TW200918065A - Imidazopyridazine derivatives - Google Patents

Abstract

The present invention provide a novel low molecular compound with TNF- α production inhibiting activity, useful as the therapeutic agent for an inflammatory disease and / or an autoimmune disease and having the oral administration possibility. The present invention relates to a compound of the following formula(I) [wherein R1 represents a group of the formula -X1-X2, X1 represents a single bond etc.; X2 represents a C1-C6 alkyl group, R2 represents a hydrogen atom etc., R3 represents a group of the formula alkylene- Y, Y represents an amino group etc., R4 represents a group of the formula -Z1-Z2, Zl represents an alkylene group or a group of the formula alkylene -O-alkylene, Z2 represents an amino group etc.,], the salt or the solvate thereof.

Description

200918065 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a TNF-o: production inhibitor having a novel imidazo[1,2-b] arable structure. [Prior Art] Tumor Necrosis Factor-alpha (TNF-a) is one of inflammatory cytokinins reported to exhibit a variety of physiological activities. It is known that TNF-q: excessive production is greatly involved in inflammation such as rheumatoid arthritis (sickness and/or progression of disease-causing diseases and/or autoimmune diseases. Excessive TNF-α is involved in joint rheumatism, Bechet , disease, allergic dermatitis, atopic dermatitis, bronchial asthma, sepsis, inflammatory bowel disease, dryness, thrombosis, hepatitis, diabetes, chronic obstructive pulmonary disease, cerebral infarction and other inflammatory diseases and / or In the case of the report of the body's immune disease, the agent which exhibits the inhibitory effect of TNF-α is expected to be useful as a therapeutic and/or preventive agent for various inflammatory diseases and autoimmune diseases. ί In recent years, various inflammatory diseases and/or self The body immune disease is treated by a biological agent having an anti-TNF-α action in a clinical trial. As a result, an eUnercept, Immunex/Wyeth ', and an anti-TNF-α chimera belonging to a fusion protein belonging to a soluble TNF-α receptor are known. Human and mouse antibodies to infliximab, Centocor' are shown to be highly effective in the treatment of rheumatoid arthritis, and these biological agents are also effective in the treatment of Crohn's disease (non-patented) 1). It is therefore very important to prove that TNF-α is the molecular standard of the drug. 200918065 The biological agents have high clinical effects, and the cost of the drug is extremely high. Oral absorption, oral administration can not be effective, it is necessary to inject intravenous or subcutaneous administration and other cumbersome investment methods. There are also indications of side effects such as infectious diseases or malignant tumors. A low molecular compound which has a high clinical effect and can be orally administered to inhibit TNF-α production. Conventionally, as a compound having an inhibitory effect on TNF-α production, there is an anilinopyrimidine derivative (Patent Document 1) , imidazo[1,2-a]quinoxaline derivative (Non-Patent Document 2), 1,4-dihydro-2H-pyrido[2,3-d][l,3]噚耕-2 -ketone derivative (Non-Patent Document 3), 1-(pyrazol-3-yl)-3-(naphthalen-1-yl)urea derivative (Non-Patent Document 4), 4-phenyl-5-pyridine- 1,3-thiazole derivative (Non-Patent Document 5), 2-phenyl-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydropyridine·4-ylpyrrole derivative (Non-Patent Document 6) and the like. Although there are several reports of physiologically active imidazo[1,2-b]indole derivatives, there is no inhibition of TNF-α production (Patent Documents 2 to 6, Non- [Patent Document 1 to 9] [Patent Document 1] Japanese Patent Application Laid-Open No. 2004-523479 (Patent Document 2) International Publication No. 2005/066 1 77 pp. [Patent Document 3] US Patent Application Publication No. 2004/0067948 [Patent Document 4] International Publication No. 2007/0 1 357 pp. [Patent Document 5] International Publication No. 2007/025090 Booklet [Patent Document 6] US Patent Application Publication No. 2007/0093490 No. 200918065 Specification [Non-patent Document 1] Exp. Opin_Invest_Drugs, Jan 9(l): 103-11 (2000) [Non-Patent Document 2] J. Biol. Chem_, 27 8 (3), 1 450 - 1 45 6 (2003) [Non-Patent Document 3 Br.hPharmacol., 145(2), 1 78- 1 92 (2005) [Non-Patent Document 4] J. Med. Chem., 46(22), 4676-4686 (2003) [Non-Patent Document 5] J [Med. Chem., 48 (19), 5966-5979 (2005) [Non-Patent Document 6] Eur_J. Pharmacol., 506, 285-295 (2005) [ [Non-Patent Document 7] J. Med. Chem., 48 ( twenty four) , 7604-76 1 4 (2005) [Non-Patent Document 8] J. Med. Chem., 46 (20), 433 3-434 1 (2003) [Non-Patent Document 9] J. Med. Chem., 44 ( 3), 350-36 1 (200 1 ) [Summary of the Invention] (Problems to be solved by the invention) The present invention provides an in vivo mode of exhibiting high TNF-〇: an inhibitory effect, as an inflammatory disease and/or an autoimmune disease. Therapeutic agents are useful and novel low molecular compounds that can be administered orally are the subject. 1/ (Means for Solving the Problem) In order to solve the above problems, the inventors of the present invention have found a novel compound having a structure of imipenem [l,2-b] oxime in a mouse in vivo mode. The present invention has finally been completed by oral administration and the action of reducing TNF-〇 in the blood of mice, and as an active ingredient of a therapeutic agent for inflammatory diseases and/or an autoimmune disease agent which can be administered orally. That is, the present invention provides: [1] a compound represented by the following formula (I), a salt thereof or a solvate thereof: (i) (i) 200918065

Wherein R1 is a group represented by Cl~C6 alkyl-X1-X2, wherein XI is a single bond, 0, S, S〇 or s〇2, and X2 is a C1 to C6 alkyl group, and the C1 to C6 are used in the C1 to C6 The alkyl group represented by the alkyl group - X b X2 may have a substituent selected from the group consisting of a halogen group, a C1 to C6 alkoxy group and a halogenated group C1 to a C6 alkoxy group, and the substituents are the same or different. It may be selected from the group consisting of a hydrogen atom, a halogen group, a hydroxyl group, a carboxyl group, an amine group, a C1 to C6 alkylamino group, an amine carbenyl group, a C1 to C6 alkylamine carbenyl group, and a C1 to C6 alkanoyl group. 1 or 2 groups, R3 is a group represented by C1 to C6 alkyl-Y, wherein Y is an amine group, a C1 to C6 alkylamino group or a 3 to 6 member nitrogen-containing heterocycloalkyl group, and the 3 to 6 The nitrogen-containing heterocycloalkyl group may have the same or different halo group, hydroxy 'C1 to C6 alkyl group, C1 to C6 alkoxy group, halogen C1 to C6 alkoxy group, carboxy C1 to C6 alkoxy group, hydroxy C1. The group selected from the group consisting of a C6 alkyl group and a carboxy group C1 to C6 alkyl group is 1 to 3 substituents, and R4 is a group represented by Z1 to Z2, wherein Z1 is a C1 to C6 alkylene group or a C1 to C6 alkylene group. - Ο-Cl~C6 alkyl group represented by the alkyl group, or a C1~C6 alkyl group or a C1~C6 alkyl group - Ο-Cl~C6 alkyl group C 3~C6 cycloalkyl substituted '-9-200918065 Z2 is an amine group, a Cl~C6 alkanoguanamine group, an amine methyl sulfhydryl group, a Cl~C0 amphetamine group, a hydroxyl group, a carboxyl group, a phenyl group or a 4 to 10 member. The heterocyclic group of the monocyclic or fused ring, the heterocyclic group of the phenyl group or the monocyclic or fused ring of 4 to 10 members may have the same or different halo group, C1 to C6, and halogen C1. ~C6 hospital base, C1~C6 yard base, C1~C6 hospital oxygen C1~C6 yard base, warp base, C1~C6 institute oxy, tooth C1~C6 hospital oxy, sulfhydryl, C1~C6 courtyard Base, C1~C6 courtyard oxycarbonyl, C1~C6 compound amidyl, amine, C1~C6 {alkylamino, C1~C6 alkanoamine, phenyl, carboxyphenyl, C1~C6 alkoxy The group selected from the group consisting of a phenyl group and an oxy group is 1 to 3 substituents]. Further, the present invention provides: [2, wherein XI of JJ1 is a single bond or a compound of [1], a salt thereof or a solvate thereof. [X2 of 3JR1 is a compound of the above-mentioned [1] or [2] which has a halogen-substituted C1 to C6 alkyl group, a salt thereof or a solvate thereof. [4] The compound according to any one of [1] to [3], wherein R2 is a hydrogen atom or a halogen group, or a salt thereof or a solvate thereof. [5] The compound of any one of [1] to [4], or a salt thereof or a solvate thereof, which is a compound of any one of [1] to [4]. [6] Y of R3 is a compound of the 3~6 member nitrogen-containing heterocycloalkyl group substituted with a halogen group [5], a salt thereof or a solvate thereof. [7] Z1 of R is a compound, a salt thereof or a solvate thereof as described in any one of [1] to [6] of the C1 to C6. [8] Z2 of R4 is a heterocyclic ring of a hydroxy group, a phenyl group or a 4-membered ring or a fused ring-10-200918065 A ring group (a heterocyclic ring of a monocyclic or fused ring of the phenyl group or 4 to 10 members) The base may have the same or different halo group, C1~C6 alkyl group, halogen C1~C6 alkyl group, C1~C6 alkyl group, C1~C6 alkoxy group C1~C6 alkyl group, hydroxyl group, ci~C6 courtyard oxygen Base, halo-cl-c6 alkoxy group, carboxyl group, C1~C6 alkanoyl group, C1~c6 alkoxycarbonyl group, C1~C6 alkylaminecarbamyl group, amine group, C1~C6 compound amine group, Cl~C6 alkane group a compound selected from the group consisting of an amine group, a phenyl group, a carboxyphenyl group, a C1~ alkoxylated group and a benzyloxy group, and a group selected from the group consisting of 1 to 3 substituents [丨]~ [7] , a salt thereof or a solvate thereof. [9] Z of R is selected from the group consisting of the same or different halo group, ci~C6 alkoxy group, halogen C1~C6 alkoxy group, carboxyphenyl group and C1~C6 alkoxycarbonylphenyl group. A compound of the formula [8], a salt thereof or a solvate thereof, which is a substituted or substituted phenyl group or a 4- to 10-membered monocyclic or fused ring heterocyclic group. [10] The compound according to any one of [1] to [9], a salt thereof or a solvate thereof, which is an active ingredient. [11] A medicine described in [10] for inhibiting the production of TNF-a. [12] A medicine described in [10] for preventing or treating inflammatory diseases and/or autoimmune diseases. [1 3 ] Medicines used to prevent or treat joint rheumatism [1 〇 ]. [14] The use of a compound, a salt thereof or a solvate thereof according to any one of [1] to [9] for the production of a pharmaceutical active ingredient. [15] The use of medicines to inhibit the production of TNF-a [14] is used [16] Medicine is used to prevent or treat inflammatory diseases and/or autoimmune -11 - 200918065 14] Use of the record. [17] Medicine is used in the medicine [14] used to prevent or treat joint rheumatism. [18] A method comprising the compound according to any one of [1] to [9], a salt thereof or a solvate thereof, which is administered to a mammal to inhibit the production of TNF-α. [19] The compound according to any one of [1] to [9], a salt thereof or a solvate thereof, is administered to a mammal for prevention or treatment of an inflammatory disease and/or autoimmune The method of disease. [20] A method comprising the compound according to any one of [1] to [9], a salt thereof or a solvate thereof, which is administered to a mammal for prevention or treatment of joint rheumatism. [2] A compound according to any one of [1] to [9], or a salt thereof, for use in the prevention or treatment of an inflammatory disease and/or an autoimmune disease. [22] A compound or a salt thereof according to any one of the items [9], which is for use in the prevention or treatment of a joint rheumatism. (Effects of the Invention) The oral administration of the imidazo[l,2-b]indole derivative of the present invention inhibits the production of TNF-q: thereby preventing and/or treating various types of TNF-α production. Diseases such as inflammatory diseases such as joint rheumatism and/or autoimmune diseases. [Embodiment] (Best Mode for Carrying Out the Invention) The substituents in the present specification will be described below. -12- 200918065 In the present specification, the "halo" moiety of the "halo" or halogen C1 to C6 alkyl or haloCl~C6 alkoxy group is a fluoro group, a chloro group, a bromo group or an iodine group. In the present specification, "C1 to C6 alkyl group" or C1 to C6 alkylamino group, C1 to C6 alkylamine carbenyl group, hydroxy C1 to C6 alkyl group, carboxy C1 to C6 alkyl group "halogen C1 to C6 alkyl group or C1" The "C1~C6 alkyl" moiety of the C6 alkoxy C1 to C6 alkyl group is a monovalent group of a linear or branched chain saturated hydrocarbon having 1 to 6 carbon atoms, such as methyl or ethyl. Base, n-propyl, isopropyl, n-butyl or tert-butyl. (: In this specification, "C 1~C 6 stretched base" or C 1~C 6 stretched base - X1-X2 or C1~C6 alkyl - Ο-Cl~C6 alkyl The "C1~C6 alkylene group" portion is a divalent group formed by a linear or branched chain saturated hydrocarbon having 1 to 6 carbon atoms. The "C1 to C6 alkylene group" may be, for example, a methylene group. a group, an ethyl group, a propyl group, an exo-propyl group or a butyl group, etc., and one methylene group in the alkyl chain may be substituted by a cycloalkyl group having 3 to 6 carbon atoms to form a valence of the following formula 2 Base:

In the present specification, "C1 to C6 alkoxy group" or halogen C1 to C6 alkoxy group, carboxy C1 to C6 alkoxy group, C1 to C6 alkoxy group C1 to C6 alkyl group, C1 to C6 alkoxycarbonyl group or C1~ The "C1 to C6 alkoxy" moiety of the C6 alkoxycarbonylphenyl group is a C1 to C6 alkoxy group formed by the above C1 to C6 alkyl group, such as a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group. base. In the present specification, the "C1 to C6 alkyl fluorenyl group" or the "C1 to C6 alkyl fluorenyl group" of the C1 to C6 alkyl hydrazino group is a nail sulfhydryl group or a linear chain of a carbon number of 1 to 5-13-200918065. Or a group formed by an alkyl group of a branched chain and a carbonyl group, such as a formic acid group, an ethyl fluorenyl group, a n-propyl group, an n-butyl group or an isobutyl group. In the present specification, the "halogen C1 to C6 alkoxy group" means a group in which one or more of the above halogens are substituted based on the above C1 to C6 alkoxy groups. The substituted tooth base is preferably 1 to 3. When a plurality of halo groups are substituted, the halo groups may be the same or different. The "halogen C1 to C6 alkoxy group" may be, for example, a fluoromethoxy group, a chloromethoxy group, a fluoroethoxy group, a chloroethoxy group, a dimethoxymethoxy group, a trifluoromethoxy group or a chlorofluoromethoxy group. In the present specification, the "C1 to C6 alkylamino group" means a group in which one or two of the above C1 to C6 alkyl groups are substituted with an amine group. When two C1 to C6 alkyl groups are substituted, the C1 to C6 alkyl groups may be the same or different. The "C1 to C6 alkylamino group" may be, for example, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group or a methylethylamino group. In the present specification, "C1 to C6 alkylaminecarbamyl" means a group in which one or two of the above C1 to C6 alkyl groups are substituted with an amine carbenyl group. When two C1 to C6 alkyl groups are substituted, 'the C1 to C6 alkyl groups may be the same or different. The "C1 to C6 alkanocarbamyl group" may be, for example, methylamine, ethylamine, dimethylamine, dimethylaminomethylhydrazine or methylethylamine. In the present specification, "C1 to C6 alkanoylamino group" means a group in which one or two of the above C1 to C6 alkane are substituted with an amine group. When two C1 to C6 alkyl fluorenyl groups are substituted, the C1 to C6 alkyl fluorenyl groups may be the same or different. The "C1 to C6 alkanoylamino group" may be, for example, a formamidine group, an ethenyl group or a propylamine group. In the present specification, the "3 to 6 member nitrogen-containing heterocycloalkyl group" means a 3 to 6 membered heterocycloalkyl group having at least one nitrogen atom as a constituent atom of the ring, and the ring-14-200918065 may also contain an oxygen atom. Or a sulfur atom. The number of nitrogen atoms contained in the ring is preferably 1 or 2. The "3 to 6 membered nitrogen-containing heterocycloalkyl group" may be, for example, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, an imidazolidinyl group, a piperidinyl group, a piperidinyl group, a fluorene B group, or a salivary base. Lynn or thiolinski. In the present specification, "carboxy ci~C6 alkoxy" means the above C1 to C6 alkoxy group substituted by 1 or a plurality of carboxyl groups. The substituted carboxyl group is preferably 1 to 3 carbon atoms. The "carboxy C1 to C6 alkoxy group" may be, for example, a carboxymethoxy group or a carboxyethoxy group. f In the present specification, 'hydroxyl c 1 to C6 alkyl group' means the above C1 to C6 alkyl group substituted by 1 or a plurality of hydroxyl groups. The substituted hydroxyl group is preferably 1 to 3 carbon atoms. The "hydroxyl C1 to C6 alkyl group" may be, for example, a hydroxymethyl group or a hydroxyethyl group. In the present specification, 'carboxyl C1 to C6 alkyl group' means the above C1 to C6 alkyl group substituted by 1 or a plurality of carboxyl groups. The substituted carboxyl group is preferably 1 to 3 carbon atoms. The "carboxy C 1 -C 6 alkyl group" may be, for example, a carboxymethyl group or a carboxyethyl group. In the present specification, the "heterocyclic group of a monocyclic or fused ring of 4 to 10 members" means that the constituent atom of the ring contains a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, Ci or a plurality of 4 to 4 The basis of the valence of the 10-membered monocyclic or fused ring heterocycle. The number of hetero atoms contained in the ring is preferably 1 to 3. "4 to 1 member of a monocyclic or fused ring heterocyclic group" may be, for example, azetidine, pyrrolidine, imidazolidinium, oxazolidine, thiazolidine, piperidine, piperidine, morpholine, thiomorpholine , pyrrole, pyrazole, imidazole, triazole, tetrazole, thiophene, thiazole, isosporazole, furan, carbazole, isoxazole, pyridine, pipe trap, pyrimidine, n specific tillage, triple well, hydrazine, benzo Any of the induced groups of the heterocyclic ring selected from the group consisting of imidazole, benzotriazole, benzothiazole, quinoline and isoquinoline. -15- 200918065 In the present specification, "halogenCl~C6 alkyl group" means a group in which 1 or a plurality of halogens are substituted based on the above C1 to C6 alkyl groups. The substituted tooth base is preferred. When a plurality of halo groups are substituted, the halo groups may be the same as the "halogen C1 to C6 fluorenyl group", which may be, for example, a gas methyl group, a chloromethyl group, a gas chloroethyl group, a difluoromethyl group, a trifluoromethyl group or a chlorofluoro group. Ethyl. In the present specification, "C1 to C6 alkoxy C1 to C6 alkyl group" or a plurality of the above C1 to C6 alkoxy groups are bonded to the above C1 to C6 alkyl group. It is preferred to replace the C1 to C6 hospitaloxy groups with 1 to 3 groups. In the case of a C6 alkoxy group, the C1 to C6 alkoxy groups may be the same or the "C1 to C6 alkoxy group C1 to C6 alkyl group" may be, for example, methoxyethoxymethyl group or methoxy group B. In the present specification, the "C1 to C6 alkoxycarbonyl group" means the above alkoxy-substituted carbonyl group. "c 1 to C6 alkane" The oxycarbonyl group may be, for example, a carbonyl group, an ethoxycarbonyl group or a propoxycarbonyl group. In the present specification, "carboxyphenyl" means 1 to 3 carboxyl groups, such as carboxyphenyl or dicarboxyphenyl. In the present specification, The C1-C6 alkoxycarboxyphenyl group J refers to a phenyl group substituted with the above C1 to C6 alkoxycarbonyl group, for example, a methoxycarbonylphenoxycarbonylphenyl group. Each substituent of the formula (I) is illustrated. R1 is C1 to C6. The alkyl group is represented by an alkyl group, and the XI is a single bond, SO or S02, and X2 is a C1 to C6 alkyl group. X 1 is preferably a single bond or S. The number is 1 to 3 different. Refers to 1 substituted C 1~ different. Methyl, methyl group C 1 ~ C6 such as methoxy phenyl 1~3 base or B

, 〇, S -16 - 200918065 X2 is preferably a Cl~C4 alkyl group, more preferably a methyl group or an ethyl group. The group represented by the C1-C6 alkylene group -X1-X2 may have a substituent selected from the group consisting of a halogen group, a C1 to C6 alkoxy group and a halogen C1 to C6 alkoxy group, preferably 1 to 3, preferably 1 Or 2 substitutions. The substituent of the group represented by C1 to C6 alkyl-Xb X2 is preferably a fluorenyl group, and a fluorine group is more preferable. The C1-C6 alkylene group-X1-X2 group is preferably a straight-chain propyl group, a linear butyl group or a linear pentyl group substituted with a halogen group. R2 is the same or different from a hydrogen atom, a halogen group, a hydroxyl group, a carboxyl group, an amine group, a C1 to C3 alkylamino group, an amine methyl sulfonyl group, a C1 to C6 alkylamine carbhydryl group, and a C1 to C6 alkyl hydrazide group. The group chooses 1 or 2 bases. R2 is preferably a hydrogen atom or a fluorenyl group, and a fluorine group or a chlorine group is more preferable. R3 is a C1-C6 alkyl-Y group, Y is an amine group, a C1 to C6 alkylamine group or a 3 to 6 membered nitrogen-containing heterocycloalkyl group. Y is preferably a C1 to C6 alkylamino group or a 3 to 6 membered nitrogen-containing heterocycloalkyl group. The 3-6 membered nitrogen-containing heterocycloalkyl group may be the same or different from a halogen group, a hydroxyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogen C1 to C6 alkoxy group, a carboxy C1 to C6 alkane. The group selected from the group consisting of an oxy group, a hydroxy group C1 to C6 alkyl group and a carboxy group C1 to C6 alkyl group is preferably 1 or 3, preferably 1 or 2 substituents. The substituent of the 3 to 6 membered nitrogen-containing heterocycloalkyl group is a halogen group, a hydroxyl group, a C1 to C6 alkoxy group, a halogen C1 to C6 alkoxy group, a carboxy group (: 丨~ is preferably an alkyl group, and a halogen group is more preferable) R4 is a group represented by Z 1 - Z 2. Z1 is a C1~C6 alkyl group or a C1~C6 alkyl group-Ο-Cl~C6 alkyl group. The C1~C6 alkyl group or C1 ~C6 alkylene- Ο-Cl~ C6 extends the base group of the extended alkyl chain moiety may have a helical C3~C6 cycloalkane-17- 200918065 base identical or different 1 or 2 substitutions. One of the methylene groups in the pendant base chain of the alkyl group represented by c6 alkyl or Cl~C6 may be substituted with a cycloalkyl group having 3 to 6 carbon atoms. C1~C6 stretching base group or C1~C6 stretching base group - Ο-Cl~C6 stretching base group, the alkyl group portion of the alkyl group is substituted with a C3~C6 cycloalkyl group as a cyclopropyl group or a cyclobutyl group. Preferably, Z1 is preferably a C1 to C6 alkyl group, and a methylene group or an ethyl group is more preferred. Z2 is an amine group, a C1 to C6 alkanoguanamine group, an amine formamyl group, and a ci~C6 alkane group. a heterocyclic group of a monocyclic or fused ring of 4 to 10 members. Z2 is a monocyclic or fused ring of a hydroxyl group, a phenyl group or a 4 to 10 member. The heterocyclic group is preferably a phenyl group or a heterocyclic group of a monocyclic or fused ring of 4 to 10 members. The heterocyclic group of the phenyl group or a monocyclic or fused ring of 4 to 10 members may have The same or different halogen group, C1~C6 alkyl 'halogen C1~C6 alkyl group, hydroxyalkyl group, C1~C6 alkoxy group C1~C6 alkyl group, hydroxyl group, C1~C6 alkoxy group, halogen C1~C6 Alkoxy group, carboxyl group, C1 to C6 alkyl fluorenyl group, C1 to C6 G alkoxycarbonyl group, C1 to C6 alkylamine carbenyl group, amine group, C1 to C6 alkylamino group, C1 to C6 alkanoguanamine group, phenyl group 1, carboxyphenyl, C1~C6 alkoxycarbonylphenyl and benzyloxy group selected from 1 to 3 groups, preferably 1 or 2 substituents. Phenyl or 4 to 10 membered monocyclic or fused ring The substituent of the heterocyclic group is preferably a halogen group, a C1 to C6 alkoxy group, a halogen C1 to C6 alkoxy group, a carboxyphenyl group or a C1 to C6 alkoxycarbonylphenyl group. The compound of the formula (I) is The compound of any one of Examples 1 to 20 is preferably a salt or a solvate thereof. -18 - 200918065 When the compound of the formula (I) of the present invention has a basic group such as an amine group, it is prepared as desired. Pharmaceutically acceptable salts. Such salts may be, for example, hydrofluoric acid salts, hydrochloride salts, hydrobromic acid Hydrohalide salts such as hydroiodide; inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkanesulfonic acids such as methanesulfonate, triflate, and ethanesulfonate Salt; arylsulfonate such as besylate or p-toluenesulfonate; formic acid, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate And other organic acid salts; and aminates such as alanine and glutamate aspartate; and preferred are hydrohalide salts and organic acid salts. When the compound of the formula (I) of the present invention has an acidic group such as a carboxyl group, a general alkali additional salt can be formed. The pharmaceutically acceptable salt may be a metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an inorganic salt such as an ammonium salt; a di-ammonium salt, a morpholine salt, and a phenylglycine. Alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, hydrazine, hydrazine, _dibenzylethylenediamine salt , an organic amine salt such as a diethanolamine salt, a sulfonium-succinyl-fluorene-(2-phenylethoxy)amine salt, a piperazine salt, a tetramethylammonium salt, a hydrazinyl group, and an aminomethylamine. . The compound of the formula (I) of the present invention or a salt thereof is also present as a free form or a solvate. The solvate is not particularly limited as long as it is medically acceptable. Specifically, S' is preferably a hydrate or an ethanolate. Further, in the case where a nitrogen atom is present in the compound of the present invention represented by the formula (1), a sulfonium-oxide, such a solvate or an oxide may be included in the scope of the present invention. The compound of the formula f τ, π _ of the present invention, a salt thereof or a solvate thereof may have a geometric isomer such as an accompaniment or a trans form depending on the type of the substituent, -19-200918065 Various variants such as an isomer, an optical isomer such as a d-form or a mono-, but a compound of the present invention, if not limited thereto, includes all of the isomers, stereoisomers, and any ratio of such isomers and stereoisomers. Things. Further, the present invention also includes an active ingredient compound which is converted into an active pharmaceutical composition of the present invention by an enzyme reaction in a living body under physiological conditions, that is, a compound which is caused by hydrolysis of an enzyme or the like, or a compound which is hydrolyzed by gastric acid or the like, is changed into a compound. (I) The prior drug compound is also included in the present invention. When the compound (I) has an amine group, the above-mentioned prodrug may be a compound which is alkylated, alkylated or phosphorylated (for example, an amine group thereof, an amidino group, a pentylamine carbonyl group, (5-A) Benzyl-2-oxo-1 -alkyl-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidine methylpentaloxymethylation of 't-butylated compounds, etc.), etc., if (I) hydroxyl group is present a compound whose hydroxy group is thiolated, alkylated, or borated (for example, its hydroxyl group is acetylated, propylated, pivalylated, butylated, rich, A propylamine thiolated 'dimethylaminomethylcarbonylated compound; if the compound (I) has a carboxyl group, the compound whose carboxyl group is esterified (for example, its carboxyl group is ethylated, phenyl esterified, carboxylated) a compound of the present invention, which can be formed by a known method, such as a methyl dimethylamine methyl ester, a p-amyloxymethyl esterification, an ethoxycarbonyloxy, a guanidine or a methyl amidated compound, or the like. The prodrug of the compound of the present invention also includes (I) which can be mixed as an isomer of the isomer of the structure or a compound (I) of gastric acid. "Pharmaceutical amine-based groups are oxime-based, 3-dithiol-based, compound-specific, hexadecanoyl-phosphorylate, etc.), etc., reductive, decyl methyl esterification, ethyl ester compounds (I )Guangchuan Bookstore-20- 200918065 1 990 "Development of Pharmaceutical Products" Volume 7 Molecular Design 163 pages to 198 pages The physiological conditions described as changes in compound (I). Specific examples of the compound of the formula (I) of the present invention may be, for example, the compounds described in the following Table (1-1) or (1-2). These compounds can be synthesized according to the following [Production Method 1], [Production Method 2] or the methods described in the Examples. In the formula (1-1), the formula (1-2) and the compound table, "ci-6alkyln" is a C1 to C6 alkylene group, "pyrid-l-yl" is a pyrrolidinyl group, and "PyrU_2_71" is卩 is slightly steep-2-yl, "?7" is pyridyl, "1)}1" is phenyl, "Me" is methoxy, "Pipe" is piperidine_2. "M" Rp" is morpholin-3-yl, "TnFMeO" is trifluoromethoxy, and "carbMe" is carboxymethoxy. /.

【Table 1】

-21 - 200918065 /

R1 R2' or R2·. R3 R4 〇1- γ1 γ2 6alkyln Balkyln Y Z1 z2 A1 1-1 (CHj)3CH2F H (CHj)2 Pyrld-1-yl ch2 4-CI-Ph A2 1-1 ( CHj)3CH2F H (CH2)z N(CH2CH3)2 ch2 4-CI-Ph A3 1-1 (CHj)3CH2F H (ch2)2 Pyrld-1-yl ch2 4~MeO—Ph A4 1-1 (CH2) 4CHzF H (ch2)2 N(CHjCH3)j ch2 4-CI-Ph A5 Μ (ch2),ch2f H (CHj);, Pyrld-1-yl ch2 4-CI-Ph A6 Μ (ch2)3ch2f H (CH2 ) 2 Pyrld-1-yl ch2 3-F-2-Py A7 1-1 (CH2)3CH2F F (ch2)z Pyrld-1-yl ch2 3-F-2-Py A8 1-2 ch2ch2f OH (ch2) 2 Pyrld-1-yl ch2 4-CI-Ph A9 1-2 (CHj)2CH2F COOH CH(CH .,)CH, Pyrld-1-yl ch2 4-CI-Ph A10 1-2 (ch2)3ch2f nh2 ( CH2)2 Pyrld-1-yl ch2 4-CI-Ph A11 1-2 (ch2)3ch2f n(ch3)2 (ch2)2 Pyrld-1-yl gh2 4-CI-Ph A12 1-2 (ch2)3ch2f Conh2 (CH2)z Pyrld-1 -yl ch2 4-CI-Ph A13 1-2 (ch2)3ch2f CONHC Ha (ch2)2 Pyrld-1-yl ch2 4-CI-Ph A14 1-2 (CHz)3CH2F CON (C H3)2 (ch2)2 Pyrld-1 -yl ch2 4-CI-Ph A15 1-2 (CHj)3CH2F NHCOC H3 (ch2)2 Pyrld-1 -yl ch2 4-CI-Ph A16 1-2 ( Ch2)3ch2f NHCOC h2ch3 (ch2)2 Pipe ch2 4-CI-Ph A17 1-1 (CH2)3CHjF H (ch2)3 Pyrld-1-yl ch2 4-CI-Ph A18 1-1 CH(CH3)CH2F H (ch2)4 Pyrld-1-yl ch2 4-CI-Ph A19 1-1 ch(ch2ch3)ch2f H (ch2)2 nh2 ch2 4-CI-Ph A20 1-1 (CH2)3CHzF H (ch2)2 3-F-Pyrld-2 - yl ch2 4-CI-Ph A21 1-1 (CH2)3CH2F H (ch2)2 4-OH-Pyrld- 2-yl ch2 4-CI -Ph A22 1-1 (CHj)3CH2F H (ch2)2 4-Me〇- Pyrld-2-yl ch2 4-CI-Ph A23 1-1 (ch2)3ch2f H (ch2)2 3-Me〇- Pyrld -2-yl ch2 4-Ci-Ph A24 1-1 (ch2)3ch2f H (ch2)2 Pyrld-1—yl A25 1-1 (ch2)3ch2f H (ch2)2 Pyrld-1 -yl A26 It (CH2 3CH2F H (ch2)2 Pyrld-1 -yl ch2- 〇-CHz Ph A27 1-1 (CHj)3CH2F H (ch2)2 Pyrld-1 -yl ch2- 0- (CH2)2 4-CI-Ph A28 1-1 (ch2)4ch2f H (ch2)2 Pyrld-1 -yl ch2 conh2 A29 1-1 (ch2)5ch2f H (ch2)2 Pyrld-1 -yl ch2 conhch3 A30 1-1 (ch2)6ch2f H (ch2 ) 2 Pyrld-1-yl ch2 COOH -22- 200918065 / A31 1-1 (CH2)3CH2F H (CH2)2 Pyrld-1-yl ch2 A32 1-1 (ch2)3ch2f H (CH2)2 Pyrld-1- Yl ch2 A33 1-1 (CHj)3CH2F H (ch2)2 Pyrld-1 -yl ch2 A34 1-1 (CH2)3CH2F H (ch2)2 Pyrld-1 -yl ch2 A35 1-1 (ch2)3ch2f H ( Ch2) 2 Pyrld-1-yl ch2. A chf2 A36 1-1 (ch2)3ch2f H (ch2)2 4 A F-Pyrld-2-yl ch2 hn-n, N A37 1-1 (CHj)3CH2F H (CH2)z 4-F-Pyrld- 2-yl ch2 N-N\\ A38 1-1 (ch2)3ch2f H (CH2)j 4-F-Pyrld- 2-yl ch2 H Plant N\\ A39 1-1 (CH,), s CHa H ( Ch2), Pyrld-1 -yl ch2 4-CI-Ph A40 1-1 (CH2)2 s ch3 H (ch2)2 N(CH3)2 ch2 4-CI-Ph A41 1-1 (ch2)2 s ch3 H (ch2)2 N(CH2CH3)j ch2 4-CI-Ph A42 1-1 (CHj)2 s ch3 H (ch2), Pyrld-1-yl ch2 4—MeO-Ph A43 1-1 (CH2)zs Ch3 H (ch2)2 N(CH3)2 ch2 4-Me〇-Ph A44 1-1 (ch2)2 s ch3 H (ch2)2 n(ch2ch3)2 ch2 4—Me〇—Ph A45 1-1 ( Ch,)3 s ch3 H (ch2)2 Pyrld-1 -yl ch2 4-COOH-Ph A46 1-1 (ch2)3 s ch3 H (ch2)2 n(ch3)2 ch2 4-Ci-Ph Ml M (ch2)3 s ch3 H (ch2)2 N(CHjCH3)j ch2 4-CI-Ph A48 1-1 (CH,)S s ch3 H (CH,)? Pyrld-1 -yl ch2 4-CI-Ph A49 1-1 (ch2)2 s ch3 H (CH2)j Pyrld-1-yl ch2 3-F-2-Py A50 M (ch2)2 s ch3 H ch2 4-F-Pyrld- 2-yl ch2 -23 - 200918065 /

A51 1-1 (ch2)2 s ch3 H ch2 4-F-Pyrld- 2-yl ch2 A52 Μ ch2 s ch3 H (ch2)2 Pyrld-1-yl ch2 2-CI-Ph A53 1-2 ch2 s CHZC H3 OH (ch2)2 Pyrld-1 -yl ch2 4-CI-Ph A54 1-2 (CH2)2 s ch3 COOH (CH,), Pyrld-1-yl ch2 4-CI-Ph A55 1-2 (ch2 ) 2 s ch3 nh2 (CH2)2 Pyrtd-1 -yl ch2 4-CI-Ph A56 1-2 (CH2)2 s CHa n(ch3)2 (ch2)2 Pyrld-1-yl ch2 4-CI-Ph A57 1-1 (CHj)2 s ch3 F ch2 3-F-Pyrld- 2-yl ch2 4-CI-Ph A58 1-1 (ch2)2 s ch3 H (ch2)2 4-CH2OH- Pyrld-2- Yl ch2 4-CI-Ph A59 1-1 (ch2)2 s ch2c h3 H (ch2)3 4- CH2COOH- Pyrld-2-yl ch2 4-CI-Ph A60 1-1 (CH2)zs (ch2) 2ch3 H (CHz) 2 4-TriFMeO- Pyrld-2-yl ch2 4-CI-Ph A61 1-1 (CHz)2 s ch3 H (CH2)z 4-CarbMeO- Pyrld-2-yl ch2 4-Ct-Ph A62 1-1 (ch2)2 s ch3 H (CH2)j Pyrld-1 -yl ch2 -KT A63 1-1 (ch2)2 s ch3 H (ch2)2 Pyrld-1 -yl CH(CH 3) A64 1 -1 (ch2)2 s ch3 H (ch2)2 Morp CH(CH 3) A65 1-1 (ch2)2 s ch3 H (ch2)2 Morp ch2- o-ch2 Ph A66 i-1 (ch2)2 s Ch3 H (ch2)2 Pipe ch2- 0- (CH2)2 4-CI-Ph A67 1-1 (CH?)2 0 ch3 H (ch2)2 Pyrld-1 -yl ch2 2-CI-Ph A68 1- 2 (ch2)2 0 ch3 OH (ch2)2 Pyrld-1 -yl ch2 4-CI-Ph A69 1-1 (ch2)2 0 ch3 H (ch2)2 Pyrld-1-yl ch2 A 1 A70 1-1 (ch2)2 o ch3 H (ch2)2 Pyrld -1-yl ch2 _r^0H -24- 200918065 f A71 1-1 (CH2)2 0 ch3 H (CHz)2 Pyrld-1-yl ch2 A72 1-1 (CHj)2 0 ch3 H (ch2)2 Pyrld -1-yl ch2 A73 1-1 (ch2)2 0 ch3 H (ch2)2 Pyrld-1 -yl ch2 A74 1-1 (ch2)2 0 ch3 H (ch2)2 Pyrld-1 -yl ch2 3prOH A75 1 -1 (CHj,)2 0 ch3 H (CHz)2 Pyrld-1 -yl ch2 A76 1-1 (ch2)2 so ch3 H (ch2)2 Pyrld-1 -yl CH? 4-CI-Ph A77 1- 2 (ch2)2 so ch3 OH (ch2)2 Pyrld-1 -yl ch2 4-Cl-Ph A78 1-2 (CH2)2 so ch3 COOH (ch2)2 Pyrld-1-yl ch2 4-ChPh A79 1- 2 (CHj)2 so ch3 nh2 (CH?)? Pyrld-1-yl ch2 4-C!-Ph A80 ϊ-2 (CH,), so ch3 N(CH3)2 (CHz)2 Pyrld-1-yl CH? 4-Cl-Ph A81 1-1 (CH2)3 so ch3 H ch2 n(ch3)2 ch2 A82 1-1 (ch2)3 so CH(C H3)2 H (ch2)2 n(ch3)z CHZ L. A83 1-1 (ch2)4 so ch3 H (ch2)3 N(CH3)z CHZ o A84 1-1 (ch2)4 so ch3 H (ch2)2 n(ch2ch3)2 ch2 3AC〇〇 H A85 1-1 (ch2)4 so ch3 H (ch2)2 nh2 ch2 A86 1-1 (ch2)2 so2 ch3 H (CH2)j Pyrld-1 -yl ch2 4-Cl-Ph A87 1-2 (ch2 )2 so2 ch3 OH (ch2)2 Pyrld-1 -yl ch2 4-Cl-Ph A88 1-2 (ch2)2 so2 ch3 COOH (CH?)? Pyrld-1 -yl CHZ 4-Cl-Ph A89 1-2 (ch2) 2 so2 ch3 nh2 (CH2)2 Pyrld-1 -yl ch2 4-Ct-Ph A90 1-2 (ch2), so2 ch3 n(ch3)2 (ch2)2 Pyrld-1 -yl ch2 4-Cl-Ph - 25 - 200918065 A91 1-1 (CH2)3 so2 ch3 ch2 n(ch3>2 ch2 A92 1-1 CH(CH S02 ch3 H (CHj), n(ch3)2 ch2 A93 1-1 (ch2)4 S02 ch3 H (CHs)3 n(ch3)2 ch2 A94 1-1 (CHj)4 S02 ch3 H CH{CH 3)ch2 N(CH2CH3)j CHj w, A95 1-1 CH(CH 2CH3)CH, so2 ch3 H (ch2) 2 nh2 ch2 The preparation method of the compound represented by the formula (i) is described. However, the method of production is not limited to the following methods. The compound of the formula (I) and the intermediate for the production thereof can be produced by various known reactions as described below. At this time, the functional group is protected by a suitable protecting group at the stage of the raw material or the intermediate. Such a functional group may be, for example, a hydroxyl group, a carboxyl group, an amine group or the like, a kind of a protecting group, and the conditions for introduction and removal of the protecting groups. For example, refer to Protective Groups in Organic Synthesis (TW Green and PG M. W uts, J). Ohn Wiley & Sons, Inc., New York, 2006). The compound (I) of the present invention can be produced by the following [Production Method 1]. [Method 1] -26- 200918065

The compound (I) of the present invention is a nucleophilic substitution reaction of the compound (1) and the amine (2), and if necessary, a general protecting group is introduced to produce the compound (3), and the compound (3) is a carboxylic acid derivative. The compound (4) is produced by condensing the compound (4) and the amine (5), and deprotecting if necessary. The detailed description of each project of [Method 1]. In Process [1], the method of producing compound (3) by nucleophilic substitution reaction of compound (1) and amine (2) is explained below. [Method 1-1]

Br -27 200918065 The compound (3) is produced by subjecting the compound (1) to a chemical amount of the amine (2) in the presence of a base, which can be produced by a nucleophilic substitution reaction and, if necessary, a general protecting group. As the test, an excess amount of the amine (2) may be used, and a reaction solvent may also be used. The amine (2) can be produced by a commercially available or by a known method. The base to be used may be an organic amine such as triethylamine or diisopropylethylamine. The amount of the base to be used is preferably in the range of 2 to 10 times the molar equivalent of the compound (1). The amount of the amine (2) used may be 1 to 2 molar equivalents when using a base, and preferably 2 to 30 moles per mole of the compound (1) when no base is used. There is no limit to the ability to dissolve the starting materials to some extent, such as guanidine, guanidine-dimethylformamide (DMF), N-methyl-2-pyrrolidone and other guanamine solvents, dimethyl hydrazine (DMSO). As the solvent such as an anthraquinone solvent, DMF, DMS 0 or the like is preferred. The reaction temperature is preferably in the range of from 80 to 1 60 °C. The reaction time is preferably from 1 to 24 hours. When the compound (3) wherein R1 is a C1-C6 alkyl group-X1-X2 group substituted with a halogen group is synthesized, the amine (2) having a hydroxyl group at a suitable position can be reacted with the compound (1). After the appropriate protecting group X is introduced into a nitrogen atom, the compound (3) is synthesized by fluorinating with a fluorinating reagent such as a halogenating agent (diethylaminosulfur difluoride or the like). In the [Production Method 1-2], the method for producing the compound (4) will be described below. [Method 1-2] -28- 200918065

Or R2°a& R2°b is an integral to form a C1-C6 alkylene group, R21 is a carboxyl group, a decyl group or a C1-C6 alkoxycarbonyl group, and r1, R2 and X are the same as defined above). The compound (4) wherein f is a carboxylic acid derivative is a compound (4a) obtained by coupling a compound (3) with an organic boronic acid derivative (6) to produce a compound (4a), wherein (i) is a compound of R21 The formazan group is produced by hydrolysis while (ii) R21 is a Cl~C6 alkoxycarbonyl group. The compound (4a) can be produced by subjecting the compound (3) to a coupling reaction with an organic boronic acid derivative (6) in the presence of a metal catalyst and a base. In the present coupling reaction, an appropriate additive can also be used to promote the reaction. The organic boronic acid derivative (6) can be produced by a commercially available method or by a known method, and the reference method of the organic boronic acid derivative (6) and the coupling reaction is "Chemical Reviews, 1995, 95, 2457-2483". The amount of the organic boronic acid derivative (6) to be used is preferably in the range of 1 to 2 times the molar equivalent of the compound (3). The metal catalyst is preferably a palladium catalyst, such as [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)/dichloromethane (1:1), or dichlorobis (triphenylphosphine) pin (II) and hydrazine (triphenylphosphine) palladium (ruthenium) and the like. The amount of the metal catalyst used is preferably in the range of the compound (3) 〇·〇!~〇. 2 times the molar equivalent. -29- 200918065 The base may be, for example, an inorganic base such as tripotassium phosphate (hydrate), potassium carbonate or carbonic acid plan, or a tripotassium phosphate (hydrate) or potassium carbonate. The amount of the base to be used is preferably in the range of 2 to 10 times the molar equivalent of the compound (3). The additive may be an organic phosphorus compound such as 1,1'-bis(diphenylphosphino)ferrocene (dppf) or triphenylphosphine, and the amount of the additive used is in the range of 0.05 to 0.2 molar equivalents to the compound (3). Preferably. The solvent of the coupling reaction is not limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent. For example, an ethyl ether solvent such as 1,4-dioxane or 1,2-dimethoxyethane, N,N- A guanamine solvent such as dimethylformamide (DMF) or N-methyl-2-pyrrolidone; a hydrocarbon solvent such as toluene or benzene; an alcohol solvent such as methanol or ethanol: a polar solvent such as acetonitrile or water. Preferably, two or more kinds of mixed solvents may be used as the solvent. The reaction temperature may range from 50 ° C to the boiling point of the solvent, preferably from 70 to 150 ° C. The reaction time is preferably from 1 to 50 hours. The compound (4) can be produced by oxidizing the compound (4a) which is an aldehyde derivative (i.e., when R21 is a formazan group). The oxidation reaction is preferably carried out by using, for example, sodium chlorite or the like, and the reference for the reaction conditions may be a lecture on experimental chemistry (fourth edition, ν〇1·22·edited by the Chemical Society of Japan, Jiushan Company) "Organic Synthesis IV" : Acid, amino acid, peptide, Ρ1~Ρ6, etc. Further, the compound (4) can be produced by hydrolyzing the compound (4a) which is a C1 to C6 vinegar derivative (i.e., when R21 is a C1 to C6 oxycarbonyl group). The hydrolysis reaction is preferably carried out by well-known alkali hydrolysis. The reference literature can be a lecture on experimental chemistry (fourth edition, V〇l.22. edited by the Chemical Society of Japan, Jiushan Company) "Organic Synthesis IV: Acid. Amino Acid. , P6~P11" and so on. -30-200918065 [Process 1-3] A method for producing the compound (I) by a condensation reaction of the compound (4) with the amine (5) will be described. Compound (I) can be produced according to [Pathway 1] or [Pathway 2]. [Method 1-3] [Pathway 1]

OH H-N. (5)

N R

[Pathway 2] X I

OH

H-N \ (5a) H or R4

〇 /r3 N.,

Or R

(wherein R1, R2, R3, R4 and X are the same as defined above). The compound (I) can be produced by condensing the compound (4) with the amine (5) in the presence of the condensing agent -31 - 200918065 as shown in [Path 1]. This condensation reaction promotes the reaction and can be carried out in the presence of a base and/or an additive. The amine (5) is commercially available or can be produced by the method described below. The amount of the amine (5) used is preferably in the range of 0.6 to 4.0 times the molar amount of the compound (4). The condensing agent may be, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), benzotriazol-1-yloxyglycol (dimethylamino) scale six Fluorophosphate (Β0Ρ), 0·benzotriazol-1-yl-N,N,N′,N′-tetramethylurea hexafluorophosphate, 4-(4,6·dimethoxy-1 , 3,5-trin-2-yl)-4-methylchloromorpholine (DMTMM) and its analogs, with 1-ethyl-3-(3-dimethylaminopropyl)carbamate Amine hydrochloride (EDC), benzotriazol-1-yloxy ginseng (dimethylamino) hexafluorophosphate (Β0Ρ), 0-benzotriazol-1-yl-oxime, oxime, Ν' ,Ν'-Tetramethylurea hexafluorophosphate and 4-(4,6-dimethoxy-1,3,5-trimethyl-2-yl)-4-methylchloromorpholine (DMTMM) Preferably. The amount of the condensing agent to be used is preferably in the range of 0.8 to 3 times the molar equivalent of the compound (4). The reaction solvent is not limited to a certain extent as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, a guanamine solvent such as N,N-dimethylformamide or N-methyl-2-pyrrolidone, or dichloromethane. A halogenated hydrocarbon solvent such as chloroform, an ether solvent such as diethyl ether or tetrahydrofuran, or a hydrocarbon solvent such as toluene or benzene is preferred, and these solvents may be used in combination of two or more. The additive may be, for example, 1-hydroxybenzotriazole (Η Ο B t) or the like. The amount used when the additive is used is preferably in the range of 1.1 to 1 times the molar equivalent of the compound (4). The base is preferably an organic amine base such as triethylamine or diisopropylethylamine, more preferably -32 to 200918065. The amount used in the case of using an alkali is preferably in the range of 1 to 8 moles per mole of the compound (4). The reaction temperature is preferably in the range of from 0 ° C to the boiling point of the solvent. The reaction time is usually from 1 hour to 4 days. The amount of the amine (5) used is preferably in the range of from 0.6 to 4.0 moles per mole of the compound (4). Further, as shown in [Pathway 2], the compound (I) can be condensed with the amine (5a) in the presence of a condensing agent to synthesize the compound (4b), and further introduced into R3 or R4 Γ to obtain a compound (4c). ) 'When necessary, remove the protective base to make. The condensation reaction is carried out to promote the reaction, and it can also be carried out in the presence of a base and/or an additive. The amine (5a) is commercially available or can be produced by a known method. When the compound (I) obtained by the process has a functional group on R3 and R4, the functional group can also be protected, and the removal of the protective group can be carried out by a general method as described above. Further, the functional group may be subjected to chemical modification such as alkylation or thiolation by a usual method to introduce various substituents. The compound (I) of the present invention is produced by the following [Production Method 2], and may be produced according to [Method] or [Channel]. [Method 2] -33- 200918065 [Pathway A] 俨0

(1) Br

[Pathway B] (7b) R— Η Η ^ 2

R-N

X

X

(4) (wherein R1, R2, R3, R4, R2°a, R2Db, R21 and χ are the same as above). [Pathway A] The compound of the formula (I) can be produced from the compound (1) and the organoboric acid derivative (6) by the coupling reaction shown in [Production Method 1 - 2] to produce the compound (7 a ) from the compound (7 a). Process 1-2] A compound (7b) which is a residual acid derivative is produced by a method other than the method, and the compound (7b) is produced by a condensation reaction of the compound (7b) and the amine (5) by [Production Process 1-3], The compound (8) and the amine (2) are produced by a nucleophilic substitution reaction shown in [Formula 1]. [Pathway B] The compound of the formula (I) can be a compound of the carboxylic acid derivative (7b) -34- 200918065. After the compound (4) is produced by the nucleophilic substitution reaction with the amine (2), the compound (4) is produced. It is produced by a condensation reaction with the amine (5) shown in [Production Process 1-3]. When the compound (8) or the compound (I) has a functional group such as an amine group on R3 or R4, a functional group such as an amine group can be protected, and the protective group can be removed by a general general method as described above. Further, the functional group such as an amine group may be subjected to alkylation or thiolation or the like according to a general method, and the amine (5) which is converted to a substituted functional group based on [Process 1] and [Process 2] is commercially available or It can be produced by the method shown in the following [Method A-1] or [Process A_2]. H/N—R4 (5) [wherein R3 and R4 are the same as above] [Process A-1] or (5a)

Η (9) [Reducing agent Η R3 / N - R4 (5) (Formula Φ R3 and R4 are the same as above. U is an amine formed by the reaction. (5) can be a substituent of R3 or R4. If necessary, a general protecting group can be used. Deprotection after protection and reduction reaction 'will become an unprotected functional group modification in U to produce an amine (5).) Amine (5) may be an amine (5a) or a salt thereof and an aldehyde (9) It is produced by a reductive amination reaction in the presence of a reducing agent. The above amine (5a) or -35-200918065 is commercially available as a salt or a aldehyde body (9) for a reductive amination reaction, or can be produced by a known method. The reference for the reductive amination reaction can be lectured in Experimental Chemistry (Fourth Edition, Vol. 20. edited by the Chemical Society of Japan, Jiushan Company) "Organic Synthesis II: Alcohol. Amine, P300 to P302". The amount of the amine (5a) or its salt to be used is preferably in the range of 0.1 to 4 times the molar equivalent of the compound (9). The reducing agent is preferably a metal hydride or the like, and is preferably, for example, sodium borohydride, sodium cyanoborohydride or sodium triethoxy borohydride. The amount of the reducing agent to be used is preferably in the range of 0.2 to 4 times the molar equivalent of the compound (9). The reaction solvent is not limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent. For example, a hydrocarbon solvent such as toluene, xylene, benzene, heptane or hexane, chloroform, dichloromethane or 1,2-dichloroethane. A halogenated hydrocarbon solvent, an ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, or an alcohol solvent such as methanol or ethanol. 特, Ν-dimethylformamide, N-methyl A phthalamide solvent such as -2-U pyrrolidone, an anthraquinone solvent such as dimethyl hydrazine, a polar solvent such as acetonitrile, water or acetic acid, etc., may be used. These solvents may be used in combination of two or more kinds. To 2 0. . ~8 (TC 曰 degree.

(5) The reaction temperature is preferably in the range of from 0 ° C to the boiling point of the solvent. The reaction time is usually 1 hour to 3 [Process A-2]

HN\ PG

(11) R4 (1〇a) (10) 200918065 (wherein PG is a protecting group, R3 and R4 are the same as above. L is a leaving group, and w is a substitution which may be substituted by R3 or R4 due to introduction into the amine body (10). After the introduction or the introduction, the functional group which is previously introduced into the protective group of W is deprotected or deprotected to form a substituent of R3 or R4.) The amine (5) is a protected amine ( 10) An alkylation reaction which is treated with an alkylating agent (1 〇a) in the presence of a general-purpose base, and if necessary, the above functional group conversion is carried out to synthesize the compound (11), and the obtained compound (11) is deprotected. To manufacture. The reference for the alkylation reaction can be lectures on experimental chemistry (Part 4 (Vol. 20, edited by the Chemical Society of Japan, Jiushan Company) "Organic Synthesis II: Alcoholamine, P284~P288", etc. (10) is commercially available, or may be produced by a known method. The base used for alkylation is, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N- An organic amine such as dimethylamino)pyridine or an inorganic base such as potassium carbonate, carbonic acid or sodium hydride is preferred. The amount of the base may be in the range of 1 to 30 equivalents for the amine (10), preferably 1 to 10 The range of equivalents. The reaction time is usually about 1 to 48 hours. t The alkylating agent can be produced by a commercially available or known method (10a). The leaving group L can be, for example, a halogen group or a C1 to C6 alkanesulfonate. The oxy group may have a phenylsulfonyloxy group such as a substituent, and particularly preferably a bromine atom 'iodine atom, a methanesulfonyloxy group, a benzenesulfonyloxy group or a p-toluenesulfonyloxy group. The solvent is not limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent. For example, a halogenated hydrocarbon solvent such as chloroform or dichloromethane, toluene, benzene, etc. A hydrocarbon solvent, an ether solvent such as diethyl ether or tetrahydrofuran, -37-200918065, an alcohol solvent such as methanol or ethanol, a guanamine solvent such as hydrazine or hydrazine-dimethylformamide, or a polar solvent such as acetonitrile or water. Preferably, the solvent may be used in combination of two or more kinds of solvents. The reaction temperature may be in the range of -20 ° c to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C. The reaction time is usually 1 〜 The compound (I) of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, chromatography, recrystallization, recrystallization, etc. Further, if the compound of the present invention ( I) or the intermediates produced have asymmetric optical carbons. 'There are optical isomers. These optical isomers can be recrystallized separately according to the recrystallized salt of the appropriate salt (salt partitioning) or column chromatography. The separation and purification of the respective isomers. The reference for the method of dividing the optical isomers by the racemate may be "En an ti 〇m er s, R ac e ma tes and Resolution," John Wiley And Sons, Inc." As mentioned earlier, TNF-α is produced. The biosuppressive agent can be used as a therapeutic agent for various inflammatory diseases such as joint rheumatism or autoimmune diseases, etc. The inflammatory diseases can be, for example, articular rheumatism, rheumatic spondylitis, osteoarthritis, asthma, bronchitis, allergic rhinitis, chronic Obstructive pulmonary disease, sputum fibrosis, inflammatory bowel disease, irritable bowel syndrome, mucinous colitis, ulcerative colitis, Crohn's disease, multiple sclerosis, etc. Autoimmune diseases may be, for example, collagen diseases, Systemic lupus erythematosus, rheumatoid arthritis, spondylitis, osteoarthritis, gout, sepsis, septic shock, toxic shock syndrome, atopic dermatitis, -38- 200918065 contact with dermatitis, multiple sclerosis , Bechet disease, renal syndrome, renal tubular nephritis, glomerulonephritis, Hugh's disease syndrome, lupus erythematosus, cachexia, mesothelioma, polymyositis, dryness, inflammatory bowel disease, Crohn's disease, mixed type Combined with tissue disease, chronic closed-chain lung disease, retention of cardiac arrest, pulmonary fibrosis, primary mucinous edema, Edison disease, poor regeneration Anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune diabetes, insulin resistance, uveitis, anti-receptor disease, myasthenia gravis, thyroid poisoning , thyroiditis, Hashimoto's disease, viral infection, AIDS, etc. When the compound of the present invention represented by the formula (I), a salt thereof or a solvate thereof is administered to a mammal (specially human), it can be administered systemically or locally, orally or non-D. The medicine of the present invention can be produced by a method in which a suitable form is selected according to the method of administration. The form of the oral medicine can be a tablet, a nine-dose, a powder, a granule, a capsule, a liquid, a suspension, an emulsion, a syrup, an expectorant, and the like. The preparation of these forms of medicine can be used as an additive commonly used as an additive, such as a binder, a binder, a slip agent, a swelling agent, a swelling aid, a coating agent, a plasticizer, a stabilizer, a preservative, an antioxidant, A coloring agent, a dissolution aid, a suspending agent, an emulsifier, a sweetener, a preservative, a buffer, a diluent, a wetting agent, and the like are optionally used as needed, and are carried out according to a usual method. The form of the non-oral medicine can be an injection, an ointment, a gel-39-200918065, a cream, a wet cloth, a patch, a spray, an inhalant, a spray, an eye drop, and a nasal spray. , seat, inhalant, etc. The preparation of such a form of medicine can be used as a stabilizer, a preservative, a dissolution aid, a moisturizer, a preservative, an antioxidant, a flavoring agent, a gelling agent, a neutralizing agent, a dissolution aid, and the like, which are usually used as an additive. Buffering agents, isotonic agents, surfactants, coloring agents, buffering agents, tackifiers, wetting agents, gargles, absorption enhancers, suspending agents, binding agents, etc., are suitably selected as needed, and The law is implemented. The pharmaceutical of the present invention may be a compound represented by the formula (I), a salt thereof or a solvate thereof, an immunosuppressant, an antibody for immunosuppression, a therapeutic drug for rejection, an antibiotic, a nonsteroidal anti-inflammatory drug, One or two or more kinds of (NSAIDs) and steroid drugs are selected into a medicine. In the present invention, the compound of the present invention represented by the formula (I), a salt thereof or a solvate thereof is administered in combination with one or more other agents, and the present invention is represented by the formula (I). The compound, the salt thereof or the solvate thereof may be a mixture of the two components in the formulation, or may be administered in separate formulations. When each dose is administered, each preparation may be administered at the same time or may be administered at intervals. The administration method of each preparation may be the same or different. These medicines are compounds represented by formula (I), salts thereof or solvates thereof, immunosuppressive agents, antibodies for immunosuppression, therapeutic agents for rejection, antibiotics, and non-steroidal anti-inflammatory drugs (NS AIDs). And a combination of one or more steroid drugs selected from other agents. More specifically, the immunosuppressive agent, the antibody for immunosuppression, and the therapeutic agent for rejection may be, for example, cyclosporin A, tacrolimus (FK506), -40-200918065

Sirolimus (rapamycin), azathioprine, Mizoribine, Methotrexate, Mycophenolate Mofetil, Cyclophosphamide, Everolimus, Dehydropicitol, Methyl Dehydrogenation Peptitol, Orthoclone OK: T3, anti-human lymphoglobulin, Deoxyspergualin, and the like. The antibiotic may be, for example, Cefuroxime sodium, Meropenem trihydrate, Netilmicin sulfate, Sisomicin sulfate, ceftibuten, PA-1806, IB-367, Tobramycin 'PA-1420, doxorubicin, Astromicin sulfate, cefetamet pivoxil hydrochloride, and the like. Non-steroidal anti-inflammatory drugs (NS AIDs) can be, for example, aspirin, salicylic acid, diclofenac, 卩 哄 哄 , ,, new 'ibuprofen, ketoprofen, loxoprofen, naproxen, Piroxicam, Meroximac, aceclofenac, Actarit, diacerein, Etodolac, Celecoxib, Lumiracoxib, etc. = steroids may be, for example, Clobetasol propionate, Diflorasone 'Fluocinonide, furanoseone, Betamethasone, Betamethasone, Betamethasone, Difluprednate, budesonide, Diflucortolone 'Amcinonide , Halcinonide, dexamethasone, dexamethasone propionate, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrogenated cortisone butyrate, propionate Acid Deprodone, prednisolone, Fluocinolone, beclomethasone, Triamcinolone acetonide, Flumethasone, propionate-41 - 200918065

Alclometasone, Clobetasone butyrate, dehydropicitol, beclomethasone propionate, Fludroxycortide, cortisone acetate, hydrocortisone, sodium hydrocortisone, sodium hydrocortisone succinate, Fludrocone acetate, acetic acid Dehydropicitol, sodium dehydrosodium succinate, dehydropicanol butyl acetate, sodium dehydrogenation of sodium phosphate, Halopredone acetate, methyl dehydrogenol, methyl dehydrogenol acetate, succinic acid Sodium methyl dehydropecitate, triamcinolone, triamcinolone acetate, dexamethasone phosphate, dexamethasone hexaderate, paramethasone acetate, Betamethasone, Futicasone propionate, Flunisolide 'ST-126P, Ciclesonide, dexamethasone hexadecanoic acid Ester, Mometasone furan carboxylate, Prasterone sulfonate, Algestone, methyl dehydrogenol sulphate, methyl dehydropepine sodium succinate, and the like. The amount of the compound of the present invention represented by the formula (I), the salt thereof or the solvate thereof may vary depending on the symptom, the age, the body weight, the type and amount of the agent administered in combination, and the usual compound (1). The amount of conversion is in the range of O.OOlmg~lOOmg for adults-persons, and is administered systemically or partially by mouth or by mouth for one or several times a day or one day for a period of one hour to 24 hours. Intravenous is preferred. The pharmaceutical-containing compound containing the compound of the present invention is administered once per adult for one day, and is preferably repeated at appropriate intervals. The dosage is 〇. (the range of nmg~2000mg, preferably in the range of O.lmg~lOOmg, more preferably lmg~5 OOmg ° and the present invention does not impair the range of the effect of the present invention, and if necessary, joint rheumatoid medicine can be used together, Anti-dry drug, bronchodilator, anti-bronchial asthma-42-200918065 Medicine or anti-diabetic agent. The present invention also includes a method and/or a treatment method for preventing the aforementioned diseases by administering the compound of the present invention or a salt thereof. The invention also includes the use of the compound of the invention, a salt thereof or a solvate thereof of the invention described above. [Examples] The present invention is described in detail by the following examples, but the scope of the invention is not limited to the infrared spectrum ( IR) use Japan Bunko FT/IR-6100 type A, ST Japan Durascope (Diamond/KRS-5), Hitachi 270-30 spectrometer or Horiba FT-720 (S_T. Japan Durascope (Diamond/KRS-5), KBr Determination by spindle method or KC1 tablet method. Nuclear magnetic resonance spectrum (NMR) is determined by using E0L JNM-EX400 or JNM-ECX400P. Unless otherwise indicated, it refers to proton NMR (IH-NMR) and internal standard. Base decane and 1H-NMR multiplicity s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br s = broad singlet. The tannin used for column chromatography is Kiesel-gel 60 (particle size 0.060-0.200mm) from E-Merck Further, the sheet of thin layer chromatography (TLC) was Kieselgel 60 F254 manufactured by E-Merck Co., Ltd. This example uses the following abbreviation. -43- 200918065

B oc tert-butoxycarbonyl B oc 2 Ο di-tert-butyl diamine carboxylic acid CDC 1 3 heavy chloroform cd3 〇d heavy methanol DMSO-de dimethyl sulfoxide-d 6 DMTMM 4-(4,6-dimethoxy Base-1,3,5-tripa-2-yl)-4-methylchloromorpholine DMAP 4-(N,N-dimethylamino)pyridine DMF hydrazine, hydrazine-dimethylmethyl DMSO - ^•甲亚枫 EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOB t 1-hydroxybenzotriazole TEA triethylamine THF tetrahydrofuran TLC thin film chromatography HP LC High-speed liquid chromatography [Reference Example 1] 3-bromo-6-chloroimidazo[1,2-b] oxime (engineering 1) 6-chloroimidazo[1,2-b] fluorene acetaldehyde Ethyl acetal (260ml, 1. A mixture of 73 mol), 47% hydrogen bromide water (65 ml) and water (65 ml) was stirred under reflux for 2 hours. After the reaction mixture was cooled at room temperature, it was poured into 1,2-dimethoxyethane (2000 ml). The mixture was neutralized by adding sodium hydrogencarbonate (powder). The resulting insoluble matter was filtered off with diatomaceous earth. Add 3-amino-6-chloropurine trap to the filtrate (107g, 0. 826 m〇l), stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure to about half amount. The resulting precipitate was collected by suction filtration, and washed with 1,2-dimethoxyethane and diethyl ether to give a crystalline powder. The obtained crystalline powder was poured into a saturated aqueous sodium hydrogencarbonate solution (1 200 ml), and stirred vigorously to stop foaming. The precipitate was filtered under reduced pressure and filtered, washed with saturated sodium bicarbonate aqueous solution -44 - 200918065 and water. The obtained solid was dried under reduced pressure to give the title compound (94 g, 74%). NMRCCDC13) (5 : 7 · 0 6 (1 Η, d, J = 9 · 3 Η z), 7. 7 9 (1 Η, d, J = 1.  2 Η z), 7. 92 (lH, dJ = 9. 3Hz), 7. 95 (lH, brs).  (Engineering 2) 3-Bromo-6-chloroimidazo[1,2-b] oxime trap 6-Chloroimidazo[1,2-b] oxime (74 g, 482 mmol) was dissolved in glacial acetic acid (500 ml) Bromine (32 ml, 625 mmol) was added dropwise with stirring at room temperature for 2 hours. After the end of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. The resulting precipitate was suction-filtered, washed with glacial acetic acid and diethyl ether to give a crystalline powder. Further, the filtrate was concentrated under reduced pressure, and the obtained precipitate was suction filtered, and washed with glacial acetic acid and diethyl ether to give a crystalline powder. The obtained crystalline powder was dissolved in dichloromethane (1000 ml), and washed with a 1N aqueous sodium hydroxide solution (1000 ml). The dichloromethane layer was separated and dried over anhydrous sodium sulfate. After the insoluble material was filtered, the filtrate was concentrated under reduced pressure. The obtained solid was suspended in hexane / ethyl acetate (10:1). NMR (CDC13) 5 : 7 .  1 2 (1 Η,d,J = 8. 8 H z), 7. 7 9 (1 Η, s), 7. 9 0 (1 Η, d, J = 8. 8Hz). [Example 1] Ν-(4-chlorobenzyl)-4-[6-[[2-(methylthio)ethyl]amino]imidazo[l,2-b]indole-3-yl ]-N-(2-pyrrolidin-1-ylethyl)benzylguanamine (A39 of the compound table) (Engineering 1) Ν-(4-chlorobenzyl)-2-pyrrolidin-1-ylethylamine 4-chlorobenzylaldehyde (703 mg, 5 mmol), 1-(2-aminoethyl)pyrrolidine (0. 76ml, 6. a mixture of 0 mmol) and dichloromethane (20 ml), under ice cooling -45-200918065 plus acetic acid (0. 34ml, 6mmol) and sodium cyanoborohydride (1. 59g, 7. 5 mmol) was stirred under nitrogen for 24 hours at room temperature. After the reaction mixture was stirred with a saturated aqueous solution of sodium hydrogencarbonate for 1 hour, it was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.  1 g, 9 3 %). (Engineering 2) 3-Bromo-N-[2-(methylthio)ethyl]imidazo[i,2-b]indole-6-amine in 3-di-6-chloromethane and [l, 2-b] tower 哄 (3. 70g, 15. 9mmol) plus 2-methylthioethylamine (l_48ml, 15. 9mmol) and TEA (5. 54ml, 39. 7 mmol), heated in a sealed tube at 110 ° C for 24 hours. After cooling at room temperature, the reaction mixture was added with water. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and water (100 ml) was evaporated. The solid which precipitated was collected by filtration, and the solid was washed in the order of water (100 ml) and diethyl ether (50 ml). After drying under reduced pressure at 80 C, the title compound was obtained. 2 8 g, 7. 9 4 m m ο 1) Tea Brown powder. Further, the mixture was evaporated under reduced pressure of water and diethyl ether. The mixture obtained was extracted twice with chloroform / 2-propanol = 3 / 1 and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAc m. 32g, 4. 60 mmol) yellow powder (total yield 79%). (Engineering 3) (3-Bromoimidazo[1,2-1)]non-6-yl)[2-(methylthio)ethyl]aminecarboxylic acid tert-butyl ester 3-bromo-N-[ 2-(Methylthio)ethyl]imidazo[l,2-b]indole-6-amine (3. 59 £, 12. 5111111〇1) Dissolved in 01^?(381111), plus 6〇. 20 (5. 5〇£,25. 2 mmol), TEA (7. 0ml, 50. 2mmol), and D M A P (7 7 Omg, 6. 3 0 -46- 200918065 mmol) was stirred at 60 ° C for 2 hours. After cooling to room temperature, it was concentrated under reduced pressure to give water (30 m 1). The resulting mixture was extracted with ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. 23g, 10. 9 mmol, 87%). (Engineering 4) 4-[6-[(Tertidinoxycarbonyl)[2·(methylthio)ethyl]amino]imidazo[l,2-b]indol-3-yl]benzoic acid (3-Bromoimidazo[l,2-b]indole-6-yl)[2-(methylthio)ethyl]aminecarboxylic acid tert-butyl ester (2. 05g, 5. 29mmol), 4-carboxyphenylboronic acid (1. 32g, 7. 94 mmol), dichlorobis(triphenylphosphine)palladium&gt;(π)(ι 86 mg, 0. 265mmol) and 2M aqueous potassium carbonate / 1,4-dioxane mixture (21. 2ml/32. The mixture of 0 ml) was stirred at 90 ° C for 5 hours under a nitrogen stream. After cooling the reaction mixture to room temperature, the 1,4-di-Bf alkane was distilled off under reduced pressure. After the residue was added with diethyl ether and stirred, the diethyl ether layer was removed by liquid separation, and the aqueous solution was saturated with aqueous citric acid to make it acidic. Stir at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with water. The obtained solid was dissolved in chloroform/methanol (5:1), dried over anhydrous sodium sulfate and EtOAc. 3 3 g, 1〇〇%). (Engineering 5) N-(4-Chlorobenzyl)·4·[6-[[2-(methylthio)ethyl]amino]imidazo[l,2-b]indole-3-yl] -N-(2-pyrrolidin-1-ylethyl)benzylamine in 4-[6-[(t-butoxycarbonyl)[2-(methylthio)ethyl]amino]imidazo[l ,2-b]indole-3-yl]benzoic acid (3〇〇mg, 〇. 700 mmol), N-(4-chlorobenzyl)-2-pyrrolidin-1-ylethylamine (200 mg, 0. Mix of 840mmol) and DMF (lOml) -47- 200918065 Mixture, add EDC (202mg, 1. 05mmol), H〇Bt (94. 0mg'0·700 mmol) and TEA (0. 09 8ml, 0. 700 mmol), spoiled for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform, and washed with aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate. The resulting residue was dissolved in trichloroacetic acid (3 ml) (3 ml) and stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was evaporated to ethylamine (yield: EtOAc: EtOAc:于 Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ The chloroform layer was washed with brine and dried over anhydrous sodium sulfate. [Example 2] N-(4-chlorobenzyl)-N-[2-(dimethylamino)ethyl]-M6-[[2-(methylthio)ethyl]amino]imidazo[ 1,2-b]indole-3-yl]benzylguanamine (A 4 0 of the compound table) (Engineering 1) N'-(4-chlorobenzyl)-N,N-dimethylethane-1 , 2-diamine, 4-chlorine awakening (703mg, with 5. 00 mmol) and hydrazine, hydrazine-dimethylethylenediamine (0 · 6 5 6 m 1, 6 · 0 0 m ο 1), m. (Engineering 2) N-(4-chlorobenzyl)-indole[2-(dimethylamino)ethyl]-4-[6-[[2-(methylthio)ethyl]amino]imidazole And [l,2-b]indole-3-yl]benzylamine with 4-[6-[(t-butoxycarbonyl)[2-(methylthio)ethyl]amino]imidazo[l ,2-b]嗒-3-yl]benzoic acid (3〇〇mg, 〇. 700 mmol) and Ν'-(4-chlorobenzyl)-indole, hydrazine-dimethylethane-1,2-diamine (179 mg, 0. 840 mmol), imitation -48-200918065 The work of Example 5 of Example 1 gave the title compound (164, 43%). [Example 3] N-(4-chlorobenzyl)-N-[2-(diethylamino)ethyl]-4-[6-[[2-(methylthio)ethyl]amino]imidazole And [ub]嗒-3-yl] benzalkonium (Compound Table A41) (Engineering 1) N'-(4-Chlorobenzyl)-N,N-diethylethane-i,2 - II Amine with 4-chlorobenzylaldehyde (703 mg, 5. 00mmol) and N,N-diethylethylenediamine (0. 697ml, 6. 00 mmol), working in the same manner as in Example 1 of Example 1, to obtain the title compound (1. 20g, 99%). (Engineering 2) Ν-(4·Chlorobenzyl)-Ν·[2-(diethylamino)ethyl]_4-[6-[[2-(methylthio)ethyl]amino]imidazolium [l,2-b]indole-3-yl]benzylamine with 4-[6-[(t-butoxycarbonyl)[2-(methylthio)ethyl]amino]imidazo[l, 2-b]嗒耕-3-yl]benzoic acid (300 mg, 0. 700 mmol) and N,-(4-chloro-yl)-indole, Ν·diethyl ethene-1,2-diamine (202 mg, 0. The title compound (I47 mg, 37%) was obtained. [Example 4] Ν-(4.methoxybenzyl)-4-[6·[[2-(methylthio)ethyl]amino]imidazo[l,2-b]indole-3- ]]-Ν-(2-pyrrolidin-1·ylethyl)benzylguanamine (Compound Table 42) (Engineering 1) N'-(4-Methoxybenzyl)-2-pyrrolidine·ΐ-yl Ethylamine with 4-methoxyl aldehyde (0. 609ml, 5. 00 mmol) and 1-(2-aminoethyl)pyrrolidine (0-760 ml, 6-00 mmol) were obtained from the work of Example 1 to give the title compound. 〇 2g, 87%). (Engineering 2) N-(4-Methoxybenzyl)-4-[6-[[2-(methylthio)ethyl]amino]imidazo[1,2-b]indole-3-yl ]-N-(2-pyrrolidin-1-ylethyl)benzylamine 4-(6-[(t-butoxycarbonyl)[2-(methylthio)ethyl]amino]imidazolium- 49- 200918065 [l,2-b]嗒-3-yl]benzoic acid (300mg, 0. 700 mmol) and N,-(4-methoxyindolyl)-2-indole-slightly steep-1-ylethylamine (I97 mg, 0. The title compound (i7 〇mg, 42%) was obtained from the procedure of </RTI> [Example 5] N-[2-(dimethylamino)ethyl]-N-(4-methoxybenzyl)-4-[6-[[2-(methylthio)ethyl]amino group Imidazo[1,2-b]indole-3-yl]benzylamine (A43 of the compound table) (Engineering 1) N'-(4-methoxybenzyl)-N,N-dimethyl 4-methoxybenzyl aldehyde with alkane-1,2-diamine (〇. 6091111, 5. 0〇111111〇1) and heart 1^-dimethylglyoxime (〇_656ml, 6. 00 mmol), in the same manner as in the operation of Example 1, the title compound (1. 04g, 99%). (Engineering 2) N-[2-(Dimethylamino)ethyl]-N-(4-methoxybenzyl)-4-[6-[[2-(methylthio)ethyl]amino] Imidazo[l,2-b]indole-3-yl]benzylamine with 4-[6-[(t-butoxycarbonyl)[2-(methylthio)ethyl]amino]imidazo[ l,2-b]indole-3-yl]benzoic acid (300 mg, 0. 700 mmol) and NT-(4-methoxybenzyl)-N,N-dimethylethane-1,2-diamine (175 mg, 0. The title compound (169 mg, 44%) was obtained. ί [Example 6] N-[2-(Diethylamino)ethyl]-N-(4-methoxybenzyl)-4-[6-[[2-(methylthio)ethyl]amine Imidazo[1,2-b]indole-3-yl]benzylamine 2 hydrochloride (Compound Table A44) (Engineering 1) N,N-Diethyl-Ν' -(4-A Oxybenzyl)ethane-1,2-diamine with 4-methoxybenzylaldehyde (0. 6091111, 5. 00111111〇1) and 叱1 diethylethylenediamine (0. 697 ml, 6. 00 mmol), in the same manner as in the operation of Example 1, the title compound (1. 1 7 g, 9 9 %). (Engineering 2) N-[2-(Diethylamino)ethyl]-N-(4-methoxybenzyl)-4-[6--50- 200918065 [[2-(methylthio)ethyl) Amino]imidazo[1)2_b]indole-3-yl]benzylamine 2 hydrochloride with 4-[6-[(t-butoxycarbonyl)[2-(methylthio)ethyl]amine Imidazo[l,2-b]indole-3-yl]benzoic acid (300rng,0. 700 mmol) and N,N-diethyl-oxime-(4-methoxybenzyl)ethane-oxime, 2-diamine (199 mg, 0. 840 mmol), working in the same manner as in Example 1 of Example 1, and adding the concentrated residue to the obtained residue.  The title compound (184 mg, 39%) was obtained. [Example 7] 4-[[[4-[6-[(t-butoxycarbonyl)[3-(methylthio)propyl]] ylamino] imidazo[l,2-b] oxime- 3-yl]benzylindenyl](2-pyrrolidin-1-ylethyl)amino]methyl]benzoic acid 0. 75 formate (A45 of the compound table) (Engineering 1) 4-[[(2-pyrrolidin-1-ylethyl)amino]methyl]benzoic acid methyl ester with methyl 4-methylmercaptobenzoate (820mg, 5. 00mmol) and 1-(2-aminoethyl)pyrrolidine (0_7 60ml, 6. 00 mrnol), i.e., the operation of Example 1 of Example 1, to obtain the title compound (1.  2 3 g, 9 3 %). (Engineering 2) 3-Bromo-N-[3-(methylthio)propyl]imidazo[1,2-b]indole-6- U amine with 3-bromo-6-chloroimidazo[1, 2-b] 嗒 well (5. 81g, 25. 0mmol) and 3-methylthiopropylamine (2. 80ml, 25. Ommol), following the operation of Example 2 of Example 1, gave the title compound (7. 22g, 24. 0 mmol) colorless powder (96% yield). (Engineering 3) (3-Bromoimidazo[1,2-b]indole-6-yl)[3-(methylthio)propyl]carbamic acid tert-butyl ester with 3-bromo-N-[3 -(Methylthio)propyl]imidazo[l,2-b]indole-6-amine (7. 22g, 24. 0mmol), working in the same manner as in Example 3, to obtain a brownish brown -51 - 200918065 oily title compound (8. 44g, 21. 0 mmol, 88%). (Engineering 4) 4-(6-[(Tertidinoxycarbonyl)[3-(methylthio)propyl]amino]imidazo[1,2-b]indole-3-yl)benzoic acid (3-Bromoimidazo[l,2-b]indole-6-yl)[3-(methylthio)propyl]aminecarboxylic acid tert-butyl ester (2. 69g, 6. 70 mmol) and 4-(dihydroxyboroboryl)benzoic acid (2,91 g, 17. 5 mmol), following the work of Example 4 of Example 1, gave the title compound (2. 53§, 5. 72111111〇1,85%) brown powder. (Engineering 5) 4-[[[4-[6-[(T-Butoxycarbonyl)[3-(methylthio)propyl]amine]]]imidazo[1,2-b]indole-3 -yl]benzylidene](2-pyrrolidin-1-ylethyl)amino]methyl]benzoic acid methyl ester in 4-[6-[(t-butoxycarbonyl)[3-(methylthio) )propyl]amino]imidazo[l,2-b]indole-3-yl]benzoic acid (110 mg, 0. 250 mmol), 4·[[(2·pyrrolidin-1-ylethyl)amino]methyl]benzoic acid methyl ester (79 mg, 0. A mixture of 300 mmol) and DMF (2 ml), ED C (7 2 m g, 0 · 3 7 5 mm ο 1), Η Ο B t (34 mg, 0. 25 0mmol) and TEA (0. 035ml,0. 250 mmol), stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAcjjjjjjj (Engineering 6) 4-[[[4-[6-[[3-(methylthio)propyl]amino]]imidazo[1,2-b]indole-3-yl]benzylidene]( 2-pyrrolidin-1-ylethyl)amino]methyl]benzoic acid 0. 75-formate-52- 200918065 in 4-[[[4-[6-[(t-butoxycarbonyl)[3-(methylthio)propyl]amino]imidazo[1,2-b] Methyl 3-benzyl]benzyl indenyl](2-pyrrolidin-1-ylethyl)amino]methyl]benzoic acid methyl ester (187 mg, 0. A mixture of 250 mmol) and methanol (6 ml) was added EtOAc. After the reaction mixture was neutralized by adding 1 N aqueous hydrochloric acid, the mixture was evaporated. The residue was concentrated in chloroform (4 ml). The reaction mixture was concentrated under reduced pressure, and the residue was evaporated to ethylamine. The mixture was neutralized with a 5% aqueous solution of sodium hydrogencarbonate, and the acetonitrile was concentrated under reduced pressure. The residue was concentrated to hexane and methanol. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The obtained solid was washed with hexane to give the title compound (33. 3mg, 21%). [Example 8] N-(4-chlorobenzyl)-N-[2-(dimethylamino)ethyl]-4-(6-[[3·(methylthio)propyl]amino] Imidazo[l,2-b]indole-3-yl)benzamide 2. 0 hydrochloride (A46 of the compound table) will be Ν'-(4-chlorobenzyl)-indole, hydrazine-dimethylethane-1,2-diamine (199 mg, 0. 936mmol) dissolved in DMF (5. 4 ml), 4-(6-[(Table dibutoxycarbonyl)[3-(methylthio)propyl]amino] imidazo[l,2-b]indole-3-yl)benzoic acid ( 3 5 0mg, 0. 79 lmmol), TEA (3 50 &quot; 1,2_51 mmol) and DMTMM (351 mg, 1. 20mmol). After stirring at room temperature for 64 hours, water (15 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with water, washed with saturated brine for one time, and dried with anhydrous sodium sulfate. After the insoluble material was filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by chromatography (ethyl acetate /methanol, and chloroform/methanol). The oily substance is dissolved in dichloromethane (4. Lml), adding trifluoroacetic acid at 0 ° C (1. 9 ml) and stir for 5 minutes. Warm up to room temperature and stir. After 5 hours, the reaction mixture was evaporated. The resulting mixture was extracted 3 times with chloroform / 2-propanol = 3:1 and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography, EtOAc EtOAc EtOAc EtOAc Add 0. The title compound (193 mg, 0. 292 mmol, 37%) light yellow powder. [Example 9] N-(4-chlorobenzyl)-N-[2-(diethylamino)ethyl]-4-(6-[[3-(methylthio)propyl]amino] Imidazo[1,2-b]indole-3-yl)benzamide 1. 83 hydrochloride (A47 of the compound table) with Ν'-(4-chlorobenzyl)-indole, hydrazine-diethylethane-1,2-diamine (211 mg, 0-876 mmol) and 4-(6-[ (t-butoxycarbonyl)[3-(methylthio)propanyl; yl]amino]imidazo[1,2-b]indole-3-yl)benzoic acid (329 mg, 0. The title compound (270 mg, 0. 404 mmol, 54%) colorless powder. [Example 1 Ν] Ν-(4-chlorobenzyl)-4-(6-[[3-(methylthio)propyl]amino]imidazo[l,2-b]indole-3- -N-(2-pyrrolidine-i-ylethyl)benzamide 1. 8 hydrochloride (A48 of the compound table) with N-(4-chlorophenyl)-2-pyrrole-thyl-1-ethylethylamine (221 mg, 0. 926mmol) and 4-(6-[(t-butoxycarbonyl)[3-(methylthio)propyl]amino]imidazo-54- 200918065 [l,2-b]Tower -3·yl) Benzoic acid (348mg, 〇. 786inm〇i), imitation Example 8 Operation 'title compound (203mg, 0. 303 mmol, 39%) colorless powder. [Example 1 1] Ν-(4-chlorobenzyl)-4-[6-(4-fluorobutylamino)imidazo[1,2-1)]]]-3-yl]-^(2 -pyrrolidin-1-ylethyl)benzylguanamine (A1 of the compound table) (Engineering 1) 4-[(3-Bromoimidazo[i,2-b]indole-6-yl)amino]- 1-butanol is a 3-bromo-6-chloroimidazo[l,2-b]indole as described in Reference Example 1 (5 g, 21. 5mmol) and 4-amino-1.butanol (2. 9 ml, 32 mmol), according to the procedure 2 of Example f 1 to give the title compound (4. 6g, 75%). (Engineering 2) 3-Bromo-N-(4-methoxybenzyl)-N-[4-[(4-methoxybenzyl)oxy] butyl]imidazo[l,2-b]fluorene trap -6-amine in 4-[(3-bromoimidazo[l,2-b]indole-6-yl)amino]-1-butanol (6. 8g, 23. 8mmol) plus DMF (125 ml), sodium hydrosulfide under ice cooling (2. 5g, 57mmo 〇, stirring 30 minutes. Add 4-methoxybenzyl chloride (7. 9 m 1, 57 mmol), stirred at room temperature for 3 hours. Methanol (15 ml) was added under ice-cooling, and concentrated under reduced pressure. ethyl acetate and brine were evaporated and evaporated. The ί machine layer was washed with water and saturated brine, and dried with anhydrous sodium carbonate. After the insoluble material was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to EtOAc EtOAc (EtOAc)  3 g , 90%). (Engineering 3) 4-[(3-Bromoimidazo[1,2-b]indole-6-yl)(4-methoxybenzyl)amino]butan-1-ol 3-bromo-N- (4-methoxybenzyl)-N-[4-[(4-methoxybenzyl)oxy]butyl]imidazo[1,2-b]indole-6-amine (1. 28g, 2. 44mmol) dissolved in methanol -55- 200918065 (26ml) 'Add water to its solution (2. 9ml). The resulting mixture was added at 〇 ° C with diammonium nitrate (1 乂) (4. 03 £, 7. 35111111〇1). After stirring for 5 minutes (5 minutes after stirring, the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and water (20 ml) was then taken and extracted twice with dichloromethane. After (30 ml), the mixture was extracted with methylene chloride (m.sub.2), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue was concentrated under reduced pressure. , the title compound (452mg, 1. 12 mmol, 46%) yellow oil. ί (Engineering 4) 4-[(3-Bromoimidazo[l,2-b]indole-6-yl)-(4-methoxybenzyl)amino]methanesulfonate butyl 4-(( 3-bromoimidazo[l,2-b]indole-6-yl)-(4-methoxybenzyl)amino]butanol (1. 41g, 3. 48 mmol) was dissolved in pyridine (14 ml) and added with methanesulfonyl chloride at 0 °C (0. 54ml, 6. 96 mmol), stirred for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to chromatography (Biot. 40S, solvent elution, chloroform:methanol = 100: 0 to 95: (. .  5) Refined to obtain the title compound (1. 48 g, 88%) light yellow oil. (Engineering 5) (3-Bromoimidazo[l,2-b]indole-6-yl)-(4-fluorobutyl)-(4-methoxybenzyl)amine 4-[(3-bromo) Imidazo[l,2-b]indole-6-yl)-(4-methoxybenzyl. Amino] butyl sulfonate (2. 27g, 4. 70 mmol) was dissolved in tetrahydrofuran (40 ml), and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 14. 10ml, 14. 10 mmol), heated to reflux for 1 hour. After the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate -56 - 200918065. After filtration, the filtrate was concentrated under reduced pressure. EtOAc m. 58 g, 82%) light yellow oil. (Engineering 6) (3-Bromoimidazo[l,2-b]indole-6-yl)-(4-fluorobutyl)amine (3-bromoimidazo[l,2-b]indole- 6-yl)-(4-fluorobutyl)-(4-methoxybenzyl)amine (1. 58g, 3. 88 mmol) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature for 2 hr. The reaction solution was slowly poured into saturated sodium hydrogencarbonate water to make an alkali, and extracted with dichloromethane. The extract was washed with saturated brine (dried with anhydrous sodium sulfate). After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (Biotage 40S, solvent eluted, chloroform:methanol = 100:0 to 95: 5) Refined to obtain the title compound (1. 0 5g, 9 4%) light yellow solid 〇 (engineering 7) (3-bromoimidazo[1,2-b] oxime-6-yl M4-fluorobutyl)aminecarboxylic acid tert-butyl ester (3· Bromoimidazo[1,2-b]indole-6-yl)-(4-fluorobutyl)amine (1. 05g, 3. 66 mmol), which was operated in the same manner as in Example 1 of Example 1, to obtain the title compound (1. 42 g, 10% by weight) light brown oil. (Engineering 8) 4-[6-[(Tertidinoxycarbonyl)(4-fluorobutyl)amino]imidazo[1,2-b]indole-3-yl]benzoic acid (3-bromo) Imidazo[l,2-b]indole-6-yl)(4-fluorobutyl)aminecarboxylic acid tert-butyl ester (168 mg, 0. 434 mmol) and 4-(dihydroxyboroboryl)benzoic acid (189 mg, 1. The title compound (163 mg, 0. 380 mmol, 88%) light yellow powder. (Engineering 9) [3-[4-[(4-Chlorobenzyl M2-pyrrolidin-1-ylethyl)aminemethanthine-57- 200918065]]phenyl]imidazo[Hb]嗒 well_6_ Tertyl]_(4-fluorobutyl)aminecarboxylic acid tert-butyl ester with 4-[6-[t-butoxycarbonyl-(4-fluorobutyl)amino]imidazolyl-1,2-b] 3-yl]benzoic acid (2〇〇mg, 〇47mm〇1) and (4-chlorobenzyl)_(2•pyrroleth-1-ylethyl)amine (278mg, 1. 17 mmol), the work of Example 7 was followed by the operation of the title compound (〇.  3 1 g, 1 〇 〇 %) Light yellow oil. (Engineering 10) N-(4-Chlorobenzyl)-4-[6-(4-fluorobutylamino)imidazo[l,2-b]indole-3-yl]-N-(2-pyrrole Pyridin-1-ylethyl)benzamide ([3_[4-[(4-chlorobenzyl)·(2-pyrrolidin-1-ylethyl)aminemethanyl]phenyl]imidazo[ 1,2-b] tertyl-6-yl]-(4-fluorobutyl)aminecarboxylic acid tert-butyl ester (310 mg, 0. 48 mmol) was dissolved in dichloromethane (4 ml). The reaction mixture was diluted with sodium hydrogencarbonate to give a weak basic, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAc m. Amorphous solid. [Example 12] Ν-(4-chlorobenzyl)-indole-(2-diethylaminoethyl)-4-[6-(4-fluorobutylamino)imidazo[l,2-b]indole Well-3-yl]benzylamine (Compound Table 2) (Engineering 1) [3-[4-[(4-Chlorobenzyl)-(2-diethylamineethyl)aminemethanyl]phenyl) Imidazo[1,2-b]indole-6-yl]-(4-fluorobutyl)aminecarboxylic acid tert-butyl ester using 4-[6-[t-butoxycarbonyl-() described in Example 11 4-fluorobutyl)amino]imipid [l,2-b] ta -3-yl]benzoic acid (2 〇〇 mg, 〇. 47 mmol) and (4-chlorobenzyl)-(2-diethylamine ethyl)amine (225 mg, 0. The title compound (298 mg, 98%) was obtained as a pale yellow oil (yield: N) (N-(4-chlorobenzyl)-N-(2-). Diethylamine ethyl)-4-[6-(4-fluorobutylamino)imidazo[l,2-b]indole- 3. -[3-[4-[(4-chlorobenzyl)-(2-diethylaminoethyl)amine-carbamoyl]phenyl]imidazo[l,2-b]indole -6-yl]-(4-fluorobutyl)aminecarboxylic acid tert-butyl ester (298 mg, 0. The title compound (197 mg, 78%) was obtained as a pale yellow amorphous solid. ί [Example 13] 4-[6-(4-fluorobutylamino)imidazo[l,2-b]indole-3-yl]-indole-(4-methoxybenzyl)-indole-( 2-pyrrolidin-1-ylethyl)benzylguanamine (A3 of the compound table), (Engineering 1) 4-fluorobutyl-[3-[4-[(4-methoxybenzyl)-(2- Pyrrolidin-1-ylethyl)amine-carbamoyl]phenyl]imidazo[l,2-b]pyridin-6-yl]-tert-butyl ester of tert-butyl ester. 4-[6- described in Example 11 [Third butoxycarbonyl_(4-fluorobutyl)amino]imidazo[l,2-b]indole-3-yl]benzoic acid (150 mg, 0. 35 mmol) and (4-Ίmethoxybenzyl)-(2-anthracet-1-ylethyl)amine (205 mg, 0. The title compound (I89 mg, 84%) was obtained as pale yellow oil. (Engineering 2) 4-[6-(4-Fluorobutylamino)imidazo[i,2-b]indole-3-yl]-N-(4-methoxybenzyl)-N-(2- 4-fluorobutyl-[3-[4-[(4-methoxybenzyl)-(2-pyrrolidin-1-ylethyl)aminecarboxamide for pyrrolidine-bukiethyl)benzamide Phenyl]imidazo[l,2-b]indol-6-yl]-tert-butyl carboxylic acid tert-butyl ester (189 mg, 0. 29 mmol), following the procedure of Example 11 to give the title compound - 59 - 2009 18065 Compound (1 4 9 m g, 93%) as a pale yellow amorphous solid. [Example 14] N-(4-chlorobenzyl)-N-[2-(diethylamino)ethyl]_4-[6-[(5-pentyl)amino]mi[i][i] , 2-b] 哄 哄 -3-yl] decylamine 2. 0 hydrochloride (A4 of the compound table) (Engineering 1) 5-[(3-bromoimidazo[i,2-b]indole-6-yl)amino]pentan-1-ol Reference Example 1 g 3 -Bromo-6-chloroimidazo[i,2-b] arable (7. 85g, 33. 8 mmol) and 5-amino-1-pentanol (i3. 93g, 135mm 〇 1), the engineering 2 operation of the same example 1 was obtained as the title compound (9. 8 〇 g, 32_8 mmol, 97%) pale yellow powder. (Engineering 2) 3-bromo-indole-(4-methoxybenzyl)·ν·[5-[(4-methoxybenzyl)oxy]pentyl]imidazo[1,2-b], hydrazine 5-[(3-bromoimidazo[l,2-b]indole-6-yl)amino]pentan-1-ol is used as the well-6-amine. 79g, 3 2. 7mmol), imitation example! The engineering 2 operation of 1 gives the title compound (16. 86g, 31. 25 mmol, 96%) brown oily substance. (Engineering 3) 5-[(3-Bromoimidazo[i,2_b]indole-6-yl)(4-methoxybenzyl)amino]pentan-1-ol ij with 3-bromo-N-( 4-methoxybenzyl)·Ν-[5-[(4-methoxybenzyl)oxy]pentyl]imidazo[l,2-b]indole-6-amine (16. 86g, 31. 25 mmol), working in the same manner as in Example 11 to give the title compound (71 〇 2, 16. 9111111〇1,54%) tea brown oily substance. (Engineering 4) (3-Bromoimidazo[i,2-b]indole-6-yl)(5-fluoropentyl)aminecarboxylic acid tert-butyl ester 5-[(3-bromoimidazo[l, 2-b]嗒-6-yl)(4-methoxybenzyl)amino]pentan-1-ol (7. 10g, 16. 9mmol) dissolved in tetrahydrofuran (150ml), add -60- 200918065 sub-screen 4 A (9. 06g), p-toluenesulfonate fluoride (4. 44g, 25. 5mm〇l), and tetrabutylammonium fluoride 1. 0M tetrahydrofuran solution (85 ml), heated at 85 t. 5 hours. At intervals of 30 minutes, add p-toluenesulfonate fluoride back 3 (4. 49g, 4. 50g, 4. 45g). After cooling at room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and water (EtOAc) The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAc (EtOAc m. 8 8g). The obtained oily substance was added with trifluoroacetic acid (3 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced vacuo. The resulting mixture was extracted twice with dichloromethane and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. EtOAc m. 23g). The resulting oily substance was dissolved in DMF (5. 9ml), plus Boc20 (3. 26g, 1 4. 9mmol) 'TEA(4·2m 1,30· 1 mmo 1), and DMAP (461 mg, 3. After the mixture was stirred at room temperature for 2 hours, EtOAc was evaporated. The mixture was washed with brine and dried over anhydrous sodium sulfate. EtOAc was evaporated. 20g). The oily substance obtained was purified by fractional high-speed liquid chromatography (column: NOMURA Develosil Combi-RP-5, mobile phase: acetonitrile / water / formic acid) to give the title compound (1. 27§, 3. 16111111〇1,19%) Light yellow oily substance. -61 - 200918065 (Engineering 5) 4-[6-[(Tertidinoxycarbonyl)(5-fluoropentyl)amino]imidazo[l,2-b]indole-3-yl]benzoic acid (3-Bromoimidazo[l,2-b]fluorene -6-yl)(5-fluoropentyl)aminecarboxylic acid tert-butyl ester (1. 27g’3. 16 mmol) and 4-(dihydroxyboroboryl)benzoic acid (1. 39g’8. 38 mmol) was subjected to the work of Example 4 of Example 1 to give the title compound (1. 222, 2_76! 111] 1 〇 1, 87%) gray powder. (Engineering 6) N-(4-chlorobenzyl)·Ν-[2-(diethylamino)ethyl]·4_[6-[(5-fluoropentyl)amino]imidazo[1,2 -b]嗒-3-yl]benzylamine 2. 0 hydrochloride salt Ν'-(4-chlorobenzyl)-indole, hydrazine-diethylethane-hydrazine, 2-diamine (264 mg, 1. 10 mmol) and 4-[6-[(t-butoxycarbonyl)(5-fluoropentyl)amino]imidazo[l,2-b]indole-3-yl]benzoic acid (401 mg, 〇. 9〇6mm〇1), imitate the operation of Example 8 to obtain the title compound (4071112, 0. 604111111〇1,67%) White blister substance. [Example 1 5 ] N - (4-chlorobenzyl)-4 - [ 6 - [(5-fluoropentyl)amino] imidazo[l,2-b]indole-3-yl]-N -(2-pyrrolidin-1-ylethyl)benzylguanamine (A5 of the compound table) N-(4-chlorobenzyl)-2-pyrrolidin-1-ethylethylamine described in Example 1 (260 mg ,1. 09mmol) and 4-[6-[(t-butoxycarbonyl)(5-fluoropentyl)amino] miso[l,2-b]t--3-yl]-formic acid (400mg, 0. 904 mmol), imitating the work of Example 1 for the operation of the title compound (249 mg, 0. 4 3 2mmol, 48%) light yellow blister. [Example 16] 4-[6-(4-fluorobutylamino)imidazo[i,2-b]indole-3-yl]-indole-(3·fluoropyridin-2-ylmethyl)- N-(2-pyrrolidin-1-ylethyl)benzylguanamine (Compound Table A6) -62- 200918065 (Engineering 1) (3-Fluoropyridin-2-ylmethyl)-(2-pyrrolidine- 1-fluoroethyl)amine with 3-fluoropyridine-2-carbaldehyde (1. 〇〇g, 7. 99mmol) and 1-(2-aminoethyl)pyrrolidine (1. 22ml, 9. 59 mmol), the engineering operation of Example 1 was carried out to obtain the title compound (1. 07g, 60%) light brown oil. (Engineering 2) (4-Fluorobutyl)-[3-[4-[(3-fluoropyridin-2-ylmethyl)-(2-pyrrolidin-1-ylethyl)aminemethanyl]benzene Imidazo[l,2-b]indole-6-yl]-tributic acid tert-butyl ester with 4-[6-[t-butoxycarbonyl-(4-fluorobutyl)amino]imidazole [1,2-b] tau-3-yl]benzoic acid (161 mg, 0. 38 mmol) and (3-Fluoro-B-steep 2-ylmethyl)-(2-pyrrolidin-1-ylethyl)amine (168 mg, 0-75 mmol), m. 1 8 7 mg, 7 9 %) pale yellow oil 〇 (Engineering 3) 4-[6-(4-fluorobutylamino)imidazo[l,2-b]indole-3-yl]-N_ (3-fluoropyridin-2-ylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzylamine with (4-fluorobutyl)-[3-[4-[(3-fluoro) Pyridin-2-ylmethyl)-(2-pyrrolidinylethyl)aminecarboxyl]phenyl]imidazo[l,2-b]indole-6-yl]-carbamic acid tert-butyl ester ( 187mg, 0. The title compound (15 l mg, 96%) was obtained as a pale yellow amorphous solid. [Example 17] N_(3-fluoropyridin-2-ylmethyl)-4-[6-(2-methylthioethylamino)imidazo[l,2-b]indole-3-yl] -N-(2-pyrrolidin-1-ylethyl)benzylguanamine (A 4 9 of the compound table) (Engineering 1) [3-[4-[(3-fluoropyridin-2-ylmethyl)-) (2-pyrrolidin-1-ylethyl)amine-mercapto]phenyl]imidazo[l,2-b]indole-6-yl]-(2-methylsulfanylethyl)-carbamic acid Tributyl ester-63 - 200918065 4-[6-[Tertidinoxycarbonyl-(2-methylsulfanylethyl)amino]imidazo[l,2-b]indole-3-yl]benzoic acid (208mg, 0. 49 mmol) and (3-fluoropyridin-2-ylmethyl)-(2-pyrrolidin-1-ylethyl)amine (217 mg, 0. The title compound (29 3 mg, 95%) was obtained as a pale yellow oil. (Engineering 2) N-(3-Fluoropyridin-2-ylmethyl)-4-[6-(2-methylsulfanylethylamino)imidazo[l,2-b]indole-3-yl] -N-(2-pyrrolidin-1-ylethyl)benzylamine with [3-[4-[(3-fluoropyridin-2-ylmethyl)-(2-pyrrolidin-1-ylethyl) Aminomethane]phenyl]imidazo[l,2-b]indole-6-yl]-(2-methylsulfanylethyl)-carbamic acid tert-butyl ester (293 mg, 0. The title compound (1 15 mg, 47%) was obtained as a pale yellow amorphous solid. [Example 18] 2-fluoro-4-[6-(4-fluorobutylamino)imidazo[l,2-b]indole-3-yl]-N-(3-fluoropyridin-2-yl) Methyl)-N-(2-pyrrolidin-1ylethyl)benzylguanamine (A7 of the compound table) (Engineering 1) (4-fluorobutyl)-[3-[3-fluoro-4-[ (3-fluoropyridin-2-ylmethyl)-(2-pyrrolidin-1-ylethyl)amine-methylindenyl]phenyl]imidazo[1,2-anthracene-6-L]- Tert-butyl carbamate with 4-[6·[Tertidinoxycarbonyl-(4-fluorobutyl)amino]imidazo[l,2-b]indole-3-yl]-2-fluorobenzene Formic acid (i99mg, 0. 45 mmol) and (3-fluoropyridin-2-ylmethyl)-(2-pyrrolidin-1-ylethyl)amine (199 mg, 0-89 mmol), m. 0 mg , 1 00 %) light yellow oil. (Engineering 2) 2-Fluoro-4-[6-(4-fluorobutylamino)imidazo[1,2-b]indole-3-yl]-N-(3-fluoropyridine-2-ylmethyl) -N-(2-pyrrolidin-1ylethyl)benzamide-64- 200918065 Using (4-fluorobutyl)-[3-[3-fluoro-4-[(3-fluoropyridine)- 2-butylmethyl)-(2-pyrrolidin-1-ylethyl)amine-methylmethyl]phenyl]imidazo[1,2-b]indole-6-yl]-carbamic acid tert-butyl ester (290mg, 0. The title compound (21 9 mg, 89%) was obtained as a pale yellow amorphous solid. [Example 19] 4'-[[[[(2 3,41〇-4-fluoropyrrolidin-2-yl]methyl][4-[6-[[2-(methylthio)ethyl]]] Amino]imidazo[1,2-b]indole-3-yl)benzylidene]amino]methyl]biphenyl-4-carboxylic acid methyl ester (A50 of the compound table) (Engineering l) ( 2S,4R)-4-fluoro-2-[[(methylsulfonyl)oxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester in (2S,4R)-4-fluoro-2-( Hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (31. 6g, 0. A mixture of 14 mol), TEA (41 ml, 294 mmol) and dichloromethane (300 ml) was added with methanesulfonium chloride (17 ml, 220 mmol) at 0 ° C and stirred at room temperature for 18 hours. The reaction solution was added with water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate (MgSO4). Third butyl pyridine-1-carboxylate in (2S,4R)-4-fluoro-2-[[(methylsulfonyl)oxy]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (2 . 5g, 8. Mixture of 4mmol) and DMF (30ml), add sodium azide (2. 73 g, 42 mmol) was stirred at 70 ° C for 24 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained residue was subjected to EtOAc (EtOAc) (EtOAc) 3g, 63%) -65- 200918065 (Engineering 3) (2S,4R)-2-(Aminomethyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester in (2S,4R)-2 -(azidomethyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1. 3g, 5. A solution of 3 mmol) in ethanol (50 ml) was added with 5% palladium carbon (300 mg). After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give the title compound (1. 2g, 100%). (Engineering 4) (2S,4R)-4-fluoro-2-[[[[4'-(methoxycarbonyl)biphenyl-4-yl]methyl]amino]methyl]pyrrolidine-1- (3S,4R)-2-(Aminomethyl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (454 mg, 2. 08 mmol) and commercially available 4'-methylmercapto[1,1'-biphenyl]-4-carboxylic acid methyl ester (500 mg, 2. The title compound (3 4 3 m g, 37%) was obtained from the work of the procedure of Example 1 in the procedure of Example 1. (Engineering 5) 4'-[[[(25,411)-4-Fluoropyridin-2-yl)methyl][4-[6-[[2-(methylthio)ethyl]amino]]imidazole And [1,2-b]indole-3-yl]benzylindolyl]amino]methyl]biphenyl-4-carboxylic acid methyl ester with (2S,4R)-4-fluoro-2-[[ [[4'-(Methoxycarbonyl)biphenyl-4-yl]methyl]amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (168 mg, 0.  3 8 mmo 1) and 4-[6·[(t-butoxycarbonyl)[2-(methylthio)ethyl]amino]imidazo[1,2-b] as described in the work of Example 1. The title compound (5 3 mg, 21%) was obtained from the work of the procedure of Example 1 to give the title compound (5 3 mg, 21%). [Example 20] 4'-[[[[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl][4-[6-[[2-(methylthio)ethyl]amine) Imidazo[1,2-b]indole-3-yl]benzylindolyl-66- 200918065]amino]methyl]biphenyl-4-carboxylic acid (compound table A51) will 4' - [[[(2S,4R)-4-fluoropyrrolidin-2-yl)methyl] 4-[6-[[2-(methylthio)ethyl]amino]imidazo[1,2-b嗒 -3--3-yl]benzyl hydrazide]amino]methyl]biphenyl-4-carboxylic acid methyl ester (53 mg, 0. The mixture was dissolved in THF (5 ml) and methanol (5 m1). The reaction solution was concentrated under reduced vacuo. EtOAc (EtOAc)EtOAc. The g of the stomach was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc m. Machine data for each of the examples were shown in a list.

-67- 200918065

#▲Example NMR IR 1 Engineering 1 NMR (CDC13) δ :1.72-1.79 (4Η,β), 2. 49-2. 52(4Η,ιη)(2.61-2.64(2Η.·), 2. 71-2 74 (2Η, η), 3. 78 (2Η, s), 7. 24*7. 30 (4Η, η). 1 Engineering 2 NMR(CDC13) δ : 2.18(3Η, s), 2.85( 2Η, t, J=6. 4Ηζ), 3. 67(2Η, dt, J=6. 4,6. 1Hz), 4.85-4.97(ΐΗ.π), 6. 47(1Η? ά, J =9. 6Ηζ), 7. 48(1Η, s), 7. 60(1Η, d, J=9. 6Hz). 1 Engineering 3 NMR(CDCla) δ :1.55(9Η, s), 2.20(3H, s), 2. 90-2. 97 (2Η, η), 4. 12-4. l8(2H.m), 7.55 (1Η,d, J=10· 09Ηϊ) , 7, 69 (1Η, s),7,80(lH,d, J=9. 63Ηζ) · 1 Engineering 4 NMR(DMS〇-de) δ : 1. 50 (9Η, s), 2. 07 (3Η, s), 2, 83-2, 90(2Η, ηι)» 4. 04-4.11 (2Η&gt; m) , 7.58(ΙΗ, d, J=9. 77Hz), 8. 05 (2Η, d, J=8. 54Hz ), 8. 16(1Η, d, J=9. 77Hz), 8. 24(2Η ,d(J=8.54Hz), 8. 33(ΐΗ,ε). 1 r-range 5 NMR(CDC13) δ : 1.64-1.85(4H,m), 2. 13 (3Η, s), 2. 27-2. 43 (2Η, m), 2. 52-2. 69 (3 Η,β), 2.84(3Η, tJ =6. 2Hz)f 3. 36-3. 50(1Η, η), 3. 57-3. 70(3Η, m), 4. 73(2Η, d, J= 42. 6Hz), 4. 95 (1H, t, J=5. 5Hz), 6. 51 (1H, d, J=9 6Hz), 7.16(1H, s) ? 7. 29-7. 37 (3 Η, η), 7. 53 (2H, d, J=8. 3Hz), 7. 69 (1H, d, J= 9. 6Hz), 7. 83 (1H, s), 8. 13 (2H, d, J=4. 6Hz). IR(KBr) cm·1: 3268,304 4,2961, 2915,2791, 162 4 , 1577, 1491, 1293, 117 2,837,807. 2 Engineering 1 NMR (CDC13) 6 : 2. 20 (6H, s), 2. 42 (2H, t, J=6. 19H2), 2. 67 (2H, t , J=5. 96Hz), 3. 77 (2H, s), 7. 23-7· 32(昍,m) ' 2 Engineering 2 NMR(CDCls) δ : 1. 99-2. 47(11H, m ), 2. 52-2. 69 (1H, m), 2. 84 (2H, t, J=6. 42Hz), 3 .25-3. 4B (1H, m), 3. 47-3. 68 (3H, m), 4. 72 (2H, d, J=49. 06Hz), 4. 95 (1HP t, J=5. E0 Hz), 6.50 (lH, d, J=9.63Hi), 7. (1H, d, J=9. 63Hz) , 7. 83(1H, s), 8. 13 (2H, s). IRCKB^cm-1: 3287, 304 A, 2940, 2820, 2769, 162 6, 1577, 1491, 1293, 117 1,837,806. Rent 1 NMR (CDC13) 5 :1. 00 (6H, 1,1=7. 03Hz), 2. 50 (5H, q, J=7. 03Ha), 2. 56(2H, t, J=6. 1 9Hz), 2. 66 (2H, t, J=E. 96Hz), 3. 77 (2H, s). 7. 23-7. 31 (4H. m). 3 Engineering 2 NMR (CDC13) b : 0. 82-1. 10 (6H, m), 2.13 (3H, s). 2. 29-2. 37(2H, 0), 2. 45-2.60 (3 H_n).2. 72-2. 78(lH.«), 2.84&lt;2H,t, J=6. 19Ηζ), 3.29- 3-37 (ΐΗ, α0, 3. 49-3·57(1 Η. b) , 3. 62 (2H, q. J=5. 96Hz), 4. 74 (2H, df J=42. 64Hz) , 4.94 (1H, t, J=5. 73Hz), 6. SO (IH, d, J*9. 63Hz&gt;, 7. 15 UH, s), 7. 32-7· 36 (3Η· b), 7· 53 (2H, s), 7. 69(1H, d· J= 9. 63Hz), 7.83(lH, s), 8. 13(2H, s). IR(KBr)cB*': 3295, 304 6, 2966, 2917, 2807, 161 2, 1577, 1491, 1293, 117 l, 837, 807. 4 Engineering 1 NMR (CDCla) 6 : 1. 76-1. 80(4H, π), 2. 51*2 55(4H, m) f 2. 65 (2H, t, J=6. l9Hz), 2.7 6(2H, t, J=6. 19Hz), 3. 78(2H, d, J=16. 96Hz ), 3. 80 &lt;3H, s), 6. 86 (2H, d, J=8. 71Hz), 7.24(2H, d, J=8. 71Hz). 4 Engineering 2 NMIUCDCU) δ : 1·64 -1·88 (4Η,·&gt;, 2.03-2·19(3Η·η), 2·27-2·41 (2Η·β&gt;, 2.53-2 .71 &lt;3H,β), 2.75 -2. 90 (3H,b) · 3. 32-3. 44 (IH, mh 3· 57-3. 68(3H, m), 3· 81 &lt;3H, s), 4. 58-4. 82 (2H, d, J=5. 49Hz). 6. 50 (1H, d, J=9. 52Hz). 6. 89 (2H, d, J =8. B4Hz) , 7. 06-7. 18(1HP m), 7. 23-7. 36(lH,m), 7. 54(2H, Dt J=8. 06Hz), 7. 68(1H ,d, J=9. 52Hz), 7.83(lH, s), 8. 12(2H, d, J=8.〇6Hz). IR(KBr) Cm-1: 3296,306 7. 2958, 2930, 2796, 161 1, 1679. 1294, 1245, 117 4, 837, 813. 5 Engineering 1 NMR (CDC13) δ : 2. 19 (6H, s), 2.42 (2H(t, J=6.19Hz), 2.68(2H, t, J=6.l9Hz).3.74 &lt;2Hf s), 3. 80 (3H, s), 6. 84-6. 87(2H, ), 7. 22-7. 25 (2Η» 0). 5 Engineering 2 NMR (CDCla) 6 : 2. 12(3H, s), 2. 20-2.45(6H, m), 2. 54~2. 66(1H, b) . 2. 83 (2H, t, J = 6.35Hz), 3. 28-3. 39(lHf m), 3. 53*3. 65 (3Hf m), 3. 81 ( 3H, s), 4. 55-4. 82 (2H, m), 5.09OH, t, J=5. 49Hz), 6. 50(1H, d, J=9. 77Hz)t 6. 89(2H , d, J=8. 06Hz), 7.13(1H, s), 7. 31(1H, s), 7. 54(2H, d, J=8. 06Hz), 7.67(lH, d , J=9. 77Hz). 7. 82(lH, s)(8. 1 3(2H, d, J=7. O8H2). IRCKBricm'1: 3298,306 7,2939,2832,2773, 161 2 , 1579, 1294, 1246, 117 4, 1034, 837, 814. 6 NMR (CDCU) δ U· 00 (6H, t, J: 7.11Hz), 2. 50(4H, q, J=7·11Hz), 2· 57(2H, t, J=6. 4 -68 - 200918065 Engineering 1 2Hz), 2. 68 (2Hf t, J=6. 42Hz), 3. 74 (2H, s), 3. 80 (3H , s), 6. 84*6. 87 (2H, b) , 7. 22-7. 25 (2H, m) 6 Engineering 2 NMR (DMS〇-de) 6 : 0. 92-1. 26(6H, a). 2. 〇4(3H, s), 2. 46-2. 5l(4H,m), 2 67-2. 76 (2H, b), 2.82-2.92 {1H, bi), 3. 06-3. 18(2H, m), 3. 2〇-3. 28 (1H, m), 3, 64-3. 71 (2H, id), 3. 73(3H, s), 4. 48-4. 73 (2H, m), 6. 92 (2H, d, J=8. 06Hz), 7. 15(2H, d? J=8. 06Hz ), 7. 26(1H, d, J=9. 77Hz), 7. 66 (2H, d( J=7. 81Hz), 8. 06 (iH, d , J=9. 77Hz), 8.11-8 .16 0H, a), 8. 20(2H, d, J=7. 81Hz), 8. 49 (1H, s). IR(KC1 pellet oethod Jen·1 : 3393, 3241, 3065 , 2977, 2657, 1611, 1511 , 1245, 1027, 824. 7 Engineering 1 NMR (CDClj) 6 : 1. 79-1. 83(4H,b), 2. 57-2. (4H, n), 2. 69(2H, t, J=5. 96H2), 2. 7 7(2H, t, J=5. 96Hz), 3. 87(2H, s), 3. 9L ( 3H, s), 7. 41 (2H, d, J=8. 25H2), 7. 99(2H, d ,]~B. 25Hz). 7 Engineering 2 NMR(DMS0*de) δ : 1. 85- i. 93(2H, m), 2. 07(3H, s)t2.58(2H, t, J=7. 34Hz), 3. 30-3 .39(2H,m),6.69(1H , d, J=9. 63Hz), 7.18(1H, t, J=5. 27Hz), 7.47C1H, s), 7. 69(IH ,d, J=9. 63Hz). 7 Engineering 3 NMR (CDC1S) 6 : 1. 54 (9H, s), 2. 05-2. 17 (2H, m), 2. 13 (3H, s), 2. 61 (2H( t, J=7. 34H 2 ), 4 01-4. 07 (2H, ¢), 7, 53 (1^(1, J=9. 63Hz), 7. 69(1H, s)t7.80(lH, d, J=10. 09H z 7 XS4 NMR (DMS 〇-dB) δ : 1.48 (9H, s), l.95-2. 07 (2H, n), 2.01 (3H, s&gt;, 2.56 (2H, t, J=7. 1 1 Hz), 3. 91-3. θ9 (2H, m) , 7. 54 (1H, d, J=10. 09Hz), 8. 05 (2H, d, J=8. 71Hz) f 8. 15 ( 1H, d. J=9. 63Hz), 8. 20(2H,d,J=8.25Hz), 8.30(IH, s). 7 Engineering 5 NMR(CDC13) 6 :l.54(9H, s ) t i. 63-1. 84 (3H, m), 2. 00-2. 10 (4H, m), 2. 22~2. 86 (6H , ni), 3.35-3. 72(6H, m ), 3. 93(3H. s), 3. 98-4.06(2H,m), 4, 71-4. 93(2H, m), 7. 21-7. 25(1H, b), 7. 40-7. 47(IH, m)f7. 50(lH, d, J=10. 09Hz), 7. 58(2Hf d, J=7.34Hz), 7. 89(1H, d, J=9. 63 Hz), 7. 97-8. 10(5H, m). 7 Engineering 6 NMR (DMSO-dfl) δ : 1. 54-1. 79 (4H, m), 1. 85-1. 96 (2H, ), 2. 04(3H, s), 2. 15-2. 29 (2H, m) ( 2. 55-2. 65 (4H, m), 3. 17-3. 57 (6H, η), 4. 66-4. 88(2Hf n), 6. 71 (IH, d, J=9 • 77Hz), 7. 15-7. 19(lH,m),7.33-7.59(4H.n&gt;,7.76 (lH, &lt;U=9.77 Hz), 7.95 (3H, d.J=8.06 Hz). 8.30 (2H?s). IRaB^ca*1: 3264,305 7,2966, 2915,1607, 155 9, 1496, 1386, 1298, Π7 6. 836, 780. 8 NMR (DMS0-d8, 80*C) δ : 1. 8B-1. 95 (2H. m). 2. 04 (3H, s), 2. 58 (2H, t, J =7. 34Hz), 2. 77 (6HP br s), 3. 34 (2H, tp J=6. 88Hz), 3. 36-3. 43 (2H, n), 3, 74(2H, t, J=6, 42Hz ), 4. 65 (2H, s), 7. 15 &lt;1H, d, J=9. 63Hz), 7. 28 (2H, d. J^6. 42Hz)f 7. 40 (2H, d, J=8. 7 1Hz), 7. 65 (2Hf d, J=8. 25Hz), 7. 96 (1H( d. J=9. 63Hz), 8.21 (2H, d. J= 8. 25Hz), 8. 3 0(LH,s), lO.8KlH.br s). IRCKB^cb'1: 3240.306 5, 2915,2670, 1606, 150 5, U66, 1426» 1406,.824 805,765. 9 NMR (DMSO-de, 80^:) δ : 1. 14-1. 28 (6H. m). 1. 86-1. 95 (2H. n), 2. 04 (3H, s) t 2. 58 (2H, t, J=7. 11Hz), 3. 01-3·16(4H,d〇,3.19-3· 29 (2H,b), 3_36-3·42(2H,·) , 3.76 (2H, t, J=7. 34Hz), 4. 66(2Hr s), 7. 17(iH, d, J=9. 63Hz), 7.31 (2HP d, J=7. 34Hz), 7 . 41 (2H, d, J=8. 25Hz), 7, 63 (2H, d, J=8. 71Hz), 7. 97 (IH, d, J=9. 63Hz), 8. 22(2H, df J=8. 25Hz), 8.32(lH,s), 10.74(1H, br s). IR(KBr)c«_1: 3231, 306 3, 2915, 2658, 1606, 150 5, 1466, 1427, 1406, 13S 6( 824,766. 10 NMR(DMS0-da, 80*0) δ : 1. 81-2. 02(6H, m), 2. 04(3H, s), 2.58(2H, t, J=7.11Hz), 2.87-3. 07(2H,m), 3. 31-3. 43 (6ΗιΠ), 3.73 (2H, tJ=6. 42Hz), 4.66(2«, 5), 7, 16( IH, df J=10. 09Hz), 7. 28(2H, d, J=8. 25Hz), 7. 40(2H, d, J=8. 25Hz), 7. 66(2H, d, J= 8.25Hz) t7.96(lH,d,J=9. 63Hz ), 8.21 (2H, d, J=8. 25Hz), 8. 31 (IH, s), 11. 08(1H, br s). IR(KBr&gt;cm·丨:3231,306 2, 2916, 2670 , 1606, 150 5, 1462, 1426, 1406v 135 6,825,766. 11 Engineering 1 NMR (CDC13) δ : 1.5 (lH, br s), 1. 7-1.8 (2H, m), 1. 8-1. 8 ( 2Ht m), 3. 5 (2H, q, J=6. 0 Ηζ&gt;,3·8(2Η, dd, J=l(K8, 6. 2Hzh4.6(lH,s), 6. 4(1H , d, J=9. 6Hz), 7.5(lH, s), 7.6 (IH, d, J=9. 6Hz). 11 Engineering 2 NMR(CDC1,) δ :1.62-1.82(4H,m) , 3.50 (2H, t, J = 6.3 Hz) r3. 57 (2H, t, J = 7. 3 Hz), 3.79 (3H, s), 3.80 (3H, s), 4.43 (2H, s ), 4.67 (2H, s), 6. 65 (1H, d. J=l〇. 0Hz), 6. 83- -69- 200918065 6. 88(4H, n), 7.23(2H, d, J= 2.4 Hz).7. 25 (2H, d, J=2.4H2), 7.49 (lH, s), 7. 56 (1H, d. J=9. 8Hi). 11 Engineering 3 NMR (CDClj) δ :1. 58-1.68(2H.n), 1. 74-1. 84(2Ht m) r 3. 62(2H, t, J=7. 56Hz), 3. 7 2 (2H , tr J=6. 34H2), 3. 79 (3H, s), 4. 68(2H, s), 6. 69(1H, d, J=10. 00Hz), 6. 84*6. 8 9 (2H. ·). 7.20-7. 25(2H, 0), 7.51 (lH.s), 7. 62(1H, d, J=9. 76Hz). 11 Engineering 4 NMR(CDCls) θ :1.82- 1.86(4H,m), 3. 00(3H, s), 3. 6L-3. 67(2H, n), 3. 80(3H, s), 4 .29-4. 31 (2H, m) , 4. 66 (2H, s), 6. 67 (1H&gt; d, J=10.1Hz) ( 6. 87 (2H, d, J=fi. 7Hx), 7. 2 1 (2H. d. T= 8. 7Hz), 7. 51 (1H, s), 7. 61 (1H, d, J=10. 1Hz). 11 Engineering 5 NMR(CDClj) δ :1. 71-1. 87(4H.m) , 3. 63(2H, t, J=7. ΙΗϊ), 3. 80(3H, s), 4. 45(1H, t , J=B. 7Hz), 4. 67(1H, t, J= B· 3Hz). 4.68C2H, s), 6. 66(1H, d, J=9. 6Hz). 6. 87 (2H, d .T=8.1Hz). 7. 23 (2H, d, J= 8. 3Hz). 7.50 (1H, s), 7. 60 (1H, d, J=10. 1Hz). 11 Engineering 6 NMR(CDCls) δ : 1. 79-1. 91 (4H, m), 3 50(2H, q, J=6. 3Hz), 4. 44-4. 49(2Hf m)f 4. 60 (1H. t. T=5.5Hz), 6. 43(1H, d. 1= 9. 6 Hz), 7. 48 (lH, s), 7. 69 (1H, d, J = 9. 6 Hz). 11 Engineering 7 NMR (CDCla) δ : 1.54 (9H, s) t 1. 74-1 96(4H,m), 4. 00(2H, t, J=7. 3Hz), 4. 45(lH, t, J=6. 〇Hz), 4. S7(lHf t, J^6. 0H2), 7.52 (1H.d, J=9. 6Hz) , 7. 69(1H, s), 7.80(lH,d (J=10.1Hz). Π Engineering 8 NMR(DMS〇-de) δ : 1. 48 (9H, s), 1. 62-1 89 (4H, m), 3. 90(2H, t, J=7. 34Hz) p 4. 48 (2 H,dt,J=47. 38, 5.85Hz), 7.55(lH,d,J= I0.09Hz), 8.05(2H,d,J=8.71Hz), 8. 17(1 H. d. T=10. 09Hz), 8. 26 (2H, d, J=8. 25Hz), 8. 35 (1H, s). 11 Engineering 9 NMR (CDC1'3) 6*1. 54(9H, s), 1.65-1. 94 (8H, m), 2. 21-2. 82(6H, m) , 3. 34*3. 63 (2H , b), 3.91-3. 99(2H(n), 4. 39(lHf m) f 4. 51 (1H, m) t 4. 63-4. 83 ( 2H, n) , 7. 26-7. 27 ( 1H, m) ( 7. 34(3H, dt J=7. 3Hz), 7. 50 (1H, d, J=9. 6Hz), 7. 55 (2H, d, J=8. 3Hz), 7. 89 ( 1H. d. .T=l〇. 1Hz), 8. 01 (1H, s), 8. 05(2H?br s). 11 Works 10 NMR (DMS〇-de, 703⁄4) δ : 1. 60-1. 62(4H,o), 1. 70-1. 84 (4H, m), 2. 29~2. 33 (4H, m) , 2. 57 (2H, t, J=6. 7Hz), 3. 3Z~3. 41 (4H, m), 4. 40-4. 43(lH?in), 4. 53 (1H, t, J=6. OH z), 4. 67(2Hf s), 6. 71 (1H, d, J=9. 6Hz), 6. 96 (1H, t, J=5. 3Hz) ( 7. 33- 7. 35(2H, b), T. 39-7. 41 (2Hf m), 7. 48 (2H, dt J=8. 3Hz), 7. 71 (1H, d, J=9. 6Hz), 7. 89 (1H, 5), 8. 2 4(2H, d, J =8. 3Hz). IR(KBr) cm'1: 3250,295 4.2784, 1626.1588.149 3, 1471, 1405, 1177, 833,816. 12 Engineering 1 NMR(CDCla) δ :〇. 81-1. 08 (6H,ro)f 1. 54(9H, s), 1. 68Ί. 79(2H,m), 1. 88Ί. 92(2H ,n), 2. 28-2· 56(6H, m), 3. 29-3. 32(1H. n), 3. 50-3. 53(lH,ra), 3. 95-3.97(2H,n), 4. 39-4. BO (2H, m) t 4. 68-4. 80 (2H, m), 7. 14-7. 19 (1H, m), 7. 33-7. 36 (3H, b) , 7. 4 8-7. 55(3H, m), 7. 89(1H, d, J=9. 6H2&gt;, 8. 01-8. 05 (3H, a). 12 Engineering 2 NMRiDMSO-de^or) δ : 0. 85-0. 92( 6H,m), 1.70-1.84(^,0),2.31-2.51(6^0) (3. 30-3. 36 (4H, m), 4. 41 (1H, t, J=5. 7Hz) , 4. 53 (1H, t, J=6. 0Hz), 4. 66 (2B, s), 6. 7l (lH,d, J=9.6Hz), 6.96 (lH,t,J=5.3Hz) , 7.31-7. 35 (2H, n), 7. 39-7. 42 (2H, m>, 7. 48 (2H, d, J=8. 3Hz), 7. 71 (1H, d, J= 9. 6Hz), 7. 89 (lH, s), 8. 24 (2H, d, J=8. 7Hz). IR(KBr)cm_1: 3247, 296 7, 1634,1587, 1493, 147 1, 1422 , 1175,833,817. 13 Engineering 1 NMR(CDC1S) 6 :l.54(9H, s), 1.70-1. 94 (8Ht m), 2. 29-2. 79(6H, m), 3. 36- 3. 65 (2H, s), 3.81 (3H, s), 3. 94-3. 97(2H, m), 4. 39-4 . 51 (2H, n), 4. 60-4. 76(2Htm)f 6. 87( 2H, dd, J=17. 9,8. 4Hz), 7. 12-7. 24(2H, m) , 7. 49(1H, d, J=9. 8Hz)t 7. 56(2H, d, J=8 .1^), 7.89(1^(1,1=9. 8Hz), 8. OX ( 1H, s), 8. 04-8. 〇6(2H,m). 13 XS2 NMR(DMS〇-de, 7〇Ό) δ : 1. 62*1. 64(4H, a), l. 74 -1. 84 (4Hf m), 2. 34-2. 58(6H, 〇), 3. 34-3. 36(4H,m)· 3.75 (3H,s), 4. 37-4. 42( 1Η·η), 4. 54(lH,t,J=5,7Hz), 4.60( 2H, s), 6. 71 (1H, d, J=9. 6Hz), 6. 86-6. 97 ( 3Hf n). 7. 23 (2H, d, J=8. 7Hr), 7. 48(2H, d, J=8. 2Hz), 7. 71 (1H, d, J=9. 6Hz), 7 90 (1H, s), 8. 24 (2H, d, J=8. 2Hi). IR(KBi*&gt;cn k 3250. 294 5f1625,1586,1512, 149 3, 1471, 1248. 1176,835 , 818. 14 Engineering 1 NMR (DMS〇-de) δ : 1. 34-1. 53(4H, m), 1. S6-1. 66(2H, o), 3. 22-3. 29(2Η , β), 3. 38-3. 45 (2H, m), 4. 37 (lH, t, J=5. 27Hz), 6. 69 (1H, d, J=9. 63Hz), 7. 11 (1H, t, J=5. 04H 2), 7. 46(1H, s), 7. 67(1H, d, J=9. 63Hz). -70- 200918065 14 Engineering 2 NMR(CDCls) δ : 1. 38-1. 49(2H. n) r 1. 6l-i. 74(4Η. ), 3. 46 (2Η, t, J=6. l9Hz), 3.5 4(2H, t, J=7 . 57Hz), 3.79(3H, s) , 3.80(3H, s)f4.42(2H, s), 4. 66(2H, s), 6. 64(1H J=10. 09Hz).6.83-6.89(4H.b), 7. 22-7. 26(4H, m), 7. 49(1H, s), 7. E8(1H, d, J = 10.09Hz>· 14 Engineering 3 NMR(CD30P) δ :1.40-1.51 (2H, m), 1. 55Ί. 66C2H, m), 1. 69-L. 81 (2H, m), 3.56 (2H, t, J=6. 42Hz), 3. 69 (2H, t, J=7. 57Hz), 3.76(3H, s), 4· 81 (2H, s) 6. 86-6. 93(2H, n), 7.26-7.34(2H,m), T. 48(lH,dt J =10. 09Hz), 7. 93UH, d, J=10.09H〇t8. 03 (1H , s). 14 Engineering 4 NMR(CDC13) 6 :1. 46-1.56(2^0), 1.53 (9H, s), 1. 68-1. 89(4H, m), 3. 96(2H, t, J= 7. 34Hz), 4. 46 (2H, dt, J=47. 23, 5. 96Hz), 7. 51 (1H, d, J=9. 63Hz), 7. 68 UH, s), 7. 79(1H, dr J=10. 09Hz). . . Η Engineering 5 NMR(DMS〇-de) δ : 1. 38-1.49(2H, m), 1. 48 (9Hf s), 1. 58-1. 82 (4Hr m), 3. 87 (2H, t, J=7. 20Hs), 4. 42 (2H, dt, J=47. 53, 6.04Hz), 7. 54 (LH, d, J=9. 77Hz), 8. 04 (2H, d, J = 8. 30Hz), 8. 16 ( 1H, d, J-9. 77Hz) ? 8. 24 (2H. d, J=8. 30Hz), 8. 33 (1H, s). 14 Engineering 6 NMR (DMS〇-d0, 80*0 δ : 1- (1H, n), 1. 1-3. 17(4H,ni)1 3. 20~3. 31 (2H, a), 3. 31 (2H, t, J=7. UHz), 3. 76(2H, t, J=7 . 1 1 Hz) f 4. 42 (2H, dt, J=47. 53, 6. 19Hz) t 4. 66 (2H, s), 7. 18 (1H, d, J=9. 63Hz), 7. 2 5-7. 35(2H, m), 7. 41 (2H, d, J=8. 25Hz), 7. 62(2H, d, J=8. 71Hz), 7. 97 (1H(d, J=9. 6 3Hz), 8. 21 (2H, d, J=8. 25Hz), 8. 31 (1H, s), 10. 82 (1H, br s). IR(KBr)cni-1: 3232, 3062 . 2940, 2656, 1606, 1506, 1466, 1434, 1406, 825. 15 NMR (DMS〇-dBl 80t:) 6 : 1. 43-1. 53(2H,m), 1. 56-1 78 (8H, n), 2. 26-2. 37 (4H, n) , 2. 57 (2H, t, J=6. 65Η»), 3. 31 (2Ht dd, J=12. 38, 6. 88Hz). 3. 39(2H, t. J=6. 65Hz), 4. 43 (2H, dt, J=47. 53, 6. 19Hz), 4. 67(2H, s), 6. 71 (1H, d, J=9.63HzK 6.88(lHf t, J=5. 27Hz), 7. 31-7. 37 (2H, m), 7. 37-7. 42 (2H, m), 7. 48 (2H, d, J=8. 25Hz), 7. 70 (1 H, d, J=9. 63Hz), 7. 88 (lH, s), 8. 23(2Ht d, J=8. 25Hz IROCBiOcb·1: 3308,295 7.2872, 2792, 1612, 157 9,1492, 1462,1432, 129 4. 16 : L-step 1 NMR (CDC13) δ :1· 72-1. 81 (4H,m) , 2,09 (lH, br s), 2. 47-2.51 (4H, mh 2.64 (2H, t, J=6.4Hz), 2.8 0(2H, t, J=6. 6Hz), 4. 01 (2Η» d, J=2. 3Hz), 7. 17*7. 22(lHf n), 7. 3 3-7. 37(1H , m), 8. 38(1H, td, J=3. 0, 1. 5Ha). 16 Engineering 2 NMR(CDCls) 6 :1. 54C9H, s), i. 65-1. 80 (6H, b ), 1. 89-1. 93 (2H, m), 2. 29*2. 81 (6H , 〇), 3. 53-3. 65 (2H, m), 3. 93-3. 98 (2H , m), 4. 40-4. 51 (2H, b) , 4. 83-5. 04 (2H, m), 7. 21-7. 27 (1H, m), 7. 33-7. 40 (1H, m), 7. 49(1H, d, J=9. 6Hz), 7. 64(2H, d, J=7. 3Hz )(7. 89(1H, d, J=9. 6Hz) , 7. 98-8. 08(3H, m), 8. 44 (1H, br s). 16 Engineering 3 NMR (DMSO-da, 70*C) B ' 1. 66-1. 83 (8H, m ), 2. 40-2. 72 (6H, n), 3. 34 (2H, q, J=6. 3 Hz) · 3. 52 (2H, br s), 4. 42 (1H, t, J =5. 7Hz), 4. 53 (1H,t, J=6- 0Hz), 4. 83(2H,s), 6.71(1H, d, J=9. 6Hz)f 6. 96(1H , t, J=6. 5Hz), 7. 39-7. 43 (lHt n), 7. 47 (2H, d, J=8. 7 Hz), 7.64 (lH, t, J=8. 7Hz&gt; , 7.7l &lt; lH, d, J = 9. 6Hz>, 7.88 (lH, s), 8.2l (2H, d, J = 8 * 3 Hz), 8.44 (lH. td, J = 3. 0, l .5Hz). IR(KBr)cm_l: 3252,295 4,1641,1588,1495, 144 4, 1175, 835, 813. 17 Engineering 1 NMR (CDCla&gt; δ: 1.55 (9H, s&gt;, 1.70-1.78 ( 4H,n ), 2. 〇7(3H, s), 2.34(2H, br s), 2.6 1-2. 88(6H, n), 3. 54-3. 67 (2H. ) t 4. 12 (2H. Br s). 4. 83-5. 04 (2H, o), 7. 23-7. 27 (1Η, πι), 7.35 (1Η^γ s), 7. 62 (lHf d, J=9. 6Hz ), 7. 65(2Hf d, J=7. 3Hi), 7. 89(1H, df J=9. 6Hx), 7. 97-8. 06(3H,m), 8. 44(1H, br s). 17 Engineering 2 NMR (DMS〇-de, 70*C) δ : 1.64 (4Htbr s). 2. 10(3H, s)f 2. 40 (4H, br s), 2.66 (2H, brs) , 2.76(2H, t, J=7-1Hz), 3. 48U5(4H· _h 4. 83(2H, sh 6. 73(1H, d, J=9. 6Hz), 7. 10(lH , s), 7. 39-7.43(lHfm)t7.4?(2Hid, J=8.3H2), 7.65(lH,t, J=9. 4Hz), 7.73 (1H, d, J= 9. 6Hz), 7. 89 (lHr s) t 8. 20 (2H, d, J=8. 3Hz), 8. 44 (1H, d, J=4. 6Hz). IRiKBrJcm'1: 3251,295 9,1622.1494,1445, 129 3, 1170, 799. 18 Engineering 1 NMK(CDC13) δ : 1. 55 (9H, s), 1.65-1. 84(6H,d), 1. 92-1.95 (2H, (m), 2. 32 (2H, s) 3. 98(2Hf q, J=7. 1Hz), 4.42 (1H, 〇, J=5. 5Hz), 4. 54 (1H, q, J=5. 5Hz). 4. 77 (1H, s), 5. 08 (1H, s), 7. 22-7. 43 -71 - 200918065 (2H,b), 7. 52-7. 57(2H, d), 7. 71-T. 83 ( 1 Η, π), 7. 88-7. 97(2H,m), 8. 03 (1Η, d, J=1 5.6Ηζ), 8. 41(1Η, t, J=S.7Hz). 18 Engineering 2 NMR(DMS〇-d6) ί : 1. 56-1. 80 (8Η, ο), 2. 21 (2Η, br s) , 2. 42-2. 67 (4Η, m), 3. 31- 3. 39(3Η, π), 3. 55-3. 60(1Η, m), 4. 42-4. 46&lt;lH,n), 4. 56(1Η, td, J=5. 8, 2.5 Ηζ), 4. 7 0(1Η, s), 4.93(lH, s)f6. 74(1Η, dd, J=9. 6, 5. 5Hz), 7. 26(1Η, s), 7. 35 -7. 47(2Η, m ), 7. 63-7. 74 (1Η, m), 7. 78(lHt ddp J=9. 6, 5. 5Hz), 7. 97-8. 12 (2Η, m), 8. 25 (1Η, t, J-12. 2Hz), 8. 44(1Η, dd, J=4. 9, 1. 4Hz). IRUBricm'1: 2960,162 2, 1579,1493, 1447, 129 7,878,809. 19 Engineering 1 NMR(CDC1S) δ :1. 5(9Η, s), 2. 1-2. 3(1Η, η), 2. 3-2. 5(LH, π), 3 0(3Η, s), 3. 3-3. 5 (1Η,πι),3.8-4.1(1Η,π), 4. 1~4. 4(2Η, m), 4. 8-4. 4 (1Η, m), 5. 2(1Η, d, J=52. 7Ηζ). 19 Engineering 2 NMR(CDCla) δ : 1. 5 (9Η, s), 2. 0-2. 2(1Η, m ), 2. 2-2. 4 (1Η, in), 3. 3 (1Η, dd, J=35. 3, 13. 2 Hz), 3. 4(ΙΗ,dd, J=36. 8, 13 0Η2), 3. 7-4. 2(3Η, mh 5. 2 (1Η, d, J=52. 7Hz). 19 Engineering 3 NMR(CDC18) δ :1. 0-1.3&lt;2H , m), 1.5 (9H, s), l· 9-2, 2 (lH, m), 2. 3-2.4 (1Η, π), 2. 7-3. 1 (2Hf a), 3. 3 -3. 5 (1H, m), 4. 2-3. 8 (2H, m), 5. 1 (1H, d, J=52. 7Hz). 19 Engineering 4 NMR(CDCls) δ : 1. 4 (9H, d, J=17. 4Hz), 2. 0*2.3 (1H, ο), 2. 3-2. 4 (1H, π), 2. 7-2. 8( 1H, m), 3 . 0 (1H, s), 3. 4 (1H, ddd, J=36. 7,13.3, 3. 2Hz), 3. 9 (3H, t, J=17.2Hz), 3. 9 (3H, s ), 4. 0-4. 2 (1H, m), 5. 1 (1H, d, J=53. 2Hz), 7. 4 (2H, d, J=7. 3Hz), 7. 6 (2H , d, J = 7. 8Ηϊ), 7. 7 (2H, d, J=8. 3Hi), 8. 1 (2H, d, J=8. 7Hz). 19 Engineering 5 NMR(CDCls) δ :1 2-1. 3(2H,n), 1. 8-2. 2(4H,m), 2. 6-2. 8(2H.a). 2. 9-3. 1 (2H, b) , 3, Bu 3. 3 (lH, n), 3, 4-3.8 (4H, ra), 3.9 (3H, s), 4.7-5. l (2H, m).5.2 (lH.d, J= 6l.4 Hz), 6.7 (lH, d, J=10·1Hz), 7. 3-7.4 (2H, m), 7.4-7. 6(3H,m), 7.7-7. 8(3H , a), 7. 8-7.9 (2H, m), 8. 0 (1H, brs), 8. 0 (2H, d, J=8. 3Hz), 8. 3 (2H, brs). 20 NMR (DMS〇-de) δ : 2. 0-2. 4 (5H, m), 2. 6-3.1 (4H. m) 13. 5-3. 9 (6H. m). 4. 4-4. 8 (lH, m), 4. 9-5. 4(1H, m), 6. 8 (1H, dd, J=9. 6, 6. 0Hz), 7. 7-7. 2 (9H, b ),7 . 8 (1H, dd, J=9. 6, 4. 6Hz), 7. 9 (2H, t, J= . $Hz), 8. 0 (1H, s), 8. 3 (2Hf df J= 8. 3 Hz). (Formulation Example) (Formulation Example 1) Powder 5 g of the compound of Example 1, lactose 895 g, and corn starch 10 g were mixed in a mixer to obtain a powder. (Formulation Example 2) Granules 5 g of the compound of Example 5, 895 g of lactose and 100 g of low-substituted hydroxypropylcellulose were mixed, and then 300 g of a 10% aqueous hydroxypropylcellulose solution was added thereto to knead. This was granulated by an extrusion granulator and dried to obtain granules. (Formulation Example 3) Tablets 5 g of the compound of Example 12, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate were mixed by a mixer, and the tablets were tableted in a tablet-72-200918065. Get a lozenge. [Test Example 1] Test tube test: Inhibition of TNF-α release induced by LPS in peripheral blood cells of mice. 6-week-old BALB/c mice were anesthetized with ether, and anticoagulant was used for heparin. Blood is collected from the lower major vein. Red blood cells were dissolved in blood 10 V L plus Turkic staining solution (Semiconductor Technology Inc.) to determine the number of white blood cells. Mouse whole blood was diluted in RPMI-1 640 medium, and the number of white blood cells was adjusted to 250,000 cells/mL. ί The DMSO solution (control group) and the test substance dissolved in the DMS0 test substance solution (test substance addition group) were dispensed into a 96-well plate at a concentration of 20/zL/point (DMSO final concentration 0.3%) as described above. The mouse whole blood was diluted with RPMI-1 640 medium and the solution was adjusted at 160 // L/hole. Further, LPS solution 20#L/point (final concentration 1/zg/mL; Escherichia coli .0111: B4, C a 1 b i 〇 c h e m) was placed at 37 ° C for 4 hours. The 96-well plate was centrifuged (2000 rpm, 5 minutes), and the resulting supernatant was recovered 150/iL, and the quantitatively produced I TNF- was produced by ELISA [mouse TNF (Mono/Mono) ELISA set &gt; BD Biotech]. a quantity. The inhibitory activity (%) of the test substance was determined from the ratio of the amount of TNF-α in the control group to the amount of TNF-α in the test substance-added group, and the 50% inhibitory concentration of the test substance [IC 5 was calculated. ( # Μ)]. The results are shown in the table below. -73- 200918065 [Table 4] Test substance ICs 〇 ( // Μ ) Example 1 3.0 Example 2 2.4 Example 4 1.8 Example 6 0.94 Example 8 1.30 Example 15 2.50 The results of the test were found to be The compound of the invention inhibits the release of TNF-α from mouse peripheral whole blood cells by LPS induction. [Test Example 2] In vivo test of the test substance in mice: inhibition test of TNF-α production induced by LPS 1

Male Balb/c mice of 7 to 8 weeks old were divided into a control group and a test substance-administered group. In the control group, 0.5% methylcellulose solution (w/v%) was orally administered to 10 mL/kg, and the test substance was administered to the group of mice, which was suspended in 0.5% methylcellulose solution (w/ v%) of the test substance solution (10 mg/mL), and oral administration of 10 mL/kg. After the 0.5% methylcellulose solution or the test substance solution was administered for 30 minutes, a solution containing 0.02 mg of LPS per 1 mL of physiological saline was intravenously administered from the tail vein at 10 mL/kg. One hour after the administration of LPS, heparin was used as an anticoagulant from the lower major vein under ether anesthesia. The collected blood was centrifuged (3 000 rpm, 4 ° C, 30 minutes) while the upper layer was recovered as plasma. One portion of the plasma was diluted 10-fold with the dilution solution attached to the kit, and the amount of TNF-α was measured in an ELISA kit (mouse TNF ELISA KIT, QUANTIKINETM R&amp;D Systems, Inc.). -74- 200918065 The inhibition rate (%) was determined by the ratio of the amount of TNF-α produced by the control group to the amount of TNF-α produced by the test substance addition group. [Table 5] Test substance Obstruction rate (%) Example 6 45 As a result of the test, it was found that the compound of the present invention inhibits TNF-α production by LPS induction in a mouse model. [Simple description of the map] to. [Main component symbol description] te. j\w

-75 -

Claims (1)

200918065 X. Patent application scope: 1. A compound of the following formula (1), a salt thereof or a solvate thereof, N Wherein R1 is a group represented by C1 to C6 alkyl-X1-X2, wherein XI is a single bond, hydrazine, S, SO or S02, and X2 is a C1 to C6 substituent, and the alkyl group is C1 to C6. The substituent represented by -X1-X2 may have 1 to 3 substituents selected from the group consisting of a halogen group, a C1 to C6 alkoxy group and a halogen C1 to C6 alkoxy group, and R2 may be the same or different. a group selected from the group consisting of a hydrogen atom, a halogen group, a hydroxyl group, a carboxyl group, an amine group, a C1 to C6 alkylamino group, an amine carbenyl group, a C1 to C6 alkylamine methyl group, and a C1 to C6 alkano group. 2 groups, R3 is a group represented by C1 to C6 alkyl-Y, wherein Y is an amine group, a C1 to C6 alkylamino group or a 3 to 6 member nitrogen-containing heterocycloalkyl group, which is contained in the 3 to 6 member. The azacycloalkyl group may have the same or different halo group, hydroxyl group, C1 to C6 alkyl group, C1 to C6 alkoxy group, halogen C1 to C6 alkoxy group, carboxy C1 to C6 alkoxy group, hydroxy group C1 to C6. The alkyl group and the carboxyl group C1 to C6 alkyl group are selected from the group consisting of 1 to 3 substituents, and R4 is a group represented by Z1 to Z2, wherein Z1 is a C1 to C6 alkyl group or a C1 to C6 alkyl group-? -Cl~C6 alkyl group represented by the alkyl group in the C1~C6 alkyl group or C1~C6 alkyl group-Ο-Cl~C6 alkyl group-76-2009180 65 points may have the same or different screw type C3~C6 cycloalkyl group 1 or 2 substituents, Z2 is an amine group, C1~C6 alkanoguanamine group, amine methyl sulfonyl group, C1~C6 compound amidyl group, hydroxyl group a heterocyclic group of a carboxy or phenyl group or a monocyclic or fused ring of 4 to 10 members, wherein the heterocyclic group of the phenyl or 4 to 10 membered monocyclic or fused ring may have the same or different halogen a group, a C1 to C6 alkyl group, a halogen C1 to C6 alkyl group, a C1 to C6 alkyl group, a ci~C6 alkoxy group C1 to C6 alkyl group, a hydroxyl group, a C1 to C6 alkoxy group, a halogen C1 to C6 alkoxy group. , carboxyl group, C1~C6 alkyl fluorenyl group, C1 f - C6 alkoxycarbonyl group, Cl~C6 alkylamine carbenyl group, amine group, Cl~C6 compound amine group, C1~C6 alkanoguanamine group, phenyl group, carboxybenzene a group selected from the group consisting of C1 to C6 alkoxy phenyl and benzyloxy groups, 1 to 3 substituents]. 2 _ The compound of claim 1, or a salt thereof or a solvate thereof, wherein XI of R1 is a single bond or S. 3. A compound according to claim 1 or 2, a salt thereof or a solvate thereof, wherein X2 of R1 is a C1-C6 alkyl group substituted with a halogen group. 4. A compound, a salt thereof or a solvate thereof according to any one of claims 1 to 3, wherein R2 is a hydrogen atom or a halogen group. The compound of any one of claims 1 to 4, a salt thereof or a solvate thereof, wherein R3 is a C1 to C6 alkylamino group or a 3 to 6 member nitrogen-containing heterocycloalkyl group. . 6. A compound according to claim 5, a salt thereof or a solvate thereof, wherein R3 is a 3 to 6 membered nitrogen-containing heterocycloalkyl group substituted with a halogen group. 7. A compound, a salt thereof or a solvate thereof according to any one of claims 1 to 6 wherein R1 is a C1 to C6 alkylene group. The compound of any one of clauses i to 7 of the patent application, or a salt thereof or a solvate thereof, wherein Z2 of R4 is a hydroxy group, a phenyl group or a monocyclic ring of 4 to 10 members or a heterocyclic group of a fused ring (the heterocyclic group of the phenyl or 4 to 10 membered monocyclic or fused ring may have the same or different halo group, C1 to C6 alkyl group, halogen C1 to C6 alkyl group , hydroxy C1 to C6 alkyl, C1 to C6 alkoxy C1 to C6 alkyl, hydroxy, C1 to C6 alkoxy, halogen C1 to C6 alkoxy, carboxy, C1 to C6 alkyl fluorenyl, C1 to C6 alkane Oxycarbonyl, C1 to C6 alkylamine, mercapto, 'C1 to C6 alkylamino, C1 to C6 alkylamino, phenyl, carboxyphenyl, C1 to C6 alkoxycarbonylphenyl and benzyloxy The group of choices is based on 1 to 3 substitutions). 9. A compound according to claim 8 of the patent scope, a salt thereof or a solvate thereof, wherein Z2 of R4 may have the same or different halo group, C1 to C6 alkoxy group, halogen C1 to C6 alkoxylate a group selected from the group consisting of a carboxyphenyl group and a C1 to C6 alkoxycarbonylphenyl group, or a substituted phenyl group or a heterocyclic group of a monocyclic or fused ring of 4 to 10 members. 10. A pharmaceutical product comprising a compound, a salt thereof or a solvate thereof, as in any one of items k to ninth of the patent application, as an active ingredient. U. The pharmaceutical of claim 10, which is used to inhibit the production of TNF-α. 12. The medicine of claim 1 of the patent application is for preventing or treating an inflammatory disease and/or an autoimmune disease. Π · The medicine of the first paragraph of the patent application is used to prevent or treat rheumatism. A use of a compound according to any one of claims 1 to 9 or a salt of the -78-200918065 or a solvate thereof for use in the manufacture of a pharmaceutical active ingredient. 15. The use of claim 14 in which the pharmaceutical is a medicament for inhibiting the production of TNF-α. 16. For use as set forth in claim 14, wherein the medicine is a medicine for preventing or treating an inflammatory disease and/or an autoimmune disease. 17. For the use of Article 14 of the patent application, the medicine is a medicine for preventing or treating joint rheumatism. A method for inhibiting the production of TNF-α, which comprises administering a compound, a salt thereof or a solvate thereof, according to any one of claims 1 to 9 to a mammal. Engineering. A method for preventing or treating an inflammatory disease and/or an autoimmune disease, which comprises a compound, a salt thereof or a solvate thereof, according to any one of claims 1 to 9 An effective amount is administered to a mammalian project. 20. A method for preventing or treating articular rheumatism, comprising administering to a mammal a compound, a salt thereof or a solvate thereof, according to any one of claims 1 to 9 Engineering. 21. A compound or salt of any one of claims 1 to 9 of the invention, for use in the prevention or treatment of an inflammatory disease and/or an autoimmune disease. 2. A compound or a salt thereof according to any one of claims -9 to prevent or treat joint rheumatism. -79- 200918065 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the symbol of this representative figure to. J \ NN 8. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: Η