl) -2-hydroxyacetate (20.0 mg) in carbon tetrachloride / dichloromethane = Dissolved in l / l (2ml) solvent, Chromic acid, polymer-supported (203.8mg, Aldrich, 35,982-3, 20-50 mesh, ~ 2.5mmol / g) was added and stirred at room temperature for 18 hours . The reaction solution was filtered and concentrated. The obtained residue was applied to a silica gel column (hexane / ethyl acetate = 2/1) to give 1.3 mg of the title compound. LC-MS: HPLC retention time 5.58 minutes (LC condition 1), m / z 396 (M + H).

Example 38 (E) -3- (5- (4- (4- (2-Ethoxy-2-oxoethyl) phenylamino) -5-ethyl-6-methylpyrimidine-2-yl) thiophene 2-yl) ethyl acrylate

The compound of Example 29 (23 mg) was dissolved in dimethylformamide (0.5 ml). 12.6 mg (manufactured by Kokusan Chemical Co., Ltd.) and tetraptylammonium chloride (13.9 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) were added, and the mixture was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was filtered through celite, washed with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to obtain 14.5 mg of the title compound. LC-MS: HPLC retention time 3.55 minutes (LC condition 1), m / z 397 (M + H). Example 39 (E) -2- (4- (5-Ethyl-2- (5- (4-hydroxybut-1-enyl) thiophen-2-yl) -6-methylpyrimidine-4-ylamino ) Fuel) Ethyl acetate

 (E)-2- (4- (2- (5- (4- (t-Butyldimethylsiloxy) but-1-yl) thiophen-2-yl)-5-ethyl-6-methylpyrimidine- 4-ylamino) phenol) ethyl acetate (42.5 mg) was dissolved in tetrahydrofuran (0.5 ml), tetraptylammonium fluoride (19.6 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred at room temperature for 2 hours. Water and saturated aqueous sodium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to give the title 14.5 mg of compound was obtained. LC-MS: HPLC retention time 3.69 minutes (LC condition 1), m / z 453 (M + H).

 <Example 40> 2- (4- (2- (5-cyclopropylthiophen-2-yl) -5-ethyl) -6-methylbilimidine-4-ylamino) phenol) ethyl acetate

 The compound of Example 29 (45.9 mg) was dissolved in toluene (0.5 ml), and cyclopropylboronic acid (11 • 2 mg, manufactured by Aldrich), potassium phosphate (74.3 mg, manufactured by Aldrich), tricyclohexylphosphine (2.8 mg, manufactured by Aldrich), palladium acetate (0.5 mg, manufactured by Wako Pure Chemical Industries) and water (251) were added, followed by stirring at 100 ° C. for 19 hours in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through celite, washed with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated, and the resulting residue was subjected to preparative thin-layer chromatography (hexane / ethyl acetate = 4/1). This gave 11.8 mg of the title compound. LC-MS: HPLC retention time 1.82 min (LC condition 4), m / z 422 (M + H).

 <Example 41> 2- (4- (5-Ethyl-2- (5- (1-hydroxyethyl) thiophen-2-yl) -6-methylpyrimidine-4-ylamino) phenol) acetic acid Yetil

2- (4- (2- (5-acetylethylthiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) ethyl acetate (8.lmg) in methanol (lml ), Sodium borohydride (5 mg, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 15 minutes. A small amount of water was added to the reaction mixture, the solvent was distilled off, ethyl acetate was added, 1N aqueous hydrochloric acid solution was neutralized and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Shrinking afforded 10.6 mg of the title compound. LC-MS: HPLC retention time 0.52 min (LC condition 4), m / z 426 (M + H).

 <Example 42> 2- (4- (2- (5-dimethylamino) thiophen-2-yl) -5-ethyl-6-methylbilimidine-4-ylamino) phenyl) ethyl acetate

 2- (4- (2- (5-Bromothiophen-2-yl) -5-ethyl-3-ethylpyrimidine-4-ylamino) phenol) ethyl acetate (30 mg), (±) -2,2, -Bis (diphenylphosphino) -Ι, -Binaphthalene (20.8mg, Aldrich), Tripotassium phosphate (12.2mg, Wako Pure Chemical Industries), Dimethylamine (261 μL, 2.0M tetrahydrofuran solution) and Tris (Dibenzylideneacetone) dipalladium (6.0 mg, manufactured by Aldrich) was dissolved in toluene (654 L), and the mixture was stirred at 90 ° C. for 16 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite and concentrated, and the obtained residue was subjected to column chromatography (black mouth form / methanol = 90/1) to give the title compound lO.Omg. LC-MS: HPLC retention time 3.79 minutes (LC condition 1), m / z 425 (M + H).

<Example 43> 2- (4- (2- (5-Ethyl-2- (4- (2-methoxyethylamino) thiophen-2-yl) -6-methylpyrimidine-4-ylamino) phenol -L) Ethyl acetate

 The compound of Example 35 (41.5 mg), 1-bromo-2-methoxyethane (19.8 L manufactured by Wako Pure Chemical Industries, Ltd.) and 2,6-lutidine (36.6 manufactured by TCI) were mixed with Ν, Ν-dimethylformamide (l. OmL) and stirred at 80 ° C. for 48 h. After cooling the reaction mixture to room temperature, water (5 mL) is added, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated, and the resulting residue is subjected to column chromatography. (Chromium mouth form / methanol = 90/1) to give 16.0 mg of the title compound. LC-MS: HPLC retention time 3.55 min (LC condition 1), m / z 455 (M + H). <Example 44> 2- (4- (5-Ethyl-6-methyl-2- (5-biphenyl) -Luthiophene-2-yl) pyrimidine-4-ylamino) phenol) ethyl acetate

The compound of Example 29 (91.8 mg) was dissolved in 1-propanol (2 ml), and potassium butyl trifluoroborane (32.2 mg, manufactured by LANCASTER), (1,1, -bis (diphenylphosphino) phenolate) dichloro Palladium 'dichloromethane complex (3.26 mg, manufactured by Aldrich) and triethylamine (27.91, manufactured by Wako Pure Chemical Industries, Ltd.) were added, and the mixture was stirred at 105 ° C for 4.5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting residue was subjected to column chromatography (hexane / vinegar). Acid ester = 5/1) gave 52.9 mg of the title compound. LC-MS: HPLC retention time 2.43 minutes (LC condition 4), m / z 408 (M + H).

 Example 45 2- (4- (5-Ethyl-2- (5- (2-hydroxyethyl) thiophen-2-yl) -6-methylpyrimidine-4-ylamino) phenol) acetic acid Yetil

 The compound of Example 44 (23.4 mg) was dissolved in tetrahydrofuran (0.4 ml), and a solution of borane / tetrahydrofuran complex in tetrahydrofuran (66.2 1, manufactured by Kanto Sugaku Co., Ltd.) was stirred and stirred for 5 minutes. Thereafter, the mixture was stirred at room temperature for 22 hours. Cool the reaction mixture to -15 ° C, add 30% hydrogen peroxide solution (391, manufactured by Pure Chemicals), stir for 30 minutes, and then add 2N sodium hydroxide aqueous solution (921, Wako Pure Chemical). The mixture was stirred for 1 hour and then further stirred at room temperature for 2 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting residue was subjected to preparative thin-layer chromatography (hexane / ethyl acetate). = 2/1) to give 5.7 mg of the title compound. LC-MS: HPLC retention time 3.79 minutes (LC condition 1), m / z 426 (M + H).

 Example 46 2- (4- (5-Ethyl-2- (5-odothiophen-2-yl) -6-methylpyrimidine-4-ylamino) fur) ethyl acetate

 The compound of Example 29 (45.9 mg) was dissolved in 1,4-dioxane (0.5 ml), and copper iodide (1 mg, manufactured by Wako Pure Chemical Industries, Ltd.), sodium iodide (30 mg, manufactured by Wako Pure Chemical Industries, Ltd.) and ( 1S, 2S)-(+)-Ν, Ν, -dimethylcyclohexane 1,2-diamin (1.421, manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred at 110 ° C for 23 hours. The reaction mixture was cooled to room temperature, 25% aqueous ammonia solution (0.5 ml, Wako Pure Chemical Industries, Ltd.) was added and stirred, water was further added, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to give 39.5 mg of the title compound. LC-MS: HPLC retention time 5.76 minutes (LC condition 1), m / z 508 (M + H).

 <Example 47> 2- (4- (5-Ethyl-2- (5- (3-methoxy-1-propyl) thiophen-2-yl) -6-methylpyrimidine-4-ylamino) phenol) Ethyl acetate

The compound of Example 46 (22.9 mg) was dissolved in benzene (0.3 ml), dichlorobis (triphenylphosphine) palladium (3.2 mg, manufactured by Aldrich), methylpropargyl ether (7.6 μ1, Aldrich) and triethylamine. (0.1 ml, Wako Pure Chemical Industries, Ltd.) was stirred at room temperature for 21 hours. The residue obtained by concentrating the reaction mixture was subjected to preparative thin-layer chromatography (hex Sun / ethyl acetate = 5/1) gave 7.9 mg of the title compound. LC-MS: HPLC retention time 5.56 min (LC condition 1), m / z 450 (M + H).

 <Example 48> 2- (4- (5-Ethyl-2- (5- (3-methoxypropyl) thiophene) -2-yl) -6-methylpyrimidine-4-ylamino) phenol) acetic acid Yetil

 The compound of Example 47 (7.9 mg) was dissolved in methanol (0.5 ml), and sodium hydroxide palladium (2 mg, Pd type, manufactured by EN Chemcat) was added and stirred for 13 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with ethyl acetate and chloroform, and concentrated to give 8. lmg of the title compound. LC-MS: HPLC retention time 4.47 minutes (LC condition 1), m / z 454 (M + H).

<Example 49> 2- (4- (5-Ethyl-6-methyl-2- (5- (3- (methylamino) propyl) thiophen-2-yl) pyrimidine-4-ylamino) phenol) Ethyl acetate

 2- (4- (5-Ethyl-6-methyl-2- (5- (3-oxopropyl) thiophen-2-yl) pyrimidine-4-ylamino) fur) acetyl acetate (15 mg) in methanol (1.5 1 ml), add palladium hydroxide (5 mg, Pd type) and benzylmethylamine (8.8 μ1, Tokyo Kasei Co., Ltd.) under a hydrogen atmosphere of 3.4 to 4 atm. For 24 hours. The reaction mixture was filtered through celite, washed with methanol and concentrated to give 20 mg of the title compound. LC-MS: HPLC retention time 3.73 min (LC condition 1), m / z 453 (M + H).

<Method for producing intermediate used in Examples 28-49>

The production methods of the intermediates in Examples 28 to 49 are shown in Table 2. The meanings of the symbols in Table 2 are as shown below. “Exp.”: Example number, “Ref.” Production method of the corresponding intermediate. The symbols in the Ref. Column indicate the production method of the intermediate as follows. “A”: the production method shown in Reference Example 1, “B”: the production method shown in Reference Example 2, “C”: the production method shown in Reference Example 3, “D”: shown in Reference Example 4 Production method, “E”; production method shown in Reference Example 5, “F”; production method shown in Reference Example 6, “G”; production method shown in Reference Example 7, “H”; Production method shown, “I”; Production method shown in Reference Example 9, “; Production method shown in Reference Example 10,“ K ”; Production method shown in Reference Example 11,“ L ”; Reference Example 12 Production method shown, “M”: Production method shown in Reference Example 13, “N”: Production method shown in Reference Example 14, “0”; Production method shown in Reference Example 15, “P”; Reference Production method shown in Example 16, “Q”; Production method shown in Reference Example 17, “R”; Production method shown in Reference Example 18, “S”; Production method shown in Reference Example 19, “T” "; The production method shown in Reference Example 20," U "; shown in Reference Example 21 Production method, “V”; production method shown in Reference Example 22, “W”; production method shown in Reference Example 23, “X”; production method shown in Reference Example 24, “Y”; Reference Example 25 “A”; production method shown in Example 1, “b”; production method shown in Example 28, “c”; production method shown in Example 29, “d”; Production method shown in Example 30, “e”; Production method shown in Example 31, “f”; Production method shown in Example 32, “g”; Production method shown in Example 33, “h” "Production method shown in Example 34," i "; Production method shown in Example 35," j "; Production method shown in Example 36," k "; Production method shown in Example 37, “1”: production method shown in Example 38, “m”: production method shown in Example 39, “n”: production method shown in Example 40, “o”: production shown in Example 41 The production method shown in Example 42, “q”; The production method shown in Example 43, “r”; Production method shown in 44, “s”; production method shown in Example 45, “t”; production method shown in Example 46, “u”; production method shown in Example 47, “v”; The production method shown in Example 48, “w”; the production method shown in Example 49.

[Table 2]

<Examples 50 to 267>

The production of the compounds of Examples 50 to 267 is shown below. Details of Examples 50 to 267 are shown in Table 3. The meanings of the symbols in Table 3 are as shown below. “E xp.”; Example number, “Str.”; Example compound, “RT”; Retention time of liquid chromatography in LCMS (minutes), “LC”; “MS”: LCMS mass spectral data, “Ref.” Corresponding intermediate production method, “Ex.” Corresponding example compound production method. The symbols in the Ref. Column and Ex. Column indicate the manufacturing method as follows. “A”: production method shown in Reference Example 1, “B”: production method shown in Reference Example 2, “C”: production method shown in Reference Example 3, “D”: production shown in Reference Example 4 “E”; production method shown in Reference Example 5, “F”; production method shown in Reference Example 6, “G”; production method shown in Reference Example 7, “H”; Manufacturing method shown, “I”; manufacturing method shown in Reference Example 9, “; manufacturing method shown in Reference Example 10,“ K ”; manufacturing method shown in Reference Example 11,“ L ”; Manufacturing method shown, “M”; manufacturing method shown in Reference Example 13, “N”; manufacturing method shown in Reference Example 14, “0”; manufacturing method shown in Reference Example 15, “P”; Reference Example Production method shown in 16, “Q”; production method shown in Reference Example 17, “R”; production method shown in Reference Example 18, “S”; production method shown in Reference Example 19, “T”; Production method shown in Reference Example 20, “U”; Production method shown in Reference Example 21, “V”; Production shown in Reference Example 22. “W”: production method shown in Reference Example 23, “X”: production method shown in Reference Example 24, “Y”: production method shown in Reference Example 25, “a”; shown in Example 1 Manufacturing method shown in Example 28, “c”; manufacturing method shown in Example 29, “d”; manufacturing method shown in Example 30, “e”; “F”; production method shown in Example 32, “g”; production method shown in Example 33, “h”; production method shown in Example 34, “i”; The production method shown in Example 35, “j”; the production method shown in Example 36, “k”; the production method shown in Example 37, “1”; the production method shown in Example 38, “ m ”: production method shown in Example 39,“ n ”: production method shown in Example 40,“ o ”: production method shown in Example 41,“; production method shown in Example 42, ” “Q”: production method shown in Example 43, “r”; production method shown in Example 44, “s”; “T”; the production method shown in Example 46, “u”; the production method shown in Example 47, “v”; the production method shown in Example 48, “w”; The manufacturing method shown in Example 49.

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<Reference Example 26> 4-Black mouth-2- (4-Ethoxythiophen-2-yl) -5-ethyl-6-methylpyrimidine

5- (4-Chloro-5-ethyl-3-ethylpyrimidin-2-yl) thiophen-3-ol (49.1 mg) was dissolved in tetrahydrofuran (2 mL), and ethanol (35) was added to this solution. Triphenylphosphine (159 mg) was added. Diisopropylpropenoreazodicarboxylate (120 / z L) was added dropwise at 0 ° C under a nitrogen atmosphere, and the mixture was stirred at 0 ° C for 5 minutes and further stirred at room temperature overnight. Distilled water (1 mL) was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and the organic layer was washed with anhydrous magnesium sulfate. After drying with Nesmu and concentrating, 43.5 mg of the title compound was obtained.

 <Reference Example 27> 4-Black mouth-5-ethyl-2- (5-chloromethylthiophen-2-yl) -6-methylbilimidine

 The compound of Reference Example 22 (61 mg) was dissolved in phosphorus oxychloride (4 mL) and stirred at 100 ° C. for 2.5 hours under a nitrogen atmosphere. Concentrate the reaction mixture, add saturated aqueous sodium hydrogen carbonate solution (5 mL) and water (25 mL) to the residue, extract with ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and concentrate to give 62 mg of the title compound. Got.

 <Reference Example 28> 4-Chlomouth-5-ethyl-2- (5-dimethylaminomethylthiophen-2-yl) -6-methylpyrimidine

 Dissolve the compound of Reference Example 27 (32 mg) in tetrahydrofuran / Ν, Ν-dimethylformamide = 1/1 (6 mL), triethylamine (76 / zg, manufactured by Wako Pure Chemical Industries), potassium carbonate (75 mg, Wako Pure Chemical Industries, Ltd.) And a solution of dimethylamine in tetrahydrofuran (2.0 M, 2.19 mL, manufactured by Aldrich) and stirred at 50 ° C. for 61 hours. Water (25 mL) was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained residue was subjected to preparative thin layer chromatography (black mouth form / methanol = 20/1) to obtain 9 mg of the title compound. <Reference Example 29> Methyl 2- (3-fluorophenyl) acetate

 2- (3-Fluorophenyl) acetic acid (5.53 g, manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in methanol (11 ml), concentrated hydrochloric acid (1.1 ml) was added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated and then applied to a silica gel column (hexane / ethyl acetate = 9/1 to 4/1) to obtain 5.61 g of the title compound.

<Reference Example 30> Methyl 2- (3-fluoro-4-trifluoro) acetate

 Methyl 2- (3-fluorophenyl) acetate (10.76 g) was dissolved in concentrated sulfuric acid (16.5 ml), cooled to 0 ° C., concentrated nitric acid (2.99 ml) was added, and the mixture was stirred for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The obtained residue was applied to a silica gel column (hexane / ethyl acetate = 93/7 to 79/21) to obtain 1.18 g of the title compound.

<Reference Example 31> Methyl 2- (4-amino-3-fluorophenyl) acetate

2- (3-Fluoro-4-trifluoro) acetic acid methyl (532.1 g) and nickel chloride (37.0 mg) were dissolved in methanol (26.6 ml), cooled to 0 ° C, and then sodium borohydride (354.2mg) 3 times After adding in portions, the mixture was stirred for 1 hour. The reaction mixture was saturated with saturated aqueous sodium hydrogen carbonate, and the reaction was stopped, followed by extraction with ethyl acetate. The obtained residue was subjected to preparative thin-layer chromatography (black mouth form / methanol = 99/1 X 2) to obtain 312.0 mg of the title compound. <Reference Example 32> 4- (2- (5-Bromothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) -N- (2-methoxypropane-2-yloxy) benzamide

 (1-Methoxy-1-methylethyl) oxyamine obtained by a method described in known literature (Tetrahedron 1988, 44, 6013-6020.) Was dissolved in Ν, Ν-dimethylformamide (2 mL), and 4- (2- (5-Bromothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) benzoic acid (50 mg), triethylamine (22 g, manufactured by Wako Pure Chemical Industries), 1-ethyl chloride -3- (3-Dimethylaminopropyl) carbodiimide (30 mg, manufactured by Dojindo) and 1-hydroxybenzotriazole (21 mg, manufactured by Nacalai Testa) were sequentially added and stirred for 24 hours. Water (50 mL) was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting residue was subjected to column chromatography (black mouth form / methanol = 19/1) to obtain 40 mg of the title compound.

<Reference Example 33> 2- (3-Methyl-4-nitrofuryl) acetic acid

2- (3-Methyl-4--trifluoro) acetonitrile (232.4 mg) synthesized according to the method described in known literature (J. Org. Chem. 1995, 60, 6389-6396) was added to concentrated sulfuric acid (5 ml). After dissolution, water (5 ml) was added, and the mixture was stirred at 115 ° C for 1 hour 30 minutes. The reaction mixture was allowed to cool to room temperature, poured into ice water, and extracted three times with black mouth form. The organic layer was dried over sodium sulfate and then concentrated to obtain 226.6 mg of the title compound.

 <Reference Example 34> 4-Bromo-5-methylthiophene-2-carboxaldehyde

5-Methylthiophene-2-carboxaldehyde (1.01 g, manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in acetic acid (6 ml), and a solution of bromine (512 1) dissolved in acetic acid (6 ml) was slowly added dropwise in the dark. . The reaction mixture was stirred at room temperature for 18 hours, then slowly transferred to a saturated aqueous sodium hydrogen carbonate solution (100 ml), extracted with jetyl ether (50 ml), washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and water, and then with magnesium sulfate. Dried. The residue obtained by concentrating the organic layer was subjected to column chromatography (hexane / ethyl acetate = 20/1) to give 775 mg of the title compound. <Reference Example 35> 2-Methoxy-acetoethyl acetate

 Boron trifluoride jetyl ether complex (1.27 mL, Tokyo Chemical Industry Co., Ltd.), acetoacetate acetate (1.28 mL, Tokyo Chemical Industry Co., Ltd.) in a methanol (40 mL) suspension of podosobenzene (2.20 g, Tokyo Chemical Industry Co., Ltd.) And the mixture was stirred for 6.5 hours under a nitrogen atmosphere. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution (20 mL) was added, extracted with dichloromethane, dried over magnesium sulfate and concentrated. The resulting residue was subjected to column chromatography (hexane / ethyl acetate = 5/1) to obtain 1.27 g of the title compound.

 <Reference Example 36> Methyl 2- (4- (tert-butoxycarbol) -2-nitrophenyl) acetate 2- (4-Bromo-2--trophenyl) synthesized according to a known methyl esterification method Methyl acetate (1.1662 g) is dissolved in 1,4-dioxane (40 ml), cesium carbonate (1.9398 g), tris (benzylideneacetone) dipalladium (0) (393.7 mg), xantphos (991.4 mg, commercially available) Product) and tertiary butyl carbamate (506.7mg). The mixture was stirred at 100 ° C for 17.5 hours under a nitrogen atmosphere. Methylene chloride was added in large excess, followed by filtration. The reaction mixture was concentrated and then subjected to silica gel column (hexane / ethyl acetate = 4/1 to 2/1) to obtain 1.0659 g of the title compound.

<Reference Example 37> Methyl 2- (4-amino-2-nitrophenol) acetate

 Methyl 2- (4- (tert-butoxycarbol) -2-nitrophenyl) acetate (202.6 g) was dissolved in 4N ethyl acetate solution (4.72 ml) and stirred at room temperature for 3 hours. Jetyl ether was added to the reaction mixture, and the precipitated solid was separated by filtration and washed with jetyl ether. The obtained residue was dried under reduced pressure to obtain 118.9 mg of the title compound.

Reference Example 38> 2- (2-Methoxy-4-trophenyl) acetonitrile

1-bromo-2-methoxy-4-trobenzene (3.99 g, manufactured by Wako Pure Chemical Industries, Ltd.), tris (benzylideneacetone) dipalladium (0X207.3 mg), xanthophos (259.0 mg, commercially available), In a nitrogen atmosphere, a solution of trimethylsilylacetonitrile (2.9523 g, Aldrich) dissolved in DMF (25 ml) was added. After stirring at room temperature for a while, zinc fluoride (1.3231 g, manufactured by Aldrich) was added, and the mixture was stirred at 90 ° C. for 8 hours under a nitrogen atmosphere. The mixture was concentrated and then applied to a silica gel column (hexane / ethyl acetate = 4/1 to 2/1) to obtain 1.0346 g of the title compound.

<Reference Example 39> Ethyl 2- (methylthio) thiazole-5-carboimidate

Dissolve 2-bromothiazole-5-carbo-tolyl (300 mg) in ethanol (10 mL) at room temperature Sodium thiomethoxide (334 mg, manufactured by Aldrich) was stirred for 4 hours. The reaction mixture was concentrated, water (50 mL) was added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography (hexane / ethyl acetate = 1/1) to obtain 23 lmg of the title compound.

 <Reference Example 40> 5- (Bromomethyl) -2- (5-chlorothiophen-2-yl) -6-methylpyrimidin-4 (3H) -one

 2- (5-Chlorothiophene-2-yl) -5,6-dimethylpyrimidin-4 (3H) -one (499.5 mg) and N-bromosuccinimide (444.4 mg) and 2-2, -azobis (Isobutiguchi-tolyl) (34.0 mg) was dissolved in vigorous tetra-carbon carbon (10 ml), heated to 100 ° C. and stirred for 2 hours. The reaction mixture was filtered while hot and then washed with chloroform. The obtained residue was dried under reduced pressure to obtain 468.4 mg of the title compound.

 <Example 268> 4- (2- (5-Bromothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) -N-hydroxybenzamide

 The compound of Reference Example 32 (40 mg) was dissolved in methanol (2 mL), 2N hydrochloric acid (79 L, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture was washed with a mixed solvent of diethyl ether and methanol to obtain 22 mg of the title compound. LC- MS: H PLC retention time 4.00 min (LC condition 1), m / z 433 (M + H).

 <Example 269> 2- (4- (2- (5-Chromium-4-methylthiophen-2-yl) -5,6-jetylpyrimidine-4-ylamino) phenol) ethyl acetate

 2- (4- (2- (5-Bromo-4-methylthiophen-2-yl) -5,6-jetylpyrimidine-4-ylamino) phenol) ethyl acetate (5 lmg) It was dissolved in Ν-dimethylformamide (2 mL), copper (I) chloride (2 lmg, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at 110 ° C. for 71 hours under a nitrogen atmosphere. To the reaction mixture was added 28% aqueous ammonia solution (lmL) and water (25mL), extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated. The resulting residue was subjected to column chromatography (hexane / ethyl acetate = 3/1) to obtain 32 mg of the title compound. LC-MS: HPL C retention time 6.94 minutes (LC condition 2), m / z 444 (M + H).

<Example 270> Methyl 2- (4- (2- (5-chlorothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) -2-hydroxyphenyl) acetate 2- (4- (2- (5-Chlorothiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) -2-methoxyphenyl) acetic acid methyl (9.0 mg) in pyridine hydrochloride Salt (191.5 mg) was stirred at 200 ° C for 5 minutes. The reaction mixture is allowed to cool to room temperature, water is added, and the mixture is extracted with ethyl acetate and concentrated. The resulting residue is subjected to preparative thin-layer chromatography (black mouth form / methanol = 90/10) to give the title compound. 4.0 mg was obtained. LC-MS: HPLC retention time 5.01 min (LC condition 1), m / z 41 8 (M + H).

 Example 271 2- (4- (5-Ethyl-6-methyl-2- (5- (methylsulfol) thiophen-2-yl) pyrimidine-4-ylamino) phenol) ethyl acetate

 2- (4- (5-Ethyl-6-methyl-2- (5- (methylthio) thiophen-2-yl) pyrimidine-4-ylamino) phenol) ethyl acetate (75 mg) in dichloromethane (5 mL 3-Chloroperbenzoic acid (66 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture was added 5% aqueous sodium sulfite solution (5 mL) and water (10 mL), extracted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated. The obtained residue was subjected to preparative thin layer chromatography (hexane / ethyl acetate = 1/2) to obtain 49 mg of the title compound. LC-MS: HPLC retention time 5.01 min (LC condition 1), m / z 460 (M + H).

<Example 272> 2- (4- (2- (5- (dimethylamino) -4-methylthiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) methyl acetate

 2- (4- (2- (5-amino-4-methylthiophen-2-yl) -5-ethyl) -6-methylpyrimidine-4-ylamino) phenyl) ethyl acetate (16 mg) 2 mL), 37% formaldehyde solution (48 manufactured by Wako Wako Pure Chemical Industries, Ltd.) and sodium cyanoborohydride (19 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) were added at 60 ° C, and the mixture was stirred as it was for 12 hours. Water (15 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL) were added to the reaction mixture, extracted with black mouth form, washed with saturated brine, dried over magnesium sulfate, and concentrated to give 10 mg of the title compound. LC-MS: HPLC retention time 3.81 minutes (LC condition 1), m / z 425 (M + H).

<Methods for producing intermediates used in Examples 268 to 272>

The production methods of the intermediates used in Examples 268 to 272 are shown in Table 4. The meanings of the symbols in Table 4 are as shown below. “Exp.”: Example number, “Ref.” A corresponding intermediate production method. Symbols in the Ref. Column indicate the production method of the intermediate as follows . “A”: Production method shown in Reference Example 1, “B”: Production method shown in Reference Example 2, “C”: Production method shown in Reference Example 3, “D”: Production shown in Reference Example 4 Method “E”: Production method shown in Reference Example 5, “F”; Production method shown in Reference Example 6, “G”; Production method shown in Reference Example 7, “H”; Reference Example 8 Production method shown, “I”; production method shown in Reference Example 9, “; production method shown in Reference Example 10,“ K ”; production method shown in Reference Example 11,“ L ”; Production method shown, “M”; production method shown in Reference Example 13, “N”; production method shown in Reference Example 14, “0”; production method shown in Reference Example 15, “P”; Reference Example Production method shown in 16, “Q”; production method shown in Reference Example 17, “R”; production method shown in Reference Example 18, “S”; production method shown in Reference Example 19, “T”; Production method shown in Reference Example 20, “U”; Production method shown in Reference Example 21, “V”; Production shown in Reference Example 22. Method, “W”: production method shown in Reference Example 23, “X”: production method shown in Reference Example 24, “Y”: production method shown in Reference Example 25, “Ζ”; shown in Reference Example 26 Production method shown in Reference Example 27, “ΑΒ”; production method shown in Reference Example 28, “AC”; production method shown in Reference Example 29, “AD”; Reference Example 30 “AE”; production method shown in Reference Example 31, “AF”; production method shown in Reference Example 32, “AG”; production method shown in Reference Example 33, “AH”; Production method shown in Reference Example 34, “AI”; Production method shown in Reference Example 35, “AJ”; Production method shown in Reference Example 36, “AK”; Production method shown in Reference Example 37, “AL” ”; Production method shown in Reference Example 3 8,“ AM ”; Production method shown in Reference Example 39,“ AN ”; Production method shown in Reference Example 40,“ a ”; Production shown in Example 1 “B”: the production method shown in Example 28, “c”: the production method shown in Example 29 “D”: production method shown in Example 30, “e”: production method shown in Example 31, “f”; production method shown in Example 32, “g”; production shown in Example 33 "H"; the production method shown in Example 34, "i"; the production method shown in Example 35, "j"; the production method shown in Example 36, "k"; shown in Example 37 Manufacturing method shown in Example 38, “m”; manufacturing method shown in Example 39, “n”; manufacturing method shown in Example 40, “o”; Example Production method shown in 41, “p”; Production method shown in Example 42, “q”; Production method shown in Example 43, “ _r ”; Production method shown in Example 44, “s”; Manufacturing method shown in Example 45, “t”; manufacturing method shown in Example 46, “u”; manufacturing method shown in Example 47, “v”; manufacturing method shown in Example 48, “w” "Production method shown in Example 49," x "; Production method shown in Example 268," y "; Example 269, the production method shown in Example 270, "aa"; the production method shown in Example 271, "ab"; the production method shown in Example 272. [Table 4]

Example 273-389>

The production of the compounds of Examples 273 to 389 is shown below. Details of Examples 273 to 389 are shown in Table 5. The meanings of the symbols in Table 5 are as shown below. “Exp.”; Example number, “Str.”; Example compound, “RT”; Retention time of liquid chromatography in LCMS (min), “LC”; Solvent conditions for liquid chromatography in LCMS, “ MS ”; mass spectral data in LCMS,“ Ref. ”Corresponding intermediate production method, ΓΕχ.” Corresponding example compound production method. The symbols in the Ref. Column and Ex. Column indicate the manufacturing method as follows. “A”: production method shown in Reference Example 1, “B”: production method shown in Reference Example 2, “C”: production method shown in Reference Example 3, “D”: production shown in Reference Example 4 “E”: production method shown in Reference Example 5, “F”: production method shown in Reference Example 6, “G”: production method shown in Reference Example 7, “H”: shown in Reference Example 8 Manufacturing method shown in Reference Example 9, “;” manufacturing method shown in Reference Example 10, “K”; manufacturing method shown in Reference Example 11, “L”; shown in Reference Example 12. Manufacturing method shown in Reference Example 13, “N”; manufacturing method shown in Reference Example 14, “0”; manufacturing method shown in Reference Example 15, “P”; Reference Example 16 “Q”; the production method shown in Reference Example 17, “R”; the production method shown in Reference Example 18, “S”; the production method shown in Reference Example 19, “T”; Production method shown in Example 20, “U”; production method shown in Reference Example 21, “V”; production shown in Reference Example 22. Method, “W”: production method shown in Reference Example 23, “X”: production method shown in Reference Example 24, “Y”: production method shown in Reference Example 25, “Ζ”; shown in Reference Example 26 Manufacturing method shown in Reference Example 27, “ΑΒ”; manufacturing method shown in Reference Example 28, “AC”; manufacturing method shown in Reference Example 29, “AD”; Reference Example Production method shown in 30, “AE”; production method shown in Reference Example 31, “AF”; in Reference Example 32 Production method shown, “AG”; production method shown in Reference Example 33, “AH”; production method shown in Reference Example 34, “AI”; production method shown in Reference Example 35, “”; Reference Example 36 “AK”; the production method shown in Reference Example 37, “AL”; the production method shown in Reference Example 38, “AM”; the production method shown in Reference Example 39, “AN”; The production method shown in Reference Example 40, “a”; the production method shown in Example 1, “b”; the production method shown in Example 28, “c”; the production method shown in Example 29, “d” "Production method shown in Example 30," e "; Production method shown in Example 31," f "; Production method shown in Example 32," g "; Production method shown in Example 33 , “H”; production method shown in Example 34, “i”; production method shown in Example 35, “j”; production method shown in Example 36, “k”; shown in Example 37 “1”; the production method shown in Example 38, “m”; the production method shown in Example 39, “N”: production method shown in Example 40, “o”: production method shown in Example 41, “; production method shown in Example 42,“ q ”; production method shown in Example 43 , “R”; production method shown in Example 44, “s”; production method shown in Example 45, “t”; production method shown in Example 46, “u”; shown in Example 47 Production method, “v”; Production method shown in Example 48, “w”; Production method shown in Example 49, “x”; Production method shown in Example 268, Γ y ”; The production method shown in Example 270, “aa”; the production method shown in Example 271, “ab”; the production method shown in Example 272.

[Table 5]

e

<Example 390> 2- (4- (2- (5- (Difluoromethoxy) thiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) ethyl acetate 2- (4- (2- (5-hydroxythiophen-2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenyl) ethyl acetate (61 mg) was added to Ν, を -dimethyl Dissolve in formamide (4 mL), add lithium carbonate (34 mg, manufactured by Kanto Chemical Co., Inc.) and t-butyl chlorodifluoroacetate (86 mg, manufactured by Apollo) sequentially, and stir at 90 ° C for 1 hour in a nitrogen atmosphere. did. Water (15 mL) was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained residue was subjected to preparative thin layer chromatography (hexane / ethyl acetate = 2/1) to obtain 22 mg of the title compound. LC-MS: HPLC retention time 5.08 min (LC condition 1), m / z 448 (M + H). The raw material 2- (4- (2- (5-hydroxythiophene- 2-yl) -5-ethyl-6-methylpyrimidine-4-ylamino) phenol) ethyl acetate was produced according to the production methods described in the following Reference Examples and Examples. Reference Example 4, Reference Example 5, Reference Example 6, Reference Example 2, Reference Example 3, Reference Example 21, Example 29.

<Examples 391 to 393>

The production of the compounds of Examples 391 to 393 is shown below. Details of Examples 391 to 393 are shown in Table 6. The meanings of the symbols in Table 6 are as shown below. “Ac”: the production method shown in Example 390. The other symbols have the same meaning as in Table 5.

[Table 6]

<Examples 394 to 402>

The production of the compounds of Examples 394 to 402 is shown below. Details of Examples 394-402 Are shown in Table 7. The meaning of the symbols in Table 7 is the same as the meaning of the symbols in Table 6.

[Table 7]

<Test Example 1> PDE4 enzyme activity inhibitory action

(1) Purification of PDE4 from U937 cells

PDE4 enzyme protein was also purified from U937 cells, which are cells derived from lymphoma. Buffer U937 cells with protease inhibitor cocktail (Sigma) (20 mM Tris HCl (pH 6.5), ImM MgCl, 0. ImM EGTA, 3 mM 2-mercaptoethanol

2

 The cells were disrupted by sonication, disrupted by sonication, and ultracentrifuged (100,000G, 30 minutes, 4 ° C) to obtain a soluble fraction. A 1.6 × 25 cm Q Sepharose column equilibrated with Buffer A was packed with the resulting soluble fraction. The packed soluble fraction was eluted with buffer A containing a linear gradient of 0-1M sodium acetate. The elution rate was 1.33 ml Z and 11 ml fractions were collected. Each fraction was examined for cAMP metabolizing PDE activity and the fraction containing PDE4 enzyme protein was determined. It was also confirmed that this PDE4 fraction did not degrade cGMP.

 (2) Measurement of PDE4 enzyme activity inhibitory action

 Test compounds at desired concentrations of 40 mM Tris-HCl (pH 7.4), 5 mM MgCl, 4 mM

 2

The reaction was carried out at 30 ° C. for 10 minutes in a reaction mixture (100 1) containing M 2 -mercaptoethanol, 3 cAMP, 0.83 μCi [ ³ H] —cAMP and PD E4 fractions. The enzyme reaction was stopped by adding triclonal acetic acid 25 1 to the reaction mixture. The reaction solution was packed in a neutral alumina column equilibrated with 0.1M 2-[[Tris (hydroxylmethyl) methyl] amino]-1-ethanesulfonic acid (TES) buffer (pH 8.0) After washing with an amount of 0.1M TES buffer, it was eluted with 2N NaOH. [] —500 1 of the eluate containing 5 ′ AMP product was placed in a scintillation vial containing 5 ml of a scintillation cocktail (Perkin Elma), and the radioactivity was measured. All measurements were made within the linear range of response. As a result, as representatively shown in Table 8, the compound of the present invention, a salt thereof, or a prodrug thereof exhibited an excellent PDE4 activity inhibitory action. PDE4 activity inhibitory action was expressed as an IC50 value (nM). In Table 8, Ex. No. represents the example number.

[Table 8] Εχ.Να 1CS0 (nM)

 3 356

 5 1389

 6 2937

 7 409

 11 1166

 13 186

 15 490

 17 9

 18 1679

 20 191

 23 633

 24 3248

 26 312

 56 61

 59 41

 61 84

 79 117

 82 90

 85 76

 105 116

 155 84E

 185 156

 168 59

 191 90

 192 89

 193 70

 198 105

 201 133

 209 192

 Examples of compounds that showed PDE4 inhibitory activity of 50% or more at a compound concentration of 20 / M are shown below.

 Example number force 0, 57, 58, 59, 60, 78, 81, 83, 84, 86, 96, 101, 103, 110, 111, 116, 120, 128, 133, 146, 147, 148, 154, 159, 169, 175, 180, 21 5, 220, 236, 241, 243, 244, 250, 253, 254, 257, 264, 265

<Test Example 2> Inhibition of TNF-a production using mouse mononuclear cells (in-vitro system) Mouse mononuclear cells were isolated from peripheral blood of C3HZHe mice (Japan SLC, male) and 10% bovine serum Suspended in a culture solution (RPMI1640; GIBCO). Cells to 96-well plate The test compound was added to a desired concentration and left in a 37 ° C, 5% CO incubator for 15 minutes. Then LPS at a final concentration of 5 gZml

 2

 And left in the incubator for 21 hours.

[0156] The culture medium containing the produced TNF-a was collected and measured with a mouse TNF-a measurement ELISA kit (R & D System) according to the attached protocol. As a result, as representatively shown in Table 9, the compound of the present invention, a salt thereof, or a prodrug thereof exhibited an excellent TNF-production inhibitory action. The inhibitory effect on TNF- _α production was expressed as an IC50 value (nM). In Table 9, “V” and “Ex. No.” represent example numbers.

[0157] [Table 9]

1 16 10

 127 72

 129 85

 148 676

 157 80

 181 57

 186 80

 188 46

 191 44

 193 39

 203 86

 220 59

 221 53

 234 48

 253 504

<Test Example 3> Effect on gastric acid secretion

 According to the method of BergLindh and Obrink (Acta Physiol. Scand, 97: 401-414, 1976) and Sack and Speney (Am J. Physiol. 243: G313-G319, 1982) (as an indicator of side effects) A test for secretion capacity was performed.

 That is, gastric glands were collected by collagenase enzyme treatment using male rabbits (Japanese white species, oriental yeast).

[0159] Test compound, ¹⁴ C-Aminopyrine (1.0 nmol / ml; 0.1 μ Ci / nmol), and histamine (0.3-1.0

 M) Incubate for a certain period of time in the presence, centrifuge and wash, then dissolve the gastric gland cell pellet with 100 μl IN-ΚΟΗ and place in a scintillation vial containing 3 ml of a scintillation cocktail (Perkin Elma). Activity was measured. The gastric acid secretion ability by the test compound was calculated as an EC50 value, and the ratio of the TNFa production inhibition IC50 value described in Test Example 2 (deviation A) was determined by the following formula. A larger value of the degree of deviation A is more preferable. As a result, as representatively shown in Table 10, the compound of the present invention, a salt thereof, or a prodrug thereof exerted less gastric acid secretion than the TNFa production inhibitory effect. In Table 10, Ex.No. represents the example number.

[0160] Deviation A = Gastric acid secretion capacity EC50 value ZTNFa production inhibition IC50 value [0161] [Table 10]

<Test Example 4> Inhibition of TNF- _α production induced by LPS in mice (in-vi vo system)

 C3HZHe mice (Enomoto SLC, male) were used as experimental animals. The desired concentration of test compound was suspended in a 0.5% methylcellulose solution. Mice were weighed and the test compound solution was orally administered in a volume of lOmlZkg, and the control group received only 0.5% methylcellulose solution. The number of animals per group was 5-7. LPS was dissolved in physiological saline and 10 g was intraperitoneally administered to each mouse. The test compound was administered first, and LPS was administered 60 minutes later. Ninety minutes later, blood was collected from the abdominal vena cava in the presence of heparin, and plasma was obtained by centrifugation. The plasma TNF-protein content was measured with the mouse TNF-α measurement ELISA kit (R & D System) according to the attached protocol. As a result, as representatively shown in Table 11, the compound of the present invention, a salt thereof, or a prodrug thereof exhibited an excellent TNF-a production inhibitory action. The inhibitory effect on TNF-a production was expressed as an ED50 value (mg / kg). In Table 11, “Ex.No.” represents an example number.

[0162] [Table 11] Ex. No. ED50 (mg / kg)

 1 1 26

 15 13

 17 3

 18 37

 57 24

 59 6

 83 22

 86 8

 58 8

 84 17

 103 37

 110 31

 111 15

 116 12

 128 24

 133 27

 148 12

 205 21

 220 41

 221 24

 238 20

 239 22

 241 39

 253 14

 254 38

 293 18

 274 25

 289 18

 292 25

 344 27

 345 37

 373 19

 376 12

 386 50

<Test Example 5> Mouse gastric emptiness test (in-vivo system)

C3H, He mice (Japan SLC, male) fasted for 21-24 hours were used as experimental animals. The desired concentration of test compound was suspended in a 0.5% methylcellulose solution. The body weight of the mice was measured, and the test compound solution was orally administered in a volume of lOmlZkg, and only 0.5% methylcellulose solution was administered to the control group. The number of animals per group was 5. As the test meal solution, a 1.5% methylcellulose solution containing 0.05% phenol red was used. First, the test compound was administered, and 60 ml later, 0.2 ml of test meal was orally administered. Further, 15 minutes after that, the stomach was taken out so that the test meal did not leak, homogenized in 10 ml 0. IN NaOH, and the tissue was removed by centrifugation. To 5 ml of the supernatant, 0.5 ml of 10% trichloroacetic acid was added, followed by centrifugation to remove proteins. A solution obtained by adding 2N NaOH 125 1 to 1 ml of the supernatant obtained by this centrifugation was measured with a spectrophotometer (550 nm), and the gastric force was also expressed as an IC50 value (mgZkg) indicating inhibition of transport to the small intestine. As a result, the compound of the present invention, a salt thereof, or a prodrug thereof showed a divergence between the drug effect and the side effect of vomiting, indicating that there are few side effects. For example, the compound of Example No. 17 has an IC50 value of 14 mgZkg, which is 4.7 times as large as the TNF-supplement inhibition shown in Table 11. In addition, the IC50 value of the compound of Example No. 148 was 85 mgZkg, showing a 7.1-fold deviation from the TNF production inhibition shown in Table 11. In addition, Example No. 253, 373, 376, etc. showed the same degree of deviation as Example 17.

<Test Example 6> Vomiting effect using ferret

A male marshall ferret (body weight: 1 to 1.5 kg, Nippon Chirurus' River) was used as an experimental animal. The desired concentration of test compound was suspended in 0.5% methylcellulose solution. The body weight of the ferret was measured, the test compound solution was orally administered in a volume of 1 to 8 mlZkg, and the control group was administered with only 0.5% methylcellulose solution. The number of animals per group was 4. For vomiting behavior observation, we observed the behavior of vomiting and vomiting by observing the behavior for more than 6 hours using an observation board made of acrylic plate. As a result, it was found that the compound of the present invention, a salt thereof, or a prodrug thereof showed a difference between the drug effect and the side effect of vomiting and had few side effects. For example, the mouse TNFa production inhibition ED50 value shown in Table 11 for the compound of Example No. 17 was 3 mgZkg. The emesis caused by ferrets was not observed even at 50 mgZkg. Similarly, the inhibition of mouse TNFa production shown in Table 11 for the compound of Example No. 148 was ED50 value of 12 mg / kg. The emesis expression by ferret was lOOmgZkg. But it was not observed.

Claims

The scope of the claims

 The following general formula (1)

[Chemical 43] 2

[In the general formula (1), Ar ¹ is a furyl group, Choi - group, Toriazoriru group, a thiazolyl group, Okisazo Lil group, or base indicates Nzochiazoriru group; Ar ¹ may be substituted; Ar ² is - E—Ar ² GQ (Ar ²¹ represents a benzene ring or a naphthalene ring; E represents a single bond or an alkylene group; G represents a single bond, an alkylene group or an alkylene group; Q represents a carboxy group, — CON (R ⁴¹ ) (R ⁴² ) (R ⁴¹ and R ⁴² may be the same or different, and each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group, or a substituted one. The force indicating a loyalyl group, or R ⁴¹ and R ⁴² together form a 3- to 7-membered ring, and N (R ⁴¹ ) (R ⁴² ) represents a cyclic amine, provided that R ⁴¹ is a hydroxyl group R ⁴² is a group other than a hydroxyl group), or —COOR ⁴³ (R ⁴³ is an optionally substituted alkyl group or Represents an optionally substituted aryl group))), E—Ar ²¹ — G ² — GQ (E, Ar ²¹ , G, Q are as defined above, G ² is one O, 1 S, 1 SO, 1 SO—, or 1 NR ^G21

 2

1 (R ^G21 represents a hydrogen atom, an ^optionally substituted alkyl group, an optionally substituted acyl group, or an optionally substituted sulfonyl group). Or Ar ² may be substituted; R ¹ and R ² may be the same or different and each independently , A hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted group A good alkylthio group, substituted, may be an alkylsulfier group, or substituted !, may! / Represents an alkylsulfonyl group, and R ³ may be a hydrogen atom or substituted An alkyl group is shown. ], Possible stereoisomers or racemates thereof, or pharmacologically acceptable Salts, hydrates, solvates, or prodrugs thereof.

[2] Ar ¹ may be substituted and may be [furyl group or chael group], the compound according to claim 1, its possible stereoisomer or racemate, or its pharmacological Acceptable salts, hydrates, solvates, or prodrugs thereof.

[3] Ar ¹ is [halogen atom, substituted !, may be alkyl group, substituted, alkyloxy group, optionally substituted alkylthio group, optionally substituted amino group; The compound according to claim 1 or 2, which may be substituted by one or a plurality of groups each independently selected from the group consisting of an acyl group] force, and its possible stereoisomerism Or racemate, or a pharmacologically acceptable salt, hydrate, solvate, or prodrug thereof.

[4] The compound according to any one of claims 1 to 3, wherein R ¹ is a lower alkyl group, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt, hydrate, or solvent thereof. Japanese or prodrugs of these.

[5] The compound according to any one of claims 1 to 4, wherein R ² is a lower alkyl group or a lower alkenyl group, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt thereof, Hydrates, solvates, or prodrugs thereof.

[6] The compound according to any one of claims 1 to 5, wherein R ³ is a hydrogen atom, possible stereoisomers or racemates thereof, or a pharmaceutically acceptable salt, hydrate, or solvent thereof. Japanese or these prodrugs.

[7] The compound according to any one of claims 1 to 6, wherein Ar ² is —E—Ar ²¹ —G—Q (E, Ar ²¹ , G, Q are as defined above), and possible steric thereof Isomers or racemates, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof.

[8] The compound according to any one of claims 1 to 7, wherein Ar ²¹ is a benzene ring, possible stereoisomers or racemates thereof, or pharmaceutically acceptable salts, hydrates thereof, Solvates or their prodrugs.

[9] The compound according to any one of claims 1 to 8, wherein E is a single bond, and [G is a single bond or a lower alkylene group], possible stereoisomers or racemates thereof, or drugs thereof Physiologically acceptable salts, hydrates, solvates, or prodrugs thereof. [10] The compound according to any one of claims 1 to 9, wherein E is a single bond, and G is a lower alkylene group, possible stereoisomers or racemates thereof, or pharmacologically acceptable conditions thereof. Salts, hydrates, solvates, or prodrugs thereof.

 [11] Q is a carboxy group. The compound according to any one of LO, its possible isomer or racemate, or a pharmaceutically acceptable salt, hydrate, solvent thereof Japanese or these prodrugs.

[12] Ar ² is to one or more groups chosen each independently from the group consisting of [hydroxyl group, a halogen atom, is replaced! I alsoヽ, alkyl group, and an alkoxy group which may be substituted] Or a substituted isomer, or a possible stereoisomer or racemate thereof, or a pharmaceutically acceptable salt or hydrate thereof. , Solvates, or prodrugs thereof.

[13] Ar ¹ is a chael group, and Ar ¹ is a [halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, a substituted Te, I also, Amino groups and substituted, by also, Yogu Ar ² optionally substituted by one or more groups selected each independent from Ashiru radical forces also the group is -! E —Ar ²¹ — GQ, Ar ²¹ is a benzene ring or a benzene ring substituted with one or more halogen atoms, E is a single bond, G is a methylene group, and Q is a carboxy group Further, Ar 2 has no further substituent, R ¹ is a methyl group or an ethyl group, R ² is an aryl group, an ethyl group, or a hydroxymethyl group, and R ³ is a hydrogen atom. The compound according to 1, a possible stereoisomer or racemate thereof, or a drug thereof Physically acceptable salts, hydrates, solvates, or prodrugs thereof.

[14] Ar ¹ is a [norogen atom, lower alkyl group, trifluoromethyl group, hydroxymethyl group, hydroxychetyl group, lower alkoxy group, trifluoromethoxy group, 2-methoxyethoxy group, 1 NH group, lower group Alkylamino group, lower dialkylamino group, acylamino group, lower

2

The compound according to claim 1, its possible stereoisomer or racemate, each substituted with one or more groups independently selected from the group consisting of an alkylsulfonylamino group] Or a pharmacologically acceptable salt, hydrate, solvate or prodrug thereof. [15] The compound according to any one of claims 1 to 14, its possible stereoisomer or racemate, or a pharmaceutically acceptable salt, hydrate, solvate thereof, or a prodrug thereof As an active ingredient.

16. The medicament according to claim 15, which is a preventive and Z or therapeutic agent for inflammation.

17. The medicament according to claim 15, which is a preventive and Z or therapeutic agent for chronic obstructive pulmonary disease.

[18] The compound according to any one of claims 1 to 14, its possible stereoisomer or racemate

Or a pharmacologically acceptable salt, hydrate, solvate thereof, or a PDE4 activity inhibitor containing these prodrugs as an active ingredient.