MXPA00009342A

MXPA00009342A - Pyridine derivative and pharmaceutical containing the same

Info

Publication number: MXPA00009342A
Application number: MXPA/A/2000/009342A
Authority: MX
Inventors: Kouji Edamatsu; Takao Nagahama; Hayakawa Satoshi; Yutaka Kojima; Makoto Sakamoto; Koichi Yasumura
Original assignee: Kouji Edamatsu; Hayakawa Satoshi; Yutaka Kojima; Takao Nagahama; Otsuka Pharmaceutical Co Ltd; Makoto Sakamoto; Koichi Yasumura
Priority date: 1998-03-25
Filing date: 2000-09-22
Publication date: 2001-07-09

Abstract

A pyridine derivative represented by formula (1) [wherein R1 represents a halogen atom or a halogen-substituted lower alkyl;R2 and R3 respectively represent a hydrogen atom or a halogen atom;V represents a group:-C(=O)NH-, -NHC(=O) or NH-;and A represents A1, A2 or A3:(groups in A1 to A3 respectively represent a hydrogen atom, a lower alkyl, a lower alkanoyl, hydroxyl, benzoyl or an oxo group)]or a pharmaceutically acceptable salt thereof. The compound (1) inhibits collagen production and is useful for preventing or treating fibrosis.

Description

DERIVATIVE OF PIRIDINE AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME TECHNICAL FIELD The present invention relates to a novel pyridine derivative or to a salt thereof, which inhibits the synthesis of collagen, and to a pharmaceutical composition containing said compound, which is useful for the prophylaxis or treatment of fibrosis. 10 PREVIOUS TECHNIQUE * r In the present, it is said that there are 130 types of diseases or more called fibrosis, among which strange diseases are included.

The typical fibrosis disease includes, for example, pulmonary fibrosis, hepatic fibrosis, glomerulosclerosis, etc. Pulmonary fibrosis generally refers to a syndrome in which lung function has been lost due to a reconstituted lesion in the alveolar region, that is, an alveolar structure is broken by the reaction inflammatory cell that causes the growth of fibroblasts and an excessive increase of the extracellular matrix composed mainly of collagen, which results in pulmonary sclerosis.

On the other hand, hepatic fibrosis refers to the condition of the diseases in which the necrosis of the hepatocytes is caused by various liver diseases such as chronic viral hepatitis, alcoholic liver disease, etc. and, therefore, the extracellular matrix increases to recruit for the site, which generates hepatic fibrogenesis. The terminal state of this disease condition leads to liver cirrhosis where all the liver tissue atrophies and sclerose. Conventional drugs that inhibit hepatic fibrogenesis described above include, for example, the penicillamine known 10 as a remedy for Wiikinson's disease that occurs due to the accumulation of copper in the liver as a result of a metabolism.

»Abnormal copper, Lufironil that has been studied as an inhibitor of proline hydroxylase, etc. However, these drugs are not enough as a drug to prevent hepatic fibrogenesis in view of side effects and validity. At present, a remedy (or therapy) that is effective for fibrosis represented by hepatic fibrogenesis has not been established, and the production of fibrogenesis has been specifically inhibited. As described in the foregoing, it has been known that it is generated an excessive increase of the extracellular matrix composed mainly of collagen in the production of fibrogenesis in lung tissues and hepatocytes. It has also been known that an increase in the extracellular matrix in hepatocytes is generated mainly in a Disse space of the sinusoidal wall and that Ito cells such as the mesenchymal cells of the liver constitute an important source of production. Accordingly, it is important that an excessive increase in the extracellular matrix (i.e., collagen) is inhibited in order to inhibit fibrogenesis of the liver, lung, etc. Thus, an object of the present invention is to provide a novel compound that has a greater inhibitory effect on the production of collagen, and a pharmaceutical composition with content thereof, useful for the prophylaxis or treatment of fibrosis.

DESCRIPTION OF THE INVENTION The present inventors have studied intensively to solve the problems described above. As a result, they have learned that a pyridine derivative represented by the general formula (1) described below and a pharmaceutically acceptable salt thereof has a greater inhibiting effect on collagen production; in this way completing the present invention. Therefore, the present invention relates mainly to: (1) A pyridine derivative represented by the general formula 0) [wherein R1 represents a halogen atom or a halogen-substituted lower alkyl group; R2 and R3 are the same or different and represent a hydrogen atom or a halogen atom; V represents a group: -C (= O) -NH-, a group -NH-C (= 0) -, a group: -NH-C (= 0) -NH- or a group: -CH = CH-; A represents a group A1: (wherein R 4 represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, a 2-lower alkyl-1,3-dioxolane group or a hydroxy-substituted lower alkyl group, R 5 represents a hydrogen atom, a group 2 lower alkyl-1,3-dioxolane, a lower alkyl group or a lower alkanoyl group, and R6 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group), a group A2: (wherein R7 represents a hydrogen atom or a lower alkyl group, and R8 is the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group: (wherein k represents an integer of 1 to 3) or a group: = N-OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); p represents an integer from 1 to 2; represents a simple link or a double link; Y represents a group: - (CH2) m-, a group: = CH (CH2) m _? - or a group: - (CH2) m_? CH =; and m represents an integer from 1 to 3) or a group A3: (wherein R9 is the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group: (wherein k represents an integer from 1 to 3) or a group: = N-OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); q represents an integer from 1 to 2; represents a simple link or a double link; Z represents a group: - (CH2) n-, a group: = CH (CH2) n-? or a group: - (CH2) n-? CH =; and n represents an integer from 1 to 3)] or a salt thereof; (2) A pharmaceutical composition comprising a compound of the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof; (3) A pharmaceutical composition for the prophylaxis or treatment of fibrosis, comprising an effective amount of a compound of the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof and a carrier, diluent and / or excipient pharmaceutically acceptable; and (4) A method for inhibiting fibrogenesis caused by excess collagen production of a mammal comprising administering to said mammal a pharmaceutically effective amount of a compound of the general formula (1) of claim 1 or a salt thereof. pharmaceutically acceptable. The pyridine derivative (1) or a pharmaceutically acceptable salt thereof has a greater inhibitory effect on the production of collagen, as described above, and has characteristics such as prolonged duration of drug efficacy, good blood transition and low toxicity.

Accordingly, the pyridine derivative (1) or a salt thereof is effective for the prophylaxis or treatment of diseases related to fibrogenesis caused by excessive production of collagen, for example, (i) diseases in organs such as pulmonary fibrosis. sudden and interstitial, pneumoconiosis, ARDS, hepatic fibrosis, neonatal hepatic fibrosis, liver cirrhosis, mucoviscidosis and myelofibrosis; (ii) skin diseases such as scleroderma, elephantiasis, morphea, wound and scar and hypertrophic keloid after burn injury; (iii) vascular diseases such as atherosclerosis and arteriosclerosis; (iv) ophthalmic diseases such as diabetic retinopathy, fibroplasia retrolentalis, vascularization concomitant with corneal transplantation, glaucoma, proliferative vitreoretinopathy and post-surgical corneal scar; (v) kidney diseases such as contracted kidney, nephrosclerosis, interstitial nephritis, IgA nephritis, glomerulosclerosis, membranoproliferative nephritis, diabetic nephropathy, chronic interstitial nephritis and chronic glomerulonephritis; and (vi) cartilage and bone diseases, such as rheumatic arthritis, chronic arthritis and osteoarthritis. Among them, the pyridine derivative (1) and a salt thereof of the present invention have a greater fibrogenesis-inhibiting effect accompanied by the diseases in the organs mentioned in point (i) above, and can be used as a preventive or remedy for pulmonary fibrosis and liver fibrosis.

The pyridine derivative represented by the general formula (1) of the present invention includes, for example, the following compounds: (1-1) a pyridine derivative wherein R1 to R3, R7 to R10, m, n, p, • q, k, V, Y and Z are as defined in general formula (1) and A is an A2 5 or an A3 group, or a pharmaceutically acceptable salt thereof; (1-2) a pyridine derivative, wherein R1 to R6 and V are as defined in the general formula (1) and A is a group A1, or a pharmaceutically acceptable salt thereof; (1-3) a pyridine derivative wherein R1 to R3, R7 to R8, m, p, k, 10 V and Y are as defined in the general formula (1) and A is a group A2, or a salt of the same pharmaceutically acceptable; (1-4) a pyridine derivative wherein R1 to R3, R9, R10, n, q, k, V and Z are as defined in the general formula (1) and A is a group A3, or a salt of the same pharmaceutically acceptable; 15 (1-5) a pyridine derivative wherein R1 to R10, m, n, p, q, k, A, Y and Z are as defined in general formula (1), V is a group -C (= O) -NH-, NH-C (= O) -NH- or -NH-C (= O) -, or a pharmaceutically acceptable salt thereof; (1-6) a pyridine derivative wherein R 1 to R 10, m, n, p, q, k, A, 20 Y and Z are as defined in general formula (1) and V is a -C ( = O) - NH-, or a pharmaceutically acceptable salt thereof; (1-7) a pyridine derivative wherein R1 to R10, m, n, p, q, k, A, Y and Z are as defined in general formula (1) and V is a group -NH- C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-8) a pyridine derivative wherein R1 to R10, m, n, p, q, k, A, Y and Z are as defined in general formula (1) and V is a group -NH- C (= O) -, or a pharmaceutically acceptable salt thereof; (1-9) a pyridine derivative wherein R1 to R3, R1 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1) V is a group -NH- C (= O) -NH- and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof; (1-10) a pyridine derivative wherein R1 to R6 are as defined in the general formula (1) and V is a group -NH-C (= 0) -, or a pharmaceutically acceptable salt thereof; (1-11) a pyridine derivative wherein R1 to R3, R7, R8, m, p, k, and Y are as defined in general formula (1), V is a group -NH-C (= O ) -NH- and A is an A2 group, or a pharmaceutically acceptable salt thereof; (1-12) a pyridine derivative wherein R1 to R3, R7, R8, m, p, k, and Y are as defined in general formula (1), V is a group -NH-C (= O ) - and A, is an A2 group, or a pharmaceutically acceptable salt thereof; (1-13) a pyridine derivative wherein R1 to R3, R9, R10, q, k, n and Z are as defined in general formula (1), V is a group -NH-C (= O) -NH- and A is an A3 group, or a pharmaceutically acceptable salt thereof; (1-14) a pyridine derivative wherein R1 to R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in general formula (1), V is a -C group (= O) -NH- and A is an A2 group or an A3 group, or a pharmaceutically acceptable salt thereof; (1-15) a pyridine derivative wherein R a R 6 are as defined in the general formula (1), V is a group -C (= O) -NH- and A is a group A1, or a salt of the same pharmaceutically acceptable; (1-16) a pyridine derivative wherein R 1 to R 3, R 7, R 8, m, p, ke Y are as defined in general formula (1), V is a group -C (= O) -NH- and A is an A2 group, or a pharmaceutically acceptable salt thereof; (1-17) a pyridine derivative wherein R1 to R3, R9, R10, n, q, k, and Z are as defined in general formula (1), V is a group -C (= O) - NH- and A is an A3 group, or a pharmaceutically acceptable salt thereof; (1-18) a pyridine derivative wherein R3 to R9, R10, n, m, p, q, k, V, Y, Z and A are as defined in general formula (1) and R1 and R2 are respectively a halogen atom, or a pharmaceutically acceptable salt thereof; (1-19) a pyridine derivative wherein R2 to R10, n, m, p, q, k, V, Y, Z and A are as defined in the general formula (1) and R1 is a lower alkyl group halogen-substituted, or a pharmaceutically acceptable salt thereof; (1-20) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, V, Y and Z are as defined in general formula (1), R1 is a group lower halogen-substituted alkyl and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof; (1-21) a pyridine derivative wherein R2 and R3 to R6 are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group and A is a group A1, or a pharmaceutically salt thereof acceptable; (1-22) a pyridine derivative wherein R 2, R 3, R 7, R 8, m, p, k, V and Y are as defined in general formula (1), R 1 is a halogen-substituted lower alkyl group and A is an A2 group, or a pharmaceutically acceptable salt thereof; (1-23) a pyridine derivative wherein R2, R3, R9, R10, n, q, k, V, and Z are as defined in the general formula (1), R1 is a halogen-substituted lower alkyl group and A is an A3 group, or a pharmaceutically acceptable salt thereof; (1-24) a pyridine derivative wherein R3, R7 to R10, n, m, p, q, k, V, Y and Z are as defined in general formula (1), R1 and R2 are respectively a halogen atom and A is a group A2 or a group A3, or a pharmaceutically acceptable salt thereof; (1-25) a pyridine derivative wherein R3 to R6 and V are as defined in the general formula (1), R1 and R2 are respectively a halogen atom and A is a group A1, or a pharmaceutically salt thereof acceptable; (1-26) a pyridine derivative wherein R3, R7, R8, m, p, k, V and Y are as defined in general formula (1), R1 and R2 are respectively a halogen atom and A is an A2 group, or a pharmaceutically acceptable salt thereof; (1-27) a pyridine derivative wherein R3, R9, R10, n, q, k, V and Z are as defined in general formula (1), R1 and R2 are respectively a halogen atom and A is an A3 group, or a pharmaceutically acceptable salt thereof; (1-28) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, Y, and Z are as defined in the general formula (1), R1 is an alkyl group lower halogen-substituted, A is a group A2 or a group A3 and V is a group -C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-29) a pyridine derivative wherein R2 to R6 are as defined in general formula (1), R1 is a substituted lower halogen alkyl group, A is a group A1 and V is a group -C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-30) a pyridine derivative wherein R2, R3, R7, R8, m, p, k, and Y are as defined in general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A2 and V is a group -C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-31) a pyridine derivative wherein R2, R3, R9, R10, n, q, k, and Z are as defined in general formula (1), R1 is a lower halogen-substituted lower alkyl group, is a group A and V is a group -C (= 0) -NH-, or a pharmaceutically acceptable salt thereof; (1-32) a pyridine derivative wherein R3 R7 to R10, n, m, p, q, k, • Y and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A2 or a group A3 and V is a group -C (= O) -NH- , or a pharmaceutically acceptable salt thereof; (1-33) a pyridine derivative wherein R3 to R6 are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A1 and V is a group -C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-34) a pyridine derivative wherein R3, R7, R8, m, p, k, and Y are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A2 and V is a group -C (= O) -NH-, or a pharmaceutically acceptable salt thereof; 15 (1-35) a pyridine derivative wherein R3, R9, R10, n, q, k, and Z are as defined in general formula (1), R1 and R2 are respectively a halogen atom, A is a group A3 and V is a group -C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-36) a pyridine derivative wherein R 2, R 3, R 7, a R 10, n, m, p, 20 q, k, Y and Z are as defined in general formula (1), R 1 is a group lower halogen-substituted alkyl, A is a group A2 or a group A3 and V is a group -NH-C (= 0) -, or a pharmaceutically acceptable salt thereof; (1-37) a pyridine derivative wherein R2, R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in general formula (1), R1 is a lower alkyl group halogen-substituted, A is a group A2 or a group A3 and V is a group -NH-C (= 0) -NH-, or a pharmaceutically acceptable salt thereof; (1-38) a pyridine derivative wherein R2 to R6 are as defined in the general formula (1), R1 is a halogeno substituted lower alkyl group, A is a group A1 and is a group -NH-C (= O ) -, or a pharmaceutically acceptable salt thereof; (1-39) a pyridine derivative wherein R 2, R 3, R 7, R 8, m, p, k, and Y are as defined in general formula (1), R 1 is a halogen-substituted lower alkyl group, A is a group A2 and V is a group -NH-C (= O) -, or a pharmaceutically acceptable salt thereof; (1-40) a pyridine derivative wherein R 2, R 3, R 7, R 8, m, p, k, and Y are as defined in general formula (1), R 1 is a halogen-substituted lower alkyl group, A is a group A2 and V is a group -NH-C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-41) a pyridine derivative wherein R2, R3, R9, R10, n, q, k, and Z are as defined in general formula (1), R1 is a halogen-substituted lower alkyl group, A is a group A3 and V is a group -NH-C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-42) a pyridine derivative wherein R3, R7 to R10, n, m, p, q, k, Y and Z are as defined in the general formula (1), R1 and R2 are respectively an halogen, A is a group A2 or a group A3 and V is a group -NH-C (= 0) -NH-, or a pharmaceutically acceptable salt thereof; (1-43) a pyridine derivative wherein R3 to R6 are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A1 and V is a group -NH-C (= O) -, or a pharmaceutically acceptable salt thereof; (1-44) a pyridine derivative wherein R 3, R 7, R 8 m, p, ke Y are as defined in the general formula (1), R 1 and R 2 are respectively a halogen atom, A is a group A2 and V is a group -NH-C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-45) a pyridine derivative wherein R3, R9, R10, n, q, k, and Z are as defined in the general formula (1), R1 and R2 are respectively a halogen atom, A is a group A3 and V is a group -NH-C (= O) -NH-, or a pharmaceutically acceptable salt thereof; (1-46) a pyridine derivative wherein R1 to R3, R7 to R9, p, q, k,V, Y and Z are as defined in the general formula (1), A is a group A2 or a group A3 and m and n are respectively 1, or a pharmaceutically acceptable salt thereof; (1-47) a pyridine derivative wherein R1 to R3, R7, R8, p, k, V and Y are as defined in the general formula (1), A is a group A2 and m is 1, or a salt of the same pharmaceutically acceptable; (1-48) a pyridine derivative wherein R1 to R3, R9, R10, q, k, V, and Z are as defined in general formula (1), A is a group A3 and n is 1, or a pharmaceutically acceptable salt thereof; (1-49) a pyridine derivative wherein R1 to R3, R7, p, q, k, V, Y and Z are as defined in general formula (1), A is a group A2 or a group A3, m and n are respectively 1 and R8 and R9 are respectively an oxo group, or a pharmaceutically acceptable salt thereof; (1-50) a pyridine derivative wherein R1 to R3, R7, R10 p, q, k, V, and Z are as defined in general formula (1), A is a group A2 or A3, m and n are respectively 1, and R8 and R9 are respectively a lower alkanoioxy group, or a pharmaceutically acceptable salt thereof; (1-51) a pyridine derivative wherein R1 and R2 are, respectively, a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group, a lower alkanoyloxy group or a hydroxyl group, Y is a group: - (CH2) m- or - (CH2) m_? CH = ym is 1, or a salt of the same pharmaceutically acceptable; (1-52) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, and is a group: - (CH) m- or - (CH2) m-? CH = ym is 1, or a salt thereof pharmaceutically acceptable; (1-53) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, and is a group: - (CH2) m- or - (CH2) m-? CH = and m is 2, or a pharmaceutically acceptable salt thereof; (1-54) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: - (CH2) m- or - (CH2) m-1 CH = ym is 3, or a pharmaceutically acceptable salt thereof; (1-55) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A1, R4 is a 2- lower alkyl-1,3-dioxolane group, R5 is a hydrogen atom and R6 is a hydrogen atom, or a pharmaceutically acceptable salt thereof; (1-56) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -NH-C (= O) -NH-, A is a group A2 , R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, and is a group: - (CH2) m- or - (CH2) m-? CH = ym is 1 or 2, or a salt of the same pharmaceutically acceptable; (1-57) a pyridine derivative wherein Z is as defined in the general formula (1), R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -NH-C (= O) -NH-, A is a group A R9 is an oxo group or a lower alkanoyloxy group and n is 1, or a pharmaceutically acceptable salt thereof; (1-58) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: -NH-C (= O) -NH-, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group - (CH2) m- and m is 1, or a pharmaceutically acceptable salt thereof; (1-59) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: -NH-C (= O) -, A is a group A2, R7 is a hydrogen atom, R8 is an oxo group or a lower alkanoyloxy group, Y is a group: - (CH2) m- and m is 1, or a pharmaceutically acceptable salt thereof; (1-60) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A2, R7 is a hydrogen atom, R8 is a hydrogen atom and Y is a group: = CH (CH2) m-? or a group: - (CH2) m-? CH =, or a pharmaceutically acceptable salt thereof; (1-61) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A1, R4 is a hydrogen atom, R5 is a lower alkyl group and R6 is a lower alkyl group, or a pharmaceutically acceptable salt thereof; (1-62) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A1, R4 is a lower alkanoyl group and R5 and R6 are respectively a hydrogen atom, or a pharmaceutically acceptable salt thereof; (1-63) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -NH-C (= O) -, A is a group A1, R4 is a lower alkanoyl group R5 and R6 are respectively a hydrogen atom, or a pharmaceutically acceptable salt thereof; (1-64) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: -NH-C (= O) -, A is a group A1, R4 is a lower alkanoyl group and R5 and R6 are respectively a hydrogen atom, or a pharmaceutically acceptable salt thereof; (1-65) a pyridine derivative wherein R1 is a halogen-substituted lower alkyl group, R2 and R3 are respectively a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A1, R4 is a lower alkanoyl group, R5 is a hydrogen atom or a lower alkyl group, and R6 is a hydrogen atom, or a pharmaceutically acceptable salt thereof; (1-66) a pyridine derivative wherein R1 and R2 are respectively a halogen atom, R3 is a hydrogen atom, V is a group: -C (= O) -NH-, A is a group A2, Y is a group: - (CH2) m-, m is 1, R7 is a hydrogen atom or a lower alkyl group and R8 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. The respective groups shown in the general formula (1) are specifically explained as follows. The lower alkyl group includes, for example, a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl. and hexyl. The hydroxy-substituted lower alkyl group includes, for example, a hydroxy lower alkyl group whose alkyl portion is a straight or branched chain alkyl group having from 1 to 6 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 1, 1 -dimethyl-2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl, 5-hydroxypentyl, 1-hydroxypentyl and 6-hydroxyhexyl. The halogeno-substituted lower alkyl group includes, for example, an alkyl group having 1 to 6 carbon atoms which is substituted with 1 to 3 halogen atoms, such as monochloromethyl, monobromomethyl, monoiodomethyl, monofluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl. , difluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, trifluoromethyl, monochloroethyl, monobromoethyl, monoiodoethyl, dichloroethyl, dibromoethyl, difluoroethyl, dichlorobutyl, diiodobutyl, difluorobutyl, chlorohexyl, bromohexyl and fluorohexyl.

The group 2-lower alkyl-1,3-dioxolane includes, for example, a 2-lower alkyl-1,3-dioxolane group whose alkyl portion is an alkyl group having from 1 to 6 carbon atoms, such as 2- methyl-1,3-dioxolane, 2-ethyl-1,3-dioxolane and 2-propyl-1,3-dioxolane, 2-butyl-1,3-dioxolane and 2-hexyl, 1,3-dioxolane. The halogen atom includes, for example, fluorine, chlorine, bromine and iodine. The alkanoyl portion of the lower alkanoyloxy group and the lower alkanoyl group includes, for example, a straight or branched chain alkanoyl group whose alkyl portion has from 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl , isovaleryl, pivaloyl, pentanoyl and hexanoyl. The aroyl moiety of the aroyloxy group includes, for example, benzoyl, toluoyl, naphthoyl, salicyloyl, anisoyl and phanthanoyl. The lower alkoxy group includes, for example, a straight or branched chain alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy and hexyloxy. The process for producing the pyridine derivative (1) of the present invention will be explained later.

REACTION SCHEME (1-a): (2. 3) (1-A) (wherein R1, R2, R3 and A are as defined in the foregoing) This reaction is a process for obtaining a pyridine derivative (1-A) wherein V is -C (= O) -NH- of the present invention. That is, the pyridine derivative (1-A) is obtained by the condensation of a carboxylic acid (2) with a 3-aminopyridine derivative (3) without a solvent or a suitable solvent, using a water-soluble carbodiimide such as hydrochloride of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide as a condensing agent or a carbodiimide such as N, N-dicyclohexylcarbodiimide (DCC). In this case, when a tertiary amine is added, the basicity of the amine compound (3) improves, and as a result, the reaction progresses.

In the present invention, instead of the carbodiimide, a condensing agent such as isobutyl chloroformate, diphenium phosphinic chloride and carbonyl diimidazole can also be used. The solvent may be any that does not adversely affect the reaction, and examples thereof include an inert solvent such as tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, toluene and 1,2-dimethoxyethane. The tertiary amine includes, for example, triethylamine, tributylamine, pyridine, N-methylmorpholine, quinoline, lutidine and 4-dimethylaminopyridine. The condensing agent is used in an amount of at least 1 mol, and preferably 1 to 5 mol, per mol of the compound (2). The 3-aminopyridine derivative (3) is used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the compound (2). The reaction is usually carried out by adding the condensing agent to the carboxylic acid (2) at about -20 to 180 ° C, and preferably at 0 to 150 ° C, for 5 minutes to 3 hours and further adding the 3-aminopyridine derivative ( 3), and the reaction is completed within about 30 minutes to 30 hours after adding the 3-aminopyridine derivative (3) REACTION SCHEME (1-b): (2) (4) (1 -A) (wherein R1 to R3 and A are as defined in the foregoing, and X represents a halogen atom) This reaction is another process for obtaining the pyridine derivative (1-A). That is, the pyridine derivative (1-A) is obtained by reacting a carboxylic acid (2) with a suitable halogenating agent in a solvent-free state or in a suitable solvent in order to obtain an acid halide (4), and reacting the acid halide (4) with a 3-aminopyridine derivative (3).

In that case, the hydrogen halide is removed from the reaction system by adding a tertiary amine and, consequently, the reaction proceeds. The solvent employed in this reaction includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbon such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbon such as benzene and toluene; and N, N-dimethylformamide (DMF). The halogenating agent includes, for example, thionyl halide such as thionyl chloride and thionyl bromide; hydrogen halide such as hydrogen chloride, hydrogen bromide and hydrogen iodide; and phosphorus halide such as phosphorus trichloride and phosphorus tribromide. The amount of the halogenating agent used is at least 1 mole, and preferably 1 to 5 moles, per mole of the carboxylic acid (2). The amount of the 3-aminopyridine derivative (3) used is at least 1 mole, and preferably 1 to 5 moles, per mole of acid halide (4). The reaction is carried out at about -20 to 180 ° C, and preferably at 0 to 150 ° C, and is completed within about 5 minutes to 30 hours.

REACTION SCHEME (II): (5) (6) (1 B) (wherein R1, R2, R3 and A are as defined in the foregoing). This reaction is a process to obtain the pyridine derivative (1-B) wherein V is -NH-C (= O) - of the present invention. That is, the pyridine derivative (1-B) of the present invention is obtained by reacting the pyridinecarboxylic acid (5) with an aniline derivative (6) according to the process described in the above reaction scheme (I-a). The solvent, the tertiary amine and the condensing agent employed includes, for example, those listed in the preceding reaction scheme (I-a).

The condemning agent is used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the pyridinecarboxylic acid (5). The aniline derivative (6) is used in an amount of at least 1 mole, and preferably 1 to 5 moles, per mole of the pyridinecarboxylic acid (5). The reaction is usually carried out by adding the condensing agent to the pyridinecarboxylic acid (5) at about -20 to 180 ° C, and preferably at 0 to 150 ° C, for 5 minutes to 3 hours and further adding the aniline derivative (6). ), and the reaction is completed within about 30 minutes to 30 hours after adding the aniline derivative (6). In the pyridine derivative (1) of the present invention, the pyridine derivatives of the following points ® to se can be produced by reducing a pyridine derivative (1-a) wherein at least one of the R8 is an oxo group or a pyridine derivative (1-a ') wherein at least one of the R 9 is an oxo group. ®: a pyridine derivative (1-b) wherein Y in the group A2 in A is a group: - (CH2) m- and at least one of the R8 is a hydroxyl group. ©: a pyridine derivative (1-b ') wherein Z in the group A3 in A is a group: - (CH2) n- and at least one of the R9 is a hydroxyl group. For example, the pyridine derivative (1-b) of the F-point is obtained by reducing the pyridine derivative (1-a) wherein at least one of the R8 is an oxo group in a suitable solvent, as shown in following reaction scheme (II Ia). REACTION SCHEME (lll-a): REDUCTION (1 B) (wherein R1, R2, R3, V, p and m are as defined in the foregoing, R8a represents an oxo group, R8"8a represents a group wherein R8a is deleted from R8; s represents 0 or 1, with the exception of where s represents 0 when n is 2, and R8b represents a hydroxyl group.) In the above reaction scheme, the case where A is a group A2 was illustrated, but the case where A is a group A3 can also be carried out from In the same way, in the following reaction scheme, the case is described where A is a group A2, but the compound where A is a group A3 can also be synthesized by the corresponding reaction scheme. adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether, halogenated hydrocarbon such as methylene chloride and chloroform, and aromatic hydrocarbon such as benzene and toluene. reduction includes, for example, a catalytic reduction process in a suitable solvent, or a process employing a tai reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane and Raney nickel. The reducing agent is also used in the amount of 0.25 to 5 moles, and preferably 1 to 3 moles, per mole of the pyridine derivative (1-a) in the case of an oxo group (R8a). In the case of two oxo groups (R8a), the reducing agent is also used in the amount of 2 to 10 moles, and preferably 2 to 6 moles. The reaction is usually carried out at a temperature of 0 to 30 ° C and is completed within about 1 to 30 hours. In the pyridine derivative (1) of the present invention, even if R8 in the group A2 or R9 A3 of A is a group: = N-OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group ), can also be produced by using, as a starting material, a pyridine derivative (1-a) or (1-a ') wherein R8 or R9 is an oxo group.

The process for producing pyridine derivatives (1-f-1) to (1-f-3) wherein R 10 in the group: = N-OR 10 is a hydrogen group, a lower alkyl group or a lower alkanoyl group, will be explained in order by means of R8 in group A2 as the example. First, a pyridine derivative (1-f-1) wherein R 8 is a group: = N-OH (R 10 is a hydrogen atom) is obtained by reaction of the pyridine derivative (1-a) with hydroxylamine hydrochloride in a suitable solvent in the presence of a base, as shown in the following reaction scheme.

REACTION SCHEME (lll-b): (1-f-1) (wherein R1, R2, R3, V, R8a, R8"8, p, mys are as defined in the foregoing, and R8c represents a group: = N-OH). any which does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; lower alcohols such as methanol, ethanol and isopropanol; and acetic acid and water. for example trialkylamine such as triethylamine, alkali metal carbonate such as potassium carbonate, barium carbonate and sodium carbonate, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, and pyridine 1,4-diazabicyclo [2. 2 2] octane (DABCO), sodium acetate and piperidine The amount of the base used ranges from 1 to 100 moles, and preferably from 2 to 10 moles, per mole of the pyridine derivative (1-a). Hydroxylamine hydrochloride used ranges from 1 to 50 moles, and preferably from 2 to 10 moles, per mole of the pyridine derivative (1-a-). The reaction is usually carried out at a temperature of -20 to 150 ° C, and is completed between about 5 minutes and 24 hours. Then, a pyridine derivative (1-f-2) can be produced wherein R8 is a group: = N-OR10a (R10a represents a lower alkyl group) by reaction according to the same way described in the reaction scheme (III-B) except for the use of O-alkyloxyhydroxylamine hydrochloride in place of the preceding hydroxylamine hydrochloride.

For example, in the pyridine derivative (1-f-2), a pyridine derivative (1-f-21) can be produced wherein R 10a is a methyl group, by reaction according to the same way as described in I preceded it except for • the use of O-methylhydroxylamine hydrochloride in place of the preceding hydroxylamine hydrochloride. A pyridine derivative (1-f-3) wherein R8 is a group: = N-OR10b (R10b represents a lower alkanoyl group) is obtained by reacting the pyridine derivative (1-f-1), obtained from the derivative of pyridine (1- a) wherein R8 is an oxo group according to the process described in previous reaction scheme (I I 1-b), with an acylating agent in a suitable solvent as shown in the following reaction scheme (III-c). In that case, when a tertiary amine is added, the basicity of the pyridine derivative (1 -f-1) is improved and, therefore, the reaction progresses.

REACTION SCHEME (IH-c): (wherein R1, R2, R3, V, R8c, R8"8 *, p, mys are as defined in the foregoing and R ^ represents a group: = N-OR10b (R10b is as defined in the foregoing). The solvent can be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether, halogenated hydrocarbon such as methylene chloride and chloroform, and aromatic hydrocarbon such as benzene and toluene, and dimethylformamide The acylating agent includes acid anhydride or acid halide corresponding to the lower alkanoyl group such as R 10b, and examples thereof include acetic anhydride, acetyl halide, propionyl halide, isobutyryl halide, halide of pivaloyl and hexanoyl halide In specifically explanatory terms, acetic anhydride and acetyl halide (eg, acetyl chloride, acetyl fluoride, acetyl iodide, acetyl bromide, etc.) can be used as the acylating agent to obtain a piperidine derivative (1-f-31) wherein R10b is an acetyl group in the above pyridine derivative (1-f-3). The tertiary amine includes, for example, trialkylamine (eg triethylamine, etc.), pyridine, quinoline, lutidine, N-methylmorpholine, 4-dimethylaminopyridine and midazole. The amount of the acylating agent used generally ranges from 1 to 20 moles, and preferably from 1 to 5 moles, per mole of the pyridine derivative (1-f-1) in the case of an R8c. The amount of the acylating agent used is generally between 2 and 40 moles, and preferably between 2 and 10 moles, per mole of the pyridine derivative (1 -f-1) in the case of two R8c. The reaction is usually carried out at a temperature of -20 to 150 ° C, and is completed within 5 minutes to 24 hours. The pyridine derivatives (1-f-1) to (1-f-3) wherein R9 in the group A3 is a group: = N-OR10 (R10 is as defined in the foregoing) is produced by reaction in accordance in the same manner as described in the preceding reaction schemes (II lb) and (II lc) except for the use of the pyridine derivative (1-a ') in place of the pyridine derivative (1-a).

In the pyridine derivative (1) of the present invention, the pyridine derivatives shown in the following points to © can be produced using a pyridine (1-g) wherein Y in the group A2 is a group: - (CH2) m- and at least one of the R8 is a hydroxyl group or a pyridine (1-g ') wherein Y in the group A3 is a group - (CH2) n- and at least one of the R9 is a group hydroxyl as a starting material for dehydration in a suitable solvent. A pyridine derivative (1-c) wherein Y in the group A2 in A is a group: = CH (CH2) m _? - or a group; - (CH2) -? CH = and at least one of the R8 is a hydrogen atom or a pyridine derivative (1-c ') wherein Z in the group A3 in A is a group: = CH (CH2) n -? - or a group : - (CH2) n-? CH = and at least one of R9 is a hydrogen atom. The procedure for synthesizing the above pyridine derivative (1-c) of point © will be explained by way of example.

REACTION SCHEME (IV-a): (1-9-1) (1-0-1) (wherein R1, R2, R3, R8, V and m are as defined in the foregoing) According to this reaction, a pyridine derivative (1-c-1) wherein Y is a group: - (CH2) m -? CH = is obtained by dehydrating a pyridine derivative (1-g-1) having a hydroxyl group in a suitable solvent, using a reaction reagent such as pyridinium bromide bromide, dioxane dibromide, bromine, etc. . The solvent may be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride, chloroform, and carbon tetrachloride; aromatic hydrocarbon such as benzene and toluene; and acetic acid, trifluoroacetic acid and methanesulfonic acid. The amount of pyridinium bromide per bromide used ranges generally between 1 and 5 moles, and preferably between 1 and 3 moles, per mole of the pyridine derivative (1-g-1). The reaction is usually carried out at a temperature of -10 to 150 ° C, and is completed within 30 minutes to 24 hours. A pyridine derivative (1-c-2) wherein Y is a group: = CH (CH2) m _? - in the pyridine derivative (1-c) of the preceding point F can be produced by reaction in the same way than that described in the reaction scheme (IV-a) except for the use of a pyridine derivative (1-g-2) represented by the general formula: (wherein R1, R2, R3, R8, V and m are as defined in the foregoing) in place of the above pyridine derivative (1 -g-1). In the pyridine derivative (1) of the present invention, the pyridine derivatives (1-d) to (1-e) and (1-d ') to (1-e') shown in the following points. can be produced using, as a starting material, a pyridine derivative (1-h) wherein Y in the group A2 is a group: - (CH2) m- and at least one of the R8 is an oxo group or a derivative of pyridine (1-h ') wherein Z in the group A3 is a group: - (CH2) n- and at least one of the R9 is an oxo group. © a pyridine derivative (1-d) where Y in group A2 is a group = CH (CH2) m-? or a group: - (CH2) m_? CH = and at least one of R8 is a lower alkanoyloxy group or a pyridine derivative (1-d ') wherein Z in group A3 is a group: = CH ( CH2) nr or a group: - (CH2) n-? CH = and at least one of R9 is a lower alkanoyloxy group or a pyridine derivative (1-e) wherein Y in group A2 is a group: = CH (CH2) m -? - or a group: - (CH2) m-? CH = and at least one of R8 is a lower alkoxy group or a pyridine derivative (1-e ') wherein Z in the group A3 is a group: = CH (CH2) n -? - or a group: - (CH2) n_? CH = and at least one of the R9 is a lower alkoxy group. The process for producing the pyridine derivatives (1-d) to (1-e) of the above points © and © will be explained by means of R8 in group A2, by way of example. First, the procedure to produce the pyridine derivative (1-d) of point © will be explained through the use of the following reaction scheme (IV-b).

REACTION SCHEME (IV-b): (1-d-1) (wherein R1, R2, R3, R8, V and m are as defined in the foregoing, and R represents a lower alkanoyloxy group). According to this reaction, a pyridine derivative (1-d-1) wherein Y is a group: - (CH 2) m-? CH = and has a lower alkanoyloxy group is obtained by the reaction of a pyridine derivative ( 1-h-1) having an oxo group with an acylating agent without solvent or in a suitable solvent in presence of an acid or a base. The solvent may be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride and chloroform; aromatic hydrocarbon such as benzene and toluene; and dimethylformamide and acetic acid. The acylating agent includes acid anhydride, acid halide or esters (eg, isopropenyl ester, etc.) corresponding to the alkanoyl portion of R8e, and examples thereof include acetic anhydride, acetyl halide, isopropenyl acetate, priopionyl halide, isopropenyl propionate, isobutyryl halide, pivaloyl halide and hexanoyl halide. In specifically explanatory terms, acetic anhydride, isopropyl acetate and acetyl halide (eg, acetyl chloride, acetyl fluoride, acetyl iodide, acetyl bromide, etc.) can be used as the acylating agent in order to obtain a pyridine derivative (1-d-11) wherein R 8e is an acetyloxy group in the preceding pyridine derivative (1-d-1). The acid includes, for example, Lewis acid such as boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, boron trifluoride ethyl ether and zinc chloride complex; hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen fluoride and hydrogen iodide; inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid; organic acid such as trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid; and anion exchange resin.

The base includes, for example, trialkylamine (for example, triethylamine, etc.), pyridine, dimethylaminopyridine, lithium diisopropylamide (LDA), potassium hydride, sodium hydride, sodium methoxide, potassium acetate, sodium acetate and resin. of cation exchange. The amount of the acylating agent used usually ranges from 1 to 100 moles, and preferably from 2 to 5 moles, per mole of the pyridine derivative (1-h-1). The amount of the acid or base usually ranges from 0.01 to 10 moles, and preferably from 0.02 to 0.1 moles, per mole of the pyridine derivative (1-h-1). The reaction is usually carried out under conditions of -78 to 150 ° C for 1 minute to 3 days, and preferably around 15 minutes to 24 hours. A pyridine derivative (1-d-2) wherein Y is a group: = CH (CH2) m -? - in the pyridine derivative (1-d) of the preceding point may be produced by reaction according to the same as described in the reaction scheme (IV-b) except for the use of a pyridine derivative represented by the general formula (1-h-2): (1-h-2) (wherein R1, R2, R3, R8, V and m are as defined in the foregoing) in place of the above pyridine derivative (1-h-1). The pyridine derivative (1-d ') of the above dot © can • produced by reaction according to the same way as that described in the reaction scheme (IV-b) except for the use of a pyridine derivative (1-h ') wherein at least one of the R 9 is an oxo group instead of the pyridine derivative (1-h-1). The procedure for producing the pyridine derivative (1-e) of the above point se will be explained below through the use of the following reaction scheme (IV-c).

REACTION SCHEME (IV-c .: (1-e-l) (wherein R1, R2, R3, R8, V and m are as defined in the foregoing, and R8f represents a lower alkoxy group). According to this reaction, a pyridine derivative (1-e-1) having a lower alkoxy group is obtained by reacting the pyridine derivative (1-h-1) with a lower alkyl ester of orthophoric acid in a suitable solvent in the presence of an acid . In that case, when anhydrous magnesium sulfate or A4 molecular sieve is added, the water is easily removed from the reaction system, and therefore, the reaction proceeds. The solvent can be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; lower alcohols such as methanol and ethanol; halogenated hydrocarbon such as methylene chloride and chloroform; aromatic hydrocarbon such as benzene and toluene; and nitromethane. The acid includes, for example, Lewis acid (eg boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, boron ethyl trifluoride ether complex and zinc chloride, etc.), p-toluenesulfonic acid, trichloroacetic acid , trifluoroacetic acid, methanesulfonic acid, acetic acid and (±) -IO-camphorsulfonic acid. The lower alkyl orthoformate includes, for example, alkyl orthoformate whose alkyl portion has 1 to 6 carbon atoms, such as methyl orthoformate, ethyl orthoformate, butyl orthoformate and hexyium orthoformate. In specifically explanatory terms, ethyl orthoformate can be used as the lower alkyl orthoformate in the case of obtaining a pyridine derivative (1-e-11) wherein R 8f is an ethoxy group in the above pyridine derivative (1 -e-1). The amount of the lower alkyl orthoformate used, usually ranges from 1 to 100 moles, and preferably from 5 to 20 moles, per mole of the pyridine derivative (1-h-1). The amount of the acid used generally ranges between 0.01 and 2 moles, and preferably between 0.1 and 1.5 moles, per mole of the pyridine derivative (1-h-1). The reaction is usually carried out at a temperature of -78 to 150 ° C, and is completed within 1 minute to 24 hours. A pyridine derivative (1-e-2) where Y is a group: = CH (CH) m -? - in the pyridine derivative (1-e) of the above point can be produced by reaction according to the same way as that described in the reaction scheme (IV-c) except the use of a pyridine derivative (1-h-2) in place of the above pyridine derivative (1-h-1). The preceding pyridine derivative (1-e ') of the dot © can be produced by reaction according to the same way as that described in the reaction scheme (IV-c) except for the use of a pyridine derivative (1-h) ') wherein at least one of the R9 is an oxo group in place of the pyridine derivative (1-h-1).

REACTION SCHEME (V): (7) (8) (9) REDUCTION (3) (where A and V are as defined in the preceding) According to this reaction, the above compound (3) is obtained as starting material of the reaction scheme (I-a) or the scheme of Reaction (lb) by reacting a monohalogenonitropyridine (7) with a compound (8) to give a 3-nitropyridine derivative (9) and by reducing this 3-nitropyridine derivative (9) in a suitable solvent using a catalytic reduction process, or reduction in the presence of an acid using a catalyst such as zinc, iron and tin. The reaction to obtain the 3-nitropyridine derivative (9) of the monohalogenonitropyridine derivative (7) and the compound (8) is carried out without a solvent, or in a suitable solvent. In that case, potassium carbonate or sodium carbonate may also be added in order to improve the nucleophilic property of the compound (8). The solvent may be any that does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbon such as methylene chloride and chloroform; and dimethylformamide and dimethyl sulfoxide. The amount of the compound (8) used is generally 1 mol, and preferably between 1 and 5 mol, per mol of the monohalogenonitropyridine derivative (7). The reaction is usually carried out at a temperature of 0 to 150 ° C, and preferably 20 to 80 ° C, and the reaction is completed within about 1 to 30 hours. The reaction to obtain a compound (3) of a 3-nitropyridine derivative (9) is carried out without a solvent, or in a suitable solvent. The solvent may be any that does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; and dimethoxymethane, dimethoxyethane and water. The amount of reducing agent used usually ranges from 0. 05 and 5 moles, and preferably between 0.2 and 3 moles, per mole of the 3-nitropyridine derivative (9).

The reaction is generally carried out at a temperature of -10 to 150 ° C, and preferably 0 to 50 ° C, and the reaction is completed within about 30 minutes to 30 hours. An aminopyridine derivative (3-b) wherein R 4 or R 5 in the group A1 in A is a 2-lower alkyl-1,3-dioxolane group is synthesized by the following reaction scheme (VI).

REDUCTION (wherein R 11 represents a lower alkyl group).

That is, the preceding aminopyridine derivative (3-b) is obtained by reacting a nitro compound (9-a) with ethylene glycol in a suitable solvent in the presence of an acid to give a cyclic acetal compound (dioxolane) (9-b). ) and by reduction of this compound (9-b) according to the same way as that described in the reaction scheme (V). The solvent may be any that does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbon such as benzene and toluene; and dimethoxyethane. As the acid, for example, p-toluenesulfonic acid, trichloroacetic acid, is preferably used, trifluoroacetic acid, methanesulfonic acid, acetic acid and (±) -IO-camphorsulfonic acid. Among them, (±) -IO-camphorsulfonic acid is preferably used. The amount of ethylene glycol used is generally 1 mol, and preferably between 1 and 5 mol, per mol of the nitro compound (9-a). The amount of acid used generally ranges from 0.01 to 0.1 moles, and preferably from 0.01 to 0.05 moles, per mole of nitro compound (9-a). The reaction is usually carried out at a temperature of -10 to 150 ° C, and preferably from room temperature to 100 ° C, and the reaction is completed within about 1 to 30 hours.

In the present invention, the pyridine derivative (1) wherein R4 or R5 in the group A1 in A is a 2-lower alkyl-1,3-dioxolane group of the present invention can be produced using the aminopyridine derivative (3- b) obtained in the reaction scheme (VI) as a starting material, or it can also be produced by synthesizing a pyridine derivative wherein R 4 or R 5 in the group A1 in A is a lower alkanoyl group (with the exception that it is eliminated) a formyl group) and converting said oxo group into a cyclic acetal according to the process described in the preceding reaction scheme (VI). The pyridine derivative wherein R8 in the group A2 in A or R9 in the group A3 is a group: (CH2) k (wherein k is as defined in the above) can also be produced in the same way as that of the case of R4 or R5 in the preceding group A1. In the above 3-aminopyridine derivative (3), the 3-aminopyridine derivatives (3-d) to (3-d ') shown in the following points (i) to (i) can also be produced using, as a starting material, a 3-nitropyridine derivative (9-c) wherein Y in the group A2 is a group: - (CH2) m- and at least one of the R8 is an oxo group or a derivative of 3- nitropyridine (9-c ') wherein Z in group A is a group: - (CH2) n- and at least one of R is an oxo group. (i) a 3-aminopyridine derivative (3-d) wherein Y in the group A2 in A is a group = CH (CH2) m -? - or a group: (CH2) m-.CH = and R8 is a lower alkanoyloxy group (ii) a 3-aminopyridine derivative (3-d ') wherein Z in the group A3 in A is a group: = CH (CH2) n -? - or a group: - (CH2) n -? CH = and R9 is a lower alkanoyloxy group. The process for producing 3-aminopyridine (3-d-1) wherein Y in the group A2 is a group: - (CH2) m_? CH = of the preceding point (i) will be explained by way of example.

REACTION SCHEME (VH-a): (9-d-1) REDUCTION (3-d-1) (wherein R8, m and R8a are as defined in the foregoing) That is, as shown in the preceding reaction scheme (Vll-a), the 3-aminopyridine derivative (3-d-1) is obtained by reaction of the 3-nitropyridine derivative (9-c-1) with an acylating agent to give a 3-nitropyridine derivative represented by the general formula (9-d-1) and by reduction of this compound (9-d-1) using a catalytic reduction process. The reaction to obtain the compound (9-d-1) of the 3-nitropyridine derivative (9-c-1) is carried out without a solvent or in a suitable solvent in the presence of an acid or a base. The solvent may be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as methylene chloride and chloroform; aromatic hydrocarbon such as benzene and toluene; and dimethylformamide and acetic acid. As an acylating agent, for example, acid anhydride, acid halide or esters (eg, ispropenyl ester, etc.) corresponding to the alkanoyl portion of R8a can be used. In specifically explanatory terms, as the lower alkanoyl portion of R8a is acetyl when a compound (3-d-11) is obtained wherein R8a is an acetyloxy group, for example, acetic anhydride, acetyl chloride and isopropenyl acetate can be used as the acylating agent (acetylating agent in this case). The acid includes, for example, Lewis acid such as boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, ethyl ether boron trifluoride complex and zinc chloride; hydrogen halide such as hydrogen chloride, hydrogen bromide and hydrogen iodide; inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid; organic acid such as trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid; and anion exchange resin. The base includes, for example, trialkylamine (eg triethylamine, etc.), pyridine, dimethylaminopyridine, lithium diisopropylamide (LDA), potassium hydride, sodium hydride, sodium methoxide, potassium acetate, sodium acetate and exchange resin. cations. The amount of the acylating agent used generally ranges from 1 to 100 moles, and preferably from 2 to 5 moles, per mole of the 3-nitropyridine derivative (9-c-1). The amount of acid or base used generally ranges from 0.01 to 10 moles, and preferably from 0.02 to 0.1 moles, per mole of the 3-nitropyridine derivative (9-c-1). The reaction is usually carried out under conditions of -78 to 150 ° C for 1 minute to 3 days, and preferably around 15 minutes to 24 hours. The reaction to obtain the compound (3-d-1) of the compound (9-d-1) is carried out in a suitable solvent. The solvent can be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF) and dioxane; and dimethoxyethane, diethoxyethane and water. As the reducing agent used in the reduction includes, for example, platinum dioxide, palladium carbon (Pd-C) and Raney nickel. Among them, platinum dioxide is superior in selective reduction.

The amount of the reducing agent used generally ranges between 0.01 and 5 moles, and preferably between 0.02 and 0.1 moles, per mole of the 3-nitropyridine derivative (9-c-1). The reaction is usually carried out at a temperature of -10 to 150 ° C, and preferably between 0 and 50 ° C, and the reaction is completed within about 10 minutes to 30 hours. A pyridine derivative (3-d-2) wherein Y is a group: = CH (CH2) m -? = In the 3-aminopyridine derivative (3-d) of (i) above can be produced by reaction according to the same manner as that described in the reaction scheme (Vll-a) except for the use of a 3-nitropyridine derivative represented by the general formula (9-c-2): (wherein R8 and m are as defined in the foregoing) in place of the above 3-nitropyridine derivative (9-C-1). The 3-aminopyridine derivative (3-d ') of item (ii) above can be produced by reaction according to the same manner as that described in the reaction scheme (Vll-a) except for the use of a derivative of -nitropyridine (9-c ') in place of the 3-nitropyridine derivative (9-c-1).

In the 3-aminopyridine derivative (3), the 3-aminopyridine (3-e) to (3-e ') derivatives shown in the following items (iii) to (iv) can also be produced using, as a starting, a derivative of 3-nitropyridine wherein at least one of the R8 is an acetyloxy group, such as a compound (9-d-11) obtained by the above reaction scheme (Vll-a), or derivatives of -nitropyridine (3-d'-11) to (3-d'-21) wherein at least one of the R8 is an acetyloxy group. (Ii) a 3-aminopridinine derivative (3-e) wherein Y in the group A2 in A is a group: = CH (CH2) m -? - or a group: - (CH2) m-? CH = and at least one of the R8 is an aroyloxy group or a lower alkanoyloxy group with the exception of the acetoxy group (iv) (a 3-aminopyridinine derivative (3-e ') wherein Z in the group A3 in A is a group : = CH (CH2) n -? - or a group: - (CH2) n_? CH = and at least one of the R9 is an aroyloxy group or a lower alkanoyloxy group with the exception of the acetoxy group. -aminopridinine (3-e-1) wherein Y in group A2 is a group: - (CH2) m.1CH = from the above point (ii) will be explained using the following reaction scheme (VI lb).

REACTION SCHEME (Vll-b): (9-f-1) (3-e-1) (wherein R8 and m are as defined in the foregoing, and R8g represents an aroyloxy group or an inner alkanoyloxy group with the exception of the acetoxy group) According to this reaction, the preceding 3-aminopyridine derivative (3-e-1) is obtained by reaction of a compound (9-d-11) obtained in the reaction scheme (Vll-a) with an acid halide without solvent or in a suitable solvent in the presence of an acid to give a compound represented by the general formula (9-f-1) and by reduction of this compound (9-f-1) using a catalytic reduction process in accordance with same way as in the case of the reaction scheme (Vll-a). The solvent may be any that does not adversely affect the reaction, and examples thereof include ethers such as tetrahydrofuran (THF), dioxane and diethyl ether; halogenated hydrocarbon such as carbon tetrachloride, methylene chloride and chloroform; and aromatic hydrocarbon such as benzene and toluene. As the acid halide, for example, the acid halide corresponding to the acyl portion of R8s can be used and examples thereof include propionyl halide, isobutyl halide, pivaloyl halide, hexanoyl halide and benzoyl halide. In specifically explanatory terms, the banzoyl halide such as benzoyl chloride, benzoyl bromide, benzoyl iodide and benzoyl fluoride can be used when a compound (3-e-11) is obtained wherein the acyl portion of the acyloxy group is benzoyl. The acid includes, for example, Lewis acid such as boron trifluoride, boron trichloride, stannic chloride, titanium tetrachloride, ethyl ether tri-boron lutein complex and zinc chloride; hydrogen halide such as hydrogen chloride, hydrogen bromide, hydrogen fluoride and hydrogen iodide: inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid and sulfuric acid; organic acid such as trichloroacetic acid, trifluoroacetic acid and p-toluenesulfonic acid; and anion exchange resin.

The amount of the acid halide used generally ranges from 1 to 100 moles, preferably from 5 to 10 moles, per mole of the 3-nitropyridine derivative (9-d-11). The amount of the acid or base used generally ranges from 0.01 to 10 moles and preferably from 0.02 to 0.1 moles, per mole of the 3-nitropyridine derivative (9-d-11). The reaction is usually carried out under conditions of -78 to 150 ° C for 1 minute to 3 days, and preferably 15 minutes to 24 hours. A pyridine derivative (3-e-2) wherein Y is a group = CH (CH2) m -? - in the 3-aminopyridine derivative (3-e) of the above item (iii) can be produced by reaction according to in the same manner as that described in the reaction scheme (VI lb) except for the use of a pyridine derivative represented by the general formula (9-d-21): (where R8 and m are as defined in the preceding) in place of the above pyridine (9-d-11). The 3-aminopyridine derivative (3-e ') of the preceding point (iv) can be produced by reaction according to the same way as that described in the reaction scheme (VI lb) except for the use of a pyridine derivative ( 9-d'-11) or (9-d'-21) where Z is n group = CH (CH2) n -? - or a group: - (CH2) n-? CH = and at least one of R9 is an acetyloxy group in the place of the preceding pyridine derivative (9-d-11) REACTION SCHEME (VIII): (10) (8) (11) (5) (where A, X and R11 are as defined in the preceding). According to this reaction, the preceding carboxylic acid (5) as a starting material of the reaction scheme (II) is obtained by reacting a monohalopyridinecarboxylate (10) with a compound (8) to give a pyridinecarboxylate derivative (11) and hydrolyzing a protecting group in this compound (11).

In order to obtain the pyridinecarboxylate derivative (11) of the monohalopyridinecarboxylate (10), the reaction can be carried out in the same manner as that described in the preceding reaction scheme (V). The amount of the compound (8) used is generally 1 mol, and preferably 1 to 5 mol, per mol of the monohalopyridinecarboxylate (10). The reaction is usually carried out at a temperature of 0 to 150 ° C, and preferably 20 to 80 ° C, and the reaction is completed within 1 to 30 hours. The pyridinecarboxylate derivative (11) is hydrolyzed in a suitable solvent in the presence of a basic compound. The basic compound includes, for example, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; alkali metal carbonate such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonate such as sodium hydrogen carbonate and carb? potassium hydrogen ato; trialkylamine such as triethylamine and tributylamine; and an organic base such as pyridine, picoline and 1,4-diazabicyclo [2. 2. 2] octane. The solvent may be any that does not adversely affect the reaction, and examples thereof include lower alcohols such as methanol, ethanol, and isopropanol; ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane; water or a solvent mixture thereof. This hydrolysis reaction is usually carried out between -10 • and 200 ° C, and preferably between 30 and 60 ° C, and the reaction is completed within about 30 minutes to 24 hours.

REACTION SCHEME (IX) (13) (wherein R1, R2, R3 and A are as defined in the foregoing). This reaction is a process for obtaining a pyridine derivative (13) which is a compound in which V is -NH-C (= O) -NH- in the general formula (1). According to this reaction, the urea derivative (13) is obtained by the addition of a 3-amino-pyridine derivative (3) to the isocyanate compound (12) without a solvent or in an inert solvent and amines can be added to the system of reaction. Solvents include, for example, benzene, toluene, chlorobenzene, dichloromethane, acetone or tetrahydrofuran and the like. Amines include, for example, tertiary amines such as triethylamine, triisopropylamine and pyridine. The amount of the amine used generally ranges from 1 to 5 moles, and preferably from 1 to 2 moles, per mole of the isocyanate compound (12). The 3-amino-pyridine derivative (3) used generally is from 1 to 10 moles, and preferably from 1 to 3 moles, per mole of the compound isocyanate (12). The reaction is usually carried out under conditions of -10 to 150 ° C, and is completed within 10 minutes to 24 hours.

REACTION SCHEME (X) (14) (15) According to this reaction, a compound (15) is obtained by the saponification of an enol ester derivative (14) using an alkali, and the reaction is carried out in a suitable solvent. The alkali includes, for example, alkali metal hydroxide, salts, alkaline earth metal hydroxide, salts and amines. The solvent may be a protonic solvent, and examples thereof include water; alcohols such as methanol and dioxane; and a mixed solvent of these solvents and ethers such as tetrahydrofuran and dioxane, acetonitrile and dimethylformamide. The amount of the alkali used generally ranges from 1 to 10 moles, and preferably from 1 to 30 moles, per mole of the compound (14). The reaction is usually carried out at a temperature of -10 to 150 ° C, and is completed within about 30 minutes to 24 hours.

REACTION SCHEME (XI) (18) " This reaction is a process for obtaining a pyridine derivative (18) which is a compound where V is -CH = CH- in the general formula (1). According to this reaction, the pyridine derivative (18) is obtained by subjecting the phosphorus-ylide generated from the compound (16) to condensation (Witting reaction) with the aldehyde compound (17). The phosphorus-ylide is generated from the phosphonium salt (16) under anhydrous condition with an appropriate combination of a base and a solvent. The combination of a base and a solvent includes, for example, sodium ethoxide-ethanol, N, N-dimethylformamide, sodium methoxide-methanol-ether; N, N-dimethylformamide, potassium t-butoxide-tetrahydrofuran, dichloromethane; n-butyl lithium ether; phenyl lithium ether and the like. The base used is usually 1 to moles, and preferably 1 to 2 moles, per mole of the phosphonium salt (16).

The reaction is usually carried out at a temperature of -10 to 150 ° C, and is completed within 30 minutes to 24 hours. The phosphoricide is reacted with the aldehyde compound (17) in a solvent mentioned in the foregoing, and the compound (17) used generally ranges from 1 to 10 moles, and preferably from 1 to 3 moles per mole of the compound (16). The reaction is carried out at a temperature of -10 to 150 ° C, and is completed within 30 minutes to 24 hours. A salt of the pyridine derivative (1) in the present invention includes a pharmaceutically acceptable salt thereof. Said salt includes, for example, inorganic acid salt such as hydrochloride, hydrobromide, nitrate, sulfate and phosphate; and salt of organic acid such as methanesulfonate, p-toluenesulfonate, acetate, citrate, tartrate, maleate, fumarate, malate and lactate. Next we will explain a pharmaceutical preparation that • contains the pyridine derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical preparation is prepared in the form of a usual pharmaceutical preparation using the pyridine derivative (1) of the present invention, and is usually prepared using diluents and / or excipients, such as fillers, additives, binders, humectants, disintegrants, surfactants. and lubricants, and that are generally employed. The pharmaceutical preparation can be selected in various ways according to the purpose of treatment, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories and injections (for example, solution, suspension, etc.). In the case of tablet formation, a conventionally known one can be widely used as a carrier. For example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinyl pyrrolidone; disintegrators such as dehydrated starch, sodium alginate, agar powder, laminarin powder, sodium hydrogen carbonate, calcium carbonate, sorbitan polyoxyethylene fatty esters, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil; absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonia and silicic colloidal acid; and lubricants such as purified talc, stearate, boron powder and polyethylene glycol. If necessary, the tablets can be coated with tablets to form sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or two-layer tablets and multi-layer tablets. In the case of the formation of pills, a conventionally known carrier can be widely used as a carrier. For example, excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin and talc may be used; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; and disintegrators such as laminarin and agar. In the case of suppository formation, a conventionally known one can be widely used as a carrier. For example, polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic and glyceride can be used.

In the case of the preparation of injections, for example, the solutions, emulsions and suspensions are preferably sterilized and are sotonic with blood. In the case of the formation of solutions, emulsions and suspensions, a conventionally known diluent can be used as diluent. For example, water, ethanol, propylene glycol, ethoxylated steroaryl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty esters can be used. In this case, the pharmaceutical preparation may also contain sodium chloride, glucose or glycerin in an amount sufficient to prepare an isotonic solution. It may also contain normal solubilizers, pH regulators, and softening agents and, if necessary, may also contain colorants, preservatives, perfumes, flavors, sweeteners and other pharmaceutical compositions. The amount of the pyridine derivative (1) or a salt thereof which is to contain the pharmaceutical preparation may not be specifically limited and broadly selected, but preferably ranges from 1 to 70% by weight based on the total composition. The process for the administration of the pharmaceutical preparation of the present invention is not specifically limited and the pharmaceutical preparation is administered in accordance with the various preparation forms, age and sex of the patients, disease conditions and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally.

The injections are administered intravenously as they are, or after combining them with a normal regenerator such as glucose and amino acid. Also, injections can be administered alone, in a • intramuscular, intracutaneous or subcutaneous, if necessary. Suppositories are administered intrarectally. The dosage of the pharmaceutical preparation can be appropriately selected according to the instructions for use, age and sex of the patients, disease conditions and other conditions, and the pharmaceutical preparation is administered from 1 to several times per day with a daily dose ranging between 0.01 and 100 mg / kg, and preferably from 0.1 to 50 mg / kg. Of course, as the dosage varies according to the different conditions, the dosage is sometimes sufficient when it is lower than the preceding range, or sometimes a dosage higher than that is required. preceding rank.

Best way to Snow out the invention. The following reference examples, examples, preparation examples and test examples further illustrate in detail the present invention.

REFERENCE EXAMPLE 1 Synthesis of 4-F (5-nitro-2-pyridinyl) oxy1-1-indanone 1.0 g of 4-hydroxy-1-indanone, 1.07 g of 2-chloro-5-nitropyridine and 5 g of anhydrous potassium carbonate were dissolved in 10 ml of N, N-dimethylformamide (DMF) and the mixture was stirred at room temperature. environment for 17 hours. After completing the reaction, 50 ml of water was added to the reaction solution and the solution was extracted with ethyl acetate. After washing the organic layer (ethyl acetate) with water and drying over anhydrous sodium sulfate, the solvent was distilled. The resulting residue was recrystallized from ethyl acetate in order to obtain the title compound (1.36 g, pale yellow powder). Melting point: 130-132 ° C EXAMPLE OF REFERENCE 2 Synthesis of 6-r (5-niro-2-pyridinyl) oxy1-1-indanone In accordance with the same manner as that described in Reference Example 1 except for the use of an equimolar amount of 6-hydroxy-1-ndanone instead of 4-hydroxy-1-indanone, the reaction was carried out for get the title compound. 1 H-NMR (CDCl 3) d ppm: 2.76-2.80 (m, 2H), 3.17-3.21 (m, 2H), 7.11 (d, 1 H), 7.39 (dd, 1 H), 7.53-7.58 (m, 2H ), 8.48-8.53 (m, 1 H), 9.01 (d, 1 H).

REFERENCE EXAMPLE 3 Synthesis of 2,3-dihydro-1 H-inden-5-yl (5-nitro-2-pyridinyl) ether According to the same manner as that described in reference example 1 except for the use of an equimolar amount of 5-indanol instead of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound . 1 H-NMR (CDCl 3) d: 2.1 (m, 2 H), 2.9 (m, 4 H), 6.8-9.0 (m, 6 H).

EXAMPLE OF REFERENCE 4 Synthesis of 5-r (5-nitro-2-pyridinyl) oxy-3,4-dihydro- (2H) -naphthalenone According to the same manner as that described in reference example 1 except for the use of an equimolar amount of 5-hydroxy-3,4-dihydro-1 (2H) -naphthalenone instead of 4-hydroxy-1-indanone , the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.05-2.15 (m, 2H), 2.65-2.69 (m, 2H), 2.74-2.79 (m, 2H), 7.12 (d, 1H), 7.30 (dd, 1H), 7.42 (t, 1H), 8.04 (d, 1H), 8.52 (dd, 1 H), 9.01 (d, 1 H).

REFERENCE EXAMPLE 5 Synthesis of 3-i (5-nitro-2-pyridinyl) oxp-6J, 8,9-tetrahydro-5H-benzo [a1c] cycloheptene-5-one According to the same manner as that described in reference example 1 except for the use of an equimolar amount of 3-hydroxy-6,7,8,9-tetrahydro-5H-benzo (a) cycloheptene-5-one in Instead of 4-hydroxy-1-ndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.85-1.95 (m, 4H), 2.76-2.80 (m, 2H), 2.96-3.01 (m, 2H), 7.06 (d, 1 H), 7.23 (dd, 1 H ), 7.23 (dd, 1 H), 7.31 (d, 1 H), 7.54 (d, 1H), 8.49 (dd, 1H), 9.03 (d, 1 H).

REFERENCE EXAMPLE 6 Synthesis of 1- ^ 3-r (5-nitro-2-pyridinyl) oxy-phenyl) -1-ethanone According to the same manner as that described in reference example 1 except for the use of an equimolar amount of 1- (3-hydroxyphenyl) -1-ethanone instead of 4-hydroxy-1-ndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.63 (s, 3 H), 7.11 (d, 1 H), 7.36-7.41 (m, 1 H), 7.57 (t, 1 H), 7.76 (m, 1 H), 7.87- 7.90 (m, 1H), 8.52 (dd, 1 H), 9.02 (d, 1H).

REFERENCE EXAMPLE 7 Synthesis of 1-f2-iT5-nit.O-2-pyridinyl) oxy-phenyl} -1-Etanone According to the same manner as that described in reference example 1 except for the use of an equimolar amount of 1- (2-hydroxyphenyl) -1-ethanone instead of 4-hydroxy-1-indanone, the reaction was out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.6 (s, 3 H), 7.09-9.0 (m, 7 H).

EXAMPLE OF REFERENCE 8 Synthesis of 1-f4-r (5-nitro-2-pyridinyl) oxy-phenyl-1-ethanone According to the same manner described in relation to reference example 1 except that an equimolar amount of 1- (4-hydroxyphenyl) -1-ethanone was used in place of 4-hydroxy-1-indanone, the reaction was out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.6 (s, 3 H), 7.1-9.0 (m, 7 H).

REFERENCE EXAMPLE 9 Synthesis of. { 4-r (5-nitro-2-pyridinyl) oxy} > phenyl (phenyl) methanone According to the same way as that described in reference example 1 except that an equimolar amount of (4-hydroxyphenyl) (phenyl) methanone was used instead of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 7.14 (d, 1H), 7.29 (d, 2H), 7.48-7.65 (m, 3H), 7.82-7.92 (m, 2H), 7.94 (d, 2H), 8.54 ( dd, 1 H), 9.07 (d, 1 H).

REFERENCE EXAMPLE 10 Synthesis of 1-f2-methyl-4-r (5-nitro-2-pyridinyl) oxy phenyl) -1-ethanone In accordance with the same manner as that described in reference example 1 except that an equimolar amount of 1- (4-hydroxy-2-methyl-phenyl) -1- ethanone was used instead of 4-hydroxy-1-indanone, the reaction was carried out for the title compound. 1 H-NMR (CDCl 3) d ppm: 2.58 (s, 3 H), 2.61 (s, 3 H), 7.05-7.11 (m, 3 H), 7.83 (d, 1 H), 8.49-8.54 (m, 1 H), 9.05 (d, 1 H).

REFERENCE EXAMPLE 11 Synthesis of 1-. { 4-r (5-nitro-2-pyridinyl) oxy-phenyl) -1-propanone According to the same way as that described in reference example 1 except that an equimolar amount of 1- (4-hydroxyphenyl) -1-propanone was used instead of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.25 (t, 3 H), 3.02 (q, 2 H), 7.10-7.13 (m, 1 H), 7.23-7.29 (m, 2 H), 8.06-8.11 (m, 2 H) , 8.50-8.55 (m, 1 H), 9.03-9.04 (m, 1H).

REFERENCE EXAMPLE 12 Synthesis of 2,3-dihydro-1 H -inden-4-yl- (5-n-t-2-pyridinyl) ether According to the same manner as that described in reference example 1 except that an equimolar amount of 4-indanol was used in place of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.02-2.13 (m, 2H), 2.67-2.73 (m, 2H), 3.00 (t, 2H), 6.90-6.94 (m, 1 H), 7.01 (d, 1 H ), 7.17-7.26 (m, 2H), 8.44-8.48 (m, 1 H), 9.03-9.04 (m, 1 H).

EXAMPLE OF REFERENCE 13 Synthesis of 2,3-dihydro-7-methyl-1 H-inden-4-yl (5-nitro-2-pyridinyl) ether According to the same manner as described in reference example 1 except that an equimolar amount of 7-methyl-4-indanol was used instead of 4-hydroxy-1-indanone, the reaction was carried out to obtain the compound of the title. 1 H-NMR (CDCl 3) d ppm: 2.28 (s, 3 H), 2.02-2.13 (m, 2 H), 2.74 (t, 2 H), 2.90 (t, 2 H), 6.84 (d, 1 H), 6.99-7.06 (m, 2H), 8.43-8.48 (m, 1 H), 9.04 (d, 1 H).

EXAMPLE OF REFERENCE 14 Synthesis of 5-nitro-2- (5-6,7,8-tetrahydro-1-naphthalenyloxy) pyridine According to the same way as that described in reference example 1 except that an equimolar amount of 5,6,7,8-tetrahydro-1-naphthalenol was used instead of 4-hydroxM-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.75-1.78 (m, 4H). 2.49-2.54 (m, 2H), 2.81-2.85 (m, 2H), 6.89 (d, 1 H), 7.00 (d, 1 H), 7.05 (d, 1 H), 7.19 (t, 1 H), 8.44-8.48 (m, 1 H), 9.04 (d, 1 H).

REFERENCE EXAMPLE 15 Synthesis of 2- (2,3-dimethylphenoxy) -5-nitropyridine According to the same manner to that described in Reference Example 1 except that an equimolar amount of 2,3-dimethyphenol was used in place of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound . 1 H-NMR (CDCl 3) d ppm: 2.06 (s, 3 H), 2.34 (s, 3 H), 6.90-6.93 (m, 1 H), 6.98-7.02 (m, 1 H), 7.11-7.21 (m, 2H ), 8.44-8.49 (m, 1 H), 9.04 (d, 1 H).

EXAMPLE OF REFERENCE 16 Synthesis of 5-nytro-2-phenoxypyridine According to the same manner as described in reference example 1 except that an equimolar amount of phenol was used in place of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 7.00-7.05 (m, 1 H), 7.13-7.24 (m, 2H), 7.26-7.34 (m, 1H), 7.42-7.50 (m, 2H), 8.44-8.50 ( m, 1H), 9.05 (d, 1H).

REFERENCE EXAMPLE 17 Synthesis of 4-r (5-amino-2-pyridinyl) oxy1-1-indanone 1 g of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone obtained in reference example 1 was dissolved in 25 ml of methanol and the mixture subjected to catalytic reduction at room temperature and normal pressure in the presence of 100 mg of 10% palladium-carbon. After 20 hours, the catalyst was removed by filtration and the filtrate was concentrated under low pressure to obtain a brown solid. The solid was purified by silica gel chromatography (eluent: ethyl acetate) to obtain 840 mg of the title compound as a pale yellow powder. Melting point: 119-123 ° C.

EXAMPLE OF REFERENCE 18 Synthesis of 6-r (5-amino-2-pyridinyl) oxp-1-ndanone According to the same way to that described in reference example 17 except that an equimolar amount of 6 - [(5-nitro-2-pyridinyl) oxy] -1-indanone obtained in reference example 2 was used instead of 4- [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.70-2.74 (m, 2H), 3.09-3.13 (m, 2H), 6.82 (d, 1 H), 7.09-7.13 (m, 1 H), 7.33-7.37 (m , 2H), 7.44-7.48 (m, 1 H), 7.69 (d, 1 H).

EXAMPLE OF REFERENCE 19 Synthesis of 6- (2,3-dihydro-1H-inden-5-yloxy) -3-pyridinylamine According to the same way to that described in reference example 17 except that an equimolar amount of 2,3-dihydro-1 H-inden-5-yl (5-nitro-2-pyridinyl) ether obtained in the reference example 3 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.0 (m, 2 H), 2.8 (m, 4 H), 3.5 (brs, 2 H), 6.8-9.0 (m, 6 H).

REFERENCE EXAMPLE 20 Synthesis of 5-α (5-amino-2-pyridinyl) oxy-3,4-dihydro-1 (2H) -naphthalenone According to the same manner as that described in reference example 17 except that an equimolar amount of 5 - [(5-nitro-2-pyridinyl) oxy] -3,4-dihydro-1 ( 2H) -naphthalenone obtained in the reference example 4 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.05-2.15 (m, 2H), 2.62-2.67 (m, 2H), 2.85-2.90 (m, 2H), 3.53 (br, 2H), 6.78 (d, 1 H) , 7.11 (dd, 1 H), 7.18 (dd, 1 H), 7.30 (t, 1H), 7.66 (d, 1 H), 7.88 (dd, 1 H).

SYNTHESIS OF REFERENCE 21 Synthesis of 3-r (5-amino-2-pyridinyl) oxy1-6.7.8,9-tetrahydro-5H-benzo cyclohepten-S-one According to the same way to that described in reference example 17 except that an equimolar amount of 3 - [(5-nitro-2-pyridinyl) oxy] -6,7,8,9-tetrahydro-5H-benzo was used (a) Cyclohepten-5-one obtained in Reference Example 5 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound . 1 H-NMR (CDCl 3) d ppm: 1.81-1.88 (m, 4 H), 2.69-2.74 (m, 2 H), 2.87-2.92 (m, 2 H), 6.76 (d, 1 H), 7.06 (dd, 1 H ), 7.11-7.19 (m, 2H), 7.39 (d, 1 H), 7.66 (d, 1 H).

REFERENCE EXAMPLE 22 Synthesis of 1- (3-r.5-amino-2-pyridine) oxphenyl} -1-Etanone According to the same way as that described in reference example 17 except that an equimolar amount of 1- was used. { 3 - [(5-nitro-2-pyridinyl) oxy] phenyl} -1-ethanone obtained in Reference Example 6 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-nndanone, the reaction was carried out to obtain the title compound. Yellow oily substance with an Rf value of 0.36 in silica gel thin layer chromatography using ethyl acetate / hexane (2: 1) as a developing solvent.

REFERENCE EXAMPLE 23 Synthesis of 1 -12- (5-amino-2-pyridinyl) oxypihenyl > -1-Etanone • According to the same way as that described in reference example 17 except that an equimolar amount of 1- was used. { 2- (5-nitro-2-pyridinium) oxy] phenyl} -1-ethanone obtained in the reference example 7 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.6 (s, 3 H), 3.6 (brs, 2 H), 6.8-7.8 (m, 7H).

REFERENCE EXAMPLE 24 Synthesis of 1-. { 4-r (5-amino-2-pyridine? 'L) oxflfeni.) - 1 -ethanone According to the same way as that described in reference example 17 except that an equimolar amount of 1- was used. { 4 - [(5-nitro-2-pyridinyl) oxy] phenyl} -1-ethanone obtained in Reference Example 8 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 20 1 H-NMR (CDCl 3) d ppm: 2.5 (s, 3 H), 3.6 (brs, 2 H), 6.8-7.9 (m, 7H).

REFERENCE EXAMPLE 25 Synthesis of. { 4-F (5-amino-2-pyridinyl) oxy-phenyl-phenyl) methanone • According to the same way as that described in reference example 17 except that an equimolar amount of. { 4 - [(5-nitro-2-pyridinyl) oxy] phenyl} (phenyl) methanone obtained in Reference Example 9 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 3.6 (brs, 2H), 6.8-7.8 (m, 12H). 10 REFERENCE EXAMPLE 26 Synthesis of 1 -. { 4-f (5-amino-2-pyridinyl) oxy-1-2-methylphenyl} -1-Etanone According to the same way as that described in the example of reference 17 except that an equimolar amount of 1 - was used. { 2-methyl-4 - [(5-nitro-2-pyridinyl) oxy] phenyl} -1-ethanone obtained in reference example 10 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.53 (s, 3 H), 2.55 (s, 3 H), 6.82 (d, 1 H), 20 6.88-6.92 (m, 2 H), 7.09-7.13 (m, 1 H) 7.30-7.76 (m, 2H).

REFERENCE EXAMPLE 27 Synthesis of 1-. { 4-r (5-amino-2-pyridinyl) oxy-phenyl-1-propanone According to the same way as that described in reference example 17 except that an equimolar amount of 1- was used. { 4 - [(5-nitro-2-pyridinyl) oxy] phenyl} -1-Propanone obtained in Reference Example 11 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-nndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.22 (t, 3H), 2.97 (q, 2H), 3.63 (brs, 2H), 6.83 (d, 1 H), 7.05-7.07 (m, 2H), 7.10-7.14 (m, 1 H), 7.74-7.76 (m, 1H), 7.94-7.99 (m, 2H).

EXAMPLE OF REFERENCE 28 Synthesis of 6- (2,3-dihydro-1 H-inden-4-yloxy) -3-pyridyl-amine According to the same manner as that described in reference example 17 except that an equimolar amount of 2,3-dihydro-1 H-inden-4-yl (5-nitro-2-pyridinyl) ether obtained in the Reference example 12 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.98-2.03 (m, 2H), 2.71-2.77 (m, 2H), 2.91-2.97 (m, 2H), 6.70-673 (m, 1 H), 6.80-6.83 ( m, 1 H), 7.02-7.09 (m, 2H), 7.10-7.16 (m, 1 H), 7.69-7.70 (m, 1 H).

REFERENCE EXAMPLE 29 Synthesis of 6-f (7-methyl-2-3-dihydro-1 H -inden-4-yl) oxy} -3-pyridine-amine • According to the same manner as that described in reference example 17 except that an equimolar amount of 2,3-dihydro-7-methyl-1 H-inden-4-yl (5-nitro) was used. 2-pyridinyl) ether obtained in reference example 13 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out for get the title compound. 1 H-NMR (CDCl 3) d ppm: 1.97-2.08 (m, 2H), 2.22 (s, 3H), 2.74 (t, 2H), 2.81-2.87 (m, 2H), 3.40 (brs, 2H), 6.69 (d, 2H), 6.76 (d, 2H), 6.95 (d, 1 H), 7.02-7.05 (m, 1 H) ), 7.66 (d, 1 H).

REFERENCE EXAMPLE 30 Synthesis of 6- (5,6,7,8-tetrahydro-1-naphthalenyloxy) -3-pyridinylamine 15 According to the same manner as that described in reference example 17 except that an equimolar amount was used of 5-nitro-2- (5,6,7,8-tetrahydro-1-naphthalenyloxy) pyridine obtained in Reference Example 14 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1- Indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.21-1.80 (m, 4H), 2.63-2.65 (m, 2H), 2.79 (m, 2H), 6.68 (dd, 1H), 6.76-6.79 (m, 1H), 6.89-6.91 (m, 1H), 7.03-7.11 (m, 2H), 7.69 (dd, 1 H) EXAMPLE OF REFERENCE 31 Synthesis of 6- (2,3-dimethylphenoxy) -3-pyridinylamine • According to the same way as that described in reference example 17 except that an equimolar amount of 2- (2,3-dithmethoxy) -5-nitropyridine obtained in the reference example was used 15 in place of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.12 (s, 3 H), 2.30 (s, 3 H), 6.65-6.69 (m, 1 H), 6.81-6.84 (m, 1 H), 6.96-6.99 (m, 1 H), 7.03-7.10 (m, 1 H), 7.68-7.69 (m, 1 H).

REFERENCE EXAMPLE 32 Synthesis of 6-phenoxy-3-pyridinylamine 15 According to the same manner as that described in reference example 17 except that an equimolar amount of 5-nitro-2-phenoxypyridine obtained in the example of reference 16 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the compound of the title. 1 H-NMR (CDCl 3) d ppm: 6.75-6.78 (m, 1 H), 7.02-7.15 (m, 4 H), 7.31-7.38 (m, 2 H), 7.72-773 (m, 1 H).

EXAMPLE OF REFERENCE 33 Synthesis of 2-f4- (2-methyl-1,3-dioxolane-2-yl) phenoxy-5-nitropyridine 380 mg of 1- were dissolved. { 4 - [(5-n, t-2-pyridinyl) oxy] phenyl} -1-ethanone in 5 ml of benzene and, after adding 98 μl of ethylene glycol and 3 mg of (±) -IO-camphorsulfonic acid, the mixture was heated to reflux. After 3 hours, the reaction solution was stirred with ethyl acetate. In turn, the organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under low pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate / n-hexane (1: 4)) to obtain the title compound (280 mg). H-NMR (CDCl 3) d ppm: 1.6 (s, 3 H), 3.8 (m, 2 H), 4.0 (m, 2 H), 7.0-9.0 (m, 7 H).

EXAMPLE OF REFERENCE 34 Synthesis of 2-r3- (2-methyl-1,3-dioxolane-2-yl) phenoxy-5-nitropyridine According to the same way as that described in reference example 33 except that an equimolar amount of 1- was used. { 3 - [(5-nitro-2-pyridinol) oxy] phenyl} -1-ethanone obtained in reference example 6 instead of 1-. { 4 - [(5-nitro-2-pyridinyl) oxy] phenol} -1-ethanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.7 (s, 3 H), 3.6 (m, 2 H), 3.8 (m, 2 H), 7.0 (d, 1 H), 7.1 (dd, 1 H), 7.3 (ddd, 1 H), 7.4 (ddd, 1 H), 7.6 (dd, 1 H), 8.4 (dd, 1 H), 9.0 (d, 1 H).

EXAMPLE OF REFERENCE 35 Synthesis of 6-f4- (2-methyl-1,3-dioxolane-2-yl) phenoxy-3-pyridinylamine According to the same way as that described in reference example 17 except that an equimolar amount of 2- was used. { 4 - [(2-methyl-1,3-dioxolane-2-yl) phenoxy] -5-nitropyridine obtained in reference example 33 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1 -indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.6 (s, 3 H), 3.5 (brs, 2 H), 3.8 (m, 2 H), 4.0 (m, 2 H), 6.7-7.7 (m, 7 H).

REFERENCE EXAMPLE 36 Synthesis of 6-f3- (2-methyl-1,3-dioxolane-2-yl) phenoxy-3-pyridine-amine According to the same way as that described in reference example 17 except that an equimolar amount of 2- was used. { 3 - [(2-methyl-1,3-dioxo-Iano-2-yl) phenoxy] -5-nitropyridine obtained in reference example 34 instead of 4 - [(5-nitro-2-pyrid)] nil) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.9 (s, 3 H), 3.8 (m, 2 H), 4.0 (m, 2 H), 6.8 (d, 1 H), 7.0 (dd, 1 H), 7.2 (m, 2H), 7.3 (dd, 1 H), 7.6 (dd, 1 H), 7.7 (d, 1 H).

REFERENCE EXAMPLE 37 Synthesis of 1-4-r (5-amino-2-pyridinyl) oxylphenip-1-ethanol 8.14 g of 1- were dissolved. { 4 - [(5-nitro-2-pyridinyl) oxy] phenyl} -1-ethanone in 15 ml of ethyl acetate, and after adding 2 g of 10% palladium-carbon, the mixture was stirred overnight at 0 ° C under partial hydrogen pressure. After the reaction was completed, the reaction solution was filtered with celite and the filtrate was concentrated under low pressure. The resulting residue was purified by silica gel chromatography. The compound synthesized in reference example 24 was obtained from a fraction prepared by using an eluent (ethyl acetate / n-hexane (2: 1)), in that the title compound (193 mg) was obtained from a fraction prepared by using an eluent (ethyl acetate / n-hexane (3: 1)). 1 H-NMR (CDCl 3) d ppm: 1.50 (d, 3 H), 3.52 (brs, 2 H), 4.90 (q, 1 H), 6.77 (d, 1 H), 7.02-7.11 (m, 3 H), 7.33- 7.38 (m, 2H), 7.72 (m, 1 H).

EXAMPLE OF REFERENCE 38 Synthesis of ethyl 6-r (1-oxo-2,3-dihydro-1H-inden-4-yl) oxpnicotinate 1.86 g of ethyl 6-chloronicotinate and 1.48 g of 4-hydroxy-1-indanone were dissolved in 15 ml of DMF. 0.97 g of potassium carbonate was added to the resulting solution and the mixture was stirred at 120 ° C. After 1 hour, ethyl acetate and water were added to the reaction solution, therefore there was partition between an organic layer and an aqueous layer. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated at low pressure. The residual oily substance was purified by column chromatography (eluent: ethyl acetate / n-hexane (1: 4)) to obtain the title compound (2.52 g) as an oily substance. H-NMR (CDCl 3) d ppm: 1.39 (t, 3H, J = 7 Hz), 2.68 (m, 2H), 2.94 (m, 2H), 4.38 (q, 2H, J = 7 Hz), 7.05 (d, 1 H, J = 8 Hz), 7.38 (d, 1 H, J = 8 Hz), 7.46 (t, 1H, J = 8 Hz), 7.69 (d, 1H, J = 8 Hz), 8.33 (d, 1 H, J = 8 Hz), 8.78 (s, 1H).

EXAMPLE OF REFERENCE 39 Synthesis of ethyl 6-r (1-oxo-2,3-dihydro-1H-inden-5-yl) oxynicotinnate According to the same manner as that described in reference example 38 except that an equimolar amount of 5-hydroxy-1-indanone was used instead of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.39 (t, 3 H), 2.73 (t, 2 H), 3.16 (t, 2 H), 4.39 (q, 2 H), 7.04-8.83 (m, 6 H).

EXAMPLE OF REFERENCE 40 Synthesis of ethyl 6-F (5-oxo-5,67,8-tetrahydro-1-naphthalenyl) oxylnicotinate According to the same manner as that described in Reference Example 38 except that an equimolar amount of 5-hydroxy-3,4-dihydro-1 (2H) -naphthalenone was used in place of 4-hydroxy-1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.4 (t, 3H), 2.1 (m, 2H), 2.6 (m, 2H), 2.7 (m, 2H), 4.4 (dd, 2H), 7.0-8.8 (m, 6H).

EXAMPLE OF REFERENCE 41 Synthesis of ethyl 6- (4-acetylphenoxy) nicotinate According to the same manner as that described in reference example 38 except that an equimolar amount of 1- (4-hydroxyphenyl) -1-ethanone was used instead of 4-hydroxy-1-indanone, the reaction was carried out out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.4 (t, 3 H), 2.6 (s, 3 H), 4.4 (dd, 2 H), 7.0-8.8 (m, 6 H).

EXAMPLE OF REFERENCE 42 Synthesis of 6-r (1-oxo-2,3-dihydro-1H-inden-4-yl) oxyflutinic acid 1.49 g of ethyl 6 - [(1-oxo-2) was dissolved, 3-dihydro-1 H-inden-4-yl) nicotinate in a mixed solvent of 10 ml of tetrahydrofuran and 10 ml of ethanol. To the resulting solution was added 15 ml of an aqueous solution of 1 N sodium hydroxide and the mixture was stirred at room temperature. After 30 minutes, the reaction solution was concentrated under low pressure. To the resulting residue, water was added and the solution was neutralized with 1 N hydrochloric acid. The deposited crystal was separated by filtration, washed with water and then dried at 40 ° C under low pressure to obtain 1.27 g of the title compound as a pale yellow crystal. 1 H-NMR (CDCl 3) d ppm: 2.63 (m, 2 H), 2.82 (m, 2 H), 7.24 (d, 1 H, J = 8 Hz), 7.56 (m, 3 H), 8.33 (d, 1 H, J = 8 Hz), 8.65 (s, 1 H), 13.25 (brs, 1 H).

EXAMPLE OF REFERENCE 43 Synthesis of 6-r (1-oxo-2,3-dihydro-1H-inden-4-yl) oxynicotonic acid According to the same manner as that described in reference example 42 except that an equimolar amount of ethyl 6 - [(1-oxo-2,3-dihydro-1H-inden-5-yl) oxy] nicotinate was used. obtained in reference example 39 instead of ethyl 6 - [(1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy] nicotinate, the reaction was carried out to obtain the composed of the title. 1 H-NMR (DMSO-de) d ppm: 2.67 (t, 2 H), 3.11 (t, 2 H), 7.20-7.25 (m, 2 H), 7.39 (s, 1 H), 7.70 (d, 1 H), 8.31-8.36 (m, 1 H), 8.69-870 (m, 1 H), 1.32 (brs, 1H).

EXAMPLE OF REFERENCE 44 Synthesis of 6-r (5-oxo-5,6J, 8-tetrahydro-1-naphthalenyl) oxpnicotonic acid In accordance with the same manner as that described in reference example 42 except that an equimolar amount of ethyl 6 - [(5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] nicotinate obtained was used in reference example 40 instead of ethyl 6 - [(1-oxo-2,3-dihydro-1 H -inden-4-yl) oxy] nicotinate, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.0 (m, 2H), 2.6 (m, 4H), 7.2-8.6 (m, 6H).

REFERENCE EXAMPLE 45 Synthesis of 6- (4-acetylphenoxy) nicotonic acid According to the same manner as that described in reference example 42 except that an equimolar amount of ethyl 6- (4-acetylphenoxy) nicotinate 1 obtained in reference example 41 was used in place of ethyl 6 - [(1 - oxo-2, 3-dihydro-1 H-inden-4-yl) oxy] nicotinate, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-d 6) d ppm: 2.6 (s, 3 H), 7.2-8.7 (m, 6 H), 13.3 (brs, 1 H).

EXAMPLE OF REFERENCE 46 Synthesis of 4-r (5-nitro-2-pyridinyl) oxy-1-indanone ethylene ketal According to the same manner as that described in reference example 33 except that an equimolar amount of 4- was used. { (5-nitro-2-pyridinyl) oxy] -1-indanone obtained in reference example 1 instead of 1-. { 4 - [(5-nitro-2-pyridinyl) oxy] phenol} -1-ethanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.29 (t, 2 H, J = 6.93 Hz), 2.73 (t, 2 H, J = 6.93 Hz), 4.09-4.22 (m, 4 H), 7.02 (d, 1 H, J = 9.24 Hz), 7.10-7.13 (m, 1 H), 7.32-7.37 (m, 2H), 8.45-8.49 (m, 1 H), 9.03 (d, 1 H, J = 2.31 Hz).

EXAMPLE OF REFERENCE 47 Synthesis of 4-r (5-amino-2-pyridinyl) oxy-1-indanone ethylene ketal According to the same manner as that described in reference example 17 except that an equimolar amount of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone ethylene ketal obtained in reference example 46 was used. instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound as an oily substance.

Ms m / e = 284 (M *) for C16H? 6N2O3 EXAMPLE OF REFERENCE 48 Synthesis of 3-acetyloxy-7-r (5-nitro-2-pyridinyl) oxp-1 H-indene To 5.00 g of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone was added 10 ml of isopropylene acetate and 70 mg of p-toluenesulfonic acid and the mixture was stirred at 80 ° C. After 7.5 hours, the reaction solution was concentrated under low pressure. To the resulting residue, ethyl acetate was added and the solution was washed in turn with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled. The resulting residue was washed with isopropyl ether in hot state to obtain 4.70 g of the title compound. 1 H-NMR (CDCl 3) d ppm: 2.35 (s, 3 H), 3.26 (d, 2 H, J = 2.31 Hz), 6. 34 (t, 1 H, J = 2.31 Hz), 7.03-7.09 (m, 2H), 7.28 (d, 1 H, J = 9.24 Hz), 7.38-7.44 (m, 1 H), 8.48 (dd, 1 H, J = 9.24, 2.97 Hz), 9.01 (d, 1 H, J = 2.97 Hz).

EXAMPLE OF REFERENCE 49 Synthesis of 3-acetyloxy-7-r (5-amino-2-pyridinyl) oxy-1 H-indene To a solution of 3-acetyloxy-7 - [(5-nitro-2-pyridinyl) oxy] -1 H-indene (4.00 g) obtained in reference example 48 in tetrahydrofuran (120 ml), 47 was added. mg of platinum dioxide as a catalyst and the mixture was stirred at room temperature under a flow of hydrogen gas. After 1 hour, the catalyst was removed from the reaction solution by filtration and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate (1: 1)) to obtain 1.67 g of the title compound. 1 H-NMR (CDCl 3) d ppm: 2.32 (s, 3 H), 3.26 (d, 2 H, J = 2.31 Hz), 3.42 (brs, 2 H), 6.28 (t, 1 H, J = 2.31 Hz), 6.74 ( d, 1 H, J = 8.58 Hz), 6.90 (d, 1 H, J = 7.92 Hz), 7.02 (dd, 1 H, J = 8.58, 2.97 Hz), 7.11 (d, 1 H, J = 7.26 Hz ), 7.26-7.32 (m, 1 H), 7.64 (d, 1H, J = 2.97 Hz).

REFERENCE EXAMPLE 50 Synthesis of 3-benzoyloxy-7-r (5-nitro-2-pyridinyl) oxp-1 H-indene To 500 mg of 3-acetyloxy-7 - [(5-nitro-2-pyridinyl) oxy] -1 H-indene, 5 ml of benzoyl chloride and 15 mg of p-toluenesulfonic acid were added and the mixture was stirred at 100 ° C. After 1.5 hours, ethyl acetate was added to the reaction solution and the solution was washed in turn with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate (10: 1)) to obtain 130 mg of the title compound as a white powder. 1 H-NMR (CDCl 3) d ppm: 3.34 (d, 2 H, J = 2.31 Hz), 6.52 (t, 1 H, • J = 2.31 Hz), 7.06-7.12 (m, 2H), 7.38-770 (m, 5H), 8.23-8.27 (m, 2H), 8.51 (dc, 1H, J = 8.91, 2.64 Hz), 9.04 ( d, 1H, J = 2.64 Hz).

EXAMPLE OF REFERENCE 51 Synthesis of 7-r (5-amino-2-pyridinyl) oxp-3-benzoyloxy-1 H-indene According to the same manner as that described in Reference Example 49 except that an equimolar amount of 3-benzoyloxy-7- [(5-nitro-2-pyridinyl) oxy] -1 H-indene obtained in the reference example 50 instead of 3-acetyloxy-7 - [(5-nitro-2-pyridinyl) oxy] -1 H-indene, the reaction was carried out to obtain the title compound. 15 1 H-NMR (CDCl 3) d ppm: 3.34 (d, 2 H, J = 2.31 Hz), 6.46 (t, 1 H, J = 2.31 Hz), 6.77 (d, 1 H, J = 8.57 Hz), 6.93-6.96 (m, 1 H), 7.04-7.09 (m, 1 H), 7.22-7.32 (m, 2H), 7.49- 7.69 (m, 4H), 8.22-8.25 (m, 2H).

EXAMPLE OF REFERENCE 52 Synthesis of 3-isobutyryloxy-7-r (5-nitro-2-pyridinyl) oxp-1 H-indene According to the same manner as that described in reference example 50 except that isobutyryl chloride was used in place of benzoyl chloride, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.35 (d, 6 H, J = 7 Hz), 2.81-2.92 (m, 1 H), 3.26 (d, 2 H, J = 2 Hz), 6.35 (t, 1 H, J = 2 Hz), 7.03-7.09 (m, 2H), 7.25-7.44 (m, 2H), 8.47-8.52 (m, 1 H), 9.02 (d, 1 H, J = 3 Hz).

EXAMPLE OF REFERENCE 53 Synthesis of 7-r (5-nitro-pyridinyl) oxp-3-pivaloyloxy-1 H-indene According to the same manner as that described in reference example 50 except that pivaloyl chloride was used in place of benzoyl chloride, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.40 (s, 9 H), 3.26 (d, 2 H, J = 2 Hz), 6.34 (t, 1 H, J = 2 Hz), 7.03-7.08 (m, 2 H), 7.25-7.27 (m, 1 H), 7.39-7.44 (m, 1 H), 8.49 (dd, 1H, J = 9 Hz, 3 Hz), 9.01 (d, 1 H, J = 3 Hz).

REFERENCE EXAMPLE 54 Synthesis of 1-acetoxy-5-r (nitro-2-pyridinyl) oxy-3,4-dihydronaphthalene In accordance with the same manner as that described in reference example 48 except that 5 - [(5-nrtro-2-pyridinyl) oxy] -3,4-dihydro-1 (2H) -naphthalenone was used obtained in Reference Example 4 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.32 (s, 3 H), 2.40-2.44 (m, 2 H), 2.66-2.72 (m, 2 H), 5.75 (t, 1 H, J = 5 Hz), 6.98-7.26 (m, 4H), 8.48 (dd, 1 H, J = 3 Hz, 9 Hz), 9.03 (t, 1 H, J = 1 Hz).

REFERENCE EXAMPLE 55 Synthesis of 1-acetoxy-5-r (5-amino-2-pyridinyl) oxy-3,4-dihydronaphthalene In accordance with the same manner as that described in reference example 49 except that 1-acetoxy-5 - [(5-nitro-2-pyridinyl) oxy] -3,4-dihydronaphthalene obtained in the example of reference 54 in place of 3-acetyloxy-7 - [(5-nitro-2-pyridinyl) oxy] -1 H-indene, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.30 (s, 3 H), 2.32-2.44 (m, 2 H), 2.80 (t, 2 H, J = 8 Hz), 5.71 (t, 1 H, J = 5 Hz), 6.69 (d, 1 H, J = 9 Hz), 6.89-6.95 (m, 2H), 7.07 (dd, 1 H, J = 9 Hz, 3 Hz), 7.15 (t, 1 H, J = 8 Hz) , 7.68 (d, 1 H, J = 3 Hz).

EXAMPLE OF REFERENCE 56 Synthesis of 6-r (5-nitro-2-pyridinyl) oxyl-3,4-dihydro-1 (2H) -naphthalenone • According to the same manner as that described in Reference Example 1 except that an equimolar amount of 6-hydroxy-3,4-dihydro-1 (2H) naphthalenone was used instead of 4-hydroxy-1-indanone , the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.14-2.32 (m, 2H), 2.66-271 (m, 2H), 2.98-3.03 (m, 2H), 7.07-7.12 (m, 3H), 8.15 (d, 1 H, J = 3 Hz), 8.50-8.54 (m, 1 H), 9.05 (d, 1 H, J = 3 Hz).

EXAMPLE OF REFENCE 57 Synthesis of 1-acetoxy-6-r (5-n-tro-2-pyridinyl) oxy-3,4-dlhydronaphthalene According to the same manner as that described in reference example 48 except that 4 - [(5-nitro-2-pyridinol) oxy] -3,4-dihydro-1 (2H) was used. NaphthaIenone obtained in Reference Example 56 instead of 4 - [(5-nitro-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 20 1 H-NMR (CDCl 3) d ppm: 2.31 (s, 3 H), 2.45-2.53 (m, 2 H), 2.90 (t, 2H, J = 8 Hz), 5.73 (t, 1 H, J = 5 Hz), 6.95-6.97 (m, 2H), 7.03 (d, 1 H, J = 9 Hz), 7.16 (d, 1 H, J = 9 Hz), 8.47 (dd, 1 H, J = 9 Hz, 3 Hz), 9.05 (d, 1 H, J = 3 Hz).

EXAMPLE OF REFERENCE 58 Synthesis of 1-acetoxy-6-r.5-amino-2-pyridine) oxy1-3.4-dihydronaphthalene In accordance with the same manner as that described in reference example 49 except that 1-acetoxy-5 - [(5-nitro-2-pyridinium) oxy] -3,4-dihydronaphthalene obtained in reference example 57 was used in place of 3-acetyloxy-7 - [(5-n-t-2-pyridinyl) oxy] -1 H-indene, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.28 (s, 3 H), 2.41-2.47 (m, 2 H), 2.83 (t, 2 H, J = 8 Hz), 5.63 (t, 1 H, J = 5 Hz), 674-6.85 (m, 3H), 7.04-7.10 (m, 2H), 7.72 (d, 1 H, J = 3 Hz).

EXAMPLE OF REFERENCE 59 Synthesis of 4-F (5-cyano-2-pyridinyl) oxy-1-indanone According to the same manner as that described in Reference Example 1 except that 5-cyano-2-chloropyridine was used in place of 2-chloro-5-nitropyridine, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.68-272 (m, 2 H), 2.92-2.96 (m, 2 H), 7.14 (dd, 1 H, J = 1 Hz, 9 Hz), 7.37 (dd, 1 H, J = 1 Hz, 8 Hz), 7.45-7.51 (m, 1 H), 770-773 (m, 1H), 7.98 (dd, 1 H, J = Hz, 9 Hz), 8.43 (dd, J = 1 Hz, 2 Hz).

REFERENCE EXAMPLE 60 Synthesis of 4-f (5-formyl-2-pyridinyl) oxp-1-indanone To a solution prepared by suspending 4.6 g of 4 - [(5-cyano-2-pyridinol) oxy] -1-indane obtained from reference example 59 in 4.4 ml of water and 11 ml of formic acid, 2.6 g of Raney nickel was added at 60 ° C. The reaction solution was stirred at the same temperature for 5 hours and subjected to filtration. To the filtrate, ethyl acetate was added under cooling with ice. After neutralizing the reaction solution with 5 N sodium hydroxide, the organic layer was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and dried over anhydrous magnesium. The solvent was distilled at low pressure. The resulting residue was purified by silica column chromatography (eluent: hexane / ethyl acetate = 5/1) to obtain 2.98 g of the title compound. 1 H-NMR (CDCl 3) d ppm: 2.68-272 (m, 2 H), 2.93-2.98 (m, 2 H), 7.16 (d, 1 H, J = 9 Hz), 7.39-7.42 (m, 1 H), 7.46-7.52 (m, 1 H), 770-773 (m, 1 H), 8.25 (dd, 1 H, J = 2 Hz, 9 Hz), 8.59 (d, 1 H, J = 2 Hz), 10.00 (s, 1 H).

EXAMPLE 1 Synthesis of 3,4-dichloro-N 1 -f 6 -r (1 -oxo-2,3-dihydro-1 H -inden-4-yl) oxn-3-pyridinyl > benzamide To 5 ml of a solution prepared by dissolving 300 mg of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone obtained in reference example 17 and 240 mg of 3,4-acid Dichlorobenzoic acid in DMF, 250 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added under cooling with ice and the mixture was stirred at room temperature. After 24 hours, 10 ml of water was poured into the reaction solution and the solution was extracted with ethyl acetate. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled at low pressure. The resulting residue was recrystallized from ethyl acetate to obtain 380 mg of the title compound as a white powder. Melting point: 202-204 ° C.

EXAMPLE 2 Synthesis of N1-6-p -oxo-2,3-dihydro-1 H-inden-4-yl) oxp-3-pyridinyl > -4- (trifluoromethyl) benzamide According to the same manner as that described in Reference Example 1 except that 4- (trifluoromethyl) benzoic acid was used in place of 3,4-dichlorobenzoic acid, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.65-2.69 (m, 2H), 2.95-2.98 (m, 2H), 7.06-7.09 (m, 1 H), 7.37-7.44 (m, 2H), 7.60-779 (m, 2H). m, 3H), 7.94 (brs, 1 H), 7.90-8.02 (m, 2H), 8.24-8.36 (m, 2H).

EXAMPLE 3 Synthesis of 4-chloro-N1 -. { 6-F (1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy1-3- pridiniDbenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 4-chlorobenzoic acid was used in place of 3,4-dichlorobenzoic acid, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.64-2.68 (m, 2H), 2.94-2.98 (m, 2H), 7.02-7.06 (m, 1 H), 7.25-7.48 (m, 4H), 7.61-7.64 ( m, 1 H), 7.82-7.85 (m, 2H), 8.04 (brs, 1 H), 8.23-8.29 (m, 2H).

EXAMPLE 4 Synthesis of 2,4-dichloro-N 1 -. { 6-r (1-oxo-2,3-dihydro-1 H-inden-4-yl) oxp-3-pyridinilibenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 2,4-dichlorobenzoic acid was used in place of 3,4-dichlorobenzoic acid, the reaction was carried out to obtain the compound of Title. 1 H-NMR (CDCl 3) d ppm: 2.66-270 (m, 2H), 2.95-3.00 (m, 2H), 7.05-7.08 (m, 1H), 7.34-7.49 (m, 4H), 7.62-775 (m , 2H), 8.03-8.30 (m, 2H).

EXAMPLE 5 Synthesis of 3,4-dichloro-N 1 -6- (3-oxo-2,3-dihydro-1 H -inden-5-yl) oxy-3-pyridinylbenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 6 - [(5-amino-2-pyridinyl) oxy] -1-indanone obtained in reference example 18 was used instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 272-276 (m, 2 H), 3.14 (t, 2 H), 7.00-7.03 (m, 1 H), 7.39 (dd, 1 H), 7.45 (d, 1 H) , 7.51 (d, 1 H), 7.56 (d, 1 H), 7.72 (dd, 1 H), 8.00 (d, 1 H), 8.08 (brs, 1 H), 8.21-8.24 (m, 2H).

EXAMPLE 6 Synthesis of N 1 -f 6 -r (3-oxo-2,3-dihydro-1 H -nden-5-yl) oxy-3-pyridinyl-4- (trifluoromethyl) benzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 4- (trifluoromethyl) benzoic acid was used in place of 3,4-d-chlorobenzoic acid and an equimolar amount of 6 - [( 5-amino-2-pyridinyl) oxy] -1-indanone obtained in reference example 18 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.04-276 (m, 2H), 3.12-3.17 (m, 2H), 7.01-7.04 (m, 1H), 7.37-7.41 (m, 1 H), 7.46-7.47 ( m, 1H), 7.50-7.59 (m, 1 H), 774-777 (m, 2H), 7.99-8.02 (m, 2H), 8.10 (brs, 1 H), 8.25-8.29 (m, 2H).

EXAMPLE 7 Synthesis of 3,4-dichloro-N 1 -f 6 -r (2,3-dihydro-1 H -inden-5-yl) oxy-3-pyridinyl > - benzamide According to the same manner as that described in reference example 1 except that an equimolar amount of 6 - [(2,3-dihydro-1H-inden-5-yl) oxy] -3-pyridinylamine obtained in the reference example 19 instead of 4 - [(5-amino-2-pyridinium) oxy] -1-indanone, the reaction was carried out to obtain the title compound.

H-NMR (CDCl 3) d ppm: 2.0 (m, 2H), 2.8 (m, 4H), 6.8-8.5 (m, 9H), 10.5 (brs, 1 H).

EXAMPLE 8 Synthesis of N1 -. { 6-r (2,3-dihydro-1 H-inden-5-yl) oxy-3-pyridinyl} -3,4- difluorobenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 3,4-difluorobenzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 6 - [(2,3 -dihydro-1 H-inden-5-yl) oxy] -3-pyridinylamine obtained in reference example 19 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1 - Indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.0 (m, 2 H), 2.8 (m, 4 H), 6.8-8.5 (m, 9 H), 10.4 (brs, 1 H).

EXAMPLE 9 Synthesis of 3,4-dichloro-N 1 -. { 6-r (5-oxo-5-67.8-tetrahydro-1-naphthalenyl) oxyl-3-pyridiniumbenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 5 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydro-1 (2H) acid was used - Naphthalenone obtained in Reference Example 20 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.05-2.14 (m, 2H), 2.63-2.67 (m, 2H), 2.81-2.85 (m, 2H), 6.99-7.02 (m, 1 H), 7.25-7.39 ( m, 2H), 7.57-7.60 (m, 1 H), 770-774 (m, 1 H), 7.92-7.99 (m, 3H), 8.19-8.25 (m, 2H).

EXAMPLE 10 Synthesis of 3,4-dichloro-N1- (6-r (9-oxo-6J.8.9-tetrahydro-5H-benzoFa1cyclohepten-2-yl) oxy-3-pyridinyl > benzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 3 - [(5-amino-2-pyridinyl) oxy] -6,7,8,9 was used. -tetrahydro-5H-benzo [a] cyclohepten-5-one obtained in reference example 21 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.81-1.91 (m, 4H), 272-276 (m, 2H), 2.91-2.95 (m, 2H), 6.94 (d, 1 H), 7.17-7.26 (m, 2H), 7.45 (d, 1 H), 7.53 (d, 1 H), 7.70 (dd, 1 H), 7.97 (d, 1 H), 8.17 (dd, H), (m, 1 H).

EXAMPLE 11 Synthesis of N 1 -F 6 - (3-acetylphenoxy) -3-pyridin-3,4-dichlorobenzamide According to the same manner as that described in reference example 1 except that an equimolar amount of 1 - was used. { 3 - [(5-amino-2-pyridinyl) oxy] phenyl} -1 ethanone obtained in the reference example 22 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-nndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.61 (s, 3 H), 7.01 (d, 1 H), 7.33-7.37 (m, 1 H), 7.47-7.58 (m, 2 H), 770-7.80 (m, 3 H) ), 7.98-8.04 (m, 2H), 8.20-8.26 (m, 2H).

EXAMPLE 12 Synthesis of N 1 -r 6 - (2-acetylphenoxy) -3-pyridinin-3,4-dichlorobenzamide According to the same manner as that described in reference example 1 except that an equimolar amount of 1- was used. { 2 - [(5-amino-2-pyridinyl) oxy] phenyl} -1-ethanone obtained in reference example 23 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.5 (s, 3 H), 7.2-8.4 (m, 10 H), 10.6 (brs, 1 H).

EXAMPLE 13 Synthesis of N 1 -F 6 - (2-acetyl-phenoxy) -3-pyridin-3H-3,4-d-fluorobenzamide In accordance with the same manner as that described in reference example 1 except that an equimolar amount of 3,4-difluorobenzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 1-. { 2 - [(5-amino-2-pyridinyl) oxy] phenyl} -1-ethanone obtained in Reference Example 23 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.5 (s, 3H), 7.2-8.4 (m, 10H), 10.5 (brs, 1H).

EXAMPLE 14 Synthesis of N1-F6- (4-acetylphenoxy) -3-pyridinyl-3,4-dichlorobenzamide According to the same manner as that described in reference example 1 except that an equimolar amount of 1 - was used. { 4 - [(5-amino-2-pyridinyl) oxy] phenyl} 1-ethanone obtained in the reference example 24 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.6 (s, 3 H), 7.2-8.6 (m, 11 H), 10.6 (brs, 1 H).

EXAMPLE 15 Synthesis of N 1 -F 6 - (4-acetylphenoxy) -3-pyridin-4- (trifluoromethyl) benzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 4- (trifluoromethyl) benzoic acid was used in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 1-. { 4 - [(5-amino-2-pyridinyl) oxy] phenyl} -1-ethanone obtained in the reference example 24 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.6 (s, 3 H), 7.2-8.6 (m, 11 H), 10.7 (brs, 1 H).

EXAMPLE 16 Synthesis of N1-Fß- (4-benzo-phenoxy) -3-pyridinin-3,4-dichlorobenzamide According to the same manner as that described in reference example 1 except that an equimolar amount of. { 4 - [(5-amino-2-pyridinyl) oxy] phenyl} (phenyl) methanone obtained in reference example 25 instead of 4 - [(5-amino-2-pyridinol) oxy] -1-indanone, the reaction was carried out to obtain the title compound . 1 H-NMR (DMSO-de) d ppm: 7.21-8.59 (m, 15H), 10.57 (brs, 1 H), 10.7 (brs, 1 H).

EXAMPLE 17 Synthesis of N 1 -r 6 - (4-benzoylphenoxy) -3-pyridinin-3,4-difluorobenzamide In accordance with the same manner as that described in reference example 1 except that an equimolar amount of 3,4-difluorobenzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 1-. { 4 - [(5-amino-2-pyridinol) oxy] phenol} (phenyl) methanone obtained in Reference Example 25 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 7.2-8.6 (m, 15H), 10.6 (brs, 1 H), 10.7 (brs, 1 H).

EXAMPLE 18 Synthesis of 3,4-difluoro-N 1 -6-F 4 -. 2 -methyl-1,3-dioxolane-2-yl) phenoxy-3-pyridinylbenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 3,4-difluorobenzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 6- [4- (2 -methyl-1,3-d-oxolane-2-yl) phenoxy] -3-pyridineamine obtained in reference example 35 instead of 4 - [(5-amino-2-pyridinyl) ox ] -1-ndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 1.5 (s, 3 H), 3.7 (m, 2 H), 4.0 (m, 2 H), 7.0-8.5 (m, 10 H), 10.5 (brs, 1 H).

EXAMPLE 19 Synthesis of 3,4-dichloro-N 1 -6-r 3 - (2-methyl-1,3-dioxolane-2-yl) phenoxy 1-3-pyridinylbenzamide According to the same manner as that described in Reference Example 1 except that an equimolar amount of 6- [3- (2-methyl-1,3-dioxolane-2-yl) phenoxy] -3- was used pyridinylamine obtained in Reference Example 36 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-nndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 1.6 (s, 3 H), 3.7 (m, 2 H), 4.0 (m, 2 H), 7.0-8.5 (m, 10 H), 10.6 (brs, 1 H).

EXAMPLE 20 Synthesis of N1-. { 6-r4- (1-hydroxyethyl) phenoxy-3-pyridinyl} -4- (trifluoromethyl) benzamide In the same manner as that described in Reference Example 1 except that an equimolar amount of 4- (trifluoromethyl) benzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 1- was used. { 4 - [(5-amino-2-pyridinyl) oxy] phenol} -1-ethanol obtained in reference example 37 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 1.3 (d, 3 H), 4.7 (m, 1 H), 5.1 (d, 1 H), 7.0-8.5 (m, 11 H), 10.6 (brs, 1 H).

EXAMPLE 21 Synthesis of N 1 -r 6 - (4-acetyl-3-methylphenoxy) -3-pyridinyl-3,4-dichlorobenzamide According to the same manner as that described in Example 1 except that an equimolar amount of 1- was used. { 4 - [(5-amino-2-pyridinyl) oxy] -2-methylphenyl} -1-ethanone obtained in the reference example 26 instead of 4- [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.55 (s, 3 H), 2.58 (s, 3 H), 6.99-7.04 (m, 3 H), 7.58 (d, 1 H), 770-773 (m, 1 H), 7.89 (brs, 1 H), 7.99 (d, 1 H), 8.21-8.26 (m, 1 H), 8.33 (d, 1 H).

EXAMPLE 22 Synthesis of N1-F6- (4-acetyl-3-methylphenoxy) -3-pyridinin-4- (trifluoromethyl) benzamide In the same manner as that described in example 1 except that an equimolar amount of 4- (trifluoromethyl) benzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 1- was used. { 4 - [(5-amino-2-pyridinyl) oxy] -2-methylene} -1-ethanone obtained in Reference Example 26 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound . 1 H-NMR (CDCl 3) d ppm: 2.56 (s, 3 H), 2.58 (s, 3 H), 6.99-7.06 (m, 2 H), 776-7.81 (m, 3 H), 7.95 (brs, 1 H), 7.99 -8.02 (m, 2H), 8.25-8.32 (m, 2H).

EXAMPLE 23 Synthesis of 3,4-dichloro-N 1 -F 6 - (4-propionylphenoxy) -3-pyridinophenylbenzamide According to the same manner as that described in reference example 1 except that an equimolar amount of 1- was used. { 4 - [(5-amino-2-pyridinyl) oxy] phenyl} -1-Propanone obtained in Reference Example 27 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.23 (t, 3 H), 3.00 (q, 2 H), 7.04 (d, 1 H), 7.17-7.20 (m, 2 H), 7.58 (d, 1 H), 770-774 ( m, 1H), 7.96 (brs, 1H), 7.99-8.03 (m, 3H), 8.23-8.30 (m, 2H).

EXAMPLE 24 Synthesis of N1-r6- (4-propionylphenoxy) -3-pyridinyl-4- (trifluoromethyl) benzamide According to the same manner as that described in Example 1 except that an equimolar amount of 4-trifluoromethylbenzoic acid was used in place of 3,4-dichlorobenzoic acid and an equimolar amount of 1- was used. { 4 - [(5-amino-2-pyridinyl) oxy-phenyl} -1-propanone obtained in reference example 27 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction is • 10 carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.23 (t, 3 H), 3.00 (q, 2 H), 7.04-7.07 (m, 1 H), 7.18-7.22 (m, 2 H), 776-779 (m, 2 H) , 7.98 (brs, 1 H), 8.00-8.27 (m, 4H), 8.28-8.32 (m, 2H).

EXAMPLE 25 Synthesis of 3,4-dichloro-N 1 -6-r (2,3-dihydro-1 H -inden-4-yl) oxy-3-pyridinyl benzamide According to the same way as that described in example 1 except that an equimolar amount of 6 - [(2,3-dihydro-1 H -inden-4-yl) oxy] -3-pyridinylamine obtained in reference example 28 was used instead of 4- [(5- amino-2-pyridinyl) oxy] -1-ndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.99-2.10 (m, 2H), 270-275 (m, 2H), 2.94-2.99 (m, 2H), 6.88-6.93 (m, 2H), 7.09-7.12 (m , 1 H), 7.16-7.22 (m, 1H), 7.57 (d, 1H), 7.68-772 (m, 1H), 7.79 (brs, 1H), 7.97 (d, 1 H), 8.14, 8.19 (m , 1 H), 8.22 (d, 1 H).

EXAMPLE 26 Synthesis of 3,4-dichloro-N 1 - 6-r (7-methyl-2,3-dihydro-1 H -inden-4-yl) oxp-3-pyridinylbenzamide According to the same manner as that described in Example 1 except that an equimolar amount of 6 - [(7-methyl-2,3-dihydro-1 H -den-4-yl) oxy] -3 was used pyridinylamine obtained in Reference Example 29 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.99-2.10 (m, 2H), 2.25 (s, 3H), 2.70- 2.76 (m, 2H), 2.84-2.89 (m, 2H), 6.82 (d, 1 H) , 6.90 (d, 1 H), 7.00 (d, 1 H), 7.56 (d, 1 H), 7.67-771 (m, 1 H), 7.80 (brs, 1 H), 7.97 (d, 1 H) , 8.12-8.16 (m, 1 H), 8.20 (d, 1 H).

EXAMPLE 27 Synthesis of N 1 -f 6 - [α 7-methyl-2,3-dihydro-1 H -inden-4-yl.oxp3-pyridinyl} -4- (trifluoromethyl) benzamide • According to the same manner as that described in Example 1 except that an equimolar amount of 4- (trifluoromethyl) benzoic acid was used in place of 3,4-dichlorobenzoic acid and an amount was used equimolar of 6- [(7-methyl-2,3-dihydro-1 H -den-4-yl) oxy] -3-pyridinylamine obtained in reference example 29 instead of 4 - [( -amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.99-2.11 (m, 2H), 2.26 (s, 3H), 2.71- 2.76 (m, 2H), 2.84-2.90 (m, 2H), 6.83 (d, 1 H) , 6.92 (d, 1 H), 7.00 (d, 1 H), 7.74- 7.77 (m, 2H), 7.83 (brs, 1 H), 7.97-8.00 (m, 2H), 8.16-8.22 (m, 2H ).

EXAMPLE 28 Synthesis of 3,4-dichloro-N 1 - 6-r (5,67,8-tetrahydro-1-naphthalene) oxy-3-pyridinylbenzamide According to the same way as that described in example 1 except that an equimolar amount of 6 - [(5,6,7,8-tetrahydro-1-naphthalenyl) oxy] -3-pyridinyllamine obtained in reference example 30 was used instead of 4- [ (5-amino-2-pyridinyl) oxy] -1-ndanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 173-177 (m, 4H), 2.56-2.60 (m, 2H), 279-2.81 (m, 2H), 6.84-6.91 (m, 2H), 6.96-6.98 (m , 1 H), 7.10-7.16 (m, 1 H), 7.57 (d, 1 H), 7.68-771 (m, 1 H), 7.80 (brs, 1 H), 7.97 (d, 1 H), 8.13 -8.17 (m, 1 H), • 8.20 (d, 1 H).

EXAMPLE 29 Synthesis of 3,4-dichloro-N 1 -F 6 - (2,3-dimethylphenoxy) -3-pyridinylbenzamide According to the same way as that described in example 1 except that an equimolar amount of 6- (2,3-dimethylphenoxy) -3-pyridinylamine obtained in reference example 31 was used in place of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone , the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.09 (s, 3 H), 2.32 (s, 3 H), 6.87-6.90 (m, 2H), 7.03-7.06 (m, 1 H), 7.10-7.16 (m, 1 H), 7.57 (d, 1 H), 7.68-772 (m, 1 H), 7.81 (brs, 1 H), 7.97 (d, 1 H), 8.13-8.17 (m, 1 H), 8.20 (d, 1 H).

EXAMPLE 30 Synthesis of 3.4-dichloro-N1- (6-phenoxy-3-pir¡dinil) benzamide 20 According to the same manner as described in Example 1 except that an equimolar amount of 6-phenoxy-3- was used pyridinylamine obtained in reference example 32 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 6.86 (d, 1 H), 7.04-7.07 (m, 2H), 7.14-7.19 (m, 1 H), 7.32-7.38 (m, 2H), 7.46 (d, 1H ), 7.63-7.67 (m, 1 H), 7.91 (d, 1H), 8.08-8.12 (m, 1H), 8.20 (d, 1H), 8.63 (brs, 1H).

EXAMPLE 31 Synthesis of N 1 - (6-phenoxy-3-pyridinyl) -4- (trifluoromethyl) benzamide According to the same manner as that described in example 1 except that an equimolar amount of 4- (trifluoromethyl) benzoic acid was used in place of 3,4-d-chlorobenzoic acid and an equimolar amount of 6-phenoxy was used. 3-pyridinylamine obtained in reference example 32 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-ndanone, the reaction was carried out to obtain the title compound. H-NMR (CDCl 3) d ppm: 6.96 (d, 1 H), 7.11-7.15 (m, 2H), 7.17-7.24 (m, 1H), 7.38-7.43 (m, 2H), 774-777 (m, 2H), 7.94 (brs, 1H), 7.97-8.00 (m, 2H), 8.19-8.24 (m, 1 H), 8.26 (d, 1 H).

EXAMPLE 32 Synthesis of 3,4-dichloro-N 1 -6-F (1-oxo-2,3-dihydro-1 H -inden-4-yl) oxy-3-pyridinylbenzamide hydrochloride After dissolving 0.27 g of 3,4-dichloro-N1-. { 6 - [(1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy] -3-pyridinyl} Benzamide obtained in Example 1 in a mixed solvent of 5 ml of ethyl acetate and 2 ml of methanol in a hot state, 1.3 ml of a 4N solution of hydrogen chloride in ethyl acetate was added to the solution with stirring. Then, the reaction solution was cooled with ice and the deposited crystal was isolated by filtration and dried under low pressure to obtain 0.27 g of the title compound as a white powder. Melting point: 200-207 ° C 1 H NMR (DMSO-de) d ppm: 2.62-2.67 (m, 2H), 2.84-2.88 (m, 2H), 7.18-7.22 (m, 1H), 7.45-7.52 ( m, 3H), 7.83-7.98 (m, 2H), 8.24-8.28 (m, 2H), 8.50 (m, 1 H), 10.64 (s, 1 H).

EXAMPLE 33 Synthesis of 3,4-dichloro-N 1 -! 6f 4 - (2-methyl-1,3-d-oxolane-2-yl) phenoxy-3-pyridiniumbenzamide According to the same manner as that described in example 1 except that an equimolar amount of 6- [4- (2-methyl-1,3-dioxolane-2-yl) phenoxy] -3-pyridinylamine obtained in the reference example 35 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 1.5 (s, 3 H), 3.7 (m, 2 H), 4.0 (m, 2 H), 7.0-8.5 (m, 10 H), 10.5 (brs, 1 H).

EXAMPLE 34 Synthesis of 3,4-dichloro-N 1 -. { 6-I? 1-hydroxy-2,3-dihydro-1 H-inden-4-yl) oxy 1-3-pyridinylbenzamide After dissolving 413 mg of 3,4-dicioro-N1-. { 6 - [(1-Oxo-2,3-dihydro-1 H -inden-4-yl) oxy] -3-pyridinyl} Benzamide in a solvent mixture of 4 ml of tetrahydrofuran and 1 ml of water, 23 mg of sodium tetrahydroborate was added and the mixture was stirred at room temperature. After 4 hours, acetone was added to the reaction solution to decompose the excess sodium tetrahydroborate. Then water was added and the solution was extracted with ethyl acetate. The organic layer (ethyl acetate) was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under low pressure. To the resulting oily substance, diethyl ether was added and the deposited crystal was isolated by filtration to obtain 289 mg of the title compound. 1 H-NMR (DMSO-d 6) d ppm: 1.8 (m, 1 H), 2.37-27 (m, 3 H), 5.1 (m, 1 H), 5.3 (d, 1 H), 6.9-8.4 (m, 9 H) ), 10.5 (brs, 1 H).

EXAMPLE 35 Synthesis of 3,4-dichloro-N 1 -. { 64 (1 H-inden-7-yl) oxy-3-pyridinyl} benzamide 1.50 g of 3,4-dichloro-N 1 - [6- (1-hydroxy-2,3-dihydro-1 H -inden-4-yloxy) -3-pyridinyl] benzamide obtained in the Example 34 in 15 ml of acetic acid, and 1.16 g of pyridinium bromide perbromide was added to the resulting reaction solution and the mixture was stirred at 80 ° C. At 4 hoursThe reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under low pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane (1: 3)) to obtain 430 mg of the title compound. 1 H-NMR (DMSO-de) d ppm: 3.0 (d, 1 H), 3.5 (dd, 1 H), 5.1 (d, 1 H), 6.0 (s, 1 H), 7.8-8.5 (m, 9H ), 10.6 (brs, 1 H).

EXAMPLE 36 Synthesis of 3,4-dichloro-N 1 -. { 6-F4- (1-hydroxyethyl) phenoxy-3-pyridinium-benzamide In accordance with the same manner as that described in example 1 except that an equimolar amount of 1 - was used. { 4 - [(5-amino-2-pyridinyl) oxy] phenyl} -1-ethanol obtained in the reference example 37 instead of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone, the reaction was carried out to obtain the compound of the title. 1 H-NMR (DMSO-de) d ppm: 1.3 (d, 3 H), 4.7 (m, 1 H), 57 (d, 1 H), • 7.0-8.5 (m, 10H), 10.6 (brs, 1 H).

EXAMPLE 37 Synthesis of N3- (3,4-dichloropneyl) -6r (1-oxo-2,3-dihydro-1 H-lden-4-oxoxynicotinamide 188 mg of 6 - [(1-oxo-2,3-dihydro-1 H -inden-4-yl) oxy] nicotinic acid obtained in reference example 42 and 113 mg of 3,4-dichloroaniline were dissolved in 2 ml of DMF. To the resulting reaction solution, 114 mg of 1-hydroxybenzotriazole and 161 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbcarbodiimide hydrochloride were added and the mixture was stirred at room temperature.

At 2 hours, water was added to the reaction solution and the deposited solid was isolated by filtration. Then, the filtrate was extracted with a solvent mixture of ethyl acetate and tetrahydrofuran (THF) (first: last = 1: 1). The organic layer was washed in turn with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate. and then concentrated at low pressure. The resulting solid was washed with diethyl ether to obtain 72 mg of the title compound as a pale yellow crystal. 1 H-NMR (DMSO-de) d ppm: 2.6 (m, 2H), 2.8 (m, 2H), 7.3-8.7 (m, 9H), 10.6 (brs, 1 H).

EXAMPLE 38 Synthesis of N3- (3,4-difluorophenyl) -6-r (1-oxo-2,3-dihydro-1 H-inden-4- Doxylnicotinamide According to the same manner as that described in Example 37 except that an equimolar amount of 3,4-difluoroaniline was used in place of 3,4-dichloroaniline, the reaction was carried out to obtain the title compound. H-NMR (DMSO-de) d ppm: 2.6 (m, 2H), 2.9 (m, 2H), 7.3-8.7 (m, 9H), 10.5 (brs, 1 H).

EXAMPLE 39 Synthesis of 6-r (1-oxo-2,3-dihydro-1H-inden-4-yl) oxy-N3-r4- (trifluoromethyl) phenynicotinamide According to the same manner as that described in Example 37 except that an equimolar amount of 4- (trifluoromethyl) aniline was used in place of 3,4-dichloroaniline, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.65 (m, 2 H), 2.86 (m, 2 H), 7.32 (d, 1 H, J = 8 Hz), 7.54 (m, 3 H), 7.74 (d, 2 H) , J = 8 Hz), 7.98 (d, 2H, J = 8 Hz), 8.43 (d, 1H, J = 8 Hz), 8.71 (s, 1 H), 10.65 (s, 1 H). • EXAMPLE 40 Synthesis of N3- (3,4-dichlorophenyl) -6-r (1-oxo-2,3-dihydro-1 H -inden-5-D-oxynicotinamide According to the same way as that described in the example • 10 37 except that an equimolar amount of 6 - [(1-oxo-2,3-dihydro-1 H -inden-5-yl) oxy] nicotinic acid obtained in reference example 43 was used instead of 6 - [(1-Oxo-2,3-dihydro-1 H -inden-4-yl) oxy] nicotinic, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.6 (m, 2 H), 3.1 (m, 2 H), 7.2-8.7 (m, 15 9 H), 10.4 (brs, 1 H).

EXAMPLE 41 Synthesis of N3- (3,4-difluorophenyl) -6-r (5-oxo-5,67,8-tetrahydro-1-naphthaleniDoxylnicotinamide 20 According to the same manner as that described in Example 37 except that a equimolar amount of 6 - [(5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] nichnitol obtained in reference example 44 instead of 6 - [(1- oxo-2,3-dihydro-1H-inden-4-yl) oxy] nicotinic acid and an equimolar amount of 3,4-difluoroaniline was used in place of 3,4-dichloroaniline, the reaction was carried out to obtain the compound of the title. • 1 H-NMR (DMSO-de) d ppm: 2.0 (m, 2H), 2.6 (m, 2H), 2.7 (m, 2H), 7.0-8.6 (m, 9H), 10.5 (brs, 1 H).

EXAMPLE 42 Synthesis of N3- (3,4-dichlorophenyl) -6-r (5-oxo-5-6 J.8-tetrahydro-1-naphthalenyl) oxynicotinamide 10 According to the same manner as that described in example 37 except that an equimolar amount of 6 - [(5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl) oxy] nicotinic acid obtained in reference example 44 was used instead of 6 - [( 1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy] nitinic, the reaction was out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.0 (m, 2H), 2.7 (m, 4H), 7.2-87 (m, 9H), 10.5 (brs, 1 H).

EXAMPLE 43 20 Synthesis of 6- (4-acetyl-phenoxy) -N3- (3,4-dichlorophenyl) nicotinamide According to the same manner as that described in example 37 except that an equimolar amount of 6- (4-acetylphenoxy) nicotinic acid obtained in reference example 45 was used in place of 6 - [(1-oxo-2 , 3-dihydro-1 H-inden-4-yl) oxy-nicotinic acid, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.6 (s, 3 H), 7.3-8.7 (m, 10 H), 10.6 (brs, 1 H).

EXAMPLE 44 Synthesis of 6- (4-acetylphenoxy) -N3-r4- (trifluoromethyl) phenynicotinamide According to the same way as that described in the example 37 except that an equimolar amount of 6- (4-acetylphenoxy) nicotinic acid obtained in Reference Example 45 was used instead of 6 - [(1-oxo-2,3-dihydro-1 H-inden-4- 1) oxy) nicotinic and the equimolar amount of 4- (trifluoromethyl) aniline was used in place of 3,4-dichloroaniline, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 2.6 (s, 3 H), 7.3-8.8 (m, 10 H), 10.7 (brs, 1 H).

EXAMPLE 45 Synthesis of 3,4-dichloro-N 1 -rβ-fp - (1,3-dioxolane-2-yl) -2,3-dihydro-1 H -inden-4-inoxi > -3-pyridinylbenzamide To 1.97 g of 4 - [(5-amino-2-pyridinyl) oxy] -1-indanone ethylene ketal obtained in reference example 47 and 35 ml of a solution of triethylamine (2.9 ml) in tetrahydrofuran , 15 ml of a solution of 3,4-dichlorobenzoate chloride (1.45 g) in tetrahydrofuran was added dropwise at 0 ° C and the reaction solution was stirred at the same temperature for 5 minutes. Then the reaction mixture was extracted by the addition of ethyl acetate and water. The resulting solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled. The resulting residue was washed in turn with ether and diisopropyl ether in a hot state to obtain 2.69 g of the title compound. 1 H-NMR (CDCl 3) d ppm: 2.14-2.20 (m, 2H), 2.57-2.62 (m, 2H), 3. 98-4.17 (m, 4H), 7.06-7.11 (m, 2H), 7.22 (dd, 1 H, J = 7.58 Hz, J = 0.98 Hz), 7.29-7.34 (m, 1 H), 7.84 (d, 1 H, J = 8.57 Hz), 7.92-7.96 (m, 1 H), 8.18-8.23 (m, 2H), 8.45 (d, 1 H, J = 2.63 Hz), 10.55 (s, 1 H).

EXAMPLE 46 Synthesis of N1 -. { 6-r (3-acetoxy-1 H-inden-7-yl) oxy-1-3-pyridinyl-3,4-dichlorobenzamide • A mixture of 1.00 g of 3,4-di-oro-N1- [6- (1-oxo-2,3-dihydro-1 H-n-4-4-) was stirred overnight at 70 ° C. il) oxy] -3-pyridinyl] benzamide obtained in Example 1, 50 mg of p-toluenesulfonic acid and 5 ml of isopropenyl acetate. After completion of the reaction, the reaction mixture was concentrated and the resulting residue was extracted with ethyl acetate. This solution The extract was washed in turn with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate (2: 1)) to obtain the title compound (230 mg, white powder). Melting point: 161-164 ° C 1 H-NMR (CDCl 3) d ppm: 2.35 (s, 3 H), 3.29 (d, 2 H, J = 1.98 Hz) 6.32 (t, 1 H, J = 1.98 Hz), 6.97 -7.04 (m, 2H), 7.22 (d, 1 H, J = 7.58 Hz), 7.38 (t, 1 H, J = 7.58 Hz), 7.59 (d, 1 H, J = 8.25 Hz), 773-775 (m, 1 H), 7.88 (brs, 1 H), 8.01 (d, 1 H, J = 1.65 Hz), 8.26-8.29 (m, 2H).

EXAMPLE 47 Synthesis of 3,4-dichloro-N 1 -. { 64 (1-Hydroximino-2,3-dihydro-1 H-inden-4-yl) oxy-3-pyridine > benzamida 800 mg of 3,4-dichloro-N1- was suspended. { 6 - [(1-oxo-2,3-dihydro-1 H -inden-4-yl) oxy] -3-pyridinyl} Benzamide obtained in Example 1 and 670 mg of hydroxyammonium chloride (hydroxylamine hydrochloride) in 40 ml of ethanol and after adding 5.4 ml of pyridine to the resulting suspension, the mixture was stirred at 60 ° C. After 30 minutes, the reaction solution was distilled at low pressure. To the resulting residue, 60 ml of ethyl acetate was added and the solution was washed in turn with water and a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After having distilled the ethyl acetate, ether was added and the deposited crystal was isolated by filtration and then washed with ether to obtain the title compound (430 mg, white powder). , 1 H-NMR (DMSO-de) d ppm: 2.76 (s, 4H), 7.09 (d, 1 H, J = 8 Hz), 7.11 (d, 1 H, J = 8 Hz), 7.33 (t, 1 H, J = 8 Hz), 7.43 (d, 1 H, J = 8 Hz), 7.84 (d, 1 H, J = 8 Hz), 7.94 (dd, 1 H, J = 8 Hz, 2 Hz), 8.21 (dd, 1 H, J = 8 Hz; 2 Hz), 8.22 (s, 1 H), 8.46 (d, 1 H, J = 8 Hz), 10.56 (s, 1 H), 10.96 (s, 1 H).

EXAMPLE 48 Synthesis of 3,4-dichloro-N 1 -. { 64 (1-methoxyimino-2,3-dihydro-1 H -inden-4-yl) oxy] 1-3-pyridinyl > benzamida According to the same manner as that described in Example 47 except that an equimolar amount of O-methylhydroxyammonium chloride was used in place of hydroxyammonium chloride, the reaction was carried out to obtain the title compound (530 mg, white powder ). 1 H-NMR (DMSO-de) d ppm: 2.77 (m, 4 H), 3.09 (s, 3 H), 7.13 (d, 1 H, J = 8 Hz), 7.14 (d, 1 H, J = 8 Hz) , 7.35 (t, 1 H, J = 8 Hz), 7.44 (d, 1 H, J = 8 Hz), 7.84 (d, 1H, J = 8 Hz), 7.94 (d, 1 H, J = 8 Hz ), 8.22 (d, 1H, J = 8 Hz), 8.22 (s, 1 H), 8.46 (s, 1 H), 10.58 (s, 1 H).

EXAMPLE 49 Synthesis of N1 -. { 64 (1-acetoxyimino-2,3-dihydro-1 H-inden-4-yl) oxyl-3-pyridinyl > -3,4-dichlorobenzamide 650 mg of N1-. { 6- [1-hydroxyimino-2,3-dihydro-1 H-inden-4-yl) oxy] -3-pyridinyl} The benzamide obtained in example 47 was dissolved in 10 ml of tetrahydrofuran. To the resulting reaction solution, 1.2 ml of pyridine and 0.7 ml of acetic anhydride were added and the mixture was stirred at room temperature. After 17 hours, the reaction solution was distilled at low pressure and 15 ml of ethyl acetate and 15 ml of water were added to the resulting residue.

Subsequently, the deposited powder was isolated by filtration and washed in turn with water and ethyl acetate to obtain the title compound (310 mg). 1 H-NMR (DMSO-de) d ppm: 2.20 (s, 3 H), 2.84 (m, 2 H), 3.01 (m, 2 H), 7.16 (d, 1 H, J = 8 Hz), 7.28 (d, 1 H, J = 8 Hz), 7.44 (t, 1 H, J = 8 Hz), 7.59 (d, 1 H, J = 8 Hz), 7.84 (d, 1 H, J = 8 Hz), 7.95 (d , 1 H, J = 8 Hz), 8.22 (s, 1 H), 8.24 (d, 1 H, J = 8 Hz), 8.47 (s, 1 H), 10.59 (s, 1 H).

EXAMPLE 50 Synthesis of 3,4-dichloro-N 1 -. { 6- (3-ethoxy-1H-inden-7-yloxy) -3- pyridinylbenzamide 3.5 g of 3,4-dichloro-N 1 - was suspended. { 6- (1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy] -3-pyridinyl} benzamide obtained in example 1, in 140 ml of ethanol. To the suspension, 14 ml of ethyl orthoformate, 820 mg of (+) - 10-camphorsulfonic acid and 3.5 g of molecular filter 4A were added and the mixture was heated to reflux for 30 minutes. After cooling with air, the reaction mixture was filtered. To the filtrate, 8.5 ml of an aqueous 1 N sodium hydroxide solution was added and the solvent was distilled at low pressure. To the resulting residue, 100 ml of ethyl acetate was added and the solution was washed with water and a saturated sodium hydrogen carbonate solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate (4: 1)) to obtain the title compound (white powder, 530 mg). 1 H-NMR (DMSO-de) d ppm: 1.38 (t, 3H, J = 7 Hz), 3.05 (d, 2H, J = • 2 Hz), 4.07 (q, 2H, J = 7 HZ), 5.37 (t, 1 H, J = 2 Hz), 6.99 (d, 1 H, J = 8 Hz), 7.10 (d, 1H, J = 8 HZ), 7.20 (d, 1 H, J = 8 Hz), 7.36 (t, 1 H, J = 8 Hz), 7.84 (d, 1 H, J = 8 Hz), 7.94 (d, 1 H , J = 8 Hz), 8.20 (dd, 1 H, J = 8 Hz, 3 Hz), 8.22 (s, 1 H), 8.44 (d, 1H, J = 3 Hz), 10.56 (s, 1H).

EXAMPLE 51 • 10 Synthesis of N1464 (3-acetyloxy-1 H-inden-7-yl) oxy-1-3-pyridinyl > -4- (trifluoromethyl) benzamide According to the same manner as that described in example 1 except that an equimolar amount of 3-acetyloxy-7 - [(5-amino-2-pyridinyl) oxy] -1 H-indene obtained in the example was used of reference 49 instead of 4- [(5-amino-2-pyridinyl) oxy] -1-indanone and the equimolar amount of 4- (trifluoromethyl) benzoic acid was used instead of 3,4-dichlorobenzoic acid, the reaction was carried out to obtain the title compound. MS m / e = 454 (M +) for C 24 H 17 F 3 N 2 O 4 20 1 H-NMR (CDCl 3) d ppm: 2.35 (s, 3 H), 3.28 (d, 2 H, J = 2.31 Hz), 6. 32 (t, 1 H, J = 2.31 Hz), 6.97-7.04 (m, 2H), 7.19-7.40 (m, 2H), 7.68 (d, 2H, J = 8.10 Hz), 7.89 (brs, 1 H) , 7.99 (d, 2H, J = 7.83), 8.23-8.25 (m, 2H).

EXAMPLE 52 Synthesis of N1 64 (3-benzoyloxy-1 H -inden-7-yl) oxy-3-pyridinyl-3,4-dichlorobenzamide • According to the same way as that described in Example 45 except that used an equimolar amount of 7 - [(5-amino-2-pyridinyl) oxy] -3-benzoyloxy-1 H-indene acid obtained in reference example 51 instead of 4 - [(5-amino-2 pyridinyl) oxy] -1-indanone ethylene ketal, the reaction was carried out to obtain the title compound. • 10 1-NMR (CDCI) d ppm: 3.35 (d, 2H, J = 2.31 Hz), 6.49 (t, 1 H, J = 2.31 Hz), 6.98-7.06 (m, 2H), 7.30-7.39 (m , 2H), 7.52-773 (m, 5H), 7.82 (brs, 1 H), 7.99 (d, 1 H, J = 1.98 Hz), 8.20-8.26 (m, 4H).

EXAMPLE 53 15 Synthesis of 3,4-dichloro-N 1 -. { 64 (3-isobutyryloxy-1 H-inden-7-yl) oxy] -3-pyridinylbenzamide To a solution of 3-α-butyryloxy-7 - [(5-nitro-2-pyridinol) oxy] -1 H-indene (280 mg) obtained in reference example 52 in THF (50 mg). ml), 10 mg of platinum oxide was added and catalytic reduction was carried out in a flow of hydrogen gas at room temperature and normal pressure. After 45 minutes, the reaction solution was filtered and 0.125 ml of triethylamine was added to the filtrate. To the reaction solution, a solution of 3,4-dichlorobenzoyl chloride (170 mg) in THF (5 ml) was added under cooling with ice and the mixture was stirred for 10 minutes. After filtering and concentrating the reaction solution, ethyl acetate was added to the residue and the solution was washed with water.

The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled. The residue was washed with ether to obtain 72 mg of the title compound as a white solid. 1 H-NMR (CDCl 3) d ppm: 1.35 (d, 6 H, J = 7 Hz), 2.81-2.91 (m, 1 H), 3.23 (d, 2 H, J = 2 Hz), 6.28 (t, 1 H, J = 2 Hz), 6.92-7.00 (m, 2H), 7.16 (dd, 1 H, J = 7 Hz, 1 HZ), 7.31-7.36 (m, 1 H), 7.53 (d, 1 H, J = 9 Hz), 7.68 (dd, 1 H, J = 8 Hz, 2 • 10 Hz), 7.96 (d, 1 H, J = 2 Hz), 8.12-8.21 (m, 3H).

EXAMPLE 54 Synthesis of 3,4-dichloro-N 1 -. { 64 (3-pivaloyloxy-1 H-inden-7-yl) oxyl-3-pyridiniumbenzamide 15 According to the same manner as that described in example 53 except that an equimolar amount of 7 - [(5-nitro) 2-pyridinyl) oxy] -3- pivaloyloxy-1 H-indene obtained in Reference Example 53 in place of 3-isobutyriol-7 - [(5-nitro-2-pyridinyl) oxy] -1 H-indeno, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 1.40 (s, 9 H), 3.25 (d, 2 H, J = 2 Hz), 6.95 (d, 1 H, J = 9 Hz), 7.00 (d, 1 H, J = 8 Hz), 7.17 (d, 1 H, J = 8 Hz), 7.17 (d, 1 H, J = 7 Hz), 7.32-7.38 (m, 1 H), 7.55 (d, 1 H, J = 7 Hz), 7.69-773 (m, 1 H), 7.98 (d, 1 H, J = 2 Hz), 8.06-8.23 (m, 3H).

• EXAMPLE 55 5 Synthesis of N1464 (1-acetoxy-3,4-dihydronaphthalene-5-yl) oxy-pyridine-3-8l > - 3-4-dichlorobenzamide According to the same way as that described in the example 45 except that an equimolar amount of 1-acetoxy-5 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene obtained in reference example 55 was used instead of 4 - [(5- amino-2-pyridinyl) oxy] -1-indanone ethylene ketal, the reaction was carried out to obtain the title compound. 1 H-NMR (CDCl 3) d ppm: 2.31 (s, 3 H), 2.35-2.43 (m, 2 H), 2.74 (t, 2 H, J = 8 Hz), 5.72 (t, 1 H, J = 5 Hz), 6.91 (d, 1 H, J = 9 Hz), 6.97-7.02 (m, 2H), 15 7.18-7.24 (m, 1 H), 7.57 (d, 1 H, J = 8 Hz), 7.68-772 ( m, 1 H), 7.85 (bs, 1 H), 7.98 (d, 1 H, J = 2 Hz), 8.15-8.21 (m, 2H).

EXAMPLE 56 Synthesis of N1464 (1-acetoxy-3,4-dihydronaphthalen-6-yl) oxppiridin-3-yl) -N3-20 (3,4-dichlorophenyl) urea To 360 mg of 1-acetoxy-6 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene obtained in reference example 58 and a solution of triethylamine (0.34 ml) in THF (10 mL), a solution of 3,4-dichlorophenyl (230 mg) in THF (10 mL) was added dropwise under cooling with ice. The reaction solution was stirred for 3 hours gradually returning to room temperature. The reaction solution was concentrated under low pressure and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate (1: 1)) to obtain 340 mg of the title compound as a white powder. 1 H-NMR (CDCl 3) d ppm: 2.30 (s, 3 H), 2.39-2.44 (m, 2 H), 2.75-2.81 (m, 2 H), 5.66 (t, 1 H, J = 5 Hz), 6.83-6.86 (m, 3H), 7.04-7.14 (m, 2H), 7.25-7.28 (m, 1 H), 7.48 (d, 1 H, J = 2 Hz), 7.67 (bs, 1 H), 7.80 (bs, 1 H), 7.91-7.96 (m, 2H).

EXAMPLE 57 Synthesis of N1 64 (3-acetoxy-1 H-inden-7-yl) oxy.pyridin-3-yi > -N3- (3,4- dichlorophenide) According to the same manner as that described in Example 56 except for the use of an equimolar amount of 3-acetyloxy-7 - [(5-amino-2-pyridinyl) oxy] -1H-indene obtained in the example of reference 49 in place of 1-acetoxy-6 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 9.10 (s, 1 H), 8.91 (s, 1 H), 8.15 (d, 1 H, J = 2 Hz), 8.01 (dd, 1 H, J = 9 Hz, 2 Hz), 7.87 (d, 1 H, J = 2 Hz), 7.52 (d, 1 H, J = 9 Hz), 7.37 (t, 1 H, J = 8 Hz), 7.35 (d, 1 H, J = 9 Hz), 7.17 (d, 1 H, J = 8 Hz), 7.08 (d, 1 H, J = 9 Hz), 6.99 (d, 1 H, J = 8 Hz), 6.26 (s) , 1 H), 3.21 (s, 2H), 2.35 (s, 3H).

EXAMPLE 58 Synthesis of N1 64 (3-acetoxy-1 H-inden-7-yl) oxppiridin-3-yl > -N3- (4- trifluoromethylDfeninurea According to the same manner as that described in Example 56 except for the use of an equimolar amount of 3-acetyloxy-7 - [(5-amino-2-pyridinyl) oxy] -1 H-indene obtained in the reference example 49 in place of 1-acetoxy-6 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene and using 4- (trifluoromethylphenyl) isocyanate in place of 3,4-dichlorophenyl-isocyanate, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-d 6) d ppm: 9.19 (s, 1 H), 8.88 (s, 1 H), 8.16 (d, 1H, J = 3 Hz), 8.03 (dd, 1 H, J = 9 Hz, 3 Hz), 7.64 (s, 4H), 7.36 (t, 1 H, J = 8 Hz), 7.17 (d, 1 H , J = 8 Hz), 7.08 (d, 1 H, J = 9 Hz), 6.99 (d, 1 H, J = 8 Hz), 6.26 (s, 1 H), 3.21 (s, 2 H), 2.35 ( s, 3H).

EXAMPLE 59 Synthesis of N1 64 (1-oxo-2,3-dihydro-1H-inden-4-yl) oxy-pyridin-3-yl-N344- (trifluoromethyl) phenylurea • According to the same way as that described in the example 56 except for the use of an equimolar amount of 4 - [(5-amino-2-pyridinyl) oxy] -1- indanone obtained in reference example 17 instead of 1 -acetoxy-6 - [( 5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene and using 4- (trifluoromethyl) phenylisocyanate in place of 3,4-dichlorophenyl isocyanate, the reaction was carried out • 10 to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 9.20 (S, 1 H), 8.90 (s, 1 H), 8.19 (d, 1 H, J = 2 Hz), 8.04 (dd, J = 9 Hz, 2 Hz ), 7.65 (s, 4H), 7.35-7.55 (m, 3H), 7.13 (d, 1 H, J = 9 Hz), 2.87 (t, 2H, J = 6 Hz), 2.64 (t, 2H, J = 6 Hz).

EXAMPLE 60 Synthesis of N1 -. { 64 (1-acetoxy-3,4-dihydronaphthalene-6-yl) oxphlpyridin-3-yl} - N3- (4- (trifluoromethyl) phenyl) urea According to the same manner as that described in Example 56 except for the use of an equimolar amount of 4- (trifluoromethylphenyl) isocyanate in place of 3,4-dichlorophenyl isothiocyanate, the reaction was carried out to obtain the compound of the title. 1 H-NMR (DMSO-de) d ppm: 2.28 (s, 3 H), 2.34-2.42 (m, 2 H), 2.76- 2.81 (m, 2 H), 5.67 (t, 1 H, J = 5 Hz), 6.87 -7.12 (m, 4H), 7.64-7.69 (m, 4H), 7.98- 8.03 (m, 1 H), 8.22 (d, 1 H, J = 3 Hz), 8.90 (s, 1 H), 9.20 ( s, 1 H). • EXAMPLE 61 Synthesis of N1 64 (1-acetoxy-3,4-d-hydronaphthalen-5-yl) oxylpyridin-3-yl-N3- (3,4-dichlorophenyl) urea According to the same way as that described in example 56 Except for the use of an equimolar amount of 1-acetoxy-5 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene obtained in reference example 55 instead of 1-acetoxy-6 [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 9.07 (s, 1 H), 8.68 (s, 1 H), 8.12 (d, 1H, J = 3 Hz), 7.99 (dd, 1 H, J = 9 Hz, 3 Hz), 7.86 (d, 1 H, J = 3 Hz), 7.52 (d, 1 H, J = 9 Hz), 7.34 (dd, 1 H, J = 9 Hz, 3 Hz), 7.23 (t, 1 H, J = 8 Hz), 7.02 (d, 1 H, J = 9 Hz), 6.99 (d, 2H, J = 9 Hz), 5.74 (t, 1 H, J = 5 Hz), 2.62 (t, 2H, J = 8 Hz), 2.33 (m, 2H), 2.30 (s, 3H).

EXAMPLE 62 Synthesis of N1464 (5-oxo-5,67,8-tetrahydro-1-naphthalenyl) oxy-pyridin-3-yl > - N3- (3,4-dichlorophenyl) urea According to the same manner as that described in Example 56 except for the use of an equimolar amount of 5 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydro-1 (2H) -naphthalenone obtained in Reference Example 20 instead of 1-acetoxy-6 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 9.09 (s, 1 H), 8.87 (s, 1 H), 8.13 (d, 1 H, J = 3 Hz), 8.00 (dd, 1 H, J = 9 Hz , 3Hz), 7.86 (d, 1 H, J = 3 Hz), 7.77 (d, 1 H, J = 8 Hz), 7.52 (d, 1H, J = 9 Hz), 7.30-7.45 (m, 3H) , 7.08 (d, 1 H, J = 9 Hz), 2.74 (t, 2H, J = 6 Hz), 2.60 (t, 2H, J = 6 Hz), 2.00 (m, 2H).

EXAMPLE 63 Synthesis of N1 64 (1-acetoxy-3,4-d-hydronaphthalen-5-yl) oxlpyridin-3-yl > -N3- r4- (trifluoromethyl) pheninurea According to the same manner as that described in Example 56 except for the use of an equimolar amount of 1-acetoxy-5 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene obtained in the example reference 55 instead of 1 -acetoxy-6 - [(5-amino-2-pyridinyl) oxy] -3, 4-dihydronaphthalene and using 4- (trifluoromethyl) phenyl isocyanate in place of 3,4-dichlorophenyl isocyanate, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d 9.35 (s, 1 H), 9.03 (s, 1 H), 8.15 (d, 1 H, J = 3 Hz), 8.01 (dd, 1 H, J = 9 Hz ), 7.67 (d, 2H, J = 9 Hz), 7.62 (d, 2H, J = 9 Hz), 7.23 (t, 1 H, J = 8 Hz), 7.03 (d, 1 H, J = 8 Hz ), 6.99 (d, 2H, J = 8 Hz), 5.74 (t, 1 H, J = 5 Hz), 2.62 (t, 2H, J = 8 Hz), 2.32 (m, 2H), 2.30 (s, 3H).

EXAMPLE 64 Synthesis of N1 64 (5-oxo-5-67.8-tetrahydro-1-naphthalenyl) oxylpyridin-3-yl} - N344- (trifluoromethyl) phennurea According to the same manner as that described in Example 56 except for the use of the equimolar amount of 5 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydro-1 (2H) -naphthalenone obtained in reference example 20 in the place of 1-acetoxy-6 - [(5-amino-2-pyridinyl) oxy] -3,4-dihydronaphthalene and using 4- (trifluoromethylphenyl) isocyanate in place of 3,4-dichlorophenyl isocyanate , the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) dppm: 9.31 (s, 1 H), 8.99 (s, 1 H), 8.16 (d, 1 H, J = 3 Hz), 8.02 (dd, 1 H, J = 9 Hz , 3 Hz), 7.77 (d, 1 H, J = 8 Hz), 7.67 (d, 2 H, J = 9 Hz), 7.63 (d, 2 H, J = 9 Hz), 7.40 (t, 1 H, J = 8 Hz), 7.33 (d, 1 H, J = 8 Hz), 7.08 (d, 1 H, J = 8 Hz), 2.74 (t, 2H, J = 6 Hz), 2.61 (t, 2H, J = 6 Hz), 1.99 (m, 2H).

EXAMPLE 65 Synthesis of N1 64 (3,4-dihydro-1 (2H) -naphthalenon-6-yl) oxy! Pyridin-3-yl} -N344- (trifluoromethyl) phenylurea To a solution of N1-. { 1-Acetoxy-6 - [(3,4-dihydronaphthalene-6-yl) oxy] pyridine-3-yl} -N3- [4- (trifluoromethyl) phenyl] urea (450 mg) in ethanol (20 ml), 980 mg of potassium carbonate was added and the mixture was stirred at room temperature for 40 minutes. After the reaction mixture was filtered and concentrated, the residue was dissolved in ethyl acetate and the solution was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled. The residue was washed with ether to obtain 290 mg of the title compound as a white powder. 1 H-NMR (DMSO-de) d ppm: 1.99-2.08 (m, 2H), 2.56-2.61 (m, 2H), 2.92 (t, 2H, J = 6 Hz), 7.00-7.02 (m, 2H), 7.12 (d, 1 H. J = 9 Hz), 7.62-770 (m, 4H), 7.88-7.92 (m, 1 H), 8.03-8.08 (m, 1 H), 8.29 (d, 1H, J = 3 Hz), 8.97 (s, 1 H), 9.24 (s, 1 H).

EXAMPLE 66 Synthesis of E-1 64 (1-oxo-2,3-dihydro-1 H -denden-4-yl) oxp-3-pyridinyl} -244- (trifluoromethylphenyl) phenylenethylene To a solution of 4 - [(5-formyl-2-pyridinyl) oxy] -1-indanone (1.0 g) obtained in reference example 60 in dichloromethane (5 ml), [4- (trifluoromethyl) phenyl] benzyltriphenylphosphonium (2.0 g) and potassium t-butoxide (0.46 g) under ice-cooling. The reaction mixture was stirred for 5 hours gradually returning to room temperature. To the reaction mixture, dichloromethane and water were added and then the organic layer was washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3: 2) to obtain 160 mg of the title compound. 1 H-NMR (CDCl 3) d ppm: 2.63-2.68 (m, 2H), 2.92-2.96 (m, 2H), 6.60 (d, 1 H, J = 12 Hz), 6.69 (d, 1 H, J = 12 Hz), 6.87 (d, 1 H, J = 9 Hz), 7.39-7.44 (m, 1 H), 7.50-7.56 (m, 3H), 7.61-7.64 (m, 1 H), 8.00 (d, 1 H, J = 2 Hz).

EXAMPLE 67 Synthesis of Z-1 64 (1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy-3-pyridinyl} -244- (trifluoromethyl) phenylenethylene According to the same manner as that described in example 66, the title compound was obtained. 1 H-NMR (CDCl 3) d ppm: 2.66-271 (m, 2H), 2.96-3.00 (m, 2H), 7. 03-7.17 (ml, 3H), 7.37-7.40 (m, 1 H), 7.43-7.48 (m, 1 H), 7.57-7.64 (m, 4H), 7.65-7.68 (m, 1 H) 7.94-7.98 (m, 1 H), 8.24 (d, 1 H, J = 2 Hz).

EXAMPLE 68 Synthesis of E-1464 (1-oxo-2,3-dihydro-1 H-indene-4-yl) oxy-3-pyridinyl} -2- (3,4-dichlorophenyl) ethylene According to the same manner described in Example 66 except that (3,4-dichlorophenyl) benzyltriphenylphosphonium bromide is used in place of (4-trifluorophenyl) benzyltriphenylphosphonium bromide, obtaining the title compound. 1 H-NMR (CDCl 3) d ppm: 2.66-271 (m, 2H), 2.95-2.99 (m, 2H), • 10 6.92 (d, 1H, J = 17 Hz), 7.00-7.06 (m, 2H), 7.32 (dd, 1 H, J = 2 Hz, 9 Hz), 7.36- 7.40 (m, 1 H), 7.41 -7.48 (m, 2H), 7.58 (d, 1 H, J = 2 Hz) 7.65-7.68 (m, 1 H), 7.90- 7.95 (m, 1 H), 8.21 (d, 1 H, J = 2 Hz).

EXAMPLE 69 Synthesis of Z-1 64 (1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy-3-pyridinyl > -2- (3,4- dichloropheniDethylene In accordance with the same manner as that described in Example 68, obtaining the title compound. 20 1 H-NMR (CDCl 3) d ppm: 2.64-2.68 (m, 2H), 2.91-2.95 (m, 2H), 6. 57 (s, 2H), 6.87-6.91 (m, 1 H), 7.05 (dd, 1 H, J = 2 Hz), 7.29 (d, 1 H, J = 2 Hz), 7.31 (d, 1 H, J = 8 Hz), 7.34-7.37 (m, 1 H) 7.397.45 (m, 1 H), 7.54-7.58 (m, 1 H), 7.61-7.64 (m, 1 H), 7.98 (d, 1 H, J = 2 Hz).

EXAMPLE 70 Synthesis of 64 (3-acetoxy-1 H -inden-7-yl) oxp-N344- (trifluoromethyl) phenynicotinamide According to the same manner as that described in example 46 except for the use of an equimolar amount of 6 - [(1-oxo-2,3-dihydro-1H-inden-4-yl) oxy] -N3- [4- (Trifluoromethyl) phenyl] n-cyanamide obtained in reference example 39 in the place of 3-4-dichloro-N 1 -. { 6 - [(1-oxo-2,3-dihydro-1 H-inden-4-yl) oxl] -3-pyridinyl} benzamide, the reaction was carried out to obtain the title compound. 1 H-NMR (DMSO-de) d ppm: 10.63 (s, 1 H), 8.70 (s, 1 H), 8.40 (dd, 1 H, J = 9 Hz, 3 Hz), 7.98 (d, 2H, J = 9 Hz), 7.74 (d, 2H, J = 9 Hz), 7.42 (t, 1 H, J = 8 Hz), 7.25 (m, 2H), 7.11 (d, 1 H, J = 8 Hz), 6.28 (s, 1 H), 3.23 (s, 2H), 2.36 (s, 3H).

EXAMPLE OF PREPARATION The preparation example is described below.

EXAMPLE OF PREPARATION 1 After obtaining 3,4-dichloro-N1-. { 6 - [(1-oxo-2,3-dihydro-1 H-inden-4-yl) oxy] -3-pyridinyl} benzamide in example 1, mix and crush ablicel, corn starch and magnesium stearate, compress the mixture with a punch for the coating with sugar R10 mm. The tablets obtained are coated with a film coating agent containing TC-5, polyethylene glycol-6000, castor oil and ethanol to produce film-coated tablets of the aforementioned composition.

Test Example The pyridine derivatives (test compounds) obtained in examples 1 -2, 9-10, 21, 25, 29, 33-37, 39, 42, 44 and 46 were subjected to the following synthesis test of Collagen [Test for the inhibition of collagen synthesis] (Preparation of plasma-derived serum (PDS)) The plasma obtained from the centrifugation of rabbit blood was again subjected to centrifugation to remove the platelets, and the dialysis of the supernatant was carried out against a Phosphate buffered saline solution (PBS) with 0.01% (w / v) calcium chloride and 0.01% (w / v) magnesium chloride. Then, another centrifugation was performed to remove the residue and the resulting supernatant was immobilized for 30 minutes at 56 ° C. The immobilized supernatant was sterilized by means of a filter (0.22 μM) to prepare the serum derived from the plasma (PDS).

(Method for determination) Cultured human "Ito" cells (LOO) were inoculated into a modified Eagle medium of DULBECCO (DMEM) with 10% fetal bovine serum and cultured in an incubator with 5% carbon dioxide (C02) during 24 hours at 37 ° C, and subsequently washed with PBS and cultured in Eagle's minimal essential medium (MEM) containing 2% PDS for another 3 days. The cultured cells were washed with PBS and cultured together with the test compounds in MEM with 10 PM hTGF (transforming growth factor) ß-? (with 2% of PDS on the basis of total MEM) for 16 hours. Subsequently, culture L190 was washed with PBS and marked Rl (radioisotopes) in MEM with 3H proline as radioactivated compound and 0.25 mM ascorbic acid for 24 hours. This cultivated supernatant was precipitated with trichloroacetic acid (TCA), and then the radioactivity was measured in an acid soluble fraction and the resulting measured value was considered as the activity of collagen synthesis. When comparing the radioactivity in the cultured supernatant containing the test compound with the radioactivity in the cultured supernatant that did not contain the test compound (control), the inhibition activity of collagen synthesis (T / C) was calculated by the following equation: T / C = (the radioactivity in the supernatant grown with test compound) / (the radioactivity in the supernatant cultured control). IC50 was determined as the concentration (μM) at which the synthesis of collagen can be inhibited by 50% (concentration of the test compound where IC5o = T / C corresponds to 0.5). These test results are found in Table 1.

TABLE 1 ICso iuM) Example 1 2.14 Example 2 2.90 Example 9 2.34 Example 10 2.60 Example 21 2.92 Example 25 2.70 Example 29 1.58 Example 33 3.88 Example 34 2.15 Example 35 2.43 Example 36 3.72 Example 37 2.52 Example 39 0.55 Example 42 2.29 Example 44 0.92 Example 46 1.12 Field of Industrial Application The pyridine derivative of the present invention is superior in inhibiting the production of collagen. The pyridine derivative of the present invention is also superior in characteristics such as the time during which drug efficacy, stability, absorption / excretion capacity and other similar characteristics are maintained. Accordingly, the pyridine derivative can be used in preventive treatments or in cases of fibrosis (for example, in the case of liver fibrosis, pulmonary fibrosis, etc.) caused by an increase in collagen production.

The description of Japanese patent applications Nos. 10-78083 and 10-251552, which were filed on March 25, 1998 and September 4, 1998, respectively, are incorporated herein by reference.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A derivative of pyridine represented by the general formula [wherein R1 represents a halogen atom or a lower alkyl group substituted with halogen; R2 and R3 are identical or different and represent a hydrogen atom or a halogen atom; V represents a group: -C (= 0) -NH-, a group: -NH-C (= O) -, a group: -NH-C (= O) -NH- or a group: -CH = CH -; A represents a group A1: (where R 4 represents a hydrogen atom, a lower alkanoyl group, a benzene group, a 2-lower alkyl group, 1,3-dioxolane or a lower alkyl group substituted with hydroxy; R 5 represents a hydrogen atom, a 2- group lower alkyl -1,3-dioxolane, a lower alkyl group or a lower alkanoyl group, and R6 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group) a group A2: (where R7 represents a hydrogen atom or a lower alkyl group, and R8 may be the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group: (where k represents an integer from 1 to 3) or a group: = N-OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); p represents an integer from 1 to 2; represents a simple link or a double link; And represents a group: - (CH2) m-, a group: = CH (CH2) m _? _ Or a group: - (CH2) m-? CH =; and m represents an integer from 1 to 3 or a group A3:

A (where R9 may be the same or different and represents a hydrogen atom, a hydroxyl group, an oxo group, a lower alkanoyloxy group, an aroyloxy group, a lower alkoxy group, a group: (where k represents an integer from 1 to 3) or a group: = N-OR10 (R10 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group); q represents an integer from 1 to 2: • 10 represents a simple link or a double link; z represents a group: - (CH2) n-, a group: = CH (CH2) n _? - or a group: - (CH2) n_? CH =; and n represents an integer from 1 to 3)] or a salt thereof. 2. The pyridine derivative according to claim 1, characterized in that A is the group A2 or A3, or a salt thereof.

3. The pyridine derivative according to claim 2, characterized in that m and n are 1 or 2 or a salt thereof.

4. The pyridine derivative according to claim 3, Characterized in that R8 and R9 are an oxo group or a lower alkanoyloxy group, or a salt thereof.

5. - The pyridine derivative according to claim 1, characterized in that V is the group: -C (= O) -NH-, the group: -NH-C (= O) - or the group: -NH-C ( = O) -NH-, or a salt thereof.

6. The pyridine derivative according to claim 5, characterized in that A is the group A2 or A3, or a salt thereof.

7. The pyridine derivative according to claim 1, characterized in that R1 and R2 are respectively a halogen atom, or a salt thereof.

8. The pyridine derivative according to claim 1, characterized in that R1 is a lower alkyl group substituted with halogen, or a salt thereof.

9. The pyridine derivative according to claim 6, characterized in that R1 and R2 are respectively a halogen atom, or a salt thereof.

10. The pyridine derivative according to claim 6, characterized in that R1 is an alkyl group substituted with halogen, or a salt thereof.

11. The pyridine derivative according to claim 7, characterized in that A is the group A2, or a salt thereof.

12. The pyridine derivative according to claim 11, characterized in that V is the group: -C (= 0) -NH-, or a salt thereof.

13. The pyridine derivative according to claim 11, characterized in that V is the group: -NH-C (= 0) -NH-, or a salt thereof. 55

14. - The pyridine derivative according to claim 7, characterized in that A is the group A3, or a salt thereof.

15. The pyridine derivative according to claim 14, characterized in that V is the group: -NH-C (= O) -NH-, or a salt thereof.

16. The pyridine derivative according to claim 8, characterized in that A is the group A2, or a salt thereof.

17. The pyridine derivative according to claim 8, characterized in that A is the group A3, or a salt thereof.

18. The pyridine derivative according to claim 16, characterized in that V is the group: -NH-C (= O) -, or a salt thereof.

19. The pyridine derivative according to claim 16, characterized in that V is the group: -NH-C (= 0) -NH-, or a salt thereof.

20. The pyridine derivative according to claim 17, characterized in that V is the group: -NH-C (= 0) -NH-, or a salt thereof.

21. The pyridine derivative according to claim 12, characterized in that Y is a group: -CH = or -CH2-, R7 is a hydrogen atom, R8 is an oxo group, a lower alkanoyloxy group or the group: -O-CH2-CH2-0-, or a salt thereof.

22. The pyridine derivative according to claim 13, characterized in that Y is the group: -CH =, -CH2-CH2 or -CH2-CH =, R7 is a hydrogen atom, R8 is an oxo group, or a lower alkanoyloxy group, or a salt thereof.

23. The pyridine derivative according to claim 15, characterized in that Z is a group: -CH 2 -CH =, R 9 is a lower alkanoyloxy group, or a salt thereof.

24. The pyridine derivative according to claim 18, characterized in that Y is the group: -CH2-, R7 is a hydrogen atom, R8 is an oxo group, or a salt thereof.

25. The pyridine derivative according to claim 19, characterized in that Y is the group: -CH2-; -CH = or -CH2-CH =, R7 is a hydrogen atom, R8 is a lower alkanoyloxy group, or a salt thereof.

26. The pyridine derivative according to claim 20, characterized in that Z is the group: -CH2-CH =, R9 is a lower alkanoyloxy group, or a salt thereof.

27. A pharmaceutical product characterized in that it contains a compound of the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition for the prophylaxis or treatment of fibrosis, characterized in that it contains a sufficient quantity of the compound of the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof and an agent, diluent and / or pharmaceutically acceptable excipient.

29. The use of a compound of the general formula (1) as claimed in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting fibrogenesis caused by the production of excess collagen in the a mammal.