EP2 antagonist

Abstract

The purpose of the present invention is to provide a drug for the prevention and / or treatment of a disease associated with the activation of an EP2 receptor, the drug containing, as an active ingredient, a compound having an antagonistic activity on a EP2 receptor.　A compound represented by general formula (I-A) (wherein all symbols have the same meanings as those described in the description) or a pharmaceutically acceptable salt thereof is useful as a drug component having a potent antagonistic activity on an EP2 receptor in the prevention and / or treatment of a disease associated with the activation of an EP2 receptor.

Description

[Technical field]

[0001] The present invention relates to 2 The present invention relates to a compound having receptor antagonist activity or a pharma- ceutical salt thereof, and a medicine containing the compound or the salt as an active ingredient.

[0002] [ka] (wherein all symbols have the same meaning as described below) or a pharma- ceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention), and a medicament containing the compound or salt as an active ingredient. [Background technology]

[0003] Prostaglandin E 2 (P.G.E. 2 ) is known to be a metabolic product in the arachidonic acid cascade and is known to have cell protective effects, uterine contraction effects, pain threshold lowering effects, gastrointestinal peristalsis promotion effects, awakening effects, gastric acid secretion inhibition effects, blood pressure lowering effects, and diuretic effects.

[0004] PGE 2 There are subtypes of receptors, each with a different role. 1 Receptor, EP 2 Receptor, EP 3 Receptor, EP 4 These are called receptors (Non-Patent Document 1).

[0005] Among these subtypes, EP 2 The receptor is involved in cAMP signaling, and is therefore known to be involved in the relaxation of the circular muscles of the trachea and ileum and the dilation of various blood vessels. 2 The receptors are known to be involved in the expression of PI3K, Akt, or GSK-3β, as well as IL-1β, IL-6, IL-12, IL-23, and IL-27. 2The receptor is thought to be involved in suppressing MCP-1 production from macrophages, suppressing TNF-α, IL-2, and IFN-γ production from lymphocytes, and in anti-inflammation by enhancing IL-10 production, vasodilation, angiogenesis, suppressing elastic fiber formation, and controlling MMP-9 expression. 2 The receptor is also thought to be involved in cancer immune control via myeloid derived suppressor cells, regulatory T cells and natural killer cells.

[0006] From these, EP 2 The receptor is known to be involved in anti-inflammatory, neuroprotective and antitumor effects, and EP 2 Compounds that bind strongly to the receptor and have antagonistic effects are known as EP 2 It is believed to be useful for the prevention and / or treatment of diseases caused by receptor activation, such as endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative pain, interstitial cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic diseases, hypertension, brain disorders, ischemia, stroke, renal diseases, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, vasculitis, and autoimmune diseases (Non-Patent Documents 2-4).

[0007] On the other hand, it is described that the compound represented by the following general formula (A) described in Patent Document 1 is used for the treatment of diseases associated with SRS-A, such as allergic diseases, ischemic heart disease, or inflammation.

[0008] The general formula (A) is

[0009] [ka] (In the formula, A A represents a hydrogen atom, a phenyl group, or a phenoxy group; n A represents an integer between 3 and 10; R 1A represents a hydrogen atom or a lower alkoxy group; X 1A is -CO-Y 2A -(Y 2A represents -NH-, etc.;

[0010] [ka] teeth,

[0011] [ka] etc., R 2A represents a hydrogen atom, a halogen, a lower haloalkyl group, or the like; X 2A -Y 3A -Y 4A - represents Y 3A represents a single bond, etc., and Y 4A represents an alkylene group having 1 to 6 carbon atoms, or the like; D A represents a carboxy group, a lower alkoxycarbonyl group, etc. (The definitions of the groups are partially excerpted.)

[0012] Also, the EP 2 Known examples of antagonists include a compound represented by the following general formula (B) in Patent Document 2 and a compound represented by the following general formula (C) in Patent Document 3.

[0013] The general formula (B) is

[0014] [ka] (In the formula, A B is NR 5B etc.; U B CX 5B or N; W B CX 6B or N; n B represents 1, 2, 3, or 4; R 1B represents a carbocycle, an aryl, a heterocycle, etc.; X 1B , X 2B , X 3B , X 4B may be the same or different and represent a hydrogen atom, an alkyl group, a halogen, or the like; R 5B represents a hydrogen atom, an alkyl group, or the like; X 5B , X 6B may be the same or different and represent a hydrogen atom, an alkyl group, or the like. (The definition of the group is partially excerpted.)

[0015] The general formula (C) is

[0016] [ka] (In the formula, A c represents an optionally substituted C5-12 heteroaryl group; R ’c HA-S(O) p represents a -C1 to C6 alkyl group, and p is 0 to 2; R 1c represents a hydrogen atom or a C1-C6 alkyl group, etc.; R 2c , R 3c , R 4c each represents a hydrogen atom or a halogen, etc.; X c represents -C=C- etc.; Y c is -(CH 2 ) n -, and n is 2 or 3 (a partial excerpt from the definition of the group).

[0017] Patent Document 4 describes methyl 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2-chlorophenyl]propanoate and 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2-chlorophenyl]propanoic acid.

[0018] However, none of the prior art documents describes or suggests the compound of the present invention. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 1986 / 005779 Pamphlet [Patent Document 2] International Publication No. 2012 / 177618 Brochure [Patent Document 3] International Publication No. 2008 / 152097 Brochure [Patent Document 4] International Publication No. 2007 / 052843 Brochure [Non-patent literature]

[0020] [Non-Patent Document 1] Journal of Lipid Mediators and Cell Signalling, Vol. 12, pp. 379-391, 1995 [Non-Patent Document 2] Journal of the Medicinal Chemistry, Vol. 57, pp. 4454-4465, 2014 [Non-Patent Document 3] Trends in Pharmacological Science, Vol. 34, pp. 413-423, 2013 [Non-Patent Document 4] International Journal of molecular medicine, Vol. 42, pp. 1202-1214, 2018 Summary of the Invention [Problem to be solved by the invention]

[0021] The object of the present invention is to 2 It has strong antagonistic activity against the EP receptor. 2 The objective of the present invention is to find compounds that are useful as preventive and / or therapeutic agents for diseases caused by receptor activation. [Means for solving the problem]

[0022] Means of the Invention The present inventors have conducted intensive research to solve the above problems and have found that a compound represented by the below-described general formula (I) solves the above problems, thereby completing the present invention.

[0023] That is, the present invention provides [1] General formula (IA):

[0024] [ka] (In the formula, L 1 CR 38 R 39 )-(CR 40 R 41 )-, R 38 , R 39 , R 40 and R 41 each independently represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C1-4 alkyl group; R 38 , R39 , R 40 and R 41 each C1-4 alkyl group may be independently substituted with a halogen atom; R 38 , R 39 , R 40 and R 41 When two substituents selected from the group consisting of are C1-4 alkyl groups, they may be taken together with the carbon atom to which they are attached to form a C3-6 saturated carbocyclic ring; L 2 represents (1) a bond, (2) a C1-8 alkylene group, (3) a C2-8 alkenylene group, or (4) a C2-8 alkynylene group, in which 1 to 2 carbon atoms are optionally replaced by an oxygen atom or an optionally oxidized sulfur atom, and the C1-8 alkylene group, C2-8 alkenylene group, and C2-8 alkynylene group are optionally substituted by 1 to 8 halogen atoms; Y represents (1) a bond, (2) an oxygen atom, or (3) an optionally oxidized sulfur atom; R 1 (1) COOR 10 , (2) SO 3 H, (3)SO 2 NHR 11 , (4) CONHSO 2 R 12 , (5) SO 2 NHCOR 13 , (6) CONR 14 R 15 , (7) a tetrazolyl group, or (8) a hydroxamic acid (CONHOH), R 10 , R 11 , R 12 , R 13 , R 14 and R 15 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 2 represents (1) a hydrogen atom or (2) a C1-4 alkyl group, R 3represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a 3- to 6-membered cyclic group, (7) (3- to 6-membered cyclic group) -O-, or (8) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 3 (2) to (8) in the table are 1 to 9 R 16 may be substituted with R 3 If there are multiple, multiple R 3 may be the same or different, R 16 is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 17 R 18 represents R 16 If there are multiple, multiple R 16 may be the same or different, R 17 and R 18 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 4 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a 3- to 6-membered cyclic group, (7) (3- to 6-membered cyclic group) -O-, or (8) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 4 (2) to (8) in the table are 1 to 9 R 19 may be substituted with R 4 If there are multiple, multiple R 4 may be the same or different, R 19 is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 20 R 21 represents R 20 and R 21 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 19 If there are multiple, multiple R 19 may be the same or different, R 5 represents (1) a hydrogen atom, (2) a C3-10 carbocyclic ring, or (3) a 3- to 10-membered heterocyclic ring, and the C3-10 carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from 1 to 5 R 22 may be substituted with However, L 2 If is a bond, R 5 is not a hydrogen atom, R 22 is (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a C3-6 cycloalkyl group, (5) a C1-6 alkoxy group, (6) a C3-6 cycloalkyloxy group, (7) a C2-6 acyl group, (8) a C2-6 acyloxy group, (9) a C1-6 alkylthio group, (10) a C3-6 cycloalkylthio group, (11) a C1-6 alkylsulfinyl group, (12) a C3-6 cycloalkylsulfinyl group, (13) a C1-6 alkylsulfonyl group, (14) a C3-6 cycloalkylsulfonyl group, (15) a C1-6 alkoxycarbonyl group, (16) a 5-6 membered cyclic group, (17) (5-6 membered cyclic group)-(C1-4 alkylene)-, (18) (5-6 membered cyclic group)-(C1-4 alkylene)-O- group, (19) (5-6 membered cyclic group)-C1-4 acyl group, (20) a halogen atom, (21) a hydroxyl group, (22) a nitro group, (23) a cyano group, (24) -NR 23 R 24 , (25)-CONR 25 R 26 or (26)-SO 2 NR 27 R 28 represents R 23 , R 24 , R 25 , R 26 , R 27 and R 28each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group; R 22 Among these, the groups (1) to (19) each contain 1 to 9 R 29 may be substituted with R 22 If there are multiple, multiple R 22 may be the same or different, R 29 is (1) a C1-4 alkyl group, (2) a C1-4 alkoxy group, (3) a C2-6 acyl group, (4) a C3-6 cycloalkyl group, (5) a hydroxyl group, or (6) -NR 30 R 31 or (7) a halogen atom, R 30 and R 31 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 29 If there are multiple, multiple R 29 may be the same or different, Q represents (1) an oxygen atom or (2) a sulfur atom; X is (1) CR 6 or (2) NR 7 represents R 6 represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a 3- to 6-membered cyclic group, (7) (3- to 6-membered cyclic group) -O-, or (8) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 6 (2) to (8) in the table are 1 to 9 R 32 may be substituted with R 32 is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 33 R 34 represents R 33 and R 34each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 32 If there are multiple, multiple R 32 may be the same or different, R 7 represents (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a 3- to 6-membered cyclic group, or (5) a (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R 7 is 1 to 9 R 35 may be substituted with R 35 is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR 36 R 37 represents R 36 and R 37 each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R 35 If there are multiple, multiple R 35 may be the same or different, Ring A represents (1) a benzene ring or (2) a 5- or 6-membered nitrogen-containing aromatic heterocycle; In ring A

[0025] [ka] represents a single or double bond, n represents an integer of 1 to 4; m represents an integer of 0 to 3; However, 3-[3-[(2,6-dimethoxybenzoyl)amino]-4-propoxyphenyl]propanoic acid, 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2-chlorophenyl]methyl propanoate, 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2-chlorophenyl]propanoic acid, α-Ethyl-3-[N-(1'-phenyl-5'-methyl-1',2',3'-triazolecarbonyl)]amino-2,4,6-triiodohydrocinnamic acid, and A compound represented by the formula: α-ethyl-3-{N-(1'-(4"-iodophenyl)-5'-methyl-1,2,3-triazolecarbonyl]}amino-2,4,6-triiodohydrocinnamic acid is excluded.) or a pharma- ceutically acceptable salt thereof; [2] General formula (I):

[0026] [ka] (wherein all symbols have the same meanings as those in the above [1]), or a pharma- ceutically acceptable salt thereof. [3] General formula (IB):

[0027] [ka] (In the formula, X a is CR 6a or NR 7a represents R 6a represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) (3- to 6-membered cyclic group) -O-, or (7) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 6a (2) to (7) in the table are 1 to 9 R 32 may be substituted with R 7a represents (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a 3- to 6-membered cyclic group, or (5) a (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R 7a is 1 to 9 R35 may be substituted with R 3a , R 3b and R 3c each independently represents (1) a hydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group, (4) a C2-6 alkenyl group, (5) a C2-6 alkynyl group, (6) a C1-6 alkoxy group, (7) a 3- to 6-membered cyclic group, (8) (3- to 6-membered cyclic group) -O-, or (9) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 3a , R 3b and R 3c (3) to (9) in the table are 1 to 9 R 16 may be substituted with However, R 3a , R 3b and R 3c At least one of represents a substituent other than a hydrogen atom, The same symbols as those described in [1] above have the same meanings as those described in [1] above, However, 3-[3-[(2,6-dimethoxybenzoyl)amino]-4-propoxyphenyl]propanoic acid is excluded.) or a pharma- ceutically acceptable salt thereof, [4] General formula (I-1):

[0028] [ka] (wherein p represents an integer of 1 to 4, and the other symbols have the same meanings as those in the above [1]), or a pharma- ceutically acceptable salt thereof. [5] General formula (IC):

[0029] [ka] (In the formula, X a is CR 6a or NR 7a represents R 6arepresents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) (3- to 6-membered cyclic group) -O-, or (7) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 6a (2) to (7) in the table are 1 to 9 R 32 may be substituted with R 7a represents (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a 3- to 6-membered cyclic group, or (5) a (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R 7a is 1 to 9 R 35 may be substituted with R 3a , R 3b and R 3c each independently represents (1) a hydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group, (4) a C2-6 alkenyl group, (5) a C2-6 alkynyl group, (6) a C1-6 alkoxy group, (7) a 3- to 6-membered cyclic group, (8) (3- to 6-membered cyclic group) -O-, or (9) (3- to 6-membered cyclic group) -(C1-4 alkylene)-; R 3a , R 3b and R 3c (3) to (9) in the table are 1 to 9 R 16 may be substituted with However, R 3a , R 3b and R 3c At least one of represents a substituent other than a hydrogen atom, p represents an integer of 1 to 4; The same symbols as those described in [1] above have the same meanings as those described in [1] above.) A compound according to any one of [1] to [4] above, or a pharma- ceutically acceptable salt thereof, [6] The compound according to any one of the above [1] to [5], wherein ring A is a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, or a pharma- ceutically acceptable salt thereof. [7] L 2is a C1-8 alkylene group, a C2-8 alkenylene group, or a C2-8 alkynylene group, in which 1 to 2 carbon atoms are optionally replaced by oxygen atoms, and the C1-8 alkylene group, C2-8 alkenylene group, and C2-8 alkynylene group are optionally substituted by 1 to 8 halogen atoms, the compound according to any one of the above [1] to [6], or a pharma- ceutically acceptable salt thereof; [8] R 5 represents a C3-6 carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the C3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are each independently selected from 1 to 5 R 22 The compound according to any one of the above [1] to [7], or a pharma- ceutically acceptable salt thereof, which may be substituted by [9] The compound according to any one of the above [1] to [8], or a pharma- ceutically acceptable salt thereof, wherein ring A is a benzene ring or a pyrrole ring.

[10] The compound according to any one of the above [1] to [9], wherein ring A is a pyrrole ring and Y is a bond, or a pharma- ceutically acceptable salt thereof.

[11] The compound according to any one of the above [1] to [9], wherein ring A is a benzene ring and Y is an oxygen atom, or a pharma- ceutically acceptable salt thereof.

[12] (1) rel-(1R,2S)-2-[3-({[1-sec-butyl-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (2) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (3) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (4) rel-(1R,2R)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (5) rel-(1R,2S)-2-{5-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (6) rel-(1R,2R)-2-{5-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (7) (1S,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-methoxyphenyl}cyclopropanecarboxylic acid, (10) (1S,2R)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (11) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (12) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-chlorophenyl}cyclopropanecarboxylic acid, (13) (1R,2S)-2-{3-[({5-[2-(benzyloxy)ethyl]-1-[(2S)-2-butanyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (14) rel-(1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-chloro-6-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (16) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-[2-(2-chloro-3,5-difluorophenoxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (17) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-[2-(2,4-difluorophenoxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(1-methyl-1H-pyrazol-4-yl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (19) rel-(1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (20) (1R,2S)-2-[3-{[2,6-dimethyl-4-(3-phenylpropyl)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (21) (1R,2S)-2-[3-({4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (22) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-fluorophenyl)cyclopropanecarboxylic acid, (23) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-fluorophenyl)cyclopropanecarboxylic acid, (24) (1R,2S)-2-[2-chloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-(4-chloro-3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid, (26) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid, (27) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (29) (1S,2R)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (30) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (31) (1R,2S)-2-[3-{[4-(2-cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (32) (1R,2S)-2-{3-[(2,6-dimethyl-4-propoxybenzoyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (33) (1R,2S)-2-[3-{[4-(hexyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (34) (1R,2S)-2-[3-{[4-(benzyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (35) (1R,2S)-2-[3-{[4-(2-methoxyethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (36) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (37) (1R,2S)-2-[3-({4-[2-(2-furyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (38) (1R,2S)-2-[3-({4-[2-(2-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (39) (1R,2S)-2-[3-({4-[2-(3-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (40) (1R,2S)-2-[3-({4-[2-(1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (41) (1R,2S)-2-[3-({4-[2-(2,6-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (42) (1R,2S)-2-[3-({4-[2-(3,5-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (43) (1R,2S)-2-[3-({4-[(6-chloro-2-pyrazinyl)oxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (44) (1R,2S)-2-[3-{[4-(6-fluoro-3-pyridinyl)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (45) (1R,2S)-2-[3-({4-[2-(4-hydroxyphenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (46) 3-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]propanoic acid, (47) 3-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]butanoic acid, (48) 3-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]-2-methylpropanoic acid, (49) (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclobutanecarboxylic acid, or (50) The compound according to the above [1], or a pharma- ceutically acceptable salt thereof, selected from (1R,2R)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]-1-methylcyclopropanecarboxylic acid;

[13] (1) (1R,2S)-2-[3-{[2-methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (2) (1R,2S)-2-[3-{[2-chloro-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (3) (1R,2S)-2-[3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (4) (1R,2S)-2-[3-{[4-(1H-indazol-5-ylmethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (5) (1R,2S)-2-[3-{[2,6-dimethyl-4-(1,2,3,4-tetrahydro-1-naphthalenylmethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (6) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(3-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (7) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(4-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(2-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-[3-({4-[2-(2-chloro-1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (10) (1R,2S)-2-[3-({4-[2-(2-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (11) (1R,2S)-2-[3-({4-[2-(3-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (12) (1R,2S)-2-[3-({4-[2-(4-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (13) (1R,2S)-2-[3-{[2,6-dimethyl-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (14) (1R,2S)-2-[3-{[2,6-dimethyl-4-(3,3,3-trifluoro-2-methylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-{3-[(2,6-dimethyl-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}benzoyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (16) (1R,2S)-2-[3-{[2,6-dimethyl-4-(pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (17) rel-(1R,2S)-2-(3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-methylphenyl)cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[4-(benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (19) (1R,2S)-2-[3-{[2-isopropyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (20) (1R,2S)-2-[3-{[2-isopropyl-4-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (21) (1R,2S)-2-[3-{[3-(benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (22) (1R,2S)-2-[3-{[2-isopropyl-3-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (23) (1R,2S)-2-[3-{[2-isopropyl-3-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (24) (1R,2S)-2-[4-(trifluoromethyl)-3-{[2,3,5-trimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-[3-({[3-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (26) (1R,2S)-2-[3-({[5-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (27) (1R,2S)-2-[3-({[2,6-dimethyl-4-(2-phenylethoxy)phenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-({[4-(2-cyclopropylethoxy)-2,6-dimethylphenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (29) (1R,2S)-2-[3-({[2-sec-butyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (30) (1R,2S)-2-[3-({[2-isopropyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or (31) The compound according to the above [1], selected from (1R,2S)-2-[3-({[2-(2-methyl-2-propanyl)-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or a pharma- ceutically acceptable salt thereof.

[14] A pharmaceutical composition comprising the compound according to any one of [1] to

[13] above or a pharma- ceutical acceptable salt thereof as an active ingredient, and further comprising a pharma- ceutical acceptable carrier.

[15] EP 2 The pharmaceutical composition according to the above

[14] , which is a receptor antagonist.

[16] EP 2 The pharmaceutical composition according to

[14] or

[15] above, which is an agent for treating and / or preventing a disease caused by receptor activation.

[17] EP 2The pharmaceutical composition according to the above

[16] , wherein the disease caused by receptor activation is endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative pain, interstitial cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic disease, hypertension, brain disorder, ischemia, stroke, kidney disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, vasculitis, or autoimmune disease.

[18] EP 2 The pharmaceutical composition according to the above

[16] or

[17] , wherein the disease caused by receptor activation is cancer, and the cancer is breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, uveal melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis / ureter cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (e.g., malignant melanoma, etc.), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, brain tumor, or multiple myeloma.

[19] The pharmaceutical composition according to any one of

[14] to

[18] above, which is administered in combination with at least one selected from the group consisting of alkylating agents, metabolic antagonists, anticancer antibiotics, botanical preparations, hormones, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, and immunomodulators.

[20] The compound according to any one of [1] to

[13] above, or a pharma- ceutically acceptable salt thereof, or the composition according to

[14] or

[15] above, 2 The present invention relates to a method for the prevention and / or treatment of a disease caused by activation of a receptor, comprising administering the method to a patient in need of the prevention and / or treatment of a disease caused by activation of a receptor. 2 A method for preventing and / or treating a disease caused by receptor activation,

[21] EP 2The compound according to any one of the above [1] to

[13] , or a pharma- ceutical acceptable salt thereof, for use in the prophylaxis and / or treatment of a disease caused by receptor activation.

[22] EP 2 Use of the compound according to any one of the above [1] to

[13] or a pharma- ceutical acceptable salt thereof for the manufacture of an agent for the prophylaxis and / or treatment of a disease caused by receptor activation. Effect of the Invention

[0030] The compound of the present invention is EP 2 EP has strong antagonistic activity against the receptor and good pharmacokinetic properties (e.g., solubility and hepatic microsomal stability). 2 These compounds are useful for preventing and / or treating diseases caused by receptor activation. [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 shows the antitumor effect of the compound of the present invention in an allograft model of mouse colon cancer cell line CT26. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The present invention will be described in detail below.

[0033] In this specification, halogen atoms include fluorine, chlorine, bromine and iodine atoms.

[0034] In the present specification, C1-4 alkyl groups include methyl, ethyl, propyl, butyl groups and isomers thereof.

[0035] In the present specification, C1-6 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl groups and isomers thereof.

[0036] In the present specification, the term "C2-6 alkenyl group" means, for example, a C2-6 alkenyl group having 1 to 2 double bonds, specifically, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, and isomers thereof.

[0037] In the present specification, the C2-6 alkynyl group means, for example, a C2-6 alkynyl group having 1 to 2 triple bonds, specifically, ethynyl, propynyl, butynyl, butadiynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl groups, and isomers thereof.

[0038] In the present specification, C1-4 alkylene groups include methylene, ethylene, propylene, butylene groups and isomers thereof.

[0039] In the present specification, C1-8 alkylene groups include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene groups and isomers thereof.

[0040] In the present specification, the C2-8 alkenylene group means, for example, a C2-6 alkenylene group having 1 to 2 double bonds, and includes ethenylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, heptenylene, heptadienylene, octenylene, octadienylene, and isomers thereof.

[0041] In the present specification, the C2-8 alkynylene group means, for example, a C2-8 alkynylene group having 1 to 2 triple bonds, and specifically includes ethynylene, propynylene, butynylene, butadiynylene, pentynylene, pentadiynylene, hexynylene, hexadiynylene, heptynylene, heptadiynylene, octynylene, octadiynylene groups, and isomers thereof.

[0042] In the present specification, C1-4 alkoxy means methoxy, ethoxy, propoxy, butoxy and the isomers thereof.

[0043] In the present specification, C1-6 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isomers thereof.

[0044] In the present specification, C1-6 alkylthio groups include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio groups, and isomers thereof.

[0045] In the present specification, C1-6 alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl groups, and isomers thereof.

[0046] In the present specification, C1-6 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl groups, and isomers thereof.

[0047] In the present specification, C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0048] In the present specification, C3-6 cycloalkyloxy group means cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy groups.

[0049] In the present specification, C3-6 cycloalkylthio group is cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio group.

[0050] In the present specification, C3-6 cycloalkylsulfinyl group means cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl and cyclohexylsulfinyl groups.

[0051] In the present specification, C3-6 cycloalkylsulfonyl group means cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl groups.

[0052] In the present specification, C1-6 alkoxycarbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and isomers thereof.

[0053] In the present specification, C1-4 acyl means methanoyl, ethanoyl, propanoyl, butanoyl and isomers thereof.

[0054] In the present specification, C2-6 acyl means ethanoyl, propanoyl, butanoyl, pentanoyl, hexanoyl and isomers thereof.

[0055] In the present specification, C2-6 acyloxy groups include ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy groups, and isomers thereof.

[0056] In the present specification, C3-6 saturated carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings.

[0057] In the present specification, the 5-membered nitrogen-containing aromatic heterocycle means a 5-membered aromatic heterocycle containing one or more nitrogen atoms, and specific examples thereof include pyrrole, imidazole, triazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole rings.

[0058] In the present specification, the term "5- to 6-membered nitrogen-containing aromatic heterocycle" means a 5- or 6-membered aromatic heterocycle containing one or more nitrogen atoms, and specific examples thereof include pyrrole, imidazole, triazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, thiazole, and isothiazole rings.

[0059] In the present specification, the 5-6 membered cyclic group refers to a C5-6 carbocyclic ring and a 5-6 membered heterocyclic ring.

[0060] Examples of C5-6 carbocyclic rings include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and benzene.

[0061] Examples of the 5- to 6-membered heterocycle include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydro Examples of such rings include thiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, and dithiane rings.

[0062] In the present specification, the 3- to 6-membered cyclic group refers to a C3-6 carbocyclic ring and a 3- to 6-membered heterocyclic ring.

[0063] C3-6 carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene rings.

[0064] The 3- to 6-membered heterocycle includes aziridine, azetidine, oxirane, oxetane, thiirane, thietane, and the above 5- to 6-membered heterocycle.

[0065] In the present specification, C3-10 carbocyclic ring means, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene ring.

[0066] In the present specification, the 3- to 10-membered heterocycle includes, for example, the 5- to 6-membered heterocycle, as well as aziridine, azetidine, oxirane, oxetane, thiirane, thietane, azepine, diazepine, oxepine, thiepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, synthane, cyclohexanone ... Nolin, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydroo perhydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydrobenzofuran, perhydroisobenzofuran, dihydroisobenzofuran, dihydroisobenzothiophene ... tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,Dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxaindan, benzodioxane, chroman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane, azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane ring, etc. ,

[0067] In the present invention, the compound represented by the general formula (IA) is preferably a compound represented by the general formula (I):

[0068] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0069] In the present invention, the compound represented by the general formula (IA) is preferably a compound represented by the general formula (Ia):

[0070] [ka] (wherein ring A-1 represents a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, and the other symbols have the same meanings as above), or a pharma- ceutically acceptable salt thereof.

[0071] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ib):

[0072] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0073] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ic):

[0074] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0075] In the present invention, the compound represented by general formula (IA) is more preferably a compound represented by general formula (I-1):

[0076] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0077] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Id):

[0078] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0079] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ie):

[0080] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0081] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (If):

[0082] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0083] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ig):

[0084] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0085] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ih):

[0086] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0087] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (IB):

[0088] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0089] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ii):

[0090] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0091] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ij):

[0092] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0093] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (Ik):

[0094] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0095] In the present invention, another preferred embodiment of the compound represented by general formula (IA) is a compound represented by general formula (IL):

[0096] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0097] In the present invention, the compound represented by the general formula (IA) is more preferably a compound represented by the general formula (Im):

[0098] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0099] In the present invention, the compound represented by the general formula (IA) is more preferably a compound represented by the general formula (In):

[0100] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0101] In the present invention, the compound represented by the general formula (IA) is more preferably a compound represented by the general formula (Io):

[0102] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0103] In the present invention, the compound represented by the general formula (IA) is more preferably a compound represented by the general formula (Ip):

[0104] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0105] In the present invention, the compound represented by general formula (IA) is more preferably a compound represented by general formula (Iq):

[0106] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0107] In the present invention, the compound represented by the general formula (IA) is more preferably a compound represented by the general formula (IC):

[0108] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0109] In the present invention, the compound represented by the general formula (IA) is preferably a compound represented by the general formula (II):

[0110] [ka] (wherein all symbols have the same meaning as defined above), or a pharma- ceutically acceptable salt thereof.

[0111] In the present invention, R 1 Preferably as COOR 10 or CONR 14 R 15 and more preferably COOR 10 and more preferably COOH.

[0112] In the present invention, R 10 is preferably a hydrogen atom.

[0113] In the present invention, R 2 is preferably a hydrogen atom.

[0114] In the present invention, R 3is preferably a halogen atom, an optionally halogen-substituted C1-6 alkyl group, or an optionally halogen-substituted C1-6 alkoxy group, more preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, or a trifluoromethyl group, and most preferably a trifluoromethyl group.

[0115] In the present invention, R 3a , R 3b , and R 3c At least one of R represents a substituent other than a hydrogen atom. 3a , R 3b , and R 3c As a combination of R 3b is a substituent other than a hydrogen atom, and R 3a and / or R 3c may be a hydrogen atom, R 3c is a substituent other than a hydrogen atom, and R 3a and / or R 3b may be a hydrogen atom, R 3a and R 3b is a substituent other than a hydrogen atom, and R 3c may be a hydrogen atom, R 3a and R 3c is a substituent other than a hydrogen atom, and R 3b may be a hydrogen atom, R 3b and R 3c is a substituent other than a hydrogen atom, and R 3a may be a hydrogen atom, R 3a ~R 3c may be a substituent other than a hydrogen atom, but preferably R 3a is a substituent other than a hydrogen atom, and R 3b and / or R 3c is a hydrogen atom. More preferably, R 3a is a substituent other than a hydrogen atom, and R 3b and R 3cis a hydrogen atom. The substituent other than the hydrogen atom is preferably a halogen atom, an optionally halogen-substituted C1-6 alkyl group, or an optionally halogen-substituted C1-6 alkoxy group, more preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, or a trifluoromethyl group, and most preferably a trifluoromethyl group.

[0116] In the present invention, R 4 is preferably a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, more preferably a C1-6 alkyl group, and even more preferably a methyl group.

[0117] In the present invention, R 5 is preferably a hydrogen atom, a C3-6 carbocyclic ring, or a 3-6 membered heterocyclic ring, more preferably a C3-6 carbocyclic ring, or a 3-6 membered heterocyclic ring, or more preferably a hydrogen atom, cyclopropane, benzene, or a 5-6 membered heterocyclic ring, more preferably a cyclopropane, benzene, imidazole, pyrazole, pyridine, furan, or tetrahydropyran ring, and most preferably a benzene ring. 5 is 1 to 5 R 22 may be substituted with.

[0118] In the present invention, R 22 is preferably a halogen atom, a hydroxyl group, or a C1-6 alkyl, and more preferably a fluorine atom, a chlorine atom, a hydroxyl group, or a methyl group.

[0119] In the present invention, R 6 is preferably a halogen atom, or an optionally halogen-substituted C1-6 alkyl group, more preferably a C1-6 alkyl group, further preferably a methyl or isopropyl group, and particularly preferably a methyl group.

[0120] In the present invention, R 6ais preferably a halogen atom, or an optionally halogen-substituted C1-6 alkyl group, more preferably a C1-6 alkyl group, further preferably a methyl or isopropyl group, and particularly preferably a methyl group.

[0121] In the present invention, R 7 is preferably a C1-6 alkyl group or a 3- to 6-membered cyclic group, more preferably an isopropyl, 2-butyl, 3-pentyl, or cyclopropyl group, more preferably an isopropyl, 3-pentyl, or 2-butyl group, and even more preferably a 2-butyl group.

[0122] [ka] If is a double bond, R 7 does not exist.

[0123] In the present invention, R 7a is preferably a C1-6 alkyl group or a 3- to 6-membered cyclic group, more preferably an isopropyl, 2-butyl, 3-pentyl, or cyclopropyl group, more preferably an isopropyl, 3-pentyl, or 2-butyl group, and even more preferably a 2-butyl group.

[0124] [ka] If is a double bond, R 7a does not exist.

[0125] In the present invention, R 38 , R 39 , R 40 , R 41 are preferably each independently a hydrogen atom or a C1-4 alkyl group.

[0126] In the present invention, Q is preferably an oxygen atom.

[0127] In the present invention, L1 As the preferable

[0128] [ka] (In the formula, * represents a benzene ring or R 1 and the bond may be oriented in either direction.

[0129] [ka] (In the formula, * represents a benzene ring or R 1 The bonding position with L may be in either direction. 1 is preferably a C3-6 saturated carbocyclic ring.

[0130] In the present invention, ring A is preferably a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, more preferably a benzene, pyrrole, or pyrazole ring, and particularly preferably a benzene or pyrrole ring.

[0131] In the present invention, Y is preferably a bond or an oxygen atom.

[0132] In the present invention, preferred combinations of ring A and Y include a combination in which ring A is a benzene ring and Y is an oxygen atom, and a combination in which ring A is a 5-membered nitrogen-containing aromatic heterocycle (more preferably a pyrrole or pyrazole ring, particularly preferably a pyrrole ring) and Y is a bond.

[0133] In the present invention, L 2 is preferably a bond or a C1-8 alkylene group in which one carbon atom may be replaced by an oxygen atom, more preferably a C1-8 alkylene group in which one carbon atom may be replaced by an oxygen atom, and further preferably ethylene, propylene, -OCH 2 CH 2 -, or -CH 2 OCH 2 CH 2-It is.

[0134] In the present invention, ring A-1 is preferably a benzene, pyrrole, or pyrazole ring, more preferably a benzene or pyrrole ring.

[0135] In the present invention, p is preferably 1 or 2, and more preferably 1.

[0136] In the present invention, m is preferably 0, 1 or 2, and more preferably 0 or 1.

[0137] In the present invention, n is preferably 1, 2 or 3, and more preferably 1.

[0138] In the present invention, in the above general formula (IA), general formula (I), general formula (I-1), general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id), general formula (Ie), general formula (If), general formula (Ig), general formula (Ih), general formula (Ii), general formula (Ij), general formula (Ik), general formula (IL), general formula (Im), general formula (In), general formula (Io), general formula (Ip), general formula (Iq), general formula (IB), general formula (IC), or general formula (II), each independently represents L 2 is preferably a bond or a C1-8 alkylene group optionally containing one oxygen atom, more preferably a C1-8 alkylene group optionally containing one oxygen atom, and further preferably ethylene, propylene, -OCH 2 CH 2 -, or -CH 2 OCH 2 CH 2 - and R 5 is preferably a C3-6 carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the C3-6 carbocyclic ring and the 3- to 6-membered heterocyclic ring are preferably 22 and R 1 is preferably COOH, and R 2 is preferably a hydrogen atom.

[0139] In the present invention, the general formula (IA) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , Q, ring A, L 1 , L 2 , any combination of the preferred definitions of X, Y, n, and m.

[0140] In the present invention, the general formula (I) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , ring A, L 1 , L 2 , any combination of the preferred definitions of X, Y, n, and m.

[0141] In the present invention, the general formula (I-1) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , ring A, L 2 , any combination of the preferred definitions of X, Y, p, n, and m.

[0142] In the present invention, the general formula (Ia) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , Ring A-1, L 1 , L 2 , any combination of the preferred definitions of X, Y, n, and m.

[0143] In the present invention, the general formula (Ib) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2, Y, n, and m are each a combination of the preferred definitions.

[0144] In the present invention, the general formula (Ic) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , L 1 , L 2 , n, and m are each a combination of preferred definitions.

[0145] In the present invention, the general formula (Id) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , Ring A-1, L 2 , any combination of the preferred definitions of X, Y, p, n, and m.

[0146] In the present invention, the general formula (Ie) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 38 , R 40 , L 2 , Y, p, n, and m are each a combination of preferred definitions.

[0147] In the present invention, the general formula (If) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 38 , R 40 , L 2 , p, n, and m are each a combination of preferred definitions.

[0148] In the present invention, the general formula (Ig) is preferably the above-mentioned R1 , R 2 , R 3 , R 4 , R 5 , Q, ring A, L 1 , L 2 , X a , Y, n, and m are each a combination of the preferred definitions.

[0149] In the present invention, the general formula (Ih) is preferably the above-mentioned R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , Q, ring A, L 1 , L 2 , and combinations of the preferred definitions of X, Y, and m.

[0150] In the present invention, the general formula (Ii) is preferably the above-mentioned R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , Q, ring A-1, L 1 , L 2 , X a , Y, and m are each a combination of the preferred definitions.

[0151] In the present invention, the general formula (Ij) is preferably the above-mentioned R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , R 6a , Q, L 1 , L 2 , Y, and m are each a combination of the preferred definitions.

[0152] In the present invention, the general formula (Ik) is preferably the above-mentioned R 1 , R 2 , R 3a , R3b , R 3c , R 4 , R 5 , R 7a , Q, L 1 , L 2 and each of the preferred definitions of m.

[0153] In the present invention, the general formula (IL) is preferably the above-mentioned R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , R 6a , Q, L 1 , L 2 and each of the preferred definitions of m.

[0154] In the present invention, the general formula (Im) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , Q, ring A, L 2 , any combination of the preferred definitions of X, Y, p, n, and m.

[0155] In the present invention, the general formula (In) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 38 , R 40 , Q, ring A-1, L 2 , any combination of the preferred definitions of X, Y, p, n, and m.

[0156] In the present invention, the general formula (Io) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 38 , R40 , Q, L 2 , Y, p, n, and m are each a combination of preferred definitions.

[0157] In the present invention, the general formula (Ip) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 38 , R 40 , Q, L 2 , p, n, and m are each a combination of preferred definitions.

[0158] In the present invention, the general formula (Iq) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 38 , R 40 , Q, L 2 , p, n, and m are each a combination of preferred definitions.

[0159] In the present invention, the general formula (IB) is preferably the above-mentioned R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , Q, ring A, L 1 , L 2 , X a , Y, and m are each a combination of the preferred definitions.

[0160] In the present invention, the general formula (IC) is preferably the above-mentioned R 1 , R 2 , R 3a , R 3b , R 3c , R 4 , R 5 , R 38 , R 40 , ring A, L 2 , Xa , Y, p, and m are each a combination of the preferred definitions.

[0161] In the present invention, the general formula (II) is preferably the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 , ring A, L 1 , L 2 , any combination of the preferred definitions of X, Y, n, and m.

[0162] In the present invention, the most preferred other embodiment of the general formula (IA) is the example compound described in the examples below, or a pharma- ceutical acceptable salt thereof.

[0163] In the present invention, all isomers are included unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include straight-chain and branched-chain isomers. In addition, isomers (E, Z, cis, trans) in double bonds, rings, and condensed rings, isomers due to the presence of asymmetric carbons (R, S, α, β, enantiomers, diastereomers), optically active isomers with optical rotation (D, L, d, l), polar isomers (high polarity, low polarity) obtained by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of these in any ratio, and racemic mixtures are all included in the present invention. In addition, all isomers due to tautomerism are also included in the present invention.

[0164] In the present invention, unless otherwise specified, the symbols

[0165] [ka] represents a bond beyond the plane of the paper (i.e., α-configuration),

[0166] [ka] indicates that the molecule is bonded to the front side of the paper (i.e., the β-configuration),

[0167] [ka] represents any mixture of α- and β-configurations. [salt] The compound represented by the formula (IA) can be converted into a salt by a known method.

[0168] The salt is a pharma-ceutically acceptable salt.

[0169] The salt is preferably water-soluble.

[0170] Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

[0171] Acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate.

[0172] Examples of the alkali metal salt include potassium salts and sodium salts.

[0173] Alkaline earth metal salts include, for example, calcium salts and magnesium salts.

[0174] The ammonium salt includes, for example, tetramethylammonium salt.

[0175] Examples of amine salts include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris(hydroxymethyl)aminomethane salt, lysine salt, arginine salt, and N-methyl-D-glucamine salt.

[0176] The compound of the present invention can be converted into an N-oxide by any method. The term "N-oxide" refers to a compound in which the nitrogen atom of the compound represented by formula (IA) is oxidized.

[0177] The compound represented by the general formula (IA) and its salts may exist in a non-solvated form or in a solvated form with a pharma- ceutically acceptable solvent such as water, ethanol, etc. The solvate is preferably a hydrate. The compound represented by the general formula (IA) and its salts may be converted into a solvate.

[0178] The compound of formula (IA) can form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharma- ceutically acceptable one formed with a pharma- ceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules with intermolecular interactions other than ionic bonds. A co-crystal may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, for example, by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO2006 / 007448.

[0179] In the present invention, all references to the compounds of the present invention include the compounds represented by the general formula (IA), their salts, their N-oxides, their solvates (e.g., hydrates), or their co-crystals, or the N-oxides of the salts of the compounds represented by the general formula (IA), their solvates (e.g., hydrates), or their co-crystals.

[0180] [Prodrug] The prodrug of the compound represented by the general formula (IA) refers to a compound that is converted into the compound represented by the general formula (IA) in vivo by a reaction caused by an enzyme, gastric acid, or the like. Examples of the prodrug of the compound represented by the general formula (IA) include, when the compound represented by the general formula (IA) has an amino group, a compound in which the amino group has been acylated, alkylated, or phosphorylated (for example, a compound in which the amino group of the compound represented by the general formula (IA) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when the compound represented by the general formula (IA) has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxyl group of the compound represented by the general formula (IA) has been acetylated, palmitoylated, propanoylated, or the like). yl, pivaloyl, succinyl, fumarylate, alanylate, dimethylaminomethylcarbonylated compounds, etc.); when the compound represented by the general formula (IA) has a carboxy group, the carboxy group is esterified or amidated (for example, the carboxy group of the compound represented by the general formula (IA) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methylamidated compounds, etc.). These compounds can be produced by known methods. The prodrug of the compound represented by the general formula (IA) may be either a hydrate or a non-hydrate. In addition, the prodrug of the compound represented by general formula (IA) may be one that is converted into the compound represented by general formula (IA) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, published by Hirokawa Shoten in 1990.

[0181] Furthermore, each atom constituting the compound represented by the general formula (IA) may be an isotope thereof (e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 16 N, 17 O. 18 O. 18 F, 35 S, 36 Cl, 77 Br, 125 I, etc.) may be substituted.

[0182] [Method of producing the compound of the present invention] The compound of the present invention can be produced by appropriately improving and combining known methods, such as the methods shown below, methods similar thereto, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or the methods shown in the examples. The starting material may be a salt. The order of carrying out each reaction can be appropriately changed depending on the protective group introduced and the reaction conditions.

[0183] The compounds of the present invention represented by the general formula (IA) can be prepared according to reaction scheme 1.

[0184] [ka] (In reaction scheme 1, R 1-1 R is optionally protected 1 and the other symbols have the same meanings as above.) In the reaction scheme 1, reaction 1-1 is an amidation reaction. The amidation reaction is known and can be carried out, for example, as follows: (1) A method using an acid halide, (2) A method using a mixed acid anhydride, (3) A method using a condensing agent, The specific methods are as follows: (1) The method using an acid halide is carried out, for example, by reacting a carboxylic acid with an acid halide agent (oxalyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent at −20° C. to reflux temperature, and reacting the obtained acid halide with an amine in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at a temperature of 0 to 40° C. Alternatively, the reaction can be carried out by reacting the obtained acid halide with an amine in an organic solvent (dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (sodium bicarbonate solution or sodium hydroxide solution, etc.) at 0 to 40° C.

[0185] (2) The method using a mixed acid anhydride is carried out, for example, by reacting a carboxylic acid with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent at 0 to 40°C, and then reacting the resulting mixed acid anhydride with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at 0 to 40°C.

[0186] (3) The method using a condensing agent is carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without a solvent, in the presence or absence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, PPA, etc.), with or without the use of 1-hydroxybenzotriazole (HOBt), at 0 to 40°C.

[0187] The reactions (1), (2) and (3) are preferably carried out in an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

[0188] In the reaction scheme 1, reaction 1-2 is a thiolation reaction. The thiolation reaction is known and can be produced by reacting a compound represented by general formula 1c in an organic solvent (e.g., tetrahydrofuran, toluene, benzene, acetonitrile, dichloromethane, pyridine, etc.) in the presence or absence of a base (e.g., sodium hydrogen carbonate), at room temperature to reflux temperature in the presence or absence of a thiolation reagent (e.g., Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide), tetraphosphorus deca sulfide, diphosphorus pentasulfide, hydrogen sulfide, sulfur, etc.) and a phosphine reagent (e.g., trichlorophosphate, etc.).

[0189] In reaction scheme 1, a compound represented by general formula (IA) can be prepared by subjecting a compound represented by general formula 1c or 1d to a deprotection reaction, if necessary.

[0190] Examples of carboxyl-protecting groups include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

[0191] Examples of the protecting group for an amino group or a tetrazolyl group include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, a trifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn) group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, and a 2-(trimethylsilyl)ethoxymethyl (SEM) group.

[0192] Examples of protecting groups for hydroxyl groups or hydroxamic acids include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), and the like.

[0193] The deprotection reaction is known and can be carried out by the following method. For example, (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) deprotection by hydrogenolysis, (4) deprotection reaction of the silyl group, (5) Deprotection reaction using metals, (6) Deprotection reaction using a metal complex, etc.

[0194] To explain these methods in detail, (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40°C.

[0195] (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0 to 100°C.

[0196] (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., an ether (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), an alcohol (e.g., methanol, ethanol, etc.), a benzene (e.g., benzene, toluene, etc.), a ketone (e.g., acetone, methyl ethyl ketone, etc.), a nitrile (e.g., acetonitrile, etc.), an amide (e.g., N,N-dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.), under normal or increased pressure in a hydrogen atmosphere or in the presence of ammonium formate, at 0 to 200°C.

[0197] (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile, etc.) at 0 to 40° C. Also, for example, it is carried out in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C.

[0198] (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution having a pH of 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as tetrahydrofuran) in the presence of zinc powder at 0 to 40° C., if necessary, with ultrasonication.

[0199] (6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (e.g., dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trapping reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine-based reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.), at 0 to 40°C.

[0200] In addition to the above, the deprotection reaction can be carried out, for example, by the method described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014.

[0201] Representative examples of carboxylic acids of general formula 1a can be prepared according to Scheme 2.

[0202] [ka] (In reaction scheme 2, R x represents a protecting group for a carboxylic acid, and Z 1 represents a hydroxyl group or a thiol group, and Z 2 represents a halogen atom or a hydroxyl group, and Z 3 H 2 C=CH- group, hydroxyl group, amino group, boronic acid group, boronic acid ester group, trialkyltin group, trialkylsilane group or zinc halide group, and other symbols have the same meaning as above. In reaction scheme 2, reaction 2 is known. 2 When is a halogen atom, a compound represented by the general formula 2c can be prepared by a halogen substitution reaction.

[0203] The halogen substitution reaction is known and is carried out, for example, in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or a carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof, or a mixture thereof, at 0 to 100°C.

[0204] In reaction scheme 2, Z 1 is a hydroxyl group or a thiol group, and Z 2 When is a hydroxyl group, a compound represented by the general formula 2c can be prepared by the Mitsunobu reaction.

[0205] The Mitsunobu reaction is known and is carried out, for example, in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of an azo compound (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and a phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) by reacting with the corresponding alcohol compound at 0 to 60°C.

[0206] As another method for producing the compound represented by general formula 2c, the compound represented by general formula 2d can be triflated, and then subjected to a coupling reaction with the compound represented by general formula 2f using a palladium catalyst.

[0207] The triflation is known and can typically be carried out by reacting 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide or trifluoromethanesulfonic anhydride in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in an organic solvent (e.g., dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene).

[0208] Examples of coupling reactions using a palladium catalyst include Suzuki coupling, Stille coupling, Buchwald coupling, Negishi coupling, Heck reaction, and Hiyama coupling.

[0209] These reactions are known and can be carried out, for example, in an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.) using a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture thereof, and a catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), bis(triphenylphosphine)palladium dichloride (PdCl 2 (PPh 3 ) 2 ), palladium acetate (Pd(OAc) 2 ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl 2 (dppf) 2 ), diallylpalladium dichloride (PdCl 2 (allyl) 2 ), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh 3 ) 2 The reaction is carried out in the presence of, for example,

[0210] The compound represented by the general formula 2c can be used to carry out the above-mentioned deprotection reaction of the carboxyl group to produce the carboxylic acid represented by the general formula 1a.

[0211] Representative examples of amine compounds of general formula 1b can be prepared according to reaction scheme 3.

[0212] [ka] (In the formula, Z 4 represents a halogen atom, and the other symbols have the same meanings as above. In Reaction Scheme 3, the reduction reaction of the nitro group is known and is carried out, for example, in a water-miscible solvent (ethanol, methanol, tetrahydrofuran, etc.) in the presence or absence of an acid (hydrochloric acid, hydrobromic acid, ammonium chloride, acetic acid, ammonium formate, etc.) using a metal reagent (zinc, iron, tin, tin chloride, iron chloride, samarium, indium, sodium borohydride-nickel chloride, etc.) at a temperature of 0 to 150°C.

[0213] In reaction scheme 3, the coupling reaction using a palladium catalyst can be carried out under the same reaction conditions as described above to produce a compound represented by formula 3d or formula 1b.

[0214] In reaction scheme 3, the reductive amination reaction is known and can be carried out, for example, in an organic solvent (dichloroethane, dichloromethane, dimethylformamide, acetic acid, a mixture thereof, etc.) in the presence of a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.) at a temperature of 0 to 40°C to produce a compound represented by general formula 3f or general formula 1b.

[0215] In the compound represented by the general formula (IA), Q is an oxygen atom and L 1 is a C3-6 saturated carbocyclic ring, that is, a compound represented by the general formula (I-1):

[0216] [ka] (wherein all symbols have the same meanings as defined above) can be prepared according to reaction scheme 4.

[0217] [ka] (Wherein, -B(OR Y ) 2represents a boronic acid or a boronic acid ester (e.g., dimethyl borate, dioxaborolane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, dioxaborinane, 5,5-dimethyl-1,3,2-dioxaborinane, etc.), and the other symbols have the same meanings as above. In reaction scheme 4, reaction 4-1 is publicly known, and a compound represented by general formula 3f and a compound represented by general formula 4a can be subjected to the above-mentioned Suzuki coupling reaction conditions to produce a compound represented by general formula 4b. As another method for producing a compound represented by general formula 4b, a compound represented by general formula 3f can be converted to a boronic acid ester represented by general formula 4c by reaction 4-2, and then a compound represented by general formula 4d can be used to carry out reaction 4-3 to produce an amine compound represented by general formula 4b.

[0218] Reaction 4-2 is known and can be produced, for example, by Suzuki coupling reaction using bis(pinacolato)diboron.

[0219] Reaction 4-3 is known, and a compound represented by general formula 4b can be produced by subjecting a compound represented by general formula 4c and a compound represented by general formula 4d to Suzuki coupling reaction.

[0220] The compound represented by the general formula 4e can be produced by amidating the amine compound represented by the general formula 4b with the carboxylic acid compound represented by the general formula 1a by the above-mentioned method.

[0221] The compound represented by general formula (I-1) can be prepared by deprotecting the compound represented by general formula 4e as necessary.

[0222] The compound represented by general formula (I-1) can also be produced by amidating a compound represented by general formula 1a and a compound represented by general formula 3f, then reacting the compound with a compound represented by general formula 4a (4-1), and then deprotecting the compound as necessary.

[0223] The compound represented by general formula (I-1) can also be produced by amidating a compound represented by general formula 1a and a compound represented by general formula 3f, carrying out reaction 4-2, and then carrying out reaction 4-3 with a compound represented by general formula 4d, followed by deprotection as necessary.

[0224] Among the compounds represented by the general formula (IA), Q is an oxygen atom, ring A is a 5-membered nitrogen-containing aromatic heterocycle, and X is NR 7 Y is a bond, and L 1 is a C3-6 saturated carbocyclic ring, that is, a compound represented by the general formula (I-2):

[0225] [ka] (In the formula, X 1 , X 2 are independently CH, CR 4 or a nitrogen atom, and other symbols have the same meanings as above.) can be prepared according to reaction scheme 5 shown below.

[0226] [ka] (In the formula, all symbols have the same meaning as above.) Reaction 5-1 is known and can be carried out by CH activation reaction using norbornene. For example, as described in Angewandte Chemie-International Edition, 2013, vol.52, #23, p.6080-6083, the compound represented by general formula 5c can be produced by using the compound represented by general formula 5a and the compound represented by general formula 5b, adding norbornene and a palladium catalyst (e.g., bis(acetonitrile)dichloropalladium(II) etc.) in the presence of a base (e.g., potassium carbonate, potassium bicarbonate etc.) in an organic solvent (e.g., N,N-dimethylacetamide, acetonitrile etc.), and carrying out the reaction at a temperature of 70°C to 90°C.

[0227] In reaction scheme 5, reaction 5-2 is known, and the compound represented by general formula 5e can be produced by subjecting it to the above-mentioned halogen substitution reaction or the above-mentioned Mitsunobu reaction.

[0228] The deprotection of the carboxylic acid, the amidation and the deprotection reaction of the compound represented by the general formula 5e can be carried out in the same manner as described above.

[0229] Among the compounds represented by the general formula (IA), Q is an oxygen atom, ring A is a 5-membered nitrogen-containing aromatic heterocycle, and X is CR 6 Y is a bond, and L 1 is a C3-6 saturated carbocyclic ring, that is, a compound represented by the general formula (I-3):

[0230] [ka] (wherein all symbols have the same meaning as above) can be used to react a compound represented by general formula 5f in reaction scheme 5 with a compound represented by general formula 6d:

[0231] [ka] (wherein all symbols have the same meaning as above) The compound represented by formula 6d can be prepared by reaction scheme 6.

[0232] [ka] (In the formula, all symbols have the same meaning as above.) In Reaction Scheme 6, the halogen substitution reaction and the deprotection reaction of the carboxylic acid can be carried out under the same conditions as above.

[0233] In the compound represented by the general formula (IA), Q is an oxygen atom, ring A is a benzene ring, Y is an oxygen atom, and L 1 is a C3-6 saturated carbocyclic ring, that is, a compound represented by the general formula (I-4):

[0234] [ka] (In the formula, X 1 , X 2 , X 3 are each independently CH, or CR 4 The compound represented by the formula (I) can be prepared according to the reaction scheme 7 shown below.

[0235] [ka] (In the formula, all symbols have the same meaning as above.) In reaction scheme 7, reaction 7 is known. 3 When is a hydroxyl group, the compound represented by the general formula 7c can be produced by carrying out the above-mentioned Mitsunobu reaction.

[0236] Z 2 is a hydroxyl group, and Z 3 When is a halogen atom, a compound represented by the general formula 7c can be prepared by Ullmann etherification reaction.

[0237] This Ullmann etherification reaction is known and can be carried out, for example, by reacting in an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.) in the presence of a phosphine ligand (triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xanthophos), etc.), a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture of these, and a catalyst (copper iodide, etc.) at room temperature to 130°C.

[0238] In reaction scheme 7, the deprotection of the carboxylic acid, the amidation and the deprotection reaction of the compound represented by formula 7c can be carried out in the same manner as described above.

[0239] Among the compounds of the present invention, compounds other than those shown above are as follows: In each reaction in the present specification, the compounds represented by general formula 2a, general formula 2b, general formula 2d, general formula 2f, general formula 3a, general formula 3c, general formula 3e, general formula 4a, general formula 4d, general formula 5a, general formula 5b, general formula 5d, general formula 6a, general formula 6b and general formula 7a used as starting materials are known or can be easily produced by combining known methods, such as the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or methods in which known methods have been partially modified.

[0240] Furthermore, the compound used in the present invention having an amino group, a carboxy group, or a hydroxyl group can be produced, as necessary, by using a compound protected with a protecting group commonly used for these groups, for example, a protecting group described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and carrying out a known deprotection reaction after an appropriate reaction step.

[0241] Among the compounds used in the present invention, optically active compounds can be produced by using optically active starting materials or reagents, by optically resolving a racemic production intermediate and then leading to the compound of the present invention, or by optically resolving the racemic compound of the present invention.

[0242] This optical resolution is well known, and examples of the method include forming a salt or complex with another optically active compound, recrystallizing it, and then isolating the target compound, or directly separating it using a chiral column.

[0243] In each reaction in the present specification, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.

[0244] In each reaction herein, a solid-phase supported reagent supported on a high molecular weight polymer (eg, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0245] In each reaction in the present specification, the reaction product can be purified by a conventional purification method, for example, distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin or column chromatography, washing, recrystallization, etc. Purification may be carried out for each reaction or after completion of some reactions. [toxicity] Since the compounds of the present invention have low toxicity, they can be safely used as pharmaceuticals. [Application to pharmaceuticals] The object of the present invention is to 2 We have developed a compound with strong antagonistic activity against the receptor, 2 The objective of the present invention is to find compounds that are useful as preventive and / or therapeutic agents for diseases caused by receptor activation.

[0246] The compound of the present invention is EP 2 It exhibits strong antagonistic activity against the receptor, 2The compound is useful as a preventive and / or therapeutic agent for diseases caused by receptor activation, such as endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, postoperative pain, interstitial cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic diseases, hypertension, brain disorders, ischemia, stroke, kidney diseases, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, vasculitis, autoimmune diseases, etc.

[0247] More specifically, examples of cancer include breast cancer, ovarian cancer, colorectal cancer (e.g., colon cancer, etc.), lung cancer (e.g., non-small cell lung cancer, etc.), prostate cancer, head and neck cancer (e.g., oral squamous cell carcinoma, head and neck squamous cell carcinoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, acoustic neuroma, etc.), lymphoma (e.g., B cell lymphoma, T cell lymphoma, etc.), uveal malignant melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, and ten. Examples of the cancer include bidenmal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis / ureter cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (e.g., malignant melanoma, etc.), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia (e.g., acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), myelodysplastic syndrome, brain tumor, or multiple myeloma. Examples of the autoimmune disease include amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome, systemic lupus erythematosus, and AIDS. Examples of the allergic disease include allergic conjunctivitis, allergic rhinitis, contact dermatitis, and psoriasis. Examples of the headache include migraine, tension headache, or a mixture of these, or cluster headache.

[0248] In order to use the compound of the present invention for the purpose of preventing and / or treating the above-mentioned diseases, the substance as an active ingredient is usually formulated together with a pharma- ceutically acceptable carrier such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, the pharma- ceutically acceptable carrier means a substance other than the active ingredient that is generally used in the formulation of a pharmaceutical product. The pharma- ceutically acceptable carrier is preferably one that does not show a pharmacological action at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, the pharma- ceutically acceptable carrier can also be used for the purpose of increasing the usefulness of the active ingredient and the formulation, facilitating formulation, stabilizing the quality, or improving usability. Specifically, a substance such as that described in "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nipposha in 2000, may be appropriately selected according to the purpose.

[0249] The compounds of the present invention are administered to a mammal, preferably a human, more preferably a human patient, in a pharma- ceutical effective amount.

[0250] The dosage of the compound of the present invention will inevitably vary depending on age, body weight, symptoms, desired therapeutic effects, administration route, duration of treatment, etc. In general, it is orally administered in the range of 0.1 mg to 1000 mg per patient per dose, or parenterally administered in the range of 0.01 mg to 100 mg per patient per dose, or continuously administered intravenously.

[0251] Of course, as mentioned above, the dosage varies depending on various conditions, so that in some cases a smaller dosage than the above-mentioned is sufficient, and in other cases a dosage exceeding the range is necessary.

[0252] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, gargles, etc.), injectable preparations (e.g., injectables, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enteral injections, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, patches, etc.).

[0253] [Oral formulation] Oral preparations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc. Oral preparations include rapidly disintegrating preparations in which the release of the active ingredient from the preparation is not particularly adjusted, and release-adjusted preparations, such as enteric preparations and sustained-release preparations, in which the release is adjusted according to the purpose by a specific preparation design and manufacturing method. Enteric preparations are preparations designed to release the active ingredient not in the stomach but mainly in the small intestine, for the purpose of preventing the active ingredient from being decomposed in the stomach or reducing the irritating effect of the active ingredient on the stomach, and can usually be manufactured by applying a coating using an acid-insoluble enteric base. Sustained-release preparations are preparations in which the release rate, release time, and release site of the active ingredient from the preparation are adjusted for the purpose of reducing the number of administrations or reducing side effects, and can usually be manufactured by using an appropriate sustained-release agent. Among preparations for oral administration, capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as sugars or sugar alcohols, polymeric compounds, etc., for the purpose of facilitating administration or preventing decomposition of the active ingredient.

[0254] (1) Tablets Tablets are solid preparations having a certain shape that are administered orally, and include those generally called tablets, such as plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and dry-coated tablets, as well as oral rapid disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. When plain tablets are manufactured, the following method (a), (b), or (c) is usually used: (a) Add excipients, binders, disintegrants, and other additives to the active ingredient, mix them together to make a homogeneous mixture, granulate them using water or a solution containing a binder in an appropriate manner, add lubricants, mix, and compress into a mold; (b) The active ingredient is mixed with additives such as a diluent, binder, and disintegrant to form a homogeneous mixture, and then directly compressed and molded; or the active ingredient and lubricant are added to granules previously prepared with additives, mixed to form a homogeneous mixture, and then compressed and molded; (c) Add excipients, binders and other additives to the active ingredient, mix them homogeneously, wet the mixture with a solvent, pour it into a mold, and then dry it in an appropriate manner; is used. Film-coated tablets can usually be produced by coating plain tablets with a thin coating of a suitable coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating plain tablets with a coating agent containing sugars or sugar alcohols. Multi-layer tablets can be produced by stacking powders of different compositions in layers and compressing them using an appropriate method. Dry-coated tablets can be produced by covering an inner core tablet with an outer layer of different composition. Tablets can also be made into enteric-coated or sustained-release tablets using a known appropriate method. Oral rapid disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have unique functions imparted to them by appropriate selection of additives, and can be produced in accordance with the manufacturing method of the above-mentioned tablets. In addition, an intraoral rapid disintegrating tablet is a tablet that can be taken by dissolving or disintegrating quickly in the oral cavity; a chewable tablet is a tablet that is taken by chewing; an effervescent tablet is a tablet that dissolves or disperses while effervescently rapidly in water; a dispersible tablet is a tablet that is dispersed in water before taking; and a dissolving tablet is a tablet that is dissolved in water before taking. Effervescent tablets can be produced by using an appropriate acidic substance, carbonate, bicarbonate, etc. as an additive.

[0255] (2) Capsules Capsules are preparations filled into capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, and the like. Hard capsules can be produced by mixing an active ingredient with an additive such as an excipient to make it homogeneous, or by forming it into a granular or shaped form by an appropriate method, and filling the mixture directly or lightly into a capsule. Soft capsules can be produced by encapsulating an active ingredient with an additive and encapsulating it into a certain shape with an appropriate capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, or the like. Capsules can be made into enteric capsules or sustained-release capsules using a known appropriate method, and colorants, preservatives, and the like can also be added to the capsule base.

[0256] (3) Granules Granules are preparations granulated into a granular form, and include not only those generally called granules, but also effervescent granules, etc. Granules are usually produced using the following (a), (b), or (c) method: (a) The powdered active ingredient is mixed with an excipient, binder, disintegrant, or other additive to obtain a homogeneous mixture, and then granulated by a suitable method; (b) Add excipients and other additives to the active ingredient that has already been prepared into granules and mix until homogeneous; (c) Adding excipients and other additives to the active ingredient that has already been granulated, mixing the mixture, and forming the mixture into granules by a suitable method; The granules can be coated with a coating if necessary, and can be made into enteric granules or sustained-release granules by using a known suitable method. The effervescent granules can be produced by using a suitable acidic substance, carbonate, bicarbonate, etc. as an additive. The effervescent granules refer to granules that dissolve or disperse in water while effervescently foaming. The granules can also be made into fine granules by adjusting the particle size.

[0257] (4) Powders A powder is a preparation in powder form, and can usually be produced by adding an excipient or other additives to an active ingredient, mixing them together, and making them homogenous.

[0258] (5) Oral liquid Oral liquids are preparations in the form of liquid or viscous gel with fluidity, and include those generally referred to as oral liquids, as well as elixirs, suspensions, emulsions, lemonades, etc. Oral liquids can usually be produced by adding additives and purified water to the active ingredient, mixing and dissolving homogeneously, or emulsifying or suspending, and filtering as necessary. Elixirs refer to clear liquid oral liquids containing sweet and aromatic ethanol, and can usually be produced by adding ethanol, purified water, flavorings, and white sugar, other sugars, or sweeteners to a solid active ingredient or its exudate, dissolving it, and filtering or other methods to make it a clear liquid. Suspensions refer to oral liquids in which the active ingredient is finely and homogeneously suspended, and can usually be produced by adding suspending agents or other additives and purified water or oil to a solid active ingredient, suspending it in an appropriate manner, and homogenizing the whole. An emulsion is an oral liquid preparation in which the active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it in an appropriate manner, and making the whole homogeneous. Note that a lemonade is an oral liquid preparation that is clear and has a sweet and sour taste.

[0259] (6) Syrups A syrup is a viscous liquid or solid preparation containing sugars or sweeteners, and includes syrup preparations. A syrup can usually be produced by adding an active ingredient to a solution of white sugar, other sugars, or sweeteners, or a simple syrup, dissolving, mixing, suspending, or emulsifying the active ingredient, boiling the mixture as necessary, and then filtering it while hot. A syrup preparation is a granular or powdered preparation that becomes a syrup when water is added, and is sometimes called a dry syrup. A syrup preparation can usually be produced using sugars or sweeteners as additives in accordance with the production method of the granules or powders.

[0260] (7) Oral jelly Oral jellies are non-flowable, molded gel-like preparations, and can usually be produced by mixing the active ingredient with an additive and a polymer gel base, gelling it using an appropriate method, and molding it into a specific shape.

[0261] [Injectable preparations] (1) Injectables Injections are solutions, suspensions, or emulsions, or solid sterile preparations that are dissolved or suspended just before use and are administered subcutaneously, intramuscularly, or directly into internal tissues or organs such as blood vessels. In addition to what is generally called an injection, these include freeze-dried injections, powder injections, pre-filled syringes, cartridges, infusions, implanted injections, and sustained release injections. Injections are usually manufactured using the following method (a) or (b): (a) The active ingredient, either as is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to obtain a homogeneous solution, which is then filled into a container for injection, sealed, and sterilized; (b) The active ingredient, either as is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents, etc., to obtain a homogeneous mixture, which is then filtered through a sterile filter, or the homogeneous mixture is prepared under aseptic conditions and filled into a container for injection and sealed; is used. A freeze-dried injection can usually be produced by dissolving the active ingredient as it is, or the active ingredient and additives such as excipients in water for injection, sterilizing and filling it into a container for injection, followed by freeze-drying, or freeze-drying it in a dedicated container and filling it directly into a container. A powder injection can usually be produced by processing it by sterile filtration, followed by adding a powder obtained by crystallization or a sterilized additive to the powder, and filling it into a container for injection. A filled syringe can usually be produced by filling a syringe with the active ingredient as it is, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. A cartridge refers to an injection that is used by putting a cartridge filled with a drug solution into a dedicated syringe, and a cartridge filled with a drug solution can usually be produced by filling the cartridge with the active ingredient as it is, or by preparing a solution, suspension, or emulsion using the active ingredient and additives. An infusion refers to an injection that is usually 100 mL or more and is administered intravenously. The implantable injection refers to a solid or gel-like injection that is applied subcutaneously, intramuscularly, etc., using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time. The implantable injection can usually be produced by using a biodegradable polymer compound to make it into pellets, microspheres, or gels. The sustained release injection refers to an injection that is applied intramuscularly, etc., with the aim of releasing the active ingredient over a long period of time, and can usually be produced by dissolving or suspending the active ingredient in vegetable oil, etc., or by making it into a suspension of microspheres using a biodegradable polymer compound.

[0262] The compound of the present invention is 1) complementing and / or enhancing the prophylactic and / or therapeutic effects of the compound; 2) Improving the kinetics and absorption of the compound, reducing the dosage, and / or 3) Reducing the side effects of the compound For this purpose, it may be administered in combination with other drugs as a combination drug.

[0263] The combination of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are combined in one preparation, or in the form of separate preparations. When the components are administered in separate preparations, this includes simultaneous administration and administration with a time lag. In addition, administration with a time lag may be such that the compound of the present invention is administered first and the other drug is administered later, or the other drug is administered first and the compound of the present invention is administered later. The administration methods of each may be the same or different.

[0264] There are no particular limitations on the diseases for which the above-mentioned concomitant drug can exert a preventive and / or therapeutic effect, so long as the preventive and / or therapeutic effect of the compound of the present invention can be complemented and / or enhanced.

[0265] Other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention against cancer include, for example, alkylating agents, metabolic antagonists, anticancer antibiotics, botanical preparations, hormones, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, and immunomodulators.

[0266] Examples of alkylating agents include cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine hydrochloride, ranimustine, bendamustine, thiotepa, and carboquone.

[0267] Examples of the antimetabolite include methotrexate, pemetrexed, fluorouracil, tegafur, tegafur-uracil, tegafur-gimestat-otastat potassium, doxifluridine, capecitabine, cytarabine, gemcitabine hydrochloride, fludarabine, nelarabine, carmofur, and procarbazine hydrochloride.

[0268] Examples of the anticancer antibiotics include mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin, chromomycin A3, bleomycin, peplomycin sulfate, and terarubicin.

[0269] Examples of botanical preparations include irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate, docetaxel hydrate, eribulin mesylate, and paclitaxel.

[0270] Examples of hormonal agents include estramustine sodium phosphate, flutamide, bicalutamide, goserelin acetate, leuprorelin acetate, tamoxifen citrate, toremifene citrate, anastrozole, letrozole, exemestane, mepitiostane, medroxyprogesterone acetate, epithiostanol, fosfestrol, fadrozole hydrochloride hydrate, abiraterone, fulvestrant, and aminoglutethimide.

[0271] Platinum compounds include, for example, carboplatin, cisplatin, nedaplatin, and oxaliplatin.

[0272] Examples of topoisomerase inhibitors include, for example, topotecan and sobuzoxane.

[0273] Examples of kinase inhibitors include EGFR inhibitors such as erlotinib, gefitinib, and afatinib, HER2 inhibitors such as lapatinib, BCR-ABL inhibitors such as imatinib, ALK inhibitors such as crizotinib, and multikinase inhibitors such as regorafenib and dasatinib.

[0274] Anti-CD20 antibodies include, for example, rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.

[0275] Examples of anti-HER2 antibodies include trastuzumab, trastuzumab emtansine, and pertuzumab.

[0276] Anti-EGFR antibodies include, for example, cetuximab and panitumumab.

[0277] An example of an anti-VEGF antibody is bevacizumab.

[0278] Proteasome inhibitors include, for example, bortezomib.

[0279] HDAC inhibitors include, for example, vorinostat.

[0280] Immunomodulatory drugs include, for example, thalidomide, lenalidomide, pomalidomide, BCG, and interferon preparations.

[0281] Any two or more of the other drugs may be administered in combination.

[0282] Furthermore, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention include not only those that have been discovered so far but also those that will be discovered in the future, based on the above-mentioned mechanisms.

[0283] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0284] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0285] [Synthesis Example] The solvents in parentheses shown in the chromatographic separations and TLCs indicate the eluting or developing solvents used, and the ratios are by volume.

[0286] The solvent in parentheses in the NMR section indicates the solvent used in the measurement.

[0287] The names of compounds used in this specification were generated using ACD / Name (registered trademark), a computer program that generally performs naming according to the IUPAC rules, or Chemdraw Ultra (Version 12.0, Cambridge Soft), or in accordance with the IUPAC nomenclature method.

[0288] LC-MS / ELSD was performed under the following conditions. Condition A; Column: Waters Triart C 18 (Particle size: 1.9 x 10 -6 m; column length: 30 x 2.0 mm ID); flow rate: 1.0 mL / min; column temperature: 30 °C; mobile phase (A): 0.1% trifluoroacetic acid aqueous solution (hereinafter abbreviated as TFA); mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (ratio of mobile phase (A): mobile phase (B) is indicated): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95:5; [1.5 min] 95:5; detector: UV (PDA), ELSD, MS. Condition B; Column: Waters Triart C 18 (Particle size: 1.9 x 10 -6 m; column length: 30 x 2.0 mm ID); flow rate: 1.0 mL / min; column temperature: 30 °C; mobile phase (A): 0.1% TFA; mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (ratios of mobile phase (A):mobile phase (B) are listed): [0 min] 95:5; [0.15 min] 95:5; [1.15 min] 5:95; [2.80 min] 5:95; [2.81 min] 95:5; [3 min] 95:5; detector: UV (PDA), ELSD, MS. Condition C; Column: ACQUITY UPLC BEH C 18 (Particle size: 1.7 x 10 -6 m; column length: 50 x 2.1 mm); flow rate: 0.6 mL / min; column temperature: 35 °C; mobile phase (A): 0.1% TFA; mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (ratios of mobile phase (A):mobile phase (B) are listed): [0 min] 97:3; [0.4 min] 97:3; [2.5 min] 2:98; [3.5 min] 2:98; [4.01 min] 97:3; detectors: UV (PDA), ELSD, MS. Condition D; Column: Xbridge C 18 (Particle size: 3.5 x 10 -6 m); flow rate: 1,000 mL / min; column temperature: 35 °C; mobile phase (A): 10 mM ammonium bicarbonate aqueous solution; mobile phase (B): acetonitrile; gradient (ratios of mobile phase (A):mobile phase (B) are listed): [0 min] 95:5; [0.8 min] 95:5; [5 min] 2:98; [6 min] 2:98; [8.01 min] 95:5; detector: UV (PDA), ELSD, MS. Condition E; Column: ACQUITY UPLC BEH C 18 (Particle size: 1.7 x 10 -6 m; column length: 50 x 2.1 mm); flow rate: 0.6 mL / min; column temperature: 35 °C; mobile phase (A): 0.05% TFA; mobile phase (B): 0.05% TFA-acetonitrile solution; gradient (ratios of mobile phase (A):mobile phase (B) are listed): [0 min] 97:3; [0.4 min] 97:3; [2.5 min] 2:98; [3.5 min] 2:98; [3.8 min] 97:3; detectors: UV (PDA), ELSD, MS. Condition F; Column: ACQUITY UPLC BEH C 18 (Particle size: 1.7 x 10 -6m; column length: 50 x 2.1 mm); flow rate: 0.6 mL / min; column temperature: 35 °C; mobile phase (A): 0.07% TFA; mobile phase (B): 0.07% TFA-acetonitrile solution; gradient (ratios of mobile phase (A):mobile phase (B) are listed): [0 min] 97:3; [0.4 min] 97:3; [2.5 min] 2:98; [3.5 min] 2:98; [3.8 min] 97:3; detectors: UV (PDA), ELSD, MS.

[0289] Unless otherwise specified, the HPLC retention time indicates the retention time under condition A described in the LC-MS / ELSD above.

[0290] The microwave reaction device used was Initiator 60 EXP manufactured by Biotage.

[0291] Separation and purification by high performance liquid chromatography (hereinafter abbreviated as HPLC) was carried out under the following conditions. Mobile phase A (0.1% TFA): Mobile phase B (0.1% TFA / acetonitrile) = 95:5 → 5:95

[0292] Reference Example 1: Ethyl 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylate To a solution of ethyl 1H-pyrrole-2-carboxylate (CAS number: 2199-43-1, 2.50 g) in N,N-dimethylacetamide (hereinafter abbreviated as DMA) (3 mL), bicyclo[2.2.2]-2-heptene (hereinafter abbreviated as norbornene) (CAS number: 498-66-8, 3.40 g), potassium bicarbonate (5.40 g), and bis(acetonitrile)dichloropalladium(II) (CAS number: 14592-56-4, 230 mg) were added and degassed by ultrasonication. 1-Bromo-3-phenylpropane (CAS number: 637-59-2, 7.20 g) was added to the reaction mixture and stirred at 90°C for 20 hours. The reaction solution was diluted with ethyl acetate:hexane (1:1) and filtered through Celite (trade name). The filtrate was washed with saturated aqueous ammonium chloride solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→3:1) to give the title compound (3.82 g) having the following physical properties: HPLC retention time (min): 1.12; MS(ESI, Pos.):258(M+H) + .

[0293] Reference Example 2: Ethyl 1-(butan-2-yl)-5-(3-phenylpropyl)-1H-pyrrole-2-carboxylate 2-Butanol (0.78 g) and cyanomethylenetributylphosphorane (hereinafter, abbreviated as CMBP) (CAS number: 157141-27-0, 0.76 g) were added to a toluene (5 mL) solution of the compound (0.27 g) produced in Reference Example 1, and the mixture was stirred for 3 hours at 130° C. using a microwave device. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→9:1) to obtain the title compound (0.24 g) having the following physical properties. HPLC retention time (min): 1.34; MS(ESI, Pos.):314(M+H) + .

[0294] Reference Example 3: 1-(butan-2-yl)-5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid Methanol (2 mL) and 50% aqueous potassium hydroxide solution (1 mL) were added to a solution of the compound (0.24 g) produced in Reference Example 2 in 1,2-dimethoxyethane (hereinafter abbreviated as DME) (2 mL), and the mixture was stirred at 90° C. for 22 hours. The reaction solution was allowed to cool, then acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→4:1) to give the title compound (0.18 g) having the following physical properties. HPLC retention time (min): 1.13; MS(ESI, Pos.):286(M+H) + .

[0295] Reference examples 3-1~3-2: The title compound having the following physical properties was obtained by carrying out the same reaction as in Reference Example 2→Reference Example 3 using the corresponding alcohol instead of 2-butanol.

[0296] Reference Example 3-1: 1-[(2S)-butan-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid HPLC retention time (min): 1.10; MS(ESI, Pos.):286(M+H) + .

[0297] Reference Example 3-2: 5-(3-phenylpropyl)-1-(propan-2-yl)-1H-pyrrole-2-carboxylic acid HPLC retention time (min): 1.10; MS(ESI, Pos.):272(M+H) + .

[0298] Reference Example 4: Ethyl rel-(1R,2S)-2-[3-amino-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate racemic mixture Ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (CAS number: 1215107-29-1, 3g), 2M potassium phosphate aqueous solution (18.8mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (CAS number: 95464-05-4, 1g) were added to a solution of 5-bromo-2-(trifluoromethyl)aniline (CAS number: 703-91-3, 3g) in 1,4-dioxane (60mL) and stirred at 100°C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the title compound (0.8g) having the following physical properties. HPLC retention time (min): 1.03; MS(ESI, Pos.):273(M+H) + .

[0299] Reference Example 5: 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-2-(trifluoromethyl)aniline To a solution of 5-bromo-2-(trifluoromethyl)aniline (1g) and bis(neopentyl glycolate)diboron (CAS number: 201733-56-4, 1.9g) in dimethyl sulfoxide (hereinafter abbreviated as DMSO) (10mL), potassium acetate (1.2g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (340mg) were added and stirred at 100°C for 2 hours. The reaction solution was diluted with water and extracted with 2-methoxy-2-methylpropane (hereinafter abbreviated as MTBE). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (1g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ1.55, 3.76, 4.06-4.15, 7.16-7.21, 7.39-7.42.

[0300] Reference Example 6: Ethyl (1R,2S)-2-[3-amino-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate To a solution of the compound (491 mg) produced in Reference Example 5 and ethyl (1S,2S)-2-iodocyclopropanecarboxylate (CAS number: 1629125-76-3, 400 mg) in 1,4-dioxane (10 mL), 2M aqueous cesium carbonate solution (2.2 mL) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)(2'-aminobiphenyl-2-yl)palladium(II) (hereinafter abbreviated as XPhos Pd G2) (CAS number: 1310584-14-5, 236 mg) were added and stirred for 4.5 hours at 100° C. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica) (hexane:ethyl acetate=9:1→0:1) and silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to give the title compound (110 mg) having the following physical properties. HPLC retention time (min): 0.95; MS(ESI, Pos.):274(M+H) + .

[0301] Reference Example 7: Ethyl (1R,2S)-2-[5-amino-2-chloro-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate N-chlorosuccinimide (CAS number: 128-09-6, 37 mg) was added to a solution of the compound (50 mg) produced in Reference Example 6 in DMF (1 mL) and the mixture was stirred at 60° C. for 1 hour. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (13 mg) having the following physical properties. HPLC retention time (min): 1.02; MS(ESI, Pos.):308(M+H) + .

[0302] Reference Example 8: Ethyl rel-(1R,2S)-2-[3-{[1-(butan-2-yl)-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate racemic mixture To a dichloromethane (1 mL) solution of the compound (105 mg) produced in Reference Example 4 and the compound (100 mg) produced in Reference Example 3, N,N-diisopropylethylamine (hereinafter, abbreviated as DIPEA) (CAS number: 7087-68-5, 135 mg) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (hereinafter, abbreviated as TCFH) (CAS number: 94790-35-9, 147 mg) were added and stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain the title compound (100 mg) having the following physical properties. HPLC retention time (min): 1.39; MS(ESI, Pos.):541(M+H) + .

[0303] Example 1: rel-(1R,2S)-2-[3-({[1-sec-butyl-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid Racemic mixture

[0304] [ka] A 5N aqueous sodium hydroxide solution (0.5mL) was added to a solution of the compound (95mg) produced in Reference Example 8 in tetrahydrofuran (hereinafter abbreviated as THF) (2.5mL) and methanol (2.5mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of the present invention (82mg) having the following physical properties. HPLC retention time (min): 1.22; MS(ESI, Pos.):513(M+H) + ; 1 H-NMR (CDCl 3 ):δ0.58-0.82, 1.34-1.53, 1.61-2.22, 2.54-2.81, 4.63-5.18, 5.93-6.04, 6.58-6.71, 7.07-7.13, 7.17-7.24, 7.28-7.35, 7.46-7.54, 7.86-7.97, 8.06-8.18.

[0305] Reference Example 9: N-[5-bromo-2-(trifluoromethyl)phenyl]-1-[(2S)-butan-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carboxamide The title compound having the following physical properties was obtained by carrying out the same reaction as in Reference Example 8 using 5-bromo-2-(trifluoromethyl)aniline instead of the compound prepared in Reference Example 4 and the compound prepared in Reference Example 3-1 instead of the compound prepared in Reference Example 3. HPLC retention time (min): 1.43; MS(ESI, Pos.):507(M+H) + .

[0306] Reference Example 10: Ethyl 2-[3-({1-[(2S)-butan-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate To a 1,4-dioxane solution (2 mL) of the compound (200 mg) produced in Reference Example 9, ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (94 mg), 2M aqueous potassium phosphate solution (0.59 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (96 mg) were added and stirred at 120° C. for 1 hour using a microwave device. This reaction solution was used in the next reaction as it was without purification.

[0307] Example 2: rel-(1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid diastereomeric mixture

[0308] [ka] A 5N aqueous sodium hydroxide solution (1 mL) was added to the reaction solution obtained in Reference Example 10 and stirred at 50° C. for 2 hours. The reaction solution was acidified with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by HPLC to obtain the compound of the present invention (45 mg) having the following physical properties. HPLC retention time (min): 1.22; MS(ESI, Pos.):513(M+H) + ; 1 H-NMR (CDCl 3):δ0.76, 1.36-1.45, 1.51, 1.62-1.72, 1.73-1.87, 1.90-2.14, 2.57-2.79, 4.58-5.27, 5.98, 6.65, 7.03, 7.17-7.24, 7.28-7.35, 7.47, 7.94, 8.22.

[0309] Examples 2-1 to 2-4: The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 9 → Reference Example 10 → Example 2 using the corresponding aniline derivative instead of 5-bromo-2-(trifluoromethyl)aniline and ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate or the corresponding boronic acid ester.

[0310] Example 2-1: rel-(1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid diastereomeric mixture

[0311] [ka] HPLC retention time (min): 1.36; MS(ESI, Pos.):459(M+H) + ; 1 H-NMR (CDCl 3 ):δ0.68-0.81, 1.31-1.39, 1.50, 1.61-1.87, 1.96-2.12, 2.26-2.30, 2.51-2.80, 4.21-5.10, 5.95, 6.61, 6.83, 7.11-7.36, 7.58.

[0312] Example 2-2: rel-(1R,2R)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid diastereomeric mixture

[0313] [ka] HPLC retention time (min): 1.38; MS(ESI, Pos.):459(M+H) + ; 1 H-NMR (CDCl3 ): δ 0.76, 1.36 - 1.47, 1.52, 1.57 - 1.66, 1.71 - 2.08, 2.31, 2.49 - 2.61, 2.65 - 2.81, 4.43 - 5.37, 5.95, 6.59, 6.65, 7.09 - 7.36, 7.49 - 7.57.

[0314] Example 2-3: rel-(1R,2S)-2-{5-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid diastereomeric mixture

[0315]

Chem.

[0316] Example 2-4: rel-(1R,2R)-2-{5-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid diastereomeric mixture

[0317]

Chem.

[0318] Examples 3-1 to 3-2: The compound of the present invention having the following physical properties was obtained by carrying out the same reactions as in Reference Example 2 → Reference Example 3 → Reference Example 9 → Reference Example 10 → Example 1 using isopropanol instead of 2-butanol and using the corresponding boronic acid ester instead of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate.

[0319] Example 3-1: (1S,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0320] [ka] HPLC retention time (min): 1.19; MS(ESI, Pos.):499(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.39-1.47, 1.52, 1.64-1.74, 1.96-2.13, 2.58-2.80, 5.00-5.21, 5.97, 6.65, 6.90-7.17, 7.17-7.24, 7.28-7.36, 7.48, 7.95, 8.26.

[0321] Example 3-2: (1R,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0322] [ka] HPLC retention time (min): 1.21; MS(ESI, Pos.):499(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.45-1.51, 1.54, 1.66-1.76, 1.96-2.09, 2.60-2.83, 5.05-5.18, 5.97, 6.65, 6.89, 7.18-7.24, 7.28-7.34, 7.51, 7.98, 8.17.

[0323] Reference Example 11: 4-Iodo-1-methoxy-2-nitrobenzene A 28% sodium methoxide methanol solution (7.3 mL) was added to a solution of 1-fluoro-4-iodo-2-nitrobenzene (CAS number: 364-75-0, 3.2 g) in methanol (10 mL) and stirred for 15 hours at 50° C. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.3 g) having the following physical properties. HPLC retention time (min): 0.94; 1 H-NMR (CDCl 3 ):δ3.95, 6.87, 7.81, 8.12.

[0324] Reference Example 12: 5-Iodo-2-methoxyaniline Water (1 mL) and iron powder (1.4 g) were added to a solution of the compound (2.3 g) produced in Reference Example 11 in acetic acid (10 mL) and the mixture was stirred at 50° C. for 6 hours. The reaction solution was diluted with MTBE and hexane and filtered through Celite (trade name). The filtrate was washed with 2N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH silica) (hexane:ethyl acetate=9:1→1:1) to obtain the title compound (1.8 g) having the following physical properties. HPLC retention time (min): 0.63; MS(ESI, Pos.):250(M+H) + .

[0325] Reference Example 13: 1-[(2S)-butan-2-yl]-N-(5-iodo-2-methoxyphenyl)-5-(3-phenylpropyl)-1H-pyrrole-2-carboxamide The title compound having the following physical properties was obtained by carrying out a reaction similar to that in Reference Example 8 using the compound prepared in Reference Example 12 instead of the compound prepared in Reference Example 4 and the compound prepared in Reference Example 3-1 instead of the compound prepared in Reference Example 3. HPLC retention time (min): 1.41; MS(ESI, Pos.):517(M+H) + .

[0326] Reference Example 14: 1-[(2S)-butan-2-yl]-N-[5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-2-methoxyphenyl]-5-(3-phenylpropyl)-1H-pyrrole-2-carboxamide To a DMSO (1 mL) solution of the compound (50 mg) produced in Reference Example 13 and bis(neopentyl glycolate)diboron (43 mg), potassium acetate (28 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (8 mg) were added and stirred at 100°C for 1 hour. The reaction solution was diluted with MTBE, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (35 mg) having the following physical properties. HPLC retention time (min): 1.14.

[0327] Reference Example 15: Ethyl (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-methoxyphenyl}cyclopropanecarboxylate To a 1,4-dioxane solution (1 mL) of the compound (35 mg) prepared in Reference Example 14 and ethyl (1S,2S)-2-iodocyclopropanecarboxylate (22.3 mg), a 2M aqueous cesium carbonate solution (0.17 mL) and XPhos Pd G2 (11 mg) were added and stirred for 30 minutes at 100° C. The reaction solution was used in the next reaction as it was without purification.

[0328] Example 4: (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-methoxyphenyl}cyclopropanecarboxylic acid

[0329] [ka] Methanol (1 mL) and 5N aqueous sodium hydroxide solution (1 mL) were added to the reaction solution of Reference Example 15, and the mixture was stirred at 50° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with 5N hydrochloric acid, and extracted with MTBE. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the compound of the present invention (3 mg) having the following physical properties. HPLC retention time (min): 1.39; MS(ESI, Pos.):475(M+H) + ; 1 H-NMR (CDCl 3):δ0.72-0.81, 1.33-1.44, 1.48-1.55, 1.62-1.71, 1.75-2.16, 2.59-2.79, 3.83-3.87, 4.62-5.16, 5.93-5.99, 6.59-6.66, 6.75-6.81, 6.87-6.94, 7.14-7.24, 7.27-7.35, 8.17-8.27, 8.32-8.36.

[0330] Reference Example 16: (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl rel-(1R,2S)-2-[3-({1-[(2S)-butan-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate diastereomeric mixture DIPEA (63 mg), L-menthol (45 mg), 4-dimethylaminopyridine (hereinafter abbreviated as DMAP) and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (hereinafter abbreviated as CyCIU) (CAS number: 135540-11-3, 65 mg) were added to a solution of the compound (50 mg) produced in Example 2 in dichloromethane (1 mL) and acetonitrile (1 mL), and the mixture was stirred at 70° C. for 2 hours. The reaction solution was concentrated and used for the next resolution.

[0331] Reference example 16-1~16-2: Division The mixture obtained in Reference Example 16 was purified by HPLC to give the title compound having the following physical properties:

[0332] Reference Example 16-1: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl (1S,2R)-2-[3-({1-[(2S)-butan-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate HPLC retention time (min): 1.67 (condition B); MS(ESI, Pos.):651(M+H) + .

[0333] Reference Example 16-2: (1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl (1R,2S)-2-[3-({1-[(2S)-butan-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate HPLC retention time (min): 1.70 (condition B); MS(ESI, Pos.):651(M+H) + .

[0334] Example 5: (1S,2R)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

[0335] [ka] A 5N aqueous sodium hydroxide solution (1mL) was added to a solution of the compound prepared in Reference Example 16-1 in methanol (1mL) and THF (1mL), and the mixture was stirred at 50°C for 1 hour. The reaction solution was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of the present invention (16mg) having the following physical properties. HPLC retention time (min): 1.29; MS(ESI, Pos.):513(M+H) + ; 1 H-NMR (CDCl 3 ):δ0.72-0.81, 1.17-1.47, 1.48-1.54, 1.63-1.87, 1.92-2.16, 2.58-2.80, 4.38-4.84, 5.95-6.01, 6.62-6.68, 7.03-7.08, 7.17-7.24, 7.28-7.35, 7.44-7.51, 7.91-7.98, 8.19-8.24.

[0336] Example 6: (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

[0337] [ka] A 5N aqueous sodium hydroxide solution (1mL) was added to a solution of the compound prepared in Reference Example 16-2 in methanol (1mL) and THF (1mL), and the mixture was stirred at 50°C for 1 hour. The reaction solution was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of the present invention (11mg) having the following physical properties. HPLC retention time (min): 1.29; MS(ESI, Pos.):513(M+H) + ; 1 H-NMR (CDCl 3):δ0.76, 1.37-1.46, 1.52, 1.62-1.72, 1.73-1.86, 1.89-2.17, 2.56-2.82, 4.34-5.29, 5.98, 6.65, 7.02, 7.17-7.24, 7.27-7.35, 7.47, 7.94, 8.22.

[0338] Example 7: (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-chlorophenyl}cyclopropanecarboxylic acid

[0339] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 9→Reference Example 10→Example 1 using 5-bromo-2-chloroaniline instead of the compound prepared in Reference Example 4. HPLC retention time (min): 1.41; MS(ESI, Pos.):479(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ0.62-0.69, 1.11-1.51, 1.63-2.12, 2.34-2.80, 4.58-5.26, 5.88-6.00, 6.83-6.88, 6.97-7.07, 7.12-7.41, 7.50-7.56, 9.20-9.24, 11.90.

[0340] Reference Example 17: Ethyl 5-[2-(benzyloxy)ethyl]-1H-pyrrole-2-carboxylate Potassium hydrogen carbonate (80 g), 2-bromoethoxymethylbenzene (CAS number: 1462-37-9, 57 g) and bis(acetonitrile)dichloropalladium(II) (3.5 g) were added to a solution of ethyl 1H-pyrrole-2-carboxylate (37 g) and norbornene (50 g) in DMA (265 mL) and stirred at 100° C. for 24 hours. Water was added to the reaction solution, which was then filtered through Celite (trade name), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:1 → 6:1). The resulting residue was dissolved in heptane, washed with a mixture of methanol and water 1:1, and the heptane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 99:1 → 6:4) to obtain the title compound (11 g) having the following physical properties. TLC: Rf 0.34 (hexane:ethyl acetate=5:1); HPLC retention time (min): 1.04; MS(ESI, Pos.):274(M+H) + .

[0341] Reference Example 18: Ethyl 5-[2-(benzyloxy)ethyl]-1-[(2S)-butan-2-yl]-1H-pyrrole-2-carboxylate To a solution of the compound (6g) produced in Reference Example 17 in toluene (22mL), (R)-(-)-2-butanol (CAS number: 14898-79-4, 12mL) and CMBP (12mL) were added, and the mixture was stirred for 3 hours at 130°C using a microwave device. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to give the title compound (4.6g) having the following physical properties. HPLC retention time (min): 1.32; MS(ESI, Pos.):330(M+H) + .

[0342] Reference Example 19: 5-[2-(benzyloxy)ethyl]-1-[(2S)-butan-2-yl]-1H-pyrrole-2-carboxylic acid A solution of the compound (3g) produced in Reference Example 18 in 1-methylpyrrolidinone (hereinafter abbreviated as NMP) (8 mL) and methanol (2.7 mL) was added with 50% aqueous potassium hydroxide solution (2.7 mL) and stirred at 85°C for 1 hour. MTBE was added to the reaction solution, which was then cooled on ice and adjusted to pH 5 with a 10% aqueous phosphoric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2.7 g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ0.69-0.80, 1.45-1.55, 1.74-1.92, 1.96-2.08, 2.91-3.11, 3.69-3.78, 4.53-4.59, 5.16-5.92, 5.95-6.02, 7.09-7.15, 7.27-7.40.

[0343] Reference Example 20: Ethyl (1R,2S)-2-{3-[({5-[2-(benzyloxy)ethyl]-1-[(2S)-2-butanyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylate The title compound (305 mg) having the following physical properties was obtained by carrying out the same procedure as in Reference Example 8 using the compound prepared in Reference Example 19 instead of the compound prepared in Reference Example 3 and the compound prepared in Reference Example 6 instead of the compound prepared in Reference Example 4. HPLC retention time (min): 1.27; MS(ESI, Pos.):557(M+H) + .

[0344] Example 8: (1R,2S)-2-{3-[({5-[2-(benzyloxy)ethyl]-1-[(2S)-2-butanyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

[0345] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Example 1, except that the compound prepared in Reference Example 20 was used instead of the compound prepared in Reference Example 8. HPLC retention time (min): 1.13; MS(ESI, Pos.):529(M+H) + ; 1 H-NMR (CDCl 3):δ0.61-0.70, 1.05-1.31, 1.33-1.46, 1.80-2.03, 2.20-2.39, 2.93-3.02, 3.69-3.75, 4.53-4.57, 4.64-4.95, 5.94-5.98, 6.61-6.66, 7.13-7.39, 7.41-7.48, 7.57-7.64, 7.80-7.87.

[0346] Reference Example 21: Ethyl 1-[(2S)-butan-2-yl]-5-(2-hydroxyethyl)-1H-pyrrole-2-carboxylate Palladium hydroxide (CAS number: 12135-22-7, 300 mg) was added to a solution of the compound (1.5 g) produced in Reference Example 18 in ethyl acetate (30 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction solution was filtered through Celite (trade name) and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0347] Reference Example 22: Ethyl 1-[(2S)-butan-2-yl]-5-{2-[(2-fluoropyridin-4-yl)oxy]ethyl}-1H-pyrrole-2-carboxylate CMBP (2.2 g) was added to a solution of the reaction mixture produced in Reference Example 21 and 2-fluoropyridin-4-ol (CAS number: 22282-69-5, 1 g) in toluene (15 mL), and the mixture was stirred at 90° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (0.95 g) having the following physical properties. HPLC retention time (min): 1.20; MS(ESI, Pos.):335(M+H) + .

[0348] Reference Example 23: 1-[(2S)-butan-2-yl]-5-{2-[(2-fluoropyridin-4-yl)oxy]ethyl}-1H-pyrrole-2-carboxylic acid A 5N aqueous sodium hydroxide solution (5mL) was added to a solution of the compound (0.95g) produced in Reference Example 22 in NMP (15mL) and stirred at 80°C for 2 hours. After washing the reaction solution with MTBE, the aqueous layer was neutralized with a 5% aqueous phosphoric acid solution and extracted with MTBE. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) and column chromatography using diol silica (manufactured by Fuji Silysia Chemical, Chromatorex DIOL60) to obtain the title compound (0.19g) having the following physical properties. HPLC retention time (min): 0.95; MS(ESI, Pos.):307(M+H) + .

[0349] Example 9: rel-(1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid diastereomeric mixture

[0350] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 8→Example 1, except that the compound prepared in Reference Example 23 was used instead of the compound prepared in Reference Example 3. HPLC retention time (min): 1.11; MS(ESI, Pos.):534(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ0.70, 1.20-1.28, 1.32-1.39, 1.42-1.57, 1.71-1.87, 2.04-2.12, 2.63-2.74, 3.12-3.20, 4.35-4.41, 4.68-5.27, 6.05, 6.81, 6.92-6.96, 7.29, 7.36-7.41, 7.61, 8.04, 9.44, 11.98.

[0351] Reference Example 24: Ethyl (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(2-hydroxyethyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylate A solution of the compound (220 mg) produced in Reference Example 20 in dichloromethane (10 mL) was added with 1M boron tribromide in dichloromethane (CAS number: 10294-33-4, 0.6 mL) under ice cooling and stirred at room temperature for 2.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:9→0:1) to obtain the title compound (140 mg) having the following physical properties. HPLC retention time (min): 1.02; MS(ESI, Pos.):467(M+H) + .

[0352] Reference Example 25: Ethyl (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-chloro-6-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylate 2-Chloro-6-fluoropyridin-4-ol (CAS number: 1807206-99-0, 0.3 g) and CMBP (0.5 g) were added to a suspension of the compound (0.8 g) produced in Reference Example 24 in toluene (20 mL), and the mixture was stirred at 90° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:97→1:1) to give the title compound (0.9 g) having the following physical properties. HPLC retention time (min): 1.43; MS(ESI, Pos.):596(M+H) + .

[0353] Example 10: (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-chloro-6-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0354] [ka] To a solution of the compound (900 mg) produced in Reference Example 25 in 1,4-dioxane (10 mL), sulfuric acid (2 mL) was added and the mixture was stirred at 100° C. for 48 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the compound of the present invention (300 mg) having the following physical properties. HPLC retention time (min): 1.31; MS(ESI, Pos.):568(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ0.67-0.73, 1.21-1.29, 1.33-1.41, 1.43-1.50, 1.51-1.58, 1.71-1.84, 2.03-2.20, 2.63-2.73, 3.10-3.19, 4.39-4.45, 4.94-5.44, 6.02-6.07, 6.77-6.84, 6.87-6.93, 7.15-7.20, 7.25-7.31, 7.37-7.40, 7.61, 9.42-9.46, 11.98.

[0355] Examples 10-1 to 10-3: The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 25→Example 10, using the corresponding alcohol instead of 2-chloro-6-fluoropyridin-4-ol.

[0356] Example 10-1: (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-[2-(2-chloro-3,5-difluorophenoxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid HPLC retention time (min): 1.37; MS(ESI, Pos.):585(M+H) + ; 1 H-NMR (CDCl 3 ):δ0.83, 1.42-1.53, 1.61, 1.68-1.80, 1.83-1.97, 2.02-2.16, 2.63-2.77, 3.26-3.33, 4.22-4.30, 4.71-5.33, 6.07-6.14, 6.47-6.62, 6.65-6.70, 7.11-7.16, 7.50-7.56, 7.90-7.97, 8.14-8.20.

[0357] Example 10-2: (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-[2-(2,4-difluorophenoxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid HPLC retention time (min): 1.32; MS(ESI, Pos.):551(M+H) + ; 1H-NMR (CDCl 3 ):δ0.82, 1.41-1.52, 1.59, 1.69-1.77, 1.83-1.95, 1.98-2.25, 2.61-2.76, 3.16-3.29, 4.27, 4.69-5.28, 6.08, 6.67, 6.74-6.98, 7.12, 7.48-7.55, 7.94, 8.18.

[0358] Example 10-3: (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(1-methyl-1H-pyrazol-4-yl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.14; MS(ESI, Pos.):519(M+H) + ; 1 H-NMR (CDCl 3 ):δ 0.82, 1.40-1.51, 1.58, 1.67-1.75, 1.78-1.92, 1.95-2.21, 2.60-2.74, 3.15, 3.84, 4.14, 4.66-5.21, 6.03, 6.66, 7.06-7.16, 7.48-7.56, 7.94, 8.19.

[0359] Reference Example 26: Methyl 2,6-dimethyl-4-(2-phenylethoxy)benzoate Potassium carbonate (5.8 g) and 2-bromoethylbenzene (CAS number: 103-63-9, 7.7 g) were added to a solution of methyl 4-hydroxy-2,6-dimethylbenzoate (CAS number: 83194-70-1, 2.5 g) in DMF (10 mL) and the mixture was stirred at 80° C. for 15 hours. Further, 2-bromoethylbenzene (1.4 g) and potassium carbonate (1 g) were added and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and hexane, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 → 7:3) to obtain the title compound (3.3 g) having the following physical properties. HPLC retention time (min): 1.15; MS(ESI, Pos.):285(M+H) + ; 1 H-NMR (CDCl 3):δ 2.29, 3.08, 3.88, 4.16, 6.56, 7.11-7.46.

[0360] Reference Example 27: 2,6-Dimethyl-4-(2-phenylethoxy)benzoic acid A 50% aqueous potassium hydroxide solution (4 mL) was added to a solution of the compound (2 g) produced in Reference Example 26 in NMP (2 mL) and stirred at 120° C. for 3 hours. The reaction solution was washed with ethyl acetate and hexane, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was slurry-washed with hexane to obtain the title compound (0.83 g) having the following physical properties. HPLC retention time (min): 0.98; MS(ESI, Pos.):271(M+H) + .

[0361] Example 11: rel-(1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid Racemic mixture

[0362] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Reference Example 8→Example 1, except that the compound prepared in Reference Example 27 was used instead of the compound prepared in Reference Example 3. HPLC retention time (min): 1.15; MS(ESI, Pos.):498(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.47, 1.66-1.77, 2.11-2.22, 2.35, 2.62-2.74, 3.10, 4.17, 6.60, 7.14, 7.21-7.37, 7.43-7.54, 8.27.

[0363] Examples 11-1 to 11-3: The corresponding phenol compound was used instead of methyl 4-hydroxy-2,6-dimethylbenzoate, and the compound prepared in Reference Example 6 was used instead of the compound prepared in Reference Example 4, and the same operations as in Reference Example 26 → Reference Example 27 → Reference Example 8 → Example 1 were carried out to obtain the compound of the present invention having the following physical properties.

[0364] Example 11-1: (1R,2S)-2-[3-{[2-methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0365] [ka] HPLC retention time (min): 2.28 (condition C); MS(ESI, Pos.):484(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ0.95-1.02, 1.21-1.29, 1.70-1.79, 2.04-2.13, 2.40, 3.05, 4.24, 6.83-6.89, 7.20-7.27, 7.29-7.43, 7.44-7.52, 9.76.

[0366] Example 11-2: (1R,2S)-2-[3-{[2-chloro-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0367] [ka] HPLC retention time (min): 2.31 (condition C); MS(ESI, Pos.):504(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.36-1.41, 1.51-1.59, 2.07-2.15, 2.64-2.75, 3.05, 4.29, 7.02-7.07, 7.05, 7.21-7.28, 7.29-7.37, 7.42-7.52, 7.65, 10.06, 12.01.

[0368] Example 11-3: (1R,2S)-2-[3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0369] [ka] HPLC retention time (min): 2.32 (condition C); MS(ESI, Pos.):538(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.30-1.38, 1.45-1.56, 2.02-2.13, 2.56-2.69, 3.08, 4.35, 7.20-7.41, 7.55-7.67, 10.19, 12.01.

[0370] Reference Example 28: Methyl 2,6-dimethyl-4-[(1E)-3-phenylprop-1-en-1-yl]benzoate Allylbenzene (CAS number: 300-57-2, 0.73 g), palladium acetate (CAS number: 3375-31-3, 46 mg), tri-2-tolylphosphine (CAS number: 6163-58-2, 0.19 g) and DIPEA (1.6 g) were added to a solution of methyl 4-bromo-2,6-dimethylbenzoate (CAS number: 90841-46-6, 1 g) in DMF (1 mL), and the mixture was stirred at 90 ° C for 6 hours and at 120 ° C for 3 hours under a nitrogen atmosphere. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3 → 2: 3) to obtain the title compound (1.1 g) having the following physical properties. HPLC retention time (min): 1.27; MS(ESI, Pos.):281(M+H) + .

[0371] Reference Example 29: Methyl 2,6-dimethyl-4-(3-phenylpropyl)benzoate Palladium hydroxide (45 mg) was added to a solution of the compound (180 mg) produced in Reference Example 28 in ethyl acetate (1 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction solution was filtered through Celite (trade name) and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5) to obtain the title compound (160 mg) having the following physical properties. 1 H-NMR (CDCl 3 ):δ1.87-1.97, 2.29, 2.57, 2.64, 3.90, 6.85, 7.15-7.23, 7.25-7.32.

[0372] Reference Example 30: 2,6-Dimethyl-4-(3-phenylpropyl)benzoic acid Water (2 mL) and potassium hydroxide (600 mg) were added to a solution of the compound (160 mg) produced in Reference Example 29 in NMP (2 mL) and the mixture was stirred at 120° C. for 21 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (210 mg) having the following physical properties. 1 H-NMR (CDCl 3 ):δ1.89-1.97, 2.40, 2.59, 2.65, 6.88, 7.15-7.24, 7.26-7.33.

[0373] Reference Example 31: 4-(Acetyloxy)-2,6-dimethylbenzoic acid Acetic anhydride (2 mL) and pyridine (1.8 mL) were added to a suspension of 4-hydroxy-2,6-dimethylbenzoic acid (CAS number: 75056-97-2, 3 g) in ethyl acetate (18 mL) and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was slurry washed with hexane and ethyl acetate to give the title compound (2.9 g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ 2.30, 2.45, 6.82.

[0374] Reference Example 32: Benzyl 4-hydroxy-2,6-dimethylbenzoate Potassium carbonate (50 g) and benzyl bromide (43 g) were added to a solution of the compound (50 g) produced in Reference Example 31 in DMF (175 mL) and stirred at room temperature for 3 hours. Methanol (125 mL) and potassium carbonate (50 g) were added to the reaction solution and stirred at room temperature for 1 hour. The reaction solution was diluted with 5N hydrochloric acid and water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was slurry washed with hexane to obtain the title compound (57 g) having the following physical properties. TLC: Rf 0.60 (hexane:ethyl acetate=2:1); 1 H-NMR (DMSO-d 6 ):δ2.13, 3.32, 5.27, 6.44, 7.31-7.48, 9.63.

[0375] Reference Example 33: Benzyl 4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoate To a solution of the compound (1.6 g) produced in Reference Example 32 in THF (10 mL), 2-(2,4-difluorophenyl)ethanol (CAS number: 81228-02-6, 1 g), triphenylphosphine (2.5 g) and a toluene solution (2.2 M, 4.3 mL) of diethyl azodicarboxylate (hereinafter abbreviated as DEAD) were added and stirred at room temperature for 5 hours. A toluene solution (2.2 M, 2 mL) of DEAD was further added and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 → 75:25) to obtain the title compound (1.8 g) having the following physical properties. TLC: Rf 0.79 (hexane:ethyl acetate=3:1).

[0376] Reference Example 34: 4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoic acid 10% palladium / carbon (0.6 g) was added to a solution of the compound (1.8 g) produced in Reference Example 33 in methanol (20 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3.5 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure to give the title compound (1.4 g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ2.40, 3.08, 4.15, 6.57, 6.76-6.88, 7.17-7.28.

[0377] Reference Example 35: Ethyl (1R,2S)-2-{3-[2,6-dimethyl-4-(3-phenylpropyl)benzamido]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate To a suspension of the compound (23 mg) prepared in Reference Example 30 in toluene (1 mL), thionyl chloride (0.01 mL) was added and stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (1 mL). The compound (20 mg) prepared in Reference Example 6 was added to the reaction solution, and the mixture was stirred at room temperature for 21 hours. The reaction solution was concentrated and used in the next reaction.

[0378] Example 12: (1R,2S)-2-[3-{[2,6-dimethyl-4-(3-phenylpropyl)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0379] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Example 1, except that the compound prepared in Reference Example 35 was used instead of the compound prepared in Reference Example 8. HPLC retention time (min): 1.32; MS(ESI, Pos.):496(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.46-1.54, 1.67-1.79, 1.89-2.00, 2.16-2.24, 2.36, 2.56-2.74, 6.90, 7.15-7.23, 7.26-7.32, 7.46-7.57, 8.17.

[0380] Example 13: (1R,2S)-2-[3-({4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 35→Example 12 using the compound prepared in Reference Example 34 instead of the compound prepared in Reference Example 30.

[0381] [ka] HPLC retention time (min): 1.27; MS(ESI, Pos.):534(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.46-1.56, 1.75, 2.15-2.27, 2.35, 2.66-2.78, 3.09, 4.15, 6.59, 6.76-6.89, 7.16-7.32, 7.46-7.57, 8.23.

[0382] Reference Example 36: Ethyl 2-(2,3-dichloro-4-fluorophenyl)cyclopropane-1-carboxylate 1-Bromo-2,3-dichloro-4-fluorobenzene (CAS number: 1093092-14-8, 200 mg) in 1,4-dioxane (6 mL) solution was added with ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (197 mg), 2M potassium phosphate aqueous solution (1.2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (134 mg), and stirred at 100 ° C. for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 97:3 → 3:1) to obtain a mixture (150 mg) containing the title compound having the following physical properties. HPLC retention time (min): 1.12, 1.17; MS(ESI, Pos.):277(M+H) + .

[0383] Reference Example 37: Ethyl 2-(2,3-dichloro-4-fluoro-5-nitrophenyl)cyclopropane-1-carboxylate A mixture of concentrated sulfuric acid (0.15 mL) and fuming nitric acid (0.07 mL) was added dropwise to a solution of the mixture (150 mg) produced in Reference Example 36 in concentrated sulfuric acid (0.15 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured onto ice and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was used in the next reaction as it was without purification.

[0384] Reference Example 38: Ethyl 2-(5-amino-2,3-dichloro-4-fluorophenyl)cyclopropane-1-carboxylate The compound prepared in Reference Example 37 was used instead of the compound prepared in Reference Example 11, and the same procedure as in Reference Example 12 was carried out to obtain a mixture containing the title compound.

[0385] Examples 14-1 to 14-2: The compound prepared in Reference Example 27 was used instead of the compound prepared in Reference Example 30, and the compound prepared in Reference Example 38 was used instead of the compound prepared in Reference Example 6, and the same procedure as in Reference Example 35 → Example 1 was carried out, followed by separation and purification by HPLC to obtain the compound of the present invention having the following physical properties.

[0386] Example 14-1: rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-fluorophenyl)cyclopropanecarboxylic acid racemic mixture

[0387] [ka] HPLC retention time (min): 1.31; MS(ESI, Pos.):516(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.53-1.60, 1.69-1.77, 2.23-2.31, 2.34, 2.57-2.66, 3.10, 4.18, 6.60, 7.20-7.37, 7.39-7.43, 8.37.

[0388] Example 14-2: rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-fluorophenyl)cyclopropanecarboxylic acid racemic mixture

[0389] [ka] HPLC retention time (min): 1.32; MS(ESI, Pos.):516 (M+H) + ; 1 H-NMR (CDCl 3 ):δ1.50-1.62, 1.68-1.81, 1.85-1.94, 2.33, 2.74-2.87, 3.10, 4.18, 6.61, 7.21-7.38, 7.44, 8.25.

[0390] Reference Example 39: Ethyl (1R,2S)-2-{2-chloro-5-[2,6-dimethyl-4-(2-phenylethoxy)benzamido]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate DIPEA (4 mg) and phosphorus oxychloride (3 mg) were added to an acetonitrile (0.5 mL) solution of the compound (8 mg) produced in Reference Example 27 and the compound (6 mg) produced in Reference Example 7, and the mixture was stirred for 2 hours at 50° C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→4:1) to give the title compound (6 mg) having the following physical properties. HPLC retention time (min): 1.25; MS(ESI, Pos.):560(M+H) + .

[0391] Example 15: (1R,2S)-2-[2-chloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0392] [ka] A 5N aqueous sodium hydroxide solution (0.05mL) was added to a solution of the compound (6mg) produced in Reference Example 39 in methanol (0.3mL) and stirred at room temperature for 17 hours. A 5N aqueous sodium hydroxide solution (0.05mL) was added to the reaction solution and stirred for 3 hours. DME (0.1mL) was added and stirred for 1 hour. A 5N aqueous sodium hydroxide solution (0.1mL) was added to the reaction solution and stirred for 22 hours. The reaction solution was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture (4mg) containing the compound of the present invention having the following physical properties. HPLC retention time (min): 1.12; MS(ESI, Pos.):532(M+H) + ; 1 H-NMR (CDCl 3 :δ1.54-1.62, 1.67-1.76, 2.22-2.37, 2.59-2.66, 3.10, 4.16-4.20, 6.59, 7.18-7.37, 7.45, 7.59, 8.30.

[0393] Example 16: (1R,2S)-2-(4-chloro-3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid

[0394] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 8 → Reference Example 14 → Reference Example 15 → Reference Example 35 → Example 1 using 5-bromo-2-chloroaniline instead of the compound prepared in Reference Example 4 and using the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 3. MS(ESI, Pos.):464(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.21-1.27, 1.30-1.36, 1.42-1.49, 2.00-2.07, 2.28-2.32, 2.99-3.05, 4.19, 6.67, 7.06-7.10, 7.19-7.24, 7.28-7.34, 7.36-7.41, 7.49, 9.90, 11.94.

[0395] Examples 17-1 to 17-2: The same operations as in Reference Example 12 → Reference Example 35 → Reference Example 10 → Example 1 were carried out using 3-bromo-4,5-dichloronitrobenzene instead of the compound prepared in Reference Example 11, the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 30, and the corresponding boronic acid ester instead of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate, and then the compound of the present invention having the following physical properties was obtained by separating and purifying it by HPLC.

[0396] Example 17-1: rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid racemic mixture

[0397] [ka] HPLC retention time (min): 1.30; MS(ESI, Pos.):498(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.44-1.69, 2.32, 2.56-2.70, 3.07-3.12, 4.13-4.19, 6.58, 7.20-7.38, 7.91.

[0398] Example 17-2: rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid racemic mixture

[0399] [ka] HPLC retention time (min): 1.32; MS(ESI, Pos.):498(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.39-1.49, 1.67-1.73, 1.81-1.88, 2.32, 2.73-2.90, 3.10, 4.17, 6.59, 7.19-7.42, 7.72.

[0400] Reference Example 40: N-[5-bromo-2-(trifluoromethyl)phenyl]-2,6-dimethyl-4-(2-phenylethoxy)benzamide DIPEA (0.72 g) and phosphorus oxychloride (0.62 g) were added to an acetonitrile solution (10 mL) of the compound (1 g) produced in Reference Example 27 and 5-bromo-2-(trifluoromethyl)aniline (1.1 g), and the mixture was stirred at 50° C. for 12 hours. Phosphorus oxychloride (0.12 g) was added to the reaction solution, and the mixture was stirred for 6 hours. The reaction solution was returned to room temperature, and 1N aqueous sodium hydroxide solution (10 mL) was added and the mixture was stirred for 10 minutes. The precipitate was filtered and washed with hexane to obtain the title compound (1.5 g) having the following physical properties. HPLC retention time (min): 1.26; MS(ESI, Pos.):492(M+H) + .

[0401] Reference Example 41: N-[5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-2-(trifluoromethyl)phenyl]-2,6-dimethyl-4-(2-phenylethoxy)benzamide To a solution of the compound (500 mg) produced in Reference Example 40 in DME (5 mL), bis(neopentyl glycolate)diboron (459 mg) and potassium acetate (300 mg) were added and degassed, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (83 mg) was added and stirred at 88°C for 1.5 hours. The reaction solution was diluted with MTBE and filtered through Celite (trade name). The filtrate was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:4) to obtain the title compound (508 mg) having the following physical properties. HPLC retention time (min): 1.03.

[0402] Reference Example 42: Ethyl (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamido]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate Ethyl (1S,2S)-2-iodocyclopropanecarboxylate (185 mg) and 2M cesium carbonate aqueous solution (1.2 mL) were added to a solution of the compound (488 mg) produced in Reference Example 41 in 1,4-dioxane (5.4 mL) and degassed, and XPhos Pd G2 (122 mg) was added and stirred at 100 ° C. for 1.5 hours. The reaction solution was diluted with MTBE, washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 0: 1) to obtain the title compound (316 mg) having the following physical properties. HPLC retention time (min): 1.20; MS(ESI, Pos.):526(M+H) + .

[0403] Example 18: (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0404] [ka] A 5N aqueous sodium hydroxide solution (1.5mL) was added to a solution of the compound (500mg) produced in Reference Example 42 in THF (1.5mL) and methanol (1.5mL) under ice cooling, and the mixture was stirred at 50°C for 1 hour. Water was added to the reaction solution and the mixture was washed with hexane. 5N hydrochloric acid was added to the aqueous layer to neutralize it, and the mixture was extracted with MTBE. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:1) to obtain the compound of the present invention (395mg) having the following physical properties. HPLC retention time (min): 1.06; MS(ESI, Pos.):498(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.39-1.51, 1.64-1.75, 2.09-2.21, 2.34, 2.62-2.73, 3.10, 4.15-4.21, 6.59, 7.11-7.18, 7.22-7.37, 7.45-7.53, 8.24.

[0405] Example 19: (1S,2R)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0406] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 42→Example 18 using the corresponding iodine compound instead of ethyl (1S,2S)-2-iodocyclopropanecarboxylate. HPLC retention time (min): 1.08; MS(ESI, Pos.):498(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.43-1.53, 1.68-1.77, 2.10-2.21, 2.34, 2.63-2.76, 3.10, 4.17, 6.59, 7.17, 7.22-7.36, 7.47-7.58, 8.22.

[0407] Reference Example 43: Ethyl (1R,2S)-2-{3-[4-(acetyloxy)-2,6-dimethylbenzamido]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate To a suspension of the compound (914 mg) produced in Reference Example 31 in toluene (5 mL), thionyl chloride (0.4 mL) and DMF (42 mg) were added and stirred at 75 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and an acetonitrile solution of the compound (1 g) produced in Reference Example 6 was added to the resulting residue and stirred at 55 ° C for 2 hours. The reaction solution was diluted with hexane and MTBE, washed with 1N aqueous sodium hydroxide solution, 5N hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to obtain the title compound (1.4 g) having the following physical properties. HPLC retention time (min): 1.03; MS(ESI, Pos.):464(M+H) + .

[0408] Reference Example 44: Ethyl (1R,2S)-2-[3-(4-hydroxy-2,6-dimethylbenzamido)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate Potassium carbonate (1.3 g) was added to a solution of the compound (1.4 g) produced in Reference Example 43 in ethanol (40 mL) and stirred at room temperature for 22 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (1.1 g) having the following physical properties. HPLC retention time (min): 0.94; MS(ESI, Pos.):422(M+H) + .

[0409] Example 20: (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0410] [ka] 2-(1-methyl-1H-pyrazol-4-yl)ethanol (CAS number: 176661-75-9, 12 mg) and CMBP (17 mg) were added to a solution of the compound (20 mg) produced in Reference Example 44 in toluene (0.5 mL), and the mixture was stirred at 80° C. for 2 hours. CMBP (17 mg) was added to the reaction solution, and the mixture was stirred for 1.5 hours. The reaction solution was concentrated, and the resulting residue was dissolved in methanol (0.3 mL), and 5N aqueous sodium hydroxide solution (0.05 mL) was added and the mixture was stirred at 50° C. for 14 hours. The reaction solution was neutralized with 5N hydrochloric acid, and purified using HPLC to obtain the compound of the present invention (4 mg) having the following physical properties. HPLC retention time (min): 1.05; MS(ESI, Pos.):502(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.45-1.53, 1.71-1.78, 2.15-2.23, 2.36, 2.64-2.76, 2.93, 3.87, 4.04-4.11, 6.61, 7.18, 7.27, 7.40, 7.48, 7.53, 8.29.

[0411] Examples 20-1 to 20-23: The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Example 20, except that the corresponding alcohol was used instead of 2-(1-methyl-1H-pyrazol-4-yl)ethanol.

[0412] Example 20-1: (1R,2S)-2-[3-{[4-(2-cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0413] [ka] HPLC retention time (min): 1.24; MS(ESI, Pos.):462(M+H) + ; 1 H-NMR (CDCl 3): δ 0.09 - 0.17, 0.47 - 0.53, 0.77 - 0.91, 1.44 - 1.55, 1.65 - 1.78, 2.20, 2.36, 2.63 - 2.75, 4.04, 6.62, 7.20, 7.46 - 7.58, 8.18。

[0414] Example 20-2: (1R,2S)-2-{3-[(2,6-dimethyl-4-propoxybenzoyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid HPLC retention time (min): 1.19; MS (ESI, Pos.): 436 (M + H) + ; 1 H-NMR (CDCl 3 ): δ 1.04, 1.45 - 1.53, 1.66 - 1.87, 2.11 - 2.26, 2.35, 2.62 - 2.74, 3.93, 6.60, 7.20, 7.44 - 7.58, 8.17。

[0415] Example 20-3: (1R,2S)-2-[3-{[4-(hexyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.14; MS (ESI, Pos.): 478 (M + H) + ; 1 H-NMR (CDCl 3 ): δ 0.86 - 0.98, 1.04 - 1.16, 1.03 - 1.55, 1.72 - 1.83, 1.84 - 1.95, 2.19 - 2.31, 3.95, 6.53, 7.07 - 7.14, 7.31 - 7.39, 7.46 - 7.57, 7.67 - 7.76。

[0416] Example 20-4: (1R,2S)-2-[3-{[4-(benzyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.22; MS (ESI, Pos.): 484 (M + H) + ; 1 H-NMR (CDCl 3 ): δ 1.43 - 1.55, 1.73, 2.14 - 2.27, 2.36, 2.65 - 2.76, 5.07, 6.69, 7.20, 7.31 - 7.46, 7.49 - 7.59, 8.17。

[0417] Example 20-5: (1R,2S)-2-[3-{[4-(2-methoxyethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.07; MS (ESI, Pos.): 452 (M+H) + ; 1 1H-NMR (DMSO-d 6 ): δ 1.35 - 1.43, 1.49 - 1.59, 2.05 - 2.15, 2.30, 2.63 - 2.79, 3.30, 3.60 - 3.68, 4.08, 6.67, 7.27 - 7.34, 7.44, 7.58 - 7.68, 9.95, 12.03。

[0418] Example 20-6: (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.21; MS (ESI, Pos.): 506 (M+H) + ; 1 1H-NMR (CDCl 3 ): δ 1.22 - 1.76, 1.80 - 1.96, 2.15 - 2.24, 2.35, 2.63 - 2.77, 3.35 - 3.60, 3.91 - 4.18, 6.62, 7.19, 7.46 - 7.57, 8.19。

[0419] Example 20-7: (1R,2S)-2-[3-({4-[2-(2-furyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.20; MS (ESI, Pos.): 488 (M+H) + ; 1 1H-NMR (CDCl 3 ): δ 1.45 - 1.55, 1.69 - 1.76, 2.16 - 2.23, 2.35, 2.62 - 2.77, 3.13, 4.22, 6.15, 6.32, 6.61, 7.20, 7.29 - 7.40, 7.44 - 7.59, 8.18。

[0420] Example 20-8: (1R,2S)-2-[3-({4-[2-(2-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.30; MS (ESI, Pos.): 532 (M+H) + ; 1 H-NMR(CDCl 3 ): δ 1.43 - 1.53, 1.67 - 1.78, 2.18, 2.34, 2.61 - 2.74, 3.24, 4.20, 6.61, 7.14 - 7.26, 7.32 - 7.42, 7.44 - 7.50, 7.50 - 7.56, 8.22。

[0421] Example 20-9: (1R,2S)-2-[3-({4-[2-(3-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.30; MS(ESI, Pos.): 532(M + H) + ; 1 H-NMR(CDCl 3 ): δ 1.44 - 1.55, 1.67 - 1.77, 2.16 - 2.24, 2.35, 2.65 - 2.74, 3.07, 4.17, 6.59, 7.14 - 7.31, 7.45 - 7.55, 8.20。

[0422] Example 20-10: (1R,2S)-2-[3-({4-[2-(1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 0.84; MS(ESI, Pos.): 488(M + H) + ; 1 H-NMR(CDCl 3 ): δ 1.46 - 1.55, 1.69 - 1.78, 2.17 - 2.27, 2.33, 2.65 - 2.74, 4.28 - 4.34, 4.52 - 4.59, 6.55, 7.19 - 7.30, 7.37, 7.48, 7.53 - 7.57, 8.18, 8.96。

[0423] Example 20-11: (1R,2S)-2-[3-({4-[2-(2,6-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.26; MS(ESI, Pos.): 534(M + H) + ; 1 H-NMR(CDCl 3): δ 1.45 - 1.56, 1.67 - 1.79, 2.15 - 2.26, 2.34, 2.65 - 2.76, 3.18, 4.16, 6.60, 6.83 - 6.94, 7.14 - 7.25, 7.45 - 7.57, 8.19。

[0424] Example 20-12: (1R,2S)-2-[3-({4-[2-(3,5-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.27; MS (ESI, Pos.): 534 (M + H) + ; 1 H-NMR (CDCl 3 ): δ 1.57 - 1.58, 1.70 - 1.79, 2.15 - 2.28, 2.36, 2.68 - 2.78, 3.07, 4.17, 6.60, 6.65 - 6.73, 6.78 - 6.88, 7.17 - 7.23, 7.50, 7.55, 8.23。

[0425] Example 20-13: (1R,2S)-2-[3-{[4-(1H-indazol-5-ylmethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.09; MS (ESI, Pos.): 524 (M + H) + ; 1 H-NMR (DMSO-d 6 ): δ 1.35 - 1.47, 1.51 - 1.60, 2.32, 2.65 - 2.74, 5.21, 6.79, 7.31 - 7.36, 7.40 - 7.48, 7.54 - 7.60, 7.65, 7.84, 8.09, 9.95, 12.62 - 13.37。

[0426] Example 20-14: (1R,2S)-2-[3-{[2,6-dimethyl-4-(1,2,3,4-tetrahydro-1-naphthalenylmethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.33; MS (ESI, Pos.): 538 (M + H) + ; 1 H-NMR (DMSO-d 6): δ 1.34 - 1.46, 1.49 - 1.58, 1.62 - 2.02, 2.04 - 2.20, 2.28 - 2.35, 2.65 - 2.80, 3.16 - 3.28, 3.99 - 4.10, 4.15 - 4.22, 6.73, 7.07 - 7.19, 7.29 - 7.37, 7.46, 7.61 - 7.70, 9.94, 12.1。

[0427] Example 20-15: (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(3-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 0.89; MS (ESI, Pos.) 499: (M + H) + ; 1 ¹H-NMR (DMSO-d 6 ): δ 1.35 - 1.46, 1.50 - 1.58, 2.04 - 2.20, 2.31, 2.62 - 2.77, 3.21, 4.29, 6.68, 7.31 - 7.39, 7.45, 7.66, 7.81, 8.27 - 8.30, 8.70, 8.80 9.93, 11.48 - 12.44。

[0428] Example 20-16: (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(4-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 0.88; MS (ESI, Pos.): 499 (M + H) + ; 1 ¹H-NMR (DMSO-d 6 ): δ 1.38 - 1.43, 1.50 - 1.59, 2.07 - 2.18, 2.31, 2.66 - 2.75, 3.16 - 3.19, 4.31, 6.68, 7.34, 7.45, 7.60, 7.66, 8.63, 9.94, 11.70 - 12.35。

[0429] Example 20-17: (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(2-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 0.90; MS (ESI, Pos.): 499 (M + H) + ; 1 ¹H-NMR (DMSO-d 6): δ 1.34 - 1.44, 1.49 - 1.59, 2.05 - 2.17, 2.31, 2.66 - 2.79, 3.36, 4.40, 6.67, 7.30 - 7.38, 7.45, 7.66, 7.73 - 7.85, 8.09 - 8.36, 8.73, 9.93, 12.03。

[0430] Example 20-18: (1R,2S)-2-[3-({4-[2-(2-chloro-1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.05; MS (ESI, Pos.): 522 (M + H) + ; 1 H-NMR (DMSO-d 6 ): δ 1.33 - 1.47, 1.50 - 1.59, 2.05 - 2.18, 2.31, 2.67 - 2.75, 4.25 - 4.31, 4.33 - 4.39, 6.66, 6.91 - 6.96, 7.30 - 7.37, 7.38 - 7.41, 7.44 - 7.48, 7.65, 9.95。

[0431] Example 20-19: (1R,2S)-2-[3-({4-[2-(2-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.25; MS (ESI, Pos.): 516 (M + H) + ; 1 H-NMR (DMSO-d 6 ): δ 1.33 - 1.45, 1.48 - 1.59, 2.10 - 2.16, 2.31, 2.63 - 2.77, 3.08, 4.21, 6.68, 7.12 - 7.23, 7.25 - 7.38, 7.39 - 7.49, 7.65, 9.95, 12.10。

[0432] Example 20-20: (1R,2S)-2-[3-({4-[2-(3-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.24; MS (ESI, Pos.): 516 (M + H) + ; 1 H-NMR (DMSO-d 6): δ 1.34 - 1.46, 1.48 - 1.60, 2.05 - 2.19, 2.31, 2.64 - 2.78, 3.07, 4.22, 6.69, 7.02 - 7.10, 7.15 - 7.24, 7.30 - 7.40, 7.45, 7.65, 9.95, 12.10。

[0433] Example 20-21: (1R,2S)-2-[3-({4-[2-(4-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.23; MS (ESI, Pos.): 516 (M + H) + ; 1 H-NMR (DMSO-d 6 ): δ 1.38 - 1.45, 1.50 - 1.61, 2.08 - 2.17, 2.31, 2.64 - 2.73, 3.03, 4.19, 6.68, 7.11 - 7.19, 7.29 - 7.42, 7.45, 7.65, 9.94, 12.06。

[0434] Examples 20-22: (1R,2S)-2-[3-{[2,6-dimethyl-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.17; MS (ESI, Pos.): 490 (M + H) + ; 1 H-NMR (DMSO-d 6 ): δ 1.38 - 1.46, 1.50 - 1.58, 2.07 - 2.17, 2.33, 2.68 - 2.74, 2.74 - 2.85, 4.22, 6.72, 7.34, 7.46, 7.66, 9.98, 12.02。

[0435] Example 20-23: (1R,2S)-2-[3-{[2,6-dimethyl-4-(3,3,3-trifluoro-2-methylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.20; MS (ESI, Pos.): 504 (M + H) + ; 1 H-NMR (DMSO-d 6):δ1.21, 1.36-1.48, 1.50-1.62, 2.07-2.18, 2.33, 2.64-2.74, 2.82-3.02, 4.03-4.19, 6.72, 7.30-7.37, 7.46, 7.66, 9.97, 11.99.

[0436] Reference Example 45: Ethyl (1R,2S)-2-[3-{4-[(6-chloropyrazine-2-yl)oxy]-2,6-dimethylbenzamido}-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate 2,6-Dichloropyrazine (CAS number: 4774-14-5, 21 mg) and potassium carbonate (25 mg) were added to a solution of the compound (50 mg) produced in Reference Example 44 in DMF (1 mL) and stirred at 50° C. for 2 hours. The reaction solution was diluted with MTBE, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0437] Example 21: (1R,2S)-2-[3-({4-[(6-chloro-2-pyrazinyl)oxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0438] [ka] To a solution of the crude product prepared in Reference Example 45 in 1,4-dioxane (0.2 mL), water (0.2 mL) and concentrated sulfuric acid (0.05 mL) were added and stirred at 100° C. for 15 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the compound of the present invention (30 mg) having the following physical properties. HPLC retention time (min): 1.16; MS(ESI, Pos.):506(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.46-1.55, 1.70-1.77, 2.16-2.24, 2.41, 2.66-2.76, 6.89, 7.21, 7.53-7.59, 8.20, 8.31, 8.32.

[0439] Examples 21-1 to 21-2: The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 45→Example 21 using the corresponding chlorinated compound instead of 2,6-dichloropyrazine.

[0440] Example 21-1: (1R,2S)-2-{3-[(2,6-dimethyl-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}benzoyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

[0441] [ka] HPLC retention time (min): 1.21; MS(ESI, Pos.):539(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.37-1.47, 1.52-1.61, 2.09-2.19, 2.37, 2.66-2.80, 6.98, 7.27-7.43, 7.48, 7.68, 8.02-8.27, 10.22, 12.05.

[0442] Example 21-2: (1R,2S)-2-[3-{[2,6-dimethyl-4-(pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0443] [ka] HPLC retention time (min): 1.06; MS(ESI, Pos.):511(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.39-1.46, 1.52-1.59, 2.10-2.17, 2.39, 2.69-2.81, 6.38, 6.83, 7.03, 7.36, 7.49, 7.68, 8.08, 9.08, 10.27, 12.16.

[0444] Reference Example 46: Ethyl (1R,2S)-2-[3-{2,6-dimethyl-4-[(trifluoromethanesulfonyl)oxy]benzamido}-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (CAS number: 37595-74-7, 127 mg) and triethylamine (72 mg) were added to a solution of the compound (100 mg) produced in Reference Example 44 in THF (3 mL), and the mixture was stirred at room temperature for 88 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→1:1) to obtain the title compound (120 mg) having the following physical properties. HPLC retention time (min): 1.14; MS(ESI, Pos.):554(M+H) + .

[0445] Reference Example 47: Ethyl (1R,2S)-2-{3-[4-(6-fluoropyridin-3-yl)-2,6-dimethylbenzamido]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate 2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS number: 444120-95-0, 127 mg), 2M aqueous cesium carbonate solution (0.08 mL) and XPhos Pd G2 (8 mg) were added to the 1,4-dioxane solution (3 mL) of the compound (30 mg) produced in Reference Example 46, and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to obtain the title compound having the following physical properties. HPLC retention time (min): 1.07; MS(ESI, Pos.):501(M+H) + .

[0446] Example 22: (1R,2S)-2-[3-{[4-(6-fluoro-3-pyridinyl)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0447] [ka] A 5N aqueous sodium hydroxide solution (0.3 mL) was added to a methanol (1 mL) solution of the compound prepared in Reference Example 47, and the mixture was stirred at 50° C. for 17 hours. The reaction solution was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by HPLC to obtain the compound of the present invention (12 mg) having the following physical properties. HPLC retention time (min): 1.13; MS(ESI, Pos.):473(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.46-1.58, 1.71-1.80, 2.16-2.28, 2.47, 2.66-2.78, 7.01-7.09, 7.18-7.27, 7.52-7.61, 7.94-8.03, 8.21, 8.43.

[0448] Reference Example 48: 2-{4-[(4-methoxybenzyl)oxy]phenyl}ethanol Potassium carbonate (3 g) and 4-methoxybenzyl chloride (CAS number: 824-94-2, 2.5 g) were added to a solution of 4-(2-hydroxyethyl)phenol (CAS number: 501-94-0, 2 g) in DMF (10 mL) and the mixture was stirred at 50° C. for 14 hours. Water was added to the reaction solution, and the precipitate was collected by filtration. The resulting crude product was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.4 g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ2.81, 3.75-3.90, 4.97, 6.85-6.98, 7.11-7.19, 7.33-7.38.

[0449] Reference Example 49: (1R,2S)-2-{3-[4-(2-{4-[(4-methoxyphenyl)methoxy]phenyl}ethoxy)-2,6-dimethylbenzamido]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid The compound (25 mg) prepared in Reference Example 48 and CMBP (17 mg) were added to a solution of the compound (20 mg) prepared in Reference Example 44 in toluene (0.5 mL) and stirred at 80° C. for 27 hours. The reaction solution was concentrated under reduced pressure, and methanol (0.3 mL), THF (0.3 mL) and a 5N aqueous sodium hydroxide solution (0.05 mL) were added to the residue, which was stirred at 50° C. for 2 hours and further stirred at room temperature for 21 hours. The reaction solution was neutralized with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was used in the next reaction without purification.

[0450] Example 23: (1R,2S)-2-[3-({4-[2-(4-hydroxyphenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0451] [ka] A solution of the crude product obtained in Reference Example 49 in acetic acid (1 mL) was heated and stirred for 15 minutes at 150° C. using a microwave reaction apparatus. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (manufactured by Fuji Silysia Chemical, Chromatorex DIOL60, hexane:ethyl acetate=9:1→0:1) to obtain the compound of the present invention (18 mg) having the following physical properties. HPLC retention time (min): 1.13; MS(ESI, Pos.):514(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.43-1.51, 1.64-1.75, 2.17, 2.34, 2.63-2.72, 3.02, 4.13, 6.59, 6.75-6.82, 7.08-7.20, 7.45-7.49, 7.50-7.55, 8.16-8.24.

[0452] Reference Example 50: Ethyl (2E)-3-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamido]-4-(trifluoromethyl)phenyl}prop-2-enoate To a 1,4-dioxane solution (1 mL) of the compound (30 mg) produced in Reference Example 40, ethyl acrylate (18 mg), DIPEA (24 mg), and tetrakis(triphenylphosphine)palladium(0) (CAS number: 14221-01-3, 14 mg) were added and stirred overnight at 100° C. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1), and the obtained title compound was used in the next reaction.

[0453] Reference Example 51: (2E)-3-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamido]-4-(trifluoromethyl)phenyl}prop-2-enoic acid A 2N aqueous sodium hydroxide solution (0.5mL) was added to a THF / methanol (1mL) solution of the compound prepared in Reference Example 50, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0454] Example 24: 3-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]propanoic acid

[0455] [ka] Palladium hydroxide (3 mg) was added to a solution of the residue obtained in Reference Example 51 in THF (1 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction solution was filtered through Celite (trade name) and concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain the compound of the present invention (0.62 mg) having the following physical properties. HPLC retention time (min): 1.20; MS(ESI, Pos.):486(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ2.30, 2.56-2.62, 2.92, 3.02, 4.19, 6.66, 7.19-7.25, 7.28-7.34, 7.34-7.37, 7.41, 7.67, 9.92, 12.11-12.32.

[0456] Examples 24-1 to 24-2: The compounds of the present invention having the following physical properties were obtained by carrying out the same operations as in Reference Example 50→Reference Example 51→Example 24 using ethyl crotonate or ethyl methacrylate instead of ethyl acrylate.

[0457] Example 24-1: 3-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]butanoic acid

[0458] [ka] HPLC retention time (min): 1.23; MS(ESI, Pos.):500(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.24, 2.30, 2.55-2.63, 2.96-3.05, 3.20-3.29, 4.19, 6.66, 7.17-7.25, 7.28-7.35, 7.38-7.43, 7.66-7.69, 9.91, 12.06-12.24.

[0459] Example 24-2: 3-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]-2-methylpropanoic acid

[0460] [ka] HPLC retention time (min): 1.23; MS(ESI, Pos.):500(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.08, 2.29, 2.64-2.78, 2.94-3.04, 4.15-4.23, 6.66, 7.18-7.25, 7.27-7.36, 7.39, 7.67, 9.92, 12.25.

[0461] Reference Example 52: N-[5-iodo-2-(trifluoromethyl)phenyl]-2,6-dimethyl-4-(2-phenylethoxy)benzamide The compound prepared in Reference Example 27 was used instead of the compound prepared in Reference Example 31, and 5-iodo-2-(trifluoromethyl)aniline (CAS number: 1544-89-4) was used instead of the compound prepared in Reference Example 6, and the same procedure as in Reference Example 43 was carried out to obtain the title compound (1.45 g) having the following physical properties. HPLC retention time (min): 1.25; MS(ESI, Pos.):540(M+H) + .

[0462] Reference Example 53: 2-Methyl-2-propanyl [1-(dimethylamino)-1-oxo-3-phenyl-2-propanyl]carbamate 2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)-3-phenylpropanoic acid (CAS number: 13734-34-4, 6.6 g), 1-hydroxybenzotriazole (CAS number: 2592-95-2, 3.4 g) and dimethylamine hydrochloride (CAS number: 506-59-2, 4.5 g) were added to a dichloromethane (200 mL) solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (CAS number: 25952-53-8, 5.7 g) and DIPEA (10 mL) under ice cooling and stirred at room temperature for 1 hour. The reaction solution was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0463] Reference Example 54: 2-Amino-N,N-dimethyl-3-phenylpropanamide hydrochloride The crude product prepared in Reference Example 53 was dissolved in a 4N hydrochloric acid in ethyl acetate solution (25 mL) and stirred at room temperature for 5 minutes. A 4N hydrochloric acid in ethyl acetate solution (10 mL) was added and stirred at room temperature for 3 hours. The precipitate was collected by filtration to obtain the title compound (1.45 g) having the following physical properties. HPLC retention time (min): 0.49; 1 H-NMR (DMSO-d 6 ):δ2.63, 2.79, 2.88-3.00, 3.00-3.10, 4.50-4.61, 7.14-7.24, 7.27-7.42, 8.24.

[0464] Reference Example 55: (2S)-N1,N1-dimethyl-3-phenyl-1,2-propanediamine A suspension of the compound (3g) prepared in Reference Example 54 in THF (30mL) was added dropwise to a suspension of lithium aluminum hydride (0.94g) in THF (20mL) under ice cooling, and the mixture was stirred at 50°C for 2 hours. The reaction solution was ice-cooled, and purified water (1mL), 4N aqueous sodium hydroxide solution (1mL) and purified water (3mL) were added and stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes, filtered through Celite (trade name), and concentrated under reduced pressure to obtain the title compound (2.2g) having the following physical properties. HPLC retention time (min): 0.34; MS(ESI, Pos.):179(M+H) + ;

[0465] Reference Example 56: N-[(2S)-1-(dimethylamino)-3-phenyl-2-propanyl]acetamide Acetyl chloride (1 mL) was added to the compound (2.1 g) produced in Reference Example 55 in dichloromethane (20 mL) under ice cooling, stirred at room temperature for 5 minutes, and the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in MTBE, washed with a 5N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was slurry-washed with hexane to obtain the title compound (1.5 g) having the following physical properties. HPLC retention time (min): 0.50; MS(ESI, Pos.):221(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.97, 2.12-2.23, 2.26-2.36, 2.72-2.90, 2.93-3.04, 4.08-4.27, 5.50-5.65, 7.11-7.40.

[0466] Example 25: (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclobutanecarboxylic acid

[0467] [ka] Cyclobutanecarboxylic acid (CAS number: 3721-95-7, 19 mg), silver carbonate (25 mg), sodium carbonate (15 mg), the compound prepared in Reference Example 56 (4 mg) and palladium acetate (25 mg) were added to a solution of the compound prepared in Reference Example 52 (50 mg) in 1,1,1,3,3,3-hexafluoro-2-propanol (CAS number: 29463-77-2, 0.5 mL), and the mixture was stirred at 85° C. for 20 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→0:1) to obtain the compound of the present invention (10 mg) having the following physical properties. HPLC retention time (min): 1.12; MS(ESI, Pos.):512(M+H) + ; 1 H-NMR (CDCl 3 ):δ2.22-2.48, 2.58-2.74, 3.10, 3.58-3.70, 4.03-4.24, 6.60, 7.18, 7.23-7.39, 7.47, 7.57, 8.14.

[0468] Example 26: (1R,2R)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]-1-methylcyclopropanecarboxylic acid

[0469] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Example 25 using 1-methylcyclopropane-1-carboxylic acid (CAS number: 6914-76-7) instead of cyclobutanecarboxylic acid. HPLC retention time (min): 1.30; MS(ESI, Pos.):512(M+H) + ; 1 H-NMR (CDCl 3 ):δ1.23-1.30, 1.52, 1.92-2.00, 2.35, 2.41-2.49, 3.10, 4.18, 6.60, 7.12-7.20, 7.20-7.37, 7.44-7.54, 8.13.

[0470] Example 27: rel-(1R,2S)-2-(3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-methylphenyl)cyclopropanecarboxylic acid racemic mixture

[0471] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 40→Reference Example 4→Example 1 using 5-bromo-2-methylaniline (CAS number: 39478-78-9) instead of 5-bromo-2-(trifluoromethyl)aniline. HPLC retention time (min): 2.19 (condition B); MS(ESI, Pos.):444(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.20-1.45, 1.75-2.02, 2.21, 2.31, 3.03, 4.20, 6.68, 6.94-6.99, 7.05-7.11, 7.20-7.37, 9.65.

[0472] Reference Example 57: Methyl 4-(benzyloxy)-2-bromobenzoate Potassium carbonate (4.78 g) and benzyl bromide (2.1 mL) were added to a DMF solution (20 mL) of methyl 2-bromo-4-hydroxybenzoate (CAS number: 101085-03-4, 4.0 g), and the mixture was stirred at 70°C for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification. HPLC retention time (min): 2.38; (condition E) MS(ESI, Pos.):321(M+H) + .

[0473] Reference Example 58: Methyl 4-(benzyloxy)-2-isopropenylbenzoate A solution of the compound prepared in Reference Example 57 in ethanol (15 mL) and water (3.6 mL) was degassed, and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (CAS number: 126726-62-3, 2.64 g), 2,6-di-tert-butyl-4-methylphenol (CAS number: 128-37-0, 0.58 g), palladium acetate (0.44 g), tricyclohexylphosphine (CAS number: 2622-14-2, 0.37 g), and potassium phosphate (8.32 g) were added and stirred at 90° C. for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (3 g) having the following physical properties. HPLC retention time (min): 2.46; (condition E) MS(ESI, Pos.):283(M+H) + .

[0474] Reference Example 59: Methyl 4-(benzyloxy)-2-isopropylbenzoate Platinum oxide (CAS number: 1314-15-4, 10 mg) was added to a methanol (2.4 mL) solution of the compound prepared in Reference Example 58, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was used in the next reaction without purification. HPLC retention time (min): 2.56; (condition E) MS(ESI, Pos.):285(M+H) + .

[0475] Reference Example 60: 4-(benzyloxy)-2-isopropylbenzoic acid Lithium hydroxide hydrate (CAS number: 1310-66-3, 88 mg) was added to a solution of the compound prepared in Reference Example 59 in methanol (0.5 mL), THF (0.5 mL), and water (0.5 mL), and the mixture was stirred at 60° C. for 16 hours. The reaction solution was concentrated, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used in the next reaction without purification. HPLC retention time (min): 2.20; (condition E) MS(ESI, Pos.):271(M+H) + .

[0476] Example 28: (1R,2S)-2-[3-{[4-(benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0477] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Reference Example 8→Example 1, except that the compound prepared in Reference Example 60 was used instead of the compound prepared in Example 3. HPLC retention time (min): 2.36 (condition C); MS(ESI, Pos.):498(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.20, 1.31-1.40, 1.51-1.59, 2.03-2.12, 2.62-2.71, 3.33-3.45, 5.17, 6.93-6.96, 7.01, 7.30-7.51, 7.63, 9.91, 12.02.

[0478] Examples 28-1 to 28-2 The compounds of the present invention having the following physical properties were obtained by carrying out the same operations as in Reference Example 57 → Reference Example 58 → Reference Example 59 → Reference Example 60 → Reference Example 8 → Example 1 using the corresponding bromo compound instead of benzyl bromide.

[0479] Example 28-1: (1R,2S)-2-[3-{[2-isopropyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0480] [ka] HPLC retention time (min): 2.42 (condition C); MS(ESI, Pos.):512(M+H) + ; 1 H-NMR (DMSO-d 6):δ1.20, 1.30-1.38, 1.49-1.56, 2.01-2.13, 2.55-2.66, 3.06, 3.33-3.45, 4.25, 6.83-6.94, 7.20-7.27, 7.29-7.45, 7.62, 9.89.

[0481] Example 28-2: (1R,2S)-2-[3-{[2-isopropyl-4-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0482] [ka] HPLC retention time (min): 2.52 (condition C); MS(ESI, Pos.):526(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.19, 1.32-1.41, 1.51-1.59, 1.99-2.14, 2.60-2.72, 2.77, 3.34-3.49, 4.04, 6-83-6.89, 6.93, 7.16-7.46, 7.64, 9.91, 11.83.

[0483] Examples 29-1 to 29-3 The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 57 → Reference Example 58 → Reference Example 59 → Reference Example 60 → Reference Example 8 → Example 1 using 2-bromo-3-hydroxybenzoate methyl (CAS number: 1260783-82-1) instead of 2-bromo-4-hydroxybenzoate and using the corresponding bromo compound instead of benzyl bromide or benzyl bromide.

[0484] Example 29-1: (1R,2S)-2-[3-{[3-(benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0485] [ka] HPLC retention time (min): 4.96 (condition D); MS(ESI, Pos.):498(M+H) + ; 11H-NMR (DMSO-d 6 ): δ 1.17 - 1.55, 1.91 - 2.04, 2.40 - 2.59, 3.11 - 3.25, 5.18, 6.97, 7.15, 7.21 - 7.53, 7.59, 10.02.

[0486] Example 29-2: (1R,2S)-2-[3-{[2-isopropyl-3-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0487]

Chem.

[0488] Example 29-3: (1R,2S)-2-[3-{[2-isopropyl-3-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0489]

Chem.

[0490] Reference Example 61: 4-Bromo-2,3,6-trimethylphenol A solution of bromine (1.6 mL) in dichloromethane (30 mL) was added to a solution of 2,3,6-trimethylphenol (CAS number: 2416-94-6, 4.0 g) in dichloromethane (60 mL) and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5.9 g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ2.19, 2.21, 2.34, 4.56, 7.18.

[0491] Reference Example 62: 1-Bromo-2,3,5-trimethyl-4-(2-phenylethoxy)benzene 2-Phenylethanol (1.36 g) and triphenylphosphine (4.87 g) were added to a solution of the compound (2.0 g) produced in Reference Example 61 in THF (20 mL). Then, DEAD (3.23 g, 40% toluene solution) was added dropwise and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:1) to obtain the title compound (1.5 g) having the following physical properties. 1 H-NMR (CDCl 3 ):δ2.11, 2.14, 2.30, 3.09, 3.89, 7.20-7.22, 7.27-7.32.

[0492] Reference Example 63: 2,3,5-trimethyl-4-(2-phenylethoxy)benzoic acid A solution of the compound (0.3 g) prepared in Reference Example 62 in THF (6 mL) was added with a hexane solution of n-butyllithium (2.5 mol / L, 0.46 mL) at -78°C, and the mixture was stirred at -78°C for 15 minutes. Carbon dioxide gas was passed through the reaction solution at -78°C for 5 minutes, and the mixture was stirred at -78°C for 20 minutes. Hydrochloric acid was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used in the next reaction without purification. HPLC retention time (min): 2.59 (condition F); MS(ESI, Pos.):285(M+H) + .

[0493] Example 30: (1R,2S)-2-[4-(trifluoromethyl)-3-{[2,3,5-trimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl]cyclopropanecarboxylic acid

[0494] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Reference Example 8→Example 1 using the compound prepared in Reference Example 66 instead of the compound prepared in Reference Example 3. HPLC retention time (min): 2.42 (condition C); MS(ESI, Pos.):512(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.31-1.36, 1.50-1.56, 2.04-2.13, 2.23, 2.55-2.66, 3.07, 3.93, 7.12, 7.22-7.26, 7.30-7.39, 7.42, 7.62, 9.90.

[0495] Reference Example 64: (1) Methyl 3-isopropyl-1-(3-phenylpropyl)-1H-pyrazole-4-carboxylate, and (2) Methyl 5-isopropyl-1-(3-phenylpropyl)-1H-pyrazole-4-carboxylate Potassium carbonate (0.985 g) and 1-bromo-3-phenylpropane (1.42 g) were added to a solution of methyl 3-isopropyl-1H-pyrazole-4-carboxylate (CAS number: 1186537-97-2, 0.4 g) in DMF (5 mL), and the mixture was stirred at 60° C. for 16 hours. The reaction solution was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 88:12) to obtain the title compound (0.41 g, mixture) having the following physical properties. MS(ESI, Pos.):287(M+H) + .

[0496] Examples 31-1 to 31-2 The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 27→Example 11, except that the compound prepared in Reference Example 64 was used instead of the compound prepared in Reference Example 26.

[0497] Example 31-1: (1R,2S)-2-[3-({[3-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0498] [ka] HPLC retention time (min): 2.26 (condition C); MS(ESI, Pos.):500(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.15-1.21, 1.31-1.42, 1.50-1.58, 2.04-2.13, 2.55-2.73, 3.44-3.53, 4.09, 7.16-7.41, 7.62, 8.26, 9.37, 12.00.

[0499] Example 31-2: (1R,2S)-2-[3-({[5-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0500] [ka] HPLC retention time (min): 2.25 (condition C); MS(ESI, Pos.):500(M+H) + ; 1 H-NMR (DMSO-d 6 ):δ1.16-1.32, 1.38-1.48, 1.90-2.09, 2.38-2.51, 2.59-2.68, 4.15, 7.15-7.25, 7.26-7.37, 7.56, 7.95, 9.53.

[0501] Reference Example 65: Ethyl (1R,2S)-2-[3-({[2,6-dimethyl-4-(2-phenylethoxy)phenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylate Phosphorus pentasulfide (CAS number: 1314-80-3, 42 mg) was added to a solution of the compound (50 mg) produced in Reference Example 42 in benzene (CAS number: 71-43-2, 2 mL) at 0°C, and the mixture was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification. HPLC retention time (min): 2.93 (condition F); MS(ESI, Pos.):542(M+H) + ;

[0502] Example 32: (1R,2S)-2-[3-({[2,6-dimethyl-4-(2-phenylethoxy)phenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0503] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Example 18, except that the compound prepared in Reference Example 65 was used instead of the compound prepared in Reference Example 42. HPLC retention time (min): 2.39 (condition F); MS(ESI, Pos.):514(M+H) + ; 1 H-NMR (DMSO-d6): δ1.21-1.34, 1.66-1.82, 2.28, 2.32-2.61, 3.01, 4.13, 6.45, 6.81-6.92, 7.05-7.14, 7.19-7.27, 7.29-7.36.

[0504] Example 33: (1R,2S)-2-[3-({[4-(2-cyclopropylethoxy)-2,6-dimethylphenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0505] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same operation as in Reference Example 65→Example 18 using ethyl (1R,2S)-2-[3-{[4-(2-cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylate, which is an intermediate of Example 20-1, instead of the compound prepared in Reference Example 42. HPLC retention time (min): 2.36 (condition F); MS(ESI, Pos.):478(M+H) + ; 1 H-NMR(DMSO-d6):δ0.10-0.15, 0.41-0.47, 0.78-0.89, 1.37-1.44, 1.51-1.56, 1.59-1.66, 2.10-2.15, 2.34, 2.35, 2.67-2.75, 4.03, 6.68, 7.38-7.44, 7.68-7.73, 11.73, 12.02.

[0506] Reference Example 66: Ethyl 2-sec-butyl-1H-pyrrole-3-carboxylate A mixture of ethyl 4-methyl-3-oxohexanoate (CAS number: 98192-72-4, 1.0 g) and 2-chloroacetaldehyde aqueous solution (CAS number: 107-20-0, 50 wt%, 0.815 mL) was added to an ammonia solution (28% NH 3 Aqueous solution (3.2 mL) and water (3.2 mL) were added and stirred at 70° C. for 20 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (300 mg) having the following physical properties. LC-MS m / z 196(M+H) + ; 1 H-NMR (CDCl 3 ):δ0.91, 1.28, 1.37, 1.58-1.70, 3.65-3.73, 4.24-4.33, 6.58-6.61, 6.61-6.63, 8.19.

[0507] Reference Example 67: Ethyl 2-sec-butyl-1-(3-phenylpropyl)-1H-pyrrole-3-carboxylate Cesium carbonate (0.184 g) was added to a solution of the compound (110 mg) produced in Reference Example 66 and (3-bromopropyl)benzene (123 mg) in DMF (1 mL), and the mixture was stirred at 80° C. for 20 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain the title compound (98 mg) having the following physical properties. LC-MS m / z 314(M+H) + ; 1 H-NMR (CDCl 3 ):δ0.82, 1.32-1.40, 1.74, 1.88, 2.00-2.12, 2.68, 3.23, 3.84-3.97, 4.25, 6.46, 6.59, 7.16-7.21, 7.21-7.27, 7.31-7.36.

[0508] Reference Example 68: 2-sec-butyl-1-(3-phenylpropyl)-1H-pyrrole-3-carboxylic acid A 10N NaOH aqueous solution (0.1mL) was added to a solution of the compound (126mg) produced in Reference Example 67 in THF / methanol (1:1, 1mL) and stirred at 80°C for 20 hours. The reaction solution was cooled to room temperature, and acetic acid (0.2mL) was added. Then, dichloromethane (5mL) and water (5mL) were added. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (90mg) having the following physical properties. LC-MS m / z 286(M+H) + ; 1 H-NMR (DMSO-d6): δ0.71, 1.25, 1.63, 1.80, 1.89-2.06, 2.61, 3.20-3.39, 3.93, 6.37, 6.66, 7.18-7.26, 7.31.

[0509] Example 34: (1R,2S)-2-[3-({[2-sec-butyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0510] [ka] The compound of the present invention having the following physical properties was obtained by carrying out the same procedure as in Reference Example 8→Example 1, except that the compound prepared in Reference Example 68 was used instead of the compound prepared in Reference Example 3. LC-MS m / z 513(M+H) + ; 1 H-NMR(DMSO-d6):δ0.72, 1.16-1.31, 1.38, 1.47-1.58, 1.58-1.69, 1.78, 1.88-2.03, 2.03-2.20, 2.59-2.75, 3.32, 3.94, 6.54, 6.73, 7.19-7.28, 7.28-7.34, 7.50, 7.60, 8.94.

[0511] Examples 34-1 to 34-2 The compound of the present invention having the following physical properties was obtained by carrying out the same operations as in Reference Example 66 → Reference Example 67 → Reference Example 68 → Reference Example 8 → Example 1 using the corresponding compound instead of ethyl 4-methyl-3-oxohexanoate.

[0512] Example 34-1: (1R,2S)-2-[3-({[2-isopropyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0513] [ka] LC-MS m / z 499(M+H) + ; 1 H-NMR(DMSO-d6):δ1.27, 1.38, 1.51-1.56, 1.97, 2.07-2.13, 2.58-2.71, 3.35-3.59, 3.95, 6.52, 6.70, 7.18-7.28, 7.28-7.34, 7.51, 7.60, 8.95.

[0514] Example 34-2: (1R,2S)-2-[3-({[2-(2-methyl-2-propanyl)-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

[0515] [ka] LC-MS m / z 513(M+H) + ; 1 H-NMR(DMSO-d6):δ1.30-1.35, 1.38, 1.49, 1.98-2.16, 2.57-2.63, 2.70, 3.99-4.16, 6.09, 6.76, 7.20-7.25, 7.25-7.31, 7.31-7.37, 7.42, 7.60, 9.39.

[0516] Pharmacological Experiment Examples: Pharmacological Experiment Example 1: EP using prostanoid receptor expressing cells 2 Antagonistic activity measurement experiment According to the method of Nishigaki et al. (FEBS Letters, Vol. 364, pp. 339-341, 1995), human EP 2 CHO cells expressing the receptor were prepared and cultured at 1.5x10 7 The cells were frozen and stored at 5x10 cells / mL / vial for the experiment. 5 The cells were suspended in assay medium (D-PBS containing 1 mmol / L IBMX, 2 μmol / L Diclofenac) at a final concentration of 10 nmol / L. 2 The reaction was initiated by adding a solution (10 μL) containing either the compound alone or in combination with the test compound. After reacting at room temperature for 1 hour, the amount of cAMP in the cells was quantified according to the method described in the cAMP Gs Dynamic kit (CISBIO).

[0517] The antagonistic effect of the test compound (IC 50 value) is PGE 2 The IC was calculated as the inhibition rate relative to the reaction at 10 nM, which is a concentration that shows submaximal cAMP production by itself. 50 The value was calculated.

[0518] The above pharmacological experiments showed that the compound of the present invention has a strong EP 2 It has been found that some of the compounds of the present invention have receptor antagonistic activity. 50 The values ​​were as shown in Table 1 below.

[0519] [Table 1] EP of Example 43 compound described in Patent Document 1 2 The receptor antagonist activity was >10000 nM.

[0520] Pharmacological Experiment Example 2: Antitumor effect in an allograft model of mouse colon cancer cell line CT26 The antitumor effect of the compound of the present invention was evaluated in an allograft model of CT26, a mouse colon cancer cell line. CT26 was cultured in RPMI-1640 medium containing 10 vol% heat-inactivated fetal bovine serum (FBS), 100 units / mL penicillin, and 100 μg / mL streptomycin under CO 2 The cells were cultured in an incubator. On the day of transplantation, the culture supernatant was removed, and the CT26 cells were washed with phosphate buffer solution (hereinafter abbreviated as PBS) and then harvested. The harvested CT26 cells were suspended in PBS to prepare cells for transplantation. Under anesthesia, 300,000 cells for transplantation were subcutaneously transplanted into the right dorsal region of female Balb / C mice (Charles River Biosciences Japan, Inc.). Four days after transplantation, the mice were assigned to two groups, a vehicle group and a compound A group, 10 mice each. The compound of the present invention was repeatedly administered to the mice at 10 mg / kg as the vehicle and compound A once on the 4th day of transplantation, and twice daily from the 5th day of transplantation to the 25th day of transplantation. Tumor volume (mm 3 ) The short and long diameters of the tumor were measured using electronic calipers, and the tumor volume was calculated using the following formula 1. Note that mice in which ulcers were formed in the tumor during the administration period were excluded from the evaluation from that point onwards.

[0521]

number

[0522] Kinetics Experiment Example 1: Liver microsome stability test (1) Preparation of test substance solution A DMSO solution of the test substance (10 mmol / L; 5 μL) was diluted with a 50% aqueous acetonitrile solution (195 μL) to prepare a 250 μmol / L test substance solution.

[0523] (2) Preparation of standard sample (sample immediately after the start of the reaction) 245μL of 0.1mol / L phosphate buffer (pH7.4) containing NADPH-Co-Factor (BD-Bioscience) and 1mg / mL rat and human liver microsomes was added to a reaction vessel preheated to 37℃ in a water bath, and pre-incubated for 5 minutes. 5μL of the test substance solution was added thereto to start the reaction (final concentration 1μmol / L). Immediately after the start of the reaction, 20μL of the reaction solution was collected and added to 180μL of acetonitrile (containing the internal standard candesartan) to stop the reaction. The solution in which the reaction was stopped (20μL; sample solution immediately after the start of the reaction) was stirred with 50% acetonitrile (180μL) on a protein removal filter plate, then suction filtered, and the filtrate was used as a standard sample. (3) Preparation of reaction sample (sample after 60 minutes of reaction) After incubating the reaction solution at 37°C for 60 minutes, 20μL of the reaction solution was taken and added to 180μL of acetonitrile (containing the internal standard candesartan) to stop the reaction. The solution after the reaction (20μL; sample solution reacted for 60 minutes) was stirred with 50% acetonitrile (180μL) on a protein removal filter plate, and then suction filtered to obtain the filtrate as the reaction sample. (4) Evaluation method Using the peak areas obtained by LC-MS / MS, the residual rate (%) of the test substance was calculated from the amount of the test substance in the standard sample (X) and the amount of the test substance in the reaction sample (Y) according to the following formula.

[0524] Survival rate (%)=(Y / X)x100 X: Amount of test substance in standard sample (Ratio = peak area of ​​test substance / peak area of ​​internal standard substance) Y: Amount of test substance in reaction sample (Ratio = peak area of ​​test substance / peak area of ​​internal standard substance) (5) Results The compound of the present invention was found to have high stability to human liver microsomes.

[0525] Dynamics Experiment Example 2: Solubility Measurement Test (1) Preparation of calibration curve solution The calibration curve solutions were prepared by diluting a DMSO solution of the test substance (10 mmol / L) with acetonitrile and adding acetonitrile containing the internal standard (nicardipine) to prepare solutions at 5, 20, and 100 nmol / L. (2) Preparation of sample solution The sample solution was prepared by adding 5μL of a DMSO solution of the test substance (10mmol / L) to 495μL of the Local Method II solution, stirring at room temperature for 5 hours, transferring the solution to a solubility filter plate, suction filtering, diluting 10μL of the filtrate with acetonitrile, and adding acetonitrile containing the internal standard substance (nicardipine). (3) Evaluation 5μL of the calibration curve solution and sample solution were injected into an LC-MS (Thermo Scientific Q Exactive Focus) and quantified (quantitative range: 5-100nmol / L). The solubility was calculated by multiplying the quantitative value by 1000. If the value was below the quantitative range, the solubility was <5μmol / L, and if the value was above the quantitative range, the solubility was 100μmol / L. (4) Results The compounds of the present invention were found to have good solubility.

[0526] [Formulation example] Formulation examples The following ingredients are mixed in a conventional manner and compressed into tablets to obtain approximately 10,000 tablets, each containing 10 mg of active ingredient. (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-chlorophenyl}cyclopropanecarboxylic acid ……100g Calcium carboxymethylcellulose (disintegrant) …… 20g Magnesium stearate (lubricant) …… 10g Microcrystalline cellulose ……870g [Industrial Applicability]

[0527] The compound of the present invention is EP 2 It has antagonistic activity against the receptor, 2 It is effective in preventing and / or treating diseases caused by receptor activation.

Claims

1. General formula (I-1): 【Chemistry 1】 (In the formula, R 38 and R 40 each independently represent (1) a hydrogen atom, (2) a halogen atom, or (3) a C1-4 alkyl group; R ３８ and each C1-4 alkyl group in R40 may independently be substituted with a halogen atom; L ２ represents (1) a bond, (2) a C1-8 alkylene group, (3) a C2-8 alkenylene group, or (4) a C2-8 alkynylene group, in which 1 to 2 carbon atoms are optionally replaced by an oxygen atom or an optionally oxidized sulfur atom, and the C1-8 alkylene group, C2-8 alkenylene group, and C2-8 alkynylene group are optionally substituted by 1 to 8 halogen atoms; Y represents (1) a bond, (2) an oxygen atom, or (3) an optionally oxidized sulfur atom; R １ (1) COOR １０ , (2) SO ３ H, (3) SO ２ NHR １１ , (4) CONHSO ２ R １２ , (5) SO ２ NHCOR １３ , (6) CONR １４ R １５ (7) a tetrazolyl group, or (8) a hydroxamic acid; R １０ , R １１ , R １２ , R １３ , R １４ and R １５ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group, R ２ represents (1) a hydrogen atom or (2) a C1-4 alkyl group, R ３ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a 3- to 6-membered cyclic group, (7) (3- to 6-membered cyclic group)-O-, or (8) (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ３ (2) to (8) in the table are 1 to 9 R １６ may be substituted with R ３ If there are multiple R ３ may be the same or different, R １６ is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR １７ R １８ represents R １６ If there are multiple R １６ may be the same or different, R １７ and R １８ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ４ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a 3- to 6-membered cyclic group, (7) (3- to 6-membered cyclic group)-O-, or (8) (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ４ (2) to (8) in the table are 1 to 9 R １９ may be substituted with R ４ If there are multiple R ４ may be the same or different, R １９ is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ２０ R ２１ represents R ２０ and R ２１ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R １９ If there are multiple R １９ may be the same or different, R ５ represents (1) a hydrogen atom, (2) a C3-10 carbocyclic ring, or (3) a 3- to 10-membered heterocyclic ring, and the C3-10 carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from 1 to 5 R ２２ may be substituted with However, L ２ When is a bond, R ５ is not a hydrogen atom, R ２２ means (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a C3-6 cycloalkyl group, (5) a C1-6 alkoxy group, (6) a C3-6 cycloalkyloxy group, (7) a C2-6 acyl group, (8) a C2-6 acyloxy group, (9) a C1-6 alkylthio group, (10) a C3-6 cycloalkylthio group, (11) a C1-6 alkylsulfinyl group, or (12) a C3-6 cycloalkylsulfinyl group, (13) a C1-6 alkylsulfonyl group, (14) a C3-6 cycloalkylsulfonyl group, (15) a C1-6 alkoxycarbonyl group, (16) a 5- to 6-membered cyclic group, (17) a (5- to 6-membered cyclic group)-(C1-4 alkylene)-, (18) a (5- to 6-membered cyclic group)-(C1-4 alkylene)-O- group, (19) a (5- to 6-membered cyclic group)-C1-4 acyl group, (20) a halogen atom, (21) a hydroxyl group, (22) a nitro group, (23) a cyano group, (24) -NR ２３ R ２４ , (25)-CONR ２５ R ２６ Or (26)-SO ２ N.R. ２７ R ２８ represents R ２３ , R ２４ , R ２５ , R ２６ , R ２７ and R ２８ each independently represents (1) a hydrogen atom, (2) a C1-6 alkyl group, (3) a C2-6 acyl group, or (4) a C1-6 alkylsulfonyl group, R ２２ Among these, the groups (1) to (19) each have 1 to 9 R ２９ may be substituted with R ２２ If there are multiple R ２２ may be the same or different, R ２９ is (1) a C1-4 alkyl group, (2) a C1-4 alkoxy group, (3) a C2-6 acyl group, (4) a C3-6 cycloalkyl group, (5) a hydroxyl group, or (6) -NR ３０ R ３１ or (7) a halogen atom, R ３０ and R ３１ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ２９ If there are multiple R ２９ may be the same or different, X is (1) CR ６ Or (2) N.R. ７ represents R ６ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a 3- to 6-membered cyclic group, (7) (3- to 6-membered cyclic group)-O-, or (8) (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ６ (2) to (8) in the table are 1 to 9 R ３２ may be substituted with R ３２ is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ３３ R ３４ represents R ３３ and R ３４ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ３２ If there are multiple R ３２ may be the same or different, R ７ represents (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a 3- to 6-membered cyclic group, or (5) a (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ７ is 1 to 9 R ３５ may be substituted with R ３５ is (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, (4) a C2-6 acyl group, (5) a C3-6 cycloalkyl group, (6) a hydroxyl group, or (7) -NR ３６ R ３７ represents R ３６ and R ３７ each independently represents (1) a hydrogen atom or (2) a C1-4 alkyl group; R ３５ If there are multiple R ３５ may be the same or different, Ring A represents (1) a benzene ring or (2) a 5- or 6-membered nitrogen-containing aromatic heterocycle; In ring A 【Chemistry 2】 represents a single or double bond, n represents an integer of 1 to 4; m represents an integer of 0 to 3; and p represents an integer of 1 to 4, or a pharma- ceutically acceptable salt thereof.

2. General formula (IC): 【Chemistry 3】 (In the formula, X ａ is CR ６ａ Or N.R. ７ａ represents R ６ａ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) (3- to 6-membered cyclic group)-O-, or (7) (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ６ａ (2) to (7) in the table are 1 to 9 R ３２ may be substituted with R ７ａ represents (1) a C1-6 alkyl group, (2) a C2-6 alkenyl group, (3) a C2-6 alkynyl group, (4) a 3- to 6-membered cyclic group, or (5) a (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ７ａ is 1 to 9 R ３５ may be substituted with R ３ａ , R ３ｂ and R ３ｃ each independently represents (1) a hydrogen atom, (2) a halogen atom, (3) a C1-6 alkyl group, (4) a C2-6 alkenyl group, (5) a C2-6 alkynyl group, (6) a C1-6 alkoxy group, (7) a 3- to 6-membered cyclic group, (8) (3- to 6-membered cyclic group)-O-, or (9) (3- to 6-membered cyclic group)-(C1-4 alkylene)-; R ３ａ , R ３ｂ and R ３ｃ (3) to (9) in the table are 1 to 9 R １６ may be substituted with However, R ３ａ , R ３ｂ and R ３ｃ At least one of represents a substituent other than a hydrogen atom, The same symbols as those in claim 1 have the same meanings as those in claim 1. The compound according to claim 1, represented by the formula (I), or a pharma- ceutically acceptable salt thereof.

3. 3. The compound according to claim 1 or 2, wherein ring A is a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, or a pharma- ceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein ring A is a pyrrole ring and Y is a bond, or a pharma- ceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 3, wherein ring A is a benzene ring and Y is an oxygen atom, or a pharma- ceutically acceptable salt thereof.

6. (1) rel-(1R,2S)-2-[3-({[1-sec-butyl-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (2) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (3) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (4) rel-(1R,2R)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (5) rel-(1R,2S)-2-{5-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (6) rel-(1R,2R)-2-{5-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (7) (1S,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-methoxyphenyl}cyclopropanecarboxylic acid, (10) (1S,2R)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (11) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (12) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl)amino]-4-chlorophenyl}cyclopropanecarboxylic acid, (13) (1R,2S)-2-{3-[({5-[2-(benzyloxy)ethyl]-1-[(2S)-2-butanyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (14) rel-(1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(2-chloro-6-fluoro-4-pyridinyl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (16) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-[2-(2-chloro-3,5-difluorophenoxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (17) (1R,2S)-2-{3-[({1-[(2S)-2-butanyl]-5-[2-(2,4-difluorophenoxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[(1-[(2S)-2-butanyl]-5-{2-[(1-methyl-1H-pyrazol-4-yl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (19) rel-(1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (20) (1R,2S)-2-[3-{[2,6-dimethyl-4-(3-phenylpropyl)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (21) (1R,2S)-2-[3-({4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (22) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-fluorophenyl)cyclopropanecarboxylic acid, (23) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-fluorophenyl)cyclopropanecarboxylic acid, (24) (1R,2S)-2-[2-chloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-(4-chloro-3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid, (26) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid, (27) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl)cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (29) (1S,2R)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (30) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (31) (1R,2S)-2-[3-{[4-(2-cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (32) (1R,2S)-2-{3-[(2,6-dimethyl-4-propoxybenzoyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (33) (1R,2S)-2-[3-{[4-(hexyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (34) (1R,2S)-2-[3-{[4-(benzyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (35) (1R,2S)-2-[3-{[4-(2-methoxyethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (36) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (37) (1R,2S)-2-[3-({4-[2-(2-furyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (38) (1R,2S)-2-[3-({4-[2-(2-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (39) (1R,2S)-2-[3-({4-[2-(3-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (40) (1R,2S)-2-[3-({4-[2-(1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (41) (1R,2S)-2-[3-({4-[2-(2,6-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (42) (1R,2S)-2-[3-({4-[2-(3,5-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (43) (1R,2S)-2-[3-({4-[(6-chloro-2-pyrazinyl)oxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (44) (1R,2S)-2-[3-{[4-(6-fluoro-3-pyridinyl)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (45) (1R,2S)-2-[3-({4-[2-(4-hydroxyphenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (49) (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclobutanecarboxylic acid, or (50) The compound according to claim 1, which is (1R,2R)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]-1-methylcyclopropanecarboxylic acid, or a pharma- ceutically acceptable salt thereof.

7. (1) (1R,2S)-2-[3-{[2-methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (2) (1R,2S)-2-[3-{[2-chloro-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (3) (1R,2S)-2-[3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (4) (1R,2S)-2-[3-{[4-(1H-indazol-5-ylmethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (5) (1R,2S)-2-[3-{[2,6-dimethyl-4-(1,2,3,4-tetrahydro-1-naphthalenylmethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (6) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(3-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (7) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(4-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2S)-2-[3-({2,6-dimethyl-4-[2-(2-pyridinyl)ethoxy]benzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-[3-({4-[2-(2-chloro-1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (10) (1R,2S)-2-[3-({4-[2-(2-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (11) (1R,2S)-2-[3-({4-[2-(3-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (12) (1R,2S)-2-[3-({4-[2-(4-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (13) (1R,2S)-2-[3-{[2,6-dimethyl-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (14) (1R,2S)-2-[3-{[2,6-dimethyl-4-(3,3,3-trifluoro-2-methylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-{3-[(2,6-dimethyl-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}benzoyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (16) (1R,2S)-2-[3-{[2,6-dimethyl-4-(pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (17) rel-(1R,2S)-2-(3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-methylphenyl)cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[4-(benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (19) (1R,2S)-2-[3-{[2-isopropyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (20) (1R,2S)-2-[3-{[2-isopropyl-4-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (21) (1R,2S)-2-[3-{[3-(benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (22) (1R,2S)-2-[3-{[2-isopropyl-3-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (23) (1R,2S)-2-[3-{[2-isopropyl-3-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (24) (1R,2S)-2-[4-(trifluoromethyl)-3-{[2,3,5-trimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-[3-({[3-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (26) (1R,2S)-2-[3-({[5-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (27) (1R,2S)-2-[3-({[2,6-dimethyl-4-(2-phenylethoxy)phenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-({[4-(2-cyclopropylethoxy)-2,6-dimethylphenyl]carbonothioyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (29) (1R,2S)-2-[3-({[2-sec-butyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (30) (1R,2S)-2-[3-({[2-isopropyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or (31) The compound according to claim 1, which is (1R,2S)-2-[3-({[2-(2-methyl-2-propanyl)-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or a pharma- ceutically acceptable salt thereof.

8. (1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or a pharma- ceutically acceptable salt thereof.

9. A compound having the following structure: 【Chemistry 4】

10. A pharma- ceutically acceptable salt of a compound having the structure: 【Chemistry 5】

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharma- ceutical acceptable salt thereof, the compound according to claim 9, or the salt according to claim 10 as an active ingredient, and further comprising a pharma- ceutical acceptable carrier.

12. EP ２ The pharmaceutical composition of claim 11, which is a receptor antagonist.

13. EP ２ The pharmaceutical composition according to claim 11 or 12, which is an agent for treating and / or preventing a disease caused by receptor activation.

14. EP 2216266, comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, a compound according to claim 9, or a salt according to claim 10. ２ A pharmaceutical composition for the prevention and / or treatment of diseases caused by receptor activation.

15. EP ２ The pharmaceutical composition according to claim 13 or 14, wherein the disease caused by activation of the receptor is endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative pain, interstitial cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic disease, hypertension, brain disorder, ischemia, stroke, kidney disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, vasculitis, or autoimmune disease.

16. EP ２ The pharmaceutical composition according to any one of claims 13 to 15, wherein the disease caused by receptor activation is cancer, and the cancer is breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, uveal melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis and ureter cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer, malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, brain tumor, or multiple myeloma.

17. The pharmaceutical composition according to any one of claims 11 to 16, which is administered in combination with at least one selected from the group consisting of alkylating agents, metabolic antagonists, anticancer antibiotics, botanical preparations, hormones, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, and immunomodulators.

18. EP ２ Use of a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, a compound according to claim 9, or a salt according to claim 10, for the manufacture of an agent for the prophylaxis and / or treatment of a disease caused by receptor activation.

Images