Pyridine derivatives

1. A pyridine derivative of the formula (I)

wherein —R 1 represents

in which R 11 is hydrogen, C 1-6 alkyl, halogen, hydroxy, C 1-12 alkoxy, nitro, amino, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, di (C 1-6 alkyl)amino, C 1-6 alkanoylamino, phenyl C 1-6 alkylamino, phenylsulfonylamino, or —O—(CH 2 ) n —R 111 ,

wherein n represents an integer selected from 0 to 6, and R 111 is C 2-6 alkenyl, benzoyl, diphenylmethyl, di (C 1-6 alkyl)amino, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, or a 3 to 10 membered saturated or unsaturated ring having 0 to 3 heteroatoms selected from the group consisting of S, O and N as heteroatoms and is optionally substituted by C 1-6 alkyl, mono or di halogen, halogen substituted C 1-6 alkyl, nitro, cyano, C 1-6 alkoxycarbonyl, phenyl, hydroxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkanoylamino, C 1-6 alkoxy, or carbamoyl;

R 2 represents hydrogen or halogen;

R 3 represents 1,2,3,6-Tetrahydro-pyridine, or

 —CR 31 R 32 R 33 ,

wherein R 31 is hydrogen or C 1-6 alkyl,

R 32 and R 33 form, together with the carbon atom to which they are attached, a 5 to 8 membered saturated ring having 0 to 3 heteroatoms selected from the group consisting of N, O and S as heteroatoms, which ring is optionally substituted by phenyl-C 1-6 alkyl, C 1-6 alkoxy substituted phenyl-C 1-6 alkyl, C 1-6 alkyl, amino, cyano, hydroxy, carbamoyl, carboxy, C 1-6 alkylamino, C 1-6 alkoxycarbonyl, di(C 1-6 alkyl)amino, benzylamino, C 1-6 alkylsulfonyl, piperidino C 1-6 alkyl carbonyl, or optionally fused by benzene;

R 4 represents hydroxycarbonyl, C 1-6 alkanoyl, carbamoyl, cyano, nitro, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, C 1-6 alkylamino, 5 to 10 membered heteroaryl (hydroxy) methyl, 5 to 10 membered heteroaryl-C 1-6 alkyl, or methyl substituted by hydroxy and a 5 to 7 membered saturated cyclic ring, C 1-6 alkyl optionally substituted by one selected from the group consisting of hydroxy, C 1-6 alkoxy, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonylamino, C 5-10 aryl, C 5-10 arylsulfonyl, C 5-10 arylsulfanyl, C 5-10 aryloxy, imidazolyl, or dioxo substituted pyrolidino-oxy,

—(CH 2 ) p NHCOR 41 , —(CH 2 ) p NHC(═S)R 41

wherein p represents any of integer from 1 to 6 and R 41 represents C 1-6 alkoxy, amino, phenylamino, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-10 cycloalkylamino,

R 5 represents NR 51 R 52 ,

wherein R 51 is hydrogen, C 1-6 alkyl,

R 52 is hydrogen, C 1-6 alkyl, phenyl, benzyl, C 1-6 alkanoyl, or NR 51 R 52 may form a saturated 5-6 membered ring optionally containing NH or O as another heteroatom in addition to the N atom to which R 51 and R 52 are attached,

or a salt thereof.

2. The compound or a salt thereof as claimed in claim 1 , wherein:

—R 1 represents

in which R 11 is hydrogen, C 1-6 alkyl, halogen, hydroxy, C 1-12 alkoxy, amino, C 1-6 alkanoylamino, phenyl C 1-6 alkylamino, phenylsulfonylamino, or —O—(CH 2 ) n —R 111 ,

wherein n represents an integer selected from 1 to 6, and R 111 is C 2-6 alkenyl, benzoyl, diphenylmethyl, di (C 1-6 alkyl)amino, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, or a 3 to 10 membered saturated or unsaturated ring having 0 to 3 heteroatoms selected from the group consisting of S, O and N as heteroatoms and is optionally substituted by C 1-6 alkyl, mono or di halogen, halogen substituted C 1-6 alkyl, nitro, cyano, C 1-6 alkoxycarbonyl, phenyl;

R 2 represents hydrogen;

R 3 represents 1,2,3,6-tetrahydro-pyridine or

—CR 31 R 32 R 33 ,

wherein R 31 is hydrogen or C 1-6 alkyl,

R 32 and R 33 form, together with the carbon atom to which they are attached, a 5 to 8 membered saturated ring having 0 to 3 heteroatoms selected from the group consisting of N, O and S as heteroatoms, which ring is optionally substituted by phenyl-C 1-6 alkyl, C 1-6 alkoxy substituted phenyl-C 1-6 alkyl, C 1-6 alkyl, amino, carboxy, C 1-6 alkylamino, C 1-6 alkoxycarbonyl, di(C 1-6 alkyl)amino, benzylamino, C 1-6 alkylsulfonyl, piperidino C 1-6 alkyl carbonyl, or optionally fused by benzene;

R 4 represents hydroxycarbonyl, C 1-6 alkanoyl, carbamoyl, cyano, carboxyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, C 1-6 alkylamino, 5 to 10 membered heteroaryl (hydroxy) methyl, 5 to 10 membered heteroaryl-C 1-6 alkyl, or methyl substituted by hydroxy and a 5 to 7 membered saturated cyclic ring, C 1-6 alkyl optionally substituted by one selected from the group consisting of hydroxy, C 1-6 alkoxy, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonylamino, C 5-10 aryl, C 5-10 arylsulfanyl, C 5-10 arylsulfenyl, C 5-10 aryloxy, imidazolyl, or dioxo substituted pyrolidino-oxy,

—(CH 2 ) p NHCOR 41 , —(CH 2 ) p NHC(═S)R 41

wherein p represents any integer from 1 to 6 and R 41 represents C 1-6 alkoxy, amino, phenylamino, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-10 cycloalkylamino,

R 5 represents NR 51 R 52 ,

wherein R 51 is hydrogen, C 1-6 alkyl,

R 52 is hydrogen, C 1-6 alkyl, phenyl, benzyl, C 1-6 alkanoyl, or NR 51 R 52 may form piperidino.

3. The compound or a salt thereof as claimed in claim 1 , wherein:

—R 1 represents

in which R 11 is hydrogen, C 1-12 alkoxy, or —O—(CH 2 ) n —R 111 ,

wherein n represents an integer selected from 1 to 6, and R 111 is phenyl, C 3-8 cycloalkyl;

R 2 represents hydrogen;

R 3 represents 1,2,3,6-tetrahydro-pyridine, or

—CR 31 R 32 R 33 ,

wherein R 31 is hydrogen,

and

R 32 and R 33 form, together with the adjacent carbon atom to which they are attached, a 5 to 8 membered saturated ring interrupted by NH, which ring is optionally substituted by phenyl-C 1-6 alkyl, C 1-6 alkoxy substituted phenyl-C 1-6 alkyl, C 1-6 alkyl, amino, carboxy, C 1-6 alkylamino, C 1-6 alkoxycarbonyl, di(C 1-6 alkyl)amino, benzylamino, C 1-6 alkylsulfonyl, piperidino C 1-6 alkyl carbonyl, or optionally fused by benzene;

R 4 represents cyano, C 1-6 alkyl optionally substituted by hydroxy or C 1-6 alkoxy, or

 —(CH 2 ) p NHCOR 41 , —(CH 2 ) p NHC(═S)R 41

wherein p represents any of integer from 1 to 6 and R 41 represents C 1-6 alkoxy, amino, phenylamino, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-10 cycloalkylamino;

R 5 represents amino.

4. The compound or a salt thereof as claimed in claim 1 , wherein

—R 1 represents

in which R 11 is hydrogen, C 1-6 alkoxy, or —O—CH 2 —R 111 ,

wherein R 111 is phenyl, C 3-4 cycloalkyl;

R 2 represents hydrogen;

R 3 represents 1,2,3,6-tetrahydro-pyridine, or

—CR 31 R 32 R 33 ,

wherein R 31 is hydrogen,

and

R 32 and R 33 form, together with the carbon atom to which they are attached, piperidine or pyrrolidine, which piperidine or pyrrolidine is optionally substituted by C 1-6 alkyl;

R 4 represents cyano, hydroxymethyl, or —CH 2 NHCOR 41 ,

wherein R 41 represents C 1-6 alkoxy, amino, phenylamino, C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-10 cycloalkylamino;

R 5 represents amino.

5. A compound selected from the group consisting of the following compounds:

2-amino-6-[2-(benzyloxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinonitrile;

2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(3-piperidinyl)nicotinonitrile;

2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(benzyloxy)phenol;

2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)nicotinonitrile;

2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-propoxyphenol;

2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;

2-[6-amino-5-(hydroxymethyl)-4-(4-piperidinyl)-2-pyridinyl]-3-(cyclopropylmethoxy)phenol;

6′-amino-5′-(hydroxymethyl)-4′-(3-piperidinyl)-2,2′-bipyridin-3-ol;

2-[6-amino-5-(hydroxymethyl)-4-(3-piperidinyl)-2-pyridinyl]-3-(neopentyloxy)phenol;

2-[6′-amino-5′-(hydroxymethyl)-1,2,5,6-tetrahydro-3,4′-bipyridin-2′-yl]phenol;

N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}acetamide;

2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinonitrile;

N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}-N′-propylurea;

ethyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;

2-amino-6-{2-hydroxy-6-[(4-methylpentyl)oxy]phenyl}-4-(4-piperidinyl)nicotinonitrile;

N-{[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methyl}urea;

2-amino-6-(2-hydroxy-6-propoxyphenyl)-4-(4-piperidinyl)nicotinonitrile;

2-amino-6-[2-(cyclobutylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinonitrile;

2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinonitrile;

isopropyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;

neopentyl [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(3-piperidinyl)-3-pyridinyl]methylcarbamate;

2-amino-6-[2-(hexyloxy)-6-hydroxyphenyl]-4-(4-piperidinyl)nicotinonitrile;

or a salt thereof.

6. A pharmaceutical composition comprising a compound or a salt thereof as claimed in claim 1 plus a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound or a salt thereof as claimed in claim 1 together with one or more pharmaceutically acceptable excipients.

8. A method for treating an inflammatory disease in a mammal comprising administering a compound or a salt thereof as claimed in claim 1 .

9. The method as claimed in claim 8 , wherein said disease is selected from the group consisting of asthma; allergic rhinitis; atopic dermatitis; hives; conjunctivitis; vernal catarrh; chronic arthrorheumatism; systemic lupus erythematosus; psoriasis; diabrotic colitis; systemic inflammatory response syndrome (SIRS); sepsis; polymyositis; dermatomyositis (DM); Polyaritis nodoa (PN); mixed connective tissue disease (MCTD); Sjoegren's syndrome; and gout.

10. A method of promoting immunosuppression in a mammal comprising administering a compound or a salt thereof as claimed in claim 1 .

11. A method of treating ischemia in a mammal comprising administering a compound or a salt thereof as claimed in claim 1 .

12. A method of treating tumors in a mammal comprising administering a compound or a salt thereof as claimed in claim 1 .