JPH10152462A - Differentiation-inducing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzamide derivative having differentiation inducing acton, useful as a medicine for treating and improving malignant tumor, autoimmune disease, dermatitis and parasitic infectious disease. SOLUTION: This compound is shown by formula I A is a (substituted) phenyl or a heterocycle (which may contain 1 to 4 substituent groups such as a halogen, hydroxyl group, amino, nitro and cyano); X is a direct bond, (CH2 )e , (CH2 )g -O-(CH2 )e , etc. ((e) is 1-4; (g) is 0-4); Q is a structure shown by formula II [R7 is H, a 1-4C (substituted) alkyl], etc.; R1 and R2 are each H, a halogen, etc.; R3 is a hydroxyl group or amino}. The compound of formula I is obtained, for example, by subjecting a compound of the formula A-X-R9 [R9 is C(=G)OH (G is oxygen or sulfur) or NH2 ] and a compound of formula III [R9 and R10 are not the same and one is C(=G)OH and the other is NH2 ; R11 is a protected hydroxyl group] to condensation reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a differentiation inducer. More specifically, the present invention relates to the use of a novel benzamide derivative or a novel alinide derivative for anticancer drugs and other drugs based on the differentiation-inducing action.

[0002]

2. Description of the Related Art At present, cancer is the most common cause of death, overtaking heart disease and cerebrovascular disease, and many studies have been carried out with great expense and time. However, cancer has not been overcome despite research on a variety of treatments such as surgery, radiation therapy, and hyperthermia. Among them, chemotherapy is one of the major pillars of cancer treatment, but even today, no satisfactory drug has been found.
Anticancer drugs with low toxicity and high therapeutic effects are eagerly awaited.
Many anticancer drugs so far act on cells, mainly DNA, to exert cytotoxicity, thereby damaging cancer cells and exhibiting an anticancer effect. However, because the selectivity between cancer cells and normal cells is not sufficient, side effects expressed in normal cells are the limits of treatment.

However, among the anticancer agents, the differentiation inducing agent is not a direct killing of cells but an object of promoting differentiation of the cancer cells and suppressing infinite proliferation of the cancer cells. Therefore, in regression of cancer, it is not as good as anticancer drugs that kill cells directly,
Low toxicity and different selectivity can be expected. Indeed, it is well known that retinoic acid, a differentiation inducer, is used in therapy and shows high effects in acute promyelocytic leukemia [Hua
ng et al; Blood , 72 , 567-572 (1988), Castaign.
Blood , 76 , 1704-1709, (1990); Warrell et al .; N.
ew Engl. J. Med. 324 , 1385-1393 (1991), etc.]. In addition, since vitamin D derivatives show differentiation-inducing effects, many applications to cancer drugs have been studied [Olsson et al .; Cancer
Res. 43 , 5862-5867 (1983) and others].

[0004] In response to these studies, a vitamin D derivative which is a differentiation inducer (JP-A-6-179622),
Isoprene derivatives (JP-A-6-192073),
Tocopherol (JP-A-6-256181), quinone derivatives (JP-A-6-305595), acyclic polyisoprenoids (JP-A-6-316520), benzoic acid derivatives (JP-A-7-206765), Application to anticancer agents such as glycolipids (JP-A-7-258100) has been reported. However, none of these studies has reached a level sufficient for cancer treatment, and there is a strong demand for a drug that is effective and highly safe against various cancers.

[0005]

An object of the present invention is to provide a compound which has a differentiation-inducing effect and is useful as a drug for treating or improving malignant tumors, autoimmune diseases, skin diseases, and parasitic infections. Is to do.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a novel benzamide derivative and a novel alinide derivative having a differentiation-inducing effect exhibit an antitumor effect, and completed the present invention. I let it. That is, the present invention provides: [1] Formula (1)

[0007]

Embedded image [In the formula, A represents a phenyl group or a heterocyclic ring which may be substituted (as a substituent, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, 1 carbon atom
Acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms, carboxyl group, Having 1 to 4 groups selected from the group consisting of an alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group, and a heterocyclic ring). X is a direct bond or a compound of the formula (2)

[0008]

Embedded image 中 In the formula, e represents an integer of 1 to 4. g and m each independently represent an integer of 0-4. R4 is a hydrogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms or a group represented by the formula (3):

[0009]

Embedded image (In the formula, R6 represents an optionally substituted alkyl group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a phenyl group or a heterocyclic ring). R5 represents any of the structures represented by｝ representing a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms. n represents the integer of 0-4. However, when X is a direct bond, n does not become 0. Q is the formula (4)

[0010]

Embedded image (Wherein, R 7 and R 8 each independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms).

R1 and R2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a C1-4
Alkyl group, alkoxy group having 1 to 4 carbon atoms, 1 carbon atom
1 to 4 aminoalkyl groups, C1 to C4 alkylamino groups, C1 to C4 acyl groups, C1 to C4 acylamino groups, C1 to C4 alkylthio groups, C1 to C1
4 perfluoroalkyl group, C 1-4 perfluoroalkyloxy group, carboxyl group or 1 carbon atom
Represents an alkoxycarbonyl group of 1 to 4. R3 represents a hydroxyl group or an amino group. A benzamide derivative and a pharmaceutically acceptable salt represented by the formula:

[2] The benzamide derivative according to [1], wherein n is an integer of 1 to 4, and a pharmaceutically acceptable salt;

[3] Q is the formula (5)

[0014]

Embedded image (Wherein, R 7 and R 8 have the same meanings as defined above), and the benzamide derivative according to [2] and a pharmaceutically acceptable salt thereof;

[4] The benzamide derivative according to [3], wherein A is a heterocyclic ring which may be substituted, and a pharmaceutically acceptable salt;

[5] The benzamide derivative according to [4], wherein A is a pyridyl group which may be substituted, and a pharmaceutically acceptable salt;

[6] The benzamide derivative according to [4], wherein X is a direct bond, and a pharmaceutically acceptable salt;

[7] The benzamide derivative and pharmaceutically acceptable salt according to [6], wherein R1 and R2 are hydrogen atoms.

[8] The benzamide derivative according to [7], wherein R3 is an amino group, and a pharmaceutically acceptable salt;

[9] X is the formula (6)

[0021]

Embedded image (Wherein e is as defined above), which is a benzamide derivative and a pharmaceutically acceptable salt according to [5],

[10] The benzamide derivative and a pharmaceutically acceptable salt according to [9], wherein n is 1 and R1 and R2 are hydrogen atoms.

[11] R3 is an amino group [10]
A benzamide derivative and a pharmaceutically acceptable salt according to the above,

[12] X is the formula (7)

[0025]

Embedded image (Wherein, e, g and R4 have the same meanings as described above.) The benzamide derivative according to [5], which is any of the structures shown, and a pharmaceutically acceptable salt,

[13] The benzamide derivative and the pharmaceutically acceptable salt according to [12], wherein n is 1 and R1 and R2 are hydrogen atoms.

[14] R3 is an amino group [13]
A benzamide derivative and a pharmaceutically acceptable salt according to the above,

[15] X is the formula (8)

[0029]

Embedded image (Wherein, g, m and R5 are as defined above). The benzamide derivative according to [5], which is any of the structures shown, and a pharmaceutically acceptable salt,

[16] The benzamide derivative and a pharmaceutically acceptable salt according to [15], wherein n is 1 and R1 and R2 are hydrogen atoms.

[17] R3 is an amino group [16]
A benzamide derivative and a pharmaceutically acceptable salt according to the above,

[18] The benzamide derivative according to [1], wherein n is 0, and a pharmaceutically acceptable salt;

[19] The benzamide derivative according to [18], wherein Q is any of the structures represented by formula (5), and a pharmaceutically acceptable salt;

[20] The benzamide derivative according to [19], wherein A is a heterocyclic ring which may be substituted, and a pharmaceutically acceptable salt.

[21] The benzamide derivative according to [20], wherein A is a pyridyl group which may be substituted, and a pharmaceutically acceptable salt;

[22] The benzamide derivative and the pharmaceutically acceptable salt according to [21], wherein R1 and R2 are hydrogen atoms.

[23] R3 is an amino group [22]
A benzamide derivative and a pharmaceutically acceptable salt according to the above,

[24] Formula (9) [Formula 22]

[0039]

Embedded image A benzamide derivative and a pharmaceutically acceptable salt according to [1],

[25] Formula (10) [Formula 23]

[0041]

Embedded image A benzamide derivative and a pharmaceutically acceptable salt according to [1],

[26] Formula (11) [Formula 24]

[0043]

Embedded image A benzamide derivative and a pharmaceutically acceptable salt according to [1],

[27] Formula (12)

[0045]

Embedded image A benzamide derivative and a pharmaceutically acceptable salt according to [1],

[28] Formula (13)

[0047]

Embedded image [In the formula, A and B represent an optionally substituted phenyl group or a heterocyclic ring (as a substituent, a halogen atom, a hydroxyl group,
Amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aminoalkyl group having 1 to 4 carbon atoms, alkylamino group having 1 to 4 carbon atoms, 1 carbon atom Acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms, carboxyl group, Having 1 to 4 groups selected from the group consisting of an alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group, and a heterocyclic ring).

Y has any of —CO—, —CS—, —SO— and —SO ₂ — in the structure, and represents a chain, a ring, or a combination thereof connecting A and B. . R3 represents a hydroxyl group or an amino group. ]
The distance between the center of gravity of ring B (W1), the center of gravity of ring A (W2), and the oxygen or sulfur atom (W3) serving as a hydrogen bond acceptor in Y is W1 to W2 = 6.0 to 11.0 °, respectively. ,
W1-W3 = 3.0-8.0 °, W2-W3 = 3.0-
An anilide derivative and a pharmaceutically acceptable salt capable of taking a configuration of 8.0 °;

[29] A wherein A is an optionally substituted heterocyclic ring, R3 is an amino group, and Y is -CO-
And the pharmaceutically acceptable salt according to [28], wherein the anilide derivative is a chain, a ring, or a combination thereof, linking B and B.

[30] A phenyl group in which B may be substituted, W1 to W2 = 7.0 to 9.5 °, W1 to W3 = 3.
0 to 5.0%, W2 to W3 = 5.0 to 8.0%, and the anilide derivative and a pharmaceutically acceptable salt according to [29];

[31] a carcinostatic agent comprising at least one of the compounds according to any one of [1] to [30] as an active ingredient;

[32] A drug containing at least one of the compounds according to any one of [1] to [30] as an active ingredient.

[0053]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The term "C1-4" as used herein refers to the number of carbon atoms per unit substituent. That is, for example, in the case of dialkyl substitution, it means having 2 to 8 carbon atoms.

The heterocyclic ring in the compounds represented by the formulas (1) and (13) is a monocyclic heterocyclic ring comprising a 5- or 6-membered ring containing 1 to 4 nitrogen, oxygen or sulfur atoms. A ring or a bicyclic fused heterocycle, for example, as a monocyclic heterocycle, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole,
Isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine, tetrahydrofuran, morpholine, thiomorpholine, etc. Examples thereof include condensed pyridine rings such as oxazolopyridine, imidazolopyridine, and thiazolopyridine, benzofuran, benzothiophene, and benzimidazole.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Examples thereof include an isobutyl group, a sec-butyl group, and a tert-butyl group.

The alkoxy group having 1 to 4 carbon atoms includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. And the like. Examples of the aminoalkyl group having 1 to 4 carbon atoms include an aminomethyl group, a 1-aminoethyl group, and a 2-aminopropyl group.

The alkylamino group having 1 to 4 carbon atoms includes, for example, N-methylamino group, N, N-dimethylamino group,
N, N-diethylamino group, N-methyl-N-ethylamino group, N, N-diisopropylamino group and the like can be mentioned. Examples of the acyl group having 1 to 4 carbon atoms include an acetyl group, a propanoyl group, and a butanoyl group.

The acylamino group having 1 to 4 carbon atoms includes, for example, an acetylamino group, a propanoylamino group and a butanoylamino group. Examples of the alkylthio group having 1 to 4 carbon atoms include a methylthio group, an ethylthio group, and a propylthio group.

The perfluoroalkyl group having 1 to 4 carbon atoms includes, for example, a trifluoromethyl group and a pentafluoroethyl group. Examples of the perfluoroalkyloxy group having 1 to 4 carbon atoms include a trifluoromethoxy group and a pentafluoroethoxy group.

The alkoxycarbonyl group having 1 to 4 carbon atoms includes, for example, a methoxycarbonyl group and an ethoxycarbonyl group. Examples of the optionally substituted alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Isobutyl group, sec-butyl group, tert-butyl group and the like, and a substituent selected from a group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a phenyl group and a heterocyclic ring; Those having four can be cited.

In the compound represented by the formula (13), important factors for exhibiting high differentiation-inducing activity include (a) ring A and ring B and an oxygen atom or sulfur as a hydrogen bond receptor as described below. The presence of atoms, (b) the distance defined by their steric configuration. Therefore, Y is not particularly limited as long as it has a hydrogen bond acceptor in its structure and regulates the steric configuration of ring A and ring B at a required position. That is, a structure having any of —CO—, —CS—, —SO— or —SO ₂ — of Y in the structure, and a chain or ring connecting A and B, or a combination thereof is defined as: (A) In a linear or branched chain structure composed of carbon atoms, hetero atoms, and the like, -CO
-, - CS -, - SO -, - SO 2 - structure linking A and B containing, (b) -CO the cyclic structure -, - CS-,
A structure connecting A and B having —SO—, —SO ₂ —,
(C) The cyclic structure and the chain structure are combined to form one structure, in which -CO-, -CS-, -SO-,-
It means any of the structures linking A and B, including SO ₂ —.

The basic structure of the cyclic structure includes a ring structure containing a carbon atom or a hetero atom of a 4- to 7-membered ring, or a condensed ring thereof. Cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, oxetane ring, oxolane ring, oxane ring, oxepane ring, pyrrolidine ring, imidazolidine ring, pyrazolidine ring, piperidine ring, piperazine ring, indoline ring, isoindoline ring, thiolane A ring, a thiazolidine ring, an oxazolidine ring and the like can be mentioned, and the structure can have an unsaturated bond, a hydrogen bond acceptor or a substituent.

By analyzing the compound represented by the formula (13) in consideration of the degree of conformational freedom, a compound exhibiting high differentiation-inducing activity can be used for a bio-drug interaction such as a hydrophobic interaction or a hydrogen bond. Have been found to be in a particular spatial arrangement.

Specifically, the three-dimensional structure of a highly active compound is generated using molecular modeling software (SYBYL6.3), and the most stable structure is obtained by performing a conformational analysis on all rotatable bonds. Was. Here, the evaluation of the energy was performed using a Tripos force field after generating charges on each atom by the Gasteiger-Huckel method. Then, using the most stable structure as a starting structure, superimposition considering conformation was performed by DISCO / SYBYL, and as a result, it was found that a specific spatial arrangement was necessary for the expression of high differentiation-inducing activity.

In the above analysis operation, another commercially available calculation package [CATALYST (MSI), Cerius2 / QSAR + (MSI
And SYBYL / DISCO (Tripos) etc.], and the distance information obtained by the present invention is not limited by a specific calculation program.

The center of gravity of the ring used for defining the spatial arrangement can be defined as the average of the X, Y and Z axes of the atoms constituting the ring. When the target ring structure is a condensed polycyclic system, either the center of gravity of the entire condensed ring or the center of gravity of a part of the ring can be used as the center of gravity for defining the space.

To be able to adopt a steric configuration means that a conformer satisfying the spatial configuration exists within 15 kcal / mol from the energetically most stable structure, more preferably within 8 kcal / mol. It is desirable to do. The details of the calculation method can be performed according to the method described in Sybyl manual: M. Clark or J. Comput. Chem. 10. 982 (1989).

The salts of pharmaceutically acceptable compounds include inorganic acids commonly used in this field, such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like.
Examples thereof include salts with organic acids such as fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid. For example, N
-(2-aminophenyl) -4- [N- (pyridine-3
-Yl) methoxycarbonylaminomethyl] benzamide hydrochloride, N- (2-aminophenyl) -4- [N-
(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide hydrobromide, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide sulfate,

N- (2-aminophenyl) -4- [N-
(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide phosphate, N- (2-aminophenyl)
-4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide acetic acid salt, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide lactic acid Salt, N
-(2-aminophenyl) -4- [N- (pyridine-3
-Yl) methoxycarbonylaminomethyl] benzamide tartaric acid, N- (2-aminophenyl) -4- [N-
(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide malate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide succinate, N-
(2-aminophenyl) -4- [N- (pyridine-3-
Yl) methoxycarbonylaminomethyl] benzamide fumarate,

N- (2-aminophenyl) -4- [N-
(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide maleate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide citrate, N-
(2-aminophenyl) -4- [N- (pyridine-3-
Yl) methoxycarbonylaminomethyl] benzamide trifluoroacetic acid, N- (2-aminophenyl) -4-
[N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide p-toluenesulfonate, N
-(2-aminophenyl) -4- [N- (pyridine-3
-Yl) methoxycarbonylaminomethyl] benzamide methanesulfonate.

[0086] Pharmaceuticals include not only anticancer drugs but also drugs for treating and / or improving autoimmune diseases, skin diseases, parasitic infections and the like.

When the compounds represented by the formulas (1) and (13) have an asymmetric carbon, they can exist in different stereoisomeric forms or a mixture of stereoisomeric forms including racemic forms. That is, the present invention also includes various forms defined as described above, and these can be similarly used as the active ingredient compound.

The formulas (1) and (13) of the present invention will be described below.
Table 1 [Table 1-Table 24], Table 2 [Table 25-Table 26], Table-3 [Table 27-Table 28] and Table-4 [Table 29-Table 30] Specific examples are shown below. Note that the present invention is not limited to these examples.

[0074]

[Table 1]

[0075]

[Table 2] Table 1

[0076]

[Table 3] Table 1 continued 2

[0077]

[Table 4] Table 1 continued 3

[0078]

[Table 5] Table 1 continued 4

[0079]

[Table 6] Table 1 Continuation 5

[0080]

[Table 7] Table 1 continued 6

[0081]

[Table 8] Table 1 continued 7

[0082]

[Table 9] Table 1 continued 8

[0083]

[Table 10] Table 1 continued 9

[0084]

[Table 11] Table 10

[0085]

[Table 12] Table 1 continued 11

[0086]

[Table 13] Table 1 continued 12

[0087]

[Table 14] Table 1 continued 13

[0088]

[Table 15] Table 1 continued 14

[0089]

[Table 16] Table 1 Continuation 15

[0090]

[Table 17] Table 1 continued 16

[0091]

[Table 18] Table 1 continued 17

[0092]

[Table 19] Table 1 continued 18

[0093]

[Table 20] Table 1 continued 19

[0094]

[Table 21] Table 1 continued 20

[0095]

[Table 22] Table 1 continued item 21

[0096]

[Table 23] Table 1 continued 22

[0097]

[Table 24] Table 1 continued 23

[0098]

[Table 25]

[0099]

[Table 26] Table 2 Continuation 1

[0100]

[Table 27] Table-3

[0101]

[Table 28] Table 3 Continuation 1

[0102]

[Table 29] Table-4

[0103]

[Table 30] Table-4 Continuation 1

The compound of the present invention can be produced, for example, by the following method. (A) Formula (14)

[0105]

Embedded image [Wherein, A and X are as defined above. R9 is -C (= G)
OH (G represents an oxygen atom or a sulfur atom) or-
Represents NH ₂ . And a compound represented by the formula (15)
8]

[0106]

Embedded image [Wherein, R1, R2 and n are as defined above. R10 is R
When 9 is -C (= G) OH (G is as defined above)
It represents H _2, when R9 is -NH ₂ -C (= G) OH
(G is as defined above). R11 represents an amino group protected with a protecting group such as a tert-butoxycarbonyl group used in a usual peptide forming reaction or a hydroxyl group protected with a protecting group such as a benzyl group used in a usual peptide forming reaction. Or a compound represented by the formula (16):

[0107]

Embedded image Compound represented by (wherein, A and X are defined as above .R12 represents -OH or -NH _2.) And the formula (17)
[Formula 30]

[0108]

Embedded image (Wherein, R1, R2, R11 and n are as defined above. R
13 represents -OH or -NH _2. ) Is converted to N, N'-carbonyldiimidazole, N, N '
Formula (1) obtained by subjecting to condensation reaction using thiocarbonyldiimidazole, phosgene or thiophosgene, etc.
8) [Formula 31]

[0109]

Embedded image (Wherein A, X, Q, n, R1, R2 and R11 have the same meanings as described above), whereby the compound of the present invention can be obtained by removing the protective group. (C) a compound represented by the formula (14) and a compound represented by the formula (19):

[0110]

Embedded image (Wherein, R1, R10 and n are as defined above. R14
Represents a methyl group, an ethyl group or a tert-butyl group. (D) is subjected to a condensation reaction, or (d) a compound represented by the formula (16) and a compound represented by the formula (20)

[0111]

Embedded image (Wherein R1, R13, R14 and n have the same meanings as described above), and condensed with N, N′-carbonyldiimidazole, N, N′-thiocarbonyldiimidazole, phosgene or thiophosgene, etc. Formula (21) obtained by the reaction

[0112]

Embedded image (Wherein, A, X, Q, n, R1 and R14 have the same meanings as described above).
2) [Chemical 35]

[0113]

Embedded image (Wherein A, X, Q, n and R1 have the same meanings as described above) by converting a compound represented by the formula (23)

[0114]

Embedded image (Wherein R2 and R11 have the same meanings as described above). The compound of the present invention can also be obtained by removing the protecting group of the compound represented by the formula (18) obtained by subjecting the compound to a condensation reaction. Can be. (E) a compound represented by the formula (22) and a compound represented by the formula (24):

[0115]

Embedded image (Wherein R2 and R3 have the same meanings as described above). The compound of the present invention can also be obtained by subjecting the compound to a condensation reaction.

The synthesis of a typical intermediate will be described. The compound represented by the formula (15) is represented by the formula (25)

[0117]

Embedded image (Wherein R1, R10 and n are as defined above), after introducing a suitable protecting group into the benzoic acid derivative represented by the formula (23), subject to a condensation reaction with the compound represented by the formula (23) and further deprotection. Can be obtained. The compound represented by the formula (17) is represented by the formula (26)

[0118]

Embedded image (Wherein R1, R13 and n are as defined above), after introducing a suitable protecting group into the benzoic acid derivative, followed by subjecting it to a condensation reaction with the compound represented by the formula (23), and further deprotection. Can be obtained. The compound represented by the formula (23) can be obtained by introducing a protecting group into the compound represented by the formula (24).

Next, the reaction will be described. The condensation reaction of (a) can be carried out by a method of forming an amide bond in a usual peptide, for example, a method of active ester or mixed acid anhydride or acid chloride. For example, a carboxylic acid component [in the formula (14), R9 is -C (= G) OH
(G is as defined above) or a compound represented by the formula (1)
5) a compound in which R10 is -C (= G) OH (G is as defined above)] and a phenol such as 2,4,5-trichlorophenol, pentachlorophenol or 4-nitrophenol, or N- N such as hydroxysuccinimide, N-hydroxybenztriazole
The hydroxy compound is condensed in the presence of dicyclohexylcarbodiimide and converted into the active ester form,
An amine component [compound of the formula (14), wherein R 9 is —NH ₂ or, in the formula (15), R 10 is —NH ₂
And a compound represented by the formula:

Further, a carboxylic acid component [a compound represented by the formula (14) wherein R9 is -C (= G) OH (G is as defined above) or R10 is a compound represented by -C (=
G) a compound represented by OH (G is as defined above)] with oxalyl chloride, thionyl chloride, phosphorus oxychloride and the like to convert into an acid chloride, and then an amine component [formula (14)
Wherein R 9 is —NH ₂ or a compound of formula (1)
In 5) R10 can be carried out by condensation with the compound represented by the formula] with -NH _2.

Further, a carboxylic acid component [in the formula (14), R9 is a compound represented by -C (= G) OH (G is as defined above) or in the formula (15), R10 is -C (=
G) a compound represented by OH (G is as defined above)] with isobutyl chlorocarbonate or methanesulfonyl chloride to obtain a mixed acid anhydride, and then an amine component [in the formula (14), R9 is -NH in a compound or the formula represented by ₂ (15) R10 can be carried out by condensation with the compound represented by the formula] with -NH _2.

Further, the condensation reaction is carried out by a peptide condensation such as dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, diphenylphosphate azide, diethylphosphate cyanide, 2-chloro-1,3-dimethylimidazolonium chloride. It can also be performed using the reagent alone.

The reaction is usually carried out at -20 to + 50 ° C. for 0.5 to
Perform for 48 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, and N, N-dimethylformamide. Examples thereof include alcohols such as methanol and ethanol, and mixtures thereof. If necessary, an organic base such as triethylamine or pyridine is added to react.

In the condensation reaction (b), one of the compounds represented by the formulas (16) and (17) is converted to phosgene,
It can be carried out by activating with thiophosgene, N, N'-carbonyldiimidazole, N, N'-thiocarbonyldiimidazole or the like, followed by reacting with another compound. The reaction is usually performed at −20 to + 50 ° C.
For 0.5 to 48 hours. As the solvent used, for example, benzene, aromatic hydrocarbons such as toluene,
Ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as methylene chloride and chloroform; N, N-dimethylformamide;
Or a mixture thereof. If necessary, an organic base such as triethylamine or pyridine is added to carry out the reaction.

The condensation reaction (c) can be carried out in the same manner as the condensation reaction (a). The condensation reaction of (d) can be performed by the same method as the condensation reaction of (b).

The removal of the protecting group of the compound represented by the formula (17) is carried out under the conditions used for a usual peptide formation reaction. For example, in the equation (18), R11 is tert.
In the case of an amino group protected with a -butoxycarbonyl group, the deprotection reaction can be carried out by treating with an acid such as hydrochloric acid or trifluoroacetic acid.

The salts of the compounds represented by the formulas (1) and (13) can be obtained by a reaction for producing the compounds represented by the formulas (1) and (13), but are pharmaceutically acceptable. It can easily form salts with acids. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, and p-toluenesulfonic acid. Acids can be mentioned. These salts can also be used as the active ingredient compound of the present invention, like the free form compounds of the formulas (1) and (13).

The compounds represented by the formulas (1) and (13) can be separated from the reaction mixture by a conventional separation means such as an extraction method.
It can be isolated and purified by a method such as a recrystallization method and column chromatography.

The novel benzamide derivatives and novel alinide derivatives of the present invention have a differentiation-inducing action and are useful as therapeutic and / or ameliorating agents for malignant tumors, autoimmune diseases, skin diseases, parasitic infections and the like.

Here, malignant tumors include hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, and macroglobulinemia, as well as colorectal cancer, brain tumor, head and neck cancer,
Breast, lung, esophageal, gastric, liver, gallbladder, bile duct, pancreatic, islet cell, renal cell, adrenal cortical, bladder, prostate, testicular, ovarian, uterine, choriocarcinoma, thyroid cancer,
Malignant carcinoid tumor, skin cancer, malignant melanoma, osteosarcoma,
Examples include solid tumors such as soft tissue sarcoma, neuroblastoma, Wilms tumor, and retinoblastoma.

Autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, ulcerative colitis and the like. Skin diseases include psoriasis, acne, eczema, atopic dermatitis and the like. Parasitic infection refers to a disease caused by infection of a parasite such as malaria infection. The target disease of the present invention is not limited to these.

The active ingredient compounds of the present invention are useful as pharmaceuticals, and they are used in the form of general medical preparations. The formulation contains commonly used fillers, extenders, binders,
It is prepared using diluents or excipients such as humectants, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspensions). And suppositories.

In molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, glucose, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose and silicic acid, water, ethanol,
Propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, polyvinylpyrrolidone, disintegrants such as dry starch, sodium alginate, agar powder, carmellose calcium, starch, lactose, White sugar,

Disintegration inhibitors such as cocoa butter and hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite and colloidal silicic acid Adsorbents such as talc, stearate, polyethylene glycol and the like. Furthermore, tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.

In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples include crystalline cellulose, lactose, starch,
Excipients such as hardened vegetable oil, kaolin, talc, etc., binders such as gum arabic powder, tragacanth powder, gelatin and the like, disintegrants such as carmellose calcium, agar and the like can be mentioned.

Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the resulting mixture into hard gelatin capsules, soft capsules, and the like, according to a conventional method.

When prepared as an injection, the liquid preparation, emulsion and suspension are preferably sterilized and isotonic with blood, and when formed into these forms, they are commonly used as diluents in this field. Things, such as water,
Ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, an amount of salt, glucose or glycerin necessary for preparing an isotonic solution may be contained in the pharmaceutical preparation,
Further, ordinary solubilizers, buffers, soothing agents and the like may be added.

In the case of molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include semi-synthetic glycerides, cocoa butter, higher alcohols, esters of higher alcohols, polyethylene glycol and the like.

Further, if necessary, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals can be contained in the pharmaceutical preparation. The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range.
The content is preferably about 70% by weight, preferably about 5% to 50% by weight.

The administration method of these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered according to various preparation forms, the age, sex, degree of disease and other conditions of patients. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally, and injections are
It is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acids, and if necessary, intramuscularly, subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dose of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, the age, sex, degree of disease and other conditions of the patient. Usually, the amount of the active ingredient compound is one per kg of body weight. It is preferable to use about 0.0001 to 100 mg per day. It is desirable that the active ingredient compound be contained in a dosage unit form in a range of about 0.001 to 1,000 mg. The compounds of the present invention represented by the formulas (1) and (13) and salts thereof do not show a problematic toxicity at a pharmacologically effective dose.

[0142]

The present invention will be described below in detail with reference to examples.
The present invention is not limited to these. The numbers in parentheses in the title are the numbers of the compounds exemplified in the detailed description.

Example 1 Synthesis of N- (2-aminophenyl) -4- (N-benzoylaminomethyl) benzamide hydrochloride (Table 1: hydrochloride of compound No. 1) (1-1) 4-aminomethyl 21.16 g of benzoic acid
To a suspension of (140 mmol) in dichloromethane (450 ml) was added 42 ml (300 mmol) of triethylamine.
Was added. Under ice cooling, a solution of 60.4 g (287 mmol) of trifluoroacetic anhydride in dichloromethane (50 ml) was added dropwise while maintaining the internal temperature at 3 to 8 ° C., and the mixture was stirred for 3 hours. After the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, the solution was further acidified with a 10% aqueous hydrochloric acid solution. The precipitated gel precipitate was collected by filtration and dried to give 30.4 g of 4- (N-trifluoroacetylaminomethyl) benzoic acid (yield 87.8).
%) As an opalescent solid. 1H NMR (270MHz, DMSO-d6) δppm: 4.47 (2H, d, J = 5.8Hz),
7.39 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 10.08 (1H,
t, J = 5.8Hz), 12.95 (1H, br.s).

(1-2) o-phenylenediamine 10
To a solution of 8 g (1.0 mol) in dioxane (1000 ml) was added a 1 N aqueous solution of sodium hydroxide (500 ml), and under ice cooling, 218 g of ditert-butyl dicarbonate.
A solution of (1.1 mol) in dioxane (500 ml) was added. After stirring at room temperature for 6 hours, the mixture was left overnight. Solvent 1 /
After concentrating to 2 volumes, it was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform). The obtained solid was washed with ethyl ether to give N-tert-butoxy. Carbonyl-o-
68.4 g of phenylenediamine (32.8% yield) was obtained as a white solid. 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 3.75 (2H,
s), 6.26 (1H, s), 6.77 (1H, d, J = 8.1Hz), 6.79 (1H, dd, J =
7.3,8.1Hz), 7.00 (1H, dd, J = 7.3,8.1Hz), 7.27 (1H, d, J =
8.1Hz).

(1-3) A suspension of 30.0 g (121 mmol) of the compound obtained in the step (1-1) in dichloromethane (200 ml) was added while cooling with ice (internal temperature 10 to 1).
5 ° C) 21 g (165 mmol) of oxalyl chloride
Was gradually added dropwise. At that time, DMF was added occasionally (approximately 0.1 ml for every 2 ml added). After dripping the whole amount,
The mixture was stirred until foaming stopped, and then stirred at 40 ° C. for 1 hour. After the solvent was distilled off, excess oxalyl chloride was azeotropically distilled with toluene, and dichloromethane (100 ml) was added again.
Was dissolved. Compound 22.8 obtained in step (1-2)
8 g (110 mmol) of dichloromethane (100 m
l) The acid chloride solution prepared above was added dropwise to a solution of -pyridine (200 ml) under ice cooling (internal temperature 7 to 9 ° C).

After the completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was left overnight. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture, the mixture was extracted with chloroform, washed with saturated saline, dried, and the solvent was distilled off. Methanol-diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert-butoxycarbonyl).
[Aminophenyl] -4- (N-trifluoroacetylaminomethyl) benzamide (28.1 g, yield 58%) was obtained as a pale yellow solid. 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.48 (2H,
d, J = 5.9Hz), 7.12-7.23 (2H, m), 7.44 (2H, d, J = 8.1Hz),
7.54 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.68 (1H, b
rs), 9.83 (1H, s), 10.10 (1H, br.t, J = 5.9Hz).

(1-4) Compound 1 of Step (1-3)
3.12 g (30 mmol) of methanol (120 m
l) To a suspension of water (180 ml) was added potassium carbonate 4.70.
g (34.0 mmol) was added, and the mixture was heated and stirred at 70 ° C. for 4 hours. After extraction with chloroform, the organic layer was washed with saturated saline, dried, and the solvent was distilled off.
-Aminomethyl-N- [2- (N-tert-butoxycarbonyl) aminophenyl] benzamide 10.3 g
(Quantitative) was obtained as a pale yellow amorphous solid. 1H NMR (270MHz, DMSO-d6) δppm: 3.80 (2H, s), 7.13-7.2
3 (2H, m), 7.48-7.58 (4H, m), 7.90 (2H, d, J = 8.1Hz), 8.69
(1H, br.s), 9.77 (1H, br.s).

(1-5) Compound of step (1-4)
To a solution of 11 g (0.44 mmol) in pyridine (5 ml) was added 0.08 g (0.53 g) of benzoyl chloride under ice-cooling.
(mmol), and the mixture was stirred for 8 hours while gradually raising the temperature to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, and the residue obtained by evaporating the solvent was washed with diisopropyl ether, and the obtained solid was dried to give N- [2-
(N-tert-butoxycarbonyl) aminophenyl] -4- (N-benzoylaminomethyl) benzamide (0.14 g, yield 71.4%) was obtained as a white solid. 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.56 (2H,
d, J = 5.9Hz), 7.11-7.22 (2H, m), 7.46-7.56 (7H, m), 7.90
-7.94 (4H, m), 8.67 (1H, s), 9.15 (1H, t, J = 5.9Hz), 9.81
(1H, s).

(1-6) Compound 0 of step (1-5)
10 g (0.224 mmol) of dioxane (5 ml)
4N hydrochloric acid-dioxane (5 ml) was added to a methanol (1 ml) solution, and the mixture was stirred at room temperature for 7 hours. Diisopropyl ether was added to the residue from which the solvent was distilled off, and the obtained solid was collected by filtration and dried to give N- (2-aminophenyl) -4- (N-benzoylaminomethyl) benzamide hydrochloride (0.08 g) ( (93% yield) as a light brown solid. mp. 206-209 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.57 (2H, d, J = 5.8Hz),
7.27-7.38 (4H, m), 7.47-7.59 (5H, m), 7.92 (1H, d, J = 8.1H
z), 8.05 (1H, d, J = 8.1Hz), 9.19 (1H, t, J = 5.8Hz), 10.38 (1
H, br.s) .IR (KBr) cm-1: 3286,3003 (br.), 1630,1551,1492,1306,12
50, 749, 695. In the same manner as in Example 1, Examples 2 to 44 were used.
Was synthesized. The melting point of the compound (mp.), 1
The measured values of 1 H NMR and IR are shown.

Example 2 N- (2-aminophenyl) -4- [N- (2-chlorobenzoyl) aminomethyl] benzamide (Table 1: Compound No. 14) mp. 201-204 ° C. (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.52 (2H, t, J = 5.9Hz),
4.89 (2H, br.s), 6.60 (1H, ddd, J = 1.5,7.3,8.1Hz), 6.78
(1H, dd, J = 1.5,8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz),
7.17 (1H, d, J = 8.1Hz), 7.38-7.54 (6H, m), 7.97 (2H, d, J =
8.1Hz), 9.06 (1H, br.t, J = 5.9Hz), 9.63 (1H, br.s) .IR (KBr) cm-1: 3268,1649,1458,1304,748.

Example 3 N- (2-aminophenyl) -4- [N- (2-nitrobenzoyl) aminomethyl] benzamide hydrochloride (Table 1: hydrochloride of compound No. 18) mp. 210-212 ° C. (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.55 (2H, t, J = 5.9Hz),
7.20-7.40 (3H, m), 7.50-7.60 (1H, m), 7.53 (2H, d, J = 8.1H
z), 7.60-7.70 (2H, m), 7.83 (1H, ddd, J = 1.5,8.1,8.1Hz),
8.00-8.10 (3H, m), 9.34 (1H, t, J = 5.9Hz), 10.43 (1H, br.
s) .IR (KBr) cm-1: 3283,2500-3000 (br.), 1648,1534,1461,13
62,1314,754,701.

Example 4 N- (2-aminophenyl) -4- [N- (4-methylbenzoyl) aminomethyl] benzamide hydrochloride (Table 1: hydrochloride of compound No. 28) mp. (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 2.37 (3H, s), 4.56 (2H,
d, J = 5.0Hz), 7.20-7.30 (6H, m), 7.47 (4H, d, J = 8.8Hz),
7.82 (2H, d, J = 8.8Hz), 8.03 (2H, d, J = 8.8Hz), 9.09 (1H, t,
J = 5Hz), 10.36 (1H, br.s) .IR (KBr) cm-1: 3269 (br.), 2861 (br.), 1743,1636,1534,15
05,1456,1308,1120,753.

Example 5 N- (2-aminophenyl) -4- [N- (3-methoxybenzoyl) aminomethyl] benzamide (Table 1:
Compound No. 30) mp. 182-185 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.81 (3H, s), 4.54 (2H,
d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3H
z), 6,78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 6.6,7.3Hz),
7.11 (1H, dd, J = 1.5,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.35-
7.51 (5H, m), 7.94 (2H, d, J = 8.1Hz), 9.12 (1H, br.t, J = 5.9
Hz), 9.63 (1H, br.s) .IR (KBr) cm-1: 3301,1637,1524,1489,1457,1314,1248,75
2.

Example 6 N- (2-aminophenyl) -4- [N- (4-methoxybenzoyl) aminomethyl] benzamide (Table 1:
Compound No. 31) mp. 149-151 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.82 (3H, s), 4.53 (2H,
d, J = 5.9Hz), 4.88 (2H, s), 6.59 (1H, dd, J = 7.3,7.3Hz),
6.77 (1H, d, J = 8.1Hz), 6.94-7.00 (1H, m), 7.02 (2H, d, J =
8.8Hz), 7.16 (1H, d, J = 8.1Hz), 7.43 (2H, d, J = 8.1Hz), 7.
89 (2H, d, J = 8.8Hz), 7.94 (2H, d, J = 8.1Hz), 8.98 (1H, br.t,
J = 5.9Hz), 9.61 (1H, br.s) .IR (KBr) cm-1: 3297,1630,1527,1505,1457,1256,1177,10
24,843,749.

Example 7 N- (2-aminophenyl) -4- [N- (3,4,5
-Trimethoxybenzoyl) aminomethyl] benzamide (Table 1: Compound No. 33) mp. 208-210 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.71 (3H, s), 3.83 (6H ,
s), 4.55 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd,
J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.
6,8.1Hz), 7,16 (1H, d, J = 8.1Hz), 7.26 (2H, s), 7.44 (2H,
d, J = 8.1Hz), 7.95 (2H, d, J = 8.8Hz), 9.07 (1H, t, J = 5.9H
z), 9.62 (1H, br.s) .IR (KBr) cm-1: 3267,1635,1582,1457,1237,1132,755.

Example 8 N- (2-aminophenyl) -4- [N- [4- (N,
N-dimethyl) aminobenzoyl] aminomethyl] benzamide (Table 1: Compound No. 36) mp. 216-219 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.98 (6H, s), 4.51 (2H,
d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 8.1,8.1H
z), 6.71 (2H, d, J = 8.8Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J = 8.1Hz), 7.78 (2H, d, J
J = 8.8Hz), 7.93 (2H, d, J = 8.1Hz), 8.77 (1H, t, J = 5.9Hz),
9.63 (1H, br.s) .IR (KBr) cm-1: 3301,1632,1519,1457,1298,754.

Example 9 N- (2-aminophenyl) -4- [N- (4-trifluoromethylbenzoyl) aminomethyl] benzamide (Table 1: Compound No. 42) mp. 243-246 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz),
4.88 (2H, br.s), 6.59 (1H, dd, J = 6.6,7.3Hz), 6.77 (1H, d,
J = 8.1Hz), 6.94 (1H, dd, J = 5.9,6.6Hz), 7.16 (1H, d, J = 8.1
Hz), 7.45 (2H, d, J = 8.1Hz), 7.88 (2H, d, J = 8.8Hz), 7.95
(2H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz), 9.38 (1H, t, J = 5.
9Hz), 9.64 (1H, br.s) .IR (KBr) cm-1: 3301,1640,1549,1523,1458,1334,1162,11
20,1070,856,750.

Example 10 N- (2-aminophenyl) -4- [N- (4-carboxybenzoyl) aminomethyl] benzamide hydrochloride (Table 1: hydrochloride of compound No. 45) mp. (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz),
7.29-7.37 (3H, m), 7.49 (3H, d, J = 8.1Hz), 8.02-8.06 (6H,
m), 9.36 (1H, t, J = 5.9Hz), 10.4 (1H, br.s) .IR (KBr) cm-1: 3432 (br.), 1718,1637,1542,1499,1303 (b
r.), 1116, 1018, 757.

Example 11 N- (2-aminophenyl) -4- [N- (4-methoxycarbonylbenzoyl) aminomethyl] benzamide (Table 1: Compound No. 46) mp. 204-209 ° C. (dec.) .1H NMR (270MHz, DMSO-d6) δppm: 3.89 (3H, s), 4.57 (2H,
d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3H
z), 6.78 (2H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3H
z), 7.16 (1H, d, J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.95 (2
H, d, J = 8.1Hz), 8.03 (2H, d, J = 8.8Hz), 8.07 (2H, d, J = 8.8H
z), 9.35 (1H, t, J = 5.9Hz), 9.64 (1H, br.s) .IR (KBr) cm-1: 3287 (br.), 1721,1634,1281,1113,750,70
3.

Example 12 N- (2-aminophenyl) -4- (N-picolinoylaminomethyl) benzamide (Table 1: Compound No. 17)
3) mp. 173-178 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.57 (2H, d, J = 6.6Hz),
4.88 (2H, br.s), 6.59 (1H, dd, J = 7.3,8.1Hz), 6.77 (1H, d,
J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3
Hz), 7.44 (2H, d, J = 8.1Hz), 7.60-7.65 (1H, m), 7.93 (2H,
d, J = 8.1Hz), 7.98-8.08 (2H, m), 8.67 (1H, d, J = 4.4Hz),
9.45 (1H, t, J = 6.6Hz), 9.61 (1H, br.s) .IR (KBr) cm-1: 3330,1656,1634,1523,1456,1294,752.

Example 13 N- (2-aminophenyl) -4- [N- (6-methylpicolinoyl) aminomethyl] benzamide (Table 1:
Compound No. 178) mp. 172-173 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.51 (3H, s), 4.57 (2H,
d, J = 6.6Hz), 5.0 (2H, br.s), 6.61 (1H, dd, J = 7.3,8.1Hz),
6.79 (1H, d, J = 7.3Hz), 6.98 (1H, dd, J = 7.3,8.1Hz), 7.17
(1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1Hz), 7.43-7.49 (1H,
m), 7.84-7.90 (2H, m), 7.94 (2H, d, J = 8.1Hz), 9.27 (1H,
t, J = 5.9Hz), 9.64 (1H, br.s) .IR (KBr) cm-1: 3331,1675,1634,1594,1523,1454,1307,12
92,750.

Example 14 N- (2-aminophenyl) -4- (N-nicotinoylaminomethyl) benzamide (Table 1: Compound No. 7)
1) mp. 193-196 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d), 4.88 (2H,
br.s), 6.60 (1H, t), 6.78 (1H, d), 6.97 (1H, t), 7.16 (1
H, d), 7.46 (2H, d), 7.53 (1H, dd), 7.95 (2H, d), 8.24 (1
H, ddd), 8.73 (1H, dd), 9.07 (1H, d), 9.32 (1H, br.t), 9.
63 (1H, br.s) IR (KBr) cm-1: 3301,1639,1522,1457,1314,749,705.

Example 15 N- (2-aminophenyl) -4- [N- (2-methylnicotinoyl) aminomethyl] benzamide (Table 1)
Compound No. 141) mp. 191-194 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.53 (3H, s), 4.53 (2H,
d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,8.1H
z), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.17 (1H, d, J = 7.3Hz), 7.29 (1H, dd, J = 5.1,8.1Hz), 7.47
(2H, d, J = 8.1Hz), 7.77 (1H, dd, J = 1.5,8.1Hz), 7.97 (2H,
d, J = 8.1Hz), 8.51 (1H, dd, J = 1.5,5.1Hz), 9.06 (1H, t, J =
5.9Hz), 9.64 (1H, s) .IR (KBr) cm-1: 3261,1642,1523,1310,753.

Example 16 N- (2-aminophenyl) -4- [N- (6-methylnicotinoyl) aminomethyl] benzamide (Table 1:
Compound No. 143) mp. 186-190 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.36 (3H, s), 4.56 (2H,
d, J = 5.9Hz), 4.88 (2H, s), 6.60 (1H, dd, J = 7.4,7.8Hz),
6.78 (1H, d, J = 7.8Hz), 6.97 (1H, dd, J = 6.9,6.9Hz), 7.16 (1H, dd, J = 6.9,6.9Hz)
H, d, J = 7.4Hz), 7.37 (1H, d, J = 8.3Hz), 7.45 (2H, d, J = 8.3H
z), 7.95 (2H, d, J = 8.3Hz), 8.13 (1H, dd, J = 2.0,8.3Hz),
8.96 (1H, s), 9.24 (1H, t, J = 5.9Hz), 9.63 (1H, br.s) .IR (KBr) cm-1: 3302,1636,1602,1523,1489,1457,1313, 75
1.

Example 17 N- (2-aminophenyl) -4- [N- (2-chloronicotinoyl) aminomethyl] benzamide (Table 1)
Compound No. 154) mp. 176-178 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.54 (2H, t, J = 5.9 Hz),
4.90 (2H, br.s), 6.60 (1H, ddd, J = 1.5,7.3,7.3Hz), 6.78
(1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.18
(1H, d, J = 8.1Hz), 7.48-7.54 (3H, m), 7.94-7.99 (3H, m),
8.49 (1H, dd, J = 2.1,5.1Hz), 9.23 (1H, br.t, J = 5.9Hz), 9.
65 (1H, br.s) .IR (KBr) cm-1: 3264,1649,1524,1400,1309,751.

Example 18 N- (2-aminophenyl) -4- [N- (6-chloronicotinoyl) aminomethyl] benzamide (Table 1)
Compound No. 156) mp. 205-208 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 5.57 (2H, d, J = 5.9 Hz),
6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.96
(1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.45 (2H,
d, J = 8.1Hz), 7.66 (1H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1H
z), 8.27-8.32 (1H, m), 8.90 (1H, d, J = 2.1Hz), 9.38 (1H, t,
J = 5.9Hz), 9.63 (1H, s) .IR (KBr) cm-1: 3318 (br.), 2929,1646,1590,1525,1503,14
54,1108,745.

Example 19 N- (2-Aminophenyl) -4- (N-isonicotinoylaminomethyl) benzamide (Table 1: Compound No. 183) mp. 234-237 ° C. (dec.). 1H NMR ( 270MHz, DMSO-d6) δppm: 4.57 (2H, t, J = 5.9Hz),
4.88 (2H, br.s), 6.59 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d,
J = 8.1Hz), 6.96 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3
Hz), 7.45 (2H, d, J = 8.1Hz), 7.81 (2H, d, J = 1.5,4.4Hz),
7.95 (2H, d, J = 8.1Hz), 8.75 (2H, d, J = 6.6Hz), 9.41 (1H, t,
J = 5.9Hz), 9.62 (1H, br.s) .IR (KBr) cm-1: 3298,1646,1550,1525,1457,1304,843,76
0,695.

Example 20 N- (2-aminophenyl) -4- [N- (pyrazine-
2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 191) mp. 207 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.58 (2H, d, J = 5.9 Hz),
4.88 (2H, br.s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d,
J = 8.1Hz), 6.94 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.15 (1H, d,
J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz),
8.77 (1H, d, J = 1.5Hz), 8.90 (1H, d, J = 2.1Hz), 9.21 (1H,
s), 9.55-9.61 (2H, m) .IR (KBr) cm-1: 3368 (br.), 1657,1524,1455,1295,1023,75
1.

Example 21 N- (2-aminophenyl) -4- [N- (thiophen-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 201) mp. 202-205 ° C (dec. 1H NMR (270MHz, DMSO-d6) δppm: 4.52 (2H, t, J = 5.9Hz),
4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d,
J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.15-7.18 (2H,
m), 7.43 (2H, d, J = 8.1Hz), 7.78 (1H, d, J = 4.4), 7.82 (1H,
d, J = 3.7Hz), 7.95 (2H, d, J = 8.1Hz), 9.12 (1H, br.t, J = 5.9
Hz), 9.62 (1H, br.s) .IR (KBr) cm-1: 3306,1633,1523,1456,1297,750,716.

Example 22 N- (2-aminophenyl) -4- [N- (furan-2
-Yl) carbonylaminomethyl] benzamide (Table-
1: Compound No. 205) mp. 197 ° C (dec.).

1H NMR (270 MHz, DMSO-d6) δ ppm: 4.59 (2H,
d, J = 6.6Hz), 4.86 (2H, br.s), 6.59 (1H, dd, J = 6.6,6.6H
z), 6.63 (1H, dd, J = 1.5,3.6Hz), 6.78 (1H, d, J = 8.1Hz),
6.96 (1H, dd, J = 7.3,6.6Hz), 7.10-7.20 (2H, m), 7.41 (2H,
d, J = 8.1Hz), 7.84 (1H, s), 7.94 (2H, d, J = 8.1Hz), 9.00 (1
H, br.t, J = 5.9Hz), 9.62 (1H, s) .IR (KBr) cm-1: 3245,1651,1573,1545,1323,1241,745.

Example 23 N- (2-aminophenyl) -4- [N- (pyrrole-
2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 209) mp. 216-220 ° C. (dec.) 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.50 (2H, d, J = 5.9 Hz) ,
4.88 (2H, br.s), 6.10 (1H, dd, J = 2.1,5.9Hz), 6.59 (1H, d
d, J = 7.3,7.3Hz), 6.77 (1H, dd, J = 1.5,8.1Hz), 6.84-6.88
(2H, m), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J =
7.3Hz), 7.41 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.
62 (1H, br.t, J = 5.9Hz), 9.62 (1H, br.s) .IR (KBr) cm-1: 3275,1655,1584,1534,1458,1316,747.

Example 24 N- (2-Aminophenyl) -4- [N- (1-methyl-1H-pyrrol-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 210) mp. 177 -179 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 3.84 (3H, s), 4.46 (2H,
d, J = 5.9Hz), 4.88 (2H, br.s), 6.03 (1H, dd, J = 2.1,4.4H
z), 6.59 (1H, dd, J = 8.1,8.1Hz), 6.77 (1H, d, J = 8.1Hz),
6.84-6.97 (2H, m), 7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J =
8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.61 (1H, t, J = 5.9Hz), 9.
62 (1H, br.s) .IR (KBr) cm-1: 3325 (br.), 1630,1551,1520,1507,1324,12
65,1154,740.

Example 25 N- (2-aminophenyl) -4- [N- (isoxazol-5-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 212) mp. 183-185 ° C. (dec) .). 1H NMR (270MHz, DMSO-d6) δppm: 4.53 (2H, d, J = 6.6Hz),
4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d,
J = 7.3Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.12 (1H, d, J = 2.1
Hz), 7.16 (1H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.95
(2H, d, J = 8.1Hz), 8.76 (1H, d, J = 1.5Hz), 9.61 (1H, t, J = 5.
9Hz), 9.64 (1H, br.s) .IR (KBr) cm-1: 3278 (br.), 1636,1576,1522,1458,1220,74
9.

Example 26 N- (2-aminophenyl) -4- [N- (3-methylisothiazol-5-yl) carbonylaminomethyl]
Benzamide (Table 1: Compound No. 213) mp. 168-169 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.47 (3H, s), 4.54 (2H,
d, J = 5.9Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3H
z), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.0,7.3,8.1H
z), 7.17 (1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1Hz), 7.73 (1
H, s), 7.96 (2H, d, J = 8.1Hz), 9.44 (1H, t, J = 5.9Hz), 9.64
(1H, br.s) .IR (KBr) cm-1: 3310,1637,1503,1294,751.

Example 27 N- (2-aminophenyl) -4- [N- (imidazol-4-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 214) mp. (Amorphous). 1H NMR ( 270MHz, DMSO-d6) δppm: 4.49 (2H, d, J = 6.4Hz),
4.87 (2H, br.s), 6.59 (1H, dd, J = 6.9,6.9Hz), 6.77 (1H, d,
J = 6.9Hz), 6.96 (1H, dd, J = 7.4,7.4Hz), 7.16 (1H, d, J = 6.9
Hz), 7.41 (2H, d, J = 6.9Hz), 7.64 (1H, br.s), 7.73 (1H, b
rs), 7.92 (2H, d, J = 6.9Hz), 8.56 (1H, br.t, J = 6.4Hz),
9.61 (1H, s), 12.5 (1H, br.s) .IR (KBr) cm-1: 3278 (br.), 1636,1576,1522,1458,1220,74
9.

Example 28 N- (2-aminophenyl) -4- [N- (3-aminophenyl) acetylaminomethyl] benzamide (Table
1: Compound No. 23) mp. 171-176 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.34 (2H, d, J = 5.9 Hz),
5.24 (4H, br.s), 6.48-6.63 (4H, m), 6.78-6.81 (1H, m),
6.94-7.00 (2H, m), 7.18 (1H, d, J = 8.1Hz), 7.34 (2H, d, J =
8.1Hz), 7.92 (2H, d, J = 8.1Hz), 8.50 (1H, t, J = 5.9Hz), 9.
61 (1H, s).

Example 29 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) acetylaminomethyl] benzamide (Table-
1: Compound No. 74) mp. 127 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.84 (2H, s), 4.40 (2H,
d, J = 5.8Hz), 7.15-7.29 (3H, m), 7.37 (1H, d, J = 6.6Hz),
7.43 (2H, d, J = 8.8Hz), 7.96 (1H, m), 7.98 (2H, d, J = 8.8H
z), 8.40 (1H, d, J = 8.8Hz), 8.79-8.87 (3H, m), 10.20 (1H,
s).

Example 30 N- (2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propionyl] aminomethyl] benzamide (Table 1: Compound of Compound No. 75) mp. 183 -186 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 2.51 (2H, t, J = 7.3Hz),
2.88 (2H, d, J = 7.3Hz), 4.31 (2H, d, J = 5.9Hz), 4.89 (2H, b
rs), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz),
6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz),
7.23 (2H, d, J = 8.8Hz), 7.28-7.33 (1H, m), 7.63 (1H, d, J =
8.1Hz), 7.89 (2H, d, J = 8.1Hz), 8.41-8.45 (3H, m), 9.62
(1H, br.s) .IR (KBr) cm-1: 3407,3313,1640,1552,1522,1456,1309,74
6,717.

Example 31 N- (2-aminophenyl) -4- [N- [4- (pyridin-3-yl) -1,4-dioxobutyl] aminomethyl] benzamide (Table 1: Compound No. 100) mp. 145-147 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 2.37-2.50 (2H, m), 2.6
2-2.68 (2H, m), 4.13 (2H, s), 4.86 (2H, s), 6.56-6.61 (1
H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.10-7.39
(4H, m), 7.43-7.46 (1H, m), 7.78 (2H, d, J = 8.1Hz), 8.60-
8.64 (1H, m), 9.58 (1H, s) .IR (KBr) cm-1: 3348,1691,1655,1534,1508,1458,1395,131
5,1083,746.

Example 32 N- (2-Aminophenyl) -4- [N- (5-chloropyridin-3-yl) oxyacetylaminomethyl] benzamide (Table 1: Compound No. 158) mp. 201 ° C.1H NMR (270MHz, DMSO-d6) δppm: 4.43 (2H, d, J = 6.6Hz),
4.75 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16 (1H, d, J = 8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.59 (1H, d,
J = 2.2Hz), 7.93 (2H, d, J = 8.1Hz), 8.25 (1H, d, J = 1.5Hz),
8.81 (1H, t, J = 6.6Hz), 9.64 (1H, s) .IR (KBr) cm-1: 3288,3058,1675,1633,1523,1457,1314,91
2,755.

Example 33 N- (2-amino-5-methoxyphenyl) -4- [N
-(Pyridin-3-yl) oxyacetylaminomethyl] benzamide (Table 1: Compound No. 175) mp. 141-144 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.66 (3H, s), 4.43 ( 2H,
d, J = 5.9Hz), 4.49 (2H, br.s), 4.68 (2H, s), 6.62 (1H, dd,
J = 2.9,8.8Hz), 6.75 (1H, d, J = 8.8Hz), 6.91 (1H, d, J = 2.2H
z), 7.37 (4H, m), 7.92 (2H, d, J = 8.8Hz), 8.21 (1H, dd, J =
1.5,4.4Hz), 8.35 (1H, d, J = 2.7Hz), 8.81 (1H, s), 9.65 (1
H, s).

Example 34 N- (2-Aminophenyl) -4- [N- [3- (pyridin-3-yl) -1,3-dioxopropyl] aminomethyl] benzamide (Table 1: Compound No. 98) mp. 204-206 ° C. 1H NMR (270 MHz, DMS
O-d6) δppm: 4.08 (4 / 3H, s), 4.39 (4 / 3H, d, J = 5.9H
z), 4.49 (2 / 3H, d, J = 5.9Hz), 4.90 (2H, br.s), 5.93 (1/3
H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97
(1H, t, J = 7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.3-7.7 (3H, m),
7.8-8.4 (3H, m), 8.6-9.2 (3H, m), 9.64 (1H, s), 14.74 (1
/ 3H, s). (2: 1 equilibrium mixture) IR (KBr) cm-1: 3282,1690,1645,1527,1421,1314,1217,102
8,994,911,753,701.

Example 35 N- (2-Aminophenyl) -4- [N- [N- (pyridin-3-yl) aminoacetyl] aminomethyl] benzamide (Table 1: Compound No. 96) mp. 1H NMR (270MHz, DMSO-d6) δppm: 3.77 (2H, d, = 6.6Hz),
4.37 (2H, d, J = 5.9Hz), 4.87 (2H, br.s), 6.27 (1H, t, J = 5.9Hz)
Hz), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, 7.3Hz), 6.
87 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.09 (1H
H, d, J = 4.4Hz), 7.12 (1H, d, J = 4.4Hz), 7.16 (1H, d, J = 8.1H
z), 7.33 (2H, d, J = 8.8Hz), 7.81 (1H, d, J = 4.4Hz), 7.91 (2
H, d, J = 7.3Hz), 7.99 (1H, d, J = 2.9Hz), 8.59 (1H, br.t, J =
5.1Hz), 9.63 (1H, br.s) .IR (KBr) cm-1: 3350,1658,1525,1502,1314,750.

Example 36 N- (2-aminophenyl) -4- [N- (2-aminothiazol-4-yl) acetylaminomethyl] benzamide (Table 1: Compound No. 220) mp. (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 3.34 (2H, s), 4.35 (2H,
d, J = 5.9Hz), 4.87 (2H, s), 6.25 (1H, s), 6.59 (1H, dd, J =
7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.87 (2H, s), 6.96 (1H, d, J = 7.3Hz)
H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.37 (2H, d, J
= 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.44 (1H, t, J = 5.9Hz),
9.62 (1H, s).

Example 37 N- (2-aminophenyl) -4- [N- (quinoline-
6-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 231) mp. 209-210 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.62 (2H, d, J = 5.9 Hz),
4.88 (2H, s), 6.60 (1H, t, J = 7.7Hz), 6.78 (1H, d, J = 7.3H
z), 6.95 (1H, d, J = 7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.49 (2
H, d, J = 8.8Hz), 7.62 (1H, dd, J = 4.4,8.1Hz), 7.96 (2H, d, J
= 8.8Hz), 8.10 (1H, d, J = 8.8Hz), 8.23 (1H, dd, J = 2.2,8.8H
z), 8.38 (1H, m), 8.49 (1H, d, J = 8.1Hz), 8.58 (1H, s), 8.
99 (1H, s), 9.64 (1H, s) .IR (KBr) cm-1: 3301,1640,1614,1545,1496,1312,910,853,
745.

Example 38 N- (2-aminophenyl) -4- [N- (furo [3,
2-b] pyridin-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 233) mp. 191 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.58 (2H, d, J = 5.9Hz),
4.88 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93
-6.99 (1H, m), 7.15-7.25 (1H, m), 7.45-7.52 (3H, m), 7.7
4 (1H, s), 7.95 (2H, d, J = 8.1Hz), 8.13 (1H, d, J = 8.8Hz),
8.63 (1H, d, J = 3.7Hz), 9.54 (1H, t, J = 5.9Hz), 9.64 (1H,
s) .IR (KBr) cm-1: 3406,1662,1529,1507.1420,1313,1209,113
9,1170,1139,924,741.

Example 39 N- (2-aminophenyl) -4- [N- (furo [2,
3-c] pyridin-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 234) mp. 210 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.58 (2H, J = 6.6Hz), 4.
87 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93-
6.99 (1H, m), 7.14-7.17 (1H, m), 7.47 (2H, d, J = 8.1Hz),
7.66 (1H, s), 7.82 (1H, d, J = 4.4Hz), 7.96 (2H, d, J = 8.1H
z), 8.48 (1H, d, J = 5.1Hz), 9.06 (1H, s), 9.60-9.64 (2H,
m) .IR (KBr) cm-1: 3320,1653,1632,1598,1457,1424,1308,118
7,1033,853,749.

Example 40 N- (2-hydroxyphenyl) -4- [N- [3-
(Pyridin-3-yl) propionyl] aminomethyl]
Benzamide (Table 1: Compound No. 125) mp. (Amorphous). 1H NMR (270 MHz, CD3OD) δ ppm: 2.61 (2H, t, J = 7.3 Hz), 3.
00 (2H, t, J = 7.3Hz), 4.39 (2H, s), 7.04 (1H, ddd, J = 1.5,8.
1,8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.33 (1H, dd, J = 5.1,8.1
Hz), 7.69 (1H, d, J = 8.1Hz), 7.85 (2H, d, J = 8.1Hz), 7.86
(1H, d, J = 8.1Hz), 8.41 (2H, br.s) .IR (neat) cm-1: 3276,1645,1614,1536,1509,1435,1415,13
85,1333,1280,1247,1091,737.

Example 41 N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide (Table 1: Compound No. 93) mp. (Amorphous). 1H- NMR (270 MHz, DMSO-d6): 4.43 (2H, d, J = 6.6 Hz), 4.69 (2
H, s), 6.83 (1H, t, J = 6.6Hz), 6.91 (1H, d, J = 8.1Hz), 7.68
(1H, d, J = 6.6Hz), 7.82 (2H, d, J = 8.1Hz), 8.21 (1H, d, J = 4.
4Hz), 8.35 (1H, d, J = 2.2Hz), 8.81 (1H, t, J = 6.6Hz), 9.4
8 (1H, s), 9.75 (1H, s) .IR (KBr) cm-1: 3399,1664,1535,1236,1064.

Example 42 N- (2-Hydroxyphenyl) -4- [N- (pyridin-3-yl) acetylaminomethyl] benzamide (Table 1: Compound No. 117) mp. 201-202 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 3.56 (2H, s), 4.37 (2H,
d, J = 5.9Hz), 6.83 (1H, ddd, J = 1.5,8.1,8.1Hz), 6.92 (1H,
br.d, J = 8.1Hz), 7.03 (1H, ddd, J = 1.5,8.1,8.1Hz), 7.34 (1
H, dd, J = 3.7,8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.70 (2H, d, J
= 8.1Hz), 7.91 (2H, d, J = 8.1Hz), 8.45 (1H, br.d, J = 3.7H
z), 8.49 (1H, s), 8.73 (1H, t, J = 5.9Hz), 9.47 (1H, s), 9.
73 (1H, br.s) .IR (KBr) cm-1: 3272,3067,1661,1647,1598,1536,1455,133
4,1288,1194,1024,742.

Example 43 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) oxyacetyl-N- [3- (pyridin-3
-Yl) propyl] aminomethyl] benzamide (Table-
1: Compound No. 91) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 1.77-1.93 (2H, m), 2.5
0-2.63 (2H, m), 3.16-3.30 (2H, m), 4.63 (1.2H, s), 4.71
(0.8H, s), 4.88 (1.2H, s), 4.95 (0.8H, s), 5.05 (2H, s),
6.57-6.63 (1H, m), 6.77-6.79 (1H, m), 6.94-7.00 (1H, m),
7.11-7.42 (5H, m), 7.58-7.64 (1H, m), 7.92-8.02 (2H, m),
8.15-8.43 (5H, m), 9.65 (0.6H, s), 9.69 (0.4H, s). (Mixture of rotamers)

Example 44 N- (2-aminophenyl) -4- [N-methyl-N-
(Pyridin-3-yl) oxyacetyl] aminomethylbenzamide (Table 1: Compound No. 92) mp. 117-120 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.84 and 2.99 (total
3H, s), 4.60 and 4.69 (total 2H, s), 4.90 (2H, br.s),
4.99 and 5.08 (total 2H, s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz),
7.16 (1H, d, J = 7.3Hz), 7.30-7.43 (4H, m), 7.95 and 8.01
(total 2H, d, J = 8.1Hz), 8.17 (1H, d, J = 4.4Hz), 8.31 (1H,
d, J = 2.9Hz), 9.65 and 9.68 (total 1H, br.s). (mixture of rotamers) IR (KBr) cm-1: 3298,1665,1501,1425,1310,1276,1254,107
8,799,746,703.

Example 45 N- (2-aminophenyl) -4- [N- (pyridine-
Synthesis of 3-yl) oxamoylaminomethyl] benzamide (Table 1: Compound No. 95) (45-1) N- (pyridin-3-yl) oxamic acid ethyl ester 388 mg (2 mmol) and Example 1
638 mg (2 mm) of the compound obtained in step (1-4)
ol) was dissolved in ethanol, and the mixture was heated and stirred at 40 to 50 ° C for 2.5 hours. The precipitated crystals are collected by filtration, and ethanol 2
Washed with 3 ml of ethyl ether and 3 ml of ethyl ether. The obtained crystals are dried, and N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) oxamoylaminomethyl] benzamide 724m
g (74% yield). 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.49 (2H,
d, J = 5.9Hz), 7.10-7.30 (2H, m), 7.35-7.57 (5H, m), 7.93
(2H, d, J = 8.1Hz), 8.21 (1H, br.d, J = 5.1Hz), 8.35 (1H, dd,
J = 1.5,5.1Hz), 8.68 (1H, br.s), 9.00 (1H, d, J = 2.9Hz),
9.70 (1H, t, J = 5.9Hz), 9.82 (1H, s), 10.98 (1H, br.s).

(45-2) The compound (720 mg) obtained in the step (45-1) was suspended in methanol (8 ml), and 4N hydrochloric acid was added.
8 ml of dioxane solution was added. The mixture was stirred for 3 hours, poured into a dilute aqueous sodium hydroxide solution and made alkaline, and the precipitated crystals were collected by filtration. The obtained crystals were washed with THF / methanol
Recrystallization was performed at 1/1 to obtain 280 mg of the desired product. mp.254-258 ° C (dec.) 1H NMR (270MHz, DMSO-d6) δppm: 4.67 (2H, d, J = 5.9Hz),
4.89 (2H, br.s), 6.59 (1H, dd, J = 7.3Hz), 6.77 (1H, d, J = 8.
1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz),
7.38-7.44 (1H, m), 7.43 (2H, d, J = 8.1Hz), 7.95 (2H, d, J =
8.1Hz), 8.18-8.24 (1H, m), 8.34 (1H, dd, J = 1.5,4.4Hz),
9.00 (1H, d, J = 2.1Hz), 9.63 (1H, s), 9.69 (1H, br.t, J = 6.6
Hz), 10.97 (1H, br.s) .IR (KBr, cm-1): 3312,3270,1663,1636,1521,1312,1296,10
19

Example 46 N- (2-aminophenyl) -4- [N- (pyridine-
Synthesis of 3-yl) oxyacetylaminomethyl] benzamide (Table-1: Compound No. 61) (46-1) Sodium hydride (60% oil suspension)
To a suspension of 0.22 g (5.5 mmol) in DMF (2 ml) was added 0.48 g (5.0 mm) of 3-hydroxypyridine.
ol) in DMF (2 ml) was added dropwise at room temperature.
Stirred for hours. The resulting brown solution was ice-cooled, and then bromoacetic acid tert-butyl ester 0.81 ml (5.5
mmol), and the mixture was stirred under ice cooling for 1 hour and at room temperature for 2 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) to give 3-
Pyridyloxyacetic acid tert-butyl ester 0.3
4 g (yield 32.5%) was obtained as a colorless oil. 1H NMR (270MHz, CDCl3) δppm: 1.49 (9H, s), 4.56 (2H,
s), 7.18-7.24 (2H, m), 8.26 (1H, dd, J = 1.5,3.6Hz), 8.32
(1H, d, J = 2.9Hz).

(46-2) 0.14 g (0.67 mmol) of the compound of step (46-1) in dichloromethane (2
ml) to the solution, add 2 ml of trifluoroacetic acid and add
Stirred for hours. After evaporating the solvent, diisopropyl ether was added, and the precipitated solid was collected by filtration and dried to give 3-pyridyloxyacetic acid trifluoroacetate 0.1.
5 g (83.8% yield) was obtained as a pale yellow solid. 1H NMR (270MHz, DMSO-d6) δppm: 4.86 (2H, s), 7.57 (1H,
(dd, J = 4.4,8.1Hz), 7.67 (1H, ddd, J = 1.5,1.5,8.8Hz), 8.3
1 (1H, d, J = 5.1Hz), 8.46 (1H, d, J = 2.1Hz), 13.00 (1H, br.
s).

(46-3) 100 mg (0.37 mmol) of the compound of Step (46-2) and 255 mg (0.75 mm) of the compound obtained in Step (1-4) of Example 1
ol) in dichloromethane (5 ml) was added with 0.14 ml (1.0 mmol) of triethylamine and cooled with ice. Under ice-cooling, a solution of 140 mg (0.83 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (6 ml) was added, and the mixture was stirred for 7 hours while warming to room temperature, and then allowed to stand at room temperature overnight. After adding water and saturated saline, the mixture was extracted with chloroform.

The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2 0.37 g (quantitative) of-(N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide was obtained as a colorless oil. mp. 154-155 ° C 1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 4.62 (2H,
s), 4.63 (2H, d, J = 7.3Hz), 6.76 (1H, br.s), 6.90-7.00 (1
H, br.s), 7.15-7.35 (5H, m), 7.40 (2H, d, J = 8.1Hz), 7.82
(1H, d, J = 8.1Hz), 7.95 (2H, d, J = 8.1Hz), 8.32 (1H, dd, J =
2.1,4.4Hz), 8.37 (1H, d, J = 2.8Hz), 9.20 (1H, br.s).

(46-4) 175 mg (0.37 mmol) of the compound of step (46-3) in dioxane (2 m
l) 4N hydrochloric acid-dioxane (2 ml) was added to a -methanol (2 ml) solution, and the mixture was stirred at room temperature for 2 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was added with methanol and diisopropyl ether, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl). 90 mg (yield 64.6%) of 4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide was obtained as a milky white solid. 1H NMR (270MHz, DMSO-d6) δppm: 4.42 (2H, d, J = 5.9Hz),
4.69 (2H, s), 4.89 (2H, br.s), 6.59 (1H, dd, J = 7.3,8.1H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz),
7.16 (1H, d, J = 7.3Hz), 7.33-7.39 (4H, m), 7.92 (2H, d, J =
8.1Hz), 8.21 (1H, dd, J = 1.5,4.4Hz), 8.35 (1H, d, J = 2.9H
z), 8.80 (1H, br.t, J = 5.9Hz), 9.63 (1H, br.s) .IR (KBr) cm-1: 3307,1672,1631,1523,1456,1429,1269,12
31,803,756.

Example 47 N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) oxy] propionylaminomethyl]
Synthesis of benzamide (Table-4: Compound No. 3)

(47-1) Sodium hydride (60%
Oil suspension) 1.20 g (30.0 mmol) of dry DM
To a suspension of F (10 ml) was added 2.85 g (30 mmol) of 3-hydroxypyridine at room temperature in dry DMF (10 m
l) The solution was added dropwise while keeping the temperature at 40 ° C. or lower, and then stirred at room temperature for 90 minutes. 5-10 ° C internal temperature under ice cooling
6.28 g (30 mmol) of 2-bromopropionic acid tert-butyl ester in dry DMF
(10 ml) The solution was gradually added dropwise, followed by stirring for 4 hours while the temperature was raised to room temperature. The mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 2- (pyridine). -3
-Yl) oxypropionic acid tert-butyl ester 4.15 g (yield 62%) was obtained as a brown oil. 1H-NMR (270MHz, CDCl3) δppm: 1.44 (9H, s), 1.61 (3H, d,
J = 7.3Hz), 4.66 (1H, q, J = 7.3Hz), 7.13-7.23 (2H, m) 8.24
(1H, dd, J = 1.5,4.4Hz), 8.29 (1H, d, J = 2.1Hz).

(47-2) Trifluoroacetic acid (9 ml) was added to a solution of 1.65 g (7.4 mmol) of the compound obtained in step (47-1) in dichloromethane (9 ml) while maintaining the temperature at 30 ° C. or lower. And stirred at room temperature for 8 hours.
After evaporating the solvent, diisopropyl ether was added, and the precipitated solid was collected by filtration and dried to give 1.86 g of 2- (pyridin-3-yl) oxypropionic acid trifluoroacetate (yield 43.5%). Was obtained as a light brown solid. 1H-NMR (270MHz, DMSO-d6) δppm: 1.53 (3H, d, J = 6.6Hz),
5.12 (1H, q, J = 6.6Hz), 7.60-7.75 (2H, m), 8.35 (1H, d, J =
5.1Hz), 8.47 (1H, s), 12.9 (1H, br.s).

(47-3) 0.98 g (3.5 mmol) of the compound obtained in the step (47-2) and 1.02 g (3.0 mmol) of the compound obtained in the step (1-4) of Example 1.
Was suspended in dichloromethane (20 ml), 1.3 ml (9.0 mmol) of triethylamine was added, and the mixture was cooled with ice. Under ice-cooling, a solution of 0.59 g (3.5 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (5 ml) was added dropwise, and the mixture was further stirred for 2 hours. The mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- (N-tert-). Butoxycarbonylamino) phenyl] -4- [N- [2- (pyridine-
1.64 g of 3-yl) oxypropionyl] aminomethyl] benzamide were obtained as a mixture with 1,3-dimethyl-2-imidazolinone. 1H-NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 1.64 (3H, d,
J = 7.3Hz), 4.54 (2H, m), 4.78 (1H, q, J = 6.6Hz), 6.87 (2H, b
rs), 7.13-7.30 (6H, m), 7.81 (1H, d, J = 7.3Hz), 7.90 (2H,
d, J = 8.1Hz), 8.29 (1H, dd, J = 1.5,4.4Hz), 8.33 (1H, d, J =
2.1Hz), 9.22 (1H, br.s).

(47-4) 1.64 g of the compound obtained in the step (47-3) was dissolved in dioxane (10 ml) -methanol (4 ml). A 4N hydrochloric acid-dioxane solution (10 ml) was added at room temperature, and the mixture was stirred for 2 hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. To the residue obtained, methanol and diisopropyl ether were added, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl) -4. -[N- [2- (pyridin-3-yl) oxy] propionylaminomethyl] benzamide 0.7
1 g (60.5% yield at 2 steps) was obtained as a white solid.

Mp. 171-173 ° C. (dec.). 1H-NMR (270 MHz, DMSO-d6) δ ppm: 1.51 (3H, d, J = 6.6 Hz), 4.
36 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 4.90 (1H, t, J = 6.6H
z), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d, J = 8.1Hz),
6.97 (1H, dd, J = 6.6,7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.27
(2H, d, J = 8.1Hz), 7.33-7.37 (2H, m), 7.89 (2H, d, J = 8.1H
z), 8.21 (1H, dd, J = 2.9,2.9Hz), 8.32 (1H, d, J = 1.5Hz),
8.82 (1H, t, J = 5.9Hz), 9.63 (1H, br.s).

Example 48 N- (2-aminophenyl) -4- [N- (pyridine-
Synthesis of 3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 82) (48-1) 384 mg of 3-pyridinemethanol
(3.52 mmol) in 5 ml of dry THF,
523 mg of N, N'-carbonyldiimidazole (3.
22 mmol) was added at room temperature. After stirring for 1 hour, 1.0 g of the compound of Step (1-4) of Example 1 (2.93 m
(mol) of a dry THF solution.

After leaving at room temperature overnight, chloroform 100m
1 was added and washed three times with 20 ml of water. Then, the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1).
1.27 g of [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide was obtained as an amorphous solid (quantitative). 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.45 (2H, d,
J = 5.9Hz), 5.16 (1H, s), 7.10-7.50 (7H, m), 7.70 (1H, d, J =
8.1Hz), 7.80 (1H, d, J = 7.3Hz), 7.93 (1H, d, J = 8.1Hz), 8.
57 (1H, d, J = 4.4Hz), 8.63 (1H, s), 9.17 (1H, s).

(48-2) 1.2 g (2.8 mmol) of the compound of the step (48-1) was dissolved in 10 ml of methanol. 20 ml of 4N hydrochloric acid-dioxane solution was added,
Stir at room temperature for 1.5 hours. After pouring into a dilute aqueous sodium hydroxide solution, the mixture was extracted three times with 60 ml of chloroform. After washing twice with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated to obtain 0.88 g of crystals. Then, recrystallization was carried out with 16 ml of ethanol to obtain 668 mg of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (yield 7).
3%).

Mp. 159-160 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J = 5.9 Hz),
4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1H
H, d, J = 7Hz), 6.97 (1H, t, J = 7Hz), 7.17 (1H, d, J = 8Hz), 7.
30-7.50 (3H, m), 7.78 (1H, d, J = 8Hz), 7.93 (2H, d, J = 8Hz),
8.53 (1H, d, J = 3.7Hz), 8.59 (1H, s), 9.61 (1H, s) .IR (KBr) cm-1: 3295,1648,1541,1508,1457,1309,1183,74
2. The compounds of Examples 49 to 87 were synthesized in the same manner as in Example 48. Below, the melting point of the compound (m
p.), 1H NMR and IR measurements.

Example 49 N- (2-aminophenyl) -4- [N- (benzyloxycarbonyl) aminomethyl] benzamide (Table-
1: Compound No. 11) mp. 174-178 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J = 5.9 Hz),
4.89 (2H, br.s), 5.06 (2H, s), 6.59 (1H, dd, J = 7.3,8.1H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16 (1H, d, J = 7.3Hz), 7.30-7.40 (6H, m), 7.93 (3H, m),
9.63 (1H, s) .IR (KBr) cm-1: 3332,1687,1652,1536,1456,1279,747.

Example 50 N- (2-aminophenyl) -4- [N- (4- (imidazol-1-yl) benzyl) oxycarbonylaminomethyl] benzamide (Table 1: Compound No. 47) mp. 195 -198 ° C.1H NMR (270MHz, DMSO-d6) δppm: 4.29 (2H, d, J = 6.6Hz),
4.88 (2H, s), 5.10 (2H, s), 6.60-6.63 (1H, m), 6.78 (1H,
d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz), 7.11 (1H, s), 7.16 (1
H, d, J = 7.3Hz), 7.37 (2H, d, J = 8.1Hz), 7.49 (2H, d, J = 8.8H
z), 7.66 (2H, d, J = 8.1Hz), 7.74 (1H, s), 7.92-7.96 (3H,
m), 8.25 (1H, s), 9.62 (1H, s).

Example 51 N- (2-aminophenyl) -4- [N- (pyridine-
2-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 171) mp. 166-167 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.30 (2H, d, J = 5.9 Hz),
4.88 (2H, br.s), 5.12 (2H, s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1H
z), 7.16 (1H, d, J = 7.3Hz), 7.33 (1H, dd, J = 3.7,7.3Hz),
7.40 (3H, d, J = 8.1Hz), 7.83 (1H, ddd, J = 1.5,7.3,8.1Hz),
7.94 (2H, d, J = 8.1Hz), 8.03 (1H, t, J = 5.9Hz), 8.55 (1H, d,
J = 5.1Hz), 9.62 (1H, br.s) .IR (KBr) cm-1: 3334,1694,1632,1580,1276,755.

Example 52 N- (2-Aminophenyl) -4- [N- [2- (pyridin-2-yl) ethoxycarbonyl] aminomethyl]
Benzamide (Table-1: Compound No. 172) mp. 146-148 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.04 (2H, t, J = 6.6 Hz),
4.23 (2H, d, J = 5.9Hz), 4.36 (2H, t, J = 6.6Hz), 4.88 (2H, b
rs), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz),
6.97 (1H, dd, J = 7.3,8.1Hz), 7.15-7.30 (3H, m), 7.34 (2
(H, d, J = 8.1Hz), 7.69-7.77 (2H, m), 7.92 (2H, d, J = 7.3Hz),
8.50 (1H, d, J = 4.4Hz), 9.62 (1H, br.s) .IR (KBr) cm-1: 3330,1690,1633,1594,1524,1277,760.

Example 53 N- (2-Aminophenyl) -4- [N- (6-methylpyridin-2-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 179) mp. 1H NMR (270MHz, DMSO-d6) δppm: 2.47 (3H, s), 4.30 (2
H, d, J = 5.9Hz), 5.07 (4H, s), 6.63 (1H, t, J = 8.1Hz), 6.80
(1H, d, J = 7.34), 6.98 (1H, t, J = 8.1Hz), 7.18 (3H, d, J = 7.3
Hz), 7.40 (2H, d, J = 8.1Hz), 7.71 (1H, t, J = 8.1Hz), 7.94
(2H, d, J = 8.1Hz), 8.03 (1H, t, J = 5.9Hz), 9.66 (1H, s) .IR (KBr) cm-1: 3335,1693,1634,1259.

Example 54 N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) ethoxycarbonyl] aminomethyl]
Benzamide (Table-1: Compound No. 83) mp. 120-125 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.91 (2H, t, J = 6.6 Hz),
4.22 (4H, t, J = 6.6Hz), 4.89 (2H, s), 6.55-6.63 (1H, m),
6.78 (1H, dd, J = 8.1,1.5Hz), 6.97 (1H, t, J = 6.6Hz), 7.17 (1
H, d, J = 6.6Hz), 7.33 (3H, d, J = 8.1Hz), 7.69 (1H, d, J = 8.1H
z), 7.79 (1H, t, J = 6.6Hz), 7.93 (2H, d, J = 8.0Hz), 8.43-
8.49 (2H, m), 9.62 (1H, s) .IR (KBr) cm-1: 3234,1705,1655,1260.

Example 55 N- (2-Aminophenyl) -4- [N- [3- (pyridin-3-yl) propyloxycarbonyl] aminomethyl] benzamide (Table 1: Compound No. 84) mp. 121 -124 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 1.83-1.94 (2H, m), 2.6
7 (2H, t, J = 7.3Hz), 3.98 (2H, t, J = 6.6Hz), 4.26 (2H, d, J =
5.9Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 8.1,8.1Hz), 6.
78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.
16 (1H, d, J = 8.1Hz), 7.29-7.33 (1H, m), 7.37 (1H, d, J = 8.1H
z), 7.64 (1H, d, J = 8.1Hz), 7.81 (1H, dd, J = 5.9,6.6Hz),
7.94 (2H, d, J = 8.1Hz), 8.40-8.44 (2H, m), 9.63 (1H, br.
s) .IR (KBr) cm-1: 3348,1696,1635,1523,1458,1302,1272,11
41,1019,754,713.

Example 56 N- (2-Aminophenyl) -4- [N- (2-methylpyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 142) mp. 164-165 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 2.49 (3H, s), 4.28 (2
H, d, J = 6.6Hz), 4.89 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J =
6.6Hz), 6.78 (1H, d, J = 8.1Hz), 6.90 (1H, t, J = 7.3Hz), 7.
17 (1H, d, J = 7.3Hz), 7.21-7.26 (1H, m), 7.37 (2H, d, J = 8.1
Hz), 7.68 (1H, d, J = 6.6Hz), 7.92-8.00 (3H, m), 8.39 (1H,
d, J = 4.4Hz), 9.62 (1H, s) .IR (KBr) cm-1: 3332,1719,1630,1260.

Example 57 N- (2-Aminophenyl) -4- [N- (6-methylpyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 144) mp. 164-165 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 2.46 (3H, s), 4.27 (2
H, d, J = 6.6Hz), 4.88 (2H, s), 5.05 (2H, s), 6.59 (1H, dt, J
= 1.5,8.1Hz), 6.78 (1H, dd, J = 8.1,1.5Hz), 6.97 (1H, dt, J
= 1.5,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.26 (1H d, J = 8.1H
z), 7.36 (2H, d, J = 8.1Hz), 7.67 (1H, dd, J = 8.1,2.2Hz),
7.93 (3H, d, J = 8.1Hz), 8.45 (1H, d, J = 1.5Hz), 9.62 (1H,
s) .IR (KBr) cm-1: 3293,1701,1632,1260.

Example 58 N- (2-Aminophenyl) -4- [N- (2-chloropyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 155) mp. (Amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 5.9Hz),
5.00 (2H, s), 5.13 (2H, s), 6.61 (1H, t, J = 7.3Hz), 6.79
(1H, dd, J = 8.1,1.5Hz), 6.98 (1H, dt, J = 1.5,7.3Hz), 7.17
(1H, d, J = 6.6Hz), 7.39 (2H, d, J = 8.8Hz), 7.47-7.52 (1H, d
m), 7.91-7.96 (3H, m), 8.08 (1H, t, J = 5.9Hz), 8.40 (1H, d
d, J = 4.4,1.5Hz), 9.64 (1H, s) .IR (KBr) cm-1: 3340,1702,1632,1273.

Example 59 N- (2-aminophenyl) -4- [N- (6-chloropyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 157) mp. 180-185 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.24 (2H, d, J = 5.9Hz),
4.89 (2H, br.s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.
78 (1H, d, J = 8.1Hz), 6.97 (1H, dt, J = 1.5,8.1Hz), 7.16 (1
H, d, J = 6.6Hz), 7.37 (2H, d, J = 8.1Hz), 7.56 (1H, d, J = 8.1H
z), 7.85-8.02 (4H, m), 8.44 (1H, d, J = 2.2Hz), 9.62 (1H,
s) .IR (KBr) cm-1: 3346,3282,1696,1533,1271.

Example 60 N- (2-aminophenyl) -4- [N- (pyridine-
4-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 181) mp. 180-183 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.30 (2H, d, J = 6.6 Hz),
4.89 (2H, s), 5.12 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz),
6.78 (1H, dd, J = 1.5,7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1
Hz), 7.16 (1H, d, J = 7.3Hz), 7.34 (2H, d, J = 5.9Hz), 7.39
(2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.09 (1H, t, J = 5.
9Hz), 8.57 (1H, d), 9.64 (1H, br.s) .IR (KBr) cm-1: 3394,3290,1711,1645,1624,1535,1504,13
21,1251,1138,1049,763.

Example 61 N- (2-aminophenyl) -4- [N- [2- (thiophen-3-yl) ethoxycarbonyl] aminomethyl] benzamide (Table 1: Compound No. 203) mp. (Amorphous 1H NMR (270MHz, DMSO-d6) δppm: 2.90 (2H, t, J = 7.3Hz),
4.17-4.26 (4H, m), 4.89 (2H, s), 6.60 (1H, t, J = 8.1Hz),
6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.3Hz), 7.06 (1H, d,
J = 5.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.26 (1H, s), 7.36 (2H,
d, J = 8.1Hz), 7.47 (1H, t, J = 2.2Hz), 7.81 (1H, t, J = 5.9H
z), 7.93 (2H, d, J = 8.1Hz), 9.63 (1H, s) .IR (KBr) cm-1: 3314,1716,1638,1252.

Example 62 N- (2-Aminophenyl) -4- [N- (3-phenyloxazol-5-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 211) mp. 192-195 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 5.9Hz),
4.89 (2H, s), 5.25 (2H, s), 6.60 (1H, t, J = 6.6Hz), 6.68 (1
(H, d, J = 8.1Hz), 6.94 (1H, t, J = 7.3Hz), 7.09 (1H, s), 7.16
(1H, d, J = 7.3Hz), 7.39 (2H, d, J = 8.1Hz), 7.51 (4H, d, J = 2.
2Hz), 7.87-7.96 (5H, m), 8.12 (1H, t, J = 5.9Hz), 9.63 (1
H, s) .IR (KBr) cm-1: 3292,1718,1630,1262.

Example 63 N- (2-aminophenyl) -4- [N- (thiazol-5-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 216) mp. (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.91 (2H, br.s), 5.30 (2H, s), 6.60 (1H, dd, J = 7.3,7.3H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16 (1H, d, J = 7.3Hz), 7.36 (2H, d, J = 8.1Hz), 7.91-8.00
(4H, m), 9.09 (1H, s), 9.63 (1H, s) .IR (KBr) cm-1: 3346 (br.), 1697,1636,1525,1456,1271,87
3,753.

Example 64 N- (2-aminophenyl) -4- [N- [2- (4-
Methylthiazol-5-yl) ethoxycarbonyl] aminomethyl] benzamide (Table 1: Compound No. 21
7) mp. 130-133 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 2.32 (3H, s), 3.07 (2
H, t, J = 5.9Hz), 4.15 (2H, t, J = 5.9Hz), 4.25 (2H, d, J = 6.6H
z), 4.89 (2H, s), 6.60 (1H, t, J = 5.9Hz), 6.78 (1H, dd, J =
7.3,1.5Hz), 6.97 (1H, dt, J = 1.5,7.3Hz), 7.16 (1H, d, J =
8.1Hz), 7.35 (2H, d, J = 8.1Hz), 7.83 (1H, t, J = 5.9Hz), 7.
94 (2H, d, J = 8.1Hz), 8.85 (1H, s), 9.62 (1H, s) .IR (KBr) cm-1: 3350,1691,1635,1270.

Example 65 N- (2-aminophenyl) -4- [N- (1-methylpiperidin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 225) mp. 130-135 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 1.49-1.78 (3H, m), 1.
83-2.01 (3H, m), 2.30 (3H, s), 2.85 (2H, s), 3.74-3.94 (2
H, m), 4.25 (2H, d, J = 5.8Hz), 6.55-6.62 (3H, m), 6.78 (1
H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz), 7.16 (1H, d, J = 8.1H
z), 7.37 (2H, d, J = 8.1Hz), 7.79 (1H, t, J = 6.6Hz), 7.93 (2H, t, J = 6.6Hz)
H, d, J = 8.0Hz), 9.66 (1H, s) .IR (KBr) cm-1: 3323,2722,1702,1648,1263.

Example 66 N- (2-aminophenyl) -4- [N- (4-methylpiperazin-1-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 227) mp. (Amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 1.73 (2H, t, J = 6.6Hz),
2.36-2.63 (13H, m), 4.00 (2H, t, J = 6.6Hz), 4.30 (2H, d, J
= 5.8Hz), 6.55-6.63 (4H, m), 6.78 (1H, d, J = 6.6Hz), 6.97
(1H, t, J = 7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.37 (2H, d, J = 8.
7Hz), 7.73 (1H, t, J = 5.9Hz), 7.94 (2H, d, J = 8.0Hz), 9.66
(1H, s) .IR (KBr) cm-1: 3341,2706,1701,1262.

Example 67 N- (2-aminophenyl) -4- [N- (tetrahydrofuran-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 221) mp. (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 1.50-1.60 (1H, m), 1.8
8-2.00 (1H, m), 2.44-2.54 (1H, m), 3.41-3.47 (1H, m), 3.
56-3.77 (3H, m), 3.85-4.04 (2H, m), 4.25 (2H, d, J = 5.9H
z), 4.89 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H,
d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.17 (1H, d, J =
8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.81 (1H, t, J = 5.9Hz), 7.
94 (2H, d, J = 8.1Hz), 9.62 (1H, br.s) .IR (KBr) cm-1: 3349,1695,1635,1523,1457,1259,754.

Example 68 N- (2-Aminophenyl) -4- [N- (phenoxycarbonyl) aminomethyl] benzamide (Table 1: Compound No. 12) mp.174-175 ° C. 1H NMR (270 MHz, DMSO -d6) δppm: 4.36 (2H, d, J = 5.9Hz),
4.90 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d
d, J = 7.3,7.3Hz), 6.98 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.05-
7.24 (4H, m), 7.39-7.46 (4H, m), 7.97 (2H, d, J = 8.1Hz),
8.41 (1H, t, J = 5.9Hz), 9.65 (1H, br.s) .IR (KBr) cm-1: 3443,3362,3313,1732,1706,1636,1527,14
93,1458,1305,1217,748.

Example 69 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) oxycarbonylaminomethyl] benzamide (Table 1: Compound No. 81) mp. 209 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.38 (2H, d, J = 6.6 Hz) ,
4.90 (2H, br.s), 6.55-6.63 (1H, m), 6.78 (1H, d, J = 8.1H
z), 7.00 (1H, dd, J = 7.3,7.3Hz), 7.17 (1H, d, J = 8.8Hz),
7.37-7.47 (3H, m), 7.64 (1H, d, J = 8.8Hz), 7.97 (2H, d, J =
8.1Hz), 8.43 (2H, d, J = 3.1Hz), 8.59 (1H, t, J = 5.9Hz), 9.
66 (1H, br.s).

Example 70 N- (2-amino-5-fluorophenyl) -4- [N
-(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 110) mp. 160-162 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J = 6.6) Hz),
4.81 (2H, s), 5.10 (2H, s), 6.70-6.90 (2H, m), 7.10-8.00
(8H, m), 8.53 (1H, d, J = 3.6Hz), 8.59 (1H, s), 9.61 (1H,
s) .IR (KBr) cm-1: 3269,1716,1638,1488,1436,1247,1141,104
3,744.

Example 71 N- (2-aminophenyl) -4- [N- (2-aminophenyl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 51) mp. 149-151 ° C. (dec. ) 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.88 (2H, s), 4.96 (2H, s), 5.06 (2H, s), 6.53 (1H, dd, J =
7.3,7.3Hz), 6.56-6.67 (2H, m), 6.78 (1H, dd, J = 1.5,8.1H
z), 6.93-7.12 (3H, m), 7.16 (1H, d, J = 6.6Hz), 7.38 (2H, m
d, J = 8.1Hz), 7.86 (1H, t-like, J = 5.9Hz), 7.93 (2H, d, J =
8.1Hz), 9.61 (1H, s) .IR (KBr) cm-1: 3336,1685,1632,1527,1276,748.

Example 72 N- (2-Aminophenyl) -4- [N- (quinuclidin-3-yl) oxycarbonylaminomethyl] benzamide (Table 1: Compound No. 228) mp. (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 1.30-1.90 (4H, m), 1.9
0 (1H, br.s), 2.45-2.80 (6H, m), 3.04-3.13 (1H, m), 4.15
(2H, d, J = 5.9Hz), 4.55-4.60 (1H, m), 4.88 (2H, br.s), 6.
60 (1H, ddd, J = 1.5,7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.
97 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.17 (1H, d, J = 6.6Hz), 7.
37 (2H, d, J = 8.1Hz), 7.78 (1H, t, J = 5.9Hz), 7.94 (1H, d, J =
7.3Hz), 9.62 (1H, s) .IR (KBr) cm-1: 3328,2942,1700,1648,1504,1259,749.

Example 73 N- (2-aminophenyl) -4- [N- (3-aminophenyl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 52) mp. 149-153 ° C. (dec. ) 1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 5.9Hz),
4.88 and 4.89 (total 4H, each br.s), 5.08 (2H, s), 6.
47-6.63 (3H, m), 6.78 (1H, d, J = 8.1Hz), 6.94-7.02 (2H, m
m), 7.15 (1H, dd, J = 7.3,8.8Hz), 7.37 (2H, d, J = 8.1Hz),
7.84 (1H, t, J = 5.9Hz), 7.93 (2H, d, J = 8.8Hz), 9.61 (1H, br.
s) .IR (KBr) cm-1: 3367,1682,1632,1523,1457,1261,754.

Example 74 N- (2-Aminophenyl) -4- [N- (1-methylimidazol-5-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 218) mp. 162-165 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 3.62 (3H, s), 4.27 (2H,
d, J = 5.9Hz), 4.91 (2H, br.s), 5.05 (2H, s), 6.60 (1H, dd,
J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.95-7.00 (2H, m),
7.16 (1H, d, J = 7.3Hz), 7.36 (2H, d, J = 8.1Hz), 7.63 (1H, d, J = 8.1Hz)
s), 7.87-7.95 (3H, m), 9.64 (1H, br.s) .IR (KBr) cm-1: 3293,1688,1651,1534,1506,1259,1121,104
3,748.

Example 75 N- (2-amino-4-chlorophenyl) -4- [N-
(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 113) mp. 167-170 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J = 5.9 Hz) ),
5.10 (2H, s), 5.21 (2H, s), 6.72 (1H, dd, J = 2.2,8.1Hz),
6.81 (1H, d, J = 2.2Hz), 7.16 (1H, d, J = 8.1Hz), 7.37 (2H, d,
J = 8.1Hz), 7.78 (1H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz),
8.53 (1H, d, J = 4.4Hz), 8.59 (1H, s), 9.60 (1H, s) .IR (KBr) cm-1: 3347,3062,2931,1653,1576,1505,1456,142
8,1301,1232,1114,1070,1019.

Example 76 N- (2-Aminophenyl) -4- [N- (5-methoxypyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 161) mp. 169-170 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 3.83 (3H, s), 4.29 (2H,
d, J = 6.6Hz), 4.87 (2H, s), 5.09 (2H, s), 6.57-6.62 (1H,
m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.14-7.18 (1
H, m), 7.36-7.39 (3H, m), 7.91-7.99 (3H, m), 8.19-8.30
(2H, m), 9.63 (1H, s) .IR (KBr) cm-1: 3330,1694,1633,1524,1457,1298,1269,104
5,760.

Example 77 N- (2-aminophenyl) -4- [N- (pyrazine-
2-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 192) mp. 182 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.30 (2H, d, J = 6.6 Hz),
4.88 (2H, br.s), 5.20 (2H, s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,8.1Hz),
7.16 (1H, d, J = 7.3Hz), 7.39 (2H, d, J = 8.8Hz), 7.94 (2H, d,
J = 8.8Hz), 8.08 (1H, t-like, J = 6.6Hz), 8.61 (1H, s), 8.6
5 (1H, s), 8.68 (1H, s), 9.63 (1H, s) .IR (KBr) cm-1: 3266,1709,1632,1535,1508,1284,1055,102
2,744.

Example 78 N- (2-amino-5-methoxyphenyl) -4- [N
-(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 121) mp. 141-143 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.66 (3H, s), 4.29 ( 2H,
d, J = 5.9Hz), 4.51 (2H, br.s), 5.10 (2H, s), 6.63 (1H, dd,
J = 2.9,8.8Hz), 6.74 (1H, d, J = 8.8Hz), 6.91 (1H, d, J = 2.2H
z), 7.38 (2H, d, J = 8.8Hz), 7.41 (1H, s), 7.79 (1H, d, J = 8.
1Hz), 7.92 (2H, d, J = 8.1Hz), 7.98 (1H, t, J = 5.9Hz), 8.54
(1H, d, J = 3.7Hz), 8.60 (1H, s), 9.65 (1H, s).

Example 79 N- (2-aminophenyl) -4- [N- (pyridine 3
-Yl) methyl-N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 109) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.50 (2H, s), 4.56 (2H,
s), 4.87 (2H, s), 5.21 (2H, s), 6.60 (1H, t, J = 7.7Hz), 6.
78 (1H, d, J = 7.3Hz), 6.97 (1H, d, J = 7.3Hz), 7.17 (1H, d, J =
7.3Hz), 7.20-7.50 (4H, m), 7.60-8.00 (4H, m), 8.40-8.6
0 (4H, m), 9.65 (1H, s) .IR (KBr) cm-1: 3268,1700,1504,1246,1120,940,714.

Example 80 N- (2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propyl] -N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table -1. Compound number 120) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 1.75-1.90 (2H, m), 2.4
8-2.62 (2H, m), 3.20-3.36 (2H, m), 4.55 (2H, s), 4.89 (2
H, s), 5.16 (2H, s), 6.57-6.63 (1H, m), 6.76-6.80 (1H,
m), 6.94-6.99 (1H, m), 7.14-7.17 (1H, m), 7.32-7.74 (6
H, m), 7.94 (2H, d, J = 8.1Hz), 8.30-8.65 (4H, m), 9.64 (1
H, s).

Example 81 N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) methyl-N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table
1: Compound No. 115) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6): 4.52 (2H, s), 4.57 (2H, s),
5.20 (2H, s), 6.84 (1H, t, J = 6.6Hz), 6.93 (1H, d, J = 6.6H
z), 7.03 (1H, d, J = 7.3Hz), 7.37 (4H, m), 7.68 (2H, dd, J =
1.5,8.1Hz), 7.92 (2H, br.s), 8.53 (4H, m), 9.49 (1H, s),
9.77 (1H, br.s) .IR (KBr) cm-1: 3035,1698,1243,1118,754,640.

Example 82 N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 111) mp. 162-164 ° C. 1H NMR (270 MHz, DMSO-d6): 4.29 (1H, d, J = 5.9 Hz), 5.10
(2H, s), 6.83 (1H, t, J = 8.1Hz), 6.92 (1H, d, J = 6.6Hz), 7.
07 (1H, t, J = 6.6Hz), 7.39 (2H, d, J = 8.8Hz), 7.43 (1H, d, J =
5.1Hz), 7.68 (2H, d, J = 8.1Hz), 7.80 (1H, d, J = 8.1Hz), 7.
92 (2H, d, J = 8.1Hz), 7.99 (1H, t, J = 5.9Hz), 8.54 (1H, d, J =
4.4Hz), 8.60 (1H, s), 9.49 (1H, s), 9.76 (1H, br.s) .IR (KBr) cm-1: 3333,3259,1694,1645,1529,1267,720.

Example 83 N- (2,4-dihydroxyphenyl) -4- [N-
(Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 116) mp. (Amorphous) 1H NMR (270 MHz, DMSO-d6): 4.27 (2H, d, J = 6.6 Hz), 5.10
(2H, s), 6.20 (2H, dd, J = 2.2,8.1Hz), 6.39 (2H, d, J = 2.9H
z), 6.88 (2H, d, J = 8.8Hz), 7.33 (1H, d, J = 8.1Hz), 7.41 (1
H, dd, J = 5.1,7.1Hz), 7.89 (1H, d, J = 8.8Hz), 7.98 (1H, t, J
= 6.6Hz), 8.05 (2H, s), 8.52 (1H, m), 8.59 (1H, s), 9.30
(2H, br.s) .IR (KBr) cm-1: 3387,1702,1612,1311,1169,845.

Example 84 N- (2-hydroxy-5-methylphenyl) -4-
[N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 118) mp. 155-155.5 ° C. 1H NMR (270 MHz, DMSO-d6): 2.22 (3H, s), 4.29 (2H, d, J =
5.8Hz), 5.11 (2H, s), 6.82 (2H, m), 7.39 (2H, d, J = 8.8H
z), 7.42 (2H, m), 7.51 (1H, s), 7.79 (1H, d, J = 8.1Hz), 7.9
2 (1H, d, J = 8.1Hz), 7.98 (1H, t, J = 5.9Hz), 8.54 (1H, d, J =
4.4Hz), 8.60 (1H, s), 9.48 (2H, d, J = 8.1Hz). IR (KBr) cm-1: 3306,1723,1655,1525,801,639.

Example 85 N- (2-hydroxy-5-methoxyphenyl) -4-
[N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 119) mp. 175-176 ° C. 1H NMR (270 MHz, DMSO-d6): 3.69 (3H, s), 4.29 (2H, d, J =
5.9Hz), 5.10 (2H, s), 6.63 (1H, dd, J = 2.9,8.7Hz), 6.84
(1H, d, J = 8.8Hz), 7.41 (4H, m), 7.79 (1H, d, J = 8.1Hz), 7.
91 (1H, d, J = 8.1Hz), 7.99 (1H, t, J = 5.9Hz), 8.54 (1H, d, J =
5.1Hz), 8.60 (1H, s), 9.31 (1H, s), 9.45 (1H, s) .IR (KBr) cm-1: 3305,1687,1573,1262,1039,868.

Example 86 N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) ethoxycarbonyl] amino] benzamide (Table 1: Compound No. 124) mp. (Amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 3.00 (2H, t, J = 6.6H),
4.37 (2H, t, J = 6.6Hz), 4.87 (2H, br.s), 6.60 (1H, t, J = 7.3
Hz), 6.97 (1H, t, J = 7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.36 (1
H, dd, J = 4.4,8.1Hz), 7.56 (2H, d, J = 8.8Hz), 7.92 (2H, d, J
= 8.8Hz), 8.46 (1H, d, J = 4.4Hz), 8.54 (1H, d, J = 2.2Hz),
9.95 (1H, s) .IR (KBr) cm-1: 3285,1695,1519,1315,1233,1079.

Example 87 N- (2-aminophenyl) -5-[(pyridine-3-
Yl) methoxycarbonyl] aminobenzofuran-2-
Carboxamide (Table-3: Compound No. 2) mp.173-174 ° C. 1H NMR (270 MHz, DMSO-d6) δppm: 5.22 (2H, s), 6.60 (1H,
dd, J = 8.1,8.1Hz), 6.79 (1H, dd, J = 1.5,8.1Hz), 7.00 (1H, d
d, J = 8.1,8.1Hz), 7.20 (1H, dd, J = 1.5,8.1Hz), 7.44 (1H, m),
7.48 (1H, dd, J = 1.5,8.8Hz), 7.61 (1H, d, J = 8.8Hz), 7.67
(1H, s), 7.88 (1H, dd, J = 1.5,8.1Hz), 7.96 (1H, d, J = 1.5H
z), 8.56 (1H, dd, J = 1.5,4.8Hz), 8.68 (1H, d, J = 1.5Hz), 9.
83 (1H, s), 9.91 (1H, s) .IR (KBr) cm-1: 3308,1707,1667,1584,1536,1452,1316,124
8,1157,1128,1070,955,879,795,748,710.

Example 88 N- (2-aminophenyl) -4- [N- (pyridine-
Synthesis of 3-yl) methoxythiocarbonylaminomethyl] benzamide (Table-1: Compound No. 86) (88-1) 20 mg of 3-pyridinemethanol (0.
18 mmol) was dissolved in 5 ml of dry THF and N,
N'-thiocarbonyldiimidazole 30 mg (0.1
6 mmol) was added at room temperature. After stirring overnight, 50 mg (0.14 mmol) of the compound of step (1-4) of Example 1 was obtained.
l) was added.

After leaving overnight at room temperature, chloroform 100m
1 was added and washed three times with 20 ml of water. Then, the mixture was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and N- [2
70 mg (88% yield) of-(N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) methoxythiocarbonylaminomethyl] benzamide was obtained as an amorphous. 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.73 (2H,
d, J = 5.9Hz), 5.52 (2H, s), 6.73-7.33 (3H, m), 7.35-7.43
(2H, m), 7.58-7.95 (5H, m), 8.14-8.65 (3H, m), 9.80 (1H,
s), 9.91 (1H, br.t).

(88-2) 50 mg (0.10 mmol) of the compound of the step (88-1) was dissolved in 3 ml of methanol. 3N of 4N hydrochloric acid-dioxane solution was added, and the mixture was stirred at room temperature for 1.5 hours. After pouring into a diluted sodium hydroxide aqueous solution to neutralize hydrochloric acid, the mixture was extracted three times with 10 ml of chloroform. After washing twice with a saturated saline solution, the extract was dried over anhydrous magnesium sulfate and concentrated to obtain 34 mg (yield 87%) of N-
(2-aminophenyl) -4- [N- (pyridine-3-
Yl) methoxythiocarbonylaminomethyl] benzamide. mp.154-156 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.73 (2H, d, J = 5.9Hz),
4.88 (2H, s), 5.52 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.77 (1
H, d, J = 8.1Hz), 6.96 (1H, t, J = 8.1Hz), 7.16 (1H, d, J = 7.3H
z), 7.29-7.41 (3H, m), 7.83-7.95 (3H, m), 8.50-8.56 (1
H, m), 8.65 (1H, s), 9.62 (1H, s), 9.93 (1H, s) .IR (KBr) cm-1: 3204,3035,1631,1523,1456,1289,1191,92
0,753.

Example 89 Synthesis of N- (2-aminophenyl) -4- [N ′-(pyridin-3-ylmethyl) ureidomethyl] benzamide (Table 1: Compound No. 88) (89-1) 3- 0.28 g of picolylamine (2.6
mmol) in THF (10 ml) at room temperature.
0.42 g of carbonyldiimidazole (2.4 mmol
l) was added and stirred for 1 hour. 0.58 g of the compound obtained in the step (1-4) of Example 1 (1.
8 mmol), stirred for 3 hours, and left overnight.

After water was added for dilution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate-methanol = 10: 1) to give N-
[2- (N-tert-butoxycarbonyl) amino]
Phenyl-4- [N '-(pyridin-3-ylmethyl)
Ureidomethyl] benzamide 0.77 g (yield 90
%) Was obtained as a white amorphous solid. 1H NMR (270MHz, CDCl3) δppm: 1.46 (9H, s), 4.20 (2H, d,
J = 5.1Hz), 4.28 (2H, d, J = 4.3Hz), 6.10-6.30 (2H, m), 7.0
0-7.25 (4H, m), 7.33 (1H, d, J = 7.3Hz), 7.49-7.54 (2H, m),
7.58-7.64 (3H, m), 7.75 (1H, s), 8.28 (1H, br.s), 8.39
(1H, d, J = 5.1Hz), 9.65 (1H, br.s).

(89-2) 0.63 g (1.32 mmol) of the compound obtained in the step (89-1) was treated with dioxane (4
ml) -methanol (2 ml) solution, 4N hydrochloric acid-dioxane (4 ml) was added, and the mixture was stirred at room temperature for 2 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate-methyl ethyl ketone. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was washed with diisopropyl ether to give N- (2-aminophenyl) -4- [N '.
-(Pyridin-3-ylmethyl) ureidomethyl] benzamide (0.37 g, yield 74.7%) was obtained as a brown solid.

Mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.27 (2H, d, J = 5.9 Hz),
4.31 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 6.57-6.63 (3H,
m), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.17 (1H, d, J = 7.3Hz), 7.32-7.38 (3H, m), 7.66 (1H, d, J =
8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.44 (1H, d, J = 5.1Hz), 8.
49 (1H, d, J = 2.1Hz), 9.63 (1H, br.s) .IR (KBr) cm-1: 3344,3241,1645,1560,1527,1505,1283,75
1,708.

Example 9 was carried out in the same manner as in Example 89.
From Example No. 95, the compound of Example 95 was synthesized. The melting point (mp.), 1H NMR, and IR measurement values of the compound are shown below.

Example 90 N- (2-aminophenyl) -4- [N '-(3-aminophenyl) ureidomethyl] benzamide (Table 1:
Compound No. 24) mp. 206-208 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.35 (2H, d, J = 5.9 Hz),
4.93 (4H, br.s), 6.13 (1H, d, J = 7.3Hz), 6.51-6.62 (3H,
m), 6.74-6.98 (3H, m), 7.12-7.18 (1H, m), 7.41 (2H, d, J =
8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.28 (1H, s), 9.61 (1H,
s) .IR (KBr) cm-1: 3356,3269,1640,1555,1495,1458,1308,123
6,753.

Example 91 N- (2-aminophenyl) -4- [N ′-(pyridin-3-yl) ureidomethyl] benzamide (Table 1:
Compound No. 87) mp. 187-190 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.39 (2H, d, J = 5.9 Hz),
4.89 (2H, br.s), 6.59 (1H, d, J = 7.3,7.3Hz), 6.77 (1H, d, J
= 6.6Hz), 6.88 (1H, t, J = 5.9Hz), 6.97 (1H, ddd, J = 1.5,6.
6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.26 (1H, dd, J = 4.4,8.1
Hz), 7.42 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1Hz), 7.89-
7.96 (1H, m), 8.12 (1H, dd, J = 1.5,4.4Hz), 8.56 (1H, d, J =
3.0Hz), 8.85 (1H, s), 9.62 (1H, s) .IR (KBr) cm-1: 3248,1663,1541,1423,1280,1054.

Example 92 N- (2-aminophenyl) -4- [N '-(3-aminophenyl) thioureidomethyl] benzamide (Table-
1: Compound No. 25) mp. 123 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.80 (2H, d, J = 5.1 Hz),
4.87 (2H, s), 5.12 (2H, s), 6.36 (1H, dd, J = 1.5,8.1Hz),
6.48-6.63 (3H, m), 6.78 (1H, d, J = 6.6Hz), 6.94-7.00 (2H, m
m), 7.17 (1H, d, J = 8.1Hz), 7.42 (2H, d, J = 8.1Hz), 7.92-
8.01 (3H, m), 9.46 (1H, s), 9.61 (1H, s) .IR (KBr) cm-1: 3335,1616,1528,1503,1456,1311,864,75
1.

Example 93 N- (2-aminophenyl) -4- [N ′-(3-nitrophenyl) thioureidomethyl] benzamide (Table-
1: Compound No. 20) mp. 160 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.87 (2H, d, J = 5.1 Hz),
7.27-7.33 (3H, m), 7.46-7.63 (5H, m), 7.89-7.95 (2H, m),
8.05 (2H, d, J = 8.1Hz), 8.70 (1H, s), 8.84 (1H, t, J = 8.9H
z), 10.37 (1H, s).

Example 94 N- (2-amino-5-fluorophenyl) -4- [N '
-(Pyridin-3-yl) methylureidomethyl] benzamide (Table 1: Compound No. 112) mp. (Amorphous). 1H-NMR (270 MHz, DMSO-d6): 4.77 (4H, d, J = 5.1 Hz) , 4.85
(2H, s), 6.81 (2H, m), 7.16 (1H, dd, J = 2.9,10.3Hz), 7.39
(1H, dd, J = 5.1,8.1Hz), 7.53 (2H, d, J = 8.1Hz), 7.81 (1H,
d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.51 (1H, dd, J = 1.5,
5.1Hz), 8.62 (1H, d, J = 1.5Hz), 9.66 (1H, s) .IR (KBr) cm-1: 3399,1730,1638,1508,1444,1411.

Example 95 N- (2-hydroxyphenyl) -4- [N ′-(pyridin-3-yl) methylureidomethyl] benzamide (Table 1: Compound No. 114) mp. (Amorphous). NMR (270 MHz, DMSO-d6): 4.43 (2H, d, J = 6.6 Hz), 4.69
(2H, s), 6.83 (1H, t, J = 6.6Hz), 6.91 (1H, d, J = 8.1Hz), 7.
68 (1H, d, J = 6.6Hz), 7.82 (2H, d, J = 8.1Hz), 8.21 (1H, d, J =
4.4Hz), 8.35 (1H, d, J = 2.2Hz), 8.81 (1H, t, J = 6.6Hz), 9.
48 (1H, s), 9.75 (1H, s) .IR (KBr) cm-1: 3399,1664,1535,1236,1064.

Example 96 Synthesis of N- (2-aminophenyl) -4- [2- [N- (pyridin-3-yl) acetylamino] ethyl] benzamide (Table 1: Compound No. 77) 1) 3.40 g of terephthalaldehyde acid (2
Thionyl chloride (4 ml) was added to a suspension of (2.6 mmol) in toluene (25 ml), and the mixture was heated and stirred at 80 ° C. for 2 hours. After cooling, the solvent was distilled off, and the resulting residue was washed with THF.
(50 ml) to prepare acid chloride. 4.16 g (20.0 m) of the compound of Step (1-2) of Example 1
mol) in THF (10 ml), triethylamine (6 ml, 42.8 mmol) was added, and the acid chloride prepared above was added dropwise over 30 minutes under ice-cooling.

After stirring for 5 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (chloroform → chloroform: ethyl acetate = 10: 1) to give N- [2- (N- [tert-Butoxycarbonyl) aminophenyl] -4-formylbenzamide (3.42 g, yield 50.2%) was obtained as a light brown solid. 1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 6.77 (1H, b
rs), 7.16-7.18 (2H, m), 7.23-7.26 (1H, m), 7.88 (1H, d, J
= 8.8Hz), 7.98 (2H, d, J = 8.8Hz), 8.13 (2H, d, J = 8.8Hz),
9.57 (1H, br.s), 10.11 (1H, br.s) .IR (KBr) cm-1: 3326,3251,1707,1696,1659,1603,1165.

(96-2) 3.0 g (8.82 mmol) of the compound obtained in the step (96-1) and 4.5 g of ethoxycarbonylmethyltriphenylphosphine (1
(2.9 mmol) in toluene (10 ml) was stirred at 80 ° C. for 5.5 hours under a nitrogen stream. After allowing to cool, the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and dried. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1) to give ethyl 4- [N- [2-
3.3 g of (N-tert-butoxycarbonyl) aminophenyl] aminocarbonyl] cinnamate (yield 9
1.1%) as a yellow amorphous solid. 1H NMR (270MHz, CDCl3) δppm: 1.35 (3H, t, J = 7.3Hz), 1.
52 (9H, s), 4.28 (2H, q, J = 7.3Hz), 6.52 (1H, d, J = 15.1Hz),
6.80 (1H, br.s), 7.16-7.25 (3H, m), 7.61 (2H, d, J = 8.1H
z), 7.71 (1H, d, J = 15.1Hz), 7.82 (1H, d, 7.3Hz), 7.98 (2
(H, d, J = 8.1Hz), 9.34 (1H, br.s).

(96-3) 2.50 g (6.09 mmol) of the compound obtained in the step (96-2) was treated with THF (3
0 ml) -methanol (40 ml) solution under a nitrogen stream.
After adding 0% Pd / C (water-containing, 0.5 g), the mixture was stirred for 30 minutes under a hydrogen stream. After purging with nitrogen, the catalyst was filtered. Diisopropyl ether was added to the residue obtained by evaporating the solvent of the filtrate, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- (2- 2.23 g (88.8% yield) of ethoxycarbonylethyl) benzamide were obtained as a white solid. 1H NMR (270MHz, CDCl3) δppm: 1.25 (3H, t, J = 7.3Hz), 1.
52 (9H, s), 2.65 (2H, t, J = 7.3Hz), 3.02 (2H, t, J = 7.3Hz),
4.13 (2H, q, J = 7.3Hz), 6.77 (1H, br.s), 7.16-7.33 (5H,
m), 7.78 (1H, d, J = 8.1Hz), 7.89 (2H, d, J = 8.8Hz), 9.06 (1
H, br.s).

(96-4) Lithium hydroxide monohydrate was added to a suspension of 2.21 g (5.36 mmol) of the compound obtained in step (96-3) in methanol (10 ml) -water (15 ml). 37 g (8.82 mmol) were added and 40
Stirred at C for 3 hours. After cooling, 10% hydrochloric acid aqueous solution was added,
Extracted with ethyl acetate. After washing the organic layer with saturated saline,
The residue obtained by drying and distilling off the solvent was added with diisopropyl ether, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert-butoxycarbonyl).
Aminophenyl] -4- (2-carboxyethyl) benzamide (1.87 g, yield 90.8%) was obtained as a white solid. 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 2.59 (2H,
t, J = 7.3Hz), 2.91 (2H, t, J = 7.3Hz), 7.13-7.20 (2H, m),
7.40 (2H, d, J = 8.1Hz), 7.54 (2H, dd, J = 7.3,2.1Hz), 7.88 (2
(H, d, J = 8.1Hz), 8.66 (1H, br.s), 9.79 (1H, br.s).

(96-5) 0.12 g (0.3 mmol) of the compound obtained in the step (96-4) in benzene (5
0.1 ml of triethylamine (0.7 m
mol) and 0.3 g of molecular sieve 4A, and the mixture was stirred for 0.5 hour under a nitrogen stream. 0.15 ml (0.7 mmol) of diphenylphosphoryl azide was added to this solution.
Was added and the mixture was heated under reflux for 2 hours. After cooling, 0.4 ml (3.8 mmol) of benzyl alcohol was added, and further 2.
The mixture was refluxed for 5 hours. After dilution with ethyl acetate, the mixture was washed with water and saturated saline.

After the organic layer was dried, the solvent was distilled off, and the residue obtained was purified by silica gel column chromatography (chloroform: ethyl acetate = 4: 1) to give N
-[2- (N-tert-butoxycarbonyl) aminophenyl] -4- [2- (N-benzyloxycarbonylamino) ethyl] benzamide 129 mg (88%)
Was obtained as a colorless oil. 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 2.89 (2H, t,
J = 7.3Hz), 3.45-3.54 (2H, m), 4.80 (1H, m), 5.10 (2H, s),
6.76 (1H, br.s), 7.20-7.38 (10H, m), 7.79 (1H, d, J = 8.8H
z), 7.89 (2H, d, J = 8.1Hz), 9.10 (1H, br.s).

(96-6) A solution of 129 mg (0.26 mmol) of the compound obtained in the step (96-5) in methanol (10 ml) was added with 10% Pd / C (hydrous,
0.05 g), and the mixture was stirred for 2 hours under a hydrogen stream. After the catalyst was distilled off, the residue obtained by drying was dissolved in dichloromethane (5 ml). 0.18 g (1.04 mmol) of 3-pyridineacetic acid hydrochloride was added to this solution, and 0.28 g (2.0 mmol) of triethylamine was further added.
l) was added and the mixture was cooled with ice. 2-Chloro-1,3- under ice-cooling
0.17 g of dimethyl imidazolinium chloride (1.
0 mmol) and stirred for 2 hours. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was subjected to silica gel column chromatography (ethyl acetate: methanol =
10: 1) to give N- [2- (Nt
tert-butoxycarbonyl) aminophenyl] -4-
[2- [N- (pyridin-3-yl) acetylamino]
Ethyl] benzamide (50 mg, yield 40%) was obtained as a colorless oil.

1H NMR (270 MHz, CDCl3) δ ppm: 1.48 (9H,
s), 2.80 (2H, t, J = 6.6Hz), 3.42 (2H, m), 3.52 (2H, s), 6.3
3 (1H, t-like, J = 5.9Hz), 7.09 (2H, d, J = 8.1Hz), 7.14-7.2
0 (2H, m), 7.24 (1H, dd, J = 4.4,7.3Hz), 7.41 (1H, dd, J = 3.
7,5.9Hz), 7.50 (1H, s), 7.58 (1H, dd, J = 1.5,5.9Hz), 7.6
9 (1H, dd, J = 3.7,5.9Hz), 7.75 (2H, d, J = 8.1Hz), 8.22 (1H,
d, J = 2.1Hz), 8.44 (1H, dd, J = 1.5,4.4Hz), 9.49 (1H, br.
s).

(96-7) 50 mg (0.10 mmol) of the compound of Step (96-6) in dioxane (2 ml)
4N hydrochloric acid-dioxane (2 ml) was added to a methanol (1 ml) solution, and the mixture was stirred at room temperature for 2.5 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was dried to give N- (2-aminophenyl) -4.
22 mg (59% yield) of-[2- [N- (pyridin-3-yl) acetylamino] ethyl] benzamide was obtained as an amorphous solid.

Mp. (Amorphous) .1H NMR (270 MHz, DMSO-d6) δ ppm: 2.70-2.90 (4H, m), 3.4
2 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz),
6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.16 (1
(H, d, J = 7.3Hz), 7.29-7.32 (3H, m), 7.59 (1H, d, J = 8.1Hz),
7.89 (1H, d, J = 8.1Hz), 8.22 (1H, t-like), 8.41-8.43 (2
H, m), 9.62 (1H, br.s).

Example 97 N- (2-aminophenyl) -4- [2- [N- (3-
Synthesis of picolyl) aminocarbonyl] ethyl] benzamide (Table 1: Compound No. 80) (97-1) 0.58 g (1.5 mmol) of the compound obtained in Step (96-4) of Example 96 in dichloromethane (1.5 mmol) 5 ml) 0.23 g of 3-picolylamine in the suspension
(2.0 mmol) and 0.56 m of triethylamine
1 (4.0 mmol) was added. 2-Chloro- under ice-cooling
1,3-dimethylimidazolinium chloride 0.39
g (2.0 mmol) in dichloromethane (5 ml) was added and stirred for 1.5 hours. After adding saturated aqueous sodium bicarbonate,
Extracted with chloroform.

The organic layer was washed with water and saturated saline, dried,
The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 100: 10: 1) to give N-
0.71 g of [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [2- [N- (3-picolyl) aminocarbonyl] ethyl] benzamide (yield 94
%) As a light brown oil. 1H NMR (270MHz, CDCl3) δppm: 1.45 (9H, s), 2.42 (2H, t,
J = 7.3Hz), 2.98 (2H, t, J = 7.3Hz), 4.32 (2H, d, J = 6.6Hz),
6.44 (1H, t, J = 6.6Hz), 7.14-7.27 (5H, m), 7.48-7.57 (3H,
m), 7.63-7.68 (3H, m), 7.90 (1H, d, J = 2.1Hz), 8.43 (1H, d
d, J = 1.4,4.4Hz), 9.86 (1H, br.s).

(97-2) 0.70 g (1.47 mmol) of the compound of step (97-1) in dioxane (5 m
l) 4N hydrochloric acid-dioxane (5 ml) was added to the solution,
Further, methanol (2 ml) was added and the mixture was stirred at room temperature for 2 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline, dried, and the solvent was distilled off. Diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl) -4. 0.42 g of-[2- [N- (3-picolyl) aminocarbonyl] ethyl] benzamide (yield 7
6.3%) as an opalescent solid.

Mp. 168-170 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.47-2.53 (2H, m), 2.9
3 (2H, t, J = 7.3Hz), 4.27 (2H, d, J = 5.9Hz), 4.90 (2H, br.
s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz),
6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 6.6Hz), 7.28-
7.35 (1H, m), 7.33 (2H, d, J = 8.1Hz), 7.49 (1H, dd, J = 2.1,
5.9Hz), 7.89 (2H, d, J = 8.1Hz), 8.39-8.44 (3H, m), 9.62
(1H, br.s) .IR (KBr) cm-1: 3313,1641,1523,1457,1300,748,713.

Example 98 N- (2-aminophenyl) -4-[(pyridine-3-
Yl) Methylaminocarbonyloxymethyl] benzamide (Table-1: Compound No. 85) (98-1) 1.99 g (12.0 mmol) of methyl 4-hydroxymethylbenzoate in THF (20 m
l) To the solution was added 1.78 g (11.0 mmol) of N, N'-carbonyldiimidazole at room temperature, and the mixture was stirred for 1 hour. 1.08 g of 3-picolylamine was added to this solution at room temperature.
(10.0 mmol) and stirred for 3.5 hours.
Left overnight. Water was added to the mixture for dilution, followed by extraction with ethyl acetate.

The organic layer was washed with brine, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate) to give N- (4-methoxycarbonyl) benzyloxycarbonyl- 2.76 g (91.9% yield) of 3-picolylamine were obtained as a white waxy solid. 1H NMR (270MHz, CDCl3) δppm: 3.91 (3H, s), 4.40 (2H, d,
J = 5.9Hz), 5.18 (2H, s), 5.50 (1H, br.s), 7.24-7.28 (1H,
m), 7.40 (2H, d, J = 8.1Hz), 7.65 (1H, d, J = 7.3Hz), 8.02 (2H, d, J = 7.3Hz)
(H, d, J = 8.8Hz), 8.50-8.53 (2H, m).

(98-2) 2.40 g (8.0 mmol) of the compound of step (98-1) in methanol (10 m
l) To a suspension of water (20 ml) was added 0.42 g (10.0 mmol) of lithium hydroxide monohydrate, and the mixture was stirred at room temperature for 5 hours. Add 10% aqueous hydrochloric acid and add acidic (pH 2
After 4), the precipitated solid was collected by filtration and dried to obtain 1.83 g (yield: 79.9%) of N- (4-carboxy) benzyloxycarbonyl-3-picolylamine as a white solid. . 1H NMR (270MHz, DMSO-d6) δppm: 4.24 (2H, d, J = 5.9Hz),
5.13 (2H, s), 7.33-7.38 (1H, m), 7.46 (2H, d, J = 8.1Hz),
7.94 (2H, d, J = 8.1Hz), 7.95-8.01 (1H, m), 8.46 (1H, d, J =
5.1Hz), 8.49 (1H, d, J = 1.5Hz), 13.0 (1H, br.s).

(98-3) 1.26 g (4.4 mmol) of the compound of Step (98-2) was added to dichloromethane (20
oxalyl chloride 1.0 ml (1 ml)
(1.4 ml) was gradually added, and several drops of DMF were further added, followed by stirring at room temperature for 10 minutes and further at 40 ° C. for 30 minutes.
After cooling, the solvent was distilled off, and excess oxalyl chloride was further distilled off with toluene. After dichloromethane (10 ml) was added to the residue, the mixture was ice-cooled, and 0.83 g (4.0 mm) of the compound obtained in Step (1-2) of Example 1 was further added.
ol) in dichloromethane (8 ml) -pyridine (8 m
l) After the solution was added dropwise, the mixture was stirred for 7 hours while raising the temperature to room temperature, and left overnight.

After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. Toluene was added to the obtained residue. Further excess pyridine was azeotroped. The obtained residue is purified by silica gel column chromatography (ethyl acetate) to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4-[(pyridin-3-yl) methylaminocarbonyloxymethyl ] 1.40 g of benzamide
(73.4% yield) as a light brown solid. 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.40 (2H, d,
J = 5.9Hz), 5.19 (2H, s), 5.56 (1H, m), 7.07 (1H, br.s), 7.
14-7.31 (4H, m), 7.43 (2H, d, J = 8.1Hz), 7.65 (1H, d, J = 8.1
Hz), 7.76 (1H, d, J = 7.3Hz), 7.95 (2H, d, J = 8.1Hz), 8.52
(2H, d, J = 4.1Hz), 9.32 (1H, br.s).

(98-4) 1.00 g (2.10 mmol) of the compound of step (98-3) in dioxane (10 m
l)-4N hydrochloric acid in a methanol (2 ml) solution at room temperature-
Dioxane (9 ml) was added and the mixture was stirred for 2 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate-methyl ethyl ketone (1: 1). After washing the organic layer with saturated saline,
After drying and distilling off the solvent, methanol-diisopropyl ether was added to the obtained residue, and the resulting solid was collected by filtration and dried to give N- (2-aminophenyl) -4-.
0.79 g (quantitative) of [(pyridin-3-yl) methylaminocarbonyloxymethyl] benzamide was obtained as a white solid.

Mp.139-141 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.25 (2H, d, J = 5.9 Hz),
4.90 (2H, s), 5.13 (2H, s), 6.60 (1H, dd, J = 6.6,7.3Hz),
6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.17 (1
H, d, J = 7.3Hz), 7.36 (1H, dd, J = 4.4,8.1Hz), 7.47 (2H, d, J
= 8.1Hz), 7.67 (1H, d, J = 8.1Hz), 7.97 (2H, d, J = 7.3Hz),
7.90-8.00 (1H, m), 8.46 (1H, dd, J = 1.5,5.1Hz), 8.49 (1H, m
d, J = 2.1Hz), 9.65 (1H, br.s) .IR (KBr) cm-1: 3326 (br), 1694,1637,1526,1458,1147,75
0,712.

Example 99 N- (2-Aminophenyl) -4- [3- (imidazol-1-yl) propylaminocarbonyloxymethyl] benzamide (Table 1: Compound No. 215) Method similar to that in Example 98 Was synthesized. mp. (amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 1.80-1.89 (2H, m), 2.9
4-3.02 (2H, m), 3.98 (2H, t, J = 7.3Hz), 4.88 (2H, s), 5.11
(2H, s), 6.55-6.63 (1H, m), 6.76-6.97 (3H, m), 7.10-7.1
8 (2H, m), 7.43-7.48 (3H, m), 7.61 (1H, s), 7.98 (2H, d, J =
8.1Hz), 9.66 (1H, s).

Example 100 Synthesis of N- (2-aminophenyl) -4- (phenylacetylamino) benzamide (Table 1: Compound No. 2) (100-1) In Step (1-2) of Example 1, 16.6 g (80 mmol) of the obtained compound in dichloromethane (12
0 ml) solution with 16.8 ml (120 ml) of triethylamine.
mmol), and a solution of 16.0 g (86.4 mmol) of 4-nitrobenzoyl chloride in dichloromethane (40 ml) was gradually added under ice-cooling, followed by stirring for 7 hours. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with chloroform.

The organic layer was treated with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution,
After washing with a saturated saline solution, it was dried and the solvent was distilled off. The obtained residue was washed with diisopropyl ether to give 28.0 g of N- [2- (N-tert-butoxycarbonylamino) phenyl] -4-nitrobenzamide.
(98% yield) as a pale yellow solid. 1H NMR (270MHz, CDCl3) δppm: 1.53 (9H, s), 7.17-7.29
(4H, m), 7.85 (1H, br.d, J = 7.3Hz), 8.17 (2H, d, J = 8.8Hz),
8.32 (2H, d, J = 8.8Hz), 9.88 (1H, br.s).

(100-2) 24.0 g (67.2 mmol) of the compound obtained in the step (100-1) was treated with THF (8
0%)-methanol (80 ml) was added with 10% Pd / C (hydrous, 2.4 g) under a nitrogen stream and stirred for 1.5 hours under a hydrogen stream. After the absorption of hydrogen was stopped, diisopropyl ether and ethyl acetate were added to the residue obtained by filtering off the solvent and evaporating the solvent, and the obtained solid was collected by filtration and dried to give N- [2- (N-tert-
Butoxycarbonylamino) phenyl] -4-aminobenzamide (18.96 g, yield 86%) was obtained as a white solid. 1H NMR (270 MHz, DMSO-d6) δ ppm: 1.46 (9H.s), 5.84 (2H,
s), 6.61 (2H, d, J = 8.8Hz), 7.10-7.18 (2H, m), 7.46-7.55
(2H, m), 7.68 (2H, d, J = 8.8Hz), 8.67 (1H, s), 9.49 (1H,
s).

(100-3) 0.8 ml (9.9 mm) of pyridine was added to a methylene chloride solution (15 ml) of 1.6 g (4.88 mmol) of the compound obtained in the step (100-2).
ol), 0.96 ml of phenylacetyl chloride
(7.26 mmol) was added and stirred for 1 day. After completion of the reaction, water was added, and the precipitated crystals were collected by filtration and N- [2- (N
-Tert-butoxycarbonylamino) phenyl]-
4- (phenylacetylamino) benzamide 1.66
g (76% yield).

(100-4) 0.8 g of iodotrimethylsilane was added to a solution of 1 g (2.24 mmol) of the compound obtained in the step (100-3) in acetonitrile (25 ml) at room temperature.
8 ml (6.18 mmol) was added and stirred for 3 hours. After completion of the reaction, the solvent was concentrated, and the obtained residue was recrystallized from methanol to give N- (2-aminophenyl) -4- (phenylacetylamino) benzamide (0.29 g, yield 38%) as white crystals. As obtained.

Mp. 232-237 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.69 (2H, s), 4.90 (2H,
s), 6.60 (1H, t, J = 7.3Hz), 6.77 (1H, d, J = 7.3Hz), 6.96 (1H
H, t, J = 7.3Hz), 7.15 (1H, d, J = 7.4Hz), 7.22-7.35 (5H, m),
7.72 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 9.57 (1H,
s), 10.43 (1H, s) IR (KBr) cm-1: 2937,2764,1660,1598,15
06,1459.

In the same manner as in Example 100, the compounds of Examples 101 to 128 were synthesized. less than,
The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown.

Example 101 N- (2-aminophenyl) -4-[(4-phenylbutanoyl) amino] benzamide (Table 1: Compound No. 4) mp. (Amorphous). 1H NMR (270 MHz, DMSO- d6) δppm: 1.91 (2H, hep, J = 7.3H
z), 2.37 (2H, t, J = 7.3Hz), 2.64 (2H, t, J = 7.3Hz), 5.0 (2H,
br.s), 6.61 (1H, t, 7.0Hz), 6.79 (1H, dd, J = 1.5,8.1Hz),
6.97 (1H, t, J = 7.0Hz), 7.10-7.40 (6H, m), 7.71 (2H, d, J =
8.8Hz), 7.94 (2H, d, J = 8.8Hz), 9.57 (1H, s), 10.15 (1H,
s) .IR (KBr) cm-1; 3344,1687,1603,1542,1460,1315,103
3,842,737.

Example 102 N- (2-Aminophenyl) -4-[(4-chlorophenylacetyl) amino] benzamide (Table 1: Compound No. 15) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) ) δppm: 3.72 (2H, s), 7.29-7.43
(8H, m), 7.77 (2H, d, J = 8.8Hz), 8.00 (2H, d, J = 8.8Hz), 10.29
(1H, s), 10.52 (1H, s) .IR (KBr) cm-1: 3300,2868,1664,163
8,1520.

Example 103 N- (2-Aminophenyl) -4-[(2-nitrophenylacetyl) amino] benzamide hydrochloride (Table-
1: Hydrochloride of Compound No. 19) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.20 (2H, s), 7.20-7.3
0 (3H, m), 7.40-7.45 (1H, m), 7.60 (2H, d), 7.71-7.77 (3
H, m), 8.02-8.10 (4H, m), 10.27 (1H, br.s), 10.64 (1H, b
rs) .IR (KBr) cm-1: 3263,1676,1647,1518,1184,759.

Example 104 N- (2-Aminophenyl) -4-[(4-nitrophenylacetyl) amino] benzamide (Table 1: Compound No. 21) mp. 222-226 ° C. 1H NMR (270 MHz, DMSO -d6) δppm: 3.90 (2H, s), 4.96 (2H,
br.s), 6.60 (1H, dt, J = 1.5,6.6Hz), 6.78 (1H, dd, J = 1.5,
6.6Hz), 6.97 (1H, dt, J = 1.5,6.6Hz), 7.15 (1H, dd, J = 1.5,
6.6Hz), 7.63 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.
95 (2H, d, J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz), 9.59 (1H, s), 1
0.54 (1H, s) .IR (KBr) cm-1: 3395,3334,1671,1630,1519,1346.

Example 105 N- (2-Aminophenyl) -4-[(2-aminophenylacetyl) amino] benzamide (Table 1: Compound No. 22) mp. 177-182 ° C. (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 3.54 (2H, s), 4.88 (2H,
br.s), 5.09 (2H, br.s), 6.55 (1H, dd, J = 6.6,7.3Hz), 6.59
(1H, dd, J = 7.3,7.3Hz), 6.68 (1H, d, J = 7.3Hz), 6.78 (1H,
d, J = 7.3Hz), 6.96 (2H, dd, J = 7.3,7.3Hz), 7.06 (1H, d, J =
6.6Hz), 7.15 (1H, d, J = 7.3Hz), 7.71 (2H, d, J = 8.8Hz), 7.
95 (2H, d, J = 8.8Hz), 9.57 (1H, br.s), 10.39 (1H, br.s) .IR (KBr) cm-1: 3374,3256 (br.), 1683,1597, 1503,1317,12
62,1180,1153,747.

Example 106 N- (2-Aminophenyl) -4-[(4-aminophenylacetyl) amino] benzamide (Table 1: Compound No. 26) mp. 219-226 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 3.46 (2H, s), 4.93 (4H,
br.s), 6.52 (2H, d, J = 8.1Hz), 6.59 (1H, dt, J = 1.5,7.3H
z), 6.77 (1H, dd, J = 1.4,7.3H), 6.97 (1H, dt, J = 1.4,7.3H
z), 6.99 (2H, d, J = 8.1Hz), 7.15 (1H, dd, J = 1.5,7.3Hz),
7.70 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz) .IR (KBr) cm-1: 3278,3032,1675,1628,1516.

Example 107 N- (2-Aminophenyl) -4-[(4-methoxyphenylacetyl) amino] benzamide (Table 1: Compound No. 32) mp. (Amorphous). 1H NMR (270 MHz, DMSO- d6) δppm: 3.62 (2H, s), 3.74 (3
H, s), 6.90 (2H, d, J = 8.8Hz), 7.26 (2H.dJ = 8.8Hz), 7.30
(3H, m), 7.39 (1H, m), 7.77 (2H, d, J = 8.8Hz), 7.99 (2H, d,
J = 8.8Hz), 10.26 (1H, s), 10.44 (1H, s) .IR (KBr) cm-1: 3300,2759,1670,1638,1514,1250.

Example 108 N- (2-aminophenyl) -4-[[4- (N, N-
Dimethylamino) phenylacetyl] amino] benzamide (Table 1: Compound No. 53) mp. 140 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.04 (6H, s), 3.67 (2H,
s), 7.16 (2H, d, J = 8.1Hz), 7.29-7.40 (6H, m), 7.76 (2H,
d, J = 8.8Hz), 7.99 (2H, d, J = 8.8Hz), 10.29 (1H, s), 10.47
(1H, s) .IR (KBr) cm-1: 3244,2951,2639,1647,1599,1507.

Example 109 N- (2-Aminophenyl) -4-[(4-trifluoromethylphenylacetyl) amino] benzamide (Table 1: Compound No. 43) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δppm: 3.84 (2H, s), 6.89 (1H,
t, J = 7.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.11 (1H, t, J = 7.4H
z), 7.25 (1H, d, J = 7.4Hz), 7.57 (2H, d, J = 8.8Hz), 7.71 (2
H, d, J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz), 7.97 (2H, d, J = 8.8H
z), 9.87 (1H, s), 10.54 (1H, s) .IR (KBr) cm-1: 3260,1664,1605,1521,1327,1119.

Example 110 N- (2-aminophenyl) -4-[(pyridine-2-
Yl) acetylamino] benzamide dihydrochloride (Table-
1: hydrochloride of Compound No. 174) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.60 (2H, s), 7.30-7.4
6 (3H, m), 7.56 (1H, d, J = 7.4Hz), 7.79 (2H, d, J = 8.8Hz),
7.95 (1H, t, J = 6.6Hz), 8.01 (1H, d, J = 7.4Hz), 8.11 (2H, d,
J = 8.8Hz), 8.49 (1H, t, J = 7.4Hz), 8.87 (1H, d, J = 5.1Hz),
10.46 (1H, s).

Example 111 N- (2-aminophenyl) -4-[(pyridine-3-
Yl) acetylamino] benzamide dihydrochloride (Table-
1: hydrochloride of Compound No. 68) mp. 182-189 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.12 (2H, s), 7.29-7.5
9 (4H, m), 7.80 (2H, d, J = 8.8Hz), 8.05 (1H, m), 8.11 (2H,
d, J = 8.8Hz), 8.57 (1H, d, J = 8.1Hz), 8.85 (1H, d, J = 5.2H
z), 8.95 (1H, s), 10.25 (1H, s), 10.48 (1H, s).

Example 112 N- (2-Aminophenyl) -4-[[3- (pyridin-3-yl) propanoyl] amino] benzamide (Table 1: Compound No. 69) mp. NMR (270MHz, DMSO-d6) δppm: 2.80 (2H, t, J = 7.3Hz),
3.08 (2H, t, J = 7.3Hz), 6.87 (1H, t, J = 8.0Hz), 6.99 (1H, d
d, J = 1.4,8.0Hz), 7.11 (1H, dt, J = 1.4,8.0Hz), 7.25 (1H,
d, J = 8.0Hz), 7.70 (2H, d, J = 8.8Hz), 7.77 (1H, dd, J = 5.8,
8.0Hz), 7.96 (2H, d, J = 8.8Hz), 8.22 (1H, d, J = 8.0Hz), 8.
75 (1H, d, J = 1.4Hz), 9.83 (1H, s), 10.25 (1H, s).

Example 113 N- (2-aminophenyl) -2-chloro-4- [3-
(Pyridin-3-yl) propanoylamino] benzamide (Table 1: Compound No. 123) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.70 (2H, t, J = 8.1 Hz),
2.96 (2H, t, J = 7.3Hz), 4.74 (2H, br.s), 6.60 (1H, t, J = 6.
6Hz), 6.78 (1H, d, J = 6.6Hz), 6.95 (1H, t, J = 6.6Hz), 7.19
(1H, dd, J = 1.5,7.3Hz), 7.29 (1H, dd, J = 5.1,7.3Hz), 7.66
(2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz), 8.48 (1H, d, J = 2.2
Hz), 9.37 (1H, s), 10.00 (1H, s) .IR (KBr) cm-1: 3273,1675,1519,1315,1181,852,747.

Example 114 N- (2-Aminophenyl) -4-[[N- (pyridin-3-yl) methyl-N-trifluoroacetylamino] acetylamino] benzamide (Table-1: Compound No. 107) mp.145 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.18 and 4.42 (total
2H, s), 4.73 and 4.83 (total 2H, s), 4.87 (2H, br.s),
6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.96 (1
H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.35-7.45 (1
H, m), 7.66 (2H, d, J = 5.9Hz), 7.70-7.80 (1H, m), 7.90-8.
00 (2H, m), 8.51-8.55 (1H, m), 8.58 (1H, s), 9.60 (1H, br.
s), 10.36 and 10.43 (total 1H, br.s).

Example 115 N- (2-aminophenyl) -4-[[N- (pyridin-3-yl) methylamino] acetylamino] benzamide (Table 1: Compound No. 105) mp. 160 ° C. (dec) .). 1H NMR (270MHz, DMSO-d6) δppm: 3.30 (2H, s), 3.79 (2H,
s), 4.88 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H,
d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J =
8.1Hz), 7.74 (2H, d, J = 8.8Hz), 7.80 (1H, d, J = 7.3Hz), 7.
95 (2H, d, J = 8.1Hz), 8.46 (1H, d, J = 3.7Hz), 8.57 (1H, s),
9.57 (1H, s), 10.08 (1H, br.s) .IR (KBr) cm-1: 3298,1693,1637,1602,1544,1454,1262,84
8,762.

Example 116 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) methyloxamoylamino] benzamide (Table 1: Compound No. 104) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.43 (2H, d, J = 6.6 Hz),
4.90 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d,
J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3Hz), 7.16 (1H, d,
J = 7.3Hz), 7.37 (1H, dd, J = 4.4,8.1Hz), 7.73 (1H, d, J = 8.1
Hz), 7.96 and 7.96 (4H, AA'BB ', J = 9.4Hz), 8.47 (1H, dd,
J = 1.5,5.1Hz), 8.56 (1H, d, J = 1.5Hz), 9.59 (1H, s), 9.67
(1H, t, J = 6.6Hz), 10.92 (1H, br.s) .IR (KBr) cm-1: 3299,1644,1518,1320,1119,748.

Example 117 N- (2-Aminophenyl) -4-[[N- (pyridin-3-yl) methyl-N-nicotinoylamino] acetylamino] benzamide (Table 1: Compound No. 106) mp . (amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 4.11 (major 2H, s), 4.
26 (minor 2H, s), 4.75 (major 2H, s), 4.65 (minor 2H, s)
s), 4.88 (total 2H, br.s), 6.60 (total 1H, dd, J = 7.3,8.
1Hz), 6.78 (total 1H, d, J = 7.3Hz), 6.97 (total 1H, dd, J
= 7.3,8.1Hz), 7.15 (total 1H, d, J = 8.1Hz), 7.41-7.95 (t
otal 8H, m), 8.46-8.52 (total 1H, m), 8.63-8.70 (total
2H, m), 9.59 (total 1H, s), 10.22 (major 1H, br.s), 1
0.37 (minor 1H, br.s) .IR (KBr) cm-1: 3269,1701,1637,1603,1534,1506,1312,125
4,752.

Example 118 N- (2-Aminophenyl) -4-[[4- (pyridin-3-yl) butanoyl] amino] benzamide (Table
1: Compound No. 70) mp. 165-167 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 1.88-1.99 (2H, m), 2.6
8 (2H, t, J = 7.3Hz), 2.39 (2H, t, J = 7.3Hz), 6.78-6.81 (1H,
m), 6.94-6.99 (1H, m), 7.15-7.18 (1H, m), 7.34-7.39 (1
H, m), 7.69-7.72 (3H, m), 7.94 (2h, d, J = 8.8Hz), 8.43-8.
48 (2H, m) .IR (KBr) cm-1: 3291,1660,1626,1308,1261,1182,1027,82
5,747.

Example 119 N- (2-Aminophenyl) -4-[[N- (pyridin-3-yl) methyl-N-methylamino] acetylamino] benzamide (Table-1: Compound No. 108) mp. Fifteen
4-155 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 2.28 (3H, s), 3.27 (2H,
s), 3.71 (2H, s), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.
3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16 (1H, d, J = 8.1Hz), 7.38 (1H, dd, J = 2.9,8.1Hz), 7.77
(2H, d, J = 8.8Hz), 7.75-7.85 (1H, m), 7.95 (2H, d, J = 8.8H
z), 8.47 (1H, d, J = 1.5Hz), 8.49 (1H, s), 9.56 (1H, s), 1
0.02 (1H, br.s).

Example 120 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) oxyacetylamino] benzamide (Table-
1: Compound No. 65) mp. 175-179 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.86 (2H, s), 4.90 (2H,
br.s), 6.60 (1H, d, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz),
6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.34
-7.47 (2H, m), 7.76 (2H, d, J = 8.8Hz), 7.98 (2H, d, J = 8.8H
z), 8.22 (1H, d, J = 3.6Hz), 8.39 (1H, d, J = 2.9Hz), 9.60 (1H
H, br.s), 10.40 (1H, br.s) .IR (KBr) cm-1: 3321,1655,1530,1276,1231,1068,757.

Example 121 N- (2-aminophenyl) -4- [4- (pyridine-
3-yl) -1,4-dioxobutylamino] benzamide (Table 1: Compound No. 99) mp. 190-194 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.08 (2H, t, J = 6.4Hz),
3.41 (2H, t, J = 6.4Hz), 4.86 (2H, s), 6.59 (1H, t, J = 5.6H
z), 6.78 (1H, d, J = 7.9Hz), 6.96 (1H, t, J = 7.4Hz), 7.15 (1
H, d, J = 7Hz), 7.58 (1H, dd, J = 4.9,7.9Hz), 7.70 (2H, d, J =
8.9Hz), 7.94 (2H, d, J = 8.9Hz), 8.35 (1H, d, J = 7.9Hz), 8.
81 (1H, d, J = 4Hz), 9.18 (1H, s), 9.56 (1H, s), 10.32 (1H,
s) .IR (KBr) cm-1: 3317,1691,1652,1601,1522,1312,982,84
7,764,701.

Example 122 N- (2-Aminophenyl) -4- [3- [N- (pyridin-3-yl) amino] -1,3-dioxopropylamino] benzamide (Table 1: Compound No. 94) mp. 196 ° C. (dec.) 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.57 (2H, s), 4.87 (2H,
s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1
H, m), 7.14-7.17 (1H, m), 7.33-7.38 (1H, m), 7.73 (2H, d,
J = 8.8Hz), 7.97 (2H, d, J = 8.8Hz), 8.05-8.08 (1H, m), 8.2
7-8.30 (1H, m), 8.75-8.76 (1H, m), 9.59 (1H, s), 10.44 (1
H, s), 10.47 (1H, s) .IR (KBr) cm-1: 3410,3315,1685,1655,1625,1536,1428,13
62,1263,1201,744.

Example 123 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) methoxyacetylamino] -3-methylbenzamide (Table 1: Compound No. 102) mp. 178-181 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.28 (3H, s) , 4.22 (2H,
s), 4.71 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.
3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16 (1H, d, J = 7.3Hz), 7.43 (1H, dd, J = 4.4,8.1Hz), 7.71
(1H, d, J = 8.1Hz), 7.79-7.89 (3H, m), 8.54 (1H, dd, J = 1.5,
4.4Hz), 8.66 (1H, d, J = 1.5Hz), 9.36 (1H, br.s), 9.60 (1
H, br.s) .IR (KBr) cm-1: 3394,3269,1683,1630,1593,1521,1460,113
1,750,716.

Example 124 N- (2-Aminophenyl) -4- [N- (thiophen-3-yl) methoxyacetylamino] benzamide (Table 1: Compound No. 204) mp. 186-189 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.11 (2H, s), 4.63 (2H,
s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H
H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.12-7.19 (2
H, m), 7.53-7.57 (2H, m), 7.78 (2H, d, J = 8.8Hz), 7.95 (2H
H, d, J = 8.8Hz), 9.58 (1H, br.s), 10.04 (1H, br.s) .IR (KBr) cm-1: 3341,3248,1694,1631,1611,1506,1314, 11
26.

Example 125 N- (2-aminophenyl) -4- [N-methyl-N-
(Pyridin-3-yl) methoxyacetylamino] benzamide (Table-1: Compound No. 103) mp. 180-183 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.24 (3H, s), 4.08 (2H,
br.s), 4.50 (2H, s), 4.94 (2H, br.s), 6.60 (1H, dd, J = 7.
3,7.3Hz), 6.79 (1H, d, J = 8.1Hz), 6.98 (1H, dd, J = 7.3,8.1
Hz), 8.03 (1H, d, J = 8.1Hz), 8.48-8.50 (2H, m), 9.72 (1H,
br.s) .IR (KBr) cm-1: 3395,3283,1683,1639,1604,1506,1459,13
07,1124.

Example 126 N- (2-aminophenyl) -4- [N- (pyridine-
2-yl) methoxyacetylamino] benzamide (Table 1: Compound No. 176) mp. 171-173 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.26 (2H, s), 4.74 (2H,
s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 6.6,8.1Hz), 6.78 (1H
H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1
H, d, J = 7.3Hz), 7.35 (1H, dd, J = 5.1,6.6Hz), 7.80 (2H, d, J
= 8.1Hz), 7.80-7.89 (1H, m), 7.97 (2H, d, J = 8.1Hz), 8.59
(1H, d, J = 4.4Hz), 9.59 (1H, br.s), 10.30 (1H, br.s) .IR (KBr) cm-1: 3391,3258,1678,1629,1593,1517,1128 , 76
7,742.

Example 127 N- (2-Aminophenyl) -4- [N- (N-nicotinoylamino) acetylamino] benzamide (Table-
1: Compound No. 97) mp. 218-220 ° C (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.13 (2H, d, J = 5.9 Hz),
4.89 (2H, s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d, J =
8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.15 (1H, d, J = 7.3H
z), 7.55 (1H, dd, J = 5.1,8.1Hz), 7.73 (2H, d, J = 8.8Hz),
7.96 (2H, d, J = 8.8Hz), 8.25 (1H, d, J = 8.1Hz), 8.74 (1H, d, J
= 5.1Hz), 9.07 (1H, d, J = 1.5Hz), 9.13 (1H, t-like, J = 5.9H
z), 9.58 (1H, s), 10.36 (1H, s).

Example 128 N- (2-Aminophenyl) -5- [3- (pyridine-
3-yl) propionamide] benzofuran-2-carboxamide (Table-3: Compound No. 1) mp. 267-272 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.51 (2H, t, J = 7.3 Hz) ),
2.97 (2H, t, J = 7.3Hz), 6.61 (1H, dd, J = 8.1,8.8Hz), 6.80
(1H, dd, J = 1.5,8.1Hz), 6.99 (1H, dd, J = 8.1,8.8Hz), 7.20
(1H, dd, J = 1.5,8.1Hz), 7.32 (1H, dd, J = 5.2,8.1Hz), 7.49
(1H, dd, J = 1.5,8.8Hz), 7.61 (1H, d, J = 8.8Hz), 7.67 (1H,
s), 7.70 (1H, m), 8.15 (1H, d, J = 1.5Hz), 8.40 (1H, dd, J =
1.5,5.2Hz), 8.51 (1H, d, J = 1.5Hz), 9.84 (1H, s), 10.1 (1
H, s) .IR (KBr) cm-1: 3333,3272,1666,1583,1561,1458,1314,12
47,1143,807,746,713.

Example 129 Synthesis of N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) oxypropionyl] amino] benzamide (Table-4: Compound No. 2) 1) 0.34 g (1.2 mmol) of the compound obtained in the step (47-2) of Example 47, and 0.34 g (1.0 m) of the compound obtained in the step (100-2) of Example 100
mol) was dissolved in dichloromethane (10 ml), and 0.5 ml (3.6 mmol) of triethylamine was further added. This solution was cooled with ice and 0.21 g of 2-chloro-1,3-dimethylimidazolinium chloride (1.24 m
mol.) in dichloromethane (5 ml) was added, and the mixture was further stirred under ice-cooling for 2 hours. After neutralization with saturated aqueous sodium hydrogen carbonate, the mixture was diluted with water and extracted with chloroform.

The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- 0.68 g of (N-tert-butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin-3-yl) oxypropionyl] amino] benzamide as a mixture of 1,3-dimethyl-2-imidazolinone Obtained. 1H-NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 1.70 (3H, d,
J = 6.6Hz), 4.84 (1H, q, J = 6.6Hz), 6.89 (1H, br.s), 7.12-
7.31 (6H, m), 7.68 (2H, d, J = 8.8Hz), 7.79 (1H, d, J = 8.1H
z), 7.96 (2H, d, J = 8.8Hz), 8.34 (1H, d, J = 2.9,2.9Hz), 8.
43 (1H, d, J = 1.5Hz), 9.25 (1H, br.s).

(129-2) 15% (vol / vol) trifluoroacetic acid / dichloromethane solution (10 ml) was added to a dichloromethane (5 ml) solution of 0.68 g of the compound obtained in the step (129-1) at room temperature. Stir for 4.5 hours. Saturated aqueous sodium hydrogen carbonate was added for neutralization, and then dichloromethane was distilled off. This solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue was added with methanol and diisopropyl ether, and the resulting precipitate was collected by filtration and dried to give N- (2-aminophenyl) -4-. [N- [2- (pyridin-3-yl)
Oxypropionyl] amino] benzamide 0.22 g
(2 steps, 58% yield) as an opalescent solid. mp. 193-196 ° C. 1H-NMR (270MHz, DMSO-d6) δppm: 1.60 (3H, d, J = 6.6Hz),
4.88 (2H, br.s), 5.04 (1H, q, J = 6.6Hz), 6.60 (1H, dd, J = 6.
6,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1
Hz), 7.15 (1H, d, J = 7.3Hz), 7.32-7.39 (2H, m), 7.75 (2H,
d, J = 8.8Hz), 7.96 (2H, d, J = 8.1Hz), 8.20 (1H, dd, J = 1.5,
3.7Hz), 8.35 (1H, d, J = 2.1Hz), 9.59 (1H, br.s), 10.44 (1
H, br.s).

Example 130 N- (2-Aminophenyl) -4-[(pyridine-3-
Yl) methoxyacetylamino] benzamide (Table-
1: Synthesis of compound No. 101) (130-1) Sodium hydride (60% oil suspension)
To a suspension of 4.4 g (110 mmol) in THF (300 ml) was added 10.91 g of 3-pyridinemethanol at room temperature.
After a solution of (100 mmol) in THF (20 ml) was added dropwise, the mixture was stirred at room temperature for 2 hours. The obtained white suspension is ice-cooled, and bromoacetic acid ter is kept while maintaining the internal temperature at 10 to 12 ° C.
19.51 g (100 mmol) of t-butyl THF
(20 ml) solution was added dropwise. The suspension was stirred for 3 hours while heating to room temperature, and then left overnight. After adding water and saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → ethyl acetate).
7.56 g (33.8%) of (pyridine-3-yl) methoxyacetic acid tert-butyl ester were obtained as a brown oil.

1H NMR (270 MHz, CDCl3) δ ppm: 1.49 (9H,
s), 4.03 (2H, s), 4.64 (2H, s), 7.30 (1H, dd, J = 4.9,7.3H
z), 7.76 (1H, d, J = 7.3Hz), 8.56 (1H, d, J = 4.9Hz), 8.60 (1
(130-2) Compound obtained in step (130-1).
Trifluoroacetic acid (12 ml) was added to 5 g (15.7 mmol) under ice-cooling, followed by stirring at room temperature for 6 hours. Thereafter, trifluoroacetic acid was partially removed by distillation, and a mixture of (pyridin-3-yl) methoxyacetic acid and trifluoroacetic acid was 6.5 g.
I got To this was added dichloromethane (70 ml) to dissolve, and then pyridine (25 ml) was added. Furthermore, compound 4.2 obtained in step (100-2) of Example 100
6 g (13 mmol) were added. 2-Chloro- under ice-cooling
1,3-dimethylimidazolinium chloride 2.37
g (14.0 mmol) of dichloromethane (20 ml)
The solution was slowly added dropwise over 30 minutes.

After further stirring for 5 hours under ice cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was stirred at room temperature until foaming ceased. After extraction with chloroform, the obtained organic layer was washed with saturated saline,
The residue obtained by drying and distilling off the solvent was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 10: 1) to give N- [2- (N-tert).
-Butoxycarbonyl) aminophenyl] -4- [N-
(Pyridin-3-yl) methoxyacetylamino] benzamide (4.78 g, yield 62%) was added to DMI (1,3-
1: 1 (mol) with dimethyl-2-imidazolinone)
Obtained as a mixture. 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.15 (2H,
s), 4.70 (2H, s), 6.92 (1H, br.s), 7.15-7.29 (3H, m), 7.
37 (1H, dd, J = 7.3,5.1Hz), 7.67 (2H, d, J = 8.8Hz), 7.71-7.
79 (2H, m), 7.96 (2H, d, J = 8.8Hz), 8.41 (1H, s), 8.62-8.6
6 (2H, m), 9.23 (1H, br.s).

(130-3) A 15% (vol / vol) trifluoroacetic acid / dichloromethane solution (55 ml) was added to a solution of 2.39 g (4.0 mmol) of the compound obtained in the step (130-2) in dichloromethane (28 ml). Was added and stirred at room temperature for 7 hours. Saturated aqueous sodium hydrogen carbonate was added to neutralize the mixture, and water was added, followed by stirring at room temperature. The reaction mixture was mixed with ethyl acetate-methyl ethyl ketone (2: 1), ethyl acetate-THF.
(2: 1), extraction was performed with ethyl acetate in order, and the whole organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate is concentrated, methanol and diisopropyl ether are added to the obtained residue, and the precipitated solid is collected by filtration and dried to give N- (2-aminophenyl) -4- [N- 1.29 g of (pyridin-3-yl) methoxyacetylamino] benzamide (85.6 yield)
%) As a brown solid.

1H NMR (270 MHz, DMSO-d6) δ ppm: 4.19 (2H,
s), 4.68 (2H, s), 4.90 (2H, br.s), 6.60 (1H, ddd, J = 1.5,
7.3,8.1Hz), 6.78 (1H, dd, J = 1.5,8.1Hz), 6.97 (1H, dd, J =
7.3,7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.42 (1H, dd, J = 4.4,
8.1Hz), 7.77 (2H, d, J = 8.8Hz), 7.85 (1H, d, J = 7.3Hz), 7.
96 (2H, d, J = 8.8Hz), 8.54 (1H, dd, J = 1.5,5.1Hz), 8.63 (1
H, s), 9.58 (1H, s), 10.09 (1H, s) .IR (KBr) cm-1: 3403,3341,3250,1694,1630,1610,1506,13
14,1259,1118,764.

Example 131 N- (2-Aminophenyl) -4- [N- [2- (pyridin-3-yl) methoxypropionyl] amino] benzamide (Table-4: Compound No. 1) (131-1) ) Sodium hydride (60% oil suspension)
1.24 g (31 mmol) in dry THF (90 ml)
Pyridine methanol at room temperature.
A solution of 7 g (30 mmol) in dry THF (10 ml) was added dropwise over 5 minutes. After stirring the obtained white suspension for 1 hour at room temperature, 2-bromopropionic acid t was added at room temperature.
A solution of 6.27 g (30 mmol) of ert-butyl ester in dry THF (10 ml) was added dropwise over 5 minutes.
Stirred at room temperature for 11.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give (pyridine-3-yl) methoxy Acetic acid ter
4.01 g (yield 56.3%) of t-butyl ester was obtained as a brown oil. 1H-NMR (270MHz, CDCl3) δppm: 1.42 (3H, d, J = 7.3Hz), 1.
50 (9H, s), 3.96 (1H, q, J = 6.6Hz), 4.47, 4.69 (2H, ABq, J =
11.0Hz), 7.29 (1H, dd, J = 5.1,8.1Hz), 7.75 (1H, d, J = 8.1H
z), 8.50 (1H, d, J = 4.4Hz), 8.60 (1H, s).

(131-2) Trifluoroacetic acid (8 ml) was added to a solution of 1.09 g (4.59 mmol) of the compound obtained in step (131-1) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 9.5 hours. Dichloromethane (25 ml) was added to the residue obtained by evaporating the solvent, and further pyridine (3 ml) was added. Under ice cooling, 0.70 g of 2-chloro-1,3-dimethylimidazolidinium chloride (4.
(1 mmol) in dichloromethane (8 ml) was added dropwise, followed by stirring for 30 minutes. 0.98 g (3.0 mm) of the compound obtained in the step (100-2) of Example 100 was added to this solution.
ol) in dichloromethane (20 ml) -pyridine (10
ml) solution was gradually added dropwise over 15 minutes under ice cooling, and then stirred for 8 hours while the temperature was raised to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was diluted with water and extracted with chloroform.

The organic layer was washed with brine, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate-methanol = 8: 1) to give N- [2- ( N-tert-butoxycarbonylamino) phenyl] -4- [N- [2- (pyridine-3)
1.19 g of -yl) methoxypropionyl] amino] benzamide were obtained as a 2: 3 (molar ratio) mixture with 1,3-dimethyl-2-imidazolinone. 1H-NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 1.54 (3H, d,
J = 6.6Hz), 4.13 (1H, q, J = 6.6Hz), 4.65, 4.71 (2H, ABq, J =
11.7Hz), 7.12-7.18 (2H, m), 7.28-7.37 (3H, m), 7.65 (2H
H, d, J = 8.1Hz), 7.73 (2H, br.d, J = 5.9Hz), 7.96 (2H, d, J =
8.8Hz), 8.59-8.64 (3H, m), 9.39 (1H, br.s).

(131-3) To a solution of 1.19 g (1.8 mmol) of the compound obtained in the step (131-2) in dichloromethane (10 ml) was added a 15% (vol / vol) trifluoroacetic acid / dichloromethane solution (20 ml). In addition,
Stir at room temperature for 4.5 hours. After opening in saturated sodium bicarbonate water,
The aqueous layer obtained by concentrating dichloromethane was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. To the residue obtained, methanol and diisopropyl ether were added, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl) -4. -[N- [2-
585 mg of (pyridin-3-yl) methoxypropionyl] amino] benzamide were obtained as a light brown solid.

Mp. 144-148 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 1.40 (3H, d, J = 6.6 Hz),
4.14 (1H, q, J = 6.6Hz), 4.56 and 4.65 (2H, ABq, J = 11.8H
z), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H
H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J
= 7.3Hz), 7.40 (1H, dd, J = 4.4Hz, 7.3Hz), 7.78-7.85 (3H,
m), 7.97 (2H, d, J = 8.8Hz), 8.52 (1H, dd, J = 1.5,5.1Hz),
8.61 (1H, d, J = 2.1Hz), 9.60 (1H, s), 10.15 (1H, s).

Example 132 N- (2-Aminophenyl) -4- (N-benzylamino) carbonylbenzamide (Table 1: Compound No. 8)
(132-1) Monomethyl terephthalate 13.0 g
Thionyl chloride (10 ml) was added dropwise to a suspension of (72.2 mmol) in toluene (100 ml) at room temperature.
After stirring at 80 ° C. for 3 hours, the solvent and excess thionyl chloride were distilled off. The obtained residue is treated with dioxane (1
00 ml) and then 2-nitroaniline 9.9.
8 g (72.2 mmol) was added, and the mixture was heated under reflux for 4 hours.

After cooling, the solvent was distilled off, and the obtained residue was washed with methanol to give N- (2-nitrophenyl) -4-methoxycarbonylbenzamide 20.3.
g (93.7% yield) as a yellow solid. 1H NMR (270MHz, DMSO-d6) δppm: 3.91 (3H, s), 7.43-7.4
9 (1H, m), 7.76-7.78 (2H, m), 8.03 (1H, d, J = 8.1Hz), 8.08
(2H, d, J = 8.8Hz), 8.14 (2H, d, J = 8.8Hz), 10.94 (1H, s).

(132-2) TH of 4.24 g (14.12 mmol) of the compound obtained in the step (132-1)
F (50 ml)-methanol (50 ml) mixed solution,
After adding 0.4 g of 10% Pd / C under a nitrogen stream, the mixture was stirred for 1.5 hours under a hydrogen stream. After filtration of the catalyst, the solvent was distilled off, and the resulting residue was washed with methanol to give N
3.4 g (yield: 87.5%) of-(2-aminophenyl) -4-methoxycarbonylbenzamide was obtained as a pale yellow solid. 1H NMR (270MHz, DMSO-d6) δppm: 3.90 (3H, s), 4.95 (2H,
s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 7.3Hz),
6.99 (1H, dd, J = 7.3,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 8.08 (2
H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz), 9.85 (1H, s)

(132-3) A 5% aqueous sodium hydroxide solution was added to a solution of 2.71 g (10.0 mmol) of the compound obtained in step (132-2) in dioxane (100 ml) -water (50 ml) under ice-cooling. After adding,
2.62 g of rt-butyl dicarbonate (12.0 mm
ol) in dioxane (40 ml) was added dropwise. After stirring at room temperature for 4 hours, the mixture was left overnight. After adding saturated saline and ethyl acetate and separating into two layers, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried, and the residue obtained by evaporating the solvent was washed with methanol to give N- [2- (N-tert-butoxycarbonyl).
[Aminophenyl] -4-methoxycarbonylbenzamide (3.54 g, yield 95.7%) was obtained as a light brown solid. 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 3.90 (3H,
s), 7.12-7.24 (2H, m), 7.55-7.58 (2H, m), 8.09 (2H, d, J =
8.8Hz), 8.10 (2H, d, J = 8.8Hz), 8.72 (1H, s), 10.00 (1H,
s).

(132-4) A solution of 3.00 g (8.10 mmol) of the compound obtained in the step (132-3) in methanol (50 ml) -0.5N aqueous lithium hydroxide solution (25
ml) The suspension was heated and stirred at 40 ° C for 5 hours. After methanol was distilled off, a 1N aqueous hydrochloric acid solution was added to the obtained residue, followed by extraction with ethyl acetate. The organic layer was washed with a small amount of water and saturated saline, and then dried. The residue obtained by evaporating the solvent was washed with methanol to give 2.24 g (yield 77.6%) of terephthalic acid mono-2- (N-tert-butoxycarbonyl) aminoanilide as a pale brown solid. Obtained. 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 7.12-7.2
1 (2H, m), 7.53-7.58 (2H, m), 8.06 (2H, d, J = 8.8Hz), 8.10
(2H, d, J = 8.8Hz), 8.71 (1H, s), 9.97 (1H, s).

(132-5) 0.14 g of benzylamine was added to a suspension of 0.20 g (0.56 mmol) of the compound obtained in the step (132-4) in 4 ml of dichloromethane.
(1.3 mmol), and 0.21 ml (1.5 mmol) of triethylamine was further added. 0.25 g (1.48 mmol) of 2-chloro-1,3-dimethylimidazolium chloride was added to this solution under ice-cooling, and the mixture was further stirred under ice-cooling for 1 hour and at room temperature for 1 hour. After dilution with chloroform, water was added, and the aqueous layer was extracted with chloroform.

The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (chloroform: methanol = 10: 1).
By washing the obtained solid with ethyl ether,
279 mg (62.6% yield) of N- (2-tert-butoxycarbonylaminophenyl) -4- (N-benzylamino) carbonylbenzamide were obtained as a white solid. 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.52 (2H,
d, J = 5.8Hz), 7.13-7.28 (4H, m), 7.34-7.35 (3H, m), 7.56
(2H, d, J = 8.1Hz), 8.05 (4H, s), 8.71 (1H, br.s), 9.23 (1
H, t), 9.94 (1H, s).

(132-6) To 151 mg (0.339 mmol) of the compound obtained in the step (132-5) was added a 4N hydrochloric acid-dioxane solution (5 ml) at room temperature, and the mixture was stirred for 4 hours. After evaporating the solvent, the residue was separated with ethyl acetate / saturated aqueous sodium hydrogen carbonate, and the precipitated precipitate was removed. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with saturated saline, dried,
Ethyl ether was added to the residue obtained by evaporating the solvent, and the resulting precipitate was collected by filtration and dried to give N- (2-aminophenyl) -4- (N-benzylamino) carbonylbenzamide (78 mg, yield 67). %) As a white solid. mp.239-241 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.51 (2H, s), 4.93 (2H,
br.d), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1H
z), 6.95 (1H, dd, J = 7.3,8.3Hz), 7.18 (1H, d), 7.23-7.35
(5H, m), 8.01 (2H, d, J = 8.8Hz), 8.07 (2H, d, J = 8.8Hz), 9.
22 (1H, br.t), 9.81 (1H, br.s).

In the same manner as in Example 132, the compound of Example 133 was synthesized. Below, the melting point of the compound (m
p.), 1H NMR and IR measurements.

Example 133 N- (2-Aminophenyl) -4- [N- (2-phenylethyl) amino] carbonylbenzamide (Table 1:
Compound No. 9) mp. 237-240 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 2.87 (2H, t, J = 7.3 Hz),
3.51 (2H, dt, J = 5.9,7.3Hz), 4.94 (2H, br.s), 6.60 (1H, d
d, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.98 (1H, dd, J =
7.3,7.3Hz), 7.15-7.34 (6H, m), 7.93 (2H, d, J = 8.1Hz),
8.04 (2H, d, J = 8.1Hz), 8.73 (1H, t, J = 5.1Hz), 9.76 (1H, br.
s) .IR (KBr) cm-1: 3396,3320,1625,1602,1539,1458,131
3,699.

Example 134 N- (2-Aminophenyl) -4- [N- (4-nitrophenoxyacetyl) amino] benzamide (Table 1:
Synthesis of Compound No. 54) (134-1) DMF of 3 g (9.2 mmol) of the compound obtained in step (100-2) of Example 100 and 2.16 g (11.0 mmol) of 4-nitrophenoxyacetic acid
1. Dicyclohexylcarbodiimide was added to the solution (7 ml).
82 g (13.8 mmol) of a DMF solution (5 ml),
A catalytic amount of N, N-dimethylaminopyridine was added and stirred for one day. After completion of the reaction, ethyl acetate was added, insolubles were filtered through celite, and the solvent was distilled off.

The obtained residue was recrystallized from chloroform to obtain 2.34 g of N- [2- (tert-butoxycarbonylamino) phenyl] -4-[(4-nitrophenoxyacetyl) amino] benzamide (yield: 50). %). 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.97 (2H,
s), 7.12-7.26 (3H, m), 7.23 (2H, d, J = 8.8Hz), 7.53 (1H, d
t, J = 2.2,7.3Hz), 7.79 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.
8Hz), 8.25 (2H, d, J = 8.8Hz), 8.71 (1H, s), 9.79 (1H, s),
10.52 (1H, s).

(134-2) To a solution of 0.7 g (1.38 mmol) of the compound obtained in the step (134-1) in acetonitrile (10 ml) was added 1.26 ml (8.85 mmol) of iodotrimethylsilane at room temperature. Stir for 2 hours. After completion of the reaction, the solvent was concentrated, ethyl acetate was added, and the mixture was stirred for 20 minutes, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in methyl ethyl ketone, washed successively with a saturated aqueous solution of sodium thiosulfate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was washed with ethyl acetate, and N- (2-aminophenyl) -4- was used.
[N- (4-nitrophenoxyacetyl) amino] benzamide (0.22 g, yield 39%) was obtained as white crystals.

Mp. 212-215 ° C. (dec.). 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.97 (2H, s), 6.88 (1H,
t, J = 7.3Hz), 6.99 (1H, d, J = 7.3Hz), 7.11 (1H, t, J = 7.3H
z), 7.23 (2H, d, J = 8.8Hz), 7.24 (1H, m), 7.77 (2H, d, J = 8.
8Hz), 8.00 (2H, d, J = 8.8Hz), 8.25 (2H, d, J = 8.8Hz), 9.89
(1H, s), 10.52 (1H, s) .IR (KBr) cm-1: 3382,3109,1650,1591,1508,1341.

Example 135 Synthesis of N- (2-aminophenyl) -4-[(4-aminophenoxyacetyl) amino] benzamide (Table 1: Compound No. 55) In Step (134-1) of Example 134 The obtained compound (1.41 g, 2.78 mmol) in methanol (15 m
l) 10% Pd-C was added to -THF (25 ml) solution, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After completion of the reaction, the catalyst was filtered, the solvent was concentrated, and the mixture was sludged with diisopropyl ether to give N- [2- (tert-butoxycarbonylamino) phenyl] -4-[(4-aminophenoxyacetyl) amino] benzamide 1 .1 g were obtained.

This was dissolved in 15 ml of acetonitrile,
0.74 ml of iodotrimethylsilane (5.20 mmol
l) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was concentrated and washed with methyl ethyl ketone to obtain 0.86 g (83% yield) of N- (2-aminophenyl) -4-[(4-aminophenoxyacetyl) amino] benzamide. mp. (amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 4.82 (2H, s), 7.13 (2H,
d, J = 8.8Hz), 7.30-7.48 (6H, m), 7.82 (2H, d, J = 8.8Hz),
8.03 (2H, d, J = 8.8Hz), 10.34 (1H, s), 10.46 (1H, s) .IR (KB
r) cm-1: 2873,2590,1680,1602,1505,1243.

Example 136 Synthesis of N- (2-aminophenyl) -4- (5-phenoxymethyl-1,3-oxazolin-2-one-3-yl) benzamide (Table 2: Compound No. 1) 136
1) 0.7 g (2.14 mmol) of 4- (N-benzyloxycarbonylamino) benzoic acid t-butyl ester
1.33 ml (2.25 mmol) of n-butyllithium was added dropwise to a THF solution (10 ml) of 1) at -78 ° C over 5 minutes. After stirring at the same temperature for another 1.5 hours,
0.31 ml of phenylglycidol (2.29 mmol
l) was added and the mixture was further stirred at the same temperature for 1 hour. After allowing to stand at room temperature for 1 day, a saturated aqueous solution of ammonium chloride was added, extracted twice with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from ether to give N- [4- (tert-butoxycarbonyl) phenyl] -5-phenoxymethyl-1,3-oxazolidin-2-one (0.31 g, yield 39%). Obtained. 1H NMR (270MHz, DMSO-d6) δppm: 1.53 (9H, s), 3.97 (1H,
(dd, J = 6.0,8.8Hz), 4.23-4.34 (3H, m), 5.11 (1H, m), 6.94
-7.00 (3H, m), 7.31 (2H, m), 7.71 (2H, d, J = 8.8Hz), 7.93 (2H, m)
(H, d, J = 8.8Hz).

(136-2) Trimethylsilyl iodide was added to a solution of 0.26 g (0.704 mmol) of the compound of step (136-1) in acetonitrile (4 ml).
15 ml (1.05 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated and the resulting concentrate was sludged with ethyl acetate-methyl ethyl ketone to give N-
(4-carboxyphenyl) -5-phenoxymethyl-
0.2 g of 1,3-oxazolidin-2-one (yield 91
%). 1H NMR (270MHz, DMSO-d6) δppm: 3.98 (1H, dd, J = 6.6,9.6
Hz), 4.23-4.34 (3H, m), 5.10 (1H, m), 6.94-6.99 (3H, m),
7.30 (2H, t, J = 8.1Hz), 7.72 (2H, d, J = 8.8Hz), 7.98 (2H, d, J
J = 8.8Hz), 12.85 (1H, s).

(136-3) A catalytic amount of DMF was added to a methylene chloride solution (7 ml) containing 0.15 g (0.479 mmol) of the compound of step (136-2), and then oxalyl chloride was added in 0.12 ml (1. 40 mmol) and stirred at room temperature for 2 hours. Next, the solvent was concentrated, azeotroped twice with toluene, dissolved in methylene chloride (4 ml), and cooled under ice-cooling. 0.105 g of the compound of Step (1-2) of Example 1
(0.504 mmol), pyridine 0.12 g (1.5
(2 mmol) in methylene chloride (1 ml) was added, followed by heating to room temperature and stirring for 1 hour. After completion of the reaction, water was added, and the mixture was extracted twice with chloroform, and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off.
The obtained residue is sludged with isopropyl ether, and N- [2- (N-tert-butoxycarbonylamino) phenyl] -4- (5-phenoxymethyl-1,
0.25 g (quantitative) of 3-oxazolin-2-one-3-yl) benzamide was obtained. 1H NMR (270MHz, DMSO-d6) δppm: 1.52 (9H, s), 4.11 (1H,
(dd, J = 5.9,6.6Hz), 4.21-4.27 (3H, m), 5.01 (1H, m), 6.84
(1H, br.s), 6.91 (2H, d, J = 8.8Hz), 7.01 (1H, t, J = 7.4Hz),
7.12-7.34 (5H, m), 7.68 (2H, d, J = 8.8Hz).

(136-4) To a solution of 0.22 g (0.437 mmol) of the compound of step (136-3) in acetonitrile (4 ml) was added 0.1 ml (0.703 mmol) of trimethylsilyl iodide at room temperature, and the mixture was stirred for 2 hours. . After adding a saturated aqueous solution of sodium thiosulfate, the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from methanol to give N- (2-aminophenyl) -4- (5-phenoxymethyl-1,3-oxazolin-2-one-3.
-Yl) benzamide (0.13 g, yield 74%) was obtained as white crystals. mp. 165-170 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.01 (1H, dd, J = 6.6,9.6)
Hz), 4.28-4.34 (3H, m), 5.12 (1H, m), 5.23 (2H, br.s), 6.
64 (1H, t, J = 7.4Hz), 6.81 (1H, d, J = 8.1Hz), 6.95-7.00 (3
H, m), 7.18 (1H, d, J = 6.6Hz), 7.31 (2H, t, J = 8.1Hz), 7.72
(2H, d, J = 8.8Hz), 8.05 (2H, d, J = 8.8Hz), 9.69 (1H, s) .IR (KBr) cm-1: 3393,1740,1610,1508,1253.

The compounds of Examples 137 to 143 were synthesized in the same manner as in Example 136. The melting point (mp.), 1H NMR, and IR measurement values of the compound are shown below.

Example 137 N- (2-Aminophenyl) -4- [5- (4-nitrophenoxy) methyl-1,3-oxazolin-2-one-3-yl] benzamide (Table 2: Compound No. 2) mp. 162-164 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 3.97 (1H, dd, J = 6.6,9.5)
Hz), 4.10 (1H, dd, J = 5.1,11.0Hz), 4.17 (1H, dd, J = 3.7,1
1.0Hz), 4.27 (1H, t, J = 8.8Hz), 6.53-6.80 (6H, m), 6.97 (1
H, t, J = 8.1Hz), 7.16 (1H, d, J = 6.6Hz), 7.72 (2H, d, J = 8.8H
z), 8.04 (2H, d, J = 8.8Hz), 9.65 (1H, s) .IR (KBr) cm-1: 3356,2365,1741,1609,1510,1247.

Example 138 N- (2-Aminophenyl) -4- (5-benzyloxymethyl-1,3-oxazolin-2-one-3-yl) benzamide hydrochloride (Table-2: Compound No. 3 Hydrochloride) mp. 181-183 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.69 (1H, dd, J = 5.2,11.
0Hz), 3.76 (1H, dd, J = 3.7,11.0Hz), 3.91 (1H, dd, J = 5.9,
8.8Hz), 4.59 (2H, s), 4.93 (1H, m), 7.26-7.41 (8H, m),
7.51 (1H, m), 7.74 (2H, d, J = 8.8Hz), 8.15 (2H, d, J = 8.8H
z), 10.42 (1H, s).

Example 139 N- (2-aminophenyl) -4- [5- (pyridine-
3-yl) oxymethyl-1,3-oxazoline-2-
On-3-yl] benzamide (Table-2: Compound No. 4) mp. 199-201 ° C. 1H NMR (270 MHz, DMSO-d6) δppm: 4.01 (1H, dd, J = 6.6,8.8)
Hz), 4.28-4.46 (3H, m), 4.96 (2H, br.s), 5.14 (1H, m), 6.
61 (1H, t, J = 7.4Hz), 6.79 (1H, d, J = 7.4Hz), 6.98 (1H, t, J =
7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.36 (1H, dd, J = 4.4,8.1H
z), 7.44 (1H, dd, J = 1.5,8.1Hz) .IR (KBr) cm-1: 2815,2631,2365,1752,1610,1520,1225.

Example 140 N- (2-aminophenyl) -4- [5- (pyridine-
3-yl) methyloxymethyl-1,3-oxazolin-2-one-3-yl] benzamide (Table 2: Compound No. 5) mp. 160-164 ° C. (dec.). 1H NMR (270 MHz, DMSO— d6) δppm: 3.73 (1H, dd, J = 5.2,11.
7Hz), 3.79 (1H, dd, J = 2.9,11.7Hz), 3.91 (1H, dd, J = 5.9,
8.8Hz), 4.21 (1H, t, J = 8.8Hz), 4.62 (2H, s), 4.91 (3H, b
rs), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.4Hz), 6.98
(1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.38 (1H, dd, J =
4.4,7.4Hz), 7.69 (2H, d, J = 8.8Hz), 7.71 (1H, m), 8.03 (2
H, d, J = 8.8Hz), 8.51 (1H, dd, J = 1.5,4.4Hz), 8.54 (1H, d, J
= 1.5Hz), 9.65 (1H, s) .IR (KBr) cm-1: 3368,1742,1648,1608,1492,1226.

Example 141 N- (2-Aminophenyl) -4- [5- (3-nitrophenoxy) methyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 6) mp. 230 ° C (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.04 (1H, t, J = 8.8Hz),
4.32 (1H, t, J = 8.8Hz), 4.41-4.53 (2H, m), 4.91 (2H, s),
5.15 (1H, m), 6.61 (1H, t, J = 7.4Hz), 6.79 (1H, d, J = 7.4H
z), 6.98 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.46 (1
H, dd, J = 1.5,8.1Hz), 7.61 (1H, t, J = 8.1Hz), 7.71-7.79 (3
H, m), 7.87 (1H, d, J = 8.1Hz), 8.06 (2H, d, J = 8.8Hz), 9.66
(1H, s) .IR (KBr) cm-1: 3363,3095,2365,1741,1608,1529.

Example 142 N- (2-aminophenyl) -4- [5- (pyridine-
2-yl) methyloxymethyl-1,3-oxazolin-2-one-3-yl] benzamide (Table 2: Compound No. 7) mp. 172-174 ° C. 1 H NMR (270 MHz, DMSO-d6) δ ppm: 3.79 (1H, dd, J = 5.2,11.
0Hz), 3.85 (1H, dd, J = 2.9,11.0Hz), 3.95 (1H, dd, J = 6.6,
9.6Hz), 4.23 (1H, t, J = 9.6Hz), 4.67 (2H, s), 4.90 (2H,
s), 4.95 (1H, m), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.
4Hz), 6.97 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.29
(1H, dd, J = 5.2,6.6Hz), 7.40 (1H, d, J = 6.6Hz), 7.70 (2H, d,
J = 8.8Hz), 7.78 (1H, dt, J = 2.2,7.4Hz), 8.03 (2H, d, J = 8.8
Hz), 8.51 (1H.d, J = 4.4Hz), 9.64 (1H, s) .IR (KBr) cm-1: 3369,1743,1651,1608,1492,1283.

Example 143 N- (2-aminophenyl) -4- [5- (pyridine-
2-yl) oxymethyl-1,3-oxazoline-2-
On-3-yl] benzamide (Table-2: Compound No. 8) mp. (Amorphous). 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.96 (1H, dd, J = 5.9,9.6)
Hz), 4.21-4.40 (3H, m), 4.90 (2H, s), 5.03 (1H, m), 6.28
(1H, t, J = 6.6Hz), 6.43 (1H, d, J = 9.6Hz), 6.60 (1H, t, J = 6.
6Hz), 6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.4Hz), 7.15
(1H, d, J = 6.6Hz), 7.46 (1H, dt, J = 7.4,1.5Hz), 7.67 (2H, d,
J = 8.8Hz), 7.69 (1H, m), 8.03 (2H, d, = 8.8Hz), 9.64 (1H,
s).

Example 144 N- (2-aminophenyl) -4- [N- [3-[(pyridin-3-yl) methylamino] cyclobutene-1,
2-Dion-4-yl] aminomethyl] benzamide (Table-2: Compound No. 9) (144-1) 0.073 g of 3,4-di-n-butoxy-3-cyclobutene-1,2-dione (0 .323m
mol) in a THF solution (2 ml).
After adding 0.1 g (0.293 mmol) of the compound of -4) and stirring for 4 hours, 0.033 ml (0.327 mmol) of 3-aminomethylpyridine was further added and reacted for 1 day. After completion of the reaction, water was added and methyl ethyl ketone was added.
Extracted times. After drying the organic layer over anhydrous magnesium sulfate,
The solvent was distilled off.

The obtained residue was sludged with methanol to give N- [2- (N-tert-butoxycarbonylamino) phenyl] -4- [N- [3-[(pyridine-
3-yl) methylamino] cyclobuten-1,2-dione-4-yl] aminomethyl] benzamide 0.12 g
(78% yield). 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.75-4.8
1 (4H, m), 7.15 (1H, dt, J = 2.2,7.4Hz), 7.20 (1H, dt, J = 2.
2,7.4Hz), 7.40 (1H, dd, J = 2.2,7.4Hz), 7.47 (2H, dJ = 8.1
Hz), 7.54 (2H, dd, J = 2.2,7.4Hz), 7.73 (1H, m), 7.94 (2H,
d, J = 8.1Hz), 8.50 (1H, m), 8.55 (1H, d, J = 1.5Hz), 8.67 (1
H, s), 9.82 (1H, s).

(144-2) 0.1 g (0.19 mmol) of the compound of the step (144-1) in dioxane (4 m
1) 4N hydrochloric acid-dioxane (4 ml) was added to a 1-methanol (1 ml) solution and reacted for 2 hours. After completion of the reaction, the solvent was concentrated and neutralized with saturated aqueous sodium hydrogen carbonate, methyl ethyl ketone was added, and the obtained crystals were collected by filtration and N- (2-aminophenyl) -4- [N- [3-[(pyridine- 3-yl) methylamino] cyclobuten-1,2-dione-4-yl]
Aminomethyl] benzamide 0.04 g (49% yield)
I got mp.230 ° C.1H NMR (270MHz, DMSO-d6) δppm: 4.76 (2H, s), 4.79 (2H,
s), 4.90 (2H, s), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.
4Hz), 6.97 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.39
(1H, m), 7.43 (2H, d, J = 8.1Hz), 7.73 (1H, d, J = 8.1Hz), 7.
97 (2H, d, J = 8.1Hz), 7.99 (1H, br.s), 8.51 (1H, d, J = 8.1H
z), 8.55 (1H, s), 9.64 (1H, s).

Example 145 N- (2-aminophenyl) -4- [3- (pyridine-
3-yl) methylimidazolin-2-one-1-yl]
Methylbenzamide (Table-2: Compound No. 10) (145-1) 4.92 g of ethylene urea (57 mmo)
l), methyl 4-bromomethylbenzoate 5.73
g (25 mmol), tetra-n-butylammonium iodide 1.85 g (5.0 mmol) of DMF (3
7.88 g (57 mmo) of potassium carbonate in the solution.
l) was added, and the mixture was heated and stirred at 80 ° C for 5 hours.

After allowing to cool, the solid was collected by filtration and then washed with ethyl acetate. After the filtrate was concentrated, the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1), diisopropyl ether was added to the obtained pale yellow oil, and the precipitated solid was collected by filtration and dried. To give 3.36 g of N- (4-methoxycarbonylphenylmethyl) imidazolin-2-one.
(57.4% yield) as a light brown solid. 1H-NMR (270MHz, CDCl3) δppm: 3.28-3.35 (2H, m), 3.41-
3.47 (2H, m), 3.92 (3H, s), 4.42 (2H, s), 4.61 (1H, br.s),
7.35 (2H, d, J = 8.1Hz), 8.01 (2H, d, J = 8.1Hz).

(145-2) To 2.05 g (12.5 mmol) of 3-chloromethylpyridine hydrochloride was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. Toluene was added to the residue, which was azeotroped. DMF (5 ml) was added to the obtained residue, and tetranormal butyl ammonium iodide was added. .37 g (1.0 mmol) was added to prepare a benzyl halide DMF solution. Sodium hydride (60%
Oily suspension) 0.30 g (7.5 mmol) of DMF (5
ml) in suspension at room temperature, 1.17 g (5.0 mmol) of the compound obtained in step (145-1) in DMF (10 ml)
After the solution was slowly added dropwise, the mixture was stirred at room temperature for 30 minutes. After adding the previously prepared benzyl halide solution to this solution,
The mixture was heated and stirred at 80 ° C. for 7 hours.

[0369] The plate was left overnight at room temperature. After concentrating DMF, ethyl acetate and water were added for separation. Further, the aqueous layer was extracted with ethyl acetate-methyl ethyl ketone (2: 1).
The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- (4-methoxycarbonylphenylmethyl)- N '-(pyridine-
1.17 g of 3-yl) methylimidazolin-2-one
(72.3% yield) as a brown oil. 1H NMR (270MHz, CDCl3) δppm: 3.20 (4H, s), 3.92 (3H,
s), 4.44 (2H, s), 4.46 (2H, s), 7.27-7.36 (3H, m), 7.64-
7.69 (1H, m), 8.01 (2H, d, J = 8.1Hz), 8.53-8.56 (2H, m).

(145-3) To a solution of 0.55 g (1.7 mmol) of the compound obtained in the step (145-2) in methanol (8 ml) -water (8 ml) was added 110 mg of lithium hydroxide monohydrate (2 ml) at room temperature. .62 mmol) and 50 ° C
After heating and stirring for 1.5 hours, lithium hydroxide 1
A hydrate (0.05 g, 1.2 mmol) was added, and the mixture was stirred at 50 ° C for 1.5 hours. After acidification (pH 3 to 4) using a 10% aqueous hydrochloric acid solution, saturated saline was added, and ethyl acetate-methyl ethyl ketone (1: 2) was added twice with ethyl acetate.
Extracted once in 1). The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was dried to give 4-
[3- (pyridin-3-yl) methylimidazoline-2
-On-1-yl] methylbenzoic acid 0.32 g (yield 6
1%) as a brown oil. 1H NMR (270MHz, DMSO-d6) δppm: 3.17 (2H, s), 3.20 (2H,
s), 4.36 (2H, s), 4.38 (2H, s), 7.35-7.42 (3H, m), 7.68
(1H, dd, J = 6.6Hz), 7.92 (2H, d, J = 8.1Hz), 8.51 (2H, m).

(145-4) Oxalyl chloride was added to a solution of 0.31 g (1.0 mmol) of the compound obtained in the step (145-3) in dichloromethane (12 ml) at room temperature.
3 ml (3.5 mmol) was added dropwise and then at room temperature for 30 minutes,
Stirred at 40 ° C. for 1.5 hours. After the solvent was distilled off, the residue was azeotropically distilled with toluene and suspended in 10 ml of dichloromethane. After the reaction suspension was cooled with ice, a solution of 0.21 g (1.0 mmol) of the compound of Step (1-2) of Example 1 in dichloromethane (2 ml) -pyridine (2 ml) was added dropwise. After stirring while heating to room temperature, the mixture was left at room temperature overnight.
After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform.

The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate-methanol = 20: 1) to give N- (2-tert- 0.10 g (20% yield) of butoxycarbonylaminophenyl) -4- [3- (pyridin-3-ylmethyl) imidazolin-2-one-1-yl] methylbenzamide was obtained as a brown oil. 1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 3.20 (4H,
s), 4.45 (2H, s), 4.48 (2H, s), 6.75 (1H, br.s), 7.15-7.4
0 (5H, m), 7.65-7.70 (2H, m), 7.83 (1H, d, J = 7.3Hz), 7.94
(2H, d, J = 8.1Hz), 8.50-8.60 (3H, br.m).

(145-5) After dissolving 100 mg (0.20 mmol) of the compound obtained in the step (145-4) in dioxane (2 ml), 4N hydrochloric acid-dioxane (2
ml), and methanol (0.5 ml) was added to dissolve. After stirring for 2 hours, the mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried, and the solvent was distilled off. The residue obtained was dried at room temperature under reduced pressure to give N- (2-aminophenyl) -4- [3-
(Pyridin-3-yl) methylimidazolin-2-one-1-yl] methylbenzamide 47 mg (yield 58
%) As a brown oil. mp. (amorphous) .1H NMR (270MHz, DMSO-d6) δppm: 3.20 (4H, s), 4.37 (2H,
s), 4.39 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.
3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz),
7.16 (1H, d, J = 7.3Hz), 7.35-7.41 (3H, m), 7.68 (1H, d, J =
8.1Hz), 7.90-8.00 (2H, m), 8.50 (2H, br.s), 9.63 (1H, b
rs).

Example 146 N- (2-aminophenyl) -4- [N- (pyridine-
Synthesis of 3-yl) methoxycarbonylaminomethyl] benzamide 0.5 fumarate (Table 1: fumarate of compound No. 82) 310 mg of the compound obtained in Example 48 was treated with methanol 1
0 ml and heated to dissolve. 96mg fumaric acid
Was dissolved in methanol, and then cooled. The precipitated crystals were collected by filtration and recrystallized from 5 ml of methanol to obtain 200 mg of the desired product (yield: 56%).

Mp. 166-167 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J = 6.6 Hz),
5.10 (2H, s), 6.60 (1H, t, J = 8.0Hz), 6.63 (1H, s), 6.78 (1H
(H, d, J = 8.0Hz), 6.90-7.50 (5H, m), 7.70-8.00 (4H, m), 8.
53 (1H, d, J = 3.6Hz), 8.60 (1H, s), 9.63 (1H, s) .IR (KBr) cm-1: 3332,1715,1665,1505,1283,1136,1044,98
3,760,712.

The compounds of Examples 147 to 149 were synthesized in the same manner as in Example 146. The melting point (mp.), 1H NMR, and IR measurement values of the compound are shown below.

Example 147 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) methoxycarbonylaminomethyl] benzamide maleate (Table 1: maleate of Compound No. 82) mp. 123-124 ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.28 (2H, d, J = 6.6Hz),
5.11 (2H, s), 6.24 (2H, s), 6.66 (1H, t, J = 8.0Hz), 6.83 (1
H, d, J = 8.0Hz), 6.90-8.00 (9H, m), 8.56 (1H, d, J = 3.6Hz),
8.62 (1H, s), 9.69 (1H, s) .IR (KBr) cm-1: 3298,1719,1546,1365,1313,1250,1194,11
49,1044,993,862,751.

Example 148 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) methoxycarbonylaminomethyl] benzamide hydrochloride (Table 1: hydrochloride of compound No. 82) mp. 140 (dec.) ° C. 1H NMR (270 MHz, DMSO-d6) δ ppm: 4.31 (2H, d, J = 5.8Hz),
5.24 (2H, s), 7.10-7.60 (6H, m), 7.90-8.50 (5H, m), 8.70
-8.90 (2H, m), 10.46 (1H, s) .IR (KBr) cm-1: 2553,1715,1628,1556,1486,1254,1049,77
8,687.

Example 149 N- (2-aminophenyl) -4- [N- (pyridine-
3-yl) oxyacetylaminomethyl] benzamide 0.7 fumaric acid (Table 1: fumarate salt of compound No. 61) It was synthesized from the compound of Example 46 in the same manner as in Example 146. mp. 154-155 ° C. 1H NMR (270MHz, DMSO-d6) δppm: 4.42 (2H, d, J = 5.9Hz),
4.69 (2H, s), 6.60 (1H, t, J = 8.0Hz), 6.63 (0.7H, s), 6.78
(1H, d, J = 8.0Hz), 6.90-7.50 (6H, m), 7.93 (2H, d, J = 8.0H
z), 8.20-8.40 (2H, m), 8.82 (1H, br.s), 9.63 (1H, s) .IR (KBr) cm-1: 3324,1709,1631,1521,1457,1428,1260, Ten
64,806,698.

Reference Example 1 N- (3-aminophenyl) -4- [N- (pyridine-
3-yl) methoxycarbonylaminomethyl] benzamide It was synthesized in the same manner as in Example 48. mp.156 ° C.1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 6.6Hz),
5.06 (2H, s), 5.10 (2H, s), 6.20-6.40 (1H, m), 6.80-7.10
(3H, m), 7.30-7.50 (3H, m), 7.70-8.00 (4H, m), 8.53 (1H,
d, J = 3.6Hz), 8.59 (1H, s), 9.88 (1H, s) .IR (KBr) cm-1: 3327,3218,1708,1639,1536,1279,1147,10
50,859,788.

Reference Example 2 N- (4-aminophenyl) -4- [N- (pyridine-
3-yl) methoxycarbonylaminomethyl] benzamide It was synthesized in the same manner as in Example 48. mp.204-205 ° C.1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 6.6Hz),
4.91 (2H, s), 5.10 (2H, s), 6.52 (2H, d, J = 8.8Hz), 7.30-
7.50 (5H, m), 7.70-8.00 (4H, m), 8.50-8.60 (2H, m), 9.80
(1H, s) .IR (KBr) cm-1: 3336,3224,1706,1638,1530,1279,1145,10
50,1005,827.

Pharmacological Test Example 1 Test for Inducing Differentiation on A2780 Cells An increase in alkaline phosphatase (ALP) activity is known as an index of human colon cancer cell differentiation. For example, it is known that sodium butyrate increases ALP activity. [Young et al .; Cancer Res. , 4
5 , 2976 (1985); Morita et al; Canc.
er Res. , 42 , 4540 (1982)]. Therefore, the differentiation inducing action was evaluated using ALP activity as an index.

(Experimental Method) 0.1 ml of A2780 cells was placed in a 96-well plate at 15,000 cells / well.
Then, the next day, 0.1 ml of the test drug solution serially diluted with the medium was added. After culturing for 3 days, the cells on the plate were washed with TBS buffer (20 mM Tris, 137 mM
NaCl, pH 7.6) twice. Then,
P-nitrophenyl phosphate at a concentration of 6 mg / ml (9.6% diethanolamine, 0.5 mM Mg
0.05 ml of a Cl ₂ (pH 9.6) solution was added thereto, and the mixture was incubated at room temperature for 30 minutes. After terminating the reaction with 0.05 ml of 3N aqueous sodium hydroxide solution,
The absorbance at 5 nm was measured to determine the minimum concentration (ALPmin) of the drug that caused an increase in ALP activity. (Experimental results) The experimental results are shown in Table 5 [Table 31].

[0384]

Table 5 Table 5: Differentiation inducing action on A2780 cells Test compound ALPmin (μM) Compound of Example 1 1 Compound of Example 2 3 Compound of Example 3 3 Compound of Example 4 1 Compound of Example 5 1 Compound of Example 6 1 Compound of Example 7 1 Compound of Example 8 Compound 1 of Example 9

Compound of Example 10 3 Compound of Example 11 1 Compound of Example 13 1 Compound of Example 15 3 Compound of Example 16 3 Compound of Example 17 3 Compound of Example 18 3 Compound of Example 23 1 Compound of Example 24 1 Compound of Example 25 3

Compound of Example 26 1 Compound of Example 27 10 Compound of Example 28 10 Compound of Example 29 Compound of Example 30 0.1 Compound of Example 31 10 Compound of Example 32 3 Compound of Example 33 0.3 Compound of Example 34 0.1 Compound of Example 35

Compound of Example 36 10 Compound of Example 37 1 Compound of Example 38 3 Compound of Example 39 0.1 Compound of Example 40 10 Compound of Example 41 0.3 Compound of Example 42 10 Compound of Example 43 3 Compound of Example 44 0.01 Compound of Example 45 0.003

Compound of Example 46 0.1 Compound of Example 48 0.1 Compound of Example 49 1 Compound of Example 50 1 Compound of Example 51 1 Compound of Example 52 1 Compound of Example 53 3 Compound of Example 54 1 Compound of Example 55 1 Compound 3 of Example 56

Compound of Example 57 3 Compound of Example 58 3 Compound of Example 59 3 Compound of Example 60 3 Compound of Example 63 Compound 3 of Example 64 Compound 3 of Example 65 3 Compound of Example 66 3 Compound 3 of Example 67 3 Compound 3 of Example 68

Compound of Example 70 0.1 Compound of Example 71 10 Compound of Example 72 10 Compound of Example 73 3 Compound of Example 74 10 Compound of Example 76 1 Compound of Example 77 3 Compound of Example 79 0.1 Compound of Example 80 0.1 Compound of Example 81 10

Compound of Example 82 1 Compound of Example 85 3 Compound of Example 86 0.3 Compound of Example 87 0.1 Compound of Example 88 0.1 Compound of Example 89 0.3 Compound of Example 90 3 Compound of Example 91 0.1 Compound 3 of Example 92 Compound 3 of Example 93

Compound of Example 94 3 Compound of Example 95 3 Compound of Example 96 10 Compound of Example 97 0.1 Compound of Example 98 0.1 Compound of Example 99 3 Compound of Example 100 1 Compound of Example 101 3 Compound of Example 102 3 Compound 1 of Example 103

Compound of Example 104 1 Compound of Example 105 1 Compound of Example 106 1 Compound of Example 107 1 Compound of Example 108 3 Compound of Example 109 1 Compound of Example 110 3 Compound of Example 111 3 Compound of Example 112 0.1 Compound of Example 113 0.3

Compound of Example 114 3 Compound of Example 115 0.01 Compound of Example 116 0.01 Compound of Example 119 3 Compound of Example 120 0.3 Compound of Example 121 3 Compound of Example 122 0.03 Compound of Example 123 3 Compound of Example 124 3 Compound of Example 125 0.1

Compound of Example 126 3 Compound of Example 127 0.3 Compound of Example 128 0.1 Compound of Example 129 1 Compound of Example 130 0.03 Compound of Example 131 0.3 Compound of Example 132 10 Compound of Example 133 3 Compound of Example 134 3 Compound of Example 135

Compound of Example 136 1 Compound of Example 137 1 Compound of Example 138 1 Compound of Example 139 0.3 Compound of Example 140 0.3 Compound of Example 141 1 Compound of Example 142 0.1 Compound of Example 143 3 Compound of Example 145 3 Compound of Comparative Example 1> 100 Compound of Comparative Example 2> 100

Pharmacological Test Example 2 Antitumor Test (Experimental Method) Mouse Myeloid Leukemia Cell WEHI-3
(1-3 × 10 ⁶ cells) were implanted intraperitoneally into Balb / c mice, and drug administration was started the next day. This was the first day, and thereafter, the drug was orally administered once a day on the 1st to 4th days and the 7th to 11th days. The number of days after transplantation was observed, and Con
The ratio (T / C,%) of the days of survival of the drug-administered group to the days of survival of the trol group was calculated, and this was evaluated as a life-prolonging effect. (Experimental results) The experimental results are shown in Table-6 [Table 32].

[0398]

Table 6: Antitumor activity on WEHI-3 cells Test compound Dose (μmol / kg) T / C (%) Compound 16 138 of Example 45 Compound 32 141 of Example 46 Compound 32 141 of Example 48 Compound 130 190 Compound 130 189 of Example 130

Pharmacological Test Example 3 Antitumor Action Test (Experimental Method) Tumor cells (HT-29, KB-3-1) subcutaneously subcutaneously transplanted into nude mice and the volume was reduced to about 20 to 100 mm 3. When engraftment was confirmed, administration of the drug was started. This was the first day, and 1-5 days, 8-12 days, 15-19 days and 22
Drugs were administered orally on days ２６26. The tumor volume was determined by (tumor volume) = 1/2 × (major axis) × (minor axis) 2.

(Experimental Results) The experimental results of the compound of Example 48 (dose of 66 μmol / kg) on HT-29 are shown in FIG.

The experimental results of the compound of Example 48 (dose: 66 μmol / kg) on KB-3-1 are shown in FIG.
It was shown to.

Calculation Examples (Construction of Superposition Model Using Highly Active Compounds) Examples 45 and 46 which are compounds showing high differentiation inducing activity
Using the compound of Example 48, a three-dimensional structure was superimposed in order to extract information on the spatial arrangement of atomic groups required for expressing the activity.

For this purpose, commercially available calculation packages [CATALYST (MSI), Cerius2 / QSAR + (MSI
SYBYL / DISCO (Tripos), etc.] can be used to perform the same analysis. However, for the creation and analysis of the superimposed structure, SYBYL / DISCO (Tripo
s company).

For the compound of Example 48, a three-dimensional structure was generated using the sketch function of SYBYL, and Gasteiger-Hu
After a point charge was applied to each atom by the ckel method, the structure was optimized using the Tripos force field. Next, interactions such as a hydrophobic interaction site (aromatic ring, aliphatic side chain) and a hydrogen bonding site (carbonyl oxygen, hydroxyl group, amino group, etc.) considered to be important for drug-biological interaction are assumed. Dummy atoms were placed at sites where interaction is possible in order to identify the sites where they could interact.

At this time, in order to distinguish types of interaction such as hydrophobic interaction, hydrogen bond and electrostatic interaction site, the interaction was classified and different dummy atom types were set. In addition, a conformer rotated for the rotatable bond was generated, and the one in which the distance between dummy atoms arranged at the assumed interaction site was changed was saved as a new conformation in a conformation file. For the compounds of Example 45 and Example 46, a three-dimensional structure was formed and a conformation was similarly generated.

The compound of Example 48 was used as a template molecule, and the respective conformations of the compounds of Examples 45 and 46 were overlapped so that dummy atoms exhibiting the same kind of interaction in all conformations overlapped. A matching structure was created.

For the obtained superimposed structure, analysis of three-dimensional QSAR using the number of dummy atoms (the number of common interactions) used in superimposition, the degree of three-dimensional overlap (overlap volume) and the activity value Based on the results, etc., the optimal superposition structure was selected.

In the superposed structure obtained this time, the expression (1)
The center of gravity of ring B (W1) and the center of gravity of ring A (W
2) and hydrogen bond acceptors (such as carbonyl oxygen) (W
In 3), W1 to W2 = 8.34 °, W1 to W3 =
3.80 [deg.], W2 to W3 = 5.55 [deg.].

(Calculation Example 1: Compound of Example 130) An example in which seven suitable atoms were selected from the assumed interaction site of the compound of Example 130 and the constituent atoms of the benzamide structure, and used for the above superposition. Using the compounds of Examples 45, 46 and 48 as target structures, the compound of Example 130 was subjected to constrained potential to optimize the structure. Next, the constrained potential was released and the structure was optimized, whereby an active conformation of the compound of Example 130 was obtained. For this active conformation, the center of gravity (W1) of the benzene ring, the center of gravity (W2) of the pyridine ring and the carbonyl oxygen (W3) of benzamide were defined, and parameters of the spatial configuration were extracted.

Also, all conformations were generated for rotatable bonds, the energy in each conformation was calculated, and the most stable structure was obtained. The energy in the most stable structure was calculated, and the energy difference from the active conformation was calculated. As a result, in the structure obtained this time, W1 to W2 = 8.43 ° and W1 to W3 = 3.82.
Å, W2 to W3 = 5.88Å (energy difference from the most stable structure: 2.86 kcal / mol).

[0411] The same result was obtained by performing an analysis operation using the dummy atoms obtained by the construction of the superposed structure model as target structures. (Calculation result)
The calculation results are shown in Table 7 [Table 33]. Table 7: Calculation results of spatial arrangement parameters

[0412]

[Table 33]

[0413]

[0414]

[0415]

EFFECT OF THE INVENTION The novel benzamide derivatives and novel alinide derivatives of the present invention have a differentiation inducing action,
It is useful as a drug for treating and improving autoimmune diseases, skin diseases and parasitic infections. In particular, it is highly effective as an anticancer agent and is effective against hematopoietic tumors and solid cancers.

[Brief description of the drawings]

FIG. 1. Example 48 against tumor cells (HT-29)
FIG. 7 is a graph showing changes in tumor volume when a compound is administered.

FIG. 2 Example 4 against tumor cells (KB-3-1)
8 is a graph showing changes in tumor volume upon administration of compound No. 8. FIG.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/38 ADS A61K 31/38 ADS 31/415 31/415 31/42 ABA 31/42 ABA 31/425 31/425 31 / 44 ADA 31/44 ADA 31/445 AEA 31/445 AEA 31/495 ADV 31/495 ADV 31/505 31/505 C07C 255/31 C07C 255/31 271/18 271/18 271/40 271/40 275 / 24 275/24 275/28 275/28 323/52 323/52 323/62 323/62 327/48 327/48 335/16 335/16 C07D 207/34 C07D 207/34 209/42 209/42 211 / 24 211/24 213/30 213/30 213/40 213/40 213/56 213/56 213/65 213/65 213/70 213/70 213/74 213/74 213/75 213/75 213/81 213 / 81 213/82 213/82 233/34 233/34 233/42 233/42 233/64 103 233/64 103 239/28 239/28 241/14 241/14 261/08 261/08 261/10 261 / 10 263/48 263/48 275/02 275/02 277/24 277/24 277/40 277/40 295/08 295/08 A 307/12 307/12 307/68 307/68 307/84 307/84 333/16 333/16 333/38 333/38 333/62 333/62 401/06 233 401/06 233 239 239 401/12 207 401/12 207 233 233 405/12 213 405/12 213 409/12 213 409/12 213 413/12 213 413/12 213 453/02 453/02 491/048 491/048 495/04 105 495/04 105A 521/00 521/00 275/02 (72) Inventor Osamu Nakanishi 1900-1, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemicals Co., Ltd. (72) Inventor Akiko Saito 1,900-1, Togo, Mobara-shi, Chiba Prefecture Mitsui Toatsu Chemicals In-house (72) Inventor Shun Yamashita 1900-1, Togo, Mobara-shi, Chiba Mitsui Toatsu Chemicals Inc. (72) Inventor Kengo Shiraishi 3-42-7 Hirado, Totsuka-ku, Yokohama-shi, Kanagawa-ken Inventor Eiji Tanaka 1144 Togo, Mobara City, Chiba Prefecture Mitsui Toatsu Chemicals, Inc.

Claims (32)

[Claims] 1. A compound represented by the formula (1): [In the formula, A represents a phenyl group or a heterocyclic ring which may be substituted (as a substituent, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, 1 carbon atom
Acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms, carboxyl group, Having 1 to 4 groups selected from the group consisting of an alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group, and a heterocyclic ring). X is a direct bond or a compound of the formula (2) 中 In the formula, e represents an integer of 1 to 4. g and m each independently represent an integer of 0-4. R4 is a hydrogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms or a group represented by the formula (3): (In the formula, R6 represents an optionally substituted alkyl group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a phenyl group or a heterocyclic ring). R5 represents any of the structures represented by｝ representing a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms. n represents the integer of 0-4. However, when X is a direct bond, n does not become 0. Q is the formula (4) [Formula 4] (Wherein, R 7 and R 8 each independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms). R1 and R2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having 1 to 4 carbon atoms,
C4 to C4 alkoxyamino group, C1 to C4 aminoalkyl group, C1 to C4 alkylamino group, C1 to C4 acyl group, C1 to C4 acylamino group, C1 to C1
4 represents an alkylthio group, a perfluoroalkyl group having 1 to 4 carbon atoms, a perfluoroalkyloxy group having 1 to 4 carbon atoms, a carboxyl group, or an alkoxycarbonyl group having 1 to 4 carbon atoms. R3 represents a hydroxyl group or an amino group. And a pharmaceutically acceptable salt thereof. 2. The benzamide derivative and the pharmaceutically acceptable salt according to claim 1, wherein n is an integer of 1 to 4. 3. Q is a compound represented by the formula (5). (Wherein R7 and R8 have the same meanings as described above). 4. The benzamide derivative and the pharmaceutically acceptable salt according to claim 3, wherein A is an optionally substituted heterocycle. 5. The benzamide derivative and the pharmaceutically acceptable salt according to claim 4, wherein A is an optionally substituted pyridyl group. 6. The benzamide derivative and the pharmaceutically acceptable salt according to claim 4, wherein X is a direct bond. 7. The benzamide derivative and the pharmaceutically acceptable salt according to claim 6, wherein R1 and R2 are hydrogen atoms. 8. The benzamide derivative and the pharmaceutically acceptable salt according to claim 7, wherein R3 is an amino group. 9. X is a compound of the formula (6) The benzamide derivative and pharmaceutically acceptable salt according to claim 5, wherein the benzamide derivative has a structure represented by the formula: wherein e is as defined above. 10. The benzamide derivative and the pharmaceutically acceptable salt according to claim 9, wherein n is 1 and R1 and R2 are hydrogen atoms. 11. The benzamide derivative and the pharmaceutically acceptable salt according to claim 10, wherein R3 is an amino group. X is a compound represented by the formula (7): (Wherein e, g and R4 have the same meanings as defined above). The benzamide derivative and a pharmaceutically acceptable salt according to claim 5, wherein 13. The benzamide derivative and a pharmaceutically acceptable salt according to claim 12, wherein n is 1 and R1 and R2 are hydrogen atoms. 14. The benzamide derivative and the pharmaceutically acceptable salt according to claim 13, wherein R3 is an amino group. 15. X is a compound represented by the formula (8): (Wherein g, m and R5 have the same meanings as defined above). The benzamide derivative and a pharmaceutically acceptable salt according to claim 5, wherein 16. The benzamide derivative and a pharmaceutically acceptable salt according to claim 15, wherein n is 1 and R1 and R2 are hydrogen atoms. 17. The benzamide derivative and the pharmaceutically acceptable salt according to claim 16, wherein R3 is an amino group. 18. The benzamide derivative and the pharmaceutically acceptable salt according to claim 1, wherein n is 0. 19. The benzamide derivative and a pharmaceutically acceptable salt according to claim 18, wherein Q is any of the structures represented by the formula (5). 20. The benzamide derivative and the pharmaceutically acceptable salt according to claim 19, wherein A is an optionally substituted heterocycle. 21. The benzamide derivative and the pharmaceutically acceptable salt according to claim 20, wherein A is a pyridyl group which may be substituted. 22. The benzamide derivative and the pharmaceutically acceptable salt according to claim 21, wherein R1 and R2 are hydrogen atoms. 23. The benzamide derivative and the pharmaceutically acceptable salt according to claim 22, wherein R3 is an amino group. 24. Formula (9) [Formula 9] The benzamide derivative according to claim 1, which is represented by the formula: and a pharmaceutically acceptable salt thereof. 25. A compound represented by the formula (10): The benzamide derivative according to claim 1, which is represented by the formula: and a pharmaceutically acceptable salt thereof. 26. A compound of the formula (11) The benzamide derivative according to claim 1, which is represented by the formula: and a pharmaceutically acceptable salt thereof. 27. Formula (12) [Formula 12] The benzamide derivative according to claim 1, which is represented by the formula: and a pharmaceutically acceptable salt thereof. 28. A compound of the formula (13) [In the formula, A and B represent an optionally substituted phenyl group or a heterocyclic ring (as a substituent, a halogen atom, a hydroxyl group,
Amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aminoalkyl group having 1 to 4 carbon atoms, alkylamino group having 1 to 4 carbon atoms, 1 carbon atom Acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms, carboxyl group, Having 1 to 4 groups selected from the group consisting of an alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group, and a heterocyclic ring). Y is -CO
-, - CS -, - SO- and -SO ₂ - has one of the structures, the chain connecting the A and B, represent a cyclic or their combined structure. R3 represents a hydroxyl group or an amino group. ], The distance between the center of gravity of ring B (W1), the center of gravity of ring A (W2), and the oxygen or sulfur atom (W3) serving as a hydrogen bond acceptor in Y is W1 to W1, respectively.
W2 = 6.0-11.0 °, W1-W3 = 3.0-8.
Anilide derivatives and pharmaceutically acceptable salts capable of having a configuration of 0 °, W2 to W3 = 3.0 to 8.0 °. 29. A ring in which A is optionally substituted, R
29. The anilide derivative and a pharmaceutically acceptable salt according to claim 28, wherein 3 is an amino group, and Y is a chain, a cyclic structure or a combination thereof connecting A and B having -CO- in the structure. 30. A phenyl group wherein B is optionally substituted, W
1-W2 = 7.0-9.5 °, W1-W3 = 3.0-
30. The anilide derivative and a pharmaceutically acceptable salt according to claim 29, wherein 5.0% and W2 to W3 = 5.0 to 8.0%. 31. A carcinostatic agent comprising at least one of the compounds according to claim 1 as an active ingredient. A pharmaceutical comprising at least one of the compounds according to any one of claims 1 to 30 as an active ingredient.