 4-Imidazolin-2-one compounds
专利摘要:
公开号:AU2004201666A1 申请号:U2004201666 申请日:2004-04-21 公开日:2004-05-13 发明作者:Hajime Hiramatus；Ritsuo Imashiro；Akira Kubo；Hidetaka Miyoshi；Tatsuo Nakajima；Tetsu Nakane；Akihito Ogasawara；Hiroaki Sakurai 申请人:Tanabe Seiyaku Co Ltd； IPC主号:A61K31-4439
专利说明:
AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Tanabe Seiyaku Co., Ltd. Actual Inventor(s): Akira Kubo, Ritsuo Imashiro, Hiroaki Sakurai, Hidetaka Miyoshia, Akihito Ogasawara, Hajime Hiramatsu, Tatsuo Nakajima, Tetsu Nakane Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: 4-IMIDAZOLIN-2-ONE COMPOUNDS Our Ref: 718215 POF Code: 96621/87539 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): 1 la 4-IMIDAZOLIN-2-ONE COMPOUNDS BACKGROUND OF THE INVENTION 1. Field of the Invention This application is a divisional of Australian patent application number 2002363108 the entire disclosure of which is incorporated herein by reference. The present invention relates to a novel 4-imidazolin-2-one compound which has an excellent p38MAP kinase inhibitory action and is useful for a medicament. 2. Background Art Mitogen-activated protein (MAP) kinase is a member of serine-threonine kinases which transfers a y-phosphate group of adenosine triphosphate (ATP) to a hydroxy of specific serine or threonine which constitutes a protein, and is involved in various cellular responses against extracellular signals. p38 MAP kinase is an about 38 kDa protein and cloned as a homologue of MAP kinases. p38MAP kinase is activated by inflammatory cytokines such as tumor necrosis factor a (TNF-a) and interleukin 1 and by stimulation caused by stress such as ultraviolet irradiation. p38 MAP kinase recognizes various transcription factors and protein kinases as a substrate. It has been clearly shown that, being activated by p38 MAP kinase, these transcription factors and protein kinases become involved in promoting transcription, post-transcriptional regulation stabilizing mnRNA and promoting protein translation) or stabilizing proteins, etc. of various proteins including inflammatory cytokines, which are involved in inflammatory reactions. From these findings, it is thought that p38 MAP kinase is critically involved in the various inflammatory reactions by regulating the production and the signal transduction of inflammatory cytokines, and an inhibitor of p38 MAP kinase can highly expected to serve as a therapeutic agent for various diseases including inflammatory diseases. As the inhibitors for p38 MAP kinase, there have been disclosed imidazole derivatives in PCT Japanese Provisional Y:Mao.NI NO DELETE MR2002363108.doc Patent Publication No.2000-503304, 1,3-thiazole derivatives in Japanese Provisional Patent Publication No. 2001-114690, 1,3-thiazole derivatives and 1,3-oxazole derivatives in Japanese Provisional Patent Publication No. 2001-114779, imidazole derivatives, pyrrole derivatives, furan derivatives, 3-pyrazolin-5-one derivatives, pyrazole derivatives and thiophene derivative, etc. in Expert Opinion on Therapeutic Patents (2000) 10(1) :25-37, respectively. However, there has been no description on 4-imidazolin-2-one derivatives in any of these. An object of the present invention is to provide a novel compound having an excellent p38 MAP kinase inhibitory action and is useful as a pharmaceutical. SUMMARY OF THE INVENTION The present inventions are as disclosed as follows. A compound of the formula 0 N SN-(CH 2 )n-R' 2 4 A Z7 N Z wherein G' is an alkyl which is substituted by a halogen atom or an alkoxy, or a group of the formula: B -Wwherein ring B is benzene ring, naphthalene ring, a monocyclic or bicyclic aromatic heterocycle or a cycloalkane, and the benzene ring, the naphthalene ring, the monocyclic or bicyclic aromatic heterocycle and the cycloalkane may be substituted by 1 to 3 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbamoyl, hydroxy and cyano, W is a single bond, or a ci c 4 alkylene which may be substituted by 1 or 2 alkyl(s), Q 1 and Q2 may be the same or different, and each is hydrogen atom, a halogen atom or an alkyl, n is 0, 1, 2, 3 or 4, R 1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, Z 1 Z 2 Z 3 and Z 4 may be the same or different, and each is CH or N, provided that 3 or more of Z 2 Z 3 and Z 4 should not be N at the same time, G 2 is hydrogen atom, -NR R 4 -OR 5 -SR 5 -COR -CHR or a heterocyclic group, where R 3 to R 8 each independently is hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, hydroxy, an alkoxy, an optionally substituted amino, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an alkoxyoxalyl, an alkylsulfonyl, an optionally substituted cycloalkyl, an.optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl, a carbonyl substituted by an optionally substituted phenyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. A compound of the formula [Ia]: N-(CH 2 )n-R 1 [la] R 2 wherein ring A is benzene ring or a monocyclic aromatic heterocycle, and the benzene ring and the monocyclic aromatic heterocycle may be substituted by 1 to 3 substituent(s), which is(are) the same or different, and selected from the group consisting of a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbamoyl, hydroxy and cyano, Q 1 is hydrogen atom, a halogen atom or. an alkyl, W is a single bond, or a cl c 4 alkylene which may be substituted by 1 or 2 alkyl(s), n is 0, 1, 2, 3 or 4, R 1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, Z is CH or N, R 2 is hydrogen atom, -NR 3 R 4 -OR 5 -COR 6 or -CHR'R 8 where R 3 to R 8 each independently is hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, hydroxy, an alkoxy, an optionally substituted amino, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an alkoxyoxalyl, an alkylsulfonyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl, a carbonyl substituted by an optionally substituted phenyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. The compound according to wherein Q 1 is hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound according to or wherein the ring A is a benzene ring which may be substituted by 1 to 3 substituent(s), which is(are) the same or different, and selected from the group consisting of a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino and cyano, and W is a single bond, or a pharmaceutically acceptable salt thereof. The compound according to any one of to wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof The compound according to any one of to wherein n is 0 and R' is an optionally substituted alkyl, n is 1 and R 1 is an optionally substituted cycloalkyl, n is 1 and R 1 is an optionally substituted phenyl, n is 1 and R 1 is an optionally substituted heterocyclic group, n is 0 and R 1 is an optionally substituted cycloalkyl, and n is 0 and R 1 is an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. The compound according to any one of to wherein R 2 is -NR 3 R 4 or -OR 5 or a pharmaceutically acceptable salt thereof. The compound according to any one of to wherein R 2 is -NHR 4 and R 4 is an optionally substituted alkyl, an alkenyl, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. The compound according to wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino and cyano, W is a; single bond, n is 0 or 1, R 1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, Z is CH or N, R 2 is hydrogen atom, -NR 3 R 4 -OR 5 -COR 6 or -CHRR" 8 Where R3 to R 8 each .independently is hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkoxy, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an alkoxyoxalyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. The compound according to wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, an alkyl optionally substituted by halogen(s), an alkoxy, an amino optionally substituted by alkyl(s) and cyano, W is a single bond, n is 0. or 1,. R 1 is hydrogen atom, an alkyl optionally substituted by group(s) selected from the group consisting of phenyl, an alkoxy, an alkylamino, a dialkylamino, an alkanoylamino, an alkylsulfonylamino, a carbamoyl optionally substituted by alkyl(s), hydroxy, carboxy and cyano, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following to hydroxy, (ii) an alkoxy optionally substituted by alkoxy(s), (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl, (iv) a carbamoyl optionally substituted by alkyl and an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy and amino, a phenyl optionally substituted by group(s) selected from the group consisting of the following to (vi): a halogen atom, (ii) an alkyl optionally substituted by group(s) selected from the group consisting of a halogen atom, hydroxy and phenylsulfonyl, (iii) cyano, (iv) an alkoxy, an amino optionally substituted by group selected from the group consisting of an alkyl and an alkylsulfonyl, (vi) a carbonyl substituted by a heterocyclic group, or a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (iv): an alkoxycarbonyl, (ii) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy and a carbamoyl optionally substituted by alkyl (iii) an alkanoyl and (iv) an alkylsulfonyl, Z is CH or N, R2 is hydrogen atom, -N R R, -OR -COR 6 or -CHR R, where R 3 to R 8 each independently is: hydrogen atom, an alkyl optionally substituted'by group(s) selected from the group consisting of the following to (vii): hydroxy, (ii) an alkoxy, (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl, (iv) an alkoxycarbonyl, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to g): a) hydroxy, b) an amino optionally substituted by alkyl(s), c) an alkanoylamino, d) an alkylsulfonylamino, e) an alkyl optioinally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy, amino, a carbamoyl optionally substituted by alkyl(s), f) carboxy and g) a carbamoyl optionally substituted by alkyl(s), (vi) a phenyl optionally substituted by group(s) selected from the group consisting of a halogen atom, an alkoxy and morpholinylcarbonyl, and (vii) a heterocyclic group optionally substituted by alkyl(s), an alkenyl, an alkoxy, .an alkanoyl optionally substituted by group(s) selected from the. group consisting of the following (i) to (iv): hydroxy, (ii) an alkoxy, (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl and an alkanoyl, (iv) an alkoxycarbonyl, a carbamoyl optionally substituted by alkyl(s), an alkoxyoxalyl, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vii): a halogen atom, (ii) hydroxy, (iii) an alkoxy, (iv).an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl, an alkyl optionally substituted by group selected from the group consisting of hydroxy, an alkoxy, amino, a carbamoyl optionally substituted by alkyl(s), (vi) an alkanoyloxy and (vii) a carbamoyl optionally substituted by alkyl(s), a phenyl optionally substituted by group(s) selected from the group consisting of a halogen atom and an alkoxy, (10) a heterocyclic group optionally substituted by group(s) selected from the group consisting .of the following to (vii): an alkyl optionally substituted by group(s) selected from the group consisting of phenyl,. hydroxy, an alkoxy, amino and a carbamoyl optionally substituted by alkyl(s), (ii) an alkoxycarbonyl, (iii) an alkanoyl, (iv) an alkylsulfonyl, oxo, (vi) a carbamoyl optionally substituted by alkyl(s), (vii) an aminosulfonyl optionally substituted by alkyl(s), (11) a. carbonyl substituted by a cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and an alkanoylamino, or (12) a heterocyclic group-substituted carbonyl, or a pharmaceutically acceptable salt thereof. [11] The compound according to wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent which is (are) the same or different, and selected from the group consisting of fluorine atom, chlorine atom, an alkyl optionally substituted by halogen(s) and an alkoxy, W is a single bond, n is 0 or 1, R 1 is hydrogen atom, an alkyl optionally substituted by group(s) selected from the group consisting of phenyl, an alkoxy, an alkylamino, a dialkylamino, an alkanoylamino, an alkylsulfonylamino, a carbamoyl optionally substituted by alkyl(s), hydroxy, carboxy, cyano, and cycloalkyl, a cycloalkyl. optionally substituted by group(s) selected from the group consisting of the following (i) to hydroxy, (ii) an alkoxy optionally substituted by alkoxy(s), (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl, (iv) a carbamoyl optionally substituted by alkyl(s), an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy and amino, a phenyl optionally substituted by.group(s) selected from the group consisting of the following to (iv): a halogen atom, (ii) an alkyl optionally substituted by halogen atom(s), (iii) cyano, and an alkoxy, or a heterocyclic group optionally substituted by alkylsulfonyl or alkanoyl, .Z is CH or N, R 2 is hydrogen atom, -NR3R 4 -OR 5 or -COR 6 Where R3 to R each independently is: hydrogen:atom, an alkyl optionally substituted by group(s) selected from the group consisting of the following to (vii): hydroxy, (ii) an alkoxy, (iii) an alkoxycarbonyl, (iv) a cycloalkyl optionally substituted by group(s) selected from the group. consisting of the following a) to e): a) hydroxy, b) an amino optionally substituted by alkyl(s), c) an alkanoylamino, an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl. optionally substituted by alkyl and e) a carbamoyl optionally substituted by alkyl(s), a phenyl optionally substituted by alkoxy(s), (vi) a heterocyclic group, and (vii) an amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s), an alkenyl, an alkoxy, an alkanoyl optionally substituted by group(s) selected from the group consisting of an alkoxy, an amino optionally substituted by alkanoyl(s), and an alkoxycarbonyl, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to hydroxy, (ii) an alkoxy, (iii): an amino optionally substituted by group(s) selected.from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl, (iv) an alkyl. optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by alkyl(s), a carbamoyl optionally substituted by alkyl(s), a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (vi): an alkyl optionally substituted by phenyl(s), (ii) an alkoxycarbonyl, (iii) an alkylsulfonyl (iv) an alkanoyl, a carbamoyl optionally substituted by alkyl and (vi) an aminosulfonyl optionally substituted by alkyl(s),. a carbonyl substituted by a cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy and amino, or a heterocyclic group-substituted carbonyl, or a pharmaceutically acceptable salt thereof. [12] A compound of the formula [Ib]: N Z HN R wherein R 1 is-a group selected from the group consisting of hydrogen atom, a halogen atom, a ci- c 4 alkyl optionally substituted by halogen(s) and a ci- c 4 alkoxy, k is 1 or 2, and when k is 2, two of R 1 s may be the same or different, R 12is a cl- c 5 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy, cyano, amino, tetrahydropyranyl, tetrahydrofuryl and a carbamoyl optionally substituted by alkyl(s), a c 3 c 4 cycloalkylmethyl, a c3 c 4 cycloalkyl, carbamoylmethyl, a benzyl optinally substituted by group(s) selected from the group consisting of cyano, a halogen atom, a ci c 3 alkoxy, a c 1 c 3 alkyl and a halogen-substituted c 1 c 3 alkyl, tetrahydropyranyl, tetrahydrofuryl and a piperidyl optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl, an alkoxycarbonyl and a carbamoylalkyl optionally substituted by alkyl(s), Z 5 is CH or N, R 13 is a ci c 6 alkyl optionally substituted by group(s) selected from the group consisting of the following to (xiv): a c 5 c 7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e): a) hydroxy b) an amino optionally substituted by cl- c 4 alkyl(s), c) a c i C 4 alkanoylamino, d) a ci- c 4 alkyl optionally substituted by group (s) selected from'the group consisting of hydroxy, amino, and a carbamoyl optionally substituted by ci c 4 alkyl(s), and e) a carbamoyl optionally substituted by ci- c4 alkyl(s), (ii) hydroxy, (iii) a carbamoyl optionally substituted by ci- c4 alkyl(s), (iv) a piperidyl optionally substituted by group (s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl and oxo, a pyrrolidinyl optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl and oxo, a tetrahydropyranyl optionally substituted by hydroxy(s), (vii) an imidazolinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo, (viii) an imidazolidinyl optionally substituted by group selected from the group consisting of an alkyl and oxo, (ix) a piperadinyl optionally substituted by group selected from the group consisting of an alkyl and oxo, a hexahydropyrimidinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo, (xi) a pyridyl optionally substituted by alkyl(s), (xii) furyl, (xiii) tetrahydroisothiazolyl optionally substituted by oxo(s), and (xiv) amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s), a c 5 c7 cycloalkyl optionally substituted by group (s) selected from the group consisting of the following to hydroxy, (ii) a cI c 4 alkoxy, (iii) a ci- c 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by ci c 4 alkyl(s), (iv) a carbamoyl optionally substituted by ci- c4 alkyl(s), and an amino optionally substituted by group(s) selected from the group consisting of ci c 4 alkyl (s) and cl c 4 alkylsulfonyl(s), or a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (vii): an alkyl optionally substituted.by group(s) selected from the group consisting of a halogen, amino, hydroxy, phenyl and oxo, (ii) an aminosulfonyl optionally substituted by alkyl(s), (iii) an alkylsulfonyl optionally substituted by halogen(s), (iv) a carbamoyl optionally substituted by alkyl(s), hydroxy, (vi) an alkoxycarbonyl, and (vii) oxo, or a pharmaceutically acceptable salt thereof. [13] The compound according to [12],wherein R 12 is c C 5 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, alkoxy, tetrahydropyranyl and tetrahydrofuryl a c 3 c 4 cycloalkylmethyl, a c 3 c 4 cycloalkyl, carbamoylmethyl, a benzyl optinally substituted by group(s) selected from the group consisting of cyano, a halogen atom, a c 1 c 3 alkoxy, a c 1 c 3 alkyl and a halogen-substituted c 1 c 3 alkyl, tetrahydropyranyl, tetrahydrofuryl, or a piperidyl optionally substituted by alkylsulfonyl or alkanoyl, R 13 is a ci c 6 alkyl optionally substituted by group(s) selected from the group consisting of the following to a c 5 c 7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e): a) hydroxy b) an amino optionally substituted by ci- c 4 alkyl(s), c) a c 1 c 4 alkanoylamino, d) a c- C 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino, and a carbamoyl optionally substituted by ci c 4 alkyl(s), and a carbamoyl optionally substituted by ci- c4 alkyl(s), (ii) hydroxy, (iii) a carbamoyl optionally substituted by ci C4 alkyl(s), and (iv) an amino optionally substituted by the group (s) selected from alkanoyl(s) and alkylsulfonyl(s), a c 5 -c 7 cycloalkyl optionally substituted by group (s) selected from the group consisting of the following .to hydroxy, (ii) a ci c 4 alkoxy, (iii) a ci- c 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by c c 4 alkyl(s), (iv) a carbamoyl optionally substituted by ci c4 alkyl and an amino optionally substituted by group(s) selected from the group consisting of ci c 4 alkyl (s) and ci- c 4 alkylsulfonyl(s), or a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (vi): alkylsulfonyl(s), (ii) alkoxycarbonyl(s), (iii) carbamoyl(s) optionally substituted by alkyl(s), (iv) alkanoyl(s), aminosulfonyl(s) optionally substituted by alkyl(s), and (vi) alkyl(s), or a pharmaceutically acceptable salt thereof. [14] The compound according to [12] or wherein R 11 is a group selected from the group consisting of hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl and methoxy, k is 1 or 2, and when k is 2, two of R 11 s may be the same or different, R 12 is a ci- c 5 alkyl optionally substituted by hydroxy, cyclopropylmethyl, cyclobutyl, carbamoylmethyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyranylmethyl, tetrahydrofurylmethyl or piperidyl optionally substituted by the group selected from alkylsulfonyl and alkanoyl, or a pharmaceutically acceptable salt thereof. [15] The compound according to [12] or wherein R 1 is hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl or methyl, k is 1, R 12 is ethyl, isopropyl, isobutyl, 2-hydroxy-2-methylpropyl, cyclopropylmethyl, cyclobutyl, carbamoylmethyl, 4-tetrahydropyranyl, 3-tetrahydrofuryl, tetrahydropyranylmethyl, tetrahydrofurylmethyl methoxymethyl, 3-hydroxy-3-methylbutyl or 4-piperidyl substituted by methanesulfonyl or acetyl, R 13 is a ci- c 6 alkyl optionally substituted by group(s) selected from the-group consisting of the following and (iii): a c 5 c 7 cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy, a ci c 4 alkyl, a hydroxy Ci c 4 alkyl, an amino optionally substituted by ci c 4 alkyl(s) and a carbamoyl optionally substituted by ci 4 alkyl(s), (ii) hydroxy, and (iii) an amino optionally substituted by group(s) selected from the group consisting of alkyl(s) and alkylsulfonyl(s), a c 5 c 7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following to hydroxy, (ii) a ci c 4 alkoxy, (iii) a ci c 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by ci c4 alkyl(s), (iv) a carbamoyl optionally substituted by ci c4 alkyl(s), and an amino optionally substituted by group(s) selected from the group consisting of alkyl(s) and alkylsulfonyl.(s), piperidinyl optionally substituted by group(s) selected from the group consisting of the following to (vi): alkylsulfonyl(s), (ii) alkoxycarbonyl(s), (iii) carbamoyl(s) optionally substituted by alkyl(s), (iv) alkanoyl(s), aminosulfonyl(s) optionally substituted by alkyl(s), and (vi) alkyl(s), pirrolidinyl optionally substituted by alkylsulfonyl, or a pharmaceutically acceptable salt thereof. [16] A pharmaceutical composition comprising the compund according to any one of to [15] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [17] The method of inhibiting of p38 MAP kinase which comprises administering the compound according to any one of to or a pharmaceutically acceptable salt thereof to a human in need thereof. [18] The-method of prophylaxis or treatment for diseases related to the activation of p38 MAP kinase or the excessive production of inflammatory mediators concerned with p38 MAP kinase, which comprises administering the compound according to any one of to [15] or a pharmaceutically acceptable salt thereof to a human in need thereof. [19] The method of prophylaxis or treatment for diseases selected from the group consisting of arthritis, inflammatory bowel disease, inflammatory dermal disease, inflammatory respiratory disease, inflammatory optical disease, nephritis, hepatitis, systemic inflammatory disease, shock, cerebrovascular disease, ischemic cardiac diseases, osteoporosis, multiple sclerosis, diabetes, malignant tumor, cachexia, Alzheimer's disease, Parkinson's disease, acquired immunodeficiency syndrome, arterial sclerosis, disseminated intravascular coagulation syndrome, rejection and graft-versus-host diseases by organ transplantation, which comprises administering the compound according to any one of to [15] or a pharmaceutically acceptable salt thereof to a human in need thereof. DETAILED DESCRIPTION OF THE INVENTION In the present invention, "an alkyl" and alkyls in "an alkylthio", "an alkylsulfinyl" and "an alkylsulfonyl" are exemplified by a straight or branched chain Ci-C 6 alkyl, and specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. Preferred is a cl-c 4 alkyl. "An alkoxy" and alkoxys in "an alkoxycarbonyl" and "an alkoxyoxalyl" are exemplified by a straight and branched chain C 1 -C6 alkoxy, and specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexoxy, etc. Preferred is a Ci-C 4 alkoxy. "An alkenyl" is exemplified by a straight or branched chain C 2 -C 7 alkenyl, and specifically, vinyl, allyl, 3-butenyl, 2-pentenyl, 3-hexenyl, etc. Preferred is a C2-C5 alkenyl, etc. "An alkynyl" is exemplified by a straight or branched chain C2-C7 alkynyl, and specifically, ethynyl, propargyl, 3-butynyl, 2-pentynyl, 3-hexynyl, etc. Preferred is a C2-Cs alkynyl. "An alkanoyl" is exemplified by a straight or branched chain C 2 -C 7 ,alkanoyl, and specifically, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, etc. Preferred is a C2-C5 alkanoyl. "A cycloalkyl" is exemplified by a C 3 -C8 cycloalkyl, and preferred is a C3-C6 cycloalkyl. "A cycloalkane" is exemplified by a C3-C8 cycloalkane, and preferred is a Cs-C7 cycloalkane. "A halogen atom" is exemplified by fluorine atom, chlorine atom, bromine atom, iodine atom, and preferred are fluorine atom and chlorine atom. "A heterocyclic group" is exemplified by a partially or completely saturated monocyclic, bicyclic or tricyclic heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom. Preferred is a 5- or 6-membered monocyclic heterocyclic group, and specific examples are furyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiapyranyl, thienyl, tetrahydrothienyl, thiazolyl, isothiazolyl, tetrahydroisothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyridyl, pyridazinyl, pyrimidinyl, hexahydropyrimidinyl, pyrazinyl, triazinyl, piperidinyl, pyrazolyl, piperazinyl, morpholinyl, dioxanyl, imidazolyl, triazolyl, imidazolinyl, pyrazolinyl, thiazinyl, tetrahydrothiazinyl, etc. "A monocyclic or bicyclic aromatic heterocycle" is exemplified by a monocyclic or bicyclic aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom. Additionally, "monocyclic aromatic heterocycle" is exemplified by a monocyclic aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom, for example, or 6-membered monocyclic aromatic heterocycle. Specific examples for the monocyclic and bicyclic aromatic heterocycle include thiophene, furan, furazane, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinazoline, isoquinoline, phthalazine, naphthyridine, quinazoline, quinoline, chromene, indolizine, isoindole, indole, purine, benzofuran, benzothiophene, etc. Preferred monocyclic aromatic heterocycles are thiophene, furan, etc. When a substituent of the ring B in the compound or a substituent of the ring A in the compound [Ia] is "an optionally substituted alkyl", examples for substituent of the alkyl include a halogen atom, hydroxy, amino, etc. The said alkyl may have 1 to 3 substituents mentioned above, and when the number of the substituents is two or more, each of the substituents may be the same or different. Specific examples for the substituted alkyl include hydroxymethyl, trifluoromethyl, aminomethyl, chloroethyl, etc. When a substituent of the ring B or a substituent of the ring A is "an optionally substituted alkoxy", examples for substituent of the alkoxy include hydroxy, amino, etc. The said alkoxy may have 1 to 3 substituents mentioned above, and when the number of the substituents is two or more, each of the substituents may be the same or different. When a substituent of the ring B or a substituent of the ring A is "an optionally substituted amino", examples for the substituent of.the amino include an alkyl (said alkyl may be substituted with 1 to 3 groups which are the same or different, selected from the group consisting of an alkoxy, amino and carboxy), an alkanoyl, etc. The said amino may have 1 or 2 substituents mentioned above, and when the number of.the substituents is two, each of the substituents may be the same or different. When a substituent of the ring B or a substituent of the ring A is "an optionally substituted carbamoyl", examples for the substituents of the carbamoyl include alkyl, etc. The said carbamoyl may have 1 or 2 substituents mentioned above, and when the number of the substituents is two, each of the substituents may be the same or different. A substituent of the ring B in the compound or a substituent of the ring A in the compound [Ia] is preferably exemplified by a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino,, and cyano. Particularly preferred are a halogen atom, a Ci-c 4 alkyl, a ci-c 4 alkoxy, etc., and specific examples are fluorine atom, chlorine atom, methyl, methoxy, etc.. When R 1 of the compound and the compound [Ia] is "an optionally substituted alkyl", examples for substituent of the alkyl include an alkynyl, cyano, an alkoxy, hydroxy, amino (said amino may be substituted with 1 or 2 substituents selected from the group consisting of an alkyl, an alkanoyl, and an alkylsulfonyl.), carboxy, an alkoxycarbonyl, carbamoyl (said carbamoyl may be substituted with 1 or 2 alkyl(s).), phenyl, naphthyl, etc. The said alkyl may have 1 to 3 substituents mentioned above, and when the number of the substituents is two or more, each of the substituents may be the same or different. Specific examples for the substituents include cyano, an alkoxy, hydroxy, amino, carboxy, a carbamoyl which may be substituted by an alkyl, phenyl, etc. When R 1 is "an optionally substituted cycloalkyl", examples for the substituents of the cycloalkyl include (1) hydroxy, an alkoxy (said alkoxy may be substituted by 1 to 3 alkoxy(s)) amino [said amino may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of the following to an alkyl, (ii) an alkanoyl, (iii) an alkoxycarbonyl, (iv) carbamoyl said carbamoyl may be substituted by 1 or 2 alkyl and(v) an alkylsulfonyl] carboxy, an alkyl (said alkyl may be substituted by a group selected form the group consisting of hydroxy, an alkoxy and amino), a carbamoyl which may be substituted by alkyl(s), etc. The said cycloalkyl may have 1 to 3 substituents mentioned above, and when the number of the substituents is two or more, each of the substituents may be the same or different. When R 1 is "an optionally substituted phenyl", examples for the substituents of the phenyl include a halogen atom, nitro, an alkyl. (said alkyl may be substituted by 1 to 3 group(s) being the same or different, selected from the group consisting of a halogen atom, hydroxy, amino, carboxy, and phenylsulfonyl), an alkenyl, cyano, hydroxy, an alkoxy (said alkoxy may be substituted by 1 to 3 group(s), being the same or different, and selected from the group consisting ,of a halogen atom, carboxy, an alkoxycarbonyl, carbamoyl, phenyl and morpholinylcarbonyl), amino [said amino may be substituted with 1 or 2 group(s), being the same or different, and selected from the group consisting of the following to (iv) an alkyl, (ii) an alkanoyl, (iii)carbamoyl (said carbamoyl may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl and a cycloalkyl), and (iv) an alkylsulfonyl], an alkanoyl, (10) carboxy, (11) an alkoxycarbonyl, (12)carbamoyl [said carbamoyl may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of the following and an alkyl (said alkyl may be substituted by 1 to 3 hydroxy(s)) and (ii) a cycloalkyl] (13) an alkylthio, (14) an alkylsulfinyl, (15) an alkylsulfonyl, (16) phenyl, (17) tetrazolyl, (18) a heterocyclic group-substituted carbonyl (said heterocyclic group may be substituted by 1 to 3 group(s) being the same or different, and selected from the group consisting of an alkyl and an alkoxycarbonyl), etc. When R 1 is an optionally substituted phenyl, said phenyl may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. Preferred substituents are a halogen atom, an alkyl (said alkyl may be substituted by 1 to 3 group(s), being the same or different, and selected from the group.consisting of a halogen atom, hydroxy, amino, carboxy, and phenylsulfonyl), cyano, an alkoxy (said alkoxy may be substituted by 1 to 3 group(s), being the same or different, and selected from the group consisting of a halogen atom, carboxy, an alkoxycarbonyl, carbamoyl, phenyl and morpholinyl carbonyl), etc. There is no limitation regarding positions of the substituents, as long as it is possible to substitute, and a particularly preferred position is 2-position. When R 1 is "a phenyl substituted by a heterocyclic group-substituted carbonyl", examples for the heterocyclic group include the above-mentioned heterocyclic groups, and preferred are 5- or 6-membered monocyclic nitrogen-containing aliphatic heterocyclic groups. Specific examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, etc. When R 1 is "an optionally substituted heterocyclic group", examples for the heterocyclic group include the above-mentioned heterocyclic groups, and preferred are 5- or 6-membered monocyclic heterocyclic groups. Specific examples are furyl, tetrahydrofuryl, thienyl, thiazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, tetrazolyl, tetrahydropyranyl, etc. Particularly preferred are piperidinyl, tetrahydropyranyl, etc. Further, the substituents of the heterocyclic group are exemplified by a halogen atom, nitro, an alkyl (said alkyl may be substituted by a group selected from the group consisting of hydroxy, an alkoxy, a carbamoyl which may be substituted by alkyl(s) and carboxy(s)), cyano, hydroxy, amino, an alkanoyl, carboxy, an alkoxycarbonyl, carbamoyl (said carbamoyl may be substituted by 1 or 2 alkyl(s)), an alkylsulfonyl, phenyl, etc. The said heterocyclic group may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. A preferred combination of n and R 1 in the compound [I] and the compound [Ia] are exemplified by those in which n is 0 and R 1 is an optionally substituted alkyl, those in which n is 1 and R 1 is an optionally substituted cycloalkyl, those in which n is 1 and R 1 is an optionally substituted phenyl, those in which n is 1 and R 1 is an optionally substituted heterocyclic group, those in which n is 0 and R 1 is an optionally substituted cycloalkyl, and those in which n is 0 and R 1 is an optionally substituted heterocyclic group, etc. Particularly preferred are those in which n is 0 and R 1 is an optionally substituted alkyl, those in which n is 1 and R 'is an optionally substituted phenyl, (3) those in which n is 0 and R 1 is an optionally substituted cycloalkyl, and those in which n is 0 and R 1 is an optionally substituted heterocyclic group, etc. Further preferred are those in which-n is 0 and R 1 is a Ci-C4 alkyl optionally substituted by hydroxy, those in which n is 1 and R 1 is a phenyl (said phenyl may be substituted by a group selected from the group consisting of cyano, fluorine atom, chlorine atom and methyl), those in which n is 0 and R 1 is C3-C4 cycloalkyl, and those in which n is 0 and R 1 is 4-tetrahydropyranyl, etc. When R 3 to R 8 in the compound and the compound [Ia] is "an optionally substituted alkyl", the substituents of the alkyl are exemplified by hydroxy, an alkoxy group, (3) amino (said amino may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl, an. alkanoyl and an alkylsulfonyl), an alkoxycarbonyl, a cycloalkyl [said cycloalkyl may be substituted by 1 to 3 group(s), being the same or different, and selected from the group consisting of hydroxy, an amino which may be substituted by alkyl(s), an alkanoylamino, an alkylsulfonylamino, an alkyl (said alkyl may be substituted by a group selected from hydroxy, an alkoxy, amino and a carbamoyl which may be substituted by alkyl carboxy and a carbamoyl which may be substituted by alkyl(s)], phenyl [said phenyl may be substituted by 1 to 3 group being the same or different, and selected from the group consisting of the following to a halogen atom, (ii) an alkoxy, (iii) amino. (said amino maybe substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl and an alkoxycarbonyl), (iv) an alkoxycarbonyl, carbamoyl, and (vi) morpholinylcarbonyl], a heterocyclic group [said heterocyclic group may be substituted by 1 to 3 group(s), being the same or different, and selected from the group consisting of the following to (viii): an alkyl (said alkyl may be substituted by 1 to 3 hydroxy hydroxy, (iii) amino, (iv) an alkoxycarbonyl, carbamoyl, (vi) alkanoyl, (vii) alkylsulfonyl and (viii) oxo], mercapto, etc. When R 3 to R 8 is an optionally substituted alkyl, said alkyl may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "a heterocyclic group-substituted alkyl", said heterocyclic group are exemplified by the above-mentioned heterocyclic groups, and preferred are 5- or 6-membered monocyclic heterocyclic groups. Specific examples are pyridyl, pyrimidinyl, pyrazinyl, piperidyl, pyrrolidinyl, morpholinyl, thienyl, furyl, tetrahydropyranyl, imidazolinyl, imidazolidinyl, piperazinyl, hexahydropyrimidinyl, etc. When R 3 to R 8 is "an optionally substituted amino", substituents of the amino are exemplified by an alkyl (said alkyl may be substituted by 1 to 3 group(s)., being the same or different, and selected from the group consisting of hydroxy, an alkoxy and a heterocyclic group), a cycloalkyl (said cycloalkyl may be substituted by 1 to 3 hydroxy(s)), a heterocyclic group, etc. The said amino may have 1 or 2 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "an amino substituted by a heterocyclic group-substituted alkyl" or "an amino substituted by a heterocyclic group", the heterocyclic group are exemplified by the above-mentioned heterocyclic groups. Preferred are 5- or 6-membered monocyclic heterocyclic groups, specific examples are pyridyl, piperidyl, pyrrolidinyl, morpholinyl, etc.. When R 3 to R 8 is "an optionally substituted alkanoyl", substituents of the alkanoyl are exemplified by hydroxy, an alkoxy, amino (said amino may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl and an alkanoyl), an alkoxycarbonyl, etc. The said alkanoyl may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "an optionally substituted carbamoyl", substituents of the carbamoyl are exemplified by an alkyl, a cycloalkyl, a heterocyclic group, etc. The said carbamoyl may have 1 or 2 substituent mentioned above, and when the number of the substituents is 2, each of the substituents may be the same or different. When R 3 to R 8 is "carbamoyl substituted by a heterocyclic group", the heterocyclic group is exemplified by the above-mentioned heterocyclic group, and preferred are 5- or 6-membered monocyclic heterocyclic groups. Specific examples are pyridyl, pyrimidinyl, piperidinyl, etc. When R 3 to R 8 is "an optionally substituted cycloalkyl", substituents of the cycloalkyl are exemplified by a halogen atom, an alkyl (said alkyl may be substituted by 1 to 3 group (s) selected from the group consisting of hydroxy, mercapto, an alkoxy, amino and a carbamoyl which may be substituted by an alkyl), hydroxy, an alkoxy, amino (said amino may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl, an alkanoyl, carboxy, an alkoxycarbonyl, a carbamoyl optionally substituted by alkyl(s)., an aminosulfonyl optionally substituted by alkyl and an alkylsulfonyl optionally substituted by halogen(s)), carboxy, an alkanoyloxy, an alkoxycarbonyl, a carbamoyl (said carbamoyl may be substituted by 1 or 2 group being the same or different, and selected from the group consisting of an alkyl, a cycloalkyl and a heterocyclic group), a carbamoyloxy optionally substituted by alkyl(s), etc. Preferable examples are an alkyl [said alkyl may be substituted by 1 to 3 group(s) selected from the group consisting of hydroxy and a carbamoyl which may be substituted by alkyl(s)], hydroxy, amino [said amino may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl],an alkanoyloxy, and a carbamoyl which may be substituted by alkyl(s). When R 3 to R 8 is an optionally substituted cycloalkyl, the said cycloalkyl may have 1 to 3 substituent (s) mentioned above, and when the number of the substituents is 2 or more, each'of the substituents may be the same or different. Preferable examples of the substituted cycloalkyl are 4-hydroxycyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-aminocyclohexyl, 4-acetylaminocyclohexyl, 4-dimethylaminocyclohexyl, 4-carbamoylmethylaminocyclohexyl, 4-acetoxycyclohexyl, 4-hydroxymethylcyclohexyl, 2-hydroxycyclopentyl, 4-carbamoylcyclohexyl, 4-methanesulfonylaminocyclohexyl, 4-methoxycarbonylaminocyclohexyl, 4-methylcarbamoylcyclohexyl, 4-(1-hydroxy-l-methylethyl)cyclohexyl, 1-hydroxymethylcyclopentyl, etc. When R 3 to R 8 is "a cycloalkyl substituted by a heterocyclic group-substituted carbamoyl", the heterocyclic group is exemplified by the above-mentioned heterocyclic groups, and preferred are 5- or 6-membered monocyclic heterocyclic groups. Specific examples are pyridyl, pyrimidinyl, piperidinyl, etc. When R 3 to R 8 is "an optionally substituted phenyl", substituents for the phenyl are exemplified by an alkyl optionally substituted by hydroxy, hydroxy, an alkoxy, a halogen atom, amino (said amino may be substituted by 1 or 2 alkyl(s) or alkylsulfonyl(s)), etc. The said phenyl may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "an optionally substituted heterocyclic group", the heterocyclic group is exemplified by the above-mentioned heterocyclic groups, and preferred are 5- or 6-membered monocyclic heterocyclic groups. Specific examples are piperazinyl, piperidyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolidinyl, morpholinyl, oxazolyl, thiazolyl, tetrahydropyranyl, tetrahydrothienyl, hexahydropyrimidinyl, tetrahydrothiapyranyl, tetrahydroisothiazolyl, tetrahydrothiazinyl, etc. Preferable examples of the heterocyclic group are piperazinyl, piperidyl, pyridyl, tetrahydropyranyl, tetrahydrothienyl, hexahydropyrimidinyl, tetrahydrothiapyranyl, tetrahydroisothiazolyl or tetrahydrothiazinyl. Further, substituents of the heterocyclic group are exemplified by an alkyl (said alkyl may be substituted by 1 to 3 group(s), being the same or different, and selected from the group consisting of phenyl, hydroxy, a halogen atom, oxo, an alkoxy, amino and a carbamoyl which may be substituted by an alkyl), carboxy, an alkoxycarbonyl, an alkanoyl, an alkylsulfonyl optionally substituted by halogen(s), a carbamoyl optionally substituted by alkyl(s), hydroxy, an aminosulfonyl optionally substituted by alkyl oxo, etc. The said heterocyclic group may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "a carbonyl substituted by an optionally substituted cycloalkyl", substituents of the cycloalkyl are exemplified.by hydroxy, an alkoxy, amino (said amino may be substituted by 1 or 2 group(s), being the same or different, and selected from the group consisting of an alkyl and an alkanoyl), an alkoxycarbonyl,. etc. The said cycloalkyl may have 1 to 3 substituent mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "a carbonyl substituted by an optionally substituted phenyl", substituents of the phenyl are exemplified by a halogen atom, hydroxy, an alkoxy, amino (said amino may be substituted by 1 or 2 group(s), being the same or different, selected from the group consisting of an alkyl and an alkanoyl) etc. The said phenyl may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different. When R 3 to R 8 is "a carbonyl substituted by an optionally substituted heterocyclic group", the heterocyclic group is. exemplified by the above-mentioned heterocyclic groups, and preferred are 5- or 6-membered monocyclic heterocyclic groups. Specific examples are piperidyl, pyrrolidinyl, pyridyl, pyrimidinyl, morpholinyl, etc. Further, substituents of the heterocyclic group are exemplified by a halogen atom, an alkyl, hydroxy, amino (said amino may be substituted by 1 or 2 alkyl an alkanoyl, oxo, etc. The said heterocyclic group may have 1 to 3 substituent(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or. different. R 2 in the compound [Ia] are preferably exemplified by -NR 3 R 4 and -OR 5 and particularly preferably exemplified by -NRR, and further more preferably exemplified by -NHR 4 When R 2 is -NHR 4 preferred examples of R 4 may include an optionally substituted alkyl, an alkenyl, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl and a carbonyl substituted by an optionally substituted heterocyclic group. Particularly preferred examples are an optionally substituted alkyl, an optionally substituted cycloalkyl and an optionally substituted heterocyclic group, and more preferred examples are a C3-C6 alkyl (said alkyl may be substituted by hydroxy(s)), a C5-C7 cycloalkyl (said cycloalkyl may be substituted by a group selected from the group consisting of hydroxy, methyl, hydroxymethyl and carbamoyl), 4-piperidinyl (said 4-piperidinyl may be substituted by a Ci-C3 alkylsulfonyl, CI-C 3 alkylcarbamoyl or Ci-C3 alkoxycarbonyl) and 4-tetrahydropyranyl etc. Although an optical isomer based on an asymmetric carbon can be present in the compounds [Ia] and [Ib] of the present invention, the present invention includes any of these optical isomers as well as mixtures thereof. The compounds [Ia] and [Ib] can be used for a pharmaceutical use, in either a free form or in a form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt of the compound [Ia] and [Ib] are exemplified by an inorganic acid salt such as a hydrochloride, a sulfate, a phosphate and a hydrobromide, and an organic acid salt such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate and maleate, etc. Further, in case of having a substituent such as carboxy, etc., there are mentioned a salt with a base (for example, an alkali metal salt such as a sodium salt, a potassium salt, etc. and an alkaline earth metal such as a calcium salt). The compounds [Ia] and [Ib] of the present invention or a salt thereof include an internal salt thereof and a solvate thereof, such as alhydrate, etc. The compounds [Ia] and [Ib] of the present invention or a pharmaceutically acceptable salt thereof have an excellent p38 MAP kinase inhibitory action and is useful for the prophylaxis and treatment for diseases related to the activation of p38 MAP kinase and the excessive production of inflammatory mediators concerned with p38 MAP kinase such as TNF-a, IL-1, etc. Therefore, the compounds [Ia] and [Ib] of the present invention or a pharmaceutically acceptable salt thereof is expected to be useful for a therapeutic and prophylactic agent for inflammatory diseases, etc. such as arthritis (rheumatoid arthritis, osteoarthritis, infectious arthritis, gouty arthritis, traumatic arthritis, synovitis, periarthritis, etc.), inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), inflammatory dermal disease [soriasis, dermatitis (atopic dermatitis, contact dermatitis urticaria, eczema, etc.), etc.], inflammatory respiratory disease (asthma, bronchitis, pneumonia, pleurisy, pharyngitis, rhinitis, etc.), inflammatory optical disease (conjunctivitis, keratitis, uveitis, etc.), nephritis, hepatitis, systemic inflammatory disease (Behcet's syndrome, systemic lupus erythematosus, etc.), shock (septic shock, endotoxin shock, etc.), cerebrovascular disease (cerebral hemorrhage, cerebral infarction, cerebral edema, etc.), ischemic cardiac diseases (angina pectoris, cardiac infarction, congestive heart failure, etc.), osteoporosis, multiple sclerosis, diabetes, malignant tumor, cachexia, Alzheimer's disease, Parkinson's disease, acquired immunodeficiency syndrome, arterial sclerosis, disseminated intravascular coagulation syndrome, rejection and graft-versus-host diseases by organ transplantation, etc. The compound of the present invention can be used in combination with one or more drugs selected from the group consisting of non-steroidal anti-inflammatory drugs, anti-rheumatic drugs, anti-cytokine drugs, immunosuppressants and steroids. Examples of the non-steroidal anti-inflammatory drug include alcofenac, aceclofenac, sulindac, tolmetin, fenoprofen, thiaprofenic acid, tenoxicam, lornoxicam, aspirin, mefenamic acid, flufenamic acid, diclofenac, loxoprofen, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, flurbiprofen, pranoprofen, piroxicam, zaltoprofen, celecoxib, rofecoxib, valdecoxib, salts thereof and the like. Examples of the anti-rheumatic drug include gold preparation (Auranofin, etc.), penicillamine, bucillamine, lobenzarit, actarit, sulfasalazine, chloroquine, leflunomide, and the like. Examples of the anti-cytokine drug include etanercept, infliximab, soluble TNF-a.receptor, anti-TNF-a antibody, anti-interleukin-6 antibody, anti-interleukin-12 antibody and the like. Examples of the immunosuppressant include methotrexate, cyclophosphamide, brequinar sodium, deoxyspergualin, mizoribine, 2-morphorinoethyl mycophenolate, rimexolone, cyclosporine, rapamycin, tacrolimus, gusperimus, azathiopurine and the like. Examples of the steroid include dexamethasone, betamethasone, triamcinolone, fluocinonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone and the like. When the compound of the present invention is used in combination with one or more drugs above, two or more ingredients can be administered simultaneously, subsequently or separately with intervals. The present compound or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier therefor. The pharmaceutically acceptable carriers include diluents, binders syrup, gum arabic, gelatine, sorbit, tragacanth, polyvinylpyrrolidone), excipients lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine), lubricants magnesium stearate, talc, polyethylene glycol, silica), disintegrants potato starch) and wetting agents sodium lauryl sulfate), and the like. The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and be used as an appropriate pharmaceutical preparation. Examples of an appropriate preparation for oral administration include solid preparations (tablets, granules, capsules, powders, etc.), solutions, suspensions and emulsions. Examples of an appropriate preparation for parenteral administration include suppository, injections or preparation for continuous infusion prepared using distilled water for injection, physiological saline or aqueous glucose solution, etc., or inhalant. An administration amount of the compound [Ia] and [Ib] of the present invention or a pharmaceutically acceptable salt thereof depends on an administration method, age, body weight, and condition of the patient, and usually, it is preferably 0.003 to 30 mg/kg, and particularly preferably, 0.01 to 10 mg/kg. The compounds [Ia] and [Ib] of the present invention can be prepared suitably by a method selected from the following [Method A] to [Method however, it is not limited to these. Production method will be described in detail using the compound which is the compound [Ia] wherein Q 1 is hydrogen as follow, however, the other compounds [Ia] and [Ib] can be produced in a similar manner. [Method A] RO NHR (CH2)nR NH-(CH 2 )-R 1 NZ W-NCO N-(CH 2 R [II] [NII] N Z 2 (wherein R is an alkyl, and other symbols have the same meanings as mentioned above.) The compound of the present invention can be produced by reacting a compound [II] with a compound [III], followed by treating the reaction product with an acid. This reaction can be carried out in a solvent (Journal of Medicinal Chemistry, 9, 858(1966)). As the solvent, there is no limitation as long as it does not affect the reaction, for example, there are mentioned tetrahydrofuran (THF), chloroform, methylene chloride, dioxane, ethyl acetate, ether, toluene, etc. The present reaction proceeds preferably at to 80 C, particularly preferably at 0 to 30 Further, as an acid for an acid treatment, there are mentioned, for example, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, etc. Additionally, as an alkyl of R in the formula there are mentioned, for example, methyl, ethyl, propyl, butyl, etc., and particularly preferred are methyl and ethyl. [Method B] A W NH y-(CH 2 )nl-Rla.- N [IV] N-(CH 2 )n-Rla N I-A] N R2 [I-B] (wherein Y is a halogen atom, hydroxy, or dihydroxyboranyl, nl is 0, 1,2,3 or 4, R 1 a is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, or an optionally substituted heterocyclic group (provided that the case where n1 is 0 and R. is hydrogen atom is excluded.), and other symbols have the same meanings as the above.) The compound which is categorized in the compound can be produced by reacting a compound which is a compound [Ia' where n is 0 and R 1 is hydrogen atom, with a compound [IV] for alkylation. When Y in the formula [IV] is a halogen atom, this reaction can be carried out in a solvent, in the presence of a base. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, dimethylformamide (DMF), dimethylsulfoxide,1-methylpyrrolidone, 1,3,-dimethyl-2-imidazolidinone, etc. As the base, there are mentioned, for example, sodium hydride, sodium hydroxide, potassium t-butoxide, butyllithium, lithium diisopropylamide, etc. The reaction proceeds preferably at -20to 100°C, particularly preferably at 0 to 30°C. Further, as the halogen atom at Y, there are mentioned chlorine, bromine and iodine, and bromine and iodine are particularly preferred. When Y in the formula [IV] is hydroxy, the reaction can be carried out in a solvent, in the presence of an additive and an activator (Synthesis, 1 (1981)). Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, THF, dioxane, chloroform, etc. As the additive, there are mentioned, for example, triphenylphosphine, tributylphosphine, trimethylphosphine, etc. As the activator, there are mentioned, for example, diethyl azodicarboxylate, dimethyl azodicarboxylate, 1,1-azobis(N,N-dimethylformamide), 1,1-(azodicarbonyl)dipiperidine, etc. This reaction proceeds preferably at -30 to 100°C, and particularly preferably at 0 to When Y in the formula [IV] is dihydroxyboranyl, the reaction can be carried out in a solvent, in the presence of a catalyst andabase (Tetrahedron Letters, 39, 2933(1998)) Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, chloroform, DMF, etc. As the catalyst, there are mentioned, for example, copper (II) acetate, etc. As the base, there are mentioned, for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine, etc. This reaction proceeds preferably at -10 to 100°C, and particularly preferably at to [Method C] HN4 [VI] A N-(CH 2 )n-R 1 Na-O-R 5 [VII] N-(CH2)-R 1 N H-R 6 a [VIII] N I C] R 21 (wherein R21 is -NR R -OR 5 or -COR 6a R 6 a is an alkoxy, and other symbols have the same meanings as the above.) The compound which is categorized in the compound [Ia' of the present invention can be produced by reacting a compound with a compound a compound [VII] or a compound [VIII]. The reaction between the compound and the compound [VI] can be carried out in a solvent, in the presence of a catalyst, a base and an additive (Journal of Organic Chemistry, 61, 7240(1996)). Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, toluene, xylene, dimethoxyethane, dioxane, etc. As the catalyst, there are mentioned, for example, palladium acetate, bis(dibenzylideneacetone)dipalladium, etc. As the base, there are mentioned, for example, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, triethylamine, etc. As the additive, there are mentioned, for example, 2,2'-bis(diphenylphosphino)-1,1'binaphthyl, etc. The reaction proceeds preferably at 30 to 150°C, and particularly preferably at 60 to The reaction between the compound and the compound [VII] can be carried out in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, THF, dioxane, DMF, toluene, methanol, ethanol, etc. The reaction proceeds preferably at 20 to 150°C, and particularly preferably at 70 to 100°C. The reaction between the compound and the compound [VIII] can be carried out in a solvent, in the copresence of carbon monoxide, and in the presence of a catalyst and an additive (Tetrahedron, 55, 393(1999)). Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, toluene, dioxane, DMF, etc. As the catalyst, there are mentioned, for example, palladium acetate, palladium chloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, etc. As the additive, there are mentioned, for example, 1,1'-bis(diphenylphosphino)ferrocene, 1,4-bis(diphenylphosphino)butane, 1,3-bis(diphenylphosphino) propane, triphenylphosphine, etc. The reaction proceeds preferably at 30 to 250°C, and particularly preferably at 80 to 120°C. [Method D] HN [V0I] N. (CH2)n_ R H [N-(CH2)- HO-R 5 [X] N N N N S()m-M [IX] 22 (wherein m is 1 or 2, R 22 is -NR 3 R 4 or -OR 5 and other symbols have the same meanings as the above.) The compound which is categorized in the compound [Ia' of the present invention can be produced by reacting a compound [IX] with a compound [VI] or a compound The reaction between the compound [IX] and the compound [VI] can be carried out in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, dioxane, THF, DMF, dimethylsulfoxide, etc. The reaction proceeds preferably at 0 to 150 and particularly preferably at 50 to 100'C. The reaction between the compound [IX] and the compound can be carried out in a solvent, in the presence of a base. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, THF, dioxane, DMF, dimethylsulfoxide, etc. As the base, there are mentioned, for example, sodium hydride, sodium hydroxide, potassium t-butoxide, butyllithium, etc. The reaction proceeds preferably at -30 to 100 and particularly preferably at 0 to The compound [Ia' produced above can also be derived to other compounds [Ia' by converting a functional group using properly a conventionally known organic chemistry reaction. Such a method for converting a functional group may be suitably selected depending on a kind of a desired functional group. For example, a conversion of a functional group of R 2 in the compound [Ia' can be carried out according to the following (method a) to (method g). (Method a) [1-1 1-2] (wherein the symbols have the same meanings as the above.) The compound [I-1 can be produced by reacting a compound [I1-2] with a hydrogen halide. As the hydrogen halide, there are mentioned hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, etc., and particularly preferred is hydrogen bromide. This reaction proceeds preferably at 0 to 150°C, particularly preferably at 60 t S(Method b) w 0 A- R 41 N NH 2 N N C H2 R1 N T.[1-4] R 4 1 NR41 (wherein R 41 is an alkanoyl which may be substituted, an alkylsulfonyl, carbonyl substituted by a cycloalkyl which may be substituted, carbonyl substituted by a phenyl which may be substituted, or carbonyl substituted by a heterocyclic group which may be substituted. A is a halogen atom or hydroxy. Other symbols have the same meanings as the above.) The compound and compound can be produced by reacting a compound with a compound [XI]. When A in the formula [XI] is a halogen atom, this reaction can be carried out in a solvent in the presence of a base. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, chloroform, THF, DMF, etc. As the base, there are mentioned, for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine, etc. The reaction proceeds preferably at -40 to 100'C, particularly preferably at -10 to Further, as the halogen atom at X, there are mentioned fluorine, chlorine, bromine, and iodine, and particularly preferred are chlorine and.bromine. When A in the formula [XI] is hydroxy, this reaction can be carried out in a solvent in the presence of a condensing agent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, chloroform, THF, DMF, etc. As the condensing agent, there are mentioned, for example, 1,1'-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc. The reaction proceeds preferably at to 100°C, particularly preferably at -10 to (Method c) W 0 [XII] w A R [N-(CH 2 )n-R 1 triphosgene N-(CH2)-R 1 HN' XIII] N 9 NH 2 R-NCO HN N 1 0 [XIV] 0 (wherein R 9 and R 10 are independently hydrogen atom, or an alkyl. R 10 a is an alkyl. X is a halogen atom. Other symbols have the same meanings as the above.) The compound can be produced by reacting a compound with a compound [XII], with triphosgene and a compound [XIII], or with a compound [XIV]. The compound can be produced by reacting a compound with a compound [XII] in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, chloroform, THF, etc. As the halogen atom at X in the formula [XII], fluorine, chlorine, bromine, and iodine are mentioned, and preferred is chlorine. The reaction proceeds preferably at -20 to 100°C and particularly at 10 to Further, the compound [I1-5] can be produced by reacting a compound with triphosgene in a solvent, and then, by reacting with a compound [XIII]. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, chloroform, THF, etc. The reaction proceeds preferably at -20 to 100°C and particularly at 10 to Still further, a compound in which R 9 is a hydrogen atom and R 10 is an alkyl can be produced by reacting a compound with a compound [XIV] in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, THF, methylene chloride, chloroform, etc. The reaction proceeds preferably at -20 to 100°C and particularly at 10 to (Method d) [1-7] 1-6] (wherein R is an alkyl, and other symbols have the same meanings as the above.) The compound can be produced by hydrolyzing a compound .by a conventional method. (Method e) W-WY 0 H-R 6 W' N- N-(CH2)-R 1 XV N-(CH2)-Ri N N N COOH [1-6 161 (wherein R 61 is an amino which may be substituted, and other symbols have the same meanings as the above.) 'The compound can be produced by reacting a compound with a compound [XV] in a solvent, in the presence of a condensing agent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, acetonitrile, DMF, THF, etc. As the condensing agent, there are mentioned, for example, 1,1'-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc. The reaction proceeds preferably at to 100°C and particularly at 0 to (Method f) COOH N -C ,N-(CH 2 )n--R 1 [1-9 S.N-(CH2 riR OH N. COOR [1-7] (wherein symbols have the same meanings as the above.) The compound can be produced by reducing a compound or a compound in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, THF, diethyl ether, etc. As the reducing agent, there are mentioned, for example, lithium aluminum hydride, sodium borohydride, lithium borohydride, etc. The reaction proceeds preferably at -20 to 70°C and particularly at 0 to (Method g) (A A N-(CH2)r-R- N_(CH2)r-R N N [1-9 -10 OH R 8 1 (wherein R 8 1 is an optionally substituted amino, and other symbols have the same meanings as the above.) The compound [I-10] can be produced by reacting a compound with a compound [XVI] in a solvent, in the presence of a base and an activating agent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, THF, chloroform, toluene, etc. As the base, there are mentioned, for example, triethylamine, diisopropylethylamine, pyridine, etc. As the activating agent, there are mentioned, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, etc. The reaction proceeds preferably at -10 to 60 C and particularly at 0 to The compound [Ia' of the present invention obtained according to the above described [Method A] to [Method D] or (Method a) to (Method g) can be optionally converted to a pharmaceutically acceptable salt. Conversion to a pharmaceutically acceptable salt may be carried out by methods known to the person skilled in the art. In the following, production methods for starting materials used in the above methods are described. A The starting material [II] can be produced as follows. 0 N-OH N Me NH20H CH 3 CI-SO2 Me R 2 N2 R [2] NOSO2 Me RO OR Me NaOR fN N H 2 N Z N Z R 2 R [3a] RO OR .IX NH-(CH 2 )n-R 1 N Z R2 (wherein the symbols have the same meanings as the above.) The reaction for producing the compound from the compound and hydroxylamine can be carried out in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, ethanol, methanol, etc. The reaction proceeds preferably at 0 to 150 C, and particularly preferably at 60 to The reaction for producing the compound from the compound and tosyl chloride can be carried out in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methylene chloride, chloroform, THF, toluene, etc. As the base, there are mentioned, for example, triethylamine, diisopropylethylamine, pyridine, etc. The reaction proceeds preferably at -20 to 80°C, and particularly preferably at 0 to "C. The reaction for producing the compound [3a] from the compound can be carried out in a solvent, by reacting the compound with sodium alkoxide, followed by treating the reactant with an acid. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methanol, ethanol, dioxane, THF, dimethoxyethane, etc. :As the acid, there are mentioned, for example, hydrogen chloride, etc. The reaction proceeds preferably at -20 to 60 C, and particularly preferably at 0 to The reaction for producing the compound [II] from the compound [3a] can be carried out by reacting a corresponding aldehyde using a conventional reductive alkylation (Journal of Organic Chemistry, 61, 3849(1996)). A starting material can be produced, for example, as follows. 0 0 N'OH OH MeLi I Me NH 2 OH [r Me N N Cl Cl Cl [6] N'OSO2 _/Me C-SO-2 Me Me NaOR N Cl [7] RO OR A NH 2 A W I W-NCO [111] NH CI N [9] Y-(CH 2 )n-R 1 O 0 [IV] wN I V N N-(CH2)n-R 1 N C1 I (wherein the symbols have the same meanings as the above.) The reaction for producing the compound from the compound and methyl lithium can be carried out in a solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, THF, diethyl ether, dimethoxyethane, etc. The reaction proceeds preferably at -90 to 0°C, and particularly preferably at to The method for producing the compound from the compound via the compound and the compound can be carried out in a similar manner to the above-mentioned method for producing the compound [III from the compound via the compound and the compound The reaction for producing the compound from the compound and the compound [III] can be carried out in a similar manner to the above-mentioned [Method A]. The. reactioni for producing the compound from the compound []and the compound [IV] can be carried out in asimilar manner to. the above-mentioned [Method B]. A starti ng m aterial can be produced, for example, as follows. Me Me~XMMe"N OMe 0[10] MeO OMe S Me SMe. [13]. Me Meo OMe m'N IVVH 2 N NH 2 0 [12] 0 CZZI Me N ~.N SMe [14] CH 2 tr.'Zz~c (C 4 H 9 3 Sn 0 C 2 H 5 CH 2 N N [16] rI A 0C 2 H 5 HCI 14 SMe S 1 [17] 0 NOH (I oHS I---Me ^-Me NH 2 OH Me CI-SO2 _Me N N NN SMe [14] SMe [18] NOSO2 Me N 0 RO OR Me NaOR N NH 2 NYN N N SMe 19] l W-NCO [II] NH N H [NN NN N 21] N [22] SMe S(O)mMe Y-(CH 2 )n-R 1 [IV] Y-(CH 2 )n-R 1 [IV] SA N. [23] N I X] SMe S(O)mMe (wherein m is 1 or 2, and other symbols have the same meanings as the above.) The reaction for producing the compound [12] from the compound [10] and the compound [11] can be carried out in a solvent or without solvent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, toluene, xylene, dioxane, etc. The reaction proceeds preferably at 50 to 150°C, and particularly preferably at 80 to 120°C. The reaction for producing the compound [13] from the compound [12] can be carried out by reacting the compound [12] with thiourea in a solvent, in the presence of a base, and then, by reacting an alkylating agent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, methanol, THF, dioxane, etc. As the base, there are mentioned, for example, sodiummethoxide, sodium hydroxide, potassium t-butoxide, etc. As the alkylating agent, there are mentioned, for example, methyl iodide, dimethyl sulfate, etc. The reaction proceeds preferably at 0 to 100°C, and particularly preferably at 30 to The reaction for producing the compound [14] from the compound [13] can be carried out in a solvent, in the presence of an acid. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, water, acetone, THF, dioxane, etc. As the acid, there are mentioned, for example, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, etc. The reaction proceeds preferably at -10 to 80°C, and particularly preferably at 0 to The compound [14] can be also produced from the compound via the compound [17]. The reaction for producing the compound [17] from the compound [15] and the compound [16] can be carried out in a solvent, in the presence of a catalyst. Any solvent can be used as long as it does not affect the.reaction, and there are mentioned, for example, DMF, toluene, xylene, etc. As the catalyst, there are mentioned, for example, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, etc. The reaction proceeds preferably at 50 to 150°C, and particularly preferably at 70 to The reaction for producing the compound [14] from the compound [17] can be carried out in a similar manner to the above-mentioned method for producing the compound [14] from the compound [13]. The reaction for producing the compound [20] from the compound [14] via the compound [18] and the compound [19] can be carried out in a similar manner to the above-mentioned method for producing the compound [II] from the compound via the compound and the compound The reaction for producing the compound [21] from the compound [20] and the compound [III] can be carried out in a similar manner to the above-mentioned [Method A]. The reaction for producing the compound [22] from the compound [21] can be carried out in a solvent, using an oxidizing agent. Any solvent can be used as long as it does not affect the reaction, and there are mentioned, for example, water, methanol, THF, dioxane, chloroform, methylene chloride, etc. As the oxidizing agent, there are mentioned, for example, Oxon (trade name, manufactured by DuPont Co. Ltd.), 3-chloroperoxybenzoic acid, hydrogen peroxide, etc. The reaction proceeds preferably at -20 to 60°C, and particularly preferably at -10 to The reaction for producing the compound [IX] from the compound [22] and the compound [IV] can be carried out in a similar manner to the above-mentioned [Method B]. The compound [IX] can be also produced from the compound [21] via the compound [23]. The reaction for producing the compound [23] from the compound [21] and the compound [IV] can be carried out in a similar manner to the above-mentioned [Method B]. -The reaction for producing the compound [IX] from the compound [23] can be carried out in a similar manner to the reaction for producing the compound [22] from the compound [21]. Incidentally, in the above production methods, it is possible to optionally protect or deprotect a functional group. As the protecting group for the functional group, those used in a field of conventional organic synthetic chemistry can be used, examples of which include those described in "Protective Groups in Organic Synthesis" by T. W. Greene, P. M. G. Wuts, (published by John Wiley and Sons, 1991). For conditions for introducing protecting groups or condition for de-protection, the method described in the above reference can be mentioned. Further, each compound and each intermediate produced in the above production. methods can be purified by means of a conventional method, for example, column chromatography, recrystallization, etc. As a solvent for recrystallization, there are mentioned, for example, an alcohol solvent such as methanol, ethanol, 2-propanol, etc., an ether solvent such as diethyl ether, etc., an ester solvent such as ethyl acetate, etc., an aromatic solvent such as toluene, etc., a ketone solvent such as acetone, etc., a hydrocarbon solvent such as hexane, etc., water, etc., and a mixed solvent thereof. Further, the compounds [Ia] and [Ib] of the present invention can .be converted to a pharmaceutically acceptable salt according to the conventional method, and recrystallization can be carried out afterwards. EXAMPLES Hereinbelow, the present invention will be explained in more detail with reference to the following Examples, which should not be construed as limiting the scope of the present invention. Each of the following symbols used in the present specification represents the meaning as described below. Me methyl Et ethyl THF: tetrahydrofuran DMF: N,N-dimethylformamide t- tert- Example 1 1-(4-Fluorophenyl)-5-(pyridin-4-yl)-4-imidazolin-2-one A solution of 3.00 g of 2,2-diethoxy-2-pyridin-4ylethylamine (a compound obtained in Reference Example 2) dissolved in 30 ml of THF was cooled by water, and 1.97 g of 4-fluorophenylisocyanate was added by dropwise. After addition, the reaction mixture was concentrated under reduced pressure, and then, 30 ml of conc. hydrochloric acid was added to the obtained residue, and the mixture was stirred at room temperature overnight. To 180 ml of an ice cold aqueous 2N NaOH solution was added the reaction mixture for neutralization, and precipitated crystals were collected by filtration. They were washed with water and ether, air-dried at 60°C, to give 3.10 g of the title compound as colorless crystals. Melting point: 261"C (decomposed) Example 2 l-Cyclopentylmethyl-3-(4-fluorophenyl)-4-(pyridin-4-yl)-4imidazolin-2-one *hydrochloride F NN 128 mg of 1-(4-Fluorophenyl)-5-(pyridin-4-yl)-4-imidazolin-2-one (the compound of Example 61 pl of cyclopentylmethanol, 197 mg of triphenylphosphine and 295 pl of diethyl azodicarboxylate were dissolved in 2.5 ml of methylene chloride, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform ethyl acetate 19 1) The obtained compound was treated with hydrochloric acid, to give 75 mg of the title compound as powder. Example 3 1-(Oxolan-3-yl)-3-(4-fluorophenyl)-4-(pyridin-4-yl)-4-imida zolin-2-one The title compound was given by treating the corresponding starting material in a similar manner to that in Example 2. Melting point 132-134°C Example 4 1-(2-Cyanobenzyl)-3-(4-fluorophenyl)-4-[(2-(1-(S)-phenylethylamino)pyridin-4-yl)]-4-imidazolin-2-one N 50 mg of 4-(2-Chloropyridin-4-yl)-3-.(4-fluorophenyl)-1-(2-cyanobenzy 1)-4-imidazolin-2-one (a compound of Reference Example 1 79 pl of (S)-(-)-a-methylbenzylamine, 5.5 mg of palladium acetate, 15mg of 2,2'-bis(diphenylphsophino)-1,1'-binaphthyl and 17 mg of sodium t-butoxide were suspended in 1 ml of toluene, and the mixture was stirred at 70 °C for 18 hours, under nitrogen flow. The reaction mixture was diluted by ethyl acetate, and insoluble matter was removed by filtration through Celite. To the filtrate was added 6N hydrochloric acid, and after separation, an aqueous layer was made alkaline with aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane ethyl acetate 1 to give 38 mg of the title compound as colorless powder. Examples 5 12 Compounds in Table 1 were obtained by treating the corresponding starting materials in a similar manner to that in Example 4. Table 1 Physical Exam- R R properties, ple etc. Melting 2-Cyanophenyl 4-Methoxybenzylamino point 167 0 C Melting 6 2-Cyanophenyl 2-Thienylmethylamino Melpoint poMetint 171gC 7 2 (S)-l-t-Butoxycarbon- Melting 7 2-Cyanophenyl ylethylamino point ylethylamino 191-1930C Melting 8 2-Cyanophenyl Isopropylamino point 170-171 0 C Melting 9 2-Cyanophenyl Allylamino point 163C Melting 2-Methoxyphenyl 2-Pyridylmethylamino point 248-250 0 °C 2-(2-Pyridyl)ethyl- Melting 11 2-Fluorophenyl aminoPyridyethyl- point amino_ 132-134 0 C 12** 2-Trifluoro- 2-(2-Pyridyl)ethyl- Powder methylphenyl amino **:Dihydrochloride Example 13 4-(2-Aminopyridin-4-yl)-1- (2-cyanobenzyl)-3-(4-fluorophenyl)-4-imidazolin-2-one F SN CN NH 2 To 1.5 g of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-[2- (4-methoxybenzylamino)pyridin-4-yl]-4-imidazolin-2-one (Compound of Example 5) was added 3 ml of 25% hydrogen bromide-acetic acid solution, and the mixture was stirred at 0 C for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was made alkali with an aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 572 mg of the title compound'as colorless crystal. Melting point :182-183 0 C. Example 14 4-(2-N-Isobutyroylaminopyridin-4-yl)-1-(2-cyanobenzyl)-3- (4-fluorophenyl)-4-imidazolin-2-one F N ON N C HN 0 Example 4-(2-N,N-Diisobutyroylaminopyridin-4-yl)-1-(2-cyanobenzyl)- 3-(4-fluorophenyl)-4-imidazolin-2-one A suspension of 50 mg of 4-(2-aminopyridin-4-yl)-1- (2-cyanobenzyl)-3-(4-fluorophenyl)-4-imidazolin-2-one (Compound of Example 13) and 20 pl of isobutyroyl chloride in methylene chloride was ice-cooled, and after adding 54 p1 of triethylamine by dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: acetone=20:1) to give 22 mg of the title compound (Example 14) as colorless crystal and 10 mg of the title compound (Example as colorless crystal, respectively. Melting point:196°C (Example 14), 185-1870C (Example Example 16 4-(2-Ethoxycarbonylpyridin-4-yl)-1-(2-cyanobenzyl)-3-(4fluorophenyl)-4-imidazolin-2-one F /^0 N4 N ON N 0 In 20 ml of ethanol were suspended 1 g of 4-(2-chloropyridin-4-yl)-3-(4-fluorophenyl)-1-(2-cyanobenzyl)-4-imidazolin-2-one [Compound of Reference example 55 mg of palladium acetate, 137 mg of 1,1'-bis(diphenylphosphino)ferrocene and 608 mg of sodium acetate, the mixture was stirred under carbon monoxide atmosphere at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, treated with activated charcoal and then filtered. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=l:2) to give 887 mg of the title compound as colorless crystal. Melting point:164°C. Example 17 1-(2-Cyanobenzyl)-3-(4-fluorophenyl)-4-[2-(3-hydroxypropylamino):pyrimidin-4-yl]-4-imidazolin-2-one F N4 N NNN HN OH A mixture of 70 mg of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)- 4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 7 60.6 mg of 3-aminopropanol and 2 ml of dioxane was stirred at for 5 hours. The reaction mixture was concentrated and then purified by silica gel column chromatography (chloroform: methanol=19:1) and crystallized from ether to give 44.6 mg of the title compound. Melting point: 166-167°C. Examples 18 to 24 The corresponding starting materials were treated in the same manner as in Example 17 to give Compounds in Table 2. Table 2 N N Physical Exam properties, pie etc. Melting 18 2-Cyanophenyl 2-Furylmethylamino point 174-1750C Melting 19 2-Cyanophenyl, ,3-Methoxypropylamino point 168-169 0 C Melting 2 0: 2-Cyanophenyl Isobutylamino point 145-146 0 C Melting 21 2-Cyanophenyl Allylamino point 189-1900C Melting 22. 2-Cyanophenyl .47Hydroxybutylamino point 166-167 0 C Melting 23, 2-Methoxyphenyl Isopropylamino point 17 1-172C Melting 24, 2-Fluorophenyl. Isopropylamino point 120-122 0 C Example 1- (2-Cyanobenzyl) (4-f luorophenyl) (2-isopropoxypyrimidin-4-yl) -4-imidazolin-2-one In 5 ml of isopropanol was suspended 100 mg of l-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 26.3 mg of sodium hydride was added to the mixture and the resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture were successively added an aqueous citric acid solution and an aqueous sodium bicarbonate solution, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed, dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 68 mg of the title compound as powder. Examples 26 to 79 The compound of Reference example 1(5) and the corresponding starting materials were subjected to N-alkylation in the same manner as in Example 2 or Reference example and then, subjected to amination in the same manner as in Example 4 to give the compounds shown in Tables 3 to 6. Table 3 C Hz- R Exam- MS pile 26 2-Cyaniophenyl.. Benzylamino 4C6 27 2-Cyanophenyl Cyclopropylamino 426 2 8 2-Cyanophenyl 2 -Furylmethylamino 466 29o 2-Cyanophenyl 2-Pyridylmethylamino 477 2-Cyanophenyl Cyclopentylamino 454 31 2-Cyanophenyl 4-Chlorobenzylamino 510 32. 2-Cyanophenyl 2-Methoxybenzylamino 506 33 .2-Cyanophenyl .3-Methoxybenzylamino 506 34 2-Cyanophenyl 3-Pyridylmethylamino 477 -Canoheyl 2-Methylpyridin-4-ylmethyl 491 2-Cynophnyl amino 36 2-Cyanophenyl 2-(2-Pyridyl) -ethylamino 491 37 2-yanopenyl (4-Methyl-l-piperazinyl)- 48 2-Cynophnyl amino 38 2-Cyanophenyl 3-Methoxypropylamino 458 39 2-Cyanophenyl 3-Propoxypropylamino 486 Table 4 Exam- 12MS 2-Cyanophenyl Cyclopropylmethylamino 440 41 2-Cyanophenyl 3-Isopropoxypropylamino 486 42 2-Fluorophenyl 2-Pyridylmethylamino 470 43 2-Trifluoro- 2Prdlehlmn 2 methyiphenyl2-yiyetyann 44 2-Cyanophenyl Isobutylamino 442 2-Cyanophenyl 2-Ethoxyethylamino 458 2-Trifluoro- 46 mehihnlIsopropylamino 471 47 2-Fluorophenyl Isopropylamino 421 48 2-Methoxyphenyl Isopropylamino 433 49 2-Fluorophenyl Isobutylamino 435 2-Methoxyphe nyl Isobutylamino 447 51 2-Cyanophenyl t-Butylamino 442 52 2-Cyanophenyl 4-Tetrahydropyranylamino 470 53 -Canoheyl(S)-1-(2-Pyridyl) .ethyl- 491 2-Cynophnylamino Dihydrochloride Table CHZ 2 -R 1 Exam- .MS Pie trans-4-Hydroxycyclo- 54 2-Fluorophenyl h47amn7____ 4-Methoxyphenyl Isopropylamino 433 56 2-yanopenyl trans-4 -Hydroxycyclo-48 hexylamino 57 Metoxypenyl (S)-l-(2-Pyridyl)ethyl- 49 4-Metoxypenyl amino 58 2-Fluorophenyl 4-Methoxybenzylamino 499 cis-4 -Methoxy- _____methoxycyclohexylIsbtamn48 cis-4-Me Ithoxy- trans-4-Hydroxycyclo-52 _____methoxycyclohexyl hexylarnino 61 cis-4-Methoxy- Isopropylamino 469 methoxycyclohexyl 62 2-Fluorophenyl (l-Methyl-4-piperidyl)- 47 amino* (1-t-Butoxycarbonyl-4-pi 63 2-Fluorophenyl 562 periclyl) amino 64 2-Cyanophenyl (1-Methyl-4-piperidyl)- 48 amino .Cyclopentyl Isopropylamino 395 .66 Cyclopentyl trans-4-Hydroxycyclo- 451 hexylamino. 67* 4-Tetrahydro- Isopropylamino 411 __pyranyl__ Monohydrochioride Dihydrochioride Table 6 Exam- MS pie 8* 4-Tetrahyclro- trans-4-Hydroxycyclo-46 ___pyranylmethyl. hexylamino 69 2-Methoxyeth .yl trans-4 -Hydroxycyclo- 427 hexylamino____ 7 Metoxymthyltrans-4 I-Hydroxycyclo-41 _____hexylamino 71 Methoxcymethyl Isopropylamino 357 72 Methyltrans-4 -Hyciroxycyclo-38 hexylamino 73* Ethyltrans-4-H-ydroxycyclohexylamino____ trans-4 -Hydroxycyclo- 74 Isopropyl hexylamino 4121 trans-4-Aminocyclohexyl- 41 amino41 trans-4-Acetylanino- 76 Is opropyl cylhx aio452 77* N-Isopropyl- Iorplmn 1 ___carbamoylmethyl Iorplmn 1 78** Ispropyltrans-4-Dimethylamino-43 Ioprpy cyclohexylamino43 Iorpltrans-4-Carbamoylmethyl-- 467 Isopopy amino-cyclohexylamino Monohydrochloride :Dihydrochloride Example FN N F HN NH *2HC1 To 146 mg of the compound in Example 63 were added 0.2 ml of ethyl acetate and 1. 7 ml of a 4N hydrogen chloride-ethyl acetate solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue and powder was collected by filtration to give 128 mg of the title dompound. MS 462 Example 81 F O N OH HN To 2 ml of methanol was dissolved 148 mg of the compound in Example 61, 1 ml of conc. hydrochloric acid was added to the mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a 4N aqueous NaOH solution and extracted with chloroform. After drying and concentration, diethyl ether and diisopropyl ether were added to the residue and the resulting powder was collected by filtration to give 58 mg of the title compound. MS 425([M+H] Examples 82 to 107 The compounds of Examples 26 to 79 or the corresponding starting materials obtained in the similar method were treated in the same manner as in Example 80 or Example 81 to give the compounds shown in Tables,7 to.9. Table 7 RC Exam'- MS pie, 82* 4-Piperidyl Isopropylamino 410 83"~ 2-Cyanophenyl 4-Piperidylamino 469 ci~s-4-Hydroxy- 84 cyclohexyliobtain cis-4-Aminocyclo- Iorplmn 2 hexyl ci.s-4-Arninocyclo- trans-4-Hydroxycyclo- 480 _____hexyl hexylamino 87 cis-4-Hydroxy- trans-4-Hydroxycyclo- 48 ______cyclohexyl hexylamino cis-4-Hydroxy- (1-Methyl-4-Piperidyl) 88 480 cyclohexyl. amino 8 91 trans-4-Amino- trans-4-Hydroxycyclo- 480 cyclohexyl hexylamino 4-Piperidyl Isobutylamino 424 trans-4 -Hydroxycyclo- 91" 4-Piperidyl heyaio466 92* trans-4 -Amino- 92 cyclohexyl Isobutylamino 438 93 cis-4-Aminocyclo- Isobutylamino43 ______hexyl 94 cis-4-Aminocyclo- 4-Piperidylamino 465 hexyl_____ **:Dihydrohlide Trihydrochloride Table 8 OHl- R R 2 Exam-. MS pie s--ydoy 4-Piperidlylamino 466 cyclohekyl trans-4-Amino- 96, y*o*y 4-Piperidylamino 465 trans-4 -Amino- 9y7hey Isopropylamino 424 98 2-F'luorop henyl trans-4-Aminocyclohexyl 476 amino. 2Caohnl trans-4-Axninocyclohexyl 483 2-Cynophnylamino trans-4--ydroxy- Iorplmn cyclohexyl 101* trans-4-Hydroxy- Isobutylamino 439 cyclohexyl 10:2 trans-4- Hydroxy- trans-4-Hydroxycyclo-48 cyclohexyl hexylamino____ 103 1-Hyciroxycyclo- Isopropylamino38 propyl38 104* 1-Hyciroxycyclo- trans-4-Hyclroxycyclo-43 propyl hexylamino____ :Monohydrochloride **Dihydrochloride Trihyclrochloricle Table 9 N- R 1 N S H'N"NH 2 Example R 1 MS 105 Methoxymethyl 412 106** 2-Methoxyethyl 426 107**. Ethyl 396 **:Dihydrochloride Examples 108 to 126 The compound of Reference example 8.and a corresponding isocyanate were reacted in the same manner as in Example 1 to carry out cyclization, and the corresponding amine was reacted in the same manner as in Example 4 to give the compounds shown in Tables 10 and 11. Table Example. Ring A MS 108 Phenyl 459 109*. 2-Fluorophenyl 477 110* 3-Fluorophenyl 477 111* 3,4-Difluorophenyl 495 112* 2,4-Difluorophenyl 495 113* 4-Chiorophenyl 493 114* .4-Methyiphenyl 473 115* 4-Methoxyphenyl 489 1* 3-Methoxyphenyl 489 117* 4-Fluorobenzyl 491 118 3-Trifluoromethyiphenyl .527 119*. 3-.Chiorophenyl 493 120' 3-Methyiphenyl 473 121* 4-Fluoro-3-Methoxyphenyl 507 122* 3-Hydroxyphenyl 475 123* 2-Thienyl 465 Monohycirochloride Table 11 Example R 2 MS 124* Isopropylamino 439 125* Isobutylamino 453 126** (1-Methyl-4-piperidyl)amino 494 *:Monohydrochloride **:Dihydrochloride Example 127 HN 2HC 1 ^""OH The compoud of Reference example 9 was subjected to amination in the same manner as in Example 4, and then, treated in the same manner as in Example 80 to give the title compound. MS 452([M+H] Examples 128 to 141 The compound of Reference example 8 or Reference example 10 and a corresponding starting compound were subjected to amination in the same manner as in Example 4, and then, the resulting compound was treated with a corresponding isocyanate in the same manner as in Example 1 to carry out cyclization to give the compounds shown in Tables 12 and Table 13. Table 12 Example Ring A MS 128* 3-Amino-4-fiuorophenyl 492 129* 3-Aminophenyl 474 130* 3-hyclroxymethylphenyl 489 131* 2-Aminophenyl 474 132* 2-Nitrophenyl 504 133* 4-Fluoro-2-nitrophenyl 522 134* 2-Cyanophenyl 484 135* 3, 5-Difluorophenyl 495 136* 2-Carbamayiphenyl 502 Monohycirochioricle Table 13 •h.N-IEt HN N'"OH Example Ring A MS 137* 3-Chlorophenyl 413 138* 3-Methylphenyl 393 139* 3,4-Difluorophenyl 415 140* 4-Chlorophenyl 413 141* 2-Cyanophenyl 404 *:Monohydrochloride Examples 14 2 to 156 The compound of Reference example 11 and a corresponding starting compound were subjected to N-alkylation in the same manner as in Reference example 8, and then, the resulting compound was treated with a corresponding isocyanate to carry out cyclization in the same manner as in Example 1 to give the compounds shown in Table 14 and Table Table 14 N Example RiMS 14.2 A -Tetrahydropyranyl 397 1431** 1-Methy.1-4-piperidyl 410 144* Cydclohexyl 395 145*' Cyclopentyl 381 146* Cyclobutyl 367 14 7* 4-Piperidyl 396 Monohydrochioride :Dihydrochioride Table Exam- Ms. pieRing A n R[+H~ 148* phenyl 1 trans-4-Hyclroxycyclo- hexyl phenyl_40 hexyl 1509*1 3-Chiuorophenyl 1y y441 .hexyl 151 3-ethipheyl 1.trans-4-Hyclroxycyclo- 42 *hexyl 152* 3-Mehoxyheny ~.trans-4-Hydroxycyclohexyl 2,4-Difluoro- trans-4 -Hydroxycyclo- 153* 443 ____phenyl .hexyl 314-Difluoro- 1 trans-4-Hydroxycyclo- 43 p henyl hexyl 155* *.4-Chiorophenyl 1 trans-4-Hydroxycyclo- 441 hexyl 156* 2-Ca Irbamoyl- 0 Isopropyl 380 _phenyl__ Monohydrochloride Examples 157 to 161 By using the compound of Example 147, it was reacted with a corresponding starting compound to carry out acylation in the same manner as in Example 14 to give the compounds of Examples 157 and 158 shown in Table 16. Also, by using the compound of Example 14 7 it was reacted with a corresponding starting compound to carry out N-alkylation in the same manner as in Reference example 10 to give the other compounds shown in Table 16. Incidentally, in synthesis of the compound of Example 160, t-butyl bromoacetate was used as a corresponding starting compound, and after the reaction, the ester was hydrolyzed under the same conditions as in Example Table 16 F0 N N-R a H N Example Ra MS 1.57* Acetyl 438 158* Ethoxycarbonyl 468 159** Carbamoylmethyl 453 160** Carboxymethyl 454 161** N-Methylcarbamoylmethyl 467 *:Monohydrochloride ;**:Dihydrochloride Examples 162 to 168 By using the compound of Reference example 11, it was reacted with a corresponding starting compound to carry out N-alkylation in the same manner as in Reference example 10, and then, the resulting compound was subjected to cyclization in the same manner as in Example 1 to give the compound of Table 17. Table 17 N- NN CONH 2 HN Example Ring A MS 162* 3-Fluorophenyl 370 163* 3-Chlorophenyl 386 164* 3-Methylphenyl 366 165* 3-Trifluoromethylphenyl 420 166* Phenyl 352 167* 2,4-Difluorophenyl 388 168* 4-Chlorophenyl 386 *:Monohydrochloride Example 169 HN_ The compound (2.12 g) of Reference example 12 was subjected to cyclization in the same manner as in Example 1 and simultaneously t-butyl ester was hydrolyzed to give 1.28 g of the title compound. MS 385 Example 170 N N CONHEt H C 1 N. HN A mixture comprising 100 mg of the compound of Example 169, 48 mg of 1-hydroxybenzotriazole, 60 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 ml of methylene chloride was stirred at room temperature for one hour. To the reaction mixture was added 1 ml of a 2N ethylamine-THF solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was successively washed with water, a saturated aqueous sodium bicarbonate solutionand brine, and dried over anhydrous magnesium sulfate. To the residue obtained by concentration under reduced pressure was added diethyl ether to collect colorless crystal by filtration. The compound obtained in was dissolved in 2 ml of a mixed solvent comprising chloroform-methanol, and after adding 0.2 ml of 4N hydrochloric acid-ethyl acetate, and the resulting mixture was concentrated under reduced pressure. To the residue was added ethyl acetate and collected by filtration to give 75 mg of the title compound. MS 412([M+H]+) Examples 171 to 173 The compound of Example 169 was reacted with a corresponding amine in the same manner as in Example 170 to give the compounds shown-in Table 18. Table 18 F 0 N. N-CONRbRc N HN Example NRbR c MS 171* Amino 384 172* Methylamino 398 173* Dimethylamino 412 *:Monohydrochloride Examples 174 to 178 The compound of Reference example 11 was reacted with a corresponding isocyanate in the same manner as in Example 1 to give the compounds shown in Table 19. Table 19 NO NH N HN- Example Ring A MS 174* 3,4-Difluorophenyl 331 175* 4-Methoxyphenyl 325 176* 3-Trifluoromethylphenyl 363 177* 3-Chlorophenyl 329 178* 3-Methylphenyl 309 :Monohydrochloride Example 179 FN N SOOH HN N To 5 ml of 25% HBr-acetic acid solution was added 490 mg of the compound of Example 57, and the mixture was stirred at 70 C for 15 hours. After cooling the reaction mixture, an aqueous sodium bicarbonate solution was added to neutralize the mixture, and the resulting mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 237 mg of the title compound as colorless powder. MS 482 Example 180 FNYN NH N HNr, N To 200 mg of the compound of Example 179 was added 2 ml of HBr-acetic acid solution, and the mixture was stirred under heating at 8000 for 3 days. After cooling the reaction mixture, an aqueous sodium bicarbonate solution was added thereto to make alkaline, and the mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 71 mg of the title compound as colorless powder. MS 376 Examples 181 to 183 By using the compound of Example 55, it was reacted in the same manner as in Examples 179 and 180 to give the compounds of Examples 181 and 182 shown in Table 20. Also, in the same manner as in Example 55, a corresponding compound having isobutylamino group was synthesized, and subsequently the compound was reacted in the same manner as in Example 180 to give the compound of Example 183. Table F N 0 N-(CH2 )n-R 1 N R2 Example R i n R 2 MS 181 4-Hydroxyphenyl 1 Isopropylamino 419 182 Hydrogen atom 0 Isopropylamino 313 183 Hydrogen atom 0 Isobutylamino 327 Examples 184 and 185 By using the compound of Example 70 or the compound of Example 105, it was reacted under the same conditions (conc. hydrochloric acid was used in place of HBr-acetic acid) as in Example 179 to give the compounds shown in Table 21. Table 21 F 0O NH N 2 Example R 2 MS 184 trans-4-Hydroxycyclohexylamino 369 185 trans-4-Aminocyclohexylamino 368 Examples 186 to 197 The compound of Reference example 13 was subjected-to amination in the same manner as. in Example 4, and then, reacted with a corresponding isocyanate in the same manner as in Example 1, and, if necessary, subjected to acetylation according to the conventional manner to give the compounds shown in Table 22. Table 22 NH N R2 Exam- MS Ring A RM p 186 3-Fluorophenyl Isobutylamino 327 187 3-Fluorophenyl Isopropylamino 313 188 2,4-Difluorophenyl Isopropylamino 331 189 2-Fluorophenyl Isopropylamino 313 190 2,4-Difluorophenyl Isobutylamino 345 191 3-Methoxyphenyl Isopropylamino 325 192 Phenyl Isopropylamino 295 trans-4-Acetoxycyclo- 132-Fluorophenyl 411 hexylamino 194 '3'-Fluorophenyl trans-4-Acetoxycyclo- 411 hexylamino trans-4-Acetoxycyclo- 195 2,4-Difluorophenyl tra4 o 429 1 96 Phenyl trans-4-Acetoxycyclohexylamino 197 3-Methoxyphenyl trans-4-Acetoxycyclo- 423 hexylamino Example 198 N NHOMe F O EI,. .OMe EtO OEtH F F 0 EtO OEtH N N HNN OMe NH 2 (2) The compound (6.30 g) of Reference example 13 was reacted with 2, 4-dimethoxybenzylamine in the same manner as in Example 4 to give Compound. Then, Compound was treated in the same manner as in Example 1 to give 744 mg of Compound MS 2.71 Examples 199 to 221 The compound of Example 182, 192, 189, 187 or 188 was reacted with a corresponding halide in the same manner as in Reference example 1(6) to subject to alkylation to give the compounds shown in Tables 23 and 24. Incidentally, the compound of Example 211 was synthesized by protecting the amino group with a t-butoxycarbonyl for the reaction and deprotecting in the same manner as in Example 80. Also, the compound of Example 214 was synthesized by eliminating a methoxymethyl group of the compound of Example 213 in the same manner as in Example 81. Table 23 Example n RM 19*0 Methyl 327 200 3-hydroxypropyl 371 0 Butyl 369 202 0 2-Methoxyethyl 371 203* 0 Carbamoylmethyl 370 204 0 Ethyl 341 205* 0 Isopropyl 355 206* 1 Cyclobutyl 381 207* 0 Isobutyl 369 208* 0 Cyanomethyl 352 209* 0 Isopentyl 383 210* 1 Cyclopropyl 367 211 .0 3-Aminopropyl 370 212* 0 'Propyl 355 213 0 2-Methoxymethoxyethyl 401 214* 0 2-Hydroxyethyl 357 215* 0 1-Carbarnoylethyl 384 Monohydrochioride;**Dihydrochioride Table 24 Example Ring A R 1 MS 216 Phenyl Ethyl 323 .217 2-Fluorophenyl Ethyl 341 218 3-Fluorophenyl Ethyl 341 219* 2,4-Difluorophenyl Ethyl 359 220 Phenyl Methoxymethyl 339 221 2,4-Difluorophenyl Methoxymethyl 375 *:Monohydrochloride Examples 222 to 225 The corresponding starting materials obtained in the same manner as in Example 192 were reacted with a corresponding halide in the same manner as in Reference example 1(6) to subject to alkylation to give the compounds shown in Table Table Example Ring A R 1 MS 222 3-Fluorophenyl Ethyl 397 223 2,4-Difluorophenyl Ethyl 415 224 3-Methoxyphenyl Ethyl 409 225 2,4-Difluorophenyl Methoxymethyl 431 Example 226 ONHMe HC 1 HN T HN (1) The.compound of Example 182 was reacted with a corresponding halide in the same manner as in Reference example 1(6) to subject to alkylation to synthesize Compound A mixture comprising 226 mg of Compound 1.1 ml of IN aqueous NaOH solution and 1.1 ml of ethanol was stirred at room temperature for 3 hours. The resulting mixture was neutralized with IN hydrochloric acid, and precipitated crystals were collected by filtration to give 184 mg of the corresponding carboxylic acid. 148 mg of the obtained crystals was reacted with methylamine in the same manner as in Example 170 to give 96 mg of Compound MS 384 Example 227 CONHEt HC 1 HN The compound of Example 226(1) was reacted with ethylamine in the same manner as in Example 226(2) to give the title compound. MS 398 Examples 228 and 229 The compound of Reference example 1(5) was reacted with a corresponding compound in the same manner as in Reference example subsequently the resulting compound was treated in the same manner as in Examples 5 and 13 to give the compounds shown in Table 26. Incidentally, the compound of Example 229 was synthesized by using 2,4-dimethoxybenzyl in place of 4-methoxybenzyl, and deprotecting with conc. hydrochloric acid/THF (700C). Table 26 F O N-(CH 2 )n-R 1 N NH 2 Example n R 1 MS 228 1 2-Fluorophenyl 379 229 0 Isopropyl 313 :Monohydrochloride Example 230 F O F O -N NBoc N N NH N NBoc N N N CI NH 2 NH 2 (2) The compound (1.5 g) of Reference example 9 was reacted with 2, 4-dimethoxybenzylamine and deprotected in the same manner as in Example 229 to give 707 mg of Compound This compound (707 mg) was dissolved in 7 ml of THF, and 410 mg of was added and the resulting mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, diethyl ether was added to the mixture and precipitates were collected by filtration to give 770 mg of Compound as colorless crystals. MS 454 Examples 231 to 242 By using the compounds of Example 13 and Examples 228 to 230, they were reacted with an acid halide in the same manner as in Example 14, and if necessary, by removing t-butoxycarbonyl in the same manner as in Example 80 to give the compounds shown in Table 27. Table 27 F <I0 Exam-. MS pie n 231 ~.2-Cyanophenyl Acetylamino 428 232 1 2-Cyanophenyl 2yiylabnamn 491 0 233 1 2-Fluorophenyl Acetylamino 421 234 1 2-Fluorophenyl Propionylamino 435 235 12-F'luorophenyl Isobutyrylamino 449 236 12-Floropenyl Methoxycarbonylacetyl amino 237 1 2-Fluorophenyl 3-Methoxypropionyl- 465 amino 238 12-Floropenyl Cyclopropylcarbonyl- 23 18 1 -Flurophnyl amino47 239* 0 Isopropyl Cyclopropylcarbonyl- 381 amino 240* 0 Isopropyl Cyipnycroy-409 amino 241 0 4-Piperidyl Isobutyrylamino 424 242 0 4-Piperidyl Cyclopropylcarbonyl- 422 amino Monohydrochioride Dihydrochioride Example 243 FN N N HN NH 2 O HCI In 45 ml of acetonitrile was dissolved 4.5 g of cis-4-(methoxymethoxy)cyclohexane carboxylic acid, 3.73 g of '1,'-carbonyldiimidazole was added to the solution, and the mixture was stirred at room temperature for one hour. To the mixture were added 4.07 g of the compound of Example 229 and 45 ml of acetonitrile, and the resulting mixture was refluxed under heating.for 4 days. Water and an aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 50 ml of methanol was added to the residue and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give an amide compound. This compound was treated in the same manner as in Example 81 to obtain 5.26 g of the title compound. MS 439 Examples 244 to 263 By using the compounds of Examples 228 to 230, they were reacted with a corresponding carboxylic acid in the same manner as in Example 243, and if necessary, by removing t-butoxycarbonyl in the same manner as in Example 80 to give the compounds shown in Tables 28 and 29. Table 28 Example R2MS 244 .(Acetylamino)acetylamino 478 2 45 -2-Amino7p ropionylamino 450 246 -2-Methylamino-propionylamino 464 247 -2-Ainino-3-rethoxy-propionylamino 480 248 3-Anino-propionylamino 450 249** 2 -Pyrrolidinylcarbonylamino 476 250 cis- 4 -Ainino-cyclohexylcarbonylamino 504 251 4-Piperidylcarbonylamino 490 252 3 -Acetylamino-propionylamino 492 253 (1-Acetyl-4-piperidyl) carbonylamino 532 *:Dihydrochloride Table 29 F N-(CH 2 1 N Exam- nR1 R2 M+HS pie [M R 254 12-Floropenyl (S)-5-Oxopyrrolidin-2- _____________ylcarbonylamino49 255* 1 2Fluoophnyl cis-4-Hydroxy-cyclohexylcarbonylamino 505 cis-4 -Acetylamino- 256 .1 Fluoroph enyl cyclohexylcarbonyl- 546 amino 257 1 2-Fluorophenyl (S)-1-Acetylpyrroli- 518 ______din-2-ylca.rbonylamino 258 1 2- Fluoro .phenyl trans-4-Aniino-cyclo- 504 hexylcarbonylamino 259* 1 2-Fluorophenyl trans-4-Hydroxy-Pyclo- 505 hexylcarbonylamino 260* 0 1Isopropyl -5-Oxopyrrolidin-2- 424 ylcarbonylamino 261 0 Isopropyl ci--mn-yl-438 _____________hexylcarbonylamino 262 0 4Pipeidyltrans-4-Hydroxy-cyclo- 48 ______hexylcarbonylamino 263 0 4-Piperidyl cis-4-Hydroxy-cyclo- 480 ____________hexylcarbonylamino I :Monohydrochloride Dihydrochioride, Examples 264 to 267 By using the compounds of Reference examples 14 and 15, they were reacted with a corresponding isocyanate in the same manner as in Example 1, subsequently, the resulting compounds were reacted with a corresponding carboxylic acid in the same manner as in Example 243 to give the compounds shown in Table Table MS Example Ring A RM 264* 3-Chlorophenyl Isopropyl 455 265.*. 3-Methylphenyl Isopropyl 435 266* 3-Chlorophenyl ethyl 441 267* 3-Methylphenyl ethyl 421 *:Monohydrochloride Example 268 N NH NH NH SNHBoc N ,NH NH 2 HN HN O O HCI (2) In 5 ml of acetonitrile were dissolved 540 mg of cis-4-(t-butoxycarbonyl(amino)cyclohexane carboxylic acid and 396 mg of 1,1'-carbonyldiimidazole, and the mixture was stirred at room temperature for an hour. Then, to the reaction mixture were added 200 mg of the compound of Example 198 and 5 ml of acetonitrile, and the mixture was refluxed under heating for 2 days. To the reaction mixture was added an aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform. The extract was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 5 ml of methanol, and 102 mg of potassium carbonate was added to the mixture. The resulting mixture was diluted with chloroform, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 255 mg of Compound as colorless powder. MS 496 Compound (50 mg) was dissolved in a mixed solvent of methanol and chloroform, 0.5 ml of 4N hydrochloric acid-ethyl acetate solution was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 46 mg of Compound as yellowish powder. MS 396 Example 269 NN HN NH) N H 2 2HCI Compound (100 mg) of Example 268 was dissolved in 5 ml of methylene chloride, and to the mixture were added 132 mg of diethylazodicarboxylate (40% solution in toluene), 79 mg of triphenylphosphine and 55 mg of t-butyl (4-hydroxymethylcyclohexyl) carbamate, and the resulting mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography, and dissolved in 1 ml of methanol. 1 ml of 4N Hydrochloric acid-dioxane was added to the mixture, and the resulting mixture was stirred at room temperature for an hour. The reaction mixture was concentrated to give 118 mg of the title compound as yellowish powder. MS 507 Example 270 NH N The compound of Reference example 7(1) was reacted with benzylamine in the same manner as in Example 17 to give the title compound.. MS. 362 Examples 271 to 336 The compound of Reference example 5(4) was reacted in the same manner as in Example 2 or Reference example oxidized with 3-chloroperoxybenzoic acid in the same manner as in Reference example subsequently reacted with a corresponding amine in the same manner as in Example 17, and further, if necessary, t-butoxycarbonyl or methoxymethyl is removed in the same manner as in Example 80 or 81 to give the compounds shown in Tables 31 to Table 31 N -N Example MS 271. Benzylamino 477 272 2-Methoxyethylamino 445 273 Cyclopropylamino 427 274 Butyl-amino 443 275 Isopropylamino 429 276 Ethylamino 415 277 Cyclopropylmnethylamino 441 278 trans-4-Hyclroxycyclohexylamino 485 279 (S)-1-Hydroxymethyl-ethylamino 445 280 -1-Hyclroxymethyl-propylamino 459 Table 32 N Example. MS 281 1 Hyciroxym'ethyl-2-methylpropylamino 282 -1-Hycroxyrethyl-ethylamino 445 283* .Mthl4pieiylmn 484 284 1-Benzyl-4-piperidylamino 560 285 l-Ethoxycarbonyl-4-piperilylamino 542 286 1-Hydroxymethyl-cyclopentylamino 485 287 1-t-Butoxycarbonyl-4-piperidylamino 570 288 4-Piperidylamino 470 289 4-Methoxybenzylamino 507 290* trans-4-Aminocyclohexylamino 484 :Monohydrochioride Dihydrochloride Table 33 F 0 N.r Example n f MS 291 1 2-Fluorophenyl trans-4-Rydroxy- .478 ________cyclohexylamino trans-4-Hydroxy- 292 1 2-Methoxyphenlyl 490 cyclohexylamino 293 1 4-Piperidyl trans-4-Hyciroxy-46 _____________cyclohexylamino 294 4-Pip eridyl Isopropylamino 411 295 1 2-Fluorophenyl Isobutylamino 436 296"* 1 4-Piperidyl Isobutylamino 425 297 1 2-Fluorophenyl 4-Piperidylamino 463 298* 0 Methyl. trans-47Hydroxy- 384 ____cyclohexylamino 299** 0 Methyl trans-4-Aminocy- 383 clohexylamino____ 300* 0 Ethyl trans-4-Hydroxy- 398 301* 0 Ethyl Isobutylamino 356 302* 0 Isopropyl trans-4-Hydroxy- 412 cyclohexylanino 303** 0 Isopropyl- trans-4-Aminocyclo 411 304 0 ethyl trans-4-Aminocyclo 39 ________hexylamino 3* 1 cis-4-Hydroxy- Isopropylamino42 cyclohexyl Monohydrochloride Dihydrochlorile Table *34 F 0 p 2 Example n 2M 306 1 cis-4-Hydroxycy clohexyl 307* 1 trn--yloy Isopropylamino 426 308* 1 tra Ins-4-Hydroxy Isobutylamino 440 cyplohexyl 309 cis-4-Aminocycl42 309___ 1 ohexyl Isopropylamino42 c is-4-Aminocycl 1 ohexyl Isobutylamino43 311 1 cis-4-Aminocycl trans-4-Hyclroxycyclo 48 ohexyl hexylamino 312* 0 Ethyl. trans-4-acetylamino- 439 ________cyclohexylanino 313* 0 Iopropyltrans-4-acetylamino- 31* 0 sprplcyclohexylamino 453___ 314*** 1 cis-4-Aminocycl trans-4-Aminocyclo- 48 34 1 ohexyl -hex ylamino 480___ trans-4-Aminocy Iorplmn 315 1 coey spoyai 425 clohexyl_____ trans-4-Aminocy Irasobutymioxyy 316* 1 coey eyai 439 clohexyl 317* 1 tras-4-Ainiocy trans-4-Hydroxycyclo 481 clohexyl hexylamino 319' 1 cIs-4-ydoxy trans-4-Hydroxycyclo 426 c1 hey hexylamino :Monohydrochloride *:Dihydrochloride; Trihydrochloride Table N -N Exam-.nRIR2M pie. 321* 0bpopy trans-4-Hydroxycyclo-41 hexylamino 3* bu.tltrans-,4-Hyciroxycyclo- 42 322 0 butylhexylamino42 3 23* 0Cyanomethyl trans-.4-Hydroxycyclo- 409 ~hexylamino______ 324* 0 2-Methoxyethyl ta-4Hdoyyl-428 ______hexylamino 325*1 0.t 3-hydroxyprop yl trans-4-Hydroxycyclo- 428 hexylamino 326* 1Cycloropyltrans-4-Hydroxycyclo- 2 hexylamino 327* 1 Cyclobutyl trans-4-Hydroxycyclo- 438 328* 0 E thyl 4-Tetrahydropyranyl- 384 ______amino 329* 0 Ehl(S) -1-Hydroxymethyl- 358 Ethylethylamino 3* 0Ehl2-Hydroxy-1, 1-du-37 330 0 Ethylmethylethylamino37 331* 0 Ethyl 1-Hydroxymethyl-cyclop 398 332 0 Ethyl 3-Methoxypropylamino 372 333 0 Isopropyl 2-yoy,d tyl 386 ethyl amino 334 0Iorpl1-_Hydroxymethyl-cyclop 412 0 Isoropylentylamino 335 0Ethyl cis-4-Hydroxycyclohexy 398 0 lamino 336 0Iorplcis-4-Hydroxycyclohexy 412 0 Isoropyllamino Monohydrochloride 100 Examples 337. to 343 The compound of Reference example 16 was reacted with a corresponding isocyanate in the same manner as in Example 1, oxidized with 3-chloroperoxybenzoic acid in the same manner as in Reference example subsequently reacted with a corresponding amine in the same manner as in Example 17 to give the compounds shown in Table 36. Table 36 N N HN MS Example Ring A 337* 3-Fluorophenyl 412 338* 3-Methylphenyl. 408 339* Phenyl 394 340* 3-Chlorophenyl 428 341* 4-Chlorophenyl 428 342* 2,4-Difluorophenyl 430 343* 3-Methoxyphenyl 424 *:Monohydrochloride Examples 344 to 349 The compound of Reference example 17(3) was reacted with a corresponding isocyanate in the same manner as in Example 1 to give the compounds shown in Table 37. 101 Table 37 A. 0 Q NN N -N E xample Ring A MS 344* 3-Chiorophenyl 414 345* 3-Methyiphenyl 394 3 4 6* 3-Trifluoromethyiphenyl 448 3 47 4-Chiorophenyl 414 348* Phenyl 380 349* 3-Fluorophenyl -398 Monohydrochioride Example 350 MeO OMe MeO OMeH H NH2 SMe. SMe(1 F MeOOMeH H 0 NYN N N-NH N N 0 F N SO 2 Me (2) To 300 ml of a diethyl ether solution containing 52. 0 g of the compound of Reference example 5 was added dropwise 100 ml of a diethyl ether solution containing 30.2 g of 4-fluorophenyl isocyanate under ice-cooling, and the mixture 102 was stirred at room temperature for 30 minutes. After concentration under reduced pressure, diisopropyl ether was added to the reaction mixture and crystals were collected by filtration togive 75.0 g of Compound as colorless crystals. In chloroform was dissolved 30.0 g of Compound and under ice-cooling, 46.4 g of 3-chloroperoxybenzoic acid was added to the solution and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, diethyl ether was added to the reaction mixture and crystals were collected by filtration to give 30.8 g of Compound as colorles,s crystals. To the compound obtained by treating 20.0 g of Compound (2) with a corresponding starting material in the same manner as in Example 17 was added 100 ml of conc. hydrochloric acid, and the mixture was stirred at room temperature overnight. A.2N aqueous sodium hydroxide solution was added to the mixture to neutralize the same, ethyl acetate was added to the same and after stirring, precipitated crystals were collected by filtration to give 12.4 g of the title compound as colorless crystals. MS 314 Examples 351 to 354 The compound of Reference example 5(3) and a corresponding starting material were treated in the same manner as in Example 350 to give the compounds shown in Table 38. 103 Table 38 N NH N -N R 2 Exam- 2 MS SRing A R pie trans-4-Hydroxycyclo- 351 4-Fluorophenyl 370 hexylamino 352* 4-Fluorophenyl Isobutylamino 328 353 2,4-Difluorophenyl. .Isopropylamino 332 354 Phenyl Isopropylamino 296 *:Monohydrochloride Examples 355 to 367 By using the compound of Example 350, 353 or 354, or the compound produced by the same manner as in Example 350, they were treated in the same manner as in Reference example 1(6) to give the compounds shown in Table 39. 104 Table 39 NN-N HNT, Example Ring A R 1 M 3 55* 4-Fluorophenyl Methyl 328 35.6* 4-Fluorophenyl Ethyl 342 357 .4-Fluorophenyl Methoxymethyl 358 358 2,4-Difluorophenyl Ethyl 360 3.59 Phenyl Ethyl 324 360 4-Chlorophenyl Ethyl 358 361 3-Fluorophenyl Ethyl 342 362 3-Methoxyphenyl Ethyl 354 363. 2,4-Difluorophenyl Methoxymethyl 376 364, Phenyl Methoxymethyl 340 365 4-Ch lorophenyl Methoxymethyl 374 366* 4-Fluorophenyl 2-Methoxyethyl 372 367* 4-Fluorophenyl Cyanomethyl 353 Monohydrochloride Examples 368 to 382 The compound of Reference example 5 was reacted in the same manner as in Example 2 or Reference example 1 oxidized with 3-chloroperoxybenzoic acid in the same manner as in Reference 105 example 6 subsequently reacted with a corresponding amine in the same manner as in Example 17, and if necessary, t-butoxycarbonyl was removed in the same manner as in Example to give the compounds shown in Table Table N N Example RR2MS 368* Ethylcis-4-Hydroxymethyl-41 369* Ethyl trn--yrxmty-412 cyclohexylamino 370 3-Hydrox4-y2, 2-dmethyl-38 36 Ethyl prp1amn cyclohexylamino 372* sopropyl trans- -ydroxymethyl-42 crylhxyino38 373 3-Hydroxy-2,d2-imethyl-40 37. Isopropyl 42py6mn 374* Iopropyc(S)-2hydry prmiop a n 37 376* Is opropyl 1rn-Hydroxyloeyl- 426 methlamino 2-Hydroxy-1,-droxty- 377 Isopropyl mty- meh ehy-402 amiolmn 378 Isopropyl 4S-ipery rplmn 372 375* Isopropyl amino drxprplaio 7 380* Isopropyl (i,2--Hydroxycyclo 398 etylamino :Monohydrochloride :Dihydrochioride 106 (Continued) N- N -N R2 Examples MSR (lS,2S,)-2-Hyclroxycyclo- 381* Ethyl 384 pentylamino, 382* Ethyl trans-4-Carbamoylcyclo- 42 ________hexylamino Monohydrochioride Dihydrochloride Examples 383 to 386 The compound of Example 303 or 304 was subjected to methanesulfonylation or methoxycarbonylation according to the conventional methods to give the compounds shown in Table 41. 107 Table 41 F N 1 N-R N N Examples R R 2 trans-4-Methanesulfonyl- 383 Isopropyl 489 aminocyclohexylamino 384* Isopropyl trans-4-Methoxycarbonyl- 384 Isopropyl 469 aminocyclohexylamino trans-4-Methanesulfonyl- 385 Ethyl 475 aminocyclohexylamino trans-4-Methoxycarbonyl- 386 Ethyl 455 aminocyclohexylamino :Monohydrochloride Example 387 ~NH N N The compound of Example 1 (100 mg), 4-acetylphenylboronic acid (129 mg), copper (II) acetate (72 mg) and triethylamine (220 pl) were suspended in 10 ml of methylene chloride, and the suspension was stirred at room temperature for 24 hours. To the readction mixture, 28% aqueous ammonia was added and the mixture was extracted with chloroform, washed with brine, and dried over anhydrous magnesium sulfate. The resultant mixture was concentrated under reduced pressure, and ether was added to the residue and precipitated crystals were collected by 108 filtration to give 92 mg of the title compound. Melting point: 206 0 C (decomposed) Examples 388 to 389 The compound of Example 1 and the corresponding starting materials were reacted in the same manner as in Example 387 to give the compounds shown in Table 42. Table 42 N-R 1 N0, Melting point Examples. R 1 388 4-Pyridyl 189 389 3-Thienyl 193-195 Example 390 NCN NH 2 F N N N NHCONHEt To a solution of the compound of Example 13 (50 mg) in THF was added ethyl isocyanate (12 pl), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 19 mg of the title conpound as colorless crystal. Melting point: 209 210 0 C Examples 391 to 394 109 The compound of Example 16 and the compounds prepared in the same manner as in Example 16 were subjected to hydrolysis followed by amidation according to the conventional methods, or subjected to reduction followed by mesylation and dimethylamination, to give the compounds shown in Table 43. Table 43 F 1 N-R Melting point Examples R 1 R 135 391 2-Cyanobenzyl Carboxy (decomposed) 209-210 392 2-Cyanobenzyl Carbamoyl (decomposed) 157-158 393 2-Fluorobenzyl Hydroxymethyl (decomposed) Dimethylamino- 231-236 394 2-Fluorobenzyl methyl (decomposed) Examples 395 to 398 The corresponding starting materials were reacted in the same manner as in Example 368 to give the compounds shown in Table 44. 110 Table 44 MS Examples R i R2 trans-4-Hydroxycyclohexyl- 395* Ethyl 412 methylamino 396trans-4-Hydroxycyclohexyl- 396 Isopropyl 426 spp methylamino cis-4-Hydroxycyclohexyl- 397* Ethyl 412 methylamino cis-4-Hydroxycyclohexyl- 398 Isopropy ethyaino 426 methylamino *:Monohydrochloride Examples 399 to 416 The compound of Reference example 5(4) and the corresponding starting materials were reacted in the same manner as in Reference example oxidized with 3-chloroperbenzoic acid in the same manner as in Reference example subsequently reacted with the corresponding amine in the same manner as in Example 17, and, if necessary, subjected to removal of t-butoxycarbonyl in the same manner as in Example to give the compounds in Tables 45 and 46. :11*1 Table. 4 N~N-N R Example MSR 1, 1-Dioxotetrahyclrothiop 41 Ethylhen-3.ylamino 400* Ehy trans-4- (Methylcarbamoyl _________cyclohexylamino. 401* Ethyl1, 5-Dimethyl-5-hydroxyhe 42 ________xylamino, 402* Isopopyl 1, 1. xylamino 403* Ethyl cis-4-Hydroxy-4-methylcy 412 clohexylamino 404* Isopopyltrans-4-I-ydroxy-4-methyl 42 cyclohexylarnino 405* Isopropyl trans-4- (l-Hydroxy--l-met 454 hylethyl) cyclohexylamino 406* Ethyltrans-4-Hydroxy-4-methyl 41 ________cyclohexylamino 407* Isopropy! cis-4-IHydroxy-4-methylcy 426 ionohycrochloride 2.12 Table 46 NA N -N R Example R R 2 M 408* Ethyl trans-4- (l-Hydroxy-1-met 440 hylethyl) cyclohexylamino 2-Dimethyl-2-hydro. 409* Ethyl 386 xypropylamino 410* soprpyl (S)-1,2-Dimethyl-2-hydro40 ________xypropylamino 411* Ethyl1, 3-Dimethyl-3-hydroxybu40 tylamino 412* Isopropyl 1, 3-Dimethyl-3-hydroxybu 414 tylamino_____ 413* Isopropyl 2-Mercapto-2-methylpropy 402 lamino 4* Iorpl 1, 1-Bishydroxyrnethyiprop41 ylamino_____ 415* Isopropyl 2-Hyciroxy-2-methylpropyl 386 amino 416** Ethyl 4-Piperid~ylamino 38 3 :monohydrochloride; *:di hydrochloride Examples 417 to 433 The compound of Reference example 5 was reacted in the same manner as in Example 2 or Reference example 1 C6) reacted with methymagnesium bromide if necessary, subsequently oxidized with 3-chloroperbenzoic acid in the same manner as in Reference example and reacted with the corresponding amine in the same manner as in Example 17 to give the compounds -I 113 in Tables 47 and 48. Table 47 NAN-R 1 NyN R Exam- MS ple 417* 12Dety-hy Isopropylamino 400 ,dro xyp ropyl 418* 1,2-Dimethyl-2-hy cis-4-Hydroxy-4-meth 47 droxypropyl ylcyclohexylamino 419 l2-Dimethyl-2-hy (S)-l,2-Dimethyl-2-h .droxypropyl ydroxypropylamino 1,2-Dimethyl-2-hy Trans-4-Hydroxy-4-me 47 420* droxypropyl thylcyclohexylamino 421* 2-Hydroxy-l, 1, 2-t rietylroy Isopropylamino 414 422 12-Hydroxy-l,l,2-t Trans-4-Hydroxy-4-me 48 *rimethylpropyl thylcyclohexylamino 423* 3-Hydro 'xy-3-methy Iorplmn 0 lbutyl Iorplmn 0 424 .*3-Hydroxy-3-methy l-Dimethyl-2-hydro 43 lbutyl xyethylamino_____ monohydrochloride -I 114 Table 48 N N R2 ExampleMS Examle R R( 425* 3-Hyclroxy-3-met 2,2-Dimethyl-3-hydro hylbutyl xypropylamino 3-H-ycroxy-3-met 1-Hydroxynethylcyclo 426* hylbutyl pentylamino 427* 3-Hydroxy-3-met trans-4-Hydroxy-4-me 47 ______hylbutyl thylcyclohexylamino 428 -Hydoxy--met4-Tetrahydropyranyla ______hylbutyl mino 42* 3-Hydroxy-3-met (R)-l,2-Dimethyl-2-h hylbutylyrxyrplmn 430* 3-Hyclroxy-3-met (S)-l,2-Dimethyl-2-h hyibutyl yrxpoyaio 431* 3-Hydroxy-3-met trans-4-Hydroxycyclo _______hylbutyl hexylamino 432* 3-Hydroxy-3-met 1-Methanesulfonylpip 519 ______hylbutyl eridin-4-ylamino 433* 3-Hydroxy-3-met 1-Ethanesulfonylpipe hylbutyl ridin-4-ylamino monohydrochloride Examples 434 to 460 The compound of Reference example 5(3) and the corresponding starting materials were reacted in the same manner as in Reference example 9, oxidized with 3-chloroperbenzoic acid in the same manner as in Reference example 6 and subsequently reacted with the corresponding -I 115 compound in the same manner as in Example 17 to give the compounds in Tables 49. to 51. Table 49 N- N -N R2 Exam- 2 1 MS pie 434* 4-Tetrahydropyra. sbtlmn 412 nylIsbtamo 3* 4-Tetrahydropyra Ispoyaio398 Iorplmn 436* 4-Tetrahydropyra trans-4-Hydroxy-4-met 46 hylcyclohexylamino 46 437* 4-Tetrahydropyra Ccorplmn 9 437 nyl Ccorplmn 9 438* 4-Tetrahydropyra 2, 2-Dimethylpropylami 426 nyl no 439*1 1-Acetylpiperidi .trans-4--Hydroxy-4-met hylcyclohexylamino 440* -Acetylpiperidi 2,2-Dimethylpropylami 467 441* 1-ct pprd Isopropylamino 439 n-4-yl 442* 1-AcetylpiperidiIsbt 442 n-4-yl 443* 1-Acetylpiperidi Cyclopropylamino 437 n-4-yl 444* 4-Tetrahydropyra CR) -1,2-Dimethyl-2-hy 4__44_ nyl droxypropylamino .442 445* 4-Tetrahydropyra (S)-1,2-Dimethyl-2-hy 442 droxypropylamino 446* 4-Tetrahydropyra -2-Hydroxy- 1-methy 41 nyl lethylamino41 *:monohydrochloride 116 Table N~N-N R2 Exam- 2MS pie C[M+H]) 447* 4-Tetrahydropyra -l-Hydroxymethylpr 42 niyl opylamino_____ 448* 4-Tetrahydropyra 1, 1-Dimethyl-2-hydrox42 yethylamino_____ 4-Tetrahydropyra 4-Tetrahydropyranylam 449 440 ino+ 450* 1-Acetylpiperidi. 1,1-Dimethyl-2-hydrox 46 .yethylamino_____ 1-Acetylpiperidi .4-Tetrahydropyranylam 48 n-4-yl ino 1-Acetylpiperidi (S)-1-Hydroxymethylpr 452 469 opylamino 1-Acetylpiperidi (S)-1,2-Dimethyl-2-hy 453*+ 483 n-4-yl droxypropylaminoI monohydrochioride 117 Table 51 N~N-N .Y 2 R Exam-. MS pie 454* 4-Tetrahydropyra trans-4-Hydroxycycloh nyl exylamino 1-Acetylpiperidi trans-4-Hydroxycycloh n-4-yl exylamino 456* 1-Methanesulfony trans-4-Hydroxycycloh53 lpiperidin-4-yl exylarnino 1-Methanesulfony trans-4-Hydroxy-4-met -1piperidin-4-yl hylcyclohexylamino 458* 1Mtaeufn Isopropylamino 475 ______lpiperidin-4-yl 459* 4-Tetrahydropyra 1-Methanesulfonylpipe 459* 517 nyl ridin-4-ylamino 460* 1-Acetylpiperidi 1-Methanesulfonylpipe 558 n-4-yl. Iridin-4-ylamino ronohydrochloride Examples 461 to 476 The compound of Example 378 or Example 416 was subjected to alkylsulfonylation and acylation by the conventional manner, or reacted with isocyanate to give the compounds in Tables 52 and 53. 118 Table .52 F 0 N-N R2 Exam- MS pie 461* Isopopyl 1-Acetylpiperidin-4 -ylam ino 462* -Isopropyl 1-Methanesulfonylpiperid 47 ______in-4-ylamino 4 .63* Isopropyl (isopropylsulfonyl) pip 503 ______eridin-4-ylamino 464' Isopropyl 1- (Propylsulfonyl) piperi 503 cin-4-ylamino 465* sorpl 1- (But Iylsulfonyl) piperid 517 in-4-ylamino, 466* Isopopyl 1- (Isobutyloxycarbonyl)p iperidin-4-ylamino 467' Ispropyl 1-butyrylpiperidin-4-yla 46 inino 468' Ethyl 1-Acetylpiperidin-4-ylan 425 ino monohydrochloride 119 Table 53 N- Nd-NR Exam- MS pie 469* Ethyl1-Methanesulfonylpiperid 46 in-4-ylamino 470*~~ Ehl-Ethanesulfonylpiperidi. n-4-ylamino 471* Ispropyl -Ethylcarbamoylpiperidi 46 n-4-ylamino_____ 472* Ispropyl 1-Propylcarbamoylpiperid 48 in-4,-ylamino_____ 1-Isopropylcarbamoylpipe48 Isoprpyl ridin-4-ylamino 474* Ispropyl 1-Ethanesulfonylpiperidi 48 475* 1-Met hoxycarbonylpiperid Isopopyl in-4-ylarnino 476* Ispropyl 1-Ethoxycarbonylpiperidi 46 n n-4-ylamnino_____ monohydrochioride Examples 477, 478 The compound of Example 147 was subjected to alkylsulfonylation by the conventional manner to give the compounds in Table 54. 120 Table 54 Exam- 2MS pie 1-Methanesulfony 477* Isopropylamino 474 lpiperidin-4 -yl 47 8* 1- Ethanesulfonyl Isopropylamino 488 ______piperidin-4-yl monohydrochioride -In a similar manner to those described in the Examples above the following compounds were prepared. 121 Table N-R' NN Exam- 1(2m+Hs pie 47* 1- (methanesulfony (iS) 2-Dimethyl-2- 51 _____1).piperidin-4-yl hydroxypropylamino 48 -Hydroxy-2-methy 1- (Isopropylsulfonyl 53 propyl )piperidin-4-ylamino 481 Ispropyl(3R) -3-pyrrolidinyla 38 mino (3R) -1-Methanesulfon 482* Isopropyl ylpyrrolidin-3-ylani 461 no 483* Iobutyl1-(Ethanesulfony.)pi.50 perid Iin-4 -ylamino 503___ 484* Isobutyl 1-(Isopropylsulfonyl 517 _______________piperidin-4-ylamino 485 Cclopopylmthyl 1-(Methanesulfonyi)p 48 oroylety iperidin-4 -ylamino 487___ trans-4- (N-Methanesu 486* Isopropyl lfonyl-N-methylamino 503 _______________cyclohexylamino 487* 4-Tetrahydropyran 1-(Ethanesulfonyl)pi 531 peridin-4-ylamino. 48k 4-Tetrahydropyran 1- (Isopropylsulfonyl )piperidin-4-ylamino 489* 4-Tetrahydropyran 1- (Methoxycarbonyl)p 497 iperidin-4-ylamino 49k 4-Tetrahydropyran 1-propionylpiperidin 49 -4-ylamino 49* 4-Tetrahydropyran 1-Acetylpiperidin-4- 48 yl ylamino monohydrochioride 122- Table, 56 -R N N Exam- 2MS pie 492* Iobutyl1-Apetylpipericiin-4-yla45 mino 1- (Ethanesulfonyl)piper 493*. Methoxymethyl 491 -ylamino 49* Me thoxymethy 1- ____________peridin-4-ylamino 495* 4-Tetrahydrop 1-(Dimethylaminosulfony yranyl l)piperidin-4-ylamino- 496* 4-Terahyroptrans-4- (Methanesulfony yranyl lamino)cyclohexylamino 2-hyciroxy-2-m 2-Dimethyl-2-hyd 4 97*, 430 :ethyipropyl roxypropylamino 498* tycloutyl trans-4 -Hydroxycyclohex42 ______ylamino trans-4-Methyl-4-hylrox43 49* Cyclobutyl ycyclohexylamino43 1- (Methanesulfonyl) pipe 50.0* Cyclobutyl ridin-4-ylamino 487 501* ycloutyl 1-.(Ethanesulfonyl) piper 0 cobty idin-4-ylamino 501___ 502* Cyclobutyl 1- (Isopropylsulfonyl)pi 515 ~peridin-4-ylamino_____ 503t* ylouy 1- (Dimethylaminosulfony 516 Cycloutyl 1) piperidin-4-ylamino monohydrochiorile 123 Table 57 N-R 1 Exam- RR2MS pie 4-Tetrahyciro trans-4- (N-Methanesulfon 504*, pyranyl yl-N-methylarnino)cyclohe 545 505* Cyclobutyl (S 1,2Dmty-hdr412 ___________oxypropylamino 506* Ispropyl(3S) -1-(Methanesulfonyl)47 ____________pipericlin-3-ylamino Methoxymethy .1-'(Dimethylaminosulfonyl50 1 )pipericlin-4-ylarnino 2-Hydroxy-2- 1-(Dimethylaminosulfonyl53 methyipropyl piperidin-4-ylamino 3-Hydroxy-3- .1-(Dimethylaminosuifonyl54 ___methylbutyl .)piperidin-4-ylamino *trans-4- (N-Methanesulfon 10 .2-Hydroxy-2- yl-N-methylamino)cyclohe 533 methyipropyl ~xylamino_____ trans-4- (N-Methanesulfon 3-Hydroxy-3- 511* .yl-N-methylamino)cyclohe 547 methylbutyl xlmn 4-Tetrahydro trans-4- (N-Ethyl-N-metha 512* pyranyl .nesulfonylamino)cyclohex 559 ~~ylamino_____ 513 Isopropyl 3-Amino-2, 2-dimethylprop 399 ~ylamino_____ 2-amino-2-methylpropylam 514 Isopropyl 385 515* sobuyl .trans-4-Hydroxy-4-methyl40 __________cyclohexylamino_____ 516** Cycloutyl trans-4-aminocyclohexyla.42 mino monohydrochloride, dihydrochloride 124 Table 58 N R N N Ea-R 1 R 2 Ring A M pie 1-Acetylpi t rans-4-Hyciroxy- 3Mty 517*. periciin-4- 4-methylcyclohex phnl 505 ylamino phenyl 4-Tetrahyd (iS) 2-Dimethy 3Mty 518*, ropyranyl 1-2-hyciroxypropy phnl 438 4-Tetahyd (1S)-1,2-Dimethy 3Cir 519* ropyranyl 1-2-hyclroxypropy phnl 458 lamino pey 4-Tetrahyd 207-209 520* ropyanyl trans-4-Hydroxyc 3-Methyl 0 ~et yclohexylamino phenyl gpit 4-Tetrahyi trans-4-Hydroxy- 3-ehl212-214 521* ropyranyl 4-methylcyclohex 0 C (melti phenyl_ ng point) 4-Tetrahyd trans-4-Hydroxy- 4-Chloro 195-199 522* ropyranyl 4-methylcyclohex 0 C(melti ______ylamino phnl ng point) 4--Tetrahyd -ho 272-275 523* ropyranyl t n-4H rxy 4Cho o 0 C (melti yclohexylarnino phenyl gpit 4-Tetrahyi trans-4-Hydroxy- 213-215 3-Chloro 524* ropyranyl 4-methylcyclohex OC(melti ______ylamino phnl ng point) 4-Ttraydtrans-4-Hydroxy- 4-Fluoro 23-6 525 ropyranyl 4-methylcyclohex ph0y C(melti Ylamino point) *monohydrochioride 125 Table 59 N-R NN-N R Exam- 12MS ple 4-Tetrahydrop 1, 1-Dioxotetrahyclrothia 526* 488 yranyl pyran-4-ylamino 527* Ispropyl2-Acetylamino-2-rnethylp42 ropylamino 528* Ispropyl2-Methanesulfonylamino-46 __________2-methyipropylamino 3-Acetylamino-2, 2-climet 529* Isopropyl hypoyaio441 52* 2, 2-Dimethyl-3-mnethanes47 Isopropylulfonylarninopropylamino_____ 531* Cyclopentyl trans-4-Hydroxymethylcy 452 532* 1l-Ethanesulfonylpiperid51 Cycloentyl in-4-ylamino monohycirochioride 126 Table I-'R NIN R Exam.- 2MS pie 533* 1-Isopropylsulfonylpipe52 ~yc~oen~y± riclin-4-ylamino 534* 1-Methanesulfonylpiperi50 534 Cy clopentyl cin-4-ylamino50 535* yclopntyl 4-Tetrahyciropyranylamin42 0. 536* yclopntyl trans-4-Hydroxy-4-methy45 cyclohexylamino_____ 537* (1S)-1,2-Dimethyl-2-hyi42 Cycloentyl roxypropylarnino 1, 1-Dimethyl-2-hydroxye 538* Cyclopentyl 412 539* 2, 2-Dimethyl-3-hydroxyp42 Cycloentyl ropylamino 540* C Iyclo .pentyl trans-4-Hydroxycyclohex 438 ______ylamino 541* yclopntyl trans-4-aininocyclohexyl ~amino_____ 542* ycloexyl trans-4-hydroxymethylcy46 543* Cyclohexyl 1-Ethanesulfonylpiperid 529 ~in- 4-ylamino_____ 44* Cylhxl 1-Isopropylsulfonylpipe54 Cycloexyl riclin-4-ylamino monohydrochioride 127 .Table 61 N-R 1 NN Exam- RiR2MS pie 545* Cyclohexyl 1-Methanesulfonylpiperidin-4 .515 546* Cyclohexyl 4-Tetrahydropyranylamino 438 547* trans-4-Hydroxy-4-methylcyci 6 Cycloexyl ohexylamino 548* Cyclohexyl (iS) -1,2-Dimethyl-2-hydroxyp 440 549* 1, 1-Dirnethyl-2-hyclroxyethyla42 54* Cyclohexyl min ___426 550* Cyclohexyl 2, 2-Dimethyl-3-hydroxypropyi 440 amino_____ 551* ycloexyl trans-4-Hydroxycyclohexylami45 no 552* Cyclohexyl trans-4-aminocyclohexylamino 451 2, 2-Dimethyl-3- (N-methanesul 553* Isopropyl fonyl-N-methylamino)propylam 491 o_ 554* Iorpl 2- (N-Methanesulfonyl-N-methy47 Isopopyl larnino) -2-methyipropylamino *monohydrochloride 128 .Table 62 N-R' Exam R 2 Ring A M E 555* 4-Tet-rahydro 1.-Methanesulfonyip 3-Methy 51+3 pyranyl iperidin-4-ylamino iphenyl 4-Tetrahydro 1-Methanesulfonyip 3-Chior53 _____pyranyl iperidin-4-ylamino ophenyl ionohydrochloride In a similar manner to those described in the Examples above, the following compounds are prepared. 129 Table 63 N-R N 2 No. RR2 Ring A 1 4-Tetrahyiro .1-Acetyl-4-methylpiperi 4Furpey ___pyranyl din-4-ylamino________ -4-Tetrahydro, 1-Methanesulfonyl-4-met 4Furpey __pyranyl hylpiperidin-4-ylamino 4 Tetrahydro tran s-4 -amino.-.4-methylc 4-Fluorophenyl __pyranyl yclohexylamino________ 4'-Tetrahyciro trans-4-Methoxycyclohex 4_ yrnijyan 4-Fluorophenyl 4-,Tetrahydro trans-4-H-ydroxymethylcy.4Furpey __pyranyl clohexylamino________ trans-4- (1-Hydroxy-1-ne 4-Tetrahydro 6 thylethyl)cyclohexylami 4-Fluorophenyl pyranyl no 4'-Tetrahydro cis-4-Hydroxycyclohexyl 4Furpey pyranyl methylarnino________ 8 -Tetrahydro cis-4-Hyclroxy-4-methylc 4Furpey pyranyl yclohexylmethylamino 4-Tetrahyiro 1-Acetyl-4-methylpiperi 3Mtypey pyranyl din-4-ylamino 4-Tetrahydro 1-Methanesulfonyl-4-met 3Mtypey __pyranyl. hylpipericlin-4-ylamino 11 4-Tetrahydro trans-4-amino-4-methylc 3-Methyiphenyl __pyranyl yclohexylamino 12 4-Te .trahydro trans-4-Methoxycyclohex 3-Methyiphenyl. __pyranyl ylamino 13 4-Tetrahydro trans-4-Hydroxymethylcy 3Mtypey __pyranyl clohexylamino 130 Table, 64 N-R No. R 2 Ring A trans-4- (1-Hydroxy-1-me 144-Tetrahydro 1 yrn4 thylethyl) cyclohexylami 3-Methyiphenyl 4-Tetrahydro. cis-4.1yroyHloey ydoyylhxl 3-Methyiphenyl __pyranyl methylamino 16 -Tetrahyciro cis-4-Hy-droxy-4-methylc ___pyranyl yclohexylmethylamino 3Mtypey 4-Tetrahydro 1-Acetyl-4-methylpiperi 3Cirpey 17,3Clrpey __pyranyl din-4-ylamiio 18 4-Tetrahydro 1-Methanesulfonyl-4-met 3Cirpey ___pyranyl hylpbiperidin74-ylamino 19 4- Tetrahydro trans-4 -amino-4--methylc ___pyranyl yclohexylamino 3Cirpey 4-Tetrahyiro trans-4-Methoxycyclohex pyranyl ylamino 3Cirpey 21 4-Tetrahydro trans-4-H-ydroxymethylcy.3Cirpey __pyranyl clohexylamino________ trans'-4- (1-Hydroxy-1-me 4-Tetrahydro tyehl)ccoeyai 3Cirpey 22 pyranyl tyehlccoeyai3Clrpey no 23 4-Tetrahyciro cis-4-Hyclroxycyclohexyl 3Cirpey 23_ pyranyl methylamino 24 4-Tetrahydro cis-4-Hydroxy-4-methylc 3Cirpey __pyranyl yclohexylmethylamino 4-Tetrahydro 1-Acetylpiperidin-4-yla 3-Trifluoromet __pyranyl mino hyiphenyl Table N -R NN 2 No. R 2Ring A 264-Tetrahydrop .1-Me'thanesulfonylpiper 3-Trifluoromet __yranyl idin-4-ylamino hyiphenyl 27 4-Tetrahydrop 1.-Ethanesulfonylpiperi 3-Trifluoronet ___yranyl .din-4-ylamnino hyiphenyl 284-Tetrahydrop l-Isopropylsulfonylpip 3-Trifluoromet ___yranyl ,eridin-4-ylamino. .hyiphenyl 29 4-Tetrahydrop 1-Acetyl-4-rnethylpiper 3-Trifluoronet II yranyl icin-4-ylamino hyiphenyl -Tetrahydrop,1Mtaeufnl4m 3-Trifluoromet ny thylpiperidin-4-ylaninhypey ___yranyl ccoeyaio.hyiphenyl 324-Tetrahydrop trans-4-Hydroxycyctl 3-Trifluoromet -yranyl cyhxylamino hyiphenyl 4-Tetrahydrop trans-4-Methoxycyclohe 3-Trifluoromet ___yranyl xylamino hyiphenyl 4-Tetrahycirop cias-4-ydroxycyclohey 3-Trifluoromet __yranyl imylamino hyiphenyl 4-Tetrahydrop cias-4-Hylroxy-4-meth 3-Trifluoromet 36 ___yranyl ycyclohexyletamino hyiphenyl *4-Tetrahydrop (13) -1-dimtyl-2hy 3-Trifluoromet __yranyl droxprylamino hyiphenyl 38 *4-Tetrahydrop 1i-eypridn-4-tyl 4-Tfluoroey __yranylmethyl jamino 132 Table 66 Q~N-R No. Ri.R 2 Ring A 4-Tetrahydrop 1-Methanesulfonylpiper 4Furpey __yranylmethyl idin-4-ylamino________ 4-erahydrop l-Ethanesulfonylpiperi 4-Fluorophenyl __yrainylmethyl .din-4-ylamino 4'4 Tet Irahydrop. 1-Isopropylsulfonylpip 4Furpey __yranylmethyl eridin-4-ylainino 4-Tetrahydrop 1-Acetyl-4-inethylpiper 4Furpey 42 -4Furpey __yranylmethyl idin-4-ylamino 4-Terahyrop 1-Methanesulfonyl-4-me 43 4-erhdothylpipericiin-4-ylamin 4-Fluorophenyl yranfyline thy 1 0 4-Tetrahydrop trans-4-Amino-4-methyl 4Furpey 44_ yranylmethyl Icyclohexylainino4-.Furpey 4-Tetrahydrop trans-4-Methoxycyclohe 4 -Fluorophenyl __.yranylmethyl xylamino 46 4Tetrahydrop trans-4-Hydroxy-4-meth.4Furpey yranylmethyl ylcyclohexylamino,4Furpey trans-4- CN-rethanesulf 4. 4-Tetrahydrop onyl-N-rnethylanino) cyc 4-Fluorophenyl yranylinethyl lhxlmn 48 4-Tetrahydrop cis-4-Hydroxycyclohexy 4-Fluorophenyl __yranylmethyl imethylamino 49 4-Tetrahydrop cis-4-Hydroxy-4-methyl 4Furpey __yranylmethyl cyclohexylmethylanino 4Furpey 4-Tetrahydrop (iS) -1,2-Dirnethyl-2-h y 4-Fluorophenyl __yranylmethyl droxypropylainino________ 514-Tetrahydrop 2, 2-Dirnethyl-3-hydroxy 51_ yranylrnethyl 1propylarnino I 4-Fluorophenyl 133 Table 67 N R' No. R 1 R 2 Ring A 3-Tetrahydro 1-Acetylpiperidin-4-yla 52 4 -Fluorophenyl ___furyl mino 3-Tetrahydro 1-Methanesulfonylpiperi 4Furpey __furyl din-.4-ylamino________ 3-Tetrahyiro 1-Ethanesulfonylpiperid 514 4 -Fluorophenyl ___furyl in-4-ylamino________ 3-Tetrahyiro 1-Isopropylsulfonylpipe 4Furpey f uryl ridin-4--ylamino 56 3-T etrahydro 1-Acetyl-4-methylpiperi ___furyl din-4-ylarnino 4Furpey 3-Tetrahydro 1-Methanesulfonyl-4-net 57. 4-Fluorophenyl __furyl, hylpiperidin-4-ylamino 58 3-Te trahydro trans-4-Aihino-4-methylc 4Furpey 58 erhdo tas--ehxccoe 4-Fluorophenyl __furyl yclxlamino 3-Tetrahylro trans-4-Hydroxycyclohex 4 -Fluorophenyl furyl ylamino 3-Tetrahydro trans-4-Hydroxy-4-moeh -lorpey furyl lcyclohexylainino trans-4- (N-methanesulfo 62 3Terhdonyl-N-methylamino) cyclo 4-Fluorophenyl furyl hexylamino 63 3-Tetrahylro cis-4-Hydroxycyclohexyl 4Furpey __furyl methylamino________ 64 3-Tetrahydro cis-4-Hydroxy-4-methylc 4-Fluorophenyl __furyl lyclohexylmethylamino 134 Table 68 N R NA N~ No. 2 1 Ring A 3-Tetrahydrofu (lS)-l1,2-Dimethyl-2-h 4Furpey ryl: ydroxypropylamino 3-Tetrahydrofu 2, 2-Dimethyl -3-hydrox 4Furpey 66 rylypropyiamino 1.-Acetylpiperidin-4-y 4 urpey 67 1-Methyipropylopeny 68 ~~~1-Methanesulfonylpipe 4Furpey 1-Mthyproylridin-4-ylamino 69 1-ethyprop l1-Ethanesulfonylpiper idin-4 -ylarnino 4Furpey 1-Isopropylsulfonylpi 4-lurhny 1Metyiprpylperidin-4-ylamino 71 1-Methyipropyl 1Aey--ehpie 4-Fluorophenyl -ylaxnino 1-Methane suit onyl-4 -m, 72 1-M ethyipropyl ethylpiperidin-4-ylam 4-Fluorophenyl trans-4-Axnino-4-methy 4Furpey 1-Mehyirop licyclohexylamino trans-4-Methoxycycloh 4Furpey 1Mhyipoy exylamino trans-4-Hydroxycycloh 4Furpey 1-Mthyproylexylamino 76 1Metylprpyltrans-4 -Hydroxy-4-met 4Furpey 76 1-ethypropl hylcyclohexylamino -Fuoophny 135 Table 69 N-R 1 NN_ No. R 1 Ring A trans-4- (N-methanesul 77 .1-MethyipropyL. flonyl-N-methylanino) c 4-Fluorophenyl _____________yclohexylamino 78 1 1-Methyipropyl is4Hdo cylhx 4-Fluorophenyl ylmethyl-amino cis-4 -Hydiroxy-47-methy 791 1-Methyipropyl Icyclohexylmethylamin 4-F'luoropheny. 0 1.:-Methyipropyl ()-12Diehl -h 4-Fluorophenyl .ydroxypropylamino________ 81, 1.-Methyipropyl 2, 2-Dimethyl-3-hydrox 4-Fluorophenyl I lypropylamino________ According to the production methods described in the above .Exampies and the present specification and methods conventionally employed in the field of organic synthetic chemistry., compounds, which is respectively combined with each of the substitutents shown in Tables 70 to 77, can be produced. 136 Table R-R N x-Z R methyl, ethyl, isopropy1, O 'OH Ra R bab .CNRb R 3 RRb, NJ OH CONR R CO ab -CJO -(7JNCOMe -(7JNS 2 Me Z =CH, N rJ>HHN "'YOH HNI ,Y,,NMe 2 HIN! HN OH, H 'OH HNT-XOH IIO HN NR H I Raa RBR 0 II I I b H H'RHNN NR b R HNN NSOR R 0 0 Ra Ra R 00 Ra, Rb each independently, hydrogen, CI-COa alkyl 137 Table 71 Fla 0 N -Z R R= methyl., ethyl, isopropyl, OH O H Ra Rb aRb x R OH CONRaR b I ,,CONRR CO NCOMe -NSO 2 Me Z CH, N 2 R=HN aHN HN~ HN NRa 'NO0'0N NO-- 0 I aI 0Ra Ra R HNHN N H I oN~ HN o RW 'a la Ra Ra H -OS0RHN H NS0R N 2 a, N -OH N0QH Hr 0 Ra 0 HxNNaHN N0 RaN- R b d Nb 2 Nr HN N R Rc R R~ NRb RcR d Ra, R b, Rc, Rd each independently, hydrogen, Cl-C 3 alkyl 138 Table 72 N-R N I-Z R R 1 methy1, ethy1, isopropyl, H RH ROH CONRRb ,CONRaRb -C NCOMe -CNSO 2 Me Z CH, N R2 N HN HNJ a HN ,OH R H OH O HNklN HN NH 2 HN NH 2 NH 2 HHN <R Ra-0 b <Ra b NRcSO2R bNRcCO 2 R HN NRCSO 2 Rb HN cN CO2Rb I I aR H OHN OH HN HN HO Ra, Rb Rc Rd each independently, hydrogen, Ci-C3 alkyl 139 Table 73 F R N Z R R1= methyl, ethy1, isopropyl, O R CONRaRb CONRa Rb O QNCOMe NSO 2 M Z OH, N HN OH HN HN HO0 OHH HOH HN H 'a~CONR aR b HN H NRaS02R ,CNR C02R HN 0 H NR aS02Rb a N -,N'Ra HN a b HN NRaSO 2 Rb HN NRaCO 2 Rb HN NRaSO2Rb HN NRaCO 2 Rb R a, Rb Rc each independently, hydrogen, Ci-C3 alkyl 140 Table 74 F NO N- N Z R R methyl, ethyl, isopropyl, RH Rb CO b ,^.CONRaRb R R OH KCO -JNCOMe -CNSO 2 Me Z CH, N R= HN OHHN OH HN OH HN OH ,HN OH HN OH HN OH HN OH HN HN EOH OOR HN OH' H OH HOH HOH HN HN NHS2 HN NHSO 2 Ra, O Ra, Rb each independently, hydrogen, Ci-C alkyl 141 Table N-R N Z R 2 R methy1, ethyl, isopropyl, a b R aCNR ab ~NKOH H CONRaRb CONR R Ra, Rb0H CO -JNCOMe NSO 2 Me Z CH,- N 2 I Ra Rb R~ R HN HN OH H N R H OH' 1' A a b RR OH Ia H HN OH HN N RaRb R Rb N Ra Rb b Ht& CONR aR N CORb NR HNcT rNRa Rb N rCNaRb 0 o HN N CF3 ,HNN SO2C3 N-SO 2 NRaRb HN HNH HN 'NCF3 I HN rN-SO2CF HN N-ONab b=h n nt do 3 NfaS0 2 NRaRb Ra, Rb each independently, hydrogen, CI-C3 alkyl 142 Table 76 N-R N Z 2 R R methyl, ethyl, isopropyl, H ROH R R b ,,,_,CONRaRb Ra Rb, RH -CO -JNCOMe -JNSO 2 Me Z CH, N R2H HN 00 a R HN NRaRb HN NRRb RC R a Rc RC RQ Rc Ra 0 HN N NRR H N ,CF 3 HN 3 00 00. Ra HN CONRaRb HN CONRaRb HN CONRaRb Hr~4 0 0 0 HNN -'YO HN Na R aNdb HC NH NNRa .d HN NR RC Rd Ra, Rb Rc d each independently, hydrogen, C-C 3 alkyl 143, T7able 77 N-R' N- -Z R 1 =methyl, ethyl, isopropyl, O ~OH, R Rb b amb Ra~ ~O a R ~-,CONR R -CO jNCOMe -CNS 2 Me Z. C H, N HN,'N R bRC a H I JyfIIN-R Rt)Rc 0 H -CN-SO 2 Ra HI! XCN-CORa R bRc Rb Rc HN N-S0 2 R a HN N-CORa Rb Rc 0 HNCS: Hl K. NRa H N N-S0 2 Ra R bRC HN N.,P CORa Rb R HN 1 RbRC3 Ra, Rb, Rc, Rd each independently, hydrogen, Cl-C3 alkyl 144 Reference example 1 N CN C In 440 ml of THF was suspended 22 g of 2-chloroisonicotinic acid, and under nitrogen flow, the mixture was cooled to or lower., 245 ml of methyl lithium (1.14 M solution in diethyl ether) was added dropwise to the mixture. After stirring at the same temperature for an hour, a temperature of the mixture was raised to 0 C over an hour, and stirred at the same temperature for further an hour. To the reaction mixture was added:500, ml of water, and the reaction mixture was extracted with ethyl acetate, washed.with brine and dried over magnesium sulfate. Activated charcoal was added to the mixture, and after filtration, the filtrate was concentrated under reduced pressure to give 19.5 g of 4-acetyl-2-chloropyridine as colorless crystals. Melting point: 36 0 C. In 550 ml of ethanol were suspended 55.1 g of the compound obtained in 49.2 g of hydroxylamine hydrochloride and 58.1 g of sodium acetate, and the mixture was refluxed under heating for an hour. After cooling the mixture to room temperature by allowing to stand, ethanol was distilled away under reduced pressure and precipitated crystals were collected by filtration and washed with water. The crystals were. air-dried at 60 0 C overnight to give 55 g of 1-(2-chloropyridin-4-yl)ethanone oxime as colorless crystals. Melting point: 143 0 C. In methylene chloride were suspended 105 g of the compound obtained in and 123 g of tosyl chloride, and under ice-cooling, 94 ml of triethylamine was added dropwise to the mixture, and the mixture was raised to room temperature and stirred for 4 hours. To the reaction mixture was added 500 ml of water, and the mixture was extracted with methylene chloride, washed with brine and dried over magnesium sulfate. After 145 filtration, the mixture was concentrated under reduced pressure, and the resulting crystals were collected by filtration and washed with isopropyl ether to give 192 g of 1-(2-chloropyridin-4-yl)ethanone oxime tosylate as colorless crystals.. Melting point: 153 0 C. Under nitrogen flow, 3.11 g of sodium metal was added to 220 ml of anhydrous ethanol at room temperature, and the mixture was dissolved under stirring. The solution was ice-cooled, and g of the compound obtained in was added thereto, then the mixture was stirred at room temperature for an hour. To the mixture was added 220 ml of anhydrous ether, and insoluble matters were removed. To the filtrate was added 62 ml of 4N hydrochloric acid/dioxane solution under ice-cooling and the mixture was stirred for 15 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and the solution was made alkaline by addition of potassium carbonate. This mixture was extracted with ethyl acetate several times, and the combined extracts were washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, 100 ml of hexane was added to the residue and red insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure, hexane was again added to the concentrate and insoluble matters were removed by filtration through Celite. The filtrate was concentrated under reduced pressure and dried by a vacuum pump to give 26.9 g of 2-(2-chloropyridin-4-yl)- 2,2-diethoxyethylamine as reddish oily product. A solution, in which 20 g of the compound obtained in (4) was dissolved in 50 ml of THF, was water-cooled, and 11.2 g of 4-fluorophenylisocyanate was added dropwise thereto. After dropwise addition, the reaction mixture was concentrated under reduced pressure, and 30 ml of conc. hydrochloric acid was added to the obtained residue and the mixture was stirred at room temperature overnight. The reaction mixture was added to ice-cooled 180 ml of 2N aqueous NaOH solution to neutralize the mixture, and after collecting the precipitated crystals by 146 filtration, the crystals were washed with water and ether. The crystals were air-dried at. 60 0 C to give 22.3 g of 5-(2chloropyridin-4-yl)-l-(4-fluorophenyl)-4-imidazolin-2-one as colorless crystals. Melting point: 2700C. In 50 ml of DMF was suspended 10 g of the compound obtained in and under ice-cooling, 1.46 g of 63% sodium hydride was added to the suspension, then the mixture was stirred at room temperature for 30 minutes. The mixture was again ice-cooled, and after adding 7.44 g of 2-cyanobenzyl bromide, the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 250 ml of ice-cold water, extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 11.4 g of 4-(2chloropyridin-4-yl)-3-(4-fluorophenyl)-1-(2-cyanobenzyl)- 4-imidazolin-2-one as colorless crystals. Melting point: 1090C. Reference example 2 EtO: OEt NH 2 N r By using 4-acetylpyridine (commercially available product) as a starting material, the same treatments as in Reference examples 1(2) to were carried out to give 2,2-diethoxy- 2-pyridin-4-yl ethylamine as brownish oily product. Reference example 3 O N.N H 3 CS A mixture of 100 g of 3,3-dimethoxy-2-butanone and 99.2 g of N,N-dimethylformamide dimethylacetal was stirred at 1000°C for 42 hours. After cooling the reaction mixture, the mixture was concentrated under reduced pressure to give 141 g of 1-dimethylamino-4,4-dimethoxy-l-penten-3-one. 147 In 800 ml of methanol was dissolved 141 g of the compound obtained in and after adding 114 g of thiourea and 292 g of 28% sodium methoxide-methanol, the mixture was stirred at 700°C for 3 hours. The mixture was ice-cooled, and after adding 215 g of methyl iodide drowise, the mixture was stirred at room temperature for an hour. After concentration of the reaction mixture, water was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated to give 142 g of 4-(1,l1-dimethoxyethyl)-2-methylsulfanylpyrimidine. In 5,70 ml of acetone was dissolved 142 g of the compound obtained in and under ice-cooling, 114 ml of 6M hydrochloric acid was added to the solution and the mixture was stirred at room temperature for 3 hours. After adding 450 ml of water:to the mixture, the solvent was removed and the residue was extracted with ethyl acetate. The organic layer was washed, dried and concentrated to give 107 g of 1-(2-methylsulfanylpyrimidin-4-yl)ethanone. Reference example 4 O N ,,N H 3 cS A mixture comprising 16.4 g of 4-chloro-2-methylsulfanylpyrimidine, 38 g of tributyl(l-ethoxyvinyl) tin, 1.43 g of bis(triphenylphosphine)palladium (II) dichloride and 100 ml of DMF was stirred at 800°C for 3 hours. After cooling the reaction mixture, 300 ml of ethyl acetate and 17.8 gof potassium fluoride were added to the mixture, and the resulting mixture was stirred at room temperature overnight. After filtration with Celite, the filtrate was washed, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethylacetate=20:1) to give 18.9 g of 4-(1-ethoxyvinyl)-2-methylsulfanylpyrimidine. In 200 ml of acetone was dissolved 18.9 g of the compound obtained in 60 ml of 4M hydrochloric acid was added to the 148 solution; and the mixture was stirred at room temperature for an hour. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed, dried and concentrated to give 15.9 g- of l-(2-methylsulfanylpyrimidin-4-yl)ethanone. Reference example F N NH N N -S H 3 C In 180 ml of methanol was dissolved 17.6 g of the compound obtained in Reference example 3(3) or Reference example 4(2), 14.5 g of hydroxylamine hydrochloride and 17.2 g of sodium acetate were added to the solution, and the mixture was refluxed under heating for 30 minutes. After cooling the reaction mixture, the solvent was removed, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated. To the residue was added hexane and the precipitated crystals were collected by filtration to give 18.3 g of 1-(2-methylsulfanylpyrimidin- 4-yl)ethanone oxime. Melting point: 150-152oC. In 1200 ml of methylene chloride was suspended 89 g of the compound obtained in and 81.2 ml of triethylamine and 102 g oftosyl chloride were added to the suspension, and the mixture was stirred at room temperature overnight. The reaction mixture was washed, dried and concentrated. To the residue was added diethyl ether and the precipitated crystals were collected by filtration to give 159 g of 1-(2-methylsulfanylpyrimidin-4- yl)ethanoneoxime tosylate. Melting point: 141-1420C. To 30 ml of methanol solution containing 12.9 g of 28% sodium methoxide-methanol was added dropwise 120 ml of a THF solution containing 15 g of the compound obtained in under ice-cooling, and the mixture was stirred at room temperature overnight. To the mixture was added 100 ml of 4M hydrochloric 149 acid-dioxane solution under ice-cooling, and after stirring at room temperature for 4 hours, the reaction mixture was concentrated. The residue was added to an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol= 15:1) to give 8.14 -g of 2,2-dimethoxy-2-(2-methylsulfanylpyrimidin-4-yl):ethylamine. To 120 ml of a THF solution containing 8 g of the compound obtained in was added dropwise under ice-cooling 30 ml of a THE solution containing 4.78 g of 4-fluorophenyl isocyanate, and the mixture was stirred at room temperature for 30 minutes. After 120 ml of conc. hydrochloric acid was added to the mixture under ice-cooling, the resulting mixture was stirred at room temperature overnight. Precipitated crystals were collected by filtration, washed with water and ether, and dried to give 7.35 g of 1-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin- 4-yl)-4-imidazolin-2-one. Melting point: 260-261°C. Reference example 6 F N- N N-N H 3 C'S To 40 ml of a DMF solution containing 2.6 g of the compound obtained in Reference example 5(4) was added 327 mg of sodium hydride at room temperature, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 1.77 g of 2-cyanobenzyl bromide, and after stirring at room temperature for 30 minutes, 33 mg of sodium hydride and 85 mg of 2-cyanobenzyl bromide were added to the mixture, and the resulting mixture was stirred at room temperature for an hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated, and crystallized from diethyl ether to 150 give 3.28 g of l-( 2 -cyanobenzyl)-3-(4-fluorophenyl)- 4-(2-methylsulfanylpyrimidin-4-yl)-4-imidazolin-2-one. Melting point: 141-142 0 C. To:a chloroform solution containing 3.27 g of the compound obtained in was added 2.03 g of 3-chloroperoxybenzoic acid at room temperature, and the mixture was stirred at room temperaturefor an hour. To the reaction mixture was added 1.16 g of calcium hydroxide and the mixture was stirred at room temperature for 2 hours, and then, filtered through Celite, and the filtrate was concentrated. The residue was crystallized from ethyl acetate to give 2.39 g of 1-(2-cyanobenzyl)-3- (4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4imidazolin-2-one. Melting point: 133-1360C. Reference example 7 N CN N-N H 3 C 0 To 150 ml of a methanol solution containing 1.47 g of the compound obtained in Reference example 5(4) was added dropwise ml of an aqueous solution containing 1.79 g of Oxone® at room temperature. After 30 minutes and 2 hours, 2 ml of an aqueous solution containing 299 mg of Oxone® was added dropwise, and the mixture was stirred at room temperature for 2 hours. After removing insoluble matters by filtration, the filtrate was concentrated, an aqueous sodium bicarbonate solution was added to the concentrate and the mixture was extracted with chloroform. The organic layer was washed, dried and concentrated, and the precipitated crystals were collected by a mixed solvent of ethyl acetate-ether to give 1.03 g of 1-(4-fluorophenyl)-5-(2-methylsulfinylpyrimidin-4-yl)-4imidazolin-2-one. Melting point: 208-211°C (decomposed). The compound (930 mg) obtained in was treated in the same manner as in the above-mentioned Reference example 6(1) to give 541 mg of l-(2-cyanobenzyl)-3-(4-fluorophenyl)- 4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one. Reference example 8 EtO OEt EtO OEtH NNH 2 NN CI Cl In 10 ml of methanol was dissolved 1.0 g of the compound obtained in Reference example 0.51 g of 2-fluorobenzaldehyde was added to the solution, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 155 mg of sodium borohydride, and the resulting mixture was further stirred at room temperature for an hour. After concentration under reduced pressure, water was added to the reside and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethylacetate=2:1) to give 1.45 g the title compound as an oily product. Reference example 9 SO F EtO OEt EtO OEt H 0 I N N- NBoc N N NBoc cI C 1 N (2) CI The compound (5 g) obtained in Reference example 1(4) and a corresopnding starting material were treated in the same manner as in Reference example 8 to give 8. 47 g of Compound Compound (3 g) was treated in the same manner as in Example 1 to carry out cyclization, subsequently the resulting compound was dissolved in 20 ml of THF, 1.1 g of Boc20 was added thereto. The resulting mixture was stirred at room temperature for minutes, concentrated under reduced pressure and diisopropyl ether was added to the residue, and the residue was collected by filtration to give 2.53 g of Compound Reference example 152 EtO OEt EtO. OEtH NH 2 i N "N Cl CI A mixture comprising 3. 8 g of the compound. obtained in Reference example 1 1.7 ml of ethyl iodide and 3.0 ml of triethylamine was stirred at 50 0 C overnight. After neutralizing with 2N aqueous NaOH solution, the reaction mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The resulting mixture was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:l) to give 1.9 g of the title compound as an oily product. Reference example 11 EtO OEt EtO OEt t O N H 2 N H 2 Cl HN In 75 ml of toluene were suspended 5. 0 g of the compound obtained in Reference example 35 ml of isopropylamine, 458 mg of palladium acetate, 1.28 g of 2,2'-bis(diphenylphosphino)- 1,1'-binaphthyl and 3.0 g of sodium t-butoxide, and under nitrogen flow, the mixture was stirred under heating at 70 0 °C for 8 hours. After concentration under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol= 10:1) to give 4.3 g of the title compound as an oily product. Reference example 12 EtO OEt EtO OEt H EtO OEt S NH 2 N COOCfOOtBuN COOBu Cl Cl HN (2) CI CI HN, (2) 153 A mixture comprising 2. 0 g of the compound obtained in Reference example 0.82 mlof t-butyl acrylate and 10 ml of THF was stirred under reflux for 4 days. The reaction mixture was concentrated under reduced pressure to give 3.1 g of Compound as an oily product. Then, Compound and a corresponding starting material were treated in the same manner as in Example 4 :to give 2.12 g of Compound as an oily product. Reference example 13 EtO OEt EtO OEt H OMe NH 2 t N H N N OMe CI Cl The compound (5.0 g) obtained in Reference example 1(4) was reacted with 2,4-dimethoxybenzaldehyde in the same manner as in Reference example 8 to give 6.4 g of the title compound. Reference example 14 EtO OEtH EtO OEtH N /N OMe CI HN OMe The compound (1.39 g) of Reference example 10 was reacted with 2,4-dimethoxybenzylamine in the same manner as in Reference example 11 to give 1.58 g of the title compound. Reference example EtO OEt EtO OEt H EtO OEt H NH 2 N N NV N N OMe CI Cl HN OMe The compound (10.0 g) of Reference example 1(4) was reacted with a corresponding starting material in the same manner as in Reference example 8, and then, reacted with 2,4-dimethoxybenzylamine in the same manner as in Reference example.11 to give 9.75 g of the title compound. Reference example 16 154 MeO OMe MeO OMeH NH 2 N NfN N fN SMe SMe The compound (26.8 g) of Reference example 5(3) and a corresponding starting material were treated in the same manner as in Reference example 8 to give 30.8 g of the title compound. Reference example 17 MeO OMe MeO OME MeO OMe Cbz NH 2 N Cb. N_ NN N-N N SMe SMe S02Me SO 2 Me( 2 MeO OMEH OMe N H2N 'O N N HN AOMe (3) In 30 ml of methylene chloride was dissolved 3.0 g of the compound of Reference example 3.65 ml of triethylamine was added to the solution, and under ice-cooling, 3.35 g of benzyloxycarbonyl chloride was added dropwise to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 2.23 g of Compound as colorless crystals. MS 364 In 17 ml of DMF was dissolved 4.2 g of Compound and under ice-cooling, 528 mg of sodium hydride was added to the solution, and the mixture was stirred at room temperature for an hour. The mixture was again ice-cooled, 1.39 ml of ethyl iodide was added thereto, and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the 155 reaction mixture and the mixture was extracted with ethyl acetate, the extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in 50 ml of chloroform, 6..26 g of 3-chloroperoxybenzoic acid was added to the mixture at room temperature, and the resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 2. 58 g of calcium hydroxide and after stirring the mixture, the insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to give 4.55 g of Compound as a colorless oily product. MS 423 In 30 ml of dioxane was dissolved 2.19 g of Compound 1.65 g of trans-4-(Methoxymethoxy)cyclohexylamine and 1.08 ml of 1,l'-diisopropylethylamine were added to the solution, and the mixture was stirred at 100°C for 14 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give g of a brownish oily product. This product was dissolved in 40 ml of methanol, 1 g of 10% palladium-carbon was added thereto, and the mixture was subjected to catalytic reduction under hydrogen pressure (2.7 atm) for 2 hours. Palladium was removed by filtration, and after concentration under reduced pressure, the residue was purified by NH silica gel column chromatography to give 1.04 g of Compound as a brownish oily product. MS 369 Experimental Example 1 (pharmacological test) Inhibition of lipopolysaccharide (LPS)-stimulated TNF- a production in mice in vivo Tests were carried out to measure an inhibitory effects of the compounds of the present invention on LPS-stimulated 156 TNF-a production in mice,. To, Balb/cAnNCrj mice (6-8 weeks old, female, available from Japan Charlesriver, Co.) were administered test compounds mg/kg, dissolved in 0.5% methyl cellulose and 0.2% PEG-60 hydrogenated caster oil (HCO60, available from Nikko Chemicals, After 30 minutes, LPS coli 0111:B4, available from Difco, with a final concentration of 1 mg/kg adjusted by phosphate buffered saline) was administered (0.4 ml/head, 90 minutes later, blood was collected from abdominal vein of the mouse under diethyl ether anesthesia. The collected blood was subjected to centrifugation with 3000g to collect serum. TNF-a in the sera was measured by DuoSet mouse TNF-a ELISA kit (trade name, available from genzymeTECHNE). As a result, the compounds of the present invention significantly reduced the production of TNF-a as shown in Table78. Table 78 Examples TNF-a inhibition rate 182 64% 202 57% 239 69% 296 52% 300 57% Industrial Applicability According to the present invention, a novel 4-imidazolin-2-one compound having excellent p38MAP kinase inhibitory activity, which is useful as a medicine, can be provided.
权利要求:
Claims (16) [1] 1. A compound of the formula G 0N S N-(CH2)n-R 1 3Z 2I Q N Z G 2 wherein G 1 is an alkyl which is substituted by a halogen atom or an alkoxy, or a group of the formula: wherein ring B is benzene ring, naphthalene ring, a monocyclic or bicyclic aromatic heterocycle or a cycloalkane, and the benzene ring, the naphthalene ring, the monocyclic or bicyclic aromatic heterocycle and the cycloalkane may be substituted by 1 to 3 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbamoyl, hydroxy and cyano, W is a single bond, or a ci c 4 alkylene which may be substituted by 1 or 2 alkyl(s), QI and Q 2 may be the same or different, and each is hydrogen atom, a halogen atom or an alkyl, n is 0, 1, 2, 3 or 4, R 1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, 158 Z 1 Z 2 Z 3 and Z 4 may be the same or different, and each is CH or N, provided that 3 or more of Z 1 Z 2 Z 3 and Z 4 should not be N at the same time, G 2 is hydrogen atom, -NR R -OR 5 -SR 5 -COR 6 -CHR R 8 or a heterocyclic group, where R 3 to R8 each independently is hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, hydroxy, an alkoxy, an optionally substituted amino, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an alkoxyoxalyl, an alkylsulfonyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl, a carbonyl substituted by an optionally substituted phenyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. [2] 2. A compound of the formula [Ia]: N-4 N-(CH 2 )n-R a] N -Z 01 R 2 wherein ring A is benzene ring or a monocyclic aromatic heterocycle, and the benzene ring and the monocyclic aromatic heterocycle may be substituted by 1 to 3 substituent(s), which is (are) the same or different, and selected from the group consisting of a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an 159 optionally substituted carbamoyl, hydroxy and cyano, Q 1 is hydrogen atom, a halogen atom or an alkyl, W is a single bond, or a. c c 4 alkylene which may be substituted by 1 or 2 alkyl(s), n is 0, 1, 2, 3 or 4, R 1 is hydrogen atom, an optionally substituted alkyl, an optionally-substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, Z is CH or N, R 2 is hydrogen atom, -NR R 4 -OR 5 -COR 6 or -CHR R 8 where R 3 to R 8 each independently is hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkynyl, hydroxy, an alkoxy, an optionally substituted amino, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an alkoxyoxalyl, an alkylsulfonyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl, a carbonyl substituted by an optionally substituted phenyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. [3] 3. The compound according to Claim 2, wherein Q 1 is hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound according to Claim 2, wherein the ring A is a benzene ring which may be substituted by 1 to 3 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino and cyano, and W is a single bond, or a .pharmaceutically acceptable salt thereof. 160 The compound according to Claim 2, wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof [4] 6. The compound according, to Claim 2, wherein n is 0 and R 1 is an optionally substituted alkyl, n is 1 and R 1 is an optionally substituted cycloalkyl, n is 1 and R 1 is an optionally substitutedphenyl, n is 1 and R 1 is an optionally substituted heterocyclic group, n is 0 and R 1 is an optionally substituted cycloalkyl, and n is 0 and R 1 is an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. [5] 7. The compound according to Claim 2, wherein R 2 is -NR 3 R 4 or -OR 5 or a pharmaceutically acceptable salt thereof. [6] 8. The compound according to Claim 2, wherein R 2 is -NHR 4 and R 4 is an optionally substituted alkyl, an alkenyl, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl or a carbonyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. [7] 9. The compound according to Claim 3, wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino and cyano, W is a single bond, n is 0 or 1, R 1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted 161 phenyl or an optionally substituted heterocyclic group, Z is CH or N, R 2 is hydrogen atom, -NR3 R, OR -COR 6 or -CHR R 8 Where R 3 to R 8 each independently is hydrogen atom, an optionally substituted alkyl, an alkenyl, an alkoxy, an optionally substituted alkanoyl, an optionally substituted carbamoyl, an alkoxyoxalyl, an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted heterocyclic group, a carbonyl substituted by an optionally substituted cycloalkyl or a carbpnyl substituted by an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof. [8] 10. The compound according to Claim 3, wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent which is (are) the same or different, and selected from the group consisting of a halogen atom, an alkyl optionally substituted by halogen(s), an alkoxy, an amino optionally substituted by alkyl(s) and cyano, W is a single bond, n is 0 or 1, R 1 is hydrogen atom, an alkyl optionally substituted by group(s) selected from the group consisting of phenyl, an alkoxy, an alkylamino, a dialkylamino, an alkanoylamino, an alkylsulfonylamino, a carbamoyl optionally substituted by alkyl(s), hydroxy, carboxy and cyano, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following to hydroxy, (ii) an alkoxy optionally substituted by alkoxy(s), (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl, 162 a carbamoyl optionally substituted by alkyl(s), and an alkyl:optionally substituted by group selected from the group consisting of hydroxy, an alkoxy and amino, a phenyl optionally substituted by group(s) selected from the group consisting of the following to (vi): a halogen atom, (ii) an alkyl optionally substituted by group(s) selected from the group consisting of a halogen atom, hydroxy and phenylsulfonyl, (iii) cyano, (iv) an alkoxy, an amino optionally substituted by group(s) selected from the group consisting of an alkyl and an alkylsulfonyl, (vi) a carbonyl substituted by a heterocyclic group, or a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (iv): an alkoxycarbonyl, (ii) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy and a carbamoyl optionally substituted by alkyl(s), (iii) an alkanoyl and (iv) an alkylsulfonyl, Z is CH or N, R 2 is hydrogen atom, -NR R -OR 5 -COR 6 or -CHR R, where R 3 to R 8 each independently is: hydrogen atom, an alkyl optionally substituted by group(s) selected from the group consisting of the following to (vii): hydroxy, (ii) an alkoxy, (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an 163 alkanoyl and an alkylsulfonyl, (iv) an alkoxycarbonyl, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to g): a) hydroxy, b) an amino optionally substituted by alkyl(s), c) an alkanoylamino, d) an alkylsulfonylamino, e) an alkyl optioinally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy, amino, a carbamoyl optionally substituted by alkyl(s), f) carboxy and g) a carbamoyl optionally substituted by alkyl (vi) a phenyl optionally substituted by group(s) selected from the group consisting of a halogen atom, an alkoxy and morpholinylcarbonyl, and (vii) a heterocyclic group optionally substituted by alkyl(s), an alkenyl, an alkoxy, an alkanoyl optionally substituted by group(s) selected from the group consisting of the following (i) to (iv): hydroxy, (ii) an alkoxy, (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl and an alkanoyl, (iv) an alkoxycarbonyl, a carbamoyl optionally substituted by alkyl(s), an alkoxyoxalyl, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vii): 164 a halogen atom, (ii) hydroxy, (iii) an alkoxy, (iv) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl, an alkyl optionally substituted by group selected from the group consisting of hydroxy, an alkoxy, amino, a carbamoyl optionally substituted by alkyl(s), (vi) an alkanoyloxy and (yii) a carbamoyl optionally substituted by alkyl(s), a phenyl optionally substituted by group(s) selected from the group consisting of a halogen atom and an alkoxy, (1 O a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (vii): an alkyl optionally substituted by group(s) selected from the group consisting of phenyl, hydroxy, an alkoxy, amino and a carbamoyl optionally substituted by alkyl(s), (ii) an alkoxycarbonyl, (iii) an alkanoyl, (iv) an alkylsulfonyl, oxo, (vi) a carbamoyl optionally substituted by alkyl(s), (vii) an aminosulfonyl optionally substituted by alkyl(s), (11) a carbonyl substituted by a cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and an alkanoylamino, or (12) a heterocyclic group-substituted carbonyl, or a pharmaceutically acceptable salt thereof. [9] 11. The compound according to Claim 3, wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent which is (are) the same or different, and selected from the group 165 consisting of fluorine atom, chlorine atom, an alkyl optionally substituted by halogen(s) and an alkoxy, W is a single bond, n is 0 or 1, R 1 is hydrogen atom, an alkyl optionally substituted by group(s) selected from the group consisting of phenyl, an alkoxy, an alkylamino, a dialkylamino, an alkanoylamino, an alkylsulfonylamino, a carbamoyl optionally substituted by alkyl(s), hydroxy, carboxy, cyano, and cycloalkyl, a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to hydroxy, (ii) an alkoxy optionally substituted by alkoxy(s), (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl, (iv) a carbamoyl optionally substituted by alkyl(s), an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy and amino, a phenyl optionally substituted by group(s) selected from the group consisting of the following to (iv): a halogen atom, (ii) an alkyl optionally substituted by halogen atom(s), (iii) cyano, and (iv) an alkoxy, or a heterocyclic group optionally substituted by alkylsulfonyl or alkanoyl, Z is CH or N, R 2 is hydrogen atom, -NR 3 R 4 -OR 5 or -COR 6 Where R 3 to R 6 each independently is: hydrogen atom, an alkyl optionally substituted by group(s) selected from the group consisting of the following to (vii): 166 hydroxy, (ii) an alkoxy, (iii) an.alkoxycarbonyl, (iv) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e): a) hydroxy, b) an amino optionally substituted by alkyl(s), c) an alkanoylamino, d) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by alkyl(s), and e) a carbamoyl optionally substituted by alkyl(s), a phenyl optionally substituted by alkoxy(s), (vi) a heterocyclic group, and (vii) an amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s), an alkenyl, an alkoxy, an alkanoyl optionally substituted by group(s) selected from the group consisting of an alkoxy, an amino optionally substituted by alkanoyl(s), and an alkoxycarbonyl, a cycloalkyl optionally substituted by group(s) selected from the:group consisting of the following (i) to hydroxy, (ii) an alkoxy, (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl, (iv) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by alkyl(s), a carbamoyl optionally substituted by alkyl(s), 167 a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (vi): an alkyl optionally substituted by phenyl(s), (ii) an alkoxycarbonyl, (iii) an alkylsulfonyl (iv) an alkanoyl, a carbamoyl optionally substituted by alkyl and (vi) an aminosulfonyl optionally substituted by alkyl(s), a carbonyl substituted by a cycloalkyl optionally substituted by group selected from the group consisting of hydroxy and amino, or a heterocyclic group-substituted carbonyl, or a pharmaceutically acceptable salt thereof. [10] 12. A compound of the formula [Ib]: S(R 11 N-R 1 2 N r5 N Z HN R13 wherein R 11 is a group selected from the group consisting of hydrogen atom, a halogen atom, a ci c 4 alkyl optionally substituted by halogen(s) and a ci- c 4 alkoxy, k is 1 or 2, and when k is 2, two of R"s may be the same or different, R is a ci-c5 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy, cyano, amino, tetrahydropyranyl, tetrahydrofuryl and a carbamoyl optionally substituted by alkyl(s), a c 3 c 4 cycloalkylmethyl, a c 3 c 4 cycloalkyl, 168 carbamoylmethyl, a benzyl optinally substituted by group(s) selected from the group consisting of cyano, a halogen atom, a ci c 3 alkoxy, a ci c 3 alkyl and a halogen-substituted ci- c 3 alkyl, tetrahydropyranyl, tetrahydrofuryl, and a piperidyl optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl, an alkoxycarbonyl and a carbamoylalkyl optionally substituted by alkyl(s), Z 5 is CH or N, R 13 is a ci 66 alkyl optionally substituted by group (s) selected from the group consisting of the following to (xiv): a c 5 c 7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e): a) hydroxy b) an amino optionally substituted by ci- c 4 alkyl(s), c) a ci c 4 alkanoylamino, d) a ci c 4 alkyl optionally substituted by group (s) selected from the group consisting of hydroxy, amino, and a carbamoyl optionally substituted by ci c 4 alkyl(s), and e) a carbamoyl optionally substituted by ci- c4 alkyl(s), (ii) hydroxy, (iii) a carbamoyl optionally substituted by ci c4 alkyl(s), (iv) a piperidyl optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl and oxo, a pyrrolidinyl optionally substituted by group(s) selected from the group consisting of 169 an alkyl, an alkanoyl, an alkylsulfonyl and oxo, (vi) a tetrahydropyranyl optionally substituted by hydroxy(s), (vii) an imidazolinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo, (viii) an imidazolidinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo, (ix) a piperadinyl optionally substituted by group selected from the group consisting of an alkyl and oxo, a hexahydropyrimidinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo, (xi) a pyridyl optionally substituted by alkyl(s), (xii) furyl, (xiii) tetrahydroisothiazolyl optionally substituted by oxo(s), and (xiv) an amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s), a c 5 c7 cycloalkyl optionally substituted by group (s) selected from the group consisting of the following to hydroxy, (ii) a ci c 4 alkoxy, (iii) a c 1 c 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by ci c 4 alkyl(s), (iv) a carbamoyl optionally substituted by ci- c4 alkyl(s), and an amino optionally substituted by group(s) selected from the group consisting of ci- c4 170 alkyl(s) and ci- c 4 alkylsulfonyl(s), or a heterocyclic group optionally substituted by ,group(s) selected from the group consisting of the following to (vii): an alkyl optionally substituted by group(s) selected from the group consisting of a halogen, amino, hydroxy, phenyl and oxo, (ii) an aminosulfonyl optionally substituted by alkyl(s), (iii) an alkylsulfonyl optionally substituted by halogen(s), (iv) a carbamoyl optionally substituted by alkyl hydroxy, (vi) an alkoxycarbonyl, and (vii) oxo, or a pharmaceutically acceptable salt thereof. [11] 13. The compound according to Claim 12,wherein R 12 is a ci- c 5 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, alkoxy, tetrahydropyranyl and tetrahydrofuryl, a c 3 c 4 cycloalkylmethyl, a c 3 C 4 cycloalkyl, carbamoylmethyl, a benzyl optinally substituted by group(s) selected from the group consisting of cyano, a halogen atom, a c 1 c 3 alkoxy, a c 1 c 3 alkyl and a halogen-substituted ci- c 3 alkyl, tetrahydropyranyl, tetrahydrofuryl, or a piperidyl optionally .substituted by alkylsulfonyl or alkanoyl, R 13 is a ci c 6 alkyl optionally substituted by group(s) selected from the group consisting of the following to (iv): a cs c 7 cycloalkyl optionally substituted by 171 group(s) selected from the group consisting of the following a) to e): a) hydroxy b) an amino optionally substituted by ci- c 4 alkyl(s), c) a ci c 4 alkanoylamino, d) a c- c 4 alkyl optionally substituted by group (s) selected from the group consisting of hydroxy, amino, and a carbamoyl optionally substituted by C C 4 alkyl(s), and e) a carbamoyl optionally substituted by ci- c4 alkyl(s), (ii) hydroxy, (iii) a carbamoyl optionally substituted by ci- c4 alkyl(s), and (iv) amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s), a c 5 c7 cycloalkyl optionally substituted by group (s) selected from the group consisting of the following to hydroxy, (ii) a c 1 C 4 alkoxy (iii) a ci- c 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by ci c 4 alkyl(s), (iv) a carbamoyl optionally substituted by ci- c4 alkyl(s), and an amino optionally substituted by group(s) selected from the group consisting of ci- c 4 alkyl (s) and ci c 4 alkylsulfonyl(s), or a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following to (vi): alkylsulfonyl(s), 172 (ii) alkoxycarbonyl(s), (iii) carbamoyl(s) optionally substituted by alkyl(s), (iv) alkanoyl(s), aminosulfonyl(s) optionally substituted by alkyl(s),. and (vi) alkyl(s) or a pharmaceutically acceptable salt thereof. [12] 14. The compound according to Claim 13, wherein R 11 is a group selected from the group consisting of hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl and methoxy, k is 1 or 2, and when k is 2, two of R 1 s may be the same or different, R 12 is a ci c 5 alkyl optionally substituted by hydroxy, cyclopropylmethyl, cyclobutyl, carbamoylmethyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyranylmethyl, tetrahydrofurylmethyl or piperidyl optionally substituted by the group selected from alkylsulfonyl and alkanoyl, or a pharmaceutically acceptable salt thereof. The compound according to Claim 13, wherein R 11 is hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl or methyl, k is 1, R 12 is ethyl, isopropyl, isobutyl, 2-hydroxy-2-methylpropyl, cyclopropylmethyl, cyclobutyl, carbamoylmethyl,4-tetrahydropyranyl, 3-tetrahydrofuryl, tetrahydropyranylmethyl, tetrahydrofurylmethyl, methoxymethyl, 3-hydroxy-3-methylbutyl or 4-piperidyl substituted by methanesulfonyl or acetyl, R 13 is a ci c 6 alkyl optionally substituted by group(s) selected from the group consisting of the following and (iii): a c 5 c 7 cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy, a hydroxy ci c 4 alkyl, a ci- c 4 alkyl, amino 173 and a carbamoyl optionally substituted by ci- c4 alkyl(s), hydroxy, and (iii) an amino optionally substituted by group(s) selected from the group consisting of alkyl (s) and alkylsulfonyl(s), a c 5 c 7 cycloalkyl optionally substituted by group (s) selected from the group consisting of the following to hydroxy, (ii) a c 1 c 4 alkoxy (iii) a c 1 c 4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by ci c 4 alkyl(s), (iv) a carbamoyl optionally substituted by ci c4 alkyl(s),and an amino optionally substituted by group(s) selected from the group consisting of alkyl(s) and alkylsulfonyl(s), piperidinyl optionally substituted by group(s) selected from the group consisting of the following to (vi) alkylsulfonyl.(s), (ii) alkoxycarbonyl(s), (iii) carbamoyl(s) optionally substituted by alkyl (iv) alkanoyl(s), aminosulfonyl(s) optionally substituted by alkyl(s), and (vi) alkyl(s) pirrolidinyl optionally substituted by alkylsulfonyl, or a pharmaceutically acceptable salt thereof. [13] 16. A pharmaceutical composition comprising the compound 174 according to any one of Claims 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [14] 17. A method for inhibiting p38 MAP kinase, which comprises administering the compound according to any one of Claims 1 to or a pharmaceutically acceptable salt thereof to a human in need thereof. [15] 18. A method of prophylaxis or treatment for diseases related to the activation of p 38 MAP kinase or the excessive production of inflammatory mediators concerned with p38 MAP kinase, which comprises administering the compound according to any one of Claims 1 to 15 or a pharmaceutically acceptable salt thereof to a human in need thereof. [16] 19. A method of prophylaxis or treatment for diseases selected from the group consisting of arthritis, inflammatory bowel disease, inflammatory dermal disease, inflammatory respiratory disease, inflammatory optical disease, nephritis, hepatitis, systemic inflammatory disease, shock, cerebrovascular disease, ischemic cardiac diseases, osteoporosis, multiple sclerosis, diabetes, malignant tumor, cachexia, Alzheimer's disease, Parkinson's disease, acquired immunodeficiency syndrome, arterial sclerosis, disseminated intravascular coagulation syndrome, rejection and graft-versus-host diseases by organ transplantation, which comprises administering the compound according to any one of Claims 1 to 15 or a pharmaceutically acceptable salt thereof to a human in need thereof. DATED: 21 April 2004 PHILLIPS ORMONDE FITZPATRICK Attorneys for: TANABE SIYAKU CO., LTD. 4"a6f
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公开号 | 公开日 AU2004201666C1|2006-10-12|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US3538104A|1969-02-28|1970-11-03|Geigy Chem Corp|Pyridyl-2-imidazolones| US4532250A|1983-11-23|1985-07-30|American Hospital Supply Corporation|5-Heteroarylimidazol-2-ones having cardiotonic activity|
法律状态:
2004-08-26| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE NAME OF A CO-INVENTOR FROM MIYOSHIA, HIDETAKA TO MIYOSHI,HIDETAKA | 2006-06-08| DA2| Applications for amendment section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 21 APR 2006. | 2006-07-20| FGA| Letters patent sealed or granted (standard patent)| 2006-10-12| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 21 APR 2006 | 2013-05-16| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|
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申请号 | 申请日 | 专利标题 JP2001-324029||2001-10-22|| JP2002-263680||2002-09-10|| AU2002363108A|AU2002363108A1|2001-10-22|2002-10-22|4-imidazolin-2-one compounds| JP2003116076||2003-04-21|| JP2003-116076||2003-04-21|| 相关专利
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