Homocysteine synthase inhibitor

1. An amide derivative represented by the following formula (I)

wherein

R 1 is a hydrogen atom or a C 1 -C 3 alkyl group,

R 2 is an optionally substituted heterocyclic group (said heterocyclic group contains at least one nitrogen atom in the ring), or —N(R 2a )(R 2b ),

R 2a and R 2b are independently selected and each is a hydrogen atom, a C 1 -C 6 alkyl group, a haloalkyl group or an optionally substituted aryl group,

R 3 is a hydrogen atom,

R 4 , R 5 , R 6 , R 7 are independently selected and each is a hydrogen atom or a C 1 -C 4 alkyl group,

L is a linker represented by the following formula

wherein s is an integer of 0-2,

t is an integer of 0-2,

R 8a , R 8b , R 8c and R 8d are independently selected and each is a hydrogen atom or a C 1 -C 3 alkyl group,

Ar is a substituent represented by any of the following formulas (II)-(IV),

wherein

l is an integer of 0-4,

k is an integer of 0-4,

Cy 1 and Cy 2 are independently selected and each is a carbocyclic group, a heterocyclic group or a heteroaryl group,

X is a bond, an oxygen atom or a sulfur atom,

R 9 is a halogen atom or R 12 ,

wherein

R 12 is

a hydrogen atom,

an optionally substituted C 1 -C 6 alkyl group,

an optionally substituted C 2 -C 6 alkenyl group,

an optionally substituted C 2 -C 6 alkynyl group,

an optionally substituted C 3 -C 8 cycloalkyl group,

an optionally substituted heterocyclic group,

an optionally substituted aryl group,

an optionally substituted heteroaryl group, or

an optionally substituted arylalkyl group,

R 10 is

a halogen atom,

a cyano group,

an optionally substituted C 1 -C 6 alkyl group,

—CF 3 ,

—O—R 13 ,

—CO—R 14 ,

an optionally substituted amino group,

an optionally substituted aryl group,

an optionally substituted heteroaryl group,

an optionally substituted heterocyclic group, or

an —S(O) m —C 1 -C 6 alkyl group wherein m is an integer of 0-2,

R 11 is a halogen atom, an optionally substituted C 1 -C 4 alkyl group or CF 3 ,

R 13 is a hydrogen atom, a C 1 -C 4 alkyl group, or —CF 3 ,

R 14 is a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or an optionally substituted amino group,

A is

an optionally substituted aryl group,

an optionally substituted aryl-C 1 -C 4 alkyl group,

an optionally substituted heteroaryl-C 1 -C 4 alkyl group,

a C 3 -C 6 alkynyl group,

an optionally substituted C 3 -C 8 cycloalkyl group, or

a group represented by any of the following formulas (V)-(VIII)

wherein

-----

is a single bond or a double bond,

n is an integer of 0-2,

g is an integer of 0-2,

h is an integer of 0-1,

i is an integer of 1-2,

R 15 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a cyano group or a halogen atom,

R 16 is a C 1 -C 4 alkyl group,

W is ═CH— or ═N—, and

D is an oxygen atom, a sulfur atom, ═N-(E)u-R 17 or ═CH—R 17 , u is an integer of 0-1, E is —SO 2 — or —CO—, R 17 is a hydrogen atom, a C 1 -C 4 alkyl group, an aryl group, a C 1 -C 4 alkylamino group, a C 1 -C 6 alkoxy group, an arylamino group or an aryloxy group, or a pharmacologically acceptable salt thereof.

2. The amide derivative according to claim 1 , which is represented by the following formula (IX)

the formula (IX) shows that R 3 is a hydrogen atom, and R 4 , R 5 , R 6 and R 7 are each a hydrogen atom in the formula (I), and other symbols are the same as defined in claim 1 , or a pharmacologically acceptable salt thereof.

3. The amide derivative according to claim 1 wherein R 1 is a C 1 -C 3 alkyl group, or a pharmacologically acceptable salt thereof.

4. The amide derivative according to claim 1 , wherein A is selected from the groups represented by the following formulas (V)-(VIII)

wherein

-----

is a single bond or a double bond,

n is an integer of 0-2,

g is an integer of 0-2,

h is an integer of 0-1,

i is an integer of 1-2,

R 15 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a cyano group or a halogen atom,

R 16 is a C 1 -C 4 alkyl group,

W is ═CH— or ═N—,

D is an oxygen atom, a sulfur atom, ═N-(E)u-R 17 or ═CH—R 17 , u is an integer of 0-1, E is —SO 2 — or —CO—, R 17 is a hydrogen atom, a C 1 -C 4 alkyl group, an aryl group, a C 1 -C 4 alkylamino group, a C 1 -C 6 alkoxy group, an arylamino group or an aryloxy group, or a pharmacologically acceptable salt thereof.

5. The amide derivative according to claim 1 , wherein A is a group represented by the following formula (V)

wherein

-----

is a single bond or a double bond,

n is an integer of 0-2,

h is an integer of 0-1,

i is an integer of 1-2,

R 15 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a cyano group or a halogen atom,

W is ═CH— or ═N—,

or a pharmacologically acceptable salt thereof.

6. The amide derivative according to claim 1 , wherein L is a linker represented by the following formula

wherein R 8a , R 8b , R 8c and R 8d are each a hydrogen atom,

or a pharmacologically acceptable salt thereof.

7. The amide derivative according to claim 1 , wherein R 10 is

a halogen atom,

a cyano group,

—CO—R 14 ,

an optionally substituted aryl group,

an optionally substituted heteroaryl group, or

an optionally substituted heterocyclic group,

or a pharmacologically acceptable salt thereof.

8. The amide derivative according to claim 1 , wherein R 10 is a heteroaryl group having a substituent, or a heterocyclic group having a substituent, or a pharmacologically acceptable salt thereof.

9. The amide derivative according to claim 1 , wherein the heteroaryl group for R 10 is selected from a furyl group, a thienyl group, a pyrazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, an isoxazolyl group, a 1,2,4-oxadiazolyl group, a 1,3,4-oxadiazolyl group, a 1,3,4-thiadiazolyl group, a pyridyl group, a pyrazinyl group and a pyrimidyl group, or a pharmacologically acceptable salt thereof.

10. The amide derivative according to claim 1 , wherein R 10 is a heteroaryl group having a substituent, and the substituent is a group selected from a halogen atom, a cyano group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a —CH 2 OH group, a —CF 3 group, a —CHF 2 group, a —CH 2 F group, a —OCF 3 group, a —OCHF 2 group, a —OCH 2 F group, a —CONH 2 group, a —CONHCH 3 group and a —CON(CH 3 ) 2 group, or a pharmacologically acceptable salt thereof.

11. The amide derivative according to claim 1 , wherein R 12 is

an optionally substituted C 1 -C 6 alkyl group,

an optionally substituted C 2 -C 6 alkenyl group,

an optionally substituted C 2 -C 6 alkynyl group,

an optionally substituted C 3 -C 8 cycloalkyl group,

an optionally substituted aryl group, or

an optionally substituted heteroaryl group,

or a pharmacologically acceptable salt thereof.

12. An amide derivative selected from the following compounds, or a pharmacologically acceptable salt thereof:

N 2 -(5-acetyl-2-methylphenyl)-N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -(5-acetyl-2-methylphenyl)-N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 2 -[2-(ethylamino)ethyl]glycinamide,

N 2 -(5-cyano-2-methylphenyl)-N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -(5-cyano-2-methylphenyl)-N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[(5-methoxy-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[5-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methylphenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(2-methyl-5-pyrimidin-2-ylphenyl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(1-ethyl-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(1-ethyl-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,6-dimethyl-1,2-benzisoxazol-5-yl)-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,6-dimethyl-1,2-benzisoxazol-5-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,5-dimethyl-1,2-benzisoxazol-6-yl)-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,5-dimethyl-1,2-benzisoxazol-6-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,6-dimethyl-1,3-benzoxazol-2(3H)-on-5-yl)-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,6-dimethyl-1,3-benzoxazol-2(3H)-on-5-yl)-N 2 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,5-dimethyl-1,3-benzoxazol-2(3H)-on-6-yl)-N 1 -[2-(isopropylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(3,5-dimethyl-1,3-benzoxazol-2(3H)-on-6-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -(4-acetyl-2-methylphenyl)-N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -(4-acetyl-2-methylphenyl)-N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -(6-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -(6-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -(6-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)-N 1 -[2-(ethylamino)ethyl]glycinamide,

N 2 -{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide, and

N 2 -{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N 2 -[2-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N 1 -[2-(ethylamino)ethyl]glycinamide.

13. A pharmaceutical composition comprising the amide derivative according to claim 1 , or a pharmacologically acceptable salt thereof, as an active ingredient.

14. A pharmaceutical composition comprising the amide derivative according to claim 12 , or a pharmacologically acceptable salt thereof, as an active ingredient.