Halogen Substituted Heterocyclic Compound

DESCRIPTION HALOGEN-SUBSTITUTED HETEROCYCLIC COMPOUND 5 TECHNICAL FIELD

[0001] The present invention relates to a novel a-halogen-substituted thiophene compound or a pharmacologically acceptable salt thereof. Since the a-halogen-substituted thiophene compound of the present invention has an antagonist activity on a lysophosphatidic acid (LP A) receptor, it would be useful for the prevention 10 and/or the treatment of diseases caused by LP A. BACKGROUND ART

[0002] Lysophosphatidic acid (LPA) is a physiologically active phospholipid which is present in a living body. LPA transduces a signal in a cell and modulates the 15 proliferation, differentiation, survival, migration, adhesion, infiltration, morphogenesis of a cell by binding to a specific G-protein-coupled receptor (LPA 1, LP A2, LPA3, LPA4, LPA5, LPA6). Further, it has been known that LPA is involved with a disease accompanied with fibrosis in various organs.

[0003] Regarding liver, it has been reported that LPA accelerates the proliferation or 20 contraction of stellate cell which plays an important role in the process of hepatic fibrosis, or the migration ofmyofibroblast (refer to Non-Patent Documents 1, 2 and 3). Regarding kidney, it has been reported that the production ofLPA or the expression of LP A 1 is facilitated in a mouse with unilateral ureteral ligation, which is an animal model of renal fibrosis, and that the renal fibrosis is suppressed by LPAl 25 deficiency or administration of an LPA receptor-antagonist (refer to Non-Patent Documents 4 and 5).

[0004] Regarding lung, it has been reported that the LPA concentration in bronchoalveolar lavage fluid of a patient with idiopathic pulmonary fibrosis is elevated; and that LPA 1 is most expressed in fibroblast having an important role in the process of 30 pulmonary fibrosis and LPA makes the fibroblast migrate. Further, it has been reported that fibrosis is suppressed by LPA 1 deficiency or administration of an LPA receptor-antagonist in a mouse to which bleomycin was intratracheally administered, which is an animal model of pulmonary fibrosis (refer to Non-Patent Documents 6 and 7). 35 [0005] Regarding skin, it has been reported that fibrosis of skin is suppressed by LPAl deficiency or administration of an LPA receptor-antagonist in a mouse to which -2-bleomycin was subcutaneously administered, which is a sclerodermia animal model (refer to Non-Patent Document 8).

[0006] It has also been known to that LPA is involved with immunological or inflammatory diseases. It has been reported that LP A facilitates the migration of 5 human monocyte; and that LPA is involved with the proliferation or infiltration ofT cells. Further, it has been reported that synovial cells of patient with rheumatoid arthritis express LPA receptor and migrate or produce IL-6 and IL-8 by the LPA stimulation; and that these actions are inhibited by an LPA receptor antagonist (refer to Non-Patent Documents 9, 10 and 11). 10 [0007] In addition, it has been reported that LPA and LPA1 are involved with the development of neuropathic pain (refer to Patent Document 12); that LP A is involved with urologic diseases by contracting an extracted urethra specimen and a prostatic specimen to increase the intraurethral pressure (refer to Patent Document 1); and that LPA is involved with cancer-related diseases by accelerating the infiltration of cancer 15 cells, by accelerating the proliferation of ovary cancer cells, or by accelerating the proliferation of prostate cancer cells (refer to Non-Patent Documents 13, 14 and 15).

[0008] Based on these findings, a medicament which antagonizes the LP A receptor (particularly, LPA1 receptor) is considered to be useful for the prevention and/or treatment of a disease accompanying fibrosis, an immunological or inflammatory 20 disease, a central or peripheral nervous system disease, an urologic disease, a cancer-related disease, etc.

[0009] On the other hand, as a compound having antagonizing action ofLPA receptor, ([1, 1 '-biphenyl]-4-yl)acetic acid derivatives are disclosed in Patent Documents 2 to 19, and Non-Patent Documents 7, 8, 16 and 17; (2'-methoxy-[1,1'-biphenyl]-4-yl) acetic 25 acid derivatives are disclosed in Patent Document 17; and 3-chloroisothiazole derivatives are disclosed in Patent Document 19, but there is no disclosure on the compound ofthe present invention. PRIOR ART DOCUMENTS 30 Patent Documents 35

[0010] Patent Document 1: WO 2002/062389 Patent Document 2: WO 2010/077882 Patent Document 3: WO 2010/077883 Patent Document 4: WO 20101141761 Patent Document 5: WO 2010/141768 Patent Document 6: WO 2011/017350 5 10 - 3- Patent Document 7: WO 20111041461 Patent Document 8: WO 20111041462 Patent Document 9: WO 20111041694 Patent Document 10: WO 2011/041729 Patent Document 11: WO 2011/091167 Patent Document 12: WO 2011/159632 Patent Document 13: WO 20111159633 Patent Document 14: WO 20111159635 Patent Document 15: WO 2012/078593 Patent Document 16: WO 2012/078805 Patent Document 17: WO 2012/138648 Patent Document 18: WO 2012/138797 Patent Document 19: WO 2013/025733 15 Non-Patent Document 20 25 [00 11] Non-Patent Document 1: Biochemical and Biophysical Research Communications, 248 (1998) 436-440 Non-Patent Document 2: Biochemical and Biophysical Research Communications, 277 (2000) 72-78 Non-Patent Document 3: Journal of Biomedical Science, 10 (2003) 352-358 Non-Patent Document 4: Journal of the American Society ofNephrology, 18 (2007) 3110-3118 Non-Patent Document 5: The Journal of Pharmacology and Experimental Therapeutics, 336 (2011) 693-700 Non-Patent Document 6: Nature Medicine, 14 (2008) 45-54 Non-Patent Document 7: British Journal of Pharmacology, 160 (2010) 1699-1713 Non-Patent Document 8: Arthritis & Rheumatism, 63 (2011) 1405-1415 Non-Patent Document 9: Journal of Biological Chemistry, 270 (1995) 30 25549-25556 Non-Patent Document 10: Biochimica et Biophysica Acta, 1582 (2002) 168-174 Non-Patent Document 11: Molecular Pharmacology, 73 (2008) 587-600 Non-Patent Document 12: Nature Medicine, 10 (2004) 712-718 35 Non-Patent Document 13: Biochemical and Biophysical Research Communications, 193 (1993) 497-503 -4- Non-Patent Document 14: Biochemical Journal, 309 (1995) 933-940 Non-Patent Document 15: The Journal of Urology, 163 (2000) 1027-1032 Non-Patent Document 16: The Journal of Pharmacology and Experimental Therapeutics, 336 (20 11) 693-700 5 Non-Patent Document 17: Journal ofMedicinal Chemistry, 55 (2012) 7920-7939 DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention 10 [0012] The present inventors carried out a research on various halogen-substituted heterocyclic compounds in order to develop an excellent medicament for the treatment or prevention of a disease accompanying fibrosis, an immunological or inflammatory disease, a central or peripheral nervous system disease, an urologic disease, a cancer-related disease, etc., and found out that a novel a-halogen-substituted thiophene 15 compound having a specific structure has an excellent LP A receptor-antagonist action and is useful as a medicament (particularly, for the prevention and/or treatment of a disease accompanying fibrosis, an immunological or inflammatory disease, a central or peripheral nervous system disease, an urologic disease, a cancer-related disease) to accomplish the present invention. 20 [0013] The present invention provides a novel a-halogen-substituted thiophene compound or a pharmacologically acceptable salt thereof which has a potent LP A receptor-antagonist action and is useful as a medicament for the treatment and/or prevention (preferably, a medicament for the treatment) of, particularly, a disease accompanying fibrosis, an immunological or inflammatory disease, a central or 25 peripheral nervous system disease, an urologic disease or a cancer-related disease. Means for Solving the Problems

[0014] The present invention provides:

[0015] (1) A compound represented by the general formula (I): 30 [0016] [Chemical Formula 1] - 5- (I) X [00 17] wherein A represents, a phenyl ring, a thiophene ring, or an isothiazole ring; R1 is the same or different, and represents a halogen atom, or a C1-C3 alkyl 5 group; R2 represents a hydrogen atom, or a C1-C6 alkyl group; p represents an integer of 0 to 5; V represents CR3 wherein R3 represents a hydrogen atom, an amino group, a nitro group, or a C1-C3 alkoxy group, or V represents a nitrogen atom; 10 X represents a halogen atom, 15 and, a pharmacologically acceptable salt thereof.

[0018] (2) The compound according to (1) which is represented by the general formula (Ia):

[0019] [Chemical Formula 2] {I a)

[0020] wherein R 1 is the same or different, and represents a halogen atom, or a C 1-C3 alkyl group, R2 represents a hydrogen atom, or a C1-C6 alkyl group; - 6-p represents an integer of 0 to 5; V represents CH or a nitrogen atom; X represents a halogen atom, and, a pharmacologically acceptable salt thereof. 5 [0021] (3) The compound according to (2) wherein, in the general formula (Ia), the group:

[0022] [Chemical Formula 3] (R'),-~ is selected from a group consisting of the groups: 10 [0023] [Chemical Formula 4] Cl ~ ~c1J) .. uh F-· F~u- -.Fu0 -. FuF~.., FFu~F_-. Fh0 -. F {5\Me F& F'd.: ~ I~ I~ I ..& b Cl and b M Cl F e

[0024] and, a pharmacologically acceptable salt thereof.

[0025] (4) The compound according to (2) wherein, in the general formula (Ia), the group: 15 [0026] [Chemical Formula 5] (R'), ~

[0027] is selected from a group consisting of the groups:

Chemical Formula 6

Cl ~ b Me F& I~ and ,&; F 20 [0028] and, a pharmacologically acceptable salt thereof.

[0029] (5) The compound according to (2) which is selected from a group consisting of: - 7- (RS)-1- { 4 1 -[ 5-bromo-3-( {[ 1-(2-chlorophenyl)ethoxy ]carbonyl} amino)thiophen- 2-yl]-[ 1, 11 -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, 5 (R)-1-{ 4' -[ 5-chloro-3-( {[ 1-(2-chlorophenyl)ethoxy ]carbonyl} amino )thiophen- 2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, (R)-1-[ 41-(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- 10 2-yl]-[1,1 1-biphenyl]-4-yl}cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-chloro-3-( {[1-(3-fluoropheny1)ethoxy]carbonyl} amino )thiophen- 2-y1 ]-[ 1, 1 '-biphenyl ]-4-y1} cyclopropanecarboxylic acid, (R)-1-{ 4'-[ 5 -chloro-3-( { [ 1-( 4-fluorophenyl)ethoxy ]carbonyl} amino )thiophen- 2-yl ]-[ 1,1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid, 15 (R)-1-{ 4'-[ 5-chloro-3-( { [ 1-( 4-chlorophenyl)ethoxy ]carbonyl} amino )thiophen- 2-yl ]-[ 1,1 1 -biphenyl ]-4-yl} cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-chloro-3-( {[ 1-( o-tolyl)ethoxy]carbonyl} amino )thiophen-2-y1][ 1,1 '-bipheny1]-4-yl} cyclopropanecarboxylic acid, (R)-1- {4'-[5-chloro-3-( {[1-(2,4-difluorophenyl)ethoxy ]carbonyl }amino)- 20 thiophen-2-yl]-[ 1,1 '-biphenyl]-4-y1 }cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-chloro-3-( {[1-(2,5-difluorophenyl)ethoxy]carbonyl }amino)thiophen- 2-yl]-[ 1,1 '-biphenyl]-4-y1 }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, 25 (R)-1- {41-[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-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino} thiophen-2-yl)pyridin- 2-yl ]phenyl} cyclopropanecarboxylic acid, (R)-1-[ 4' -( 5-fluoro-3-{[ ( 1-phenylethoxy)carbonyl] amino} thiophen-2-yl)[ 1, 1 '- 30 bipheny1]-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, 35 (R)-1- {4'-[3-( {[1-(2-chlorophenyl)ethoxy]carbonyl} amino )-5-fluorothiophen- 2-yl] -[ 1, 1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid, - 8 - (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, 5 (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-fluoro- 10 thiophen-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, !'-biphenyl ]-4-yl} cyclopropanecarboxylic acid, 15 and, a phannacologically acceptable salt thereof.

[0030] (6) The compound according to (1) wherein, in the general formula (I), V represents CR3 in which R3 represents a hydrogen atom, an amino group, a nitro group, or a Ct-C3 alkoxy group, or V represents a nitrogen atom with the proviso that in a case where A represents a phenyl ring, V is not CH or a nitrogen atom, 20 and, a phannacologically acceptable salt thereof.

[0031] (7) The compound according to (6) which is represented by the general formula (Ib):

[0032] [Chemical Formula 7] 25 [0033] wherein R1 is the same or different, and represents a halogen atom, or a C1-C3 alkyl group; - 9- R2 represents a hydrogen atom or a C1-C6 alkyl group; p represents an integer of 0 to 5; X represents a halogen atom, and, a pharmacologically acceptable salt thereof. 5 [0034] (8) The compound according to (7) wherein, in the general formula (lb ), the group:

[0035] [Chemical Formula 8] (R'), ~ is selected from a group consisting of the groups: 10 [0036] [Chemical Formula 9]

[0037] and, a pharmacologically acceptable salt thereof.

[0038] (9) The compound according to (7) wherein, in the general formula (lb ), the group: 15 [0039] [Chemical Formula 10] (R1 )p ~ is selected from a group consisting of the groups:

[0040] [Chemical Formula 11] b_ V -·and 20 [0041] and, a pharmacologically acceptable salt thereof. F& l,p F

[0042] (10) The compound according to (7) which is selected from a group consisting of: - 10- (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 )thiophen- 2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, 5 (R)-1-{ 4'-[ 5-chloro-3-( {[ 1-(3-fluorophenyl)ethoxy]carbonyl} amino )thiophen- 2-yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-chloro-3-( {[ 1-( 4-fluorophenyl)ethoxy ]carbonyl} amino )thiophen- 2-yl]-2'-methoxy-[1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-chloro-3-( {[ 1-(2-chlorophenyl)ethoxy]carbonyl} amino )thiophen- 10 2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, (R)-1-{ 4'-[ 5-chloro-3-( {[ 1-( 4-chlorophenyl)ethoxy ]carbonyl} amino )thiophen- 2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylicacid, (R)-1-{ 4'-[5-chloro-3-( {[ 1-( o-tolyl)ethoxy]carbonyl }amino )thiophen-2-yl]-2'methoxy-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, 15 (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)ethox y ]carbonyl} amino)- 20 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, 25 (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'- 30 methoxy-[1,1 '-biphenyl]-4-yl]cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-fluoro-3-( {[1-(2-fluorophenyl)ethoxy]carbonyl} amino )thiophen- 2-yl ]-2 '-methoxy-[ 1, 1'-biphenyl ]-4-yl} cyclopropanecarboxylic acid, (R )-1- { 4 '-[ 5-fluoro-3-( { [ 1-(3-fluorophenyl )ethoxy ]carbonyl} amino )thiophen- 2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, 3 5 (R)-1- { 4 '-[ 5-fluoro-3-( {[ 1-( 4-fluorophenyl )ethoxy ]carbonyl} amino )thiophen- 2-yl ]-2'-methoxy-[ 1, 1'-biphenyl ]-4-yl} cyclopropanecarboxylic acid, - 11 - (R)-1-{ 4'-[3-( {[1-(2-chlorophenyl)ethoxy]carbonyl} amino )-5-fluorothiophen- 2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, (R)-1-{41-[3-({[1-(4-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen- 2-yl]-2' -methoxy-[ 1, 1 1 -biphenyl ]-4-yl} cyclopropanecarboxylic acid, 5 (R)-1-{ 41-[5-fluoro-3-( {[1-( o-tolyl)ethoxy]carbonyl }amino )thiophen-2-yl]-21 -methoxy-[ 1,1 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 1-biphenyl]-4-yl }cyclopropanecarboxylic acid, (R)-1-{ 4'-(3-( {[ 1-(2,5-difluorophenyl)ethoxy ]carbonyl }amino )-5-fluoro- 1 0 thiophen-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 1-biphenyl]-4-yl} cyclopropanecarboxylic acid, (RS)-1-{ 4 1-(3-( {[ 1-(2-chloro-5-fluorophenyl)ethoxy ]carbonyl }amino )-5-fluorothiophen-2-yl]-2'-methoxy-[ 1, 1'-biphenyl ]-4-yl} cyclopropanecarboxylic acid, 15 (R)-1-{ 41-[3-( {[1-(2-chloro-4-fluorophenyl)ethoxy ]carbonyl }amino )-5-fluoro- 20 thiophen-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, and, a pharmacologically acceptable salt thereof.

[0043] (11) The compound according to (6) wherein, in the general formula (I), V represents CR3 in which R3 represents a hydrogen atom or a methoxy group, or V 25 represents a nitrogen atom; and the group:

[0044] (Chemical Formula 12] is selected from a group consisting of the groups: 30 (0045] (Chemical Formula 13] c0Mb\t:C S S S Me c0 N,._l). s-N and ~J ...,. 5 - 12-

[0046] and, a pharmacologically acceptable salt thereof.

[0047] (12) The compound according to (6) wherein, in the general formula (I), the group:

[0048] [Chemical Formula 14] (R1)P'A[0049] is selected from a group consisting of the groups:

Chemical Formula 15

a\ S and MeL~ --Js (J1 ~ s and, a pharmacologically acceptable salt thereof. 13. The compound according to Claim 11 which is selected from a group consisting of: (RS)-1-{4'-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl}amino)thiophen- 2-yl ]-[ 1, 1 '-biphenyl] -4-y1} cyclopropanecarboxylic acid, 15 (R)-1- {4'-[5-chloro-3-( {[1-(thiophen-3-y1)ethoxy]carbonyl }amino )thiophen-2-yl]-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, (RS)-1-{4'-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl} amino )thiophen- 2-yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid, (R)-1-{ 4'-[5-chloro-3-( {[ 1-(thiophen-3-yl)ethoxy]carbonyl }amino )thiophen-2- 20 yl]-2'-methoxy-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (RS)-1-{4'-[5-chloro-3-( {[1-(4-methylthiophen-3-yl)ethoxy]carbonyl}amino)thiophen- 2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, (R)-1-{ 4' -[ 5-chloro-3-( { [ 1-( 4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)thiophen- 2-yl]-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxy1ic acid, 25 (RS)-1-{ 4' -[ 5-chloro-3-( { [ 1-( 4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)-thiophen-2-yl]-2'-methoxy-[ 1,1 '-bipheny1]-4-yl }cyclopropanecarboxylic acid, (RS)-1-{ 4'-[5-chloro-3-( {[1-( 4-chlorothiophen-3-yl)ethoxy]carbonyl }amino)thiophen- 2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (RS)-1-{ 4'-[5-chloro-3-( {[(1-(isothiazol-3-yl)ethoxy]carbonyl }amino )thio- 294-phen-2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (RS)-1-{4'-[5-chloro-3-( {[l-(isothiazo1-4-yl)ethoxy]carbonyl} amino )thiophen- 2-yl]-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (RS)-1-( 4-{ 5-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl }amino )thio- 5 ph en-2-yl ]pyridin-2-yl} phenyl)cyclopropanecarboxylic acid, (RS)-1-( 4-{ 5-[5-chloro-3-( {[ 1-( 4-methylthiophen-3-yl)ethoxy]carbonyl}amino )thiophen-2-yl]pyridin-2-yl }pheny1)cyclopropanecarboxylic acid, (RS)-1-{ 4'-[5-fluoro-3-( {[ 1-(thiophen-3-yl)ethoxy ]carbonyl} amino )thiophen- 2-yl]-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, 10 (R)-1-{4'-[5-fluoro-3-( {[1-(thiophen-3-y1)ethoxy]carbonyl }amino )thiophen-2-yl]-[1,1'-bipheny1]-4-y1}cyclopropanecarboxylic acid, (RS)-1-{4'-[5-fluoro-3-( {[1-(thiophen-3-yl)ethoxy ]carbonyl }amino )thiophen- 2-yl]-2'-methoxy-[1 ,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (RS)-1-{4'-[5-fluoro-3-( {[1-( 4-methylthiophen-3-yl)ethoxy]carbonyl} amino)- 15 thiophen-2-yl] -[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid, (R)-1-{ 4'-[ 5-fluoro-3-( { [ 1-( 4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)thiophen- 2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (RS)-1-{4'-[5-fluoro-3-( {[1-(2-methylthiophen-3-yl)ethoxy]carbonyl }amino)thiophen- 2-yl]-[1, 1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, 20 (RS)-1-{ 4'-[5-fluoro-3-( {[1-(4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)-thiophen-2-yl]-2'-methoxy-[1,1 '-biphenyl]-4-y1}cyclopropanecarboxylic acid, (RS)-1-{4'-[3-( {[1-( 4-chlorothiophen-3-yl)ethoxy]carbonyl}amino )-5-fluorothiophen- 2-yl]-[ 1, 1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, (RS)-1-{ 4'-[3-( {[1-( 4-chlorothiophen-3-yl)ethoxy]carbonyl }amino )-5-fluoro- 25 thiophen-2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, (R)-1-{4'-[5-chloro-3-( {[1-(thiophen-2-yl)ethoxy]carbonyl}amino)thiophen-2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylicacid, (R)-1-{4'-[5-chloro-3-( {[1-(thiophen-2-yl)ethoxy]carbonyl }amino )thiophen-2-yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid, 30 (R)-1-{ 4'-[5-fluoro-3-( {[ 1-(thiophen-2-yl)ethoxy]carbonyl} amino )thiophen-2-yl]-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid, (R)-1-{4'-[5-fluoro-3-( {[1-(thiophen-2-yl)ethoxy]carbonyl}amino)thiophen-2-yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 35 14. (R)-1-{ 4'-[5-chloro-3-( {[1-(2-chlorophenyl)ethoxy ]carbonyl} amino )thiophen- 2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically -295-acceptable salt thereof. 15. (R)-1-{4'-[5-chloro-3-( {[1-(3-fluorophenyl)ethoxy]carbonyl}amino)thiophen- 2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 5 16. (R)-1-{4'-[3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen- 2-yl]-[1, 1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 17. (R)-1-{4'-[5-fluoro-3-( {[1-(o-tolyl)ethoxy]carbonyl }amino)thiophen-2-yl]- [ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically acceptable 10 salt thereof. 18. (R)-1-[ 4' -( 5-chloro-3- { [ ( 1-phenylethoxy )carbonyl ]amino} thiophen-2-y1)- 2'-methoxy-[ 1, 1'-biphenyl ]-4-yl]cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 19. (R)-1-{ 4'-[ 5-chloro-3-( {[ 1-(2,5-difluorophenyl)ethoxy ]carbonyl}- 15 amino )thiophen-2-yl]-2'-methoxy-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 20. (R)-1- {4'-[3-( {[1-(2-chlorophenyl)ethoxy]carbonyl}amino )-5-fluorothiophen- 2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 20 21. (R)-1- {4'-[5-chloro-3-( {[ 1-(thiophen-3-yl)ethoxy]carbonyl}amino )thiophen- 2-yl]-[ 1, 1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 22. (R)-1-{4'-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl}amino)thiophen- 2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, and, a 25 pharmacologically acceptable salt thereof. 23. (R)-1-{4'-[5-chloro-3-( {[1-(4-methylthiophen-3-yl)ethoxy]carbonyl}-amino )thiophen-2-yl ]-[ 1, 1 '-bipheny1)-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 24. (R)-1-{ 4'-[5-fluoro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl }amino )thio- 30 phen-2-yl]-[1,1 '-biphenyl]-4-yl}cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 25. (R)-1-{4'-[5-fluoro-3-( {[1-(4-methylthiophen-3-yl)ethoxy]carbonyl}-amino )thiophen-2-yl]-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically acceptable salt thereof. 35 26. An LP A receptor antagonist comprising the compound or a pharmacologically acceptable salt thereof according to anyone of Claims 1 to 25 as an active ingredient. 27. A pharmaceutical composition comprising the compound or a pharmacologically acceptable salt thereof according to anyone of Claims 1 to 25 as an active ingredient. 28. The pharmaceutical composition according to Claim 27 for the treatment or prevention of a disease accompanying fibrosis, an immunological or inflammatory disease, a central or peripheral nervous system disease, an urologic disease or a cancer-related disease.