4-Imidazolin-2-one compounds

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] 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.

[0004] 2. Background Art

[0005] Mitogen-activated protein (MAP) kinase is a member of serine-threonine kinases which transfers a γ-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.

[0006] p38MAP kinase is activated by inflammatory cytokines such as tumor necrosis factor a (TNF-α) and interleukin 1 (IL-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 (e.g. stabilizing mRNA 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.

[0007] As the inhibitors for p38 MAP kinase, there have been disclosed imidazole derivatives in PCT Japanese Provisional 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.

[0008] 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

[0009] The present inventions are as disclosed as follows.

[0010] [1] A compound of the formula [I]:

[0011] wherein G1 is an alkyl which is substituted by a halogen atom or an alkoxy, or a group of the formula:

[0012] 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(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,

[0013] W is a single bond, or a c1-c4 alkylene which may be substituted by 1 or 2 alkyl(s),

[0014] Q1 and Q2 maybe the same or different, and each is hydrogen atom, a halogen atom or an alkyl,

[0015] n is 0, 1, 2, 3 or 4,

[0016] R1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group,

[0017] Z1, Z2, Z3 and Z4 may be the same or different, and each is CH or N, provided that 3 or more of Z1, Z2, z3 and Z4 should not be N at the same time,

[0018] G2 is hydrogen atom, —NR3R4, —OR5, —SR5 —COR6, —CHR7R8, or a heterocyclic group,

[0019] where R3 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,

[0020] or a pharmaceutically acceptable salt thereof.

[0021] [2] A compound of the formula [Ia]:

[0022] 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, Q1 is hydrogen atom, a halogen atom or an alkyl, W is a single bond, or a c1-c4 alkylene which may be substituted by 1 or 2 alkyl(s),

[0023] n is 0, 1, 2, 3 or 4,

[0024] R1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group,

[0025] Z is CH or N,

[0026] R2 is hydrogen atom, —NR3R4, —OR5, —COR or —CHR7R8,

[0027] where R3 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,

[0028] or a: pharmaceutically acceptable salt thereof.

[0029] [3] The compound according to [2], wherein Q1 is hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0030] [4] The compound according to [2] or [3], 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.

[0031] [5] The compound according to any one of [2] to [4], wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof

[0032] [6] The compound according to any one of [2] to [4], wherein (1) n is 0 and R1 is an optionally substituted alkyl, (2) n is 1 and R1 is an optionally substituted cycloalkyl, (3) n is 1 and R1 is an optionally substituted phenyl, (4) n is 1 and R1 is an optionally substituted heterocyclic group, (5) n is 0 and R1 is an optionally substituted cycloalkyl, and (6) n is 0 and R1 is an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0033] [7] The compound according to any one of [2] to [6], wherein R2 is —NR3R4 or —OR5, or a pharmaceutically acceptable salt thereof.

[0034] [8] The compound according to any one of [2] to [7], wherein R2 is —NHR4, and R4 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.

[0035] [9] The compound according to [3], wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent(s), 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,

[0036] W is a single bond,

[0037] n is 0 or 1,

[0038] R1 is hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group,

[0039] Z is CH or N,

[0040] R2 is hydrogen atom, —NR3R4, —OR5, —COR1 or —CHR7R8,

[0041] Where R3 to R8 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,

[0042] or a pharmaceutically acceptable salt thereof.

[0043] [10] The compound according to [3], wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent(s), 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,

[0044] W is a single bond,

[0045] n is 0 or 1,

[0046] R1 is (1) hydrogen atom,

[0047] (2) 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,

[0048] (3) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (v):

[0049] (i) hydroxy,

[0050] (ii) an alkoxy optionally substituted by alkoxy(s),

[0051] (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl,

[0052] (iv) a carbamoyl optionally substituted by alkyl(s), and

[0053] (v) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy and amino,

[0054] (4) a phenyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vi):

[0055] (i) a halogen atom,

[0056] (ii) an alkyl optionally substituted by group(s) selected from the group consisting of a halogen atom, hydroxy and phenylsulfonyl,

[0057] (iii) cyano,

[0058] (iv) an alkoxy,

[0059] (v) an amino optionally substituted by group(s) selected from the group consisting of an alkyl and,an alkylsulfonyl,

[0060] (vi) a carbonyl substituted by a heterocyclic group, or

[0061] (5) a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following (i) to (iv):

[0062] (i) an alkoxycarbonyl,

[0063] (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),

[0064] (iii) an alkanoyl and

[0065] (iv) an alkylsulfonyl,

[0066] Z is CH or N,

[0067] R2 is hydrogen atom, —NR3R4, —OR5, —COR6 or —CHR7R8,

[0068] where R3 to R8 each independently is:

[0069] (1) hydrogen atom,

[0070] (2) an alkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vii):

[0071] (i) hydroxy,

[0072] (ii) an alkoxy,

[0073] (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl,

[0074] (iv) an alkoxycarbonyl,

[0075] (v) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to g):

[0076] a) hydroxy,

[0077] b) an amino optionally substituted by alkyl(s),

[0078] c) an alkanoylamino,

[0079] d) an alkylsulfonylamino,

[0080] 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),

[0081] f) carboxy and

[0082] g) a carbamoyl optionally substituted by alkyl (3),

[0083] (vi) a phenyl optionally substituted by group(s) selected from the group consisting of a halogen atom, an alkoxy and morpholinylcarbonyl, and

[0084] (vii) a heterocyclic group optionally substituted by alkyl(s),

[0085] (3) an alkenyl,

[0086] (4) an alkoxy,

[0087] (5) an alkanoyl optionally substituted by group(s) selected from the group consisting of the following (i) to (iv):

[0088] (i) hydroxy,

[0089] (ii) an alkoxy,

[0090] (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl and an alkanoyl,

[0091] (iv) an alkoxycarbonyl,

[0092] (6) a carbamoyl optionally substituted by alkyl(s),

[0093] (7) an alkoxyoxalyl,

[0094] (8) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vii):

[0095] (i) a halogen atom,

[0096] (ii) hydroxy,

[0097] (iii) an alkoxy,

[0098] (iv) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl,

[0099] (v) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, an alkoxy, amino, a carbamoyl optionally substituted by alkyl(s),

[0100] (vi) an alkanoyloxy and

[0101] (vii) a carbamoyl optionally substituted by alkyl(s),

[0102] (9) a phenyl optionally substituted by group(s) selected from the group consisting of a halogen atom and an alkoxy,

[0103] (10) a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following (i) to (vii):

[0104] (i) 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),

[0105] (ii) an alkoxycarbonyl,

[0106] (iii) an alkanoyl,

[0107] (iv) an alkylsulfonyl,

[0108] (v) oxo,

[0109] (vi) a carbamoyl optionally substituted by alkyl(s),

[0110] (vii) an aminosulfonyl optionally substituted by alkyl(s),

[0111] (11) a carbonyl substituted by a cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and an alkanoylamino, or

[0112] (12) a heterocyclic group-substituted carbonyl, or a pharmaceutically acceptable salt thereof.

[0113] [11] The compound according to [3], wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituent(s), 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,

[0114] W is a single bond,

[0115] n is 0 or 1,

[0116] R1 is (1) hydrogen atom,

[0117] (2) 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,

[0118] (3) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (v):

[0119] (i) hydroxy,

[0120] (ii) an alkoxy optionally substituted by alkoxy(s),

[0121] (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl and an alkylsulfonyl,

[0122] (iv) a carbamoyl optionally substituted by alkyl(s),

[0123] (v) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy and amino,

[0124] (4) a phenyl optionally substituted by group(s) selected from the group consisting of the following (i) to (iv):

[0125] (i) a halogen atom,

[0126] (ii) an alkyl optionally substituted by halogen atom(s),

[0127] (iii) cyano, and

[0128] (iv) an alkoxy, or

[0129] (5) a heterocyclic group optionally substituted by alkylsulfonyl or alkanoyl,

[0130] Z is CH or N,

[0131] R2 is hydrogen atom, —NR3R4, —OR5, or —COR6,

[0132] Where R3 to R6 each independently is:

[0133] (1) hydrogen atom,

[0134] (2) an alkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vii):

[0135] (i) hydroxy,

[0136] (ii) an alkoxy,

[0137] (iii) an alkoxycarbonyl,

[0138] (iv) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e):

[0139] a) hydroxy,

[0140] b) an amino optionally substituted by alkyl(s),

[0141] c) an alkanoylamino,

[0142] 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

[0143] e) a carbamoyl optionally substituted by alkyl(s),

[0144] (v) a phenyl optionally substituted by alkoxy(s),

[0145] (vi) a heterocyclic group, and

[0146] (vii) an amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s),

[0147] (3) an alkenyl,

[0148] (4) an alkoxy,

[0149] (5) 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,

[0150] (6) a cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (v):

[0151] (i) hydroxy,

[0152] (ii) an alkoxy,

[0153] (iii) an amino optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkoxycarbonyl and an alkylsulfonyl,

[0154] (iv) an alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by alkyl(s),

[0155] (v) a carbamoyl optionally substituted by alkyl(s),

[0156] (7) a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following (i) to (vi):

[0157] (i) an alkyl optionally substituted by phenyl(s),

[0158] (ii) an alkoxycarbonyl,

[0159] (iii) an alkylsulfonyl

[0160] (iv) an alkanoyl,

[0161] (v) a carbamoyl optionally substituted by alkyl(s), and

[0162] (vi) an aminosulfonyl optionally substituted by alkyl(s),

[0163] (8) a carbonyl substituted by a cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy and amino, or

[0164] (9) a heterocyclic group-substituted carbonyl,

[0165] or a pharmaceutically acceptable salt thereof.

[0166] [12] A compound of the formula [Ib]:

[0167] wherein R11 is a group selected from the group consisting of hydrogen atom, a halogen atom, a c1-c4 alkyl optionally substituted by halogen(s) and a c1-c4 alkoxy,

[0168] k is 1 or 2, and when k is 2, two of R11s may be the same or different,

[0169] R12 is (1) a c1-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),

[0170] (2) a C3-c4 cycloalkylmethyl,

[0171] (3) a C3-c4 cycloalkyl,

[0172] (4) carbamoylmethyl,

[0173] (5) a benzyl optinally substituted by group(s) selected from the group consisting of cyano, a halogen atom, a c1-c3 alkoxy, a c1-c3 alkyl and a halogen-substituted c1-c3 alkyl,

[0174] (6) tetrahydropyranyl,

[0175] (7) tetrahydrofuryl and

[0176] (8) 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),

[0177] Z5 is CH or N,

[0178] R13is (1) a c1-c6 alkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (xiv):

[0179] (i) a C5-c7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e):

[0180] a) hydroxy

[0181] b) an amino optionally substituted by c1-c4 alkyl(s),

[0182] c) a c1-c4 alkanoylamino,

[0183] d) a c1-c4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino, and a carbamoyl optionally substituted by

[0184] C1-c4 alkyl(s), and

[0185] e) a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0186] (ii) hydroxy,

[0187] (iii) a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0188] (iv) a piperidyl optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl and oxo,

[0189] (v) a pyrrolidinyl optionally substituted by group(s) selected from the group consisting of an alkyl, an alkanoyl, an alkylsulfonyl and oxo,

[0190] (vi) a tetrahydropyranyl optionally substituted by hydroxy(s),

[0191] (vii) an imidazolinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo,

[0192] (viii) an imidazolidinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo,

[0193] (ix) a piperadinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo,

[0194] (x) a hexahydropyrimidinyl optionally substituted by group(s) selected from the group consisting of an alkyl and oxo,

[0195] (xi) a pyridyl optionally substituted by alkyl(s),

[0196] (xii) furyl,

[0197] (xiii) tetrahydroisothiazolyl optionally substituted by oxo(s), and

[0198] (xiv) amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s),

[0199] (2) a c5-c7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (v):

[0200] (i) hydroxy,

[0201] (ii) a c1-c4 alkoxy,

[0202] (iii) a c1-c4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0203] (iv) a carbamoyl optionally substituted by c1-c4 alkyl(s), and

[0204] (v) an amino optionally substituted by group(s) selected from the group consisting of c1-c4 alkyl(s) and c1-c4 alkylsulfonyl(s), or

[0205] (3) a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following (i) to (vii):

[0206] (i) an alkyl optionally substituted by group(s) selected from the group consisting of a halogen, amino, hydroxy, phenyl and oxo,

[0207] (ii) an aminosulfonyl optionally substituted by alkyl(s),

[0208] (iii) an alkylsulfonyl optionally substituted by halogen(s),

[0209] (iv) a carbamoyl optionally substituted by alkyl(s),

[0210] (v) hydroxy,

[0211] (vi) an alkoxycarbonyl, and

[0212] (vii) oxo,

[0213] or a pharmaceutically acceptable salt thereof.

[0214] [13] The compound according to [12],wherein R12 is (1) a c1-C5 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, alkoxy, tetrahydropyranyl and tetrahydrofuryl

[0215] (2) a C3-c4 cycloalkylmethyl,

[0216] (3) a C3-c4 cycloalkyl,

[0217] (4) carbamoylmethyl,

[0218] (5) a benzyl optinally substituted by group(s) selected from the group consisting of cyano, a halogen atom, a c1-c3 alkoxy, a c1-c3 alkyl and a halogen-substituted c1-c3 alkyl,

[0219] (6) tetrahydropyranyl,

[0220] (7) tetrahydrofuryl, or

[0221] (8) a piperidyl optionally substituted by alkylsulfonyl or alkanoyl,

[0222] R13 is (1) a c1-c6 alkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (iv):

[0223] (i) a c5-c7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following a) to e):

[0224] a) hydroxy

[0225] b) an amino optionally substituted by c1-c4 alkyl(s),

[0226] c) a c1-c4 alkanoylamino,

[0227] d) a c1-c4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino, and a carbamoyl optionally substituted by C1-c4 alkyl(s), and

[0228] e) a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0229] (ii) hydroxy,

[0230] (iii) a carbamoyl optionally substituted by c1-c4 alkyl(s), and

[0231] (iv) an amino optionally substituted by the group(s) selected from alkanoyl(s) and alkylsulfonyl(s),

[0232] (2) a c5-c7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (v):

[0233] (i) hydroxy,

[0234] (ii) a c1-c4 alkoxy,

[0235] (iii) a c1-c4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0236] (iv) a carbamoyl optionally substituted by c1-c4 alkyl(s), and

[0237] (v) an amino optionally substituted by group(s) selected from the group consisting of c1-c4 alkyl(s) and c1-c4 alkylsulfonyl(s), or

[0238] (3) a heterocyclic group optionally substituted by group(s) selected from the group consisting of the following (i) to (vi):

[0239] (i) alkylsulfonyl(s),

[0240] (ii) alkoxycarbonyl(s),

[0241] (iii) carbamoyl(s) optionally substituted by alkyl(s),

[0242] (iv) alkanoyl(s),

[0243] (v) aminosulfonyl(s) optionally substituted by alkyl(s), and

[0244] (vi) alkyl(s),

[0245] or a pharmaceutically acceptable salt thereof.

[0246] [14] The compound according to [12] or [13], wherein R11 is a group selected from the group consisting of hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl and methoxy,

[0247] k is 1 or 2, and when k is 2, two of R11s may be the same or different,

[0248] R12 is a c1-c5 alkyl optionally substituted by hydroxy, cyclopropylmethyl, cyclobutyl, carbamoylmethyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyranylmethyl, tetrahydrofurylmethyl or piperidyl optionally substituted by the group selected from alkylsulfonyl and alkanoyl,

[0249] or a pharmaceutically acceptable salt thereof.

[0250] [15] The compound according to [12] or [13], wherein R11 is hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl or methyl,

[0251] k is 1,

[0252] R12 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,

[0253] R13 is (1) a c1-c6 alkyl optionally substituted by group(s) selected from the group consisting of the following (i) and (iii):

[0254] (i) a c5-c7 cycloalkyl optionally substituted by group(s) selected from the group consisting of hydroxy, a c1-c4 alkyl, a hydroxy c1-c4 alkyl, an amino optionally substituted by c1-c4 alkyl(s) and a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0255] (ii) hydroxy, and

[0256] (iii) an amino optionally substituted by group(s) selected from the group consisting of alkyl(s) and alkylsulfonyl(s),

[0257] (2) ac5-c7 cycloalkyl optionally substituted by group(s) selected from the group consisting of the following (i) to (v):

[0258] (i) hydroxy,

[0259] (ii) a c1-c4 alkoxy,

[0260] (iii) a c1-c4 alkyl optionally substituted by group(s) selected from the group consisting of hydroxy, amino and a carbamoyl optionally substituted by c1-c4 alkyl(s),

[0261] (iv) a carbamoyl optionally substituted by c1-c4 alkyl(s), and

[0262] (v) an amino optionally substituted by group(s) selected from the group consisting of alkyl(s) and alkylsulfonyl(s),

[0263] (3) piperidinyl optionally substituted by group(s) selected from the group consisting of the following (i) to (vi):

[0264] (i) alkylsulfonyl(s),

[0265] (ii) alkoxycarbonyl(s),

[0266] (iii) carbamoyl(s) optionally substituted by alkyl(s),

[0267] (iv) alkanoyl(s),

[0268] (v) aminosulfonyl(s) optionally substituted by alkyl(s), and

[0269] (vi) alkyl(s),

[0270] (4) pirrolidinyl optionally substituted by alkylsulfonyl,

[0271] or a pharmaceutically acceptable salt thereof.

[0272] [16] A pharmaceutical composition comprising the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0273] [17] The method of inhibiting of p38 MAP kinase which comprises administering the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof to a human in need thereof.

[0274] [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 [1] to [15] or a pharmaceutically acceptable salt thereof to a human in need thereof.

[0275] [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 [1] to [15] or a pharmaceutically acceptable salt thereof to a human in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0276] In the present invention, “an alkyl” and alkyls in “an alkylthio”, “an alkylsulfinyl” and “an alkylsulfonyl” are exemplified by a straight or branched chain c1-c6 alkyl, and specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. Preferred is a c1-c4alkyl.

[0277] “An alkoxy” and alkoxys in “an alkoxycarbonyl” and “an alkoxyoxalyl” are exemplified by a straight and branched chain c1-c6alkoxy, and specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexoxy, etc. Preferred is a c1-c4 alkoxy.

[0278] “An alkenyl” is exemplified by a straight or branched chain c2-c7alkenyl, and specifically, vinyl, allyl, 3-butenyl, 2-pentenyl, 3-hexenyl, etc. Preferred is a c2-c5 alkenyl, etc.

[0279] “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-c5 alkynyl.

[0280] “An alkanoyl” is exemplified by a straight or branched chain c2-c7 alkanoyl, and specifically, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, etc. Preferred is a c2-c5 alkanoyl.

[0281] “A cycloalkyl” is exemplified by a c3-c8 cycloalkyl, and preferred is a c3-c6 cycloalkyl.

[0282] “A cycloalkane” is exemplified by a c3-c8 cycloalkane, and preferred is a c5-c7 cycloalkane.

[0283] “A halogen atom” is exemplified by fluorine atom, chlorine atom, bromine atom, iodine atom, and preferred are fluorine atom and chlorine atom.

[0284] “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.

[0285] “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, 5- 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.

[0286] When a substituent of the ring B in the compound [I] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] A substituent of the ring B in the compound [I] 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 c1-c4alkyl, a c1-c4alkoxy, etc., and specific examples are fluorine atom, chlorine atom, methyl, methoxy, etc.

[0291] When R1 of the compound [I] and the compound [Ia] is “an optionally substituted alkyl”, examples for substituent of the alkyl include analkynyl, cyano, analkoxy, 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.

[0292] When R1 is “an optionally substituted cycloalkyl”, examples for the substituents of the cycloalkyl include (1) hydroxy, (2) an alkoxy (said alkoxy may be substituted by 1 to 3 alkoxy(s)), (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 the following (i) to (v) : (i) an alkyl, (ii) an alkanoyl, (iii) an alkoxycarbonyl, (iv) carbamoyl (said carbamoyl may be substituted by 1 or 2 alkyl(s).), and(v) an alkylsulfonyl), (4) carboxy, (5) an alkyl (said alkyl may be substituted by a group selected form the group consisting of hydroxy, an alkoxy and amino), (6) 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.

[0293] When R1 is “an optionally substituted phenyl”, examples for the substituents of the phenyl include (1) a halogen atom, (2) nitro, (3) 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), (4) an alkenyl, (5) cyano, (6) hydroxy, (7) 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), (8) 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 (i) to (iv) : (i) 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], (9) 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 (i) and (ii): (i) 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 R1 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 (1) a halogen atom, (2) 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), (3) cyano, (4) 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.

[0294] When R1 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.

[0295] When R 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.

[0296] A preferred combination of n and R1 in the compound [I] and the compound [Ia] are exemplified by (1) those in which n is 0 and R1 is an optionally substituted alkyl, (2) those in which n is 1 and R1 is an optionally substituted cycloalkyl, (3) those in which n is 1 and R1 is an optionally substituted phenyl, (4) those in which n is 1 and R1 is an optionally substituted heterocyclic group, (5) those in which n is 0 and R1 is an optionally substituted cycloalkyl, and (6) those in which n is 0 and R1 is an optionally substituted heterocyclic group, etc. Particularly preferred are (1) those in which n is 0 and R1 is an optionally substituted alkyl, (2) those in which n is 1 and R1 is an optionally substituted phenyl, (3) those in which n is 0 and R1 is an optionally substituted cycloalkyl, and (4) those in which n is 0 and R1 is an optionally substituted heterocyclic group, etc. Further preferred are (1) those in which n is 0 and R1 is a c1-c4 alkyl optionally substituted by hydroxy, (2) those in which n is 1 and R1 is a phenyl (said phenyl may be substituted by a group selected from the group consisting of cyano, fluorine atom, chlorine atom and methyl), (3) those in which n is 0 and R1 is c3-c4 cycloalkyl, and (4) those in which n is 0 and R1 is 4-tetrahydropyranyl, etc.

[0297] When R3 to R8 in the compound [I] and the compound [Ia] is “an optionally substituted alkyl”, the substituents of the alkyl are exemplified by (1) hydroxy, (2) 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), (4) an alkoxycarbonyl, (5) 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(s)), carboxy and a carbamoyl which may be substituted by alkyl(s)], (6) phenyl [said phenyl maybe substituted by 1 to 3 group(s), being the same or different, and selected from the group consisting of the following (i) to (vi): (i) a halogenatom, (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, (v) carbamoyl, and (vi) morpholinylcarbonyl], (7) 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 (i) to (viii): (i) an alkyl (said alkyl may be substituted by 1 to 3 hydroxy(s)), (ii) hydroxy, (iii) amino, (iv) an alkoxycarbonyl, (v) carbamoyl, (vi) alkanoyl, (vii) alkylsulfonyl and (viii) oxo], (8) mercapto, etc. When R3 to R8 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.

[0298] When R3 to R8 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.

[0299] When R3 to R8 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.

[0300] When R3 to R8 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.

[0301] When R3 to R8 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.

[0302] When R3 to R8 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(s) mentioned above, and when the number of the substituents is 2, each of the substituents may be the same or different.

[0303] When R3 to R8 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.

[0304] When R3 to R8 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(s), 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(s), 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 R3 to R8 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-1-methylethyl)cyclohexyl, 1-hydroxymethylcyclopentyl, etc. When R3 to R8 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.

[0305] When R3 to R8 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.

[0306] When R3 to R8 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(s), 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.

[0307] When R3 to R8 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(s) mentioned above, and when the number of the substituents is 2 or more, each of the substituents may be the same or different.

[0308] When R3 to R8 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.

[0309] When R3 to R8 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(s)), 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.

[0310] R2 in the compound [Ia] are preferably exemplified by —NR3R4 and —OR5, and particularly preferably exemplified by —NR3R4, and further more preferably exemplified by —NHR4.

[0311] When R2 is —NHR4, preferred examples of R4 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 maybe 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 c1-c3 alkylsulfonyl, c1-c3 alkylcarbamoyl or c1-c3 alkoxycarbonyl) and 4-tetrahydropyranyl etc.

[0312] Although an optical isomer based on an asymmetric carbon can be present in the compounds [I], [Ia] and [Ib] of the present invention, the present invention includes any of these optical isomers as well as mixtures thereof. The compounds [I], [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 [I], [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 [I], [Ia] and [Ib] of the present invention or a salt thereof include an internal salt thereof and a solvate thereof, such as a hydrate, etc.

[0313] The compounds [I], [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-α, IL-1, etc. Therefore, the compounds [I], [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 [psoriasis, 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.

[0314] 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.

[0315] 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.

[0316] Examples of the anti-rheumatic drug include gold preparation (Auranofin, etc.), penicillamine, bucillamine, lobenzarit, actarit, sulfasalazine, chloroquine, leflunomide, and the like.

[0317] Examples of the anti-cytokine drug include etanercept, infliximab, soluble TNF-α receptor, anti-TNF-α antibody, anti-interleukin-6 antibody, anti-interleukin-12 antibody and the like.

[0318] Examples of the immunosuppressant include methotrexate, cyclophosphamide, brequinar sodium, deoxyspergualin, mizoribine, 2-morphorinoethyl mycophenolate, rimexolone, cyclosporine, rapamycin, tacrolimus, gusperimus, azathiopurine and the like.

[0319] Examples of the steroid include dexamethasone, betamethasone, triamcinolone, fluocinonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone and the like.

[0320] 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.

[0321] The present compound (I) or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound (I) and a pharmaceutically acceptable carrier therefor. The pharmaceutically acceptable carriers include diluents, binders (e.g., syrup, gum arabic, gelatine, sorbit, tragacanth, polyvinylpyrrolidone), excipients (e.g., lactose, sucrose, corn starch, potassium phosphate, sorbit, glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol, silica), disintegrants (e.g., potato starch) and wetting agents (e.g., sodium lauryl sulfate), and the like.

[0322] The compound (I) 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.

[0323] An administration amount of the compound [I], [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.

[0324] The compounds [I], [Ia] and [Ib] of the present invention can be prepared suitably by a method selected from the following [Method A] to [Method D], however, it is not limited to these. Production method will be described in detail using the compound [Ia′] which is the compound [Ia] wherein Q1 is hydrogen as follow, however, the other compounds [I], [Ia] and [Ib] can be produced in a similar manner.

[0325] (wherein R is an alkyl, and other symbols have the same meanings as mentioned above.)

[0326] The compound [Ia′] 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 −20 to 80° C., particularly preferably at 0 to 30° C. 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 [II], there are mentioned, for example, methyl, ethyl, propyl, butyl, etc., and particularly preferred are methyl and ethyl.

[0327] (wherein Y is a halogen atom, hydroxy, or dihydroxyboranyl, n1 is 0, 1,2,3 or 4, R1a 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 R1a is hydrogen atom is excluded.), and other symbols have the same meanings as the above.)

[0328] The compound [I-B] which is categorized in the compound [Ia′] can be produced by reacting a compound [I-A], which is a compound [Ia′] where n is 0 and R1 is hydrogen atom, with a compound [IV] for alkylation.

[0329] 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 −20 to 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.

[0330] 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 50° C.

[0331] When Y in the formula [IV] is dihydroxyboranyl, the reaction can be carried out in a solvent, in the presence of acatalystandabase (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 20 to 60° C.

[0332] (wherein R21 is —NR3R4, —OR5 or —COR6a, R6a is an alkoxy, and other symbols have the same meanings as the above.)

[0333] The compound [I-C] which is categorized in the compound [Ia′] of the present invention can be produced by reacting a compound [V] with a compound [VI], a compound [VII] or a compound [VIII].

[0334] The reaction between the compound [V] 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.

[0335] 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 80° C.

[0336] The reaction between the compound [V] 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.

[0337] The reaction between the compound [V] 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.

[0338] (wherein m is 1 or 2, R22 is —NR3R4 or —OR5 and other symbols have the same meanings as the above.)

[0339] The compound [I-D] 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 [X].

[0340] 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 ° C., and particularly preferably at 50 to 100° C.

[0341] The reaction between the compound [IX] and the compound [X] 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 ° C., and particularly preferably at 0 to 30° C.

[0342] 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 R2 in the compound [Ia′] can be carried out according to the following (method a) to (method g).

[0343] (wherein the symbols have the same meanings as the above.)

[0344] The compound [I-1] can be produced by reacting a compound [I-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 80° C.

[0345] (wherein R41 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.

[0346] Other symbols have the same meanings as the above.)

[0347] The compound [I-3] and compound [I-4] can be produced by reacting a compound [I-1] with a compound [XI].

[0348] 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 30° C. Further, as the halogen atom at X, there are mentioned fluorine, chlorine, bromine, and iodine, and particularly preferred are chlorine and bromine.

[0349] 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 −40 to 100° C., particularly preferably at −10 to 30° C.

[0350] (wherein R9 and R10 are independently hydrogen atom, or an alkyl.

[0351] R10a is an alkyl. X is a halogen atom. Other symbols have the same meanings as the above.)

[0352] The compound [I-5] can be produced by reacting a compound [I-1] with a compound [XII], with triphosgene and a compound [XIII], or with a compound [XIV].

[0353] The compound [I-5] can be produced by reacting a compound [I-1] 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 60° C.

[0354] Further, the compound [I-5] can be produced by reacting a compound [I-1] 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 60° C.

[0355] Still further, a compound [I-5] in which R9 is a hydrogen atom and R10 is an alkyl can be produced by reacting a compound [I-1] 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 60° C.

[0356] (wherein R is an alkyl, and other symbols have the same meanings as the above.)

[0357] The compound [I-6] can be produced by hydrolyzing a compound [I-7] by a conventional method.

[0358] (wherein R61 is an amino which may be substituted, and other symbols have the same meanings as the above.)

[0359] The compound [I-8] can be produced by reacting a compound [I-6] 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 −30 to 100° C. and particularly at 0 to 70° C.

[0360] (wherein symbols have the same meanings as the above.)

[0361] The compound [I-9] can be produced by reducing a compound [I-6] or a compound [I-7] 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 40° C.

[0362] (wherein R81 is an optionally substituted amino, and other symbols have the same meanings as the above.)

[0363] The compound [I-10] can be produced by reacting a compound [I-9] 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.

[0364] 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 30° C.

[0365] 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.

[0366] In the following, production methods for starting materials used in the above methods are described.

[0367] The starting material (II] can be produced as follows.

[0368] (wherein the symbols have the same meanings as the above.)

[0369] The reaction for producing the compound [2] from the compound [1] and hydroxylamine can be carried out in a solvent. 20 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 80° C.

[0370] The reaction for producing the compound [3] from the compound [2] 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 30° C.

[0371] The reaction for producing the compound [3a] from the compound [3] can be carried out in a solvent, by reacting the compound [3] 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 30° C.

[0372] 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)).

[0373] A starting material [V] can be produced, for example, as follows.

[0374] (wherein the symbols have the same meanings as the above.)

[0375] The reaction for producing the compound [5] from the compound [4] 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 −60 to −40° C.

[0376] The method for producing the compound [8] from the compound [5] via the compound [6] and the compound [7] can be carried out in a similar manner to the above-mentioned method for producing the compound [II] from the compound [1] via the compound [2] and the compound [3].

[0377] The reaction for producing the compound [9] from the compound [8] and the compound [III] can be carried out in a similar manner to the above-mentioned [Method A].

[0378] The reaction for producing the compound [V] from the compound[9] and the compound [IV] can be carried out in a similar manner to the above-mentioned [Method B].

[0379] A starting material [IX] can be produced, for example, as follows.

[0380] (wherein m is 1 or 2, and other symbols have the same meanings as the above.)

[0381] 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.

[0382] 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, sodiumhydroxide, 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 70° C.

[0383] 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 30° C.

[0384] The compound [14] can be also produced from the compound [15] via the compound [17].

[0385] 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 90° C.

[0386] 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].

[0387] 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 [1] via the compound [2] and the compound [3].

[0388] 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].

[0389] 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 30° C.

[0390] 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].

[0391] The compound [IX] can be also produced from the compound [21] via the compound [23].

[0392] 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].

[0393] 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].

[0394] 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.

[0395] 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 [I], [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

[0396] 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.

[0397] Each of the following symbols used in the present specification represents the meaning as described below.

[0398] Me : methyl

[0399] Et ethyl

[0400] THF: tetrahydrofuran

[0401] DMF: N,N-dimethylformamide

[0402] t-: tert-

Example 1

1-(4-Fluorophenyl)-5-(pyridin-4-yl)-4-imidazolin-2-one

[0403]

[0404] A solution of 3.00 g of 2,2-diethoxy-2-pyridin-4-ylethylamine (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

1-cyclopentylmethyl-3-(4-fluorophenyl)-4-(pyridin-4-yl)-4-imidazolin-2-one.hydrochloride

[0405]

[0406] 128 mg of 1-(4-Fluorophenyl)-5-(pyridin-4-yl)-4-imidazolin-2-one (the compound of Example 1), 61 μl of cyclopentylmethanol, 197 mg of triphenylphosphine and 295 μl 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

[0407]

[0408] 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)-phenyl-ethylamino)pyridin-4-yl)]-4-imidazolin-2-one

[0409]

[0410] 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 (6)), 79 μl of (S)-(−)-α-methylbenzylamine, 5.5 mg of palladium acetate, 15 mg 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: 2), to give 38 mg of the title compound as colorless powder.

Examples 5-12

[0411] Compounds in Table 1 were obtained by treating the corresponding starting materials in a similar manner to that in Example 4.

1TABLE 1

PhysicalExam-properties,pleR1R2etc.52-Cyanophenyl4-MethoxybenzylaminoMeltingpoint 167° C.62-Cyanophenyl2-ThienylmethylaminoMeltingpoint 171° C.72-Cyanophenyl(S)-1-t-Butoxycarbon-Meltingylethylaminopoint191-193° C.82-CyanophenylIsopropylaminoMeltingpoint170-171° C.92-CyanophenylAllylaminoMeltingpoint 163° C.10**2-Methoxyphenyl2-PyridylmethylaminoMeltingpoint248-250° C.112-Fluorophenyl2-(2-Pyridyl)ethyl-Meltingaminopoint132-134° C.12**2-Trifluoro-2-(2-Pyridyl)ethyl-Powdermethylphenylamino**Dihydrochloride

Example 13

4-(2-Aminopyridin-4-yl)-1-(2-cyanobenzyl)-3-(4-fluoro-phenyl)-4-imidazolin-2-one

[0412]

[0413] 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 70° 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° C.

Example 14

4-(2-N-Isobutyroylaminopyridin-4-yl)-1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-imidazolin-2-one

[0414]

Example 15

4-(2-N,N-Diisobutyroylaminopyridin-4-yl)-1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-imidazolin-2-one

[0415]

[0416] 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 μl of isobutyroyl chloride in methylene chloride was ice-cooled, and after adding 54 μl 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 15) as colorless crystal, respectively. Melting point:196° C.

(Example 14), 185-187° C. (Example 15).

Example 16

4-(2-Ethoxycarbonylpyridin-4-yl)-1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-imidazolin-2-one

[0417]

[0418] In 20 ml of ethanol were suspended 1 g of 4-(2-chloro-pyridin-4-yl)-3-(4-fluorophenyl)-1-(2-cyanobenzyl)-4-imid- azolin-2-one (Compound of Reference example 1(6)), 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=1:2) 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-hydroxypropyl-amino)pyrimidin-4-yl]-4-imidazolin-2-one

[0419]

[0420] 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(2)), 60.6 mg of 3-aminopropanol and 2 ml of dioxane was stirred at 80° C. 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

[0421] The corresponding starting materials were treated in the same manner as in Example 17 to give Compounds in Table 2.

2TABLE 2

PhysicalExam-properties,pleR1R2etc.182-Cyanophenyl2-FurylmethylaminoMeltingpoint174-175° C.192-Cyanophenyl3-MethoxypropylaminoMeltingpoint168-169° C.202-CyanophenylIsobutylaminoMeltingpoint145-146° C.212-CyanophenylAllylaminoMeltingpoint189-190° C.222-Cyanophenyl4-HydroxybutylaminoMeltingpoint166-167° C.232-MethoxyphenylIsopropylaminoMeltingpoint171-172° C.242-FluorophenylIsopropylaminoMeltingpoint120-122° C.

Example 25

1-(2-Cyanobenzyl)-3-(4-fluorophenyl)-4-(2-isopropoxy-pyrimidin-4-yl)-4-imidazolin-2-one

[0422]

[0423] In 5 ml of isopropanol was suspended 100 mg of 1-(2-cyano-benzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 7(2)), 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 extracted with 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

[0424] 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 1(6), and then, subjected to amination in the same manner as in Example 4 to give the compounds shown in Tables 3 to 6.

3TABLE 3

Exam-MSpleR1R2([M + H]+)262-CyanophenylBenzylamino476272-CyanophenylCyclopropylamino426282-Cyanophenyl2-Furylmethylamino466292-Cyanophenyl2-Pyridylmethylamino477302-CyanophenylCyclopentylamino454312-Cyanophenyl4-Chlorobenzylamino510322-Cyanophenyl2-Methoxybenzylamino506332-Cyanophenyl3-Methoxybenzylamino506342-Cyanophenyl3-Pyridylmethylamino477352-Cyanophenyl2-Methylpyridin-4-ylmethyl491amino362-Cyanophenyl2-(2-Pyridyl)-ethylamino491372-Cyanophenyl(4-Methyl-1-piperazinyl)-484amino382-Cyanophenyl3-Methoxypropylamino458392-Cyanophenyl3-Propoxypropylamino486

[0425]

4

TABLE 4

Exam-

MS

ple
R1
R2
([M + H]+)

40
2-Cyanophenyl
Cyclopropylmethylamino
440

41
2-Cyanophenyl
3-Isopropoxypropylamino
486

42
2-Fluorophenyl
2-Pyridylmethylamino
470

43**
2-Trifluoro-
2-Pyridylmethylamino
520

methylphenyl

44
2-Cyanophenyl
Isobutylamino
442

45
2-Cyanophenyl
2-Ethoxyethylamino
458

46
2-Trifluoro-
Isopropylamino
471

methylphenyl

47
2-Fluorophenyl
Isopropylamino
421

48
2-Methoxyphenyl
Isopropylamino
433

49
2-Fluorophenyl
Isobutylamino
435

50
2-Methoxyphenyl
Isobutylamino
447

51
2-Cyanophenyl
t-Butylamino
442

52
2-Cyanophenyl
4-Tetrahydropyranylamino
470

53
2-Cyanophenyl
(S)-1-(2-Pyridyl)ethyl-
491

amino

**Dihydrochloride

[0426]

5

TABLE 5

Exam-

MS

ple
R1
R2
([M + H]+)

54
2-Fluorophenyl
trans-4-Hydroxycyclo-
477

hexylamino

55
4-Methoxyphenyl
Isopropylamino
433

56
2-Cyanophenyl
trans-4-Hydroxycyclo-
484

hexylamino

57
4-Methoxyphenyl
(S)-1-(2-Pyridyl)ethyl-
495

amino

58
2-Fluorophenyl
4-Methoxybenzylamino
499

59
cis-4-Methoxy-
Isobutylamino
483

methoxycyclohexyl

60
cis-4-Methoxy-
trans-4-Hydroxycyclo-
524

methoxycyclohexyl
hexylamino

61
cis-4-Methoxy-
Isopropylamino
469

methoxycyclohexyl

62
2-Fluorophenyl
(1-Methyl-4-piperidyl)-
476

amino

63
2-Fluorophenyl
(1-t-Butoxycarbonyl-4-
562

piperidyl)amino

64
2-Cyanophenyl
(1-Methyl-4-piperidyl)-
483

amino

65*
Cyclopentyl
Isopropylamino
395

66
Cyclopentyl
trans-4-Hydroxycyclo-
451

hexylamino

67*
4-Tetrahydro-
Isopropylamino
411

pyranyl

*Monohydrochloride;

**Dihydrochloride

[0427]

6

TABLE 6

Exam-

MS

ple
R1
R2
([M + H]+)

68*
4-Tetrahydro-
trans-4-Hydroxycyclo-
467

pyranylmethyl
hexylamino

69
2-Methoxyethyl
trans-4-Hydroxycyclo-
427

hexylamino

70
Methoxymethyl
trans-4-Hydroxycyclo-
413

hexylamino

71
Methoxymethyl
Isopropylamino
357

72
Methyl
trans-4-Hydroxycyclo-
383

hexylamino

73*
Ethyl
trans-4-Hydroxycyclo-
397

hexylamino

74
Isopropyl
trans-4-Hydroxycyclo-
411

hexylamino

75**
Isopropyl
trans-4-Aminocyclohexyl-
410

amino

76*
Isopropyl
trans-4-Acetylamino-
452

cyclohexylamino

77*
N-Isopropyl-
Isopropylamino
412

carbamoylmethyl

78**
Isopropyl
trans-4-Dimethylamino-
438

cyclohexylamino

79**
Isopropyl
trans-4-Carbamoylmethyl-
467

amino-cyclohexylamino

*Monohydrochloride;

**Dihydrochloride

Example 80

[0428]

[0429] 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.

[0430] MS 462([M+H]+).

Example 81

[0431]

[0432] 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.

[0433] MS 425([M+H]+).

Examples 82 to 107

[0434] 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.

7TABLE 7

Exam-MSpleR1R2([M + H]+)82**4-PiperidylIsopropylamino41083**2-Cyanophenyl4-Piperidylamino46984cis-4-Hydroxy-Isobutylamino439cyclohexyl85**cis-4-Aminocyclo-Isopropylamino424hexyl86**cis-4-Aminocyclo-trans-4-Hydroxycyclo-480hexylhexylamino87cis-4-Hydroxy-trans-4-Hydroxycyclo-481cyclohexylhexylamino88cis-4-Hydroxy-(1-Methyl-4-Piperidyl)480cyclohexylamino89trans-4-Amino-trans-4-Hydroxycyclo-480cyclohexylhexylamino90**4-PiperidylIsobutylamino42491**4-Piperidyltrans-4-Hydroxycyclo-466hexylamino92**trans-4-Amino-Isobutylamino438cyclohexyl93**cis-4-Aminocyclo-Isobutylamino438hexyl94***cis-4-Aminocyclo-4-Piperidylamino465hexyl**Dihydrochloride; ***Trihydrochloride

[0435]

8

TABLE 8

Exam-

MS

ple
R1
R2
([M + H]+)

95**
cis-4-Hydroxy-
4-Piperidylamino
466

cyclohexyl

96***
trans-4-Amino-
4-Piperidylamino
465

cyclohexyl

97**
trans-4-Amino-
Isopropylamino
424

cyclohexyl

98**
2-Fluorophenyl
trans-4-Aminocyclohexyl
476

amino

99**
2-Cyanophenyl
trans-4-Aminocyclohexyl
483

amino

100*
trans-4-Hydroxy-
Isopropylamino
425

cyclohexyl

101*
trans-4-Hydroxy-
Isobutylamino
439

cyclohexyl

102*
trans-4-Hydroxy-
trans-4-Hydroxycyclo-
481

cyclohexyl
hexylamino

103
1-Hydroxycyclo-
Isopropylamino
383

propyl

104*
1-Hydroxycyclo-
trans-4-Hydroxycyclo-
439

propyl
hexylamino

*Monohydrochloride;

**Dihydrochloride;

***Trihydrochloride

[0436]

9

TABLE 9

Example
R1
MS ([M + H]+)

105
Methoxymethyl
412

106**
2-Methoxyethyl
426

107**
Ethyl
396

**Dihydrochloride

Examples 108 to 126

[0437] 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.

10TABLE 10

ExampleRing AMS ([M + H]+)108Phenyl459109*2-Fluorophenyl477110*3-Fluorophenyl477111*3,4-Difluorophenyl495112*2,4-Difluorophenyl495113*4-Chlorophenyl493114*4-Methylphenyl473115*4-Methoxyphenyl489116*3-Methoxyphenyl489117*4-Fluorobenzyl491118*3-Trifluoromethylphenyl527119*3-Chlorophenyl493120*3-Methylphenyl473121*4-Fluoro-3-Methoxyphenyl507122*3-Hydroxyphenyl475123*2-Thienyl465*Monohydrochloride

[0438]

11

TABLE 11

Example
R2
MS ([M + H]+)

124*
Isopropylamino
439

125*
Isobutylamino
453

126**
(1-Methyl-4-piperidyl)amino
494

*Monohydrochloride;

**Dihydrochloride

Example 127

[0439]

[0440] 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.

[0441] MS 452 ([M+H]+).

Examples 128 to 141

[0442] 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.

12TABLE 12

ExampleRing AMS ([M + H]+)128*3-Amino-4-fluorophenyl492129*3-Aminophenyl474130*3-hydroxymethylphenyl489131*2-Aminophenyl474132*2-Nitrophenyl504133*4-Fluoro-2-nitrophenyl522134*2-Cyanophenyl484135*3,5-Difluorophenyl495136*2-Carbamoylphenyl502*Monohydrochloride

[0443]

13

TABLE 13

Example
Ring A
MS ([M + H]+)

137*
3-Chlorophenyl
413

138*
3-Methylphenyl
393

139*
3,4-Difluorophenyl
415

140*
4-Chlorophenyl
413

141*
2-Cyanophenyl
404

*Monohydrochloride

Examples 142 to 156

[0444] 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 15.

14TABLE 14

ExampleR1MS ([M + H]+)142*4-Tetrahydropyranyl397143**1-Methyl-4-piperidyl410144*Cyclohexyl395145*Cyclopentyl381146*Cyclobutyl367147*4-Piperidyl396*Monohydrochloride; **Dihydrochloride

[0445]

15

TABLE 15

Exam-

MS

ple
Ring A
n
R1
([M + H]+)

148*
phenyl
1
trans-4-Hydroxycyclo-
407

hexyl

149*
3-Fluorophenyl
1
trans-4-Hydroxycyclo-
425

hexyl

150*
3-Chlorophenyl
1
trans-4-Hydroxycyclo-
441

hexyl

151*
3-Methylphenyl
1
trans-4-Hydroxycyclo-
421

hexyl

152*
3-Methoxyphenyl
1
trans-4-Hydroxycyclo-
437

hexyl

153*
2,4-Difluoro-
1
trans-4-Hydroxycyclo-
443

phenyl

hexyl

154*
3,4-Difluoro-
1
trans-4-Hydroxycyclo-
443

phenyl

hexyl

155*
4-Chlorophenyl
1
trans-4-Hydroxycyclo-
441

hexyl

156*
2-Carbamoyl-
0
Isopropyl
380

phenyl

*Monohydrochloride

Examples 157 to 161

[0446] 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 147, 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 80.

16TABLE 16

ExampleRaMS ([M + H]+)157*Acetyl438158*Ethoxycarbonyl468159**Carbamoylmethyl453160**Carboxymethyl454161**N-Methylcarbamoylmethyl467*Monohydrochloride; **Dihydrochloride

Examples 162 to 168

[0447] 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.

17TABLE 17

ExampleRing AMS ([M + H]+)162*3-Fluorophenyl370163*3-Chlorophenyl386164*3-Methylphenyl366165*3-Trifluoromethylphenyl420166*Phenyl352167*2,4-Difluorophenyl388168*4-Chlorophenyl386*Monohydrochloride

Example 169

[0448]

[0449] 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.

[0450] MS 385 ([M+H]+).

Example 170

[0451]

[0452] (1) A mixture comprising 100 mg of the compound of Example 169, 48 mg of 1-hydroxybenzotriazole, 60 mg of 1-(3-dimethylamino-propyl)-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 solution and 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.

[0453] (2) The compound obtained in (1) 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.

[0454] MS 412([M+H]+).

Examples 171 to 173

[0455] 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.

18TABLE 18

ExampleNRbRcMS ([M + H]+)171*Amino384172*Methylamino398173*Dimethylamino412*Monohydrochloride

Examples 174 to 178

[0456] 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.

19TABLE 19

ExampleRing AMS ([M + H]+)174*3,4-Difluorophenyl331175*4-Methoxyphenyl325176*3-Trifluoromethylphenyl363177*3-Chlorophenyl329178*3-Methylphenyl309*Monohydrochloride

Example 179

[0457]

[0458] 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.

[0459] MS 482 ([M+H]+).

Example 180

[0460]

[0461] To 200 mg of the compound of Example 179 was added 2 ml of 25% HBr-acetic acid solution, and the mixture was stirred under heating at 80° C. 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.

[0462] MS 376 ([M+H]+).

Examples 181 to 183

[0463] 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.

20TABLE 20

ExampleR1nR2MS ([M + H]+)1814-Hydroxyphenyl1Isopropylamino419182Hydrogen atom0Isopropylamino313183Hydrogen atom0Isobutylamino327

Examples 184 and 185

[0464] 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.

21TABLE 21

ExampleR2MS ([M + H]+)184trans-4-Hydroxycyclohexylamino369185trans-4-Aminocyclohexylamino368

Examples 186 to 197

[0465] 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.

22TABLE 22

Exam-MSpleRing AR2([M + H]+)1863-FluorophenylIsobutylamino3271873-FluorophenylIsopropylamino3131882,4-DifluorophenylIsopropylamino3311892-FluorophenylIsopropylamino3131902,4-DifluorophenylIsobutylamino3451913-MethoxyphenylIsopropylamino325192PhenylIsopropylamino2951932-Fluorophenyltrans-4-Acetoxycyclo-411hexylamino1943-Fluorophenyltrans-4-Acetoxycyclo-411hexylamino1952,4-Difluorophenyltrans-4-Acetoxycyclo-429hexylamino196Phenyltrans-4-Acetoxycyclo-hexylamino1973-Methoxyphenyltrans-4-Acetoxycyclo-423hexylamino

Example 198

[0466]

[0467] 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 (1). Then, Compound (1) was treated in the same manner as in Example 1 to give 744 mg of Compound (2).

[0468] MS 271 ([M+H]+).

Examples 199 to 221

[0469] 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.

23TABLE 23

MSExamplenR1([M + H]+)199*0Methyl32720003-hydroxypropyl3712010Butyl369202*02-Methoxyethyl371203*0Carbamoylmethyl3702040Ethyl341205*0Isopropyl355206*1Cyclobutyl381207*0Isobutyl369208*0Cyanomethyl352209*0Isopentyl383210*1Cyclopropyl367211**03-Aminopropyl370212*0Propyl35521302-Methoxymethoxyethyl401214*02-Hydroxyethyl357215*01-Carbamoylethyl384*Monohydrochloride; **Dihydrochloride

[0470]

24

TABLE 24

Example
Ring A
R1
MS ([M + H]+)

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

[0471] 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 25.

25TABLE 25

ExampleRing AR1MS ([M + H]+)2223-FluorophenylEthyl3972232,4-DifluorophenylEthyl4152243-MethoxyphenylEthyl4092252,4-DifluorophenylMethoxymethyl431

Example 226

[0472]

[0473] 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 (1). A mixture comprising 226 mg of Compound (1), 1.1 ml of 1N aqueous NaOH solution and 1.1 ml of ethanol was stirred at room temperature for 3 hours. The resulting mixture was neutralized with 1N 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 (2).

[0474] MS 384 ([M+H]+).

Example 227

[0475]

[0476] The compound of Example 226(1) was reacted with ethylamine in the same manner as in Example 226(2) to give the title compound.

[0477] MS 398 ([M+H]+).

Examples 228 and 229

[0478] The compound of Reference example 1(5) was reacted with a corresponding compound in the same manner as in Reference example 1(6), 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 (70° C.).

26TABLE 26

ExamplenR1MS ([M + H]+)22812-Fluorophenyl3792290Isopropyl313*Monohydrochloride

Example 230

[0479]

[0480] 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 (1). This compound (1) (707 mg) was dissolved in 7 ml of THF, and 410 mg of Boc2O 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 pre- cipitates were collected by filtration to give 770 mg of Compound (2) as colorless crystals.

[0481] MS 454 ([M+H]+).

Examples 231 to 242

[0482] 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.

27TABLE 27

Exam-MSplenR1R2([M + H]+)23112-CyanophenylAcetylamino42823212-Cyanophenyl2-Pyridylcarbonylamino49123312-FluorophenylAcetylamino42123412-FluorophenylPropionylamino43523512-FluorophenylIsobutyrylamino44923612-FluorophenylMethoxycarbonylacetyl479amino23712-Fluorophenyl3-Methoxypropionyl-465amino23812-FluorophenylCyclopropylcarbonyl-447amino239*0IsopropylCyclopropylcarbonyl-381amino240*0IsopropylCyclopentylcarbonyl-409amino241**04-PiperidylIsobutyrylamino424242**04-PiperidylCyclopropylcarbonyl-422amino*Monohydrochloride; **Dihydrochloride

Example 243

[0483]

[0484] In 45 ml of acetonitrile was dissolved 4.5 g of cis-4-(methoxy-methoxy)cyclohexane carboxylic acid, 3.73 g of 1,1′-carbonyl-diimidazole 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.

[0485] MS 439 ([M+H]+).

Examples 244 to 263

[0486] 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.

28TABLE 28

MSExampleR2([M + H]+)244(Acetylamino)acetylamino478245**(S)-2-Amino-propionylamino450246**(S)-2-Methylamino-propionylamino464247**(S)-2-Amino-3-methoxy-propionylamino480248**3-Amino-propionylamino450249**(S)-2-Pyrrolidinylcarbonylamino476250**cis-4-Amino-cyclohexylcarbonylamino504251**4-Piperidylcarbonylamino4902523-Acetylamino-propionylamino492253(1-Acetyl-4-piperidyl)carbonylamino532**Dihydrochloride

[0487]

29

TABLE 29

Exam-

MS

ple
n
R1
R2
([M + H]+)

254
1
2-Fluorophenyl
(S)-5-Oxopyrrolidin-2-
490

ylcarbonylamino

255*
1
2-Fluorophenyl
cis-4-Hydroxy-cyclo-
505

hexylcarbonylamino

256
1
2-Fluorophenyl
cis-4-Acetylamino-
546

cyclohexylcarbonyl-

amino

257
1
2-Fluorophenyl
(S)-1-Acetylpyrroli-
518

din-2-ylcarbonylamino

258**
1
2-Fluorophenyl
trans-4-Amino-cyclo-
504

hexylcarbonylamino

259*
1
2-Fluorophenyl
trans-4-Hydroxy-cyclo-
505

hexylcarbonylamino

260*
0
Isopropyl
(S)-5-Oxopyrrolidin-2-
424

ylcarbonylamino

261**
0
Isopropyl
cis-4-Amino-cyclo-
438

hexylcarbonylamino

262**
0
4-Piperidyl
trans-4-Hydroxy-cyclo-
480

hexylcarbonylamino

263**
0
4-Piperidyl
cis-4-Hydroxy-cyclo-
480

hexylcarbonylamino

*Monohydrochloride;

**Dihydrochloride

Examples 264 to 267

[0488] 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 30.

30TABLE 30

MSExampleRing AR1([M + H]+)264*3-ChlorophenylIsopropyl455265*3-MethylphenylIsopropyl435266*3-Chlorophenylethyl441267*3-Methylphenylethyl421*Monohydrochioride

Example 268

[0489]

[0490] 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 (1) as colorless powder.

[0491] MS 496 ([M+H]+).

[0492] Compound (1) (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 (2) as yellowish powder.

[0493] MS 396 ([M+H]+).

Example 269

[0494]

[0495] Compound (1) (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.

[0496] MS 507 ([M+H]+).

Example 270

[0497]

[0498] The compound of Reference example 7(1) was reacted with benzylamine in the same manner as in Example 17 to give the title compound.

[0499] MS 362 ([M+H]+).

Examples 271 to 336

[0500] The compound of Reference example 5(4) was reacted in the same manner as in Example 2 or Reference example 1(6), oxidized with 3-chloroperoxybenzoic acid in the same manner as in Reference example 6(2), 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 35.

31TABLE 31

ExampleR2MS ([M + H]+)271Benzylamino4772722-Methoxyethylamino445273Cyclopropylamino427274Butylamino443275Isopropylamino429276Ethylamino415277Cyclopropylmethylamino441278trans-4-Hydroxycyclohexylamino485279(S)-1-Hydroxymethyl-ethylamino445280(S)-1-Hydroxymethyl-propylamino459

[0501]

32

TABLE 32

Example
R2
MS ([M + H]+)

281
(S)-1-Hydroxymethyl-2-methylpropyl-
473

amino

282
(R)-1-Hydroxymethyl-ethylamino
445

283*
1-Methyl-4-piperidylamino
484

284
1-Benzyl-4-piperidylamino
560

285
1-Ethoxycarbonyl-4-piperidylamino
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

*Monohydrochloride;

**Dihydrochloride

[0502]

33

TABLE 33

MS

Example
n
R1
R2
([M + H]+)

291
1
2-Fluorophenyl
trans-4-Hydroxy-
478

cyclohexylamino

292
1
2-Methoxyphenyl
trans-4-Hydroxy-
490

cyclohexylamino

293**
1
4-Piperidyl
trans-4-Hydroxy-
467

cyclohexylamino

294**
1
4-Piperidyl
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-4-Hydroxy-
384

cyclohexylamino

299**
0
Methyl
trans-4-Aminocy-
383

clohexylamino

300*
0
Ethyl
trans-4-Hydroxy-
398

cyclohexylamino

301*
0
Ethyl
Isobutylamino
356

302*
0
Isopropyl
trans-4-Hydroxy-
412

cyclohexylamino

303**
0
Isopropyl
trans-4-Aminocyclo-
411

hexylamino

304**
0
ethyl
trans-4-Aminocyclo-
397

hexylamino

305*
1
cis-4-Hydroxy-
Isopropylamino
426

cyclohexyl

*Monohydrochloride;

**Dihydrochloride

[0503]

34

TABLE 34

MS

Example
n
R1
R2
([M + H]+)

306*
1
cis-4-Hydroxycy-
Isobutylamino
440

clohexyl

307*
1
trans-4-Hydroxy-
Isopropylamino
426

cyclohexyl

308*
1
trans-4-Hydroxy-
Isobutylamino
440

cyclohexyl

309**
1
cis-4-Aminocy-
Isopropylamino
425

clohexyl

310**
1
cis-4-Aminocy-
Isobutylamino
439

clohexyl

311**
1
cis-4-Aminocy-
trans-4-Hydroxycyclo-
481

clohexyl
hexylamino
481

312*
0
Ethyl
trans-4-acetylamino-
439

cyclohexylamino

313*
0
Isopropyl
trans-4-acetylamino-
453

cyclohexylamino

314***
1
cis-4-Aminocy-
trans-4-Aminocyclo-
480

clohexyl
hexylamino

315**
1
trans-4-Aminocy-
Isopropylamino
425

clohexyl

316**
1
trans-4-Aminocy-
Isobutylamino
439

clohexyl

317**
1
trans-4-Aminocy-
trans-4-Hydroxycyclo-
481

clohexyl
hexylamino

318***
1
trans-4-Aminocy-
trans-4-Aminocyclo-
480

clohexyl
hexylamino

319*
1
cis-4-Hydroxycy-
trans-4-Hydroxycyclo-
482

clohexyl
hexylamino

320*
0
Isobutyl
trans-4-Hydroxycyclo-
426

hexylamino

*Monohydrochloride;

**Dihydrochloride;

***Trihydrochloride

[0504]

35

TABLE 35

Ex-

am-

MS

ple
n
R1
R2
([M + H]+)

321*
0
propyl
trans-4-Hydroxycyclo-
412

hexylamino

322*
0
butyl
trans-4-Hydroxycyclo-
426

hexylamino

323*
0
Cyanomethyl
trans-4-Hydroxycyclo-
409

hexylamino

324*
0
2-Methoxyethyl
trans-4-Hydroxycyclo-
428

hexylamino

325*
0
3-hydroxypropyl
trans-4-Hydroxycyclo-
428

hexylamino

326*
1
Cyclopropyl
trans-4-Hydroxycyclo-
424

hexylamino

327*
1
Cyclobutyl
trans-4-Hydroxycyclo-
438

hexylamino

328*
0
Ethyl
4-Tetrahydropyranyl-
384

amino

329*
0
Ethyl
(S)-1-Hydroxymethyl-
358

ethylamino

330*
0
Ethyl
2-Hydroxy-1,1-di-
372

methylethylamino

331*
0
Ethyl
1-Hydroxymethyl-cyclo-
398

pentylamino

332
0
Ethyl
3-Methoxypropylamino
372

333
0
Isopropyl
2-Hydroxy-1,1-dimethyl-
386

ethylamino

334
0
Isopropyl
1-Hydroxymethyl-cyclo-
412

pentylamino

335
0
Ethyl
cis-4-Hydroxycyclohexyl-
398

amino

336
0
Isopropyl
cis-4-Hydroxycyclohexyl-
412

amino

*Monohydrochloride

Examples 337 to 343

[0505] 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 6(2), subsequently reacted with a corresponding amine in the same manner as in Example 17 to give the compounds shown in Table 36.

36TABLE 36

MSExampleRing A([M + H]+)337*3-Fluorophenyl412338*3-Methylphenyl408339*Phenyl394340*3-Chlorophenyl428341*4-Chlorophenyl428342*2,4-Difluorophenyl430343*3-Methoxyphenyl424*Monohydrochloride

Examples 344 to 349

[0506] 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.

37TABLE 37

ExampleRing AMS([M + H]+)344*3-Chlorophenyl414345*3-Methylphenyl394346*3-Trifluoromethylphenyl448347*4-Chlorophenyl414348*Phenyl380349*3-Fluorophenyl398*Monohydrochloride

Example 350

[0507]

[0508] (1) To 300 ml of a diethyl ether solution containing 52.0 g of the compound of Reference example 5(3) was added dropwise 100 ml of a diethyl ether solution containing 30.2 g of 4-fluorophenyl isocyanate under ice-cooling, and the mixture 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 to give 75.0 g of Compound (1) as colorless crystals.

[0509] (2) In chloroform was dissolved 30.0 g of Compound (1), 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 (2) as colorless crystals.

[0510] (3) 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.

[0511] MS 314 ([M+H]+).

Examples 351 to 354

[0512] 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.

38TABLE 38

Exam-MSpleRing AR2([M + H]+)3514-Fluorophenyltrans-4-Hydroxycyclo-370hexylamino352*4-FluorophenylIsobutylamino3283532,4-DifluorophenylIsopropylamino332354PhenylIsopropylamino296*Monohydrochloride

Examples 355 to 367

[0513] 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.

39TABLE 39

MSExampleRing AR1([M + H]+)355*4-FluorophenylMethyl328356*4-FluorophenylEthyl342357*4-FluorophenylMethoxymethyl3583582,4-DifluorophenylEthyl360359PhenylEthyl3243604-ChlorophenylEthyl3583613-FluorophenylEthyl3423623-MethoxyphenylEthyl3543632,4-DifluorophenylMethoxymethyl376364PhenylMethoxymethyl3403654-ChlorophenylMethoxymethyl374366*4-Fluorophenyl2-Methoxyethyl372367*4-FluorophenylCyanomethyl353*Monohydrochloride

Examples 368 to 382

[0514] Compound of Reference example 5(4) was reacted in the same manner as in Example 2 or Reference example 1(6), oxidized with 3-chloroperoxybenzoic acid in the same manner as in Reference example 6(2), 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 80 to give the compounds shown in Table 40.

40TABLE 40

MSR1R2([M + H]+)Example368*Ethylcis-4-Hydroxymethyl-412cyclohexylamino369*Ethyltrans-4-Hydroxymethyl412cyclohexylamino370*Ethyl3-Hydroxy-2,2-dimethyl-386propylamino371*Isopropylcis-4-Hydroxymethyl-426cyclohexylamino372*Isopropyltrans-4-Hydroxymethyl-426cyclohexylamino373*Isopropyl3-Hydroxy-2,2-dimethyl-400propylamino374*Isopropyl(S)-2-Hydroxypropylamino372375*Isopropyl(R)-2-Hydroxypropylamino372376*Isopropyl1-Hydroxycyclohexyl-426methylamino377**Isopropyl2-Hydroxy-1-hydroxy-methyl-1-methylethyl-402amino378**Isopropyl4-Piperidyl397379**Isopropyl(S)-1-(2-Pyridyl)ethyl-419amino380*Isopropyl(1S,2S)-2-Hydroxycyclo-398pentylaminoExamples381*Ethyl(1S,2S)-2-Hydroxycyclo-384pentylamino382*Ethyltrans-4-Carbamoylcyclo-425hexylamino*Monohydrochloride; **Dihydrochloride

Examples 383 to 386

[0515] 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.

41TABLE 41

MSExamplesR1R2([M + H]+)383*Isopropyltrans-4-Methanesulfonyl-489aminocyclohexylamino384*Isopropyltrans-4-Methoxycarbonyl-469aminocyclohexylamino385*Ethyltrans-4-Methanesulfonyl-475aminocyclohexylamino386*Ethyltrans-4-Methoxycarbonyl-455aminocyclohexylamino*Monohydrochloride

Example 387

[0516]

[0517] The compound of Example 1 (100 mg), 4-acetylphenylboronic acid (129 mg), copper (II) acetate (72 mg) and triethylamine (220 μl) were suspended in 10 ml of methylene chloride, and the suspension was stirred at room temperature for 24 hours. To the reaction 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 filtration to give 92 mg of the title compound. Melting point: 206° C. (decomposed)

Examples 388 to 389

[0518] 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.

42TABLE 42

Melting pointExamplesR1(° C.)3884-Pyridyl1893893-Thienyl193-195

Example 390

[0519]

[0520] To a solution of the compound of Example 13 (50 mg) in THF was added ethyl isocyanate (12 μl), 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 compound as colorless crystal. Melting point: 20.9-210° C.

Examples 391 to 394

[0521] 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.

43TABLE 43

Melting pointExamplesR1R2(° C.)3912-CyanobenzylCarboxy135(decomposed)3922-CyanobenzylCarbamoyl209-210(decomposed)3932-FluorobenzylHydroxymethyl157-158(decomposed)3942-FluorobenzylDimethylamino-231-236methyl(decomposed)

Examples 395 to 398

[0522] The corresponding starting materials were reacted in the manner as in Example 368 to give the compounds shown in 44.

44TABLE 44

MSExamplesR1R2([M + H]+)395*Ethyltrans-4-Hydroxycyclohexyl-412methylamino396*Isopropyltrans-4-Hydroxycyclohexyl-426methylamino397*Ethylcis-4-Hydroxycyclohexyl-412methylamino398*Isopropylcis-4-Hydroxycyclohexyl-426methylamino*Monohydrochloride

Examples 399 to 416

[0523] The compound of Reference example 5(4) and the corresponding starting materials were reacted in the same manner as in Reference example 1(6), oxidized with 3-chloroperbenzoic acid in the same manner as in Reference example 6(2), 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 80 to give the compounds in Tables 45 and 46.

45TABLE 45

MSExampleR1R2([M + H]+)399*Ethyl1,1-Dioxotetrahydrothio-418phen-3-ylamino400*Ethyltrans-4-(Methylcarbamoyl)439cyclohexylamino401*Ethyl1,5-Dimethyl-5-hydroxy-428hexylamino402*Isopropyl1,5-Dimethyl-5-hydroxy-442hexylamino403*Ethylcis-4-Hydroxy-4-methyl-412cyclohexylamino404*Isopropyltrans-4-Hydroxy-4-methyl-426cyclohexylamino405*Isopropyltrans-4-(1-Hydroxy-1-454methylethyl)cyclohexylamino406*Ethyltrans-4-Hydroxy-4-methyl-412cyclohexylamino407*Isopropylcis-4-Hydroxy-4-methyl-426cyclohexylamino*monohydrochloride

[0524]

46

TABLE 46

MS

Example
R1
R2
([M + H]+)

408*
Ethyl
trans-4-(1-Hydroxy-1-
440

methylethyl)cyclohexylamino

409*
Ethyl
(S)-1,2-Dimethyl-2-hy-
386

droxypropylamino

410*
Isopropyl
(S)-1,2-Dimethyl-2-hy-
400

droxypropylamino

411*
Ethyl
1,3-Dimethyl-3-hydroxy-
400

butylamino

412*
Isopropyl
1,3-Dimethyl-3-hydroxy-
414

butylamino

413*
Isopropyl
2-Mercapto-2-methylpropyl-
402

amino

414*
Isopropyl
1,1-Bishydroxymethyl-
416

propylamino

415*
Isopropyl
2-Hydroxy-2-methylpropyl-
386

amino

416**
Ethyl
4-Piperidylamino
383

*monohydrochloride;

**dihydrochloride

Examples 417 to 433

[0525] The compound of Reference example 5(4) was reacted in the same manner as in Example 2 or Reference example 1(6), reacted with methymagnesium bromide if necessary, subsequently oxidized with 3-chloroperbenzoic acid in the same manner as in Reference example 6(2), and reacted with the corresponding amine in the same manner as in Example 17 to give the compounds in Tables 47 and 48.

47TABLE 47

Exam-MSpleR1R2([M + H]+)417*1,2-Dimethyl-2-hy-Isopropylamino400droxypropyl418*1,2-Dimethyl-2-hy-cis-4-Hydroxy-4-470droxypropylmethylcyclohexylamino419*1,2-Dimethyl-2-hy-(S)-1,2-Dimethyl-2-hy-444droxypropyldroxypropylamino420*1,2-Dimethyl-2-hy-Trans-4-Hydroxy-4-470droxypropylmethylcyclohexylamino421*2-Hydroxy-1,1,2-Isopropylamino414trimethylpropyl422*2-Hydroxy-1,1,2-Trans-4-Hydroxy-4-484trimethylpropylmethylcyclohexylamino423*3-Hydroxy-3-methyl-Isopropylamino400butyl424*3-Hydroxy-3-methyl-1,1-Dimethyl-2-hy-430butyldroxyethylamino*monohydrochloride

[0526]

48

TABLE 48

MS

Example
R1
R2
([M + H]+)

425*
3-Hydroxy-3-
2,2-Dimethyl-3-hy-
444

methylbutyl
droxypropylamino

426*
3-Hydroxy-3-
1-Hydroxymethyl-
456

methylbutyl
cyclopentylamino

427*
3-Hydroxy-3-
trans-4-Hydroxy-4-
470

methylbutyl
methylcyclohexyl-

amino

428*
3-Hydroxy-3-
4-Tetrahydro-
442

methylbutyl
pyranylamino

429*
3-Hydroxy-3-
(R)-1,2-Dimethyl-2-
444

methylbutyl
hydroxypropyl-

amino

430*
3-Hydroxy-3-
(S)-1,2-Dimethyl-2-
444

methylbutyl
hydroxypropyl-

amino

431*
3-Hydroxy-3-
trans-4-Hydroxy-
456

methylbutyl
cyclohexylamino

432*
3-Hydroxy-3-
1-Methanesulfonyl-
519

methylbutyl
piperidin-4-ylamino

433*
3-Hydroxy-3-
1-Ethanesulfonyl-
533

methylbutyl
piperidin-4-ylamino

*monohydrochloride

Examples 434 to 460

[0527] 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(2), and subsequently reacted with the corresponding compound in the same manner as in Example 17 to give the compounds in Tables 49 to 51.

49TABLE 49

Exam-MSpleR1R2([M + H]+)434*4-Tetrahydro-Isobutylamino412pyranyl435*4-Tetrahydro-Isopropylamino398pyranyl436*4-Tetrahydro-trans-4-Hydroxy-4-468pyranylmethylcyclo-hexylamino437*4-Tetrahydro-Cyclopropylamino396pyranyl438*4-Tetrahydro-2,2-Dimethylpropyl-426pyranylamino439*1-Acetylpiperi-trans-4-Hydroxy-4-509din-4-ylmethylcyclo-hexylamino440*1-Acetylpiperi-2,2-Dimethylpropyl-467din-4-ylamino441*1-Acetylpiperi-Isopropylamino439din-4-yl442*1-Acetylpiperi-Isobutylamino453din-4-yl443*1-Acetylpiperi-Cyclopropylamino437din-4-yl444*4-Tetrahydro-(R)-1,2-Dimethyl-2-442pyranylhydroxypropyl-amino445*4-Tetrahydro-(S)-1,2-Dimethyl-2-442pyranylhydroxypropyl-amino446*4-Tetrahydro-(S)-2-Hydroxy-1-414pyranylmethyl-ethylamino*monohydrochloride

[0528]

50

TABLE 50

Exam-

MS

ple
R1
R2
([M + H]+)

447*
4-Tetrahydropy-
(S)-1-Hydroxymethyl-
428

ranyl
propylamino

448*
4-Tetrahydropy-
1,1-Dimethyl-2-hy-
428

ranyl
droxyethylamino

449*
4-Tetrahydropy-
4-Tetrahydropyranyl-
440

ranyl
amino

450*
1-Acetylpiperi-
1,1-Dimethyl-2-hy-
469

din-4-yl
droxyethylamino

451*
1-Acetylpiperi-
4-Tetrahydropyranyl-
481

din-4-yl
amino

452*
1-Acetylpiperi-
(S)-1-Hydroxymethyl-
469

din-4-yl
propylamino

453*
1-Acetylpiperi-
(S)-1,2-Dimethyl-2-
483

din-4-yl
hydroxypropylamino

*monohydrochioride

[0529]

51

TABLE 51

100

Exam-

MS

ple
R1
R2
([M + H]+)

454*
4-Tetrahydropy-
trans-4-Hydroxycyclo-
454

ranyl
hexylamino

455*
1-Acetylpiperi-
trans-4-Hydroxycyclo-
495

din-4-yl
hexylamino

456*
1-Methanesulfonyl-
trans-4-Hydroxycyclo-
531

piperidin-4-yl
hexylamino

457*
1-Methanesulfonyl-
trans-4-Hydroxy-4-
545

piperidin-4-yl
methylcyclohexylamino

458*
1-Methanesulfonyl-
Isopropylamino
475

piperidin-4-yl

459*
4-Tetrahydropy-
1-Methanesulfonyl-
517

ranyl
piperidin-4-ylamino

460*
1-Acetylpiperi-
1-Methanesulfonyl-
558

din-4-yl
piperidin-4-ylamino

*monohydrochloride

Examples 461 to 476

[0530] 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.

52TABLE 52

101

Exam-MSpleR1R2([M + H]+)461*Isopropyl1-Acetylpiperidin-4-yl-439amino462*Isopropyl1-Methanesulfonylpiperi-475din-4-ylamino463*Isopropyl1-(Isopropylsulfonyl)piperi-503din-4-ylamino464*Isopropyl1-(Propylsulfonyl)piperi-503din-4-ylamino465*Isopropyl1-(Butylsulfonyl)piperi-517din-4-ylamino466*Isopropyl1-(Isobutyloxycarbonyl)piperi-497din-4-ylamino467*Isopropyl1-butyrylpiperidin-4-ylamino467468*Ethyl1-Acetylpiperidin-4-ylamino425*monohydrochloride

[0531]

53

TABLE 53

102

Exam-

MS

ple
R1
R2
([M + H]+)

469*
Ethyl
1-Methanesulfonylpiperi-
461

din-4-ylamino

470*
Ethyl
1-Ethanesulfonylpiperi-
475

din-4-ylamino

471*
Isopropyl
1-Ethylcarbamoylpiperi-
468

din-4-ylamino

472*
Isopropyl
1-Propylcarbamoylpiperi-
482

din-4-ylamino

473*
Isopropyl
1-Isopropylcarbamoylpiperi-
482

din-4-ylamino

474*
Isopropyl
1-Ethanesulfonylpiperi-
489

din-4-ylamino

475*
Isopropyl
1-Methoxycarbonylpiperi-
455

din-4-ylamino

476*
Isopropyl
1-Ethoxycarbonylpiperi-
469

din-4-ylamino

*monohydrochloride

Examples 477, 478

[0532] The compound of Example 147 was subjected to alkylsulfonylation by the conventional manner to give the compounds in Table 54.

54TABLE 54

103

Exam-MSpleR1R2([M + H]+)477*1-Methanesulfonyl-Isopropylamino474piperidin-4-yl478*1-EthanesulfonylIsopropylamino488piperidin-4-yl*monohydrochloride

[0533] In a similar manner to those described in the Examples above, the following compounds were prepared.

55TABLE 55

104

Exam-MSpleR1R2([M + H]+)479*1-(methanesulfonyl)(1S)-1,2-Dimethyl-2-519piperidin-4-ylhydroxypropylamino480*2-Hydroxy-2-1-(Isopropylsulfonyl)533methylpropylpiperidin-4-ylamino481Isopropyl(3R)-3-pyrrolidinyl-383amino482*Isopropyl(3R)-1-Methanesulfonyl-461pyrrolidin-3-ylamino483*Isobutyl1-(Ethanesulfonyl)503piperidin-4-ylamino484*Isobutyl1-(Isopropylsulfonyl)517piperidin-4-ylamino485*Cyclopropylmethyl1-(Methanesulfonyl)487piperidin-4-ylamino-486*Isopropyltrans-4-(N-Methane-503sulfonyl-N-methylamino)cyclohexylamino487*4-Tetrahydropyranyl1-(Ethanesulfonyl)531piperidin-4-ylamino488*4-Tetrahydropyranyl1-(Isopropylsulfonyl)545piperidin-4-ylamino489*4-Tetrahydropyranyl1-(Methoxycarbonyl)497piperidin-4-ylamino490*4-Tetrahydropyranyl1-propionylpiperidin-4954-ylamino491*4-Tetrahydropyranyl1-Acetylpiperidin-4-481ylamino*monohydrochloride

[0534]

56

TABLE 56

105

Exam-

MS

ple
R1
R2
([M + H]+)

492*
Isobutyl
1-Acetylpiperidin-4-
453

ylamino

493*
Methoxymethyl
1-(Ethanesulfonyl)piperi-
491

din-4-ylamino

494*
Methoxymethyl
1-(Isopropylsulfonyl)
505

piperidin-4-ylamino

495*
4-Tetrahydro-
1-(Dimethylaminosulfonyl)
546

pyranyl
piperidin-4-ylamino

496*
4-Tetrahydropy-
trans-4-(Methanesulfonyl-
531

ranyl
amino)cyclohexylamino

497*
2-hydroxy-2-
(1S)-1,2-Dimethyl-2-hy-
430

ethylpropyl
droxypropylamino

498*
Cyclobutyl
trans-4-Hydroxycyclo-
424

hexylamino

499*
Cyclobutyl
trans-4-Methyl-4-hy-
438

droxycyclohexylamino

500*
Cyclobutyl
1-(Methanesulfonyl)piperi-
487

din-4-ylamino

501*
Cyclobutyl
1-(Ethanesulfonyl)piperi-
501

din-4-ylamino

502*
Cyclobutyl
1-(Isopropylsulfonyl)
515

piperidin-4-ylamino

503*
Cyclobutyl
1-(Dimethylaminosulfonyl)
516

piperidin-4-ylamino

*monohydrochloride

[0535]

57

TABLE 57

106

Exam-

MS

ple
R1
R2
([M + H]+)

504*
4-Tetrahydro-
trans-4-(N-Methanesulfonyl-
545

pyranyl
N-methylamino)cyclo-

hexylamino

505*
Cyclobutyl
(1S)-1,2-Dimethyl-2-hy-
412

droxypropylamino

506*
Isopropyl
(3S)-1-(Methanesulfonyl)
475

piperidin-3-ylamino

507*
Methoxymethyl
1-(Dimethylaminosulfonyl)
506

piperidin-4-ylamino

508*
2-Hydroxy-2-
1-(Dimethylaminosulfonyl)
534

methylpropyl
piperidin-4-ylamino

509*
3-Hydroxy-3-
1-(Dimethylaminosulfonyl)
548

methylbutyl
piperidin-4-ylamino

510*
2-Hydroxy-2-
trans-4-(N-Methanesulfonyl-
533

methylpropyl
N-methylamino)cyclohexyl

511*
3-Hydroxy-3-
trans-4-(N-Methanesulfonyl-
547

methylbutyl
N-methylamino)cyclo-

hexylamino

512*
4-Tetrahydro-
trans-4-(N-Ethyl-N-
559

pyranyl
methanesulfonylamino)cyclo-

hexylamino

513
Isopropyl
3-Amino-2,2-dimethyl-
399

propylamino

514
Isopropyl
2-amino-2-methylpropyl-
385

amino

515*
Isobutyl
trans-4-Hydroxy-4-methyl
440

cyclohexylamino

516**
Cyclobutyl
trans-4-aminocyclo-
423

hexylamino

*monohydrochloride,

**dihydrochloride

[0536]

58

TABLE 58

107

Exam-

MS

ple
R1
R2
Ring A
([M + H]+)

517*
1-Acetyl-
trans-4-Hydroxy-
3-Methyl-
505

piperidin-
4-methylcyclo-
phenyl

4-yl
hexylamino

518*
4-Tetrahy-
(1S)-1,2-Dimethyl-
3-Methyl
438

dropyranyl
2-hydroxypro-
phenyl

pylamino

519*
4-Tetrahy-
(1S)-1,2-Dimethyl-
3-Chloro-
458

dropyranyl
2-hydroxypro-
phenyl

pylamino

520*
4-Tetrahy-
trans-4-Hydroxy-
3-Methyl-
207-209

dropyranyl
cyclohexylamino
phenyl
° C.(melt-

ing point

521*
4-Tetrahy-
trans-4-Hydroxy-
3-Methyl-
211-214

dropyranyl
4-methylcyclo-
phenyl
° C.(melt-

hexylamino

ing point)

522*
4-Tetrahy-
trans-4-Hydroxy-
4-Chloro-
195-199

dropyranyl
4-methylcyclo-
phenyl
° C.(melt-

hexylamino

ing point)

523*
4-Tetrahy-
trans-4-Hydroxy-
4-Chloro-
272-275

dropyranyl
cyclohexylamino
phenyl
° C.(melt-

ing point)

524*
4-Tetrahy-
trans-4-Hydroxy-
3-Chloro
213-215

dropyranyl
4-methylcyclo-
phenyl
° C.(melt-

hexylamino

ing point)

525
4-Tetrahy-
trans-4-Hydroxy-
4-Fluoro-
233-236

dropyranyl
4-methylcyclo-
phenyl
° C.(melt-

hexylamino

ing point)

*monohydrochloride

[0537]

59

TABLE 59

108

Exam-

MS

ple
R1
R2
([M + H]+)

526*
4-Tetrahydro-
1,1-Dioxotetrahydrothio-
488

pyranyl
pyran-4-ylamino

527*
Isopropyl
2-Acetylamino-2-methyl-
427

propylamino

528*
Isopropyl
2-Methanesulfonylamino-
463

2-methylpropylamino

529*
Isopropyl
3-Acetylamino-2,2-di-
441

methylpropylamino

530*
Isopropyl
2,2-Dimethyl-3-methane-
477

sulfonylaminopropylamino

531*
Cyclopentyl
trans-4-Hydroxymethylcyclo-
452

hexylamino

532*
Cyclopentyl
1-Ethanesulfonylpiperi-
515

din-4-ylamino

*monohydrochloride

[0538]

60

TABLE 60

109

Exam-

MS

ple
R1
R2
([M + H]+)

533*
Cyclopentyl
1-Isopropylsulfonylpi-
529

peridin-4-ylamino

534*
Cyclopentyl
1-Methanesulfonylpiperi-
501

din-4-ylamino

535*
Cyclopentyl
4-Tetrahydropyranylamino
424

536*
Cyclopentyl
trans-4-Hydroxy-4-methyl-
452

cyclohexylamino

537*
Cyclopentyl
(1S)-1,2-Dimethyl-2-hy-
426

droxypropylamino

538*
Cyclopentyl
1,1-Dimethyl-2-hy-
412

droxyethylamino

539*
Cyclopentyl
2,2-Dimethyl-3-hydroxy-
426

propylamino

540*
Cyclopentyl
trans-4-Hydroxycyclo-
438

hexylamino

541*
Cyclopentyl
trans-4-aminocyclohexyl-
437

amino

542*
Cyclohexyl
trans-4-hydroxymethyl-
466

cyclohexylamino

543*
Cyclohexyl
1-Ethanesulfonylpiperi-
529

din-4-ylamino

544*
Cyclohexyl
1-Isopropylsulfonylpiperi-
543

peridin-4-ylamino

*monohydrochloride

[0539]

61

TABLE 61

110

Exam-

MS

ple
R1
R2
([M + H]+)

545*
Cyclohexyl
1-Methanesulfonylpiperidin-4-
515

ylamino

546*
Cyclohexyl
4-Tetrahydropyranylamino
438

547*
Cyclohexyl
trans-4-Hydroxy-4-methylcyclo-
466

hexylamino

548*
Cyclohexyl
(1S)-1,2-Dimethyl-2-hydroxy-
440

propylamino

549*
Cyclohexyl
1,1-Dimethyl-2-hydroxyethyl-
426

amino

550*
Cyclohexyl
2,2-Dimethyl-3-hydroxypropyl-
440

amino

551*
Cyclohexyl
trans-4-Hydroxycyclohexyl-
452

amino

552*
Cyclohexyl
trans-4-aminocyclohexylamino
451

553*
Isopropyl
2,2-Dimethyl-3-(N-methanesul-
491

fonyl-N-methylamino)propyl-

amino

554*
Isopropyl
2-(N-Methanesulfonyl-N-methyl-
477

amino)-2-methylpropylamino

*monohydrochloride

[0540]

62

TABLE 62

111

Exam-

MS

ple
R1
R2
Ring A
([M + H]+)

555*
4-Tetrahydro-
1-Methanesulfonyl-
3-Methyl-
513

pyranyl
piperidin-4-ylamino
phenyl

556*
4-Tetrahydro-
1-Methanesulfonyl-
3-Chloro-
533

pyranyl
piperidin-4-ylamino
phenyl

*monohydrochloride

[0541] In a similar manner to those described in the Examples above, the following compounds are prepared.

63TABLE 63

112

No.R1R2Ring A14-Tetrahydro-1-Acetyl-4-methylpiperi-4-Fluorophenylpyranyldin-4-ylamino24-Tetrahydro-1-Methanesulfonyl-4-methyl-4-Fluorophenylpyranylpiperidin-4-ylamino34-Tetrahydro-trans-4-amino-4-methyl-4-Fluorophenylpyranylcyclohexylamino44-Tetrahydro-trans-4-Methoxycyclo-4-Fluorophenylpyranylylamino54-Tetrahydro-trans-4-Hydroxymethyl-4-Fluorophenylpyranylcyclohexylamino64-Tetrahydro-trans-4-(1-Hydroxy-1-methyl-4-Fluorophenylpyranylethyl) cyclohexylamino74-Tetrahydro-cis-4-Hydroxycyclohexyl-4-Fluorophenylpyranylmethylamino84-Tetrahydro-cis-4-Hydroxy-4-methyl-4-Fluorophenylpyranylcyclohexylmethylamino94-Tetrahydro-1-Acetyl-4-methylpiperi-3-Methyl-pyranyldin-4-ylaminophenyl104-Tetrahydro-1-Methanesulfonyl-4-3-Methyl-pyranylmethylpiperidin-4-ylaminophenyl114-Tetrahydro-trans-4-amino-4-methyl-3-Methyl-pyranylcyclohexylaminophenyl124-Tetrahydro-trans-4-Methoxycyclo-3-Methyl-pyranylhexylaminophenyl134-Tetrahydro-trans-4-Hydroxymethyl-3-Methyl-pyranylcyclohexylaminophenyl

[0542]

64

TABLE 64

113

No.
R1
R2
Ring A

14
4-Tetrahydro-
trans-4-(1-Hydroxy-1-
3-Methylphenyl

pyranyl
methylethyl)cyclohexylamino

15
4-Tetrahydro-
cis-4-Hydroxycyclohexyl-
3-Methylphenyl

pyranyl
methylamino

16
4-Tetrahydro-
cis-4-Hydroxy-4-methyl-
3-Methylphenyl

pyranyl
cyclohexylmethylamino

17
4-Tetrahydro-
1-Acetyl-4-methylpiperi-
3-Chlorophenyl

pyranyl
din-4-ylamino

18
4-Tetrahydro-
1-Methanesulfonyl-4-
3-Chlorophenyl

pyranyl
methylpiperidin-4-ylamino

19
4-Tetrahydro-
trans-4-amino-4-methyl-
3-Chlorophenyl

pyranyl
cyclohexylamino

20
4-Tetrahydro-
trans-4-Methoxycyclo-
3-Chlorophenyl

pyranyl
hexylamino

21
4-Tetrahydro-
trans-4-Hydroxymethyl-
3-Chlorophenyl

pyranyl
cyclohexylamino

22
4-Tetrahydro-
trans-4-(1-Hydroxy-1-
3-Chlorophenyl

pyranyl
methylethyl)cyclohexylamino

23
4-Tetrahydro-
cis-4-Hydroxycyclohexyl
3-Chlorophenyl

pyranyl
methylamino

24
4-Tetrahydro-
cis-4-Hydroxy-4-methyl
3-Chlorophenyl

pyranyl
cyclohexylmethylamino

25
4-Tetrahydro-
1-Acetylpiperidin-4-
3-Trifluoro-

pyranyl
ylamino
methylphenyl

[0543]

65

TABLE 65

114

No.
R1
R2
Ring A

26
4-Tetrahydro-
1-Methanesulfonylpiperi-
3-Trifluoromethyl-

pyranyl
din-4-ylamino
phenyl

27
4-Tetrahydro-
1-Ethanesulfonylpiperi-
3-Trifluoro-

pyranyl
din-4-ylamino
methylphenyl

28
4-Tetrahydro-
1-Isopropylsulfonylpiperi-
3-Trifluoro-

pyranyl
din-4-ylamino
methylphenyl

29
4-Tetrahydro-
1-Acetyl-4-methylpiperi-
3-Trifluoro-

pyranyl
din-4-ylamino
methylphenyl

30
4-Tetrahydro-
1-Methanesulfonyl-4-
3-Trifluoro-

pyranyl
methylpiperidin-4-
methylphenyl

ylamino

31
4-Tetrahydro-
trans-4-Amino-4-methyl
3-Trifluoro-

pyranyl
cyclohexylamino
methylphenyl

32
4-Tetrahydro-
trans-4-Hydroxycyclo-
3-Trifluoro-

pyranyl
hexylamino
methylphenyl

33
4-Tetrahydro-
trans-4-Methoxycyclo-
3-Trifluoro-

pyranyl
hexylamino
methylphenyl

34
4-Tetrahydro-
trans-4-Hydroxy-4-
3-Trifluoro-

pyranyl
methylcyclohexylamino
methylphenyl

35
4-Tetrahydro-
cis-4-Hydroxycyclo-
3-Trifluoro-

pyranyl
hexylmethylamino
methylphenyl

36
4-Tetrahydro-
cis-4-Hydroxy-4-methyl
3-Trifluoro-

pyranyl
cyclohexylmethylamino
methylphenyl

37
4-Tetrahydro-
(1S)-1,2-Dimethyl-2-
3-Trifluoro-

pyranyl
hydroxypropylamino
methylphenyl

38
4-Tetrahydro-
1-Acetylpiperidin-4-
4-Fluorophenyl

pyranylmethyl
ylamino

[0544]

66

TABLE 66

115

No.
R1
R2
Ring A

39
4-Tetrahydro-
1-Methanesulfonylpiperi-
4-Fluorophenyl

pyranylmethyl
din-4-ylamino

40
4-Tetrahydro-
1-Ethanesulfonylpiperi-
4-Fluorophenyl

pyranylmethyl
din-4-ylamino

41
4-Tetrahydro-
1-Isopropylsulfonylpiperi-
4-Fluorophenyl

pyranylmethyl
din-4-ylamino

42
4-Tetrahydro-
1-Acetyl-4-methylpiperi-
4-Fluorophenyl

pyranylmethyl
din-4-ylamino

43
4-Tetrahydro-
1-Methanesulfonyl-4-
4-Fluorophenyl

pyranylmethyl
methylpiperidin-4-

ylamino

44
4-Tetrahydro-
trans-4-Amino-4-methyl-
4-Fluorophenyl

pyranylmethyl
cyclohexylamino

45
4-Tetrahydro-
trans-4-Methoxycyclo-
4-Fluorophenyl

pyranylmethyl
hexylamino

46
4-Tetrahydro-
trans-4-Hydroxy-4-
4-Fluorophenyl

pyranylmethyl
methylcyclohexylamino

47
4-Tetrahydro-
trans-4-(N-methanesul-
4-Fluorophenyl

pyranylmethyl
fonyl-N-methylamino)

cyclohexylamino

48
4-Tetrahydro-
cis-4-Hydroxycyclohexyl-
4-Fluorophenyl

pyranylmethyl
methylamino

49
4-Tetrahydro-
cis-4-Hydroxy-4-methyl-
4-Fluorophenyl

pyranylmethyl
cyclohexylmethylamino

50
4-Tetrahydro-
(1S)-1,2-Dimethyl-2-
4-Fluorophenyl

pyranylmethyl
hydroxypropylamino

51
4-Tetrahydro-
2,2-Dimethyl-3-hydroxy-
4-Fluorophenyl

pyranylmethyl
propylamino

[0545]

67

TABLE 67

116

No.
R1
R2
Ring A

52
3-Tetrahydro-
1-Acetylpiperidin-4-
4-Fluorophenyl

furyl
ylamino

53
3-Tetrahydro-
1-Methanesulfonylpiperi-
4-Fluorophenyl

furyl
din-4-ylamino

54
3-Tetrahydro-
1-Ethanesulfonylpiperi-
4-Fluorophenyl

furyl
din-4-ylamino

55
3-Tetrahydro-
1-Isopropylsulfonylpiperi-
4-Fluorophenyl

furyl
din-4-ylamino

56
3-Tetrahydro-
1-Acetyl-4-methylpiperi-
4-Fluorophenyl

furyl
din-4-ylamino

57
3-Tetrahydro-
1-Methanesulfonyl-4-
4-Fluorophenyl

furyl
methylpiperidin-4-ylamino

58
3-Tetrahydro-
trans-4-Amino-4-methyl-
4-Fluorophenyl

furyl
cyclohexylamino

59
3-Tetrahydro-
trans-4-Methoxycyclo-
4-Fluorophenyl

furyl
hexylamino

60
3-Tetrahydro-
trans-4-Hydroxycyclo-
4-Fluorophenyl

furyl
hexylamino

61
3-Tetrahydro-
trans-4-Hydroxy-4-methyl-
4-Fluorophenyl

furyl
methylcyclohexylamino

62
3-Tetrahydro-
trans-4-(N-methanesul-
4-Fluorophenyl

furyl
fonyl-N-methylamino)

cyclohexylamino

63
3-Tetrahydro-
cis-4-Hydroxycyclohexyl-
4-Fluorophenyl

furyl
hexylmethylamino

64
3-Tetrahydro-
cis-4-Hydroxy-4-methyl-
4-Fluorophenyl

furyl
cyclohexylmethylamino

[0546]

68

TABLE 68

117

No.
R1
R2
Ring A

65
3-Tetrahydro-
(1S)-1,2-Dimethyl-2-
4-Fluorophenyl

furyl
hydroxypropylamino

66
3-Tetrahydro-
2,2-Dimethyl-3-hydroxy-
4-Fluorophenyl

furyl
propylamino

67
1-Methylpropyl
1-Acetylpiperidin-4-
4-Fluorophenyl

ylamino

68
1-Methylpropyl
1-Methanesulfonylpiperi-
4-Fluorophenyl

din-4-ylamino

69
1-Methylpropyl
1-Ethanesulfonylpiperi-
4-Fluorophenyl

din-4-ylamino

70
1-Methylpropyl
1-Isopropylsulfonyl-
4-Fluorophenyl

piperidin-4-ylamino

71
1-Methylpropyl
1-Acetyl-4-methylpiperi-
4-Fluorophenyl

din-4-ylamino

72
1-Methylpropyl
1-Methanesulfonyl-4-
4-Fluorophenyl

methylpiperidin-4-

ylamino

73
1-Methylpropyl
trans-4-Amino-4-methyl-
4-Fluorophenyl

cyclohexylamino

74
1-Methylpropyl
trans-4-Methoxycyclo-
4-Fluorophenyl

hexylamino

75
1-Methylpropyl
trans-4-Hydroxycyclo-
4-Fluorophenyl

hexylamino

76
1-Methylpropyl
trans-4-Hydroxy-4-
4-Fluorophenyl

methylcyclohexylamino

[0547]

69

TABLE 69

118

No.
R1
R2
Ring A

77
1-Methylpropyl
trans-4-(N-methanesul-
4-Fluorophenyl

fonyl-N-methylamino)

cyclohexylamino

78
1-Methylpropyl
cis-4-Hydroxycyclo-
4-Fluorophenyl

hexylmethylamino

79
1-Methylpropyl
cis-4-Hydroxy-4-methyl-
4-Fluorophenyl

cyclohexylmethylamino

80
1-Methylpropyl
(1S)-1,2-Dimethyl-2-
4-Fluorophenyl

hydroxypropylamino

81
1-Methylpropyl
2,2-Dimethyl-3-
4-Fluorophenyl

hydroxypropylamino

[0548] According to the production methods described in the above Examples 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.

70TABLE 70

119

R1 = methyl, ethyl, isopropyl,

120

121

122

123

124

125

126

127

128

Z = CH, NR2 =

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

Ra, Rb = each independently, hydrogen, C1˜C3 alkyl

[0549]

71

TABLE 71

146

R1 = methyl, ethyl, isopropyl,

147

148

149

150

151

152

153

154

155

Z = CH, N

R2 =

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

Ra, Rb, Rc, Rd = each independently, hydrogen, C1˜C3 alkyl

[0550]

72

TABLE 72

171

R1 = methyl, ethyl, isopropyl,

172

173

174

175

176

177

178

179

180

Z = CH, N

R2 =

181

182

183

184

185

186

187

188

189

190

191

192

193

194

Ra, Rb, Rc, Rd = each independently, hydrogen, C1˜C3 alkyl

[0551]

73

TABLE 73

195

R1 = methyl, ethyl, isopropyl,

196

197

198

199

200

201

202

203

204

Z = CH, N

R2 =

205

206

207

208

209

210

211

212

213

214

215

216

217

Ra, Rb, Rc = each independently, hydrogen, C1˜C3 alkyl

[0552]

74

TABLE 74

218

R1 = methyl, ethyl, isopropyl,

219

220

221

222

223

224

225

226

227

Z = CH, N

R2 =

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

Ra, Rb = each independently, hydrogen, C1˜C3 alkyl

[0553]

75

TABLE 75

244

R1 = methyl, ethyl, isopropyl,

245

246

247

248

249

250

251

252

253

Z = CH, N

R2 =

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

Ra, Rb = each independently, hydrogen, C1˜C3 alkyl

[0554]

76

TABLE 76

270

R1 = methyl, ethyl, isopropyl,

271

272

273

274

275

276

277

278

279

Z = CH, N

R2 =

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

Ra, Rb, Rc, Rd = each independently, hydrogen, C1˜C3 alkyl

[0555]

77

TABLE 77

295

R1 = methyl, ethyl, isopropyl,

296

297

298

299

300

301

302

303

304

Z = CH, N

R2 =

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

Ra, Rb, Rc, Rd = each independently, hydrogen, C1˜C3 alkyl

Reference Example 1

[0556]

321

[0557] (1) In 440 ml of THF was suspended 22 g of 2-chloroisonicotinic acid, and under nitrogen flow, the mixture was cooled to −70° C. 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° C.

[0558] (2) In 550 ml of ethanol were suspended 55.1 g of the compound obtained in (1), 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° C. overnight to give 55 g of 1-(2-chloropyridin-4-yl)ethanone oxime as colorless crystals. Melting point: 143° C.

[0559] (3) In methylene chloride were suspended 105 g of the compound obtained in (2) 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 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° C.

[0560] (4) 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 40 g of the compound obtained in (3) 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.

[0561] (5) 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 filtration, the crystals were washed with water and ether. The crystals were air-dried at 60° C. to give 22.3 g of 5-(2-chloropyridin-4-yl)-1-(4-fluorophenyl)-4-imidazolin-2-one as colorless crystals. Melting point: 270° C.

[0562] (6) In 50 ml of DMF was suspended 10 g of the compound obtained in (5), 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-(2-chloropyridin-4-yl)-3-(4-fluorophenyl)-1-(2-cyanobenzyl)-4-imidazolin-2-one as colorless crystals. Melting point: 109° C.

Reference Example 2

[0563]

322

[0564] By using 4-acetylpyridine (commercially available product) as a starting material, the same treatments as in Reference examples 1(2) to (4) were carried out to give 2,2-diethoxy-2-pyridin-4-yl ethylamine as brownish oily product.

Reference Example 3

[0565]

323

[0566] (1) A mixture of 100 g of 3,3-dimethoxy-2-butanone and 99.2 g of N,N-dimethylformamide dimethylacetal was stirred at 100° 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-1-penten-3-one.

[0567] (2) In 800 ml of methanol was dissolved 141 g of the compound obtained in (1), and after adding 114 g of thiourea and 292 g of 28% sodium methoxide-methanol, the mixture was stirred at 70° 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-(1,1-dimethoxyethyl)-2-methylsulfanylpyrimidine.

[0568] (3) In 570 ml of acetone was dissolved 142 g of the compound obtained in (2), 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-methyl-sulfanylpyrimidin-4-yl)ethanone.

Reference Example 4

[0569]

324

[0570] (1) A mixture comprising 16.4 g of 4-chloro-2-methyl-sulfanylpyrimidine, 38 g of tributyl(1-ethoxyvinyl) tin, 1.43 g of bis(triphenylphosphine)palladium (II) dichloride and 100 ml of DMF was stirred at 80° C. for 3 hours. After cooling the reaction mixture, 300 ml of ethyl acetate and 17.8 g of 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-ethoxy-vinyl)-2-methylsulfanylpyrimidine.

[0571] (2) In 200 ml of acetone was dissolved 18.9 g of the compound obtained in (1), 60 ml of 4M hydrochloric acid was added to the 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 1-(2-methylsulfanylpyrimidin-4-yl)ethanone.

Reference Example 5

[0572]

325

[0573] (1) 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: 150-152° C.

[0574] (2) In 1200 ml of methylene chloride was suspended 89 g of the compound obtained in (1), and 81.2 ml of triethylamine and 102 g of tosyl 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: 141-142° C.

[0575] (3) 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 (2) under ice-cooling, and the mixture was stirred at room temperature overnight. To the mixture was added 100 ml of 4M hydrochloric 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-methyl-sulfanylpyrimidin-4-yl)ethylamine.

[0576] (4) To 120 ml of a THF solution containing 8 g of the compound obtained in (3) was added dropwise under ice-cooling 30 ml of a THF 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

[0577]

326

[0578] (1) 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 give 3.28 g of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-(2-methylsulfanylpyrimidin-4-yl)-4-imidazolin-2-one. Melting point: 141-142° C.

[0579] (2) To a chloroform solution containing 3.27 g of the compound obtained in (1) was added 2.03 g of 3-chloroperoxybenzoic acid at room temperature, and the mixture was stirred at room temperature for 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)-4-imidazolin-2-one. Melting point: 133-136° C.

Reference Example 7

[0580]

327

[0581] (1) To 150 ml of a methanol solution containing 1.47 g of the compound obtained in Reference Example 5(4) was added dropwise 10 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 (1:1) to give 1.03 g of 1-(4-fluorophenyl)-5-(2-methylsulfinylpyrimiidin-4-yl)-4-imidazolin-2-one. Melting point: 208-211° C. (decomposed).

[0582] (2) The compound (930 mg) obtained in (1) was treated in the same manner as in the above-mentioned Reference Example 6(1) to give 541 mg of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one.

Reference Example 8

[0583]

328

[0584] In 10 ml of methanol was dissolved 1.0 g of the compound obtained in Reference Example 1(4), 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

[0585]

329

[0586] The compound (5 g) obtained in Reference Example 1(4) and a corresponding starting material were treated in the same manner as in Reference Example 8 to give 8.47 g of Compound (1). Compound (1) (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 Boc2O was added thereto. The resulting mixture was stirred at room temperature for 30 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 (2).

Reference Example 10

[0587]

330

[0588] A mixture comprising 3.8 g of the compound obtained in Reference example 1 (4), 1.7 ml of ethyl iodide and 3.0 ml of triethylamine was stirred at 50° 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=4:1) to give 1.9 g of the title compound as an oily product.

Reference Example 11

[0589]

331

[0590] In 75 ml of toluene were suspended 5.0 g of the compound obtained in Reference Example 1(4), 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° 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

[0591]

332

[0592] A mixture comprising 2.0 g of the compound obtained in Reference example 1(4), 0.82 ml of 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 (1) as an oily product. Then, Compound (1) and a corresponding starting material were treated in the same manner as in Example 4 to give 2.12 g of Compound (2) as an oily product.

Reference Example 13

[0593]

333

[0594] 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

[0595]

334

[0596] 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 15

[0597]

335

[0598] 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-dimethoxy-benzylamine in the same manner as in Reference Example 11 to give 9.75 g of the title compound.

Reference Example 16

[0599]

336

[0600] 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

[0601]

337

[0602] (1) In 30 ml of methylene chloride was dissolved 3.0 g of the compound of Reference Example 5(3), 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 (1) as colorless crystals.

[0603] MS 364 ([M+H]+).

[0604] (2) In 17 ml of DMF was dissolved 4.2 g of Compound (1), 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 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-chioroperoxybenzoic 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 (2) as a colorless oily product.

[0605] MS 423 ([M+H]+).

[0606] (3) In 30 ml of dioxane was dissolved 2.19 g of Compound (2), 1.65 g of trans-4- (Methoxymethoxy) cyclohexylamine and 1.08 ml of 1,1′-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 2.0 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 (3) as a brownish oily product.

[0607] MS 369 ([M+H]+).

Experimental Example 1

Pharmacological Test

Inhibition of Lipopolysaccharide (LPS)-stimulated TNF-α Production in Mice in vivo

[0608] Tests were carried out to measure an inhibitory effects of the compounds of the present invention on LPS-stimulated TNF-α production in mice.

[0609] To Balb/cAnNCrj mice (6-8 weeks old, female, available from Japan Charlesriver, Co.) were administered test compounds (10 mg/kg, p.o.) dissolved in 0.5% methyl cellulose and 0.2% PEG-60 hydrogenated caster oil (HCO60, available from Nikko Chemicals, Co.). After 30 minutes, LPS (E. 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, i.p.). 90 minutes later, blood was collected from abdominal vein of the mouse under diethyl ether anesthesia. The collected blood was subjected to centrifugation with 3000 g to collect serum. TNF-α in the sera was measured by DuoSet mouse TNF-α ELISA kit (trade name, available from genzymeTECHNE).

[0610] As a result, the compounds of the present invention significantly reduced the production of TNF-α as shown in Table 78.

78TABLE 78ExamplesTNF-α inhibition rate18264%20257%23969%29652%30057%

Industrial Applicability

[0611] 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.

Number	Date	Country
2001-324029	Oct 2001	JP
2002-263680	Oct 2002	JP
2003-116076	Apr 2003	JP

	Number	Date	Country
Parent	PCT/JP02/10937	Oct 2002	US
Child	10827294	Apr 2004	US

4-Imidazolin-2-one compounds

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Continuation in Parts (1)