Halogen-substituted heterocyclic compound

1. A method of suppressing an LPA1 receptor, comprising:

administering a therapeutically effective amount of a compound or a pharmacologically acceptable salt thereof as an active ingredient and an additive;

wherein the compound is represented by the formula (I):

wherein

A represents a phenyl ring;

R 1 is the same or different, and represents a halogen atom, or a C 1 -C 3 alkyl group;

R 2 represents a hydrogen atom, or a C 1 -C 6 alkyl group;

p represents an integer of 0 to 5;

V represents CR 3 wherein R 3 represents a hydrogen atom, an amino group, a nitro group, or a C 1 -C 3 alkoxy group;

X represents a halogen atom.

2. A method of treating pulmonary fibrosis, renal fibrosis, hepatic fibrosis, or non-alcoholic steatohepatitis (NASH), comprising:

administering a therapeutically effective amount of a compound represented by the formula (I):

wherein

A represents a phenyl ring;

R 1 is the same or different, and represents a halogen atom, or a C 1 -C 3 alkyl group;

R 2 represents a hydrogen atom, or a C 1 -C 6 alkyl group;

p represents an integer of 0 to 5;

V represents CR 3 wherein R 3 represents a hydrogen atom, an amino group, a nitro group, or a C 1 -C 3 alkoxy group;

X represents a halogen atom, or a pharmacologically acceptable salt thereof

to a patient in need thereof.

3. The method according to claim 1 , wherein the compound is the compound represented by the formula (Ia):

wherein

R 1 is the same or different, and represents a halogen atom, or a C 1 -C 3 alkyl group,

R 2 represents a hydrogen atom, or a C 1 -C 6 alkyl group;

p represents an integer of 0 to 5;

V represents CH;

X represents a halogen atom, or a pharmacologically acceptable salt thereof.

4. The method according to claim 3 , wherein the compound is the compound of the formula (Ia) wherein the group:

is selected from a group consisting of the groups:

or a pharmacologically acceptable salt thereof are administered.

5. The method according to claim 3 , wherein the compound is the compound of the formula (Ia)

wherein the group:

is selected from a group consisting of the groups:

or a pharmacologically acceptable salt thereof.

6. The method according to claim 3 wherein the compound is selected from a group consisting of:

(RS)-1-{4′-[5-bromo-3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[5-chloro-3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-[4′-(5-chloro-3-({[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-[1,1′-biphenyl]-4-yl]cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(3-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(4-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(4-chlorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(o-tolyl)ethoxy]carbonyl}amino)thiophen-2-yl][1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2,4-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2,5-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(3,4-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2-chloro-4-fluorophenyl)ethoxy]carbonyl}amino) -thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-[4′-(5-fluoro-3-({[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-[1,1′-biphenyl]-4-yl]cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(4-fluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(4-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(o-tolyl)ethoxy]carbonyl}amino)thiophen-2-yl][1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(3,4-difluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2,4-difluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2-chloro-4-fluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen -2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[3-({[1-(4-chloro-2-fluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[5-fluoro-3-({[1-(2,4,5-trifluorophenyl)ethoxy]carbonyl}amino) -thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

or a pharmacologically acceptable salt thereof

to a patient in need thereof.

7. The method according to claim 2 wherein

the compound is the compound of the formula (I) wherein V is not CH,

or a pharmacologically acceptable salt thereof.

8. The method according to claim 7 wherein

the compound is the compound represented by the formula (Ib):

wherein

R 1 is the same or different, and represents a halogen atom, or a C 1 -C 3 alkyl group;

R 2 represents a hydrogen atom or a C 1 -C 6 alkyl group;

p represents an integer of 0 to 5;

X represents a halogen atom, or a pharmacologically acceptable salt thereof.

9. The method according to claim 8 wherein the compound is the compound of formula (Ib)

wherein the group:

is selected from a group consisting of the groups:

or a pharmacologically acceptable salt thereof.

10. The method according to claim 8 wherein

the compound is the compound of the formula (Ib) wherein the group:

is selected from a group consisting of the groups:

or a pharmacologically acceptable salt thereof.

11. The method according to claim 8 wherein the compound is selected from a group consisting of:

(R)-1-[4′-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2′-methoxy-[1,1′-biphenyl]-4-yl]cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(3-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(4-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(4-chlorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(o-tolyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(3,4-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2,5-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2,4-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[5-chloro-3-({[1-(2-chloro-5-fluorophenyl)ethoxy]carbonyl}-amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2-chloro-4-fluorophenyl)ethoxy]carbonyl}amino) -thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[5-chloro-3-({[1-(5-fluoro-2-methylphenyl)ethoxy]carbonyl}-amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[5-chloro-3-({[1-(4-fluoro-2-methylphenyl)ethoxy]carbonyl}-amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-[4′-(5-fluoro-3-({[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2′-methoxy-[1,1′-biphenyl]-4-yl]cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(2-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(3-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(4-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(4-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(o-tolyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(3,4-difluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2,5-difluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2,4-difluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[3-({[1-(2-chloro-5-fluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2-chloro-4-fluorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen -2 -yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(RS)-1-{4′-[5-fluoro-3-({[1-(5-fluoro-2-methylphenyl)ethoxy]carbonyl}-amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid, and

(RS)-1-{4′-[5-fluoro-3-({[1-(4-fluoro-2-methylphenyl)ethoxy]carbonyl}-amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

or a pharmacologically acceptable salt thereof.

12. The method according to claim 2 wherein the compound is selected from a group consisting of:

(R)-1-{4′-[5-chloro-3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(3-fluorophenyl)ethoxy]carbonyl}amino)thiophen2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[5-fluoro-3-({[1-(o-tolyl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-[4′-(5-chloro-3-({[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2′-methoxy-[1,1′-biphenyl]-4-yl]cyclopropanecarboxylic acid,

(R)-1-{4′-[5-chloro-3-({[1-(2,5-difluorophenyl)ethoxy]carbonyl}amino)thiophen-2-yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

(R)-1-{4′-[3({[-1-(2-chloropheny)ethoxy]carbonyl}amino)- 5-fluorothiophen-2 -yl]-2′-methoxy-[1,1′-biphenyl]-4-yl}cyclopropanecarboxylic acid,

or a pharmacologically acceptable salt thereof.